An Increase in Vascular Stiffness is Positively Associated with Mitochondrial Bioenergetics Impairment of Peripheral Blood Mononuclear Cells in the Elderly Population.

The cardio-ankle vascular index (CAVI) is a non-invasive parameter reflecting vascular stiffness. CAVI correlates with the burden of atherosclerosis and future cardiovascular events. Mitochondria of peripheral blood mononuclear cells (PBMCs) have been identified as a non-invasive source for assessing systemic mitochondrial bioenergetics. This study aimed to investigate the relationship between CAVI values and mitochondrial bioenergetics of PBMCs in the elderly population. This cross-sectional study enrolled participants from the Electricity Generating Authority of Thailand (EGAT) between 2017 and 2018. 1640 participants with an ankle-brachial index greater than 0.9 were included in this study. All participants were stratified into three groups based on their CAVI values as high (CAVI ≥9), moderate (9 >CAVI ≥8), and low (CAVI <8), in which each group comprised 702, 507 and 431 participants, respectively. The extracellular flux analyzer was used to measure mitochondrial respiration of isolated PBMCs. The mean age of the participants was 67.9 years, and 69.6% of them were male. After adjusted with potential confounders including age, sex, smoking status, body mass index, diabetes, dyslipidemia, hypertension, and creatinine clearance, participants with high CAVI values were independently associated with impaired mitochondrial bioenergetics, including decreased basal respiration, maximal respiration, and spare respiratory capacity, as well as increased mitochondrial reactive oxygen species. This study demonstrated that CAVI measurement reflects the underlying impairment of cellular mitochondrial bioenergetics in PBMCs. Further longitudinal studies are necessary to establish both a causal relationship between CAVI measurement and underlying cellular dysfunction.

Alterations in mitochondria isolated from peripheral blood mononuclear cells and tumors of patients with epithelial ovarian cancers.

Metabolic alterations play an essential role in ovarian carcinogenesis. The flexibility of mitochondrial functions facilitates cellular adaptation to the tough environment associated with carcinogenesis. An understanding of the differences in mitochondrial functions in normal ovaries and cancers could provide a basis for further exploration of future mitochondria-based screening, diagnosis, prognostic prediction, and targeted therapy for epithelial ovarian cancers. The main objective of this study was to assess mitochondrial function profiles measured from PBMCs and ovarian tissues of epithelial ovarian cancers in comparison with normal ovaries. A total of 36 patients were recruited for the study, all of whom underwent primary surgical treatment for malignant epithelial ovarian neoplasm. Of these, 20 patients were in the early stage and 16 patients were in the advanced stage. Additionally, 21 patients who had pelvic surgery for benign gynecologic conditions, with normal ovaries incidentally removed, were recruited as controls. At the time of surgery, a blood sample was collected from each participant for PBMC isolation, and ovarian tissue was retained for molecular studies. These studies included the examination of oxidative stress, mitochondrial mass, mitochondrial respiration, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes, and mitochondrial swelling. Clinical and histopathological data were also collected and compared between different stages of epithelial ovarian cancers: early-stage (group 1), advanced-stage (group 2), and normal ovaries (group 3). The levels of cellular oxidative stress, mitochondrial mass, and mitochondrial biogenesis in the peripheral blood mononuclear cells (PBMCs) of participants with ovarian cancer were significantly lower than those of the control group. However, the mitochondrial respiratory parameters measured from the PBMCs were similar across all three groups. Furthermore, mitochondrial membrane depolarization and mitochondrial swelling were observed in ovarian tissues of both early-stage and advanced-stage cancer groups. We demonstrated the dynamic nature of mitochondrial ROS production, biogenesis, and respiratory function in response to epithelial ovarian carcinogenesis. The flexibility of mitochondrial functions under diverse conditions may make it a challenging therapeutic target for ovarian cancer.

Hyperpolarization-activated cyclic nucleotide-gated channel inhibitor in myocardial infarction: Potential benefits beyond heart rate modulation.

Myocardial infarction (MI) and its associated complications including ventricular arrhythmias and heart failure are responsible for a significant incidence of morbidity and mortality worldwide. The ensuing cardiomyocyte loss results in neurohormone-driven cardiac remodeling, which leads to chronic heart failure in MI survivors. Ivabradine is a heart rate modulation agent currently used in treatment of chronic heart failure with reduced ejection fraction. The canonical target of ivabradine is the hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in cardiac pacemaker cells. However, in post-MI hearts, HCN can also be expressed ectopically in non-pacemaker cardiomyocytes. There is an accumulation of intriguing evidence to suggest that ivabradine also possesses cardioprotective effects that are independent of heart rate reduction. This review aims to summarize and discuss the reported cardioprotective mechanisms of ivabradine beyond heart rate modulation in myocardial infarction through various molecular mechanisms including the prevention of reactive oxygen species-induced mitochondrial damage, improvement of autophagy system, modulation of intracellular calcium cycling, modification of ventricular electrophysiology, and regulation of matrix metalloproteinases.

Exercise and Caloric Restriction Exert Different Benefits on Skeletal Muscle Metabolism in Aging Condition.

Exercise and caloric restriction improve skeletal muscle metabolism. However, the benefits of exercise and caloric restriction on skeletal muscle metabolism in aging have never been compared. Seven-week-old male Wistar rats (n = 24) were divided into 4 groups (n = 6 per group) to receive either normal saline solution for 28 weeks, 150 mg/kg/day of D-galactose for 28 weeks to induce premature aging, 150 mg/kg/day of D-galactose for 28 weeks plus exercise for 16 weeks (week 13-28), or 150 mg/kg/day of D-galactose for 28 weeks plus 30% caloric restriction for 16 weeks (week 13-28). The 17-month-old rats (n = 6) were also injected with normal saline solution for 28 weeks as the naturally aged controls. At the end of week 28, total walking distance and fatty acid and carbohydrate oxidation during physical activity were determined. Then, all rats were euthanized for the collection of blood and tibialis anterior muscle. The results showed that D-galactose successfully mimicked the natural aging of skeletal muscle. Exercise and caloric restriction equally improved carbohydrate oxidation during physical activity and myogenesis. However, exercise was superior to caloric restriction in terms of improving fatty acid oxidation and oxidative phosphorylation. Interestingly, caloric restriction decreased oxidative stress, whereas exercise increased oxidative stress of skeletal muscle. All of these findings indicated that the benefits of exercise and caloric restriction on skeletal muscle metabolism during aging were different, and therefore the combination of exercise and caloric restriction might provide greater efficacy in ameliorating skeletal muscle aging.

Characteristics of gut microbiota in captive Asian elephants (Elephas maximus) from infant to elderly.

Gut microbiota play an important role in the health and disease of Asian elephants, however, its characteristics at each stage of life have not been thoroughly investigated in maintaining and regulating health of elephants. This study, therefore, aimed to characterize the profiles of the gut microbiota of captive Asian elephants from infants to the elderly. Gut microbiota were identified by 16S rRNA sequencing from the feces of captive Asian elephants with varying age groups, including infant calves, suckling calves, weaned calves, subadult and adult elephants, and geriatric elephants. The diversity of the gut microbiota was lowest in infants, stable during adulthood, and slightly decreased in the geriatric period. The gut microbiota of the infant elephants was dominated by milk-fermenting taxa including genus Bifidobacterium of family Bifidobacteriaceae together with genus Akkermansia. The fiber-fermenting taxa such as Lachnospiraceae_NK3A20_group were found to be increased in suckling elephants in differential abundance analysis by Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC). The gut microbiota profiles after weaning until the adult period has been uniform as indicated by no significant differences in beta diversity between groups. However, the composition of the gut microbiota was found to change again in geriatric elephants. Understanding of the composition of the gut microbiota of captive Asian elephants at various life stages could be beneficial for promoting good health throughout their lifespan, as well as ensuring the welfare of captive elephants.

Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury: Cumulative evidence for future cardioprotective strategies.

Cardiomyocyte death is one of the major mechanisms contributing to the development of myocardial infarction (MI) and myocardial ischemia/reperfusion (MI/R) injury. Due to the limited regenerative ability of cardiomyocytes, understanding the mechanisms of cardiomyocyte death is necessary. Pyroptosis, one of the regulated programmed cell death pathways, has recently been shown to play important roles in MI and MI/R injury. Pyroptosis is activated by damage-associated molecular patterns (DAMPs) that are released from damaged myocardial cells and activate the formation of an apoptosis-associated speck-like protein containing a CARD (ASC) interacting with NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), resulting in caspase-1 cleavage which promotes the activation of Gasdermin D (GSDMD). This pathway is known as the canonical pathway. GSDMD has also been shown to be activated in a non-canonical pathway during MI and MI/R injury via caspase-4/5/11. Suppression of GSDMD has been shown to provide cardioprotection against MI and MI/R injury. Although the effects of MI or MI/R injury on pyroptosis have previously been discussed, knowledge concerning the roles of GSDMD in these settings remains limited. In this review, the evidence from in vitro, in vivo, and clinical studies focusing on cardiac GSDMD activation during MI and MI/R injury is comprehensively summarized and discussed. Implications from this review will help pave the way for a new therapeutic target in ischemic heart disease.

Increased Efficiency of Mitochondrial Coupling With a Reduction in Other Mitochondrial Respiratory Parameters in Peripheral Blood Mononuclear Cells Is Observed in Older Adults.

Mitochondrial dysfunction is a factor potentially contributing to the Aging process. However, evidence surrounding changes in mitochondrial function and aging is still limited; therefore, this study aimed to investigate further the association between them. Possible confounding factors were included in the statistical analysis to explore the possibility of any independent associations. One thousand seven hundred and sixty-nine participants (619 middle-aged adults [age < 65] and 1,150 older adults [age ≥ 65]) from the Electricity Generating Authority of Thailand were enrolled in the study. The clinical characteristics and medical history were collected. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood and used for analysis of mitochondrial function. Several parameters pertinent to mitochondrial respiration including non-mitochondrial respiration, basal respiration, maximal respiration, proton leak, and spare respiratory capacity were found to be two to three times lower in the mitochondria isolated from the cells of older adults. Interestingly, the mitochondrial ATP production was only slightly reduced, and the percentage of coupling efficiency of PBMC mitochondria was significantly higher in the older adult group. The mitochondrial mass and oxidative stress were significantly reduced in older adult participants; however, the ratio of oxidative stress to mass was significantly increased. The association of these parameters with age was still shown to be the same from the outcome of the multivariate analyses. The mitochondrial functions and mitochondrial mass in PBMCs were shown to decline in association with age. However, the upregulation of mitochondrial oxidative stress production and mitochondrial coupling efficiency might indicate a compensatory response in mitochondria during aging.

Blood metabolomes as non-invasive biomarkers and targets of metabolic interventions for doxorubicin and trastuzumab-induced cardiotoxicity.

This study aimed to identify the alterations of blood metabolome levels and their association with cardiac dysfunction and cardiac injury following treatment with doxorubicin and trastuzumab. Eight-week-old male Wistar rats were divided into four groups (n = 6 per group) to receive intraperitoneal injection with either: (1) 1 mL of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin); (2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group); (3) 1 mL of NSS at days 0-6 (control group for trastuzumab); or (4) 4 mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was determined. The rats were then euthanized to collect venous blood and the heart for the quantification of 107 serum and 100 cardiac metabolomes using mass spectrometry-based targeted metabolomics. We observed strong relationships between 72 cardiac versus 61 serum metabolomes in doxorubicin and trastuzumab groups. Moreover, significant correlations between cardiac function and the cardiac injury biomarker versus 28 and 58 serum metabolomes were revealed in doxorubicin and trastuzumab-treated rats, respectively. Interestingly, the patterns of both serum and cardiac metabolome alterations differed between doxorubicin and trastuzumab groups. Our findings emphasize the potential role of the constituents of the blood metabolome as non-invasive biomarkers to assess severity and prognosis of heart failure induced by doxorubicin and trastuzumab. These findings may contribute to the development of metabolic-targeted therapy specific for cardioprotection during different phases of cancer treatment.

Combined caloric restriction and exercise provides greater metabolic and neurocognitive benefits than either as a monotherapy in obesity with or without estrogen deprivation.

Neurodegeneration, as indicated by brain dysfunction and cognitive decline, is one of the complications associated with obesity and estrogen deprivation. Calorie restriction and exercise regimes improved brain function in neurodegenerative diseases. However, the comparative effects of a combination of calorie restriction with exercise, calorie restriction, and an exercise regime alone on brain/cognitive function in obesity with or without estrogen deprivation have not been investigated. Sixty female rats were fed a normal diet (ND) or a high-fat diet (HFD) for 27 weeks. At week 13, the ND-fed rats underwent a sham operation with sedentary lifestyle, HFD-fed rats were divided into two groups: each having either a sham operation (HFS) or ovariectomy (HFO). At week 20, HFD-fed rats in each group were divided into four subgroups undergoing either a sedentary lifestyle, calorie restriction, exercise regime or a combination of calorie restriction and exercise for 7 weeks. Insulin resistance, cognitive decline and hippocampal pathologies were found in both HFS and HFO rats. HFO rats had higher levels of insulin resistance and hippocampal reactive oxygen species levels than HFS rats. Calorie restriction decreased metabolic disturbance and hippocampal oxidative stress but failed to attenuate cognitive decline in HFS and HFO rats. Exercise attenuated metabolic/hippocampal dysfunctions, resulting in improved cognition only in HFS rats. Combined therapies restored brain function, and cognitive function in HFS and HFO rats. Therefore, a combination of calorie restriction with exercise is probably the greatest lifestyle modification to diminish the brain pathologies and cognitive decline in obesity with or without estrogen deprivation.

High Cardiorespiratory Fitness Protects against Molecular Impairments of Metabolism, Heart, and Brain with Higher Efficacy in Obesity-Induced Premature Aging.

BACKGRUOUND: High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats. METHODS: Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a highfat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies. RESULTS: The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer's disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats. CONCLUSION: The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

Deferiprone has less benefits on gut microbiota and metabolites in high iron-diet induced iron overload thalassemic mice than in iron overload wild-type mice: A preclinical study.

AIMS: This study aimed to investigate the changes in gut microbiota in iron-overload thalassemia and the roles of an iron chelator on gut dysbiosis/inflammation, and metabolites, including short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO). MAIN METHODS: Adult male C57BL/6 mice both wild-type (WT: n = 15) and heterozygous ß-thalassemia (BKO: n = 15) were fed on either a normal (ND: n = 5/group) or a high­iron diet for four months (HFe: n = 10/group). HFe-treated WT and HFe-treated BKO groups were further subdivided into two subgroups and each subgroup given either vehicle (n = 5/subgroup) or deferiprone (n = 5/subgroup) during the last month. Gut microbiota profiles, gut barrier characteristics, levels of proinflammatory cytokines, and plasma SCFAs and TMAO were determined at the end of the study. KEY FINDINGS: HFe-fed WT mice showed distinct gut microbiota profiles from those of ND-fed WT mice, whereas HFe-fed BKO mice showed slightly different gut microbiota profiles from ND-fed BKO. Gut inflammation and barrier disruption were found only in HFe-fed BKO mice, however, an increase in plasma TMAO levels and decreased levels of SCFAs were observed in both WT and BKO mice with HFe-feeding. Treatment with deferiprone, gut dysbiosis and disturbance of metabolites were attenuated in HFe-fed WT mice, but not in HFe-fed BKO mice. Increased Verrucomicrobia and Ruminococcaceae were associated with the beneficial effects of deferiprone. SIGNIFICANCE: Iron-overload leads to gut dysbiosis/inflammation and disturbance of metabolites, and deferiprone alleviates those conditions more effectively in WT than in those that are thalassemic.

T2DM patients with depression have higher levels of hyperglycemia and cognitive decline than T2DM patients.

The cognitive impairment, depression, a decrease in the ability to perform activities of daily living (ADLs), and salivary gland dysfunction, as indicated by the reduction of alpha-amylase activity, have been reported in patients with type 2 diabetes (T2DM). However, the effects of depression on cognitive function, salivary alpha-amylase activity, and ADLs in T2DM patients have never been investigated. In this study, 115 participants were divided into three groups, including 30 healthy people, 50 T2DM patients without depression, and 35 T2DM patients with depression. Then, the cognitive function, the level of depression, salivary-alpha amylase activity, ADLs, and metabolic parameters were determined. Results showed that T2DM patients had hyperglycemia and cognitive impairment. A decrease in the salivary alpha-amylase activity was observed in T2DM patients. Interestingly, T2DM patients with depression had higher level of hyperglycemia and cognitive impairment than T2DM patients. Additionally, cognitive function was associated with the salivary-alpha amylase activity in T2DM without depression, while the severity of depression was associated with the salivary-alpha amylase activity in T2DM patients with depression. Therefore, we concluded that T2DM caused the impairment of metabolism, decreased salivary alpha-amylase activity, and cognitive impairment. Furthermore, T2DM patients with depression had higher level of hyperglycemia and cognitive decline than T2DM patients.

Human Blood Bacteriome: Eubiotic and Dysbiotic States in Health and Diseases.

The human gut microbiome is acknowledged as being associated with homeostasis and the pathogenesis of several diseases. Conventional culture techniques are limited in that they cannot culture the commensals; however, next-generation sequencing has facilitated the discovery of the diverse and delicate microbial relationship in body sites and blood. Increasing evidence regarding the blood microbiome has revolutionized the concept of sterility and germ theory in circulation. Among the types of microbial communities in the blood, bacteriomes associated with many health conditions have been thoroughly investigated. Blood bacterial profiles in healthy subjects are identified as the eubiotic blood bacteriome, whereas the dysbiotic blood bacteriome represents the change in bacterial characteristics in subjects with diseases showing deviations from the eubiotic profiles. The blood bacterial characteristics in each study are heterogeneous; thus, the association between eubiotic and dysbiotic blood bacteriomes and health and disease is still debatable. Thereby, this review aims to summarize and discuss the evidence concerning eubiotic and dysbiotic blood bacteriomes characterized by next-generation sequencing in human studies. Knowledge pertaining to the blood bacteriome will transform the concepts around health and disease in humans, facilitating clinical implementation in the near future.

Effectiveness of high cardiorespiratory fitness in cardiometabolic protection in prediabetic rats.

BACKGROUND: Caloric restriction and exercise are lifestyle interventions that effectively attenuate cardiometabolic impairment. However, cardioprotective effects of long-term lifestyle interventions and short-term lifestyle interventions followed by weight maintenance in prediabetes have never been compared. High cardiorespiratory fitness (CRF) has been shown to provide protection against prediabetes and cardiovascular diseases, however, the interactions between CRF, prediabetes, caloric restriction, and exercise on cardiometabolic health has never been investigated. METHODS: Seven-week-old male Wistar rats were fed with either a normal diet (ND; n = 6) or a high-fat diet (HFD; n = 30) to induce prediabetes for 12 weeks. Baseline CRF and cardiometabolic parameters were determined at this timepoint. The ND-fed rats were fed continuously with a ND for 16 more weeks. The HFD-fed rats were divided into 5 groups (n = 6/group) to receive one of the following: (1) a HFD without any intervention for 16 weeks, (2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks, (3) 40% caloric restriction for 16 weeks, (4) a HFD plus an exercise training program for 6 weeks followed by a ND without exercise for 10 weeks, or (5) a HFD plus an exercise training program for 16 weeks. At the end of the interventions, CRF and cardiometabolic parameters were re-assessed. Then, all rats were euthanized and heart tissues were collected. RESULTS: Either short-term caloric restriction or exercise followed by weight maintenance ameliorated cardiometabolic impairment in prediabetes, as indicated by increased insulin sensitivity, improved blood lipid profile, improved mitochondrial function and oxidative phosphorylation, reduced oxidative stress and inflammation, and improved cardiac function. However, these benefits were not as effective as those of either long-term caloric restriction or exercise. Interestingly, high-level baseline CRF was correlated with favorable cardiac and metabolic profiles at follow-up in prediabetic rats, both with and without lifestyle interventions. CONCLUSIONS: Short-term lifestyle modification followed by weight maintenance improves cardiometabolic health in prediabetes. High CRF exerted protection against cardiometabolic impairment in prediabetes, both with and without lifestyle modification. These findings suggest that targeting the enhancement of CRF may contribute to the more effective treatment of prediabetes-induced cardiometabolic impairment.

Profiles of gut microbiota in obese-insulin-resistant rats treated with biotics.

PURPOSE: Our previous studies demonstrated the beneficial effects of the probiotic Lactobacillus paracasei HII01, prebiotic xylooligosaccharide (XOS), and synbiotics on several parameters in high-fat diet (HFD)-induced obese rats. However, the gut microbiota composition in these rats has not been investigated. Therefore, this study aimed to investigate the impact of biotic therapies on gut microbiota in HFD-induced obese-insulin-resistant rats. METHODS: Male Wistar rats were fed with a normal diet (ND, n = 5) and a HFD (n = 20) for 24 weeks. At week 13, HFD-fed rats were given either a probiotic (L. paracasei, HF-Pro, n = 5), prebiotic (XOS, HF-Pre, n = 5), synbiotic (XOS + L. paracasei, HF-Syn, n = 5), or vehicle (HF-V, n = 5) for 12 weeks. ND-fed rats received vehicle (ND-V, n = 5). At week 24, all rats were decapitated, and metabolic parameters and gut microbiota were analyzed. RESULTS: HF-V rats developed an obese-insulin-resistant condition as indicated by impaired metabolic parameters. The prebiotic and synbiotic restored those metabolic parameters to the same level of ND-V rats. The gut microbiota composition of ND-V and HF-V rats differed as indicated by beta diversity. Verrucomicrobia in ND-V rats and Firmicutes and Proteobacteria in HF-V rats were dominant. Interestingly, Verrucomicrobia was also prominent in the HF-Syn rats. HF-Pre rats showed a distinct gut microbiota the predominant family being Ruminococcaceae. CONCLUSION: The changes in gut microbiota after HFD consumption included increased Firmicutes and Proteobacteria. The treatment with the prebiotic and synbiotic showed an association with the increase in Ruminococcaceae and Verrucomicrobia, respectively. These changes in gut microbiota due to biotics may mediate the beneficial effects on metabolic parameters.

Metabolomic Alterations in the Blood and Brain in Association with Alzheimer's Disease: Evidence from in vivo to Clinical Studies.

Alzheimer's disease (AD) has become a major health problem among the elderly population. Some evidence suggests that metabolic disturbance possibly plays a role in the pathophysiology of AD. Currently, the study of metabolomics has been used to explore changes in multiple metabolites in several diseases, including AD. Thus, the metabolomics research in AD might provide some information regarding metabolic dysregulations, and their possible associated pathophysiology. This review summarizes the information discovered regarding the metabolites in the brain and the blood from the metabolomics research of AD from both animal and clinical studies. Additionally, the correlation between the changes in metabolites and outcomes, such as pathological findings in the brain and cognitive impairment are discussed. We also deliberate on the findings of cohort studies, demonstrating the alterations in metabolites before changes of cognitive function. All of these findings can be used to inform the potential identity of specific metabolites as possible biomarkers for AD.

An association between fibroblast growth factor 21 and cognitive impairment in iron-overload thalassemia.

Although an increased fibroblast growth factor 21 (FGF21) level was related to mild cognitive impairment (MCI) in metabolic syndrome patients, any association regarding FGF21 and MCI in thalassemia patients as well as mechanistic insight are questionable. Therefore, the objectives of this study were: (1) to investigate the prevalence and associative risk factors of MCI in thalassemia patients, (2) to evaluate the association between levels of FGF21 and MCI in thalassemia patients, and (3) to investigate brain FGF21 signaling in iron-overload thalassemia. Thalassemia patients were enrolled onto the study (n = 131). Montreal cognitive assessment (MoCA) was used to determine cognitive performance. Plasma FGF21 level was determined in all patients. Iron-overload ß-thalassemic (HT) mice were used to investigate brain FGF21 level and signaling, the expression of synaptic proteins, and Alzheimer's like pathology. We found that 70% of thalassemia patients developed MCI. FGF21 level was positively correlated with the MCI. Interestingly, brain FGF21 resistance, as indicated by increased brain FGF21 levels with impaired FGF21 signaling, was found in iron-overload HT mice. The reduced synaptic protein expression and increased Alzheimer's like pathology were also observed. These suggest that FGF21 may play a role in MCI in thalassemia patients.

Cognitive impairment is associated with mitochondrial dysfunction in peripheral blood mononuclear cells of elderly population.

Cognitive impairment is commonly found in the elderly population. Evidence suggests that mitochondrial function in lymphocytes are potential biomarkers in the progression of neurodegeneration, as peripheral mitochondrial function is associated with mild cognitive impairment (MCI) in the elderly population. Therefore, we hypothesize that impaired mitochondrial ATP production and oxidative stress in peripheral blood mononuclear cells (PBMCs) are associated with cognitive impairment in the elderly population. Data were collected from 897 participants from the EGAT (The Electricity Generating Authority of Thailand) cohort. The participants were classified to be in the normal cognition group (n = 428) or mild cognitive impairment group (n = 469), according to their MoCA score. The association of mitochondrial function and cognitive status was analyzed by binary logistic regression analysis. MCI participants had higher age, systolic blood pressure, waist/hip ratio, and lower plasma high- and low-density lipoprotein cholesterol levels, when compared to the normal cognition group. In addition, estimated glomerular filtration rate were lower in the MCI group than those in the normal cognition group. Collectively, MCI is associated with mitochondrial dysfunction in PBMCs as indicated by decreasing mitochondrial ATP production, increasing proton leak, and oxidative stress, in the elderly population, independently of the possible confounding factors in this study.

Cognitive-Behavioural Correlates of Dysbiosis: A Review.

Evidence suggests an association between an altered gut microbiota (dysbiosis), cognitive performance and behaviour. This paper provides an overview of the current literature regarding the cognitive-behavioural correlates of dysbiosis, with special attention on the clinical and biochemical mechanisms underlying the association between dysbiosis, cognition (mild cognitive impairment and dementia) and behaviour (depression, schizophrenia, addiction). After providing an overview of the evidence, the review discusses the molecular aspects that could account for the cognitive-behavioural correlates of dysbiosis. Shedding light on this topic could provide insights regarding the pathogenesis of these burdening neuropsychiatric disorders and even suggest future therapeutic strategies.