ObjectiveThis study aims to investigate the effect of Dictamni Cortex on intestinal barrier damage in rats and its mechanism by untargeted metabolomics and targeted metabolomics for short-chain fatty acids （SCFAs）. MethodsRats were randomly divided into a control group， a high-dose group of Dictamni Cortex （8.1 g·kg^-1）， a medium-dose group （2.7 g·kg^-1）， and a low-dose group （0.9 g·kg^-1）. Except for the control group， the other groups were administered different doses of Dictamni Cortex by gavage for eight consecutive weeks. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the ileal tissue. Enzyme-linked immunosorbent assay （ELISA） was employed to detect the level of cytokines， including tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and interleukin-1β （IL-1β）， in the ileal tissue of rats. Quantitative real-time fluorescence polymerase chain reaction （Real-time PCR） technology was used to detect the expression level of tight junction proteins， including zonula occludens-1 （ZO-1）， Occludin， and Claudin-1 mRNAs， in the ileal tissue of rats to preliminarily explore the effects of Dictamni Cortex on intestinal damage. The dose with the most significant toxic phenotype was selected to further reveal the effects of Dictamni Cortex on the metabolic profile of ileal tissue in rats by non-targeted metabolomics combined with targeted metabolomics for SCFAs. ResultsCompared with the control group， all doses of Dictamni Cortex induced varying degrees of pathological damage in the ileum， increased TNF-α （P<0.01）， IL-6 （P<0.01）， and IL-1β （P<0.01） levels in the ileal tissue， and decreased the expression level of ZO-1 （P<0.05， P<0.01）， Occludin （P<0.01）， and Claudin-1 （P<0.05） in the ileal tissue， with the high-dose group showing the most significant toxic phenotypes. The damage mechanisms of the high-dose group of Dictamni Cortex on the ileal tissue were further explored by integrating non-targeted metabolomics and targeted metabolomics for SCFAs. The non-targeted metabolomics results showed that 21 differential metabolites were identified in the control group and the high-dose group. Compared with that in the control group， after Dictamni Cortex intervention， the level of 14 metabolites was significantly increased （P<0.05， P<0.01）， and the level of seven metabolites was significantly decreased （P<0.05， P<0.01） in the ileal contents. These metabolites collectively acted on 10 related metabolic pathways， including glycerophospholipids and primary bile acid biosynthesis. The quantitative data of targeted metabolomics for SCFAs showed that Dictamni Cortex intervention disrupted the level of propionic acid， butyric acid， acetic acid， caproic acid， isobutyric acid， isovaleric acid， valeric acid， and isocaproic acid in the ileal contents of rats. Compared with those in the control group， the level of isobutyric acid， isovaleric acid， and valeric acid were significantly increased， while the level of propionic acid， butyric acid， and acetic acid were significantly decreased in the ileal contents of rats after Dictamni Cortex intervention （P<0.05， P<0.01）. ConclusionDictamni Cortex can induce intestinal damage by regulating glycerophospholipid metabolism， primary bile acid biosynthesis， and metabolic pathways for SCFAs.

Colorectal cancer is a common malignant tumor in the digestive system， ranking third in incidence and second in the cause of death worldwide. In recent years， the incidence of colorectal cancer is on the rise， and the age of patients with colorectal cancer tends to be younger， with a heavy cancer burden. It is of great significance to prevent the occurrence， development， recurrence， and metastasis of colorectal cancer to reduce the incidence and mortality of colorectal cancer. Patriniae Herba has the effects of clearing heat， removing toxins， eliminating carbuncle， and discharging pus and shows good therapeutic efficacy on inflammatory bowel disease， digestive tract tumors， pelvic inflammation， gynecological tumor， and so on. Patriniae Herba is often used in the clinical treatment of colorectal cancer， but its mechanism of action is not clear. Modern studies have found that Patriniae Herba contains triterpenoids， saponins， iridoids， flavonoids， and other chemical components， with antioxidant， anti-tumor， anti-bacterial， and other pharmacological effects. The main anti-tumor components of Patriniae Herba are flavonoids. The analysis of network pharmacology and the spectrum-effect relationship has suggested that quercetin， luteolin， apigenin， isoorientin， and isovitexin play a major role in inhibiting the occurrence and development of colorectal cancer. In vivo and in vitro studies have shown that flavonoids in Patriniae Herba can play an anti-tumor role in various ways， such as preventing precancerous lesions of colorectal cancer， inhibiting the growth and proliferation of cancer cells， blocking cancer cell cycle， promoting cancer cell apoptosis， and reversing drug resistance of colorectal cancer. The oral availability of flavonoids is low. The gut is the main metabolic site of flavonoids in the body， its metabolic pathway is closely related to gut microbiota. This paper reviewed the anti-tumor mechanism of flavonoids and their influence on gut microbiota to provide a reference for further research on the mechanism of Patriniae Herba against colorectal cancer and its clinical application.

Objective To investigate the distribution and seasonal fluctuations of visceral leishmaniasis vectors sandflies in Lüliang City, Shanxi Province, so as to provide insights into assessment of the visceral leishmaniasis transmission risk and formulation of visceral leishmaniasis control measures. Methods A total of 12 natural villages were sampled from Shilou County, Lishi District, Lanxian County, Linxian County and Wenshui County in Lüliang City, Shanxi Province from June to September, 2023, and sandflies were captured using light traps from 7 breeding habitats, including farmers’ houses, sheep pens, cattle pens, chicken coops, pig pens, mule and horse pens, and loess-cave dwellings. Following morphological identification of the sandfly species, the distribution of sandflies and the seasonal fluctuations of the sandfly density were analyzed. In addition, the Leishmania was detected in sandflies using a real-time fluorescence quantitative PCR assay. Results A total of 2 831 sandflies were captured with 156 light traps in Lüliang City from June to September, 2023, including 2 638 female sandflies (93.18%) and 193 male sandflies (6.82%), and the average density was 16.91 sandflies/(light-night). The seasonal fluctuations of the sandfly density all appeared a unimodal distribution in all survey sites, and the sandfly density peaked in July and then declined rapidly. Among all types of breeding habitats, the greatest sandfly density was found in sheep pens [39.04 sandflies/(light-night)]. In addition, 4.08% (2/49) of the sandfly samples were tested positive for Leishmania nucleic acid as revealed by the real-time fluorescence quantitative PCR assay. Conclusions Sandflies were widely distributed in Lüliang City, Shanxi Province in 2023, and the peak of the sandfly density was observed in July, which had a visceral leishmaniasis transmission risk. Intensified surveillance of visceral leishmaniasis and sandfly vectors is required and targeted vector control is recommended.

Objective:To explore the effects of Jianpi Bushen Jiedu Prescription on the proliferation and migration of hepatocellular carcinoma cells; To discuss its possible mechanism.Methods:Using human highly metastatic liver cancer cell line (HCCLM3) as the research object, they were randomly divided into control group and TCM group (100, 200, 400, 800, 1 600, 3 200 μg/ml Jianpi Bushen Jiedu Prescription) and Western medicine group (2.5, 5, 10, 20, 40 μmol/L sorafenib) using a random number table method. Cell viability was detected using cell counting reagent (CCK-8) method; HCCLM3 cells were divided into control group and TCM (Jianpi Bushen Jiedu Prescription 800 μg/ml) group and combined group (Jianpi Bushen Jiedu Prescription 800 μg/ml +sorafenib 20 μmol/L). Western blot method was used to detect the protein expressions of kinase/signaling transducer and transcriptional activator (JAK2/STAT3) pathway related proteins (p-JAK2, JAK2, p-STAT3, STAT3) in each group.Results:Compared with the control group, viability and mobility of HCCLM cell in TCM group and Western medicine group decreased ( P<0.01 or P<0.05); compared with the control group, the protein expressions of P-JAK2, JAK2, P-STAT3 and STAT3 in the TCM group and the combined group decreased ( P<0.05), and the JAK2 protein expression in the combined group was lower than that in the TCM group ( P<0.05). Conclusion:Jianpi Bushen Jiedu Prescription can inhibit the proliferation and migration of HCC cells by regulating JAK2/STAT3 pathway.

Objective To investigate the levels of plasma bile acids(BA)in patients with primary liver cancer(PLC)or metastatic liver cancer(MLC)and their correlation with clinical indicators,as well as the value of plasma BAs combined with alpha-fetoprotein(AFP)in the diagnosis of PLC.Methods This study was conducted among 75 patients with PLC and 79 patients with MLC who attended Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from August 2020 to September 2021 and had a confirmed diagnosis based on histopathological and imaging findings.Peripheral blood samples were collected from all patients,and serum and plasma were separated.Colorimetry and chromatography were used to measure biochemical parameters;electrochemiluminescence immunoassay was used to measure the levels of tumor markers;liquid chromatography-tandem mass spectrometry was used to measure the content of BA.The t-test was used for comparison of normally distributed continuous data,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data;the Spearman's coefficient was used for correlation analysis;the receiver operating characteristic(ROC)curve was used to evaluate clinical diagnostic efficacy.Results The PLC group had significantly lower levels of total cholesterol,triglyceride,low-density lipoprotein cholesterol,and apolipoprotein B than the MLC group(U=1 598,1 255,909,and 889,all P＜0.05).Compared with the MLC group,the PLC group had a significantly higher level of AFP and a significantly lower level of carcinoembryonic antigen(U=1 873 and 926,both P＜0.05).Compared with the MLC group,the PLC group had significantly higher levels of TBA,CA,CDCA,UDCA,TCA,TCDCA,GCA,GCDCA,TUDCA,and GUDCA and a significantly lower level of DCA(all P＜0.05).In the total population,the levels of TBA,CDCA,GCA,GCDCA,GUDCA,TCA,TCDCA,and TUDCA were significantly positively correlated with the level of AFP(all P＜0.05).In the patients with PLC,the levels of GCA,TCA,TCDCA,and TUDCA were significantly positively correlated with the level of AFP(all P＜0.05).Combined measurement of AFP+TCA+GCA+TCDCA had an area under the ROC curve of 0.822(95%confidence interval:0.746-0.898,P＜0.000 1),suggesting that it had the highest diagnostic efficacy.Conclusion There are significant differences in the levels of plasma BA between the patients with PLC and those with MLC,and the differentially expressed BAs are closely associated with liver function impairment and the increase in AFP.BAs combined with AFP has a better clinical value in the diagnosis of PLC.

Objective:To investigate the agreement of ultrasound derived fat fraction (UDFF) with magnetic resonance imaging proton density fat fraction (MRI PDFF) on evaluating hepatic steatosis, and the performance of UDFF on diagnosing metabolic dysfunction associated steatotic liver disease (MASLD).Methods:One hundred and twenty-five volunteers and one hundred and seven inpatients who underwent abdominal ultrasound examination in Zhongda Hospital Southeast University from November 2023 to February 2024 were prospectively enrolled.UDFF and MRI PDFF were applied to evaluate hepatic steatosis. Spearman correlation test and Bland-Altman plot were applied to analyze the agreement of UDFF and MRI PDFF. Receiver operating characteristic curve (ROC) was applied to calculate the performance of UDFF on diagnosing MASLD.Results:In our participants, compared to individuals without hepatic steatosis, patients with MASLD had higher body mass index (BMI), waist-to-hip ratio, prevalence of diabetes mellitus, levels of alanine transaminase (ALT), aspertate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), triglyceride, and UDFF (all P<0.05). The percentage of hepatic steatosis measured by UDFF and MRI PDFF was strongly correlated[ρ=0.873(95% CI=0.837-0.901), P<0.001]. UDFF performed excellent for diagnosing MASLD with an area under the curve (AUC) of 0.983(95% CI=0.956-0.995, P<0.001), and was better than semi-quantitative assessment based on two-dimensional ultrasound as well as ultrasound attenuation parameter. The optimal cut off value of UDFF to diagnose MASLD was ≥6%. Conclusions:The percentage of hepatic steatosis measured by UDFF and MRI PDFF agrees with each other, and UDFF obtains an excellent performance on diagnosing MASLD, so that UDFF should be considered a reliable imaging technique for quantitively evaluating hepatic steatosis and diagnosing MASLD.

ObjectiveTo explore the possible mechanism of Yiqi Yangyin Huoxue prescription in the prevention and treatment of kidney injury of diabetic kidney disease（DKD）rats based on NOD-like receptor protein 3（NLRP3）/cysteine protease-1（Caspase-1）/gasdermin D （GSDMD）pyroptosis pathway. MethodFifty male SD rats were randomly divided into normal group （n=8） and modeling group （n=42）. The modeling group was given a one-time intraperitoneal injection of streptozotocin （STZ） after high-sugar and high-fat diet for 6 weeks to induce the establishment of a DKD rat model. After successful modeling， the rats were randomly divided into model group， valsartan group （8.33 mg·kg^-1）， and Yiqi Yangyin Huoxue prescription low-dose and high-dose group （11，22 g·kg^-1）. After continuous gavage for 6 weeks， the fasting blood glucose （FBG）， total cholesterol （CHO）， triglyceride （TG）， blood urea nitrogen （BUN）， serum creatinine （SCr） and 24-hour urine protein quantification （24 h-UTP） were detected in each group of rats. Hematoxylin-eosin （HE） staining was used to observe the pathological changes of kidney tissue. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum interleukin-1β （IL-1β） and interleukin-18 （IL-18） levels. The protein and mRNA expression levels of NLRP3/Caspase-1/GSDMD in kidney tissue of rats in each group were determined by Western blot and real-time quantitative polymerase chain reaction （Real-time PCR）. ResultCompared with the conditions in normal group， the levels of FBG， CHO， TG， BUN， SCr， 24 h-UTP and serum IL-1β and IL-18 as well as the protein and mRNA expression levels of NLRP3/Caspase-1/GSDMD in kidney tissue in model group were increased （P<0.01）， and the kidney tissue lesions were severe. Compared with the conditions in model group， the levels of FBG， CHO， TG， BUN， SCr， 24 h-UTP and serum IL-1β and IL-18 as well as the protein and mRNA expression levels of NLRP3/Caspase-1/GSDMD in kidney tissue in each intervention group were decreased （P<0.05， P<0.01）， and the degree of kidney tissue lesions was improved， with Yiqi Yangyin Huoxue prescription high-dose group showing the optimal effect. ConclusionYiqi Yangyin Huoxue prescription could inhibit pyroptosis by regulating the NLRP3/Caspase-1/GSDMD pathway， and thus relieve the inflammatory response of DKD rats and alleviate the pathological damage of the kidneys.

A case of IgG4-related hypertrophic pachymeningitis was reported. The patient was an elderly female, with the course of disease more than 8 years. Clinical manifestations included recurrent headache, vision and hearing loss, exophthalmos and thyroid dysfunction. Finally, she was diagnosed as IgG4-related disease and IgG4-related hypertrophic pachymeningitis by PET-CT and dural biopsy. After treatment with methylprednisolone and mycophenolate mofetil, the patient′s clinical symptoms improved.

The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis (NASH) remain largely unknown. We aimed to elucidate the roles of hepatic cyclooxygenase 1 (COX1) in autophagy and the pathogenesis of diet-induced steatohepatitis in mice. Human nonalcoholic fatty liver disease (NAFLD) liver samples were used to examine the protein expression of COX1 and the level of autophagy. Cox1^Δhepa mice and their wildtype littermates were generated and fed with 3 different NASH models. We found that hepatic COX1 expression was increased in patients with NASH and diet-induced NASH mice models accompanied by impaired autophagy. COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy. Mechanistically, COX1 directly interacted with WD repeat domain, phosphoinositide interacting 2 (WIPI2), which was crucial for autophagosome maturation. Adeno-associated virus (AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1^Δhepa mice, indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy. In conclusion, we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2. Targeting the COX1-WIPI2 axis may be a novel therapeutic strategy for NASH.

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.