BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the rol...BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.展开更多
Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant ...Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant challenges associated with disease recurrence and resistance to chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway plays a pivotal role in cell proliferation,growth,metabolism,and survival.Its aberrant activation is closely linked to the development and progression of TNBC,as well as treatment response and drug resistance.Currently,numerous targeted drugs specifically inhibiting this signaling pathway are being developed and undergoing clinical trials.These include inhibitors targeting PI3K,AKT,or mTOR individually,as well as dual-target or multi-target inhibitors simultaneously targeting different components of this pathway.Encouragingly,some inhibitors have demonstrated promising potential in clinical trials.This review delves into the therapeutic potential of the PI3K/AKT/mTOR signaling pathway for TNBC and explores prospects for drug discovery.展开更多
The December 2023 issue of the Military Medical Research brings out an astounding discover y by Xu et al.[1]demonstrating a key role of the mysterious enzyme ADPdependent glucokinase(ADPGK)in the cellular metabolism o...The December 2023 issue of the Military Medical Research brings out an astounding discover y by Xu et al.[1]demonstrating a key role of the mysterious enzyme ADPdependent glucokinase(ADPGK)in the cellular metabolism of prostate cancer(PCa).The ADPGKs are enzymes typically found in thermophilic archaea where they mediate the indispensable,first step of glucose metabolism,i.e.phosphorylation of glucose to glucose-6-phosphate.Strikingly,ADPGKs utilize ADP as a phosphate donor instead of ATP typically used to initiate glycolysis by four“classical”eukaryotic hexokinases(HKⅠ–Ⅲand glucokinase).Thus,the discovery made by Ronimus and Morgan[2]of the functional form of ADPGK in mice,opened an intriguing question of the specific role of this enzyme in the metabolism of eukaryotic cell.展开更多
Currently,the standard clinical practice involves the predominant use of androgen deprivation therapy to treat advanced prostate cancer(PCa),which often inevitably progresses into castration-resistant PCa[1].Because o...Currently,the standard clinical practice involves the predominant use of androgen deprivation therapy to treat advanced prostate cancer(PCa),which often inevitably progresses into castration-resistant PCa[1].Because of its unfavorable prognosis and limited treatment alternatives,studies have emphasized the pressing requirement for novel therapeutic targets to enhance the efficacy of advanced PCa treatment and prolong patient survival.展开更多
Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle p...Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.展开更多
Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung ...Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung cancer potential.We aimed to explore the anti–lung cancer effect of BBR and related mechanisms by targeting the glycogen synthase kinase 3β(GSK3β)/β-catenin pathway.Methods:Lung adenocarcinoma(LUAD)cells A549 and NCI-H1975 were treated with BBR.Results:Our results showed that BBR inhibited cell proliferation by decreasing c-Myc levels and induced cel cycle arrest in the G0/G1 phase by lowering cyclin D1 levels.BBR induced apoptosis by upregulating cleaved caspase 3 levels.BBR inhibited cell migration and invasion by decreasing N-cadherin levels.Furthermore,BBR upregulated the expression of GSK3βprotein and phospho-β-catenin proteins in the cytoplasm,while decreasing the expression ofβ-catenin protein.Next,LUAD cel s were exposed to CHIR-99021(a GSK3βinhibitor).This treatment led to an increase in c-Myc,cyclin D1,andβ-catenin levels at specific concentrations.BBR partially reversed the effects of CHIR-99021.Finally,LUAD cells were treated with CHIR-99021(4μmoL/L)combined with BBR(30 and 60μmoL/L)for 24 h.The expression of programmed death ligand 1(PD-L1)was assessed by Western blot analysis.Jurkat T cells and A549 cel s were cocultured for 24 h to examine the lactate dehydrogenase release rate.Results suggested that BBR suppressed the expression of PD-L1 and heightened the immune lethality of T cells.Conclusions:BBR suppressed the proliferative activity of LUAD cell lines A549 and NCI-H1975 in vitro,induced cell cycle arrest and cancer cel apoptosis in the G0/G1 stage,and repressed the migration and invasion of cancer cells.BBR reduced the PD-L1 protein expression and enhanced T-cell–mediated cytotoxicity.These effects appear to be related to BBR's regulation of the GSK3β/β-catenin pathway.展开更多
The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enh...The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.展开更多
BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progr...BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.展开更多
BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine recept...BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.展开更多
Ginsenosides are the main active components of ginseng,which have been reported to target brain tissues and produce multiple neuroprotective effects.Ginsenosides have been shown to improve learning ability and memory ...Ginsenosides are the main active components of ginseng,which have been reported to target brain tissues and produce multiple neuroprotective effects.Ginsenosides have been shown to improve learning ability and memory in normal aged animals,and in an animal model of memory impairment.However,its underlying pharmacological mechanisms are very complicated,especially with regard to its effects on the activation of protein kinases in neurons.Previous reports have shown that some protein kinases may be affected by ginsenosides,including protein kinase C,calcium/calmodulin-dependent protein kinase Ⅱ,c-Jun-N terminal kinase,and protein tyrosine kinase.In this paper,protein kinases that may underlie the mechanisms of ginsenosides will be discussed.展开更多
Pancreatic cancer is a dismal disease with high incidence and poor survival rates.With the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently needed.Protein kinases a...Pancreatic cancer is a dismal disease with high incidence and poor survival rates.With the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently needed.Protein kinases are key regulatory players in basically all stages of development,maintaining physiologic functions but also being involved in pathogenic processes.c-Jun N-terminal kinases(JNK)and p38 kinases,representatives of the mitogen-activated protein kinases,as well as the casein kinase 1(CK1)family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors,DNA damage,and others.In their physiologic roles,they are responsible for the regulation of cell cycle progression,cell proliferation and differentiation,and apoptosis.Dysregulation of the underlying pathways consequently has been identified in various cancer types,including pancreatic cancer.Pharmacological targeting of those pathways has been the field of interest for several years.While success in earlier studies was limited due to lacking specificity and off-target effects,more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results.Consequently,targeting of JNK,p38,and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases.However,further studies are warranted,especially involving in vivo investigation and clinical trials,in order to advance inhibition of stress-activated kinases to the field of translational medicine.展开更多
Objective： Extracellular signal-regulated kinases （ERKs） can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global c...Objective： Extracellular signal-regulated kinases （ERKs） can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia. Methods Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot. Results Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate （NMDA） receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca^2＋/calmodulin-dependent protein kinase Ⅱ （CaMKⅡ） activities. With the inhibition of Src family tyrosine kinases or CaMKⅡ by administration of PP2 or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated. Conclusions Src family tyrosine kinases and CaMKⅡ might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.展开更多
Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing ...Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing epithelial-mesen-chymal transition.Although their multilevel approach integrating clinical data,functional assays,and xenograft models demonstrated a key role for RGS4 in GC pathogenesis,several limitations should be considered.The mechanism of the RGS4-focal adhesion kinase interaction remains unclear,specifically whether it involves direct binding or intermediaries.The clinical analysis of 90 patients lacks stratification by GC subtypes or immune features,potentially limiting generaliz-ability.Furthermore,fully validating RGS4’s oncogenic role requires additional studies,including functional assays in chemotherapy-resistant and metastatic cell lines,metastasis models including orthotopic implantation and tail vein injection,and comparison with other RGS family members.Addressing these via targeted mechanistic studies and expanded clinical validation could strengthen RGS4’s po-tential as a therapeutic target in GC.展开更多
Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicyla...Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicylates,corticosteroids,and biologics,offer limited efficacy,safety,and durability of response.The advancement in small-molecule Janus kinase(JAK)inhibitors has introduced a novel,oral therapeutic option that targets intracellular signaling pathways implicated in UC pathogenesis.Tofacitinib is the first approved JAK inhibitor for the treatment of moderate-to-severe UC.This drug,despite offering promising efficacy,has various safety concerns,especially the occurrence of thromboembolic events.These adverse effects have stressed the devel-opment of more selective agents such as upadacitinib and filgotinib.This mini-review explores the current perspectives of JAK inhibitors in UC,particularly focusing on their mechanisms of action,safety profiles,clinical trial outcomes,and emerging strategies to enhance their use.This review also highlights future directions,including the potential of selective JAK1 inhibition and the role of personalized medicine in refining therapeutic decisions.Understanding the emerging place of JAK inhibitors within the UC treatment strategies offers excellent opportunities to increase patient care and long-term disease management.展开更多
BACKGROUND In patients with colorectal cancer(CRC),tumour metastasis is the leading cause of death.The search for key genes involved in metastasis of CRC is imperative for improved prognoses and treatments.SPDL1 has b...BACKGROUND In patients with colorectal cancer(CRC),tumour metastasis is the leading cause of death.The search for key genes involved in metastasis of CRC is imperative for improved prognoses and treatments.SPDL1 has been implicated in the deve-lopment of CRC,however,its mechanism of action remains unclear.AIM To investigate the role and mechanism of action by which SPDL1 inhibits the development and metastasis of CRC.METHODS In this study,we examined the relationship between SPDL1 expression and CRC prognosis using immunohistochemistry.Survival analyses were performed using Kaplan-Meier analysis and log-rank test.After knocking down SPDL1 in the HCT116 cancer cell line changes in cell viability,migration,invasion,and gene expression were examined using a cell counting kit 8 assay,Transwell assay,and Western blot.The effect of SPDL1 on the cell cycle was assessed using flow cy-tometry.RNA sequencing was used to analyse the effect of SPDL1 on gene expression of CRC cells.The mechanism of action of SPDL1 in CRC was further clarified using U0126,an inhibitor of the mitogen-activated protein kinase signaling pathway.RESULTS SPDL1 is expressed at low levels in tissues of patients with CRC,and this reduced expression is associated with poor prognosis.Functionally,low expression of SPDL1 in CRC promotes cell proliferation,migration,invasion,and affects the cell cycle.Mechanistically,SPDL1 affects the progression of CRC through its regulation of the process of epithelial-mesenchymal transition(EMT)and of the epidermal growth factor receptor(EGFR)/extracellular signal-regulated kinase(ERK)signaling pathways.CONCLUSION This study showed that the loss of SPDL1 may induce EMT and promote cell migration and invasion in CRC through the EGFR/ERK pathway.展开更多
BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of ch...BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of checkpoint kinase 1(CHEK1),a cell cycle checkpoint kinase,in CRC has not been fully clarified.We hypothesize that the upregulation of CHEK1 may enhance the proliferation of CRC cells,indicating its potential as a novel therapeutic target for CRC therapy.AIM To investigate the expression and function of CHEK1 in CRC,this study utilizes single-cell RNA sequencing and tissue microarray data.METHODS Single-cell RNA sequencing technology was employed to analyze CRC cells from the GSE144735 dataset,and immunohistochemistry was conducted to confirm the expression of CHEK1 in CRC and adjacent tissues.We also integrated mRNA expression data from multiple public databases to assess global CHEK1 expre-ssion in CRC.Molecular docking experiments were performed to explore the in-teraction between CHEK1 and the potential drug nitidine chloride(NC),as well as to investigate the influence of CHEK1 on CRC cell proliferation.RESULTS We found comparatively elevated CHEK1 expression in the malignant epithelial cells of CRC,with marked upregulation of its mRNA levels in CRC tissues.Immunohistochemical analysis further confirmed the high expression of CHEK1 in CRC tissues,and the receiver operating characteristic curve demonstrated high accuracy(area under the curve=0.964)for CHEK1 as a biomarker.Analysis of global datasets indicated a statistically significant overexpression of CHEK1 in CRC(standard mean difference=1.81,P<0.01),with summary receiver operating characteristic analysis yielding sensitivity and specificity values of 0.83 and 0.88,respectively.Molecular docking studies indicated that NC specifically targeted CHEK1,while clustered regularly interspaced short palindromic repeats knockout experiments demonstrated that CHEK1 promoted CRC cell proliferation.CONCLUSION Upregulation of CHEK1 promotes CRC cell proliferation.However,the dataset's diversity is limited,requiring further investigation into its specific mechanisms.展开更多
This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single...This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.展开更多
BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the i...BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the impact of MV on acute liver injury(ALI)is unknown.AIM To investigate the hepatoprotective potential of MV against liver damage caused by APAP and to examine the underlying mechanisms.METHODS Mice were divided into three groups:Saline,APAP and APAP+MV.MV(10 mg/kg)was given intraperitoneally one hour before APAP(300 mg/kg)administration.Twenty-four hours after APAP exposure,serum transaminase levels,liver necrotic area,inflammatory responses,nitrotyrosine accumulation,and c-jun-N-terminal kinase(JNK)activation were assessed.Additionally,we analyzed reactive oxygen species(ROS)levels,JNK activation,and cell death in alpha mouse liver 12(AML12)cells.RESULTS MV pre-treatment in vivo led to a reduction in the rise of aspartate transaminase and alanine transaminase levels,mitigated liver damage,decreased nitrotyrosine accumulation,and blocked JNK phosphorylation resulting from APAP exposure,without affecting glutathione production.Similarly,MV diminished the APAP-induced increase in ROS,JNK phosphorylation,and cell death in vitro.CONCLUSION Our study suggests that MV treatment alleviates APAP-induced ALI by reducing ROS and JNK activation.展开更多
OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-...OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.展开更多
Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadia...Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.展开更多
基金Supported by the National Research Foundation of Korea Grant Funded by the Korea Government,No.RS-2024-00440477the Korea Institute of Science and Technology Institutional Program,No.2E33111-24-042.
文摘BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.
基金Supported by the Scientific Research Fund of Tai’an Science and Technology Agency,No.2019NS180.
文摘Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant challenges associated with disease recurrence and resistance to chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway plays a pivotal role in cell proliferation,growth,metabolism,and survival.Its aberrant activation is closely linked to the development and progression of TNBC,as well as treatment response and drug resistance.Currently,numerous targeted drugs specifically inhibiting this signaling pathway are being developed and undergoing clinical trials.These include inhibitors targeting PI3K,AKT,or mTOR individually,as well as dual-target or multi-target inhibitors simultaneously targeting different components of this pathway.Encouragingly,some inhibitors have demonstrated promising potential in clinical trials.This review delves into the therapeutic potential of the PI3K/AKT/mTOR signaling pathway for TNBC and explores prospects for drug discovery.
文摘The December 2023 issue of the Military Medical Research brings out an astounding discover y by Xu et al.[1]demonstrating a key role of the mysterious enzyme ADPdependent glucokinase(ADPGK)in the cellular metabolism of prostate cancer(PCa).The ADPGKs are enzymes typically found in thermophilic archaea where they mediate the indispensable,first step of glucose metabolism,i.e.phosphorylation of glucose to glucose-6-phosphate.Strikingly,ADPGKs utilize ADP as a phosphate donor instead of ATP typically used to initiate glycolysis by four“classical”eukaryotic hexokinases(HKⅠ–Ⅲand glucokinase).Thus,the discovery made by Ronimus and Morgan[2]of the functional form of ADPGK in mice,opened an intriguing question of the specific role of this enzyme in the metabolism of eukaryotic cell.
文摘Currently,the standard clinical practice involves the predominant use of androgen deprivation therapy to treat advanced prostate cancer(PCa),which often inevitably progresses into castration-resistant PCa[1].Because of its unfavorable prognosis and limited treatment alternatives,studies have emphasized the pressing requirement for novel therapeutic targets to enhance the efficacy of advanced PCa treatment and prolong patient survival.
基金supported by The National Natural Science Foundation of China(No.31902283)Research Foundation for Master students at the Affiliated Hospital of Zunyi Medical College(No.22-2018).
文摘Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.
基金Supported by a grant from the National Natural Science Foundation of China(no.82174457)。
文摘Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung cancer potential.We aimed to explore the anti–lung cancer effect of BBR and related mechanisms by targeting the glycogen synthase kinase 3β(GSK3β)/β-catenin pathway.Methods:Lung adenocarcinoma(LUAD)cells A549 and NCI-H1975 were treated with BBR.Results:Our results showed that BBR inhibited cell proliferation by decreasing c-Myc levels and induced cel cycle arrest in the G0/G1 phase by lowering cyclin D1 levels.BBR induced apoptosis by upregulating cleaved caspase 3 levels.BBR inhibited cell migration and invasion by decreasing N-cadherin levels.Furthermore,BBR upregulated the expression of GSK3βprotein and phospho-β-catenin proteins in the cytoplasm,while decreasing the expression ofβ-catenin protein.Next,LUAD cel s were exposed to CHIR-99021(a GSK3βinhibitor).This treatment led to an increase in c-Myc,cyclin D1,andβ-catenin levels at specific concentrations.BBR partially reversed the effects of CHIR-99021.Finally,LUAD cells were treated with CHIR-99021(4μmoL/L)combined with BBR(30 and 60μmoL/L)for 24 h.The expression of programmed death ligand 1(PD-L1)was assessed by Western blot analysis.Jurkat T cells and A549 cel s were cocultured for 24 h to examine the lactate dehydrogenase release rate.Results suggested that BBR suppressed the expression of PD-L1 and heightened the immune lethality of T cells.Conclusions:BBR suppressed the proliferative activity of LUAD cell lines A549 and NCI-H1975 in vitro,induced cell cycle arrest and cancer cel apoptosis in the G0/G1 stage,and repressed the migration and invasion of cancer cells.BBR reduced the PD-L1 protein expression and enhanced T-cell–mediated cytotoxicity.These effects appear to be related to BBR's regulation of the GSK3β/β-catenin pathway.
基金supported by the National Natural Science Foundation of China,No.82003965the Science and Technology Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine,No.2024MS167(to LH)+2 种基金the Xinglin Scholar Program of Chengdu University of Traditional Chinese Medicine,No.QJRC2022033(to LH)the Improvement Plan for the'Xinglin Scholar'Scientific Research Talent Program at Chengdu University of Traditional Chinese Medicine,No.XKTD2023002(to LH)the 2023 National Project of the College Students'Innovation and Entrepreneurship Training Program at Chengdu University of Traditional Chinese Medicine,No.202310633028(to FD)。
文摘The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
基金Supported by the Fundamental Research Program of Shanxi Province,No.202203021222418Research Program of Shanxi Provincial Health Commission,No.2023061+2 种基金Fundamental Research Cooperation Program of Beijing-Tianjin-Hebei Region of Natural Science Foundation of Tianjin,No.22JCZXJC00140Tianjin Major Science and Technology Project,No.21ZXJBSY00110Tianjin Health and Science and Technology Project,No.TJWJ2024ZK001.
文摘BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.
基金Supported by Grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute,funded by the Ministry of Health&Welfare,Republic of Korea,No.RS-2022-KH129889.
文摘BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.
基金National Natural Science Foundation of China(the Study of Electrochemical Mechanism on the Common Syndrome Factors Concerning Alzheimer's Disease and Parkinson's Disease,No.81273629)Prescription-syndrome Effect of Dihuang Yinzi Treating Alzheimer Disease and Parkinson Disease Based on the Theory of Syndrome Factor,No.81273898+2 种基金Study on the Synergistic Mechanism of Polygala Tenuifolia and Acorus Gramineus Improving Memory Through Modulating Synaptic Plasticity Molecular Network,No.81473375Shanxi Scholarship Council of China(the Study of Electrochemical Mechanism on the Common Syndrome Factors Concerning Brain Degenerative Diseases,No.2013-134)Shanxi Provincial Project of International Science Technology Cooperation(R&D of Screen System for Chinese Medicines of Anti-Neuronal Apoptosis Based on the Modulation Mechanism of Neuroglial Cells,No.2010081065)
文摘Ginsenosides are the main active components of ginseng,which have been reported to target brain tissues and produce multiple neuroprotective effects.Ginsenosides have been shown to improve learning ability and memory in normal aged animals,and in an animal model of memory impairment.However,its underlying pharmacological mechanisms are very complicated,especially with regard to its effects on the activation of protein kinases in neurons.Previous reports have shown that some protein kinases may be affected by ginsenosides,including protein kinase C,calcium/calmodulin-dependent protein kinase Ⅱ,c-Jun-N terminal kinase,and protein tyrosine kinase.In this paper,protein kinases that may underlie the mechanisms of ginsenosides will be discussed.
基金German Research Foundation(DFG),No.TR1663/1-1 and No.KN356/9-1and Else Kröner-Fresenius-Stiftung,No.2017_A142.
文摘Pancreatic cancer is a dismal disease with high incidence and poor survival rates.With the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently needed.Protein kinases are key regulatory players in basically all stages of development,maintaining physiologic functions but also being involved in pathogenic processes.c-Jun N-terminal kinases(JNK)and p38 kinases,representatives of the mitogen-activated protein kinases,as well as the casein kinase 1(CK1)family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors,DNA damage,and others.In their physiologic roles,they are responsible for the regulation of cell cycle progression,cell proliferation and differentiation,and apoptosis.Dysregulation of the underlying pathways consequently has been identified in various cancer types,including pancreatic cancer.Pharmacological targeting of those pathways has been the field of interest for several years.While success in earlier studies was limited due to lacking specificity and off-target effects,more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results.Consequently,targeting of JNK,p38,and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases.However,further studies are warranted,especially involving in vivo investigation and clinical trials,in order to advance inhibition of stress-activated kinases to the field of translational medicine.
基金Acknowledgements： This work was supported by the Natural Science Foundation of Jiangsu Province, China （No. 04KJB310082） and the Science and Technology Development Foundation of Nanjing Medical University （No. 06NMUZ002）.
文摘Objective： Extracellular signal-regulated kinases （ERKs） can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia. Methods Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot. Results Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate （NMDA） receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca^2＋/calmodulin-dependent protein kinase Ⅱ （CaMKⅡ） activities. With the inhibition of Src family tyrosine kinases or CaMKⅡ by administration of PP2 or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated. Conclusions Src family tyrosine kinases and CaMKⅡ might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.
文摘Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing epithelial-mesen-chymal transition.Although their multilevel approach integrating clinical data,functional assays,and xenograft models demonstrated a key role for RGS4 in GC pathogenesis,several limitations should be considered.The mechanism of the RGS4-focal adhesion kinase interaction remains unclear,specifically whether it involves direct binding or intermediaries.The clinical analysis of 90 patients lacks stratification by GC subtypes or immune features,potentially limiting generaliz-ability.Furthermore,fully validating RGS4’s oncogenic role requires additional studies,including functional assays in chemotherapy-resistant and metastatic cell lines,metastasis models including orthotopic implantation and tail vein injection,and comparison with other RGS family members.Addressing these via targeted mechanistic studies and expanded clinical validation could strengthen RGS4’s po-tential as a therapeutic target in GC.
文摘Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicylates,corticosteroids,and biologics,offer limited efficacy,safety,and durability of response.The advancement in small-molecule Janus kinase(JAK)inhibitors has introduced a novel,oral therapeutic option that targets intracellular signaling pathways implicated in UC pathogenesis.Tofacitinib is the first approved JAK inhibitor for the treatment of moderate-to-severe UC.This drug,despite offering promising efficacy,has various safety concerns,especially the occurrence of thromboembolic events.These adverse effects have stressed the devel-opment of more selective agents such as upadacitinib and filgotinib.This mini-review explores the current perspectives of JAK inhibitors in UC,particularly focusing on their mechanisms of action,safety profiles,clinical trial outcomes,and emerging strategies to enhance their use.This review also highlights future directions,including the potential of selective JAK1 inhibition and the role of personalized medicine in refining therapeutic decisions.Understanding the emerging place of JAK inhibitors within the UC treatment strategies offers excellent opportunities to increase patient care and long-term disease management.
基金Supported by the Natural Science Foundation of Guangxi Province,No.2019GXNSFAA185030 and No.2023GXNSFBA026129the Scientific Research Project of the Second Affiliated Hospital of Guangxi Medical University,No.EFYKY2020013the Cultivation Science Foundation of the Second Affiliated Hospital of Guangxi Medical University,No.GJPY2023005 and No.GJPY2023009.
文摘BACKGROUND In patients with colorectal cancer(CRC),tumour metastasis is the leading cause of death.The search for key genes involved in metastasis of CRC is imperative for improved prognoses and treatments.SPDL1 has been implicated in the deve-lopment of CRC,however,its mechanism of action remains unclear.AIM To investigate the role and mechanism of action by which SPDL1 inhibits the development and metastasis of CRC.METHODS In this study,we examined the relationship between SPDL1 expression and CRC prognosis using immunohistochemistry.Survival analyses were performed using Kaplan-Meier analysis and log-rank test.After knocking down SPDL1 in the HCT116 cancer cell line changes in cell viability,migration,invasion,and gene expression were examined using a cell counting kit 8 assay,Transwell assay,and Western blot.The effect of SPDL1 on the cell cycle was assessed using flow cy-tometry.RNA sequencing was used to analyse the effect of SPDL1 on gene expression of CRC cells.The mechanism of action of SPDL1 in CRC was further clarified using U0126,an inhibitor of the mitogen-activated protein kinase signaling pathway.RESULTS SPDL1 is expressed at low levels in tissues of patients with CRC,and this reduced expression is associated with poor prognosis.Functionally,low expression of SPDL1 in CRC promotes cell proliferation,migration,invasion,and affects the cell cycle.Mechanistically,SPDL1 affects the progression of CRC through its regulation of the process of epithelial-mesenchymal transition(EMT)and of the epidermal growth factor receptor(EGFR)/extracellular signal-regulated kinase(ERK)signaling pathways.CONCLUSION This study showed that the loss of SPDL1 may induce EMT and promote cell migration and invasion in CRC through the EGFR/ERK pathway.
基金Supported by Innovation Project of Guangxi Graduate Education,No.YCBZ2023096Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z20210442+1 种基金China Undergraduate Innovation and Entrepreneurship Training Program,No.S202410598185Future Academic Star of Guangxi Medical University,No.WLXSZX24101.
文摘BACKGROUND Colorectal cancer(CRC)is a prevalent malignant tumor characterized by a high mortality rate,with significant challenges persisting in the identification and management of its metastatic stage.The role of checkpoint kinase 1(CHEK1),a cell cycle checkpoint kinase,in CRC has not been fully clarified.We hypothesize that the upregulation of CHEK1 may enhance the proliferation of CRC cells,indicating its potential as a novel therapeutic target for CRC therapy.AIM To investigate the expression and function of CHEK1 in CRC,this study utilizes single-cell RNA sequencing and tissue microarray data.METHODS Single-cell RNA sequencing technology was employed to analyze CRC cells from the GSE144735 dataset,and immunohistochemistry was conducted to confirm the expression of CHEK1 in CRC and adjacent tissues.We also integrated mRNA expression data from multiple public databases to assess global CHEK1 expre-ssion in CRC.Molecular docking experiments were performed to explore the in-teraction between CHEK1 and the potential drug nitidine chloride(NC),as well as to investigate the influence of CHEK1 on CRC cell proliferation.RESULTS We found comparatively elevated CHEK1 expression in the malignant epithelial cells of CRC,with marked upregulation of its mRNA levels in CRC tissues.Immunohistochemical analysis further confirmed the high expression of CHEK1 in CRC tissues,and the receiver operating characteristic curve demonstrated high accuracy(area under the curve=0.964)for CHEK1 as a biomarker.Analysis of global datasets indicated a statistically significant overexpression of CHEK1 in CRC(standard mean difference=1.81,P<0.01),with summary receiver operating characteristic analysis yielding sensitivity and specificity values of 0.83 and 0.88,respectively.Molecular docking studies indicated that NC specifically targeted CHEK1,while clustered regularly interspaced short palindromic repeats knockout experiments demonstrated that CHEK1 promoted CRC cell proliferation.CONCLUSION Upregulation of CHEK1 promotes CRC cell proliferation.However,the dataset's diversity is limited,requiring further investigation into its specific mechanisms.
文摘This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.
基金Supported by Guangxi Natural Science Foundation of China,No.2024GXNSFAA010040Special Fund of the Central Government Guiding Local Scientific and Technological Development by Guangxi Science and Technology Department,No.GuikeZY21195024National Natural Science Foundation of China,No.82260499 and No.82460463.
文摘BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the impact of MV on acute liver injury(ALI)is unknown.AIM To investigate the hepatoprotective potential of MV against liver damage caused by APAP and to examine the underlying mechanisms.METHODS Mice were divided into three groups:Saline,APAP and APAP+MV.MV(10 mg/kg)was given intraperitoneally one hour before APAP(300 mg/kg)administration.Twenty-four hours after APAP exposure,serum transaminase levels,liver necrotic area,inflammatory responses,nitrotyrosine accumulation,and c-jun-N-terminal kinase(JNK)activation were assessed.Additionally,we analyzed reactive oxygen species(ROS)levels,JNK activation,and cell death in alpha mouse liver 12(AML12)cells.RESULTS MV pre-treatment in vivo led to a reduction in the rise of aspartate transaminase and alanine transaminase levels,mitigated liver damage,decreased nitrotyrosine accumulation,and blocked JNK phosphorylation resulting from APAP exposure,without affecting glutathione production.Similarly,MV diminished the APAP-induced increase in ROS,JNK phosphorylation,and cell death in vitro.CONCLUSION Our study suggests that MV treatment alleviates APAP-induced ALI by reducing ROS and JNK activation.
基金National Natural Science Foundation of China:Basic Research on the Mechanism of Organ Immune Damage and the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine(No.32141005)。
文摘OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.
文摘Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.
