Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority. Our previous research demonstrated the efficacy of artesunate (ART) in alleviating liver fibrosis by eliminating activated hepatic stellate cells (HSCs). However, the underlying mechanism remains unclear despite these findings. Notably, endocytic adaptor protein (NUMB) has significant implications for treating hepatic diseases, but current research primarily focuses on liver regeneration and hepatocellular carcinoma. The precise function of NUMB in liver fibrosis, particularly its ability to regulate HSCs, requires further investigation. This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs. We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs, exhibiting a negative correlation with the progression of liver fibrosis. Additionally, ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor (P53) axis. We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate. This research examines the specific target of ART in eliminating activated HSCs, providing both theoretical and experimental evidence for the treatment of liver fibrosis.
Hepatic Stellate Cells/cytology* ; Liver Cirrhosis/genetics* ; Artesunate/pharmacology* ; Cellular Senescence/drug effects* ; Membrane Proteins/genetics* ; Animals ; Humans ; Nerve Tissue Proteins/genetics* ; Tumor Suppressor Protein p53/genetics* ; Male ; Mice

Objective:To investigate the construction of containing CT imaging features Nomograms model of postoperative intraluminal thromus (ILT) formation in patients with aortic dissective aneurysm (ADA).Methods:One hundred and twenty patients with Stanford type B ADA treated with overlapping stent endoluminal repair and multilayer spiral CT (MSCT) examination in Affiliated Hospital of Jining Medical College from May 2020 to February 2022 were selected. The patients were divided into the modeling population (84 patients) and the validation population (36 patients) according to a 7∶3 ratio. The factors influencing postoperative ILT formation in ADA patients were analyzed by univariate and Logistic multifactor regression models, and the prediction model of postoperative ILT formation was constructed based on the influencing factors.Results:In the modeled population, the rate of ILT formation within 1 month after luminal repair with overlapping stents was 27.38%(23/84), including 5 cases in the aortic arch and 18 cases in the abdominal aorta. In the modeled population, the results of univariate analysis showed that the sex, age, body mass index(BMI), smoking, drinking, hypertension, hyperlipidemia, rupture diameter, rupture distance from left subclavicular artery, involvement of important branches, uneven thickening of aneurysm wall, low density on plain scan and operation timing between the ILT formation group and non-ILT formation group had no statistically significant ( P>0.05). The diabetes mellitus, irregular inner wall, calcified plaque, postoperative anticoagulant therapy, B-type brain natriuretic peptide (BNP), fibrinogen (Fib), D-dimer (D-D) and C-reactive protein (CRP) between the two groups had statistical differences: 43.48%(10/23) vs. 11.48%(7/61), 86.96%(20/23) vs. 57.38%(35/61), 91.30%(21/23) vs. 62.30%(38/61), 21.74%(5/23) vs. 57.38%(35/61), (523.60 ± 128.74) ng/L vs.(271.83 ± 109.65) ng/L, (3.82 ± 0.96) g/L vs. (2.85 ± 0.83) g/L, (601.37 ± 75.62) μg/L vs. (389.20 ± 68.79)μg/L, (0.63 ± 0.19) mg/L vs. (0.48 ± 0.15) mg/L, P<0.05. The results of Logistic multifactor regression analysis showed that diabetes mellitus, irregular inner wall, calcified plaque, postoperative anticoagulant therapy and BNP, Fib, D-D CRP levels were influential factors for postoperative ILT formation in Stanford type B ADA patients ( P<0.05). The C-index of the model was 0.903 and 0.894 for the modeled and validated populations, respectively, which had good discrimination and was good at predicting ILT formation after operation in Stanford type B ADA patients. The model had good clinical utility in predicting postoperative ILT formation in Stanford B ADA patients. Conclusions:The Nomograms model can help to screen and identify patients with high risk of ILT formation at an early clinical stage.

Flavonoid glycosides are the main active constituents of Epimedii Folium and its related plants. They can be divided into polyglycosides and low glycosides according to the number of glycosyl group. The polyglycosides of Epimedii Folium can be transformed into low glycosides after biotransformation ；pharmacological activities of low glycosides in anti-tumor ，tonifying kidney yang and anti-osteoporosis are stronger than those of polyglycosides. In this paper ， the research progress about biotransformation technology of flavonoid glycosides of Epimedii Folium was reviewed. It was found that the main biotransformation pathway of flavonoid glycosides of Epimedii Folium was to obtain low glycosides by removing glycosyl group ； related methods were mainly enzymatic hydrolysis and microbial transformation ，and also included plant cell transformation ，acid hydrolysis method and synthesis method.

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of -OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.

Ulcerative colitis(UC)is a chronic inflammatory bowel disease caused by many factors including colonic inflammation and microbiota dysbiosis.Previous studies have indicated that celastrol(CSR)has strong anti-inflammatory and immune-inhibitory effects.Here,we investigated the effects of CSR on colonic inflammation and mucosal immunity in an experimental colitis model,and addressed the mechanism by which CSR exerts the protective effects.We characterized the ther-apeutic effects and the potential mechanism of CSR on treating UC using histological staining,intestinal permeability assay,cytokine assay,flow cytometry,fecal microbiota transplantation(FMT),16S rRNA sequencing,untargeted metabolomics,and cell differentiation.CSR administra-tion significantly ameliorated the dextran sodium sulfate(DSS)-induced colitis in mice,which was evidenced by the recovered body weight and colon length as well as the decreased disease activity index(DAI)score and intestinal permeability.Meanwhile,CSR down-regulated the production of pro-inflammatory cytokines and up-regulated the amount of anti-inflammatory mediators at both mRNA and protein levels,and improved the balances of Treg/Thl and Treg/Th1 7 to maintain the colonic immune homeostasis.Notably,all the therapeutic effects were exerted in a gut microbiota-dependent manner.Furthermore,CSR treatment increased the gut microbiota diversity and changed the compositions of the gut microbiota and metabolites,which is probably associated with the gut microbiota-mediated protective effects.In conclusion,this study provides the strong evidence that CSR may be a promising therapeutic drug for UC.

Objective To measure set-up errors in intensity modulated radiotherapy of postoperative rectal cancer (IMRTPRC), and analyze the effects of target volumes and normal tissues by set-up errors in IMRTPRC. Methods electrical field device was used to measure the set-up errors of 30 patients in IMRTPRC; we randomly selected 6 patients, and simulated their radiotherapy set-up errors in TPS. Then were counted the dose distribution and analyze relative dosimetrical parameters of target volumes, normal tissues and got the set-up errors effecting on dosimetry. Statistical analysis was performed using an SPSS statistical package(Version 19.0). Results The set-up errors on X, Y and Z direction are (−0.82 ± 2.67) mm, (0.42 ± 2.91) mm and (0.47 ± 1.64) mm respectively. In regard to set-up errors of L5, R7, G8, T5, B6 and A4, most of statistical properties of PTV’s D_98%, D_95%, D_50%, D_2%, Hi and Ci are smaller than 0.05, so the differences have statistical values; In L5-Hi, G8-D_2%, T5-D_50% and B6-D_2%, so these differences have not statistical value (P>0.05). In L5, R7, G8, T5, B6 and A4, about half of the statistical properties of normal tissue like bowl, bladder and femur heads, are smaller than 0.05 and have statistical value, and the rest of them are negative. Conclusion The dose of PTV is decreased due toset-up error. Uniformity and conformity is also gone bad. So the dosimetry quantity of PTV can not get reach to the initial design level. However, the dose of normal tissues like bowl, bladder and femur heads, are increased unexpectedly.

Objective:To analyze the predictive value of P504S for pathological upgrading of gastric low-grade intraepithelial neoplasia (LGIN) after endoscopic submucosal dissection (ESD).Methods:Data of 117 patients (119 lesions) who underwent ESD for LGIN at Huadong Hospital from January 2015 to March 2019 were analyzed retrospectively. Biopsy and ESD specimens were collected. According to pathology, specimens were divided into the LGIN group (postoperative pathology of non-upgrade) and the upgrade group (postoperative pathology of upgrade). The positive rates of P504S were compared between biopsy and postoperative specimens of the LGIN group, and between biopsy and postoperative specimens of the upgrade group. The consistency of the expression of P504S was examined between the biopsy specimens and the postoperative specimens in the LGIN group and the upgrade group. Receiver operator characteristic (ROC) curve of the prediction of pathological upgrading was drawn by the results of P504S in biopsy, and the cutoff value of immunohistochemical staining score was calculated.Results:The positive rate of P504S in the biopsy specimens of the LGIN group (46.8%, 36/77) was lower than that in the biopsy specimens of the upgrade group (73.2%, 30/41) with significant difference ( P=0.006). The positive rate of P504S in the postoperative specimens of the LGIN group (51.9%, 40/77) was lower than that in the postoperative specimens of the upgrade group (82.9%, 34/41) with significant difference ( P=0.001). In the LGIN group, the positive rate of P504S in biopsy specimens (46.8%, 36/77) was lower than that in postoperative specimens (51.9%, 40/77) without significant difference ( P=0.289). The expression of P504S was consistent between biopsy specimens and postoperative specimens with good consistency( K=0.793, P<0.001). In the upgrade group, the positive rate of P504S in biopsy specimens (73.2%, 30/41) was lower than that in the postoperative specimens (82.9%, 34/41) without significant difference ( P=0.219). The expression of P504S was consistent between biopsy and postoperative specimens, and the consistency was general ( K=0.579, P<0.001). ROC curve was drawn for the prediction of pathological upgrading by the results of P504S in biopsy, and the cutoff value of immunohistochemical staining score was 100. The sensitivity and specificity of pathological upgrading for positive result were 0.659 and 0.740, respectively. Conclusion:P504S staining of the postoperative specimens facilitates identification of the degree of gastric mucosal neoplasia. When the cutoff value of staining score is 100, the staining of P504S in biopsy tissue plays a role in predicting the pathological upgrading.

Objective To evaluate the value of near focus narrow-band imaging ( NF-NBI ) in differentiating hyperplastic polyp ( HP ) and sessile serrated adenomas/polyp ( SSA/P ) . Methods Data of 65 cases of pathologically confirmed HP or SSA/P with clear NF-NBI images in Huadong Hospital Affiliated to Fudan University from October 2017 to September 2018 were retrospectively analyzed. Three senior doctors observed the images of NF-NBI, including expanded crypt opening ( ECO ) and thick & branched vessel ( TBV) . The results were compared with pathological results in order to analyze differential diagnostic value of ECO and TBV for HP and SSA/P. Results Among 65 lesions, 44 were SSA/P and 21 were HP. The sensitivity, specificity, and accuracy of ECO, TBV, and ECO combined with TBV for differential diagnosis between HP and SSA/P were 80. 3％( 106/132 ) , 85. 7％( 54/63 ) and 82. 1％( 160/195 ); 38. 6％( 51/132) , 82. 5％( 52/63 ) , and 52. 8％( 103/195 ); and 84. 8％( 112/132 ) , 73. 0％( 46/63 ) , and 81. 0％(158/195), respectively. Conclusion ECO under NF-NBI has a high sensitivity for diagnosis of SSA/P . ECO combined with TBV is helpful for differential diagnosis between HP and SSA/P .

Objective To investigate the risk factors of pathological discrepancy between biopsy and excisional specimen from gastric low-grade intraepithelial neoplasia (LGIN) and early gastric cancer (EGC). Methods A retrospective analysis was conducted on the data of 235 patients who underwent endoscopic submucosal dissection or surgical resection and diagnosed as LGIN or EGC ( including high-grade intraepithelial neoplasia) by postoperative pathology. Patients were grouped by whether there was significant pathological discrepancy between biopsy and excisional specimen. Univariate and multivariate analyses were used to analyze the risk factors for significant pathological discrepancy. Results Significant pathological discrepancy occurred in 33 cases (14. 0%). Univariate analysis showed that protruding lesion, non-reddish surface, without erosion or ulcer, diffused pathological type and number of biopsy were related to the pathological discrepancy (all P＜0. 05). Multivariate analysis suggested that small number of biopsy blocks (OR＝0. 574, 95%CI: 0. 363-0. 908, P＝0. 018) was an independent risk factor for significant pathological discrepancy. Conclusion The pathological discrepancy between biopsy and excisional specimen from gastric LGIN and EGC are common. Multiple biopsies can improve the accuracy of biopsy and reduce the occurrence of pathological discrepancy with excisional specimen.

Aim To study the analgesic effect of geraniol on neuropathic pain and to explore the possible mechanism.Method A neuropathic pain rat model of Spared Nerve Injury(SNI) was established to measure changes in the threshold of paw withdrawal before and after i.p.administration of geraniol.Patch clamp whole-cell recording was performed to measure activity of sodium channels using ipsilateral L3/L4/L5 dorsal root ganglion(DRG) cells isolated from the SNI rats.In addition, HEK 293 cells expressing hNav1.7 and hTRPA1 channels were used for measuring the changes in channel activities with or without geraniol by whole-cell patch clamp.Results Geraniol had a fast analgesic effect on hypersensitivity of mechanical pain in the SNI model.It significantly inhibited sodium channels on DRGs isolated from SNI rats and hNav1.7 but not hTRPA1 channels expressed by HEK293 cells.However, high concentrations of geraniol facilitated the activation of HTRPA1 channel stimulated by AITC.Conclusion Geraniol may abirritate hypersensitivity of mechanical pain in the SNI model by specifically inhibiting Nav1.7 channel activity on the DRG cells.