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Mou L, Fu Z, Wang TB, Chen Y, Luo Z, Wang X, Pu Z. Na+/K+-ATPase: a multifunctional target in type 2 diabetes and pancreatic islets. Front Immunol 2025; 16:1555310. [PMID: 40046060 PMCID: PMC11880247 DOI: 10.3389/fimmu.2025.1555310] [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: 01/04/2025] [Accepted: 01/21/2025] [Indexed: 05/13/2025] Open
Abstract
Type 2 diabetes (T2D) is a widespread metabolic disorder marked by hyperglycemia, arising from insulin resistance and relative insulin deficiency. This review investigates the critical role of Na+/K+-ATPase (NKA), a transmembrane protein essential for maintaining cellular ion gradients, in the pathophysiology of T2D. We provide an overview of NKA's biological functions, emphasizing its involvement in cellular signaling pathways, insulin secretion, and glucose homeostasis. The potential of NKA as a therapeutic target for T2D is analyzed, showcasing innovative strategies such as NKA activators, gene therapy, and stem cell therapy aimed at enhancing NKA activity to achieve better glycemic control. Additionally, NKA's multifunctional role in maintaining cell viability and modulating immune responses in islet transplantation may offer potential benefits for improving transplant outcomes. By elucidating the complex interactions between NKA and T2D, this review aims to shed light on developing novel therapeutic interventions that meet the multifaceted needs of individuals suffering from this chronic condition, ultimately improving their health outcomes.
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Affiliation(s)
- Lisha Mou
- Department of Endocrinology, Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangxi University of Chinese Medicine, Shenzhen, Guangdong, China
- MetaLife Lab, Shenzhen Institute of Translational Medicine, Shenzhen, Guangdong, China
| | - Zhenkun Fu
- Department of Endocrinology, Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangxi University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Tony Bowei Wang
- Biology Department, Skidmore College, Saratoga Springs, NY, United States
| | - Yuxian Chen
- Department of Endocrinology, Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangxi University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Ziqi Luo
- Department of Endocrinology, Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangxi University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Xinyu Wang
- Department of Endocrinology, Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangxi University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Zuhui Pu
- MetaLife Lab, Shenzhen Institute of Translational Medicine, Shenzhen, Guangdong, China
- Imaging Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
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Meenakshi S, Bahekar T, Narapaka PK, Pal B, Prakash V, Dhingra S, Kumar N, Murti K. Impact of fluorosis on molecular predictors in pathogenesis of type 2 diabetes associated microvascular complications. J Trace Elem Med Biol 2024; 86:127506. [PMID: 39128255 DOI: 10.1016/j.jtemb.2024.127506] [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: 03/01/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 08/13/2024]
Abstract
AIM This review presents specific insights on the molecular underpinnings of the connection between fluorosis, type 2 diabetes, and microvascular complications, along with the novel biomarkers that are available for early detection. SUMMARY Fluoride is an essential trace element for the mineralization of teeth and bones in humans. Exposure to higher concentrations of fluoride has harmful effects that significantly outweigh its advantageous ones. Dental fluorosis and skeletal fluorosis are the common side effects of exposure to fluoride, which affect millions of individuals globally. Alongside, it also causes non-skeletal fluorosis, which affects the population suffering from non-communicable diseases like diabetes by impacting the soft tissues and causing diabetic microvascular complications. Previous studies reported the prevalence range of these diabetic complications of neuropathy (3-65 %), nephropathy (1-63 %), and retinopathy (2-33 %). Fluoride contributes to the development of these complications by causing oxidative stress, cellular damage, degrading the functioning capability of mitochondria, and thickening the retinal vein basement. CONCLUSION Early diagnosis is a prompt way of prevention, and for that, biomarkers have emerged as an innovative and useful technique. This allows healthcare practitioners and policymakers in endemic areas to comprehend the molecular complexities involved in the advancement of diabetic microvascular problems in the context of high fluoride exposure.
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Affiliation(s)
- Sarasa Meenakshi
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar 844102, India.
| | - Triveni Bahekar
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar 844102, India.
| | - Pavan Kumar Narapaka
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar 844102, India.
| | - Biplab Pal
- Department of Pharmacology, Lovely Professional University, Phagwara, Punjab 144402 India.
| | - Ved Prakash
- Department of Endocrinology, Indira Gandhi institute of medical sciences (IGIMS), Bailey Road, Sheikhpura, Patna, Bihar 800014, India.
| | - Sameer Dhingra
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar 844102, India.
| | - Nitesh Kumar
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar 844102, India.
| | - Krishna Murti
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar 844102, India.
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Yingping W, Lizhi L, Haiying L, Li C, Tiantian G, Xiaoyu Z, Yingying Y, Jiahui L. The effect of LINC9137 targeting miR-140-3p-NKAIN3 signal axis on the development of goose testis sertoli cells. Poult Sci 2024; 103:103724. [PMID: 38701630 PMCID: PMC11087709 DOI: 10.1016/j.psj.2024.103724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/05/2024] [Accepted: 03/31/2024] [Indexed: 05/05/2024] Open
Abstract
Sertoli cells (SC) are a type of important cells in the testes, which can provide transport proteins, regulatory proteins, growth factors, and other cytokines for the spermatogenic process. They participate in the regulation of the maturation and differentiation of spermatogenic cells and play an important supporting role in the migration, proliferation, and differentiation of germ cells at all levels in the testes. Previous studies found differential expression of LINC9137, miR-140-3p, and Sodium/Potassium Transporting ATPase Interacting 3 (NKAIN3) genesin high and low sperm motility goose testicular tissues. This study investigated the effects of the LINC9137-miR-140-3p-NKAIN3 signal axis on the proliferation and apoptosis of goose testicular sertoli cells at the cellular level, respectively. The results showed that through acridine orange staining, oil red O staining, Alkaline phosphatase (AKP) staining, and RT qPCR assay, it was comprehensively identified that the cultured testicular sertoli cells were purified in vitro. Through the dual luciferase activity detection test, it was found that LINC9137 has a targeted binding site with miR-140-3p and NKAIN3. In addition, this study found that overexpression of miR-140-3p significantly inhibited the expression of LINC9137 and NKAIN3 in sertoli cells, and their expression was significantly increased when miR-140-3p was interfered with. By measuring cell proliferation activity and apoptosis related gene expression, it was found that overexpression of LINC9137 decreased cell proliferation activity (P > 0.05), while the expression level of apoptosis factor Bcl2 Associated X Protein (Bax)/B-cell lymphoma-2 (Bcl2) increased (P > 0.05). On the contrary, when interfering with LINC9137, the cell proliferation activity of sertoli cells was significantly increased (P < 0.01), and the expression level of apoptosis factor Bax/Bcl2 was significantly reduced (P < 0.05); The effect of miR-140-3p on the proliferation and apoptosis of sertoli cells is opposite to that of LINC9137. Meanwhile, this study co transfected overexpressed LINC9137 and miR-140-3p plasmids into sertoli cells, and found that the effect of LINC9137 overexpression on supporting cell proliferation was weakened by miR-140-3p. This study elucidates the role and function of the LINC9137 miR-140-3p-NKAIN3 signaling axis in the development of goose testes and spermatogenesis, establishes a regulatory network related to spermatogenesis, and provides a theoretical basis for studying the genetic regulation of goose spermatogenesis.
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Affiliation(s)
- Wu Yingping
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830000, China
| | - Lu Lizhi
- Institute of Animal Husbandry and Veterinary Medicine, Zhejiang Academy of Agricultural Sciences, Hangzhou, Hangzhou 310021, China
| | - Li Haiying
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830000, China.
| | - Chen Li
- Institute of Animal Husbandry and Veterinary Medicine, Zhejiang Academy of Agricultural Sciences, Hangzhou, Hangzhou 310021, China
| | - Gu Tiantian
- Institute of Animal Husbandry and Veterinary Medicine, Zhejiang Academy of Agricultural Sciences, Hangzhou, Hangzhou 310021, China
| | - Zhao Xiaoyu
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830000, China
| | - Yao Yingying
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830000, China
| | - Li Jiahui
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830000, China
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Dakroub A, Dbouk A, Asfour A, Nasser SA, El-Yazbi AF, Sahebkar A, Eid AA, Iratni R, Eid AH. C-peptide in diabetes: A player in a dual hormone disorder? J Cell Physiol 2024; 239:e31212. [PMID: 38308646 DOI: 10.1002/jcp.31212] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 02/05/2024]
Abstract
C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications.
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Affiliation(s)
- Ali Dakroub
- St. Francis Hospital and Heart Center, Roslyn, New York, USA
| | - Ali Dbouk
- Department of Medicine, Saint-Joseph University Medical School, Hotel-Dieu de France Hospital, Beirut, Lebanon
| | - Aref Asfour
- Leeds Teaching Hospitals NHS Trust, West Yorkshire, United Kingdom
| | | | - Ahmed F El-Yazbi
- Faculty of Pharmacy, Alamein International University (AIU), Alamein City, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, UAE
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
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Toprak K. Effect of Serum C-Peptide Levels on the Development of Contrast-Induced Nephropathy in Diabetic Patients Undergoing Coronary Angiography. Angiology 2024; 75:139-147. [PMID: 36303403 DOI: 10.1177/00033197221132359] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Contrast-induced nephropathy (CIN) is an important cause of morbidity and mortality, in patients with diabetes who undergo coronary angiography (CAG). It is known that serum C-peptide has renoprotective effects in diabetic nephropathy. Patients with diabetes (n = 552) who underwent CAG in our center between January 2020 and December 2021 were included, retrospectively. The patients were divided into 2 groups: not-developing CIN (group 1) and developing CIN (group 2). CIN developed in 128 (23.1%) of the patients with diabetes who underwent CAG. C-peptide, albumin, hemoglobin, hematocrit, initial creatinine, ejection fraction (EF), were significantly lower in the group that developed CIN compared with the group that did not (P < .05, for all). In correlation analysis, creatinine increase rate (ΔCr) was negatively correlated with C-peptide, hematocrit, and ejection fraction (r = -.241, P < .001; r = -.135, P < .001; r = -.194, P = .001; respectively). In logistic regression analysis, C-peptide level (Odds Ratio: .404, 95% Confidence Interval: .286-.571, P < .001) was an independent predictor of CIN. In the present study, C-peptide level was an independent predictor of CIN in patients with diabetes. This study suggests that low levels of C-peptide are associated with a greater risk of CIN.
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Affiliation(s)
- Kenan Toprak
- Siverek State Hospital and Department of Cardiology, Faculty of Medicine, Harran University, Sanliurfa, Turkey
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Hu H, Liang W, Ding G. Ion homeostasis in diabetic kidney disease. Trends Endocrinol Metab 2024; 35:142-150. [PMID: 37880052 DOI: 10.1016/j.tem.2023.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/29/2023] [Accepted: 09/29/2023] [Indexed: 10/27/2023]
Abstract
The complications of type 2 diabetes are a major global public health problem with high incidence and mortality, affecting almost all individuals with diabetes worldwide. Diabetic kidney disease (DKD) is one such primary complication and has become a leading cause of end-stage renal disease in patients with diabetes. Progression from diabetes to DKD is a complex process typically involving multiple mechanisms. Recent remarkable clinical benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in diabetes and DKD highlight the critical impact of renal ion homeostasis on disease progression. This review comprehensively examines the impact of ion homeostasis on the transition from diabetes to DKD, outlining possible therapeutic interventions and addressing the ongoing challenges in this rapidly developing field.
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Affiliation(s)
- Hongtu Hu
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei 430060, China; Key Clinical Research Center of Kidney Disease, 238 Jiefang Rd, Wuhan, Hubei 430060, China
| | - Wei Liang
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei 430060, China; Key Clinical Research Center of Kidney Disease, 238 Jiefang Rd, Wuhan, Hubei 430060, China.
| | - Guohua Ding
- Division of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei 430060, China; Key Clinical Research Center of Kidney Disease, 238 Jiefang Rd, Wuhan, Hubei 430060, China.
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Kaur M, Misra S, Swarnkar P, Patel P, Das Kurmi B, Das Gupta G, Singh A. Understanding the role of hyperglycemia and the molecular mechanism associated with diabetic neuropathy and possible therapeutic strategies. Biochem Pharmacol 2023; 215:115723. [PMID: 37536473 DOI: 10.1016/j.bcp.2023.115723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/05/2023]
Abstract
Diabetic neuropathy is a neuro-degenerative disorder that encompasses numerous factors that impact peripheral nerves in the context of diabetes mellitus (DM). Diabetic peripheral neuropathy (DPN) is very prevalent and impacts 50% of diabetic patients. DPN is a length-dependent peripheral nerve lesion that primarily causes distal sensory loss, discomfort, and foot ulceration that may lead to amputation. The pathophysiology is yet to be fully understood, but current literature on the pathophysiology of DPN revolves around understanding various signaling cascades involving the polyol, hexosamine, protein-kinase C, AGE, oxidative stress, and poly (ADP ribose) polymerase pathways. The results of research have suggested that hyperglycemia target Schwann cells and in severe cases, demyelination resulting in central and peripheral sensitization is evident in diabetic patients. Various diagnostic approaches are available, but detection at an early stage remains a challenge. Traditional analgesics and opioids that can be used "as required" have not been the mainstay of treatment thus far. Instead, anticonvulsants and antidepressants that must be taken routinely over time have been the most common treatments. For now, prolonging life and preserving the quality of life are the ultimate goals of diabetes treatment. Furthermore, the rising prevalence of DPN has substantial consequences for occupational therapy because such therapy is necessary for supporting wellness, warding off other chronic-diseases, and avoiding the development of a disability; this is accomplished by engaging in fulfilling activities like yoga, meditation, and physical exercise. Therefore, occupational therapy, along with palliative therapy, may prove to be crucial in halting the onset of neuropathic-symptoms and in lessening those symptoms once they have occurred.
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Affiliation(s)
- Mandeep Kaur
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga142001, Punjab, India
| | - Sakshi Misra
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga142001, Punjab, India
| | - Priyanka Swarnkar
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga142001, Punjab, India
| | - Preeti Patel
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Balak Das Kurmi
- Department of Pharmaceutics, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Ghanshyam Das Gupta
- Department of Pharmaceutics, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Amrita Singh
- Department of Pharmacology, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga142001, Punjab, India.
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Deng J, Yan F, Tian J, Qiao A, Yan D. Potential clinical biomarkers and perspectives in diabetic cardiomyopathy. Diabetol Metab Syndr 2023; 15:35. [PMID: 36871006 PMCID: PMC9985231 DOI: 10.1186/s13098-023-00998-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication and the leading cause of death in diabetic patients. Patients typically do not experience any symptoms and have normal systolic and diastolic cardiac functions in the early stages of DCM. Because the majority of cardiac tissue has already been destroyed by the time DCM is detected, research must be conducted on biomarkers for early DCM, early diagnosis of DCM patients, and early symptomatic management to minimize mortality rates among DCM patients. Most of the existing implemented clinical markers are not very specific for DCM, especially in the early stages of DCM. Recent studies have shown that a number of new novel markers, such as galactin-3 (Gal-3), adiponectin (APN), and irisin, have significant changes in the clinical course of the various stages of DCM, suggesting that we may have a positive effect on the identification of DCM. As a summary of the current state of knowledge regarding DCM biomarkers, this review aims to inspire new ideas for identifying clinical markers and related pathophysiologic mechanisms that could be used in the early diagnosis and treatment of DCM.
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Affiliation(s)
- Jianxin Deng
- Department of Endocrinology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen Clinical Research Center for Metabolic Diseases, No. 3002, Sungang West Road, Futian District, Shenzhen, 518035, Guangdong Province, China
| | - Fang Yan
- Geriatric Diseases Institute of Chengdu, Center for Medicine Research and Translation, Chengdu Fifth People's Hospital, Chengdu, 611137, Sichuan Province, China
| | - Jinglun Tian
- Department of Geriatrics, the Traditional Chinese Medicine Hospital of Wenjiang District, Chengdu, 611130, China
| | - Aijun Qiao
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, Guangdong Province, China.
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
| | - Dewen Yan
- Department of Endocrinology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen Clinical Research Center for Metabolic Diseases, No. 3002, Sungang West Road, Futian District, Shenzhen, 518035, Guangdong Province, China.
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Alkharfy KM, Ahmad A, Siddiquei MM, Ghulam M, El-Asrar AA. Thymoquinone Attenuates Retinal Expression of Mediators and Markers of Neurodegeneration in a Diabetic Animal Model. Curr Mol Pharmacol 2023; 16:188-196. [PMID: 35049444 DOI: 10.2174/1874467215666220113105300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/07/2021] [Accepted: 10/21/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Diabetic retinopathy (DR) is a slow eye disease that affects the retina due to a long-standing uncontrolled diabetes mellitus. Hyperglycemia-induced oxidative stress can lead to neuronal damage leading to DR. OBJECTIVE The aim of the current investigation is to assess the protective effects of thymoquinone (TQ) as a potential compound for the treatment and/or prevention of neurovascular complications of diabetes, including DR. METHODS Diabetes was induced in rats by the administration of streptozotocin (55 mg/kg intraperitoneally, i.p.). Subsequently, diabetic rats were treated with either TQ (2 mg/kg i.p.) or vehicle on alternate days for three weeks. A healthy control group was also run in parallel. At the end of the treatment period, animals were euthanized, and the retinas were collected and analyzed for the expression levels of brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), nerve growth factor receptor (NGFR), and caspase-3 using Western blotting techniques in the retina of diabetic rats and compared with the normal control rats. In addition, dichlorofluorescein (DCF) levels in the retina were assessed as a marker of reactive oxygen species (ROS), and blood-retinal barrier breakdown (BRB) was examined for vascular permeability. The systemic effects of TQ treatments on glycemic control, kidney and liver functions were also assessed in all groups. RESULTS Diabetic animals treated with TQ showed improvements in the liver and kidney functions compared with control diabetic rats. Normalization in the levels of neuroprotective factors, including BDNF, TH, and NGFR, was observed in the retina of diabetic rats treated with TQ. In addition, TQ ameliorated the levels of apoptosis regulatory protein caspase-3 in the retina of diabetic rats and reduced disruption of the blood-retinal barrier, possibly through a reduction in reactive oxygen species (ROS) generation. CONCLUSION These findings suggest that TQ harbors a significant potential to limit the neurodegeneration and retinal damage that can be provoked by hyperglycemia in vivo.
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Affiliation(s)
- Khalid M Alkharfy
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Mairaj Siddiquei
- Department of Ophthalmology, College of Medicine, King Abdul Aziz Hospital, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Ghulam
- Department of Ophthalmology, College of Medicine, King Abdul Aziz Hospital, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Abu El-Asrar
- Department of Ophthalmology, College of Medicine, King Abdul Aziz Hospital, King Saud University, Riyadh 11451, Saudi Arabia
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Shi S, Ni L, Tian Y, Zhang B, Xiao J, Xu W, Gao L, Wu X. Association of Obesity Indices with Diabetic Kidney Disease and Diabetic Retinopathy in Type 2 Diabetes: A Real-World Study. J Diabetes Res 2023; 2023:3819830. [PMID: 37096235 PMCID: PMC10122582 DOI: 10.1155/2023/3819830] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/26/2023] [Accepted: 03/16/2023] [Indexed: 04/26/2023] Open
Abstract
Background Diabetic microvascular complications mainly include diabetic kidney disease (DKD) and diabetic retinopathy (DR). Obesity was recognized as a risk factor for DKD, while the reported relationship between obesity and DR was inconsistent. Moreover, whether the associations can be attributed to C-peptide levels is unknown. Methods Data from 1142 sequential inpatients with T2DM at Xiangyang Central Hospital between June 2019 and March 2022 were extracted retrospectively from the electronic medical record system. The associations between four obesity indices (body mass index (BMI), waist-hip circumference ratio (WHR), visceral fat tissue area (VFA), and subcutaneous fat tissue area (SFA)) and DKD and DR were evaluated. Whether the associations can be attributed to C-peptide levels was also explored. Results Obesity was a risk factor for DKD after adjusting for sex, HbA1c, TG, TC, HDL, LDL, smoking history, education, duration of diabetes, and insulin use (obesity indices: BMI (OR 1.050: 95% CI: 1.008-1.094; P = 0.020); WHR (OR 10.97; 95% CI: 1.250-92.267; P = 0.031); VFA (OR 1.005; 95% CI: 1.001-1.008; P = 0.008)), but it became insignificant after further adjusting for fasting C-peptide. The associations between BMI, WHR, VFA, and DKD might be U-shaped. Obesity and FCP tended to protect against DR; however, they became insignificant after adjusting for multiple potential confounders. C2/C0 (the ratio of the postprandial serum C-peptide to fasting C-peptide) was a protective factor for both DKD (OR 0.894, 95% CI: 0.833-0.959, P < 0.05) and DR (OR 0.851, 95% CI: 0.787-0.919; P < 0.05). Conclusions Obesity was a risk factor for DKD, and the effect may be attributable to C-peptide, which represents insulin resistance. The protective effect of obesity or C-peptide on DR was not independent and could be confounded by multiple factors. Higher C2/C0 was associated with both decreased DKD and DR.
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Affiliation(s)
- Shaomin Shi
- Department of Nephrology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China
- Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei 441000, China
| | - Lihua Ni
- Department of Nephrology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China
| | - Yuan Tian
- Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei 441000, China
| | - Baifang Zhang
- Department of Biochemistry, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, Hubei 430071, China
| | - Jing Xiao
- Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei 441000, China
| | - Wan Xu
- Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei 441000, China
| | - Ling Gao
- Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei 441000, China
| | - Xiaoyan Wu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China
- Department of General Practice, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China
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11
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Effect of H2O2 on Na,K-ATPase. J Bioenerg Biomembr 2022; 54:241-249. [DOI: 10.1007/s10863-022-09948-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/05/2022] [Indexed: 11/06/2022]
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12
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Smith S, Normahani P, Lane T, Hohenschurz-Schmidt D, Oliver N, Davies AH. Pathogenesis of Distal Symmetrical Polyneuropathy in Diabetes. LIFE (BASEL, SWITZERLAND) 2022; 12:life12071074. [PMID: 35888162 PMCID: PMC9319251 DOI: 10.3390/life12071074] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/13/2022]
Abstract
Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying therapies and left the reasons for failed therapies uncertain, which is critical given that current management strategies often fail to achieve long-term efficacy. In this article, the pathogenesis of DSPN is reviewed, covering pathogenic changes in the peripheral nervous system, microvasculature and central nervous system (CNS). Furthermore, the successes and limitations of current therapies are discussed, and potential therapeutic targets are proposed. Recent findings on its pathogenesis have called the definition of DSPN into question and transformed the disease model, paving the way for new research prospects.
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Affiliation(s)
- Sasha Smith
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Pasha Normahani
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Tristan Lane
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Department of Vascular Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
| | - David Hohenschurz-Schmidt
- Pain Research Group, Department of Surgery and Cancer, Imperial College London, London SW10 9NH, UK;
| | - Nick Oliver
- Section of Metabolic Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W2 1PG, UK;
- Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London W2 1NY, UK
| | - Alun Huw Davies
- Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, London W6 8RF, UK; (S.S.); (P.N.); (T.L.)
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London W6 8RF, UK
- Correspondence:
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13
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Huang Y, Wang Y, Liu C, Zhou Y, Wang X, Cheng B, Kui C, Wang Y. C-peptide, glycaemic control, and diabetic complications in type 2 diabetes mellitus: A real-world study. Diabetes Metab Res Rev 2022; 38:e3514. [PMID: 34841643 DOI: 10.1002/dmrr.3514] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 11/02/2021] [Indexed: 11/12/2022]
Abstract
OBJECTIVE To explore the relationship between C-peptide and glycaemic control rate and diabetic complications (microvascular complication and cerebral infarction) and provide evidence for stratified treatment of type 2 diabetes mellitus (T2DM)-based C-peptide. METHOD This is a cross-sectional real-world observational study. According to the inclusion and exclusion criteria, we studied 1377 patients with T2DM, grouped by fasting C-peptide and HOMA-IR. Blood samples were collected after fasting overnight. Logistic regression was used to analyse the relationship among fasting C-peptide, HOMA-IR, C2/C0 ratio (the ratio of 2 h postprandial C-peptide to fasting C-peptide), glycaemic control rate, and occurrence of diabetic complications. Restricted cubic spline (RCS) curves based on logistic regression were used to evaluate the relationship between C-peptide, glycaemic control rate, and diabetic kidney disease (DKD). RESULTS Patients were subdivided according to their fasting C-peptide in 4 groups (Q1,Q2,Q3,Q4). Patients of group Q3 (1.71 ≤ C-peptide < 2.51 ng/ml) showed the lowest incidence of DKD, diabetic retinopathy (DR), and rate of insulin absorption as welll as higher glycaemic control rate. Logistic regression shows that the probability of reaching glycemic control increased with higher levels of C-peptide, compared with group Q1, after adjusting for age, gender, duration of diabetes, body mass index, systolic blood pressure, diastolic blood pressure, creatinine, low-density lipoprotein, triglyceride, total cholesterol, and high-density lipoprotein. RCS curve shows that, when C-peptide is ≤2.68 ng/ml, the incidence of not reaching glycaemic control decreases with increasing C-peptide. The possibility of not reaching glycaemic control decreased with increasing C2/C0, when C-peptide is ≥1.71 ng/ml. RCS curve shows that the relationship between C-peptide and DKD follows a U-style curve. When C-peptide is <2.84 ng/ml, the incidence of DKD decreased with increasing C-peptide. With the increase in the C2/C0 ratio, the incidence of DKD, DR, and fatty liver did not decrease. CONCLUSION When C-peptide is ≥ 1.71 and < 2.51 ng/ml, patients with T2DM had a higher glycemic control rate. Excessive C-peptide plays different roles in DKD and DR; C-peptide may promote the incidence of DKD but protects patients from DR. Higher C2/C0 ratio is important for reaching glycaemic control but cannot reduce the risk of DKD, DR, and fatty liver.
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Affiliation(s)
- Yajing Huang
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yahao Wang
- Medicine College, Qingdao University, Qingdao, China
| | - Chuanfeng Liu
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yue Zhou
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiang Wang
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bingfei Cheng
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Che Kui
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yangang Wang
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
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14
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KAUR RAMNEEK, SODHI MONIKA, SHARMA ANKITA, SHARMA VIJAYLAKSHMI, VERMA PREETI, SWAMI SHELESHKUMAR, KATARIA RANJITS, SINGH MANOJK, K PARVESH, MUKESH MANISHI. Molecular characterization and identification of SNPs in ATP1A1 isoform of sodium-phosphate adenosine triphosphatase across diverse breeds of riverine buffaloes (Bubalus bubalis) and Indian native cattle (Bos indicus): A plausible candidate gene for heat tolerance. THE INDIAN JOURNAL OF ANIMAL SCIENCES 2021. [DOI: 10.56093/ijans.v91i7.115898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In the present study, efforts were made to sequence characterize the selected exonic region (18–21) of ATP1A1 gene to identify variations/SNPs in different breeds of Indian riverine buffaloes and native cattle. The sequence characterization of selected intronic/exonic region (17–21) of ATP1A1 gene was carried out in a total of 120 samples which included 6 animals each of 8 buffalo breeds and 72 animals of 12 cattle breeds. Genomic DNA was extracted from the whole blood by enzymatic digestion using proteinase K using phenol:chloroform method.. Three sets of primers were designed using Primer3 software to amplify genomic region from intron 17 to intron 21 of ATP1A1 gene in both cattle and buffaloes. The amplified products were purified by enzymatic method and purified PCR products were sequenced using forward primers in an ABI 3100 Automated DNA Sequencer. The chromatogram of each sequence obtained was checked manually. Base calling was performed with Phred and contig assembly was done via Phrap/Cross_match/Swat tool available in the suite Codon code Aligner v. 3.5.1. The results revealed a total of 26 variations in exons 18–21 of ATP1A1 gene in riverine buffalo. Out of 26 variations, 6 (T27006876C, C27006599T, T27006345C, T27006330C, G27006309T and T27006240C) were distributed across 4 exonic regions and the remaining 20 were located in intronic region whereas in native cattle, only 2 SNPs were identified in exonic regions (18–21). SNP T27007767C was found to be a novel one in 18 intronic region of ATP1A1 gene in Indian cattle breeds. All 7 variations found in exonic region of both buffalo and cattle breeds were synonymous with the predicted changes in amino acids. The variations identified in ATP1A1 gene in the present study could be evaluated in future for their roles in heat tolerance trait in riverine buffaloes and native cattle.
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15
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Some Kinetic Features of Na,K-ATPase and Sensitivity to Noradrenaline. Cell Biochem Biophys 2021; 80:23-29. [PMID: 34436718 DOI: 10.1007/s12013-021-01032-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 08/04/2021] [Indexed: 10/20/2022]
Abstract
A comparative kinetic analysis of albino rat brain synaptic and kidney plasma membrane fraction Na,K-ATPase was performed to comprehend the different levels of sensitivity of these fractions to the neurotransmitter noradrenaline. Noradrenaline (NA) inhibits the rat brain synaptic membrane Na,K-ATPase, changes the stoichiometry of Na+ and K+ and shifts the enzyme system from an MgATP to an Mg2+ dependent cycle. While the kidney plasma membrane fraction Na,K-ATPase is not sensitive to noradrenaline. To investigate the mechanism underlying this difference, we studied enzyme velocity dependence on the concentration of Mg2+. The 1/V = f(Mg2+) function has shown different kinetic features for the synaptic and kidney plasma membrane Na,K-ATPase. With the addition of ethylene glycol tetraacetic acid (EGTA) to the reaction medium the geometric form of 1/V = f(Mg2+) function is affected differently. We thereafter measured the essential activator number for Na+ and K+ with, in excess Mg2+. The results of these experiments reveal that, contrary to the synaptic membrane Na,K-ATPase, the kidney plasma membrane fraction Na,K-ATPase does not possess an Mg2+ dependent cycle and noradrenaline exhibits different modulatory effects on the enzyme system.
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16
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Kryvenko V, Vagin O, Dada LA, Sznajder JI, Vadász I. Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease. J Membr Biol 2021; 254:447-457. [PMID: 34114062 PMCID: PMC8192048 DOI: 10.1007/s00232-021-00184-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/08/2021] [Indexed: 12/11/2022]
Abstract
Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract ![]()
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Affiliation(s)
- Vitalii Kryvenko
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus Liebig University, Klinikstrasse 33, 35392, Giessen, Germany.,The Cardio-Pulmonary Institute (CPI), Giessen, Germany
| | - Olga Vagin
- Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.,Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Laura A Dada
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Jacob I Sznajder
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - István Vadász
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus Liebig University, Klinikstrasse 33, 35392, Giessen, Germany. .,The Cardio-Pulmonary Institute (CPI), Giessen, Germany.
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17
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Rivelli Antonelli JF, Santander VS, Nigra AD, Monesterolo NE, Previtali G, Primo E, Otero LH, Casale CH. Prevention of tubulin/aldose reductase association delays the development of pathological complications in diabetic rats. J Physiol Biochem 2021; 77:565-576. [PMID: 34097242 DOI: 10.1007/s13105-021-00820-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/12/2021] [Indexed: 11/26/2022]
Abstract
In recent studies, we found that compounds derived from phenolic acids (CAFs) prevent the formation of the tubulin/aldose reductase complex and, consequently, may decrease the occurrence or delay the development of secondary pathologies associated with aldose reductase activation in diabetes mellitus. To verify this hypothesis, we determined the effect of CAFs on Na+,K+-ATPase tubulin-dependent activity in COS cells, ex vivo cataract formation in rat lenses and finally, to evaluate the antidiabetic effect of CAFs, diabetes mellitus was induced in Wistar rats, they were treated with different CAFs and four parameters were determinates: cataract formation, erythrocyte deformability, nephropathy and blood pressure. After confirming that CAFs are able to prevent the association between aldose reductase and tubulin, we found that treatment of diabetic rats with these compounds decreased membrane-associated acetylated tubulin, increased NKA activity, and thus reversed the development of four AR-activated complications of diabetes mellitus determined in this work. Based on these results, the existence of a new physiological mechanism is proposed, in which tubulin is a key regulator of aldose reductase activity. This mechanism can explain the incorrect functioning of aldose reductase and Na+,K+-ATPase, two key enzymes in the pathogenesis of diabetes mellitus. Moreover, we found that such alterations can be prevented by CAFs, which are able to dissociate tubulin/aldose reductase complex.
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Affiliation(s)
- Juan F Rivelli Antonelli
- Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina
- INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina
| | - Verónica S Santander
- Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina
- INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina
| | - Ayelen D Nigra
- Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina
- INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina
| | - Noelia E Monesterolo
- Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina
- INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina
| | - Gabriela Previtali
- Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina
- INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina
| | - Emilianao Primo
- Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina
- INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina
| | - Lisandro H Otero
- Instituto de Investigaciones Bioquímicas de Buenos Aires, IIBBA, CONICET - Fundación Instituto Leloir, Av Patricias Argentinas 435, C1405BWE, Buenos Aires, Argentina
| | - César H Casale
- Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina.
- INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina.
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18
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Kryvenko V, Vadász I. Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19. Am J Physiol Lung Cell Mol Physiol 2021; 320:L1186-L1193. [PMID: 33689516 PMCID: PMC8238442 DOI: 10.1152/ajplung.00056.2021] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
A significant number of patients with coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) that is associated with a poor outcome. The molecular mechanisms driving failure of the alveolar barrier upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain incompletely understood. The Na,K-ATPase is an adhesion molecule and a plasma membrane transporter that is critically required for proper alveolar epithelial function by both promoting barrier integrity and resolution of excess alveolar fluid, thus enabling appropriate gas exchange. However, numerous SARS-CoV-2-mediated and COVID-19-related signals directly or indirectly impair the function of the Na,K-ATPase, thereby potentially contributing to disease progression. In this Perspective, we highlight some of the putative mechanisms of SARS-CoV-2-driven dysfunction of the Na,K-ATPase, focusing on expression, maturation, and trafficking of the transporter. A therapeutic mean to selectively inhibit the maladaptive signals that impair the Na,K-ATPase upon SARS-CoV-2 infection might be effective in reestablishing the alveolar epithelial barrier and promoting alveolar fluid clearance and thus advantageous in patients with COVID-19-associated ARDS.
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Affiliation(s)
- Vitalii Kryvenko
- Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.,The Cardio-Pulmonary Institute (CPI), Giessen, Germany
| | - István Vadász
- Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.,The Cardio-Pulmonary Institute (CPI), Giessen, Germany
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19
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Gagnon KB, Delpire E. Sodium Transporters in Human Health and Disease. Front Physiol 2021; 11:588664. [PMID: 33716756 PMCID: PMC7947867 DOI: 10.3389/fphys.2020.588664] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/06/2020] [Indexed: 12/12/2022] Open
Abstract
Sodium (Na+) electrochemical gradients established by Na+/K+ ATPase activity drives the transport of ions, minerals, and sugars in both excitable and non-excitable cells. Na+-dependent transporters can move these solutes in the same direction (cotransport) or in opposite directions (exchanger) across both the apical and basolateral plasma membranes of polarized epithelia. In addition to maintaining physiological homeostasis of these solutes, increases and decreases in sodium may also initiate, directly or indirectly, signaling cascades that regulate a variety of intracellular post-translational events. In this review, we will describe how the Na+/K+ ATPase maintains a Na+ gradient utilized by multiple sodium-dependent transport mechanisms to regulate glucose uptake, excitatory neurotransmitters, calcium signaling, acid-base balance, salt-wasting disorders, fluid volume, and magnesium transport. We will discuss how several Na+-dependent cotransporters and Na+-dependent exchangers have significant roles in human health and disease. Finally, we will discuss how each of these Na+-dependent transport mechanisms have either been shown or have the potential to use Na+ in a secondary role as a signaling molecule.
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Affiliation(s)
- Kenneth B. Gagnon
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
| | - Eric Delpire
- Department of Anesthesiology, School of Medicine, Vanderbilt University, Nashville, TN, United States
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20
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Khursheed R, Singh SK, Wadhwa S, Gulati M, Kapoor B, Awasthi A, Kr A, Kumar R, Pottoo FH, Kumar V, Dureja H, Anand K, Chellappan DK, Dua K, Gowthamarajan K. Opening eyes to therapeutic perspectives of bioactive polyphenols and their nanoformulations against diabetic neuropathy and related complications. Expert Opin Drug Deliv 2020; 18:427-448. [PMID: 33356647 DOI: 10.1080/17425247.2021.1846517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Diabetic neuropathy (DN) is one of the major complications arising from hyperglycaemia in diabetic patients. In recent years polyphenols present in plants have gained attention to treat DN. The main advantages associated with them are their action via different molecular pathways to manage DN and their safety. However, they failed to gain clinical attention due to challenges associated with their formulation development such as lipophilicity,poor bioavailability, rapid systemic elimination, and enzymatic degradation.Area covered: This article includes different polyphenols that have shown their potential against DN in preclinical studies and the research carried out towards development of their nanoformulations in order to overcome aforementioned issues.Expert opinion: In this review various polyphenol based nanoformulations such as nanospheres, self-nanoemulsifying drug delivery systems, niosomes, electrospun nanofibers, metallic nanoparticles explored exclusively to treat DN are discussed. However, the literature available related to polyphenol based nanoformulations to treat DN is limited. Moreover, these experiments are limited to preclinical studies. Hence, more focus is required towards development of nanoformulations using simple and single step process as well as inexpensive and non-toxic excipients so that a stable, scalable, reproducible and non-toxic formulation could be achieved and clinical trials could be initiated.
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Affiliation(s)
- Rubiya Khursheed
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Sheetu Wadhwa
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Bhupinder Kapoor
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Ankit Awasthi
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Arya Kr
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Rajan Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Vijay Kumar
- Department of Biotechnology, School of Bioengineering and Biosciences, Faculty of Technology and Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Krishnan Anand
- Department of Chemical Pathology, School of Pathology, Faculty of Health Sciences and National Health Laboratory Service, University of the Free State, Bloemfontein, South Africa
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Australia
| | - K Gowthamarajan
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.,Centre of Excellence in Nanoscience & Technology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
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21
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Poteryaeva ON, Usynin IF. [Molecular mechanisms of action and physiological effects of the proinsulin C-peptide (a systematic review)]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2020; 66:196-207. [PMID: 32588825 DOI: 10.18097/pbmc20206603196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The C-peptide is a fragment of proinsulin, the cleavage of which forms active insulin. In recent years, new information has appeared on the physiological effects of the C-peptide, indicating its positive effect on many organs and tissues, including the kidneys, nervous system, heart, vascular endothelium and blood microcirculation. Studies on experimental models of diabetes mellitus in animals, as well as clinical trials in patients with diabetes, have shown that the C-peptide has an important regulatory effect on the early stages of functional and structural disorders caused by this disease. The C-peptide exhibits its effects through binding to a specific receptor on the cell membrane and activation of downstream signaling pathways. Intracellular signaling involves G-proteins and Ca2+-dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+/K+-ATPase and important transcription factors involved in apoptosis, anti-inflammatory and other intracellular defense mechanisms. This review gives an idea of the C-peptide as a bioactive endogenous peptide that has its own biological activity and therapeutic potential.
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Affiliation(s)
- O N Poteryaeva
- Institute of Biochemistry, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
| | - I F Usynin
- Institute of Biochemistry, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
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Pereira-Moreira R, Muscelli E. Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review. J Diabetes Res 2020; 2020:8492467. [PMID: 32377524 PMCID: PMC7180501 DOI: 10.1155/2020/8492467] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 12/18/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023] Open
Abstract
Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.
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Affiliation(s)
- Ricardo Pereira-Moreira
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Zip Code: 13083-887, Brazil
| | - Elza Muscelli
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Zip Code: 13083-887, Brazil
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23
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Panduranga Shenoy R, Hanumaiah G, Bolar Suryakanth V, Shridharan P. Comparison of Serum Levels of Fructosamine and Erythrocyte Sodium Potassium ATPase (Na +/K + ATPase) in Gestational Diabetes Mellitus (GDM) and non-Gestational Diabetes Mellitus (non GDM) Patients. Rep Biochem Mol Biol 2019; 8:253-259. [PMID: 32274397 PMCID: PMC7103082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 04/07/2019] [Indexed: 06/11/2023]
Abstract
BACKGROUND The study aims at the comparison and correlation of serum levels of fructosamine and erythrocyte Na+/ K+ ATPase in Gestational diabetes mellitus (GDM) and Non Gestational Diabetes Mellitus (Non GDM). METHODS A total of 326 samples were divided into 4 groups. Pregnant women between the age group of 2040 years who gave samples for Oral Glucose Tolerance Test (OGTT) were included as the subjects. Anonymized and left over fasting and 2 hours' samples were collected from biochemistry laboratory, Kasturba Hospital, Manipal. RESULTS In the comparison of fructosamine levels in GDM and Non GDM, fructosamine was found to be significant (p value<0.001) in both fasting and 2 hours (G2) blood glucose condition. Na+/ K+ ATPase did not show any significant variation between the groups.Correlation was not significant between the parameters. CONCLUSION Fructosamine showed significant increase when compared between the groups, whereas significant correlation is not obtained between the parameters. Thus, the use fructosamine as a diagnosis tool becomes inconclusive. Further studies must be carried out to identify a marker which reduces the interferences observed in fructosamine and to find out the exact relationship between hyperglycaemia and Na+/ K+ ATPase activity.
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Affiliation(s)
- Revathi Panduranga Shenoy
- Department of Biochemistry, Kasturba Medical College Manipal, Manipal Academy of Higher Education Manipal, Karnataka, India.
| | - Gagana Hanumaiah
- Department of Biochemistry, Kasturba Medical College Manipal, Manipal Academy of Higher Education Manipal, Karnataka, India.
| | - Varashree Bolar Suryakanth
- Department of Biochemistry, Kasturba Medical College Manipal, Manipal Academy of Higher Education Manipal, Karnataka, India.
| | - Priyanka Shridharan
- Department of Biochemistry, Kasturba Medical College Manipal, Manipal Academy of Higher Education Manipal, Karnataka, India.
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24
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Abosheasha MA, Zahran F, Bessa SS, El-Magd MA, Mohamed TM. Association between a novel G94A single nucleotide polymorphism in ATP1A1 gene and type 2 diabetes mellitus among Egyptian patients. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2019; 24:62. [PMID: 31523248 PMCID: PMC6669993 DOI: 10.4103/jrms.jrms_975_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 02/03/2019] [Accepted: 04/14/2019] [Indexed: 12/27/2022]
Abstract
Background: Na+/K+ ATPase enzyme is essential for nerve cell membrane integrity, and reduction in its activity, probably due to ATP1A1 gene polymorphisms, is related to diabetic neuropathy progression. Therefore, the goal of the existent study is to evaluate the Na+/K+ ATPase activity in type 2 diabetes mellitus (T2DM) Egyptian patients with or without neuropathy, search for polymorphism(s) in the highly polymorphic region of ATP1A1 gene, exon 2, and study its (their) associations with T2DM with and without neuropathy. Materials and Methods: A total number of 150 individuals were subclassified into healthy controls (n = 30), T2DM without complications (n = 60), and T2DM with neuropathy (n = 60). Results: The biochemical results exhibited a significant reduction in fasting C-Peptide and activity of Na+/K+ ATPase in T2DM patients with neuropathy followed by T2DM without complication in comparison with healthy controls. ATP1A1 exon2 was amplified by polymerase chain reaction (PCR) then digested by the PstI restriction enzyme, and the obtained data from restriction fragment length polymorphism-PCR and sequencing revealed the existence of a novel synonymous G94A single nucleotide polymorphism (SNP) at nucleotide 27 in exon 2 of ATP1A1 gene (rs1060366). Diabetic groups had only allele A, while the control group had G allele. Interestingly, individuals carrying AA genotype had a significantly lower Na+/K+ ATPase, C-peptide, and higher glycosylated hemoglobin (HBA1c %) than those having GG genotype, suggesting a possible association for this SNP, and this developed phenomenon of not only T2DM but also diabetic neuropathy. Conclusion: Thus, allele A of G94A SNP (rs1060366) could be a risk allele for diabetes susceptibility among Egyptian patients.
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Affiliation(s)
- Mohammed A Abosheasha
- Department of Biochemistry, Faculty of Science, Zagazig University, Zagazig, Egypt.,Cellular Genetics Laboratory, Graduate School of Science, Tokyo Metropolitan University, Tokyo, 192-0397, Japan
| | - Faten Zahran
- Department of Biochemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Sahar S Bessa
- Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohammed A El-Magd
- Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | - Tarek M Mohamed
- Department of Chemistry, Biochemistry Division, Faculty of Science, Tanta University, Tanta, Egypt
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25
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Qu F, Liu S, He C, Zhou J, Zhang S, Ai Z, Chen Y, Yu Z, Ni D. Comparison of the Effects of Green and Black Tea Extracts on Na
+
/K
+
‐ATPase Activity in Intestine of Type 1 and Type 2 Diabetic Mice. Mol Nutr Food Res 2019; 63:e1801039. [DOI: 10.1002/mnfr.201801039] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 04/19/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Fengfeng Qu
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Shuyuan Liu
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Chang He
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Jingtao Zhou
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Shanming Zhang
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Zeyi Ai
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Yuqiong Chen
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Zhi Yu
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
| | - Dejiang Ni
- Key Laboratory of Horticultural Plant BiologyMinistry of EducationCollege of Horticulture and Forestry SciencesHuazhong Agricultural University Wuhan 430070 China
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26
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Waugh DT. Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na +, K +-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:E1427. [PMID: 31010095 PMCID: PMC6518254 DOI: 10.3390/ijerph16081427] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 04/02/2019] [Accepted: 04/08/2019] [Indexed: 12/24/2022]
Abstract
In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.
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Affiliation(s)
- Declan Timothy Waugh
- EnviroManagement Services, 11 Riverview, Doherty's Rd, P72 YF10 Bandon, Co. Cork, Ireland.
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Guo N, Li C, Liu Q, Liu S, Huan Y, Wang X, Bai G, Yang M, Sun S, Xu C, Shen Z. Maltol, a food flavor enhancer, attenuates diabetic peripheral neuropathy in streptozotocin-induced diabetic rats. Food Funct 2019; 9:6287-6297. [PMID: 30411095 DOI: 10.1039/c8fo01964a] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
SCOPE Maltol (3-hydroxy-2-methy-4-pyrone), a potent antioxidative agent, typically is used to enhance flavor and preserve food. This study evaluated its effects on preventing diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)-induced diabetic rats and explored its mechanisms. METHODS AND RESULTS We intraperitoneally injected Sprague-Dawley (SD) rats with STZ (65 mg kg-1, ip) and treated the rats with different doses of maltol after 4 weeks of injection. During treatment, we evaluated motor nerve conduction velocity (MNCV) and thermal and mechanical hyperalgesia and assayed the oxidative stress, Na+-K+-ATPase activity, and apoptosis. Repeated treatment with maltol for 12 weeks significantly improved thermal and mechanical hyperalgesia, increased the MNCV, elevated the Na+-K+-ATPase activity, and ameliorated oxidative stress and apoptosis in STZ-induced diabetic rats. We coincubated RSC96 cells, a Schwann cell line, with maltol and hydrogen peroxide (H2O2, 0.6 mM). Evidently, maltol increased cell viability and inhibited apoptosis after injury by H2O2. CONCLUSIONS Maltol was demonstrated to prevent DPN development and may provide a new alternative for the treatment of DPN.
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Affiliation(s)
- Nan Guo
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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Novac C, Radulian G, Orzan A, Balgradean M. Short Update on C-Peptide and its Clinical Value. MAEDICA 2019; 14:53-58. [PMID: 31123514 PMCID: PMC6511667 DOI: 10.26574/maedica.2019.14.1.53] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
C-Peptide (“connecting” peptide – molecular formula C112H179N35O46) is a peptide made of 31 aminoacids, making the bond between A and B chains of insulin from the pro-insulin molecule. Pro-insulin is the precursor of the insulin that is synthesized in the beta-pancreatic cells. After its discovery in 1967 by Steiner et al, together with the discovery of insulin biosynthesis, C-peptide seemed to bring new benefits, having similar effects as those of insulin. Unfortunately, the subsequent studies have classified C-peptide as a biologically inactive peptide. After the ‘90s, however, both studies on animals and those on human subjects with type 1 diabetes where C-peptide had been administered showed that it played important biological parts in improving kidney function and nerve conduction velocity, as well as in increasing blood flow in muscles, skin, kidneys, thus being seen as a possible treatment for chronic complications of type 1 diabetes. Although for a long time C-peptide has been considered to be an inert biological product, recent research has emphasized its active biological function. C-peptide bonds to the membrane of certain types of cells (neuronal, endothelial, renal tubular cells, fibroblasts) through a surface receptor coupled with a G protein, and it determines multiple effects at the cellular level: it improves the quality of red cells, generating a better oxygenation of tissues; it has a vasodilator effect for muscles, skin, kidneys; it generates blood flow increase in skeletal muscles and at the skin level; it decreases glomerular hyper-filtering; it reduces albumin urinary excretion; it improves the function and structure of nerves in patients with type 1 diabetes and C-peptide deficiency, but not in healthy subjects. Therefore, C-peptide could have a therapeutic potential in preventing some of the late complications of diabetes mellitus.
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Affiliation(s)
- Carmen Novac
- M. S. Curie" Children Emergency Hospital, Bucharest, Romania
| | - Gabriela Radulian
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Anca Orzan
- "M. S. Curie" Children Emergency Hospital, Bucharest, Romania
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Coombe L, Kadri A, Martinez JF, Tatachar V, Gallicano GI. Current approaches in regenerative medicine for the treatment of diabetes: introducing CRISPR/CAS9 technology and the case for non-embryonic stem cell therapy. AMERICAN JOURNAL OF STEM CELLS 2018; 7:104-113. [PMID: 30697454 PMCID: PMC6334205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 10/28/2018] [Indexed: 06/09/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disorder in which the body destroys its pancreatic β cells. Since these cells are responsible for insulin production, dysfunction or destruction of these cells necessitates blood glucose control through exogenous insulin shots. Curative treatment involves pancreas transplantation, but due to the incidence of transplant rejection and complications associated with immunosuppression, alternatives are being explored. Despite facing clinical challenges and issues with public perception, the field of regenerative stem cell therapy shows great promise for the treatment of diabetes. The idea of harnessing pluripotency to derive cells and tissues with characteristics of choice is astounding but feasible, and this review seeks to determine which method of stem cell derivation is preferable for diabetes treatment. In this report, we outline the methods for deriving human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and adult stem cells or progenitor cells to generate functional islet cells and related tissues. We discuss the specific uses and advantages of each method, and we comment on the ethics and public perceptions surrounding these methods and how they may affect the future of stem cell research. For the reasons outlined in this paper, we believe that non-embryonic stem cell lines, including iPSCs, somatic cell nuclear transfer lines, and adult tissue derived stem cells, offer the highest therapeutic potential for treating diabetes.
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Affiliation(s)
- Lauren Coombe
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center 3900 Reservoir Road NW, Washington DC 20007, USA
| | - Aamir Kadri
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center 3900 Reservoir Road NW, Washington DC 20007, USA
| | - Jessica Ferrer Martinez
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center 3900 Reservoir Road NW, Washington DC 20007, USA
| | - Vivas Tatachar
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center 3900 Reservoir Road NW, Washington DC 20007, USA
| | - Gary Ian Gallicano
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center 3900 Reservoir Road NW, Washington DC 20007, USA
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Li Q, Yang LZ. HEMOGLOBIN A1c LEVEL HIGHER THAN 9.05% CAUSES A SIGNIFICANT IMPAIRMENT OF ERYTHROCYTE DEFORMABILITY IN DIABETES MELLITUS. ACTA ENDOCRINOLOGICA-BUCHAREST 2018; 14:66-75. [PMID: 31149238 DOI: 10.4183/aeb.2018.66] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Context Clinical studies demonstrated erythrocyte deformability (ED) is impaired in diabetic patients and described the correlations between HbA1c and ED. Few studies further investigated what an exact elevated HbA1c level linked to the impairment of ED in diabetes. Objective This study was to determine a cut-off point of HbA1c level leading to the impairment of ED in patients with diabetes. Design This was a retrospective observational study. ROC curve analysis was used to determine an optimal cut-off value of HbA1c for the increasing HSRV. Subjects and Methods In this study, 300 type 2 diabetic patients were enrolled. The whole blood viscosity was measured. High shear reductive viscosity (HSRV) was used to indirectly estimate ED. Based on the obtained cut-off value and glycemic control criteria for HbA1c, we divided all the cases into different groups to further confirm the accuracy of the cut-off value. Results In 300 patients, ROC curve illustrated that 9.05% was the optimal cut-off value as a predictor of the increasing HSRV. And higher odds ratio (OR) for significant decrease in ED was seen in the patients with HbA1c >9.05% compared to those with HbA1c≤9.05% (OR: 3.78, 95% CI: 2.08-6.87). HSRV increased significantly in patients with HbA1c level >9.05% in comparison to patients with HbA1c levels <6.5% between 6.5 and 8.0% and between 8.0 and 9.05%. Conclusion ED decreased significantly in diabetic patients as soon as HbA1c level was higher than 9.05%.
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Affiliation(s)
- Q Li
- Shanghai Ninth People's Hospital affiliated Shanghai Jiaotong University School of Medicine, Division of Endocrinology and Metabolism, Shanghai, China
| | - L Z Yang
- Shanghai Ninth People's Hospital affiliated Shanghai Jiaotong University School of Medicine, Division of Endocrinology and Metabolism, Shanghai, China
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Jagadish S, Hemshekhar M, NaveenKumar SK, Sharath Kumar KS, Sundaram MS, Basappa, Girish KS, Rangappa KS. Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress. Toxicol Appl Pharmacol 2017; 334:167-179. [DOI: 10.1016/j.taap.2017.09.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 09/05/2017] [Accepted: 09/09/2017] [Indexed: 01/02/2023]
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Presynaptic inhibition of nociceptive neurotransmission by somatosensory neuron-secreted suppressors. SCIENCE CHINA-LIFE SCIENCES 2017. [PMID: 28624955 DOI: 10.1007/s11427-017-9061-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Noxious stimuli cause pain by activating cutaneous nociceptors. The Aδ- and C-fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae I-II of spinal cord. In the dorsal horn of spinal cord, the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons, and by serotonin, norepinepherine and dopamine from the descending inhibitory system. In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord, the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited. In this review, we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons, the BNP/NPR-A/PKG/BKCa channel pathway, the FSTL1/α1Na+-K+ ATPase pathway and the activin C/ERK pathway. These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain.
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Abstract
The sodium and potassium gradients across the plasma membrane are used by animal cells for numerous processes, and the range of demands requires that the responsible ion pump, the Na,K-ATPase, can be fine-tuned to the different cellular needs. Therefore, several isoforms are expressed of each of the three subunits that make a Na,K-ATPase, the alpha, beta and FXYD subunits. This review summarizes the various roles and expression patterns of the Na,K-ATPase subunit isoforms and maps the sequence variations to compare the differences structurally. Mutations in the Na,K-ATPase genes encoding alpha subunit isoforms have severe physiological consequences, causing very distinct, often neurological diseases. The differences in the pathophysiological effects of mutations further underline how the kinetic parameters, regulation and proteomic interactions of the Na,K-ATPase isoforms are optimized for the individual cellular needs.
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Affiliation(s)
- Michael V Clausen
- Department of Molecular Biology and Genetics, Aarhus UniversityAarhus, Denmark
| | - Florian Hilbers
- Department of Molecular Biology and Genetics, Aarhus UniversityAarhus, Denmark
| | - Hanne Poulsen
- Department of Molecular Biology and Genetics, Aarhus UniversityAarhus, Denmark
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Adisakwattana S. Cinnamic Acid and Its Derivatives: Mechanisms for Prevention and Management of Diabetes and Its Complications. Nutrients 2017; 9:nu9020163. [PMID: 28230764 PMCID: PMC5331594 DOI: 10.3390/nu9020163] [Citation(s) in RCA: 177] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 02/11/2017] [Accepted: 02/16/2017] [Indexed: 02/06/2023] Open
Abstract
With recent insight into the development of dietary supplements and functional foods, search of effective phytochemical compounds and their mechanisms involved in prevention and management of diabetes and its complications are now being assessed. Cinnamic acid and its derivatives occur naturally in high levels of plant-based foods. Among various biological activities, cinnamic acid and its derivatives are associated with a beneficial influence on diabetes and its complications. The aim of the review is to summarize the potential mechanisms of these compounds for prevention and management of diabetes and its complications. Based on several in vitro studies and animal models, cinnamic acid and its derivatives act on different mechanism of actions, including stimulation of insulin secretion, improvement of pancreatic β-cell functionality, inhibition of hepatic gluconeogenesis, enhanced glucose uptake, increased insulin signaling pathway, delay of carbohydrate digestion and glucose absorption, and inhibition of protein glycation and insulin fibrillation. However, due to the limited intestinal absorption being a result of low bioavailability of cinnamic acid and its derivatives, current improvement efforts with entrapping into solid and liquid particles are highlighted. Further human clinical studies are needed to clarify the effects of cinnamic acid and its derivatives in diabetic patients.
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Affiliation(s)
- Sirichai Adisakwattana
- Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
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Abstract
Kidney disease is a serious development in diabetes mellitus and poses an increasing clinical problem. Despite increasing incidence and prevalence of diabetic kidney disease, there have been no new therapies for this condition in the last 20 years. Mounting evidence supports a biological role for C-peptide, and findings from multiple studies now suggest that C-peptide may beneficially affect the disturbed metabolic and pathophysiological pathways leading to the development of diabetic nephropathy. Studies of C-peptide in animal models and in humans with type 1 diabetes all suggest a renoprotective effect for this peptide. In diabetic rodents, C-peptide reduces glomerular hyperfiltration and albuminuria. Cohort studies of diabetic patients with combined islet and kidney transplants suggest that maintained C-peptide secretion is protective of renal graft function. Further, in short-term studies of patients with type 1 diabetes, administration of C-peptide is also associated with a lowered hyperfiltration rate and reduced microalbuminuria. Thus, the available information suggests that type 1 diabetes should be regarded as a dual hormone deficiency disease and that clinical trials of C-peptide in diabetic nephropathy are both justified and urgently required.
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Affiliation(s)
- N J Brunskill
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
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Sahoo SS, Mishra C, Rout M, Nayak G, Mohanty ST, Panigrahy KK. Comparative in silico and protein-protein interaction network analysis of ATP1A1 gene. GENE REPORTS 2016. [DOI: 10.1016/j.genrep.2016.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Zhao J, Gregersen H. Diabetes-induced mechanophysiological changes in the esophagus. Ann N Y Acad Sci 2016; 1380:139-154. [PMID: 27495976 DOI: 10.1111/nyas.13180] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 06/17/2016] [Accepted: 06/20/2016] [Indexed: 12/13/2022]
Abstract
Esophageal disorders are common in diabetes mellitus (DM) patients. DM induces mechanostructural remodeling in the esophagus of humans and animal models. The remodeling is related to esophageal sensorimotor abnormalities and to symptoms frequently encountered by DM patients. For example, gastroesophageal reflux disease (GERD) is a common disorder associated with DM. This review addresses diabetic remodeling of esophageal properties and function in light of the Esophagiome, a scientifically based modeling effort to describe the physiological dynamics of the normal, intact esophagus built upon interdisciplinary approaches with applications for esophageal disease. Unraveling the structural, biomechanical, and sensory remodeling of the esophagus in DM must be based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The first focus of this review is DM-induced morphodynamic and biomechanical remodeling in the esophagus. Second, we review the sensorimotor dysfunction in DM and how it relates to esophageal remodeling. Finally, we discuss the clinical consequences of DM-induced esophageal remodeling, especially in relation to GERD. The ultimate aim is to increase the understanding of DM-induced remodeling of esophageal structure and sensorimotor function in order to assist clinicians to better understand the esophageal disorders induced by DM and to develop better treatments for those patients.
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Affiliation(s)
- Jingbo Zhao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Hans Gregersen
- GIOME, Department of Surgery, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong SAR.,GIOME, College of Bioengineering, Chongqing University, Chongqing, China
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Abstract
Over the past decades, hypomagnesemia (serum Mg(2+) <0.7 mmol/L) has been strongly associated with type 2 diabetes mellitus (T2DM). Patients with hypomagnesemia show a more rapid disease progression and have an increased risk for diabetes complications. Clinical studies demonstrate that T2DM patients with hypomagnesemia have reduced pancreatic β-cell activity and are more insulin resistant. Moreover, dietary Mg(2+) supplementation for patients with T2DM improves glucose metabolism and insulin sensitivity. Intracellular Mg(2+) regulates glucokinase, KATP channels, and L-type Ca(2+) channels in pancreatic β-cells, preceding insulin secretion. Moreover, insulin receptor autophosphorylation is dependent on intracellular Mg(2+) concentrations, making Mg(2+) a direct factor in the development of insulin resistance. Conversely, insulin is an important regulator of Mg(2+) homeostasis. In the kidney, insulin activates the renal Mg(2+) channel transient receptor potential melastatin type 6 that determines the final urinary Mg(2+) excretion. Consequently, patients with T2DM and hypomagnesemia enter a vicious circle in which hypomagnesemia causes insulin resistance and insulin resistance reduces serum Mg(2+) concentrations. This Perspective provides a systematic overview of the molecular mechanisms underlying the effects of Mg(2+) on insulin secretion and insulin signaling. In addition to providing a review of current knowledge, we provide novel directions for future research and identify previously neglected contributors to hypomagnesemia in T2DM.
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Affiliation(s)
- Lisanne M M Gommers
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - René J M Bindels
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
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Deb R, Sajjanar B, Singh U, Alex R, Raja TV, Alyethodi RR, Kumar S, Sengar G, Sharma S, Singh R, Prakash B. Understanding the mechanisms of ATPase beta family genes for cellular thermotolerance in crossbred bulls. INTERNATIONAL JOURNAL OF BIOMETEOROLOGY 2015; 59:1783-1789. [PMID: 25875448 DOI: 10.1007/s00484-015-0986-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/13/2015] [Accepted: 03/13/2015] [Indexed: 06/04/2023]
Abstract
Na+/K+-ATPase is an integral membrane protein composed of a large catalytic subunit (alpha), a smaller glycoprotein subunit (beta), and gamma subunit. The beta subunit is essential for ion recognition as well as maintenance of the membrane integrity. Present study was aimed to analyze the expression pattern of ATPase beta subunit genes (ATPase B1, ATPase B2, and ATPase B3) among the crossbred bulls under different ambient temperatures (20-44 °C). The present study was also aimed to look into the relationship of HSP70 with the ATPase beta family genes. Our results demonstrated that among beta family genes, transcript abundance of ATPase B1 and ATPase B2 is significantly (P < 0.05) higher during the thermal stress. Pearson correlation coefficient analysis revealed that the expression of ATPase Β1, ATPase B2, and ATPase B3 is highly correlated (P < 0.01) with HSP70, representing that the change in the expression pattern of these genes is positive and synergistic. These may provide a foundation for understanding the mechanisms of ATPase beta family genes for cellular thermotolerance in cattle.
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Affiliation(s)
- Rajib Deb
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India.
| | - Basavaraj Sajjanar
- School of Atmospheric Stress Management, ICAR-National Institute of Abiotic Stress Management, Baramati, Maharashtra, India
| | - Umesh Singh
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - Rani Alex
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - T V Raja
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - Rafeeque R Alyethodi
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - Sushil Kumar
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - Gyanendra Sengar
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - Sheetal Sharma
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - Rani Singh
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
| | - B Prakash
- Molecular Genetics Laboratory, Division of Animal Genetics & Breeding, ICAR-Central Institute for Research on Cattle, Meerut, 250001, Uttar Pradesh, India
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Altered Expression of Transporters, its Potential Mechanisms and Influences in the Liver of Rodent Models Associated with Diabetes Mellitus and Obesity. Eur J Drug Metab Pharmacokinet 2015; 41:199-210. [PMID: 26597190 DOI: 10.1007/s13318-015-0306-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus is becoming an increasingly prevalent disease that concerns patients and healthcare professionals worldwide. Among many anti-diabetic agents in clinical uses, numerous reports are available on their altered pharmacokinetics because of changes in the expression of drug transporters and metabolic enzymes under diabetic states. These changes may affect the safety and efficacy of therapeutic agents and/or drug-drug interaction with co-administered agents. Therefore, the changes in transporter expression should be identified, and the underlying mechanisms should be clarified. This review summarizes the progress of recent studies on the alterations in important uptake and efflux transporters in liver of diabetic animals and their regulatory pathways.
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Papanas N, Ziegler D. Risk Factors and Comorbidities in Diabetic Neuropathy: An Update 2015. Rev Diabet Stud 2015; 12:48-62. [PMID: 26676661 PMCID: PMC5397983 DOI: 10.1900/rds.2015.12.48] [Citation(s) in RCA: 129] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 04/27/2015] [Accepted: 05/07/2015] [Indexed: 01/01/2023] Open
Abstract
Distal symmetric sensorimotor polyneuropathy (DSPN) is the most common neurological manifestation in diabetes. Major risk factors of DSPN include diabetes duration, hyperglycemia, and age, followed by prediabetes, hypertension, dyslipidemia, and obesity. Height, smoking, insulin resistance, hypoinsulinemia, and others represent an additional risk. Importantly, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking are modifiable. Stringent glycemic control has been shown to be effective in type 1, but not to the same extent in type 2 diabetes. Antilipidemic treatment, especially with fenofibrate, and multi-factorial intervention have produced encouraging results, but more experience is necessary. The major comorbidities of DSPN are depression, autonomic neuropathy, peripheral arterial disease, cardiovascular disease, nephropathy, retinopathy, and medial arterial calcification. Knowledge of risk factors and comorbidities has the potential to enrich the therapeutic strategy in clinical practice as part of the overall medical care for patients with neuropathy. This article provides an updated overview of DSPN risk factors and comorbidities.
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Affiliation(s)
- Nikolaos Papanas
- Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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Sompong W, Cheng H, Adisakwattana S. Protective Effects of Ferulic Acid on High Glucose-Induced Protein Glycation, Lipid Peroxidation, and Membrane Ion Pump Activity in Human Erythrocytes. PLoS One 2015; 10:e0129495. [PMID: 26053739 PMCID: PMC4460125 DOI: 10.1371/journal.pone.0129495] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 05/08/2015] [Indexed: 11/29/2022] Open
Abstract
Ferulic acid (FA) is the ubiquitous phytochemical phenolic derivative of cinnamic acid. Experimental studies in diabetic models demonstrate that FA possesses multiple mechanisms of action associated with anti-hyperglycemic activity. The mechanism by which FA prevents diabetes-associated vascular damages remains unknown. The aim of study was to investigate the protective effects of FA on protein glycation, lipid peroxidation, membrane ion pump activity, and phosphatidylserine exposure in high glucose-exposed human erythrocytes. Our results demonstrated that FA (10-100 μM) significantly reduced the levels of glycated hemoglobin (HbA1c) whereas 0.1-100 μM concentrations inhibited lipid peroxidation in erythrocytes exposed to 45 mM glucose. This was associated with increased glucose consumption. High glucose treatment also caused a significant reduction in Na+/K+-ATPase activity in the erythrocyte plasma membrane which could be reversed by FA. Furthermore, we found that FA (0.1-100 μM) prevented high glucose-induced phosphatidylserine exposure. These findings provide insights into a novel mechanism of FA for the prevention of vascular dysfunction associated with diabetes.
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Affiliation(s)
- Weerachat Sompong
- Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- Research Group of Herbal Medicine for Prevention and Therapeutic of Metabolic Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Henrique Cheng
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America
| | - Sirichai Adisakwattana
- Research Group of Herbal Medicine for Prevention and Therapeutic of Metabolic Diseases, Chulalongkorn University, Bangkok, Thailand
- Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- * E-mail:
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Rodinsky AG, Zinov'eva EG, Trushenko AS, Kachan MJ. [The evoked activity of the dorsal root afferent fibres of the spinal cord of white rats in experimental diabetes mellitus]. ACTA ACUST UNITED AC 2015; 61:72-7. [PMID: 26040038 DOI: 10.15407/fz61.01.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We analyzed the functional status of the dorsal root of spinal cord in experimental diabetes mellitus (DM), for instance the parameters of the action potential (AP): threshold, chronaxy and the dynamics of the dorsal root excitability. It was revealed the 1,5 times increase in threshold of excitation when compared to the control animals (P<0,001), the amplitude of AP decreased by 21,7% (P<0,05). It was also revealed a significant increase in response to the 2nd stimulus under applying the paired stimuli on the sciatic nerve in animals with experimental DM. Under applying the stimuli of increasing intensity there was found significant decrease in the amplitude of the AP in animals of the experimental group. It was concluded that hyperglycemia made changes to the processes of excitability and refractoriness in the afferent fibers of the spinal cord.
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Zucker diabetic fatty rats, a model for type 2 diabetes, develop an inner ear dysfunction that can be attenuated by losartan treatment. Cell Tissue Res 2015; 362:307-15. [DOI: 10.1007/s00441-015-2215-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 05/12/2015] [Indexed: 12/13/2022]
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Richards JP, Yosten GLC, Kolar GR, Jones CW, Stephenson AH, Ellsworth ML, Sprague RS. Low O2-induced ATP release from erythrocytes of humans with type 2 diabetes is restored by physiological ratios of C-peptide and insulin. Am J Physiol Regul Integr Comp Physiol 2014; 307:R862-8. [PMID: 25080497 DOI: 10.1152/ajpregu.00206.2014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ATP release from erythrocytes in response to reduced oxygen (O2) tension stimulates local vasodilation, enabling these cells to direct perfusion to areas in skeletal muscle in need of O2. Erythrocytes of humans with type 2 diabetes do not release ATP in response to low O2. Both C-peptide and insulin individually inhibit low O2-induced ATP release from healthy human erythrocytes, yet when coadministered at physiological concentrations and ratios, no inhibition is seen. Here, we determined: that 1) erythrocytes of healthy humans and humans with type 2 diabetes possess a C-peptide receptor (GPR146), 2) the combination of C-peptide and insulin at physiological ratios rescues low O2-induced ATP release from erythrocytes of humans with type 2 diabetes, 3) residual C-peptide levels reported in humans with type 2 diabetes are not adequate to rescue low O2-induced ATP release in the presence of 1 nM insulin, and 4) the effects of C-peptide and insulin are neither altered by increased glucose levels nor explained by changes in erythrocyte deformability. These results suggest that the addition of C-peptide to the treatment regimen for type 2 diabetes could have beneficial effects on tissue oxygenation, which would help to ameliorate the concomitant peripheral vascular disease.
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Affiliation(s)
- Jennifer P Richards
- Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
| | - Gina L C Yosten
- Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
| | - Grant R Kolar
- Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
| | - Cory W Jones
- Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
| | - Alan H Stephenson
- Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
| | - Mary L Ellsworth
- Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
| | - Randy S Sprague
- Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri
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Calgaroto NS, Thomé GR, da Costa P, Baldissareli J, Hussein FA, Schmatz R, Rubin MA, Signor C, Ribeiro DA, Carvalho FB, de Oliveira LS, Pereira LB, Morsch VM, Schetinger MRC. Effect of vitamin D3on behavioural and biochemical parameters in diabetes type 1-induced rats. Cell Biochem Funct 2014; 32:502-10. [DOI: 10.1002/cbf.3044] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Revised: 05/30/2014] [Accepted: 06/02/2014] [Indexed: 12/18/2022]
Affiliation(s)
- Nicéia Spanholi Calgaroto
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Gustavo Roberto Thomé
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Pauline da Costa
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Jucimara Baldissareli
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Fátima Abdala Hussein
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Roberta Schmatz
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Maribel A. Rubin
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Cristiane Signor
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Daniela Aymone Ribeiro
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Fabiano Barbosa Carvalho
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Lizielle Souza de Oliveira
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Luciane Belmonte Pereira
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Vera Maria Morsch
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
| | - Maria Rosa Chitolina Schetinger
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Departamento de Química; Universidade Federal de Santa Maria, Campus Universitário; Santa Maria Rio Grande do Sul Brazil
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Latha R, Shanthi P, Sachdanandam P. Kalpaamruthaa Ameliorates Mitochondrial and Metabolic Alterations in Diabetes Mellitus Induced Cardiovascular Damage. J Diet Suppl 2014; 11:305-19. [DOI: 10.3109/19390211.2014.887599] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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49
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Askwith T. Taurine Treatment for Complications of Diabetes. OXIDATIVE STRESS IN APPLIED BASIC RESEARCH AND CLINICAL PRACTICE 2014. [DOI: 10.1007/978-1-4899-8035-9_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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50
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Uptake of advanced glycation end products by proximal tubule epithelial cells via macropinocytosis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2013; 1833:2922-2932. [DOI: 10.1016/j.bbamcr.2013.05.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 05/15/2013] [Accepted: 05/28/2013] [Indexed: 11/15/2022]
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