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PubMed1994

Delayed tumor necrosis factor alpha blockade attenuates pulmonary dysfunction and metabolic acidosis associated with experimental gram-negative sepsis.

OBJECTIVE: To ascertain the effect of delayed tumor necrosis factor alpha (TNF-alpha) on the evolution of systemic and pulmonary injury after the onset of sepsis. DESIGN: Prospective controlled trial. INTERVENTION: Anesthetized swine were made septic with a 1-hour infusion of live Pseudomonas aeruginosa, following which a treatment group received an infusion of anti-TNF-alpha monoclonal antibody (5 mg/kg). Control animals received 0.9% saline. RESULTS: Delayed anti-TNF-alpha treatment had no effect on septic pulmonary hypertension or decline in cardiac output. Late recovery in systemic arterial hypotension was associated with a reversal of arterial acidosis (P < .05 by t test and analysis of variance with Tukey's Studentized Range Test) compared with unprotected septic animals. Septic animals had a significant increase in mean (+/- SEM) plasma lactate levels at 5 hours compared with baseline values (3.8 +/- 0.7 vs 2 +/- 0.4, P < .05), but remained unchanged from baseline following anti-TNF-alpha treatment (1.5 +/- 0.1 vs 1.6 +/- 0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti-TNF-alpha treatment and was associated with downregulation (P < .05 by t test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P < .05 by t test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (+/- SEM) decrease in bronchoalveolar lavage protein indicated an attenuated permeability injury in anti-TNF-alpha animals (septic animals at 5 hours compared with baseline value, 1044 +/- 270 vs 149 +/- 28 micrograms/mL; control animals at 5 hours compared with baseline value, 217 +/- 83 vs 129 +/- 19 micrograms/mL; P < .05 by t test and analysis of variance). CONCLUSIONS: These data show that delayed anti-TNF-alpha treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti-TNF-alpha treatment reversed septic neutropenia, reduced PMN sequestration, and was associated with attenuated lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for potential therapeutic benefit of anti-TNF-alpha treatment in clinical practice.

Acidosis, Lactic↗
PubMed1993

Effects of K+ channel openers on ischemic dysfunction and metabolic disturbance in isolated perfused rat heart.

The effects of two structurally different K+ channel openers, KRN2391 and cromakalim, on cardiac mechanisms during ischemia and reperfusion were studied in isolated perfused rat hearts. Isolated buffer-perfused rat hearts pretreated with KRN2391, cromakalim and vehicle were subjected to 25 min of ischemia followed by 30 min of reperfusion. Before ischemia, KRN2391 (1-10 microM) and cromakalim (1-10 microM) increased coronary flow, but did not modify cardiac function or biochemical parameters (adenine nucleotides, energy charge potential: ECP, lactate). During ischemia, KRN2391 (3, 10 microM) and cromakalim (10 microM) significantly accelerated the reduction in cardiac function and attenuated the decreased levels of ATP and ECP, but did not change the lactate content. After 30 min of reperfusion, pretreatment with KRN2391 and cromakalim resulted in a significant improvement in cardiac function, ischemic contracture and biochemical parameters. Thus, both KRN2391 and cromakalim have beneficial effects on biochemical parameters during ischemia and reperfusion, effects which may be related to cardiodepression during ischemia.

Animals↗
PubMed1998

Perioperative determinants of morbidity and mortality in elderly patients undergoing cardiac surgery.

OBJECTIVE: To determine perioperative predictors of morbidity and mortality in patients > or =75 yrs of age after cardiac surgery. DESIGN: Inception cohort study. SETTING: A tertiary care, 54-bed cardiothoracic intensive care unit (ICU). PATIENTS: All patients aged > or =75 yrs admitted over a 30-month period for cardiac surgery. INTERVENTION: Collection of data on preoperative factors, operative factors, postoperative hemodynamics, and laboratory data obtained on admission and during the ICU stay. MEASUREMENTS AND MAIN RESULTS: Postoperative death, frequency rate of organ dysfunction, nosocomial infections, length of mechanical ventilation, and ICU stay were recorded. During the study period, 1,157 (14%) of 8,501 patients > or =75 yrs of age had a morbidity rate of 54% (625 of 1,157 patients) and a mortality rate of 8% (90 of 1,157 patients) after cardiac surgery. Predictors of postoperative morbidity included preoperative intraaortic balloon counterpulsation, preoperative serum bilirubin of >1.0 mg/dL, blood transfusion requirement of >10 units of red blood cells, cardiopulmonary bypass time of >120 mins (aortic cross-clamp time of >80 mins), return to operating room for surgical exploration, heart rate of >120 beats/min, requirement for inotropes and vasopressors after surgery and on admission to the ICU, and anemia beyond the second postoperative day. Predictors of postoperative mortality included preoperative cardiac shock, serum albumin of <4.0 g/dL, systemic oxygen delivery of <320 mL/ min/m2 before surgery, blood transfusion requirement of >10 units of red blood cells, cardiopulmonary bypass time of >140 mins (aortic cross-clamp time of >120 mins), subsequent return to the operating room for surgical exploration, mean arterial pressure of <60 mm Hg, heart rate of >120 beats/min, central venous pressure of >15 mm Hg, stroke volume index of <30 mL/min/m2, requirement for inotropes, arterial bicarbonate of <20 mmol/L, plasma glucose of >300 mg/dL after surgery, and anemia beyond the second postoperative day. During the study period, the study cohort used 6,859 (21.5%) ICU patient-days out of a total 31,867 ICU patient-days. Nonsurvivors used 2,023 (30%) ICU patient-days and patients with morbidity used 5,903 (86%) ICU patient-days. CONCLUSIONS: Severe underlying cardiac disease (including shock, requirement for mechanical circulatory support, hypoalbuminemia, and hepatic dysfunction), intraoperative blood loss, surgical reexploration, long ischemic times, immediate postoperative cardiovascular dysfunction, global ischemia and metabolic dysfunction, and anemia beyond the second postoperative day predicted poor outcome in the elderly after cardiac surgery. Postoperative morbidity and mortality disproportionately increased the utilization of intensive care resources in elderly patients. Future efforts should focus on preoperative selection criteria, improvement in surgical techniques, perioperative therapy to ameliorate splanchnic and global ischemia, and avoidance of anemia to improve the outcome in the elderly after cardiac surgery.

Aged↗
PubMed1991

Contractile dysfunction during metabolic acidosis: role of impaired energy metabolism.

To investigate the mechanisms by which acidosis depresses cardiac function, a Langendorff isolated perfused rat heart preparation was studied using 31P magnetic resonance spectroscopy. Isolated hearts were subjected to normal perfusion conditions or experimental manipulations simulating severe metabolic acidosis, substrate depletion, impairment of oxidative metabolism, or low perfusate calcium concentrations. All maneuvers resulted in marked reductions in oxygen consumption and the force of myocardial contraction (dP/dt). Metabolic acidosis had bioenergetic changes suggestive of impaired energy production, specifically, increases in Pi and decreases in phosphocreatine concentrations, which did not occur in hearts subjected to low perfusate calcium concentrations. In acidotic perfusions as well as substrate depletion and impairment of oxidative metabolism, the change in dP/dt correlated best with the change in the intracellular concentration of monovalent Pi (P(im)) (r = 0.70, P less than 0.01), whereas in hearts subjected to a low perfusate calcium concentration, there was no relationship between dP/dt and the change in Pim concentrations. More detailed analysis of the time course of the metabolic and physiological changes with metabolic acidosis revealed a discordance between changes in Pim and the decreases in dP/dt during the first 20 min of the induction of acidosis and the first 10 min of recovery from acidosis. These data suggest that metabolic acidosis has a major direct effect on energy metabolism in this model. Moreover, impairment of oxidative metabolism in concert with decreases in intracellular pH may be important in the contractile failure associated with prolonged metabolic acidosis.

Acidosis↗
PubMed1992

[Autonomic dysfunction in metabolic diseases].

Among many metabolic disorders, porphyrias and Fabry disease are known to affect autonomic nervous system. In patients with acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, autonomic symptoms such as abdominal pain, vomiting, hypertension and tachycardia are among the most prominent clinical manifestations. Fabry disease is clinically characterized by severe limb pain, hypohidrosis, angiokeratomas and various autonomic symptoms. In both porphyrias and Fabry disease, pathological changes in the central and peripheral autonomic nervous system have been documented. In porphyrias, a loss of myelinated fibers, axonal degeneration, and segmental demyelination in peripheral autonomic nerves as well as chromatolysis of several brain stem nuclei have been found. In Fabry disease, abnormal amount of the substrates of alpha-galactosidase, i.e. ceramide di- and trihexoside, are found to be accumulated in the central and peripheral autonomic nerves.

Autonomic Nervous System Diseases↗
PubMed1997

Pathogenesis of cardiac dysfunction during metabolic acidosis: therapeutic implications.

Based on work performed in many laboratories including our own, we suggest the following schematic shown in Figure 4 to explain metabolic acidosis and the effects of alkalinization therapy. Metabolic acidosis induces prompt and substantial decreases in cardiac functional performance. This is mediated by an intracellular acidosis which impairs cardiac function directly as well as leads to an impairment of cardiac energy metabolism which further impairs cardiac function. Attempts to alkalinize the cell with sodium bicarbonate therapy lead to a paradoxical intracellular acidosis and further impairment of cardiac function, whereas Carbicarb may correct the intracellular acidosis and improve physiological function. However, at the time which this paper was written, Carbicarb was not available for clinical use in the United States.

Acidosis↗
PubMed1992

[Diabetic cardiopathy. Pathophysiologic concepts and therapeutic approaches].

Epidemiological data reviewed suggest that diabetes itself increases the cardiac risk of diabetics (types I and II), independently from the development of coronary heart disease and in addition to other risk factors (hypertension, hypercholesterolemia, hypertriglyceridemia, smoking and others), presumably by a specific myocardial disease called "diabetic cardiopathy", or according to the recommendations of the WHO, "diabetic heart muscle disease." Disturbances of the left and right ventricular function as well as the autonomic function of the heart can be understood as signs of this specific cardiopathy. The pathophysiological mechanisms underlying this disease are not yet fully known; however, recent evidence is presented that diabetes leads to a facet of metabolic dysfunctions regarding glucose and energy metabolism, calcium homeostasis and the expression of specific proteins that diminish the ability of the heart to respond to increased workload and increase the vulnerability of the heart in diabetes. Since preliminary experimental data indicate that inhibitors of the angiotensin-converting enzyme can protect the heart in diabetes, it is intriguing to suggest that increased release of angiotensin II plays a significant role in the change from reduced adaptability to irreversible damage of the heart in diabetes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Pathophysiology of shock.

Shock is an acute widespread reduction in effective tissue perfusion that invokes an imbalance of oxygen supply and demand, anaerobic metabolism, lactic acidosis, cellular and organ dysfunction, metabolic abnormalities, and, if prolonged, irreversible damage and death. The pathophysiologic events in the various types of shock are different and complex with hemodynamic and oxygenation changes, alterations in the composition of the fluid compartments, and various mediators. Shock results from a change in one or a combination of the following: intravascular volume, myocardial function, systemic vascular resistance, or distribution of blood flow. The clinical types of shock include hypovolemic, cardiogenic, distributive (septic), and obstructive. An understanding of the pathophysiologic changes, rapid diagnosis, appropriate monitoring, and appropriate therapy can reduce the high morbidity and mortality in shock states.

Humans↗
PubMedDate not supplied

The effects of ischemia and reperfusion on mucosal respiratory function, adenosine triphosphate, electrolyte, and water content in the ascending colon of ponies.

OBJECTIVE: The purpose of this study was to examine the effects of ischemia and reperfusion on the biochemical integrity of equine colonic mucosa to assess the relative roles of ischemic- and reperfusion-induced damage. STUDY DESIGN: Two hours of no-flow ischemia experimentally induced by 720 degrees counterclockwise ascending colon volvulus followed by 2 hours reperfusion after derotation. ANIMALS: Ten ponies. METHODS: Ascending colon biopsies were obtained every hour for measurement of mucosal adenosine triphosphate (ATP), water, sodium, and potassium content. Additional samples were homogenized for assay of mitochondrial respiratory function. RESULTS: ATP content diminished 92% after ischemia and recovered to only 44% of control levels (P < .001 versus controls) after 2 hours reperfusion. Reperfusion increased mucosal water and decreased sodium and potassium content for the duration of the experiment. Both NADH-(pyruvate) and FADH-linked (succinate) respiration decreased after ischemia and did not recover during reperfusion indicating electron transport chain dysfunction. CONCLUSIONS: Two hours ischemia induced severe metabolic dysfunction in equine colon mucosa which persisted throughout reperfusion. Unequivocal evidence of injury specific to reperfusion was not observed in this study suggesting that much of the damage observed during reperfusion may be a continuation of injury induced during the ischemic period and not specific to reperfusion per se. CLINICAL RELEVANCE: This study suggests that greater efforts to metabolically support ischemically injured mucosa may be an important aspect of obtaining improved survival of horses affected by ascending colon volvulus (ACV).

Adenosine Triphosphate↗
PubMed2024

Construction and Analysis of a Mitochondrial Metabolism-Related Prognostic Model for Breast Cancer to Evaluate Survival and Immunotherapy.

As one of the most prevalent malignancies among women, breast cancer (BC) is tightly linked to metabolic dysfunction. However, the correlation between mitochondrial metabolism-related genes (MMRGs) and BC remains unclear. The training and validation datasets for BC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. MMRG-related data were obtained from the Molecular Signatures Database. A risk score prognostic model incorporating MMRGs was established based on univariate, LASSO, and multivariate Cox regression analyses. Independent factors affecting BC prognosis were identified through regression analysis and presented in a nomogram. Single-sample gene set enrichment analysis was employed to assess the immune levels of high-risk (HR) and low-risk (LR) groups. The sensitivity of BC patients in the two groups to common anti-tumor drugs was evaluated by utilizing the Genomics of Drug Sensitivity in Cancer database. 12 MMRGs significantly associated with survival were selected from 1234 MMRGs. A 12-gene risk score prognostic model was built. In the multivariate regression analysis incorporating classical clinical factors, the MMRG-related risk score remained an independent prognostic factor. As revealed by tumor immune microenvironment analysis, the LR group with higher survival rates had elevated immune levels. The drug sensitivity results unmasked that the LR group demonstrated higher sensitivity to Irinotecan, Nilotinib, and Oxaliplatin, while the HR group demonstrated higher sensitivity to Lapatinib. The development of MMRG characteristics provides a comprehensive understanding of mitochondrial metabolism in BC, aiding in the prediction of prognosis and tumor microenvironment, and offering promising therapeutic choices for BC patients with different MMRG risk scores.

Humans↗
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&#x2009;&#xb1;&#x2009;9&#xa0;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&#x2009;=&#x2009;1.12, 95% CI 1.03 to 1.23 in women; OR&#x2009;=&#x2009;1.18, 95% CI 1.05 to 1.32 in men), while artery OAA was linked to HF only in women (OR&#x2009;=&#x2009;1.10, 95% CI 1.01 to 1.18). Multi-organ aging (&#x2265;&#x2009;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&#x2009;=&#x2009;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↗
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-&#x3b2; 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↗