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
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
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
The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration.Adequate energy production forms the cornerstone supporting new bone formation.ET...The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration.Adequate energy production forms the cornerstone supporting new bone formation.ETS variant 2(ETV2)has been identified as a transcription factor that promotes energy metabolism reprogramming and facilitates the coordination between osteogenesis and angiogenesis.In vitro molecular experiments have demonstrated that ETV2 enhances osteogenic differentiation of dental pulp stem cells(DPSCs)by regulating the ETV2-prolyl hydroxylase 2(PHD2)-hypoxia-inducible factor-1α(HIF-1α)-vascular endothelial growth factor A(VEGFA)axis.Notably,ETV2 achieves the rapid reprogramming of energy metabolism by simultaneously accelerating mitochondrial aerobic respiration and glycolysis,thus fulfilling the energy requirements essential to expedite osteogenic differentiation.Furthermore,decreasedα-ketoglutarate release from ETV2-modified DPSCs contributes to microcirculation reconstruction.Additionally,we engineered hydroxyapatite/chitosan microspheres(HA/CS MS)with biomimetic nanostructures to facilitate multiple ETV2-DPSC functions and further enhanced the osteogenic differentiation.Animal experiments have validated the synergistic effect of ETV2-modified DPSCs and HA/CS MS in promoting the critical-size bone defect regeneration.In summary,this study offers a novel treatment approach for vascularized bone tissue regeneration that relies on energy metabolism activation and the maintenance of a stable local hypoxia signaling state.展开更多
Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies.However,a significant proportion of HCC patients exhibit poor responses.Lipid metabolic...Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies.However,a significant proportion of HCC patients exhibit poor responses.Lipid metabolic heterogeneity is considered a key driver of cancer progression.However,the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood.Herein,we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response.Patients who received PD-1/PD-L1 inhibitors were enrolled.The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models.Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism.To address HCC immunotherapy resistance,we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine(GalNAc)to conjugate siTACC3.Through clinical cohort analysis,we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy.Furthermore,we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8^(+)T lymphocytes.Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid(PUFA)metabolism in HCC cells.Additionally,TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1,which stabilize ACSL4 mRNA.The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC.In summary,tumor-derived TACC3 impairs the tumor-killing activity of CD8^(+)T lymphocytes through PUFA metabolism-associated crosstalk.Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against 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
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
Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garner...Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garnered significant attention due to its profound impact on cancer cells and the tumor microenvironment(TME).Arginine,a semi-essential amino acid,has a central role in various cellular processes,including protein synthesis,nitric oxide(NO)production,and polyamine biosynthesis.In the context of cancer aberrant arginine metabolism fuels tumor cell growth and orchestrates a complex interplay between tumor and immune cells,ultimately facilitating immune evasion and tumor progression.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
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
OBJECTIVE:To uncover the biological foundation of the prevailing TCM syndrome in individuals with Esophageal squamous cell carcinoma(ESCC),Zhengxu Xieshi(ZXXS),which is characterized by a deficiency in vital Qi and an...OBJECTIVE:To uncover the biological foundation of the prevailing TCM syndrome in individuals with Esophageal squamous cell carcinoma(ESCC),Zhengxu Xieshi(ZXXS),which is characterized by a deficiency in vital Qi and an excess in evil Qi.METHODS:We investigated shifts in vital Qi by quantifying systemic metabolic changes in the peripheral blood.Serum metabolomic profiling was conducted on the ESCC cohort 1 along with a matched healthy control cohort.Additionally,we assessed changes in evil Qi by examining metabolic perturbations in ESCC tissues.This analysis involved metabolomic and proteomic surveys of ESCC tissues and paired normal adjacent tissues as controls in an independent ESCC cohort 2.RESULTS:Serum metabolomic profiling highlighted the prevalent downregulation of differentially expressed metabolites in patient sera,in contrast to the upregulation observed in ESCC tissues,compared to their respective controls.Remarkably,the group of differential metabolites in the ESCC tissues was predominantly composed of amino acids.Thus,we focused on amino acid metabolism.Our integrative analysis showed the downregulation of a significant majority of disturbed amino acids in patient sera relative to the upregulation of an overwhelming proportion of perturbed amino acids within ESCC tissues.Enrichment analysis of these amino acids revealed seven metabolic pathways that contribute to the metabolism of antioxidants,energy intermediates,and biosynthetic precursors.Interestingly,these pathways displayed attenuation in patient sera but augmentation in ESCC tissues.Similarly,the proteomic data confirmed the activation of these pathways in ESCC tissues.CONCLUSION:This study presents a new perspective on the prevalence of ZXXS syndrome in patients with ESCC,contextualized within the realm of metabolic reprogramming.Specifically,diminished amino acid metabolism in the circulating blood corresponds to a deficiency in vital Qi.Conversely,hyperactive amino acid metabolism in ESCC tissues signifies an augmentation of local evil Qi.These findings hold potential to enrich the current medical framework and offer a deeper understanding of ESCC management by integrating the principles of ZXXS syndrome.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
Lipid metabolism plays a pivotal role in gastric cancer(GC)progression,characterized by complex metabolic reprogramming that supports tumor growth and survival.This narrative review comprehensively examines the dysreg...Lipid metabolism plays a pivotal role in gastric cancer(GC)progression,characterized by complex metabolic reprogramming that supports tumor growth and survival.This narrative review comprehensively examines the dysregulation of lipid metabolism-associated genes,including fatty acid synthase(FASN),ATPcitrate lyase,acetyl-CoA carboxylases,FA binding proteins,sterol regulatory element-binding proteins,and other key enzymes.These genes facilitate critical oncogenic processes by enhancing FA synthesis,modifying cellular signaling,and supporting cancer cell proliferation,migration,and therapy resistance.Metabolic adaptations observed in GC include increased de novo lipogenesis,altered enzymatic activities,and modified protein lipidation,which contribute to tumor aggressiveness.The review highlights the potential of targeting these metabolic pathways as a therapeutic strategy,demonstrating how inhibiting specific enzymes like FASN,ATP-citrate lyase,and stearoyl-CoA desaturase 1 can induce apoptosis,disrupt cancer stem cell properties,and potentially overcome treatment resistance.By elucidating the intricate interactions between lipid metabolism genes and cancer progression,this review provides insights into novel diagnostic and therapeutic approaches for managing GC.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
The theory of stagnation of collateral Qi(Chinese medicine refers to the most fundamental and subtle substances thatconstitute the human body and maintain life activities,and also has the meaning of physiological func...The theory of stagnation of collateral Qi(Chinese medicine refers to the most fundamental and subtle substances thatconstitute the human body and maintain life activities,and also has the meaning of physiological functions)originates from the theory of collateral disease,which refers to the deficiency of Qi in the body’s collaterals,the loss of Qi and blood,and the failure of stagnation of collateral Qi,which leads to the loss of Qi,blood and body fluid,and the formation of pathological products such as deficiency,depression,phlegm,blood stasis in the local area,and ultimately damage the pathological process of collaterals.Based on the in-depth study of the pathogenesis of collateral Qi stagnation and the previous study of meridian channels,we believe that the key pathogenesis of the formation,evolution and spread of malignant tumors is“collateral Qi deficiency stagnation,collateral Qi stagnation and collateral Qi decay”.As an important energy resonance channel of the body,meridians play a key role in the process of material transformation and energy metabolism.It is believed that the small focus caused by the pathogenesis of stagnation is the cause of malignant transformation of tumor,the reprogramming of energy metabolism induced by the lesion of collateral Qi is the basis of the progress of tumor pathogenesis,and the formation of tumor microenvironment regulated by the tumor toxin vena is the root of alienation of tumor development.Guided by this theory,focusing on the correlation between collateral Qi and tumor energy metabolism,using Professor Hua Baojin's treatment method of“Regulating Qi and detoxifying”to prescribe drugs can adjust collateral Qi function,achieve the relative balance of internal environment,and then inhibit the progress of tumor.Based on the above understanding,this study tries to enlighten new diagnosis and treatment ideas under the guidance of“stagnation of collateral Qi”in traditional Chinese medicine,in order to provide some theoretical support for the intervention of traditional Chinese medicine in the process of tumor development.展开更多
Hepatocellular carcinoma(HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due t...Hepatocellular carcinoma(HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.展开更多
Excessive reactive oxygen species(ROS)at severe burn injury sites may promote metabolic reprogramming of macrophages to induce a deteriorative and uncontrolled inflammation cycle,leading to delayed wound healing and r...Excessive reactive oxygen species(ROS)at severe burn injury sites may promote metabolic reprogramming of macrophages to induce a deteriorative and uncontrolled inflammation cycle,leading to delayed wound healing and regeneration.Here,a novel bioactive,anti-fouling,flexible polyzwitterionic hydrogel encapsulated with epigallocatechin gallate(EGCG)-copper(Cu)capsules(termed as EGCG-Cu@CBgel)is engineered for burn wound management,which is dedicated to synergistically exerting ROS-scavenging,immune metabolic regulation and pro-angiogenic effects.EGCG-Cu@CBgel can scavenge ROS to normalize intracellular redox homeostasis,effectively relieving oxidative damages and blocking proinflammatory signal transduction.Importantly,EGCG-Cu can inhibit the activity of hexokinase and phosphofructokinase,alleviate accumulation of pyruvate and convert it to acetyl coenzyme A(CoA),whereby inhibits glycolysis and normalizes tricarboxylic acid(TCA)cycle.Additionally,metabolic reprogramming of macrophages by EGCG-Cu downregulates M1-type polarization and the expression of proinflammatory cytokines both in vitro and in vivo.Meanwhile,copper ions(Cu^(2+))released from the hydrogel facilitate angiogenesis.EGCG-Cu@CBgel significantly accelerates the healing of severe burn wound via promoting wound closure,weakening tissue-damaging inflammatory responses and enhancing the remodeling of pathological structure.Overall,this study demonstrates the great potential of bioactive hydrogel dressing in treating burn wounds without unnecessary secondary damage to newly formed skin,and highlights the importance of immunometabolism modulation in tissue repair and regeneration.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
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 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.
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 National Natural Science Foundation of China (grants 82301039)the Natural Science Foundation of the Anhui Higher Education Institutions of China (grant 2022AH050758)+2 种基金Anhui Institute of Translational Medicine,Natural Sciences (grant 2022zhyx-C87)National Natural Science Foundation of China (82170951)Beijing Municipal Natural Science Foundation (7222079).
文摘The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration.Adequate energy production forms the cornerstone supporting new bone formation.ETS variant 2(ETV2)has been identified as a transcription factor that promotes energy metabolism reprogramming and facilitates the coordination between osteogenesis and angiogenesis.In vitro molecular experiments have demonstrated that ETV2 enhances osteogenic differentiation of dental pulp stem cells(DPSCs)by regulating the ETV2-prolyl hydroxylase 2(PHD2)-hypoxia-inducible factor-1α(HIF-1α)-vascular endothelial growth factor A(VEGFA)axis.Notably,ETV2 achieves the rapid reprogramming of energy metabolism by simultaneously accelerating mitochondrial aerobic respiration and glycolysis,thus fulfilling the energy requirements essential to expedite osteogenic differentiation.Furthermore,decreasedα-ketoglutarate release from ETV2-modified DPSCs contributes to microcirculation reconstruction.Additionally,we engineered hydroxyapatite/chitosan microspheres(HA/CS MS)with biomimetic nanostructures to facilitate multiple ETV2-DPSC functions and further enhanced the osteogenic differentiation.Animal experiments have validated the synergistic effect of ETV2-modified DPSCs and HA/CS MS in promoting the critical-size bone defect regeneration.In summary,this study offers a novel treatment approach for vascularized bone tissue regeneration that relies on energy metabolism activation and the maintenance of a stable local hypoxia signaling state.
基金supported by the National Natural Science Foundation of China(82430089,82202974)the China Postdoctoral Science Foundation(2024M750533)the Shanghai Anti-Cancer Association(SACA-CY22C10).
文摘Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies.However,a significant proportion of HCC patients exhibit poor responses.Lipid metabolic heterogeneity is considered a key driver of cancer progression.However,the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood.Herein,we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response.Patients who received PD-1/PD-L1 inhibitors were enrolled.The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models.Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism.To address HCC immunotherapy resistance,we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine(GalNAc)to conjugate siTACC3.Through clinical cohort analysis,we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy.Furthermore,we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8^(+)T lymphocytes.Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid(PUFA)metabolism in HCC cells.Additionally,TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1,which stabilize ACSL4 mRNA.The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC.In summary,tumor-derived TACC3 impairs the tumor-killing activity of CD8^(+)T lymphocytes through PUFA metabolism-associated crosstalk.Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against 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 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.
基金supported by grants from the National Key R&D Program of China(Grant no.2022YFC3401001)the National Natural Science Foundation of China(Grant nos.82025026,82230091,and 81872144)the Guangdong Basic and Applied Basic Research Foundation(Grant no.2023A1515140033).
文摘Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garnered significant attention due to its profound impact on cancer cells and the tumor microenvironment(TME).Arginine,a semi-essential amino acid,has a central role in various cellular processes,including protein synthesis,nitric oxide(NO)production,and polyamine biosynthesis.In the context of cancer aberrant arginine metabolism fuels tumor cell growth and orchestrates a complex interplay between tumor and immune cells,ultimately facilitating immune evasion and tumor progression.
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).
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.
基金Supported by Natural Science Foundation-funded Project:Establishment of Syndrome-Disease Warning System and Investigation of the Clinical Features and Evolution Patterns of Traditional Chinese Medicine Syndromes in Esophageal Cancer under Modern Medical Diagnosis and Treatment(2023YFC3503200,2023YFC3503201)Biological Basis of the Pathogenesis of Cancer Toxin in Traditional Chinese Medicine(2022YFC3500200,2022YFC3500202)+12 种基金Natural Science Foundation-funded Project:Mechanistic Study of the Nucleolar Methyltransferase Fibrillarin to Promote Neoplastic Growth of Esophageal Squamous Cell Carcinoma via Activating Nucleoside Synthesis(No.32170778)Mechanistic Study of Renal Cancer Neoplastic Growth Driven by Glucose Transporter 5-Mediated Fructose Metabolism Reprogramming(No.31970708)Mechanistic Study of Methionine Cycle Modulating the Growth of Esophageal Squamous Cell Carcinoma through"DNA Methylation-DNA Stability-p53/p21-cell Cycle"Pathway(No.82002953)the Antitumor Mechanism of Oleanolic Acid via Autophagy by Regulating Adenosine Monophosphate-Activated Protein Kinase-Mammalian Target of Rapamycin-Unc51 Like Kinase 1 Pathway and Inhibiting Purine Salvage Pathway(No.82004177)USP14 Cooperates with Ubiquitin C-Terminal Hydrolase L5 to Regulate Constitutive Photomorphogenic 9 Signalosome-mediated Programmed Death-Ligand 1 Deubiquitination and Promote Immune Evasion in Hepatocellular Carcinoma.(No.81972214)National Scientific and Technological Major Special Project of China:Shuang Huang Sheng Bai Oral Liquid:Efficacy and Safety Evaluation of Traditional Chinese Medicine Compound Based on Systems Biology Approaches(2019ZX09201004-002-013)A special clinical research initiative for the health business sponsored by the Shanghai Municipal Health Commission(No.202040155)Shanghai Municipal Science and Technology Commissions Special Biomedical Technology Support Plan(No.20S31904100)Shanghai"Science and Technology Innovation Action Plan"Medical Innovation Research Project--Shanghai Clinical Research Center of Traditional Chinese Medicine Oncology(21MC1930500)Shanghai 13th Five-Year Plan Key Specialty of Traditional Chinese Medicine Oncology(shslczdzk03701)Tracking Programme for Eastern Scholar at Shanghai Institutions of Higher LearningShanghai High-level Talent Leadership Programme of Traditional Chinese Medicine[ZY(2021-2023)-0403]Scientific Research Project of Industry Development Center of Shanghai University of Traditional Chinese Medicine(602076D)。
文摘OBJECTIVE:To uncover the biological foundation of the prevailing TCM syndrome in individuals with Esophageal squamous cell carcinoma(ESCC),Zhengxu Xieshi(ZXXS),which is characterized by a deficiency in vital Qi and an excess in evil Qi.METHODS:We investigated shifts in vital Qi by quantifying systemic metabolic changes in the peripheral blood.Serum metabolomic profiling was conducted on the ESCC cohort 1 along with a matched healthy control cohort.Additionally,we assessed changes in evil Qi by examining metabolic perturbations in ESCC tissues.This analysis involved metabolomic and proteomic surveys of ESCC tissues and paired normal adjacent tissues as controls in an independent ESCC cohort 2.RESULTS:Serum metabolomic profiling highlighted the prevalent downregulation of differentially expressed metabolites in patient sera,in contrast to the upregulation observed in ESCC tissues,compared to their respective controls.Remarkably,the group of differential metabolites in the ESCC tissues was predominantly composed of amino acids.Thus,we focused on amino acid metabolism.Our integrative analysis showed the downregulation of a significant majority of disturbed amino acids in patient sera relative to the upregulation of an overwhelming proportion of perturbed amino acids within ESCC tissues.Enrichment analysis of these amino acids revealed seven metabolic pathways that contribute to the metabolism of antioxidants,energy intermediates,and biosynthetic precursors.Interestingly,these pathways displayed attenuation in patient sera but augmentation in ESCC tissues.Similarly,the proteomic data confirmed the activation of these pathways in ESCC tissues.CONCLUSION:This study presents a new perspective on the prevalence of ZXXS syndrome in patients with ESCC,contextualized within the realm of metabolic reprogramming.Specifically,diminished amino acid metabolism in the circulating blood corresponds to a deficiency in vital Qi.Conversely,hyperactive amino acid metabolism in ESCC tissues signifies an augmentation of local evil Qi.These findings hold potential to enrich the current medical framework and offer a deeper understanding of ESCC management by integrating the principles of ZXXS syndrome.
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Lipid metabolism plays a pivotal role in gastric cancer(GC)progression,characterized by complex metabolic reprogramming that supports tumor growth and survival.This narrative review comprehensively examines the dysregulation of lipid metabolism-associated genes,including fatty acid synthase(FASN),ATPcitrate lyase,acetyl-CoA carboxylases,FA binding proteins,sterol regulatory element-binding proteins,and other key enzymes.These genes facilitate critical oncogenic processes by enhancing FA synthesis,modifying cellular signaling,and supporting cancer cell proliferation,migration,and therapy resistance.Metabolic adaptations observed in GC include increased de novo lipogenesis,altered enzymatic activities,and modified protein lipidation,which contribute to tumor aggressiveness.The review highlights the potential of targeting these metabolic pathways as a therapeutic strategy,demonstrating how inhibiting specific enzymes like FASN,ATP-citrate lyase,and stearoyl-CoA desaturase 1 can induce apoptosis,disrupt cancer stem cell properties,and potentially overcome treatment resistance.By elucidating the intricate interactions between lipid metabolism genes and cancer progression,this review provides insights into novel diagnostic and therapeutic approaches for managing GC.
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 Beijing Natural Science Foundation(No.7222296)Major research project of oncology of scientific and technological innovation project of China Academy of Chinese Medical Sciences(No.CI2021A01805).
文摘The theory of stagnation of collateral Qi(Chinese medicine refers to the most fundamental and subtle substances thatconstitute the human body and maintain life activities,and also has the meaning of physiological functions)originates from the theory of collateral disease,which refers to the deficiency of Qi in the body’s collaterals,the loss of Qi and blood,and the failure of stagnation of collateral Qi,which leads to the loss of Qi,blood and body fluid,and the formation of pathological products such as deficiency,depression,phlegm,blood stasis in the local area,and ultimately damage the pathological process of collaterals.Based on the in-depth study of the pathogenesis of collateral Qi stagnation and the previous study of meridian channels,we believe that the key pathogenesis of the formation,evolution and spread of malignant tumors is“collateral Qi deficiency stagnation,collateral Qi stagnation and collateral Qi decay”.As an important energy resonance channel of the body,meridians play a key role in the process of material transformation and energy metabolism.It is believed that the small focus caused by the pathogenesis of stagnation is the cause of malignant transformation of tumor,the reprogramming of energy metabolism induced by the lesion of collateral Qi is the basis of the progress of tumor pathogenesis,and the formation of tumor microenvironment regulated by the tumor toxin vena is the root of alienation of tumor development.Guided by this theory,focusing on the correlation between collateral Qi and tumor energy metabolism,using Professor Hua Baojin's treatment method of“Regulating Qi and detoxifying”to prescribe drugs can adjust collateral Qi function,achieve the relative balance of internal environment,and then inhibit the progress of tumor.Based on the above understanding,this study tries to enlighten new diagnosis and treatment ideas under the guidance of“stagnation of collateral Qi”in traditional Chinese medicine,in order to provide some theoretical support for the intervention of traditional Chinese medicine in the process of tumor development.
文摘Hepatocellular carcinoma(HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.
基金the National Natural Science Foundation of China(No.82272162,82001954)Fundamental Research Funds for the Central Universities (3332021067, 2019PT350005)+2 种基金Natural Science Fund for Distinguished Young Scholars of Tianjin (21JCJQJC00020)CAMS Innovation Fund for Medical Sciences (2021-I2M-1-052, 2021- I2M-1-058, 2021-I2M-1-065)Tianjin Innovation and Promotion Plan Key Innovation Team of Implantable and Interventional Biomedical Materials.
文摘Excessive reactive oxygen species(ROS)at severe burn injury sites may promote metabolic reprogramming of macrophages to induce a deteriorative and uncontrolled inflammation cycle,leading to delayed wound healing and regeneration.Here,a novel bioactive,anti-fouling,flexible polyzwitterionic hydrogel encapsulated with epigallocatechin gallate(EGCG)-copper(Cu)capsules(termed as EGCG-Cu@CBgel)is engineered for burn wound management,which is dedicated to synergistically exerting ROS-scavenging,immune metabolic regulation and pro-angiogenic effects.EGCG-Cu@CBgel can scavenge ROS to normalize intracellular redox homeostasis,effectively relieving oxidative damages and blocking proinflammatory signal transduction.Importantly,EGCG-Cu can inhibit the activity of hexokinase and phosphofructokinase,alleviate accumulation of pyruvate and convert it to acetyl coenzyme A(CoA),whereby inhibits glycolysis and normalizes tricarboxylic acid(TCA)cycle.Additionally,metabolic reprogramming of macrophages by EGCG-Cu downregulates M1-type polarization and the expression of proinflammatory cytokines both in vitro and in vivo.Meanwhile,copper ions(Cu^(2+))released from the hydrogel facilitate angiogenesis.EGCG-Cu@CBgel significantly accelerates the healing of severe burn wound via promoting wound closure,weakening tissue-damaging inflammatory responses and enhancing the remodeling of pathological structure.Overall,this study demonstrates the great potential of bioactive hydrogel dressing in treating burn wounds without unnecessary secondary damage to newly formed skin,and highlights the importance of immunometabolism modulation in tissue repair and regeneration.
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.
