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Alsaedi AQ, Nader MA, El-Kashef DH, Abdelmageed ME. Mangiferin mitigates dexamethasone-induced insulin resistance in rats: insight into vascular dysfunction and hepatic steatosis. Front Pharmacol 2025; 16:1572758. [PMID: 40406487 PMCID: PMC12095298 DOI: 10.3389/fphar.2025.1572758] [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: 02/07/2025] [Accepted: 04/08/2025] [Indexed: 05/26/2025] Open
Abstract
Aim Insulin resistance (IR) is a hazard to human health in which peripheral insulin-target organs, like the liver, become less sensitive to normal levels of insulin. Dexamethasone (DEX)-induced IR is a distinct model of IR. Hence, the present study investigates the efficacy of mangiferin (Mang) in the reversal of DEX-induced IR in the livers and aortas of rats. Main methods Rats were randomly assigned into six groups: control (CTRL), Mang, DEX, and three pretreated groups (received Mang 25 mg/kg, 50 mg/kg, or 100 mg/kg, orally for 14 days, with DEX (1 mg/kg) injected from day 8 to day 14). On day 15, serum, liver, and aorta tissues were obtained and examined using biochemical, histological, and immunohistochemical assessments. Key findings Mang administration attenuated DEX-induced IR, evidenced by decreased oral glucose tolerance test (OGTT) and fasting serum insulin levels, in addition to improving the DEX-induced hepatic and aortic histopathological alterations. Additionally, Mang attenuated DEX-induced alterations in liver function parameters and improved serum lipid profiles, oxidative stress, and antioxidant biomarkers. Mang also markedly increased hepatic and aortic levels of insulin receptor substrate 1 (IRS1), protein kinase B (AKT), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-gamma (PPAR-γ) levels. Mang reduced hepatic and aortic tumor necrosis factor-alpha (TNF-α), forkhead box protein O1 (FOXO-1), hepatic NOD-like receptor family pyrin domain-containing 3 (NLRP3), phosphoenol pyruvate carboxy kinase (PEPCK), and glucose 6-phosphatase (G6Pase). Mang elevated hepatic glycogen synthase kinase3 (GSK3α) and glycogen synthase (GS2) levels. Furthermore, Mang ameliorated aortic expression levels of endothelin-1 (ET-1), vascular cell adhesion molecule-1 (VCAM), c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and vascular endothelial growth factor (VEGF) and increased endothelial nitric oxide synthase (eNOS) and prostacyclin (PGI2) levels. Conclusion Mang administration could confer hepato- and vasculo-protective activity via its hypolipidemic, hepatoprotective, anti-inflammatory, and antioxidant efficacy.
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Affiliation(s)
- Abdullah Q. Alsaedi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Quality and Output Control, Branch of Ministry of Health, Madinah, Saudi Arabia
| | - Manar A. Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Egypt
| | - Dalia H. El-Kashef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Marwa E. Abdelmageed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Egypt
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Maj M, Hernik K, Tyszkiewicz K, Owe-Larsson M, Sztokfisz-Ignasiak A, Malejczyk J, Janiuk I. A complex role of chromogranin A and its peptides in inflammation, autoimmunity, and infections. Front Immunol 2025; 16:1567874. [PMID: 40370467 PMCID: PMC12074958 DOI: 10.3389/fimmu.2025.1567874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 04/09/2025] [Indexed: 05/16/2025] Open
Abstract
Chromogranin A (CgA), mostly known as a nonspecific neuroendocrine tumor marker, was the first glycoprotein from the granin family characterized as a prohormone for various bioactive peptides including vasostatin I/II (VS-I, VS-II), catestatin (CST), chromofungin (CHR), pancreastatin (PST), WE-14, and others. CgA and its derivatives present various functions, often antagonistic, in maintaining body homeostasis and influencing the immune system. This review aims to summarize the not fully understood role of CgA and its derivatives in inflammation, autoimmunity, and infections. CgA seems to be involved in the complex pathophysiology of cardiovascular disorders, neurodegenerative diseases, and other conditions where immune system dysfunction plays a role in the onset and development of the disease (e.g. systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), or rheumatoid arthritis (RA)). However, the direct immunomodulatory role of CgA is difficult to assess since many of its activities may be linked with its peptides. CST and VS-I are considered anti-inflammatory molecules, due to M2 macrophage polarization stimulation and downregulation of certain proinflammatory cytokines. Conversely, PST is reported to stimulate proinflammatory M1 macrophage polarization and Th1 lymphocyte response. Thus, the final effects of CgA in inflammation may depend on its cleavage pattern. Additionally, peptides like CST, VS-I, or CHR exert direct antimicrobial/antifungal activities. CgA, WE-14, and other less-known CgA-derived peptides have also been reported to trigger autoimmune responses, highly studied in type 1 diabetes mellitus. Overall, CgA and its derivatives have an interesting but complex role in immunity, however, their specific roles require further research.
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Affiliation(s)
- Maciej Maj
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Karolina Hernik
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Kaja Tyszkiewicz
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Maja Owe-Larsson
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Alicja Sztokfisz-Ignasiak
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Malejczyk
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
- Institute of Health Sciences, Faculty of Medical and Health Sciences, University of Siedlce, Siedlce, Poland
| | - Izabela Janiuk
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
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Yadav S, Dadge S, Garg R, Goand UK, Agarwal A, Chauhan D, Gayen JR. Pancreastatin inhibitor PSTi8 improves ovarian health in Letrozole-HFD induced PCOS rats by ameliorating metabolic and reproductive parameters. Steroids 2025; 214:109558. [PMID: 39742935 DOI: 10.1016/j.steroids.2024.109558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/24/2024] [Accepted: 12/28/2024] [Indexed: 01/04/2025]
Abstract
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder associated with insulin resistance (IR) and hyperandrogenism. IR plays a crucial role in the etiology of PCOS. An insulin-sensitizing agent like metformin is most commonly used as an off-label drug for the treatment of PCOS. PSTi8 (a pancreastatin inhibitor) is known as a promising therapeutic insulin-sensitizing agent for the treatment of IR in metabolic diseases. Thus, this study evaluates the insulin-sensitizing effects of PSTi8 compared to metformin on IR, hyperandrogenism, ovarian, and metabolic dysfunction in a PCOS model. To induce PCOS, rats were administered letrozole at a dose of 2 mg/kg via oral administration and fed a 60 % high-fat diet. Metformin and PSTi8 lowered serum insulin, testosterone, luteinizing hormone (LH) levels, and the LH/follicle-stimulating hormone ratio in the blood serum and improved steroidogenic gene expression in the PCOS ovaries. Both treatments increased the levels of sex hormone-binding globulin and estrogen hormone. Metformin and PSTi8 restore ovarian and uterine histomorphometry and improve the estrous cycle in PCOS rats. Metformin and PSTi8 treatments also improve blood glucose level and increase insulin sensitivity, inflammation, reactive oxygen species accumulation, lipid parameters, body weight, and fat mass in PCOS rats. This study revealed that PSTi8 is as helpful as metformin in decreasing hyperandrogenism by improving insulin sensitivity, free testosterone level and restoring disturbed reproductive and metabolic parameters in PCOS rats. PSTi8 has potential to serve as a therapeutic molecule for preventing IR induced by a western diet in PCOS.
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Affiliation(s)
- Shubhi Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Shailesh Dadge
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Richa Garg
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Umesh K Goand
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Arun Agarwal
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Divya Chauhan
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India
| | - Jiaur R Gayen
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziaba 201002, India.
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4
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Gupta M, Rumman M, Singh B, Mahdi AA, Pandey S. Berberine ameliorates glucocorticoid-induced hyperglycemia: an in vitro and in vivo study. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1647-1658. [PMID: 37704773 DOI: 10.1007/s00210-023-02703-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/30/2023] [Indexed: 09/15/2023]
Abstract
Berberine (BBR), a bioactive compound isolated from Coptidis Rhizoma, possesses diverse pharmacological activities including anti-bacterial, anti-inflammatory, antitumor, hypolipidemic, and anti-diabetic. However, its role as an anti-diabetic agent in animal models of dexamethasone (Dex)-induced diabetes remains unknown. Studies have shown that natural compounds including aloe, caper, cinnamon, cocoa, green and black tea, and turmeric can be used for treating Type 2 diabetes mellitus (DM). Compared to conventional drugs, natural compounds have less side effects and are easily available. Herein, we studied the anti-diabetic effects of BBR in a mice model of Dex-induced diabetes. HepG2 cell line was used for glucose release and glycogen synthesis studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. For animal studies, mice were treated with Dex (2 mg/kg, i.m.) for 30 days and effect of BBR at the doses 100, 200, and 500 mg/kg (p.o.) was analyzed. Glucose, insulin, and pyruvate tests were performed for evaluating the development of the diabetic model. Echo MRI was performed to assess the fat mass. Further, to elucidate the mechanism of action of BBR, mRNA expression of genes regulating gluconeogenesis, glucose uptake, and glycolysis was analyzed. In vitro BBR had no impact on cell viability up to a concentration of 50 μM. Moreover, BBR suppressed the hepatic glucose release and improved glucose tolerance in HepG2 cells. In vivo, BBR improved glucose homeostasis in diabetic mice as evidenced by enhanced glucose clearance, increased glycolysis, elevated glucose uptake, and decreased gluconeogenesis. Further, Dex treatment increased the total fat mass in mice, which was ameliorated by BBR treatment. BBR improves glucose tolerance by increasing glucose clearance, inhibiting hepatic glucose release, and decreasing obesity. Thus, BBR may become a potential therapeutic agent for treating glucocorticoid-induced diabetes and obesity in the future.
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Affiliation(s)
- Mrinal Gupta
- Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Mohammad Rumman
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Babita Singh
- Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Shivani Pandey
- Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India.
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Mooradian AD, Haas MJ. Cardioprotective antihyperglycemic drugs ameliorate endoplasmic reticulum stress. Am J Physiol Cell Physiol 2024; 326:C89-C94. [PMID: 38009197 DOI: 10.1152/ajpcell.00470.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/30/2023] [Accepted: 11/17/2023] [Indexed: 11/28/2023]
Abstract
Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension, and cigarette smoking cause ER stress whereas currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary antihyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors, and thiazolidinediones, metformin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors are the only antihyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease.
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Affiliation(s)
- Arshag D Mooradian
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, United States
| | - Michael J Haas
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, United States
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Goand UK, Patel I, Verma S, Yadav S, Maity D, Singh N, Vishwakarma S, Rathaur S, Garg R, Gayen JR. Immunometabolic impact of pancreastatin inhibitor PSTi8 in MCD induced mouse model of oxidative stress and steatohepatitis. Cytokine 2023; 171:156354. [PMID: 37672864 DOI: 10.1016/j.cyto.2023.156354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023]
Abstract
AIM Pancreastatin, a dysglycemic hormone that encourages inflammation and steatosis in a variety of metabolic disorder animal models. The purpose of this study is to determine the effect of the pancreastatin inhibitor PSTi8 on immunometabolic changes in the liver of MCD-induced NASH mice. MAIN METHODS Methionine and choline-deficient (MCD) diet was used for the development of NASH. Liver enzymes like SGOT, SGPT, and ALP and lipid profiles were also performed in the serum. Further, immunophenotyping study was performed in the liver through flowcytometer. Subsequently, Hematoxylin and Eosin, Picro Sirius Red and Masson's Trichrome staining were done to check the liver morphology and collagen staining, respectively. Inflammatory cytokines were measured through ELISA and gene expression through RT-PCR. The expression of α-SMA was examined using immunohistochemistry and immunofluorescence staining. KEY FINDINGS PSTi8 inhibited the expression of lipogenic genes in the liver and attenuated bad cholesterol, SGOT, SGPT, and ALP in the serum. PSTi8 improved the liver morphology and attenuated collagen deposition. Subsequently, PSTi8 attenuated inflammatory M1-macrophages, CD8+T, CD4+T cells and increased anti-inflammatory M2 macrophages, T-reg and eosinophil populations in the liver. It also attenuated the expression of pro-inflammatory genes like Mcp1, Tnfα, and Il6. Apart from this, PSTi8 attenuated the oxidative stress marker, like ROS, and MDA and fibrosis marker α-SMA in the liver. It also decreased the apoptosis and ROS and MDA level in the liver. SIGNIFICANCE Overall, these compressive studies revealed that PSTi8 exhibited beneficial effect on the liver of MCD-induced NASH mice by attenuating inflammation and oxidative stress.
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Affiliation(s)
- Umesh K Goand
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Inklisan Patel
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shubhi Yadav
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Debalina Maity
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Naveen Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sachin Vishwakarma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shivam Rathaur
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Iyer DR, Venkatraman J, Tanguy E, Vitale N, Mahapatra NR. Chromogranin A and its derived peptides: potential regulators of cholesterol homeostasis. Cell Mol Life Sci 2023; 80:271. [PMID: 37642733 PMCID: PMC11072126 DOI: 10.1007/s00018-023-04908-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/31/2023]
Abstract
Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by its proteolytic cleavage and by their wide anatomical distribution. These peptides are emerging as novel modulators of cardiometabolic diseases that are often linked to high blood cholesterol levels. However, their impact on cholesterol homeostasis is poorly understood. The dynamic nature of cholesterol and its multitudinous roles in almost every aspect of normal body function makes it an integral component of metabolic physiology. A tightly regulated coordination of cholesterol homeostasis is imperative for proper functioning of cellular and metabolic processes. The deregulation of cholesterol levels can result in several pathophysiological states. Although studies till date suggest regulatory roles for CHGA and its derived peptides on cholesterol levels, the mechanisms by which this is achieved still remain unclear. This review aims to aggregate and consolidate the available evidence linking CHGA with cholesterol homeostasis in health and disease. In addition, we also look at common molecular regulatory factors (viz., transcription factors and microRNAs) which could govern the expression of CHGA and genes involved in cholesterol homeostasis under basal and pathological conditions. In order to gain further insights into the pathways mediating cholesterol regulation by CHGA/its derived peptides, a few prospective signaling pathways are explored, which could act as primers for future studies.
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Affiliation(s)
- Dhanya R Iyer
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Janani Venkatraman
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Emeline Tanguy
- Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 and Université de Strasbourg, 5 Rue Blaise Pascal, 67000, Strasbourg, France
| | - Nicolas Vitale
- Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 and Université de Strasbourg, 5 Rue Blaise Pascal, 67000, Strasbourg, France.
| | - Nitish R Mahapatra
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India.
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Garg R, Katekar R, Parwez S, Agarwal A, Sahu S, Dadge S, Verma S, Goand UK, Siddiqi MI, Gayen JR. Pancreastatin inhibitor PSTi8 ameliorates streptozotocin-induced diabetes by suppressing hepatic glucose production. Eur J Pharmacol 2023; 944:175559. [PMID: 36764353 DOI: 10.1016/j.ejphar.2023.175559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/11/2023]
Abstract
Elevated plasma glucose concentration, as a consequence of excessive hepatic glucose production, plays a pivotal role in the development of diabetes. A chromogranin A-derived diabetogenic peptide Pancreastatin (PST) enhances hepatic glucose output leading to diabetes. Therefore, here we probed the role of PSTi8, a PST inhibitor in ameliorating diabetes by investigating the effect of high glucose (HG) or PST on glucose metabolism. Further, we also explored the action mechanism of the underlying anti-hyperglycemic effect of PSTi8. PSTi8 treatment rescue cultured L6 and HepG2 cells from HG and PST-induced insulin resistance, respectively. It also enhances insulin receptor kinase activity by interacting with the insulin receptor and enhancing GLUT4 translocation and glucose uptake. Thus, our in-silico and in-vitro data support the PST-dependent and independent activity of PSTi8. Additionally, PSTi8 treatment in streptozotocin-induced diabetic rats improved glucose tolerance by lowering blood glucose and plasma PST levels. Concomitantly, the treated animals exhibited reduced hepatic glucose production accompanied by downregulation of hepatic gluconeogenic genes PEPCK and G6Pase. PSTi8-treated rats also exhibited enhanced hepatic glycogen in line with reduced plasma glucagon concentrations. Consistently, improved plasma insulin levels in PSTi8-treated rats enhanced skeletal muscle glucose disposal via enhanced P-Akt expression. In summary, these findings suggest PSTi8 has anti-hyperglycemic properties with enhanced skeletal muscle glucose disposal and reduced hepatic gluconeogenesis both PST dependent as well as independent.
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Affiliation(s)
- Richa Garg
- Pharmaceutics & Pharmacokinetics, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shahid Parwez
- Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Arun Agarwal
- Pharmaceutics & Pharmacokinetics, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | | | | | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Umesh K Goand
- Pharmaceutics & Pharmacokinetics, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Mohammad Imran Siddiqi
- Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics, India; Pharmacology Division, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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9
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Huang H, Guo S, Chen Y, Liu Y, Jin J, Liang Y, Fan L, Xiang R. Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK-IDH2 pathway. MedComm (Beijing) 2023; 4:e226. [PMID: 36925557 PMCID: PMC10013133 DOI: 10.1002/mco2.226] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 01/28/2023] [Accepted: 02/01/2023] [Indexed: 03/16/2023] Open
Abstract
Reticulon 3 (RTN3), an endoplasmic reticulum protein, is crucial in neurodegenerative and kidney diseases. However, the role of RTN3 in liver tissues has not been described. Here, we employed public datasets, patients, and several animal models to explore the role of RTN3 in nonalcoholic fatty liver disease (NAFLD). The underlying mechanisms were studied in primary hepatocytes and L02 cells in vitro. We found an increased expression of RTN3 in NAFLD patients, high-fat diet mice, and oxidized low-density lipoprotein-treated L02 cells. The RTN3 transgenic mice exhibited the phenotypes of fatty liver and lipid accumulation. Single-cell RNA sequencing analysis indicated that increased RTN3 might induce mitochondrial dysfunction. We further showed this in primary hepatocytes, the L02 cell line, and the Caenorhabditis elegans strain. Mechanistically, RTN3 regulated these events through its interactions with glucose-regulated protein 78 (GRP78), which further inhibited the adenosine 5 monophosphate-activated protein kinase (AMPK)-isocitrate dehydrogenase 2 (IDH2) pathway. In the end, knockout of RTN3 relieved fatty liver and mitochondrial dysfunction. Our study indicated that RTN3 was important in NAFLD and lipid catabolism and that an increase in RTN3 in the liver might be a risk factor for nonalcoholic steatohepatitis and NAFLD.
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Affiliation(s)
- Hao Huang
- Department of NephrologyXiangya HospitalCentral South UniversityChangshaChina
- Department of Cell BiologySchool of Life SciencesCentral South UniversityChangshaChina
- Hunan Key Laboratory of Animal Models for Human DiseasesSchool of Life SciencesCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
| | - Shuai Guo
- Department of Cell BiologySchool of Life SciencesCentral South UniversityChangshaChina
| | - Ya‐Qin Chen
- Department of CardiologySecond Xiangya HospitalCentral South UniversityChangshaChina
| | - Yu‐Xing Liu
- Department of Cell BiologySchool of Life SciencesCentral South UniversityChangshaChina
| | - Jie‐Yuan Jin
- Department of Cell BiologySchool of Life SciencesCentral South UniversityChangshaChina
| | - Yun Liang
- Department of Cell BiologySchool of Life SciencesCentral South UniversityChangshaChina
| | - Liang‐Liang Fan
- Department of NephrologyXiangya HospitalCentral South UniversityChangshaChina
- Department of Cell BiologySchool of Life SciencesCentral South UniversityChangshaChina
- Hunan Key Laboratory of Animal Models for Human DiseasesSchool of Life SciencesCentral South UniversityChangshaChina
| | - Rong Xiang
- Department of NephrologyXiangya HospitalCentral South UniversityChangshaChina
- Department of Cell BiologySchool of Life SciencesCentral South UniversityChangshaChina
- Hunan Key Laboratory of Animal Models for Human DiseasesSchool of Life SciencesCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
- Department of CardiologySecond Xiangya HospitalCentral South UniversityChangshaChina
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10
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Garg R, Agarwal A, Katekar R, Dadge S, Yadav S, Gayen JR. Chromogranin A-derived peptides pancreastatin and catestatin: emerging therapeutic target for diabetes. Amino Acids 2023:10.1007/s00726-023-03252-x. [PMID: 36914766 DOI: 10.1007/s00726-023-03252-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 02/16/2023] [Indexed: 03/16/2023]
Abstract
Chromogranin A (ChgA) is an acidic pro-protein found in neuroendocrine organs, pheochromocytoma chromaffin granules, and tumor cells. Proteolytic processing of ChgA gives rise to an array of biologically active peptides such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin, which have diverse roles in regulating cardiovascular functions and metabolism, as well as inflammation. Intricate tissue-specific role of ChgA-derived peptide activity in preclinical rodent models of metabolic syndrome reveals complex effects on carbohydrate and lipid metabolism. Indeed, ChgA-derived peptides, PST and CST, play a pivotal role in metabolic syndrome such as obesity, insulin resistance, and diabetes mellitus. Additionally, supplementation of specific peptide in ChgA-KO mice have an opposing effect on physiological functions, such as PST supplementation reduces insulin sensitivity and enhances inflammatory response. In contrast, CST supplementation enhances insulin sensitivity and reduces inflammatory response. In this review, we focus on the tissue-specific role of PST and CST as therapeutic targets in regulating carbohydrate and lipid metabolism, along with the associated risk factors.
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Affiliation(s)
- Richa Garg
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Arun Agarwal
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Roshan Katekar
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shailesh Dadge
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shubhi Yadav
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Jiaur R Gayen
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
- Pharmacology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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11
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Immuno-metabolic effect of pancreastatin inhibitor PSTi8 in diet induced obese mice: In vitro and in vivo findings. Life Sci 2023; 316:121415. [PMID: 36690247 DOI: 10.1016/j.lfs.2023.121415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/12/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023]
Abstract
AIMS Pancreastatin (PST), an anti-insulin peptide derived from chromogranin A. Its levels increase in cases of obesity, which contributes to adipose tissue inflammation and insulin resistance. This study aims to investigate the immunometabolic effect of PST inhibitor (PSTi8) against PST by using in vitro and in vivo finding. MAIN METHODS 3T3-L1 cells were differentiated with or without PSTi8, and Oil Red O staining was performed. J774A.1 cells were used for macrophage polarization study. The diet-induced obesity and T2DM model was developed in C57BL/6 mice through high-fat diet for 8 weeks. Alzet osmotic pumps were filled with PSTi8 (release rate: 2 mg/kg/day) and implanted in mice for eight weeks. Further, insulin and glucose tolerance tests were performed. Liver and eWAT sections were stained with hematoxylin and eosin. FACS was used to measure mitochondrial ROS and membrane potential, while Oroboros O2k was used to measure oxygen consumption rate. Immunocytochemistry and qRT-PCR were done for protein and gene expression, respectively. KEY FINDINGS PSTi8 inhibited the expression of lipolytic genes and proteins in 3T3-L1 adipocytes. PSTi8 improved the inulin sensitivity, lipid profile, MMP, and OCR levels in the 3T3-L1 adipocyte and eWAT. It also increased the M1 to M2 macrophage polarization in J77A.1 cells and eWAT. Further, PSTi8 attenuated inflammatory CD4+ T, CD8+ T cells and increased the anti-inflammatory T-reg and eosinophil populations in the eWAT. It also reduced the expression of pro-inflammatory genes like Mcp1, Tnfα, and Il-6. SIGNIFICANCE Collectively, PSTi8 exerted its beneficial effect on adipose tissue inflammation and restored energy expenditure against diet-induced obesity.
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12
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Singh S, Sharma A, Ahmad S, Guru B, Gulzar F, Kumar P, Ahmad I, Tamrakar AK. Convergence of Fructose-Induced NLRP3 Activation with Oxidative Stress and ER Stress Leading to Hepatic Steatosis. Inflammation 2023; 46:217-233. [PMID: 35941320 DOI: 10.1007/s10753-022-01727-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/18/2022] [Accepted: 08/03/2022] [Indexed: 11/05/2022]
Abstract
High fructose flux enhances hepatocellular triglyceride accumulation (hepatic steatosis), which is a prime trigger in the emergence of hepatic ailments. Nevertheless, the pathophysiology underlying the process is not completely understood. Emerging evidences have revealed the inputs from multiple cues including inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in the development of hepatic steatosis. Here, we substantiated the role of NLRP3 inflammasome and its convergence with oxidative and ER stress leading to hepatic steatosis under high fructose diet feeding. Male SD rats were fed on 60% high fructose diet (HFrD) for 10 weeks and treated with antioxidant quercetin or NLRP3 inflammasome inhibitor glyburide during the last 6 weeks, followed by metabolic characterization and analysis of hepatic parameters. HFrD-induced hepatic steatosis was associated with the activation of NLRP3 inflammasome, pro-inflammatory response, oxidative, and ER stress in liver. Treatment with quercetin abrogated HFrD-induced oxidative stress, along with attenuation of NLRP3 activation in the liver. On the other hand, inhibition of NLRP3 signaling by glyburide suppressed HFrD-induced oxidative and ER stress. Both glyburide or quercetin treatment significantly attenuated hepatic steatosis, associated with mitigated expression of the lipogenic markers in liver. Our findings verified the association of NLRP3 inflammasome with oxidative and ER stress in fructose-induced lipogenic response and indicate that in addition to be a target of oxidative/ER stress, NLRP3 can act as a trigger for oxidative/ER stress to activate a vicious cycle where these cues act in a complex manner to propagate inflammatory response, leading to hepatic steatosis.
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Affiliation(s)
- Sushmita Singh
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Aditya Sharma
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Shadab Ahmad
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Bhavimani Guru
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Farah Gulzar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Pawan Kumar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Ishbal Ahmad
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Akhilesh K Tamrakar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Sec-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. .,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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13
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Goand UK, Verma S, Gupta AP, Garg R, Dadge S, Gayen JR. Pancreastatin inhibitor PSTi8 balances energy homeostasis by attenuating adipose tissue inflammation in high fat diet fed mice. Peptides 2023; 159:170902. [PMID: 36375661 DOI: 10.1016/j.peptides.2022.170902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 11/03/2022] [Accepted: 11/05/2022] [Indexed: 11/13/2022]
Abstract
Pancreastatin (PST) is an endogenous bioactive peptide. PST is generated from chromogranin A (Chga) protein which is released by chromaffin and neuroendocrine cells. PST exhibits diabetogenic effect by antagonizing the action of insulin in adipocytes. The level of PST rises during obesity, resulting in persistent low-grade inflammation in adipocytes. Pancreastatin inhibitor 8 (PSTi8), which is developed by modification of PST sequence which antagonizes the action of PST. In this study, we investigated the immunometabolic effect of PSTi8 in the diet-induced obesity (DIO) model in C57BL/6 mice. Here we found PSTi8 decreased the body weight gain, fat mass and increased the lean mass in (DIO) mice. It also showed reduction of adipocyte hypertrophy in eWAT and lipid accumulation in liver of DIO mice. Immunoprofiling of stromal vascular fraction isolated from eWAT of PTSi8 treated mice showed increased anti-inflammatory M2 macrophages, Eosinophil, T-regulatory cells and reduced pro-inflammatory M1 macrophages, CD4 and CD8 T cell population. Apart from this, PSTi8 also improved the mitochondrial function by decreasing reactive oxygen species and increasing mitochondrial membrane potential, NADPH/NADP ratio and citrate synthase activity in eWAT of DIO mice. It also increased the protein expression of pAMPK, pAKT, Arginase -1 and decreased the expression of MHC-II and iNOS in eWAT of DIO mice. In conclusion, PSTi8 exerted its beneficial effect on restoring energy expenditure by reducing adipose tissue inflammation.
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Affiliation(s)
- Umesh K Goand
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Anand P Gupta
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shailesh Dadge
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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14
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Yang K, Li J, Tao L. Purine metabolism in the development of osteoporosis. Biomed Pharmacother 2022; 155:113784. [DOI: 10.1016/j.biopha.2022.113784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
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Chen Y, Li J, Zhang M, Yang W, Qin W, Zheng Q, Chu Y, Wu Y, Wu D, Yuan X. 11β-HSD1 Inhibitor Alleviates Non-Alcoholic Fatty Liver Disease by Activating the AMPK/SIRT1 Signaling Pathway. Nutrients 2022; 14:nu14112358. [PMID: 35684158 PMCID: PMC9182913 DOI: 10.3390/nu14112358] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 05/30/2022] [Accepted: 06/05/2022] [Indexed: 12/10/2022] Open
Abstract
We investigated the effect of an 11β-HSD1 inhibitor (H8) on hepatic steatosis and its mechanism of action. Although H8, a curcumin derivative, has been shown to alleviate insulin resistance, its effect on non-alcoholic fatty liver disease (NAFLD) remains unknown. Rats were fed a high-fat diet (HFD) for 8 weeks, intraperitoneally injected with streptozotocin (STZ) to induce NAFLD, and, then, treated with H8 (3 or 6 mg/kg/day) or curcumin (6 mg/kg/day) for 4 weeks, to evaluate the effects of H8 on NAFLD. H8 significantly alleviated HFD+STZ-induced lipid accumulation, fibrosis, and inflammation as well as improved liver function. Moreover, 11β-HSD1 overexpression was established by transfecting animals and HepG2 cells with lentivirus, carrying the 11β-HSD1 gene, to confirm that H8 improved NAFLD, by reducing 11β-HSD1. An AMP-activated protein kinase (AMPK) inhibitor (Compound C, 10 μM for 2 h) was used to confirm that H8 increased AMPK, by inhibiting 11β-HSD1, thereby restoring lipid metabolic homeostasis. A silencing-related enzyme 1 (SIRT1) inhibitor (EX572, 10 μM for 4 h) and a SIRT1 activator (SRT1720, 1 μM for 4 h) were used to confirm that H8 exerted anti-inflammatory effects, by elevating SIRT1 expression. Our findings demonstrate that H8 alleviates hepatic steatosis, by inhibiting 11β-HSD1, which activates the AMPK/SIRT1 signaling pathway.
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16
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Müller SG, Heck SO, Marques LS, Zborowski VA, Nogueira CW. p-Chloro-diphenyl diselenide modulates Nrf2/Keap1 signaling and counteracts renal oxidative stress in mice exposed to dexamethasone repeated administrations. Can J Physiol Pharmacol 2022; 100:500-508. [PMID: 35395160 DOI: 10.1139/cjpp-2021-0573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Dexamethasone is a synthetic glucocorticoid that has been associated with oxidative stress in central and peripheral tissues. p-Chloro-diphenyl diselenide (p-ClPhSe)2 is an antioxidant organoselenium compound. The present study aimed to evaluate whether Nrf2/Keap-1 signaling contributes to the (p-ClPhSe)2 antioxidant effects in the kidney of mice exposed to dexamethasone. Adult Swiss mice received dexamethasone (i.p) at a dose of 2 mg/kg or its vehicle for 21 days. After, mice were treated with (p-ClPhSe)2 (i.g)(1, 5, or 10 mg/kg) for 7 days. Samples of kidneys were collected for biochemical assays. (p-ClPhSe)2 at dose of 1 mg/kg reversed the renal reactive oxygen species (ROS) and carbonyl protein (CP) levels increased by dexamethasone. (p-ClPhSe)2 at doses of 5 and 10 mg/kg was effective against the increase of TBARS (thiobarbituric acid reactive substances), ROS, and CP as well as the decrease of δ-aminolevulinic acid dehydratase (δ-ALA-D) activity and non-protein SH (NPSH) levels induced by dexamethasone. At 5 mg/kg, (p-ClPhSe)2 reduced the renal levels of 4-OH-2-HNE and HO-1 as well as modulated the Nrf2/Keap-1 signaling in mice exposed to dexamethasone. The present findings revealed that (p-ClPhSe)2 antioxidant effects were associated with the modulation of Nrf2/Keap-1 signaling pathway in the kidney of mice exposed to dexamethasone.
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Affiliation(s)
| | - Suelen Osório Heck
- Universidade Federal de Santa Maria Centro de Ciencias Naturais e Exatas, 425921, Santa Maria, Rio Grande do Sul, Brazil;
| | - Luiza Souza Marques
- Universidade Federal de Santa Maria Centro de Ciencias Naturais e Exatas, 425921, Santa Maria, Rio Grande do Sul, Brazil;
| | - Vanessa Angonesi Zborowski
- Universidade Federal de Santa Maria Centro de Ciencias Naturais e Exatas, 425921, Santa Maria, Rio Grande do Sul, Brazil;
| | - Cristina Wayne Nogueira
- Universidade Federal de Santa Maria, 28118, Av. Roraima 1000, Santa Maria, Brazil, 97105-900;
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17
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Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, Hashemi M, Hushmandi K, Ashrafizadeh M, Zarrabi A, Ertas YN, Mirzaei S, Samarghandian S. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomed Pharmacother 2022; 146:112563. [PMID: 35062059 DOI: 10.1016/j.biopha.2021.112563] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is considered as a main challenge in both developing and developed countries, as lifestyle has changed and its management seems to be vital. Type I and type II diabetes are the main kinds and they result in hyperglycemia in patients and related complications. The gene expression alteration can lead to development of DM and related complications. The AMP-activated protein kinase (AMPK) is an energy sensor with aberrant expression in various diseases including cancer, cardiovascular diseases and DM. The present review focuses on understanding AMPK role in DM. Inducing AMPK signaling promotes glucose in DM that is of importance for ameliorating hyperglycemia. Further investigation reveals the role of AMPK signaling in enhancing insulin sensitivity for treatment of diabetic patients. Furthermore, AMPK upregulation inhibits stress and cell death in β cells that is of importance for preventing type I diabetes development. The clinical studies on diabetic patients have shown the role of AMPK signaling in improving diabetic complications such as brain disorders. Furthermore, AMPK can improve neuropathy, nephropathy, liver diseases and reproductive alterations occurring during DM. For exerting such protective impacts, AMPK signaling interacts with other molecular pathways such as PGC-1α, PI3K/Akt, NOX4 and NF-κB among others. Therefore, providing therapeutics based on AMPK targeting can be beneficial for amelioration of DM.
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Affiliation(s)
- Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Danial Hashemi
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Golestan, Iran
| | - Shima Mohammadi
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Farima Fakhri
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonosis, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer 34396, Istanbul, Turkey
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri 38039, Turkey
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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18
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Valicherla GR, Katekar RA, Dadge S, Riyazuddin M, Syed AA, Singh SK, Husain A, Wahajuddin M, Gayen JR. Evaluation of the Pharmacokinetics of the Pancreastatin Inhibitor PSTi8 Peptide in Rats: Integration of In Vitro and In Vivo Findings. Molecules 2022; 27:molecules27020339. [PMID: 35056659 PMCID: PMC8780964 DOI: 10.3390/molecules27020339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 11/16/2022] Open
Abstract
PSTi8 is a pancreastatin inhibitory peptide that is effective in the treatment of diabetic models. This study investigates the pharmacokinetic (PK) properties of PSTi8 in Sprague Dawley rats, for the first time. In vitro and in vivo PK studies were performed to evaluate the solubility, stability in plasma and liver microsomes, plasma protein binding, blood-plasma partitioning, bioavailability, dose proportionality, and gender difference in PK. Samples were analyzed using the validated LC-MS/MS method. The solubility of PSTi8 was found to be 9.30 and 25.75 mg/mL in simulated gastric and intestinal fluids, respectively. The protein binding of PSTi8 was estimated as >69% in rat plasma. PSTi8 showed high stability in rat plasma and liver microsomes and the blood-plasma partitioning was >2. The bioavailability of PSTi8 after intraperitoneal and subcutaneous administration was found to be 95.00 ± 12.15 and 78.47 ± 17.72%, respectively, in rats. PSTi8 showed non-linear PK in dose proportionality studies, and has no gender difference in the PK behavior in rats. The high bioavailability of PSTi8 can be due to high water solubility and plasma protein binding, low clearance and volume of distribution. Our in vitro and in vivo findings support the development of PSTi8 as an antidiabetic agent.
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Affiliation(s)
- Guru R. Valicherla
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Roshan A. Katekar
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Shailesh Dadge
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
| | - Mohammed Riyazuddin
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
| | - Anees A. Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Sandeep K. Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Muhammad Wahajuddin
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Jiaur R. Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; (G.R.V.); (R.A.K.); (S.D.); (M.R.); (A.A.S.); (S.K.S.); (A.H.); (M.W.)
- Academy of Scientific and Innovative Research, Ghaziabad 201002, India
- Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
- Correspondence: ; Tel.: +91-522-2772450 (ext. 4845)
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19
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Antenatal corticosteroid therapy modulates hepatic AMPK phosphorylation and maternal lipid metabolism in early lactating rats. Biomed Pharmacother 2021; 144:112355. [PMID: 34794232 DOI: 10.1016/j.biopha.2021.112355] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/07/2021] [Accepted: 10/19/2021] [Indexed: 02/01/2023] Open
Abstract
Antenatal corticosteroid therapy is used to reduce neonatal mortality in preterm infants but it is currently unknown whether this intervention affects lipid metabolism at the peripartum. This study aimed to evaluate if antenatal corticosteroid therapy in pregnant rats and women affects lipid metabolism during early lactation. We evaluated women at risk of preterm delivery that received corticosteroid therapy (CASE) and women that were not exposed to corticosteroid and were not at risk of preterm delivery (CONTROL). Samples were collected to measure serum and milk triacylglycerol (TAG) three days after delivery. Rats were treated with dexamethasone (DEX) between the 15th and the 20th days of pregnancy. Samples were collected at different days after delivery (L3, L8 and L14). TAG was measured in serum, liver and mammary gland (MG). TAG appearance rates were measured after tyloxapol injection and gavage with olive oil. We also evaluated the expression of key genes related to lipid metabolism in the liver and in the MG and hepatic phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). CASE volunteers delivered earlier than CONTROL but presented unaltered milk and serum TAG concentrations. Early lactating DEX rats exhibited increased TAG in serum, MG and milk. No changes in CD36 and LPL were detected in the MG and liver. Early lactating DEX rats displayed increased TAG appearance rate and reduced hepatic AMPK/ACC phosphorylation. Our data revealed that antenatal corticosteroid therapy reduces hepatic AMPK/ACC phosphorylation during early lactation that reflects in increased TAG concentration in serum, MG and milk.
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Albracht-Schulte K, Wilson S, Johnson P, Pahlavani M, Ramalingam L, Goonapienuwala B, Kalupahana NS, Festuccia WT, Scoggin S, Kahathuduwa CN, Moustaid-Moussa N. Sex-Dependent Effects of Eicosapentaenoic Acid on Hepatic Steatosis in UCP1 Knockout Mice. Biomedicines 2021; 9:1549. [PMID: 34829779 PMCID: PMC8615653 DOI: 10.3390/biomedicines9111549] [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] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 11/26/2022] Open
Abstract
Visceral obesity may be a driving factor in nonalcoholic fatty liver disease (NAFLD) development. Previous studies have shown that the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), ameliorates obesity in high-fat (HF) fed male, C57Bl/6 mice at thermoneutral conditions, independent of uncoupling protein 1 (UCP1). Our goals herein were to investigate sex-dependent mechanisms of EPA in the livers of wild type (WT) and UCP1 knockout (KO) male and female mice fed a HF diet (45% kcal fat; WT-HF, KO-HF) with or without supplementation of 36 g/kg EPA (WT-EPA, KO-EPA). KO significantly increased body weight in males, with no significant reductions with EPA in the WT or KO groups. In females, there were no significant differences in body weight among KO groups and no effects of EPA. In males, liver TGs were significantly higher in the KO-HF group and reduced with EPA, which was not observed in females. Accordingly, gene and protein markers of mitochondrial oxidation, peroxisomal biogenesis and oxidation, as well as metabolic futile cycles were sex-dependently impacted by KO and EPA supplementation. These findings suggest a genotypic difference in response to dietary EPA supplementation on the livers of male and female mice with diet-induced obesity and housed at thermoneutrality.
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Affiliation(s)
- Kembra Albracht-Schulte
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
| | - Savanna Wilson
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
| | - Paige Johnson
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
| | - Mandana Pahlavani
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
| | - Latha Ramalingam
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
| | - Bimba Goonapienuwala
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
| | - Nishan S. Kalupahana
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
- Department of Physiology, Faculty of Medicine, University of Peradeniya, Peradeniya 20400, Sri Lanka
| | - William T. Festuccia
- Department of Physiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
| | - Shane Scoggin
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
| | - Chanaka N. Kahathuduwa
- Texas Tech University Health Sciences Center, Department of Laboratory Sciences and Primary Care, Lubbock, TX 79430, USA;
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.A.-S.); (S.W.); (P.J.); (M.P.); (L.R.); (B.G.); (N.S.K.); (S.S.)
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Xanthohumol alleviates T2DM-induced liver steatosis and fibrosis by mediating the NRF2/RAGE/NF-κB signaling pathway. Future Med Chem 2021; 13:2069-2081. [PMID: 34551612 DOI: 10.4155/fmc-2021-0241] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Hyperglycemia-associated advanced glycation end products (AGEs) and the receptor for AGE (RAGE) contribute to nonalcoholic fatty liver disease (NAFLD). Xanthohumol (XH) exhibits protective activities against liver diseases. Aim: To investigate the effects of XH on Type II diabetes mellitus (T2DM)-induced liver steatosis and fibrosis. Methods: NAFLD rat models were duplicated. Biomolecular markers were detected. Quantitative real-time PCR (RT-PCR) and western blot were used to detect mRNA and protein expression. Immunofluorescence assays were employed to identify the subcellular locations. Results: XH significantly ameliorated hyperglycemia and hyperlipidemia in rats. XH attenuated the expression of RAGE and NF-κB signaling. XH significantly alleviated inflammation and oxidation by upregulating NRF2 expression. Knockdown of NRF2 blocked XH protection in hepatocytes. Conclusion: XH protected against T2DM-induced liver steatosis and fibrosis by mediating NRF2/AGE/RAGE/NF-κB signaling.
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Herold Z, Doleschall M, Somogyi A. Role and function of granin proteins in diabetes mellitus. World J Diabetes 2021; 12:1081-1092. [PMID: 34326956 PMCID: PMC8311481 DOI: 10.4239/wjd.v12.i7.1081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
The granin glycoprotein family consists of nine acidic proteins; chromogranin A (CgA), chromogranin B (CgB), and secretogranin II-VIII. They are produced by a wide range of neuronal, neuroendocrine, and endocrine cells throughout the human body. Their major intracellular function is to sort peptides and proteins into secretory granules, but their cleavage products also take part in the extracellular regulation of diverse biological processes. The contribution of granins to carbohydrate metabolism and diabetes mellitus is a recent research area. CgA is associated with glucose homeostasis and the progression of type 1 diabetes. WE-14, CgA10-19, and CgA43-52 are peptide derivates of CgA, and act as CD4+ or CD8+ autoantigens in type 1 diabetes, whereas pancreastatin (PST) and catestatin have regulatory effects in carbohydrate metabolism. Furthermore, PST is related to gestational and type 2 diabetes. CgB has a crucial role in physiological insulin secretion. Secretogranins II and III have angiogenic activity in diabetic retinopathy (DR), and are novel targets in recent DR studies. Ongoing studies are beginning to investigate the potential use of granin derivatives as drugs to treat diabetes based on the divergent relationships between granins and different types of diabetes.
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Affiliation(s)
- Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest 1083, Hungary
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary
| | - Marton Doleschall
- Molecular Medicine Research Group, Eotvos Lorand Research Network and Semmelweis University, Budapest 1089, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary
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23
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The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease. Int J Mol Sci 2021; 22:ijms22116118. [PMID: 34204153 PMCID: PMC8201018 DOI: 10.3390/ijms22116118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023] Open
Abstract
Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.
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Singh P, Reza MI, Syed AA, Husain A, Katekar R, Gayen JR. Pancreastatin mediated regulation of UCP-1 and energy expenditure in high fructose fed perimenopausal rats. Life Sci 2021; 279:119677. [PMID: 34081990 DOI: 10.1016/j.lfs.2021.119677] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/19/2021] [Accepted: 05/27/2021] [Indexed: 12/13/2022]
Abstract
AIMS Pancreastatin (PST) is a crucial bioactive peptide derived from chromogranin A (CHGA) proprotein that exhibits an anti-insulin effect on adipocytes. Herein, we investigated the effects of PST on brown adipose tissues (BAT) and white adipose tissue (WAT) in connection with uncoupling protein-1 (UCP-1) regulated energy expenditure in high fructose diet (HFrD) fed and vinylcyclohexenediepoxide (VCD) induced perimenopausal rats. MATERIAL AND METHODS We administered VCD in rats for 17 consecutive days and fed HFrd for 12 weeks. After 12 weeks estradiol and progesterone levels were detected. Furthermore, detection of glucose tolerance, insulin sensitivity, and body composition revealed impaired glucose homeostasis and enhanced PST levels. Effects of enhanced PST on UCP-1 level in BAT and WAT of perimenopausal rats were further investigated. KEY FINDINGS Reduced serum estradiol, progesterone, and attenuated insulin response confirmed perimenopausal model development. Furthermore, enhanced PST serum level and its increased expression in BAT and WAT downregulated the UCP-1 expression. Subsequently, impaired ATP level, NADP/NADPH ratio, citrate synthase activity, enhanced mitochondrial reactive oxygen species (ROS) generation and perturbed mitochondrial membrane potential, further exacerbated mitochondrial dysfunction, cellular ROS production, and promoted apoptosis. Interestingly, PST inhibition by PST inhibitor peptide-8 (PSTi8) displayed a favorable impact on UCP-1 and energy expenditure. SIGNIFICANCE The aforementioned outcomes indicated the substantial role of PST in altering the UCP-1 expression and associated energy homeostasis. Hence our results corroborate novel avenues to unravel the quest deciphering PST's role in energy homeostasis and its association with perimenopause.
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Affiliation(s)
- Pragati Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Mohammad Irshad Reza
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Anees A Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Reza MI, Syed AA, Kumariya S, Singh P, Husain A, Gayen JR. Pancreastatin induces islet amyloid peptide aggregation in the pancreas, liver, and skeletal muscle: An implication for type 2 diabetes. Int J Biol Macromol 2021; 182:760-771. [PMID: 33862075 DOI: 10.1016/j.ijbiomac.2021.04.064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/23/2021] [Accepted: 04/10/2021] [Indexed: 12/13/2022]
Abstract
Recent findings suggest that the accumulation of misfolded aggregates of islet amyloid peptide (IAPP) plays an essential role in pancreatic damage and type 2 diabetes (T2D). Pancreastatin (PST), a chromogranin derived peptide, instigates insulin resistance (IR) and promotes T2D. Here, we aimed to investigate whether PST induces IAPP aggregation in the pancreas, liver, and skeletal muscles. Foremost, we unraveled kinetics of fibril formation by ThT kinetic assay, ANS binding, turbidity, and far UV-CD. Subsequently, we checked the microarchitecture of fibril by TEM. Moreover, the PST action on IAPP expression was examined by immunocytochemistry, immunohistochemistry, western blotting, and real-time PCR. The outcome of spectral analysis and TEM demonstrated the fibril formation in the alone IAPP group but not in the alone PST; however, PST with IAPP produced stronger fibril. Moreover, PST was found to stimulate IAPP aggregation and expression more prominently in PANC1 and HepG2 cells, and pancreas and liver tissues than in L6 and skeletal muscle. Subsequently, pancreastatin inhibitor manifested a decline in the extent of the IAPP fibril formation and its expression. To conclude, PST upon combination induces the aggregation of IAPP in the pancreas, liver, and skeletal muscle, which may have the potential to generate IR and cause T2D.
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Affiliation(s)
- Mohammad Irshad Reza
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Anees A Syed
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Pragati Singh
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India.
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26
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Chan C, Foster ST, Chan KG, Cacace MJ, Ladd SL, Sandum CT, Wright PT, Volmert B, Yang W, Aguirre A, Li W, Wright NT. Repositioned Drugs for COVID-19-the Impact on Multiple Organs. SN COMPREHENSIVE CLINICAL MEDICINE 2021; 3:1484-1501. [PMID: 33898925 PMCID: PMC8057921 DOI: 10.1007/s42399-021-00874-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/22/2021] [Indexed: 02/02/2023]
Abstract
This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs. Supplementary Information The online version contains supplementary material available at 10.1007/s42399-021-00874-8.
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Affiliation(s)
- Christina Chan
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA ,Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI USA ,Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Sean T. Foster
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Kayla G. Chan
- Integrative Neuroscience Program, Binghamton University, Binghamton, NY USA
| | - Matthew J. Cacace
- Department of Mechanical Engineering, The Pennsylvania State University, University Park, PA USA
| | - Shay L. Ladd
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Caleb T. Sandum
- Department of Chemical Engineering and Materials Sciences, Michigan State University, 428 S. Shaw Lane, Room 2100 EB, East Lansing, MI 48824 USA
| | - Paul T. Wright
- Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA USA
| | - Brett Volmert
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Weiyang Yang
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA ,Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Aitor Aguirre
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI USA ,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA
| | - Wen Li
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI USA ,Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI USA
| | - Neil T. Wright
- Department of Mechanical Engineering, Michigan State University, East Lansing, MI USA
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Liao Q, Zhou Y, Xia L, Cao D. Lipid Metabolism and Immune Checkpoints. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1316:191-211. [PMID: 33740251 DOI: 10.1007/978-981-33-6785-2_12] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Immune checkpoints are essential for the regulation of immune cell functions. Although the abrogation of immunosurveillance of tumor cells is known, the regulators of immune checkpoints are not clear. Lipid metabolism is one of the important metabolic activities in organisms. In lipid metabolism, a large number of metabolites produced can regulate the gene expression and activation of immune checkpoints through various pathways. In addition, increasing evidence has shown that lipid metabolism leads to transient generation or accumulation of toxic lipids that result in endoplasmic reticulum (ER) stress and then regulate the transcriptional and posttranscriptional modifications of immune checkpoints, including transcription, protein folding, phosphorylation, palmitoylation, etc. More importantly, the lipid metabolism can also affect exosome transportation of checkpoints and the degradation of checkpoints by affecting ubiquitination and lysosomal trafficking. In this chapter, we mainly empathize on the roles of lipid metabolism in the regulation of immune checkpoints, such as gene expression, activation, and degradation.
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Affiliation(s)
- Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Deliang Cao
- Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, USA
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28
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Singh P, Reza MI, Syed AA, Garg R, Husain A, Katekar R, Goand UK, Riyazuddin M, Gupta AP, Gayen JR. PSTi8 with metformin ameliorates perimenopause induced steatohepatitis associated ER stress by regulating SIRT-1/SREBP-1c axis. Heliyon 2020; 6:e05826. [PMID: 33426334 PMCID: PMC7779780 DOI: 10.1016/j.heliyon.2020.e05826] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/23/2020] [Accepted: 12/18/2020] [Indexed: 12/12/2022] Open
Abstract
Aims Hepatic steatosis in women confronting menopause is the manifestation of substantial fructose consumption and forms a positive feedback loop to develop endoplasmic reticulum (ER) stress. Previously pancreastatin inhibitor peptide-8 (PSTi8) and Metformin (Met) combination effectively ameliorated hepatic lipid accumulation in high fructose diet (HFrD) fed diabetic mice models at reduced doses. Moreover, SIRT-1 plays a crucial role in the regulation of SREBP-1c. Hence we hypothesized that Met and PSTi8 in combination (at therapeutic lower doses) could mitigate hepatic steatosis linked ER stress by activating SIRT-1 and precluding SREBP-1c in HFrD fed 4-Vinylcyclohexenediepoxide (HVCD) induced perimenopausal rats. Main methods HVCD rats were fed HFrD for 12 weeks, accompanied by 14 days of treatment with Met, PSTi8, and combination. We confirmed model establishment by estrus cycle study, estradiol level, and intraperitoneal glucose tolerance test. Plasma lipid profile and liver function were determined. Also, mRNA and protein expressions were examined. Moreover, distribution of SIRT-1 and SREBP-1c was detected in HepG2 cells by immunofluorescence staining. Key findings HVCD group displayed augmented insulin resistance (IR), lipogenesis, and ER stress in the liver. Combination therapy improved the estrus cyclicity, estradiol, and lipid profile of HVCD rats. Met and PSTi8 combination reduced hepatic SREBP-1c and triggered SIRT-1 expression in high fructose-induced insulin-resistant HepG2 cells; consequently, combination therapy attenuated ER stress. Significance Succinctly, present research promotes impetus concerning the remedial impact of Met with PSTi8 at lower therapeutic doses to ameliorate hepatic IR, steatosis, and associated ER stress by revamping the SIRT-1/SREBP-1c axis in perimenopausal rats.
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Affiliation(s)
- Pragati Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Mohammad Irshad Reza
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Anees A Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Umesh K Goand
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Mohammed Riyazuddin
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Anand P Gupta
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.,Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Chicoric Acid Ameliorates Nonalcoholic Fatty Liver Disease via the AMPK/Nrf2/NF κB Signaling Pathway and Restores Gut Microbiota in High-Fat-Diet-Fed Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9734560. [PMID: 33204402 PMCID: PMC7657699 DOI: 10.1155/2020/9734560] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/29/2020] [Accepted: 10/08/2020] [Indexed: 02/08/2023]
Abstract
This study examines the effects of chicoric acid (CA) on nonalcoholic fatty liver disease (NAFLD) in high-fat-diet- (HFD-) fed C57BL/6 mice. CA treatment decreased body weight and white adipose weight, mitigated hyperglycemia and dyslipidemia, and reduced hepatic steatosis in HFD-fed mice. Moreover, CA treatment reversed HFD-induced oxidative stress and inflammation both systemically and locally in the liver, evidenced by the decreased serum malondialdehyde (MDA) abundance, increased serum superoxide dismutase (SOD) activity, lowered in situ reactive oxygen species (ROS) in the liver, decreased serum and hepatic inflammatory cytokine levels, and reduced hepatic inflammatory cell infiltration in HFD-fed mice. In addition, CA significantly reduced lipid accumulation and oxidative stress in palmitic acid- (PA-) treated HepG2 cells. In particular, we identified AMPK as an activator of Nrf2 and an inactivator of NFκB. CA upregulated AMPK phosphorylation, the nuclear protein level of Nrf2, and downregulated NFκB protein level both in HFD mice and PA-treated HepG2 cells. Notably, AMPK inhibitor compound C blocked the regulation of Nrf2 and NFκB, as well as ROS overproduction mediated by CA in PA-treated HepG2 cells, while AMPK activator AICAR mimicked the effects of CA. Similarly, Nrf2 inhibitor ML385 partly blocked the regulation of antioxidative genes and ROS overproduction by CA in PA-treated HepG2 cells. Interestingly, high-throughput pyrosequencing of 16S rRNA suggested that CA could increase Firmicutes-to-Bacteroidetes ratio and modify gut microbial composition towards a healthier microbial profile. In summary, CA plays a preventative role in the amelioration of oxidative stress and inflammation via the AMPK/Nrf2/NFκB signaling pathway and shapes gut microbiota in HFD-induced NAFLD.
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Feng Z, Pang L, Chen S, Pang X, Huang Y, Qiao Q, Wang Y, Vonglorkham S, Huang Q, Lin X, Wei J. Didymin ameliorates dexamethasone-induced non-alcoholic fatty liver disease by inhibiting TLR4/NF-κB and PI3K/Akt pathways in C57BL/6J mice. Int Immunopharmacol 2020; 88:107003. [DOI: 10.1016/j.intimp.2020.107003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/04/2020] [Accepted: 09/09/2020] [Indexed: 01/23/2023]
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Singh P, Garg R, Goand UK, Riyazuddin M, Reza MI, Syed AA, Gupta AP, Husain A, Gayen JR. Combination of Pancreastatin inhibitor PSTi8 with metformin inhibits Fetuin-A in type 2 diabetic mice. Heliyon 2020; 6:e05133. [PMID: 33033766 PMCID: PMC7533370 DOI: 10.1016/j.heliyon.2020.e05133] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 09/20/2020] [Accepted: 09/28/2020] [Indexed: 01/03/2023] Open
Abstract
In the preceding study, we delineated that high-fat diet (HFD) consumption in mice increases the circulatory level of pancreastatin (PST), which additionally enhances the free fatty acid (FFA) concentration in circulation. Consequently, the aggravated FFA activates Fetuin-A, which facilitates hepatic lipid accumulation, insulin resistance (IR), and culminates in type 2 diabetes (T2D). Metformin (Met) is a widely known first-line drug for the treatment of T2D. We previously unveiled PSTi8, an inhibitor of PST, comprising antidiabetic property. Hence, we hypothesized that combination therapy of Met and PSTi8, at reduced therapeutic doses, would mitigate HFD-induced IR by inhibiting hepatic Fetuin-A in mice model of T2D. C57BL/6 mice were fed HFD for 12 weeks, followed by treatment with Met, PSTi8, and its combination for 10 days. Glucose and insulin tolerance tests were conducted. Circulatory levels of PST, Fetuin-A, and lipid markers were determined. Also, the mRNA and protein expression of Fetuin-A was assessed by qPCR, western blotting, and immunofluorescence. Moreover, the energy expenditure was measured by comprehensive laboratory animal monitoring system (CLAMS). Combination therapy displayed improved PST, Fetuin-A, and lipid profile in plasma. We also found reduced hepatic Fetuin-A, which reduced inhibitory phosphorylation of IRS and increased phosphorylation of AKT. Consequently, ameliorated hepatic lipogenesis, gluconeogenesis, and inflammation. Also, combination treatment attenuated Fetuin-A expression, lipid accumulation, and glucose production in palmitate-induced HepG2 cells. Altogether current study promulgates the beneficial effect of combination therapy of Met and PSTi8 (comparable to alone higher therapeutic doses) to ameliorate Fetuin-A activation, hepatic lipid accumulation, insulin resistance, and associated progressive pathophysiological alterations in T2D.
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Affiliation(s)
- Pragati Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Richa Garg
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Umesh K. Goand
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Mohammed Riyazuddin
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Mohammad Irshad Reza
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Anees A. Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Anand P. Gupta
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Jiaur R. Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
- Corresponding author.
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Syed AA, Reza MI, Shafiq M, Kumariya S, Singh P, Husain A, Hanif K, Gayen JR. Naringin ameliorates type 2 diabetes mellitus-induced steatohepatitis by inhibiting RAGE/NF-κB mediated mitochondrial apoptosis. Life Sci 2020; 257:118118. [PMID: 32702445 DOI: 10.1016/j.lfs.2020.118118] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/10/2020] [Accepted: 07/15/2020] [Indexed: 12/20/2022]
Abstract
AIMS Recent findings have instituted the role of hyperglycemia-related AGE/RAGE and NF-κB in instigating reactive oxygen species (ROS) mediated mitochondrial dysfunction and apoptosis of hepatocyte, which leads to steatohepatitis. Naringin, a flavanone glycoside found to possess myriads of pharmacological benefits along with its antioxidant and anti-inflammatory properties. Consequently, we aimed to decipher the effect of naringin on RAGE/NF-κB mediated mitochondrial apoptosis in type 2 diabetes mellitus (T2DM)-induced steatohepatitis. MAIN METHODS Hepatic HepG2 cells were cultured in palmitic acid medium with and without naringin. Lipid content was examined by Oil Red O and Nile Red staining. Cellular apoptosis was determined by Annexin V-FITC/PI staining. An experimental T2DM-induced steatohepatitis was developed in Sprague Dawley rats by high-fat diet (HFD) for 12 weeks. The naringin was administrated orally at a dose of 100 mg/kg, daily for eight weeks. Glucose and insulin tolerance test was performed. Liver sections were stained by hematoxylin-eosin and picrosirius red. The mRNA and protein expression of RAGE and NF-κB were determined by qPCR, Immunofluorescence, and Immunoblotting. Mitochondrial membrane potential (MMP), cellular and mitochondrial ROS were measured by FACS. KEY FINDINGS Palmitic acid encountered HepG2 cells and HFD fed rats exhibited hyperlipidemia, insulin resistance, abnormal aminotransferases, steatosis, and fibrosis. Besides, the level of AGEs, RAGE, NF-κB, and oxidative stress were exacerbated. Moreover, MMP, cellular and mitochondrial ROS were altered in diabetic rats. Nevertheless, the naringin treatment ameliorated the steatohepatitis by improving the levels of aforementioned parameters. SIGNIFICANCE Collectively, these findings suggested anti-steatohepatitis potential of naringin in diabetics.
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Affiliation(s)
- Anees Ahmed Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Mohammad Irshad Reza
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Mohammed Shafiq
- Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Pragati Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Kashif Hanif
- Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
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Chen ZJ, Zhao XS, Fan TP, Qi HX, Li D. Glycine Improves Ischemic Stroke Through miR-19a-3p/AMPK/GSK-3β/HO-1 Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2021-2031. [PMID: 32546967 PMCID: PMC7260540 DOI: 10.2147/dddt.s248104] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022]
Abstract
Purpose To explore the molecular mechanism of glycine in improving ischemic stroke. Patients and Methods The serum samples of patients with ischemic stroke and healthy people were compared. The ischemic stroke model of PC12 cells was established by oxygen-glucose deprivation (OGD). qPCR quantified miR-19a-3p and AMPK mRNA, and protein expression was detected by Western blot. MTT was used to detect cell activity. Flow cytometry was used to detect cells. Glucose metabolism kit was used to detect glucose intake and formation amount of lactic acid. Results Compared with the control group, OGD group (OGDG) showed lower cell activity and increased cell apoptosis. TNF-α, IL-1βI, L-6, Caspase 3, Caspase 9 and Bax were up-regulated, and Glut1, HK2, LDHA, PDK1, PKM2 and Bcl2 were down-regulated. At the same time, glucose intake, formation amount of lactic acid and cell apoptosis rate were reduced, and AMPK/GSK-3β/HO-1 pathway activity was down-regulated. Glycine could counteract the above phenomena in OGDG. miR-19a-3p and AMPK decreased and increased, respectively, during glycine therapy. AMPK was the target gene of miR-19a-3p. Rescue experiments demonstrated that glycine improved cell apoptosis, inflammatory response and glucose metabolism disorder of ischemic stroke through miR-19a-3p/AMPK/GSK-3β/HO-1 pathway. Conclusion Glycine improves ischemic stroke through miR-19a-3p/AMPK/GSK-3β/HO-1 pathway.
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Affiliation(s)
- Zhong-Jun Chen
- Neurological Intervention Department, Dalian Municipal Central Hospital, Dalian, Liaoning Province, People's Republic of China
| | - Xu-Sheng Zhao
- Neurological Intervention Department, Dalian Municipal Central Hospital, Dalian, Liaoning Province, People's Republic of China
| | - Tie-Ping Fan
- Neurological Intervention Department, Dalian Municipal Central Hospital, Dalian, Liaoning Province, People's Republic of China
| | - Heng-Xu Qi
- Neurological Intervention Department, Dalian Municipal Central Hospital, Dalian, Liaoning Province, People's Republic of China
| | - Di Li
- Neurological Intervention Department, Dalian Municipal Central Hospital, Dalian, Liaoning Province, People's Republic of China
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Xie X, Xiao Q, Xiong Z, Yu C, Zhou J, Fu Z. Crocin-I ameliorates the disruption of lipid metabolism and dysbiosis of the gut microbiota induced by chronic corticosterone in mice. Food Funct 2020; 10:6779-6791. [PMID: 31576875 DOI: 10.1039/c9fo01533g] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive drugs. However, chronic treatment with GCs in clinical settings has a series of side effects, such as metabolic disorders, gut microbiota dysbiosis and neurological impairment. Therefore, searching for a functional substance that can alleviate these side effects is greatly meaningful to clinical patients. Crocin is the main active ingredient of saffron, which has been reported to have numerous pharmacological activities. However, the action of crocin-I, one major member of the crocin family, on the physiological mediation in the individuals receiving GC treatment remains unclear. In this study, we aimed to evaluate the efficacy of crocin-I on lipid metabolism and the gut microbiota in a mouse model of chronic corticosterone (CORT) treatment. Our findings showed that crocin-I reduced the levels of triglycerides and total cholesterol and the ratio of low density lipoprotein to high density lipoprotein in the serum of CORT-treated mice. In addition, transcriptome analysis revealed that crocin-I was effective in mediating the amelioration of lipid metabolism, mainly in fatty acid metabolism and steroid biosynthesis in CORT-treated mice. Moreover, metabolome analysis demonstrated that crocin-I could restore the disturbed metabolites in the liver of CORT-treated mice, most of which are long-chain fatty acids. Furthermore, high-throughput sequencing of 16s rRNA revealed that crocin-I could mitigate the dysbiosis of the gut microbiota caused by CORT at a dose of 40 mg kg-1, by resulting in a significant increase in the alpha diversity of the microbes in the cecal contents and a significant reduction in the abundance of Firmicutes, whereas by increasing the abundance of Bacteroidetes. These results indicated that oral administration of crocin-I could modify the composition of the gut microbiota and alleviate hepatic lipid disorder in mice treated with a high dose of GCs.
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Affiliation(s)
- Xiaoxian Xie
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
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LC-ESI-MS/MS assay development and validation of a novel antidiabetic peptide PSTi8 in mice plasma using SPE: An application to pharmacokinetics. J Pharm Biomed Anal 2019; 180:113074. [PMID: 31891874 DOI: 10.1016/j.jpba.2019.113074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/19/2019] [Accepted: 12/21/2019] [Indexed: 12/11/2022]
Abstract
PSTi8 is a 21 amino acid pancreastatin inhibitory peptide that demonstrated potent antidiabetic activity in insulin resistant rodent models. The goal of the current work is to establish and validate the LC-ESI-MS/MS bioanalytical assay of PSTi8 in mice plasma in order to unveil its pharmacokinetic (PK) behaviour for the first time. The MS detection of PSTi8 and diprotin A (internal standard, IS) was conducted with Q1/Q3 SRM transitions at 607.80 ([M+4 H]4+)/771.20 and 342.20/229.10, respectively using positive ESI. Phenomenex Aqua 5μ 125A (250 × 4.6 mm) column was utilized to separate PSTi8 and IS with a mobile phase consists of MeOH-0.1 % formic acid (1:1, v/v) using 0.4 mL/min flow rate. SPE using medium anion exchange cartridge (Oasis MAX) was used for the extraction of analyte and IS from the mice plasma and the extraction recovery was found to be >55 %. PSTi8 displayed good linearity across the 5-1000 ng/mL concentrations range. The intra- and inter- day accuracy was observed between 99.44-110.20 % and 99.66-110.93 %, respectively. The intra- and inter- day precision was observed between 2.61-4.03 % and 2.90-7.16 %, respectively. The intra-day and inter-day accuracy and precision data was within the 100 ± 15 % nominal values recommended by the United States Food and Drug Administration bioanalytical guidance. The LC-MS/MS assay was validated effectively to investigate the PSTi8 plasma concentrations following intravenous and intraperitoneal PK studies in mice. The absolute bioavailability of PSTi8 was 52.74 ± 13.50 %.
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Valicherla GR, Gupta AP, Hossain Z, Riyazuddin M, Syed AA, Husain A, Lahiri S, Dave KM, Gayen JR. Pancreastatin inhibitor, PSTi8 ameliorates metabolic health by modulating AKT/GSK-3β and PKCλ/ζ/SREBP1c pathways in high fat diet induced insulin resistance in peri-/post-menopausal rats. Peptides 2019; 120:170147. [PMID: 31473204 DOI: 10.1016/j.peptides.2019.170147] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/26/2019] [Accepted: 08/28/2019] [Indexed: 01/03/2023]
Abstract
Increase in the prevalence of insulin resistance (IR) in peri-/post-menopause women is mainly due to hormone deficiency and lifestyle. PSTi8 (PEGKGEQEHSQQKEEEEEMAV-amide) is a pancreastatin inhibitor peptide which showed potent antidiabetic activity in genetic and lifestyle induced type 2 diabetic mice. In the present work, we have investigated the antidiabetic activity of PSTi8 in rat models of peri-/post-menopausal IR. 4-vinylcyclohexenediepoxide treated and ovariectomized rats were fed with high fat diet for 12 weeks to develop the peri-/post-menopausal IR. PSTi8 peptide was administered after the development of peri-/post-menopausal IR rats. PSTi8 (1 mg/kg, i.p) improved the glucose homeostasis which is characterized by elevated glycogenesis, enhanced glycolysis and reduced gluconeogenesis. PSTi8 suppressed palmitate- and PST- induced IR in HepG2 cells. PSTi8 treatment enhanced energy expenditure in peri-/post-menopausal IR rats. PSTi8 treatment increased insulin sensitivity in peri-/post-menopausal IR rats, may be mediated by modulating IRS1-2-phosphatidylinositol-3-kinase-AKT-GSK3β and IRS1-2-phosphatidylinositol-3-kinase-PKCλ/ζ-SREBP1c signaling pathways in the liver. PSTi8 can act as a potential therapeutic peptide for the treatment of peri-/post-menopausal IR.
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Affiliation(s)
- Guru R Valicherla
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Anand P Gupta
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Zakir Hossain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Mohammed Riyazuddin
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Anees A Syed
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Athar Husain
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Shibani Lahiri
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Kandarp M Dave
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Raibarelly, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
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