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Deep learning identification of novel autophagic protein-protein interactions and experimental validation of Beclin 2-Ubiquilin 1 axis in triple-negative breast cancer

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Oncology Research 2025年第1期33卷 67-81页

作者： XIANG LI WENKE JIN LIFENG WU HUAN WANG XIN XIE WEI HUANG BO LIU State Key Laboratory of Southwestern Chinese medicine Resources School of Pharmacy and College of Medical TechnologyChengdu University of Traditional Chinese MedicineChengdu611137China department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China

Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional *** is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of *** contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference ***:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic ***,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after *** formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate ***:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related *** network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified ***,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay ***,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 ***:This study not

关键词： Triple-negative breast cancer(TNBC) Autophagy Protein-protein interactions(PPI) Artificial intelligence(AI) Beclin 2 Ubiquilin 1

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Optimal timing for the oral administration of DaCheng-Qi decoction based on the pharmacokinetic and pharmacodynamic targeting of the pancreas in rats with acute pancreatitis

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World Journal of Gastroenterology 2017年第39期23卷 7098-7109页

作者： Yu-Mei Zhang Lin Zhu Xian-Lin Zhao Huan Chen Hong-Xin Kang Jian-Lei Zhao Mei-Hua Wan Juan Li Lv Zhu Wen-Fu Tang department of integrative medicine West China Hospital Sichuan University Digestive System department Sichuan Integrative Medicine Hospital department of integrative medicine Chengdu Integrated TCM and Western Medicine Hospital department of Pharmacology School of Preclinical and Forensic Medicine West China Medical Center Sichuan University

AIM To identify the optimal oral dosing time of Da-Cheng-Qi decoction(DCQD) in rats with acute pancreatitis(AP) based on the pharmacokinetic and pharmacodynamic *** First, 24 male Sprague-Dawley rats were divided into a sham-operated group [NG(a)] and three model groups [4 h G(a), 12 h G(a) and 24 h G(a)]. The NG(a) and model groups were administered DCQD(10 g/***) intragastrically at 4 h, 4 h, 12 h and 24 h, respectively, after AP models induced by 3% sodium taurocholate. Plasma samples were collected from the tails at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after a single dosing with DCQD. Plasma and pancreatic tissue concentrations of the major components of DCQD were determined by high-performance liquid chromatography tandem mass spectroscopy. The pharmacokinetic parameters and serum amylase were detected and compared. Second, rats were divided into a sham-operated group [NG(b)] and three treatment groups [4 h G(b), 12 h G(b) and 24 h G(b)] with three corresponding control groups [MG(b)s]. Blood and pancreatic tissues were collected 24 h after a single dosing with DCQD. Serum amylase, inflammatory cytokines and pathological scores of pancreatic tissues were detected and *** The concentrations of emodin, naringin, honokiol, naringenin, aloe-emodin, chrysophanol and rheochrysidin in the 12 h G(a) group were higher than those in the 4 h G(a) group in the pancreatic tissues(P < 0.05). The area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration values(AUC0→t) for rhein, chrysophanol, magnolol and naringin in the 12 h G(a) group were larger than those in the 4 h G(a) or 24 h G(a) groups. The 12 h G(a) group had a higher Cmax than the other two model groups. The IL-10 levels in the 12 h G(b) and 24 h G(b) groups were higher than in the MG(b)s(96.55 ± 7.84 vs 77.46 ± 7.42, 251.22 ± 16.15 vs 99.72 ± 4.7 respectively, P < 0.05), while in the 24 h G(b) group, the IL-10 leve

关键词： Da-Cheng-Qi decoction Acute pancreatitis Pharmacokinetics Oral dosing time Pharmacodynamics

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Pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction in the liver of rats with severe acute pancreatitis

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World Journal of Gastroenterology 2017年第8期23卷 1367-1374页

作者： Yu-Mei Zhang Hong-Yu Ren Xian-Lin Zhao Juan Li Jun-Yi Li Fu-Sheng Wu Hang Su Wen-Fu Tang sichuan Provincial Pancreatitis Center Department of Integrative Medicine West China Hospital Sichuan University department of integrative medicine Chengdu Integrated TCM and Western Medicine Hospital School of Acupuncture Chengdu University of Traditional Chinese Medicine

AIM To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis. METHODS healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloeemodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated. RESULTS The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-a and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG (P < 0.05), while there was no statistical difference in the MG and HDG. CONCLUSION DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.

关键词： Pharmacokinetics Pharmacodynamics Da-Cheng-Qi decoction Acute pancreatitis Acute liver injury

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Effect of Sheng-jiang powder on multiple-organ inflammatory injury in acute pancreatitis in rats fed a high-fat diet

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World Journal of Gastroenterology 2019年第6期25卷 683-695页

作者： Yi-Fan Miao Hong-Xin Kang Juan Li Yu-Mei Zhang Hong-Yu Ren Lv Zhu Huan Chen Ling Yuan Hang Su Mei-Hua Wan Wen-Fu Tang department of integrative medicine West China Hospital Sichuan University

BACKGROUND Obesity worsens inflammatory organ injury in acute pancreatitis(AP), but there is no effective preventive strategy. Sheng-jiang powder(SJP) has been shown to alleviate multiple-organ inflammatory injury in rats with high-fat diet-induced obesity. Hence, SJP is supposed to have an effect on multiple-organ inflammatory injury in AP in rats fed a high-fat *** To explore how obesity may contribute to aggravating inflammatory organ injury in AP in rats and observe the effect of SJP on multiple-organ inflammatory injury in AP in rats fed a high-fat *** Rats were randomly assigned to a control group(CG), an obese group(OG), and an SJP treatment group(SG), with eight rats per group. The rats in the OG and SG were fed a high-fat diet. From the third week, the rats in the SG were given oral doses of SJP(5 g/kg of body weight). After 12 wk, AP was induced in the three groups. Serum amylase level, body weight, Lee's index, serum biochemistry parameters, and serum inflammatory cytokine and tissue cytokine levels were assessed, and the tissue histopathological scores were evaluated and *** Compared with the CG, serum triglyceride, total cholesterol, interleukin-6, and interleukin-10 levels were significantly higher in the OG, and serum high-density lipoprotein cholesterol level was significantly lower in the OG. Moreover,enhanced oxidative damage was observed in the pancreas, heart, spleen, lung,intestine, liver, and kidney. Evidence of an imbalanced antioxidant defense system, especially in the pancreas, spleen, and intestine, was observed in the obese AP rats. Compared with the OG, serum high-density lipoprotein cholesterol, interleukin-10, and superoxide dismutase expression levels in the pancreas, spleen, and intestine were increased in the SG. Additionally, SJP intervention led to a decrease in the following parameters: body weight; Lee's index; serum triglyceride levels; serum total cholesterol levels; malondialdehyde expression levels

关键词： Obesity Acute pancreatitis Sheng-jiang powder Multiple-organ inflammatory injury Oxidative stress

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Sheng-jiang powder ameliorates obesity-induced pancreatic inflammatory injury via stimulating activation of the AMPK signalling pathway in rats

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World Journal of Gastroenterology 2018年第39期24卷 4448-4461页

作者： Yi-Fan Miao Juan Li Yu-Mei Zhang Lv Zhu Huan Chen Ling Yuan Jing Hu Xiao-Lin Yi Qiu-Ting Wu Mei-Hua Wan Wen-Fu Tang department of integrative medicine West China HospitalSichuan University

AIM To investigate the mechanisms by which Sheng-jiang powder(SJP) ameliorates obesity-induced pancreatic inflammatory *** Sprague-Dawley rats were randomized into three groups: normal group(NG), obese group(HLG), or SJP treatment group(HSG). Obesity was induced by feeding a high-fat diet in the HLG and HSG, while the NG received standard chow. Rats were euthanized after 12 wk, and blood and pancreatic tissues were collected for histopathological analyses. Nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB) and transforming growth factor beta(TGF-β) expression, serum triglyceride and adiponectin levels, and apoptosis in pancreatic acinar cells were assessed. A high-fat AR42 J acinar cell injury model was established using very low-density lipoprotein(VLDL). AR42 J acinar cell culture supernatant, treated with different interventions, was applied to seven groups of pancreatic stellate cells(PSCs). The proliferation of PSCs and the expression of fibronectin and type I collagenase were *** Compared with the NG, we found higher pathological scores for pancreatic tissues, lower serum adiponectin levels, higher expression levels of NF-κB in pancreatic tissues and TGF-β in pancreatic inflammatory cells, and increased apoptosis among pancreatic acinar cells for the HLG(P < 0.05). Compared with the HLG, we found reduced body weight, Lee's index scores, serum triglyceride levels, and pathological scores for pancreatic tissues; higher serum adiponectin levels; and lower expression levels of NF-κB, in pancreatic tissue and TGF-β in pancreatic inflammatory cells for the HSG(P < 0.05). The in vitro studies showed enhanced PSC activation and increased expression levels of fibronectin and type I collagenase after SJP treatment. An adenosine 5‘-monophosphate-activated protein kinase(AMPK) inhibitor inhibited PSC *** SJP may ameliorate obesity-induced pancreatic inflammatory injury in rats by regulating key molecules of the

关键词： Obesity Sheng-jiang powder Adiponectin Adenosine 5’-monophosphate-activated protein kinase Pancreatic inflammatory injury

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Traditional Chinese medicine syndrome-related herbal prescriptions in treatment of malignant tumors

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Journal of Traditional Chinese medicine 2013年第1期33卷 19-26页

作者： Zhizhen Liu Songyi Chen Jing Cai Enda Zhang Lan Lan Junting Zheng Lianming Liao Xuemei Yang Changen Zhou Jian Du The Academy of integrative medicine of Fujian University of tcm department of Traditional Chinese medicine The People's Hospital Affiliated Fujian University of TCM Fujian Medical University

OBJECTIVE： To investigate the distribution characteristics of tcm syndromes and the related herbal prescriptions for malignant tumors （MT）. METHODS： A clinical database of the tcm syndromes and the herbal prescriptions in treatment of 136 MT patients were established. The data were then analyzed using cluster and frequency analysis. RESULTS： According to the cluster analysis, the tcm syndromes in MT patients mainly included two patterns： deficiency of both Qi and Yin and internal accumulation of toxic heat. The commonlyprescribed herbs were Huangqi （Astraglus）, Nuizhenzi （Fructus Ligustri Lucidi）, Lingzhi （Ganoderma Lucidum）, Huaishan （Dioscorea Opposita）, Xiakucao （Prunella Vulgaris）, and Baihuasheshecao （Herba Hedyotidis）. CONCLUSION： Deficiency of Qi and Yin is the pri- mary syndrome of MT, and internal accumulation of toxic heat is the secondary syndrome. The herbs for Qi mainly heat-cl supplementation and Yin houris used, with earance and the assistance of detoxification. hment are herbs for

关键词： Carcinoma Syndromes Benefiting QiOr nourishing Yin Complementary therapies Clus-er analysis Data mining

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Clinical Observation on the Effect of Dexamethasone and Chinese Herbal Decoction for Purgation in Severe Acute Pancreatitis Patients

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Chinese Journal of integrative medicine 2011年第3期17卷 141-145页

作者：万美华李娟龚翰林薛平朱林陈光远夏庆唐文富 department of integrative medicine West China hospital Sichuan University

Objective：To investigate the effect of dexamethasone（Dx） combined with modified Dachengqi Decoction（大承气汤,DCQD）,a Chinese herbal decoction for purgation,on patients with severe acute pancreatitis（SAP） accompanied with systematic inflammatory response syndrome（SIRS）.Methods：A total of 81 patients diagnosed as SAP were randomly assigned to a control group or treatment group according to a random number table generated from an SPSS *** patients in the control group（38 cases） received standard treatment and Chinese herbal decoction for purgation;those in the treatment group（43 cases） received additional 1 mg/（kg·d） dexamethasone（Dx） treatment for three days based on the above *** mortality rate,acute respiratory distress syndrome（ARDS）,renal failure,hemorrhage,sepsis,pancreatic pseudocyst, pancreatic abscess,operability,and days of hospitalization were compared between the two ***： Three patients in the control group and eight patients in the treatment group dropped out from the study with a drop-out rate of 7.8%and 18.6%,respectively,and no statistics difference was shown between the two groups （P0.05）.Dx treatment significantly reduced ARDS rate and shortened the length of hospitalization compared to those in the control group（7/35,20.0%versus 15/35,42.9%,P=0.0394;32.5±13.2 days versus 40.2±17.5 days,P=0.0344）.Other parameters including the mortality rate were not significant different between the two ***：Dx combined with DCQD could decrease the risk of developing ARDS in SAP patients with SIRS and shorten their length of hospitalization.

关键词： severe acute pancreatitis systematic inflammatory response syndrome acute respiratory distress syndrome dexamethasone Dachengqi Decoction

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Pharmacokinetics and pharmacodynamics of Shengjiang decoction in rats with acute pancreatitis for protecting against multiple organ injury

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World Journal of Gastroenterology 2017年第46期23卷 8169-8181页

作者： Lv Zhu Jun-Yi Li Yu-Mei Zhang Hong-Xin Kang Huan Chen Hang Su Juan Li Wen-Fu Tang sichuan Provincial Pancreatitis Center Department of Integrative MedicineWest China HospitalSichuan University department of Traditional Chinese medicine Wuhan Union Hospital

AIM To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction(SJD) in rats with acute pancreatitis(AP) for protecting against multiple organ *** An AP model was established by retrograde perfusion of 3.5% sodium taurocholate into the biliopancreatic duct, and a control group(CG) received 0.9% sodium chloride instead. Twelve male Sprague-Dawley rats were randomly divided into a CG treated with SJD(CG + SJD) and a model group treated with SJD(MG + SJD), both of which were orally administered with SJD(5 g/kg) 2 h after surgery. Blood samples were collected via the tail vein at 10, 20, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after a single dose of SJD to detect its main components using high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were compared. In the pharmacodynamic experiment, 18 male SpragueDawley rats were randomly divided into a CG, an AP model group(MG), and an SJD treated AP group(SJDG). Serum amylase, lipase, and inflammatory cytokines were measured, and heart, lung, liver, spleen, pancreas, kidney, and intestine tissues were collected for pathological *** The MG + SJD displayed significantly shorter mean residence time(MRT) and higher clearance(CL) for emodin and aloe-emodin; significantly shorter time of maximum concentration and T1/2 and a lower area under curve(AUC) for aloe-emodin; a significantly higher AUC and lower CL for rhein; and longer MRT and lower CL for chrysophanol than the CG + SJD. In the pharmacodynamic experiment, the amylase, interleukin(IL)-6, IL-10, and tumor necrosis factor(TNF)-α levels in the MG were higher than those in the CG(P < 0.05). After the herbal decoction treatment, the SJDG had higher IL-10 and lower TNF-α levels than the MG(P < 0.05). The MG had the highest pathological scores, and the pathological scores of the lung, pancreas, kidney, and intestine in the SJDG were significantly lower than those in the MG(P < 0.05).CONCLUSION

关键词： Pancreatic distribution Pharmacodynamics Shengjiang decoction Pharmacokinetics Acute pancreatitis

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Exploration of the Relationship between Phlegm-Dampness Constitution and Polymorphism of Low Density Lipoprotein Receptor Genes Pvu Ⅱand AvaⅡ

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Chinese Journal of integrative medicine 2007年第3期13卷 170-174页

作者：周菁罗海明 department of Internal Cardiology Yueyang hospital of integrative Chinese and Western medicine Shanghai University of TCM

Objective： To explore the polymorphism of low density lipoprotein receptor （LDL-R） genes Pvu Ⅱ end Ave Ⅱ in e population with phlegm-dampness constitution （PDC）. Methods： Polymorphism of LDL-R genes at Pvu Ⅱ end Ave Ⅱ of 48 persons with gentle constitution （GC） end 61 with PDC were analyzed with PCR-RELP technique, end their serum contents of lipids end glucose were determined end compared as well. Results： The A＋ ellelic end P- ellelic frequency were higher end the P＋ ellelic frequency was lower in subjects with PDC then those in subjects with GC, which were 0.3083 vs 0.1771, 0.9098 vs 0.7708 end 0.0902 vs 0.2292, respectively, ell showing significant difference between the two groups （P〈0.05）. Comparison of the two groups in serum levels of triglyceride （TG）, fasting blood glucose, 2 h postprandial blood glucose, end 2 h postprandial insulin showed that ell the parameters were higher in subjects with PDC then in subjects with GC respectively, showing significant difference （P〈0.05）. Conclusion： PDC is related with the P- end A＋ ellelic frequency of higher LDL-R genes at Pvu Ⅱ end Ave Ⅱ, therefore, the polymorphism of LDL-R genes could be taken as one of the genetic markers for PDC, end humans with PDC ere more liable to suffer from blood lipids end glucose disorder then those with GC.

关键词： phlegm-dampness constitution polymorphism of low density lipoprotein receptor gene

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Effect of traditional Chinese comprehensive therapy on gestation in patients with previously failed in vitro fertilization and embryo transfer

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Journal of Traditional Chinese medicine 2015年第4期35卷 428-433页

作者： Xu Xiaojuan Jia Weining Cheng Shuhua Zhong Yanmei Xia Wanting Zeng Qian department of Gynecology Clinical College of MedicineChengdu University of Traditional Chinese Medicine department of Gynecology TCM Hospital of Luzhou The School of Foreign Languages of sichuan Normal University department of Gynecology TCM Hospital of Pi County Graduate School of Chengdu University of tcm

OBJECTIVE: To explore the effect of traditional Chinese comprehensive therapy(TCCT) on promoting gestation in patients with previously failed in vitro fertilization and embryo transfer(IVF-ET) because of kidney deficiency, liver stagnation, and blood stasis(KLB).METHODS: Sixty-seven patients were enrolled in this study and divided into two groups: a trial group with 35 patients and a control group with 32 patients. The trial group was given TCCT for 3months, then administered IVF-ET or awaited natural pregnancy. The control group was administered IVF-ET without TCCT 3 months after the previous IVF-ET or natural pregnancy attempt. The patterns of KLB were observed both before and after treatment. The natural pregnancy rate of the two groups was calculated after treatment. Differences between the two groups were compared after using IVF-ET treatment again in fertilized egg number and fertilization rate were ***: After treatment with tcm comprehensive therapy, seven patients in the treatment group became pregnant, while there were no successful conceptions in the control group. The difference in clinical pregnancy rate in the initial cycle and transfer cycle of IVF were significantly different(P <0.05). The trial group had a significantly higher conception rate than that of the control group(P <0.05).CONCLUSION: TCCT can promote the natural pregnancy rate in patients with previously failed *** could increase patients' fertilized egg number, fertilization rate, pregnancy rate, and clinical pregnancy rate after another IVF-ET *** can also relieve the symptoms of KLB.

关键词： TCCT Fertilization in vitro Embryo transfer Kidney deficiency Stagnation of liver Qi Blood stasis

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