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Wan W, Wei R, Xu B, Cao H, Zhi Y, Guo F, Liu H, Li B, Wu J, Gao Y, Zhang K. Qiwei Jinggan Ling regulates oxidative stress and lipid metabolism in alcoholic liver disease by activating AMPK. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156125. [PMID: 39388920 DOI: 10.1016/j.phymed.2024.156125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/24/2024] [Accepted: 07/09/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Alcoholic liver disease (ALD) is a severe public health concern worldwide and there is still a lack of effective treatments. Qiwei Jinggan Ling (QJL) has protective effects against various liver injuries, but its pharmacological action on ALD has received little attention. PURPOSE To investigate the effect and mechanism of QJL on ALD in vivo and in vitro. METHODS In vivo, an ALD mouse model was established by alcohol combined with a high-fat diet (HFD) and treated with QJL. Biochemical indicators, HE staining, and Oil Red O staining were employed to assess hepatic oxidative stress, steatosis, and alcohol metabolism. RNA sequencing analysis was performed, and the results were verified by qRT-PCR and Western blot to elucidate the hepatoprotective mechanism of QJL. In vitro, HepG2 cells were co-stimulated with NaOA (sodium oleate) and EtOH (ethanol), followed by intervention with Compound C (CC, AMPK inhibitor) and QJL-containing serum. Oil Red O, BODIPY (boron-dipyrromethene), and ROS (reactive oxygen species) staining were applied to validate the efficacy and mechanism of QJL-containing serum. The expression of AMP-activated protein kinase (AMPK) pathway-related factors was analyzed through qRT-PCR and Western blot for additional corroboration. Moreover, the key pharmacodynamic components of QJL were identified by UPLC-MS/MS and molecular docking. RESULTS In vivo, QJL ameliorated liver structural disorders, steatosis, oxidative stress, and impaired alcohol metabolism, as indicated by biochemical indicators and histopathological assays. RNA sequencing analysis revealed that QJL reversed the expression of genes related to alcohol metabolism, fatty acid metabolism, and cholesterol metabolism. The results of qRT-PCR and Western blot were in line with those of RNA sequencing. Furthermore, it was discovered that QJL significantly upregulated the expression of p-AMPK and downregulated the expression of sterol regulatory element binding transcription factor 1 (SREBP-1c). In vitro, biochemical indicators and staining assays demonstrated that QJL-containing serum inhibited lipid accumulation and oxidative stress. The qRT-PCR and Western blot analysis revealed that QJL-containing serum markedly enhanced the expression of p-AMPK and carnitine palmitoyltransferase 1a (Cpt1a), while suppressing the expression of SREBP-1c, fatty acid synthase (Fasn), and acetyl-coenzyme A carboxylase 1 (ACC-1). However, CC inhibited the above pharmacological activities of QJL-containing serum. Additionally, (2S)-Liquiritigenin, Glycyrrhetinate, Isovitexin, Taxifolin, and Yohimbine were proved to be the key active components of QJL. CONCLUSION QJL had the potential to be a therapeutic drug for ALD by activating the AMPK pathway, thereby regulating lipid metabolism and inhibiting oxidative stress.
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Affiliation(s)
- Weimin Wan
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Riming Wei
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Baoling Xu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China; Department of Emergency, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, Guangxi, China
| | - Houkang Cao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Yueping Zhi
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Fengyue Guo
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Haiping Liu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Bo Li
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Jianzhao Wu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Ya Gao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China
| | - Kefeng Zhang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, Guangxi, China.
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Xie Y, Shang S, Luan W, Ma J, Yang H, Qian Q, Wu Z, Li X. Apple Polyphenol Extracts Attenuated Depressive-Like Behaviors of High-Sucrose Diet Feeding Mice by Farnesoid X Receptor-Mediated Modulation of Bile Acid Circulation within the Liver-Gut-Brain Axis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:25118-25134. [PMID: 39475537 DOI: 10.1021/acs.jafc.4c07035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/14/2024]
Abstract
Although the association between high-sugar diets and depression has been verified, few studies have explored the antidepressant mechanisms of apple polyphenol extracts (APE). Therefore, fifty-four C57BL/6 male mice aged 5 weeks were randomly assigned into five groups: the control group with the standard diet (CON), the constant high-sucrose diet group (HSD), the "2 + 5" alternate diet group (A-HSD), and the 500 mg/(kg·bw) APE treatment for the HSD group (APE) and the A-HSD group (A-APE), respectively. The data of hypothalamic-pituitary-adrenal (HPA) axis function and behavioral experiments confirmed the success in the establishment of depression-like mouse models in both HSD and A-HSD groups, which were significantly alleviated after APE treatment. Meanwhile, APE reduced serum levels of corticosterone and adrenocorticotrophic hormone, alleviated histopathological damage of the liver, colon, and brain, respectively, elevated the protein expressions of Occludin, ZO-1, and MUC-2, and decreased Firmicutes/Bacteroidota ratio and Dubosiella abundance with the increased microbiota of Tannerellaceae_unclassified, Muribaculum, and Lachnospiraceae_unclassified. Moreover, APE treatment reduced Farnesoid X receptor (FXR) protein levels along with the increased expressions of CYP7A1 and TGR5, lowered the contents of serum and fecal total bile acids, and modulated fecal BA compositions, particularly glycocholic acid (GCA) and isolithocholic acid (ILCA). Thus, both the constant and alternate high-sucrose diets successfully induced depression-like behaviors in mice, and APE might be a potential nutraceutical to attenuate high-sucrose diet-induced depression by regulating BAs circulation within the liver-gut-brain axis mediated by FXR.
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Affiliation(s)
- Yisha Xie
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
- Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang 318000, China
| | - Siyuan Shang
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Wenxue Luan
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Jieyu Ma
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Hao Yang
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Qingfan Qian
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Zhengli Wu
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Xinli Li
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
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Rad NK, Heydari Z, Tamimi AH, Zahmatkesh E, Shpichka A, Barekat M, Timashev P, Hossein-Khannazer N, Hassan M, Vosough M. Review on Kidney-Liver Crosstalk: Pathophysiology of Their Disorders. CELL JOURNAL 2024; 26:98-111. [PMID: 38459727 PMCID: PMC10924833 DOI: 10.22074/cellj.2023.2007757.1376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 12/25/2023] [Accepted: 12/30/2023] [Indexed: 03/10/2024]
Abstract
Kidney-liver crosstalk plays a crucial role in normal and certain pathological conditions. In pathologic states, both renal-induced liver damage and liver-induced kidney diseases may happen through these kidney-liver interactions. This bidirectional crosstalk takes place through the systemic conditions that mutually influence both the liver and kidneys. Ischemia and reperfusion, cytokine release and pro-inflammatory signaling pathways, metabolic acidosis, oxidative stress, and altered enzyme activity and metabolic pathways establish the base of this interaction between the kidneys and liver. In these concomitant kidney-liver diseases, the survival rates strongly correlate with early intervention and treatment of organ dysfunction. Proper care of a nephrologist and hepatologist and the identification of pathological conditions using biomarkers at early stages are necessary to prevent the complications induced by this complex and potentially vicious cycle. Therefore, understanding the characteristics of this crosstalk is essential for better management. In this review, we discussed the available literature concerning the detrimental effects of kidney failure on liver functions and liver-induced kidney diseases.
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Affiliation(s)
- Niloofar Khoshdel Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Heydari
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, Moscow, Russia
| | - Amir Hossein Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ensieh Zahmatkesh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Anastasia Shpichka
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, Moscow, Russia
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Maryam Barekat
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Peter Timashev
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, Moscow, Russia
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia.
- Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. ,
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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Mezhibovsky E, Tveter KM, Villa-Rodriguez JA, Bacalia K, Kshatriya D, Desai N, Cabales A, Wu Y, Sui K, Duran RM, Bello NT, Roopchand DE. Grape Polyphenols May Prevent High-Fat Diet-Induced Dampening of the Hypothalamic-Pituitary-Adrenal Axis in Male Mice. J Endocr Soc 2023; 7:bvad095. [PMID: 37538101 PMCID: PMC10396072 DOI: 10.1210/jendso/bvad095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Indexed: 08/05/2023] Open
Abstract
Context Chronic high-fat diet (HFD) consumption causes obesity associated with retention of bile acids (BAs) that suppress important regulatory axes, such as the hypothalamic-pituitary-adrenal axis (HPAA). HFD impairs nutrient sensing and energy balance due to a dampening of the HPAA and reduced production and peripheral metabolism of corticosterone (CORT). Objective We assessed whether proanthocyanidin-rich grape polyphenol (GP) extract can prevent HFD-induced energy imbalance and HPAA dysregulation. Methods Male C57BL6/J mice were fed HFD or HFD supplemented with 0.5% w/w GPs (HFD-GP) for 17 weeks. Results GP supplementation reduced body weight gain and liver fat while increasing circadian rhythms of energy expenditure and HPAA-regulating hormones, CORT, leptin, and PYY. GP-induced improvements were accompanied by reduced mRNA levels of Il6, Il1b, and Tnfa in ileal or hepatic tissues and lower cecal abundance of Firmicutes, including known BA metabolizers. GP-supplemented mice had lower concentrations of circulating BAs, including hydrophobic and HPAA-inhibiting BAs, but higher cecal levels of taurine-conjugated BAs antagonistic to farnesoid X receptor (FXR). Compared with HFD-fed mice, GP-supplemented mice had increased mRNA levels of hepatic Cyp7a1 and Cyp27a1, suggesting reduced FXR activation and more BA synthesis. GP-supplemented mice also had reduced hepatic Abcc3 and ileal Ibabp and Ostβ, indicative of less BA transfer into enterocytes and circulation. Relative to HFD-fed mice, CORT and BA metabolizing enzymes (Akr1d1 and Srd5a1) were increased, and Hsd11b1 was decreased in GP supplemented mice. Conclusion GPs may attenuate HFD-induced weight gain by improving hormonal control of the HPAA and inducing a BA profile with less cytotoxicity and HPAA inhibition, but greater FXR antagonism.
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Affiliation(s)
- Esther Mezhibovsky
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Kevin M Tveter
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Jose A Villa-Rodriguez
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Karen Bacalia
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Dushyant Kshatriya
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Nikhil Desai
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Alrick Cabales
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Yue Wu
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Ke Sui
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Rocio M Duran
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Nicholas T Bello
- Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Diana E Roopchand
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
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Ekawaravong S, Treepongkaruna S, Poomthavorn P, Pongratanakul S, Khlairit P, Chanprasertyothin S, Mahachoklertwattana P. Overdiagnosis of adrenal insufficiency in children with biliary atresia. Clin Pediatr Endocrinol 2023; 32:147-154. [PMID: 37362167 PMCID: PMC10288293 DOI: 10.1297/cpe.2022-0083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/03/2023] [Indexed: 06/28/2023] Open
Abstract
Serum cortisol mainly binds to the cortisol-binding globulin (CBG). Children with biliary atresia (BA) may have low serum CBG levels; thus, low serum total cortisol (TC) levels and adrenal insufficiency (AI) may be overdiagnosed. This study aimed to assess adrenal function in children with BA. All the patients underwent adrenocorticotropic hormone (ACTH) stimulation tests. Plasma ACTH, serum TC, and CBG levels were measured at baseline, with additional TC measurements at 30 and 60 min during testing. Free cortisol (FC) index (FCI) and calculated FC (cFC) were also calculated. AI was defined as peak TC <500 nmol/L (<18 μg/dL), peak FCI <12 nmol/mg, or peak cFC <33 nmol/L (<1.2 μg/dL). This study enrolled 71 children with BA. The Median (IQR) age of the patients was 5.5 (1.7-11.4) years. Twenty-five (35%) patients were diagnosed with AI based on the peak TC. In the AI group, the median serum CBG level was significantly lower than that in the non-AI group (481 vs. 533 nmol/L, p = 0.03). Only eight patients (11%) met all three AI criteria (six secondary AI and two primary AI). In conclusion, low serum CBG levels contribute to reduced peak TC and, consequently, overdiagnosing AI. Peak FCI and cFC could help reduce the overdiagnosis of AI.
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Affiliation(s)
- Suparat Ekawaravong
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suporn Treepongkaruna
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Preamrudee Poomthavorn
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sarunyu Pongratanakul
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Patcharin Khlairit
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Pat Mahachoklertwattana
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Xu MY, Guo CC, Li MY, Lou YH, Chen ZR, Liu BW, Lan L. Brain-gut-liver axis: Chronic psychological stress promotes liver injury and fibrosis via gut in rats. Front Cell Infect Microbiol 2022; 12:1040749. [PMID: 36579341 PMCID: PMC9791198 DOI: 10.3389/fcimb.2022.1040749] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Background The effect of chronic psychological stress on hepatitis and liver fibrosis is concerned. However, its mechanism remains unclear. We investigated the effect and mechanism of chronic psychological stress in promoting liver injury and fibrosis through gut. Methods Sixty male SD rats were randomly assigned to 6 groups. Rat models of chronic psychological stress (4 weeks) and liver fibrosis (8 weeks) were established. The diversity of gut microbiota in intestinal feces, permeability of intestinal mucosa, pathologies of intestinal and liver tissues, collagen fibers, protein expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa β (NF-κβ), tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) in liver tissue, liver function and coagulation function in blood and lipopolysaccharide (LPS) in portal vein blood were detected and analyzed. Results The diversities and abundances of gut microbiota were significant differences in rats among each group. The pathological lesions of intestinal and liver tissues, decreased expression of occludin protein in intestinal mucosa, deposition of collagen fibers and increased protein expression of TLR4, MyD88, NF-κβ, TNF-α and IL-1 in liver tissue, increased LPS level in portal vein blood, and abnormalities of liver function and coagulation function, were observed in rats exposed to chronic psychological stress or liver fibrosis. There were significant differences with normal rats. When the dual intervention factors of chronic psychological stress and liver fibrosis were superimposed, the above indicators were further aggravated. Conclusion Chronic psychological stress promotes liver injury and fibrosis, depending on changes in the diversity of gut microbiota and increased intestinal permeability caused by psychological stress, LPS that enters liver and acts on TLR4, and active LPS-TLR4 pathway depend on MyD88. It demonstrates the possibility of existence of brain-gut-liver axis.
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Affiliation(s)
- Meng-Yang Xu
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Henan University, Kaifeng, China
| | - Can-Can Guo
- Department of Infectious Diseases, Jining No.1 People′s Hospital, Jining, China
| | - Meng-Ying Li
- Department of Gastroenterology and Hepatology, Kaifeng Central Hospital, Kaifeng, China
| | - Yu-Han Lou
- Department of Gastroenterology and Hepatology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, China
| | - Zhuo-Ran Chen
- Department of Gastroenterology and Hepatology, Henan No.3 Provincial People’s Hospital, Zhengzhou, China
| | - Bo-Wei Liu
- Department of Gastroenterology and Hepatology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, China
| | - Ling Lan
- Department of Gastroenterology and Hepatology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, China,*Correspondence: Ling Lan,
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Helman TJ, Headrick JP, Vider J, Peart JN, Stapelberg NJC. Sex-specific behavioral, neurobiological, and cardiovascular responses to chronic social stress in mice. J Neurosci Res 2022; 100:2004-2027. [PMID: 36059192 DOI: 10.1002/jnr.25115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 07/19/2022] [Accepted: 07/22/2022] [Indexed: 02/06/2023]
Abstract
Psychosocial stress promotes and links mood and cardiovascular disorders in a sex-specific manner. However, findings in animal models are equivocal, in some cases opposing human dimorphisms. We examined central nervous system (CNS), behavioral, endocrine, cardiac, and hepatic outcomes in male or female C57Bl/6 mice subjected to chronic social stress (56 days of social isolation, with intermittent social confrontation encounters twice daily throughout the final 20 days). Females exhibited distinct physiological and behavioral changes, including relative weight loss, and increases in coronary resistance, hepatic inflammation, and thigmotaxic behavior in the open field. Males evidence reductions in coronary resistance and cardiac ischemic tolerance, with increased circulating and hippocampal monoamine levels and emerging anhedonia. Shared CNS gene responses include reduced hippocampal Maoa and increased Htr1b expression, while unique responses include repression of hypothalamic Ntrk1 and upregulation of cortical Nrf2 and Htr1b in females; and repression of hippocampal Drd1 and hypothalamic Gabra1 and Oprm in males. Declining cardiac stress resistance in males was associated with repression of cardiac leptin levels and metabolic, mitochondrial biogenesis, and anti-inflammatory gene expression. These integrated data reveal distinct biological responses to social stress in males and females, and collectively evidence greater biological disruption or allostatic load in females (consistent with propensities to stress-related mood and cardiovascular disorders in humans). Distinct stress biology, and molecular to organ responses, emphasize the importance of sex-specific mechanisms and potential approaches to stress-dependent disease.
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Affiliation(s)
- Tessa J Helman
- School of Pharmacy and Medical Sciences, Griffith University, Southport, Queensland, Australia
| | - John P Headrick
- School of Pharmacy and Medical Sciences, Griffith University, Southport, Queensland, Australia
| | - Jelena Vider
- School of Pharmacy and Medical Sciences, Griffith University, Southport, Queensland, Australia
| | - Jason N Peart
- School of Pharmacy and Medical Sciences, Griffith University, Southport, Queensland, Australia
| | - Nicolas J C Stapelberg
- Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia.,Gold Coast Hospital and Health Service, Southport, Queensland, Australia
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Salehisedeh N, Parhizkar A, Yaghmaei P, Sabbaghian M. Male Idiopathic Hypogonadotropic Hypogonadism: Serum Insulin-like Growth Factor-1 and Oestradiol Levels. J Hum Reprod Sci 2022; 15:351-356. [PMID: 37033129 PMCID: PMC10077747 DOI: 10.4103/jhrs.jhrs_132_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/27/2022] [Accepted: 11/28/2022] [Indexed: 04/11/2023] Open
Abstract
Background Idiopathic hypogonadotropic hypogonadism (IHH) is a form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone from the hypothalamus. Oestradiol emerged as the main sex steroid in the regulation of the hypothalamic-pituitary-testicular axis, reproductive function and growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in men. Moreover, GH/IGF-1 axis has been suggested to play a role in IHH. Aims This study evaluated serum IGF-1 in IHH men and controls. Furthermore, we evaluated the association between serum total oestradiol (TE2) and IGF-1 levels in patients and controls. Parameters including age, body mass index and fertility history were analysed. Settings and Design This prospective study was conducted at the Royan institute. Materials and Methods In 20 men with IHH and 20 controls, serum IGF-1 levels were estimated using chemiluminescence immunoassay and serum E2 levels were assessed by means of the electrochemiluminescence method. Statistical Analysis Used Kolmogorov-Smirnov test, parametric t-test or the Mann-Whitney and the Pearson correlation coefficient were performed. SPSS version 22 was used for the analysis of data. Results There was a significant decrease in serum IGF-1 levels in IHH patients compared with controls (145.1 ± 8.9 ng/ml vs. 229.6 ± 7.3 ng/ml P < 0.001, respectively). Furthermore, a significant decrease was observed in TE2 levels in IHH male patients (12.3 ± 2.5 pg/ml) compared with controls (31.9 ± 5.3 pg/ml P < 0.001). A positive correlation was observed between serum IGF-1 and TE2 levels in the total number of participants, suggesting that E2 deficiency in IHH cases can explain the lower levels of serum IGF-1. Conclusions These findings suggest that the reduction in IGF-1 levels may be associated with the influence of E2 on the GH/IGF-1 axis, and may confirm the role of the GH/IGF-1 axis in IHH. Further investigations will be required to determine the exact mechanisms by which E2 and IGF-1 affect the reproductive neuroendocrine function.
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Affiliation(s)
- Nastaran Salehisedeh
- Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
- Department of Biology, Science and Research Branch Islamic Azad University, Tehran, Iran
| | - Amir Parhizkar
- Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Parichehreh Yaghmaei
- Department of Biology, Science and Research Branch Islamic Azad University, Tehran, Iran
| | - Marjan Sabbaghian
- Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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Liao M, Zhang R, Wang Y, Mao Z, Wu J, Guo H, Zhang K, Jing Y, Zhang C, Song H, Chen X, Wei G. Corilagin prevents non-alcoholic fatty liver disease via improving lipid metabolism and glucose homeostasis in high fat diet-fed mice. Front Nutr 2022; 9:983450. [PMID: 36071929 PMCID: PMC9443665 DOI: 10.3389/fnut.2022.983450] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 07/27/2022] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has been considered to be one of the most common chronic liver diseases. However, no validated pharmacological therapies have been officially proved in clinic due to its complex pathogenesis. The purpose of this study was to examine the protective effects of Corilagin (referred to Cori) against NAFLD in mice under a high fat diet (HFD) condition. Mice were fed either a normal control diet (NCD) or HFD with or without Cori (5 or 10 mg/kg body weight) for 15 weeks. In our results, Cori treatment significantly attenuated HFD-induced hepatic steatosis, high NAFLD activity score (NAD) and liver injury. Consistently, Cori treatment remarkably alleviated HFD-induced hepatic lipid accumulation (e.g., triglycerides (TG) and total cholesterol (TC) contents in liver), and improved plasma lipid concentrations (e.g., plasma TG, TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c)). Moreover, Cori treatment ameliorated NAFLD associated metabolic disorders such as glucose intolerance and insulin resistance in HFD-fed mice. Additionally, Cori treatment dramatically changed HFD-induced liver gene expression profiles, and identified overlapped differentially expressed genes (DEGs) between NCD vs. HFD group and HFD vs. HCR (high fat diet plus treatment with Cori) group. With these DEGs, we observed a marked enrichment of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which were closely associated with the metabolic balance in liver. Particularly, we found several potential hub proteins against NAFLD development with analyses of protein-protein interaction (PPI) network and qPCR assays. Collectively, our results revealed the important protective effects of Cori against the progress of NAFLD, which was probably mediated through improving dysregulated lipid metabolism and insulin resistance in HFD-fed mice. Additionally, Cori-dependent overlapped DEGs might serve as a featured NAFLD-associated gene expression signature for the diagnosis, treatment, as well as drug discovery and development of NAFLD in the near future.
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Affiliation(s)
- Mingjuan Liao
- Department of Traditional Chinese Medicine, The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Zhang
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongling Wang
- Department of Traditional Chinese Medicine, The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Yongling Wang,
| | - Ziming Mao
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wu
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huaqi Guo
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kaiwen Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Jing
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Caoxu Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huaidong Song
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xia Chen
- Department of Endocrinology, Shanghai Gongli Hospital, Shanghai, China
- Xia Chen,
| | - Gang Wei
- Department of Traditional Chinese Medicine, The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Hangzhou, China
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- *Correspondence: Gang Wei,
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Melino S, Mormone E. On the Interplay Between the Medicine of Hildegard of Bingen and Modern Medicine: The Role of Estrogen Receptor as an Example of Biodynamic Interface for Studying the Chronic Disease's Complexity. Front Neurosci 2022; 16:745138. [PMID: 35712451 PMCID: PMC9196248 DOI: 10.3389/fnins.2022.745138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 04/08/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction Hildegard of Bingen (1098-1179) interpreted the origins of chronic disease highlighting and anticipating, although only in a limited fashion, the importance that complex interactions among numerous genetic, internal milieu and external environmental factors have in determining the disease phenotype. Today, we recognize those factors, capable of mediating the transmission of messages between human body and environment and vice versa, as biodynamic interfaces. Aim We analyzed, in the light of modern scientific evidence, Hildegard of Bingen's medical approach and her original humoral theory in order to identify possible insights included in her medicine that could be referred to in the context of modern evidence-based medicine. In particular, the abbess's humoral theory suggests the identification of biodynamic interfaces with sex hormones and their receptors. Findings We found that the Hildegardian holistic vision of the organism-environment relationship can actually represent a visionary approach to modern endocrinology and that sex hormones, in particular estrogens, could represent an example of a biodynamic interface. Estrogen receptors are found in regions of the brain involved in emotional and cognitive regulation, controlling the molecular mechanism of brain function. Estrogen receptors are involved in the regulation of the hypothalamic-pituitary-adrenal axis and in the epigenetic regulation of responses to physiological, social, and hormonal stimuli. Furthermore, estrogen affects gene methylation on its own and related receptor promoters in discrete regions of the developing brain. This scenario was strikingly perceived by the abbess in the XIIth century, and depicted as a complex interplay among different humors and flegmata that she recognized to be sex specific and environmentally regulated. Viewpoint Considering the function played by hormones, analyzed through the last scientific evidence, and scientific literature on biodynamic interfaces, we could suggest Hildegardian insights and theories as the first attempt to describe the modern holistic, sex-based medicine. Conclusion Hildegard anticipated a concept of pathogenesis that sees a central role for endocrinology in sex-specific disease. Furthermore, estrogens and estrogen receptors could represent a good example of molecular interfaces capable of modulating the interaction between the organism internal milieu and the environmental factors.
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Affiliation(s)
- Sabrina Melino
- Research Unit of Philosophy of Science and Human Development, Faculty of Science and Technology for Humans and the Environment, University Campus Bio-Medico of Rome, Rome, Italy
| | - Elisabetta Mormone
- Fondazione IRCCS Casa Sollievo della Sofferenza, Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies, Foggia, Italy
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11
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Johnson S. In Times of Adversity: A Neuroscience Perspective on Stress, Health, and Implications for Society Post-pandemic. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2022; 95:165-170. [PMID: 35370488 PMCID: PMC8961708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The relationship between chronic stress and chronic disease (including mental illness) is well established: HPA-axis hyperactivity leads to hormonal dysregulation of primary mediators (eg, glucocorticoids, cytokines, etc.), allostatic overload, and neurological degradation, followed by clinical manifestations of disease. Amid the largest public health crisis of the century lay a myriad of challenges pushing people beyond their limit. From experiencing loss of connection or dealing with loss of life to financial shocks of COVID-19 lockdowns or infection by the SARS-CoV-2 virus, stress is at an all-time high, threatening both brain and mental health at scale. Fortunately, there is a way forward: the neuroscience of resilience teaches us that it is possible to resist, recover, and redirect the brain from trauma to re-establish balance in the body and improve well-being. At the same time, health follows a social gradient: adverse and protective psychosocial factors are shaped by wider social and economic determinants of health. This paper argues the neurobiology of stress is not separate from health disparities linked to adverse factors (ie, stress) created by complex social and economic contexts. Therefore, the field of neuroscience is challenged to inform multi-context and multi-level approaches and engage with decision-makers to enact policies and interventions aimed at promoting the resilient element in a wider population health context. Undoubtedly, achieving such a goal for current and future generations to benefit and lead healthier lives requires a heroic effort from all key stakeholders. The cost of willful neglect to resolve these issues is too expensive.
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Affiliation(s)
- Simisola Johnson
- To whom all correspondence should be addressed:
Simisola Johnson, University of Toronto, Toronto, Ontario, Canada;
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12
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Alam S, Lal BB. Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies. World J Hepatol 2022; 14:98-118. [PMID: 35126842 PMCID: PMC8790387 DOI: 10.4254/wjh.v14.i1.98] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/17/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Recent evidence points towards the role of genotype to understand the phenotype, predict the natural course and long term outcome of patients with progressive familial intrahepatic cholestasis (PFIC). Expanded role of the heterozygous transporter defects presenting late needs to be suspected and identified. Treatment of pruritus, nutritional rehabilitation, prevention of fibrosis progression and liver transplantation (LT) in those with end stage liver disease form the crux of the treatment. LT in PFIC has its own unique issues like high rates of intractable diarrhoea, growth failure; steatohepatitis and graft failure in PFIC1 and antibody-mediated bile salt export pump deficiency in PFIC2. Drugs inhibiting apical sodium-dependent bile transporter and adenovirus-associated vector mediated gene therapy hold promise for future.
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Affiliation(s)
- Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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13
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Kim YR, Park BK, Seo CS, Kim NS, Lee MY. Antidepressant and Anxiolytic-Like Effects of the Stem Bark Extract of Fraxinus rhynchophylla Hance and Its Components in a Mouse Model of Depressive-Like Disorder Induced by Reserpine Administration. Front Behav Neurosci 2021; 15:650833. [PMID: 34220460 PMCID: PMC8245701 DOI: 10.3389/fnbeh.2021.650833] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/11/2021] [Indexed: 11/14/2022] Open
Abstract
There is an urgent need to find antidepressants that can be administered for long periods without inducing severe side effects to replace conventional antidepressants that control monoamine levels, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRI). We sought to determine the antidepressant effects of Fraxinus rhynchophylla Hance (F. rhynchophylla Hance, FX) and its components on a reserpine-induced mouse model. One hour after oral administration of FX (30, 50, and 100 mg/kg), esculin (50 mg/kg), esculetin (50 mg/kg), fraxin (50 mg/kg), and fluoxetine (20 mg/kg), reserpine was delivered intraperitoneally to mice. Behavioral experiments were conducted to measure anxiety and depressive-like behaviors after 10 days of administration. FX and its components increased the number of entries into the center of an open field as well as distance traveled within it and decreased immobility duration in the forced swim and tail suspension tests. Reserpine-induced increases in plasma corticosterone concentrations were attenuated by the administration of FX and its components, which were also found to decrease the reserpine-induced enhancement of mRNA levels of interleukin (IL)-12 p40, IL-6, and tumor necrosis factor (TNF)-α, pro-inflammatory cytokines. Finally, the diminished expressions of hippocampal phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) by reserpine were increased by FX and its components. Our results suggest that FX and its components regulate anxiety and depressive-like behaviors through stress hormones, immune regulation, and the activation of neuroprotective mechanisms, further supporting the potential of FX and its components as antidepressants.
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Affiliation(s)
- Yu Ri Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Bo-Kyung Park
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Chang-Seob Seo
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - No Soo Kim
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Mi Young Lee
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
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14
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Bleach R, Sherlock M, O'Reilly MW, McIlroy M. Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers. Front Cell Dev Biol 2021; 9:630503. [PMID: 33816477 PMCID: PMC8012538 DOI: 10.3389/fcell.2021.630503] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/11/2021] [Indexed: 12/13/2022] Open
Abstract
To date, almost all solid malignancies have implicated insulin-like growth factor (IGF) signalling as a driver of tumour growth. However, the remarkable level of crosstalk between sex hormones, the IGF-1 receptor (IGF-1R) and its ligands IGF-1 and 2 in endocrine driven cancers is incompletely understood. Similar to the sex steroids, IGF signalling is essential in normal development as well as growth and tissue homoeostasis, and undergoes a steady decline with advancing age and increasing visceral adiposity. Interestingly, IGF-1 has been found to play a compensatory role for both estrogen receptor (ER) and androgen receptor (AR) by augmenting hormonal responses in the absence of, or where low levels of ligand are present. Furthermore, experimental, and epidemiological evidence supports a role for dysregulated IGF signalling in breast and prostate cancers. Insulin-like growth factor binding protein (IGFBP) molecules can regulate the bioavailability of IGF-1 and are frequently expressed in these hormonally regulated tissues. The link between age-related disease and the role of IGF-1 in the process of ageing and longevity has gained much attention over the last few decades, spurring the development of numerous IGF targeted therapies that have, to date, failed to deliver on their therapeutic potential. This review will provide an overview of the sexually dimorphic nature of IGF signalling in humans and how this is impacted by the reduction in sex steroids in mid-life. It will also explore the latest links with metabolic syndromes, hormonal imbalances associated with ageing and targeting of IGF signalling in endocrine-related tumour growth with an emphasis on post-menopausal breast cancer and the impact of the steroidal milieu.
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Affiliation(s)
- Rachel Bleach
- Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Mark Sherlock
- Academic Department of Endocrinology, Beaumont Hospital and RCSI Medical School, Dublin, Ireland
| | - Michael W O'Reilly
- Academic Department of Endocrinology, Beaumont Hospital and RCSI Medical School, Dublin, Ireland
| | - Marie McIlroy
- Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, Ireland
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15
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Mendoza N, Rivas E, Rodriguez-Roisin R, Garcia T, Bruguera M, Agusti A, Faner R. Liver epigenome changes in patients with hepatopulmonary syndrome: A pilot study. PLoS One 2021; 16:e0245046. [PMID: 33630849 PMCID: PMC7906328 DOI: 10.1371/journal.pone.0245046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 12/22/2020] [Indexed: 11/25/2022] Open
Abstract
The hepatopulmonary syndrome (HPS) is defined by the presence of pulmonary gas exchange abnormalities due to intrapulmonary vascular dilatations in patients with chronic liver disease. Changes in DNA methylation reflect the genomic variation. Since liver transplant (LT) reverts HPS we hypothesized that it may be associated with specific liver epigenetic changes. Thus, the aim of this study was to investigate the role of the liver epigenome in patients with HPS. We extracted DNA from paraffin embedded liver tissue samples from 10 patients with HPS and 10 age-, sex- and MELD (Model for End-stage Liver Disease)-matched controls. DNA methylation was determined using the 850K array (Illumina). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify modules related to defining physiologic characteristics of HPS. Only 12 out of the 20 liver biopsies (7 HPS and 5 controls) had sufficient quality to be analyzed. None of the 802,688 DNA probes analyzed in the case control comparison achieved a significant False Discovery Rate (FDR). WGCNA identified 5 co-methylated gene-modules associated to HPS markers, mainly related to nervous and neuroendocrine system, apoptotic processes, gut bacterial translocation, angiogenesis and vascular remodeling ontologies. To conclude, HPS is associated with nervous/neuroendocrine system and vascular remodeling related liver epigenetic changes.
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Affiliation(s)
- Nuria Mendoza
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Eva Rivas
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Anesthesia, Hospital Clinic, Barcelona, Spain
- Respiratory Institute, Hospital Clinic, Barcelona, Spain
| | - Roberto Rodriguez-Roisin
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Respiratory Institute, Hospital Clinic, Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Tamara Garcia
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Miquel Bruguera
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Alvar Agusti
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Respiratory Institute, Hospital Clinic, Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Rosa Faner
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- * E-mail:
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16
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DHA reduces hypothalamic inflammation and improves central leptin signaling in mice. Life Sci 2020; 257:118036. [PMID: 32622949 DOI: 10.1016/j.lfs.2020.118036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/17/2020] [Accepted: 06/29/2020] [Indexed: 01/09/2023]
Abstract
AIMS Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid β-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.
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17
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Queen NJ, Hassan QN, Cao L. Improvements to Healthspan Through Environmental Enrichment and Lifestyle Interventions: Where Are We Now? Front Neurosci 2020; 14:605. [PMID: 32655354 PMCID: PMC7325954 DOI: 10.3389/fnins.2020.00605] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 05/18/2020] [Indexed: 12/11/2022] Open
Abstract
Environmental enrichment (EE) is an experimental paradigm that is used to explore how a complex, stimulating environment can impact overall health. In laboratory animal experiments, EE housing conditions typically include larger-than-standard cages, abundant bedding, running wheels, mazes, toys, and shelters which are rearranged regularly to further increase stimulation. EE has been shown to improve multiple aspects of health, including but not limited to metabolism, learning and cognition, anxiety and depression, and immunocompetence. Recent advances in lifespan have led some researchers to consider aging as a risk factor for disease. As such, there is a pressing need to understand the processes by which healthspan can be increased. The natural and predictable changes during aging can be reversed or decreased through EE and its underlying mechanisms. Here, we review the use of EE in laboratory animals to understand mechanisms involved in aging, and comment on relative areas of strength and weakness in the current literature. We additionally address current efforts toward applying EE-like lifestyle interventions to human health to extend healthspan. Although increasing lifespan is a clear goal of medical research, improving the quality of this added time also deserves significant attention. Despite hurdles in translating experimental results toward clinical application, we argue there is great potential in using features of EE toward improving human healthy life expectancy or healthspan, especially in the context of increased global longevity.
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Affiliation(s)
- Nicholas J. Queen
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH, United States
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Quais N. Hassan
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH, United States
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
- Medical Scientist Training Program, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Lei Cao
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH, United States
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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18
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Zhao L, Ayu A, Pan W, Huang ZQ. The effect of hormones of the hypothalamic-pituitary-target gland axes in a kidney-yang deficiency syndrome model. WORLD JOURNAL OF TRADITIONAL CHINESE MEDICINE 2020. [DOI: 10.4103/wjtcm.wjtcm_38_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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19
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Vitiello L, De Bernardo M, Guercio Nuzio S, Mandato C, Rosa N, Vajro P. Pediatric liver diseases and ocular changes: What hepatologists and ophthalmologists should know and share with each other. Dig Liver Dis 2020; 52:1-8. [PMID: 31843253 DOI: 10.1016/j.dld.2019.11.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/29/2019] [Accepted: 11/17/2019] [Indexed: 12/11/2022]
Abstract
Several rare pediatric liver disorders are accompanied by ophthalmic signs whose awareness and early identification may be of value in confirming/accelerating their diagnosis. Many of these signs are asymptomatic and can only be detected with an ophthalmological examination. Corneal signs are described in patients with Wilson's disease, Alagille's syndrome and some liver storage diseases. Cataract plays an important role to diagnose galactosemia. Retinal involvement is seen in some peroxisomal disorders (e.g. Zellweger's syndrome), in mucopolysaccharidoses (pigmentary retinopathy), and in Niemann-Pick disease (macular cherry red spot). In mucopolysaccharidoses optic nerve can be involved as optic atrophy secondary to pigmentary retinopathy or to chronic papilledema. Children with neonatal cholestasis due to hypopituitarism may present septo-optic dysplasia. Several infectious agents have an ophthalmological/hepatic involvement in the fetal life and/or thereafter. Some mitochondrial liver diseases, such as Pearson's syndrome, present pigmentary retinopathy and a chronic progressive external ophthalmoplegia. Finally, some drugs while protecting the liver may damage the ocular system as seen with long-term glucocorticoids and Nitisinone administration. This review provides a synopsis of those conditions that hepatologists and ophthalmologists should share among themselves to better take care of patients. Synoptic tables are presented to facilitate the mutual understanding of the issues.
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Affiliation(s)
- Livio Vitiello
- Eye Clinic, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Baronissi, Italy
| | - Maddalena De Bernardo
- Eye Clinic, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Baronissi, Italy
| | - Salvatore Guercio Nuzio
- Pediatric Clinic, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Baronissi, Italy
| | - Claudia Mandato
- Department of Pediatrics, Children's Hospital Santobono-Pausilipon, Naples, Italy
| | - Nicola Rosa
- Eye Clinic, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Baronissi, Italy
| | - Pietro Vajro
- Pediatric Clinic, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Baronissi, Italy.
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20
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Gerber LH, Weinstein AA, Mehta R, Younossi ZM. Importance of fatigue and its measurement in chronic liver disease. World J Gastroenterol 2019; 25:3669-3683. [PMID: 31391765 PMCID: PMC6676553 DOI: 10.3748/wjg.v25.i28.3669] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 06/12/2019] [Accepted: 06/23/2019] [Indexed: 02/06/2023] Open
Abstract
The mechanisms of fatigue in the group of people with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are protean. The liver is central in the pathogenesis of fatigue because it uniquely regulates much of the storage, release and production of substrate for energy generation. It is exquisitely sensitive to the feedback controlling the uptake and release of these energy generation substrates. Metabolic contributors to fatigue, beginning with the uptake of substrate from the gut, the passage through the portal system to hepatic storage and release of energy to target organs (muscle and brain) are central to understanding fatigue in patients with chronic liver disease. Inflammation either causing or resulting from chronic liver disease contributes to fatigue, although inflammation has not been demonstrated to be causal. It is this unique combination of factors, the nexus of metabolic abnormality and the inflammatory burden of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis that creates pathways to different types of fatigue. Many use the terms central and peripheral fatigue. Central fatigue is characterized by a lack of self-motivation and can manifest both in physical and mental activities. Peripheral fatigue is classically manifested by neuromuscular dysfunction and muscle weakness. Therefore, the distinction is often seen as a difference between intention (central fatigue) versus ability (peripheral fatigue). New approaches to measuring fatigue include the use of objective measures as well as patient reported outcomes. These measures have improved the precision with which we are able to describe fatigue. The measures of fatigue severity and its impact on usual daily routines in this population have also been improved, and they are more generally accepted as reliable and sensitive. Several approaches to evaluating fatigue and developing endpoints for treatment have relied of biosignatures associated with fatigue. These have been used singly or in combination and include: physical performance measures, cognitive performance measures, mood/behavioral measures, brain imaging and serological measures. Treatment with non-pharmacological agents have been shown to be effective in symptom reduction, whereas pharmacological agents have not been shown effective.
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Affiliation(s)
- Lynn H Gerber
- Department of Medicine, Beatty Center for Liver and Obesity Research, Inova Health System, Falls Church, VA 22042, United States
| | - Ali A Weinstein
- Center for the Study of Chronic Illness and Disability, George Mason University, Fairfax, VA 22030, United States
| | - Rohini Mehta
- Beatty Center for Liver and Obesity Research, Inova Health System, Falls Church, VA 22042, United States
| | - Zobair M Younossi
- Department of Medicine, Beatty Center for Liver and Obesity Research, Inova Health System, Falls Church, VA 22042, United States
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