المؤلفون: Taylor, Savannah J, Winter, Maria G, Gillis, Caroline C, Silva, Laice Alves da, Dobbins, Amanda L, Muramatsu, Matthew K, Jimenez, Angel G, Chanin, Rachael B, Spiga, Luisella, Llano, Ernesto M, Rojas, Vivian K, Kim, Jiwoong, Santos, Renato L, Zhu, Wenhan, Winter, Sebastian E

المصدر: Microbiome. 10(1)

مصطلحات موضوعية: Microbiology, Biological Sciences, Infectious Diseases, Autoimmune Disease, Vaccine Related, Crohn's Disease, Digestive Diseases, Nutrition, Biodefense, Inflammatory Bowel Disease, Prevention, 2.1 Biological and endogenous factors, Aetiology, Infection, Oral and gastrointestinal, Good Health and Well Being, Mice, Animals, Dysbiosis, Gastrointestinal Microbiome, Escherichia coli, Lactic Acid, Lactate Dehydrogenase 5, Mice, Inbred C57BL, Inflammation, Colitis, Enterobacteriaceae, Host-microbe interactions, Lactate metabolism, Gut inflammation, Ecology, Medical Microbiology, Evolutionary biology

الوصف: BackgroundIntestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology.ResultsWe investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis.ConclusionsThe release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition. Video Abstract.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3t65c4gpTest

المؤلفون: Gillis, Caroline C, Winter, Maria G, Chanin, Rachael B, Zhu, Wenhan, Spiga, Luisella, Winter, Sebastian E

المصدر: Infection and Immunity. 87(4)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Microbiology, Emerging Infectious Diseases, Prevention, Genetics, Digestive Diseases, Infectious Diseases, Biodefense, Foodborne Illness, Vaccine Related, Aetiology, 2.1 Biological and endogenous factors, Infection, Animals, Bacterial Proteins, Female, Gene Expression Regulation, Bacterial, Humans, Intestinal Mucosa, L-Lactate Dehydrogenase, Lactic Acid, Male, Mice, Mice, Inbred C57BL, Oxygen, Salmonella Infections, Salmonella typhimurium, Transcription Factors, Salmonella, gut inflammation, microbiome, Agricultural and Veterinary Sciences, Medical and Health Sciences, Immunology, Medical microbiology

الوصف: During Salmonella enterica serovar Typhimurium infection, host inflammation alters the metabolic environment of the gut lumen to favor the outgrowth of the pathogen at the expense of the microbiota. Inflammation-driven changes in host cell metabolism lead to the release of l-lactate and molecular oxygen from the tissue into the gut lumen. Salmonella utilizes lactate as an electron donor in conjunction with oxygen as the terminal electron acceptor to support gut colonization. Here, we investigated transcriptional regulation of the respiratory l-lactate dehydrogenase LldD in vitro and in mouse models of Salmonella infection. The two-component system ArcAB repressed transcription of l-lactate utilization genes under anaerobic conditions in vitro The ArcAB-mediated repression of lldD transcription was relieved under microaerobic conditions. Transcription of lldD was induced by l-lactate but not d-lactate. A mutant lacking the regulatory protein LldR failed to induce lldD transcription in response to l-lactate. Furthermore, the lldR mutant exhibited reduced transcription of l-lactate utilization genes and impaired fitness in murine models of infection. These data provide evidence that the host-derived metabolites oxygen and l-lactate serve as cues for Salmonella to regulate lactate oxidation metabolism on a transcriptional level.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/78f1w7dhTest

المؤلفون: Bok, Robert, Lee, Jessie, Sriram, Renuka, Keshari, Kayvan, Sukumar, Subramaniam, Daneshmandi, Saeed, Korenchan, David E, Flavell, Robert R, Vigneron, Daniel B, Kurhanewicz, John, Seth, Pankaj

المصدر: Cancers. 11(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Cancer, Urologic Diseases, Rare Diseases, Biomedical Imaging, Digestive Diseases, Aging, 2.1 Biological and endogenous factors, Aetiology, hyperpolarized C-13, prostate cancer, lactate, magnetic resonance imaging, lactate dehydrogenase, hyperpolarized 13C, Oncology and carcinogenesis

الوصف: This study applied a dual-agent, 13C-pyruvate and 13C-urea, hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) ¹H magnetic resonance imaging (MRI) approach in the transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate changes in tumor perfusion and lactate metabolism during prostate cancer development, progression and metastases, and after lactate dehydrogenase-A (LDHA) knock-out. An increased Warburg effect, as measured by an elevated hyperpolarized (HP) Lactate/Pyruvate (Lac/Pyr) ratio, and associated Ldha expression and LDH activity were significantly higher in high- versus low-grade TRAMP tumors and normal prostates. The hypoxic tumor microenvironment in high-grade tumors, as measured by significantly decreased HP 13C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased Hif1α and then Ldha expression. Increased lactate induced Mct4 expression and an acidic tumor microenvironment that provided a potential mechanism for the observed high rate of lymph node (86%) and liver (33%) metastases. The Ldha knockdown in the triple-transgenic mouse model of prostate cancer resulted in a significant reduction in HP Lac/Pyr, which preceded a reduction in tumor volume or apparent water diffusion coefficient (ADC). The Ldha gene knockdown significantly reduced primary tumor growth and reduced lymph node and visceral metastases. These data suggested a metabolic transformation from low- to high-grade prostate cancer including an increased Warburg effect, decreased perfusion, and increased metastatic potential. Moreover, these data suggested that LDH activity and lactate are required for tumor progression. The lactate metabolism changes during prostate cancer provided the motivation for applying hyperpolarized 13C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7bt8n6nwTest

المؤلفون: Yang, Ling, Miura, Kouichi, Zhang, Bi, Matsushita, Hiroshi, Yang, Yoon Mee, Liang, Shuang, Song, Jingyi, Roh, Yoon Seok, Seki, Ekihiro

المصدر: Cellular and molecular gastroenterology and hepatology. 3(3)

مصطلحات موضوعية: ALT, alanine aminotransferase, BM, bone marrow, BMT, bone marrow transplantation, CDAA, choline-deficient amino acid defined, DGAT2, diacylglycerol acyltransferase 2, HFD, high-fat diet, HSC, hepatic stellate cell, Hepatocyte Apoptosis, IL, interleukin, LDH, lactate dehydrogenase, LPS, LPS, lipopolysaccharide, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis, Neutrophils, PCR, polymerase chain reaction, TLR4, TLR4, Toll-like receptor 4, TNF, tumor necrosis factor, α-SMA, α-smooth muscle actin, ALT, alanine aminotransferase, BM, bone marrow, BMT, bone marrow transplantation, CDAA, choline-deficient amino acid defined, DGAT2, diacylglycerol acyltransferase 2, HFD, high-fat diet, HSC, hepatic stellate cell, IL, interleukin, LDH, lactate dehydrogenase, lipopolysaccharide, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis, PCR, polymerase chain reaction, Toll-like receptor 4, TNF, tumor necrosis factor, α-SMA, α-smooth muscle actin, Digestive Diseases, Nutrition, Hepatitis, Chronic Liver Disease and Cirrhosis, Liver Disease, 2.1 Biological and endogenous factors, Inflammatory and Immune System, Oral and Gastrointestinal

الوصف: Background & aimsToll-like receptor 4 (TLR4) signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF). TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH) and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis.MethodsA choline-deficient amino acid defined (CDAA) diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4-/- bone marrow chimeric mice and TRIF-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined.ResultsIn the CDAA diet-induced NASH, the mice with wild-type bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4-/- bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4-/- bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4-/- recipients. Although TRIF-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wild-type mice. TRIF-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury.ConclusionsIn TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic steatosis but it inhibits injury, inflammation, and fibrosis.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0bd4d81pTest

المؤلفون: Gillis, Caroline C, Hughes, Elizabeth R, Spiga, Luisella, Winter, Maria G, Zhu, Wenhan, de Carvalho, Tatiane Furtado, Chanin, Rachael B, Behrendt, Cassie L, Hooper, Lora V, Santos, Renato L, Winter, Sebastian E

المصدر: Cell Host & Microbe. 23(1)

مصطلحات موضوعية: Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Emerging Infectious Diseases, Prevention, Biodefense, Vaccine Related, Infectious Diseases, Digestive Diseases, Foodborne Illness, 2.1 Biological and endogenous factors, Aetiology, Infection, Animals, Anti-Bacterial Agents, Butyric Acid, Clostridium, Dysbiosis, Female, Fermentation, Gastroenteritis, Gastrointestinal Microbiome, Intestinal Mucosa, L-Lactate Dehydrogenase, Lactic Acid, Male, Mice, Mice, Inbred C57BL, PPAR gamma, Salmonella Infections, Salmonella typhimurium, Triglycerides, Salmonella, gut microbiota, host metabolism during infection, host-microbe interaction, microbial metabolism, Immunology, Biochemistry and cell biology, Medical microbiology

الوصف: During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARγ agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3047034jTest

المؤلفون: Yang, Ling, Miura, Kouichi, Zhang, Bi, Matsushita, Hiroshi, Yang, Yoon Mee, Liang, Shuang, Song, Jingyi, Roh, Yoon Seok, Seki, Ekihiro

المصدر: Cellular and Molecular Gastroenterology and Hepatology. 3(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Hepatitis, Liver Disease, Nutrition, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Oral and gastrointestinal, Good Health and Well Being, TLR4, Hepatocyte Apoptosis, LPS, Neutrophils, ALT, alanine aminotransferase, BM, bone marrow, BMT, bone marrow transplantation, CDAA, choline-deficient amino acid defined, DGAT2, diacylglycerol acyltransferase 2, HFD, high-fat diet, HSC, hepatic stellate cell, IL, interleukin, LDH, lactate dehydrogenase, LPS, lipopolysaccharide, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis, PCR, polymerase chain reaction, TLR4, Toll-like receptor 4, TNF, tumor necrosis factor, α-SMA, α-smooth muscle actin, Biochemistry and cell biology, Clinical sciences

الوصف: Background & aimsToll-like receptor 4 (TLR4) signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF). TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH) and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis.MethodsA choline-deficient amino acid defined (CDAA) diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4-/- bone marrow chimeric mice and TRIF-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined.ResultsIn the CDAA diet-induced NASH, the mice with wild-type bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4-/- bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4-/- bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4-/- recipients. Although TRIF-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wild-type mice. TRIF-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury.ConclusionsIn TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic steatosis but it inhibits injury, inflammation, and fibrosis.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0bd4d81pTest

المؤلفون: Ke, Bibo, Shen, Xiu-Da, Zhang, Yu, Ji, Haofeng, Gao, Feng, Yue, Shi, Kamo, Naoko, Zhai, Yuan, Yamamoto, Masayuki, Busuttil, Ronald W, Kupiec-Weglinski, Jerzy W

المصدر: Journal of Hepatology. 59(6)

مصطلحات موضوعية: Organ Transplantation, Liver Disease, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Transplantation, Underpinning research, 1.1 Normal biological development and functioning, Inflammatory and immune system, Oral and gastrointestinal, Adaptor Proteins, Signal Transducing, Animals, Cytoskeletal Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Kelch-Like ECH-Associated Protein 1, Liver, Liver Transplantation, Macrophages, Male, Mice, Mice, Inbred C57BL, NF-E2-Related Factor 2, Neutrophils, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Reperfusion Injury, Signal Transduction, Liver ischemia/reperfusion injury, Liver transplantation, Keap1-Nrf2 redox system, HO-1, ARE, H(2)O(2), HIF-1, HKO, HRE, IRI, Keap1, Kelch-like ECH-associated protein 1, LDH, Nrf2, OLT, PI3K, TUNEL, Trx1, anti-oxidant response element, heme-oxygenase-1, hepatocyte knockout, hydrogen peroxide, hypoxia inducible factor-1, hypoxia response element, ischemia/reperfusion injury, lactate dehydrogenase, nuclear factor erythroid 2-related factor 2, orthotopic liver transplantation, phosphoinositide 3-kinase, sALT, serum alanine aminotransferase, terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling, thioredoxin 1, Clinical Sciences, Public Health and Health Services, Gastroenterology & Hepatology

الوصف: Background & aimsThe Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance.MethodsWe investigated the function/molecular mechanisms by which Keap1-Nrf2 complex may influence liver ischemia/reperfusion injury (IRI) in a mouse model of hepatic cold storage (20h at 4°C) followed by orthotopic liver transplantation (OLT).ResultsThe Keap1 hepatocyte-specific knockout (HKO) in the donor liver ameliorated post-transplant IRI, evidenced by improved hepatocellular function and OLT outcomes (Keap1 HKO→Keap1 HKO; 100% survival), as compared with controls (WT→WT; 50% survival; p

الوصول الحر: https://escholarship.org/uc/item/8n32n8nrTest

المؤلفون: Ke, Bibo, Shen, Xiu-Da, Zhang, Yu, Ji, Haofeng, Gao, Feng, Yue, Shi, Kamo, Naoko, Zhai, Yuan, Yamamoto, Masayuki, Busuttil, Ronald W, Kupiec-Weglinski, Jerzy W

المصدر: Journal of hepatology. 59(6)

مصطلحات موضوعية: Liver, Neutrophils, Macrophages, Animals, Mice, Inbred C57BL, Mice, Reperfusion Injury, Adaptor Proteins, Signal Transducing, Cytoskeletal Proteins, Liver Transplantation, Signal Transduction, Male, Proto-Oncogene Proteins c-akt, NF-E2-Related Factor 2, Hypoxia-Inducible Factor 1, alpha Subunit, Phosphatidylinositol 3-Kinases, Kelch-Like ECH-Associated Protein 1, ARE, H(2)O(2), HIF-1, HKO, HO-1, HRE, IRI, Keap1, Keap1-Nrf2 redox system, Kelch-like ECH-associated protein 1, LDH, Liver ischemia/reperfusion injury, Liver transplantation, Nrf2, OLT, PI3K, TUNEL, Trx1, anti-oxidant response element, heme-oxygenase-1, hepatocyte knockout, hydrogen peroxide, hypoxia inducible factor-1, hypoxia response element, ischemia/reperfusion injury, lactate dehydrogenase, nuclear factor erythroid 2-related factor 2, orthotopic liver transplantation, phosphoinositide 3-kinase, sALT, serum alanine aminotransferase, terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling, thioredoxin 1, Inbred C57BL, Adaptor Proteins, Signal Transducing, Hypoxia-Inducible Factor 1, alpha Subunit, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Liver Disease, Organ Transplantation, Transplantation, 1.1 Normal biological development and functioning, Oral and Gastrointestinal, Inflammatory and Immune System, Gastroenterology & Hepatology, Clinical Sciences, Public Health and Health Services

الوصف: Background & aimsThe Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance.MethodsWe investigated the function/molecular mechanisms by which Keap1-Nrf2 complex may influence liver ischemia/reperfusion injury (IRI) in a mouse model of hepatic cold storage (20h at 4°C) followed by orthotopic liver transplantation (OLT).ResultsThe Keap1 hepatocyte-specific knockout (HKO) in the donor liver ameliorated post-transplant IRI, evidenced by improved hepatocellular function and OLT outcomes (Keap1 HKO→Keap1 HKO; 100% survival), as compared with controls (WT→WT; 50% survival; p

الوصول الحر: https://escholarship.org/uc/item/8n32n8nrTest

المؤلفون: Ji, Haofeng, Zhang, Yu, Liu, Yuanxing, Shen, Xiu-Da, Gao, Feng, Nguyen, Terry T, Busuttil, Ronald W, Waschek, James A, Kupiec-Weglinski, Jerzy W

المصدر: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 19(9)

مصطلحات موضوعية: Liver, Neutrophils, Macrophages, Hepatocytes, Immune System, Animals, Mice, Inbred C57BL, Mice, Reperfusion Injury, Inflammation, Necrosis, Vasoactive Intestinal Peptide, L-Lactate Dehydrogenase, Peroxidase, Cyclic AMP-Dependent Protein Kinases, Cyclic AMP, Interleukin-10, Flow Cytometry, Apoptosis, Homeostasis, Time Factors, Male, Caspase 3, Inbred C57BL, Transplantation, Chronic Liver Disease and Cirrhosis, Organ Transplantation, Liver Disease, Digestive Diseases, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Oral and Gastrointestinal, Surgery, Clinical Sciences

الوصف: Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients.

الوصول الحر: https://escholarship.org/uc/item/66w978xjTest