• Users Online: 4087
  • Home
  • Print this page
  • Email this page

 Table of Contents  
REVIEW
Year : 2021  |  Volume : 16  |  Issue : 2  |  Page : 223-233

Inflammation/bioenergetics-associated neurodegenerative pathologies and concomitant diseases: a role of mitochondria targeted catalase and xanthophylls


1 Sistema-BioTech, LLC, Moscow, Russia
2 Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia

Date of Submission19-Feb-2020
Date of Decision23-Feb-2020
Date of Acceptance23-Mar-2020
Date of Web Publication24-Aug-2020

Correspondence Address:
Mikhail A Filippov
Sistema-BioTech, LLC, Moscow
Russia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1673-5374.290878

Rights and Permissions
  Abstract 

Various inflammatory stimuli are able to modify or even “re-program” the mitochondrial metabolism that results in generation of reactive oxygen species. In noncommunicable chronic diseases such as atherosclerosis and other cardiovascular pathologies, type 2 diabetes and metabolic syndrome, these modifications become systemic and are characterized by chronic inflammation and, in particular, “neuroinflammation” in the central nervous system. The processes associated with chronic inflammation are frequently grouped into “vicious circles” which are able to stimulate each other constantly amplifying the pathological events. These circles are evidently observed in Alzheimer's disease, atherosclerosis, type 2 diabetes, metabolic syndrome and, possibly, other associated pathologies. Furthermore, chronic inflammation in peripheral tissues is frequently concomitant to Alzheimer's disease. This is supposedly associated with some common genetic polymorphisms, for example, Apolipoprotein-E ε4 allele carriers with Alzheimer's disease can also develop atherosclerosis. Notably, in the transgenic mice expressing the recombinant mitochondria targeted catalase, that removes hydrogen peroxide from mitochondria, demonstrates the significant pathology amelioration and health improvements. In addition, the beneficial effects of some natural products from the xanthophyll family, astaxanthin and fucoxanthin, which are able to target the reactive oxygen species at cellular or mitochondrial membranes, have been demonstrated in both animal and human studies. We propose that the normalization of mitochondrial functions could play a key role in the treatment of neurodegenerative disorders and other noncommunicable diseases associated with chronic inflammation in ageing. Furthermore, some prospective drugs based on mitochondria targeted catalase or xanthophylls could be used as an effective treatment of these pathologies, especially at early stages of their development.

Keywords: algae xanthophylls; Alzheimer's disease; atherosclerosis; depression; type 2 diabetes; metabolic syndrome; mitochondria-targeted catalase; noncommunicable chronic diseases; stress


How to cite this article:
Filippov MA, Tatarnikova OG, Pozdnyakova NV, Vorobyov VV. Inflammation/bioenergetics-associated neurodegenerative pathologies and concomitant diseases: a role of mitochondria targeted catalase and xanthophylls. Neural Regen Res 2021;16:223-33

How to cite this URL:
Filippov MA, Tatarnikova OG, Pozdnyakova NV, Vorobyov VV. Inflammation/bioenergetics-associated neurodegenerative pathologies and concomitant diseases: a role of mitochondria targeted catalase and xanthophylls. Neural Regen Res [serial online] 2021 [cited 2020 Sep 19];16:223-33. Available from: http://www.nrronline.org/text.asp?2021/16/2/223/290878


  Introduction Top


Noncommunicable chronic diseases (NCDs), associated with cardiovascular, metabolic, neurological, diabetic, rheumatologic, and neurodegenerative pathologies, began to be fundamental medical problems of the 21st century (Bousquet et al., 2011). A leading role of the cardiovascular diseases (CVDs) in mortality rate in the human population seems to arise from insufficient measures to prevent CVDs through the healthy lifestyle, underestimation and poor assessment of risk factors for early diagnosis during asymptomatic phase of CVDs (Cohn et al., 2003). Furthermore, most ageing people with CVDs suffer from several diseases, which are frequently etiologically related. The risk factors for NCDs development are age, genetic predisposition, high arterial blood pressure, dyslipidemia, insulin resistance, overweight, smoking, poor nutrition, low level of physical activity, excessive amount of alcohol consumption. Thus, NCDs are caused by complex interactions between genetic, nutritional, stressful and environmental factors affecting people throughout their lives. The key role in NCDs development is chronic inflammation (frequently termed as “low grade chronic inflammation”) with systemic damage to either the whole organism or specific organs/tissues.

Inflammatory processes are mediated by various immune cells, in particular, by differentially activated M1 and M2 macrophages triggering either pro-inflammatory or resolution processes, respectively (Mescher, 2017; Oishi and Manabe, 2018). In chronic inflammation, M1/M2 balance is biased towards the prevalence of M1 macrophages targeting the potential “threat” that instead of foreign microorganisms or antigens now becomes its own “host” cells and/or proteins (Liu et al., 2014; Parisi et al., 2018). Usually, this is accompanied by infiltration of activated macrophages into inflamed internal organs. In the atherosclerosis, the macrophages infiltrate the walls of large blood vessels and capture the oxidized low-density lipoproteins which results in their subsequent transformation into “foamy cells” (Fadini and Ciciliot, 2014; Tabas and Lichtman, 2017). In diabetes of both types (1 and 2), the immune cells attack insulin-producing pancreatic beta-cells (McDevitt, 2005; Burrack et al., 2017; Zhou et al., 2018; de Candia et al., 2019). In metabolic syndrome, the macrophages infiltrate the visceral fat and can attack adipocytes (Lumeng et al., 2007; McNelis and Olefsky, 2014; Ieronymaki et al., 2019). In chronic alcoholism and non-alcoholic fatty liver disease, the macrophages attack the hepatocytes triggering the fibrosis (Ju and Mandrekar, 2015; Cha et al., 2018). In the inflammatory bowel disease, macrophages destroy the intestine (Na et al., 2019). One of the hallmarks of Alzheimer's disease (AD) is the extracellular beta-amyloid (Aβ) in the brain, which is able to activate the microglia (Klegeris et al., 1994) that triggers the “vicious circle” of neuroinflammation (Cai et al., 2014). Autoimmune reactions in the central nervous system (CNS) target the variety of own proteins of the organism: for example, myelin (in autoimmune demyelinating polyneuropathies and multiple sclerosis), synaptic proteins of the extracellular matrix leucine-rich-glioma-inactivated 1 and contactin-associated protein 2 (in autoimmune encephalitis), glutamate decarboxylase 2 and pro-insulin (in diabetes) and others. The autoimmune reactions are characterized by high concentration of antibodies against the host proteins in the blood that in turn can activate myeloid cells and thereby establish the pro-inflammatory milieu negating the immune tolerance mechanisms (Suurmond and Diamond, 2015). The peripheral macrophages can also infiltrate the brain as a consequence of ischemic stroke, epileptic seizure, autoimmune reaction and bacterial infection (Cox et al., 2013; Raj et al., 2015; Lopes Pinheiro et al., 2016; Varvel et al., 2016; Rajan et al., 2019). Hence, the peripheral macrophages in conjunction with the brain resident microglia can orchestrate the processes of neuroinflammation in the brain (Fischer and Reichmann, 2001; Sevenich, 2018). In particular, ex vivo labelled peripheral macrophages have been shown to cross the blood-brain barrier (BBB) and attack Aβ plaques together with residential microglia in AD animal models (Gate et al., 2010; Lebson et al., 2010).


  Search Strategy and Selection Criteria Top


Literature research was performed using PubMed, Google and Google Scholar databases using the following combination of keywords: “Alzheimer's disease” OR “neurodegenerative diseases” OR “atherosclerosis” OR “type 2 diabetes” OR “metabolic syndrome” AND “inflammation” OR “chronic inflammation” OR “concomitant diseases” OR “mitochondrial functions” AND “mitochondria-targeted catalase” OR “xanthophylls” OR “algae xanthophylls” OR “oxidative stress” OR “photosynthesis and oxidative stress” until February 2020. The studies identified were further screened using the following inclusion criteria: studies in animals, humans, algae and sometimes plants (i), articles and studies written in English (ii) that had available abstracts and/or full texts (iii).


  Mitochondrial Dysfunction and Metabolism Top


The chronic inflammation in NCDs is characterized by mitochondrial dysfunctions. Disturbances in mitochondria functioning are usually manifested with the oxidative stress (OS) which is expressed in the reactive oxygen species (ROS) accumulation in affected cells. OS is a characteristic of chronic inflammatory processes and observed in liver diseases (Satapati et al., 2015, 2016; Mansouri et al., 2018), metabolic syndrome (Bhatti et al., 2017), atherosclerosis (Madamanchi and Runge, 2007; Peng et al., 2019), and type 2 diabetes (De Felice and Ferreira, 2014). Genetic abnormalities in mitochondria were demonstrated in the inflammatory bowel disease (Wang et al., 2013; van Tilburg et al., 2014) and mitochondrial dysfunctions were revealed in AD (Moreira et al., 2010; Garcia-Escudero et al., 2013; De Felice and Ferreira, 2014; Swerdlow, 2018).

The studies of mechanisms of intracellular inflammatory processes indicate that the mitochondrial “dysfunction” is a natural reaction caused by the infections or trauma/stress. OS has been directly demonstrated to be a component of the immune response. In particular, the immune cells have been shown to accumulate the hydrogen peroxide that is “programmed” by impaired function of mitochondrial complex I and III (Chandel et al., 2000; Zmijewski et al., 2008, 2009). OS is also characterized by the reduction of enzymatic activity of pyruvate decarboxylase and alpha-keto-dehydrogenase that is associated with impairments in the Krebs cycle functioning (van Horssen et al., 2019) and decreased glutathione peroxidase activity resulting in hydrogen peroxide accumulation (Soto et al., 2014). The inflammation-associated alterations are essential for ROS generation and activation of the inflammasome complex (Tschopp, 2011). They are accompanied by energy deficit in the cells and in turn by greater mitochondrial dysfunctions that inevitably “push” the cells into a vicious inflammatory circle (Lopez-Armada et al., 2013; van Horssen et al., 2019).

Interestingly, the high-fat diet, so-called “the calorie bomb”, is known to attenuate the glucose intake from the extracellular medium and increase both the lipid metabolism and its oxidation. This provokes the development of insulin resistance and can generate the conditions for the pathological lipid oxidation. This in turn provokes the mitochondrial dysfunction through the oxidation and degradation of mitochondrial membranes (Hernandez-Aguilera et al., 2013; Lopaschuk, 2016). In AD, the neuroinflammation is accompanied by the endocytosis of Aβ with its subsequent entry into the mitochondria. Highly toxic Aβ(1–42), which is more hydrophobic than the “normal” Aβ(1–40), enters into membranes and catalyzes the oxidation of unsaturated lipids (Butterfield et al., 2013). The bioenergetics profile disturbances (insulin signaling impairment, abnormal mitochondrial metabolism, metabolic biases towards glycolysis) are observed in fibroblasts from AD patients (Sonntag et al., 2017), and inhibition of both basic metabolism and glycolysis in astrocytes) may play substantial role in Aβ accumulation (Fu et al., 2015).


  Residential Microglia/Macrophages and Chronic Inflammation Top


Another important aspect of chronic inflammation is the activation of residential macrophages which are not derived from bone marrow monocytes. In particular, residential brain microglia is well known to be formed from erythro-myeloid fetal bladder precursors (Lenz and Nelson, 2018; Thion et al., 2018) and Kupffer cells, which are specialized hepatic macrophages originated from the embryonic yolk sac (Lobritto, 2017) and they are capable for mitosis (Crofton et al., 1978). Functionally, Kupffer cells can also be in different states: pro-inflammatory M1 and resolving anti-inflammatory M2. There are several subtypes of M2 cells whose correct regulation may play a key role in inflammatory outcomes and thus the inflammation treatment (Dixon et al., 2013). The induced prevalence of M2 over M1 macrophages could promote the pro-inflammatory state downregulation. M1/M2 balance is dependent on genetics and environmental factors and defines the pathogenesis development. Even in intracerebral pathologies (in particular, AD), when the brain is protected by the BBB from external toxicity, M1/M2 ratio in microglia could be dependent on dietary and traumatic external factors (Katsumoto et al., 2018).

In AD animal models the enhanced levels of both pro-inflammatory M1 microglia and alternatively activated M2 microglia are observed (Wang et al., 2015b). M2 microglia provides important mechanisms for neuroprotection: it secretes interleukin (IL)-10, which suppresses the inflammation and insulin-like growth factor 1, which has essential neurotrophic function (Gray et al., 2020). At early stages of neurodegeneration, the neuroprotective M2 microglia prevails, however over time, M1 microglia activity is increased that stimulates inflammatory processes. This in turn increases beta-secretase activity that initiates Aβ production (Sastre et al., 2008). Thus, the vicious circle begins: the inflammation triggers Aβ generation, Aβ interacts with microglia that amplifies the production of tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-18 in favor of the inflammation. This circle is accompanied by hyperphosphorylation of tau protein, tau protein paired helical filament formation, that disrupts the axonal transport system in neurons, and, finally, the neuronal death (von Bernhardi et al., 2010). The initiation of the “vicious circle” can be associated with two features of capillary blood vessels: a) their endothelial cell ability to release pro-inflammatory cytokines, provoked by Aβ (Grammas and Ovase, 2001), and b) infiltration of the peripheral proinflammatory signals into the brain due to increased endothelial permeability observed in inflammation (Perry et al., 2007; Holmes et al., 2009; Kamer, 2010). Proinflammatory cytokines can pass through disturbed BBB, whereas chronic inflammation in turn increases its permeability even more (Varatharaj and Galea, 2017). Thus, peripheral macrophages infiltrate into the brain and residential M1 microglia orchestrates further development of inflammatory reactions and neurodegeneration in AD (Sevenich, 2018). This explains why AD could be associated with prolonged chronic inflammation in the peripheral organs linked with such concomitant diseases as atherosclerosis, diabetes, metabolic syndrome (MS), and chronic infections.


  Apolipoprotein-E ε4 Associated Genetic Problem Top


Genetic predisposition, stress, inappropriate lifestyle and age-related pathological processes have been shown to be the main factors initiating and supporting the development of chronic inflammation in NCDs (Hernandez-Aguilera et al., 2013). The particular interest is in common genetics among different diseases. One typical example is polymorphisms in the APOE gene encoding Apolipoprotein-E ε4 (APOE4) allele which is associated with the worst variant APOE as a cholesterol carrier. Human beings with APOE4 allele have significantly enhanced risk of AD development (25–65% of the “late onset” of AD at age of above 65 years, https://www.ncbi.nlm.nih.gov/books/NBK1161/). The same APOE4 allele increases the risk of the atherosclerosis by 4–14 times that depends on the presence of one or two copies of the allele (Mahley, 2016). The APOE knock-out mice are very sensitive to the atherosclerosis-provoking factors making this mouse line as a very usable genetic model of atherosclerosis and CVDs (Lo Sasso et al., 2016). Atherosclerosis and CVDs are dominant in the mortality list from the “developed” countries. In Europe, according to the World Health Organization, APOE4 carriers are in the cohort of patients associated with 40–75% of deaths from CVDs (Abondio et al., 2019).

Thus, the genetic polymorphisms which are considered as pathogenic in conjunction with chronic inflammation can provide the basis for the malfunction of organs/tissues and consequently their degeneration or failure. CVDs, atherosclerosis, arterial hypertension, obesity, type 2 diabetes, inflammatory diseases of the liver and intestines are factors associated with common mechanisms of pathogenesis based on the chronic inflammation processes.


  Alzheimer's Disease and Concomitant Diseases Top


Atherosclerosis and chronic inflammation

Atherosclerosis is probably the most important concomitant disease related to AD. Dyslipidemia results in accumulation of atherosclerotic plaques in the walls of large blood vessels that sooner or later may result in endothelial rupture and generation of the blood clots (Hess and Grant, 2011) raising the risk of heart attacks and/or strokes. Lipid driven immune-metabolic responses are associated with OS and subendothelial infiltration of oxidized lipoproteins followed by the migration of activated macrophages (Gistera and Ketelhuth, 2018). Activated macrophages absorb the oxidized lipoproteins followed by their transformation into the “foam cells” and atherosclerotic plaque formation. Dyslipidemia is triggered in the liver, one of its main functions is to control the cholesterol release into the bloodstream via very low density lipoproteins. Very low density lipoproteins deliver the cholesterol to organs and tissues where it is transformed to low density lipoproteins (LDL) for subsequent return into the liver. This process is controlled by the subtilisin-kexin type 9 proprotein convertase (PCSK9) which allocates low density lipoprotein receptors (LDLR) from cell surface for the endocytosis in hepatocytes (Lusis et al., 2004). PCSK9 binds to LDLR resulting in LDLR endocytosis and degradation. Large amounts of serum PCSK9 prevent LDL from LDLR absorbance that provokes LDL accumulation in the blood consequently creating favorable advantageous conditions for their infiltration into the large vessel walls. Thus, impaired cholesterol recirculation in the blood and OS evoked by inflammatory processes potentiate synergically the atherosclerotic plaques formation. Interestingly, PCSK9 gene expression, which is regulated by the nuclear transcription factor 1 in the hepatocytes, is blocked by insulin (Glerup et al., 2017). On the other hand, the insulin signal was demonstrated to be blocked by the inflammation (McNelis and Olefsky, 2014). Thus, the chronic inflammation seems to be accompanied by high levels of PCSK9, whereas, the LDL recirculation in the liver is deactivated because of LDLR endocytosis and degradation. The modern treatments for atherosclerosis include therapeutic antibodies against PCSK9 (e.g., Evolocumab or Alirocumab) which inactivate PCSK9 and consequently attenuate the pathological process (McDonagh et al., 2016). However these antibodies do not necessarily stop the inflammation. One of “traditional” approaches oriented on prevention of LDL accumulation in the blood via the inhibition of cholesterol synthesis in the liver by statins (Tian et al., 2012). However, it results in lots of side effects including pancreatitis (Jones et al., 2015), that can seriously affect patient life quality.

In some studies, PCSK9 is indeed considered as an indicator of inflammation because it induces the pro-inflammatory responses in macrophages (Ricci et al., 2018). It also promotes both Toll-like receptor (TLR) 4 expression and TLR4/NF-kappa B genetic pathway activation (Tang et al., 2017). Upregulation of TLR2 and TLR4 expression is consistent with increased serum lipids (Zhu et al., 2015). Local overexpression of TLR2/TLR4 in the vessel walls can induce the atherosclerotic plaque formation (Shinohara et al., 2007). Moreover, significant local PCSK9 expression increase was demonstrated in the endothelial cells inside of the atherosclerotic plaques (Tang et al., 2017). Thus, in chronic inflammation, the loop of TLR2/TLR4 and PCSK9 activation/expression can create the vicious circle that leads to permanent LDLR degradation on the hepatocytes surface and persistent increase of LDL level in the blood. Interestingly, people with impaired PCSK9 functions demonstrate lower levels of both LDL cholesterol and risk to develop the coronary heart disease (Kent et al., 2017). Unfortunately, they could be more susceptible to infectious diseases and sepsis (Mitchell et al., 2019).

Cholesterol recirculation via LDLR is not only the mechanism of cholesterol reverse transport to the liver. Another mechanism is associated with high density lipoproteins (HDLs), that are dedicated for uptake by hepatocytes. However, in atherosclerosis, HDL synthesis is depressed and its secretion is driven by two ATP-binding cassette transporter subfamilies: A1 (ABCA1) and G1 (ABCG1). The expressions of ABCA1 and ABCG1 have been revealed to be inhibited by the inflammation (Soumian et al., 2005; Yvan-Charvet et al., 2010) meaning that additional mechanism of excessive accumulation of cholesterol in the blood is possible.

As mentioned above, the most frequent treatment of atherosclerosis is associated with the use of statins that, unfortunately, produces many side effects (Bellosta and Corsini, 2018; Taylor and Thompson, 2018; Toth et al., 2018). More advanced approaches are based on the treatments with the use of PCSK9 specific inhibitors, Evolocumab or Alirocumab (McDonagh et al., 2016). These artificial antibodies are effective, however, they are expensive. Below, some potentially effective alternatives will be discussed.

Type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is characterized by inability of peripheral tissues to absorb the blood glucose in sufficient amounts despite hyperglycemia and hyperinsulinemia. The appearance of this condition is linked to chronic inflammation. Mechanisms of the insulin resistance include the signaling by the TNF-α in combination with activated TLR2 and TLR4, which can initiate phosphorylation of the insulin receptor 1/2 substrate blocking and in turn the insulin signaling in tissues and thus the glucose transport through the cell membrane (McNelis and Olefsky, 2014). The key role of obesity in T2DM is explained by the senescence of the fat tissue and formation of “necrotic” adipocytes which secrete TNF-α. This results in accumulation of pro-inflammatory M1 macrophages in adipose tissue facilitating even more TNF-α release (Esser et al., 2014) and thereby amplifying the inflammation. These processes form a vicious circle of chronic inflammation that is expected to be a main cause of T2DM.

The insulin resistance in the hypothalamus may result in the appearance of a permanent feeling of hunger that is controlled by the hypothalamic arcuate nucleus. The insulin resistance caused by prolonged free fatty acid exposure may end up even with gliosis in hypothalamus that completely disrupts the insulin regulation and its transport into CNS (Ono, 2019). In spite of inflammation development in the adipose tissue the process of lipogenesis and fat accumulation is continued, and the lipogenesis clearly prevails over lipolysis (Kahn and Flier, 2000). Chronic inflammation inhibition could be beneficial for the unblocking of insulin signaling that may ameliorate the described pathologies. This mechanism is expected to work until the critical degradation of beta cell population in the pancreatic Langerhans islets is reached. It should be mentioned, however, that degeneration of the islets is triggered by the inflammation and usually accompanied by autoimmune reactions (Burrack et al., 2017).

T2DM therapies usually include the use of metformin which is considered as an optimal drug (Sanchez-Rangel and Inzucchi, 2017), although the mechanism of its action is still under debate. Metformin is thought to reduce the blood glucose level via attenuation of its production by the liver. It should be mentioned, however, that some adverse effects of metformin were observed (Sanchez-Rangel and Inzucchi, 2017). Potentially effective substances for the treatment of T2DM, at least at early stages of its development, will be discussed below.

MS and chronic inflammation

MS is usually diagnosed when at least three of five criteria are met: 1) abdominal obesity, 2) arterial hypertension, 3) dysglycemia, 4) hypertriglyceridemia and 5) low level of HDL. In developed countries, the prevalence of metabolic syndrome among people over 30 is 10–20%, in the United States - 34% (44% among people over 50; Ford et al., 2002). Among the MS criteria, the enhanced blood pressure seems to be crucial (Sharma, 2011; Patel and Patel, 2015; Bhatti et al., 2017), whereas among many reasons to develop this symptom, increased activity of the sympathetic nervous system is likely dominant (Johnson et al., 2012). MS is considered as a “precondition” for the number of serious pathologies: CVDs, atherosclerosis, T2DM (Bhatti et al., 2017) and chronic renal failure (Prasad, 2014). Substantial proportion of AD patients has been shown to suffer from MS (Vanhanen et al., 2006; Razay et al., 2007).

The mechanisms of MS are not completely understood. The senescence of fat tissue is expected to initiate MS (Palmer et al., 2019) that can explain the existence of overweight people with healthy liver, normal blood pressure, however, having no MS. One of the trigger mechanisms in the inflammatory processes seems to be associated with TLR4 that is activated by Fetuin-A protein (Alpha 2-HS Glycoprotein) in the presence of “free fatty acids” (FFA, Pal et al., 2012). The Fetuin-A protein, which is very important for embryonic development, is generated in the liver. Furthermore, its expression has been shown to persist up to adulthood resulting in substantial protein accumulation in the adipose tissue in T2DM patients, in particular (Khadir et al., 2018). The Fetuin-A/FFA complex activates the TLR4 receptor in adipocytes that in turn triggers the insulin resistance (Pal et al., 2012). Finally, activation of TLR4 on macrophages triggers the inflammatory reactions (McNelis and Olefsky, 2014). FFA amount is controlled by liver, and FFA accumulation in the blood can be evoked by high-fat diets (Liu et al., 2016) resulting in dyslipidemia even in patients with normal weight (Hojland Ipsen et al., 2016). As mentioned above, the fat accumulation in obesity is associated with the appearance of necrotic adipocytes, chronic inflammation and hyperglycemia (Welty et al., 2016), whereas, the hypertension is linked with the sympathetic nervous system activation and triggered by the insulin resistance (Johnson et al., 2012) and, in part, by permanent stress (Hamer and Steptoe, 2012).

Certain lifestyle and nutrition habits seem to be very important for MS development, although pharmacological approaches have many options for the treatment. They include the use of statins (lipid profile), aspirin (as non-steroid anti-inflammatory drug) and several classes of drugs that lower the arterial blood pressure. Nevertheless, dietary modifications and regular physical exercises are more preferable. Statins, aspirin and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers should be prescribed as adjuncts rather than alternatives (Sherling et al., 2017). In particular, the dietary impact could be effective by the consumption of products with some natural plant substances like flavonoids (polyphenols) which are characterized by enhanced antioxidant activity (Duluc et al., 2012). Effects of dietary inclusion of flavonoids and some vitamins on MS are reviewed in de la Iglesia et al. (2016). One of the natural functions of flavonoids is the regulation of respiration in plants (Shimoji and Yamasaki, 2005). Given this, there is no wonder that flavonoids can also regulate the energetic process by the inhibition of mitochondrial functions in mammals (Dorta et al., 2005), that explains their apoptotic effects on some actively dividing cancer cells (Abotaleb et al., 2018) and inhibitory influences on the inflammation (Serafini et al., 2010).

Several other potentially effective substances of different origin and specific efficacies towards mitochondria will be discussed below.

AD and chronic inflammation

AD and atherosclerosis share the same genetic basis (in particular, APOE ε4 allele), that seems to be a characteristic for the most of AD and atherosclerosis cases associated with chronic inflammation and vascular pathologies. AD is characterized by concomitant cerebral amyloid angiopathy that is manifested by Aβ deposition on the outer vessels walls expressing proteoglycans Perlecan and Collagen XVIII with heparan sulfate chains, which collect excessive Aβ. Cerebral amyloid angiopathy produces mechanical damage to the vascular endothelium that can lead to hemorrhages and even more dramatic oxygen supply impairment (Grinberg et al., 2012). AD is characterized by neuroinflammation that is diagnosed post-mortem as gliosis. Unfortunately, existing anti-inflammatory drugs for AD are ineffective and traditional corticosteroid therapy can aggravate the disease making it even worse (Machado et al., 2014). The connections AD with atherosclerosis, T2DM and MS are important despite they may not be obvious at first glance as AD is rather isolated from periphery and developed behind BBB. However, AD development has been demonstrated to be very frequently accompanied by atherosclerosis (Lathe et al., 2014). Furthermore, one study demonstrated that the association rate of atherosclerotic deposits in the vessels of AD brains was about 77% (Yarchoan et al., 2012). The risk of AD development is also significantly enhanced in parallel with development of both T2DM (De Felice and Ferreira, 2014) and MS (Vanhanen et al., 2006).

TLR4 receptors of the microglia have been demonstrated to mediate the main immune responses to aggregated Aβ in AD (Walter et al., 2007). Moreover, some mutations in TLR4 elucidated the role of neuroinflammation as a primary cause of AD. TLR4 D299G mutation is associated with the resistance to AD development due to attenuation of the TLR4 signaling pathway which is responsible for the production of pro-inflammatory interleukin IL-1 (Miron et al., 2019). TLR4 D299G is well known to be hyporeactive to the lipopolysaccharide (Arbor et al., 2000). Surprisingly, TLR4 D299G carriers are resistant to AD development, however, they are more sensitive to bacterial infections (Agnese et al., 2002; Genc et al., 2004), bacterial septic shock (Lorenz et al., 2002) and some viral infections (Tal et al., 2004). Interestingly, the same D299G mutation in TLR4 delays the development of atherosclerosis (Kiechl et al., 2002) and hepatic cirrhosis (Guo et al., 2009). Thus, hyporeaction in TLR pathways may be beneficial for the development of chronic inflammation, but can be life-threatening in some infectious diseases. In any case, further studies need to be performed as TLR4 is not the only player in the cerebral immune responses.

To date, no effective approaches for AD treatment are known. The immune therapy studies produce only the disappointing results so far (Bachmann et al., 2019) despite the ample amount of available drugs and trials (Hampel et al., 2018). However, in our opinion, several prospective trials with nerve growth factor based therapy might be very promising. Generation of ex vivo autologous fibroblasts genetically modified to express the nerve growth factor were implanted in the brains of AD patients and resulted in abrogation of disease development (Tuszynski et al., 2005). However, clinical trials with NGF gene delivery using adeno-associated viral vectors did not show the real effectiveness (Rafii et al., 2018) although post-mortem analysis of the brains from treated patients demonstrated the response to NGF expressed by adeno-associated viral vectors (Tuszynski et al., 2015). NGF treatment of AD has been studied for a long time, however, NGF/TrkA signaling has been revealed to activate nociceptive perception, in particular, in inflammation (Mizumura and Murase, 2015). Inflammation-associated chronic pain could be eliminated by Tanezumab (Hefti, 2019), however, this additional treatment complicates the use of NGF therapy for AD.

Depression and chronic inflammation

Well-defined genetic polymorphisms in IL-1β, IL-6, MCP-1 (CCL2), TNF-α and C-reactive protein are related with clinically expressed depression. The existence of these polymorphisms gives an additional immunity in those ethnic groups who live in an ancestral environment. However, the appearance of such mutations in people with modern lifestyles including so-called “Western Diet” makes them vulnerable that in turn triggers the development of the depression associated disorders (Barnes et al., 2017). Up to 80% cases of severe depression are associated with an excessive amount of glucocorticoids released by the adrenal glands into the bloodstream. At abnormally high level of glucocorticoids, the brain activity and synaptic plasticity are suppressed that is aggravated by impairment of the patient's mood due to the release of corticotropin-releasing hormone, which activates the hypothalamic-pituitary-adrenocortical system (Anacker et al., 2011). Paradoxically, the systemic chronic inflammation can provide a resistance to glucocorticoids that is mediated by inflammasome resulting in the degradation of glucocorticoid receptors (Miller and Raison, 2016) and cessation of the depression. However, in certain patients, the systemic chronic inflammation can also act directly through the pro-inflammatory cytokines provoking the depression (Miller and Raison, 2016). Interferons, TNF-α, IL-1β and ROS affect the glial cells in the brain and impair the glutamate reuptake that may provoke the excitotoxicity. Pro-inflammatory cytokines can also impair the monoamine-mediated neuronal circuits which are associated with the mood regulation. These negative events can lead to anhedonia, anxiety and depression. Glucocorticoids are frequently used as the anti-inflammatory drugs via mechanisms of both the multiple inflammatory gene suppression and regulation of the anti-inflammatory gene transcription, however, the higher concentration of corticosteroids has been shown to produce side effects (Barnes, 2006).

It is sure that depression can aggravate the condition of an AD patient. However, it is possible to check it in experimental animal models only. Using the stress-level glucocorticoid administration protocol in a transgenic mouse model of AD, the synthetic corticosteroid dexamethasone has been shown to facilitate the development of both Aβ and tau-protein pathologies instead of expected suppression of the inflammation (Green et al., 2006). In another experimental model the transgenic mice Tg2576 (also model of AD), increased tau protein hyperphosphorylation, insoluble tau inclusions and neurodegeneration were observed, when mice were stressed for one month. These stress-associated changes have been shown to be prevented by an antagonist of corticotropin-releasing hormone (Carroll et al., 2011). More transgenic mouse models of AD also demonstrated aggravation of AD pathologies in stressful environments (Pedersen et al., 1999; Dong et al., 2004, 2008; Pedersen and Flynn, 2004; Lee et al., 2009). Thus, the evident synergic effect of systemic stress on AD development was demonstrated the number of times. That should be taken into account in clinical treatment of excessive inflammation by the use of glucocorticoids (Barnes, 1998; Coutinho and Chapman, 2011; Liberman et al., 2018). It should be also mentioned that glucocorticoids are able to target both glucocorticoid receptors and mineralocorticoid receptors (MRs), whose activation can be equally effective (Reul et al., 1990). That explains many side effects of glucocorticoids. Notably, the prolonged activation of MRs can potentiate the senescence in both the fat tissue (Lefranc et al., 2019), kidney (Fan et al., 2011) and cardiovascular system (Gorini et al., 2019). The secretome of senescent cells is able to produce a local chronic inflammation (Newsholme and de Bittencourt, 2014), whereas, the targeting of the senescent cells has been shown to alleviate the obesity-induced metabolic dysfunction (Palmer et al., 2019). Effects of aldosterone, a natural agonist of MR, are manifested in the cardiovascular system by cardiac fibrosis and hypertrophy because of the persistent activation of renin-angiotensin-aldosterone axis that leads to vasoconstriction, hypertension and, thus, to oxygen deficit in tissues (Cannavo et al., 2018). MRs play an important role in obesity where the OS and mitochondrial dysfunction are revealed as well (Lefranc et al., 2018). Finally, another serious complication with excessive use of corticoids is associated with the major depressive disorder (Young et al., 2003; de Kloet et al., 2016; Canet et al., 2018).

In general, depression is a very complicated topic in terms of chronic inflammation. The whole aspects require the separate review, however, the most importantly that these conditions are frequently concomitant to other diseases with chronic inflammation and, hence, are able to trigger and accelerate their development. Interestingly, these conditions can be also treated with some anti-inflammatory agents and, thus, they could be supportive for some depressive people. This topic will be in detail discussed below.


  Breaking the Vicious Circle of Chronic Inflammation Top


We propose that the normalization of mitochondria functions could have a key role for treatment of all mentioned disorders and probably many others related to the chronic inflammation in ageing. Certain substances potentially useful for the mitochondrial OS treatment are described in the following sections.

The mitochondria-targeted catalase

Mitochondrial dysfunction and OS are the common hallmarks of most of the metabolic disorders and, thus, the treatments targeting the mitochondria could be potentially very useful (Bhatti et al., 2017). One of the most interesting avenues for the potential therapeutics was a generation of transgenic mice ubiquitously expressing a “mitochondria targeted catalase” (mCAT; Schriner et al., 2005). The open reading frame of this catalase contains a modified signal peptide: an original catalase peptide for peroxisomal localization was replaced by the peptide from ornithine transcarbamylase, that targets the protein to mitochondrial matrix. Thus, the targeted catalase is reallocated to mitochondria upon the translation. This genetic engineering produced a remarkable outcome: the transgenic mice with mitochondria targeted catalase demonstrated substantially increased life span whereas those with nucleus targeted catalase had no health impact. This argues with the statement that “DNA damage contributes to aging”, especially with the development of neurodegenerative diseases (Maynard et al., 2015). In particular, in many familial cases of amyotrophic lateral sclerosis (ALS) the enzyme superoxide dismutase 1 (SOD1) has been shown to have the “gain of function” mutations (Kaur et al., 2016). SOD1 is well known to convert O2 into H2O2 and it is expressed in both nucleus and mitochondria; hence, the increased expression and activity of SOD1 will ultimately lead to H2O2 accumulation in mitochondria. Thus, these defects in familial ALS with SOD1 mutations seem to be predominantly associated with accumulated damages and harmful structural changes in mitochondria (Son and Elliott, 2014).

mCAT transgenic mice had the delayed developments of cardiac pathology and cataract and reduced ROS production due to aconitase inactivation. It supports the “free radical theory” of ageing and reinforces the importance of mitochondria as a source of free radicals. The transgenic mice were tested in several models of chronic inflammation-related diseases and demonstrated the substantial improvement of cardiac ageing and age-dependent cardiomyopathy (Dai et al., 2009, 2010), ischemic myopathy in high-fat diet mouse model (Ryan et al., 2016), and the lipid/high-fat diet-induced insulin resistance (Lee et al., 2010). Furthermore, when this mouse line was bred with Tg2576 mice, the double transgenic mice were characterized by substantial delay in development of the AD-related pathologies, improved cognitive functions and increased life span (Mao et al., 2012). Other studies in the CNS demonstrated the improved neurovascular coupling in aged mice (Csiszar et al., 2019), reverted toxicity of astrocytes towards motoneurons in an animal model of ALS (Pehar et al., 2014), and, finally, prevention of radiation-induced cognitive dysfunctions (Parihar et al., 2015). Despite that the mitochondria targeted catalase is a remarkably engineered protein, its original kinetics is similar or even more effective to that of glutathione peroxidase (Gaetani et al., 1989; Vetrano et al., 2005; Yu et al., 2005) that makes it very attractive as a potential drug. However, its delivery to targets can be very problematic even when viral vectors for gene therapy will be used. mCAT is dedicated to abrogate ROS production. ROS generation is an essential immune response against bacterial or viral infections, thus mCAT could potentially facilitate the infection development. Another obstacle for the use of transgenic tools for this enzyme expression in humans is linked with possible oncogenic transformation due to the positional effects of recombinant genetic construct integration in genomic DNA. Thus, mCAT seems to be currently unusable for the treatment in humans.

Algae xanthophylls

In plants, the pigment-protein complexes arranged in 3-dimensional “funneling-like” reaction centers, so-called “light harvesting antenna”, in photosystem complexes. They are used for the photosynthesis where the xanthophylls and carotenoids are an integral part of the centers associated with chlorophyll (Horton and Ruban, 2005). Carotenoids and xanthophylls are essential for chlorophyll activation during photosynthesis and for excessive energy dissipation (Young and Frank, 1996). Additionally, plants use a xanthophyll's cycle mechanism which provides a non-photochemical quenching for ROS elimination when the plants are exposed to excessive irradiation energy or other stressful stimuli (Latowski et al., 2011).

Recently, some xanthophylls received a lot of attention because of their exclusive anti-oxidative abilities and, respectively, their positive effect on human health (Gammone et al., 2015). Certain xanthophylls, synthesized by microalgae and seaweeds (especially, Astaxanthin and Fucoxanthin), are frequently used in studies of NCDs with chronic inflammation. Here, we review possible mechanisms of xanthophylls correction of the mitochondria damaged in chronic inflammation and analyze several diseases in animal and human studies where the xanthophylls have been used for their treatments.

In particular, multiple changes in the enzymatic activities related to mitochondria were demonstrated in aortopathies: in particular, SOD activity was frequently increased in the pathology, whereas the glutathione peroxidase activity was decreased (Soto et al., 2014). It results in the accumulation of hydrogen peroxide in the affected tissues that is normal in the short term in the cases of infections or trauma, but becomes dangerous when it turns into chronic inflammation. The astaxanthin abilities for the protection were demonstrated from both reactive oxygen (O2; Nishinoa et al., 2016) and H2O2 (Wang et al., 2015a) meaning that mechanisms of astaxanthin effects are similar to those of mCAT. However, carotenoids and xanthophylls are able to be as acceptors and donors for electrons simultaneously (Mairanovsky et al., 1975; Faller et al., 2001). The same ability is a characteristic for both astaxanthin (Kidd, 2011) and fucoxanthin that establishes their relations with the chlorophyll photosystem I complex (Ikeda et al., 2013). Compared with the recombinant enzymes, the astaxanthin/fucoxanthin have no anatomical or physiological barriers to be distributed in the organism and can be systemically (orally) applied in form of the oil capsules. Astaxanthin and fucoxanthin are enzymatically generated as a part of the lipid fraction in algae and can be enriched by carotenoids (Sun et al., 2018). Both astaxanthin and fucoxanthin are very prospective medical, nutritional and cosmetic products with an extraordinary potential (Zhang et al., 2015; Shah et al., 2016). These abilities of the xanthophylls most likely are associated with their specific transmembrane orientation that displays their reaction centers towards the hydrophilic phases on both sides of the lipid membrane, in contrast to the carotenoids located exclusively within the hydrophobic lipid layers. That provides the unique electron donor-acceptor characteristics and, respectively, biological features of xanthophylls (Grudzinski et al., 2017).

Certain drugs can accumulate in the organism due to ineffective mechanisms of their extraction or biodegradation. Xanthophylls have both acceptable pharmacokinetics and effective pathways for their biodegradation that is characteristic for humans. The metabolism of carotenoids and xanthophylls is controlled by the endogenous beta-carotene oxygenases 1 and 2 (BCO1 and BCO2). These enzymes prevent the over-accumulation of carotenoids because their excess can trigger the OS. In particular, BCO2 with its mitochondrial localization in the matrix membrane, is effectively involved in mitochondrial and cellular metabolism controlling the OS and apoptosis (Amengual et al., 2011; Lobo et al., 2012). Interestingly, BCO2 expression is inactivated in the retina that underlies the accumulation of beta-carotene, lutein and zeaxanthin and, finally, resulting in its photoprotection (Li et al., 2014). The lack of BCO2 has been shown to be associated with malfunctioning of hepatic mitochondria in the BCO2 knock-out mice (Wu et al., 2017). BCO2-mediated elimination of astaxanthin/fucoxanthin in tissues raises the question of their pharmacokinetics. In human plasma, astaxanthin's half-life has been estimated at 21 hours (Osterlie et al., 2000); fucoxanthin pharmacokinetics was only evaluated in the mouse plasma and tissues. The oral one-week consumption of fucoxanthin resulted in sustained accumulation of fucoxanthin metabolites (fucoxanthinol and amarouciaxanthin A) in the heart, liver and adipose tissue (Hashimoto et al., 2009). So far, no side effects of the xanthophylls treatment have been described in humans yet. Pharmacokinetics of astaxanthin and fucoxanthin and evidence of their positive role in NCDs allow the conclusion that they are very promising drugs. Interactions of recombinant mCAT and the xanthophylls (astaxanthin and fucoxanthin) with the mitochondria are schematically summarized in [Figure 1].
Figure 1: The healthy and pathologic condition of “chronic inflammation” in mitochondria.
The inflammation results in impaired Krebs cycle, malfunctioning of mitochondrial complexes I and III, with excessive generation of reactive oxygen (O2), increased activity of superoxide dismutases (SOD), reduced activity of glutathione peroxidases (GPX) and hydrogen peroxide accumulation (H2O2). H2O2 excess can be eliminated by mitochondria targeted catalase (mCAT). Astaxanthin/Fucoxanthin can reduce both O2 and H2O2. The excess of carotenoids and xanthophylls is eliminated by endogenous enzyme beta-carotene-oxygenase 2 (BCO2) localized in the mitochondrial matrix membrane.


Click here to view


Health benefits of xanthophylls in chronic inflammation

In the “High-Fat Diet” animal model of CVDs/atherosclerosis/type 2 diabetes, significant improvements in the lipid metabolism have been demonstrated after treatment with astaxanthin (Ikeuchi et al., 2007; Yoshida et al., 2010; Xu et al., 2014, 2017; Yang et al., 2014; Kim et al., 2017; Wang et al., 2019) and fucoxanthin (Maeda et al., 2009; Jeon et al., 2010; Woo et al., 2010; Hu et al., 2012; Ha and Kim, 2013). Positive effects of fucoxanthin on the experimental animals were more profound because of evident reduction of their weight. The effect seems to be associated with long-lasting (41-day half-life) accumulation of a fucoxanthin metabolite, amarouciaxanthin A, in the adipose tissue in mice (Hashimoto et al., 2009). The anti-obesity properties of fucoxanthin have been reviewed in Gammone and D'Orazio, 2015.

Besides the lipid profile regulation, astaxanthin affects microbiota composition in the gut (Wang et al., 2019), reduces the OS (Xu et al., 2017), inhibits both inflammation and fibrosis in the liver (Kim et al., 2017), reverses the diet-provoked insulin resistance (Ni et al., 2015), ameliorates the insulin signaling (Arunkumar et al., 2012), prevents the insulin signaling deterioration and improves the glucose metabolism in the liver of insulin resistant mice (Bhuvaneswari and Anuradha, 2012). Furthermore, ?staxanthin stimulates mitochondrial biogenesis in insulin resistant muscle (Nishida et al., 2020), protects beta-cells against glucose toxicity in diabetic db/db mice (Uchiyama et al., 2002), eliminates the endothelial dysfunction in streptozotocin-induced diabetes in male rats (Zhao et al., 2011), and prevents nephropathy in diabetic db/db mice (Naito et al., 2004). Fucoxanthin affects glucose homeostasis, lipid metabolism, and liver function in a mouse model of T2DM (Lin et al., 2017) and anti-inflammatory activity in obese mice (Tan and Hou, 2014; Maeda et al., 2015). Health benefits of the fucoxanthin treatment in the prevention of chronic diseases are reviewed in (Bae et al., 2020).

Astaxanthin has been shown to increase the levels of serum HDL-cholesterol and adiponectin in subjects with mild hyperlipidemia (Yoshida et al., 2010) and to improve glucose metabolism and reduced blood pressure in patients with T2DM (Mashhadi et al., 2018).

Xanthophylls and cognition

Well-known interplay between chronic inflammation and stress can tremendously affect CNS causing depression and cognitive impairment. Astaxanthin has been shown to prevent the depression caused by the inflammation in animals (Jiang et al., 2016; Zhou et al., 2017) and to produce an anti-hyperalgesic effect, thus, correcting comorbid depressive like behavior in mice with chronic pain (Jiang et al., 2018). Astaxanthin is able to correct cognitive deficits and OS associated with diabetes (Xu et al., 2015; Zhou et al., 2015; Al-Amin et al., 2016; Li et al., 2016) and to improve the cognition impaired by traumatic brain injury (Ji et al., 2017). In some studies, the anti-depressant astaxanthin activities have been shown to affect the serotonergic system directly (Jiang et al., 2017). Furthermore, lipopolysaccharide-induced depressive-like behavior in mice was prevented by fucoxanthin via the suppression of inflammatory pathways (Jiang et al., 2019).

Xanthophylls and AD

In vitro, both fucoxanthin and astaxanthin demonstrated evident neuroprotective activities against Aβ42, one of the main hallmarks of AD (Alghazwi et al., 2019). Fucoxanthin ameliorated OS and inflammation in Aβ42-induced BV2 microglia cells and reduced ROS generation (Pangestuti et al., 2013). Astaxanthin neuroprotective properties were demonstrated in many cellular models of neurodegenerative pathologies: AD, Parkinson's disease, and ALS (Galasso et al., 2018).

The most impressive results were obtained in animal models of AD. Fucoxanthin has been shown to inhibit Aβ assembly, to attenuate Aβ-induced toxicity, and to reduce AD-related cognitive impairments (Xiang et al., 2017). Furthermore, fucoxanthin significantly lowered OS, enhanced the brain-derived neurotrophic factor expression and enlarged choline acetyltransferase-positive regions in the hippocampus of mice. In transgenic animal model of AD (APPswe/PS1ΔE9), substantial reduction in Aβ accumulation, reduced Aβ plaque loading and increased APOE expression in the brain, and improved memory were observed after the treatment with fucoxanthin enriched extract from the seaweed Sargassum fusiforme (Bogie et al., 2019). In APPswe/PS1ΔE9 mice, astaxanthin alone and particularly in combination with docosahexaenoic acid was extremely effective in reduction of OS and tau hyperphosphorylation, in suppression of neuroinflammation by reducing the expression of inflammasome proteins and inflammasome activation (Che et al., 2018).

Conclusions

AD and other chronic neurodegenerative disorders are characterized by multiple abnormalities at systemic, cellular, macromolecular, and biochemical levels. Neurodegeneration-related pathologies are well known to be associated with inflammation, mitochondrial malfunctioning, disturbed energy metabolism, and chronic OS. Mechanisms of intracellular inflammation-related processes indicate a pre-programmable character of the “mitochondrial dysfunctions”. However, in the chronic inflammation these dysfunctions become permanent and their correction is essential. The mitochondria-targeted catalase and algae derived xanthophylls, astaxanthin and fucoxanthin, can correct the inflammation related pathologies and provide significant improvements practically in all integrative systems (cardiovascular, nervous, metabolic, immune and others) that are expected to involve similar/identical mechanism(s). Thus, intensive further studies of xanthophylls’ beneficial effects and their clinical trials could be a promising way for the operative development of therapeutic approaches oriented on actual treatments of the causes of the diseases rather than their symptoms.

Author contributions: The manuscript was conceived and wrote by MAF, edited by VVV, designed by OGT, reviewed and permitted for submission by NVP. All authors participated in the elaboration of the manuscript and approved its final version.

Conflicts of interest: The authors declare no conflicts of interest.

Financial support: None.

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

 
  References Top

1.
Abondio P, Sazzini M, Garagnani P, Boattini A, Monti D, Franceschi C, Luiselli D, Giuliani C (2019) The genetic variability of APOE in different human populations and its implications for longevity. Genes (Basel) doi: 10.3390/genes10030222.  Back to cited text no. 1
    
2.
Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A, Busselberg D (2018) Flavonoids in cancer and apoptosis. Cancers (Basel) doi: 10.3390/cancers11010028.  Back to cited text no. 2
    
3.
Al-Amin MM, Sultana R, Sultana S, Rahman MM, Reza HM (2016) Astaxanthin ameliorates prenatal LPS-exposed behavioral deficits and oxidative stress in adult offspring. BMC Neurosci 17:11.  Back to cited text no. 3
    
4.
Alghazwi M, Smid S, Musgrave I, Zhang W (2019) In vitro studies of the neuroprotective activities of astaxanthin and fucoxanthin against amyloid beta (Abeta1-42) toxicity and aggregation. Neurochem Int 124:215-224.  Back to cited text no. 4
    
5.
Amengual J, Lobo GP, Golczak M, Li HN, Klimova T, Hoppel CL, Wyss A, Palczewski K, von Lintig J (2011) A mitochondrial enzyme degrades carotenoids and protects against oxidative stress. FASEB J 25:948-959.  Back to cited text no. 5
    
6.
Anacker C, Zunszain PA, Carvalho LA, Pariante CM (2011) The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36:415-425.  Back to cited text no. 6
    
7.
Arunkumar E, Bhuvaneswari S, Anuradha CV (2012) An intervention study in obese mice with astaxanthin, a marine carotenoid--effects on insulin signaling and pro-inflammatory cytokines. Food Funct 3:120-126.  Back to cited text no. 7
    
8.
Bachmann MF, Jennings GT, Vogel M (2019) A vaccine against Alzheimer`s disease: anything left but faith? Expert Opin Biol Ther 19:73-78.  Back to cited text no. 8
    
9.
Bae M, Kim MB, Park YK, Lee JY (2020) Health benefits of fucoxanthin in the prevention of chronic diseases. Biochim Biophys Acta Mol Cell Biol Lipids doi: 10.1016/j.bbalip.2020.158618.  Back to cited text no. 9
    
10.
Barnes J, Mondelli V, Pariante CM (2017) Genetic contributions of inflammation to depression. Neuropsychopharmacology 42:81-98.  Back to cited text no. 10
    
11.
Barnes PJ (1998) Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond) 94:557-572.  Back to cited text no. 11
    
12.
Barnes PJ (2006) How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 148:245-254.  Back to cited text no. 12
    
13.
Bellosta S, Corsini A (2018) Statin drug interactions and related adverse reactions: an update. Expert Opin Drug Saf 17:25-37.  Back to cited text no. 13
    
14.
Bhatti JS, Bhatti GK, Reddy PH (2017) Mitochondrial dysfunction and oxidative stress in metabolic disorders - A step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol Basis Dis 1863:1066-1077.  Back to cited text no. 14
    
15.
Bhuvaneswari S, Anuradha CV (2012) Astaxanthin prevents loss of insulin signaling and improves glucose metabolism in liver of insulin resistant mice. Can J Physiol Pharmacol 90:1544-1552.  Back to cited text no. 15
    
16.
Bogie J, Hoeks C, Schepers M, Tiane A, Cuypers A, Leijten F, Chintapakorn Y, Suttiyut T, Pornpakakul S, Struik D, Kerksiek A, Liu HB, Hellings N, Martinez-Martinez P, Jonker JW, Dewachter I, Sijbrands E, Walter J, Hendriks J, Groen A, et al. (2019) Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model. Sci Rep 9:4908.  Back to cited text no. 16
    
17.
Bousquet J, Anto JM, Sterk PJ, Adcock IM, Chung KF, Roca J, Agusti A, Brightling C, Cambon-Thomsen A, Cesario A, Abdelhak S, Antonarakis SE, Avignon A, Ballabio A, Baraldi E, Baranov A, Bieber T, Bockaert J, Brahmachari S, Brambilla C, et al. (2011) Systems medicine and integrated care to combat chronic noncommunicable diseases. Genome Med 3:43.  Back to cited text no. 17
    
18.
Burrack AL, Martinov T, Fife BT (2017) T cell-mediated beta cell destruction: autoimmunity and alloimmunity in the context of type 1 diabetes. Front Endocrinol (Lausanne) 8:343.  Back to cited text no. 18
    
19.
Butterfield DA, Swomley AM, Sultana R (2013) Amyloid beta-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 19:823-835.  Back to cited text no. 19
    
20.
Cai Z, Hussain MD, Yan LJ (2014) Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease. Int J Neurosci 124:307-321.  Back to cited text no. 20
    
21.
Canet G, Chevallier N, Zussy C, Desrumaux C, Givalois L (2018) Central role of glucocorticoid receptors in Alzheimer's disease and depression. Front Neurosci 12:739.  Back to cited text no. 21
    
22.
Cannavo A, Bencivenga L, Liccardo D, Elia A, Marzano F, Gambino G, D'Amico ML, Perna C, Ferrara N, Rengo G, Paolocci N (2018) Aldosterone and mineralocorticoid receptor system in cardiovascular physiology and pathophysiology. Oxid Med Cell Longev 2018:1204598.  Back to cited text no. 22
    
23.
Carroll JC, Iba M, Bangasser DA, Valentino RJ, James MJ, Brunden KR, Lee VM, Trojanowski JQ (2011) Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci 31:14436-14449.  Back to cited text no. 23
    
24.
Cha JY, Kim DH, Chun KH (2018) The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Lab Anim Res 34:133-139.  Back to cited text no. 24
    
25.
Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130-25138.  Back to cited text no. 25
    
26.
Che H, Li Q, Zhang T, Wang D, Yang L, Xu J, Yanagita T, Xue C, Chang Y, Wang Y (2018) Effects of astaxanthin and docosahexaenoic-acid-acylated astaxanthin on Alzheimer's disease in APP/PS1 double-transgenic mice. J Agric Food Chem 66:4948-4957.  Back to cited text no. 26
    
27.
Cohn JN, Hoke L, Whitwam W, Sommers PA, Taylor AL, Duprez D, Roessler R, Florea N (2003) Screening for early detection of cardiovascular disease in asymptomatic individuals. Am Heart J 146:679-685.  Back to cited text no. 27
    
28.
Coutinho AE, Chapman KE (2011) The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 335:2-13.  Back to cited text no. 28
    
29.
Cox GM, Kithcart AP, Pitt D, Guan Z, Alexander J, Williams JL, Shawler T, Dagia NM, Popovich PG, Satoskar AR, Whitacre CC (2013) Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation. J Immunol 191:1043-1054.  Back to cited text no. 29
    
30.
Crofton RW, Diesselhoff-den Dulk MM, van Furth R (1978) The origin, kinetics, and characteristics of the Kupffer cells in the normal steady state. J Exp Med 148:1-17.  Back to cited text no. 30
    
31.
Csiszar A, Yabluchanskiy A, Ungvari A, Ungvari Z, Tarantini S (2019) Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice. Geroscience 41:609-617.  Back to cited text no. 31
    
32.
Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond MJ, Ngo CP, Prolla TA, Rabinovitch PS (2010) Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9:536-544.  Back to cited text no. 32
    
33.
Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, Rabinovitch PS (2009) Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119:2789-2797.  Back to cited text no. 33
    
34.
de Candia P, Prattichizzo F, Garavelli S, De Rosa V, Galgani M, Di Rella F, Spagnuolo MI, Colamatteo A, Fusco C, Micillo T, Bruzzaniti S, Ceriello A, Puca AA, Matarese G (2019) Type 2 diabetes: how much of an autoimmune disease? Front Endocrinol (Lausanne) 10:451.  Back to cited text no. 34
    
35.
De Felice FG, Ferreira ST (2014) Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 63:2262-2272.  Back to cited text no. 35
    
36.
de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MH, Hasselmann H, Kliegel D, Joels M (2016) Stress and depression: a crucial role of the mineralocorticoid receptor. J Neuroendocrinol doi: 10.1111/jne.12379.  Back to cited text no. 36
    
37.
de la Iglesia R, Loria-Kohen V, Zulet MA, Martinez JA, Reglero G, Ramirez de Molina A (2016) Dietary strategies implicated in the prevention and treatment of metabolic syndrome. Int J Mol Sci doi: 10.3390/ijms17111877.  Back to cited text no. 37
    
38.
Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE (2013) Kupffer cells in the liver. Compr Physiol 3:785-797.  Back to cited text no. 38
    
39.
Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127:601-609.  Back to cited text no. 39
    
40.
Dong H, Yuede CM, Yoo HS, Martin MV, Deal C, Mace AG, Csernansky JG (2008) Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice. Neuroscience 155:154-163.  Back to cited text no. 40
    
41.
Dorta DJ, Pigoso AA, Mingatto FE, Rodrigues T, Prado IM, Helena AF, Uyemura SA, Santos AC, Curti C (2005) The interaction of flavonoids with mitochondria: effects on energetic processes. Chem Biol Interact 152:67-78.  Back to cited text no. 41
    
42.
Duluc L, Soleti R, Clere N, Andriantsitohaina R, Simard G (2012) Mitochondria as potential targets of flavonoids: focus on adipocytes and endothelial cells. Curr Med Chem 19:4462-4474.  Back to cited text no. 42
    
43.
Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N (2014) Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 105:141-150.  Back to cited text no. 43
    
44.
Fadini GP, Ciciliot S (2014) Vascular smooth muscle cells and monocyte-macrophages accomplice in the accelerated atherosclerosis of insulin resistance states. Cardiovasc Res 103:194-195.  Back to cited text no. 44
    
45.
Faller P, Pascal A, Rutherford AW (2001) Beta-carotene redox reactions in photosystem II: electron transfer pathway. Biochemistry 40:6431-6440.  Back to cited text no. 45
    
46.
Fan YY, Kohno M, Hitomi H, Kitada K, Fujisawa Y, Yatabe J, Yatabe M, Felder RA, Ohsaki H, Rafiq K, Sherajee SJ, Noma T, Nishiyama A, Nakano D (2011) Aldosterone/mineralocorticoid receptor stimulation induces cellular senescence in the kidney. Endocrinology 152:680-688.  Back to cited text no. 46
    
47.
Fischer HG, Reichmann G (2001) Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 166:2717-2726.  Back to cited text no. 47
    
48.
Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356-359.  Back to cited text no. 48
    
49.
Fu W, Shi D, Westaway D, Jhamandas JH (2015) Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity. J Biol Chem 290:12504-12513.  Back to cited text no. 49
    
50.
Gaetani GF, Galiano S, Canepa L, Ferraris AM, Kirkman HN (1989) Catalase and glutathione peroxidase are equally active in detoxification of hydrogen peroxide in human erythrocytes. Blood 73:334-339.  Back to cited text no. 50
    
51.
Galasso C, Orefice I, Pellone P, Cirino P, Miele R, Ianora A, Brunet C, Sansone C (2018) On the neuroprotective role of astaxanthin: new perspectives? Mar Drugs doi: 10.3390/md16080247.  Back to cited text no. 51
    
52.
Gammone MA, D'Orazio N (2015) Anti-obesity activity of the marine carotenoid fucoxanthin. Mar Drugs 13:2196-2214.  Back to cited text no. 52
    
53.
Gammone MA, Riccioni G, D'Orazio N (2015) Marine carotenoids against oxidative stress: effects on human health. Mar Drugs 13:6226-6246.  Back to cited text no. 53
    
54.
Garcia-Escudero V, Martin-Maestro P, Perry G, Avila J (2013) Deconstructing mitochondrial dysfunction in Alzheimer disease. Oxid Med Cell Longev 2013:162152.  Back to cited text no. 54
    
55.
Gate D, Rezai-Zadeh K, Jodry D, Rentsendorj A, Town T (2010) Macrophages in Alzheimer's disease: the blood-borne identity. J Neural Transm (Vienna) 117:961-970.  Back to cited text no. 55
    
56.
Gistera A, Ketelhuth DFJ (2018) Lipid-driven immunometabolic responses in atherosclerosis. Curr Opin Lipidol 29:375-380.  Back to cited text no. 56
    
57.
Glerup S, Schulz R, Laufs U, Schluter KD (2017) Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease. Basic Res Cardiol 112:32.  Back to cited text no. 57
    
58.
Gorini S, Kim SK, Infante M, Mammi C, La Vignera S, Fabbri A, Jaffe IZ, Caprio M (2019) Role of aldosterone and mineralocorticoid receptor in cardiovascular aging. Front Endocrinol (Lausanne) 10:584.  Back to cited text no. 58
    
59.
Grammas P, Ovase R (2001) Inflammatory factors are elevated in brain microvessels in Alzheimer's disease. Neurobiol Aging 22:837-842.  Back to cited text no. 59
    
60.
Gray SC, Kinghorn KJ, Woodling NS (2020) Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis. Neural Regen Res 15:1208-1219.  Back to cited text no. 60
    
61.
Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM (2006) Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci 26:9047-9056.  Back to cited text no. 61
    
62.
Grinberg LT, Korczyn AD, Heinsen H (2012) Cerebral amyloid angiopathy impact on endothelium. Exp Gerontol 47:838-842.  Back to cited text no. 62
    
63.
Grudzinski W, Nierzwicki L, Welc R, Reszczynska E, Luchowski R, Czub J, Gruszecki WI (2017) Localization and orientation of xanthophylls in a lipid bilayer. Sci Rep 7:9619.  Back to cited text no. 63
    
64.
Ha AW, Kim WK (2013) The effect of fucoxanthin rich power on the lipid metabolism in rats with a high fat diet. Nutr Res Pract 7:287-293.  Back to cited text no. 64
    
65.
Hamer M, Steptoe A (2012) Cortisol responses to mental stress and incident hypertension in healthy men and women. J Clin Endocrinol Metab 97:E29-34.  Back to cited text no. 65
    
66.
Hampel H, Vergallo A, Aguilar LF, Benda N, Broich K, Cuello AC, Cummings J, Dubois B, Federoff HJ, Fiandaca M, Genthon R, Haberkamp M, Karran E, Mapstone M, Perry G, Schneider LS, Welikovitch LA, Woodcock J, Baldacci F, Lista S (2018) Precision pharmacology for Alzheimer's disease. Pharmacol Res 130:331-365.  Back to cited text no. 66
    
67.
Hashimoto T, Ozaki Y, Taminato M, Das SK, Mizuno M, Yoshimura K, Maoka T, Kanazawa K (2009) The distribution and accumulation of fucoxanthin and its metabolites after oral administration in mice. Br J Nutr 102:242-248.  Back to cited text no. 67
    
68.
Hefti F (2019) Pharmacology of nerve growth factor and discovery of tanezumab, an anti-nerve growth factor antibody and pain therapeutic. Pharmacol Res:104240.  Back to cited text no. 68
    
69.
Hernandez-Aguilera A, Rull A, Rodriguez-Gallego E, Riera-Borrull M, Luciano-Mateo F, Camps J, Menendez JA, Joven J (2013) Mitochondrial dysfunction: a basic mechanism in inflammation-related non-communicable diseases and therapeutic opportunities. Mediators Inflamm 2013:135698.  Back to cited text no. 69
    
70.
Hess K, Grant PJ (2011) Inflammation and thrombosis in diabetes. Thromb Haemost 1051:S43-54.  Back to cited text no. 70
    
71.
Hojland Ipsen D, Tveden-Nyborg P, Lykkesfeldt J (2016) Normal weight dyslipidemia: Is it all about the liver? Obesity (Silver Spring) 24:556-567.  Back to cited text no. 71
    
72.
Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768-774.  Back to cited text no. 72
    
73.
Horton P, Ruban A (2005) Molecular design of the photosystem II light-harvesting antenna: photosynthesis and photoprotection. J Exp Bot 56:365-373.  Back to cited text no. 73
    
74.
Hu X, Li Y, Li C, Fu Y, Cai F, Chen Q, Li D (2012) Combination of fucoxanthin and conjugated linoleic acid attenuates body weight gain and improves lipid metabolism in high-fat diet-induced obese rats. Arch Biochem Biophys 519:59-65.  Back to cited text no. 74
    
75.
Ieronymaki E, Daskalaki MG, Lyroni K, Tsatsanis C (2019) Insulin signaling and insulin resistance facilitate trained immunity in macrophages through metabolic and epigenetic changes. Front Immunol 10:1330.  Back to cited text no. 75
    
76.
Ikeda Y, Yamagishi A, Komura M, Suzuki T, Dohmae N, Shibata Y, Itoh S, Koike H, Satoh K (2013) Two types of fucoxanthin-chlorophyll-binding proteins I tightly bound to the photosystem I core complex in marine centric diatoms. Biochim Biophys Acta 1827:529-539.  Back to cited text no. 76
    
77.
Ikeuchi M, Koyama T, Takahashi J, Yazawa K (2007) Effects of astaxanthin in obese mice fed a high-fat diet. Biosci Biotechnol Biochem 71:893-899.  Back to cited text no. 77
    
78.
Jeon SM, Kim HJ, Woo MN, Lee MK, Shin YC, Park YB, Choi MS (2010) Fucoxanthin-rich seaweed extract suppresses body weight gain and improves lipid metabolism in high-fat-fed C57BL/6J mice. Biotechnol J 5:961-969.  Back to cited text no. 78
    
79.
Ji X, Peng D, Zhang Y, Zhang J, Wang Y, Gao Y, Lu N, Tang P (2017) Astaxanthin improves cognitive performance in mice following mild traumatic brain injury. Brain Res 1659:88-95.  Back to cited text no. 79
    
80.
Jiang X, Chen L, Shen L, Chen Z, Xu L, Zhang J, Yu X (2016) Trans-astaxanthin attenuates lipopolysaccharide-induced neuroinflammation and depressive-like behavior in mice. Brain Res 1649:30-37.  Back to cited text no. 80
    
81.
Jiang X, Wang G, Lin Q, Tang Z, Yan Q, Yu X (2019) Fucoxanthin prevents lipopolysaccharide-induced depressive-like behavior in mice via AMPK- NF-kappaB pathway. Metab Brain Dis 34:431-442.  Back to cited text no. 81
    
82.
Jiang X, Yan Q, Liu F, Jing C, Ding L, Zhang L, Pang C (2018) Chronic trans-astaxanthin treatment exerts antihyperalgesic effect and corrects co-morbid depressive like behaviors in mice with chronic pain. Neurosci Lett 662:36-43.  Back to cited text no. 82
    
83.
Jiang X, Zhu K, Xu Q, Wang G, Zhang J, Cao R, Ye J, Yu X (2017) The antidepressant-like effect of trans-astaxanthin involves the serotonergic system. Oncotarget 8:25552-25563.  Back to cited text no. 83
    
84.
Johnson MS, DeMarco VG, Whaley-Connell A, Sowers JR (2012) Insulin resistance and the autonomic nervous system. In: Primer on the autonomic nervous system, 3rd ed (Low PA, ed), pp 307-312. Cambridge: Academic Press.  Back to cited text no. 84
    
85.
Jones MR, Hall OM, Kaye AM, Kaye AD (2015) Drug-induced acute pancreatitis: a review. Ochsner J 15:45-51.  Back to cited text no. 85
    
86.
Ju C, Mandrekar P (2015) Macrophages and alcohol-related liver inflammation. Alcohol Res 37:251-262.  Back to cited text no. 86
    
87.
Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106:473-481.  Back to cited text no. 87
    
88.
Kamer AR (2010) Systemic inflammation and disease progression in Alzheimer disease. Neurology 74:1157.  Back to cited text no. 88
    
89.
Katsumoto A, Takeuchi H, Takahashi K, Tanaka F (2018) Microglia in Alzheimer's disease: risk factors and inflammation. Front Neurol 9:978.  Back to cited text no. 89
    
90.
Kaur SJ, McKeown SR, Rashid S (2016) Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis. Gene 577:109-118.  Back to cited text no. 90
    
91.
Kent ST, Rosenson RS, Avery CL, Chen YI, Correa A, Cummings SR, Cupples LA, Cushman M, Evans DS, Gudnason V, Harris TB, Howard G, Irvin MR, Judd SE, Jukema JW, Lange L, Levitan EB, Li X, Liu Y, Post WS, et al. (2017) PCSK9 loss-of-function variants, low-density lipoprotein cholesterol, and risk of coronary heart disease and stroke: data from 9 studies of blacks and whites. Circ Cardiovasc Genet 10:e001632.  Back to cited text no. 91
    
92.
Khadir A, Kavalakatt S, Madhu D, Hammad M, Devarajan S, Tuomilehto J, Tiss A (2018) Fetuin-A levels are increased in the adipose tissue of diabetic obese humans but not in circulation. Lipids Health Dis 17:291.  Back to cited text no. 92
    
93.
Kidd P (2011) Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern Med Rev 16:355-364.  Back to cited text no. 93
    
94.
Kim B, Farruggia C, Ku CS, Pham TX, Yang Y, Bae M, Wegner CJ, Farrell NJ, Harness E, Park YK, Koo SI, Lee JY (2017) Astaxanthin inhibits inflammation and fibrosis in the liver and adipose tissue of mouse models of diet-induced obesity and nonalcoholic steatohepatitis. J Nutr Biochem 43:27-35.  Back to cited text no. 94
    
95.
Klegeris A, Walker DG, McGeer PL (1994) Activation of macrophages by Alzheimer beta amyloid peptide. Biochem Biophys Res Commun 199:984-991.  Back to cited text no. 95
    
96.
Lathe R, Sapronova A, Kotelevtsev Y (2014) Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatr 14:36.  Back to cited text no. 96
    
97.
Latowski D, Kuczynska P, Strzalka K (2011) Xanthophyll cycle--a mechanism protecting plants against oxidative stress. Redox Rep 16:78-90.  Back to cited text no. 97
    
98.
Lebson L, Nash K, Kamath S, Herber D, Carty N, Lee DC, Li Q, Szekeres K, Jinwal U, Koren J, Dickey CA, Gottschall PE, Morgan D, Gordon MN (2010) Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice. J Neurosci 30:9651-9658.  Back to cited text no. 98
    
99.
Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI (2010) Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 12:668-674.  Back to cited text no. 99
    
100.
Lee KW, Kim JB, Seo JS, Kim TK, Im JY, Baek IS, Kim KS, Lee JK, Han PL (2009) Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J Neurochem 108:165-175.  Back to cited text no. 100
    
101.
Lefranc C, Friederich-Persson M, Braud L, Palacios-Ramirez R, Karlsson S, Boujardine N, Motterlini R, Jaisser F, Nguyen Dinh Cat A (2019) MR (mineralocorticoid receptor) induces adipose tissue senescence and mitochondrial dysfunction leading to vascular dysfunction in obesity. Hypertension 73:458-468.  Back to cited text no. 101
    
102.
Lefranc C, Friederich-Persson M, Palacios-Ramirez R, Nguyen Dinh Cat A (2018) Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor. J Endocrinol 238:R143-159.  Back to cited text no. 102
    
103.
Lenz KM, Nelson LH (2018) Microglia and beyond: innate immune cells as regulators of brain development and behavioral function. Front Immunol 9:698.  Back to cited text no. 103
    
104.
Li B, Vachali PP, Gorusupudi A, Shen Z, Sharifzadeh H, Besch BM, Nelson K, Horvath MM, Frederick JM, Baehr W, Bernstein PS (2014) Inactivity of human beta,beta-carotene-9',10'-dioxygenase (BCO2) underlies retinal accumulation of the human macular carotenoid pigment. Proc Natl Acad Sci U S A 111:10173-10178.  Back to cited text no. 104
    
105.
Li X, Qi Z, Zhao L, Yu Z (2016) Astaxanthin reduces type 2 diabeticassociated cognitive decline in rats via activation of PI3K/Akt and attenuation of oxidative stress. Mol Med Rep 13:973-979.  Back to cited text no. 105
    
106.
Liberman AC, Budzinski ML, Sokn C, Gobbini RP, Steininger A, Arzt E (2018) Regulatory and mechanistic actions of glucocorticoids on T and inflammatory cells. Front Endocrinol (Lausanne) 9:235.  Back to cited text no. 106
    
107.
Lin HV, Tsou YC, Chen YT, Lu WJ, Hwang PA (2017) Effects of low-molecular-weight fucoidan and high stability fucoxanthin on glucose homeostasis, lipid metabolism, and liver function in a mouse model of type II diabetes. Mar Drugs doi: 10.3390/md15040113.  Back to cited text no. 107
    
108.
Liu J, Han L, Zhu L, Yu Y (2016) Free fatty acids, not triglycerides, are associated with non-alcoholic liver injury progression in high fat diet induced obese rats. Lipids Health Dis 15:27.  Back to cited text no. 108
    
109.
Liu YC, Zou XB, Chai YF, Yao YM (2014) Macrophage polarization in inflammatory diseases. Int J Biol Sci 10:520-529.  Back to cited text no. 109
    
110.
Lo Sasso G, Schlage WK, Boue S, Veljkovic E, Peitsch MC, Hoeng J (2016) The Apoe(-/-) mouse model: a suitable model to study cardiovascular and respiratory diseases in the context of cigarette smoke exposure and harm reduction. J Transl Med 14:146.  Back to cited text no. 110
    
111.
Lobo GP, Isken A, Hoff S, Babino D, von Lintig J (2012) BCDO2 acts as a carotenoid scavenger and gatekeeper for the mitochondrial apoptotic pathway. Development 139:2966-2977.  Back to cited text no. 111
    
112.
Lobritto S (2017) Organogenesis and Histologic Development of the Liver. In: Fetal and Neonatal Physiology (Eds: Polin RA, Abman SH, Rowitch DH, Benitz WE, Fox WW), 5th Edition, Vol. 2, Pages 909-913.e2, Amsterdam, Netherlands, Elsevier.  Back to cited text no. 112
    
113.
Lopaschuk GD (2016) Fatty acid oxidation and its relation with insulin resistance and associated disorders. Ann Nutr Metab 68:15-20.  Back to cited text no. 113
    
114.
Lopes Pinheiro MA, Kooij G, Mizee MR, Kamermans A, Enzmann G, Lyck R, Schwaninger M, Engelhardt B, de Vries HE (2016) Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim Biophys Acta 1862:461-471.  Back to cited text no. 114
    
115.
Lopez-Armada MJ, Riveiro-Naveira RR, Vaamonde-Garcia C, Valcarcel-Ares MN (2013) Mitochondrial dysfunction and the inflammatory response. Mitochondrion 13:106-118.  Back to cited text no. 115
    
116.
Lumeng CN, Deyoung SM, Saltiel AR (2007) Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 292:E166-174.  Back to cited text no. 116
    
117.
Lusis AJ, Fogelman AM, Fonarow GC (2004) Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation 110:1868-1873.  Back to cited text no. 117
    
118.
Machado A, Herrera AJ, de Pablos RM, Espinosa-Oliva AM, Sarmiento M, Ayala A, Venero JL, Santiago M, Villaran RF, Delgado-Cortes MJ, Arguelles S, Cano J (2014) Chronic stress as a risk factor for Alzheimer's disease. Rev Neurosci 25:785-804.  Back to cited text no. 118
    
119.
Madamanchi NR, Runge MS (2007) Mitochondrial dysfunction in atherosclerosis. Circ Res 100:460-473.  Back to cited text no. 119
    
120.
Maeda H, Hosokawa M, Sashima T, Murakami-Funayama K, Miyashita K (2009) Anti-obesity and anti-diabetic effects of fucoxanthin on diet-induced obesity conditions in a murine model. Mol Med Rep 2:897-902.  Back to cited text no. 120
    
121.
Maeda H, Kanno S, Kodate M, Hosokawa M, Miyashita K (2015) Fucoxanthinol, metabolite of fucoxanthin, improves obesity-induced inflammation in adipocyte cells. Mar Drugs 13:4799-4813.  Back to cited text no. 121
    
122.
Mahley RW (2016) Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl) 94:739-746.  Back to cited text no. 122
    
123.
Mairanovsky VG, Engovatov AA, Ioffe NT, Samokhvalov GI (1975) Electron-donor and electron-acceptor properties of carotenoids: Electrochemical study of carotenes. J Electroanal Chem Interfacial Electrochem 66:123-137.  Back to cited text no. 123
    
124.
Mansouri A, Gattolliat CH, Asselah T (2018) Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology 155:629-647.  Back to cited text no. 124
    
125.
Mao P, Manczak M, Calkins MJ, Truong Q, Reddy TP, Reddy AP, Shirendeb U, Lo HH, Rabinovitch PS, Reddy PH (2012) Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension. Hum Mol Genet 21:2973-2990.  Back to cited text no. 125
    
126.
Mashhadi NS, Zakerkish M, Mohammadiasl J, Zarei M, Mohammadshahi M, Haghighizadeh MH (2018) Astaxanthin improves glucose metabolism and reduces blood pressure in patients with type 2 diabetes mellitus. Asia Pac J Clin Nutr 27:341-346.  Back to cited text no. 126
    
127.
Maynard S, Fang EF, Scheibye-Knudsen M, Croteau DL, Bohr VA (2015) DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a025130.  Back to cited text no. 127
    
128.
McDevitt HO (2005) Characteristics of autoimmunity in type 1 diabetes and type 1.5 overlap with type 2 diabetes. Diabetes 54:S4-10.  Back to cited text no. 128
    
129.
McDonagh M, Peterson K, Holzhammer B, Fazio S (2016) A systematic review of PCSK9 inhibitors alirocumab and evolocumab. J Manag Care Spec Pharm 22:641-653.  Back to cited text no. 129
    
130.
McNelis JC, Olefsky JM (2014) Macrophages, immunity, and metabolic disease. Immunity 41:36-48.  Back to cited text no. 130
    
131.
Mescher AL (2017) Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration. Regeneration (Oxf) 4:39-53.  Back to cited text no. 131
    
132.
Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16:22-34.  Back to cited text no. 132
    
133.
Mitchell KA, Moore JX, Rosenson RS, Irvin R, Guirgis FW, Shapiro N, Safford M, Wang HE (2019) PCSK9 loss-of-function variants and risk of infection and sepsis in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. PLoS One 14:e0210808.  Back to cited text no. 133
    
134.
Mizumura K, Murase S (2015) Role of nerve growth factor in pain. Handb Exp Pharmacol 227:57-77.  Back to cited text no. 134
    
135.
Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim Biophys Acta 1802:2-10.  Back to cited text no. 135
    
136.
Na YR, Stakenborg M, Seok SH, Matteoli G (2019) Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol 16:531-543.  Back to cited text no. 136
    
137.
Naito Y, Uchiyama K, Aoi W, Hasegawa G, Nakamura N, Yoshida N, Maoka T, Takahashi J, Yoshikawa T (2004) Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. Biofactors 20:49-59.  Back to cited text no. 137
    
138.
Newsholme P, de Bittencourt PI Jr. (2014) The fat cell senescence hypothesis: a mechanism responsible for abrogating the resolution of inflammation in chronic disease. Curr Opin Clin Nutr Metab Care 17:295-305.  Back to cited text no. 138
    
139.
Ni Y, Nagashimada M, Zhuge F, Zhan L, Nagata N, Tsutsui A, Nakanuma Y, Kaneko S, Ota T (2015) Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E. Sci Rep 5:17192.  Back to cited text no. 139
    
140.
Nishida Y, Nawaz A, Kado T, Takikawa A, Igarashi Y, Onogi Y, Wada T, Sasaoka T, Yamamoto S, Sasahara M, Imura J, Tokuyama K, Usui I, Nakagawa T, Fujisaka S, Kunimasa Y, Tobe K (2020) Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway. J Cachexia Sarcopenia Muscle 11:241-258.  Back to cited text no. 140
    
141.
Nishinoa A, Maokab M, Yasuic H (2016) Analysis of reaction products of astaxanthin and its acetate with reactive oxygen species using LC/PDA ESI-MS and ESR spectrometry. Tetrahedron Lett 57:1967-1970.  Back to cited text no. 141
    
142.
Oishi Y, Manabe I (2018) Macrophages in inflammation, repair and regeneration. Int Immunol 30:511-528.  Back to cited text no. 142
    
143.
Ono H (2019) Molecular mechanisms of hypothalamic insulin resistance. Int J Mol Sci doi: 10.3390/ijms20061317.  Back to cited text no. 143
    
144.
Osterlie M, Bjerkeng B, Liaaen-Jensen S (2000) Plasma appearance and distribution of astaxanthin E/Z and R/S isomers in plasma lipoproteins of men after single dose administration of astaxanthin. J Nutr Biochem 11:482-490.  Back to cited text no. 144
    
145.
Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279-1285.  Back to cited text no. 145
    
146.
Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, Prata LG, van Dijk TH, Verkade E, Casaclang-Verzosa G, Johnson KO, Cubro H, Doornebal EJ, Ogrodnik M, Jurk D, Jensen MD, Chini EN, Miller JD, Matveyenko A, Stout MB, et al. (2019) Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18:e12950.  Back to cited text no. 146
    
147.
Pangestuti R, Vo TS, Ngo DH, Kim SK (2013) Fucoxanthin ameliorates inflammation and oxidative reponses in microglia. J Agric Food Chem 61:3876-3883.  Back to cited text no. 147
    
148.
Parihar VK, Allen BD, Tran KK, Chmielewski NN, Craver BM, Martirosian V, Morganti JM, Rosi S, Vlkolinsky R, Acharya MM, Nelson GA, Allen AR, Limoli CL (2015) Targeted overexpression of mitochondrial catalase prevents radiation-induced cognitive dysfunction. Antioxid Redox Signal 22:78-91.  Back to cited text no. 148
    
149.
Parisi L, Gini E, Baci D, Tremolati M, Fanuli M, Bassani B, Farronato G, Bruno A, Mortara L (2018) Macrophage polarization in chronic inflammatory diseases: killers or builders? J Immunol Res 2018:8917804.  Back to cited text no. 149
    
150.
Patel H, Patel VH (2015) Inflammation and metabolic syndrome- an overview. Curr Res Nutr Food Sci doi: 10.12944/CRNFSJ.3.3.10.  Back to cited text no. 150
    
151.
Pedersen WA, Culmsee C, Ziegler D, Herman JP, Mattson MP (1999) Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer's disease. J Mol Neurosci 13:159-165.  Back to cited text no. 151
    
152.
Pedersen WA, Flynn ER (2004) Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer's disease. Neurobiol Dis 17:500-506.  Back to cited text no. 152
    
153.
Pehar M, Beeson G, Beeson CC, Johnson JA, Vargas MR (2014) Mitochondria-targeted catalase reverts the neurotoxicity of hSOD1G(9)(3)A astrocytes without extending the survival of ALS-linked mutant hSOD1 mice. PLoS One 9:e103438.  Back to cited text no. 153
    
154.
Peng W, Cai G, Xia Y, Chen J, Wu P, Wang Z, Li G, Wei D (2019) Mitochondrial dysfunction in atherosclerosis. DNA Cell Biol 38:597-606.  Back to cited text no. 154
    
155.
Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161-167.  Back to cited text no. 155
    
156.
Prasad GV (2014) Metabolic syndrome and chronic kidney disease: Current status and future directions. World J Nephrol 3:210-219.  Back to cited text no. 156
    
157.
Rafii MS, Tuszynski MH, Thomas RG, Barba D, Brewer JB, Rissman RA, Siffert J, Aisen PS (2018) Adeno-associated viral vector (Serotype 2)-nerve growth factor for patients with Alzheimer disease: a randomized clinical trial. JAMA Neurol 75:834-841.  Back to cited text no. 157
    
158.
Raj DD, Moser J, van der Pol SM, van Os RP, Holtman IR, Brouwer N, Oeseburg H, Schaafsma W, Wesseling EM, den Dunnen W, Biber KP, de Vries HE, Eggen BJ, Boddeke HW (2015) Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening. Aging Cell 14:1003-1013.  Back to cited text no. 158
    
159.
Rajan WD, Wojtas B, Gielniewski B, Gieryng A, Zawadzka M, Kaminska B (2019) Dissecting functional phenotypes of microglia and macrophages in the rat brain after transient cerebral ischemia. Glia 67:232-245.  Back to cited text no. 159
    
160.
Razay G, Vreugdenhil A, Wilcock G (2007) The metabolic syndrome and Alzheimer disease. Arch Neurol 64:93-96.  Back to cited text no. 160
    
161.
Reul JM, de Kloet ER, van Sluijs FJ, Rijnberk A, Rothuizen J (1990) Binding characteristics of mineralocorticoid and glucocorticoid receptors in dog brain and pituitary. Endocrinology 127:907-915.  Back to cited text no. 161
    
162.
Ricci C, Ruscica M, Camera M, Rossetti L, Macchi C, Colciago A, Zanotti I, Lupo MG, Adorni MP, Cicero AFG, Fogacci F, Corsini A, Ferri N (2018) PCSK9 induces a pro-inflammatory response in macrophages. Sci Rep 8:2267.  Back to cited text no. 162
    
163.
Ryan TE, Schmidt CA, Green TD, Spangenburg EE, Neufer PD, McClung JM (2016) Targeted expression of catalase to nitochondria protects against ischemic myopathy in high-fat diet-fed mice. Diabetes 65:2553-2568.  Back to cited text no. 163
    
164.
Sanchez-Rangel E, Inzucchi SE (2017) Metformin: clinical use in type 2 diabetes. Diabetologia 60:1586-1593.  Back to cited text no. 164
    
165.
Sastre M, Walter J, Gentleman SM (2008) Interactions between APP secretases and inflammatory mediators. J Neuroinflammation 5:25.  Back to cited text no. 165
    
166.
Satapati S, Kucejova B, Duarte JA, Fletcher JA, Reynolds L, Sunny NE, He T, Nair LA, Livingston KA, Fu X, Merritt ME, Sherry AD, Malloy CR, Shelton JM, Lambert J, Parks EJ, Corbin I, Magnuson MA, Browning JD, Burgess SC (2015) Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 125:4447-4462.  Back to cited text no. 166
    
167.
Satapati S, Kucejova B, Duarte JA, Fletcher JA, Reynolds L, Sunny NE, He T, Nair LA, Livingston KA, Fu X, Merritt ME, Sherry AD, Malloy CR, Shelton JM, Lambert J, Parks EJ, Corbin I, Magnuson MA, Browning JD, Burgess SC (2016) Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 126:1605.  Back to cited text no. 167
    
168.
Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909-1911.  Back to cited text no. 168
    
169.
Serafini M, Peluso I, Raguzzini A (2010) Flavonoids as anti-inflammatory agents. Proc Nutr Soc 69:273-278.  Back to cited text no. 169
    
170.
Sevenich L (2018) Brain-resident microglia and blood-borne macrophages orchestrate central nervous system inflammation in neurodegenerative disorders and brain cancer. Front Immunol 9:697.  Back to cited text no. 170
    
171.
Shah MM, Liang Y, Cheng JJ, Daroch M (2016) Astaxanthin-producing green microalga haematococcus pluvialis: from single cell to high value commercial products. Front Plant Sci 7:531.  Back to cited text no. 171
    
172.
Sharma P (2011) Inflammation and the metabolic syndrome. Indian J Clin Biochem 26:317-318.  Back to cited text no. 172
    
173.
Sherling DH, Perumareddi P, Hennekens CH (2017) Metabolic Syndrome. J Cardiovasc Pharmacol Ther 22:365-367.  Back to cited text no. 173
    
174.
Shimoji H, Yamasaki H (2005) Inhibitory effects of flavonoids on alternative respiration of plant mitochondria. Biologia Plantarum 49:117-119.  Back to cited text no. 174
    
175.
Shinohara M, Hirata K, Yamashita T, Takaya T, Sasaki N, Shiraki R, Ueyama T, Emoto N, Inoue N, Yokoyama M, Kawashima S (2007) Local overexpression of toll-like receptors at the vessel wall induces atherosclerotic lesion formation: synergism of TLR2 and TLR4. Arterioscler Thromb Vasc Biol 27:2384-2391.  Back to cited text no. 175
    
176.
Son M, Elliott JL (2014) Mitochondrial defects in transgenic mice expressing Cu,Zn superoxide dismutase mutations: the role of copper chaperone for SOD1. J Neurol Sci 336:1-7.  Back to cited text no. 176
    
177.
Sonntag KC, Ryu WI, Amirault KM, Healy RA, Siegel AJ, McPhie DL, Forester B, Cohen BM (2017) Late-onset Alzheimer's disease is associated with inherent changes in bioenergetics profiles. Sci Rep 7:14038.  Back to cited text no. 177
    
178.
Soto ME, Soria-Castro E, Lans VG, Ontiveros EM, Mejia BI, Hernandez HJ, Garcia RB, Herrera V, Perez-Torres I (2014) Analysis of oxidative stress enzymes and structural and functional proteins on human aortic tissue from different aortopathies. Oxid Med Cell Longev 2014:760694.  Back to cited text no. 178
    
179.
Soumian S, Albrecht C, Davies AH, Gibbs RG (2005) ABCA1 and atherosclerosis. Vasc Med 10:109-119.  Back to cited text no. 179
    
180.
Sun XM, Ren LJ, Zhao QY, Ji XJ, Huang H (2018) Microalgae for the production of lipid and carotenoids: a review with focus on stress regulation and adaptation. Biotechnol Biofuels 11:272.  Back to cited text no. 180
    
181.
Suurmond J, Diamond B (2015) Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J Clin Invest 125:2194-2202.  Back to cited text no. 181
    
182.
Swerdlow RH (2018) Mitochondria and mitochondrial cascades in Alzheimer's disease. J Alzheimers Dis 62:1403-1416.  Back to cited text no. 182
    
183.
Tabas I, Lichtman AH (2017) Monocyte-macrophages and T cells in atherosclerosis. Immunity 47:621-634.  Back to cited text no. 183
    
184.
Tan CP, Hou YH (2014) First evidence for the anti-inflammatory activity of fucoxanthin in high-fat-diet-induced obesity in mice and the antioxidant functions in PC12 cells. Inflammation 37:443-450.  Back to cited text no. 184
    
185.
Tang ZH, Peng J, Ren Z, Yang J, Li TT, Li TH, Wang Z, Wei DH, Liu LS, Zheng XL, Jiang ZS (2017) New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-kappaB pathway. Atherosclerosis 262:113-122.  Back to cited text no. 185
    
186.
Taylor BA, Thompson PD (2018) Statin-associated muscle disease: advances in diagnosis and management. Neurotherapeutics 15:1006-1017.  Back to cited text no. 186
    
187.
Thion MS, Ginhoux F, Garel S (2018) Microglia and early brain development: An intimate journey. Science 362:185-189.  Back to cited text no. 187
    
188.
Tian J, Gu X, Sun Y, Ban X, Xiao Y, Hu S, Yu B (2012) Effect of statin therapy on the progression of coronary atherosclerosis. BMC Cardiovasc Disord 12:70.  Back to cited text no. 188
    
189.
Toth PP, Patti AM, Giglio RV, Nikolic D, Castellino G, Rizzo M, Banach M (2018) Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs 18:157-173.  Back to cited text no. 189
    
190.
Tschopp J (2011) Mitochondria: Sovereign of inflammation? Eur J Immunol 41:1196-1202.  Back to cited text no. 190
    
191.
Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, Tong G, Potkin SG, Fallon J, Hansen L, Mufson EJ, Kordower JH, Gall C, Conner J (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11:551-555.  Back to cited text no. 191
    
192.
Tuszynski MH, Yang JH, Barba D, U HS, Bakay RA, Pay MM, Masliah E, Conner JM, Kobalka P, Roy S, Nagahara AH (2015) Nerve growth factor gene therapy: activation of neuronal responses in Alzheimer disease. JAMA Neurol 72:1139-1147.  Back to cited text no. 192
    
193.
Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T (2002) Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. Redox Rep 7:290-293.  Back to cited text no. 193
    
194.
van Horssen J, van Schaik P, Witte M (2019) Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders? Neurosci Lett 710:132931.  Back to cited text no. 194
    
195.
van Tilburg MA, Zaki EA, Venkatesan T, Boles RG (2014) Irritable bowel syndrome may be associated with maternal inheritance and mitochondrial DNA control region sequence variants. Dig Dis Sci 59:1392-1397.  Back to cited text no. 195
    
196.
Vanhanen M, Koivisto K, Moilanen L, Helkala EL, Hanninen T, Soininen H, Kervinen K, Kesaniemi YA, Laakso M, Kuusisto J (2006) Association of metabolic syndrome with Alzheimer disease: a population-based study. Neurology 67:843-847.  Back to cited text no. 196
    
197.
Varatharaj A, Galea I (2017) The blood-brain barrier in systemic inflammation. Brain Behav Immun 60:1-12.  Back to cited text no. 197
    
198.
Varvel NH, Neher JJ, Bosch A, Wang W, Ransohoff RM, Miller RJ, Dingledine R (2016) Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci U S A 113:5665-5674.  Back to cited text no. 198
    
199.
Vetrano AM, Heck DE, Mariano TM, Mishin V, Laskin DL, Laskin JD (2005) Characterization of the oxidase activity in mammalian catalase. J Biol Chem 280:35372-35381.  Back to cited text no. 199
    
200.
von Bernhardi R, Tichauer JE, Eugenin J (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112:1099-1114.  Back to cited text no. 200
    
201.
Wang J, Liu S, Wang H, Xiao S, Li C, Li Y, Liu B (2019) Xanthophyllomyces dendrorhous-derived astaxanthin regulates lipid metabolism and gut microbiota in obese mice induced by a high-fat diet. Mar Drugs doi: 10.3390/md17060337.  Back to cited text no. 201
    
202.
Wang JY, Lee YJ, Chou MC, Chang R, Chiu CH, Liang YJ, Wu LS (2015a) Astaxanthin protects steroidogenesis from hydrogen peroxide-induced oxidative stress in mouse Leydig cells. Mar Drugs 13:1375-1388.  Back to cited text no. 202
    
203.
Wang WF, Li X, Guo MZ, Chen JD, Yang YS, Peng LH, Wang YH, Zhang CY, Li HH (2013) Mitochondrial ATP 6 and 8 polymorphisms in irritable bowel syndrome with diarrhea. World J Gastroenterol 19:3847-3853.  Back to cited text no. 203
    
204.
Wang WY, Tan MS, Yu JT, Tan L (2015b) Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med 3:136.  Back to cited text no. 204
    
205.
Welty FK, Alfaddagh A, Elajami TK (2016) Targeting inflammation in metabolic syndrome. Transl Res 167:257-280.  Back to cited text no. 205
    
206.
Woo MN, Jeon SM, Kim HJ, Lee MK, Shin SK, Shin YC, Park YB, Choi MS (2010) Fucoxanthin supplementation improves plasma and hepatic lipid metabolism and blood glucose concentration in high-fat fed C57BL/6N mice. Chem Biol Interact 186:316-322.  Back to cited text no. 206
    
207.
Wu L, Guo X, Hartson SD, Davis MA, He H, Medeiros DM, Wang W, Clarke SL, Lucas EA, Smith BJ, von Lintig J, Lin D (2017) Lack of beta, beta-carotene-9', 10'-oxygenase 2 leads to hepatic mitochondrial dysfunction and cellular oxidative stress in mice. Mol Nutr Food Res doi: 10.1002/mnfr.201600576.  Back to cited text no. 207
    
208.
Xiang S, Liu F, Lin J, Chen H, Huang C, Chen L, Zhou Y, Ye L, Zhang K, Jin J, Zhen J, Wang C, He S, Wang Q, Cui W, Zhang J (2017) Fucoxanthin inhibits beta-amyloid assembly and attenuates beta-amyloid oligomer-induced cognitive impairments. J Agric Food Chem 65:4092-4102.  Back to cited text no. 208
    
209.
Xu J, Gao H, Zhang L, Chen C, Yang W, Deng Q, Huang Q, Huang F (2014) A combination of flaxseed oil and astaxanthin alleviates atherosclerosis risk factors in high fat diet fed rats. Lipids Health Dis 13:63.  Back to cited text no. 209
    
210.
Xu J, Rong S, Gao H, Chen C, Yang W, Deng Q, Huang Q, Xiao L, Huang F (2017) A combination of flaxseed oil and astaxanthin improves hepatic lipid accumulation and reduces oxidative stress in high fat-diet fed rats. Nutrients doi: 10.3390/nu9030271.  Back to cited text no. 210
    
211.
Xu L, Zhu J, Yin W, Ding X (2015) Astaxanthin improves cognitive deficits from oxidative stress, nitric oxide synthase and inflammation through upregulation of PI3K/Akt in diabetes rat. Int J Clin Exp Pathol 8:6083-6094.  Back to cited text no. 211
    
212.
Yang Y, Pham TX, Wegner CJ, Kim B, Ku CS, Park YK, Lee JY (2014) Astaxanthin lowers plasma TAG concentrations and increases hepatic antioxidant gene expression in diet-induced obesity mice. Br J Nutr 112:1797-1804.  Back to cited text no. 212
    
213.
Yarchoan M, Xie SX, Kling MA, Toledo JB, Wolk DA, Lee EB, Van Deerlin V, Lee VM, Trojanowski JQ, Arnold SE (2012) Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain 135:3749-3756.  Back to cited text no. 213
    
214.
Yoshida H, Yanai H, Ito K, Tomono Y, Koikeda T, Tsukahara H, Tada N (2010) Administration of natural astaxanthin increases serum HDL-cholesterol and adiponectin in subjects with mild hyperlipidemia. Atherosclerosis 209:520-523.  Back to cited text no. 214
    
215.
Young AJ, Frank HA (1996) Energy transfer reactions involving carotenoids: quenching of chlorophyll fluorescence. J Photochem Photobiol B 36:3-15.  Back to cited text no. 215
    
216.
Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (2003) Mineralocorticoid receptor function in major depression. Arch Gen Psychiatry 60:24-28.  Back to cited text no. 216
    
217.
Yu H, Liu J, Liu X, Zang T, Luo G, Shen J (2005) Kinetic studies on the glutathione peroxidase activity of selenium-containing glutathione transferase. Comp Biochem Physiol B Biochem Mol Biol 141:382-389.  Back to cited text no. 217
    
218.
Yvan-Charvet L, Wang N, Tall AR (2010) Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol 30:139-143.  Back to cited text no. 218
    
219.
Zhang H, Tang Y, Zhang Y, Zhang S, Qu J, Wang X, Kong R, Han C, Liu Z (2015) Fucoxanthin: a promising medicinal and nutritional ingredient. Evid Based Complement Alternat Med 2015:723515.  Back to cited text no. 219
    
220.
Zhao ZW, Cai W, Lin YL, Lin QF, Jiang Q, Lin Z, Chen LL (2011) Ameliorative effect of astaxanthin on endothelial dysfunction in streptozotocin-induced diabetes in male rats. Arzneimittelforschung 61:239-246.  Back to cited text no. 220
    
221.
Zhou T, Hu Z, Yang S, Sun L, Yu Z, Wang G (2018) Role of adaptive and innate immunity in type 2 diabetes mellitus. J Diabetes Res 2018:7457269.  Back to cited text no. 221
    
222.
Zhou X, Zhang F, Hu X, Chen J, Wen X, Sun Y, Liu Y, Tang R, Zheng K, Song Y (2015) Inhibition of inflammation by astaxanthin alleviates cognition deficits in diabetic mice. Physiol Behav 151:412-420.  Back to cited text no. 222
    
223.
Zhou XY, Zhang F, Hu XT, Chen J, Tang RX, Zheng KY, Song YJ (2017) Depression can be prevented by astaxanthin through inhibition of hippocampal inflammation in diabetic mice. Brain Res 1657:262-268.  Back to cited text no. 223
    
224.
Zhu YJ, Wang C, Song G, Zang SS, Liu YX, Li L (2015) Toll-like receptor-2 and -4 are associated with hyperlipidemia. Mol Med Rep 12:8241-8246.  Back to cited text no. 224
    
225.
Zmijewski JW, Lorne E, Banerjee S, Abraham E (2009) Participation of mitochondrial respiratory complex III in neutrophil activation and lung injury. Am J Physiol Lung Cell Mol Physiol 296:624-634.  Back to cited text no. 225
    
226.
Zmijewski JW, Lorne E, Zhao X, Tsuruta Y, Sha Y, Liu G, Siegal GP, Abraham E (2008) Mitochondrial respiratory complex I regulates neutrophil activation and severity of lung injury. Am J Respir Crit Care Med 178:168-179.  Back to cited text no. 226
    

C-Editors: Zhao M, Li JY; T-Editor: Jia Y


    Figures

  [Figure 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Search Strategy ...
Mitochondrial Dy...
Residential Micr...
Apolipoprotein-E...
Alzheimer's ...
Breaking the Vic...
References
Article Figures

 Article Access Statistics
    Viewed699    
    Printed1    
    Emailed0    
    PDF Downloaded169    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]