BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed th...BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.展开更多
BACKGROUND Acute appendicitis,a common condition with a higher prevalence among men,has shown an increasing incidence in recent years owing to lifestyle changes.It is characterized by right lower quadrant abdominal pa...BACKGROUND Acute appendicitis,a common condition with a higher prevalence among men,has shown an increasing incidence in recent years owing to lifestyle changes.It is characterized by right lower quadrant abdominal pain,rebound tenderness,and rapid onset.Its pathogenesis is complex and potentially linked to infection,environment,and genetics.Timely intervention is crucial to prevent complications.While surgery is the primary treatment,it carries risks,including postoperative infections that may necessitate re-operation.Gram-negative bacteria release endotoxin(ETX),which induces inflammation and is recognized by toll-like receptor 4(TLR4).This study evaluated ETX and TLR4 levels in patients with acute appendicitis to assess the risk of postoperative incision infections,aiding in prevention and treatment.AIM To explore ETX and TLR4 expression in the blood of patients with acute appendicitis and its association with in postoperative incision infection.METHODS A total of 153 patients with acute appendicitis treated at our hospital between April 2022 and March 2024(n=153)were included in the study.Patients were categorized into infected(n=36)and uninfected(n=117)groups according to the development of postoperative incision infections.General characteristics and blood levels of ETX and TLR4 were compared,and the factors influencing postoperative infection were identified using multivariate logistic regression.ETX and TLR4 predictive values were analyzed using receiver operating characteristic curves.RESULTS No statistically significant differences were observed between the two groups in terms of sex,age,or other general characteristics(P>0.05).Compared to the uninfected group,the infected group had a higher proportion of patients with suppurative or gangrenous appendicitis,longer surgical times,longer incision lengths,and elevated ETX and TLR4 levels(P<0.05).Multivariate logistic regression analysis identified pathological type,surgical method,surgical time,and incision length as factors influencing postoperative incision infection in acute appendicitis.Receiver operating characteristic curve analysis revealed that both ETX and TLR4 levels were predictive factors for postoperative incision infection,with higher prediction efficiency when combined.CONCLUSION Pathological type,surgical method,surgical time,and incision length significantly influence postoperative incision infection risk in patients with acute appendicitis.Elevated ETX and TLR4 levels serve as valuable predictors of post-appendectomy infections.展开更多
OBJECTIVE:To determine the effect of Traditional Chinese Medicine(TCM)Fuzheng Xuanfei Huashi prescription(扶正宣肺化湿方,FZXF)on lipopolysaccharide(LPS)-induced pneumonia in mice and identify the mechanism of FZXF in ...OBJECTIVE:To determine the effect of Traditional Chinese Medicine(TCM)Fuzheng Xuanfei Huashi prescription(扶正宣肺化湿方,FZXF)on lipopolysaccharide(LPS)-induced pneumonia in mice and identify the mechanism of FZXF in the treatment of LPS-induced lung inflammation.METHODS:The pneumonia model was established by intraperitoneal injection of 5 mg/kg LPS in mice.Cytokines were detected by enzyme-linked immuneosorbent assay(ELISA),macrophages in lung tissue were determined by immunofluorescence,and pathwayrelated data were determined by quantitative real-time polymerase chain reaction(qPCR)and Western blot.RESULTS:The liver,thymus,and spleen index values and the levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)obviously increased in LPS-treated mice.FZXF decreased the white blood cell count and reduced the increase in the lung wet weight/dry weight ratio caused by LPS.The hematoxylin-eosin staining result showed that FZXF could maintain the integrity of lung tissue structure,alleviate interstitial oedema and alveolar wall thickening,and reduce inflammatory cell infiltration.Moreover,FZXF markedly reduced the expression of proinflammatory cytokines.FZXF also significantly reduced LPS-induced malondialdehyde production and increased superoxide dismutase level in the lung.By immunofluorescence,we found that FZXF could reduce macrophage infiltration.The mRNA expression levels of cyclooxygenase-2(COX-2),prostaglandin E2(PGE2),toll-like receptor 4(TLR4)and nuclear transcription factorκB(NF-κB)in the lung tissue of mice were decreased by treatment with FZXF.In addition,FZXF inhibited the protein expression of TLR4,p-p65 and COX-2.These results indicated that FZXF could inhibit the inflammatory response of LPS induced cytokine storm in mice through TLR4/NF-κB and COX-2/PGE2 signaling pathway.CONCLUSION:These findings were suggested that FZXF prescription suppresses inflammation in LPSinduced pneumonia in mice via TLR4/NF-κB and COX-2/PGE2 pathway.展开更多
Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor ...Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.展开更多
BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primar...BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.展开更多
目的:通过检测子痫前期(PE)患者外周血Toll样受体4(TLR4)表达及其分泌促炎细胞因子的功能,探讨单核细胞TLR4在PE发病过程中的作用。方法:选取22例子痫前期患者(PE组)和23例正常孕妇(HP组)作为研究对象。经知情同意后抽取4 m L静脉血,肝...目的:通过检测子痫前期(PE)患者外周血Toll样受体4(TLR4)表达及其分泌促炎细胞因子的功能,探讨单核细胞TLR4在PE发病过程中的作用。方法:选取22例子痫前期患者(PE组)和23例正常孕妇(HP组)作为研究对象。经知情同意后抽取4 m L静脉血,肝素钠抗凝。流式细胞术(FCM)检测单核细胞TLR4表达;脂多糖(LPS)刺激单核细胞18小时,Luminex液相芯片检测培养上清液中肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6、IL-12P70和IL-10浓度;并分析PE患者单核细胞TLR4阳性频率与外周血清细胞因子浓度的相关性。结果:与HP组相比,PE组单核细胞TLR4阳性细胞频率(TLR4+:23.2(18.4-44.3)%vs59.7(19.8-79.7)%)和平均荧光强度(MFI:32.3(27.6-49.2)vs48.6(32.4-93.2)明显升高,差异均有统计学意义(P<0.05);单核细胞经50ng/m L LPS刺激培养18小时,PE组上清液TNF-α(243.5±15.2 pg/m Lvs123±81.3 pg/m L)、IL-6(3122.7±534.2 pg/m Lvs1380.4±332 pg/m L)浓度明显高于HP组,IL-10(84.2±24.9 pg/m L vs164.5±47.1 pg/m L)低于HP组,差异均有统计学意义(P<0.05);PE患者单核细胞阳性频率与外周血清中细胞因子TNF-α、IL-6具有相关性(r=0.634、r=0.528,P<0.05)。结论:PE患者外周血单核细胞TLR4表达明显增加,并处于活化状态,分泌较多的促炎细胞因子IL-6和TNF-α,参与子痫前期的疾病过程。因此,抑制单核细胞TLR4表达可能是治疗子痫前期的新途经。展开更多
基金Supported by the Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
基金Supported by Research Fund for Academician Lin He New Medicine,No.JYHL2022FMS02.
文摘BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.
文摘BACKGROUND Acute appendicitis,a common condition with a higher prevalence among men,has shown an increasing incidence in recent years owing to lifestyle changes.It is characterized by right lower quadrant abdominal pain,rebound tenderness,and rapid onset.Its pathogenesis is complex and potentially linked to infection,environment,and genetics.Timely intervention is crucial to prevent complications.While surgery is the primary treatment,it carries risks,including postoperative infections that may necessitate re-operation.Gram-negative bacteria release endotoxin(ETX),which induces inflammation and is recognized by toll-like receptor 4(TLR4).This study evaluated ETX and TLR4 levels in patients with acute appendicitis to assess the risk of postoperative incision infections,aiding in prevention and treatment.AIM To explore ETX and TLR4 expression in the blood of patients with acute appendicitis and its association with in postoperative incision infection.METHODS A total of 153 patients with acute appendicitis treated at our hospital between April 2022 and March 2024(n=153)were included in the study.Patients were categorized into infected(n=36)and uninfected(n=117)groups according to the development of postoperative incision infections.General characteristics and blood levels of ETX and TLR4 were compared,and the factors influencing postoperative infection were identified using multivariate logistic regression.ETX and TLR4 predictive values were analyzed using receiver operating characteristic curves.RESULTS No statistically significant differences were observed between the two groups in terms of sex,age,or other general characteristics(P>0.05).Compared to the uninfected group,the infected group had a higher proportion of patients with suppurative or gangrenous appendicitis,longer surgical times,longer incision lengths,and elevated ETX and TLR4 levels(P<0.05).Multivariate logistic regression analysis identified pathological type,surgical method,surgical time,and incision length as factors influencing postoperative incision infection in acute appendicitis.Receiver operating characteristic curve analysis revealed that both ETX and TLR4 levels were predictive factors for postoperative incision infection,with higher prediction efficiency when combined.CONCLUSION Pathological type,surgical method,surgical time,and incision length significantly influence postoperative incision infection risk in patients with acute appendicitis.Elevated ETX and TLR4 levels serve as valuable predictors of post-appendectomy infections.
基金Emergency Corona Virus Disease 2019(COVID-19)Response Project of Dongguan:Clinical Efficacy Observation and Mechanism Study of Fuzheng Xuanfei Huashi Formula in the Treatment of COVID-19 Based on the Lingnan Theory of Epidemic Diseases(No.202071715002124)National Natural Science Foundation of China:Study on the Mechanism of Lung Inflammatory Injury Induced by Gut-derived Lipopolysaccharide and Skatole in Spleen Deficiency Animals based on Pulmonary Alveolus Macrophage Heterogeneity(No.82274381)Guangdong Basic and Applied Basic Research Foundation:Development and Industrialization of Traditional Chinese Medicine Classic and Famous Prescription Compound Formulations(No.2021ZD006)。
文摘OBJECTIVE:To determine the effect of Traditional Chinese Medicine(TCM)Fuzheng Xuanfei Huashi prescription(扶正宣肺化湿方,FZXF)on lipopolysaccharide(LPS)-induced pneumonia in mice and identify the mechanism of FZXF in the treatment of LPS-induced lung inflammation.METHODS:The pneumonia model was established by intraperitoneal injection of 5 mg/kg LPS in mice.Cytokines were detected by enzyme-linked immuneosorbent assay(ELISA),macrophages in lung tissue were determined by immunofluorescence,and pathwayrelated data were determined by quantitative real-time polymerase chain reaction(qPCR)and Western blot.RESULTS:The liver,thymus,and spleen index values and the levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)obviously increased in LPS-treated mice.FZXF decreased the white blood cell count and reduced the increase in the lung wet weight/dry weight ratio caused by LPS.The hematoxylin-eosin staining result showed that FZXF could maintain the integrity of lung tissue structure,alleviate interstitial oedema and alveolar wall thickening,and reduce inflammatory cell infiltration.Moreover,FZXF markedly reduced the expression of proinflammatory cytokines.FZXF also significantly reduced LPS-induced malondialdehyde production and increased superoxide dismutase level in the lung.By immunofluorescence,we found that FZXF could reduce macrophage infiltration.The mRNA expression levels of cyclooxygenase-2(COX-2),prostaglandin E2(PGE2),toll-like receptor 4(TLR4)and nuclear transcription factorκB(NF-κB)in the lung tissue of mice were decreased by treatment with FZXF.In addition,FZXF inhibited the protein expression of TLR4,p-p65 and COX-2.These results indicated that FZXF could inhibit the inflammatory response of LPS induced cytokine storm in mice through TLR4/NF-κB and COX-2/PGE2 signaling pathway.CONCLUSION:These findings were suggested that FZXF prescription suppresses inflammation in LPSinduced pneumonia in mice via TLR4/NF-κB and COX-2/PGE2 pathway.
基金Supported by Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH124001-2406National Natural Science Foundation of China,No.U23A20483.
文摘Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.
文摘BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.
