Yazar "Zhang, Hao" seçeneğine göre listele
Listeleniyor 1 - 18 / 18
Sayfa Başına Sonuç
Sıralama seçenekleri
Öğe Autophagy attenuates placental apoptosis, oxidative stress and fetal growth restriction in pregnant ewes(Pergamon-Elsevier Science Ltd, 2023) Zhang, Hao; Zheng, Yi; Liu, Xiaoyun; Zha, Xia; Elsabagh, Mabrouk; Ma, Yi; Jiang, HonghuaBisphenol A (BPA)-induced oxidative stress (OS) and its potentially associated autophagy and apoptosis have not been studied previously in pregnant ewes. Accordingly, this study investigated the underlying mechanisms of BPA-induced autophagy and apoptosis in the placenta and primary trophoblasts of pregnant ewes exposed to BPA both in vivo and in vitro. In vivo experiment, pregnant Hu ewes (n = 8) were exposed to 5 mg/kg/d of BPA compared to control ewes (n = 8) receiving only corn oil from day 40 through day 110 of gestation. Exposure to BPA during gestation resulted in placental insufficiency, fetal growth restriction (FGR), autophagy, endoplasmic reticulum stress (ERS), mitochondrial dysfunction, OS, and apoptosis in type A placentomes. Regarding in vitro model, primary ovine trophoblasts were exposed to BPA, BPA plus chloroquine (CQ; an autophagy inhibitor) or BPA plus rapamycin (RAP; an autophagy activator) for 12 h. Data illustrated that exposure to BPA enhanced autophagy (ULK1, Beclin-1, LC3, Parkin, and PINK1), ERS (GRP78, CHOP10, ATF4, and ATF6) and apoptosis (Caspase 3, Bcl-2, Bax, P53) but decreased the antioxidant (CAT, Nrf2, HO-1, and NQO1)-related mRNA and protein expressions as well as impaired the mitochondrial function. Moreover, treatment with CQ exacerbated the BPA-mediated OS, mitochondrial dysfunction, apoptosis, and ERS. On the contrary, RAP treatment coun-teracted the BPA-induced trophoblast dysfunctions mentioned above. Overall, the findings illustrated that BPA exposure could contribute to autophagy in the ovine placenta and trophoblasts and that autophagy, in turn, could alleviate BPA-induced apoptosis, mitochondrial dysfunction, ERS, and OS. These results offer new mechanistic insights into the role of autophagy in mitigating BPA-induced placental dysfunctions and FGR.Öğe Determination of the trace minerals requirements for maintenance and growth of 35-50 kg Dorper x Hu crossbred ram lambs(Taylor & Francis Ltd, 2020) Zhang, Hao; Zhang, Ying; Peng, Along; Nie, Haitao; Wang, Feng; Elsabagh, Mabrouk; Loor, Juan J.This study aimed at estimating the trace minerals net requirements for maintenance and growth of Dorper x Hu ram lambs using the comparative slaughter techniques in 35 lambs of 35-50 kg body weight (BW). Seven lambs were slaughtered at the initial BW (34.93 +/- 0.37 kg) to determine the basal whole-body composition. Another seven lambs were fed ad libitum (AL) and then slaughtered when it reached 41.73 +/- 0.53 kg BW. The remained 21 lambs were assigned into three treatment groups, seven animals each, and fed 100, 70 or 40% of AL intake, respectively, and were slaughtered when they reached a BW of 49.93 +/- 1.03 kg. The net requirements of maintenance were 5.1, 429.3, 94.0 and 48.8 mu g/kg empty BW (EBW) for Mn, Fe, Zn and Cu, respectively. The net requirements of growth at 35 kg BW were 0.86, 70.41, 33.46 and 4.31 mg/kg EBW for Mn, Fe, Zn and Cu, respectively. At a BW of 50 kg, the net growth requirements were 0.93, 68.40, 35.20 and 4.15 mg/kg EBW for Mn, Fe, Zn and Cu, respectively. Our data indicated that the Mn and Zn requirements increase, whereas those of Fe and Cu decrease when BW increases. In addition, the net Cu, Mn and Fe requirements for maintenance and Zn, Cu, Mn and Fe requirements for growth of Dorper x Hu hybrid ram lambs were higher than those reported in the NRC but Zn requirements for maintenance matched that of the NRC.Öğe Dietary L-Arginine or N-Carbamylglutamate Alleviates Colonic Barrier Injury, Oxidative Stress, and Inflammation by Modulation of Intestinal Microbiota in Intrauterine Growth-Retarded Suckling Lambs(Mdpi, 2022) Zhang, Hao; Zheng, Yi; Zha, Xia; Ma, Yi; Liu, Xiaoyun; Elsabagh, Mabrouk; Wang, HongrongOur previous studies have revealed that dietary N-carbamylglutamate (NCG) and L-arginine (Arg) supplementation improves redox status and suppresses apoptosis in the colon of suckling Hu lambs with intrauterine growth retardation (IUGR). However, no studies have reported the function of Arg or NCG in the colonic microbial communities, barrier function, and inflammation in IUGR-suckling lambs. This work aimed to further investigate how dietary Arg or NCG influences the microbiota, barrier function, and inflammation in the colon of IUGR lambs. Forty-eight newborn Hu lambs of 7 d old were assigned to four treatment groups (n = 12 per group; six male, six female) as follows: CON (normal birth weight, 4.25 +/- 0.14 kg), IUGR (3.01 +/- 0.12 kg), IUGR + Arg (2.99 +/- 0.13 kg), and IUGR + NCG (3.03 +/- 0.11 kg). A total of 1% Arg or 0.1% NCG was supplemented in a basal diet of milk replacer, respectively. Lambs were fed the milk replacer for 21 d until 28 d after birth. Compared to the non-supplemented IUGR lambs, the transepithelial electrical resistance (TER) was higher, while fluorescein isothiocyanate dextran 4 kDa (FD4) was lower in the colon of the NCG- or Arg-supplemented IUGR lambs (p < 0.05). The IUGR lambs exhibited higher (p < 0.05) colonic interleukin (IL)-6, IL-1 beta, tumor necrosis factor (TNF)-alpha, reactive oxygen species (ROS), and malondialdehyde (MDA) levels than the CON lambs; the detrimental effects of IUGR on colonic proinflammatory cytokine concentrations and redox status were counteracted by dietary Arg or NCG supplementation. Both IUGR + Arg and IUGR + NCG lambs exhibited an elevated protein and mRNA expression of Occludin, Claudin-1, and zonula occludens-1 (ZO-1) compared to the IUGR lambs (p < 0.05). Additionally, the lipopolysaccharide (LPS) concentration was decreased while the levels of acetate, butyrate, and propionate were increased in IUGR + Arg and IUGR + NCG lambs compared to the IUGR lambs (p < 0.05). The relative abundance of Clostridium, Lactobacillus, and Streptococcus was lower in the colonic mucosa of the IUGR lambs than in the CON lambs (p < 0.05) but was restored upon the dietary supplementation of Arg or NCG to the IUGR lambs (p < 0.05). Both Arg and NCG can alleviate colonic barrier injury, oxidative stress (OS), and inflammation by the modulation of colonic microbiota in IUGR-suckling lambs. This work contributes to improving knowledge about the crosstalk among gut microbiota, immunity, OS, and barrier function and emphasizes the potential of Arg or NCG in health enhancement as feed additives in the early life nutrition of ruminants.Öğe Dietary N-carbamylglutamate and L-arginine supplementation improves redox status and suppresses apoptosis in the colon of intrauterine growth-retarded suckling lambs(Keai Publishing Ltd, 2022) Zhang, Hao; Zheng, Yi; Zha, Xia; Liu, Xiaoyun; Ma, Yi; Loor, Juan J.; Elsabagh, MabroukPrevious studies have revealed that dietary N-carbamylglutamate (NCG) or L-arginine (Arg) improves small intestinal integrity and immune function in suckling Hu lambs that have experienced intrauterine growth retardation (IUGR). Whether these nutrients alter redox status and apoptosis in the colon of IUGR lambs is still unknown. This study, therefore, aimed at investigating whether dietary supplementation of Arg or NCG alters colonic redox status, apoptosis and endoplasmic reticulum (ER) stress and the underlying mechanism of these alterations in IUGR suckling Hu lambs. Forty-eight 7-d old Hu lambs, including 12 with normal birth weight (4.25 +/- 0.14 kg) and 36 with IUGR (3.01 +/- 0.12 kg), were assigned to 4 treatment groups (n = 12 each; 6 males and 6 females) for 3 weeks. The treatment groups were control (CON), IUGR, IUGR + Arg and IUGR + NCG. Relative to IUGR lambs, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) content, as well as proliferation index, were higher (P < 0.05) whereas reactive oxygen species (ROS), malondialdehyde (MDA) levels and apoptotic cell numbers were lower (P < 0.05) in colonic tissue for both IUGR + Arg and NCG lambs. Both mRNA and protein levels of C/ EBP homologous protein 10 (CHOP10), B-cell lymphoma/leukaemia 2 (Bcl-2) -associated X protein (Bax), apoptosis antigen 1 (Fas), activating transcription factor 6 (ATF6), caspase 3, and glucose-regulated protein 78 (GRP78) were lower (P < 0.05) while glutathione peroxidase 1 (GPx1), Bcl-2 and catalase (CAT) levels were higher (P < 0.05) in colonic tissue for IUGR + Arg and IUGR + NCG lambs compared with IUGR lambs. Based on our results, dietary NCG or Arg supplementation can improve colonic redox status and suppress apoptosis via death receptor-dependent, mitochondrial and ER stress pathways in IUGR suckling lambs.(c) 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).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 rumen-protected L-arginine or N-carbamylglutamate enhances placental amino acid transport and suppresses angiogenesis and steroid anabolism in underfed pregnant ewes(Keai Publishing Ltd, 2023) Zhang, Hao; Zha, Xia; Zhang, Bei; Zheng, Yi; Liu, Xiaoyun; Elsabagh, Mabrouk; Ma, YiThis study aimed to investigate the effects of dietary supplementation of underfed Hu ewes from d 35 to 110 of gestation with either rumen-protected L-arginine (RP-Arg) or N-carbamylglutamate (NCG) on placental amino acid (AA) transport, angiogenic gene expression, and steroid anabolism. On d 35 of gestation, 32 Hu ewes carrying twin fetuses were randomly divided into four treatment groups, each consisting of eight ewes, and were fed the following diets: A diet providing 100% of NRC's nutrient requirements for pregnant ewes (CON); A diet providing 50% of NRC's nutrient requirements for pregnant ewes (RES); RES diet plus 5 g/d NCG (RES + NCG); or RES diet plus 20 g/d RP-Arg (RES + ARG). On the d 110 of pregnancy, blood samples were taken from the mother, and samples were collected from type A cotyledons (COT; the fetal portions of the placenta). The levels of 17 beta-estradiol and progesterone in the maternal serum and both the capillary area density (CAD) and capillary surface density (CSD) in type A COT were decreased in response to Arg or NCG supplementation when compared to the RES group. The concentrations of arginine, leucine, putrescine and spermidine in type A COT were higher (P < 0.05) in the RES + ARG or RES + NCG group than in the RES group. The mRNA expression levels of inducible nitric oxide synthase (iNOS) and solute carrier family 15, member 1 (SLC15A1) were increased (P < 0.05) while those of progesterone receptor (PGR) and fibroblast growth factor 2 (FGF2) were decreased in type A COT by supplementation with either NCG or RP-Arg compared to the RES group. The results suggest that providing underfed pregnant ewes from d 35 to 110 of gestation with a diet supplemented with NCG or RP-Arg improves placental AA transport, and reduces the expression of angiogenic growth factor genes and steroid anabolism, leading to better fetal development.(c) 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).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 Effects of the maternal gut microbiome and gut-placental axis on melatonin efficacy in alleviating cadmium-induced fetal growth restriction(Academic Press Inc Elsevier Science, 2022) Zhang, Hao; Liu, Xiaoyun; Zheng, Yi; Zha, Xia; Elsabagh, Mabrouk; Zhang, Ying; Ma, YiCadmium (Cd) is a major environmental stressor that induces fetal growth restriction (FGR). Also, changes in gut microbiome diversity-which can be modulated positively by melatonin (Mel) have implications on fetal development and placental functions. Therefore, this study aimed to explore whether the role of Mel in counteracting the Cd-induced FGR by regulating placental barrier injury, endoplasmic reticulum stress (ERS) and mitophagy in pregnant mice is mediated-in part-via the gut microbiota modulations. Pregnant mice were intraperitoneally injected with CdCl2 (5 mg/kg) and Mel (5 mg/kg) once daily, respectively, at the same time from gestational day (GD) 8 to GD18, and then the maternal colon and placental tissues were collected for detection. To investigate the inner relationship between intestinal flora and the protection of Mel on FGR caused by Cd, gut microbiota transplantation (GMT) was carried out from GD0 to GD18 after the removal of intestinal microbiota by antibiotics. Results indicated that Mel relieved barrier injury, ERS and mitophagy in the placenta, and reversed the maternal gut microbiota dysbiosis. The GMT approach suggested a role of intestinal microbiota in placental barrier injury, ERS and mitophagy induced by Cd. Overall, the results highlighted that the intestinal microbiota and gut-placental axis play a central role in the protective effect of Mel against Cd-induced FGR.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 Alleviates Hydrogen Peroxide-Induced Oxidative Damage in Ovine Intestinal Epithelial Cells by Regulating Apoptosis, Mitochondrial Function, and Autophagy(Oxford Univ Press, 2021) Zhang, Hao; Liu, Xiaoyun; Fan, Yaotian; Yu, Yin; Loor, Juan J.; Elsabagh, Mabrouk; Peng, AlongBackground: Previous studies demonstrated that dietary L-arginine (Arg) alters the equilibrium between reactive oxygen species (ROS) generation and biological defenses to resist oxidant-induced toxicity. Whether supplying Arg can protect ovine intestinal epithelial cells (OIECs) from hydrogen peroxide (H2O2)-induced oxidative damage is unclear. Objectives: The current study aimed to examine the effect of Arg on mitophagy, mitochondrial dysfunction, and apoptosis induced by H2O2 in OIECs. Methods: The OIECs were incubated in Arg-free DMEM supplemented with 100 AM Arg (CON) or 350 AM Arg (ARG) alone or with 150 mu M H2O2 (CON + H2O2, ARG + H2O2) for 24 h. Cellular apoptosis, mitochondrial function, autophagy, and the related categories of genes and proteins were determined. All data were analyzed by ANOVA using the general linear model procedures of SAS (SAS Institute) for a 2 x 2 factorial design. Results: Relative to the CON and ARG groups, H2O2 administration resulted in 44.9% and 26.5% lower (P < 0.05) cell viability but 34.7% and 61.8% greater (P < 0.05) ROS concentration in OIECs, respectively. Compared with the CON and CON + H2O2 groups, Arg supplementation led to 40.7% and 28.8% lower (P < 0.05) ROS concentration but 14.9%-49.0% and 29.3%-64.1% greater (P < 0.05) mitochondrial membrane potential, relative mitochondrial DNA content, and complex (I-IV) activity in OIECs, respectively. Compared with the CON and CON + H2O2 groups, Arg supplementation led to 33.9%-53.1% and 22.4%-49.1 % lower (P < 0.05) mRNA abundance of proapoptotic genes, respectively. Relative to the CON and CON + H2O2 groups, Arg supplementation resulted in 33.0%-59.2% and 14.6%-37.7% lower (P< 0.05) abundance of proapoptotic, mitophagy, and cytoplasmic cytochrome c protein, respectively. Conclusions: Supply of Arg protects OIECs against H2O2-induced damage partly by improving mitochondrial function and alleviating cellular apoptosis and autophagy.Öğe 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 L-Arginine inhibits hydrogen peroxide-induced oxidative damage and inflammatory response by regulating antioxidant capacity in ovine intestinal epithelial cells(Taylor & Francis Ltd, 2021) Zhang, Hao; Zhang, Ying; Liu, Xiaoyun; Elsabagh, Mabrouk; Yu, Yin; Peng, Along; Dai, SifaLittle is known how L-arginine (Arg) affects the ovine intestinal epithelial cells (IOECs) redox status induced by hydrogen peroxide (H2O2)(.) This study aimed to examine the impact of Arg on IOECs subjected to H2O2-induced oxidative damage, intestinal barrier injury, and inflammatory response. The IOECs were incubated for 16 h then classified as four groups (n = 6/group) and cultured in corresponding media including (1) control (CON) group, in which IOECs were cultured in Arg-free Dulbecco's modified Eagle's F12 Ham medium (DMEM) containing 100 mu M Arg; (2) Arg group, in which IOECs were cultured in Arg-free DMEM containing 350 mu M Arg; (3) H2O2 group, in which IOECs were cultured in CON group plus 150 mu M H2O2; (4) Arg + H2O2 group, in which IOECs were cultured in Arg group plus150 mu M H2O2. After culturing for 24 h in media, some characteristics of cells in the four groups were measured. Arg administration decreased the H2O2-induced reactive oxygen species (ROS) production compared with the H2O2 group (p < .05). Compared with H2O2, adding Arg to H2O2 increased (p < .05) transepithelial electrical resistance (TEER), but decreased (p < .05) tumour necrosis factor alpha (TNF-alpha) within the IOECs. Compared with H2O2, adding Arg to H(2)O(2-)induced injured IOECs increased (p < .05) glutathione peroxidase 1 (GPx1), zonula occludens-1 (ZO-1), and epithelial nitric oxide (NO) synthase (eNOS) protein levels, and decreased (p < .05) TNF-alpha levels within cells. Arg inhibits H2O2-induced oxidative damage, intestinal barrier injury, and inflammatory response by NO pathway within IOECs.Öğe Maternal N-carbamylglutamate and L-arginine supplementations improve foetal jejunal oxidation resistance, integrity and immune function in malnutrition sheep during pregnancy(Taylor & Francis Ltd, 2024) Zhang, Hao; Zhang, Bei; Wu, Huisi; Zha, Xia; Elsabagh, Mabrouk; Zhao, Jingwen; Wang, HongrongThe present work focused on examining the function of rumen-protected L-arginine (RP-Arg) or N-carbamylglutamate (NCG) in jejunal oxidative resistance, integrity and immune function in the ovine foetal model of intrauterine growth restriction (IUGR). Thirty-two twin-bearing Hu ewes at d 35 of gestation were randomised as 4 treatment groups (n = 8 each): Control (CON), received 100% of the recommended National Research Council (NRC) for pregnancy; Restricted (RES), received 50% of the recommended NRC for pregnancy; RES + ARG, RES ewes added with 20 g/d of RP-Arg; or RES + NCG treatment, RES ewes added with 5 g/d of NCG. Foetal jejunal samples were collected on d 110 of pregnancy and were assayed for biomarkers of oxidative damage, integrity and immune function. The villus height was elevated (p < .05) within the jejunum of the foetuses of RES ewes subjected to dietary NCG or Arg supplementation relative to the RES group. RES + NCG or RES + ARG feeding decreased (p < .05) foetal jejunal tumour necrosis factor-alpha (TNF-alpha) and Interleukin (IL)-6 levels and elevated (p < .05) foetal jejunal superoxide dismutase (SOD) activity (p < .05) in relative to RES group. The Arg/NCG supplementation downregulated (p < .05) expression of gene and proteins associated with inflammatory response (TNF-alpha), upregulated (p < .05) genes and proteins associated with antioxidation (catalase and SOD2) and integrity (claudin-1) relative to those within foetal jejunum of RES group. In conclusion, Arg and NCG supplementation of RES ewes alleviates foetal jejunal oxidative stress, improves integrity, and promotes foetal intestinal development in the ovine foetus with IUGR.Öğe Mechanisms underlying the role of endoplasmic reticulum stress in the placental injury and fetal growth restriction in an ovine gestation model(Bmc, 2023) Zhang, Hao; Zha, Xia; Zheng, Yi; Liu, Xiaoyun; Elsabagh, Mabrouk; Wang, Hongrong; Jiang, HonghuaBackground Exposure to bisphenol A (BPA), an environmental pollutant known for its endocrine-disrupting properties, during gestation has been reported to increase the risk of fetal growth restriction (FGR) in an ovine model of pregnancy. We hypothesized that the FGR results from the BPA-induced insufficiency and barrier dysfunction of the placenta, oxidative stress, inflammatory responses, autophagy and endoplasmic reticulum stress (ERS). However, precise mechanisms underlying the BPA-induced placental dysfunction, and subsequently, FGR, as well as the potential involvement of placental ERS in these complications, remain to be investigated. Methods In vivo experiment, 16 twin-pregnant (from d 40 to 130 of gestation) Hu ewes were randomly distributed into two groups (8 ewes each). One group served as a control and received corn oil once a day, whereas the other group received BPA (5 mg/kg/d as a subcutaneous injection). In vitro study, ovine trophoblast cells (OTCs) were exposed to 4 treatments, 6 replicates each. The OTCs were treated with 400 mu mol/L BPA, 400 mu mol/L BPA + 0.5 mu g/mL tunicamycin ( Tm; ERS activator), 400 mu mol/L BPA + 1 mu mol/L 4-phenyl butyric acid (4-PBA; ERS antagonist) and DMEM/ F12 complete medium (control), for 24 h. Results In vivo experiments, pregnant Hu ewes receiving the BPA from 40 to 130 days of pregnancy experienced a decrease in placental efficiency, progesterone (P4) level and fetal weight, and an increase in placental estrogen (E2) level, together with barrier dysfunctions, OS, inflammatory responses, autophagy and ERS in type A cotyledons. In vitro experiment, the OTCs exposed to BPA for 24 h showed an increase in the E2 level and related protein and gene expressions of autophagy, ERS, pro-apoptosis and inflammatory response, and a decrease in the P4 level and the related protein and gene expressions of antioxidant, anti-apoptosis and barrier function. Moreover, treating the OTCs with Tm aggravated BPA-induced dysfunction of barrier and endocrine (the increased E2 level and decreased P4 level), OS, inflammatory responses, autophagy, and ERS. However, treating the OTCs with 4-PBA reversed the counteracted effects of Tm mentioned above. Conclusions In general, the results reveal that BPA exposure can cause ERS in the ovine placenta and OTCs, and ERS induction might aggravate BPA-induced dysfunction of the placental barrier and endocrine, OS, inflammatory responses, and autophagy. These data offer novel mechanistic insights into whether ERS is involved in BPA-mediated placental dysfunction and fetal development.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] .
