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 ...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.展开更多
Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume respon...Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.展开更多
Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Na...Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.展开更多
Numerous research conducted in recent years has revealed that gut microbial dysbiosis,such as modifications in composition and activity,might influence lung tissue homeostasis through specific pathways,thereby promoti...Numerous research conducted in recent years has revealed that gut microbial dysbiosis,such as modifications in composition and activity,might influence lung tissue homeostasis through specific pathways,thereby promoting susceptibility to lung diseases.The development and progression of lung cancer,as well as the effectiveness of immunotherapy are closely associated with gut flora and metabolites,which influence immunological and inflammatory responses.During abnormal proliferation,non-small cell lung cancer cells acquire more substances and energy by altering their own metabolic pathways.Glucose and amino acid metabolism reprogramming provide tumor cells with abundant ATP,carbon,and nitrogen sources,respectively,providing optimal conditions for tumor cell proliferation,invasion,and immune escape.This article reviews the relationship of immune response with gut flora and metabolic reprogramming in non-small cell lung cancer,and discusses the potential mechanisms by which gut flora and metabolic reprogramming affect the occurrence,development,and immunotherapy of non-small cell lung cancer,in order to provide new ideas for precision treatment of lung cancer patients.展开更多
Centella asiatica L.,a medicinal herb,has attracted substantial interest in research as well as commercial domains due to its bioactive compounds which include the pentacyclic triterpenoid centellosides,and in additio...Centella asiatica L.,a medicinal herb,has attracted substantial interest in research as well as commercial domains due to its bioactive compounds which include the pentacyclic triterpenoid centellosides,and in addition,hydroxy.In addition,hydroxycinnamic acid conjugates as well as flavonoids.The latter is the major class of secondary plant metabolites and comprises various subclasses,including anthocyanidins.Anthocyanins are rarely reported in extracts from C.asiatica and differ structurally due to a flavylium(2-phenylchromenylium)ion that carries a positive charge at the oxygen atom of the C-ring of the basic flavonoid structure.Callus of C.asiatica was initiated and propagated on synthetic media and subjected to different light regimes.White callus resulted from white fluorescent illumination,while purple callus developed in response to white light emitting diode(LED)illumination.To profile the metabolites responsible for the intense purple coloration,methanolic extracts were prepared from the two cell lines.Total phenolic,flavonoid,and anthocyanin content were determined and indicated(i)very low levels of flavonoids and anthocyanins in white callus and(ii)that anthocyanins dominate the flavonoid content of the purple callus.Extracts were subjected to untargeted ultra-high-performance liquid chromatography coupled to high-definition mass spectrometry(UHPLC–MS)to profile newly synthesized anthocyanins.Metabolite annotation was based on accurate mass determination and characteristic fragmentation patterns.Here,the reprogramming of the metabolome of white C.asiatica callus due to LED illumination is reported and the profiles of cryptic anthocyanins as well as putative flavonoid and caffeoylquinic acid co-pigments in purple callus are described.展开更多
Cell plasticity,also known as lineage plasticity,refers to the ability of a cell to reprogram and change its phenotypic identity in response to various cues.This phenomenon is context-dependent,playing a crucial role ...Cell plasticity,also known as lineage plasticity,refers to the ability of a cell to reprogram and change its phenotypic identity in response to various cues.This phenomenon is context-dependent,playing a crucial role in embryonic development,tissue regeneration,and wound healing.However,when dysregulated,cell plasticity contributes to cancer initiation,progression,metastasis,and therapeutic resistance.Throughout different stages of tumor development,cancer cells exploit various forms of plasticity to evade normal regulatory mechanisms that govern cell division and homeostasis.Recent evidence highlights the complex interplay between genetic and epigenetic factors,the tumor microenvironment,and epithelial-to-mesenchymal transition in driving cancer cell plasticity.This dynamic reprogramming suggests that“deregulated cell plasticity”could be considered an additional hallmark of cancer.Advancements in next-generation sequencing and single-cell RNA analysis,combined with artificial intelligence technologies such as deep learning,along with Google’s AlphaFold may help predict the trajectories of cancer cells.By predicting protein three-dimensional structures and identifying both active and potential allosteric binding sites,AlphaFold 2 can accelerate the development of new cancer drugs and therapies.For example,allosteric drugs,bind to the allosteric rather than the active sites,can induce conformational changes in proteins,affecting their activities.This can then alter the conformation of an active site that a drug-resistant mutation has created,permitting a blocked orthosteric drug to bind and this enables the design of more effective drugs that can synergize with traditional orthosteric drugs to bind and regain its efficacy.These innovations could provide deeper insights into the intricate mechanisms of cancer progression and resistance,ultimately paving the way for more precise,durable,and personalized oncologic treatments.展开更多
Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
Despite recent advances in understanding the biology of aging,the field remains fragmented due to the lack of a central organizing hypothesis.Although there are ongoing debates on whether the aging process is programm...Despite recent advances in understanding the biology of aging,the field remains fragmented due to the lack of a central organizing hypothesis.Although there are ongoing debates on whether the aging process is programmed or stochastic,it is now evident that neither perspective alone can fully explain the complexity of aging.Here,we propose the pro-aging metabolic reprogramming(PAMRP)theory,which integrates and unifies the genetic-program and stochastic hypotheses.This theory posits that aging is driven by degenerative metabolic reprogramming(MRP)over time,requiring the emergence of pro-aging substrates and triggers(PASs and PATs)to predispose cells to cellular and genetic reprogramming(CRP and GRP).展开更多
Background:The inability of damaged neurons to regenerate and of axons to estab-lish new functional connections leads to permanent functional deficits after spinal cord injury(SCI).Although astrocyte reprogramming hol...Background:The inability of damaged neurons to regenerate and of axons to estab-lish new functional connections leads to permanent functional deficits after spinal cord injury(SCI).Although astrocyte reprogramming holds promise for neurorepair in various disease models,it is not sufficient on its own to achieve significant functional recovery.Methods:A rat SCI model was established using a spinal cord impactor.Seven days postsurgery,adeno-associated virus were injected to overexpress the transcription factors NeuroD1 and Neurogenin-2(Ngn2)in the spinal cord.The rats were then trained to walk on a weight-supported treadmill for 4 weeks,starting 14 days after modeling.The effects of these interventions on motor and sensory functions,as well as spinal cord tissue repair,were subsequently evaluated.Results:The combination of NeuroD1 and Ngn2 overexpression with weight-supported exercise training significantly improved gait compared to either inter-vention alone.The group receiving the combined intervention exhibited enhanced sensitivity in sensory assessments.Immunofluorescence analysis revealed increased colocalization of astrocytes and microtubule-associated protein 2-positive neurons in the injury area.These effects were more pronounced than those observed with spinal cord tissue repair alone.Additionally,the combined intervention significantly reduced glial scarring and the size of the injury area.Conclusion:Exercise intervention enhances the reprogramming effects of astrocytes and restores motor function,yielding better results than either intervention alone.展开更多
Ulcerative colitis(UC)is a chronic and non-specific inflammatory bowel disease(IBD).Huanglian Ganjiang decoction(HGD),derived from ancient book Beiji Qianjin Yao Fang,has demonstrated efficacy in treating UC patients ...Ulcerative colitis(UC)is a chronic and non-specific inflammatory bowel disease(IBD).Huanglian Ganjiang decoction(HGD),derived from ancient book Beiji Qianjin Yao Fang,has demonstrated efficacy in treating UC patients traditionally.Previous research established that the compatibility of cold herb Coptidis Rhizoma+Phellodendri Chinensis Cortex(CP)and hot herb Angelicae Sinensis Radix+Zingiberis Rhizoma(AZ)in HGD synergistically improved colitis mice.This study investigated the compatibility mechanisms through which CP and AZ regulated inflammatory balance in colitis mice.The experimental colitis model was established by administering 3%dextran sulphate sodium(DSS)to mice for 7 days,followed by CP,AZ and CPAZ treatment for an additional 7 days.M1/M2 macrophage polarization levels,glucose metabolites levels and pyruvate dehydrogenase kinase 4(PDK4)expression were analyzed using flow cytometry,Western blot,immunofluorescence and targeted glucose metabolomics.The findings indicated that CP inhibited M1 macrophage polarization,decreased inflammatory metabolites associated with tricarboxylic acid(TCA)cycle,and suppressed PDK4 expression and pyruvate dehydrogenase(PDH)(Ser-293)phosphorylation level.AZ enhanced M2 macrophage polarization,increased lactate axis metabolite lactate levels,and upregulated PDK4 expression and PDH(Ser-293)phosphorylation level.TCA cycle blocker AG-221 and adeno-associated virus(AAV)-PDK4 partially negated CP’s inhibition of M1 macrophage polarization.Lactate axis antagonist oxamate and PDK4 inhibitor dichloroacetate(DCA)partially reduced AZ’s activation of M2 macrophage polarization.In conclusion,the compatibility of CP and AZ synergistically alleviated colitis in mice through M1/M2 macrophage polarization balance via PDK4-mediated glucose metabolism reprogramming.Specifically,CP reduced M1 macrophage polarization by restoration of TCA cycle via PDK4 inhibition,while AZ increased M2 macrophage polarization through activation of PDK4/lactate axis.展开更多
Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as...Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is a progressive metabolic disorder that is pathologically characterized by abnormal lipid deposition in the liver and metabolic inflammation.The current ...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a progressive metabolic disorder that is pathologically characterized by abnormal lipid deposition in the liver and metabolic inflammation.The current clinical mana-gement of MASLD largely involves generalized lifestyle modifications including diet and broad-spectrum metabolic interventions such as insulin sensitizers.These approaches often yield suboptimal outcomes because of poor long-term adhe-rence,heterogeneous patient responses,and limited efficacy in advanced disease stages.Crucially,they fail to address disease-specific molecular drivers,such as aging-associated pathways exemplified by vitamin D receptor dysregulation.Given the complexity and progressive nature of MASLD,it is crucial to further elucidate its mechanisms,develop precise therapeutic strategies,and raise awareness of the disease among the public and medical community.展开更多
Thyroid cancer(TC)is one of the most common endocrine system tumors,and its incidence continues to increase worldwide.Although most TC patients have a good prognosis,especially with continuous advancements in surgery,...Thyroid cancer(TC)is one of the most common endocrine system tumors,and its incidence continues to increase worldwide.Although most TC patients have a good prognosis,especially with continuous advancements in surgery,radioactive iodine therapy,chemotherapy,endocrine therapy and targeted therapy,the effectiveness of disease treatment has significantly improved.However,there are still some cases with a higher risk of death and greater aggressiveness.In these more challenging advanced or highly aggressive cases,tyrosine kinase inhibitors appear to be an effective treatment option.Unfortunately,these drugs are less than ideal in terms of efficacy because of their toxicity and potential for intrinsic or acquired resistance.Therefore,exploring new strategies targeting the metabolic characteristics of TC cells and overcoming drug resistance barriers in existing treatments have become key topics in the current field of TC research.In recent years,lipid metabolic reprogramming has gained attention as an important aspect of cancer development.Lipid metabolic reprogramming not only participates in the formation of the cell membrane structure,but also plays an important role in signal transduction and promoting cell proliferation.In particular,fatty acid(FA)metabolic reprogramming has attracted widespread attention and plays an important role in multiple aspects such as tumor growth,metastasis,enhanced invasive ability,immune escape,and drug resistance.Although TC is considered a disease that is highly dependent on specific types of metabolic activities,a comprehensive understanding of the specific mechanism of action of FA metabolic reprogramming in this process is lacking.This article aims to review how FA metabolic reprogramming participates in the occurrence and development of TC,focusing on the impact of abnormal FA metabolic pathways and changes in the expression and regulation of related genes over the course of this disease.By examining the complex interactions between FA metabolic disorders and carcinogenic signaling pathways in depth,we aim to identify new therapeutic targets and develop more precise and effective treatments for TC.展开更多
BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers...BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers.It is known that metabolic changes occur at different stages of the cell cycle to maintain the biosynthesis and replication of both normal and cancer cells.Based on the role of SAC3D1 in mitosis,we hypothesize that abnormal expression of SAC3D1 may affect cellular metabolism.However,it remains unclear whether SAC3D1 mediates the progression of HCC by regulating metabolic reprogramming.AIM To comprehensively elucidate the impact and molecular mechanism of SAC3D1 on the progression of HCC by regulating the metabolic reprogramming.METHODS The constructed SAC3D1 overexpression and knockdown HCC cell lines were used for detecting cell proliferation,migration capabilities,as well as glycolysis and adenosine triphosphate(ATP)production rate assays.They were also employed for examining molecular markers associated with cell migration and glycolysis.The transcriptome sequencing data of cells have revealed the pathways potentially influenced by SAC3D1.The tail vein metastasis model and xenograft tumor experiments were utilized to demonstrate SAC3D1’s tumor-promoting effects in vivo.RESULTS SAC3D1 expression was upregulated and associated with poor prognosis in HCC patients.SAC3D1 enhanced the proliferation and migration abilities and reduced the population dependence of HCC cells in vitro and in vivo.The upregulation of SAC3D1 enhanced cellular glycolysis and ATP production.The cell transcriptome sequencing data revealed that SAC3D1 activated Wnt signaling pathway.SAC3D1 did not modulate the transcription ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-Catenin,could counteract the increase of c-Myc induced by SAC3D1,while also downregulating the expression of glycolysis-related proteins.CONCLUSION This study found that SAC3D1 enhances HCC cell glycolysis and ATP production via theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.展开更多
Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, grow...Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, growingevidence indicates that AR dysfunction also disrupts systemic metabolic homeostasis, predisposing affectedindividuals to insulin resistance and type 2 diabetes mellitus. This article synthesizes recent advances in genetics,transcriptomics, and physiology to elucidate how AR mutations drive tissue-specific metabolic reprogramming inkey organs, including pancreatic β-cells, skeletal muscle, liver, and adipose tissue. Particular attention is given to anewly identified familial AR variant (c.2117A>G;p.Asn706Ser), which not only broadens the known mutationalspectrum of AIS but also underscores the clinical importance of early metabolic risk screening in this population.We further examine how pubertal stage, hormone replacement therapy, and sex-specific signaling pathwaysinteract to influence long-term metabolic outcomes. Lastly, we propose an integrative management framework thatincorporates genetic diagnosis, endocrine surveillance, and personalized pharmacological strategies aimed atreducing the risk of type 2 diabetes mellitus and cardiometabolic complications in individuals with AIS. Distinctfrom previous AIS-centered reviews, this work integrates metabolic and endocrine perspectives into the traditionaldevelopmental paradigm, offering a more comprehensive understanding of disease risk and translational management.展开更多
Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabo...Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabolic reprogramming(EMR)in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD.Jiawei Xionggui Decoction(JWXG)has demonstrated effectiveness in enhancing energy supply,protecting microglia,and mitigating cognitive impairment in APP/PS1 mice.However,the mechanism by which JWXG enhances Aβphagocytosis through TREM2-mediated EMR in microglia remains unclear.This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR.Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo.The EMR level of microglia was assessed using high-performance liquid chromatography(HPLC)and enzyme-linked immunosorbent assay(ELISA)kits.The TREM2/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor-1α(HIF-1α)signaling pathway was analyzed using Western blotting in BV_(2) cells.TREM2^(−/−)BV_(2) cells were utilized for reverse validation experiments.The Aβburden,neuropathological features,and cognitive ability in APP/PS1 mice were evaluated using ELISA kits,immunohistochemistry(IHC),and the Morris water maze(MWM)test.JWXG enhanced both the phagocytosis of EMR disorder-BV_(2) cells(EMRD-BV_(2))and increased EMR levels.Notably,these effects were significantly reversed in TREM2^(−/−)BV_(2) cells.JWXG elevated TREM2 expression,adenosine triphosphate(ATP)levels,and microglial phagocytosis in APP/PS1 mice.Additionally,JWXG reduced Aβ-burden,neuropathological lesions,and cognitive deficits in APP/PS1 mice.In conclusion,JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis,thereby reducing Aβdeposition,improving neuropathological lesions,and alleviating cognitive deficits.展开更多
Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic ...Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.展开更多
Iridovirus poses a substantial threat to global aquaculture due to its high mortality rate;however,the molecular mechanisms underpinning its pathogenesis are not well elucidated.Here,a multi-omics approach was applied...Iridovirus poses a substantial threat to global aquaculture due to its high mortality rate;however,the molecular mechanisms underpinning its pathogenesis are not well elucidated.Here,a multi-omics approach was applied to groupers infected with Singapore grouper iridovirus(SGIV),focusing on the roles of key metabolites.Results showed that SGIV induced obvious histopathological damage and changes in metabolic enzymes within the liver.Furthermore,SGIV significantly reduced the contents of lipid droplets,triglycerides,cholesterol,and lipoproteins.Metabolomic analysis indicated that the altered metabolites were enriched in 19 pathways,with a notable down-regulation of lipid metabolites such as glycerophosphates and alpha-linolenic acid(ALA),consistent with disturbed lipid homeostasis in the liver.Integration of transcriptomic and metabolomic data revealed that the top enriched pathways were related to cell growth and death and nucleotide,carbohydrate,amino acid,and lipid metabolism,supporting the conclusion that SGIV infection induced liver metabolic reprogramming.Further integrative transcriptomic and proteomic analysis indicated that SGIV infection activated crucial molecular events in a phagosome-immune depression-metabolism dysregulation-necrosis signaling cascade.Of note,integrative multi-omics analysis demonstrated the consumption of ALA and linoleic acid(LA)metabolites,and the accumulation of L-glutamic acid(GA),accompanied by alterations in immune,inflammation,and cell death-related genes.Further experimental data showed that ALA,but not GA,suppressed SGIV replication by activating antioxidant and anti-inflammatory responses in the host.Collectively,these findings provide a comprehensive resource for understanding host response dynamics during fish iridovirus infection and highlight the antiviral potential of ALA in the prevention and treatment of iridoviral diseases.展开更多
Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,Br...Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.展开更多
Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells ...Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic,transcriptional,and post-transcriptional regulation.Understanding these neurogenic mechanisms is of major importance,not only for shedding light on very complex and crucial developmental processes,but also for the identification of putative reprogramming factors,that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate.The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors,as well as repressor complexes,have been identified and employed in direct reprogramming protocols to convert non-neuronal cells,into functional neurons.The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer,strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function.In particular,recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis,such as alternative splicing,polyadenylation,stability,and translation.Apart from the RNA binding proteins,microRNAs,a class of small non-coding RNAs that block the translation of their target mRNAs,have also been shown to play crucial roles in all the stages of the neurogenic process,from neural stem/progenitor cell proliferation,neuronal differentiation and migration,to functional maturation.Here,we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process,giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs.Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming,we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors,highlighting the so far known mechanisms of their reprogramming action.展开更多
基金supported by the National Natural Science Foundation of China,No.82202681(to JW)the Natural Science Foundation of Zhejiang Province,Nos.LZ22H090003(to QC),LR23H060001(to CL).
文摘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.
基金supported by the National Natural Science Foundation of China,No.31930068National Key Research and Development Program of China,Nos.2018YFA0107302 and 2021YFA1101203(all to HX).
文摘Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.
基金supported by the National Natural Science Foundation of China,No.82101327(to YY)President Foundation of Nanfang Hospital,Southern Medical University,No.2020A001(to WL)+1 种基金Guangdong Basic and Applied Basic Research Foundation,Nos.2019A1515110150,2022A1515012362(both to YY)Guangzhou Science and Technology Project,No.202201020111(to YY).
文摘Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.
基金supported by the Scientific Research Fund Project of Education Department of Yunnan Province,China(No.2024Y386).
文摘Numerous research conducted in recent years has revealed that gut microbial dysbiosis,such as modifications in composition and activity,might influence lung tissue homeostasis through specific pathways,thereby promoting susceptibility to lung diseases.The development and progression of lung cancer,as well as the effectiveness of immunotherapy are closely associated with gut flora and metabolites,which influence immunological and inflammatory responses.During abnormal proliferation,non-small cell lung cancer cells acquire more substances and energy by altering their own metabolic pathways.Glucose and amino acid metabolism reprogramming provide tumor cells with abundant ATP,carbon,and nitrogen sources,respectively,providing optimal conditions for tumor cell proliferation,invasion,and immune escape.This article reviews the relationship of immune response with gut flora and metabolic reprogramming in non-small cell lung cancer,and discusses the potential mechanisms by which gut flora and metabolic reprogramming affect the occurrence,development,and immunotherapy of non-small cell lung cancer,in order to provide new ideas for precision treatment of lung cancer patients.
文摘Centella asiatica L.,a medicinal herb,has attracted substantial interest in research as well as commercial domains due to its bioactive compounds which include the pentacyclic triterpenoid centellosides,and in addition,hydroxy.In addition,hydroxycinnamic acid conjugates as well as flavonoids.The latter is the major class of secondary plant metabolites and comprises various subclasses,including anthocyanidins.Anthocyanins are rarely reported in extracts from C.asiatica and differ structurally due to a flavylium(2-phenylchromenylium)ion that carries a positive charge at the oxygen atom of the C-ring of the basic flavonoid structure.Callus of C.asiatica was initiated and propagated on synthetic media and subjected to different light regimes.White callus resulted from white fluorescent illumination,while purple callus developed in response to white light emitting diode(LED)illumination.To profile the metabolites responsible for the intense purple coloration,methanolic extracts were prepared from the two cell lines.Total phenolic,flavonoid,and anthocyanin content were determined and indicated(i)very low levels of flavonoids and anthocyanins in white callus and(ii)that anthocyanins dominate the flavonoid content of the purple callus.Extracts were subjected to untargeted ultra-high-performance liquid chromatography coupled to high-definition mass spectrometry(UHPLC–MS)to profile newly synthesized anthocyanins.Metabolite annotation was based on accurate mass determination and characteristic fragmentation patterns.Here,the reprogramming of the metabolome of white C.asiatica callus due to LED illumination is reported and the profiles of cryptic anthocyanins as well as putative flavonoid and caffeoylquinic acid co-pigments in purple callus are described.
文摘Cell plasticity,also known as lineage plasticity,refers to the ability of a cell to reprogram and change its phenotypic identity in response to various cues.This phenomenon is context-dependent,playing a crucial role in embryonic development,tissue regeneration,and wound healing.However,when dysregulated,cell plasticity contributes to cancer initiation,progression,metastasis,and therapeutic resistance.Throughout different stages of tumor development,cancer cells exploit various forms of plasticity to evade normal regulatory mechanisms that govern cell division and homeostasis.Recent evidence highlights the complex interplay between genetic and epigenetic factors,the tumor microenvironment,and epithelial-to-mesenchymal transition in driving cancer cell plasticity.This dynamic reprogramming suggests that“deregulated cell plasticity”could be considered an additional hallmark of cancer.Advancements in next-generation sequencing and single-cell RNA analysis,combined with artificial intelligence technologies such as deep learning,along with Google’s AlphaFold may help predict the trajectories of cancer cells.By predicting protein three-dimensional structures and identifying both active and potential allosteric binding sites,AlphaFold 2 can accelerate the development of new cancer drugs and therapies.For example,allosteric drugs,bind to the allosteric rather than the active sites,can induce conformational changes in proteins,affecting their activities.This can then alter the conformation of an active site that a drug-resistant mutation has created,permitting a blocked orthosteric drug to bind and this enables the design of more effective drugs that can synergize with traditional orthosteric drugs to bind and regain its efficacy.These innovations could provide deeper insights into the intricate mechanisms of cancer progression and resistance,ultimately paving the way for more precise,durable,and personalized oncologic treatments.
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
文摘Despite recent advances in understanding the biology of aging,the field remains fragmented due to the lack of a central organizing hypothesis.Although there are ongoing debates on whether the aging process is programmed or stochastic,it is now evident that neither perspective alone can fully explain the complexity of aging.Here,we propose the pro-aging metabolic reprogramming(PAMRP)theory,which integrates and unifies the genetic-program and stochastic hypotheses.This theory posits that aging is driven by degenerative metabolic reprogramming(MRP)over time,requiring the emergence of pro-aging substrates and triggers(PASs and PATs)to predispose cells to cellular and genetic reprogramming(CRP and GRP).
文摘Background:The inability of damaged neurons to regenerate and of axons to estab-lish new functional connections leads to permanent functional deficits after spinal cord injury(SCI).Although astrocyte reprogramming holds promise for neurorepair in various disease models,it is not sufficient on its own to achieve significant functional recovery.Methods:A rat SCI model was established using a spinal cord impactor.Seven days postsurgery,adeno-associated virus were injected to overexpress the transcription factors NeuroD1 and Neurogenin-2(Ngn2)in the spinal cord.The rats were then trained to walk on a weight-supported treadmill for 4 weeks,starting 14 days after modeling.The effects of these interventions on motor and sensory functions,as well as spinal cord tissue repair,were subsequently evaluated.Results:The combination of NeuroD1 and Ngn2 overexpression with weight-supported exercise training significantly improved gait compared to either inter-vention alone.The group receiving the combined intervention exhibited enhanced sensitivity in sensory assessments.Immunofluorescence analysis revealed increased colocalization of astrocytes and microtubule-associated protein 2-positive neurons in the injury area.These effects were more pronounced than those observed with spinal cord tissue repair alone.Additionally,the combined intervention significantly reduced glial scarring and the size of the injury area.Conclusion:Exercise intervention enhances the reprogramming effects of astrocytes and restores motor function,yielding better results than either intervention alone.
基金supported by the National Natural Science Foundation of China(Nos.82374325 and 82074322)GDAS'ProjectofScience and Technology Development(No.2022GDASZH-2022010110).
文摘Ulcerative colitis(UC)is a chronic and non-specific inflammatory bowel disease(IBD).Huanglian Ganjiang decoction(HGD),derived from ancient book Beiji Qianjin Yao Fang,has demonstrated efficacy in treating UC patients traditionally.Previous research established that the compatibility of cold herb Coptidis Rhizoma+Phellodendri Chinensis Cortex(CP)and hot herb Angelicae Sinensis Radix+Zingiberis Rhizoma(AZ)in HGD synergistically improved colitis mice.This study investigated the compatibility mechanisms through which CP and AZ regulated inflammatory balance in colitis mice.The experimental colitis model was established by administering 3%dextran sulphate sodium(DSS)to mice for 7 days,followed by CP,AZ and CPAZ treatment for an additional 7 days.M1/M2 macrophage polarization levels,glucose metabolites levels and pyruvate dehydrogenase kinase 4(PDK4)expression were analyzed using flow cytometry,Western blot,immunofluorescence and targeted glucose metabolomics.The findings indicated that CP inhibited M1 macrophage polarization,decreased inflammatory metabolites associated with tricarboxylic acid(TCA)cycle,and suppressed PDK4 expression and pyruvate dehydrogenase(PDH)(Ser-293)phosphorylation level.AZ enhanced M2 macrophage polarization,increased lactate axis metabolite lactate levels,and upregulated PDK4 expression and PDH(Ser-293)phosphorylation level.TCA cycle blocker AG-221 and adeno-associated virus(AAV)-PDK4 partially negated CP’s inhibition of M1 macrophage polarization.Lactate axis antagonist oxamate and PDK4 inhibitor dichloroacetate(DCA)partially reduced AZ’s activation of M2 macrophage polarization.In conclusion,the compatibility of CP and AZ synergistically alleviated colitis in mice through M1/M2 macrophage polarization balance via PDK4-mediated glucose metabolism reprogramming.Specifically,CP reduced M1 macrophage polarization by restoration of TCA cycle via PDK4 inhibition,while AZ increased M2 macrophage polarization through activation of PDK4/lactate axis.
基金supported by the National Natural Science Foundation of China(Grant nos.82473157,82460510,82203565,82103388,31960145 and 82560591)the Natural Science Foundation of Beijing(Grant no.L248059)+1 种基金Yunnan Province applied research funds(Grant nos.202201AY070001-011,202201AY070001-043,and 202301AS070018)the Science and Technology Innovation Team of tumor metabolism research at Kunming Medical University(Grant no.CXTD202102).
文摘Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a progressive metabolic disorder that is pathologically characterized by abnormal lipid deposition in the liver and metabolic inflammation.The current clinical mana-gement of MASLD largely involves generalized lifestyle modifications including diet and broad-spectrum metabolic interventions such as insulin sensitizers.These approaches often yield suboptimal outcomes because of poor long-term adhe-rence,heterogeneous patient responses,and limited efficacy in advanced disease stages.Crucially,they fail to address disease-specific molecular drivers,such as aging-associated pathways exemplified by vitamin D receptor dysregulation.Given the complexity and progressive nature of MASLD,it is crucial to further elucidate its mechanisms,develop precise therapeutic strategies,and raise awareness of the disease among the public and medical community.
文摘Thyroid cancer(TC)is one of the most common endocrine system tumors,and its incidence continues to increase worldwide.Although most TC patients have a good prognosis,especially with continuous advancements in surgery,radioactive iodine therapy,chemotherapy,endocrine therapy and targeted therapy,the effectiveness of disease treatment has significantly improved.However,there are still some cases with a higher risk of death and greater aggressiveness.In these more challenging advanced or highly aggressive cases,tyrosine kinase inhibitors appear to be an effective treatment option.Unfortunately,these drugs are less than ideal in terms of efficacy because of their toxicity and potential for intrinsic or acquired resistance.Therefore,exploring new strategies targeting the metabolic characteristics of TC cells and overcoming drug resistance barriers in existing treatments have become key topics in the current field of TC research.In recent years,lipid metabolic reprogramming has gained attention as an important aspect of cancer development.Lipid metabolic reprogramming not only participates in the formation of the cell membrane structure,but also plays an important role in signal transduction and promoting cell proliferation.In particular,fatty acid(FA)metabolic reprogramming has attracted widespread attention and plays an important role in multiple aspects such as tumor growth,metastasis,enhanced invasive ability,immune escape,and drug resistance.Although TC is considered a disease that is highly dependent on specific types of metabolic activities,a comprehensive understanding of the specific mechanism of action of FA metabolic reprogramming in this process is lacking.This article aims to review how FA metabolic reprogramming participates in the occurrence and development of TC,focusing on the impact of abnormal FA metabolic pathways and changes in the expression and regulation of related genes over the course of this disease.By examining the complex interactions between FA metabolic disorders and carcinogenic signaling pathways in depth,we aim to identify new therapeutic targets and develop more precise and effective treatments for TC.
基金Supported by the Shanghai Yangpu District Science and Technology Commission,No.YPQ202303Shanghai Municipal Health Commission Clinical Research Special Project,No.202240122Shanghai Medical Innovation Research Special Project,No.22Y11908600.
文摘BACKGROUND Metabolic dysregulation is considered a significant hallmark of hepatocellular carcinoma(HCC).SAC3 domain containing 1(SAC3D1)functions in the cell cycle,and its expression is upregulated in various cancers.It is known that metabolic changes occur at different stages of the cell cycle to maintain the biosynthesis and replication of both normal and cancer cells.Based on the role of SAC3D1 in mitosis,we hypothesize that abnormal expression of SAC3D1 may affect cellular metabolism.However,it remains unclear whether SAC3D1 mediates the progression of HCC by regulating metabolic reprogramming.AIM To comprehensively elucidate the impact and molecular mechanism of SAC3D1 on the progression of HCC by regulating the metabolic reprogramming.METHODS The constructed SAC3D1 overexpression and knockdown HCC cell lines were used for detecting cell proliferation,migration capabilities,as well as glycolysis and adenosine triphosphate(ATP)production rate assays.They were also employed for examining molecular markers associated with cell migration and glycolysis.The transcriptome sequencing data of cells have revealed the pathways potentially influenced by SAC3D1.The tail vein metastasis model and xenograft tumor experiments were utilized to demonstrate SAC3D1’s tumor-promoting effects in vivo.RESULTS SAC3D1 expression was upregulated and associated with poor prognosis in HCC patients.SAC3D1 enhanced the proliferation and migration abilities and reduced the population dependence of HCC cells in vitro and in vivo.The upregulation of SAC3D1 enhanced cellular glycolysis and ATP production.The cell transcriptome sequencing data revealed that SAC3D1 activated Wnt signaling pathway.SAC3D1 did not modulate the transcription ofβ-Catenin,while might inhibit its degradation.Further investigations indicated that the increase of SAC3D1 leads to moreβ-Catenin accumulating in the nucleus,facilitating the expression of c-Myc,one of the upstream regulatory factors of glycolysis.The iCRT3,an antagonist ofβ-Catenin,could counteract the increase of c-Myc induced by SAC3D1,while also downregulating the expression of glycolysis-related proteins.CONCLUSION This study found that SAC3D1 enhances HCC cell glycolysis and ATP production via theβ-Catenin/c-Myc signaling axis,thereby promoting the progression of HCC.
基金Supported by the Quzhou Science and Technology Plan Project,No.2022K69.
文摘Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, growingevidence indicates that AR dysfunction also disrupts systemic metabolic homeostasis, predisposing affectedindividuals to insulin resistance and type 2 diabetes mellitus. This article synthesizes recent advances in genetics,transcriptomics, and physiology to elucidate how AR mutations drive tissue-specific metabolic reprogramming inkey organs, including pancreatic β-cells, skeletal muscle, liver, and adipose tissue. Particular attention is given to anewly identified familial AR variant (c.2117A>G;p.Asn706Ser), which not only broadens the known mutationalspectrum of AIS but also underscores the clinical importance of early metabolic risk screening in this population.We further examine how pubertal stage, hormone replacement therapy, and sex-specific signaling pathwaysinteract to influence long-term metabolic outcomes. Lastly, we propose an integrative management framework thatincorporates genetic diagnosis, endocrine surveillance, and personalized pharmacological strategies aimed atreducing the risk of type 2 diabetes mellitus and cardiometabolic complications in individuals with AIS. Distinctfrom previous AIS-centered reviews, this work integrates metabolic and endocrine perspectives into the traditionaldevelopmental paradigm, offering a more comprehensive understanding of disease risk and translational management.
基金supported by the National Natural Science Foundation of China(Nos.82074150 and 82274240)the Natural Science Foundation of Sichuan Province(No.2023NSFSC1779).
文摘Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabolic reprogramming(EMR)in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD.Jiawei Xionggui Decoction(JWXG)has demonstrated effectiveness in enhancing energy supply,protecting microglia,and mitigating cognitive impairment in APP/PS1 mice.However,the mechanism by which JWXG enhances Aβphagocytosis through TREM2-mediated EMR in microglia remains unclear.This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR.Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo.The EMR level of microglia was assessed using high-performance liquid chromatography(HPLC)and enzyme-linked immunosorbent assay(ELISA)kits.The TREM2/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor-1α(HIF-1α)signaling pathway was analyzed using Western blotting in BV_(2) cells.TREM2^(−/−)BV_(2) cells were utilized for reverse validation experiments.The Aβburden,neuropathological features,and cognitive ability in APP/PS1 mice were evaluated using ELISA kits,immunohistochemistry(IHC),and the Morris water maze(MWM)test.JWXG enhanced both the phagocytosis of EMR disorder-BV_(2) cells(EMRD-BV_(2))and increased EMR levels.Notably,these effects were significantly reversed in TREM2^(−/−)BV_(2) cells.JWXG elevated TREM2 expression,adenosine triphosphate(ATP)levels,and microglial phagocytosis in APP/PS1 mice.Additionally,JWXG reduced Aβ-burden,neuropathological lesions,and cognitive deficits in APP/PS1 mice.In conclusion,JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis,thereby reducing Aβdeposition,improving neuropathological lesions,and alleviating cognitive deficits.
基金supported by the National Natural Science Foundation of China,No.31960120Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(both to ZW).
文摘Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.
基金supported by the National Natural Science Foundation of China(31930115,32173007)China Agriculture Research System of MOF and MARA(CARS-47-G16)Basic and Applied Basic Research Foundation of Guangdong Province(2022A1515010595)。
文摘Iridovirus poses a substantial threat to global aquaculture due to its high mortality rate;however,the molecular mechanisms underpinning its pathogenesis are not well elucidated.Here,a multi-omics approach was applied to groupers infected with Singapore grouper iridovirus(SGIV),focusing on the roles of key metabolites.Results showed that SGIV induced obvious histopathological damage and changes in metabolic enzymes within the liver.Furthermore,SGIV significantly reduced the contents of lipid droplets,triglycerides,cholesterol,and lipoproteins.Metabolomic analysis indicated that the altered metabolites were enriched in 19 pathways,with a notable down-regulation of lipid metabolites such as glycerophosphates and alpha-linolenic acid(ALA),consistent with disturbed lipid homeostasis in the liver.Integration of transcriptomic and metabolomic data revealed that the top enriched pathways were related to cell growth and death and nucleotide,carbohydrate,amino acid,and lipid metabolism,supporting the conclusion that SGIV infection induced liver metabolic reprogramming.Further integrative transcriptomic and proteomic analysis indicated that SGIV infection activated crucial molecular events in a phagosome-immune depression-metabolism dysregulation-necrosis signaling cascade.Of note,integrative multi-omics analysis demonstrated the consumption of ALA and linoleic acid(LA)metabolites,and the accumulation of L-glutamic acid(GA),accompanied by alterations in immune,inflammation,and cell death-related genes.Further experimental data showed that ALA,but not GA,suppressed SGIV replication by activating antioxidant and anti-inflammatory responses in the host.Collectively,these findings provide a comprehensive resource for understanding host response dynamics during fish iridovirus infection and highlight the antiviral potential of ALA in the prevention and treatment of iridoviral diseases.
基金supported by the National Natural Science Foundation of China(82203185,82230058,82172875 and 82073094)the National Key Research and Development Program of China(2021YFF1201300 and 2022YFE0103600)+3 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-014,2021-I2M-1-022,and 2022-I2M-2-001)the Open Issue of State Key Laboratory of Molecular Oncology(SKL-KF-2021-16)the Independent Issue of State Key Laboratory of Molecular Oncology(SKL-2021-16)the Beijing Hope Marathon Special Fund of Chinese Cancer Foundation(LC2020B14).
文摘Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.
基金supported by Stavros Niarhos FoundationGreek‘Flagship Action for the Study of Neurodegenerative Diseases on the Basis of Precision Medicine’(to DT).
文摘Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic,transcriptional,and post-transcriptional regulation.Understanding these neurogenic mechanisms is of major importance,not only for shedding light on very complex and crucial developmental processes,but also for the identification of putative reprogramming factors,that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate.The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors,as well as repressor complexes,have been identified and employed in direct reprogramming protocols to convert non-neuronal cells,into functional neurons.The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer,strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function.In particular,recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis,such as alternative splicing,polyadenylation,stability,and translation.Apart from the RNA binding proteins,microRNAs,a class of small non-coding RNAs that block the translation of their target mRNAs,have also been shown to play crucial roles in all the stages of the neurogenic process,from neural stem/progenitor cell proliferation,neuronal differentiation and migration,to functional maturation.Here,we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process,giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs.Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming,we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors,highlighting the so far known mechanisms of their reprogramming action.
