Retrotransposons account for a large proportion of the genome and genomic variation, and play key roles in creating novel genes and diversifying the genome in many eukaryotic species. Although retrotransposons are abu...Retrotransposons account for a large proportion of the genome and genomic variation, and play key roles in creating novel genes and diversifying the genome in many eukaryotic species. Although retrotransposons are abundant in plants, their roles had been underestimated because of a lack of research. Here, we characterized a gibberellin Acid (GA)-insensitive dwarf mutant, 84133, in foxtail millet. Map-based cloning revealed a 5.5-kb Copia-like retrotransposon insertion in DWARF1 (D1), which encodes a DELLA protein. Transcriptional analysis showed that the Copia retrotransposon mediated the transcriptional reprogramming of D1 leading to a novel N-terminal-deleted truncated DELLA transcript that was putatively driven by Copia's LTR, namely D1-TT, and another chimeric transcript. The presence of D1-TT was confirmed by protein immunodetection analysis. Furthermore, D1-TT protein was resistant to GA3 treatment compared with the intact DELLA protein due to its inability to interact with the GA receptor, SiGID1. Overexpression of D1-TT in foxtail millet resulted in dwarf plants, confirming that it determines the dwarfism of 84133. Thus, our study documents a rare instance of long terminal repeat (LTR) retrotransposon-mediated transcriptional reprograming in the plant kingdom. These results shed light on the function of LTR retrotransposons in generating new gene functions and genetic diversity.展开更多
Long COVID is characterized by a group of persistent symptoms following the acute SARS-COV2 infection, which presented a multifaceted challenge to the healthcare systems all over the globe. The long COVID symptoms spa...Long COVID is characterized by a group of persistent symptoms following the acute SARS-COV2 infection, which presented a multifaceted challenge to the healthcare systems all over the globe. The long COVID symptoms span various organ systems including the respiratory, cardiovascular, gastrointestinal, and neurological manifestations. Mitochondrial dysfunction and immune dysregulation play crucial roles in the long COVID pathophysiology. Recently nutritional intervention gained much attention in managing post-viral syndromes. Effective interventions like supplementation of omega-3 fatty acid, macro and micro nutrients, and vitamins help to reduce systemic inflammation and counteract muscle wasting. Other approaches like nutritional recovery, dietetic interventions, continuous nutritional care post-hospital discharge, nutritional rehabilitation programs,whole-diet approaches like Mediterranean diet, plant-based diet, and caloric optimization, improve overall functional recovery. Physical activity and exercise regimes have been shown to improve fatigue, dyspnea, and cognitive function. Tailored exercise regimes may promote safe rehabilitation. Certain ineffective interventions,such as non-personalized approaches, high dose of antioxidants, use of herbal products that are not clinically validated need to be addressed. Dietary interventions such as personalized nutritional counseling have been demonstrated to improve physical performance in long COVID patients. Further research is needed to refine protocols and identify optimal combinations of dietary and movement-based therapies to support the recovery of long-COVID patients. This narrative review focuses on the ongoing researches that reveals the intricate relationship between nutrition and long COVID recovery and also establishes effective protocols for nutritional care.展开更多
Tumor metabolic reprogramming is a core hallmark of cancer,characterized by pathways such as aerobic glycolysis,aberrant lipid metabolism,and glutaminolysis that support rapid proliferation and immunosuppressive micro...Tumor metabolic reprogramming is a core hallmark of cancer,characterized by pathways such as aerobic glycolysis,aberrant lipid metabolism,and glutaminolysis that support rapid proliferation and immunosuppressive microenvironments.Circular RNAs(circRNAs)are highly stable,evolutionarily conserved non-coding RNAs that have emerged as critical modulators of these metabolic shifts.This review aims to systematically elucidate the roles and mechanisms of circRNAs in reprogramming tumor metabolism,and to discuss their clinical potential as biomarkers and therapeutic targets.Through mechanisms including miRNA sponging,protein interactions,regulation of mitochondrial dynamics,and modulation of metabolic enzymes,circRNAs influence key metabolic pathways by targeting glycolytic enzymes,lipid synthesis regulators,and glutaminolysis-related molecules to either facilitate or inhibit their expression.This review systematically summarizes the unique contributions of circRNAs to tumor metabolic reprogramming,highlighting key mechanisms such as regulation of peptide-encoding protein translation,mitochondrial localization function,gene promoter-targeted transcriptional regulation,and cross-pathway metabolic mediation,which underscore their distinct biological advantages and regulatory roles in tumor metabolism.The stability and tissue specificity of circRNAs make them promising diagnostic biomarkers,while their role in drug resistance mediated by metabolic reprogramming highlights their potential as therapeutic targets.Strategies such as circRNA inhibitors,mimics,and nanoparticle-based delivery systems are being explored to modulate tumor metabolism.Despite challenges including complex regulatory networks and limited manipulation tools,advances in high-throughput technologies and clinical trials hold promise for translating circRNA research into novel cancer therapies.展开更多
Background:Gastric cancer(GC)remains highly lethal,with metabolic reprogramming as a key hallmark.This study explores Centromere Protein F(CENPF)’s role in GC pathogenesis,specifically its regulation of glutamine met...Background:Gastric cancer(GC)remains highly lethal,with metabolic reprogramming as a key hallmark.This study explores Centromere Protein F(CENPF)’s role in GC pathogenesis,specifically its regulation of glutamine metabolism.Methods:The Cancer Genome Atlas-Stomach Adenocarcinoma(TCGA-STAD),GSE19826,and GSE27342 datasets were analyzed by bioinformatics to identify key candidate genes in GC.The function of CENPF was assessed by flow cytometry,colony formation assays,and Cell Counting Kit-8(CCK-8).RNA sequencing,metabolic profiling,chromatin immunoprecipitation(ChIP),western blot(WB),and luciferase reporter assay were employed to investigate the fundamental mechanisms.Results:CENPF was upregulated in GC tumor samples and had a high diagnostic potential.CENPF knockdown declined cell proliferation,caused G2 arrest,and promoted apoptosis in GC cells.RNA sequencing revealed that CENPF was involved in glutamine metabolism.CENPF overexpression enhanced glutamine consumption and glutamate production,while glutamine deficiency reversed CENPF-mediated cell survival.CENPF stabilized cellular myelocytomatosis(c-Myc)by preventing proteasomal degradation,bound to the glutaminase(GLS)promoter,promoting glutamine metabolism.Overexpression of GLS or c-Myc rescued the CENPF knockdown’s inhibitory effect on GC cell growth.Conclusion:Our findings identify a new CENPF/c-Myc/GLS axis that affects glutamine metabolism and cell survival in GC,implying that CENPF might be a novel target for the treatment of GC.展开更多
Metabolic reprogramming involving branched-chain amino acids(BCAAs)—leucine,isoleucine,and valine—is increasingly recognized as pivotal in cancer progression,metastasis,and immune modulation.This review comprehensiv...Metabolic reprogramming involving branched-chain amino acids(BCAAs)—leucine,isoleucine,and valine—is increasingly recognized as pivotal in cancer progression,metastasis,and immune modulation.This review comprehensively explores how cancer cells rewire BCAA metabolism to enhance proliferation,survival,and therapy resistance.Tumors manipulate BCAA uptake and catabolism via high expression of transporters like L-type amino acid transporter 1(LAT1)and enzymes including branched chain amino acid transaminase 1(BCAT1),branched chain amino acid transaminase 2(BCAT2),branched-chain alpha-keto acid dehydrogenase(BCKDH),and branched chain alpha-keto acid dehydrogenase kinase(BCKDK).These alterations sustain energy production,biosynthesis,redox homeostasis,and oncogenic signaling(especially mammalian target of rapamycin complex 1[mTORC1]).Crucially,tumor-driven BCAA depletion also shapes an immunosuppressive microenvironment,impairing anti-tumor immunity by limiting essential nutrients for T cells and natural killer(NK)cells.Innovative therapeutic strategies targeting BCAA pathways—ranging from selective small-molecule inhibitors(e.g.,LAT1 and BCAT1/2)to dietary modulation—have shown promising preclinical and early clinical efficacy,highlighting their potential to exploit metabolic vulnerabilities in cancer cells while bolstering immune responses.By integrating multi-omics data and precision targeting approaches,this review underscores the translational significance of BCAA metabolic reprogramming,positioning it as a novel frontier in cancer treatment.展开更多
Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment.Hypoxia-inducible factor-1α(HIF1α)enhances glycolytic flux,lactate accumulat...Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment.Hypoxia-inducible factor-1α(HIF1α)enhances glycolytic flux,lactate accumulation,and histone lactylation,collectively supporting metastatic colonization and immune evasion.Key metabolites including acetyl-CoA,S-adenosylmethionine(SAM),α-ketoglutarate(α-KG),fumarate,and 2-hydroxyglutarate(2-HG)-directly modify chromatin states by regulating histone acetyltransferases,DNA/histone methyltransferases,andα-KG dependent dioxygenases such as Ten-Eleven Translocation(TET)enzymes and lysine demethylases(KDMs).These metabolic shifts result in aberrant DNA methylation,histone lysine residue at position 27 on Histone H3(H3K27)trimethylation,and depletion of 5-hydroxymethylcytosine(5hmC),all of which are hallmark epigenetic alterations in brain metastasis and primary Central Nervous System(CNS)tumors.Additionally,the blood-brain barrier(BBB)and blood-tumor barrier(BTB)impose nutrient restrictions and induce metabolic dependency on glutamine,acetate,and lactate shuttling,thereby reshaping epigenetic enzyme activity.We synthesize current mechanistic evidence showing how metabolic pressures in the brain microenvironment remodel the epigenome to promote tumor plasticity,stemness,and therapeutic resistance.Understanding these coupled pathways reveals vulnerable nodes such as HIF1αsignaling,α-KG-dependent demethylation,and lactate-driven epigenetic remodeling that may be exploited for targeted treatment of metastatic brain tumors.The present review aims to provide in-depth insights into epigenetic regulation,including chromatin and histone modifications as well as noncoding RNAs and metabolic reprogramming,highlighting how the two interplay in the development and progression of metastatic brain tumors and their therapeutic potential.展开更多
Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual pat...Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual patient responses towards different drugs.This study aimed to investigate the patient-derived breast cancer culture models for drug sensitivity evaluations.Methods:Tumor and adjacent tissues from female breast cancer patients were collected during surgery.Patient-derived breast cancer cells were cultured using the conditional reprogramming technique to establish 2D models.The obtained patient-derived conditional reprogramming breast cancer(CRBC)cells were subsequently embedded in alginate-gelatin methacryloyl hydrogel microspheres to form 3D culture models.Comparisons between 2D and 3D models were made using immunohistochemistry(tumor markers),MTS assays(cell viability),flow cytometry(apoptosis),transwell assays(migration),and Western blotting(protein expression).Drug sensitivity tests were conducted to evaluate patient-specific responses to anti-cancer agents.Results:2D and 3D culture models were successfully established using samples from eight patients.The 3D models retained histological and marker characteristics of the original tumors.Compared to 2D cultures,3D models exhibited increased apoptosis,enhanced drug resistance,elevated stem cell marker expression,and greater migration ability—features more reflective of in vivo tumor behavior.Conclusion:Patient-derived 3D CRBC models effectively mimic the in vivo tumor microenvironment and demonstrate stronger resistance to anti-cancer drugs than 2D models.These hydrogel-based models offer a cost-effective and clinically relevant platform for drug screening and personalized breast cancer treatment.展开更多
Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechani...Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechanism through which metabolic reprogramming remodels the TME in HCC.Methods:HCC patient transcriptome data were subjected to bioinformatics analysis to identify differentially expressed genes and immune infiltration status.Immunohistochemical analysis was performed to determine the correlation between succinate dehydrogenase complex subunit A(SDHA)expression and M2 macrophage infiltration.SDHA-knockdown or SDHA-overexpressing HCC cells were used for in vitro experiments,including co-culturing,flow cytometry,and enzyme-linked immunosorbent assay.Western blotting assay,functional assays,and subcutaneous tumor model mice were used to elucidate the molecular mechanisms underlying succinate-mediated HCC cell-macrophage interactions in the TME.Results:Higher infiltration of M2 macrophages correlated with worse prognosis in HCC patients.SDHA was downregulated in HCC tumor tissues and showed a negative correlation with M2 macrophage infiltration.SDHA knockdown promoted M2 macrophage polarization,whereas SDHA overexpression reversed this effect.Mechanistically,SDHA deficiency in HCC cells induced succinate accumulation,which promoted M2 macrophage polarization by activating the G protein-coupled receptor 91(GPR91)/signal transducer and activator of transcription 3(STAT3)pathway.Concurrently,succinate stimulation enhanced mitochondrial oxidative phosphorylation in M2 macrophages,thereby promoting HCC progression.Serum succinate levels were elevated in HCC patients.The receiver operating characteristic curve analysis indicated that serum succinate is a promising diagnostic marker for HCC(area under the curve=0.815).Conclusion:SDHA deficiency leads to succinate accumulation,which promotes M2 macrophage polarization through the GPR91/STAT3 pathway,thereby facilitating HCC progression.Based on these findings,serum succinate could be a promising diagnostic biomarker for HCC.展开更多
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
Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders....Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.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
Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy...Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation.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
Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the up...Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the upstream regulatory mechanisms linking neural inputs to immune evasion and metabolic reprogramming remain incompletely understood.We systematically summarize current evidence from molecular,cellular,and immunological studies to elucidate how neurotransmitter-dependent mechanisms drive dynamic changes in the tumor microenvironment through the regulation of tumor cells and immune cells,and map the complex interaction networks between the nervous system and tumor progression.We propose a unifying“neuro-metabolic-immune axis”framework that highlights the dual role of neurotransmitters in suppressing anti-tumor immunity and facilitating tumor adaptation.By mapping this axis,we reveal new insights into tumor ecology and identify neural pathways as promising therapeutic targets.Targeting these pathways may enhance immunotherapy and disrupt tumor-supportive metabolism,offering new directions in precision oncology.展开更多
Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefo...Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China (31871634, 31500985)
文摘Retrotransposons account for a large proportion of the genome and genomic variation, and play key roles in creating novel genes and diversifying the genome in many eukaryotic species. Although retrotransposons are abundant in plants, their roles had been underestimated because of a lack of research. Here, we characterized a gibberellin Acid (GA)-insensitive dwarf mutant, 84133, in foxtail millet. Map-based cloning revealed a 5.5-kb Copia-like retrotransposon insertion in DWARF1 (D1), which encodes a DELLA protein. Transcriptional analysis showed that the Copia retrotransposon mediated the transcriptional reprogramming of D1 leading to a novel N-terminal-deleted truncated DELLA transcript that was putatively driven by Copia's LTR, namely D1-TT, and another chimeric transcript. The presence of D1-TT was confirmed by protein immunodetection analysis. Furthermore, D1-TT protein was resistant to GA3 treatment compared with the intact DELLA protein due to its inability to interact with the GA receptor, SiGID1. Overexpression of D1-TT in foxtail millet resulted in dwarf plants, confirming that it determines the dwarfism of 84133. Thus, our study documents a rare instance of long terminal repeat (LTR) retrotransposon-mediated transcriptional reprograming in the plant kingdom. These results shed light on the function of LTR retrotransposons in generating new gene functions and genetic diversity.
基金Chung Shan Medical University, Taichung city, Taiwan China, for its support。
文摘Long COVID is characterized by a group of persistent symptoms following the acute SARS-COV2 infection, which presented a multifaceted challenge to the healthcare systems all over the globe. The long COVID symptoms span various organ systems including the respiratory, cardiovascular, gastrointestinal, and neurological manifestations. Mitochondrial dysfunction and immune dysregulation play crucial roles in the long COVID pathophysiology. Recently nutritional intervention gained much attention in managing post-viral syndromes. Effective interventions like supplementation of omega-3 fatty acid, macro and micro nutrients, and vitamins help to reduce systemic inflammation and counteract muscle wasting. Other approaches like nutritional recovery, dietetic interventions, continuous nutritional care post-hospital discharge, nutritional rehabilitation programs,whole-diet approaches like Mediterranean diet, plant-based diet, and caloric optimization, improve overall functional recovery. Physical activity and exercise regimes have been shown to improve fatigue, dyspnea, and cognitive function. Tailored exercise regimes may promote safe rehabilitation. Certain ineffective interventions,such as non-personalized approaches, high dose of antioxidants, use of herbal products that are not clinically validated need to be addressed. Dietary interventions such as personalized nutritional counseling have been demonstrated to improve physical performance in long COVID patients. Further research is needed to refine protocols and identify optimal combinations of dietary and movement-based therapies to support the recovery of long-COVID patients. This narrative review focuses on the ongoing researches that reveals the intricate relationship between nutrition and long COVID recovery and also establishes effective protocols for nutritional care.
基金funded by National Natural Science Foundation of China(82360801).
文摘Tumor metabolic reprogramming is a core hallmark of cancer,characterized by pathways such as aerobic glycolysis,aberrant lipid metabolism,and glutaminolysis that support rapid proliferation and immunosuppressive microenvironments.Circular RNAs(circRNAs)are highly stable,evolutionarily conserved non-coding RNAs that have emerged as critical modulators of these metabolic shifts.This review aims to systematically elucidate the roles and mechanisms of circRNAs in reprogramming tumor metabolism,and to discuss their clinical potential as biomarkers and therapeutic targets.Through mechanisms including miRNA sponging,protein interactions,regulation of mitochondrial dynamics,and modulation of metabolic enzymes,circRNAs influence key metabolic pathways by targeting glycolytic enzymes,lipid synthesis regulators,and glutaminolysis-related molecules to either facilitate or inhibit their expression.This review systematically summarizes the unique contributions of circRNAs to tumor metabolic reprogramming,highlighting key mechanisms such as regulation of peptide-encoding protein translation,mitochondrial localization function,gene promoter-targeted transcriptional regulation,and cross-pathway metabolic mediation,which underscore their distinct biological advantages and regulatory roles in tumor metabolism.The stability and tissue specificity of circRNAs make them promising diagnostic biomarkers,while their role in drug resistance mediated by metabolic reprogramming highlights their potential as therapeutic targets.Strategies such as circRNA inhibitors,mimics,and nanoparticle-based delivery systems are being explored to modulate tumor metabolism.Despite challenges including complex regulatory networks and limited manipulation tools,advances in high-throughput technologies and clinical trials hold promise for translating circRNA research into novel cancer therapies.
基金funded by the Medical and Health Technology Development Programin Shandong Province.Project number:202303031600.
文摘Background:Gastric cancer(GC)remains highly lethal,with metabolic reprogramming as a key hallmark.This study explores Centromere Protein F(CENPF)’s role in GC pathogenesis,specifically its regulation of glutamine metabolism.Methods:The Cancer Genome Atlas-Stomach Adenocarcinoma(TCGA-STAD),GSE19826,and GSE27342 datasets were analyzed by bioinformatics to identify key candidate genes in GC.The function of CENPF was assessed by flow cytometry,colony formation assays,and Cell Counting Kit-8(CCK-8).RNA sequencing,metabolic profiling,chromatin immunoprecipitation(ChIP),western blot(WB),and luciferase reporter assay were employed to investigate the fundamental mechanisms.Results:CENPF was upregulated in GC tumor samples and had a high diagnostic potential.CENPF knockdown declined cell proliferation,caused G2 arrest,and promoted apoptosis in GC cells.RNA sequencing revealed that CENPF was involved in glutamine metabolism.CENPF overexpression enhanced glutamine consumption and glutamate production,while glutamine deficiency reversed CENPF-mediated cell survival.CENPF stabilized cellular myelocytomatosis(c-Myc)by preventing proteasomal degradation,bound to the glutaminase(GLS)promoter,promoting glutamine metabolism.Overexpression of GLS or c-Myc rescued the CENPF knockdown’s inhibitory effect on GC cell growth.Conclusion:Our findings identify a new CENPF/c-Myc/GLS axis that affects glutamine metabolism and cell survival in GC,implying that CENPF might be a novel target for the treatment of GC.
基金supported by a grant from the Dalian Science and Technology Innovation Fund Program(No.2024JJ13PT070)United Foundation for Dalian Institute of Chemical Physics,Chinese Academy of Sciences and the Second Hospital of Dalian Medical University(No.DMU-2&DICP UN202410)Dalian Life and Health Field Guidance Program Project(No.2024ZDJH01PT084).
文摘Metabolic reprogramming involving branched-chain amino acids(BCAAs)—leucine,isoleucine,and valine—is increasingly recognized as pivotal in cancer progression,metastasis,and immune modulation.This review comprehensively explores how cancer cells rewire BCAA metabolism to enhance proliferation,survival,and therapy resistance.Tumors manipulate BCAA uptake and catabolism via high expression of transporters like L-type amino acid transporter 1(LAT1)and enzymes including branched chain amino acid transaminase 1(BCAT1),branched chain amino acid transaminase 2(BCAT2),branched-chain alpha-keto acid dehydrogenase(BCKDH),and branched chain alpha-keto acid dehydrogenase kinase(BCKDK).These alterations sustain energy production,biosynthesis,redox homeostasis,and oncogenic signaling(especially mammalian target of rapamycin complex 1[mTORC1]).Crucially,tumor-driven BCAA depletion also shapes an immunosuppressive microenvironment,impairing anti-tumor immunity by limiting essential nutrients for T cells and natural killer(NK)cells.Innovative therapeutic strategies targeting BCAA pathways—ranging from selective small-molecule inhibitors(e.g.,LAT1 and BCAT1/2)to dietary modulation—have shown promising preclinical and early clinical efficacy,highlighting their potential to exploit metabolic vulnerabilities in cancer cells while bolstering immune responses.By integrating multi-omics data and precision targeting approaches,this review underscores the translational significance of BCAA metabolic reprogramming,positioning it as a novel frontier in cancer treatment.
文摘Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment.Hypoxia-inducible factor-1α(HIF1α)enhances glycolytic flux,lactate accumulation,and histone lactylation,collectively supporting metastatic colonization and immune evasion.Key metabolites including acetyl-CoA,S-adenosylmethionine(SAM),α-ketoglutarate(α-KG),fumarate,and 2-hydroxyglutarate(2-HG)-directly modify chromatin states by regulating histone acetyltransferases,DNA/histone methyltransferases,andα-KG dependent dioxygenases such as Ten-Eleven Translocation(TET)enzymes and lysine demethylases(KDMs).These metabolic shifts result in aberrant DNA methylation,histone lysine residue at position 27 on Histone H3(H3K27)trimethylation,and depletion of 5-hydroxymethylcytosine(5hmC),all of which are hallmark epigenetic alterations in brain metastasis and primary Central Nervous System(CNS)tumors.Additionally,the blood-brain barrier(BBB)and blood-tumor barrier(BTB)impose nutrient restrictions and induce metabolic dependency on glutamine,acetate,and lactate shuttling,thereby reshaping epigenetic enzyme activity.We synthesize current mechanistic evidence showing how metabolic pressures in the brain microenvironment remodel the epigenome to promote tumor plasticity,stemness,and therapeutic resistance.Understanding these coupled pathways reveals vulnerable nodes such as HIF1αsignaling,α-KG-dependent demethylation,and lactate-driven epigenetic remodeling that may be exploited for targeted treatment of metastatic brain tumors.The present review aims to provide in-depth insights into epigenetic regulation,including chromatin and histone modifications as well as noncoding RNAs and metabolic reprogramming,highlighting how the two interplay in the development and progression of metastatic brain tumors and their therapeutic potential.
基金supported by the Natural Science Foundation of Guangdong Province(No.2021B1515120053)Guangdong Basic and Applied Basic Research Foundation(Grant No.2024A1515140166).
文摘Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual patient responses towards different drugs.This study aimed to investigate the patient-derived breast cancer culture models for drug sensitivity evaluations.Methods:Tumor and adjacent tissues from female breast cancer patients were collected during surgery.Patient-derived breast cancer cells were cultured using the conditional reprogramming technique to establish 2D models.The obtained patient-derived conditional reprogramming breast cancer(CRBC)cells were subsequently embedded in alginate-gelatin methacryloyl hydrogel microspheres to form 3D culture models.Comparisons between 2D and 3D models were made using immunohistochemistry(tumor markers),MTS assays(cell viability),flow cytometry(apoptosis),transwell assays(migration),and Western blotting(protein expression).Drug sensitivity tests were conducted to evaluate patient-specific responses to anti-cancer agents.Results:2D and 3D culture models were successfully established using samples from eight patients.The 3D models retained histological and marker characteristics of the original tumors.Compared to 2D cultures,3D models exhibited increased apoptosis,enhanced drug resistance,elevated stem cell marker expression,and greater migration ability—features more reflective of in vivo tumor behavior.Conclusion:Patient-derived 3D CRBC models effectively mimic the in vivo tumor microenvironment and demonstrate stronger resistance to anti-cancer drugs than 2D models.These hydrogel-based models offer a cost-effective and clinically relevant platform for drug screening and personalized breast cancer treatment.
基金supported by the Central Government-Guided Local Science and Technology Development Fund Project(Science and Technology Innovation Base Project)(Grant No.236Z7749G)Hebei Provincial Precision Medicine Innovation and Development Joint Fund Incubation Project(Grant No.H2025206547)Hebei Provincial Basic Research Special Youth Science Fund Project(Grant No.H2025206274).
文摘Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechanism through which metabolic reprogramming remodels the TME in HCC.Methods:HCC patient transcriptome data were subjected to bioinformatics analysis to identify differentially expressed genes and immune infiltration status.Immunohistochemical analysis was performed to determine the correlation between succinate dehydrogenase complex subunit A(SDHA)expression and M2 macrophage infiltration.SDHA-knockdown or SDHA-overexpressing HCC cells were used for in vitro experiments,including co-culturing,flow cytometry,and enzyme-linked immunosorbent assay.Western blotting assay,functional assays,and subcutaneous tumor model mice were used to elucidate the molecular mechanisms underlying succinate-mediated HCC cell-macrophage interactions in the TME.Results:Higher infiltration of M2 macrophages correlated with worse prognosis in HCC patients.SDHA was downregulated in HCC tumor tissues and showed a negative correlation with M2 macrophage infiltration.SDHA knockdown promoted M2 macrophage polarization,whereas SDHA overexpression reversed this effect.Mechanistically,SDHA deficiency in HCC cells induced succinate accumulation,which promoted M2 macrophage polarization by activating the G protein-coupled receptor 91(GPR91)/signal transducer and activator of transcription 3(STAT3)pathway.Concurrently,succinate stimulation enhanced mitochondrial oxidative phosphorylation in M2 macrophages,thereby promoting HCC progression.Serum succinate levels were elevated in HCC patients.The receiver operating characteristic curve analysis indicated that serum succinate is a promising diagnostic marker for HCC(area under the curve=0.815).Conclusion:SDHA deficiency leads to succinate accumulation,which promotes M2 macrophage polarization through the GPR91/STAT3 pathway,thereby facilitating HCC progression.Based on these findings,serum succinate could be a promising diagnostic biomarker for HCC.
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 Key Project of Guangzhou City,No.202206060002Science and Technology Project of Guangdong Province,No.2018B030332001Guangdong Provincial Pearl River Project,No.2021ZT09Y552 (all to GC)。
文摘Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.
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Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation.
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 National Natural Science Foundation of China,No.82272719the Natural Science Foundation of Guangdong Province,No.2023A1515012724 and No.2024A1515013249the Science and Technology Projects in Guangzhou,No.2024A04J5205.
文摘Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the upstream regulatory mechanisms linking neural inputs to immune evasion and metabolic reprogramming remain incompletely understood.We systematically summarize current evidence from molecular,cellular,and immunological studies to elucidate how neurotransmitter-dependent mechanisms drive dynamic changes in the tumor microenvironment through the regulation of tumor cells and immune cells,and map the complex interaction networks between the nervous system and tumor progression.We propose a unifying“neuro-metabolic-immune axis”framework that highlights the dual role of neurotransmitters in suppressing anti-tumor immunity and facilitating tumor adaptation.By mapping this axis,we reveal new insights into tumor ecology and identify neural pathways as promising therapeutic targets.Targeting these pathways may enhance immunotherapy and disrupt tumor-supportive metabolism,offering new directions in precision oncology.
基金supported by the Science and Technology Research Project of Jilin Education Bureau(No.JJKH20230804KJ)。
文摘Immunotherapy offers the promise of a potential cure for cancer,yet achieving the desired therapeutic effect can be challenging due to the immunosuppressive tumor microenvironments(TMEs) present in some tumors.Therefore,robust immune system activation is crucial to enhance the efficacy of cancer immunotherapy in clinical applications.Bacteria have shown the ability to target the hypoxic TMEs while activating both innate and adaptive immune responses.Engineered bacteria,modified through chemical or biological methods,can be endowed with specific physiological properties,such as diverse surface antigens,metabolites,and improved biocompatibility.These unique characteristics give engineered bacteria distinct advantages in stimulating anti-cancer immune responses.This review explores the potential regulatory mechanisms of engineered bacteria in modulating both innate and adaptive immunity while also forecasting the future development and challenges of using engineered bacteria in clinical cancer immunotherapy.
