The Role of Human Adiponectin Receptor 1 in 2-Ethylhexyl Diphenyl Phosphate Induced Lipid Metabolic Disruption.

Epidemiological evidence links exposure to 2-ethylhexyl diphenyl phosphate (EHDPP) with lipid metabolic disruption, typically attributed to nuclear receptors, while the role of membrane receptors remains underexplored. This study explored the role of adiponectin receptor 1 (AdipoR1) in EHDPP-induced lipid metabolic disturbances. We examined EHDPP's binding affinity and transcriptional impact on AdipoR1. AdipoR1 knockdown (AdipoR1kd) human liver cells and coculture experiments with AdipoR1 activator (AdipoRon) were used to investigate the effect and the mechanism. EHDPP disrupted triglyceride and phospholipid synthesis and altered corresponding gene expression, mirroring effects in AdipoR1kd cells but diminishing in EHDPP-treated AdipoR1kd cells. RNA sequencing revealed that EHDPP primarily disrupted oxidative phosphorylation and insulin signaling dependent on AdipoR1. Mechanistically, EHDPP interacted with AdipoR1 and reduced AdipoR1 protein levels at 10-7 mol/L or higher, weakening the activation of the calmodulin dependent protein kinase ß (CaMKKß)/AMPK/acetyl CoA carboxylase pathway. Furthermore, EHDPP pretreatment blocked the increase in Ca2+ flux and the corresponding kinase CaMKKß, as well as liver kinase B1 (LKB1) activation induced by AdipoRon, which is necessary for AMPK activation. Collectively, these findings demonstrate that EHDPP-induced lipid imbalance is partially dependent on AdipoR1, expanding the understanding of environmental metabolic disruptors beyond nuclear receptors.

Perinatal exposure to PBEB aggravates liver injury via macrophage-derived TWEAK in male adult offspring mice under western diet.

Liver injury and inflammation are the most commonly observed adverse outcomes following exposure to penta-brominated flame retardants (penta-BFRs). However, the role of inflammation in the development of liver injury in their alternatives has not yet been explored. Our study aimed to investigate the effects and the underlying mechanism of perinatal exposure to pentabromoethylbenzene (PBEB), a penta-BDE alternative, on liver injury in adult offspring mice under both chow and western diet in later life. Results showed that perinatal exposure to PBEB at 0.2 mg/kg or above led to liver injury in male offspring upon challenge with a western diet, but not in females. Utilizing the Olink immunology panel, our study specifically revealed an upregulation of tumor necrosis factor-related weak inducer of apoptosis (TWEAK) within the livers of male mice. This cytokine was further demonstrated to derive from the secretion by infiltrating macrophages in livers both in vivo and in vitro, which facilitated a shift towards M1 macrophage polarization. TWEAK further activated the hepatic NF-κB and NLRP3 inflammasome pathways, subsequently leading to hepatic pyroptosis in male mice of maternal PBEB exposure. Inhibition of TWEAK signaling mitigated macrophage polarization and inflammasome induction in a co-culture system of macrophages and liver cells. Our findings revealed that perinatal exposure to PBEB precipitated liver injury, partially through an inflammatory pathway mediated by macrophage-derived TWEAK, in male mice offspring under western diet.

Calenduloside E Ameliorates Inflammatory Responses in Adipose Tissue via Sirtuin 2-NLRP3 Inflammasome Axis.

Obesity-related metabolic diseases are associated with a chronic inflammatory state. Calenduloside E (CE) is a triterpene saponin from sugar beet. In mouse models, CE reduced pro-inflammatory cytokines in white adipose tissue (WAT) and decreased macrophage infiltration of WAT. And CE inhibited pyroptosis in J774A.1 cells and WAT by inhibiting the activation of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome. Moreover, CE could trigger the activation of Sirtuin 2 (SIRT2), leading to a decrease in the acetylation of NLRP3, particularly at the K24 site. In addition, it has been shown that CE can reduce inflammation in adipocytes that have been induced by macrophage-conditioned medium. However, the selective SIRT2 inhibitor AGK2 hindered the beneficial effects of CE. In summary, CE has the capacity to impede NLRP3-mediated pyroptosis by triggering SIRT2 activity, thus positioning CE as a promising therapeutic avenue for combating obesity-related metabolic disorders.

Geniposide dosage and administration time: Balancing therapeutic benefits and adverse reactions in liver disease treatment.

Gardenia jasminoides Ellis, a staple in herbal medicine, has long been esteemed for its purported hepatoprotective properties. Its primary bioactive constituent, geniposide, has attracted considerable scientific interest owing to its multifaceted therapeutic benefits across various health conditions. However, recent investigations have unveiled potential adverse effects associated with its metabolite, genipin, particularly at higher doses and prolonged durations of administration, leading to hepatic injury. Determining the optimal dosage and duration of geniposide administration while elucidating its pharmacological and toxicological mechanisms is imperative for safe and effective clinical application. This study aimed to evaluate the safe dosage and administration duration of geniposide in mice and investigate its toxicological mechanisms within a comprehensive dosage-duration-efficacy/toxicity model. Four distinct mouse models were employed, including wild-type mice, cholestasis-induced mice, globally farnesoid X-activated receptor (FXR) knock out mice, and high-fat diet-induced (HFD) NAFLD mice. Various administration protocols, spanning one or four weeks and comprising two or three oral doses, were tailored to each model's requirements. Geniposide has positive effects on bile acid and lipid metabolism at doses below 220 mg/kg/day without causing liver injury in normal mice. However, in mice with NAFLD, this dosage is less effective in improving liver function, lipid profiles, and bile acid metabolism compared to lower doses. In cholestasis-induced mice, prolonged use of geniposide at 220 mg/kg/day worsened liver damage. Additionally, in NAFLD mice, this dosage of geniposide for four weeks led to intestinal pyroptosis and liver inflammation. These results highlight the lipid-lowering and bile acid regulatory effects of geniposide, but also warn of potential negative impacts on intestinal epithelial cells, particularly with higher doses and longer treatment durations. Therefore, achieving optimal therapeutic results requires a decrease in treatment duration as the dosage increases, in order to maintain a balanced approach to the use of geniposide in clinical settings.

Salvianolic acid A attenuates non-alcoholic fatty liver disease by regulating the AMPK-IGFBP1 pathway.

Non-alcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population and, to date, there is no approved drug therapy for this condition. Individuals with type 2 diabetes mellitus (T2DM) are at a significantly elevated risk of developing NAFLD, underscoring the urgency of identifying effective NAFLD treatments for T2DM patients. Salvianolic acid A (SAA) is a naturally occurring phenolic acid that is an important component of the water-soluble constituents isolated from the roots of Salvia miltiorrhiza Bunge. SAA has been demonstrated to possess anti-inflammatory and antioxidant stress properties. Nevertheless, its potential in ameliorating diabetes-associated NAFLD has not yet been fully elucidated. In this study, diabetic ApoE-/- mice were employed to establish a NAFLD model via a Western diet. Following this, they were treated with different doses of SAA (10 mg/kg, 20 mg/kg) via gavage. The study demonstrated a marked improvement in liver injury, lipid accumulation, inflammation, and the pro-fibrotic phenotype after the administration of SAA. Additionally, RNA-seq analysis indicated that the primary pathway by which SAA alleviates diabetes-induced NAFLD involves the cascade pathways of lipid metabolism. Furthermore, SAA was found to be effective in the inhibition of lipid accumulation, mitochondrial dysfunction and ferroptosis. A functional enrichment analysis of RNA-seq data revealed that SAA treatment modulates the AMPK pathway and IGFBP-1. Further experimental results demonstrated that SAA is capable of inhibiting lipid accumulation through the activation of the AMPK pathway and IGFBP-1.

Astragaloside IV ameliorates cisplatin-induced liver injury by modulating ferroptosis-dependent pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of antineoplastic drugs, such as cisplatin, in clinical practice can cause adverse effects in patients, such as liver injury, which limits their long-term use. Therefore, there is an urgent need to develop alternative therapeutic strategies or drugs to minimize cisplatin-induced liver injury. Huangqi, the root of Astragalus membranaceus, is extensively used in traditional Chinese medicine (TCM) and has been employed in treating diverse liver injuries. Astragalus membranaceus contains several bioactive constituents, including triterpenoid saponins, one of which, astragaloside IV (ASIV), has been reported to have anti-inflammatory and antioxidant stress properties. However, its potential in ameliorating cisplatin-induced liver injury has not been explored. AIM OF THE STUDY: The objective of this study was to examine the mechanism by which ASIV protects against cisplatin-induced liver injury. MATERIALS AND METHODS: This study established a model of cisplatin-induced liver injury in mice, followed by treatment with various doses of astragaloside IV (40 mg/kg, 80 mg/kg). In addition, a model of hepatocyte ferroptosis in AML-12 cells was established using RSL3. The mechanism of action of astragaloside IV was investigated using a range of methods, including Western blot assay, qPCR, immunofluorescence, histochemistry, molecular docking, and high-content imaging system. RESULTS: The findings suggested a significant improvement in hepatic injury, inflammation and oxidative stress phenotypes with the administration of ASIV. Furthermore, network pharmacological analyses provided evidence that a major pathway for ASIV to attenuate cisplatin-induced hepatic injury entailed the cell death cascade pathway. It was observed that ASIV effectively inhibited ferroptosis both in vivo and in vitro. Subsequent experimental outcomes provided further validation of ASIV's ability to hinder ferroptosis through the inhibition of PPARα/FSP1 signaling pathway. The current findings suggest that ASIV could function as a promising phytotherapy composition to alleviate cisplatin-induced liver injury. CONCLUSIONS: The current findings suggest that astragaloside IV could function as a promising phytotherapy composition to alleviate cisplatin-induced liver injury.

Xie Zhuo Tiao Zhi formula modulates intestinal microbiota and liver purine metabolism to suppress hepatic steatosis and pyroptosis in NAFLD therapy.

BACKGROUND: Current evidence indicates a rising global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), which is closely associated to conditions such as obesity, dyslipidemia, insulin resistance, and metabolic syndrome. The relationship between the gut microbiome and metabolites in NAFLD is gaining attention understanding the pathogenesis and progression of dysregulated lipid metabolism and inflammation. The Xie Zhuo Tiao Zhi (XZTZ) decoction has been employed in clinical practice for alleviating hyperlipidemia and symptoms related to metabolic disorders. However, the pharmacological mechanisms underlying the effects of XZTZ remain to be elucidated. PURPOSE: The objective of this study was to examine the pharmacological mechanisms underlying the hypolipidemic and anti-inflammatory effects of XZTZ decoction in a mouse model of NAFLD, as well as the effects of supplementing exogenous metabolites on PO induced cell damage and lipid accumulation in cultured hepatocytes. METHODS: A high-fat diet (HFD) mouse model was established to examine the effects of XZTZ through oral gavage. The general condition of mice and the protective effect of XZTZ on liver injury were evaluated using histological and biochemical methods. Hematoxylin and eosin staining (H&E) staining and oil red O staining were performed to assess inflammatory and lipid accumulation detection, and cytokine levels were quantitatively analyzed. Additionally, the study included full-length 16S rRNA sequencing, liver transcriptome analysis, and non-targeted metabolomics analysis to investigate the relationship among intestinal microbiome, liver metabolic function, and XZTZ decoction. RESULTS: XZTZ had a significant impact on the microbial community structure in NAFLD mice. Notably, the abundance of Ileibacterium valens, which was significantly enriched by XZTZ, exhibited a negative correlation with liver injury biomarkers such as, alanine transaminase (ALT) and aspartate transaminase (AST) activity. Moreover, treatment with XZTZ led to a significant enrichment of the purine metabolism pathway in liver tissue metabolites, with inosine, a purine metabolite, showing a significant positive correlation with the abundance of I. valens. XZTZ and inosine also significantly enhanced fatty acid ß-oxidation, which led to a reduction in the expression of pro-inflammatory cytokines and the inhibition of liver pyroptosis. These effects contributed to the mitigation of liver injury and hepatocyte damage, both in vivo and vitro. Furthermore, the utilization of HPLC fingerprints and UPLC-Q-TOF-MS elucidated the principal constituents within the XZTZ decoction, including naringin, neohesperidin, atractylenolide III, 23-o-Acetylalisol B, pachymic acid, and ursolic acid which are likely responsible for its therapeutic efficacy. Further investigations are imperative to fully uncover and validate the pharmacodynamic mechanisms underlying these observations. CONCLUSION: The administration of XZTZ decoction demonstrates a protective effect on the livers of NAFLD mice by inhibiting lipid accumulation and reducing hepatocyte inflammatory damage. This protective effect is mediated by the upregulation of I.valens abundance in the intestine, highlighting the importance of the gut-liver axis. Furthermore, the presesnce of inosine, adenosine, and their derivatives are important in promoting the protective effects of XZTZ. Furthermore, the in vitro approaching, we provide hitherto undocumented evidence indicating that the inosine significantly improves lipid accumulation, inflammatory damage, and pyroptosis in AML12 cells incubated with free fatty acids.

The mechanism underlying pentabromoethylbenzene-induced adipogenesis and the obesogenic outcome in both cell and mouse model.

Convergent evidence links traditional brominated flame retardants (BFRs) exposure to weight gain, while the obesogenic potency of new BFRs (NBFRs) remain largely unknown. Aiding by luciferase-reporter gene assay, the present study revealed only pentabromoethylbenzene (PBEB), an alternative for penta-BDEs, binds with retinoid X receptor α (RXRα) but not peroxisomeproliferator receptor γ (PPARγ) among the seven testing NBFRs. An apparent induction of adipogenesis in 3T3-L1 cells was observed at nanomolar of PBEB, much lower than penta-BFRs. Mechanistic research uncovered PBEB initiated the adipogenesis by demethylated CpG sites in the PPARγ promoter region. Specifically, activation RXRα by PBEB strengthened the activity of RXRα/PPARγ heterodimer, tightened the interaction between the heterodimer and PPAR response elements, and further enhanced adipogenesis. RNA sequencing combined with k-means clustering analysis exposed adenosine 5'-monophosphate (AMP)-activated protein kinase and phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling as two predominant pathways that enriched in PBEB-induced lipogenesis. The obesogenic outcome was further corroborated in offspring mice when the maternal mice exposed to environmental relevant doses of PBEB. We found the male offspring exhibited adipocyte hypertrophy and increased weight gain in the epididymal white adipose tissue (eWAT). Consistent with in vitro findings, the reduction in protein phosphorylation of both AMPK and PI3K/AKT were observed within eWAT. Thus, we posited PBEB disrupts the pathways controlling adipogenesis and adipose tissue maintenance, supporting its potential as an environmental obesogen.

Widespread missing super-emitters of nitrogen oxides across China inferred from year-round satellite observations.

Nitrogen oxides (NOx ≡ NO + NO2) play a central role in air pollution and are targeted for emission mitigation by environmental protection agencies globally. Unique challenges for mitigation are presented by super-emitters, typically with the potential to dominate localized NOx budgets. Nevertheless, identifying super-emitters still challenges emission mitigation, while the spatial resolution of emission monitoring rises continuously. Here we develop an efficient, super-resolution (1 × 1 km2) inverse model based on year-round TROPOMI satellite observations over China. Consequently, we resolve hundreds of super-emitters in virtually every corner of China, even in remote and mountainous areas. They are attributed to individual plants or parks, mostly associated with industrial sectors, like energy, petrochemical, and iron and steel industries. State-of-the-art bottom-up emission estimates (i.e., MEICv1.3 and HTAPv2), as well as classic top-down inverse methods (e.g., a CTM coupled with the Ensemble Kalman Filter), do not adequately identify these super-emitters. Remarkably, more than one hundred super-emitters are unambiguously missed, while the establishments or discontinuations of the super-emitters potentially lead to under- or over-estimates, respectively. Moreover, evidence shows that these super-emitters generally dominate the NOx budget in a localized area (e.g., equivalent to a spatial scale of a medium-sized county). Although our dataset is incomplete nationwide due to the undetectable super-emitters on top of high pollution, our results imply that super-emitters contribute significantly to national NOx budgets and thus suggest the necessity to address the NOx budget by revisiting super-emitters on a large scale. Integrating the results we obtain here with a multi-tiered observation system can lead to identification and mitigation of anomalous NOx emissions.

Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells.

Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9) were designed and synthesized. The target product (compound 9) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 µM of compound 9 reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound 9 supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy.

Salvianolic acid A regulates pyroptosis of endothelial cells via directly targeting PKM2 and ameliorates diabetic atherosclerosis.

Rescuing endothelial cells from pyroptotic cell death emerges as a potential therapeutic strategy to combat diabetic atherosclerosis. Salvianolic acid A (SAA) is a major water-soluble phenolic acid in the Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine (TCM) and health food products for a long time. This study investigated whether SAA-regulated pyruvate kinase M2 (PKM2) functions to protect endothelial cells. In streptozotocin (STZ)-induced diabetic ApoE-/- mice subjected to a Western diet, SAA attenuated atherosclerotic plaque formation and inhibited pathological changes in the aorta. In addition, SAA significantly prevented NLRP3 inflammasome activation and pyroptosis of endothelial cells in the diabetic atherosclerotic aortic sinus or those exposed to high glucose. Mechanistically, PKM2 was verified to be the main target of SAA. We further revealed that SAA directly interacts with PKM2 at its activator pocket, inhibits phosphorylation of Y105, and hinders the nuclear translocation of PKM2. Also, SAA consistently decreased high glucose-induced overproduction of lactate and partially lactate-dependent phosphorylation of PKR (a regulator of the NLRP3 inflammasome). Further assay on Phenylalanine (PKM2 activity inhibitor) proved that SAA exhibits the function in high glucose-induced pyroptosis of endothelial cells dependently on PKM2 regulation. Furthermore, an assay on c16 (inhibitor of PKR activity) with co-phenylalanine demonstrated that the regulation of the phosphorylated PKR partially drives PKM2-dependent SAA modulation of cell pyroptosis. Therefore, this article reports on the novel function of SAA in the pyroptosis of endothelial cells and diabetic atherosclerosis, which provides important insights into immunometabolism reprogramming that is important for diabetic cardiovascular disease complications therapy.

Iron-Sulfur Clusters: A Key Factor of Regulated Cell Death in Cancer.

Iron-sulfur clusters are ancient cofactors that play crucial roles in myriad cellular functions. Recent studies have shown that iron-sulfur clusters are closely related to the mechanisms of multiple cell death modalities. In addition, numerous previous studies have demonstrated that iron-sulfur clusters play an important role in the development and treatment of cancer. This review first summarizes the close association of iron-sulfur clusters with cell death modalities such as ferroptosis, cuprotosis, PANoptosis, and apoptosis and their potential role in cancer activation and drug resistance. This review hopes to generate new cancer therapy ideas and overcome drug resistance by modulating iron-sulfur clusters.

Sex-dependent effect of triphenyl phosphate on hepatic energy metabolism at the intersection of diet pattern in pubertal mice.

Triphenyl phosphate (TPhP) is mostly residual in fat-rich foodstuff and ingestion is the main route for adolescents' exposure. As a typical metabolic disruptor, however, sex-specific effect of TPhP-high fat diet (HFD) co-exposure in adolescent remains unknown. This study revealed that HFD exacerbated systematic inflammation and insulin insensitivity in female mice at pubertal stage after exposure to 25 mg/kg TPhP or above. Notably, the pattern of sexual selective metabolic disruption caused by TPhP was irrespective of diet after examined mice both in HFD and normal diet feeding. Female mice favored the energy storage in forms of D-glucose 6-phosphate, D-fructose 6-phosphate and triglyceride. That was further supported by mRNA levels of key enzymes in glycolysis, gluconeogenesis, and lipid metabolism. Contrastingly, the elevation of the corresponding genes ensuing by the depleted metabolites were observed in males. In mechanistic investigation, we observed a declination of serum estrogen, a master of energy homeostasis, in both sexes, irrespective of diet. However, only male mice displayed estrogen-hypothalamus negative feedback, supporting by the upregulation of gonadotropin-releasing hormone. Rather than the well-recognized estrogen receptor α, hepatic G protein-coupled estrogen receptor manifested sexual dichotomy, which desensitized to estrogenic response only in females. Collectively, this study posited that females were more susceptible to store energy under TPhP-HFD than males during pubertal partially through estrogenic pathway.

Remodeling on adipocytic physiology of organophosphorus esters in mature adipocytes.

The emerging endocrine disruption chemicals organophosphate esters (OPEs) pose high risk of metabolic disruption. However, limited information is available on physiological disturbance of OPEs on adipose, a major endocrine and metabolic organ. In this study, physiological change was investigated after exposing 3T3-L1fully differentiated adipocytes to six OPEs at non-cytotoxic concentrations. We found two chlorinated-OPEs (tris-(2-chloro-1-(chloromethyl) ethyl) phosphate (TDCPP) and tris(2-chloroisopropyl) phosphate (TCPP)) and two alkyl-OPEs (tributyl phosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP)) induced inflammation-like adipokines (chemoattractant protein 1 and interleukin-6), respectively. Increment of insulin-resistance-related hormones (resistin and leptin) were observed under TDCPP, TCPP, and TBP exposure. Functional and mechanistic investigation revealed that all of the compounds inhibited lipolysis at basal level through dephosphorylated HSLser563, the rate limiting enzyme of lipolysis. Triphenyl phosphate (TPhP), tricresyl phosphate (TCP), TDCPP, TBP and TBEP enhanced glucose uptake at both basal and insulin-stimulated status. We evidenced that impact was independent of the classical pIRSser639/pAKTser473 nor the insulin-independent AMPK pathway. The elevated mRNA of slc2a4 and its transcriptional factor LXRα may, at least partially, explain for the increase of glucose uptake. Given the focus within the endocrine disruption on glands, it would be prudent not to ignore endocrinal impact on adipocytes.

Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway.

BACKGROUND: Doxorubicin-induced cardiotoxicity (DIC) limits the clinical application of the drug in treatment of cancers and imposes a severe health burden on the patients. Therefore, there is an urgent need to develop alternative therapeutic strategies or drugs to minimize DIC. Salidroside is a phenylpropanoid glycoside extracted from Rhodiola rosea with multiple biological effects such as anti-inflammation and antioxidant properties. However, its mechanism of action in DIC is still poorly understood. PURPOSE: The present study was aimed to investigate the role of salidroside in DIC and associated mechanism of action for the described effects. METHODS: Cardiac dysfunction was induced through treatment of mice with doxorubicin in vivo and in vitro. The mechanism of action of salidroside was investigated using western blot assay, qPCR, immunofluorescence, histochemistry, echocardiography, and high-content imaging system. RESULTS: Results of the current study found that treatment of mice with salidroside significantly improved doxorubicin-induced cardiac dysfunction, ferroptosis-like cell damage, and fibrosis in vivo. Further, it was noted that salidroside inhibited ferroptosis in vivo and in vitro by limiting iron accumulation, restoring GPX4-dependent antioxidant capacity, and preventing lipid peroxidation at the cellular or mitochondrial levels. Mechanistically, salidroside inhibited DOX-induced mitochondrial ROS, Fe2+, and lipid peroxidation as well as restored mitochondrial membrane potential by promoting mitochondrial biogenesis, improving mitochondrial iron-sulfur clusters, and restoring mitochondrial OXPHOS complexes, thereby improving mitochondrial function. In addition, AMPK is a key protein that coordinates mitochondria, metabolism, and ferroptosis. Therefore, it was found that compound C (CC), an AMPK inhibitor, disrupted the regulation of cellular lipid metabolism and mitochondrial function of salidroside as well as led to failure of the protective effect of salidroside against ferroptotic cell death. CONCLUSIONS: The present study evidently demonstrated the cardioprotective effects of salidroside against doxorubicin-induced cardiomyopathy. Further, salidroside markedly down-regulated ferroptotic cell death by activating AMPK-dependent signaling pathways including regulating abnormal fatty acid metabolism and maintaining mitochondrial function. Therefore, salidroside is can be exploited to develop a novel medication for clinical DIC and salidroside may represent a novel treatment that improves recovery from DIC by targeting ferroptosis.

Role of PKM2-Mediated Immunometabolic Reprogramming on Development of Cytokine Storm.

The cytokine storm is a marker of severity of various diseases and increased mortality. The altered metabolic profile and energy generation of immune cells affects their activation, exacerbating the cytokine storm. Currently, the emerging field of immunometabolism has highlighted the importance of specific metabolic pathways in immune regulation. The glycolytic enzyme pyruvate kinase M2 (PKM2) is a key regulator of immunometabolism and bridges metabolic and inflammatory dysfunction. This enzyme changes its conformation thus walks in different fields including metabolism and inflammation and associates with various transcription factors. This review summarizes the vital role of PKM2 in mediating immunometabolic reprogramming and its role in inducing cytokine storm, with a focus on providing references for further understanding of its pathological functions and for proposing new targets for the treatment of related diseases.

Multiplexed quantitative evaluation on mitochondrial toxicity of tris (2,3-dibromopropyl) phosphate in hepatocyte.

The frequent detection of (2,3-dibromopropyl) phosphate (TDBPP) in environment has led to a consistent risk to organisms. However, little is known about the toxicity of TDBPP exclusive for its carcinogen. Mitochondrion that tightly relates to adverse outcomes once deteriorated is referred as a target of environmental pollutants. Here, we investigated the role of mitochondrial abnormality in development of cellular pathobiology especially lipid deposition when response to TDBPP in mitochondria-rich hepatocyte (AML12) at the same order of magnitude as the environmental concentrations (10-6 mol/L or below) via multiplexed quantitative high content analytic system. The present study claimed TDBPP shifted mitochondria from fusion morphology to fission phenotype charactering by less mitochondrial networks, larger mitochondrial areas and shorter branch length at 10-7 mol/L or above. This dynamic imbalance was triggered by high levels of fis and drp1 genes when treated with TDBPP. The deformation caused by TDBPP reciprocally influenced biogenesis through PGC1α and electron transport chains via ectopic expression of genes encoding for mitochondria complex I and III subunits. Accordingly, we observed high mitoROS level and low mitochondria membrane potential. Consequently, cells contained those abnormal mitochondria were predisposed to accumulating lipids after exposure to TDBPP. Here we showed that TDBPP deteriorated mitochondrial morphology and function, which may induce lipid generation. As for a banned while still emerged contaminant, our study also claimed further exploration on the non-carcinogenic toxicity of TDBPP.

Cynaroside prevents macrophage polarization into pro-inflammatory phenotype and alleviates cecal ligation and puncture-induced liver injury by targeting PKM2/HIF-1α axis.

The treatment of sepsis is still challenging and the liver is an important target of sepsis-related injury. Macrophages are important innate immune cells in liver, and modulation of macrophages M1/M2 polarization may be a promising strategy for septic liver injury treatment. Macrophage polarization and inflammation of liver tissue has been shown regulated by pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis and immune inflammatory pathways. Therefore, modulating PKM2-mediated immunometabolic reprogramming presents a novel strategy for inflammation-associated diseases. In this study, cynaroside, a flavonoid compound, promoted macrophage phenotypic transition from pro-inflammatory M1 to anti-inflammatory M2, and mitigated sepsis-associated liver inflammatory damage. We established that cynaroside reduced binding of PKM2 to hypoxia-inducible factor-1α (HIF-1α) by abolishing translocation of PKM2 to the nucleus and promoting PKM2 tetramer formation, as well as suppressing phosphorylation of PKM2 at Y105 in vivo and in vitro. Moreover, cynaroside restored pyruvate kinase activity, inhibited glycolysis-related proteins including PFKFB3, HK2 and HIF-1α, and inhibited glycolysis-related hyperacetylation of HMGB1 in septic liver. Therefore, this study reports a novel function of cynaroside in hepatic macrophage polarization, and cecum ligation and puncture-induced liver injury in septic mice. The findings provide crucial information with regard to therapeutic efficacy of cynaroside in the treatment of sepsis.

Comprehensive analysis of organophosphorus flame retardant-induced mitochondrial abnormalities: Potential role in lipid accumulation.

Organophosphorus flame retardants (OPFRs), a group of new emerging endocrine disruption chemicals, have been reported to cause metabolic disturbance. Currently, mitochondrial abnormality is a new paradigm for evaluating chemical-mediated metabolic disruption. However, a comprehensive correlation between these two aspects of OPFR remains elusive. In the work reported here, 3 markers for morphological abnormality, and 7 markers of mitochondrial dysfunction were detected after treatment with two aryl-OPFRs (TCP and TPhP) and three chlorinated-OPFRs (TDCPP, TCPP, and TCEP) on hepatocyte. The two aryl-OPFRs and TDCPP can cause intracellular lipid accumulation at non-cytotoxic concentrations (<10 µM), while the other two chlorinated-OPFRs only caused lipid deposition at 10 µM. Furthermore, at the tested concentrations, all of them reduced mitochondrial (mito)-network numbers, enlarged mito-area/cells, and skewed mitoATP/glycoATP. Excluding TCEP, the other four chemicals induced mito-ROS and depleted mitochondrial membrane potential (MMP). Notably, only TCP, TPhP and TDCPP impeded mitoATP generation rate and mito-respiratory rate. Based on potency estimates, the capacity for lipid accumulation was significantly correlated with mito-network numbers (R2 = 0.6481, p < 0.01), mitoATP/glycoATP (R2 = 0.5197, p < 0.01), mitoROS (R2 = 0.7197, p < 0.01), and MMP (R2 = 0.7715, p < 0.01). Remarkably, the mito-respiratory rate (R2 = 0.8753, p < 0.01) exhibited the highest correlation. Thus, the more potent lipid inducers TPhP, TCP and TDCPP could be identified. The results of this study demonstrate that aryl-OPFRs are more potent in metabolic disruption than other esters examined. Metabolic disruption should be examined further for chemicals that have the capacity to counteract the aforementioned functions of mitochondrial.

CLIC1 Inhibition Protects Against Cellular Senescence and Endothelial Dysfunction Via the Nrf2/HO-1 Pathway.

Chloride intracellular channel 1 (CLIC1) is a sensor of oxidative stress in endothelial cells (EC). However, the mechanism by which CLIC1 mediate the regulation of endothelial dysfunction has not been established. In this study, overexpressed CLIC1 impaired the ability of the vascular cells to resist oxidative damage and promoted cellular senescence. Besides, suppressed CLIC1 protected against cellular senescence and dysfunction in Human Umbilical Vein Endothelial Cells (HUVECs) through the Nrf2/HO-1 pathway. We also found that ROS-activated CLIC1-induced oxidative stress in HUVECs. Nrf2 nuclear translocation was inhibited by CLIC1 overexpression, but was enhanced by IAA94 (CLICs inhibitor) treatment or knockdown of CLIC1. The Nrf2/HO-1 pathway plays a critical role in the anti-oxidative effect of suppressing CLIC1. And inhibition of CLIC1 decreases oxidative stress injury by downregulating the levels of ROS, MDA, and the expression of EC effectors (ICAM1 and VCAM1) protein expression and promotes the activity of superoxide dismutase (SOD). The AMPK-mediated signaling pathway activates Nrf2 through Nrf2 phosphorylation and nuclear translocation, which is also regulated by CLIC1. Moreover, the activation of CLIC1 contributes to H2O2-induced mitochondrial dysfunction and activation of mitochondrial fission. Therefore, elucidation of the mechanisms by which CLIC1 is involved in these pivotal pathways may uncover its therapeutic potential in alleviating ECs oxidative stress and age-related cardiovascular disease development.