Toxicity mechanism of acrolein on energy metabolism disorder and apoptosis in human ovarian granulosa cells.

Acrolein (ACR), an unsaturated, highly reactive aldehyde, is a widespread environmental toxin. ACR exerts permanent and irreversible side effects on ovarian functions. Granulosa cells play a crucial role in supporting ovarian function. Thus, in this study, we investigated the toxicity effects of granulosa cells induced by ACR. Following treatment with varying ACR concentrations (0, 12.5, 25, 50, and 100 µM), we observed that ACR exposure induced reactive oxygen species accumulation, mitochondrial energy metabolism disorder, and apoptosis in KGN cells (a human ovarian granulosa cell line) in a dose-dependent manner. In addition, mitochondrial biogenesis in KGN cells displayed biphasic changes after ACR exposure, with activation at a low ACR dose (12.5 µM), but inhibition at higher ACR doses (≥50 µM). SIRT1/PGC-1α-mediated mitochondrial biogenesis is crucial for maintaining intracellular mitochondrial homeostasis and cellular function. The inhibition/activation of the SIRT1/PGC-1α pathway in KGN cells validated its role in ACR-induced damage. The results indicated that the inhibition of the SIRT1/PGC-1α pathway aggravated ACR-induced cell damage, whereas its activation partially counteracted ACR-induced cell damage. This study attempted to uncover a novel mechanism of ACR-induced ovarian toxicity so as to provide an effective treatment option for safeguarding female reproductive health from the adverse effects of ACR.

Bioinformatics identifies key genes and potential drugs for energy metabolism disorders in heart failure with dilated cardiomyopathy.

Background: Dysfunction in myocardial energy metabolism plays a vital role in the pathological process of Dilated Cardiomyopathy (DCM). However, the precise mechanisms remain unclear. This study aims to investigate the key molecular mechanisms of energy metabolism and potential therapeutic agents in the progression of dilated cardiomyopathy with heart failure. Methods: Gene expression profiles and clinical data for patients with dilated cardiomyopathy complicated by heart failure, as well as healthy controls, were sourced from the Gene Expression Omnibus (GEO) database. Gene sets associated with energy metabolism were downloaded from the Molecular Signatures Database (MSigDB) for subsequent analysis. Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis were employed to identify key modules and genes related to heart failure. Potential biological mechanisms were investigated through Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the construction of a competing endogenous RNA (ceRNA) network. Molecular docking simulations were then conducted to explore the binding affinity and conformation of potential therapeutic drugs with hub genes. Results: Analysis of the left ventricular tissue expression profiles revealed that, compared to healthy controls, patients with dilated cardiomyopathy exhibited 234 differentially expressed genes and 2 genes related to myocardial energy metabolism. Additionally, Benzoylaconine may serve as a potential therapeutic agent for the treatment of dilated cardiomyopathy. Conclusion: The study findings highlight the crucial role of myocardial energy metabolism in the progression of Dilated Cardiomyopathy. Notably, Benzoylaconine emerges as a potential candidate for treating Dilated Cardiomyopathy, potentially exerting its therapeutic effects by targeted modulation of myocardial energy metabolism through NRK and NT5.

Mechanisms of Gills Response to Cadmium Exposure in Greenfin Horse-Faced Filefish (Thamnaconus septentrionalis): Oxidative Stress, Immune Response, and Energy Metabolism.

Cadmium (Cd) pollution has become a global issue due to industrial and agricultural developments. However, the molecular mechanism of Cd-induced detrimental effects and relevant signal transduction/metabolic networks are largely unknown in marine fishes. Here, greenfin horse-faced filefish (Thamnaconus septentrionalis) were exposed to 5.0 mg/L Cd up to 7 days. We applied both biochemical methods and multi-omics techniques to investigate how the gills respond to Cd exposure. Our findings revealed that Cd exposure caused the formation of reactive oxygen species (ROS), which in turn activated the MAPK and apoptotic pathways to alleviate oxidative stress and cell damage. Glycolysis, protein degradation, as well as fatty acid metabolism might assist to meet the requirements of nutrition and energy under Cd stress. We also found that long-term (7 days, "long-term" means compared to 12 and 48 h) Cd exposure caused the accumulation of succinate, which would in turn trigger an inflammatory response and start an immunological process. Moreover, ferroptosis might induce inflammation. Overall, Cd exposure caused oxidative stress, energy metabolism disturbance, and immune response in greenfin horse-faced filefish. Our conclusions can be used as references for safety risk assessment of Cd to marine economic fishes.

[Progress in clinical research on potential therapeutic drugs for acute-on-chronic liver failure].

Acute-on-chronic liver failure (ACLF), has a high mortality rate and a poor prognosis. Currently, the only effective treatment for ACLF is liver transplantation. However, the number of patients who can successfully undergo liver transplantation is limited due to the rapid progression of ACLF, the occurrence of serious complications, and a dearth of liver donors. The available drug treatment indication expansion and pathogenesis exploration are expected to delay the progression of ACLF, reduce complications, and provide patients with opportunities for liver transplantation by improving portal vein pressure, inhibiting excessive inflammatory response, correcting energy metabolism disorders, reducing oxidative stress, resisting hepatic cell apoptosis, and promoting liver regeneration.

PGC 1α-Mediates Mitochondrial Damage in the Liver by Inhibiting the Mitochondrial Respiratory Chain as a Non-cholinergic Mechanism of Repeated Low-Level Soman Exposure.

This work aimed to assess whether mitochondrial damage in the liver induced by subacute soman exposure is caused by peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and whether PGC-1α regulates mitochondrial respiratory chain damage. Toxicity mechanism research may provide theoretical support for developing anti-toxic drugs in the future. First, a soman animal model was established in male Sprague-Dawley (SD) rats by subcutaneous soman injection. Then, liver damage was biochemically evaluated, and acetylcholinesterase (AChE) activity was also determined. Transmission electron microscopy (TEM) was performed to examine liver mitochondrial damage, and high-resolution respirometry was carried out for assessing mitochondrial respiration function. In addition, complex I-IV levels were quantitatively evaluated in isolated liver mitochondria by enzyme-linked immunosorbent assay (ELISA). PGC-1α levels were detected with a Jess capillary-based immunoassay device. Finally, oxidative stress was analyzed by quantifying superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG), and reactive oxygen species (ROS) levels. Repeated low-level soman exposure did not alter AChE activity, while increasing morphological damage of liver mitochondria and liver enzyme levels in rat homogenates. Complex I, II and I + II activities were 2.33, 4.95, and 5.22 times lower after treatment compared with the control group, respectively. Among complexes I-IV, I-III decreased significantly (p < 0.05), and PGC-1α levels were 1.82 times lower after soman exposure than in the control group. Subacute soman exposure significantly increased mitochondrial ROS production, which may cause oxidate stress. These findings indicated dysregulated mitochondrial energy metabolism involves PGC-1α protein expression imbalance, revealing non-cholinergic mechanisms for soman toxicity.

Transcriptome analysis of emamectin benzoate caused midgut damage by inducing oxidative stress, energy metabolism disorder and apoptosis in gypsy moth (Lymantria dispar).

BACKGROUND: Emamectin benzoate (EMB) is a semisynthetic bioinsecticide, which has been widely used in the control of forestry and agricultural pests. However, the mechanism of its toxic effects on the non-neural tissues has been rarely reported. Here, we explored the mechanism of the midgut damage induced by EMB in gypsy moth (Lymantria dispar) in order to better understand the toxicological mechanism of EMB. RESULTS: Our results confirmed that EMB caused damage to the midgut of gypsy moth by inducing apoptosis. Transcriptome showed that 1469, 650 and 950 genes were significantly differentially expressed in the midgut of gypsy moth after 24, 48 and 72 h of EMB exposure, and oxidative stress, energy metabolism disorder and apoptosis may be related to the toxic effects of EMB. The indicators related to oxidative stress, energy metabolism and apoptosis were further examined. The results showed that EMB could cause oxidative stress by increasing ROS level and inhibiting antioxidant enzymes (P < 0.05), such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), which in turn causes mitochondria injury. Subsequently, energy metabolism was inhibited by downregulating the activities and mRNA level of energy metabolism enzymes. Furthermore, the mitochondrial apoptosis pathway was activated, triggering apoptosis, and eventually causing midgut injury in gypsy moth. CONCLUSION: Our results indicated that EMB caused damage to midgut by inducing oxidative stress, energy metabolism disorder and apoptosis in gypsy moth. Our findings shed new light on the toxicological mechanism of EMB on non-neural tissues from oxidative stress, energy metabolism and apoptosis perspectives. © 2022 Society of Chemical Industry.

Brain single-nucleus transcriptomics highlights that polystyrene nanoplastics potentially induce Parkinson's disease-like neurodegeneration by causing energy metabolism disorders in mice.

With the prevalence of nanoplastics in daily life, human exposure is inevitable. However, whether and how nanoplastics cause neurotoxicity in humans remains obscure. Herein, we conducted a 28-day repeated dose oral toxicity study in C57BL/6 J mice exposed to 0.25-250 mg/kg body weight (BW) polystyrene nanoplastics (PS-NPs, 50 nm). We revealed that PS-NP-caused Parkinson's disease (PD)-like neurodegeneration in mice by multiple approaches. Furthermore, a single-nucleus RNA sequencing of 62,843 brain nuclei unearthed PS-NP-induced cell-specific responses in the mouse brains. These disturbed responses among various brain cells were primarily linked with energy metabolism disorder and mitochondrial dysfunction in all brain cells, and especially in excitatory neurons, accompanied by inflammatory turbulence in astrocytes and microglia, dysfunction of proteostasis and synaptic-function regulation in astrocytes, oligodendrocytes, and endotheliocytes. These responses may synergize in PS-NP-motivated PD-like neurodegeneration pathogenesis. Moreover, we verified these single-nucleus transcriptomics findings on different brain regions and found that PS-NPs potentially caused PD-like neurodegeneration primarily by causing energy metabolism disorder in the substantia nigra pars compacta (SNc) and striatum. This manifested as decreases in adenosine triphosphate (ATP) content and expression levels of ATP-associated genes and proteins. Given nanoplastics' inevitable and growing exposure risks to humans, the neurological health risks of nanoplastic exposure warrant serious consideration.

Metformin alleviates the cognitive impairment caused by aluminum by improving energy metabolism disorders in mice.

Long-term exposure to environmental aluminum was found to be related to the occurrence and development of neurodegenerative diseases. Energy metabolism disorders, one of the pathological features of neurodegenerative diseases, may occur in the early stage of the disease and are of potential intervention significance. Here, sub-chronic aluminum exposure mouse model was established, and metformin was used to intervene. We found that sub-chronic aluminum exposure decreased the protein levels of phosphorylation AMPK (p-AMPK), glucose transporter 1 (GLUT1) and GLUT3, taking charge of glucose uptake in the brain, reduced the levels of lactate shuttle-related proteins monocarboxylate transporter 4 (MCT4) and MCT2, as well as lactate content in the cerebral cortex, while increased hypoxia-inducible factor-1α (HIF-1α) level to drive downstream pyruvate dehydrogenase kinase 1 (PDK1) expression, thereby inhibiting pyruvate dehydrogenase (PDH) activity, and ultimately led to ATP depletion, neuronal death, and cognitive dysfunction. However, metformin could rescue these injuries. Thus, it came to a conclusion that aluminum could damage glucose uptake, interfere with astrocyte-neuron lactate shuttle (ANLS), interrupt the balance in energy metabolism, and resulting in cognitive function, while metformin has a neuroprotective effect against the disorder of energy metabolism caused by aluminum in mice.

Protective mechanism of demethylase fat mass and obesity-associated protein in energy metabolism disorder of hypoxia-reoxygenation-induced cardiomyocytes.

NEW FINDINGS: What is the central question of this study? What is the effect of fat mass and obesity-associated protein (FTO) on energy metabolism in hypoxia-reoxygenation (H/R)-induced cardiomyocytes? What is the main finding and its importance? FTO modification of N6 -methyladenosine (m6 A) is associated with myocardial cell energy metabolism disorder. FTO reduced the m6 A level of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) mRNA through demethylation, thus promoting SERCA2a expression, maintaining calcium homeostasis, and improving energy metabolism of H/R cardiomyocytes. ABSTRACT: Energy metabolism disorder is the initial physiological link of myocardial ischaemia-reperfusion injury. Fat mass and obesity-associated protein (FTO) is an N6 -methyladenosine (m6 A) demethylase implicated in several cardiac defects. This study sought to investigate the effect of FTO on energy metabolism in hypoxia-reoxygenation (H/R)-induced cardiomyocytes. FTO and sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) expression in H/R-induced cardiomyocytes were determined. Cardiomyocyte viability, cytotoxicity and apoptosis were measured. The total RNA and polyA+ RNA contents were isolated from cells. The m6 A level of RNA and the enrichment of m6 A of SERCA2a mRNA were calculated. Several indices such as the glycolytic potential, reactive oxygen species (ROS), mitochondrial activity and ATP content were evaluated. The concentration of calcium in cardiomyocytes was determined. FTO and SERCA2a were poorly expressed in H/R-induced cardiomyocytes. There was an elevated m6 A level in total RNA and enrichment of m6 A in SERCA2a mRNA. H/R treatment reduced the cell viability, mitochondrial membrane potential and ATP content in cardiomyocytes, but increased the cytotoxicity, apoptosis, ROS content and calcium concentration. Upregulation of FTO reversed the preceding findings with downregulation of the m6 A level of SERCA2a mRNA. Downregulation of SERCA2a annulled the promoting effect of FTO on calcium homeostasis and energy metabolism in H/R-induced cardiomyocytes. Collectively, the current study demonstrated that FTO reduced the m6 A level on SERCA2a mRNA through demethylation, thus promoting SERCA2a expression, maintaining calcium homeostasis and improving the energy metabolism of H/R cardiomyocytes.

Function and Mechanism of Trimetazidine in Myocardial Infarction-Induced Myocardial Energy Metabolism Disorder Through the SIRT1-AMPK Pathway.

Myocardial energy metabolism (MEM) is an important factor of myocardial injury. Trimetazidine (TMZ) provides protection against myocardial ischemia/reperfusion injury. The current study set out to evaluate the effect and mechanism of TMZ on MEM disorder induced by myocardial infarction (MI). Firstly, a MI mouse model was established by coronary artery ligation, which was then treated with different concentrations of TMZ (5, 10, and 20 mg kg-1 day-1). The results suggested that TMZ reduced the heart/weight ratio in a concentration-dependent manner. TMZ also reduced the levels of Bax and cleaved caspase-3 and promoted Bcl-2 expression. In addition, TMZ augmented adenosine triphosphate (ATP) production and superoxide dismutase (SOD) activity induced by MI and decreased the levels of lipid peroxide (LPO), free fatty acids (FFA), and nitric oxide (NO) in a concentration-dependent manner (all P < 0.05). Furthermore, an H2O2-induced cell injury model was established and treated with different concentrations of TMZ (1, 5, and 10 µM). The results showed that SIRT1 overexpression promoted ATP production and reactive oxygen species (ROS) activity and reduced the levels of LPO, FFA, and NO in H9C2 cardiomyocytes treated with H2O2 and TMZ. Silencing SIRT1 suppressed ATP production and ROS activity and increased the levels of LPO, FFA, and NO (all P < 0.05). TMZ activated the SIRT1-AMPK pathway by increasing SIRT1 expression and AMPK phosphorylation. In conclusion, TMZ inhibited MI-induced myocardial apoptosis and MEM disorder by activating the SIRT1-AMPK pathway.

Ginkgolide B­induced AMPK pathway activation protects astrocytes by regulating endoplasmic reticulum stress, oxidative stress and energy metabolism induced by Aß1­42.

Ginkgolide B (GB), the diterpenoid lactone compound isolated from the extracts of Ginkgo biloba leaves, significantly improves cognitive impairment, but its potential pharmacological effect on astrocytes induced by ß­amyloid (Aß)1­42 remains to be elucidated. The present study aimed to investigate the protective effect and mechanism of GB on astrocytes with Aß1­42­induced apoptosis in Alzheimer's disease (AD). Astrocytes obtained from Sprague Dawley rats were randomly divided into control, Aß, GB and GB + compound C groups. Cell viability and apoptosis were analyzed using Cell Counting Kit­8 and flow cytometry assays, respectively. Protein and mRNA expression levels were analyzed using western blotting and reverse transcription­quantitative PCR, respectively. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH­Px), reactive oxygen species (ROS) and ATP were determined using the corresponding commercial kits. The findings revealed that GB attenuated Aß1­42­induced apoptosis and the 5' adenosine monophosphate­ activated protein kinase (AMPK) inhibitor compound C reversed the protective effects of GB. In addition, GB reversed Aß1­42­induced oxidative damage and energy metabolism disorders, including decreases in the levels of SOD, GSH­Px and ATP and increased the levels of MDA and ROS in astrocytes, while compound C reversed the anti­oxidative effect and the involvement of GB in maintaining energy metabolism in astrocytes. Finally, GB decreased the expression levels of the endoplasmic reticulum stress (ERS) proteins and the apoptotic protein CHOP and increased both mRNA and protein expression of the components of the energy metabolism­related AMPK/peroxisome proliferator­activated receptor γ coactivator 1α/peroxisome proliferator­activated receptor α and anti­oxidation­related nuclear respiratory factor 2/heme oxygenase 1/NAD(P)H dehydrogenase (quinone 1) pathways and downregulated the expression of ß­secretase 1. However, compound C could antagonize these effects. In conclusion, the findings demonstrated that GB protected against Aß1­42­induced apoptosis by inhibiting ERS, oxidative stress, energy metabolism disorders and Aß1­42 production probably by activating AMPK signaling pathways. The findings provided an innovative insight into the treatment using GB as a therapeutic in Aß1­42­related AD.

Serum hepatokines in dairy cows: periparturient variation and changes in energy-related metabolic disorders.

BACKGROUND: During peripartum period, dairy cows are highly susceptible to energy metabolism disorders such as fatty liver and ketosis. Angiopoietin-like protein 4 (ANGPTL4) and fibroblast growth factor 21 (FGF21), known as hepatokines, play important roles in lipid metabolism. The purposes of our study were to evaluate variations of serum ANGPTL4 and FGF21 concentrations in periparturient dairy cows and changes in these serum analyte concentrations of energy-related metabolic disorders in early lactation dairy cows. This study was divided into two experiments. Experiment I: Blood parameters were measured in healthy periparturient Holstein cows from 4 wk antepartum to 4 wk postpartum (n = 219). In this experiment, weekly blood samples were obtained from 4 wk before the expected calving date through 4 wk after calving. Experiment II: Blood parameters were measured in healthy cows (n = 30) and cows with clinical ketosis (n = 29) and fatty liver (n = 25) within the first 4 wk of lactation. In the present study, all blood samples were collected from the coccygeal vein in the early morning before feeding. RESULTS: Serum ANGPTL4 and FGF21 concentrations peaked at parturition, and declined rapidly over the following 2 wk Serum ANGPTL4 and FGF21 concentrations were positively correlated with serum non-esterified fatty acids (NEFA) concentration (r = 0.856, P = 003; r = 0.848, P = 0.004, respectively). Cows with clinical ketosis and fatty liver had significantly higher serum ANGPTL4 and FGF21 concentrations than healthy cows (P < 0.01). CONCLUSION: Serum ANGPTL4 and FGF21 concentrations were elevated during peripartum period, suggesting that energy balance changes that were associated with parturition contributed significantly to these effects. Although FGF21 and ANGPTL4 could play important roles in the adaptation of energy metabolism, they may be involved in the pathological processes of energy metabolism disorders of dairy cows in the peripartum period.

Psoralen Induces Developmental Toxicity in Zebrafish Embryos/Larvae Through Oxidative Stress, Apoptosis, and Energy Metabolism Disorder.

Psoralen toxicity is an issue of wide concern. However, an assay for psoralen-induced developmental toxicity has not been reported to date. Moreover, the underlying mechanism of psoralen-induced developmental toxicity is unclear. Therefore, this study attempted to develop a psoralen-induced developmental toxicity assay in zebrafish embryos/larvae. Psoralen treatment caused a decrease in the hatching rate and body length and a significant increase in the malformation rate of zebrafish. Yolk retention, pericardial edema, swim-bladder deficiency, and curved body shape were also observed after psoralen treatment. Yolk retention might have been caused by an abnormality in lipid metabolism. Further experiments indicated that psoralen exerted toxic effects on the developing heart, liver, phagocytes, and nervous system. Increased generation of reactive oxygen species, inhibition of total superoxide dismutase activity, and increased malondialdehyde concentrations indicated inhibition of antioxidant capacity and the presence of oxidative stress. A greater number of apoptotic cells were observed after psoralen exposure, relative to the control. Furthermore, the results of gene-expression analysis showed that psoralen induced developmental toxicity by means of oxidative stress, apoptosis, and energy metabolism abnormalities. These findings will be helpful in understanding psoralen-induced toxicity.

Involvement of mitochondrial pathway in environmental metal pollutant lead-induced apoptosis of chicken liver: perspectives from oxidative stress and energy metabolism.

This study aimed to investigate the possible mechanisms of environmental metal pollutant lead (Pb)-induced apoptosis in chicken. Forty 8-day-old healthy chickens were randomly assigned to two groups (n = 20/group) after raising standard commercial diet and drinking water for 1 week: including control group and Pb group ((CH3COO)2Pb 350 mg/L of drinking water); the chickens were given euthanasia and collected livers at 90 days. A significant increase of apoptosis rate were found in Pb group and Pb induced obvious ultrastructural changes of chicken liver. The mRNA levels of glycometabolism key enzymes were significantly lower in Pb group than those in controls. Higher levels of malondialdehyde (MDA) and nitric oxide (NO) were observed in Pb group; the activities of antioxidant enzymes and ATPases were significantly lower in Pb group than those in controls, while the inducible nitric oxide synthase (iNOS) activity was on the contrary. The mRNA and protein levels of pro-apoptotic genes were all lower in Pb group than those in controls. Altogether, Pb-induced mitochondrial swelling and nuclear chromatin condensation, oxidative stress, energy metabolism disorder, thereby lead to apoptosis via mitochondrial pathway in chicken liver, suggesting that Pb-induced mitochondrial pathway apoptosis plays an important role in the mechanisms of Pb cytotoxicity to chicken liver.