AIM:To explore the therapeutic effect of Tongfeng-Qingli mixture(TFQLM)and its mechanism in hyperuricemic(HUA)rats based on uric acid(UA)transporter and Janus kinase 2(JAK2)/signal transducer and acti-vator of transcription 3(STAT3)signaling pathway.METHODS:(1)In vivo experiment:36 male SD rats were random-ly divided into control(CON)group,model(MOD)group,benzbromarone(BEN)group,low-dose TFQLM(TFQLM-L)group,medium-dose TFQLM(TFQLM-M)group,and high-dose TFQLM(TFQLM-H)group,with 6 rats in each group.In all groups except CON group,HUA was induced in rats by giving hypoxanthine(HP)combined with potassium oxybate(OP)for 35 consecutive days.The rats in CON group were given sodium carboxymethyl cellulose solution by gavage.A fully automatic biochemistry analyzer was used to detecte serum UA,serum creatinine(SCr)and blood urea nitrogen(BUN)levels.The xanthine oxidase(XOD)and adenosine deaminase(ADA)levels in the liver were detected by ELISA kits.The histopathological changes of kidneys were observed by HE staining.Immunohistochemistry was performed to de-tect urate transporter 1(URAT1)and glucose transporter 9(GLUT9),organic anion transporter 1(OAT1)and OAT3 ex-pression in the kidney.Western blot was used to measure the protein levels of URAT1,GLUT9,OAT1,OAT3,interleu-kin-6(IL-6),tumor necrosis factor-α(TNF-α),JAK2,p-JAK2,STAT3,p-STAT3 and repressor of cytokine signaling 3(SOCS3)in the kidney.(2)In vitro experiments:HUA cellular model was established by UA stimulation in HK2 cells,and the protein levels of URAT1,GLUT9,OAT1,OAT3,IL-6,TNF-α,JAK2,p-JAK2,STAT3,p-STAT3,and SOCS3 were detected by Western blot.RESULTS:Compared with MOD group,serum UA,SCr and BUN levels of the rats in all TFQLM groups were reduced(P<0.05).The XOD and ADA levels in liver tissues were significantly reduced(P<0.05).The protein levels of URAT1,GLUT9,IL-6,TNF-α,JAK2,p-JAK2,STAT3,p-STAT3 and SOCS3 were decreased(P<0.05),and OAT1 and OAT3 protein expression was increased(P<0.05)in kidneys and HK2 cells.CONCLUSION:By establishing rat and HK2 cell HUA models,it is hypothesized that TFQLM may reduce UA levels and attenuate renal inflammation in HUA rats,and its mechanism may be related to the regulation of UA transport proteins and inhibition of the JAK2/STAT3 signaling pathway.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Acute lung injury （ALI） is one of the most common and critical diseases in clinical practice， with extremely high morbidity and mortality， seriously threatening human life and health. The pathogenesis of ALI is complex， in which the inflammatory response is a key factor. Studies have shown that NOD-like receptor protein 3 （NLRP3） inflammasomes are involved in ALI through mechanisms such as inflammation induction， increased microvascular permeability， recruitment of neutrophils， oxidative stress， and pyroptosis， playing a key role in the occurrence and progression of ALI. Therefore， regulating NLRP3 inflammasomes and inhibiting the release of inflammatory factors can alleviate the damage in ALI. At present， ALI is mainly treated by mechanical ventilation and oxygen therapy， which have problems such as high costs and poor prognosis. In recent years， studies have shown that traditional Chinese medicine （TCM） can reduce the inflammatory response and the occurrence of oxidative stress and pyroptosis by regulating the NLRP3 inflammasome， thus alleviating the damage and decreasing the mortality of ALI. Based on the relevant literature in recent years， this article reviews the research progress in TCM treatment of ALI by regulating NLRP3 inflammasomes， discusses how NLRP3 inflammasomes participate in ALI， and summarizes the active ingredients， extracts， and compound prescriptions of TCM that regulate NLRP3 inflammasomes， aiming to provide new ideas for the clinical treatment of ALI and the development of relevant drugs.

AIM:To explore the therapeutic effect of Tongfeng-Qingli mixture(TFQLM)and its mechanism in hyperuricemic(HUA)rats based on uric acid(UA)transporter and Janus kinase 2(JAK2)/signal transducer and acti-vator of transcription 3(STAT3)signaling pathway.METHODS:(1)In vivo experiment:36 male SD rats were random-ly divided into control(CON)group,model(MOD)group,benzbromarone(BEN)group,low-dose TFQLM(TFQLM-L)group,medium-dose TFQLM(TFQLM-M)group,and high-dose TFQLM(TFQLM-H)group,with 6 rats in each group.In all groups except CON group,HUA was induced in rats by giving hypoxanthine(HP)combined with potassium oxybate(OP)for 35 consecutive days.The rats in CON group were given sodium carboxymethyl cellulose solution by gavage.A fully automatic biochemistry analyzer was used to detecte serum UA,serum creatinine(SCr)and blood urea nitrogen(BUN)levels.The xanthine oxidase(XOD)and adenosine deaminase(ADA)levels in the liver were detected by ELISA kits.The histopathological changes of kidneys were observed by HE staining.Immunohistochemistry was performed to de-tect urate transporter 1(URAT1)and glucose transporter 9(GLUT9),organic anion transporter 1(OAT1)and OAT3 ex-pression in the kidney.Western blot was used to measure the protein levels of URAT1,GLUT9,OAT1,OAT3,interleu-kin-6(IL-6),tumor necrosis factor-α(TNF-α),JAK2,p-JAK2,STAT3,p-STAT3 and repressor of cytokine signaling 3(SOCS3)in the kidney.(2)In vitro experiments:HUA cellular model was established by UA stimulation in HK2 cells,and the protein levels of URAT1,GLUT9,OAT1,OAT3,IL-6,TNF-α,JAK2,p-JAK2,STAT3,p-STAT3,and SOCS3 were detected by Western blot.RESULTS:Compared with MOD group,serum UA,SCr and BUN levels of the rats in all TFQLM groups were reduced(P<0.05).The XOD and ADA levels in liver tissues were significantly reduced(P<0.05).The protein levels of URAT1,GLUT9,IL-6,TNF-α,JAK2,p-JAK2,STAT3,p-STAT3 and SOCS3 were decreased(P<0.05),and OAT1 and OAT3 protein expression was increased(P<0.05)in kidneys and HK2 cells.CONCLUSION:By establishing rat and HK2 cell HUA models,it is hypothesized that TFQLM may reduce UA levels and attenuate renal inflammation in HUA rats,and its mechanism may be related to the regulation of UA transport proteins and inhibition of the JAK2/STAT3 signaling pathway.

[Purpose]To analyze the incidence and mortality trends,and survival of gallbladder cancer in Nantong City of Jiangsu Province from 2013 to 2017.[Methods]The gallbladder cancer incidence and mortality data from 2013 to 2017 were collected from Nantong cancer registries.The crude incidence/mortality rates,age-standardized incidence/mortality rates by Chinese and world standard population(ASIRC/ASMRC,ASIRW/ASMRW)were calculated by sex,age and regions(urban and rural).Joinpoint software was used to analyze the incidence and mortality trends of gallbladder cancer.The observed survival rate and relative survival rate were calculated by using life table method and Ederer Ⅱ method.[Results]From 2013 to 2017,the gallbladder cancer crude incidence and mortality rates were 6.36/105 and 4.91/105,ASIRC and ASMRC were 2.62/105 and 1.94/105,respectively.The crude incidence and mortality,and ASMRC showed an upwards trend(all P＜0.05).The ASIRC for men and women was 2.43/105 and 2.83/105,the ASMRC for men and women was 1.74/105 and 2.16/105,respectively.ASIRC and ASMRC in women were higher than those in men.The ASIRC in urban and rural areas was 2.40/105 and 2.69/105,and the ASMRC was 1.61/105 and 2.05/105,respectively.ASIRC and ASMRC in rural areas were higher than those in urban areas.The average age of onset was 70.33 years old and the average age of death was 71.86 years old.The 5-year observed survival rate was 12.90％,and the 5-year relative survival rate was 14.47％.Both the 5-year observed survival rate and relative survival rate showed an upwards trend(both P＜0.05).[Conclusion]The incidence and mortality rates of gall-bladder cancer in Nantong City are relatively high and the survival rate is generally low.It is sug-gested that targeted prevention and control measures of gallbladder cancer in Nantong City should be strengthened,particularly in rural areas and for middle-aged and elderly women.

Objective To investigate the effect of acupuncture on the inflammatory changes of α7 nicotinic acetylcholine receptors(α7 nicotinic acetylcholine receptors,α7nAChRs)in rats with chronic migraine(CM).Methods Adult male SD rats were randomly divided into control group(VEH group),model group(NTG group),acupuncture group(TA group),α7nAChRs antagonist group(MLA group)and α7nAChRs agonist group(TA group)according to basic pain threshold.The rat model of CM was established by repeated subcutaneous injection of nitroglycerin(NTG)at the neck and back every other day.TA group and MLA group received acupuncture treatment one hour before NTG injection,20 minutes every day for 9 consecutive days.The MLA group was intraperitoneally injected with α7nAChRs antagonist MLA half an hours before acupuncture,and the PNU group was intraperitoneally injected with α7nAChRs agonist PNU-282987 half an hours before NTG injection,both groups were injected continuously for 9 days.The changes of paw withdrawal mechanical threshold(Paw Withdrawal Mechanical Threshold,PWMT)and tail-flick latency(Tail-Flick Latency,TFL)were detected by Von Frey and thermal radiation pain meter.The contents of inflammatory factors IL-1β,TNF-α and TGF-β in TNC and serum were determined by ELISA.The relative fluorescence intensity and co-expression of GFAP and α7nAChRs in TNC were detected by immunofluorescence dual labeling method.Results Compared with VEH group,PWMT and TFL in NTG group were significantly decreased(P<0.05 or P<0.01),the contents of IL-1β(P<0.01)and TNF-α(P<0.01,P<0.05)in serum and TNC were significantly increased;and in TNC,the astrocytes were activated significantly(P<0.01),while the relative fluorescence intensity of α7nAChRs and the co-expression of GFAP and α7nAChRs were significantly decreased(P<0.05,P<0.01).Compared with NTG group,PWMT and TFL in TA group were increased(P<0.05 or P<0.01),the contents of IL-1β(P<0.01)and TNF-α(P<0.01,P<0.05)in serum and TNC were increased;and in TNC,the relative fluorescence intensity of GFAP was significantly decreased(P<0.01),however the relative fluorescence intensity of α7nAChRs and the co-expression of GFAP and α7nAChRs were significantly increased(P<0.01).Compared with MLA group,PWMT and TFL in TA groups and PNU groups were significantly increased(P<0.05 or P<0.01).The contents of IL-1β(P<0.05)and TNF-α(P<0.01)in serum and TNC of TA group were increased,while the contents of TGF-β(P<0.05)were decreased.The contents of IL-1β in serum and TNC of PNU group were decreased(P<0.01,P<0.05),while the contents of TGF-β(P<0.01)were significantly increased.Conclusions Acupuncture can effectively relieve CM inflammatory response and hypersensitivity to pain,and its anti-inflammatory and analgesic effects may be related to the up-regulation of α7nAChRs expression.

Objective To explore the therapeutic mechanism of Euonymus alatus for diabetic kidney disease(DKD).Methods TCMSP,PubChem and Swiss Target Prediction databases were used to obtain the active ingredients in Euonymus alatus and their targets.GEO database and R language were used to analyze the differentially expressed genes in DKD.The therapeutic targets of DKD were obtained using GeneCards,DisGeNet,OMIM and TTD databases.The protein-protein interaction network and the"drug-component-target-disease"network were constructed for analyzing the topological properties of the core targets,which were functionally annotated using GO and KEGG pathway enrichment analyses.Molecular docking was performed for the core targets and the main pharmacologically active components,and the results were verified in db/db mice.Results Analysis of GSE96804,GSE30528 and GSE30529 datasets(including 60 DKD patients and 45 normal samples)identified 111 differentially expressed genes in DKD.Network pharmacology analysis obtained 161 intersecting genes between the target genes of Euonymus alatus and DKD,including the key core target genes SRC,EGFR,and AKT1.The core active ingredients of Euonymus alatus were quercetin,kaempferol,diosmetin,and naringenin,which were associated with responses to xenobiotic stimulionus and protein phosphorylation and regulated EGFR tyrosine kinase inhibitor resistance pathways.Molecular docking suggested good binding activities of the core active components of Euonymus alatus with the core targets.In db/db mouse models of DKD,treatment with Euonymus alatus obviously ameliorated kidney pathologies,significantly inhibited renal expressions of SRC,EGFR and AKT1,and delayed the progression of DKD.Conclusion Euonymus alatus contains multiple active ingredients such as quercetin,kakaferol,diosmetin,naringenin,which regulate the expressions of SRC,EGFR,and AKT1 to affect the EGFR tyrosine kinase inhibitor resistance signaling pathway to delay the progression of DKD.

Objective To explore the therapeutic mechanism of Euonymus alatus for diabetic kidney disease(DKD).Methods TCMSP,PubChem and Swiss Target Prediction databases were used to obtain the active ingredients in Euonymus alatus and their targets.GEO database and R language were used to analyze the differentially expressed genes in DKD.The therapeutic targets of DKD were obtained using GeneCards,DisGeNet,OMIM and TTD databases.The protein-protein interaction network and the"drug-component-target-disease"network were constructed for analyzing the topological properties of the core targets,which were functionally annotated using GO and KEGG pathway enrichment analyses.Molecular docking was performed for the core targets and the main pharmacologically active components,and the results were verified in db/db mice.Results Analysis of GSE96804,GSE30528 and GSE30529 datasets(including 60 DKD patients and 45 normal samples)identified 111 differentially expressed genes in DKD.Network pharmacology analysis obtained 161 intersecting genes between the target genes of Euonymus alatus and DKD,including the key core target genes SRC,EGFR,and AKT1.The core active ingredients of Euonymus alatus were quercetin,kaempferol,diosmetin,and naringenin,which were associated with responses to xenobiotic stimulionus and protein phosphorylation and regulated EGFR tyrosine kinase inhibitor resistance pathways.Molecular docking suggested good binding activities of the core active components of Euonymus alatus with the core targets.In db/db mouse models of DKD,treatment with Euonymus alatus obviously ameliorated kidney pathologies,significantly inhibited renal expressions of SRC,EGFR and AKT1,and delayed the progression of DKD.Conclusion Euonymus alatus contains multiple active ingredients such as quercetin,kakaferol,diosmetin,naringenin,which regulate the expressions of SRC,EGFR,and AKT1 to affect the EGFR tyrosine kinase inhibitor resistance signaling pathway to delay the progression of DKD.

【Objective】 To investigate the situation of carbapenem-resistant Enterobacteriaceae(CRE) colonization in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT). 【Methods】 A total of 241 consecutive patients who underwent haplo-HSCT in the First Affiliated Hospital of Soochow University from June 1, 2021 to June 1, 2022 were enrolled. Anal swab screening was performed within 48 hours of admission and blood cultures were taken when the patient developed fever. Univariate and multivariate analysis were used to analyze the colonization rate, distribution, risk factors and the correlation between CRE colonization and post-transplant bloodstream infection(BSI). 【Results】 Among 241 patients with haplo-HSCT, there were 90 cases in CRE colonization positive group, with a colonization rate of 37.3% (90/241). Multivariate logistic regression analysis showed that sex (OR 2.42, 95% CI 1.38-4.22, P<0.05) and history of infection within 30 days before transplantation (OR 3.37, 95% CI 1.59-7.17, P<0.05) may be independent risk factors for CRE intestinal colonization. Of the 95 CRE strains, the top five species were carbapenem-resistant Klebsiella pneumoniae (38/95, 40.0%), carbapenem-resistant Escherichia coli (29/95, 30.5%), carbapenem-resistant Enterobacter cloacae (13/95, 13.6%), carbapenem-resistant Klebsiella acidophilus (6/95, 6.3%) and carbapenem-resistant Proteus mirabilis (3/95, 3.1%). The incidence of post-transplant BSI was 12.0% (29/241) in the CRE-colonized group and 3.3% (8/241) in the non-colonized group. In the colonization group, 100% of the pathogens of BSI were identical with those of CRE colonization. 【Conclusion】 Bacterial culture of anal swab during haplo-HSCT is helpful for detection of CRE colonization in intestinal tract, which provides some clinical basis for active monitoring of key flora, prevention and control of infection.

Objective Based on the theory of"gut-brain",this study explored the effect of acupuncture on the gut microbiota and central inflammation in migraine model rats,in order to explore the mechanism of acupuncture in the treatment of migraine from the perspective of"gut-brain".Methods The migraine rat model was established by subcutaneous injection of nitroglycerin.They were randomly divided into a model group and an acupuncture group,with 6 rats in each group,and a control group with 6 rats for conventional binding and fixation.Before modeling and on the 1st,5th,and 9th days after modeling,each group used electronic VonFrey to measure the plantar mechanical pain threshold of rats.After the experiment,Elisa was used to detect the expression levels of inflammatory factors IL-6 and TNF-α in the central trigeminal spinal nucleus of the rats in each group.Three-generation Pacbio full-length microbial diversity sequencing was used to perform 16S full-length rDNA sequencing on each group of fecal samples to detect the operational taxonomic unit(OTU)clustering and its abundance,Alpha diversity index,Beta diversity index,species among the samples in each group.differences in abundance.Results In migraine model rats,plantar mechanical pain threshold was significantly decreased(P<0.01),central IL-6 and TNF-α contents were significantly increased(P<0.01),and the structure and abundance of gut microbiota were abnormal.change(P<0.01).Continuous acupuncture treatment can significantly increase the plantar mechanical pain threshold in migraine rats(P<0.01),regulate the diversity of gut microbiota in migraine rats,increase Lactobacillus murine,and reduce the abundance of Lactobacillus enterobacteriaceae.degree(P<0.05),and decreased the levels of IL-6 and TNF-α in the central nervous system of migraine model rats(P<0.01).Conclusion Acupuncture can exert the"gut-brain"anti-inflammatory and analgesic effect of acupuncture in the treatment of migraine by regulating the gut microbiota structure and the expression of central IL-6 and TNF-α inflammatory factors in migraine model rats.