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Öğe Dietary N-carbamylglutamate or L-arginine supplementation improves hepatic energy status and mitochondrial function and inhibits the AMP-activated protein kinase- peroxisome proliferator-activated receptor ? coactivator-1?-transcription factor A pathway in intrauterine-growth-retarded suckling lambs(Keai Publishing Ltd, 2021) Zhang, Hao; Liu, Xiaoyun; Ren, Shengnan; Elsabagh, Mabrouk; Wang, Mengzhi; Wang, HongrongThe objective of this study was to investigate the effects of dietary administration of L-arginine (Arg) or N-carbamylglutamate (NCG) on hepatic energy status and mitochondrial functions in suckling Hu lambs with intrauterine growth retardation (IUGR). Forty-eight newborn Hu lambs of 7 d old were allocated into 4 treatment groups of 12 lambs each, in triplicate with 4 lambs per replicate (2 males and 2 females) as follows: CON (lambs of normal birth weight, 4.25 +/- 0.14 kg), IUGR (3.01 +/- 0.12 kg), IUGR thorn 1% Arg (2.99 +/- 0.13 kg), or IUGR thorn 0.1% NCG (3.03 +/- 0.11 kg). The experiment lasted for 21 d, until d 28 after birth, and all lambs were fed milk replacer as a basal diet. Compared with IUGR lambs, NCG or Arg administration increased (P < 0.05) the adenosine triphosphate (ATP) level and the activities of complexes I/III/IV, isocitrate dehydrogenase and citrate synthase in the liver. Compared with CON lambs, the relative mRNA levels of adenosine monophosphate-activated protein kinase alpha 1 (AMPK alpha 1), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1 alpha) and transcription factor A (TFAM) were increased (P < 0.05) in the liver of IUGR lambs, but were decreased (P < 0.05) in the liver of NCG- or Arg-treated lambs compared with those in the IUGR lambs. Compared with IUGR lambs, NCG or Arg administration decreased (P < 0.05) the total AMPK alpha (tAMPK alpha)-to-phosphorylated AMPK alpha (pAMPK alpha) ratio and the protein expression of PGC1a alpha and TFAM. The results suggested that dietary Arg or NCG supplements improved hepatic energy status and mitochondrial function and inhibited the AMPK-PGC1 alpha-TFAM pathway in IUGR suckling lambs. (C) 2021 Chinese Association of Animal Science and Veterinary Medicine. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.Öğe Dietary rumen-protected L-arginine or N-carbamylglutamate attenuated fetal hepatic inflammation in undernourished ewes suffering from intrauterine growth restriction(Keai Publishing Ltd, 2021) Zhang, Hao; Zhang, Ying; Ma, Yi; Elsabagh, Mabrouk; Wang, Hongrong; Wang, MengzhiThis study aimed to explore whether dietary rumen-protected L-arginine (RP-Arg) or N-carbamylglutamate (NCG) supplementation to feed-restricted pregnant ewes counteracts fetal hepatic inflammation and innate immune dysfunction associated with intrauterine growth retardation (IUGR) in ovine fetuses. On d 35 of pregnancy, twin-bearing Hu ewes (n = 32) were randomly assigned to 4 treatment groups (8 ewes and 16 fetuses per group) and fed diets containing 100% of the NRC requirements (CON), 50% of the NRC requirements (RES), RES + RP-Arg (20 g/d) (RESA), or RES + NCG (5 g/d) (RESN). At 08:00 on d 110 of gestation, fetal blood and liver tissue samples were collected. The levels of triglyceride, free fatty acid, cholesterol and beta-hydroxybutyrate in the fetal blood of RESA and RESN groups were lower (P < 0.05) than those of the RES group, but were higher (P < 0.05) than those of the CON group. The interleukin (IL)6 and IL-1 levels in fetal blood and liver tissue as well as the myeloid differentiation primary response 88 (MyD88), transforming growth factor beta (TGF beta), and nuclear factor kappa B (NF-kB) mRNA levels in the fetal liver were decreased (P < 0.05) by the NCG or RP-Arg supplementation compared to the RES treatment. Similarly, the toll-like receptor (TLR)-4, MyD88, TGFb, and p-c-Jun N-terminal kinase (JNK) protein levels in the fetal liver were reduced (P < 0.05) in the NCG and RP-Arg-supplemented groups compared to the RES group. These results showed that dietary supplementation of RP-Arg or NCG to underfed pregnant ewes could protect against IUGR fetal hepatic inflammation via improving lipid metabolism, down-regulating the TLR-4 and the inflammatory JNK and NF-kB signaling pathways, and decreasing cytokine production in ovine fetal blood and liver tissue. (C) 2021 Chinese Association of Animal Science and Veterinary Medicine. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.Öğe Dietary Supplementation of L-Arginine and N-Carbamylglutamate Attenuated the Hepatic Inflammatory Response and Apoptosis in Suckling Lambs with Intrauterine Growth Retardation(Hindawi Ltd, 2020) Zhang, Hao; Fan, Yaotian; Elsabagh, Mabrouk; Guo, Shuang; Wang, Mengzhi; Jiang, HonghuaL-arginine (Arg) is a semiessential amino acid with several physiological functions. N-Carbamylglutamate (NCG) can promote the synthesis of endogenous Arg in mammals. However, the roles of Arg or NCG on hepatic inflammation and apoptosis in suckling lambs suffering from intrauterine growth restriction (IUGR) are still unclear. The current work is aimed at examining the effects of dietary Arg and NCG on inflammatory and hepatocyte apoptosis in IUGR suckling lambs. On day 7 after birth, 48 newborn Hu lambs were selected from a cohort of 432 twin lambs. Normal-birthweight and IUGR Hu lambs were allocated randomly (n=12/group) to control (CON), IUGR, IUGR+1% Arg, or IUGR+0.1% NCG groups. Lambs were fed for 21 days from 7 to 28 days old. Compared with CON lambs, relative protein 53 (P53), apoptosis antigen 1 (Fas), Bcl-2-associated X protein (Bax), caspase-3, cytochrome C, tumor necrosis factor alpha (TNF-alpha), nuclear factor kappa-B (NF-kappa B) p65, and NF-kappa B pp65 protein levels were higher (P<0.05) in liver from IUGR lambs, whereas those in liver from IUGR lambs under Arg or NCG treatment were lower than those in IUGR lambs. These findings indicated that supplementing Arg or NCG reduced the contents of proinflammatory cytokines at the same time when the apoptosis-related pathway was being suppressed, thus suppressing the IUGR-induced apoptosis of hepatic cells.Öğe Dietary supplementation of l-arginine and N-carbamylglutamate enhances duodenal barrier and mitochondrial functions and suppresses duodenal inflammation and mitophagy in suckling lambs suffering from intrauterine-growth-restriction(Royal Soc Chemistry, 2020) Zhang, Hao; Ma, Yi; Wang, Mengzhi; Elsabagh, Mabrouk; Loor, Juan J.; Wang, HongrongThe current work aimed at investigating the effects of the dietary supplementation of N-carbamylglutamate (NCG) or l-arginine (Arg) on the duodenal mitophagy, mitochondrial function, inflammation, and barrier function in suckling lambs suffering from intrauterine-growth-retardation (IUGR). Forty-eight neonate Hu lambs were used in this study: 12 lambs with normal birth weight (NBW: 4.25 +/- 0.14 kg) and 36 lambs with IUGR (3.01 +/- 0.13 kg). Seven day old lambs were assigned to 4 treatment groups (12 lambs in each group) as follows: control group (CON), IUGR group, IUGR + Arg, and IUGR + NCG. Lambs were fed the experimental diets for 21 days from 7 days to 28 days of age. Compared with IUGR lambs, the Arg or NCG-treated IUGR lambs had a markedly higher duodenal transepithelial electrical resistance (TER) and lower fluorescein isothiocyanate dextran (FD4) (P < 0.05), respectively. The duodenal mitochondrial membrane potential change (Delta psi(m)), relative mitochondrial DNA (mtDNA) content, adenosine triphosphate (ATP) level, together with the activities of the respiratory complexes I, III, and IV were markedly higher in Arg or NCG-treated IUGR lambs than those in non-supplemented IUGR lambs (P < 0.05). The expressions of the integrity-related proteins (occludin and zonula occludens-1 (ZO-1)), antioxidant- and apoptosis-related proteins (B-cell lymphoma/leukaemia 2 (Bcl2), superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1)), and the nitric oxide-dependent pathway-related proteins (epithelial NO synthase (eNOS) and inducible NO synthase (iNOS)) were higher in NCG or Arg-supplemented IUGR lambs than those in nontreated IUGR lambs (P < 0.05). The duodenal expressions of the mitophagy-related proteins (microtubule-associated protein light chain 3 (LC3) I, LC3 II, Belin1, PTEN induced putative kinase 1 (PINK1), and Parkin) and the immune function-related proteins (myeloid differentiation factor 88 (MyD88), IL-6, nuclear factor kappa B (p65), toll-like receptor (TLR4) and TNF-alpha) were reduced (P < 0.05) in NCG or Arg-supplemented IUGR lambs compared with non-supplemented IUGR lambs. These results demonstrated that the dietary supplementation of Arg or NCG enhanced the duodenal barrier function and mitochondrial function, mitigated duodenal inflammation, and suppressed mitophagy in suckling lambs suffering from IUGR.Öğe Effects of the Gut Microbiota and Barrier Function on Melatonin Efficacy in Alleviating Liver Injury(Mdpi, 2022) Zhang, Hao; Liu, Xiaoyun; Elsabagh, Mabrouk; Zhang, Ying; Ma, Yi; Jin, Yaqian; Wang, MengzhiEnvironmental cadmium (Cd) exposure has been associated with severe liver injury. In contrast, melatonin (Mel) is a candidate drug therapy for Cd-induced liver injury due to its diverse hepatoprotective activities. However, the precise molecular mechanism by which Mel alleviates the Cd-induced liver injury, as well as the Mel-gut microbiota interaction in liver health, remains unknown. In this study, mice were given oral gavage CdCl2 and Mel for 10 weeks before the collection of liver tissues and colonic contents. The role of the gut microbiota in Mel's efficacy in alleviating the Cd-induced liver injury was evaluated by the gut microbiota depletion technique in the presence of antibiotic treatment and gut microbiota transplantation (GMT). Our results revealed that the oral administration of Mel supplementation mitigated liver inflammation, endoplasmic reticulum (ER) stress and mitophagy, improved the oxidation of fatty acids, and counteracted intestinal microbial dysbiosis in mice suffering from liver injury. It was interesting to find that neither Mel nor Cd administration induced any changes in the liver of antibiotic-treated mice. By adopting the GMT approach where gut microbiota collected from mice in the control (CON), Cd, or Mel + Cd treatment groups was colonized in mice, it was found that gut microbiota was involved in Cd-induced liver injury. Therefore, the gut microbiota is involved in the Mel-mediated mitigation of ER stress, liver inflammation and mitophagy, and the improved oxidation of fatty acids in mice suffering from Cd-induced liver injury.Öğe Gut microbiota contributes to bisphenol A-induced maternal intestinal and placental apoptosis, oxidative stress, and fetal growth restriction in pregnant ewe model by regulating gut-placental axis(Bmc, 2024) Zhang, Hao; Zha, Xia; Zhang, Bei; Zheng, Yi; Elsabagh, Mabrouk; Wang, Hongrong; Wang, MengzhiBackgroundBisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation.ResultsTwo pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure.ConclusionsOur findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR.DorkkcsjvJM4thb48aSHyrVideo AbstractConclusionsOur findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR.DorkkcsjvJM4thb48aSHyrVideo AbstractÖğe L-Arginine Inhibits Apoptosis of Ovine Intestinal Epithelial Cells through the L-Arginine-Nitric Oxide Pathway(Oxford Univ Press, 2020) Zhang, Hao; Zhao, Fangfang; Peng, Along; Guo, Shuang; Wang, Mengzhi; Elsabagh, Mabrouk; Loor, Juan J.Background: In nonruminants, many of the biological roles of L-arginine (Arg) at the intestinal level are mediated through the Arg-nitric oxide (Arg-NO) pathway. Whether the Arg-NO pathway is involved in controlling the immune response and viability in ovine intestinal epithelial cells (IOECs) is unclear. Objectives: The current study aimed to examine the role of the Arg-NO pathway in apoptosis, antioxidant capacity, and mitochondrial function of IOECs. Methods: The IOECs were incubated in Arg-free DMEM supplemented with 150 mu M Arg (CON) or 300 mu M Arg (ARG) alone or with 350 mu M Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME) (CON + NAME, ARG + NAME) for 24 h. The reactive oxygen species (ROS) concentration, antioxidant capacity, and cell apoptotic percentage were determined. Results: Arg supplementation decreased (P < 0.05) the ROS concentration (38.9% and 22.7%) and apoptotic cell percentage (57.2% and 54.8%) relative to the CON and CON + NAME groups, respectively. Relative to the CON and ARG treatments, the L-NAME administration decreased (P < 0.05) the mRNA abundance of superoxide dismutase 2 (32% and 21.3%, respectively) and epithelial NO synthase (36% and 29.1%, respectively). Arg supplementation decreased (P < 0.05) the protein abundance of apoptosis antigen 1 (FAS) (52.0% and 43.9%) but increased (P < 0.05) those of nuclear respiratory factor 1 (31.3% and 22.9%) and inducible NO synthase (35.2% and 41.8%) relative to the CON and CON + NAME groups, respectively. Conclusions: The inhibition of apoptosis in IOECs due to the increased supply of Arg is associated with the mitochondria- and FAS-dependent pathways through the activity of the Arg-NO pathway. The findings help elucidate the role of the Arg-NO pathway in IOEC growth and apoptosis.Öğe The interaction of ER stress and autophagy in trophoblasts: navigating pregnancy outcome(Oxford Univ Press Inc, 2024) Zheng, Yi; Zha, Xia; Zhang, Bei; Elsabagh, Mabrouk; Wang, Hongrong; Wang, Mengzhi; Zhang, HaoThe endoplasmic reticulum is a complex and dynamic organelle that initiates unfolded protein response and endoplasmic reticulum stress in response to the accumulation of unfolded or misfolded proteins within its lumen. Autophagy is a paramount intracellular degradation system that facilitates the transportation of proteins, cytoplasmic components, and organelles to lysosomes for degradation and recycling. Preeclampsia and intrauterine growth retardation are two common complications of pregnancy associated with abnormal trophoblast differentiation and placental dysfunctions and have a major impact on fetal development and maternal health. The intricate interplay between endoplasmic reticulum stress, and autophagy and their impact on pregnancy outcomes, through mediating trophoblast differentiation and placental development, has been highlighted in various reports. Autophagy controls trophoblast regulation through a variety of gene expressions and signaling pathways while excessive endoplasmic reticulum stress triggers downstream apoptotic signaling, culminating in trophoblast apoptosis. This comprehensive review delves into the intricacies of placental development and explores the underlying mechanisms of preeclampsia and intrauterine growth retardation. In addition, this review will elucidate the molecular mechanisms of endoplasmic reticulum stress and autophagy, both individually and in their interplay, in mediating placental development and trophoblast differentiation, particularly highlighting their roles in preeclampsia and intrauterine growth retardation development. This research seeks to the interplay between endoplasmic reticulum stress and impaired autophagy in the placental trophoderm, offering novel insights into their contribution to pregnancy complications. [GRAPHICS] .
