Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke:a special outlook on mitochondrial delivery

Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Metabolic reprogramming: a new option for the treatment of spinal cord injury

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

Unlocking the future:Mitochondrial genes and neural networks in predicting ovarian cancer prognosis and immunotherapy response

BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnosed with OC using mitochondrial genes and neural networks.METHODS Prognosis,immunotherapy efficacy,and next-generation sequencing data of patients with OC were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus.Mitochondrial genes were sourced from the MitoCarta3.0 database.The discovery cohort for model construction was created from 70% of the patients,whereas the remaining 30% constituted the validation cohort.Using the expression of mitochondrial genes as the predictor variable and based on neural network algorithm,the overall survival time and immunotherapy efficacy(complete or partial response)of patients were predicted.RESULTS In total,375 patients with OC were included to construct the prognostic model,and 26 patients were included to construct the immune efficacy model.The average area under the receiver operating characteristic curve of the prognostic model was 0.7268[95% confidence interval(CI):0.7258-0.7278]in the discovery cohort and 0.6475(95%CI:0.6466-0.6484)in the validation cohort.The average area under the receiver operating characteristic curve of the immunotherapy efficacy model was 0.9444(95%CI:0.8333-1.0000)in the discovery cohort and 0.9167(95%CI:0.6667-1.0000)in the validation cohort.CONCLUSION The application of mitochondrial genes and neural networks has the potential to predict prognosis and immunotherapy response in patients with OC,providing valuable insights into personalized treatment strategies.

Diabetes mellitus and glymphatic dysfunction:Roles for oxidative stress,mitochondria,circadian rhythm,artificial intelligence,and imaging

Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.

Effects of Ropivacaine and Bupivacaine on Rabbit Myocardial Energetic Metabolism and Mitochondria Oxidation

To compare the cardiotoxicity induced by ropivacaine and bupivacaine and to investigate the mechanism of cardiotoxicity, 24 mature New Zealand rabbits were divided randomly into control group (group C), ropivacaine group (group R) and bupivacaine group (group B). Hearts were drawn out rapidly from the anesthetized animals and cardiac perfu-sion was performed immediately. Ropivacaine 500 ng/ml (group R) or bupivacaine 500 ng/ml (group B) was added to the perfusion solution. Ventricular myocardial ATP, ADP and AMP were measured with high performance liquid chro-matogram. The ability of myocardial mitochondria oxidation to pyruvate or palmitoylcarnitine was detected with Clark electrode. Our results showed that myocardial ATP and ADP decreased significantly (P<0. 05) in group R and most significantly (P<0. 01) in group B as compared with group C. Myocardial ATP and ADP decreased most significantly (P<0. 01) in group B as compared with group R. The changes of myocardial AMP revealed significant difference among three groups. The changes of pyruvate oxidation exibited no significant difference among the three groups. Palmitoylcarnitine oxidation decreased markedly (P<0. 05) in group R and most significantly (P<0. 01) in group B as compared with group C. The present study indicated that the inhibition of lipid substrate oxidation may be responsible for the cardiotoxicity induced by bupivacaine and ropivacaine. The cardiotoxicity induced by ropivacaine is far more less than bupivacaine.

Metabolic integration during the evolutionary origin of mitochondria

Although mitochondria provide eukaryotic cells with certain metabolic advantages, in other ways they may be disadvantageous. For example, mitochondria produce reactive oxygen species that damage both nucleocytoplasm and mitochondria, resulting in mutations, diseases, and aging. The relationship of mitochondria to the cytoplasm is best understood in the context of evolutionary history. Although it is clear that mitochondria evolved from symbiotic bacteria, the exact nature of the initial symbiosis is a matter of continuing debate. The exchange of nutrients between host and symbiont may have differed from that between the cytoplasm and mitochondria in modern cells. Speculations about the initial relationships include the following. (1) The pre-mitochondrion may have been an invasive, parasitic bacterium. The host did not benefit. (2) The relationship was a nutritional syntrophy based upon transfer of organic acids from host to symbiont. (3) The relationship was a syntrophy based upon H2 transfer from symbiont to host, where the host was a methanogen. (4) There was a syntrophy based upon reciprocal exchange of sulfur compounds.The last conjecture receives support from our detection in eukaryotic cells of substantial H2S-oxidizing activity in mitochondria, and sulfur-reducing activity in the cytoplasm.

Changes of Reactive Oxygen Species and Related Enzymes in Mitochondria Respiratory Metabolism During the Ripening of Peach Fruit

The fruits of peach cultivar Yuhua 3 were used as materials to investigate the changes of active oxygen and related enzymes in mitochondria respiratory metabolism during ripening of peach fruit, involving their influence on the proceeding of peach fruit senescence. The results showed that the large decrease in firmness occurred between maturity II and IV. The decrease in firmness coincided with an increase in respiratory intensity. Obvious peaks of respiratory intensity lagging to the rapid change of fruit firmness could be shown during peach ripening. Reactive oxygen species （ROS） had a cumulative process and positively correlated with respiratory intensity. During peach ripening, the content of Ca^2＋ increased, the activities of succinic dehydrogenase （SDH）, cytochrome C oxidase （CCO）, H＋-ATPase, and Ca^2＋-ATPase decreased varying in different degree at the later step of ripening. These suggested a close relationship existed between ROS metabolism and mitochondrial respiration, namely, both ROS metabolism and mitochondrial respiration probably played important roles in ripening and senescing of peach fruit.

Mitochondrial metabolomic profiling for elucidating the alleviating potential of Polygonatum kingianum against high-fat diet-induced nonalcoholic fatty liver disease

BACKGROUND Developing mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represent attractive strategies for therapy of nonalcoholic fatty liver disease(NAFLD).Polygonatum kingianum(PK)has been traditionally used in China as a medicinal and nutritional ingredient for centuries and can alleviate high-fat diet(HFD)-induced NAFLD by promoting mitochondrial functions.To date,the underlying molecular mechanism of PK for treating mitochondrial dysfunctions and thus alleviating NAFLD remains unclear.AIM To identify the molecular mechanism behind the mitochondrial regulatory action of PK against HFD-induced NAFLD in rats.METHODS NAFLD model was induced in rats with HFD.The rats were intragastrically administered PK(4 g/kg per day)for 14 wk.Metabolites in hepatic mitochondrial samples were profiled through ultra-high performance liquid chromatography/mass spectrometry followed by multivariate statistical analysis to find the potential biomarkers and metabolic pathways.RESULTS PK significantly restored the metabolites’levels in the mitochondrial samples.Ten potential biomarkers were identified in the analyzed samples.These biomarkers are involved in riboflavin metabolism.CONCLUSION PK can alleviate HFD-induced NAFLD by regulating the riboflavin metabolism and further improving the mitochondrial functions.Thus,PK is a promising mitochondrial regulator/nutrient for alleviating NAFLD-associated diseases.

Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses

The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.

In vivo recognition of bioactive substances of Polygonum multiflorum for protecting mitochondria against metabolic dysfunction-associated fatty liver disease

BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)is a severe threat to human health.Polygonum multiflorum(PM)has been proven to remedy mitochondria and relieve MAFLD,but the main pharmacodynamic ingredients for mitigating MAFLD remain unclear.AIM To research the active ingredients of PM adjusting mitochondria to relieve highfat diet(HFD)-induced MAFLD in rats.METHODS Fat emulsion-induced L02 adipocyte model and HFD-induced MAFLD rat model were used to investigate the anti-MAFLD ability of PM and explore their action mechanisms.The adipocyte model was also applied to evaluate the activities of PM-derived constituents in liver mitochondria from HFD-fed rats(mitochondrial pharmacology).PM-derived constituents in liver mitochondria were confirmed by ultra-high-performance liquid chromatography/mass spectrometry(mitochondrial pharmacochemistry).The abilities of PM-derived monomer and monomer groups were evaluated by the adipocyte model and MAFLD mouse model,respectively.RESULTS PM repaired mitochondrial ultrastructure and prevented oxidative stress and energy production disorder of liver mitochondria to mitigate fat emulsion-induced cellular steatosis and HFD-induced MAFLD.PM-derived constituents that entered the liver mitochondria inhibited oxidative stress damage and improved energy production against cellular steatosis.Eight chemicals were found in the liver mitochondria of PM-administrated rats.The anti-steatosis ability of one monomer and the anti-MAFLD activity of the monomer group were validated.CONCLUSION PM restored mitochondrial structure and function and alleviated MAFLD,which may be associated with the remedy of oxidative stress and energy production.The identified eight chemicals may be the main bioactive ingredients in PM that adjusted mitochondria to prevent MAFLD.Thus,PM provides a new approach to prevent MAFLD-related mitochondrial dysfunction.Mitochondrial pharmacology and pharmacochemistry further showed efficient strategies for determining the bioactive ingredients of Chinese medicines that adjust mitochondria to prevent diseases.

Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis

Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury.Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury.Thus,transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease.To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke,in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site(in situ).Animal behavior tests,immunofluorescence staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,mRNA-seq,and western blotting were used to assess mouse anxiety and memory,cortical infarct area,pyroptosis,and neurogenesis,respectively.Using bioinformatics analysis,western blotting,co-immunoprecipitation,and mass spectroscopy,we identified S100 calcium binding protein A9(S100A9)as a potential regulator of mitochondrial function and determined its possible interacting proteins.Interactions between exogenous and endogenous mitochondria,as well as the effect of exogenous mitochondria on recipient microglia,were assessed in vitro.Our data showed that:(1)mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function,as well as reducing infarct area,inhibiting pyroptosis,and promoting cortical neurogenesis;(2)microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function;(3)in vitro,exogenous mitochondria enhanced mitochondrial function,reduced redox stress,and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria;and(4)S100A9 promoted internalization of exogenous mitochondria by the microglia,thereby amplifying their pro-proliferation and anti-inflammatory effects.Taken together,our findings show that mitochondrial transplantation protects against the deleterious effects of ischemic stroke by suppressing pyroptosis and promoting neurogenesis,and that S100A9 plays a vital role in promoting internalization of exogenous mitochondria.

Mitochondrial energy metabolism changes during aging-mouse cranial nerve cells treated with various doses and forms of Fructus schizandrae

BACKGROUND： During the cellular aging process, the number of mitochondria, generation of adenosine triphosphate （ATP）, activity of respiratory chain enzyme complex 1 and 4, and oxidation decrease. OBJECTIVE： To observe the effects of aqueous and spirituous extract, as well as polysaccharides from Fructus schizandrae （Magnolia Vine） on energy metabolism and mitochondrial anti-oxidation in cranial nerve cells of a D-gal-induced aging mouse model. DESIGN, TIME AND SETTING： A randomized, controlled, animal study. The experiment was conducted at the Department of Biochemistry, Qiqihar Medical College between March and July 2006. MATERIALS： Fifty healthy, Kunming mice of both sexes, aged 2 3 months old and weighing 18 22 g, were used for the present study. Fructus schizandrae was purchased from the Medical College of Jiamusi University. Aqueous extracts, spirituous extracts, and polysaccharides from Fructus schizandrae were prepared. D-galactose （D-gal） is a product of the Second Reagent Factory, Shanghai City, China. Mn-superoxide dismutase （Mn-SOD） kit, malonaldehyde （MDA） kit, protein quantification kit, and inorganic phosphorus testing kit were purchased from Jian Cheng Bioeng. Co., China. METHODS： Fifty mice were randomly divided into five groups, with 10 mice in each group： young control, aging model, aqueous Fructus schizandrae extract, spirituous Fructus schizandrae extract, and Fructus schizandrae polysaccharides. Over a course of 30 days, mice in aging model, aqueous Fructus schizandrae extract, spirituous Fructus schizandrae extract, and Fructus schizandrae polysaccharides groups were injected subcutaneously with D-gal （100 mg/kg） into the nape of the neck daily, and administered intragastrically with an equal volume of sterile, warm water （aging model）, aqueous Fructus schizandrae extract （2 g/kg）, spirituous Fructus schizandrae extract （2 g/kg）, or Fructus schizandrae polysaccharides （0.2 g/kg）, respectively. Mice in the young control group were injected into the nape of the neck with physiological saline and administered intragastrically with sterile, warm water. MAIN OUTCOME MEASURES： Respiratory chain complex I and H^＋-ATP enzyme activities, as well as Mn-SOD and MDA levels, were determined by the Coomassie brilliant blue method. RESULTS： All fifty mice were included in the final analysis. In mitochondria fiom cranial nerve cells of the aging mouse group MDA levels were significantly increased, compared with young control group （P 〈 0.01）; however, Mn-SOD levels, as well as respiratory chain complex I and H＋-ATP enzyme activity, were remarkably decreased （P 〈 0.01 ）. In each Fructus schizandrae group, Mn-SOD levels, as well as respiratory chain complex I and H＋-ATP enzyme activity was enhanced to various extents （P 〈 0.05, P 〈 0.01）, and MDA levels were decreased （P 〈 0.01）, compared with the aging model group. CONCLUSION： Aqueous and spirituous Fructus schizandrae extracts, as well as Fructus schizandrae polysaccharides delayed changes in mitochondrial energy metabolism, increased Mn-SOD levels, and decreased MDA levels in cranial nerve cell mitochondria of an aging mouse model. Fructus schizandrae polysaccharides were particularly capable of protecting mitochondria from oxidative injury.

Coated sodium butyrate ameliorates high‑energy and low‑protein diet induced hepatic dysfunction via modulating mitochondrial dynamics, autophagy and apoptosis in laying hens

Background Fatty liver hemorrhagic syndrome(FLHS),a fatty liver disease in laying hens,poses a grave threat to the layer industry,stemming from its ability to trigger an alarming plummet in egg production and usher in acute mortality among laying hens.Increasing evidence suggests that the onset and progression of fatty liver was closely related to mitochondria dysfunction.Sodium butyrate was demonstrated to modulate hepatic lipid metabolism,alle-viate oxidative stress and improve mitochondrial dysfunction in vitro and mice models.Nevertheless,there is limited existing research on coated sodium butyrate(CSB)to prevent FLHS in laying hens,and whether and how CSB exerts the anti-FLHS effect still needs to be explored.In this experiment,the FLHS model was induced by administering a high-energy low-protein(HELP)diet in laying hens.The objective was to investigate the effects of CSB on alleviating FLHS with a focus on the role of CSB in modulating mitochondrial function.Methods A total of 288 healthy 28-week-old Huafeng laying hens were arbitrarily allocated into 4 groups with 6 replicates each,namely,the CON group(normal diet),HELP group(HELP diet),CH500 group(500 mg/kg CSB added to HELP diet)and CH750 group(750 mg/kg CSB added to HELP diet).The duration of the trial encompassed a period of 10 weeks.Results The result revealed that CSB ameliorated the HELP-induced FLHS by improving hepatic steatosis and patho-logical damage,reducing the gene levels of fatty acid synthesis,and promoting the mRNA levels of key enzymes of fatty acid catabolism.CSB reduced oxidative stress induced by the HELP diet,upregulated the activity of GSH-Px and SOD,and decreased the content of MDA and ROS.CSB also mitigated the HELP diet-induced inflammatory response by blocking TNF-α,IL-1β,and F4/80.In addition,dietary CSB supplementation attenuated HELP-induced activation of the mitochondrial unfolded protein response(UPRmt),mitochondrial damage,and decline of ATPase activity.HELP diet decreased the autophagosome formation,and downregulated LC3B but upregulated p62 protein expression,which CSB administration reversed.CSB reduced HELP-induced apoptosis,as indicated by decreases in the Bax/Bcl-2,Caspase-9,Caspase-3,and Cyt C expression levels.Conclusions Dietary CSB could ameliorate HELP diet-induced hepatic dysfunction via modulating mitochondrial dynamics,autophagy,and apoptosis in laying hens.Consequently,CSB,as a feed additive,exhibited the capacity to prevent FLHS by modulating autophagy and lipid metabolism.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Elaidic acid leads to mitochondrial dysfunction via mitochondria-associated membranes triggers disruption of mitochondrial calcium fluxes

Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability or dysfunction may be the key stimulating factors to activate NLRP3 inflammasome,and sustained Ca^(2+)transfer can result in mitochondrial dysfunction.We focused on KCs to explore the damage to mitochondria by EA.After EA stimulation,cells produced an oxidative stress(OS)response with a significant increase in ROS release.Immunoprecipitation experiments and the addition of inhibitors revealed that the increase in the level of intracellular Ca^(2+)led to Ca^(2+)accumulation in the mitochondrial matrix via mitochondria-associated membranes(MAMs).This was accompanied by a significant release of m ROS,loss of MMP and ATP,and a significant increase in mitochondrial permeability transition pore opening,ultimately leading to mitochondrial instability.These findings confirmed the mechanism that EA induced mitochondrial Ca^(2+)imbalance in KCs via MAM,ultimately leading to mitochondrial dysfunction.Meanwhile,EA induced OS and the decrease of MMP and ATP in rat liver,and significant lesions were found in liver mitochondria.Swelling of the inner mitochondrial cristae and mitochondrial vacuolization occurred,with a marked increase in lipid droplets.

Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models

Metabolic dysfunction-associated fatty liver disease(MAFLD) is characterized by deregulated hepatic lipid metabolism;however, the association between MAFLD development and mitochondrial dysfunction has yet to be confirmed. Herein, we employed highresolution respirometry, blue native polyacrylamide gelelectrophoresis-basedin-gelactivity measurement and immunoblot analysis to assess mitochondrial function in obesity-induced mouse models with varying degrees of MAFLD. Results showed a slight but significant decrease in hepatic mitochondrial respiration in some MAFLD mice compared to mice fed a standard diet. However, the activities and levels of mitochondrial oxidative phosphorylation complexes remained unchanged during obesity-induced MAFLD progression. These results suggest that mitochondrial function,particularly oxidative phosphorylation, was mildly affected duringo besity-induced MAFLD development. Moreover, transcriptome profiling of mouse and human liver tissues with varying degrees of MAFLD revealed that the decreased activation of mitochondria-related pathways was only associated with MAFLD of a high histological grade, whereas the major regulators of mitochondrial biogenesis were not altered in mice or humans during MAFLD development. Collectively, our results suggest that impaired hepatic mitochondrial function is not closely associated with obesity-induced MAFLD. Therefore,therapeutic strategies targeting mitochondria for the treatment of MAFLD should be reconsidered.

Endometrial Cancer Research Based on Gut Microbiomics and Metabolomics:An Analysis of Correlation and Differences

Endometrial cancer(EC)is a malignant tumour that occurs in the epithelial cells of the endometrium and represents one of the most common malignancies involving the female reproductive system,with endometrioid adenocarcinoma as the most common type.In recent years,with an increasingly aging society and the growing number of obese people,the incidence of EC is constantly rising,posing a serious threat to women’s health.Some studies have reported that the interruption of digestion and absorption caused by imbalance in intestinal microbiota may lead to conditions such as obesity,hypertension,diabetes,and hormone imbalance,which are all risk factors for EC.Meanwhile,intestinal bacteria produce a series of metabolites during colonization and reproduction,which can rapidly respond to changes in the microenvironment of the body.Changes in their types and quantities can serve as sensitive indicators of physiological and pathological changes in the body.Patients with EC often suffer from metabolic diseases,which can lead to metabolic disorders involving carbohydrates,fats,and amino acid in their bodies.

Possible Role of Cellular Polyamine Metabolism in Neuronal Apoptosis

Recent studies have shown that cellular levels of polyamines(PAs)are significantly altered in neurodegenerative diseases.Evidence from in vivo animal and in vitro cell experiments suggests that the cellular levels of various PAs may play important roles in the central nervous system through the regulation of oxidative stress,mitochondrial metabolism,cellular immunity,and ion channel functions.Dysfunction of PA metabolism related enzymes also contributes to neuronal injury and cognitive impairment in many neurodegenerative diseases.Therefore,in the current work,evidence was collected to determine the possible associations between cellular levels of PAs,and related enzymes and the development of several neurodegenerative diseases,which could provide a new idea for the treatment of neurodegenerative diseases in the future.