المؤلفون: Chang Li, Yuning Zhou, Ruozheng Wei, Dana L. Napier, Tomoko Sengoku, Michael C. Alstott, Jinpeng Liu, Chi Wang, Yekaterina Y. Zaytseva, Heidi L. Weiss, Qingding Wang, B. Mark Evers

المصدر: Cellular and Molecular Gastroenterology and Hepatology, Vol 15, Iss 4, Pp 931-947 (2023)

مصطلحات موضوعية: Intestinal Stem Cells, Glycolysis, HK2, Metabolism, Diseases of the digestive system. Gastroenterology, RC799-869

الوصف: Background and Aims: The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. An imbalance in this highly regimented process within the intestinal crypts is associated with several intestinal pathologies. Although metabolic changes are known to play a pivotal role in cell proliferation and differentiation, how glycolysis contributes to intestinal epithelial homeostasis remains to be defined. Methods: Small intestines were harvested from mice with specific hexokinase 2 (HK2) deletion in the intestinal epithelium or LGR5+ stem cells. Glycolysis was measured using the Seahorse XFe96 analyzer. Expression of phospho-p38 mitogen-activated protein kinase, the transcription factor atonal homolog 1, and intestinal cell differentiation markers lysozyme, mucin 2, and chromogranin A were determined by Western blot, quantitative real-time reverse transcription polymerase chain reaction, or immunofluorescence, and immunohistochemistry staining. Results: HK2 is a target gene of Wnt signaling in intestinal epithelium. HK2 knockout or inhibition of glycolysis resulted in increased numbers of Paneth, goblet, and enteroendocrine cells and decreased intestinal stem cell self-renewal. Mechanistically, HK2 knockout resulted in activation of p38 mitogen-activated protein kinase and increased expression of ATOH1; inhibition of p38 mitogen-activated protein kinase signaling attenuated the phenotypes induced by HK2 knockout in intestinal organoids. HK2 knockout significantly decreased glycolysis and lactate production in intestinal organoids; supplementation of lactate or pyruvate reversed the phenotypes induced by HK2 knockout. Conclusions: Our results show that HK2 regulates intestinal stem cell self-renewal and differentiation through p38 mitogen-activated protein kinase/atonal homolog 1 signaling pathway. Our findings demonstrate an essential role for glycolysis in maintenance of intestinal stem cell function.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2352345X22002636Test; https://doaj.org/toc/2352-345XTest

الوصول الحر: https://doaj.org/article/33629a0e171c4fbe943a2cf5f3d44e37Test

المؤلفون: Qingding Wang, B. Mark Evers, Heidi L. Weiss, Chi Wang, Jinpeng Liu, Yuanyuan Wu, Greg Bauman, William B. Titlow, Shulin Zhang, Piotr Rychahou, Chang Li, Yuning Zhou, Ruozheng Wei

الوصف: The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression.Significance:This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival.See related commentary by Montrose and Galluzzi, p. 1464

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::82ed0ff309b857713675de31d2d1b45eTest
https://doi.org/10.1158/0008-5472.c.6513858.v1Test

المؤلفون: Ruozheng Wei, Yuning Zhou, Chang Li, Piotr Rychahou, Shulin Zhang, William B. Titlow, Greg Bauman, Yuanyuan Wu, Jinpeng Liu, Chi Wang, Heidi L. Weiss, B. Mark Evers, Qingding Wang

المصدر: Cancer Res

مصطلحات موضوعية: Cancer Research, Kruppel-Like Transcription Factors, Ketosis, Chemokine CXCL12, Article, Mice, Oncology, Cancer-Associated Fibroblasts, Cell Line, Tumor, Tumor Microenvironment, Animals, Humans, Immunotherapy, Colorectal Neoplasms

الوصف: The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression. Significance: This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival. See related commentary by Montrose and Galluzzi, p. 1464

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3030ccf618f523d8131620d437c9bf5Test
https://europepmc.org/articles/PMC9018557Test/

المؤلفون: Chang Li, Yuning Zhou, Ruozheng Wei, Dana L. Napier, Tomoko Sengoku, Michael C. Alstott, Jinpeng Liu, Chi Wang, Yekaterina Y. Zaytseva, Heidi L. Weiss, Qingding Wang, B. Mark Evers

المصدر: Cellular and molecular gastroenterology and hepatology.

مصطلحات موضوعية: Hepatology, Gastroenterology

الوصف: The Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. An imbalance in this highly regimented process within the intestinal crypts is associated with several intestinal pathologies. Although metabolic changes are known to play a pivotal role in cell proliferation and differentiation, how glycolysis contributes to intestinal epithelial homeostasis remains to be defined.Small intestines were harvested from mice with specific hexokinase 2 (HK2) deletion in the intestinal epithelium or LGR5HK2 is a target gene of Wnt signaling in intestinal epithelium. HK2 knockout (KO) or inhibition of glycolysis resulted in increased numbers of Paneth, goblet, and enteroendocrine cells and decreased intestinal stem cell self-renewal. Mechanistically, HK2 KO resulted in activation of p38 MAPK and increased expression of ATOH1; inhibition of p38 MAPK signaling attenuated the phenotypes induced by HK2 KO in intestinal organoids. HK2 KO significantly decreased glycolysis and lactate production in intestinal organoids; supplementation of lactate or pyruvate reversed the phenotypes induced by HK2 KO.Our results show that HK2 regulates intestinal stem cell self-renewal and differentiation through p38 MAPK/ATOH1 signaling pathway. Our findings demonstrate an essential role for glycolysis in maintenance of intestinal stem cell function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c7ebfe4b754325b1713f6a7eaa092577Test
https://pubmed.ncbi.nlm.nih.gov/36584817Test

المؤلفون: Zhou, Yuning, Ruozheng, Wei, Li, Chang, Weiss, Heidi L., Wang, Qingding, Evers, B. Mark

المصدر: Gastroenterology ; volume 162, issue 7, page S-519 ; ISSN 0016-5085

مصطلحات موضوعية: Gastroenterology, Hepatology

الإتاحة: https://doi.org/10.1016/s0016-5085Test(22)61235-6
https://api.elsevier.com/content/article/PII:S0016508522612356?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0016508522612356?httpAccept=text/plainTest

المؤلفون: Yushun Zhang, Jin Hu, Heshui Wu, Ruozheng Wei, Shen Jian

المصدر: Langenbeck's Archives of Surgery. 405:55-62

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, 030230 surgery, Gastroenterology, Pancreatic Fistula, 03 medical and health sciences, Pancreatectomy, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, medicine, Humans, Postoperative Period, Pancreas, Serum Albumin, Aged, Retrospective Studies, business.industry, Retrospective cohort study, Perioperative, Middle Aged, Vascular surgery, medicine.disease, Cardiac surgery, Pancreatic Neoplasms, Cardiothoracic surgery, Pancreatic fistula, 030220 oncology & carcinogenesis, Preoperative Period, Female, Surgery, Complication, business, Biomarkers, Abdominal surgery

الوصف: The level of albumin declines after surgery, and whether the difference between preoperative and postoperative albumin levels on postoperative day 1 has an effect on the development of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) is unclear. Our aim was to evaluate the effect of albumin difference on POPF. A retrospective analysis of consecutive patients who had undergone DP between January 2016 and October 2018 at a single institution was conducted. Patient demographic data and perioperative data were analysed using univariate and multivariate models. Pancreatic fistula was defined by the 2016 International Study Group of Pancreatic Surgery criteria. All patients were followed for up to 90 days. A total of 211 consecutive patients were identified. The POPF rate was 15.64%, and no 90-day mortality was observed. Five predictors were independently associated with POPF: albumin difference (OR 6.60, 95% CI 2.36–18.45, P

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ee217dcc9034d96418e064f73c37ee97Test
https://doi.org/10.1007/s00423-019-01849-zTest

المؤلفون: Jian Shen, Yushun Zhang, Jin Hu, Ruozheng Wei, Heshui Wu

الوصف: Background Postoperative pancreatic fistula (POPF) is a common complication following distal pancreatectomy (DP). Although the mortality from these procedures has decreased in the past decades, the rate of POPF remains high. The aim of this study was to identify risk factors associated with POPF after DP. Methods A retrospective review of a consecutive series of 211 patients who had undergone DP between January 2016 and October 2018 at a single institution was conducted. Patient demographic data, perioperative data and clinicopathological parameters were analysed to evaluate their correlation with the incidence of POPF using univariate and multivariate models. POPFs were defined by 2016 International Study Group criteria. Results Two hundred eleven consecutive patients were identified. The overall pancreatic fistula rate was 15.64%, and no 30-day or 90-day mortality was seen. Four predictors were independently associated with POPF: soft pancreatic texture (odds ratio (OR): 4.23, 95% confidence interval (CI): 1.71-10.45, P = 0.002), longer operating time (OR: 4.18, 95% CI: 1.67–10.46, P = 0.002), higher difference of albumin (OR: 6.41, 95% CI: 2.40–17.08, P

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::9cd6abfabf4d59a5840e64f6e5b4dad8Test
https://doi.org/10.21203/rs.2.13083/v1Test

المؤلفون: Pingping Xue, Ruozheng Wei, Xiaofan Yang, Zhenyu Liu, Xin Liu, Yanhua Chen, Xiang Xu, Zhenbing Chen

المصدر: Neurochemical Research. 43:659-668

مصطلحات موضوعية: Male, 0301 basic medicine, Nervous system, medicine.medical_specialty, Neuroactive steroid, Biochemistry, Rats, Sprague-Dawley, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Peripheral Nerve Injuries, Internal medicine, medicine, Animals, Autografts, Testosterone, business.industry, Dihydrotestosterone, General Medicine, Sciatic Nerve, Nerve Regeneration, Androgen receptor, Transplantation, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Peripheral nerve injury, Sciatic nerve, business, Myelin P0 Protein, 030217 neurology & neurosurgery, medicine.drug

الوصف: Neuroactive steroids such as progesterone, testosterone, and their derivatives have been widely studied for their neuroprotective roles in the nervous system. Autologous nerve transplantation is considered as the gold standard repair technique when primary suture is impossible; nevertheless, this method is far from ideal. In this study, we aimed to explore the impact of dihydrotestosterone (DHT), a 5α-reduced derivative of testosterone, on the recovery of peripheral nerve injury treated with autologous nerve transplantation. Sprague-Dawley rats were subjected to a 10-mm right side sciatic nerve reversed autologous nerve transplantation and randomly divided into groups that received DHT or DHT + flutamide (an androgen receptor blocker) daily for 8 weeks after operation. Our results demonstrated that DHT could speed up the rate of axonal regeneration and increase the expression of myelin protein zero (P0) in autograft reversal sciatic nerves. Thus, our study provided new insights into improving the prognosis of patients with long gap peripheral nerve defects.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::daa5c6c9f9082ea2b471e37ffba4d80eTest
https://doi.org/10.1007/s11064-018-2466-2Test

المؤلفون: Yuning Zhou, Chang Li, B. Mark Evers, Ruozheng Wei, Qingding Wang, Heidi L. Weiss

المصدر: Gastroenterology. 160:S-589

مصطلحات موضوعية: Hepatology, Colorectal cancer, business.industry, medicine.medical_treatment, Anti pd 1, Ketogenesis, Gastroenterology, medicine, Cancer research, Immunotherapy, medicine.disease, business

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f122e5cbb7b9093a65b22beba575e873Test
https://doi.org/10.1016/s0016-5085Test(21)02106-5

المؤلفون: Ruozheng Wei, Chang Li, Heidi L. Weiss, Qingding Wang, Yuning Zhou, B. Mark Evers

المصدر: Gastroenterology. 160:S-108

مصطلحات موضوعية: Intestinal cell, Hepatology, NFAT5, Apoptosis, Gastroenterology, Cancer research, Biology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::23181ee632e64ceaa820c7d324123f91Test
https://doi.org/10.1016/s0016-5085Test(21)01004-0