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PubMed2025

Proteome organ aging and cardiometabolic risk in a population at risk for heart failure.

BACKGROUND: Biological aging varies across individuals and tissues, influencing chronic diseases, including heart failure (HF). Emerging proteome techniques enable quantification of organ-specific aging acceleration (OAA), but whether OAA relates to HF severity and differs by sex remains unclear. We aim to assess the sex-related association between OAA of heart, artery and kidneys and HF severity, and to investigate relevant cardiometabolic risk factors of organ aging. METHODS: In 556 participants from the HELPFul cohort, we estimated predicted biological age for heart, artery, and kidneys using plasma proteomics and calculated OAA as the deviation from chronological age. Associations between OAA and HF stage, echocardiographic parameters, and cardiometabolic risk factors were evaluated using regression models. Composite indices, including triglyceride-glucose body mass index (TyG-BMI), c-reactive protein-triglyceride glucose index and triglyceride-to-HDL cholesterol ratio were assessed for associations with advanced OAA. RESULTS: Mean age was 63 ± 9 years; 65% were women. Patients were classified as HF stage A (35%), B (29%) and C/D (36%). Heart OAA was significantly associated with advanced HF (Stage C/D) in both sexes (OR = 1.12, 95% CI 1.03 to 1.23 in women; OR = 1.18, 95% CI 1.05 to 1.32 in men), while artery OAA was linked to HF only in women (OR = 1.10, 95% CI 1.01 to 1.18). Multi-organ aging (≥ 2 organs with advanced OAA) conferred over three-fold higher odds of being in Stage C/D. Heart OAA correlated with impaired cardiac structure and function, particularly reduced ejection fraction in men and increased left ventricular mass index in both sexes. Diabetes emerged as the most relevant factor of artery and kidney OAA. TyG-BMI was significantly associated with advanced kidney OAA, only in women (z-scored OR = 1.88, 95% CI 1.45 to 2.45). CONCLUSIONS: Proteome-derived organ aging correlates with HF severity, with possible sex-related patterns. Diabetes and higher TyG-BMI are associated with faster organ aging, which may reflect shared aging mechanisms between metabolic dysfunction and HF.

Humans↗

PubMed2006

Molecular profiling of antipsychotic drug function: convergent mechanisms in the pathology and treatment of psychiatric disorders.

Despite great progress in antipsychotic drug research, the molecular mechanisms by which these drugs work have remained elusive. High-throughput gene profiling methods have advanced this field by allowing the simultaneous investigation of hundreds to thousands of genes. However, different methodologies, choice of brain region, and drugs studied have made comparisons across different studies difficult. Because of the complexity of gene expression changes caused by drugs, teasing out the most relevant expression differences is a challenging task. One approach is to focus on gene expression changes that converge on the same systems that were previously deemed important to the pathology of psychiatric disorders. From the microarray studies performed on human postmortem brain samples from schizophrenics, the systems most implicated to be dysfunctional are synaptic machinery, oligodendrocyte/myelin function, and mitochondrial/ubiquitin metabolism. Drugs may act directly or indirectly to compensate for underlying pathological deficits in schizophrenia or via other mechanisms that converge on these pathways. Side effects, consisting of motor and metabolic dysfunction (which occur with typical and atypical drugs, respectively), also may be mediated by gene expression changes that have been reported in these studies. This article surveys both the convergent antipsychotic mechanisms and the genes that may be responsible for other effects elicited by antipsychotic drugs.

Animals↗

PubMed2001

Drug treatment of combined hyperlipidemia.

Combined hyperlipidemia is increasing in frequency and is the most common lipid disorder associated with obesity, insulin resistance and diabetes mellitus. It is associated with other features of the metabolic syndrome including hypertension, hyperuricemia, hyperinsulinemia and highly atherogenic subfractions of lipoprotein remnant particles including small dense low density lipoprotein-cholesterol. This review examines the mechanisms by which combined hyperlipidemia arises and the various drugs including fibric acid derivatives, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and nicotinic acid which can be used either as monotherapy or in combination to manage it and to improve prognosis from atherosclerotic disease in diabetes mellitus, insulin resistant states and primary combined hyperlipidemia. The therapeutic approach to combined hyperlipidemia involves determination of whether the cause is hepatocyte damage or metabolic derangements. Combined hyperlipidemia due to hepatocyte damage should be treated by attention to the primary cause. In the case of metabolic dysfunction because of imbalance in glucose and fat metabolism, therapy of diabetes mellitus and obesity should be optimised prior to commencement of lipid lowering drugs. Both fibric acid derivatives and HMG-CoA reductase inhibitors can be used in the treatment of combined hyperlipidemia with fibric acid derivatives having greater effects on triglycerides and HMG-CoA reductase inhibitors on LDL-C though both have effects on the other cardiovascular risk factors. There is some evidence of benefit with both interventions in mild combined hyperlipidemias and large scale trials are underway. Fibric acid derivatives and HMG-CoA reductase inhibitor therapy can be combined with care, provided that gemfibrozil is avoided, fibric acid derivatives are given in the mornings and shorter half -life HMG-CoA reductase inhibitors are used at night. Combined hyperlipidemia emergencies occur with predominant hypertriglyceridemia in pregnancy or as a cause of pancreatitis. Therapy in the former should aim to reduce chylomicron production by a low fat diet and intervention to suppress VLDL-C secretion using omega-3 fatty acids. In the latter case, fluid therapy alone and medium chain plasma triglyceride infusions usually reduce levels satisfactorily though apheresis may be required. Blood glucose levels also need aggressive management in these conditions. Combined hyperlipidemia is likely to become an increasing problem with the increase in the prevalence of obesity and diabetes mellitus and needs aggressive management to reduce cardiovascular risk.

Acute Disease↗

PubMed2026

Advanced glycation end products drive blood-brain barrier lipid dysregulation via RAGE-ABCA1 signaling to promote neurovascular dysfunction in Alzheimer's disease.

Neurovascular dysfunction is an early and critical contributor to Alzheimer's disease (AD), yet the molecular mechanisms linking vascular pathology to metabolic dysregulation remain incompletely understood. Advanced glycation end products (AGEs), which accumulate during aging and metabolic stress, have been implicated in AD pathology; however, their role in cerebrovascular lipid homeostasis is unclear. Here, we demonstrate that AGE accumulation within cerebral microvessels promotes lipid droplet (LD) formation in endothelial cells through receptor for AGE (RAGE)-dependent disruption of cholesterol efflux pathways. In aged APP transgenic mice and human AD brains, we observe increased AGE deposition concomitant with elevated RAGE, DGAT1, and perilipin expression, alongside reduced ABCA1 levels. In human brain endothelial cells, AGE exposure induces lipid metabolic reprogramming characterized by enhanced LD accumulation, upregulation of lipogenic machinery, and suppression of cholesterol efflux. Mechanistically, RAGE silencing restores ABCA1 expression and attenuates LD formation, identifying RAGE as a key upstream regulator. Pharmacological activation of ABCA1 reverses AGE-induced lipid accumulation and reduces RAGE expression, highlighting a therapeutic axis. Furthermore, AGE exposure disrupts blood-brain barrier (BBB) integrity and impairs amyloid-β transport in an in vitro BBB model. In vivo, aging is associated with progressive microvascular LD accumulation, linking metabolic dysfunction to vascular pathology. Together, our findings establish an AGE-RAGE-ABCA1 signaling axis that drives endothelial lipid dysregulation and BBB impairment, providing a mechanistic framework connecting metabolic stress to neurovascular dysfunction in AD.

Journal Article↗

PubMed1997

Mephenytoin disposition and serum bile acids as indices of hepatic function in chronic viral hepatitis.

BACKGROUND AND OBJECTIVES: The effect of chronic viral hepatitis on liver function may vary from none to hepatic failure. Changes in function are usually the result of impaired hepatocyte function or altered vascular flow and architecture. Conventional liver function tests usually cannot distinguish contributions from these mechanisms or indicate degree of hepatic metabolic dysfunction. An alternative approach is to measure the hepatic metabolism of a highly extracted compound whose oral clearance and systemic bioavailability are dependent on both hepatocyte function and degree of portosystemic shunt. METHODS: The stereoselective metabolism of racemic mephenytoin (100 mg oral dose) was investigated in 35 patients with chronic viral hepatitis and compared with 153 healthy subjects. The mephenytoin R/S enantiomeric ratio and cumulative excretion of the 4'-hydroxymephenytoin metabolite in a 0- to 8-hour urine sample were used in addition to serum bile acid levels and pathologic examination of biopsy specimens to assess the severity of hepatic dysfunction and portosystemic shunting. RESULTS: The patients as a group excreted less 4'-hydroxymephenytoin and had a smaller R/S enantiomeric ratio of mephenytoin. The two measures were discriminatory between the patient groups classified by either serum cholylglycine level or pathologic examination of biopsy specimens. Combination of the two measures of mephenytoin metabolism allowed the patients to be classified into three groups: normal hepatocyte function without portosystemic shunt, normal hepatocyte function with portosystemic shunt, and low hepatocyte function with or without portosystemic shunt. CONCLUSION: This study has shown the potential usefulness of mephenytoin metabolism as a sensitive indicator of hepatic pathologic condition with an ability to discriminate between contributory alternative mechanisms.

Adult↗

PubMed2026

Multi-omics reveals that burdock seed aglycone alleviates renal fibrosis by restoring mitochondrial oxidative phosphorylation function.

Renal fibrosis (RF), a common pathological process driving chronic kidney disease (CKD) progression to end-stage renal failure, is closely associated with oxidative phosphorylation (OXPHOS). Arctigenin (ATG), the main active component of burdock seed, exhibits anti-inflammatory and anti-fibrotic activities, but its mechanisms in RF treatment remain unclear. Here, we performed integrated transcriptomic and proteomic analyses to identify key targets and pathways of ATG in a unilateral ureteral obstruction-induced rat RF model. Multi-omics enrichment analysis revealed that NDUFS8 and NDUFS2 were the core targets of ATG, with the OXPHOS pathway as the central intersecting pathway. Our results suggest that ATG exerts anti-renal fibrosis effects by targeting the OXPHOS pathway to inhibit excessive reactive oxygen species production and oxidative stress. SIGNIFICANCE: Chronic kidney disease (CKD) continues to impose an escalating global health and socioeconomic burden, while renal fibrosis (RF), as the convergent pathological endpoint of virtually all progressive nephropathies, remains the principal determinant of irreversible renal failure and adverse clinical outcomes. Despite extensive efforts to develop antifibrotic therapies, effective clinical interventions remain elusive, largely due to the complex and multifactorial nature of RF pathogenesis. In this study, we employed an integrated multi-omics framework encompassing transcriptomics, proteomics, and metabolomics to systematically decipher the antifibrotic mechanism of arctigenin (ATG), a bioactive natural compound derived from traditional Chinese medicine. Our findings identify mitochondrial oxidative phosphorylation as the pivotal regulatory axis underlying the renoprotective effects of ATG and further establish key catalytic subunits of mitochondrial complex I as its direct molecular targets. Mechanistically, ATG not only restores complex I activity and reprograms mitochondrial energy metabolism but also preserves the intracellular stability and localization of these subunits, thereby preventing their aberrant release-mediated inflammatory activation and disrupting the self-perpetuating cycle linking metabolic dysfunction, inflammation, and fibrosis progression. Beyond revealing a previously unrecognized dual mechanism integrating metabolic and inflammatory regulation, this study provides compelling evidence that mitochondrial dysfunction is not merely a secondary consequence of tissue injury but a fundamental driver of fibrotic remodeling. Importantly, our work highlights the translational potential of natural product-based mitochondrial interventions for CKD treatment and supports a broader conceptual shift toward metabolism-centered therapeutic strategies for chronic fibrotic diseases. Given the central role of mitochondrial dysfunction across multiple organs, these findings may also have far-reaching implications for the treatment of systemic fibrosis-related disorders beyond the kidney.

Animals↗

PubMed1982

The role of vagally-medicated hyperinsulinemia in hypothalamic obesity.

Evidence that the obesity syndrome which follows ventromedial hypothalamic (VMH) lesions is at least partially the result of a primary metabolic dysfunction is reviewed, as are proposals that the altered metabolism is due to enhanced vagally-mediated insulin release. This hypothesis was based largely on experiments demonstrating the complete reversal of hypothalamic obesity by subdiaphragmatic vagotomy, but subsequent studies have revealed that hypothalamic obesity is not always prevented by prior vagal transections. Interpretation of these discrepant results has been made difficult because of the frequent use of gastric secretion, behavioral, or other indirect tests for completeness of vagotomy. A review of more recent studies which have employed either direct assessment of vagotomy effects on insulin levels, pharmacological blockade of vagal efferent activity, or selective vagotomies indicates that vagally-mediated hyperinsulinemia can account for no more than 40% of the weight gain observed in animals with VMH lesions fed ad libitum, and may not be involved in the obesity that results from some parasagittal VMH knife cuts. It is concluded that vagally-mediated hyperinsulinemia does make a substantial, although not exclusive, contribution to the increased carcass lipid content observed in VMH animals that are food-restricted or pair-fed with control animals.

Animals↗

PubMed2024

Integrated Multi-Omics Analyses Reveal Lipid Metabolic Signature in Osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease and the second leading cause of disability worldwide. Single-omics analyses are far from elucidating the complex mechanisms of lipid metabolic dysfunction in OA. This study identified a shared lipid metabolic signature of OA by integrating metabolomics, single-cell and bulk RNA-seq, as well as metagenomics. Compared to the normal counterparts, cartilagesin OA patients exhibited significant depletion of homeostatic chondrocytes (HomCs) (P = 0.03) and showed lipid metabolic disorders in linoleic acid metabolism and glycerophospholipid metabolism which was consistent with our findings obtained from plasma metabolomics. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), weidentified PLA2G2A as a hub gene associated with lipid metabolic disorders in HomCs. And an OA-associated subtype of HomCs, namely HomC1 (marked by PLA2G2A, MT-CO1, MT-CO2, and MT-CO3) was identified, which also exhibited abnormal activation of lipid metabolic pathways. This suggests the involvement of HomC1 in OA progression through the shared lipid metabolism aberrancies, which were further validated via bulk RNA-Seq analysis. Metagenomic profiling identified specific gut microbial species significantly associated with the key lipid metabolism disorders, including Bacteroides uniformis (P < 0.001, R = -0.52), Klebsiella pneumonia (P = 0.003, R = 0.42), Intestinibacter_bartlettii (P = 0.009, R = 0.38), and Streptococcus anginosus (P = 0.009, R = 0.38). By integrating the multi-omics features, a random forest diagnostic model with outstanding performance was developed (AUC = 0.97). In summary, this study deciphered the crucial role of a integrated lipid metabolic signature in OA pathogenesis, and established a regulatory axis of gut microbiota-metabolites-cell-gene, providing new insights into the gut-joint axis and precision therapy for OA.

Humans↗

PubMed2005

Metabolic syndrome and endothelial dysfunction.

The incidence of metabolic syndrome is rapidly increasing in the United States. Metabolic syndrome is associated with increased cardiovascular morbidity and mortality, and endothelial dysfunction is an early pathogenetic event in the metabolic syndrome. Endothelial dysfunction of either the coronary, the peripheral, or the cerebral vasculature is a predictor of vascular events and appears to be a marker of uncontrolled atherosclerotic risk that adds to the burden of the genetic predisposition to cardiovascular disease. Clinically and experimentally, endothelial dysfunction can be restored by several agents, including blockers/inhibitors of the renin-angiotensin-aldosterone system, as well as statins. Nevertheless, it would be premature, and most likely inappropriate, to use improvement of endothelial function as a surrogate end point to predict reduction in cardiovascular morbidity and mortality. However, a clear understanding of the mechanisms of endothelial dysfunction in the metabolic syndrome may allow the development of preventive and early therapeutic measures targeting cardiovascular disease.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2026

Metabolic convergence of diabetes and prostate cancer: from dysglycemia to tumor microenvironment reprogramming.

The relationship between diabetes mellitus and prostate cancer (PC) represents one of the most intriguing paradoxes in cancer epidemiology, with diabetic individuals exhibiting a reduced incidence of PC yet poorer prognosis following diagnosis. This apparent contradiction underscores the need for an integrated understanding of how systemic metabolic dysfunction influences prostate carcinogenesis and disease progression. The present review critically synthesizes contemporary epidemiological, mechanistic, and translational evidence to establish metabolic convergence as a unifying framework linking diabetes-associated metabolic abnormalities with PC biology. Current evidence indicates that chronic dysglycemia, hyperinsulinemia, insulin resistance, and endocrine perturbations orchestrate interconnected intracellular signaling networks involving PI3K-AKT-mTOR, AMPK, AGE-RAGE signaling, oxidative stress, mitochondrial dysfunction, and epigenetic reprogramming, collectively driving metabolic adaptation and tumor evolution. Beyond tumor-intrinsic mechanisms, diabetes profoundly remodels the prostate tumor microenvironment through alterations in stromal metabolism, cancer-associated fibroblast activation, adipocyte-tumor crosstalk, extracellular matrix (ECM) remodeling, hypoxic adaptation, and vascular dysfunction, while simultaneously promoting immunometabolic reprogramming characterized by macrophage polarization, T-cell dysfunction, immune checkpoint activation, and immune evasion. The review further examines the bidirectional interactions between antidiabetic therapies and PC treatment, critically evaluating the translational potential of metformin and emerging glucose-lowering agents within the context of precision metabolic therapeutics. Finally, future directions encompassing biomarker-guided patient stratification, longitudinal metabolic profiling, multi-omics integration, artificial intelligence, and clinically relevant mechanistic validation are discussed as essential components of next-generation precision oncology. Collectively, this review reframes diabetes as an active metabolic determinant of PC rather than a coincidental comorbidity and highlights metabolism-centered precision strategies as promising avenues for improving risk stratification, therapeutic decision-making, and clinical outcomes in diabetes-associated PC.

Humans↗

PubMed2004

Adolescent obesity: current trends in identification and management.

PURPOSE: To discuss the prevalence, identification, and clinical manifestations of adolescent obesity for the advanced practice nurse in primary care. DATA SOURCES: Selected research and clinical articles. CONCLUSIONS: Adolescent obesity has been historically attributed to inappropriate diet and exercise; however, recent research also attributes adolescent obesity to genetic factors and metabolic dysfunction. If left untreated, adolescent obesity may result in the metabolic complications of dyslipidemia, hypertension, cardiovascular disease, and early onset of type 2 diabetes. IMPLICATIONS FOR PRACTICE: Practitioners should focus on using the new body mass index (BMI) national guidelines for early identification of obesity. Essential to the management of this condition are education, parental involvement, behavior modification, and psychological support.

Adolescent↗

PubMed1980

Glucose metabolism of human mononuclear cell subpopulations.

Previous studies have demonstrated metabolic dysfunction in the mononuclear cells of some children with abnormal cell-mediated immunity. Interpretation of these observations has been complicated by the extreme heterogeneity of cell types examined. The glycolytic metabolism of relatively enriched T-cells, non-T mononuclear cells (NTM), non-T lymphocytes (NTL), and monocytes was studied in an attempt to measure the metabolism of subpopulations of mononuclear cells. Lactate production by monocytes was 11 times greater than that of T-cells and 2 1/2 times greater than that of non-T lymphocytes. Exposure to phytohemagglutinin (PHA) stimulated glycolytic metabolism in T-cells but did not stimulate glucose utilization or lactate production in NTM. Even when T-cells were maximally stimulated by PHA, their observed metabolism was still lower than that of NTL. The ATP content of T lymphocytes and NTL was similar and was constant under the conditions of incubation. The initial ATP content of monocytes was higher than that of lymphocytes, and diminished during incubation. Tricarboxylic acid cycle activity did not contribute significantly to ATP synthesis in any of the mononuclear cell subpopulations, under the conditions of incubation used in this study. Significant hexose monophosphate shunt activity was observed in all mononuclear cell types. These studies demonstrate major metabolic differences between mononuclear cell subtypes. Any correlation of metabolic observation with clinical dysfunction of mononuclear cells requires the study of relatively pure cell populations.

Adult↗

PubMed2006

The role of obesity and its bioclinical correlates in the progression of chronic kidney disease.

In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.

Animals↗

PubMed1999

Intracoronary administration of adenosine triphosphate increases coronary blood flow and attenuates the severity of myocardial ischemic injury in dogs.

ATP generates nitric oxide (NO) via activation of P2y receptors, and is degraded to adenosine. This study was undertaken to examine whether ATP causes coronary hyperemic flow via purinoceptors-, NO- and adenosine-dependent mechanisms, and attenuates the severity of contractile and metabolic dysfunction in the ischemic myocardium. In the non-ischemic canine hearts, the infusions of ATP into the coronary artery dose-dependently increased coronary blood flow. The levels of adenosine and end-product of NO in coronary venous blood over the arterial blood also increased. This hyperemic flow was partially attenuated by either 8-sulfophenyltheophylline (8SPT) or L(omega)-nitro arginine methyl ester (L-NAME), and completely blocked by the treatment with 8SPT, L-NAME and suramin (SRM). During myocardial ischemia, exogenous ATP increased coronary blood flow, and attenuated myocardial metabolic and contractile dysfunction, which was completely blunted by the treatment with 8SPT, L-NAME and SRM. We conclude that exogenous ATP increases coronary blood flow in the non-ischemic and ischemic myocardium mainly via either NO- or adenosine-dependent mechanisms.

Adenosine Triphosphate↗

PubMed2002

beta-Amyloid neurotoxicity is exacerbated during glycolysis inhibition and mitochondrial impairment in the rat hippocampus in vivo and in isolated nerve terminals: implications for Alzheimer's disease.

Senile plaques composed mainly by beta-amyloid (Abeta) protein are one of the pathological hallmarks of Alzheimer's disease (AD). In vitro, Abeta and its active fragment 25-35 have been shown either to be directly neurotoxic or to exacerbate the damaging effect of other neurotoxic insults. However, the attempts to replicate Abeta neurotoxicity in vivo have yielded conflicting results. One of the most consistent alterations in AD is a reduced resting glucose utilization. Important evidence suggests that impairment of brain energy metabolism can lead to neuronal damage or facilitate the deleterious effects of some neurotoxic agents. In the present study we have investigated the influence of glycolysis inhibition induced by iodoacetate, and mitochondrial impairment induced by 3-nitropropionic acid (3-NP), in the toxicity of Abeta. We have studied Abeta neurotoxicity during energy deficiency both in vivo in the dentate gyrus of the hippocampal formation and in presynaptic terminals isolated from neocortex and hippocampus. Results show that during metabolic inhibition an enhanced vulnerability of hippocampal neurons to Abeta peptide toxicity occurs, probably resulting from decreased glucose metabolism and mitochondrial ATP production. Synaptosomal response to energy impairment and Abeta toxicity was evaluated by the MTT assay. Results suggest that synapses may be particularly sensitive to metabolic perturbation, which in turn exacerbates Abeta toxicity. The present data provide experimental support to the hypothesis that certain risk factors such as metabolic dysfunction and amyloid accumulation may interact to exacerbate AD, and that metabolic substrates such as pyruvate may play a role as a therapeutic tool.

Adenosine Triphosphate↗

PubMed1994

Overview of coenzyme A metabolism and its role in cellular toxicity.

Coenzyme A (CoASH) has a clearly defined role as a cofactor for a number of oxidative and biosynthetic reactions in intermediary metabolism. Formation of acyl-CoA thioesters from organic carboxylic acids activates the acid for further biotransformation reactions and facilitates enzyme recognition. Xenobiotic carboxylic acids can also form CoA-thioesters, and the resulting acyl-CoA may contribute to the compound's toxicity. Generation of an unusual or poorly-metabolized acyl-CoA from a xenobiotic may lead to cellular metabolic dysfunction through several types of mechanisms including: (1) inhibition of key metabolic enzymes by the acyl-CoA; (2) sequestration of the total cellular CoA pool as the unusual acyl-CoA; (3) physical-chemical effects of the acyl-CoA; and (4) sequestration and depletion of carnitine as the acyl group is transformed from the acyl-CoA to form the corresponding acylcarnitine. Many of these toxicities are similar to sequelae observed in the inherited organic acidurias in which endogenously-generated acyl-CoAs accumulate secondary to an enzymopathy. Insights into the cellular mechanisms of xenobiotic acyl-CoA accumulation have been derived from model systems developed to understand organic acidemias, such as the methylmalonyl-CoA accumulation of the methylmalonic acidurias. The relevance of acyl-CoA accretion to human pathophysiology has now been well established, and identification of the relevant mechanism of toxicity can allow implementation of strategies to minimize the metabolic injury. Additionally, recognition of the potential for acyl-CoA mediated xenobiotic injury should result in improved rational drug design and earlier recognition of such toxicity when it develops.

Acyl Coenzyme A↗

PubMed2006

Insulin resistance is associated with cognition among HIV-1-infected patients: the Hawaii Aging With HIV cohort.

OBJECTIVE: To determine if insulin resistance (IR) is associated with lower cognitive performance among HIV-1-infected adults and to determine if advanced age magnifies risk. DESIGN: Cross-sectional analysis within the Hawaii Aging With HIV Cohort. METHODS: We calculated the homeostasis model assessment of insulin resistance (HOMA-IR) among 145 cohort participants. Values were compared to concurrent neuropsychological test performance and cognitive diagnoses. RESULTS: Hypertension, body mass index (BMI), and non-Caucasian self-identity were directly related to insulin resistance (IR); however, age, CD4 lymphocyte count, and rates of treatment with HAART were not. In logistic regression analyses and stratifying cognition status on a 3-tiered scale (normal, minor cognitive motor disorder (MCMD), and HIV-associated dementia (HAD)), we identified an increased risk of meeting a higher diagnostic category as HOMA-IR increased (OR, 1.12; 95% CI: 1.003 to 1.242 per unit of HOMA-IR, P = 0.044). In linear regression models and among nondiabetic participants, an increasing degree of IR was associated with lower performance on neuropsychological summary scores. CONCLUSIONS: IR is associated with cognitive dysfunction in this contemporary HIV-1 cohort enriched with older individuals. Metabolic dysfunction may contribute to the multifactorial pathogenesis of cognitive impairment in the era of HAART.

AIDS Dementia Complex↗

PubMed1995

Cortical abnormalities associated with subcortical lesions in vascular dementia. Clinical and position emission tomographic findings.

OBJECTIVE: To examine the effects of subcortical lesions on cortical metabolic rate and clinical symptoms in patients with vascular dementia. METHOD: Eleven elderly patients with vascular dementia who demonstrated no lesion involving the cerebral cortex on magnetic resonance imaging underwent 18F-fluorodeoxyglucose positron emission tomography to assess global cortical metabolism and metabolic activity in each cortical lobe. Subcortical lesions on magnetic resonance imaging (periventricular hyperintensities, deep white matter hyperintensities, and subcortical lacunar infarcts) were measured using a graded scale of severity. Cognitive and noncognitive symptoms were assessed with the Neurobehavioral Rating Scale. RESULTS: Reduced cortical metabolism was generally associated with the severity of subcortical pathologic changes, but there was substantial heterogeneity in the relationship between subcortical lesions and cortical metabolic activity. Mean global cortical metabolism was lower in patients with periventricular hyperintensities in anterior subcortical regions than in those without such lesions. The metabolic rate in the frontal cortex was lower in patients with a lacunar infarct of the basal ganglia or thalamus than in those without. Neurobehavioral Rating Scale total score, the Verbal Output Disturbance factor score, and the Anxiety/Depression factor score were correlated with the severity of white matter lesions. CONCLUSIONS: Cortical metabolic dysfunction is related to ischemic subcortical lesions in patients with vascular dementia. Metabolism in the frontal cortex may be particularly dependent on pathologic alterations of subcortical nuclei. Anxiety, depression, and the overall severity of neuropsychiatric symptoms in vascular dementia are associated with the extent of white matter ischemia.

Adolescent↗