Background:Diabetic kidney disease(DKD)is a microvascular complication of diabetes mellitus and is the main cause of end-stage renal failure.Suoquan pills(SQP)has a variety of pharmacological activities and multiple t...Background:Diabetic kidney disease(DKD)is a microvascular complication of diabetes mellitus and is the main cause of end-stage renal failure.Suoquan pills(SQP)has a variety of pharmacological activities and multiple therapeutic effects,and it is used clinically as a basic formula for the treatment of DKD.Methods:Public databases were used to identify SQP compounds and the potential targets of SQP and DKD.A drug-component-therapeutic target network was constructed.Protein-protein interaction network analysis,Gene Ontology functional analysis,and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were used to analyse the potential molecular mechanisms of SQP based on common targets of drugs and diseases.Molecular docking simulations were conducted to confirm the binding abity of the core compounds to key targets.The efficacy and predicted molecular mechanisms of SQP were validated using cell counting kit-8 assay,flow cytometry,and western blotting with HK-2 cells as a model.Results:Network pharmacology analysis showed that 26 compounds and 207 potential targets of SQP were involved in the treatment of DKD;boldine,denudatin B,pinocembrin,kaempferoid,and quercetin were considered core compounds,and epidermal growth factor receptor(EGFR)and proto-oncogene,non-receptor tyrosine kinase(SRC)were considered key targets.Gene Ontology enrichment analysis indicated that protein phosphorylation and negative regulation of apoptotic processes are important biological processes in the treatment of DKD by SQP.Molecular docking confirmed the excellent binding abilities of boldine,denudatin B,kaempferide,and quercetin to EGFR and SRC.The results of in vitro experiments showed that treatment with an ethanolic extract of SQP significantly protected HK-2 cells from high glucose-induced cell damage.In addition,the SQP ethanol extract inhibited the phosphorylation of EGFR and SRC,suppressed the apoptosis rate,and regulated apoptosis-related proteins in HK-2 cells under high glucose stress.Conclusion:This study systematically and intuitively illustrated the possible pharmacological mechanisms of SQP against DKD through multiple components,targets,and signalling pathways,especially the inhibition of EGFR and SRC phosphorylation and apoptosis.展开更多
β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unkno...β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.展开更多
Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau pro...Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.展开更多
Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Ro...Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells(NSCs)and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus.We found abnormal orientation of tamoxifen-induced tdTomato+(tdTom^(+))NSCs in adult mice 2 months after treatment with EtOH(5.0 g/kg,i.p.)for 7 consecutive days.EtOH markedly inhibited tdTom^(+)NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood.EtOH(100 mM)also significantly inhibited the proliferation to 39.2%and differentiation of primary NSCs in vitro.Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus,which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycinenhancer of zeste homolog 2 pathway.In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+NSCs and spatial misposition defects of newborn neurons,thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.展开更多
Chara cterized by positive symptoms(such as changes in behavior or thoughts,including delusions and hallu cinations),negative symptoms(such as apathy,anhedonia,and social withdrawal),and cognitive impairments,schizoph...Chara cterized by positive symptoms(such as changes in behavior or thoughts,including delusions and hallu cinations),negative symptoms(such as apathy,anhedonia,and social withdrawal),and cognitive impairments,schizophrenia is a chro nic,severe,and disabling mental disorder with late adolescence or early adulthood onset,Antipsychotics are the most commonly used drugs to treat schizophrenia,but those currently in use do not fully reverse all three types of symptoms characte rizing this condition.Schizophrenia is frequently misdiagnosed,resulting in a delay of or inappropriate treatment.Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of schizophrenia.The recent studies reviewed included microRNA profiling in blood-and urine-based materials and nervous tissue mate rials.From the studies that had validated the preliminary findings,potential candidate biomarkers for schizophrenia in adults could be miR-22-3p,-30e-5p,-92a-3p,-148b-5p,-181a-3p,-181a-5p,-181b-5p,-199 b-5p,-137 in whole blood,and miR-130b,-193a-3p in blood plasma.Antipsychotic treatment of schizophrenia patients was found to modulate the expression of certain microRNAs including miR-130b,-193a-3p,-132,-195,-30e,-432 in blood plasma.Further studies are warranted with adolescents and young adults having schizophrenia and consideration should be given to using animal models of the disorder to investigate the effect of suppressing or overexpressing specific microRNAs.展开更多
BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence ...BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival.However,the molecular mechanisms underlying that remain unclear.AIM To investigate the role and mechanisms of MXS in ameliorating hepatic injury,steatosis and inflammation.METHODS A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis(NASH)model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes.Liver tissues were collected for western blotting and immunohisto chemistry(IHC)assays.Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining.The serum samples were collected for biochemical assays and NMR-based metabonomics analysis.The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH.RESULTS MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress.The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation,inflammation and hepatic fibrosis in the pathogenesis of NASH.The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis.Mechanistically,we found that MXS protected against NASH by attenuating the sex hormone-related metabolism,especially the metabolism of male hormones.CONCLUSION MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones.Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.展开更多
The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administratio...The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.展开更多
Given the extremely high inter-patient heterogeneity of acute myeloid leukemia(AML),the identification of biomarkers for prognostic assessment and therapeutic guidance is critical.Cell surface markers(CSMs)have been s...Given the extremely high inter-patient heterogeneity of acute myeloid leukemia(AML),the identification of biomarkers for prognostic assessment and therapeutic guidance is critical.Cell surface markers(CSMs)have been shown to play an important role in AML leukemogenesis and progression.In the current study,we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas(TCGA)based on differential gene expression analysis and univariable Cox proportional hazards regression analysis.By using multi-model analysis,including Adaptive LASSO regression,LASSO regression,and Elastic Net,we constructed a 9-CSMs prognostic model for risk stratification of the AML patients.The predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome levels.Multivariable Cox regression analysis showed that the risk score was an independent prognostic factor for the AML patients.The AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low scores.Notably,single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy resistance.Furthermore,PI3K inhibitors were identified as potential treatments for these high-risk patients.In conclusion,we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.展开更多
Objective:The aim of this study is to explore the active ingredients and mechanism of action of danhong injection(DHI)in treating myeloproliferative neoplasms using network pharmacology.Methods:The TCMSP platform and ...Objective:The aim of this study is to explore the active ingredients and mechanism of action of danhong injection(DHI)in treating myeloproliferative neoplasms using network pharmacology.Methods:The TCMSP platform and relevant literature were used to search for the active ingredients and targets of Radix Salviae and Carthami Flos in DHI.Disease targets related to myeloproliferative neoplasms were obtained from the GEO database,GeneCards,and DisGeNET database.The queried component targets were normalized using the UniProt database.Potential targets were identified by constructing protein-protein interactions networks using STRING 11.5 and visualized and analyzed using Cytoscape 3.9.1.GO and KEGG analysis were performed using the Metascape platform,and visualization was done using the built-in plug-in CluoGO or SangerBox platforms with Cytoscape 3.9.1.Results:The active ingredients of DHI for treating myeloproliferative neoplasms mainly consist of flavonoids and o-benzoquinones,including quercetin,luteolin,kaempferol,stigmasterol,tanshinone iia,cryptotanshinone,beta-carotene,2-isopropyl-8-methylphenanthrene-3,4-dione,and neocryptotanshinone ii.The potential targets are JUN,TP53,STAT3,AKT1,MAPK1,RELA,TNF,MAPK14,IL6,and FOS.The relevant signaling pathways involved are mainly TNFαsignaling pathway,PI3K-Akt signaling pathway,apoptosis,IL-17 signaling pathway,cellular senescence,MAPK signaling pathway,p53 signaling pathway,JAK-STAT signaling pathway,and NF-kappa B signaling.Conclusions:DHI acts mainly through flavonoids and o-benzoquinones to treat myeloproliferative neoplasms in a multi-targeted and multi-pathway manner.展开更多
Inappropriate levels of hyperactivity,impulsivity,and inattention characterize attention deficit hyperactivity disorder,a common childhood-onset neuropsychiatric disorder.The cognitive function and learning ability of...Inappropriate levels of hyperactivity,impulsivity,and inattention characterize attention deficit hyperactivity disorder,a common childhood-onset neuropsychiatric disorder.The cognitive function and learning ability of children with attention deficit hyperactivity disorder are affected,and these symptoms may persist to adulthood if they are not treated.The diagnosis of attention deficit hyperactivity disorder is only based on symptoms and objective tests for attention deficit hyperactivity disorder are missing.Treatments for attention deficit hyperactivity disorder in children include medications,behavior therapy,counseling,and education services which can relieve many of the symptoms of attention deficit hyperactivity disorder but cannot cure it.There is a need for a molecular biomarker to distinguish attention deficit hyperactivity disorder from healthy subjects and other neurological conditions,which would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated.Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of attention deficit hyperactivity disorder.The recent studies reviewed had performed microRNA profiling in whole blood,white blood cells,blood plasma,and blood serum of children with attention deficit hyperactivity disorder.A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies.From the studies that had included a validation set of patients and controls,potential candidate biomarkers for attention deficit hyperactivity disorder in children could be miR-140-3p,let-7g-5p,-30e-5p,-223-3p,-142-5p,-486-5p,-151a-3p,-151a-5p,and-126-5p in total white blood cells,and miR-4516,-6090,-4763-3p,-4281,-4466,-101-3p,-130a-3p,-138-5p,-195-5p,and-106b-5p in blood serum.Further studies are warranted with children and adults with attention deficit hyperactivity disorder,and consideration should be given to utilizing rat models of attention deficit hyperactivity disorder.Animal studies could be used to confirm microRNA findings in human patients and to test the effects of targeting specific microRNAs on disease progression and behavior.展开更多
Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events.Currently,there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with...Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events.Currently,there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with and without post-traumatic stress disorder.In addition,the heterogeneity of clinical presentations of post-traumatic stress disorder and the overlap of symptoms with other conditions can lead to misdiagnosis and inappropriate treatment.Evidence suggests that this condition is a multisystem disorder that affects many biological systems,raising the possibility that peripheral markers of disease may be used to diagnose post-traumatic stress disorder.We performed a PubMed search for microRNAs(miRNAs)in post-traumatic stress disorder(PTSD)that could serve as diagnostic biomarkers and found 18 original research articles on studies performed with human patients and published January 2012 to December 2023.These included four studies with whole blood,seven with peripheral blood mononuclear cells,four with plasma extracellular vesicles/exosomes,and one with serum exosomes.One of these studies had also used whole plasma.Two studies were excluded as they did not involve microRNA biomarkers.Most of the studies had collected samples from adult male Veterans who had returned from deployment and been exposed to combat,and only two were from recently traumatized adult subjects.In measuring miRNA expression levels,many of the studies had used microarray miRNA analysis,miRNA Seq analysis,or NanoString panels.Only six studies had used real time polymerase chain reaction assay to determine/validate miRNA expression in PTSD subjects compared to controls.The miRNAs that were found/validated in these studies may be considered as potential candidate biomarkers for PTSD and include miR-3130-5p in whole blood;miR-193a-5p,-7113-5p,-125a,-181c,and-671-5p in peripheral blood mononuclear cells;miR-10b-5p,-203a-3p,-4488,-502-3p,-874-3p,-5100,and-7641 in plasma extracellular vesicles/exosomes;and miR-18a-3p and-7-1-5p in blood plasma.Several important limitations identified in the studies need to be taken into account in future studies.Further studies are warranted with war veterans and recently traumatized children,adolescents,and adults having PTSD and use of animal models subjected to various stressors and the effects of suppressing or overexpressing specific microRNAs.展开更多
γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the ...γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.展开更多
The rise of emerging infectious diseases has become notably prominent due to ecological changes and mutations in pathogens.The respiratory illness outbreak caused by the COVID-19 pandemic has spread globally.Natural p...The rise of emerging infectious diseases has become notably prominent due to ecological changes and mutations in pathogens.The respiratory illness outbreak caused by the COVID-19 pandemic has spread globally.Natural products contain numerous structures and biological activities,offering ample options for discovering new antiviral drugs with unique targets and mechanisms.Andrographis paniculata has been utilized in Indian Ayurvedic,Swedish,Traditional Thai,and Chinese medicine to alleviate coughs,colds,and influenza symptoms.Early-stage laboratory studies indicate that this herbal extract may reduce inflammation and fever,and boost the body's natural defenses against viruses,potentially leading to symptom relief.This review aims to systematically present clinical trial data about antiviral herbal formulations derived from Andrographis paniculata,delineating the antiviral effects of both natural and synthetic derivatives,along with in silico analyses.展开更多
As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative str...As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells.Due to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting.This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis.Additionally,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.展开更多
Caffeine intake during pregnancy is common,while its effect on gut microbiota composition of offspring and the relationship with susceptibility to adult diseases remains unclear.This study aimed to confirm the effects...Caffeine intake during pregnancy is common,while its effect on gut microbiota composition of offspring and the relationship with susceptibility to adult diseases remains unclear.This study aimed to confirm the effects of prenatal caffeine exposure(PCE)on the gut microbiota composition and its metabolites in female offspring rats,and to further elucidate its underlying mechanism and intervention targets in adult non-alcoholic fatty disease(NAFLD).The results showed that the gut microbiota of PCE female offspring at multiple time points from infancy to adolescence were significantly changed with depletion of butyric acid-producing bacteria,leading to a decrease in butyric acid in adulthood.It was also found that PCE female offspring rats were sensitive to NAFLD induced by a postnatal high-fat diet(HFD),which is mainly related to the enhancement of hepatic triglyceride synthesis function.Through mechanism exploration,we found that HFD further reduced the fecal and serum butyric acid levels in the PCE female offspring,which was significantly negatively correlated with hepatic SREBP-1c/FASN mRNA expression and triglyceride level.In vivo and in vitro experiments confirmed that sodium butyrate(NaB)supplementation could reduce hepatic lipid accumulation through MCT1/GPR109A-AMPK,thereby effectively decreasing the susceptibility to NAFLD in the PCE female offspring rats.展开更多
Photodynamic therapy(PDT)is a promising cancer treatment.This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-tr...Photodynamic therapy(PDT)is a promising cancer treatment.This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-triphenyl-porphyrin(DTP)mediated PDT(DTP-PDT).Cell viability,reactive oxygen species(ROS),and apoptosis were measured with a Cell Counting Kit-8 assay,DCFH-DA fluorescent probe,and Hoechst staining,respectively.Cell apoptosis-and autophagy-related proteins were examined using western blotting.RNA sequencing was used to screen differentially expressed mRNAs(DERs),and bioinformatic analysis was performed to identify the major biological events after DTP-PDT.Our results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 cells.The ROS scavenger N-acetyl-L-cysteine(NAC)and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced cytotoxicity.DTP-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2,which could also be inhibited by NAC or SB203580.The level of LC3B-Ⅱ,a marker of autophagy,was increased by DTP-PDT.A total of 3496 DERs were obtained after DTP-PDT.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes,the nuclear lumen,protein binding,cell cycle,protein targeting to the endoplasmic reticulum,and ribosomal DNA replication.Disease Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle checkpoints.Protein-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting genes.Therefore,DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy,partly through ROS and the P38 MAPK signaling pathway.Genes associated with the cell cycle,ribosomes,DNA replication,and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.展开更多
Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta(Aβ)aggregates,resulting from mutations in the amyloid precursor protein.The enzymeβ-secretase,also known asβ-site amyloid p...Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta(Aβ)aggregates,resulting from mutations in the amyloid precursor protein.The enzymeβ-secretase,also known asβ-site amyloid precursor protein cleaving enzyme 1(BACE1),plays a crucial role in generating Aβpeptides.With no targeted therapy available for Alzheimer’s disease,inhibiting BACE1 aspartic protease has emerged as a primary treatment target.Since 1999,compounds demonstrating potential binding to the BACE1 receptor have advanced to human trials.Structural optimization of synthetically derived compounds,coupled with computational approaches,has offered valuable insights for developing highly selective leads with drug-like properties.This review highlights pivotal studies on the design and development of BACE1 inhibitors as anti-Alzheimer’s disease agents.It summarizes computational methods employed in facilitating drug discovery for potential BACE1 inhibitors and provides an update on their clinical status,indicating future directions for novel BACE1 inhibitors.The promising clinical results of Elenbecestat(E-2609)catalyze the development of effective,selective BACE1 inhibitors in the future.展开更多
The recently re-emerged mpox(monkeypox)virus that causes mpox disease is a member of genus Orthopoxvirus and has unprecedentedly spread worldwide.Numerous studies have contributed to our understanding of its evolution...The recently re-emerged mpox(monkeypox)virus that causes mpox disease is a member of genus Orthopoxvirus and has unprecedentedly spread worldwide.Numerous studies have contributed to our understanding of its evolution,pathophysiology,and clinical manifestations.The current outbreak of the mpox virus depicts its novel route of transmission as a new variant.However,the exact reason for its transition from an epidemic to a pandemic remains unclear.Furthermore,other poxviruses such as vaccinia virus,variola virus,and cowpox virus,also belong to the same genus,Orthopoxvirus.In the present review,our objective was to summarize the evidence on evolution,pathophysiology,and clinical manifestations of mpox virus and its related poxviruses.The present review would aid in a better understanding of the current circulating mpox virus and its differences from other poxviruses.In addition,the shared genetic factors contributing to virulence in these Orthopoxvirus highlight their evolutionary connections and genetic similarities.While they exhibit differences in virulence,studying these genetic relationships is crucial for understanding their biology,pathogenicity,and the development of effective vaccines and antiviral therapeutics to curb mpox disease.展开更多
Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are inv...Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.展开更多
Background: Triple-negative breast cancer(TNBC), which is so called because of the lack of estrogen receptors(ER), progesterone receptors(PR), and human epidermal growth factor receptor 2(HER2) receptors on the cancer...Background: Triple-negative breast cancer(TNBC), which is so called because of the lack of estrogen receptors(ER), progesterone receptors(PR), and human epidermal growth factor receptor 2(HER2) receptors on the cancer cells, accounts for 10%–15% of all breast cancers. The heterogeneity of the tumor microenvironment is high.However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood.Methods: We analyzed single-cell RNA sequencing data from five HER2 positive, 12ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry.Results: Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2–integrin–aLb2 complex, and then release interleukin 1 beta(IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth.Conclusion: Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.展开更多
基金supported by the grants from National Natural Science Foundation of China(No.82174334)Hainan Province in 2022 postgraduate innovation research projects(No.Qhys2022-273).
文摘Background:Diabetic kidney disease(DKD)is a microvascular complication of diabetes mellitus and is the main cause of end-stage renal failure.Suoquan pills(SQP)has a variety of pharmacological activities and multiple therapeutic effects,and it is used clinically as a basic formula for the treatment of DKD.Methods:Public databases were used to identify SQP compounds and the potential targets of SQP and DKD.A drug-component-therapeutic target network was constructed.Protein-protein interaction network analysis,Gene Ontology functional analysis,and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were used to analyse the potential molecular mechanisms of SQP based on common targets of drugs and diseases.Molecular docking simulations were conducted to confirm the binding abity of the core compounds to key targets.The efficacy and predicted molecular mechanisms of SQP were validated using cell counting kit-8 assay,flow cytometry,and western blotting with HK-2 cells as a model.Results:Network pharmacology analysis showed that 26 compounds and 207 potential targets of SQP were involved in the treatment of DKD;boldine,denudatin B,pinocembrin,kaempferoid,and quercetin were considered core compounds,and epidermal growth factor receptor(EGFR)and proto-oncogene,non-receptor tyrosine kinase(SRC)were considered key targets.Gene Ontology enrichment analysis indicated that protein phosphorylation and negative regulation of apoptotic processes are important biological processes in the treatment of DKD by SQP.Molecular docking confirmed the excellent binding abilities of boldine,denudatin B,kaempferide,and quercetin to EGFR and SRC.The results of in vitro experiments showed that treatment with an ethanolic extract of SQP significantly protected HK-2 cells from high glucose-induced cell damage.In addition,the SQP ethanol extract inhibited the phosphorylation of EGFR and SRC,suppressed the apoptosis rate,and regulated apoptosis-related proteins in HK-2 cells under high glucose stress.Conclusion:This study systematically and intuitively illustrated the possible pharmacological mechanisms of SQP against DKD through multiple components,targets,and signalling pathways,especially the inhibition of EGFR and SRC phosphorylation and apoptosis.
基金supported by the National Natural Science Foundation of China,Nos.82104158(to XT),31800887(to LY),31972902(to LY),82001422(to YL)China Postdoctoral Science Foundation,No.2020M683750(to LY)partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China,No.20200307(to LY).
文摘β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.
基金supported by the Neural Regeneration Co-innovation Center of Jiangsu Province,Nantong University(to DC)the National Natural Science Foundation of China,Nos.81872853(to DC),81870941(to JHG)the Science and Technology Project of Nantong City,Nos.JC22022022(to FW)and JC2021059(to JM)。
文摘Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.
基金supported by the National Natural Science Foundation of China,Nos.31601175(to YL),81803508(to KZ),82074056(to JY)the Natural Science Foundation of Liaoning Province of China,No.20180550335(to YL)the Scientific Research Project of Educational Commission of Liaoning Province of China,No.201610163L22(to YL)。
文摘Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells(NSCs)and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus.We found abnormal orientation of tamoxifen-induced tdTomato+(tdTom^(+))NSCs in adult mice 2 months after treatment with EtOH(5.0 g/kg,i.p.)for 7 consecutive days.EtOH markedly inhibited tdTom^(+)NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood.EtOH(100 mM)also significantly inhibited the proliferation to 39.2%and differentiation of primary NSCs in vitro.Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus,which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycinenhancer of zeste homolog 2 pathway.In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+NSCs and spatial misposition defects of newborn neurons,thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.
文摘Chara cterized by positive symptoms(such as changes in behavior or thoughts,including delusions and hallu cinations),negative symptoms(such as apathy,anhedonia,and social withdrawal),and cognitive impairments,schizophrenia is a chro nic,severe,and disabling mental disorder with late adolescence or early adulthood onset,Antipsychotics are the most commonly used drugs to treat schizophrenia,but those currently in use do not fully reverse all three types of symptoms characte rizing this condition.Schizophrenia is frequently misdiagnosed,resulting in a delay of or inappropriate treatment.Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of schizophrenia.The recent studies reviewed included microRNA profiling in blood-and urine-based materials and nervous tissue mate rials.From the studies that had validated the preliminary findings,potential candidate biomarkers for schizophrenia in adults could be miR-22-3p,-30e-5p,-92a-3p,-148b-5p,-181a-3p,-181a-5p,-181b-5p,-199 b-5p,-137 in whole blood,and miR-130b,-193a-3p in blood plasma.Antipsychotic treatment of schizophrenia patients was found to modulate the expression of certain microRNAs including miR-130b,-193a-3p,-132,-195,-30e,-432 in blood plasma.Further studies are warranted with adolescents and young adults having schizophrenia and consideration should be given to using animal models of the disorder to investigate the effect of suppressing or overexpressing specific microRNAs.
基金Supported by Chongqing Fundamental Research Funds,No.jbky20210001Key Programs of Technological Innovation and Application Development of Chongqing,China,No.cstc2021jscx-dxwtBX0016+2 种基金Natural Science Foundation of Chongqing,No.cstc2021jcyjmsxmX0793Science and Technology Project in Social Livelihood of Bishan District,Chongqing,China,No.BSKJ0078 and No.BSKJ0075Performance Incentive-oriented Project of Chongqing,No.jxjl20220007。
文摘BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival.However,the molecular mechanisms underlying that remain unclear.AIM To investigate the role and mechanisms of MXS in ameliorating hepatic injury,steatosis and inflammation.METHODS A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis(NASH)model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes.Liver tissues were collected for western blotting and immunohisto chemistry(IHC)assays.Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining.The serum samples were collected for biochemical assays and NMR-based metabonomics analysis.The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH.RESULTS MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress.The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation,inflammation and hepatic fibrosis in the pathogenesis of NASH.The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis.Mechanistically,we found that MXS protected against NASH by attenuating the sex hormone-related metabolism,especially the metabolism of male hormones.CONCLUSION MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones.Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.
基金supported by the National Natural Science Foundation of China(Grant Nos.82073934,81872937,and 81673513).
文摘The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.
基金supported by the National Natural Science Foundation of China(Grant Nos.32200590 to K.L.,81972358 to Q.W.,91959113 to Q.W.,and 82372897 to Q.W.)the Natural Science Foundation of Jiangsu Province(Grant No.BK20210530 to K.L.).
文摘Given the extremely high inter-patient heterogeneity of acute myeloid leukemia(AML),the identification of biomarkers for prognostic assessment and therapeutic guidance is critical.Cell surface markers(CSMs)have been shown to play an important role in AML leukemogenesis and progression.In the current study,we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas(TCGA)based on differential gene expression analysis and univariable Cox proportional hazards regression analysis.By using multi-model analysis,including Adaptive LASSO regression,LASSO regression,and Elastic Net,we constructed a 9-CSMs prognostic model for risk stratification of the AML patients.The predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome levels.Multivariable Cox regression analysis showed that the risk score was an independent prognostic factor for the AML patients.The AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low scores.Notably,single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy resistance.Furthermore,PI3K inhibitors were identified as potential treatments for these high-risk patients.In conclusion,we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.
基金This work has been supported by grants from the Taishan Scholars Program(TSQN201812015)the Program for Multidisciplinary Research and Innovation Team of Young Scholars at Shandong University(2020QNQT007).
文摘Objective:The aim of this study is to explore the active ingredients and mechanism of action of danhong injection(DHI)in treating myeloproliferative neoplasms using network pharmacology.Methods:The TCMSP platform and relevant literature were used to search for the active ingredients and targets of Radix Salviae and Carthami Flos in DHI.Disease targets related to myeloproliferative neoplasms were obtained from the GEO database,GeneCards,and DisGeNET database.The queried component targets were normalized using the UniProt database.Potential targets were identified by constructing protein-protein interactions networks using STRING 11.5 and visualized and analyzed using Cytoscape 3.9.1.GO and KEGG analysis were performed using the Metascape platform,and visualization was done using the built-in plug-in CluoGO or SangerBox platforms with Cytoscape 3.9.1.Results:The active ingredients of DHI for treating myeloproliferative neoplasms mainly consist of flavonoids and o-benzoquinones,including quercetin,luteolin,kaempferol,stigmasterol,tanshinone iia,cryptotanshinone,beta-carotene,2-isopropyl-8-methylphenanthrene-3,4-dione,and neocryptotanshinone ii.The potential targets are JUN,TP53,STAT3,AKT1,MAPK1,RELA,TNF,MAPK14,IL6,and FOS.The relevant signaling pathways involved are mainly TNFαsignaling pathway,PI3K-Akt signaling pathway,apoptosis,IL-17 signaling pathway,cellular senescence,MAPK signaling pathway,p53 signaling pathway,JAK-STAT signaling pathway,and NF-kappa B signaling.Conclusions:DHI acts mainly through flavonoids and o-benzoquinones to treat myeloproliferative neoplasms in a multi-targeted and multi-pathway manner.
文摘Inappropriate levels of hyperactivity,impulsivity,and inattention characterize attention deficit hyperactivity disorder,a common childhood-onset neuropsychiatric disorder.The cognitive function and learning ability of children with attention deficit hyperactivity disorder are affected,and these symptoms may persist to adulthood if they are not treated.The diagnosis of attention deficit hyperactivity disorder is only based on symptoms and objective tests for attention deficit hyperactivity disorder are missing.Treatments for attention deficit hyperactivity disorder in children include medications,behavior therapy,counseling,and education services which can relieve many of the symptoms of attention deficit hyperactivity disorder but cannot cure it.There is a need for a molecular biomarker to distinguish attention deficit hyperactivity disorder from healthy subjects and other neurological conditions,which would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated.Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of attention deficit hyperactivity disorder.The recent studies reviewed had performed microRNA profiling in whole blood,white blood cells,blood plasma,and blood serum of children with attention deficit hyperactivity disorder.A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies.From the studies that had included a validation set of patients and controls,potential candidate biomarkers for attention deficit hyperactivity disorder in children could be miR-140-3p,let-7g-5p,-30e-5p,-223-3p,-142-5p,-486-5p,-151a-3p,-151a-5p,and-126-5p in total white blood cells,and miR-4516,-6090,-4763-3p,-4281,-4466,-101-3p,-130a-3p,-138-5p,-195-5p,and-106b-5p in blood serum.Further studies are warranted with children and adults with attention deficit hyperactivity disorder,and consideration should be given to utilizing rat models of attention deficit hyperactivity disorder.Animal studies could be used to confirm microRNA findings in human patients and to test the effects of targeting specific microRNAs on disease progression and behavior.
文摘Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events.Currently,there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with and without post-traumatic stress disorder.In addition,the heterogeneity of clinical presentations of post-traumatic stress disorder and the overlap of symptoms with other conditions can lead to misdiagnosis and inappropriate treatment.Evidence suggests that this condition is a multisystem disorder that affects many biological systems,raising the possibility that peripheral markers of disease may be used to diagnose post-traumatic stress disorder.We performed a PubMed search for microRNAs(miRNAs)in post-traumatic stress disorder(PTSD)that could serve as diagnostic biomarkers and found 18 original research articles on studies performed with human patients and published January 2012 to December 2023.These included four studies with whole blood,seven with peripheral blood mononuclear cells,four with plasma extracellular vesicles/exosomes,and one with serum exosomes.One of these studies had also used whole plasma.Two studies were excluded as they did not involve microRNA biomarkers.Most of the studies had collected samples from adult male Veterans who had returned from deployment and been exposed to combat,and only two were from recently traumatized adult subjects.In measuring miRNA expression levels,many of the studies had used microarray miRNA analysis,miRNA Seq analysis,or NanoString panels.Only six studies had used real time polymerase chain reaction assay to determine/validate miRNA expression in PTSD subjects compared to controls.The miRNAs that were found/validated in these studies may be considered as potential candidate biomarkers for PTSD and include miR-3130-5p in whole blood;miR-193a-5p,-7113-5p,-125a,-181c,and-671-5p in peripheral blood mononuclear cells;miR-10b-5p,-203a-3p,-4488,-502-3p,-874-3p,-5100,and-7641 in plasma extracellular vesicles/exosomes;and miR-18a-3p and-7-1-5p in blood plasma.Several important limitations identified in the studies need to be taken into account in future studies.Further studies are warranted with war veterans and recently traumatized children,adolescents,and adults having PTSD and use of animal models subjected to various stressors and the effects of suppressing or overexpressing specific microRNAs.
基金supported in part by Award 2121063 from National Science Foundation(to YM)AG66986 from the National Institutes of Health(to MSW).
文摘γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.
文摘The rise of emerging infectious diseases has become notably prominent due to ecological changes and mutations in pathogens.The respiratory illness outbreak caused by the COVID-19 pandemic has spread globally.Natural products contain numerous structures and biological activities,offering ample options for discovering new antiviral drugs with unique targets and mechanisms.Andrographis paniculata has been utilized in Indian Ayurvedic,Swedish,Traditional Thai,and Chinese medicine to alleviate coughs,colds,and influenza symptoms.Early-stage laboratory studies indicate that this herbal extract may reduce inflammation and fever,and boost the body's natural defenses against viruses,potentially leading to symptom relief.This review aims to systematically present clinical trial data about antiviral herbal formulations derived from Andrographis paniculata,delineating the antiviral effects of both natural and synthetic derivatives,along with in silico analyses.
基金National Natural Science Foundation of China[82274366]The National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine:Multi-dimensional Evaluation and Multidisciplinary Innovation Team of Southwest Traditional Chinese Medicine Resources[ZYYCXTD-D-202209]+2 种基金The Youth Talent Promotion Project of China Association of Chinese Medicine[2021-QNRC2-A09]The Major Project of Sichuan Provincial Administration of Traditional Chinese Medicine(2023ZD01)the financial support from the Indian Council of Medical Research(ICMR),New Delhi,India,through Extramural Research Grants.
文摘As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells.Due to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting.This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis.Additionally,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.
基金funded by the National Natural Science Foundation of China(82030111,U23A20407)the National Key Research and Development Program of China(2020YFA0803900)+1 种基金the Major Technological Innovation Projects of Hubei Province(2019ACA140)Hubei Province’s Outstanding Medical Academic Leader program,and the Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital,Wuhan University(ZNLH202208).
文摘Caffeine intake during pregnancy is common,while its effect on gut microbiota composition of offspring and the relationship with susceptibility to adult diseases remains unclear.This study aimed to confirm the effects of prenatal caffeine exposure(PCE)on the gut microbiota composition and its metabolites in female offspring rats,and to further elucidate its underlying mechanism and intervention targets in adult non-alcoholic fatty disease(NAFLD).The results showed that the gut microbiota of PCE female offspring at multiple time points from infancy to adolescence were significantly changed with depletion of butyric acid-producing bacteria,leading to a decrease in butyric acid in adulthood.It was also found that PCE female offspring rats were sensitive to NAFLD induced by a postnatal high-fat diet(HFD),which is mainly related to the enhancement of hepatic triglyceride synthesis function.Through mechanism exploration,we found that HFD further reduced the fecal and serum butyric acid levels in the PCE female offspring,which was significantly negatively correlated with hepatic SREBP-1c/FASN mRNA expression and triglyceride level.In vivo and in vitro experiments confirmed that sodium butyrate(NaB)supplementation could reduce hepatic lipid accumulation through MCT1/GPR109A-AMPK,thereby effectively decreasing the susceptibility to NAFLD in the PCE female offspring rats.
基金supported by the Applied Basic Research Project of Shanxi Province(201901D211470)Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi Province(201802093)The National Natural Science Foundation of China(No.81773765).
文摘Photodynamic therapy(PDT)is a promising cancer treatment.This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-triphenyl-porphyrin(DTP)mediated PDT(DTP-PDT).Cell viability,reactive oxygen species(ROS),and apoptosis were measured with a Cell Counting Kit-8 assay,DCFH-DA fluorescent probe,and Hoechst staining,respectively.Cell apoptosis-and autophagy-related proteins were examined using western blotting.RNA sequencing was used to screen differentially expressed mRNAs(DERs),and bioinformatic analysis was performed to identify the major biological events after DTP-PDT.Our results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 cells.The ROS scavenger N-acetyl-L-cysteine(NAC)and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced cytotoxicity.DTP-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2,which could also be inhibited by NAC or SB203580.The level of LC3B-Ⅱ,a marker of autophagy,was increased by DTP-PDT.A total of 3496 DERs were obtained after DTP-PDT.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes,the nuclear lumen,protein binding,cell cycle,protein targeting to the endoplasmic reticulum,and ribosomal DNA replication.Disease Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle checkpoints.Protein-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting genes.Therefore,DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy,partly through ROS and the P38 MAPK signaling pathway.Genes associated with the cell cycle,ribosomes,DNA replication,and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.
文摘Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta(Aβ)aggregates,resulting from mutations in the amyloid precursor protein.The enzymeβ-secretase,also known asβ-site amyloid precursor protein cleaving enzyme 1(BACE1),plays a crucial role in generating Aβpeptides.With no targeted therapy available for Alzheimer’s disease,inhibiting BACE1 aspartic protease has emerged as a primary treatment target.Since 1999,compounds demonstrating potential binding to the BACE1 receptor have advanced to human trials.Structural optimization of synthetically derived compounds,coupled with computational approaches,has offered valuable insights for developing highly selective leads with drug-like properties.This review highlights pivotal studies on the design and development of BACE1 inhibitors as anti-Alzheimer’s disease agents.It summarizes computational methods employed in facilitating drug discovery for potential BACE1 inhibitors and provides an update on their clinical status,indicating future directions for novel BACE1 inhibitors.The promising clinical results of Elenbecestat(E-2609)catalyze the development of effective,selective BACE1 inhibitors in the future.
文摘The recently re-emerged mpox(monkeypox)virus that causes mpox disease is a member of genus Orthopoxvirus and has unprecedentedly spread worldwide.Numerous studies have contributed to our understanding of its evolution,pathophysiology,and clinical manifestations.The current outbreak of the mpox virus depicts its novel route of transmission as a new variant.However,the exact reason for its transition from an epidemic to a pandemic remains unclear.Furthermore,other poxviruses such as vaccinia virus,variola virus,and cowpox virus,also belong to the same genus,Orthopoxvirus.In the present review,our objective was to summarize the evidence on evolution,pathophysiology,and clinical manifestations of mpox virus and its related poxviruses.The present review would aid in a better understanding of the current circulating mpox virus and its differences from other poxviruses.In addition,the shared genetic factors contributing to virulence in these Orthopoxvirus highlight their evolutionary connections and genetic similarities.While they exhibit differences in virulence,studying these genetic relationships is crucial for understanding their biology,pathogenicity,and the development of effective vaccines and antiviral therapeutics to curb mpox disease.
基金supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP)Fondo Europeo de Desarrollo Regional(MINECO-FEDER)(PID2022-139016OA-I00,PDC2022-133441-I00,to CGF and MP),Generalitat de Catalunya(2021 SGR 00357+3 种基金to CGF and MP)co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF)the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511)the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).
文摘Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.
基金funded by Young Elite Scientists Sponsorship Program by Beijing Association for science and technology(Grant No.BYESS2023226)。
文摘Background: Triple-negative breast cancer(TNBC), which is so called because of the lack of estrogen receptors(ER), progesterone receptors(PR), and human epidermal growth factor receptor 2(HER2) receptors on the cancer cells, accounts for 10%–15% of all breast cancers. The heterogeneity of the tumor microenvironment is high.However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood.Methods: We analyzed single-cell RNA sequencing data from five HER2 positive, 12ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry.Results: Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2–integrin–aLb2 complex, and then release interleukin 1 beta(IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth.Conclusion: Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.
