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Evidence-Based Dampness-Heat ZHENG(Syndrome) in Cancer: Current Progress toward Establishing Relevant animal model with Pancreatic Tumor

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Chinese Journal of Integrative Medicine 2024年第1期30卷 85-95页

作者： JIAO Ju-ying CHENG Chien-shan CAO Zhang-qi CHEN Lian-yu CHEN Zhen Department of Integrative Oncology Fudan University Shanghai Cancer CenterShanghai(200032)China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai(200032)China

Cancer is one of the deadliest diseases affecting the health of human beings. With limited therapeutic options available, complementary and alternative medicine has been widely adopted in cancer management and is increasingly becoming accepted by both patients and healthcare workers alike. Chinese medicine characterized by its unique diagnostic and treatment system is the most widely applied complementary and alternative medicine. It emphasizes symptoms and ZHENG(syndrome)-based treatment combined with contemporary disease diagnosis and further stratifies patients into individualized medicine subgroups. As a representative cancer with the highest degree of malignancy, pancreatic cancer is traditionally classified into the "amassment and accumulation". Emerging perspectives define the core pathogenesis of pancreatic cancer as "dampness-heat" and the respective treatment "clearing heat and resolving dampness" has been demonstrated to prolong survival in pancreatic cancer patients, as has been observed in many other cancers. This clinical advantage encourages an exploration of the essence of dampness-heat ZHENG(DHZ) in cancer and investigation into underlying mechanisms of action of herbal formulations against dampness-heat. However, at present, there is a lack of understanding of the molecular characteristics of DHZ in cancer and no standardized and widely accepted animal model to study this core syndrome in vivo. The shortage of animal models limits the ability to uncover the antitumor mechanisms of herbal medicines and to assess the safety profile of the natural products derived from them. This review summarizes the current research on DHZ in cancer in terms of the clinical aspects, molecular landscape, and animal models. This study aims to provide comprehensive insight that can be used for the establishment of a future standardized ZHENG-based cancer animal model.

关键词： cancer Chinese medicine syndrome ZHENG dampness-heat syndrome animal model pancreatic tumor evaluation methods

Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease

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World Journal of Hepatology 2024年第1期16卷 75-90页

作者： Matheus Truccolo Michalczuk Larisse Longo Melina Belén Keingeski Bruno de Souza Basso Gabriel Tayguara Silveira Guerreiro Jessica T Ferrari JoséEduardo Vargas Cláudia P Oliveira Carolina Uribe-Cruz Carlos Thadeu Schmidt Cerski Eduardo Filippi-Chiela Mário ReisÁlvares-da-Silva Division of Gastroenterology Hospital de Clínicas de Porto AlegrePorto Alegre 90035-903Rio Grande do SulBrazil Graduate Program in Gastroenterology and Hepatology Universidade Federal do Rio Grande do SulPorto Alegre 90035-003Rio Grande do SulBrazil Experimental Laboratory of Hepatology and Gastroenterology Hospital de Clínicas de Porto AlegrePorto Alegre 90035-903Rio Grande do SulBrazil Laboratory of Inflammatory and Neoplastic Cells Universidade Federal do ParanáParaná81530900Brazil Department of Gastroenterology(LIM07) Faculdade de Medicina da Universidade de São PauloSão Paulo 01246903Brazil Facultad de Ciencias de la Salud Universidad Católica de las MisionesPosadasMisiones 3300Argentina Unit of Surgical Pathology Hospital de Clinicas de Porto AlegrePorto Alegre 90035-903Rio Grande do SulBrazil Center of Biotechnology Universidade Federal do Rio Grande do SulPorto Alegre 90035-003Rio Grande do SulBrazil Department of Morphological Sciences Universidade Federal do Rio Grande do SulPorto Alegre 90.050-170Rio Grande do SulBrazil Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq)ResearcherBrasília 71.605-001Brazil

BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/autophagy markers in animals.METHODS Adult Sprague-Dawley rats were randomly assigned(n=8,each)and treated from 5-16 wk:Control[standard diet,water plus gavage with vehicle(Veh)],HCC[high-fat choline deficient diet(HFCD),diethylnitrosamine(DEN)in drinking water and Veh gavage],and RIF[HFCD,DEN and RIF(50 mg/kg/d)gavage].Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.RESULTS All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis,and cirrhosis,but three RIF-group did not develop HCC.Comparing animals who developed HCC with those who did not,miR-122,miR-34a,tubulin alpha-1c(Tuba-1c),metalloproteinases-2(Mmp2),and metalloproteinases-9(Mmp9)were significantly higher in the HCC-group.The opposite occurred with Becn1,coactivator associated arginine methyltransferase-1(Carm1),enhancer of zeste homolog-2(Ezh2),autophagy-related factor LC3A/B(Map1 Lc3b),and p62/sequestosome-1(p62/SQSTM1)-protein.Comparing with controls,Map1 Lc3b,Becn1 and Ezh2 were lower in HCC and RIF-groups(P0.05).miR-122 was higher in HCC,and miR-34a in RIF compared to controls(P0.05).CONCLUSION RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD

关键词： animal model Autophagy Epigenetic Hepatocellular carcinoma Metabolic dysfunction-associated steatotic liver disease Rifaximin

animal model of Aortic Valve Calcification: Their Methodology Helps Us Understand Aortic Valve Calcification

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Advances in Bioscience and Biotechnology 2024年第4期15卷 235-268页

作者： Yinze Wei Zhen Wang Miao Chen Liang Ma Departments of Cardiothoracic Surgery The Fourth Affiliated Hospital of Zhejiang University School of Medicine Yiwu China Departments of Cardiothoracic Surgery The First Affiliated Hospital of Zhejiang University School of Medicine Hangzhou China

Aortic valve calcification disease (CAVD) is the most prevalent degenerative valve disease in humans, leading to significant morbidity and mortality. Despite its common occurrence, our understanding of the underlying mechanisms remains incomplete, and available treatment options are limited and risky. A more comprehensive understanding of the biology of CAVD is essential to identify new therapeutic strategies. animal models have played a crucial role in advancing our knowledge of CAVD and exploring potential treatments. However, these models have inherent limitations as they cannot fully replicate the complex physiological mechanisms of human CAVD. In this review, we examine various CAVD models ranging from pigs to mice, highlighting the unique characteristics of each model to enhance our understanding of CAVD. While these models offer valuable insights, they also have limitations and shortcomings. We propose that the guide wire model shows promise for future CAVD research, and streamlining the methodology could enhance our understanding and expand the research scope in this field.

关键词： animal model Aortic Valve Stenosis Calcification Cardiovascular

Optimization of tracheoesophageal fistula model established with Tshaped magnet system based on magnetic compression technique

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World Journal of Gastroenterology 2024年第16期30卷 2272-2280页

作者： Miao-Miao Zhang Jian-Qi Mao Lin-Xin Shen Ai-Hua Shi Xin Lyu Jia Ma Yi Lyu Xiao-Peng Yan Department of Hepatobiliary Surgery The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061Shaanxi ProvinceChina Shaanxi Provincial Key Laboratory of Magnetic Medicine The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061Shaanxi ProvinceChina Zonglian College Xi’an Jiaotong UniversityXi’an 710061Shaanxi ProvinceChina National Local Joint Engineering Research Center for Precision Surgery&Regenerative Medicine The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061Shaanxi ProvinceChina Department of Pulmonary and Critical Care Medicine The Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710004Shaanxi ProvinceChina Department of Surgical Oncology Shaanxi Provincial People’s HospitalXi’an 710068Shaanxi ProvinceChina

BACKGROUND The magnetic compression technique has been used to establish an animal model of tracheoesophageal fistula(TEF),but the commonly shaped magnets present limitations of poor homogeneity of TEF and poor model control.We designed a Tshaped magnet system to overcome these problems and verified its effectiveness via animal experiments.AIM To investigate the effectiveness of a T-shaped magnet system for establishing a TEF model in beagle dogs.METHODS Twelve beagles were randomly assigned to groups in which magnets of the Tshaped scheme(study group,n=6)or normal magnets(control group,n=6)were implanted into the trachea and esophagus separately under gastroscopy.Operation time,operation success rate,and accidental injury were recorded.After operation,the presence and timing of cough and the time of magnet shedding were observed.Dogs in the control group were euthanized after X-ray and gastroscopy to confirm establishment of TEFs after coughing,and gross specimens of TEFs were obtained.Dogs in the study group were euthanized after X-ray and gastroscopy 2 wk after surgery,and gross specimens were obtained.Fistula size was measured in all animals,and then harvested fistula specimens were examined by hematoxylin and eosin(HE)and Masson trichrome staining.RESULTS The operation success rate was 100%for both groups.Operation time did not differ between the study group(5.25 min±1.29 min)and the control group(4.75 min±1.70 min;P=0.331).No bleeding,perforation,or unplanned magnet attraction occurred in any animal during the operation.In the early postoperative period,all dogs ate freely and were generally in good condition.Dogs in the control group had severe cough after drinking water at 6-9 d after surgery.X-ray indicated that the magnets had entered the stomach,and gastroscopy showed TEF formation.Gross specimens of TEFs from the control group showed the formation of fistulas with a diameter of 4.94 mm±1.29 mm(range,3.52-6.56 mm).HE and Masson trichrome staining showed scar tissue formation and hierarchical structural

关键词： Magnetic surgery Magnetic compression technique Tracheoesophageal fistula Magnet animal model Beagles

Ornithine aspartate effects on bacterial composition and metabolic pathways in a rat model of steatotic liver disease

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World Journal of Hepatology 2024年第5期16卷 832-842页

作者： Elisa Carolina Lange Pabulo Henrique Rampelotto Larisse Longo Laura Bainy Rodrigues de Freitas Carolina Uribe-Cruz Mario Reis Alvares-da-Silva Experimental Laboratory of Hepatology and Gastroenterology Hospital de Clínicas de Porto AlegrePorto Alegre 90035-007Brazil Graduate Program in Gastroenterology and Hepatology Universidade Federal do Rio Grande do SulPorto Alegre 90035-007Brazil Bioinformatics and Biostatistics Core Facility Universidade Federal do Rio Grande do SulPorto Alegre 91501-970Brazil Graduate Program in Biological Sciences:Pharmacology and Therapeutics Universidade Federal do Rio Grande do SulPorto Alegre 90035-007Brazil Facultad de Ciencias de la Salud Universidad Católica de las MisionesPosadasMisiones 3300Argentina Division of Gastroenterology Hospital de Clínicas de Porto AlegrePorto Alegre 90035-007RSBrazil Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq)researcher Brasília 71605-001Brazil

BACKGROUND Metabolic-dysfunction associated steatotic liver disease(MASLD)is a hepatic manifestation of metabolic syndrome.Studies suggest ornithine aspartate(LOLA)as drug therapy.AIM To analyze the influence of LOLA intake on gut microbiota using a nutritional model of MASLD.METHODS Adult male Sprague Dawley rats were randomized into three groups:Control(10 rats fed with a standard diet),MASLD(10 rats fed with a high-fat and choline-deficient diet),and LOLA(10 rats receiving 200 mg/kg/d LOLA,after the 16th week receiving high-fat and choline-deficient diet).After 28 wk of the experiment,animals were euthanized,and feces present in the intestine were collected.Following fecal DNA extraction,the V4 region of the 16S rRNA gene was amplified followed by sequencing in an Ion S5™system.RESULTS Alpha and beta diversity metrics were comparable between MASLD and LOLA.3 OTUs were differentially abundant between MASLD and LOLA,which belong to the species Helicobacter rodentium,Parabacteroides goldsteinii,and Parabacteroides distasonis.The functional prediction provided two different metabolic profiles between MASLD and LOLA.The 9 pathways differentially abundant in MASLD are related to a change in energy source,adenosine/purine nucleotides degradation as well as guanosine and adenosine deoxyribonucleotides biosynthesis.The 14 pathways differentially abundant in LOLA are associated with four major metabolic functions primarily influenced by L-aspartate,including tricarboxylic acid cycle pathways,purine/guanosine nucleotides biosynthesis,pyrimidine ribonucleotides biosynthesis and salvage as well as lipid IVA biosynthesis.CONCLUSION Although LOLA had no influence on alpha and beta diversity in this nutritional model of MASLD,it was associated with changes in specific gut microbes and their related metabolic pathways.

关键词： animal model Gut microbiota Metabolic-associated steatotic liver disease Metabolic prediction Ornithine aspartate

Establishment of a rat model of severe spontaneous intracerebral hemorrhage

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Journal of Intensive Medicine 2024年第1期4卷 108-117页

作者： Shuixiang Deng Shengjie Feng Yuewen Xin Yu He Yao Wang Mi Tian Ye Gong Department of Critical Care Medicine Huashan HospitalFudan UniversityShanghaiChina Department of Neurosurgery Huashan HospitalFudan UniversityShanghaiChina

Background:Severe intracerebral hemorrhage(ICH)is the most devastating subtype of stroke resulting in high mortality and disability.At present,the development of targeted treatments to minimize the high morbidity and mortality is limited partly due to the lack of a severe ICH animal model.In this study,we aimed to establish an accurate severe ICH model in rats and examine the pathological and physiological changes associated with ICH.Methods:A rat model of severe ICH model was established by intrastriatal injection of autologous blood using different blood volumes(ICH 100μL group,ICH 130μL group,ICH 160μL group,ICH 170μL group,and ICH 180μL group).The mortality was assessed during the 28-day post-ICH period.Short-and long-term neurological deficits were evaluated using the Longa method,foot fault,falling latency,and Morris water maze tests.Brain water content,hematoma volume,hemoglobin content,and magnetic resonance imaging were assessed to determine the extent of brain injury.Immunofluorescence staining was conducted to examine microglial activation and neuronal apoptosis.Hematoxylin and eosin(H&E)staining,lung water content,and western blotting were used to assess lung injury following ICH.Results:The mortality of ICH rats increased significantly with an increase in autologous blood injection.The 28-day mortality in the 100μL,130μL,160μL,170μL,and 180μL ICH groups were 5%,20%,40%,75%,and 100%,respectively.A significantly higher 28-day mortality was observed in the ICH 160μL group compared to the ICH 100μL group.The ICH 160μL group exhibited significantly increased neurological deficits,brain edema,hematoma volume,and hemoglobin content compared to the sham group.Compared with the sham operation group,the activation of microglia and neuronal death in ICH 160μL rats increased.The use of H&E staining and western blotting demonstrated that disruption of the intra-alveolar structure,alveolar edema,and infiltration of inflammatory cells and cytokines into the lung tissue were more severe in the ICH 160μL group than t

关键词： Severe spontaneous intracerebral hemorrhage animal model Autologous blood injection animal behavior Lung injury

Protective effects of cyclosporine and its analog NIM-811 in a murine model of hepatic ischemia-reperfusion injury

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Liver Research 2024年第1期8卷 46-53页

作者： Joshua Hefler Rena Pawlick Braulio A.Marfil-Garza Aducio Thiesen Nerea Cuesta-Gomez Sanaz Hatami Darren H.Freed Constantine Karvellas David L.Bigam A.M.James Shapiro Department of Surgery Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada Department of Medicine Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada CHRISTUS-LatAm Hub Excellence&Innovation Center MonterreyMexico Alberta Diabetes Institute University of AlbertaEdmontonABCanada Clinical Islet Transplant Program University of AlbertaEdmontonABCanada Department of Laboratory Medicine&Pathology Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada

Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of ischemia.The hallmark of IRI comprises mitochondrial dysfunction,which generates reactive oxygen species,and cell death through necrosis or apoptosis.Cyclosporine(CsA),which is a well-known immunosuppressive agent that inhibits calcineurin,has the additional effect of inhibiting the mito-chondrial permeability transition pore(mPTP),thereby,preventing mitochondrial swelling and injury.NIM-811,which is the nonimmunosuppressive analog of CsA,has a similar effect on the mPTP.In this study,we tested the effect of both agents on mitigating warm hepatic IRI in a murine model.Materials and methods:Before ischemic insult,the mice were administered with intraperitoneal normal saline(control);CsA at 2.5,10,or 25 mg/kg;or NIM-811 at 10 mg/kg.Thereafter,the mice were subjected to partial warm hepatic ischemia by selective pedicle clamping for 60 min,followed by 6 h of recovery after reperfusion.Serum alanine transaminase(ALT)was measured,and the liver tissue was examined histologically for the presence of apoptosis and the levels of inflammatory cytokines.Results:Compared with the control mice,the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower ALT levels(P<0.001,0.007,and 0.031,respectively).Moreover,the liver tissue showed reduced histological injury scores after treatment with CsA at 2.5,10,and 25 mg/kg and NIM-811(P=0.041,<0.001,0.003,and 0.043,respectively)and significant decrease in apoptosis after treatment with CsA at all doses(P=0.012,0.007,and<0.001,respectively).Levels of the pro-inflammatory cyto-kines,particularly interleukin(IL)-1β,IL-2,IL-4,IL-10,and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA(25 mg/kg)than those in the control mice.Conclusions:Premedication with CsA or NIM-811 mitig

关键词： Cyclosporine(CsA) Cyclosporine analogue Liver surgery Ischemia-reperfusion injury(IRI) animal model NIM-811

animal model-based simulation training for three emergent and urgent operations of penetrating thoracic injuries

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Chinese Journal of Traumatology 2023年第1期26卷 41-47页

作者： Wen-Qiong Du Xin Zhong Ren-Qing Jjiang Zhao-Wen Zong Yi-Jun Jia Zhao Ye Xiao-Lin Zhou State Key Laboratory of Trauma Burn and Combined InjuryDepartment for Combat Casualty Care TrainingTraining Base for Army Health CareArmy Medical UniversityChongqing400037China State Key Laboratory of Trauma Burn and Combined InjuryDepartment for Combat Casualty Care TrainingTraining Base for Army Health Care&Department of OrthopedicsXinqiao HospitalArmy Medical UniversityChongqing400037China

Purpose:To develop animal models of penetrating thoracic injuries and to observe the effects of the animal model-based training on improving the trainees’performance for emergent and urgent thoracic surgeries.Methods:With a homemade machine,animal models of lung injuries and penetrating heart injuries were produced in porcine and used for training of chest tube drainage,urgent sternotomy,and emergent thoracotomy.Coefficient of variation of abbreviated injury scale and blood loss was calculated to judge the reproducibility of animal models.Five operation teams from basic-level hospitals(group A)and five operation teams from level III hospitals(group B)were included to be trained and tested.Testing standards for the operations were established after thorough literature review,and expert questionnaires were employed to evaluate the scientificity and feasibility of the testing standards.Tests were carried out after the training.Pre-and post-training performances were compared.Post-training survey using 7-point Likert scale was taken to evaluate the feelings of the trainees to these training approaches.Results:animal models of the three kinds of penetrating chest injuries were successfully established and the coefficient of variation of abbreviated injury scale and blood loss were all less than 25%.After literature review,testing standards were established,and expert questionnaire results showed that the scientific score was 7.30±1.49,and the feasibility score was 7.50±0.89.Post-training performance was significantly higher in both group A and group B than pre-training performance.Post-training survey showed that all the trainees felt confident in applying the operations and were generally agreed that the training procedure were very helpful in improving operation skills for thoracic penetrating injury.Conclusions:animal model-based simulation training established in the current study could improve the trainees’performance for emergent and urgent thoracic surgeries,especially of the surgical teams from basic-level hos

关键词： Penetrating thoracic injuries Emergent operations Urgent operations Simulation training animal model

Unraveling the complexity of polycystic ovary syndrome with animal models

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Journal of Genetics and Genomics 2024年第2期51卷 144-158页

作者： Huanju Liu Mixue Tu Zhiyong Yin Dan Zhang Jun Ma Feng He Center for Genetic Medicine The Fourth Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310058China Key Laboratory of Women's Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology Women's HospitalZhejiang University School of MedicineHangzhouZhejiang 310006China Zhejiang Provincial Clinical Research Center for Child Health Women's HospitalZhejiang University School of MedicineHangzhouZhejiang 310006China Clinical Research Center on Birth Defect Prevention and Intervention of Zhejiang Province HangzhouZhejiang 310006China Institute of Genetics Zhejiang University International School of MedicineHangzhouZhejiang 310058China Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorder HangzhouZhejiang 310058China

Polycystic ovary syndrome (PCOS) is a highly familial and heritable endocrine disorder. Over half of the daughters born to women with PCOS may eventually develop their own PCOS-related symptoms. Progress in the treatment of PCOS is currently hindered by the complexity of its clinical manifestations and incomplete knowledge of its etiopathogenesis. Various animal models, including experimentally induced, naturally occurring, and spontaneously arising ones, have been established to emulate a wide range of phenotypical and pathological traits of human PCOS. These studies have led to a paradigm shift in understanding the genetic, developmental, and evolutionary origins of this disorder. Furthermore, emerging evidence suggests that animal models are useful in evaluating state-of-the-art drugs and treatments for PCOS. This review aims to provide a comprehensive summary of recent studies of PCOS in animal models, highlighting the power of these disease models in understanding the biology of PCOS and aiding high-throughput approaches.

关键词： Polycystic ovary syndrome animal model Genetc manipulation Developmnental progtanning Drug screening