ObjectiveTo investigate the mechanism by which Notoginsenoside R1 （NGR1） ameliorates hypoxia/reoxygenation （H/R）-induced injury in AC16 human cardiomyocyte cell lines through the regulation of mitophagy. MethodsCommon genes linked to hypoxia/reoxygenation injury and mitophagy were identified by intersecting data from GeneCards and MitoCarta databases. AC16 cell viability was assessed via CCK-8 assay under varying NGR1 concentrations （0， 6.25， 12.5， 25， 50， 100， 200， 300， 400， 500 μmol/L）. AC16 cells were divided into the following groups： control group （Control）， model group （H/R）， and treatment groups （H/R + NGR1 at 100， 200 and 300 μmol/L）. Mitochondrial membrane potential （ΔΨm） was measured using 5，5'，6，6'-tetrachloro-1，1'，3，3'-tetraethylbenzimidazolylcarbocyanine iodide （JC-1） staining. Transcriptional levels of mitophagy-related genes （Parkin， Pink1， P62） were quantified by reverse transcription-quantitative PCR （RT-qPCR）. Protein expression of mitophagy-related markers （Parkin， Pink1， P62， and LC3BⅡ） was evaluated via Western blot analysis. Mitochondrial ultrastructure was visualized by transmission electron microscopy （TEM）. ResultsCompared to the control group， cell viability in the H/R group significantly decreased （P<0.01）. Treatment with NGR1 at concentrations above 100 μmol/L significantly enhanced the cell viability of AC16 cells compared to the H/R group （P<0.01）. H/R induced a significant decrease in mitochondrial membrane potential （P<0.01）， which was restored by NGR1 treatment （P<0.01）. The mRNA levels of Parkin， Pink1， and P62 in the H/R group were upregulated compared to the control group （P<0.05）， while NGR1 intervention downregulated their expression （P<0.05）. Protein expression levels of Parkin， Pink1， and LC3BⅡ in the H/R group significantly increased， while P62 expression decreased compared to the control group （P<0.01）. In contrast， different doses of NGR1 treatment significantly reduced the expression of Parkin， Pink1， and LC3BⅡ while increasing P62 expression （P<0.05）. TEM revealed that the mitochondrial structure in the H/R group was severely disrupted， with fragmented and disorganized cristae， which was alleviated by NGR1. ConclusionNGR1 ameliorates H/R-induced AC16 cell injury， and its mechanism may be associated with modulating the Pink1/Parkin pathway to suppress excessive mitophagy.

Exportin 1 (XPO1) is aberrantly overexpressed in various malignant tumors and can lead to the loss of anti-tumor effects of important tumor suppressor proteins such as p53, RB1, and FOXO by mediating their nuclear export. Although XPO1 inhibitor Selinexor has entered clinical application, its single-agent anti-tumor activity remains suboptimal, which is closely related to the compensatory activation of multiple signaling pathways in response to XPO1 inhibition. Focusing on the core regulatory role of XPO1 in tumor cells, this article systematically summarizes the current landscape of combination therapies involving XPO1 inhibitors and various targeted agents, including inhibitors of CDK4/6, FLT3, BET, ATR, and BCL2/MDM2, aiming to provide some reference for the development of XPO1-centered combination therapy strategies.

ObjectiveTo establish preliminary diagnostic criteria for spleen and kidney deficiency syndrome in ischemic stroke patients and provide a basis for standardized diagnosis and treatment of ischemic stroke. MethodsRelevant literature on the diagnostic criteria for spleen and kidney deficiency syndrome in ischemic stroke patients was retrieved， and data were mined and extracted to form an item pool. Based on the formation of the item pool， this study used the Delphi method to initiate two rounds of questionnaire surveys with selected experts to complete the initial screening of items and the discrimination of symptom importance. A prospective clinical investigation method was adopted to collect clinical information from patients， and statistical analysis methods and data mining techniques were comprehensively used to determine their primary and secondary symptoms. Based on the clear main and secondary symptoms identified， combined with expert group discussions， the study established preliminary diagnostic criteria for spleen and kidney deficiency syndrome in ischemic stroke patients. ResultsA total of 25 relevant syndrome differentiation standards were included. After splitting， standardizing， and screening the items， the study established a pool of 48 items. The first round of questionnaire survey consulted 30 experts， with both the positive coefficient of experts and the effectiveness rate of the questionnaire reaching 100%. The Kendall's coefficient of concordance was 0.359. According to the item screening criteria， 26 items were retained in this round of questionnaire survey. A total of 176 cases were collected through clinical information investigation， including 94 cases with spleen and kidney deficiency syndrome and 82 cases without spleen and kidney deficiency syndrome. The statistical results were as follows： ① Descriptive statistics： The main symptoms with a frequency of ≥ 30% included mental fatigue and lack of strength， weakness of the lower back and knees， etc. The secondary symptoms with a frequency of ≥ 10% and ≤ 30% were lassitude and disinclination to talk， shortness of breath， etc. ② Binary logistic regression analysis： The main symptoms with an odds ratio （OR） value of ≥ 3 were mental fatigue and lack of strength， weakness of the lower back and knees， etc. The secondary symptoms with an OR value of ≥ 1 and ≤ 3 were lassitude and disinclination to talk， shortness of breath， etc. Artificial neural network： The main symptoms with a weight value（W_ij）of ≥ 0.5 and < 1 were mental fatigue and lack of strength， lassitude and disinclination to talk， etc. The secondary symptoms with W_ij of ≥ 0.3 and < 0.5 were shortness of breath， flaccid limbs， etc. In the second round of questionnaire survey， a total of 37 experts were consulted， with both the positive coefficient of experts and the effectiveness rate of the questionnaire reaching 100%. The Kendall's coefficient of concordance was 0.237. According to the criteria to determine primary and secondary symptoms based on the Delphi method， the main symptoms included in this round of the questionnaire were mental fatigue and lack of strength， lassitude and disinclination to talk， etc.， and the secondary symptoms were shortness of breath， dizziness， etc. ConclusionThe main symptoms of spleen and kidney deficiency syndrome in ischemic stroke patients are mental fatigue and lack of strength， weakness of the lower back and knees， loose stool， pale and edematous tongue texture possibly with tooth marks， and deep and thready pulse or weak pulse. The secondary symptoms include shortness of breath， dizziness， tinnitus and deafness， decreased appetite or postprandial abdominal distension， pale complexion， frequent micturition at night， dull tongue texture， and white and slippery tongue coating. The preliminarily established diagnostic criteria for spleen and kidney deficiency syndrome in ischemic stroke patients can provide a standardized and objective basis， thereby better guiding clinical diagnosis and treatment of ischemic stroke.

Non-alcoholic fatty liver disease(NAFLD)is a metabolic disease characterized by abnormal deposition of lipid in hepatocytes.If not intervened in time,NAFLD may develop into liver fibrosis or liver cancer,and ultimately threatening life.NAFLD has complicated etiology and pathogenesis,and there are no effective therapeutic means and specific drugs.Currently,insulin sensitizers,lipid-lowering agents and hep-atoprotective agents are often used for clinical intervention,but these drugs have obvious side effects,and their effectiveness and safety need to be further confirmed.Adenosine monophosphate(AMP)-activated protein kinase(AMPK)plays a central role in maintaining energy homeostasis.Activated AMPK can enhance lipid degradation,alleviate insulin resistance(IR),suppress oxidative stress and inflammatory response,and regulate autophagy,thereby alleviating NAFLD.Natural herbal medicines have received extensive attention recently because of their regulatory effects on AMPK and low side effects.In this article,we reviewed the biologically active natural herbal medicines(such as natural herbal medicine formulas,extracts,polysaccharides,and monomers)that reported in recent years to treat NAFLD via regulating AMPK,which can serve as a foundation for subsequent development of candidate drugs for NAFLD.

Objective To explore the clinical experience of Professor Wang Yan'gang in treating gastroesophageal reflux disease(GERD)using data mining methods.Methods SPSS 23.0 was used to statistically analyze the frequency,properties,flavors,and meridian tropism of Chinese herbal medicines in the prescriptions of effective GERD cases treated by Professor Wang Yan'gang in outpatient clinics from January 2020 to December 2022.Cluster analysis,factor analysis,and association rule analysis were performed on the relevant drugs.Results A total of 294 outpatient prescriptions for the treatment of GERD were collected,including 174 Chinese herbal medicines.The top 10 frequently-used drugs were Sepiae Endoconcha(Haipiaoxiao),Fritillariae Thunbergii Bulbus(Zhebeimu),Scutellariae Radix(Huangqin),Coptidis Rhizoma(Huanglian),Pinelliae Rhizoma Praeparatum Cum Alumine(Qingbanxia),Arecae Semen Tostum(Chaobinglang),Artemisiae Scopariae Herba(Yinchen),Gypsum Fibrosum(Shigao),Aurantii Fructus Immaturus(Zhishi),and Magnoliae Officinalis Cortex(Houpo).After cluster analysis,factor analysis,and association rule analysis,16 commonly-used herb pairs,such as Huangqin-Huanglian,Citri Reticulatae Pericarpium(Chenpi)-Zhuru(Bambusae Caulis in Taenia),Haipiaoxiao-Zhebeimu,Shichangpu(Acori Tatarinowii Rhizoma)-Yujin(Curcumae Radix),and Zhishi-Houpo were identified,and 9 herb groups such as"Huangqin,Huanglian,Yinchen"and"Chenpi,Zhuru,Qingbanxia"were obtained.Factor analysis was performed on 22 drugs with a usage frequency more than 110 times,and then 6 common factors were extracted after principal component analysis.Conclusion In differentiating and treating GERD,Professor Wang Yan'gang suggests that stagnated heat injuring yin should be taken as the core pathogenesis,and therapy of clearing heat and nourishing yin should be used as the core treatment method.Additionally,auxiliary methods such as soothing the throat,regulating the liver and stomach,and nourishing the heart and spirit can be adopted according to the accompanying symptoms during the disease progression.

Objective To analyze the expression levels of miR-27a-3p mRNA and Yes-associated protein 1(YAP1)mRNA in breast cancer,and to explore their relationships with clinicopathological features and the survival prognosis of patients.Methods A total of 130 breast cancer patients who underwent mastectomy in our hospital between January 2019 and January 2021 were enrolled.The expression levels of miR-27a-3p and YAP1 mRNA in breast tumor tissues and adjacent normal breast tissues were assessed by qRT-PCR.Furthermore,the relationships between their expression and clinicopathological features,as well as the survival prognosis of patients,were investigated.Results Compared with adjacent normal breast tissues,the expression of miR-27a-3p mRNA in breast tumor tissues was lower(P＜0.05),while that of YAP1 mRNA was higher(P＜0.05).A negative correlation was observed between the expression of miR-27a-3p mRNA and YAP1 mRNA in breast tumor tissues(r=-0.456,P＜0.05).The expression of miR-27a-3p mRNA was correlated with tumor diameter,histological grade,tumor staging by the TNM system,lymph node metastasis,and vascular invasion in patients with breast cancer(P＜0.05).The YAP1 mRNA expression was correlated with histological grade,tumor staging by the TNM system,lymph node metastasis,and vascular invasion(P＜0.05).Kaplan-Meier survival analysis revealed that the 3-year overall survival rate of the miR-27a-3p low-expression group was 71.60％(48/67),which was lower than the 91.50％(54/59)of the miR-27a-3p high-expression group(log-rank x2=8.211,P=0.004).The 3-year overall survival rate of the YAP1 high-expression group was 73.80％(45/61),lower than that of the YAP1 low-expression group(87.70％,57/65)(log-rank x2=4.429,P=0.035).Multivariate regression analysis indicated that lymph node metastasis(hazard ratio[HR]=1.409;95％CI,1.057-1.644;P=0.046),vascular invasion(HR=1.541;95％CI,1.076-1.869;P=0.045),low miR-27a-3p mRNA expression(HR=0.593;95％CI,0.388-0.925;P=0.018),and high YAP1 mRNA expression(HR=0.628;95％CI,0.405-0.912;P=0.022)were relevant factors affecting the 3-year overall survival of patients with breast cancer.Conclusion A significant downregulation of miR-27a-3p mRNA and upregulation of YAP1 mRNA are observed in breast tumor tissues.The low expression of miR-27a-3p mRNA and the high expression of YAP1 mRNA are associated with adverse clinicopathological features and poor survival prognosis,and are risk factors affecting the 3-year overall survival of patients with breast cancer.They show promise as new potential therapeutic targets for breast cancer.

Cholangiocarcinoma (CCA) is a fatal malignancy with steadily increasing incidence and poor prognosis. Since most CCA cases are diagnosed at an advanced stage, systemic therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, play a crucial role in the management of unresectable CCA. The recent advances in targeted therapies and immunotherapies brought more options in the clinical management of unresectable CCA. This review depicts the advances of targeted therapies and immunotherapies for unresectable CCA, summarizes crucial clinical trials, and describes the efficacy and safety of different drugs, which may help further develop precision and individualization in the clinical treatment of unresectable CCA.
Humans ; Cholangiocarcinoma/drug therapy* ; Immunotherapy/methods* ; Bile Duct Neoplasms/drug therapy* ; Molecular Targeted Therapy/methods*

Objective To study the death status of pancreatic cancer among residents in Xuhui district, Shanghai, from 1992 to 2021, and analyze its trends of change, so as to provide evidence for the prevention and treatment of pancreatic cancer. Methods Based on the database of Shanghai death registration system from 1992 to 2021, the crude mortality rate, standardized mortality rate, age-specific mortality rate and other indicators of pancreatic cancer among registered residents in Xuhui district were calculated. The Joinpoint software was used to analyze the trends of average annual percent change (AAPC) of pancreatic cancer mortality rate, and the age-period-cohort model was used to analyze the age effect, period effect and birth cohort effect pairs significant changes in pancreatic cancer mortality. Results In 2021, the mortality rate of pancreatic cancer in Xuhui district, Shanghai, ranked fourth among malignant tumors, and the winning rate and world standard rate of the whole population, males and females were 8.34/100 000 (8.81/100 000, 7.98/100 000) and 7.28/100 000 (7.69/100 000, 6.96/100 000), respectively, with males higher than females. AAPC of crude mortality rate and the standardized (6) mortality rate were higher in males than that in females. The age-specific mortality rate increased with the increase of age, and the highest mortality rate was found in 60-84 years old group. The age-period-cohort model showed that from 1992 to 2021, the annual net shift of pancreatic cancer mortality among the whole population, male and female residents in Xuhui district, Shanghai, was 1.22%, 1.58%, 1.15% (P=0.20, 0.19, 0.45) respectively, and the time trend was not significant. From the perspective of age effect, the risk of death from pancreatic cancer in the whole population and with age deviation in males had an obvious trend with increasing age (P<0.05), while the age effect in females had no obvious trend. From the perspective of period effect, no period deviation was significant in the whole population, males and females (P>0.05). In terms of cohort effects, there were significant differences in the whole population and the male cohort deviations(P<0.05). No significant cohort effect was observed in the female population. Conclusions The mortality rate of pancreatic cancer among registered residents in Xuhui district, Shanghai from 1992 to 2021, was on the rise, especially in the 60-84 years old group and male. The prevention and control of pancreatic cancer needs to develop effective epidemic prevention measures for corresponding populations.

Objective:To investigate the clinical characteristics and prognosis of T-lymphoblastic lymphoma (T-LBL).Methods:A retrospective case series study was conducted. Clinical data of patients diagnosed with T-LBL at the Affiliated Hospital of Jining Medical University from January 2013 to March 2023 were retrospectively analyzed, and their clinical characteristics and prognosis were statistically analyzed.Results:A total of 22 T-LBL patients were included. Among them, there were 19 males (86.4%) and 3 females (13.6%), and the median age at onset was 19.5 (15, 28) years old. Based on Ann Arbor staging, 3 cases (13.6%) were classified as stage Ⅰ-Ⅱ, while 19 cases (86.4%) were stage Ⅲ-Ⅳ; 10 cases (45.5%) presented with B symptoms, 12 cases (54.5%) without B symptoms; 16 cases (72.7%) showed elevated lactic dehydrogenase (LDH) level. At onset, 7 patients (31.8%) had mediastinal masses, 3 patients (13.6%) had central nervous system involvement, and 17 patients (77.3%) had bone marrow involvement. The overall response rate (ORR) and complete remission rate among the 22 patients were 81.82% (18/22) and 31.82% (7/22), respectively. The ORR was 84.21% (16/19) in 19 patients treated with ALL-like regimens. Among 3 patients treated with NHL-like regimens, 1 case achieved complete remission and 1 case achieved partial remission. Seven patients received allogeneic hematopoietic stem cell transplantation, with a median overall survival (OS) time of 22 months; the median OS time of patients without allogeneic hematopoietic stem cell transplantation was 14 months. The 3-year OS rates in the allogeneic hematopoietic stem cell transplantation group and group without allogeneic hematopoietic stem cell transplantation were 64.30% and 16.00%, and the difference in OS between the two groups was statistically significant ( P = 0.043). Two patients with disease progression prior to transplantation died of multidrug-resistant bacterial infections after transplantation. Conclusions:T-LBL is rare, and it is a highly aggressive tumor that predominantly occurs in adolescent males. Allogeneic hematopoietic stem cell transplantation can prolong OS, reduce relapse and improve the prognosis of patients.

The coinfection of respiratory viruses and bacteria is a major cause of morbidity and mortality worldwide, despite the development of vaccines and powerful antibiotics. As a macromolecule that is difficult to absorb in the gastrointestinal tract, a homogeneous polysaccharide from Houttuynia cordata (HCPM) has been reported to exhibit anti-complement properties and alleviate influenza A virus (H1N1)-induced lung injury; however, the effects of HCPM without in vitro antiviral and antibacterial activities on more complicated pulmonary diseases resulting from viral-bacterial coinfection remains unclear. This study established a representative coinfection murine pneumonia model infected with H1N1 (0.2 LD₅₀) and methicillin-resistant Staphylococcus aureus (MRSA, 10⁷ CFU). HCPM significantly improved survival rate and weight loss, and ameliorated gut-lung damage and inflammatory cytokine production. Interestingly, the therapeutic effect of HCPM on intestinal damage preceded that in the lungs. Mechanistically, HCPM inhibited the overactivation of the intestinal complement (C3a and C5a) and suppressed the activation of the NLR family pyrin domain-containing 3 (NLRP3) pathway, which contributes to the regulation of the Treg/Th17 cell balance in the gut-lung axis. The results indicate the beneficial effects of an anti-complement polysaccharide against viral-bacterial coinfection pneumonia by modulating crosstalk between multiple immune regulatory networks.