Cholangiocarcinoma (CCA) is a malignancy characterized by tumor cells originating in the liver or bile ducts, exhibiting features of cholangiocyte differentiation. It poses a significant clinical challenge due to the limited diagnostic and therapeutic options available. Robust animal models are essential for advancing our understanding of CCA pathogenesis and developing effective treatments. This review provides a comprehensive overview of CCA mouse models, highlighting various approaches, including chemical induction, genetically engineered models, and tumor xenografts. Each model is discussed in terms of its establishment techniques, pathological characteristics, and research significance, with a focus on intrahepatic CCA. Chemical induction models, such as diethylnitrosamine- and azoxymethane-induced models, offer insights into tumorigenesis processes, whereas genetically modified models involving alterations in key genes such as Kirsten rat sarcoma viral oncogene homolog, tumor protein 53, and isocitrate dehydrogenase serve as important tools for studying the molecular mechanisms underlying CCA. Xenograft models, including patient-derived xenografts, bridge the gap between experimental research and clinical applications, allowing for precise therapeutic evaluations. By comparing these models, this review underscores their respective advantages and limitations, paving the way for future studies aiming to optimize and innovate CCA modeling strategies.

Objective:To construct multimorbidity patterns among elderly individuals with chronic diseases and to explore the relationship between these patterns and frailty.Methods:A cross-sectional study was conducted involving 4, 706 elderly participants aged 60 years and older from selected prefecture-level cities in Shaanxi Province.Data were collected on general information, chronic diseases, and frailty status.The average age of the participants was 69.9±6.7 years, with males comprising 47.3%(2, 255 cases)and females comprising 52.7%(2, 481 cases)of the sample.Latent class analysis(LCA)was employed to identify multimorbidity patterns, while multivariate logistic regression analysis was utilized to examine the associations between these patterns and frailty.Results:The prevalence of multimorbidity within the study population was found to be 43.6%(2, 052 cases out of 4, 706 cases).The highest rates of multimorbidity were observed in anxiety and depression(100%, 23 cases out of 23 cases), dementia(100%, 6 cases out of 6 cases), and Parkinson's disease(100%, 11 cases out of 11 cases).Stroke followed closely with a rate of 96.8%(597 cases out of 617 cases), while rheumatoid arthritis exhibited the lowest rate of multimorbidity with other chronic diseases at 50%(4 cases out of 8 cases).Five distinct multimorbidity patterns were identified through LCA: the complex multimorbidity class(123 cases), the stroke-respiratory class(546 cases), the sleep disorders-osteoarticular class(488 cases), the cardiovascular-metabolic class(987 cases), and the relatively healthy class(2, 562 cases).When compared to the relatively healthy class, the complex multimorbidity class( OR=2.317, 95% CI: 1.573-3.412), stroke-respiratory class( OR=2.279, 95% CI: 1.862-2.788), sleep disorders-osteoarticular class( OR=1.370, 95% CI: 1.111-1.691), and cardiovascular-metabolic class( OR=1.185, 95% CI: 1.003-1.400)were all found to be significantly associated with frailty. Conclusions:The cardiovascular-metabolic class is the most prevalent among elderly individuals.Various patterns exhibit distinct associations with frailty, with the complex multimorbidity class and the stroke-respiratory class being the most significant, as they markedly elevate the risk of frailty.

Objective:To construct multimorbidity patterns among elderly individuals with chronic diseases and to explore the relationship between these patterns and frailty.Methods:A cross-sectional study was conducted involving 4, 706 elderly participants aged 60 years and older from selected prefecture-level cities in Shaanxi Province.Data were collected on general information, chronic diseases, and frailty status.The average age of the participants was 69.9±6.7 years, with males comprising 47.3%(2, 255 cases)and females comprising 52.7%(2, 481 cases)of the sample.Latent class analysis(LCA)was employed to identify multimorbidity patterns, while multivariate logistic regression analysis was utilized to examine the associations between these patterns and frailty.Results:The prevalence of multimorbidity within the study population was found to be 43.6%(2, 052 cases out of 4, 706 cases).The highest rates of multimorbidity were observed in anxiety and depression(100%, 23 cases out of 23 cases), dementia(100%, 6 cases out of 6 cases), and Parkinson's disease(100%, 11 cases out of 11 cases).Stroke followed closely with a rate of 96.8%(597 cases out of 617 cases), while rheumatoid arthritis exhibited the lowest rate of multimorbidity with other chronic diseases at 50%(4 cases out of 8 cases).Five distinct multimorbidity patterns were identified through LCA: the complex multimorbidity class(123 cases), the stroke-respiratory class(546 cases), the sleep disorders-osteoarticular class(488 cases), the cardiovascular-metabolic class(987 cases), and the relatively healthy class(2, 562 cases).When compared to the relatively healthy class, the complex multimorbidity class( OR=2.317, 95% CI: 1.573-3.412), stroke-respiratory class( OR=2.279, 95% CI: 1.862-2.788), sleep disorders-osteoarticular class( OR=1.370, 95% CI: 1.111-1.691), and cardiovascular-metabolic class( OR=1.185, 95% CI: 1.003-1.400)were all found to be significantly associated with frailty. Conclusions:The cardiovascular-metabolic class is the most prevalent among elderly individuals.Various patterns exhibit distinct associations with frailty, with the complex multimorbidity class and the stroke-respiratory class being the most significant, as they markedly elevate the risk of frailty.

Objective To explore prescription medication rules and potential mechanism of traditional Chinese medicine(TCM)in the treatment of alcoholic liver disease(ALD)based on the technology of data mining and network pharmacology.Methods The prescriptions related to the treatment of ALD were retrieved in Chinese National Knowledge Infrastructure,Wanfang,Chinese Biomedical Literature and VIP databases.After the data were collated according to the filter criteria,IBM SPSS Statistics 27.0 and IBM SPSS Modeler 18 software were used to analyze the prescription rules and association rules.Then,the medication rules of TCM in the treatment of ALD were summarized,and the core drug combinations were obtained.Active ingredients in the core drug combinations for ALD and their targets were screened by network pharmacology.GO and KEGG analysis were performed on the main targets,and molecular docking technique was used to verify the binding ability of active ingredients to main targets.Results A total of 143 prescription for ALD were screened,involving 222 Chinese medicine,among which 28 high-frequency Chinese medicine were used with a frequency≥25 times.Eight core drug combinations were obtained by associations rule analysis.It has been found that there are 215 intersection targets between"Poria-Atractylodis macrocephalae Rhizoma-Hearba Artemisiae Scopariae"and ALD,including six core targets of AKT1,TNF,VEGFA,IL-1β,SRC,EGFR.One hundred and sixty-eight of signaling pathways are involved,including cancer pathways,PI3K/AKT signaling pathways,chemical carcinogenesis-reactive oxygen species,lipid and atherosclerosis,etc.Molecular docking results showed that the main active components including cerevisterol,genkwanin and demethoxycapillarisin had good binding ability to AKT1.Conclusion The main active ingredients in"Poria-Atractylodis macrocephalae Rhizoma-Hearba Artemisiae Scopariae"can participate in the regulation of key signaling pathways such as PI3K/AKT by acting on key target proteins(AKT1,TNF,and VEGFA).Subsequently,they play a role in inhibiting inflammatory response and apoptosis,slowing down liver fibrosis,and promoting hepatocyte repair.This study provides data support and theoretical guidance for the study of TCM in the treatment of ALD.

OBJECTIVETacrolimus (FK506) is an immunosuppressive drug, which is widely used to prevent rejection of transplanted organs. However, chronic administration of FK506 leads to hypertension in solid organ transplantation patients, and its molecular mechanisms are much more complicated. In this review, we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.

DATA SOURCESThe data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed. The terms "FK506" or "tacrolimus" and "hypertension" were used for the literature search.

STUDY SELECTIONOriginal articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved, reviewed and analyzed.

RESULTSThere are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects. First, FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum. The conventional protein kinase C beta II (cPKCβII)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495, which reduces the production of NO, was activated by calcium ion leakage. Second, transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation, endothelial dysfunction, and hypertension following tacrolimus treatment. Third, the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension. Finally, the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in the pathophysiology of FK506-induced hypertension.

CONCLUSIONFK506 plays a predominant role in the pathophysiology of hypertension in solid organ transplantation subjects.

Humans ; Hypertension ; chemically induced ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Organ Transplantation ; adverse effects ; Tacrolimus ; adverse effects ; therapeutic use