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PubMed2006

Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy.

Dysregulated sphingolipid metabolism causes neuronal cell death and is associated with insulin resistance and diseases. Thus, we hypothesized that diabetes-induced changes in retinal sphingolipid metabolism may contribute to neuronal pathologies in diabetic retinopathy. ESI-MS/MS was used to measure ceramide content and ceramide metabolites in whole retinas after 2, 4, and 8 weeks of streptozotocin-induced diabetes. After 4 and 8 weeks of diabetes, a approximately 30% decrease in total ceramide content was observed, concomitant with a significant approximately 30% increase in glucosylceramide levels in fed diabetic rats compared with their age-matched controls. Acute insulin therapy as well as a short-term lowering of glucose via fasting did not affect the increase in glucosylceramide composition. To assess the putative biological consequences of the increase in glucosylceramide composition, R28 retinal neurons were treated with glucosylceramide synthase inhibitors. Inhibiting glycosphingolipid metabolism increased insulin sensitivity in retinal neurons. Glycosphingolipid inhibitors augmented insulin-stimulated p70 S6kinase activity in the presence of inhibitory concentrations of high glucose or glucosamine. Inhibition of glycosphingolipid synthesis also suppressed glucosamine- and interleukin-1beta-induced death. Consistent with these inhibitor studies, pharmacological accumulation of glycosphingolipids increased activation of the endoplasmic reticulum stress response, a putative modulator of insulin resistance and neuronal apoptosis. It is speculated that an increase in glucosylceramide, and possibly higher-order glycosphingolipids, could contribute to the pathogenesis of diabetic retinopathy by contributing to local insulin resistance, resulting in neuronal cell death. Thus, dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes, and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy.

Animals↗

PubMed2003

Metabolic presbycusis: differential changes in auditory brainstem and otoacoustic emission responses with chronic furosemide application in the gerbil.

Auditory characteristics of metabolic or strial presbycusis were investigated using an animal model in which young adult Mongolian gerbils ( Meriones unguiculates) were implanted with an osmotic pump supplying furosemide continuously to the round window. This model causes chronic lowering of the endocochlear potential (EP) and results in auditory responses very similar to those seen in quiet-aged gerbils (Schmiedt et al., J. Neurosci. 22:9643-9650, 2002). Auditory function was examined up to one week post-implant by measurement of auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). Emission "threshold" was defined as the stimulus level required to reach a criterion emission amplitude. Comparing all responses on a "threshold-shift diagram," where emission threshold increases were plotted versus ABR threshold increases, the following results were obtained: (1) On average, the increase of the emission threshold was about 55% of the increase in ABR threshold, with comparatively little scatter. (2) The main dysfunction in metabolic presbycusis appears to be a decrease in the gain of the cochlear amplifier, combined with an additional, smaller increase in neural threshold, both effects caused by a chronically low EP. (3) For ABR threshold increases over 20 dB, the points for the chronic low-EP condition were largely separate from those previously found for permanent acoustic damage. The threshold-shift diagram therefore provides a method for noninvasive differential diagnosis of two common hearing dysfunctions.

Animals↗

PubMed1995

Reduced aerobic metabolic efficiency in postischemic myocardium dysfunction in rats: role of aging.

It has been suggested that aging may enhance the deleterious effects of myocardial ischemia-reperfusion. This study evaluates the relationship between oxygen consumption and functional impairment during reperfusion following myocardial ischemia in adult and senescent rat hearts. Global ischemia induced a marked impairment of contractile function which was significantly higher in senescent than in adult hearts. During reperfusion postischemic dysfunction was more evident in senescent hearts: at the 10th minute, the developed pressure recovered less (p < 0.05) and end-diastolic pressure increased more (p < 0.05) in senescent than in adult hearts. However, oxygen consumption per unit of work was significantly higher throughout 60 min of reperfusion when compared to controls with no significant difference between adult and senescent hearts. This study demonstrates that following ischemia and reperfusion depression of function and inappropriately high oxygen consumption were observed in both adult and senescent hearts. However, aging was associated with greater contractile impairment, which occurred in the absence of further deterioration of metabolic efficiency of contraction.

Adenosine Triphosphate↗

PubMed2025

Hepatocyte-specific CLSTN3B ablation impairs lipid droplet maturation and alleviates diet-induced steatohepatitis in mice.

Excessive lipid accumulation in hepatocytes, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), can lead to progressive liver damage. Understanding the molecular mechanisms governing lipid storage in hepatocytes is essential for identifying therapeutic targets to halt MASLD progression. Here, we show a pivotal role for the protein calsyntenin 3β (CLSTN3B) in promoting lipid droplet (LD) maturation and lipid storage in hepatocytes. Previously characterized as an endoplasmic reticulum (ER)-LD contact protein that facilitates LD maturation in adipocytes, we now show that CLSTN3B expression is strongly induced in mouse hepatocytes by peroxisome proliferator-activated receptor gamma (PPARγ) in response to dietary caloric excess. Hepatocyte-specific deletion of CLSTN3B in mice significantly increases energy expenditure, reduces metabolic efficiency, and protects against diet-induced hepatic steatosis and fibrosis. Mechanistically, CLSTN3B deficiency causes reduced LD phospholipid coverage and increased lipase recruitment. This results in enhanced fatty acid oxidation driven by a futile cycle of lipolysis and re-esterification. Notably, human clinical data reveal a positive correlation between hepatic CLSTN3B expression and MASLD severity and progression, emphasizing its relevance to human disease. Together, our findings establish CLSTN3B as a key regulator of hepatocyte lipid storage and metabolic efficiency and highlight its potential as a therapeutic target in MASLD.

Journal Article↗

PubMed2005

Do vasoactive neuropeptide autoimmune disorders explain pyridostigmine's association with Gulf War syndrome?

Gulf War syndrome (GWS) is a perplexing multi-symptom condition comprising a constellation of signs and symptoms consistently described in the literature. These include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. Excessive chemical sensitivity and odour intolerance is reported. Epidemiological analysis suggests association with pyridostigmine bromide (PB) use as nerve gas prophylaxis, insect repellent, certain vaccination regimes, a variety of possible chemical exposures and physical and psychological stress. Pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are potent vasoactive (vasodilatory) neuropeptides (VNs) having pleiotropic functions as immunomodulators, neuroregulators and hormones. VNs also have neurotrophic and anti-apoptotic roles. VNs act on G protein-coupled receptors (GPCRs) to activate adenylate cyclase, an important step in cyclic AMP metabolism. Autoimmune dysfunction of these VNs or their receptors is postulated to give rise to fatigue-related conditions such as chronic fatigue syndrome (CFS). Complex mechanisms involving heat shock proteins (hsps) and cytosine-guanine dinucleotide (CpG) DNA fragments may also be associated with autoimmunity to VNs or their GPCRs in contributing to fatigue-related conditions. Dysfunction of certain VNs may be the missing link in explaining the nebulous nexus between PB and GWS. This paper explores a possible link between exposures to PB and other chemical, physical and psychological stressors in producing a fatigue-related illness possibly related to autoimmune dysfunction of certain VNs. Treatment options involving restoration of VN function are considered in the context of analogues with other neurotransmitter fatigue-related conditions such as myasthenia gravis (MG). While evidence associating these conditions is thin, vasoactive neuropeptide neurotransmitters of the VIP/PACAP family have acetylcholine co-transmission functions via specific GPCRs. Autoimmune reactions to these receptors may have parallels with muscarinic (e.g., Sjogren's syndrome) and nicotinic (e.g., MG) acetylcholine neurotransmission. Hence theoretically, treatment options such as thymectomy, corticosteroids, plasma exchange, anti-idiotype antibodies and receptor genomic expression reactivation/suppression may be considered. Paradoxically pyridostigmine may prove to have a role in therapy although VN treatment/replacement may be associated with tachyphylaxis.

Autoimmune Diseases↗

PubMed2006

Transcriptomic analysis of the cardiac left ventricle in a rodent model of diabetic cardiomyopathy: molecular snapshot of a severe myocardial disease.

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Diabetic cardiomyopathy (DCM) is increasingly recognized as a major contributor to diastolic dysfunction and heart failure in diabetes, but its molecular basis has remained obscure, in part because of its multifactorial origins. Here we employed comparative transcriptomic methods with quantitative verification of selected transcripts by reverse transcriptase quantitative PCR to characterize the molecular basis of DCM in rats with streptozotocin-induced diabetes of 16-wk duration. Diabetes caused left ventricular disease that was accompanied by significant changes in the expression of 1,614 genes, 749 of which had functions assignable by Gene Ontology classification. Genes corresponding to proteins expressed in mitochondria accounted for a disproportionate number of those whose expression was significantly modified in DCM, consistent with the idea that the mitochondrion is a key target of the pathogenic processes that cause myocardial disease in diabetes. Diabetes also induced global perturbations in the expression of genes regulating cardiac fatty acid metabolism, whose dysfunction is likely to play a key role in the promotion of oxidative stress, thereby contributing to the pathogenesis of diabetic myocardial disease. In particular, these data point to impaired regulation of mitochondrial beta-oxidation as central in the mechanisms that generate DCM pathogenesis. This study provides a comprehensive molecular snapshot of the processes leading to myocardial disease in diabetes.

Animals↗

PubMed2026

Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

PPAR gamma↗

PubMed1998

Association between breast and colorectal cancers.

BACKGROUND: The risk of breast and colorectal cancers in immigrants from non-industrialised countries is sharply increased when they adopt a Western lifestyle. In addition, epidemiological studies on Western populations show an association between the two tumours, both in the same individual and also in close relatives. Most studies agree that high energy intake, obesity and inadequate physical exercise are associated with an increased risk of both tumours. METHODS: Risk markers for each cancer are examined in order to identify causative nutritional factors or metabolic-endocrine dysfunction. The role of steroid hormones and other possible carcinogenic mechanisms is discussed, concentrating on evidence of a role for insulin and insulin-like growth factors (IGFs) in the promotion of carcinogenesis in both organs. RESULTS: Individuals with a genetic susceptibility to insulin resistance show triggering of hyperinsulinaemia following excessive weight gain or long-term diet high in saturated fat. Case-control studies show an association between hyperinsulinaemia and evidence of breast or colorectal carcinoma. Multiple laboratory studies show that increased activity of IGFs can stimulate the growth of human breast and colorectal cancer cells. CONCLUSION: It is postulated that either insulin resistance and its concomitants promote the development of breast and colorectal cancers, or that they share common risk factors. Sex steroid metabolism and organ specificity may explain age and sex differences between the tumours in relation to the role of obesity. Recent research suggests that a diet high in n-3 polyunsaturated fatty acids may reduce the risk of developing insulin resistance. This observation may be applied to test the hypothesis that an effect on hyperinsulinaemia may modify the risk of developing breast or colorectal cancer.

Breast Neoplasms↗

PubMed2003

Dysfunction of peripheral blood granulocyte oxidative metabolism in children with recurrent upper respiratory tract infections.

Granulocytes play a key role in the defence against bacterial infections. Their dysfunction may both predispose to and result from infections. The oxidative metabolism of peripheral blood granulocytes was studied in 50 children aged from 1 to 10 years, with recurrent upper respiratory tract infections and/or tonsillar hypertrophy. Four groups of patients were recruited: 15 healthy controls, seven patients with idiopathic tonsillar hypertrophy, 12 patients with upper respiratory tract infections and 16 patients with upper respiratory tract infections with concurrent tonsillar hypertrophy. The ability of granulocytes to produce reactive oxygen species was assessed by nFMLP-induced chemiluminescence. Both increased and depressed granulocyte activity was observed in all studied groups, with the exception of controls. Altered granulocyte function was observed in 30% of patients in the idiopathic tonsillar hypertrophy group. In children with recurrent infections abnormal chemiluminescence results were found in from 75% to nearly 90% of patients. This preliminary study demonstrates the possible relationship between recurrent upper respiratory tract infections, tonsillar hypertrophy and impaired peripheral blood granulocyte chemiluminescence.

Child↗

PubMed2003

Cooperation between insulin and leptin in the modulation of vascular tone.

High levels of insulin and leptin have been reported in human hypertension, suggesting a role for these metabolic hormones in blood pressure homeostasis. These hormones interact on intermediate metabolism, but nothing is known about their interaction at the vascular level. Our data demonstrate that insulin (0.6 nmol/L) is able to enhance vasodilation induced by leptin (10(-11) to 10(-6) mol/L; percentage change in maximal vasodilation, 39+/-3% vs 26+/-2%; n=6, P<0.03) but not by acetylcholine. Moreover, we demonstrate by 4,5-diaminofluorescein (DAF)-2 that insulin potentiates leptin-induced nitric oxide (NO) release. Finally, Western blotting studies show that insulin enhances the leptin-induced phosphorylation of Akt in Ser473 and Thr308 and of endothelial NO synthase in Ser1177. In conclusion, our data demonstrate that insulin and leptin cooperate in the modulation of vascular tone through enhancement of endothelial NO release. This phenomenon could have a major impact on the regulation of the cardiovascular system, principally in those clinical conditions characterized by endothelial NO dysfunction and metabolic disorders, such as arterial hypertension.

Animals↗

PubMed2025

The SELENOP Polymorphism rs7579 Predicts Hepatic Steatosis in Females With Insulin Resistance in the General Population.

CONTEXT: Selenoprotein P is a hepatokine associated with several metabolic processes. Rs7579 (C > T) is a SeP-related functional single nucleotide polymorphism. OBJECTIVE: In this study, we aimed to identify the environmental factors affecting the relationship between rs7579 and metabolic diseases, such as metabolic dysfunction-associated steatotic liver disease, in the general population. METHODS: This cross-sectional study was based on the Shika Study, a survey of residents in the Noto Peninsula of Ishikawa Prefecture. We analyzed a total of 900 adults, measuring full-length selenoprotein P (FL-SeP) serum levels using a sol-particle homogeneous immunoassay. RESULTS: We observed that selenium and FL-SeP serum levels were associated with dyslipidemia. In males, serum selenium was associated with dyslipidemia and hepatic steatosis. However, in females, FL-SeP tended to be associated with diabetes. Participants carrying the TT genotype and hepatic steatosis exhibited higher levels of liver enzymes, insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), and the homeostasis model assessment of β-cell function than those without hepatic steatosis or with other genotypes. In females carrying the TT genotype of rs7579, hepatic steatosis, hypertension, diabetes, obesity, and metabolic syndrome were associated with higher HOMA-IR levels. CONCLUSION: In this study, we revealed that the association between metabolic diseases and HOMA-IR differed single nucleotide polymorphism genotype and sex dependently. In females carrying the TT genotype of rs7579, hepatic steatosis-associated metabolic disorders (diabetes, hypertension, obesity, and metabolic syndrome) were associated with higher HOMA-IR. The results of this study open the way to genetic signatures-based personalized preventive medicines.

CCDC152↗

PubMed1996

Effects of aprindine on ischemia/reperfusion-induced cardiac contractile dysfunction of perfused rat heart.

The present study was undertaken to determine whether aprindine, a class Ib antiarrythymic agent, exerts beneficial effects on ischemia/reperfusion-induced cardiac contractile dysfunction and metabolic derangement. Isolated rat hearts were subjected to 35-min global ischemia, followed by 60-min reperfusion, and functional and metabolic alterations of the heart were determined with or without aprindine-treatment. Ischemia induced a cessation of left ventricular developed pressure (LVDP), a rise in left ventricular end-diastolic pressure (LVEDP), and an increase in myocardial sodium content and a decrease in myocardial potassium content. When the hearts were reperfused, little recovery of LVDP and sustained rise in LVEDP and perfusion pressure were observed. Ischemia/reperfusion resulted in a release of ATP metabolites and creatine kinase from perfused hearts, an increase in myocardial sodium and calcium contents, and a decrease in myocardial potassium and magnesium contents. Treatment of the perfused heart with either 10 or 30 microM aprindine for the last 3 min of pre-ischemia improved contractile recovery during reperfusion and suppressed changes in myocardial ion content during ischemia and reperfusion. Treatment with the agent also attenuated the release of ATP metabolites and creatine kinase from the heart. However, treatment with high concentrations of aprindine (70 and 100 microM) improved neither cardiac contractile dysfunction, myocardial ionic disturbance nor the release of ATP metabolites and creatine kinase during reperfusion. Two possible mechanisms for the cardioprotection by the agent have been suggested: suppression of transmembrane flux of substrates and enzymes, and prevention of accumulation of myocardial sodium during ischemia.

Animals↗

PubMed1979

Renal tubular dysfunction and abnormalities of calcium metabolism in cadmium workers.

Tubular proteinuria is generally accepted as the critical effect following long-term, low-level exposure to cadmium as seen in an industrial environment. This effect may not be of immediate importance to the health of the individual, but the significance, in terms of long-term morbidity and mortality, of the renal tubular defect of which it is an indicator is not fully understood, and certain sequelae may have remained unrecognized due to inadequate follow-up.Follow-up studies have been performed in nine of 12 workers who were initially investigated in 1962. In six of the men exposures ranged from 28 to 45 years to cadmium sulfide dust and for shorter periods in the earlier years to cadmium oxide fume and dust. These six men had tubular proteinuria when first seen, and this has persisted in the five survivors. All six men had hypercalciuria, and two of them became recurrent stone formers. One man whose urinary calcium excretion later fell to a low level more recently developed vitamin D resistant osteomalacia. In addition, each of the six men had exhibited some, but not all, of a variety of biochemical abnormalities related to other proximal renal tubular defects, and the worker who developed osteomalacia had additional evidence of a distal tubular defect. The five survivors also have evidence of slowly progressive deterioration in glomerular function.Follow-up of this small group has shown that renal tubular dysfunction in cadmium workers may continue symptom-free for long intervals, but in a proportion of cases serious clinical effects may develop after a number of years.

Aged↗

PubMedDate not supplied

Myofibril MgATPase activities and energy metabolism in cardiomyopathic mice with diastolic dysfunction.

To study the genomic physiology of cardiac myofibril proteins in the heart, we have successfully created a cardiac troponin I (cTnI; a myofibril protein) gene knockout mouse model using gene targeting techniques. The phenotype of the cTnI gene knockout mouse is a cardiomyopathy with diastolic dysfunction resulting in sudden death in neonates. In the present studies, energy metabolism was analyzed in myocardial cells from cTnI-null hearts. Myofibril MgATPase activities were determined in myocardial cells from either wild-type or cTnI mutant mouse hearts. Furthermore, the quantity and quality of the mitochondria in wild-type and cTnI mutant animals were counted and analyzed. Our results demonstrate that damaged relaxation and increased Ca(2+)-independent force production in cTnI-null hearts is in part related to the increased myofibril MgATPase activities accompanied by an increase in mitochondria quantity and mitochondrial ATPase activities. These data indicate that cardiomyopathies with diastolic dysfunction are different from cardiomyopathies caused by systolic dysfunction. The former involves the damage of cardiac relaxation due to increased MgATPase activities and increased Ca(2+)-independent force production inside of myofilaments, while the latter involves the damage of systolic contraction due to decreased MgATPase activities and decreased force production.

Animals↗

PubMedDate not supplied

Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes.

Remodeling of myocardial cell membranes is a major feature of advanced age. Mitochondrial function, crucial to sustaining energy production and management of myocardial metabolism, is impacted by age-dependent remodeling and ultimately exhibits a diminished threshold for excess Ca2+ buffering during events that stimulate increased myocardial Ca2+, such as augmented cardiac work, oxidative stress or post-ischemic reflow. Relative Ca2+, intolerance, augmented superoxide formation and reduced efficiency in the management of reactive oxygen species, are important mitochondrial factors (of many) that are apparent in senescence and predispose the myocardium to be more vulnerable to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca2+ homeostasis. Age-associated mitochondrial membrane changes include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These effects have been shown in animal studies to be exaggerated by diet rich in long chain omega-6 PUFA (i.e. arachidonic acid), and have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance, and dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.

Aged↗

PubMed1992

The roles of glucose-induced metabolic hypoxia and imbalances in carnitine metabolism in mediating diabetes-induced vascular dysfunction.

Investigations were initiated to examine the rate of imbalances in carnitine metabolism in the pathogenesis of diabetic vascular changes in the retina, peripheral nerves, aorta and kidney. It appears that glucose/diabetes-induced vascular dysfunction and early vascular structural changes are mediated by hyperglycaemic hypoxia i.e. glucose-induced metabolic imbalances that cause an increase in the reduced nicotinamide-adenine dinucleotide/nicotinic acid dehydrogenase ratio, and are linked to imbalances in carnitine metabolism.

Animals↗

PubMed1990

Possible involvement of membrane-stabilizing action in beneficial effect of beta adrenoceptor blocking agents on hypoxic and posthypoxic myocardium.

The present study was designed to elucidate a possible involvement of membrane-stabilizing action of beta blocking agents in posthypoxic recovery of cardiac contractile function and myocardial metabolism. Propranolol and acebutolol, which possess a membrane-stabilizing action, and atenolol and metoprolol, which lack this action, were used in the isolated, perfused rabbit heart. The membrane-stabilizing effects of these agents were assessed on the basis of the effects on the maximal driving frequency of the left atria. Reoxygenation of hearts for 45 min following 20-min hypoxia resulted in little recovery of cardiac contractile force, sustained rise in resting tension, insufficient recovery of myocardial high-energy phosphates, accumulation of the tissue calcium and sodium and marked release of creatine kinase and ATP metabolites from the hearts. Treatment of hypoxic hearts with either 100 microM propranolol, 200 microM acebutolol, 200 microM atenolol or 100 microM metoprolol was commenced when the contractile force declined to 30% of the initial level and terminated at 20-min hypoxia. Treatment with either propranolol or acebutolol produced a significant posthypoxic recovery of cardiac contractile force, resting tension and myocardial high-energy phosphates, and a profound suppression of the tissue calcium and sodium accumulation and the loss of ATP metabolites from perfused hearts. In contrast, neither atenolol nor metoprolol affected these changes induced by the hypoxic insult and the following reoxygenation. The results suggest that membrane-stabilizing action of beta blocking agents plays an important role in the protection against posthypoxic cardiac contractile dysfunction and metabolic disturbances.

Adenosine Triphosphate↗

PubMed2025

Plasma inflammatory proteome profiles identify MASLD among children with overweight or obesity.

BACKGROUND & AIMS: Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent among children with overweight or obesity, yet its early diagnosis remains a major clinical challenge. This study aimed to identify circulating inflammatory proteins associated with MASLD and to develop a proteomic risk score (ProScore) to improve diagnostic accuracy. METHODS: In this cross-sectional study of 161 children (median age 8.5 years) with overweight or obesity, MASLD was assessed by vibration-controlled transient elastography, with 42 cases identified. Plasma concentrations of 92 inflammation-related proteins were quantified using a high-throughput proximity extension assay. The ProScore was compared with eleven conventional anthropometric/metabolic indices (WHtR, METS-IR, SPISE, PNFI, VAI, LAP, TyG, TyG-ALT, TyG-WC, TyG-WHtR, and TyG-BMI) and a genetic risk score (GRS). Six machine learning algorithms were employed and diagnostic performance was assessed using area under the curve (AUC) with fivefold cross-validation. RESULTS: Fifteen proteins were significantly associated with MASLD. A six-protein panel (FGF-21, CDCP1, CD244, OPG, Flt3L, MCP-1) achieved the highest diagnostic accuracy (AUC = 0.84), exceeding that of all conventional indices (AUC = 0.65-0.78; all P < 0.05). ProScore performance remained robust in school-based validation (AUC = 0.83), with no substantial improvement when combined with conventional indices. Diagnostic accuracy was higher in children with lower GRS (AUC = 0.92) than in those with higher GRS (AUC = 0.80; P = 0.003). CONCLUSIONS: A proteomic signature of systemic inflammation provides accurate, non-invasive identification of MASLD in at-risk children, outperforming conventional metabolic and genetic tools, and may have utility in clinical and public health settings.

Humans↗