World Journal of Gastrointestinal Surgery
·
2023
·
IF 2
Fan Ding,Run Guo,Fang Chen,Li-Ping Liu,Zheng-Yu Cui,Yi-Xing Wang,Gang Zhao,Hai Hu
BACKGROUND Impaired interstitial cells of Cajal (ICCs) are central to the pathophysiology of acute cholecystitis (AC). Common bile duct ligation is a common model of AC, producing acute inflammatory changes and decrease in gallbladder contractility. AIM To investigate the origin of slow wave (SW) in the gallbladder and the effect of ICCs on gallbladder contractions during the process of AC. METHODS Methylene blue (MB) with light was used to establish selective impaired ICCs gallbladder tissue. Gallbladder motility was assessed using the frequency of SW and gallbladder muscle contractility in vitro in normal control (NC), AC12h, AC24h, and AC48h groups of guinea pigs. Hematoxylin and eosin and Masson-stained gallbladder tissues were scored for inflammatory changes. ICCs pathological changes alterations were estimated using immunohistochemistry and transmission electron microscopy. The alterations of c-Kit, α-SMA, cholecystokinin A receptor (CCKAR), and connexin 43 (CX43) were assessed using Western blot. RESULTS Impaired ICCs muscle strips resulted in the decrease in gallbladder SW frequency and contractility. The frequency of SW and gallbladder contractility were significantly lower in the AC12h group. Compared with the NC group, the density and ultrastructure of ICCs were remarkably impaired in the AC groups, especially in the AC12h group. The protein expression levels of c-Kit were significantly decreased in the AC12h group, while CCKAR and CX43 protein expression levels were significantly decreased in the AC48h group. CONCLUSION Loss ICCs could lead to a decrease in gallbladder SW frequency and contractility. The density and ultrastructure of ICCs were clearly impaired in the early stage of AC, while CCKAR and CX43 were significantly reduced at end stage.
研究领域:
胃肠病学
·
生理学
·
病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2022
·Vol. 14
·期 16
·6052-6065
·
IF 8.307
Ya Zou,Zishuo Zhou,Shanmei Yin,Chengyuan Huang,Hesong Tang,Zongning Yin
Gallbladder stones are a major pathogenic factor leading to cholecystitis, and it is increasingly important to explore innovative drug delivery methods for gallstones. In the present study, docosahexaenoic acid-coupled limonene bovine serum albumin nanoparticles (LIM-DHA-BSA-NPs) were constructed. The LIM-DHA-BSA-NPs are spherical structures, and the distribution was relatively uniform, and, more importantly, it has low cytotoxicity and good safety. The LIM-DHA-BSA-NPs solution shows higher uptake rates by RAW264.7 cells when compared with free limonene (LIM). The fluorescence intensity of FITC-modified BSA NPs was significantly higher than that of free FITC, which further indicated that the uptake of DHA-conjugated BSA NPs by RAW264.7 cells was stronger than that of the free drugs. Moreover, the in vivo distribution experiment showed that the enrichment of DiD-loaded BSA NPs in the gallbladder was significantly enhanced when compared with that of free DiD. The semi-quantitative fluorescence intensity results showed that the uptake of DiD-DHA-BSA-NPs was 4.5 times higher when compared with the free DiD. It is preliminarily shown that the DHA-conjugated BSA NPs that were constructed, have an ability to target the gallbladder. Furthermore, the Pearson colocalization coefficient Rcoloc from in vivo colocalization results indicates that the DHA-BSA-NPs had a good colocalization effect on the gallbladder epithelial cells (GBECs). In addition, the LIM-DHA-BSA-NPs solution not only significantly reduced the concentration of nitric oxide (NO) secreted by inflammatory model cells and the number of peripheral blood leukocytes in guinea pigs with cholecystitis, but also significantly decreased the activities of the aspartate transaminase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), glutamyl endopeptidase (GGT), total bile acid (TBA), and total bilirubin (TBIL) enzymes. Collectively, the LIM-DHA-BSA-NPs could be used as an effective anti-inflammatory agent at the cellular and animal levels. This experiment, for the first time, showed that DHA-conjugated BSA NPs could be absorbed into GBECs by megalin receptor-mediated endocytosis and then they exert an anti-cholecystitis effect because of the LIM. The active uptake of DHA-conjugated BSA NPs by the megalin receptors of the GBECs is expected to become an effective therapeutic strategy for cholecystolithiasis.
研究领域:
药剂学
·
分子生物学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2018
·Vol. 234
·期 4
·4291-4301
·
IF 3.923
Meng-Juan Lin,Lei Chen,Zhen-Peng Huang,Hu Qiu,Bao-Ping Yu
Acute cholecystitis is a common disease with gallbladder dysmotility. Disease pathogenesis involves immune cell infiltration as well as changes in gallbladder interstitial Cajal-like cells (ICLCs). However, it remains unclear if or how the immune cells affect ICLC morphology, density, distribution, and function in gallbladder tissue during acute cholecystitis. In this study, we explored the acute cholecystitis-related alterations in gallbladder ICLCs in a guinea pig model, focusing on the effects of neighboring neutrophils. Adult guinea pigs were randomly divided into four groups (control, 24 hr common bile duct ligation [CBDL], 48-hr CBDL, and antipolymorphonuclear neutrophil [PMN] treated) and analyzed using methylene blue staining and immunofluorescence. Gallbladder contractility was also monitored. To culture gallbladder ICLCs, collagenase digestion was performed on tissue from 10- to 15-day-old guinea pigs. Neutrophils isolated from the peripheral blood of experimental animals 48-hr postsurgery were also cocultured with the gallbladder ICLCs. Intracellular calcium was detected with Fluo-4 AM dye. Our results showed that gallbladder ICLC density significantly declined during acute cholecystitis and was accompanied by shortening of the cellular processes and damage to their network-like structure. However, pretreatment with anti-PMN partially prevented these changes. Gallbladder contraction was also significantly decreased during acute cholecystitis, and this appeared to be mediated by the neutrophils. Moreover, ICLCs cocultured with neutrophils also had shortened and reduced processes and impaired network-like structure formation. Intracellular calcium transient was less sensitive to contraction agonists and inhibitors when cocultured with neutrophils. Taken together, neutrophils greatly affect gallbladder ICLCs and dysmotility during acute cholecystitis.
研究领域:
胃肠病学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 1
·e70054
·
IF 3.3
Lichao Ji,Yingjie Chai,Chenhao Tong,Yanxin Hu,Jiandong Li,Baochun Lu,Jianhua Yu
Gallbladder cancer is the most prevalent malignancy of the biliary tract and has a dismal overall survival even in the present day. The development of new drugs holds promise for improving the prognosis of this lethal disease. The possible anti-neoplastic role of morusin was investigated both in vitro and in vivo. Through cell viability and colony formation assays, we observed that morusin inhibited the proliferation of gallbladder cancer cells in vitro. Wound healing and transwell assays revealed that morusin impeded the migration and invasion of gallbladder cancer cells. Given the observed morphological changes, we examined epithelial-mesenchymal transition (EMT) markers. Subsequent investigations demonstrated that morusin treatment, both in vitro and in vivo, downregulated the expression of phospho-STAT3 (Signal transducer and activator of transcription 3) and HIF-1α (Hypoxia-inducible factor 1α) in gallbladder cancer cells. Furthermore, morusin effectively reversed EMT induced by phospho-STAT3 or HIF-1α. Morusin has a reversing effect on the EMT of gallbladder cancer cells by modulating STAT3/HIF-1α signaling.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biology Direct
·
2025
·Vol. 20
·期 1
·1-18
·
IF 4.9
Liang Ruopeng,Zhang Xiaoxue,Wu Shitao,Liu Jing,Zhai Yunpeng,Lin Chaojie,Wang Zhenya,Zhang Yi,Chen Hao,Zhu Rongtao
Background Patients diagnosed with gallbladder carcinoma (GBC) accompanied by hepatic metastasis exhibit unfavorable prognoses generally. Mitochondrial dysfunction promotes cellular transformation and cancer cell survival implicating its importance in cancer development. Previous studies have indicated that dynamin 1 like (DNM1L) is a key mediator of mitochondrial fission. However, whether DNM1L regulates mitochondrial homeostasis in GBC remains unknown. Methods The morphological changes of mitochondria were investigated by transmission electron microscopy and mitoTracker red staining. Co-immunoprecipitation assay was performed to detect the interaction of ubiquitin-specific protease-3 (USP3) and DNM1L. The cell-derived xenograft and liver metastasis tumor models were established to validate the function of DNM1L in vivo . The metabolomics data from transcriptomics/metabolomics were analyzed to identify the differentially expressed genes/metabolites of DNM1L in GBC. Results DNM1L exhibited a marked upregulation in clinical GBC tissues compared to the adjacent tissues, and it promoted proliferation, invasiveness, and migration capability of GBC cells by inducing mitochondrial dysfunction. Mice subcutaneously injected with DNM1L overexpression cells exhibited elevated intrahepatic metastatic nodules within their livers. USP3, a deubiquitinating enzyme, was demonstrated to directly interact with DNM1L and it specifically cleaved the K48-linked polyubiquitin chains to deubiquitinate and stabilize DNM1L. By integrating two omics, we found several altered pathways and speculated that DNM1L disturbed DNA synthesis and glycine, serine, threonine, and pyrimidine metabolism pathways. Conclusion Our findings suggest that DNM1L is a promising clinical target for GBC treatment and that focusing on DNM1L may provide new insights into GBC strategy.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yushun Chang,Jie Lin,Bo Yang,Yuxuan Shen,Weijun Zhao,Hao Shen,Quan Yang,Haowen Lu,Xiujun Cai,Yifan Wang,Wen Hua
Background Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, exhibits anticancer activity in several malignancies, but its efficacy and mechanisms in gallbladder cancer (GBC) remain undefined. Methods Human GBC cell lines (GBCs) were treated with ALO and assessed for viability, colony formation, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation and apoptosis. Autophagic flux and related signaling were evaluated by western blotting and immunofluorescence. In vivo antitumor activity was determined in a nude mouse xenograft model. Results ALO markedly inhibited the proliferation ability of GBCs and disrupted autophagosome–lysosome fusion, leading to reactive oxygen species (ROS) accumulation and apoptosis. Furthermore, ALO induced DNA damage and nuclear release of double-stranded DNA (dsDNA) to cytoplasm, leading to cyclic-GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-mediated interferon (IFN) pathway activation and enhancing natural killer cells (NK cells) activation in vitro. In vivo, ALO reduced subcutaneous GBCs xenograft volume and weight and, along with increased cleaved caspase-3 and BAX expression in tumor tissues, confirming tumor cell apoptosis. Conclusions These findings indicate that ALO may serve as a novel therapeutic candidate for gallbladder cancer by inhibiting autophagic flux to induce ROS-mediated apoptosis while activating the cGAS–STING–IFN pathway to enhance antitumor immunity.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
免疫学
·
转化医学
·
细胞信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2023
·
IF 4.1
Hongdong Song,Qingyu Wang,Zhuwei Shao,Xinyue Wang,Hongwei Cao,Kai Huang,Xiao Guan
BACKGROUND Wheat protein intake leads to improved appetite control. However, the active components causing appetite in wheat have not been fully clarified. Gut cholecystokinin (CCK) plays a vital role in appetite control. This study aimed to investigate the ability of wheat protein digest (WPD) to stimulate CCK secretion and clarify the active components and target of action. RESULTS WPD was prepared by a simulated gastrointestinal digestion model. WPD treatment with a concentration of 5 mg mL −1 significantly stimulated CCK secretion in enteroendocrine STC-1 cells ( P < 0.05). Furthermore, oral gavage with WPD in mice significantly increased plasma CCK level at 60 min ( P < 0.01). Preparative C18 column separation was used to isolate peptide fractions associated with CCK secretion and peptide sequences were identified by liquid chromatography–tandem mass spectrometry. A new CCK-releasing peptide, RYIVPL, that potently stimulated CCK secretion was successfully identified. After pretreatment with a specific calcium-sensing receptor (CaSR) antagonist, NPS 2143, CCK secretion induced by WPD or RYIVPL was greatly suppressed, suggesting that CaSR was involved in WPD- or RYIVPL-induced CCK secretion. CONCLUSION The present study demonstrated that WPD has an ability to stimulate CCK secretion in vitro and in vivo , and determined that peptide RYIVPL in WPD could stimulate CCK secretion through CaSR. © 2023 Society of Chemical Industry.
研究领域:
营养学
·
分子生物学
·
胃肠生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2015
·Vol. 29
·期 8
·1280-1289
·
IF 1.723
Xiang Ji,Dan Li,Hua Li
A novel molecularly imprinted polymer (MIP) monolith for highly selective extraction of cholecystokinin (CCK) neuropeptides was prepared in a micropipette tip. The MIPs were synthesized by epitope imprinting technique and the polymerization conditions were investigated and optimized. The synthesized MIPs were characterized by infrared spectroscopy, elemental analyzer and scanning electron microscope. A molecularly imprinted solid-phase microextraction (MI- μ -SPE) method was developed for the extraction of CCK neuropeptides in aqueous solutions. The parameters affecting MI- μ -SPE were optimized. The results indicated that this MIP monolith exhibited specific recognition capability and high enrichment efficiency for CCK neuropeptides. In addition, it showed excellent reusability. This MIP monolith was used for desalting and enrichment of CCK4, CCK5 and CCK8 from human cerebrospinal fluid prior to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, and the results show that this MIP monolith can be a useful tool for effective purification and highly selective enrichment of multiple homologous CCK neuropeptides in cerebrospinal fluid simultaneously. By employing MI- μ -SPE combined with HPLC-ESI-MS/MS analysis, endogenous CCK4 in human cerebrospinal fluid was quantified. Copyright © 2015 John Wiley & Sons, Ltd.
研究领域:
分析化学
·
神经生物学
·
医学
✓ 已验证
DOI
高影响因子
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
·
2024
·
IF 3.7
Shenglu Liu,Haoxian Gou,Hui Wei,Shengdeng Chen,Shijie Zhuo,Ming Luo,Shu Qin,Mengyu Zhang,Jiatong Chen,Zhiwei Huang,Xianming Xia,Xiaoli Yang,Kai He
Background and Aim The impact of cholecystectomy, which blocks the cholecystohepatic shunt pathway (CHSP), on the prognosis of patients with hepatocellular carcinoma (HCC) is unclear. Hepatic secondary bile acids (BAs) inhibit natural killer T (NKT) cell-mediated immunity against HCC, and the regulation of homeostasis of hepatic secondary BAs is controlled by the CHSP. However, the influence of CHSP on NKT cell-mediated immunity against HCC remains unclear. Methods The clinical data of hospitalized patients undergoing HCC resection were collected. Meanwhile, an in situ HCC mouse model was established, and the CHSP was augmented using oleanolic acid (OA). Results After 1:1 propensity score matching, Cox regression analysis revealed that cholecystectomy was an independent risk factor for HCC recurrence after hepatectomy ( P = 0.027, hazard ratio: 1.599, 95% confidence interval: 1.055–2.422). Experimentally, when OA enhanced CHSP, a significant decrease was observed in the accumulation of secondary BAs in the livers of mice. Additionally, a significant increase was observed in the levels of C-X-C ligand 16 and interferon γ in the serum and tumor tissues. Further, the percentage of C-X-C receptor 6 (+) NKT cells in the tumor tissues increased significantly, and the growth of liver tumors was inhibited. Conclusions This clinical study revealed that cholecystectomy promoted the recurrence after radical hepatectomy in patients with HCC. Preserving the normal-functioning gallbladder as much as possible during surgery may be beneficial to the patient's prognosis. Further investigation into the mechanism revealed that CHSP enhanced NKT cell-mediated immunity against HCC by reducing the hepatic accumulation of secondary BAs.
研究领域:
胃肠病学
·
肝病学
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 39
·2202908
·
IF 15.153
Shun Xing,Donghui Wang,Haifeng Zhang,Feng Peng,Ling Wu,Lidan Liu,Yuqin Qiao,Naijian Ge,Xuanyong Liu
Gallbladder cancer is a common malignant tumor of the biliary system with a high fatality rate. Nitinol (Ni–Ti) stents, a standard treatment for prolonging patients’ lives, are susceptible to reocclusion and cannot inhibit tumor recurrence because they lack antitumor and antibacterial activity. Herein, an arsenic-loaded layered double-hydroxide film is constructed on Ni–Ti, forming a micro “chemical factory.” The LDH plays the role of a “processer” which absorbs highly toxic trivalent arsenic (As(III)) and processes it into lowly toxic pentavalent arsenic (As(V)). It also acts as a “quality-inspector,” confining As(III) in the interlayer and releasing only As(V) (the finished product) to the outside. This control mechanism minimizes the toxicity during contact with normal tissue. The acidic microenvironment and overexpression of glutathione in tumor tissues not only accelerates the release of arsenic from the platform but also triggers the in situ transformation of arsenic from lowly toxic As(V) to highly toxic As(III), exerting a strong arsenic-mediated antineoplastic effect. Such a microenvironment-responsive “chemical factory” with arsenic processing and screening functions is expected to prevent tumor overgrowth, metastasis, and bacterial infection and provide new insights into the design of Ni–Ti drug-eluting stents for gallbladder cancer treatment.
研究领域:
肿瘤学
·
生物材料
·
生物医学工程
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineering-Basel
·
2025
·Vol. 12
·期 1
·34
·
IF 3.7
Fang Chen,Run Guo,Tian Chen,Liping Liu,Fan Ding,Gang Zhao,Bo Zhang
Background: Cholesterol gallstone disease (CGS) is often accompanied by gallbladder contraction dysfunction and chronic inflammation, but effective therapeutic options remain limited. This study investigates whether a low-intensity pulsed ultrasound (LIPUS) treatment can improve gallbladder motility and alleviate chronic inflammation while exploring the underlying mechanisms. Methods: Gallbladder motility was assessed through in vitro and in vivo contraction tests, while bile condition was evaluated by observing bile crystal clearance. Tissue analysis and Western blotting were performed to examine the expression of the cholecystokinin A receptor (CCKAR) and α-smooth muscle actin (α-SMA) as markers of gallbladder smooth muscle health and the inflammatory microenvironment. Blood cholesterol levels were measured via biochemical assays. Results: LIPUS treatment obviously enhanced gallbladder contractility in response to CCK-8 stimulation and accelerated bile crystal clearance. It also reduced inflammatory cell infiltration and tissue edema, and promoted new capillary formation in the gallbladder, mitigating the progression of CGS. Furthermore, LIPUS restored CCKAR expression and improved the thickness of the gallbladder smooth muscle layer, providing a structural basis for increased smooth muscle contractility. Conclusion: LIPUS improves gallbladder motility and reduces chronic inflammation in CGS by enhancing CCKAR expression and smooth muscle integrity. These findings highlight the potential of LIPUS as a non-invasive therapeutic approach for managing CGS.
研究领域:
胃肠病学
·
超声波技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT MOLECULAR MEDICINE
·
2017
·Vol. 17
·期 5
·381-387
·
IF 2.345
Zhu F.,Guan Y.,Zhang R.
Rationale: Studies have implied the positive association of JAK2/STAT3 signaling with the onset and severity of acute pancreatitis (AP). However, definitive functional study of JAK2/STAT3 signaling in the pathogenesis of acute pancreatitis in vivo is missing and its potential as a therapeutic
target and the underlying mechanisms remain to be determined. Objectives: The aim of this study was to explore the role of JAK2/STAT3 signaling in the pathogenesis of hyperlipidemia-intensified caerulin-induced AP and its potential as a therapeutic target. Methods and Results: Using
the caerulin-induced acute pancreatitis rat model, we showed that JAK2/STAT3 signaling was activated in pancreas and systemic inflammation was increased during AP. Pharmacological suppression of JAK2 by its inhibitor AG490 robustly protected against tissue damage, attenuated JAK2/STAT3 signaling
and inflammatory responses. Local pancreatic tissue damage and phosphor- JAK2 in the pancreatic tissue were enhanced in animals fed with high fat diet compared to chow-diet fed animals. Interestingly, JAK2 inhibitor AG490 significantly inhibited pancreas necrosis and systemic inflammation
in animals fed with high fat or chow-diet, but did not affect STAT3 signaling. Conclusion: These results establish that JAK2 activation plays a significant role in the pathogenesis of caerulin-induced AP in animals on both chow and high-fat diets by regulating necrosis and systemic inflammation.
Thus, our results not only clarify novel signaling mechanisms in AP but also suggest that JAK2 might constitute a target in the management of hyperlipidemia-intensified caerulin-induced AP.
研究领域:
胃肠病学
·
药理学
·
分子生物学
·
炎症
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）