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Gholami Z, Clark CCT, Paknahad Z. The effect of psyllium on fasting blood sugar, HbA1c, HOMA IR, and insulin control: a GRADE-assessed systematic review and meta-analysis of randomized controlled trials. BMC Endocr Disord 2024; 24:82. [PMID: 38844885 PMCID: PMC11155034 DOI: 10.1186/s12902-024-01608-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 05/23/2024] [Indexed: 06/10/2024] Open
Abstract
There is equivocal evidence that psyllium can prevent or attenuate increases in fasting blood sugar. Therefore, this systematic review and meta-analysis sought to investigate the influence of psyllium on hemoglobin A1C (HbA1c), fasting blood sugar (FBS), insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA IR). We searched PubMed, ISI Web of Science (WOS), and Scopus for eligible publications, up to 15 July 2022, including randomized controlled trials (RCT) assessing the effect of psyllium on HbA1c, FBS, insulin, and HOMA IR levels in adults. Using a random effects model, we report the weighted mean differences (WMD) with 95% confidence intervals (CI). In this article, 19 RCT studies, consisting of 962 participants, were included. Psyllium significantly decreased FBS, HbA1c, and HOMA IR levels, but not insulin levels, as compared to placebo (FBS: WMD): -6.89; 95% CI: -10.62, -3.16; p < .001), HbA1c: (WMD: -0.75; 95% CI: -1.21, -0.29; p < .001), HOMA IR: (WMD: -1.17; 95% CI: -2.11, -0.23; p < .05), and insulin: (WMD: -2.08; 95% CI: -4.21, -0.035; p > .05)). Subgroup analyses illustrated differences in the effects of psyllium on FBS: dosages less than and more than 10 g/d showed significant differences (p value < 0.05). However, it was not significant in intervention durations less than 50 days (p value > 0.05). For HbA1c: psyllium consumption less than 10 g/d (p value > 0.05) was non-significant. For HOMA IR and insulin: no significant changes were noted with psyllium consumption less than vs. more than 10 g/d. In conclusion, we found that psyllium could significantly decrease FBS, HbA1c, and HOMA IR levels, but not insulin levels, as compared to placebo.
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Affiliation(s)
- Zeinab Gholami
- Ph.D Candidate of Nutrition, School of Nutrition and Food Science, Students' Research Committee , Isfahan University of Medical Sciences, Isfahan, Iran
- Department of clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Cain C T Clark
- Research Institute for Health and Wellbeing, Coventry University, CV1 5FB, Coventry, United Kingdom
| | - Zamzam Paknahad
- Professor of Nutrition, Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
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Salama RAM, Raafat FA, Hasanin AH, Hendawy N, Saleh LA, Habib EK, Hamza M, Hassan ANE. A neuroprotective effect of pentoxifylline in rats with diabetic neuropathy: Mitigation of inflammatory and vascular alterations. Int Immunopharmacol 2024; 128:111533. [PMID: 38271813 DOI: 10.1016/j.intimp.2024.111533] [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: 11/11/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 01/27/2024]
Abstract
BACKGROUND Treatment of diabetic neuropathic pain does not change the natural history of neuropathy. Improved glycemic control is the recommended treatment in these cases, given that no specific treatment for the underlying nerve damage is available, so far. In the present study, the potential neuroprotective effect of pentoxifylline in streptozotocin (50 mg/kg) induced diabetic neuropathy in rats was investigated. METHODS Pentoxifylline was administered at doses equivalent to 50, 100 & 200 mg/kg, in drinking water, starting one week after streptozotocin injection and for 7 weeks. Mechanical allodynia, body weight and blood glucose level were assessed weekly. Epidermal thickness of the footpad skin, and neuroinflammation and vascular alterations markers were assessed. RESULTS Tactile allodynia was less in rats that received pentoxifylline at doses of 100 and 200 mg/kg (60 % mechanical threshold increased by 48 % and 60 %, respectively). The decrease in epidermal thickness of footpad skin was almost completely prevented by the same doses. This was associated with a decrease in spinal tumor necrosis factor alpha (TNFα) and nuclear factor kappa B levels and a decrease in microglial ionized calcium binding adaptor molecule 1 immunoreactivity, compared to the control diabetic group. In sciatic nerve, there was decrease in TNF-α and vascular endothelial growth factor levels and intercellular adhesion molecule immunoreactivity. CONCLUSION Pentoxifylline showed a neuroprotective effect in streptozotocin-induced diabetic neuropathy, which was associated with a suppression of both the inflammatory and vascular pathogenic pathways that was not associated with a hypoglycemic effect. Thus, it may represent a potential neuroprotective drug for diabetics.
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Affiliation(s)
- Raghda A M Salama
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Fatema Ahmed Raafat
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Amany Helmy Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nevien Hendawy
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Galala University, Suez, Egypt
| | - Lobna A Saleh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Eman K Habib
- Faculty of Medicine, Galala University, Suez, Egypt; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - May Hamza
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Ahmed Nour Eldin Hassan
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Galala University, Suez, Egypt
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Kaur N, Kishore L, Farooq SA, Kajal A, Singh R, Agrawal R, Mannan A, Singh TG. Cucurbita pepo seeds improve peripheral neuropathy in diabetic rats by modulating the inflammation and oxidative stress in rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:85910-85919. [PMID: 37400700 DOI: 10.1007/s11356-023-28339-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 06/12/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND Cucurbita pepo (C. pepo) is cultivated and used traditionally as vegetable as well as medicine in different parts of the world. The aim of current study was to investigate the potential of C. pepo in attenuation of diabetic neuropathy via using streptozotocin (STZ)-induced diabetes model in male wistar rats. MATERIALS AND METHODS Diabetic neuropathy was induced by administration of STZ; 65 mg/kg, i.p. and Nicotinamide (NAD; 230 mg/kg i.p.) and assessed by measuring thermal hyperalgesia, mechanical hyperalgesia and motor nerve conduction velocity (MNCV) in experimental animals. Treatment with different doses of (100, 200 and 400 mg/kg, p.o.) petroleum ether extract of C. pepo (CPE) and hydroethanolic extract of C. pepo (CHE) was started from the 60th day of STZ/NAD administration and continued upto 90th day. RESULTS CPE and CHE significantly attenuated the behavioural changes including hyperalgesia, allodynia and MNCV linked to diabetic neuropathy. Moreover, the oxidative stress and level of TNF-α, TGF-β and IL-1β was found to be significantly attenuated in experimental animals. CONCLUSION Thus C. pepo might ameliorate the progression of diabetic neuropathy via modulation of chronic hyperglycemia and therefore and have therapeutic potential for treatment of diabetic neuropathic pain.
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Affiliation(s)
- Navpreet Kaur
- M.M. College of Pharmacy, M.M. (Deemed to Be) University, Mullana-Ambala, Haryana, 133207, India
| | - Lalit Kishore
- Faculty of Health Sciences, University of Ottawa, Montréal, ON, K1H 8L1, Canada
| | - Shah Asma Farooq
- M.M. College of Pharmacy, M.M. (Deemed to Be) University, Mullana-Ambala, Haryana, 133207, India
| | - Anu Kajal
- M.M. College of Pharmacy, M.M. (Deemed to Be) University, Mullana-Ambala, Haryana, 133207, India
| | - Randhir Singh
- College of Pharmacy, JSS Academy of Technical Education, Uttar Pradesh, Noida, 201309, India
| | - Rohini Agrawal
- Department of Pharmacology, Central University of Punjab, Ghudda, 151401, Bathinda, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
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Sher EK, Prnjavorac B, Farhat EK, Palić B, Ansar S, Sher F. Effect of Diabetic Neuropathy on Reparative Ability and Immune Response System. Mol Biotechnol 2023:10.1007/s12033-023-00813-z. [PMID: 37523019 DOI: 10.1007/s12033-023-00813-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/23/2023] [Indexed: 08/01/2023]
Abstract
The effects of diabetes can be divided into short, medium and long term and various human organ systems can be effected. The present study aimed to determine how much the duration of diabetes mellitus (DM) affect the reparative ability of the body, immune response and the development of DM complications. Interleukin 1-β (IL-1β) and Interleukin 6 (IL-6) were monitored as specific indicators of inflammatory reaction and C-reactive protein (CRP), leukocyte count (WBC) and sedimentation rate (ESR) as general markers of inflammatory reaction. Tumour necrosis factor α (TNF-α) and transforming growth factor β1 (TGF-β1) were observed as indicators of reparative ability and polyneuropathy. All interleukins were determined by ELISA and evaluated spectrophotometrically. Michigan Neuropathy Screening Instrument (MNSI) is performed for neuropathy examination. Patients with diabetes mellitus were divided into 3 groups, according to duration of diabetes mellitus. IL-6 levels correlated with clinical stage of diabetic polyneuropathy at p = 0.025 R = 0.402; with CRP at p = 0.0001, R = 0.784 as well as correlation of CRP and MNSI score (R = 0.500, p = 0.034) in a group of patients with DM lasting up to 10 years. The reparative ability of the body is reduced by physiological age and ages of DM duration. The immune response is weakened in DM additionally. The dual activity of cytokines IL-6 and TGF-β1 is present in long-duration Diabetes Mellitus.
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Affiliation(s)
- Emina Karahmet Sher
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK.
| | - Besim Prnjavorac
- Department of Pathophysiology, Faculty of Pharmacy, University of Sarajevo, Sarajevo, 71000, Bosnia and Herzegovina
| | - Esma Karahmet Farhat
- Department of Food and Nutrition Research, Faculty of Food Technology, University of Osijek Juraj Strossmayer, Osijek, 31000, Croatia
- International Society of Engineering Science and Technology, Nottingham, UK
| | - Benjamin Palić
- Department of Internal Medicine, University Clinical Hospital Mostar, Mostar, 88000, Bosnia and Herzegovina
| | - Sabah Ansar
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | - Farooq Sher
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK.
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Pușcașu C, Ungurianu A, Șeremet OC, Andrei C, Mihai DP, Negreș S. The Influence of Sildenafil-Metformin Combination on Hyperalgesia and Biochemical Markers in Diabetic Neuropathy in Mice. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1375. [PMID: 37629665 PMCID: PMC10456948 DOI: 10.3390/medicina59081375] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023]
Abstract
Background and objectives: Worldwide, approximately 500 million people suffer from diabetes and at least 50% of these people develop neuropathy. Currently, therapeutic strategies for reducing diabetic neuropathy (DN)-associated pain are limited and have several side effects. The purpose of the study was to evaluate the antihyperalgesic action of different sildenafil (phosphodiesterase-5 inhibitor) and metformin (antihyperglycemic agent) combinations in alloxan-induced DN. Methods: The study included 100 diabetic mice and 20 non-diabetic mice that were subjected to hot and cold stimulus tests. Furthermore, we determined the influence of this combination on TNF-α, IL-6 and nitrites levels in brain and liver tissues. Results: In both the hot-plate and tail withdrawal test, all sildenafil-metformin combinations administered in our study showed a significant increase in pain reaction latencies when compared to the diabetic control group. Furthermore, all combinations decreased blood glucose levels due to the hypoglycemic effect of metformin. Additionally, changes in nitrite levels and pro-inflammatory cytokines (TNF-α and IL-6) were observed after 14 days of treatment with different sildenafil-metformin combinations. Conclusions: The combination of these two substances increased the pain reaction latency of diabetic animals in a dose-dependent manner. Moreover, all sildenafil-metformin combinations significantly reduced the concentration of nitrites in the brain and liver, which are final products formed under the action of iNOS.
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Affiliation(s)
| | | | - Oana Cristina Șeremet
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.)
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Vieira WF, Malange KF, de Magalhães SF, Lemes JBP, Dos Santos GG, Nishijima CM, de Oliveira ALR, da Cruz-Höfling MA, Tambeli CH, Parada CA. Anti-hyperalgesic effects of photobiomodulation therapy (904 nm) on streptozotocin-induced diabetic neuropathy imply MAPK pathway and calcium dynamics modulation. Sci Rep 2022; 12:16730. [PMID: 36202956 PMCID: PMC9537322 DOI: 10.1038/s41598-022-19947-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 09/06/2022] [Indexed: 11/23/2022] Open
Abstract
Several recent studies have established the efficacy of photobiomodulation therapy (PBMT) in painful clinical conditions. Diabetic neuropathy (DN) can be related to activating mitogen-activated protein kinases (MAPK), such as p38, in the peripheral nerve. MAPK pathway is activated in response to extracellular stimuli, including interleukins TNF-α and IL-1β. We verified the pain relief potential of PBMT in streptozotocin (STZ)-induced diabetic neuropathic rats and its influence on the MAPK pathway regulation and calcium (Ca2+) dynamics. We then observed that PBMT applied to the L4-L5 dorsal root ganglion (DRG) region reduced the intensity of hyperalgesia, decreased TNF-α and IL-1β levels, and p38-MAPK mRNA expression in DRG of diabetic neuropathic rats. DN induced the activation of phosphorylated p38 (p-38) MAPK co-localized with TRPV1+ neurons; PBMT partially prevented p-38 activation. DN was related to an increase of p38-MAPK expression due to proinflammatory interleukins, and the PBMT (904 nm) treatment counteracted this condition. Also, the sensitization of DRG neurons by the hyperglycemic condition demonstrated during the Ca2+ dynamics was reduced by PBMT, contributing to its anti-hyperalgesic effects.
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Affiliation(s)
- Willians Fernando Vieira
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Kauê Franco Malange
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Silviane Fernandes de Magalhães
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Júlia Borges Paes Lemes
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Gilson Gonçalves Dos Santos
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Catarine Massucato Nishijima
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Alexandre Leite Rodrigues de Oliveira
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Maria Alice da Cruz-Höfling
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Cláudia Herrera Tambeli
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil
| | - Carlos Amilcar Parada
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Carl von Linnaeus n/n, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-864, Brazil.
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Dastgheib M, Shetab-Boushehri SV, Baeeri M, Gholami M, Karimi MY, Hosseini A. Rolipram and pentoxifylline combination ameliorates experimental diabetic neuropathy through inhibition of oxidative stress and inflammatory pathways in the dorsal root ganglion neurons. Metab Brain Dis 2022; 37:2615-2627. [PMID: 35922732 DOI: 10.1007/s11011-022-01060-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 07/30/2022] [Indexed: 10/16/2022]
Abstract
Diabetic neuropathy (DN) is the most challenging microvascular complication of diabetes and there is no suitable treatment for it, so the development of new agents to relieve DN is urgently needed. Since oxidative stress and inflammation play an essential role in the development of DN, clearance of these factors are good strategies for the treatment of this disease. According to key role of cyclic adenosine monophosphate (cAMP) in the regulation of oxidative stress and inflammatory pathways, it seems that phosphodiesterase inhibitors (PDEIs) can be as novel drug targets for improving DN through enhancement of cAMP level. The aim of this study was to evaluate the effects of rolipram, a selective PDE4 inhibitor, and pentoxifylline, a general PDE inhibitor on experimental model of DN and also to determine the possible mechanisms involved in the effectiveness of these agents. We investigated the effects of rolipram (1 mg/kg) and pentoxifylline (100 mg/kg) and also combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for five weeks in rats that became diabetic by STZ (55 mg/kg, i.p.). After treatments, motor function was evaluated by open-field test, then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Next, oxidative stress biomarkers and inflammatory factors were assessed by biochemical and ELISA methods, and RT-PCR analysis in DRG neurons. Rolipram and/or pentoxifylline treatment significantly attenuated DN - induced motor function deficiency by modulating distance moved and velocity. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, as well as suppressed DN - induced oxidative stress which was associated with decrease in LPO and ROS and increase in TAC, total thiol, CAT and SOD in DRG neurons. On the other hand, the level of inflammatory factors (TNF-α, NF-kB and COX2) significantly decreased following rolipram and/or pentoxifylline administration. The maximum effectiveness was with rolipram and/or pentoxifylline combination on mentioned factors. These findings provide novel experimental evidence for further clinical investigations on rolipram and pentoxifylline combination for the treatment of DN.
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Affiliation(s)
- Mona Dastgheib
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Baeeri
- Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Gholami
- Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | | | - Asieh Hosseini
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Ghazipour AM, Pourheydar B, Naderi R. The effect of tropisetron on peripheral diabetic neuropathy: possible protective actions against inflammation and apoptosis. Cell Stress Chaperones 2022; 27:513-521. [PMID: 35972643 PMCID: PMC9485520 DOI: 10.1007/s12192-022-01287-9] [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: 02/04/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 11/03/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1 diabetes was created by a single injection of streptozotocin (50 mg/kg, ip). Tropisetron (3 mg/kg, ip) was administered daily for 2 weeks. Our analysis showed that nerve fibers and their myelin sheaths were thinned with decreased myelinated fiber number in diabetic animals. The intensity of Bcl-2 staining decreased and the intensity of Bax staining increased in the sciatic nerves of diabetic rats by using immunohistochemical staining. Furthermore, diabetes significantly increased tumor necrosis factor-alpha, interleukin 1-β (TNFα and IL-1β) and Bax/Bcl-2 ratio in sciatic nerves of rats. However, intraperitoneal injection of tropisetron significantly reversed these alterations induced by diabetes. These findings suggest that tropisetron attenuates diabetes-induced peripheral nerve injury through its anti-inflammatory and anti-apoptotic effects, and may provide a novel therapeutic strategy to ameliorate the process of peripheral neuropathy in diabetes.
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Affiliation(s)
| | - Bagher Pourheydar
- Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Anatomical Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Roya Naderi
- Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran.
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Goyal S, Sood A, Gautam I, Pradhan S, Mondal P, Singh G, Jaura RS, Singh TG, Sibia RS. Serum protease-activated receptor (PAR-1) levels as a potential biomarker for diagnosis of inflammation in type 2 diabetic patients. Inflammopharmacology 2022; 30:1843-1851. [PMID: 35974263 DOI: 10.1007/s10787-022-01049-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/03/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Inflammation is a prominent clinical manifestation in type 2 diabetes mellitus (T2DM) patients, often associated with insulin resistance, metabolic dysregulation, and other complications. AIM OF THE STUDY The present study has been designed to check the serum levels of PAR-1 and correlate with various clinical manifestations and inflammatory cytokines levels in type 2 diabetic subjects. MATERIAL AND METHODS The study population was divided into two groups, healthy volunteers (n = 15): normal glycated hemoglobin (HbA1c) (4.26 ± 0.55) and type 2 diabetic subjects (n = 30): HbA1c levels (7.80 ± 2.41). The serum levels of PAR-1 (ELISA method) were studied in both groups and correlated with demographic parameters age, weight, body mass index (BMI), and conventional inflammation biomarkers like C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumour necrosis factor-alpha (TNF-α). RESULTS The demographic variables including the body weight (77.38 ± 10.00 vs. controls 55.26 ± 6.99), BMI (29.39 ± 3.61 vs. controls 25.25 ± 4.01), glycemic index HbA1c (7.80 ± 2.41 vs. controls 4.26 ± 0.55) were found to be statistically increased in T2DM subjects than the healthy control group. The levels of various inflammatory biomarkers and PAR-1 were significantly elevated in T2DM groups in comparison to healthy volunteers. The univariate and multivariate regression analysis revealed that elevated PAR-1 levels positively correlated with increased body weight, BMI, HbA1c, and inflammatory cytokines. CONCLUSION Our findings indicate that the elevated serum PAR-1 levels serve as an independent predictor of inflammation in T2DM subjects and might have prognostic value for determining T2DM progression.
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Affiliation(s)
- Sanjay Goyal
- Government Medical College, Patiala, Punjab, India
| | - Ankita Sood
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Isha Gautam
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Soumyadip Pradhan
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Puskar Mondal
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Gaaminepreet Singh
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India.
| | - Ravinder Singh Jaura
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
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Isolation of Thymol from Trachyspermum ammi Fruits for Treatment of Diabetes and Diabetic Neuropathy in STZ-Induced Rats. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8263999. [PMID: 35528161 PMCID: PMC9071892 DOI: 10.1155/2022/8263999] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/06/2022] [Indexed: 11/23/2022]
Abstract
Terpenoids and phenols from Trachyspermum ammi (T. ammi) have reported some pharmacological actions. The objective of the work was to isolate the active constituent, its identification by spectroscopic techniques, and evaluation of the antidiabetic and neuroprotective activity from T. ammi on STZ Wistar rats. The dried fruits of T ammi were kept in a hydrodistillation apparatus to collect essential oil. The isolated fraction went through TLC, UV, FTIR, HPLC, HRMS, C13, and 1H NMR for characterization. Two dosage concentrations from the isolated compound were prepared as 10 and 20 mg/kg for treatment groups. The groups were tested for thermal and mechanical hyperalgesia, writhing, grip strength, spontaneous locomotor test, neuromuscular coordination tests, and histopathological and lipid profile analysis. Diabetes was induced by streptozotocin (45 mg/kg i.p.) and 12 weeks of treatment-induced diabetic neuropathy in Wistar rats. Biomarkers were evaluated to understand the neuropathic protection of thymol on STZ-treated Wistar rats. The biomarker studies (SOD, NO, LPO, Na+K+ATPase, and TNF-α) further confirmed thymol's diabetic neuropathy protective action. This study suggests that isolated compound thymol was antidiabetic and neuroprotective as it has shown controlled glucose levels defensive nerve damage in STZ Wistar rats. P < 0.05 level of significance was observed in the levels of endogenous biomarkers, fasting blood glucose levels, actophotometer response, and response latency in treated groups compared to the diabetic group, whereas P < 0.001 level of significance during lipid profile levels, thermal algesia, and neuromuscular comparison tests was noted in treated groups compared to the diabetic group.
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Bhamidipati T, Kumar M, Verma SS, Mohanty SK, Kacar S, Reese D, Martinez MM, Kamocka MM, Dunn KW, Sen CK, Singh K. Epigenetic basis of diabetic vasculopathy. Front Endocrinol (Lausanne) 2022; 13:989844. [PMID: 36568089 PMCID: PMC9780391 DOI: 10.3389/fendo.2022.989844] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) causes peripheral vascular disease because of which several blood-borne factors, including vital nutrients fail to reach the affected tissue. Tissue epigenome is sensitive to chronic hyperglycemia and is known to cause pathogenesis of micro- and macrovascular complications. These vascular complications of T2DM may perpetuate the onset of organ dysfunction. The burden of diabetes is primarily because of a wide range of complications of which nonhealing diabetic ulcers represent a major component. Thus, it is imperative that current research help recognize more effective methods for the diagnosis and management of early vascular injuries. This review addresses the significance of epigenetic processes such as DNA methylation and histone modifications in the evolution of macrovascular and microvascular complications of T2DM.
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Affiliation(s)
- Theja Bhamidipati
- Department of Vascular Surgery, Jefferson-Einstein Medical Center, Philadelphia, PA, United States
| | - Manishekhar Kumar
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sumit S. Verma
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sujit K. Mohanty
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sedat Kacar
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Diamond Reese
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Michelle M. Martinez
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Malgorzata M. Kamocka
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kenneth W. Dunn
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chandan K. Sen
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
- *Correspondence: Kanhaiya Singh, ; Chandan K. Sen,
| | - Kanhaiya Singh
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
- *Correspondence: Kanhaiya Singh, ; Chandan K. Sen,
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12
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Gouliopoulos N, Siasos G, Bouratzis N, Oikonomou E, Kollia C, Konsola T, Oikonomou D, Rouvas A, Kassi E, Tousoulis D, Moschos MM. Polymorphism analysis of ADIPOQ gene in Greek patients with diabetic retinopathy. Ophthalmic Genet 2021; 43:326-331. [PMID: 34895017 DOI: 10.1080/13816810.2021.2015787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Several genetic polymorphisms have been identified as risk factors for diabetic retinopathy (DR) onset. The purpose of our study was to determine whether ADIPOQ rs1501299 and rs2241766 gene polymorphisms are associated with DR in a cohort of Greek diabetic patients. MATERIALS AND METHODS 218 patients with type-2 diabetes mellitus (T2DM) were included in the study; 109 suffered from DR and 109 not. All the participants underwent a complete ophthalmological examination, while clinical and demographic data were assessed. Furthermore, they were genotyped for G276T (rs1501299) and T45G (rs2241766) single nucleotide polymorphisms of ADIPOQ gene. RESULTS Between the studied groups, no significant differences were detected regarding the demographic and clinical data (p > .05 for all), except for hemoglobin A1c levels and frequency of insulin treatment (higher in DR patients). We detected that the frequency of rs1501299 GT genotype was significantly elevated in DR patients (53% vs. 34%, p = .004) and was associated with a higher risk of developing retinopathy (OR 2.31, 95% CI 1.30-4.11). Furthermore, we demonstrated that the rs1501299 GT genotype was significantly and independently associated with increased odds for DR development in diabetic subjects (OR 2.68, 95% CI 1.38-5.21, p = .004), regardless of the impact of other known risk factors. CONCLUSIONS We documented that rs1501299 GT genotype could be recognized as an independent risk factor of retinopathy in T2DM Greek patients, while no role for rs2241766 polymorphism was identified. Further research in different ethnic groups will clarify the exact association of these polymorphisms with the risk of DR development.
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Affiliation(s)
- Nikolaos Gouliopoulos
- 2nd Department of Ophthalmology, University of Athens Medical School, Athens, Greece.,1st Department of Ophthalmology, University of Athens Medical School, Athens, Greece
| | - Gerasimos Siasos
- 1st Department of Cardiology, University of Athens Medical School, Athens, Greece
| | - Nikolaos Bouratzis
- 2 Department of Ophthalmology, University of Athens Medical School, Athens, Greece
| | - Evangelos Oikonomou
- 1 Department of Cardiology, University of Athens Medical School, Athens, Greece
| | - Christina Kollia
- 1 Department of Cardiology, University of Athens Medical School, Athens, Greece
| | - Theodosia Konsola
- 1 Department of Cardiology, University of Athens Medical School, Athens, Greece
| | - Dimitra Oikonomou
- 2 Department of Ophthalmology, University of Athens Medical School, Athens, Greece
| | - Alexandros Rouvas
- 2 Department of Ophthalmology, University of Athens Medical School, Athens, Greece
| | - Eva Kassi
- 1st Department of Propaedeutic and Internal Medicine, Division of Diabetes, University of Athens Medical School, Athens, Greece
| | - Dimitrios Tousoulis
- 1 Department of Cardiology, University of Athens Medical School, Athens, Greece
| | - Marilita M Moschos
- 1 Department of Ophthalmology, University of Athens Medical School, Athens, Greece
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Ma X, Song M, Yan Y, Ren G, Hou J, Qin G, Wang W, Li Z. Albiflorin alleviates cognitive dysfunction in STZ-induced rats. Aging (Albany NY) 2021; 13:18287-18297. [PMID: 34319254 PMCID: PMC8351685 DOI: 10.18632/aging.203274] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/14/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND To explore the effect of albiflorin (AL) on streptozotocin (STZ)-induced Alzheimer's disease (AD) in rats. METHODS A mouse model of diabetic encephalopathy was established by intraperitoneal injection of 1%STZ. Step down test and water maze test were used to test the cognitive function of rats. Congo Red Staining was used to detect the distribution of Aβ plaques in the hippocampus of rats. Cytokine levels in serum and hippocampus were measured using ELISA. Serum insulin, oral glucose tolerance (OGTT), serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured by commercial kits. And the content of Nrf-2/HO-1/HMGB1/NF-kB in the hippocampus of diabetic rats were detected by western blot. RESULTS AND CONCLUSION Compared with the STZ model group, the average escape latency of rats in the AL group in the Morris water maze test was significantly shortened, and the average number of platform crossings and the ratio of distance/total swimming distance in the target quadrant were increased significantly. Staining of tissue sections and ELISA showed a decrease in Aβ plaque density in the hippocampus of rats in the AL group. And serum insulin levels of rats in the ALgroup were significantly reduced and OGTT was improved. In addition, AL could also regulate the Nrf-2/HO-1/HMGB1/NF-kB signal pathway in the hippocampus. Therefore, AL may ameliorate STZ-induced cognitive impairment in rats by regulating oxidative stress and inflammation in the brain.
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Affiliation(s)
- Xiaojun Ma
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Min Song
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yushan Yan
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Gaofei Ren
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jingwen Hou
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Guijun Qin
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Wang Wang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Zhizhen Li
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
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Fullerene C60 nanoparticle attenuates pain and tumor necrosis factor-α protein expression in hippocampus following diabetic neuropathy in rats. PHYSIOLOGY AND PHARMACOLOGY 2021. [DOI: 10.52547/phypha.26.4.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Therapeutic Potential of Polyphenols in the Management of Diabetic Neuropathy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:9940169. [PMID: 34093722 PMCID: PMC8137294 DOI: 10.1155/2021/9940169] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022]
Abstract
Diabetic neuropathy (DN) is a common and serious diabetes-associated complication that primarily takes place because of neuronal dysfunction in patients with diabetes. Use of current therapeutic agents in DN treatment is quite challenging because of their severe adverse effects. Therefore, there is an increased need of identifying new safe and effective therapeutic agents. DN complications are associated with poor glycemic control and metabolic imbalances, primarily oxidative stress (OS) and inflammation. Various mediators and signaling pathways such as glutamate pathway, activation of channels, trophic factors, inflammation, OS, advanced glycation end products, and polyol pathway have a significant contribution to the progression and pathogenesis of DN. It has been indicated that polyphenols have the potential to affect DN pathogenesis and could be used as potential alternative therapy. Several polyphenols including kolaviron, resveratrol, naringenin, quercetin, kaempferol, and curcumin have been administered in patients with DN. Furthermore, chlorogenic acid can provide protection against glutamate neurotoxicity via its hydrolysate, caffeoyl acid group, and caffeic acid through regulating the entry of calcium into neurons. Epigallocatechin-3-gallate treatment can protect motor neurons by regulating the glutamate level. It has been demonstrated that these polyphenols can be promising in combating DN-associated damaging pathways. In this article, we have summarized DN-associated metabolic pathways and clinical manifestations. Finally, we have also focused on the roles of polyphenols in the treatment of DN.
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Purohit S, Tran PMH, Tran LKH, Satter KB, He M, Zhi W, Bai S, Hopkins D, Gardiner M, Wakade C, Bryant J, Bernard R, Morgan J, Bode B, Reed JC, She JX. Serum Levels of Inflammatory Proteins Are Associated With Peripheral Neuropathy in a Cross-Sectional Type-1 Diabetes Cohort. Front Immunol 2021; 12:654233. [PMID: 33868296 PMCID: PMC8044415 DOI: 10.3389/fimmu.2021.654233] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/08/2021] [Indexed: 01/14/2023] Open
Abstract
Chronic low-grade inflammation is involved in the pathogenesis of type-1 diabetes (T1D) and its complications. In this cross-section study design, we investigated association between serum levels of soluble cytokine receptors with presence of peripheral neuropathy in 694 type-1 diabetes patients. Sex, age, blood pressure, smoking, alcohol intake, HbA1c and lipid profile, presence of DPN (peripheral and autonomic), retinopathy and nephropathy was obtained from patient’s chart. Measurement of soluble cytokine receptors, markers of systemic and vascular inflammation was done using multiplex immunoassays. Serum levels were elevated in in DPN patients, independent of gender, age and duration of diabetes. Crude odds ratios were significantly associated with presence of DPN for 15/22 proteins. The Odds ratio (OR) remained unchanged for sTNFRI (1.72, p=0.00001), sTNFRII (1.45, p=0.0027), sIL2Rα (1.40, p=0.0023), IGFBP6 (1.51, p=0.0032) and CRP (1.47, p=0.0046) after adjusting for confounding variables, HbA1C, hypertension and dyslipidemia. Further we showed risk of DPN is associated with increase in serum levels of sTNFRI (OR=11.2, p<10), sIL2Rα (8.69, p<10-15), sNTFRII (4.8, p<10-8) and MMP2 (4.5, p<10-5). We combined the serum concentration using ridge regression, into a composite score, which can stratify the DPN patients into low, medium and high-risk groups. Our results here show activation of inflammatory pathway in DPN patients, and could be a potential clinical tool to identify T1D patients for therapeutic intervention of anti-inflammatory therapies.
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Affiliation(s)
- Sharad Purohit
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States.,Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Undergraduate Health Professionals, College of Allied Health Sciences, Augusta University, Augusta, GA, United States
| | - Paul Minh Huy Tran
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Lynn Kim Hoang Tran
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Khaled Bin Satter
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Mingfang He
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Wenbo Zhi
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Shan Bai
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Diane Hopkins
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Melissa Gardiner
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Chandramohan Wakade
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Jennifer Bryant
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Risa Bernard
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States
| | - John Morgan
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Bruce Bode
- Atlanta Diabetes Associates, Atlanta, GA, United States
| | - John Chip Reed
- Southeastern Endocrine & Diabetes, Atlanta, GA, United States
| | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States.,Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, United States
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17
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Lee KA, Park TS, Jin HY. Non-glucose risk factors in the pathogenesis of diabetic peripheral neuropathy. Endocrine 2020; 70:465-478. [PMID: 32895875 DOI: 10.1007/s12020-020-02473-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 08/23/2020] [Indexed: 11/29/2022]
Abstract
In this review, we consider the diverse risk factors in diabetes patients beyond hyperglycemia that are being recognized as contributors to diabetic peripheral neuropathy (DPN). Interest in such alternative mechanisms has been encouraged by the recognition that neuropathy occurs in subjects with metabolic syndrome and pre-diabetes and by the reporting of several large clinical studies that failed to show reduced prevalence of neuropathy after intensive glucose control in patients with type 2 diabetes. Animal models of obesity, dyslipidemia, hypertension, and other disorders common to both pre-diabetes and diabetes have been used to highlight a number of plausible pathogenic mechanisms that may either damage the nerve independent of hyperglycemia or augment the toxic potential of hyperglycemia. While pathogenic mechanisms stemming from hyperglycemia are likely to be significant contributors to DPN, future therapeutic strategies will require a more nuanced approach that considers a range of concurrent insults derived from the complex pathophysiology of diabetes beyond direct hyperglycemia.
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Affiliation(s)
- Kyung Ae Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University-Jeonbuk National University Hospital, Jeonbuk National University, Medical School, Jeonju, South Korea
| | - Tae Sun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University-Jeonbuk National University Hospital, Jeonbuk National University, Medical School, Jeonju, South Korea
| | - Heung Yong Jin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University-Jeonbuk National University Hospital, Jeonbuk National University, Medical School, Jeonju, South Korea.
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18
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Saraswat N, Sachan N, Chandra P. Anti-diabetic, diabetic neuropathy protective action and mechanism of action involving oxidative pathway of chlorogenic acid isolated from Selinum vaginatum roots in rats. Heliyon 2020; 6:e05137. [PMID: 33088940 PMCID: PMC7566111 DOI: 10.1016/j.heliyon.2020.e05137] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/09/2020] [Accepted: 09/29/2020] [Indexed: 12/15/2022] Open
Abstract
Phytopharmaceuticals have always reported vital roles in the field of medicine hence the need to investigate safe and efficient drugs for treating metabolic disorders is very significant. Roots of Selinum vaginatum have therapeutic benefits and are widely used by the people of the Rohtang region for treating diabetes and its associated complications. The present study focusses on the isolation of the bioactive from the S. vaginatum roots for estimating acute toxicity studies, anti-diabetic and diabetic neuropathy protective action along with the mechanism of action in STZ induced Wistar rats. The Selinum vaginatum roots were collected from the Rohtang region, Himalayas. Chlorogenic acid was isolated and underwent identification by UV, HPLC, 1H NMR, C13 NMR, Mass, and FTIR spectroscopy methods. Chlorogenic acid was dosed at 10 and 20 mg/kg to observe the effects on experimentally induced diabetes and with time generated diabetic neuropathic complications. Biomarkers TNF-α, superoxide dismutase, nitrosative stress, lipid peroxide profile, and membrane-bound inorganic phosphate were analyzed. Histopathological evaluation of the liver and sciatic nerve was performed for all groups. Parameters like blood glucose levels, body weight, food intake, Thermal Hyperalgesia, Writhing, Cold Hyperalgesia Responses, Mechanical hyperalgesia, Grip Strength, Spontaneous Locomotor (Exploratory) Test, Neuromuscular Coordination tests, and lipid profile analysis showcased the anti-diabetic and diabetic neuropathy protective action of the drug. Inflammation, degradation, and necrosis were found to be reduced in the liver and sciatic nerve cells of treated groups. All the biomarkers used to analyze the oxidative pathway were significantly replenished indicates that chlorogenic acid produces these effects through this pathway.
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Affiliation(s)
- Nikita Saraswat
- Institute of Pharmacy, Pranveer Singh Institute of Technology, Kanpur-Agra-Delhi National Highway-2, Bhauti, Kanpur (UP), 209 305, India
| | - Neetu Sachan
- School of Pharmaceutical Sciences, IFTM University, Lodhipur Rajput, Delhi Road (NH-24), Moradabad (UP), 244 102, India
| | - Phool Chandra
- School of Pharmaceutical Sciences, IFTM University, Lodhipur Rajput, Delhi Road (NH-24), Moradabad (UP), 244 102, India
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Neurologic Manifestations of Systemic Disease: Peripheral Nervous System. Curr Treat Options Neurol 2020. [DOI: 10.1007/s11940-020-00631-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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20
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Xiao Z, Chen H, Zhang Y, Deng H, Wang K, Bhagavathula AS, Almuhairi SJ, Ryan PM, Rahmani J, Dang M, Kontogiannis V, Vick A, Wei Y. The effect of psyllium consumption on weight, body mass index, lipid profile, and glucose metabolism in diabetic patients: A systematic review and dose-response meta-analysis of randomized controlled trials. Phytother Res 2020; 34:1237-1247. [PMID: 31919936 DOI: 10.1002/ptr.6609] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/07/2019] [Accepted: 12/12/2019] [Indexed: 12/15/2022]
Abstract
Water-soluble dietary fibers have been shown to improve lipid profile and glucose metabolism in diabetes. The aim of this study was to review the effects of psyllium consumption on weight, body mass index, lipid profiles, and glucose metabolism in diabetic patients in randomized controlled trials. A comprehensive systematic search was performed in PubMed/MEDLINE, Web of Sciences, Cochrane, and Scopus by two independent researchers up to August 2019 without any time and language restrictions. The DerSimonian and Laird random-effects model method performed to calculate the pooled results. Inclusion criteria were randomized controlled trial design, adult subjects, and studies reporting the mean differences with the 95% confidence interval for outcome. Eight studies containing nine arms with 395 participants were identified and included in final analysis. Combined results found a significant reduction in triglycerides, low-density lipoprotein, fasting blood sugar, and hemoglobin A1c following psyllium consumption (weighted mean differences [WMD]: -19.18 mg/dl, 95% CI [-31.76, -6.60], I2 = 98%), (WMD: -8.96 mg/dl, 95% CI [-13.39, -4.52], I2 = 97%), (WMD: -31.71 ml/dl, 95% CI [-50.04, -13.38], I2 = 97%), and (WMD: -0.91%, 95% CI [-1.31, -0.51], I2 = 99%), respectively. There was no significant change in high-density lipoprotein, body mass index, cholesterol, and weight. In conclusion, the results demonstrated a significant reduction in triglycerides, low-density lipoprotein, fasting blood sugar, and hemoglobin A1c by psyllium intervention among diabetic patients.
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Affiliation(s)
- Zhifang Xiao
- Department of Endocrinology, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Hui Chen
- Medical Group Office, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Yu Zhang
- Department of Endocrinology, Xinchang People's Hospital, Xinchang County, China
| | - Hui Deng
- Prehospital Aid Station, Danyang People's Hospital, Danyang, China
| | - KunWei Wang
- Department of Endocrinology, Tianyou Hospital Affiliated to Tongji University, Shanghai, China
| | | | | | - Paul M Ryan
- School of Medicine, University College Cork, Cork, Ireland
| | - Jamal Rahmani
- Department of Community Nutrition, Student Research Committee, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Minyan Dang
- Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
| | | | - Andrew Vick
- Department of Nursing and Public Health, Capella University, Minneapolis, Minnesota
| | - Yuhe Wei
- Department of Endocrinology, Affiliated Wujin Hospital, Jiangsu University, Changzhou, China
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Singh P, Bansal S, Kuhad A, Kumar A, Chopra K. Naringenin ameliorates diabetic neuropathic pain by modulation of oxidative-nitrosative stress, cytokines and MMP-9 levels. Food Funct 2020; 11:4548-4560. [DOI: 10.1039/c9fo00881k] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus is a serious debilitating epidemic affecting all social strata, imposing huge health, social and economic burdens.
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Affiliation(s)
- Pratishtha Singh
- University Institute of Pharmaceutical Sciences
- Panjab University
- Chandigarh-160014
- India
| | - Seema Bansal
- University Institute of Pharmaceutical Sciences
- Panjab University
- Chandigarh-160014
- India
| | - Anurag Kuhad
- University Institute of Pharmaceutical Sciences
- Panjab University
- Chandigarh-160014
- India
| | - Anil Kumar
- University Institute of Pharmaceutical Sciences
- Panjab University
- Chandigarh-160014
- India
| | - Kanwaljit Chopra
- University Institute of Pharmaceutical Sciences
- Panjab University
- Chandigarh-160014
- India
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22
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Naseri R, Farzaei F, Fakhri S, El-Senduny FF, Altouhamy M, Bahramsoltani R, Ebrahimi F, Rahimi R, Farzaei MH. Polyphenols for diabetes associated neuropathy: Pharmacological targets and clinical perspective. Daru 2019; 27:781-798. [PMID: 31352568 PMCID: PMC6895369 DOI: 10.1007/s40199-019-00289-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 07/01/2019] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP. EVIDENCE ACQUISITION A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019. RESULTS DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP. CONCLUSION The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .
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Affiliation(s)
- Rozita Naseri
- Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fardous F El-Senduny
- Biochemistry division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
| | - Miram Altouhamy
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Roodabeh Bahramsoltani
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Farnaz Ebrahimi
- Pharmacy students` research committee, School of pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roja Rahimi
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Hosseini F, Mohammadbeigi A, Aghaali M, Borujerdi R, Parham M. Effect of pentoxifylline on diabetic distal polyneuropathy in type 2 diabetic patients: A randomized trial. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2019; 24:89. [PMID: 31741661 PMCID: PMC6856542 DOI: 10.4103/jrms.jrms_115_18] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 04/16/2019] [Accepted: 07/17/2019] [Indexed: 11/04/2022]
Abstract
Background Diabetes is one of the most common causes of peripheral neuropathy. There are no known cures for diabetic neuropathy. Pentoxifylline could theoretically be a beneficial treatment for diabetic sensory neuropathy, but there is not enough evidence to prove its effect. The aim of this study was to investigate the effect of pentoxifylline on distal diabetic neuropathy. Materials and Methods In this randomized double-blinded placebo-controlled trial, 60 patients with diabetic peripheral neuropathy were randomized into two groups. The intervention group received Vitamin B1 (100 mg twice daily) and pentoxifylline (400 mg twice daily) and control group received Vitamin B1 (100 mg twice daily) and placebo (twice daily) for 2 months. Before and after the intervention, the symptoms of distal polyneuropathy were recorded by the Michigan Neuropathy Screening Instrument. ANCOVA, Paired t-test, unpaired t-test, Chi-square, and Fisher's exact test were used to compare changes in symptoms and sign of distal polyneuropathy. Results The mean age of patients was 57.1 ± 8.02 years. There was no significant difference between the two groups in regard to the baseline variables. Blood pressure, body mass index, and blood glucose did not change significantly during the study. In the pentoxifylline group, the symptoms of peripheral neuropathy were significantly improved, in comparison with placebo group (P = 0.042). Conclusion This study showed pentoxifylline could be effective in reducing the symptoms of distal diabetic neuropathy.
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Affiliation(s)
- Frahad Hosseini
- Clinical Research Development Center, Nekooi-Hedayati- Forghani Hospital, Qom University of Medical Sciences, Qom, Iran
| | | | - Mohammad Aghaali
- Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Razieh Borujerdi
- Clinical Research Development Center, Nekooi-Hedayati- Forghani Hospital, Qom University of Medical Sciences, Qom, Iran
| | - Mahmoud Parham
- Department of Internal Medicine, Qom University of Medical Sciences, Qom, Iran
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Tang HY, Jiang AJ, Ma JL, Wang FJ, Shen GM. Understanding the Signaling Pathways Related to the Mechanism and Treatment of Diabetic Peripheral Neuropathy. Endocrinology 2019; 160:2119-2127. [PMID: 31318414 DOI: 10.1210/en.2019-00311] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/11/2019] [Indexed: 12/13/2022]
Abstract
Worldwide, the most prevalent metabolic disorder is diabetes mellitus (DM), an important condition that has been widely studied. Diabetic peripheral neuropathy (DPN), a complication that can occur with DM, is associated with pain and can result in foot ulcers and even amputation. DPN treatments are limited and mainly focus on pain management. There is a clear need to develop treatments for DPN at all stages. To make this progress, it is necessary to understand the molecular signaling pathways related to DPN. For this review, we aimed to concentrate on the main signaling cascades that contribute to DPN. In addition, we provide information with regard to treatments that are being explored.
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Affiliation(s)
- He-Yong Tang
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Ai-Juan Jiang
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jun-Long Ma
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Fan-Jing Wang
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Guo-Ming Shen
- Anhui University of Chinese Medicine, Hefei, Anhui, China
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25
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Association of apolipoprotein A-V with mRNA expression of IL-6 and NF-κB genes in type 2 diabetes with hypertriglyceridemia: a possible link with inflammation. Int J Diabetes Dev Ctries 2019. [DOI: 10.1007/s13410-018-0709-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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26
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Nutritional and Pharmacological Effects on Oxidative Stress in Soft Tissue and Bone Remodeling. J Nutr Metab 2018; 2018:4183407. [PMID: 30687551 PMCID: PMC6327261 DOI: 10.1155/2018/4183407] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 11/05/2018] [Accepted: 12/09/2018] [Indexed: 12/16/2022] Open
Abstract
Oxidative damage is the causal link to a multitude of pathologies, such as diabetes, arthritis, neuropathy, heart disease, and asthma. These conditions affect hundreds of millions of people nationwide, and billions worldwide. Even in otherwise healthy individuals, oxidative stress is a natural byproduct of metabolism that is augmented in "healthy" activities such as athletics. In many disease states, the pharmacological agents used to treat these conditions can induce oxidative damage and vitamin depletion. It is underappreciated by many that many of the most common medications prescribed result in oxidative stress. Therefore, physicians need to carefully scrutinize which medications their patients are on before surgery and treatment and during the recovery stage to obtain optimal healing results. We provide a review of the current literature of how oxidative damage and inflammation are linked to bone damage, Charcot neuroarthropathy, delayed wound healing, diabetic complications, and delayed flap consolidation. Where available, antioxidant intervention literature is offered to offset these conditions.
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Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833:472-523. [DOI: 10.1016/j.ejphar.2018.06.034] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 06/15/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
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Ignatowski TA, Spengler RN. Targeting tumor necrosis factor in the brain relieves neuropathic pain. World J Anesthesiol 2018; 7:10-19. [DOI: 10.5313/wja.v7.i2.10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/28/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023] Open
Abstract
Neuropathic pain is a chronic syndrome caused by direct damage to or disease of the somatosensory nervous system. The lack of safe, adequate and sustained pain relief offered by present analgesic treatments is most alarming. While many treatment options are available to manage chronic pain, such as antidepressants, non-steroidal anti-inflammatory agents, opioids, and anticonvulsants, chronic neuropathic pain remains largely unmanaged. Compounding the dilemma of ineffective chronic pain treatments is the need to provide relief from suffering and yet not contribute to the scourge of drug abuse. A recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioid treatment, even though opioids are rarely an effective treatment of relieving chronic pain. To make matters worse, opioids may contribute to exacerbating pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, as well as their potential for addiction and overdose deaths exist. Clearly, there is an urgent need for alternative, non-opiate treatment of chronic pain. Innovative discoveries of pertinent brain mechanisms and functions are key to developing effective, safe treatments. Pioneering work has revealed the essential effects of the pleiotropic mediator tumor necrosis factor (TNF) on brain functioning. These studies establish that TNF inhibits norepinephrine release from hippocampal neurons, and show that excess TNF production within the hippocampus occurs during neuropathic pain, which mobilizes additional mechanisms that further inhibit norepinephrine release. Significantly, it has been verified that elevated levels of TNF in the brain are actually required for neuropathic pain development. Since TNF decreases norepinephrine release in the brain, enhanced TNF levels would prevent engagement of the norepinephrine descending inhibitory neuronal pain pathways. Increased levels of TNF in the brain are therefore critical to the development of neuropathic pain. Therefore, strategies that decrease this enhanced TNF expression in the brain will have superior analgesic efficacy. We propose this novel approach of targeting the pathologically high levels of brain TNF as an effective strategy in the treatment of the devastating syndrome of chronic pain.
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Affiliation(s)
- Tracey A Ignatowski
- Department of Pathology and Anatomical Sciences and Program for Neuroscience, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, United States
- NanoAxis, LLC, Clarence, NY 14031, United States
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29
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Carrasco C, Naziroǧlu M, Rodríguez AB, Pariente JA. Neuropathic Pain: Delving into the Oxidative Origin and the Possible Implication of Transient Receptor Potential Channels. Front Physiol 2018; 9:95. [PMID: 29491840 PMCID: PMC5817076 DOI: 10.3389/fphys.2018.00095] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 01/29/2018] [Indexed: 12/25/2022] Open
Abstract
Currently, neuropathic pain is an underestimated socioeconomic health problem affecting millions of people worldwide, which incidence may increase in the next years due to chronification of several diseases, such as cancer and diabetes. Growing evidence links neuropathic pain present in several disorders [i.e., spinal cord injury (SCI), cancer, diabetes and alcoholism] to central sensitization, as a global result of mitochondrial dysfunction induced by oxidative and nitrosative stress. Additionally, inflammatory signals and the overload in intracellular calcium ion could be also implicated in this complex network that has not yet been elucidated. Recently, calcium channels namely transient receptor potential (TRP) superfamily, including members of the subfamilies A (TRAP1), M (TRPM2 and 7), and V (TRPV1 and 4), have demonstrated to play a role in the nociception mediated by sensory neurons. Therefore, as neuropathic pain could be a consequence of the imbalance between reactive oxygen species and endogen antioxidants, antioxidant supplementation may be a treatment option. This kind of therapy would exert its beneficial action through antioxidant and immunoregulatory functions, optimizing mitochondrial function and even increasing the biogenesis of this vital organelle; on balance, antioxidant supplementation would improve the patient's quality of life. This review seeks to deepen on current knowledge about neuropathic pain, summarizing clinical conditions and probable causes, the relationship existing between oxidative stress, mitochondrial dysfunction and TRP channels activation, and scientific evidence related to antioxidant supplementation.
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Affiliation(s)
- Cristina Carrasco
- Department of Physiology, Faculty of Sciences, University of Extremadura, Badajoz, Spain
| | - Mustafa Naziroǧlu
- Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey
| | - Ana B Rodríguez
- Department of Physiology, Faculty of Sciences, University of Extremadura, Badajoz, Spain
| | - José A Pariente
- Department of Physiology, Faculty of Sciences, University of Extremadura, Badajoz, Spain
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30
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Lin X, Xu L, Zhao D, Luo Z, Pan S. Correlation between serum uric acid and diabetic peripheral neuropathy in T2DM patients. J Neurol Sci 2017; 385:78-82. [PMID: 29406919 DOI: 10.1016/j.jns.2017.11.034] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 11/05/2017] [Accepted: 11/26/2017] [Indexed: 01/25/2023]
Abstract
AIM To investigate the correlation between serum uric acid (SUA) and diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. METHODS Two hundred T2DM patients were divided into four groups at the cut-off points of 5, 7, and 9mg/dL of SUA levels. Nerve conduction studies (NCS), Semmes-Weinstein monofilament testing (SWMT), and vibration perception threshold (VPT) tests were performed on these patients. RESULTS Significant differences in motor/sensory nerve amplitude and conduction velocity (CV) parameters among different SUA level groups were observed (all P<0.05). SUA levels were negatively correlated with the means of motor/sensory nerve amplitude and CV (all P<0.05). Duration of T2DM >10years, SUA >9mg/dL and total cholesterol (TC) >5.2mmol/L were found to be significantly associated with DPN (all P<0.05). Receiver-operating characteristic (ROC) analysis revealed that the cut-off points of T2DM duration combined with SUA and TC were 9years, 7.8mg/dL, and 4.97mmol/L, respectively (AUC=0.65; 95% CI: 0.53-0.77; sensitivity, 70.6%; specificity, 65.2%, P=0.009). CONCLUSION There is a significant association between elevated SUA levels and DPN, and T2DM duration, SUA, and TC may be valuable indicators to predict the occurrence of DPN in T2DM patients.
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Affiliation(s)
- Xiaopu Lin
- Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Lingling Xu
- Department of Endocrinology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Deqiang Zhao
- Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Zhiyin Luo
- Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Suyue Pan
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
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Kamalpour M, Ghalandari H, Nasrollahzadeh J. Short-Term Supplementation of a Moderate Carbohydrate Diet with Psyllium Reduces Fasting Plasma Insulin and Tumor Necrosis Factor-α in Patients with Type 2 Diabetes Mellitus. J Diet Suppl 2017; 15:507-515. [DOI: 10.1080/19390211.2017.1358791] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Mahdieh Kamalpour
- Department of Clinical Nutrition and Dietetics, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Ghalandari
- Department of Clinical Nutrition and Dietetics, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Javad Nasrollahzadeh
- Department of Clinical Nutrition and Dietetics, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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32
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Datta I, Bhadri N, Shahani P, Majumdar D, Sowmithra S, Razdan R, Bhonde R. Functional recovery upon human dental pulp stem cell transplantation in a diabetic neuropathy rat model. Cytotherapy 2017; 19:1208-1224. [PMID: 28864291 DOI: 10.1016/j.jcyt.2017.07.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 07/20/2017] [Accepted: 07/20/2017] [Indexed: 12/29/2022]
Abstract
Diabetic neuropathy (DN) is among the most debilitating complications of diabetes. Here, we investigated the effects of human dental pulp stem cell (DPSC) transplantation in Streptozotocin (STZ)-induced neuropathic rats. Six weeks after STZ injection, DPSCs were transplanted through two routes, intravenous (IV) or intramuscular (IM), in single or two repeat doses. Two weeks after transplantation, a significant improvement in hyperalgesia, grip-strength, motor coordination and nerve conduction velocity was observed in comparison with controls. A rapid improvement in neuropathic symptoms was observed for a single dose of DPSC IV; however, repeat dose of DPSC IV did not bring about added improvement. A single dose of DPSC IM showed steady improvement, and further recovery continued upon repeat IM administration. DPSC single dose IV showed greater improvement than DPSC single dose IM, but IM transplantation brought about better improvement in body weight. A marked reduction in tumor necrosis factor (TNF) α and C-reactive protein (CRP) levels was observed in the blood plasma for all treated groups, as compared with controls. With respect to inflammatory cytokines, repeat dose of DPSC IM showed further improvement, suggesting that a repeat dose is required to maintain the improved inflammatory state. Gene expression of inflammatory markers in liver confirmed amelioration in inflammation. Arachidonic acid level was unaffected by IV DPSC transplantation but showed noticeable increase through IM administration of a repeat dose. These results suggest that DPSC transplantation through both routes and dosage was beneficial for the retrieval of neuropathic parameters of DN; transplantation via the IM route with repeat dose was the most effective.
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Affiliation(s)
- Indrani Datta
- Department of Biophysics, National Institute of Mental Health and Neurosciences, an Institute of National Importance, Bengaluru, Karnataka, India.
| | - Naini Bhadri
- Department of Pharmacology, Al-Ameen College of Pharmacy, Bengaluru, Karnataka, India
| | - Pradnya Shahani
- Department of Biophysics, National Institute of Mental Health and Neurosciences, an Institute of National Importance, Bengaluru, Karnataka, India
| | - Debanjana Majumdar
- School of Regenerative Medicine, Manipal University, Bengaluru, Karnataka, India
| | - Sowmithra Sowmithra
- Department of Biophysics, National Institute of Mental Health and Neurosciences, an Institute of National Importance, Bengaluru, Karnataka, India
| | - Rema Razdan
- Department of Pharmacology, Al-Ameen College of Pharmacy, Bengaluru, Karnataka, India
| | - Ramesh Bhonde
- School of Regenerative Medicine, Manipal University, Bengaluru, Karnataka, India
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El-Badawy MA, Farrag DAB, Abd El-Rehem SMR, El-Mahdi AR, El-Sherbeny AA, Abdel Hady EAM, Abdel-Sattar HA, Abdelaziz DM. Tumor necrosis factor-α is a novel biomarker for peripheral neuropathy in type II diabetes mellitus: a clinical and electrophysiological study. EGYPTIAN RHEUMATOLOGY AND REHABILITATION 2017. [DOI: 10.4103/1110-161x.205663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Kiasalari Z, Rahmani T, Mahmoudi N, Baluchnejadmojarad T, Roghani M. Diosgenin ameliorates development of neuropathic pain in diabetic rats: Involvement of oxidative stress and inflammation. Biomed Pharmacother 2017; 86:654-661. [DOI: 10.1016/j.biopha.2016.12.068] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 11/29/2016] [Accepted: 12/16/2016] [Indexed: 12/31/2022] Open
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35
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Ma C, Long H. Protective effect of betulin on cognitive decline in streptozotocin (STZ)-induced diabetic rats. Neurotoxicology 2016; 57:104-111. [PMID: 27640960 DOI: 10.1016/j.neuro.2016.09.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 09/13/2016] [Accepted: 09/14/2016] [Indexed: 12/14/2022]
Abstract
Betulin is extracted from birch tree bark and exerts diverse pharmacological activities. The present study was designed to investigate the protective effect of betulin (BE) on cognitive decline in streptozotocin (STZ)-induced diabetic rats. The diabetic model was built by streptozotocin (STZ) (30mg/kg, ip). After 4 weeks, the diabetic rats were treated with vehicle or BE (20mg/kg, 40mg/kg) for 4 weeks. The oral glucose tolerance (OGTT) and serum insulin were detected. Three days later, Morris water maze (MWM) test was used to evaluate memory function. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in hippocampus were examined. Inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) in serum and hippocampus were measured. The protein expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NF-κB pathways-related molecules in hippocampus were examined. As a results, BE could improve glucose intolerance and modify basal learning performance. Treatment with BE significantly restored SOD activity and decreased MDA content in hippocampus. BE also markedly reduced the contents of inflammatory cytokines in serum and hippocampus. Furthermore, administration of BE effectively upregulated the expressions of Nrf2, HO-1 and blocked the phosphorylations of IκB, NF-κB. In summary, BE might exhibit protective effect on cognitive decline in STZ-induced diabetic rats through HO-1/Nrf-2/NF-κB pathway.
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Affiliation(s)
- Chunhua Ma
- Central Laboratory, Nanjing Municipal Hospital of T.C.M., The Third Affiliated Hospital of Nanjing University of T.C.M., Nanjing 210001, China
| | - Hongyan Long
- Central Laboratory, Nanjing Municipal Hospital of T.C.M., The Third Affiliated Hospital of Nanjing University of T.C.M., Nanjing 210001, China.
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36
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Chen L, Li B, Chen B, Shao Y, Luo Q, Shi X, Chen Y. Thymoquinone Alleviates the Experimental Diabetic Peripheral Neuropathy by Modulation of Inflammation. Sci Rep 2016; 6:31656. [PMID: 27545310 PMCID: PMC4992870 DOI: 10.1038/srep31656] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 07/22/2016] [Indexed: 12/22/2022] Open
Abstract
Thymoquinone has been reported to exhibit antioxidant and anti-inflammatory effects. Inflammation plays an important role in pathogenesis of diabetic peripheral neuropathy. This study investigated the effects of TQ on proliferation and apoptosis of Schwann cells exposed to high glucose conditions and electrophysiological and morphological changes of the sciatic nerve in a DPN rat model as well as relevant inflammatory mechanism. Cell proliferation and apoptosis of Schwann cells were measured using the Cell Counting Kit-8 and flow cytometry. DPN model was established in streptozotocin-induced diabetic rats. Nerve conduction velocity was measured before and after treatment. Morphologic changes were observed by H&E staining and transmission electron microscopy. COX-2, IL-1β, IL-6, and Caspase-3 expression was investigated by western blotting and Bio-Plex ProTM Assays. Finally, TQ alleviated the inhibition of Schwann cell proliferation and protected against Schwann cell apoptosis. It improved nerve conduction velocity, and alleviated the DPN-induced morphological changes and demyelination of the sciatic nerve. COX-2, IL-1β, IL-6 and Caspase-3 expression in sciatic nerve or isolated cultured Schwann cells, were also decreased by TQ. These results indicate TQ has a protective effect on peripheral nerves in a DPN rat model. The mechanism may be mediated partly by the modulation of the inflammatory reaction.
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Affiliation(s)
- Long Chen
- Department of Neurology, Jinshan Hospital, Fudan University, Shanghai 201508, P. R. China.,Department of Neurology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Bing Li
- Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, P. R.China
| | - Biqin Chen
- Department of Pediatric, Jinshan Hospital, Fudan University, Shanghai 201508, P. R.China
| | - Yiye Shao
- Department of Neurology, Jinshan Hospital, Fudan University, Shanghai 201508, P. R. China.,Department of Neurology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Qiong Luo
- Department of Neurology, Jinshan Hospital, Fudan University, Shanghai 201508, P. R. China.,Department of Neurology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Xiaohong Shi
- Department of Endocrinology, Jinshan Hospital, Fudan University, Shanghai 201508, P. R.China
| | - Yinghui Chen
- Department of Neurology, Jinshan Hospital, Fudan University, Shanghai 201508, P. R. China.,Department of Neurology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
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Omi M, Hata M, Nakamura N, Miyabe M, Kobayashi Y, Kamiya H, Nakamura J, Ozawa S, Tanaka Y, Takebe J, Matsubara T, Naruse K. Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti-inflammation phenotypes and ameliorated diabetic polyneuropathy. J Diabetes Investig 2015; 7:485-96. [PMID: 27181261 PMCID: PMC4931198 DOI: 10.1111/jdi.12452] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 11/17/2015] [Accepted: 11/19/2015] [Indexed: 12/28/2022] Open
Abstract
Aims/Introduction Dental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68‐positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC‐conditioned media on lipopolysaccharide‐stimulated murine macrophage RAW264.7 cells were investigated. Results Diabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68‐positive monocytes/macrophages and the gene expressions of M1 macrophage‐expressed cytokines, tumor necrosis factor‐α and interleukin‐1β, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor‐α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC‐conditioned media significantly increased the gene expressions of interleukin‐10 and CD206 in lipopolysaccharide‐stimulated RAW264.7 cells. Conclusions These results suggest that DPSC transplantation promoted macrophages polarization towards anti‐inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy.
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Affiliation(s)
- Maiko Omi
- Department of Removable Prosthodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Masaki Hata
- Department of Removable Prosthodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Nobuhisa Nakamura
- Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Megumi Miyabe
- Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Yasuko Kobayashi
- Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Jiro Nakamura
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Shogo Ozawa
- Department of Removable Prosthodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Yoshinobu Tanaka
- Department of Removable Prosthodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Jun Takebe
- Department of Removable Prosthodontics, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Tatsuaki Matsubara
- Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Keiko Naruse
- Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
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Nwaehujor CO, Udegbunam RI, Ode JO, Asuzu OV. Amelioration of chronic inflammation and oxidative stress indices in diabetic Wistar rats using methanol leaf extract of Bridelia micrantha (Hochst) Baill. (Euphorbiaceae). JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2015; 12:295-300. [PMID: 26247509 DOI: 10.1515/jcim-2014-0035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Accepted: 07/10/2015] [Indexed: 06/04/2023]
Abstract
BACKGROUND Ethnopharmacological practitioners in Nigeria have used aqueous and ethanol extracts of Bridelia micrantha leaves to manage conditions associated with inflammation, and these include diabetes, chest pain, edema, arthritis and joint pains. This study aimed to evaluate the effects of methanol leaf extract of B. micrantha on chronic inflammation and oxidative stress which accompany diabetic conditions, in streptozotocin-induced diabetic Albino Wistar rats. METHODS The dried leaves were extracted by percolation in 80% methanol:water for 72 h after which the mixture was filtered using Whatman No. 1 (11 μm) filter papers. Acute toxicity studies were done using Wistar rats and given orally up to a dose of 2,000 mg/kg. The animals were monitored for 48 h. The experimental design involved five (5) groups of six (6) albino Wistar diabetic rats each. Groups A, B and C rats received 100, 200 and 400 mg/kg B. micrantha respectively while groups D (negative control) and E (positive control) rats received 10 mL/kg normal saline and 200 mg/kg acetylsalicylic acid (ASA) respectively by gastric gavage for 7 days. Two sterilized cotton pellets (10 mg each) were implanted subcutaneously into both sides of the dorsal area of each diabetic rat in all the groups. Post cotton pellet implantation, rats in three groups (A, B and C) were treated with 100, 200 and 400 mg/kg B. micrantha extract, while those in two groups (D and E) were treated with acetyl salicylic acid (ASA 200 mg/kg) and normal saline (10 mL/kg) respectively by gastric gavage for 7 days. Serum obtained from the animals on Day 8 of the cotton pellet test were used for malondialdehyde (MDA), catalase, superoxide dismutase (SOD) and glutathione (GSH) assays. RESULTS The administration of the leaf extract up to a dose of 2,000 mg/kg to rats produced absolutely no death or observable signs of toxicity in 48 h. The cotton pellet granuloma weights in 200 mg/kg (44.88±1.2 mg), 400 mg/kg (42.10±1.2 mg) B. micrantha extract treated groups and ASA at 200 mg/kg (43.25±1.8 mg) were significantly lower compared to weight of granuloma (85.50±3.2 mg) obtained in the group treated with normal saline. Serum malondialdehyde (MDA) level in the 200 mg/kg (3.32±0.72 nmol/mL) and 400 mg/kg (1.88±1.27 nmol/mL) B. micrantha extract treated groups were significantly (p<0.05) lower compared to MDA level (6.88±0.79 nmol/mL) in the serum of normal saline treated group. Treatment of diabetic rats with the B. micrantha extract also caused significant (p<0.05) elevation in serum catalase, SOD and GSH levels. CONCLUSIONS The study showed that B. micrantha methanol leaf extract significantly inhibited some chronic inflammation and oxidative stress parameters in diabetes mellitus.
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El Batsh MM, El Batch MM, Shafik NM, Younos IH. Favorable effects of vildagliptin on metabolic and cognitive dysfunctions in streptozotocin-induced diabetic rats. Eur J Pharmacol 2015; 769:297-305. [PMID: 26607467 DOI: 10.1016/j.ejphar.2015.11.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Revised: 11/16/2015] [Accepted: 11/18/2015] [Indexed: 02/08/2023]
Abstract
Progression of diabetes mellitus is accompanied by metabolic disorders together with psychological deficits including cognitive dysfunctions. Herein, we used a murine streptozotocin (STZ)-induced diabetes to investigate the beneficial effects of vildagliptin not only on metabolic abnormalities, but also on diabetes-induced cognitive decline. Sixty rats were divided randomly and equally into 2 groups; one remains normal and the other serves as STZ- induced diabetic. Both groups were further divided equally into 2 groups; one received vehicle and the other received oral vildagliptin for 8 weeks. Cognitive behavior was assessed using novel object recognition test. Blood samples were collected to measure metabolic parameters and dipeptidyl peptidase (DPP)-IV activity. Brains were removed and investigated for the levels of inflammatory and oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD) and tumor necrosis factor-α (TNF-α), in addition to brain-derived neurotrophic factor (BDNF) and relative expression of nuclear factor kappa B (NF-κB)/p65. Treatment of STZ-induced diabetic rats with vildagliptin increased their body weight and corrected diabetes-induced memory and learning impairment. Moreover, vildagliptin significantly decreased serum levels of glucose and lipids (except high density lipoprotein) together with brain MDA, TNF-α, serum DPP-IV activities and NF-κB/p65 gene expression. On the other hand, vildagliptin significantly increased brain BDNF, SOD as well as serum insulin. Results suggested that vildagliptin has a protective role in counteracting both metabolic abnormalities and memory deficits in diabetic rats, possibly via its anti-hyperglycemic, anti-inflammatory, antioxidant effects, together with reduction of brain NF-κB/p65 over expression.
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Affiliation(s)
- Maha M El Batsh
- Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Egypt
| | - Manal M El Batch
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Egypt
| | - Noha M Shafik
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Egypt.
| | - Ibrahim H Younos
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Oman
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Mert T, Gisi G, Celik A, Baran F, Uremis MM, Gunay I. Frequency-dependent effects of sequenced pulsed magnetic field on experimental diabetic neuropathy. Int J Radiat Biol 2015; 91:833-42. [DOI: 10.3109/09553002.2015.1068460] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Micov A, Tomić M, Pecikoza U, Ugrešić N, Stepanović-Petrović R. Levetiracetam synergises with common analgesics in producing antinociception in a mouse model of painful diabetic neuropathy. Pharmacol Res 2015; 97:131-42. [PMID: 25958352 DOI: 10.1016/j.phrs.2015.04.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/21/2015] [Accepted: 04/26/2015] [Indexed: 01/05/2023]
Abstract
Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10-100 mg/kg), ibuprofen (2-50 mg/kg), aspirin (5-75 mg/kg), paracetamol (5-100 mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy.
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Affiliation(s)
- Ana Micov
- Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia.
| | - Maja Tomić
- Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia.
| | - Uroš Pecikoza
- Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia.
| | - Nenad Ugrešić
- Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia.
| | - Radica Stepanović-Petrović
- Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia.
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Yoo DY, Chae J, Jung HY, Yim HS, Kim JW, Nam SM, Kim DW, Choi JH, Seong JK, Yoon YS, Hwang IK. Treadmill exercise is associated with reduction of reactive microgliosis and pro-inflammatory cytokine levels in the hippocampus of type 2 diabetic rats. Neurol Res 2015; 37:732-8. [PMID: 25797150 DOI: 10.1179/1743132815y.0000000015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVES In the present study, we investigated the effects of treadmill exercise on microglial activation and the subsequent release of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1-beta in the hippocampus in a rat model of type 2 diabetes. METHODS At 30 weeks of age, diabetic (Zucker diabetic fatty, ZDF) rats and their littermate control (Zucker lean control, ZLC) rats were either placed on a stationary treadmill or made to run for 1 hour/day at 12-16 m/minute on five consecutive days, for 10 weeks. Once the rats reached 40 weeks, they were perfused and their hippocampus collected for immunohistochemistry or hippocampus collected fresh for the Western blotting or enzyme-linked immunosorbent assay (ELISA). RESULTS The whole blood glucose levels in exercised ZDF rats were significantly higher than in the sedentary or exercised ZLC rats, but were significantly lower than in the sedentary ZDF rats. In the sedentary ZLC and exercised ZLC rats, ionised calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia showed normal morphology which had small cytoplasm with ramified processes. In the sedentary ZDF rats, some Iba-1 immunoreactive microglia showed abnormal morphology which had hypertrophied cytoplasm with retracted processes. However, exercised ZDF rats had small cytoplasm with highly ramified processes. Levels of TNF-alpha, IL-6 and IL-1beta in the hippocampal homogenates were significantly increased in sedentary ZDF rats compared to sedentary ZLC rats, respectively. However, TNF-alpha, IL-6 and IL-1beta levels in the exercised ZDF rats were significantly decreased compared with those of sedentary ZDF rats, respectively. DISCUSSION These results suggest that exercise in type 2 diabetic rats reduces microglial activation and the subsequent increase of pro-inflammatory cytokine levels in the hippocampus.
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Yang XW, Liu FQ, Guo JJ, Yao WJ, Li QQ, Liu TH, Xu LP. Antioxidation and anti-inflammatory activity of Tang Bi Kang in rats with diabetic peripheral neuropathy. Altern Ther Health Med 2015; 15:66. [PMID: 25887432 PMCID: PMC4417275 DOI: 10.1186/s12906-015-0600-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 03/09/2015] [Indexed: 01/22/2023]
Abstract
Background Tang Bi Kang (TBK) is a traditional Chinese medicine granule. It has been shown to have effects on nerve conduction velocity deficits, blood-related factors and oxidative stress. This study was undertaken to evaluate proposed antioxidative and anti-inflammatory activity of Tang Bi Kang in rats with diabetic peripheral neuropathy (DPN). Methods DPN was induced in male Wistar rats by intraperitoneal administration of streptozocin (STZ) (60 mg/kg.b.w) for 8 weeks. Fasting blood glucose (FBG) levels were measured in the blood obtained by clipping the tails of the rats. Tail-flick tests were conducted with a tail-flick analgesic meter. Motor and sensory nerve conduction velocities (MNCV and SNCV) of sciatic nerve were measured directly at two sites using a Functional Experiment System. Oxidative stress makers such as malondialdehyde (MDA), superoxide-dismutase (SOD) and glutathione peroxidase (GSH-Px), inflammatory cytokines such as interleukin (IL)-6, and tumour necrosis factor (TNF)-α were estimated. The statistical analysis of results was carried out using Student t-test and one-way analysis of variance (ANOVA), followed by least-significant difference post hoc with SPSS. Results The administration of TBK for 4 weeks in DPN rats resulted in a significant decrease in FBG levels compared to untreated DPN rats. There was a significant increase in MNCV and SNCV in the DPN rats compared to untreated DPN rats. Serum level of MDA was significantly reduced while the activities of SOD and GSH-pX were significantly increased in the TBK treated DPN rats. TBK prevented DPN-induced increase in the serum levels of IL-6 and TNF-α. Conclusion The results of this study demonstrate that the therapeutic effect of TBK on DPN rats may be associated with the antioxidative and anti-inflammatory responses.
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Urabe H, Terashima T, Lin F, Kojima H, Chan L. Bone marrow-derived TNF-α causes diabetic neuropathy in mice. Diabetologia 2015; 58:402-10. [PMID: 25399355 PMCID: PMC4289451 DOI: 10.1007/s00125-014-3440-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/14/2014] [Indexed: 12/26/2022]
Abstract
AIMS/HYPOTHESIS Dysregulation of biochemical pathways in response to hyperglycaemia in cells intrinsic to the nervous system (Schwann cells, neurons, vasa nervorum) are thought to underlie diabetic peripheral neuropathy (DPN). TNF-α is a known aetiological factor; Tnf-knockout mice are protected against DPN. We hypothesised that TNF-α produced by a small but specific bone marrow (BM) subpopulation marked by proinsulin production (proinsulin-producing BM-derived cells, PI-BMDCs) is essential for DPN development. METHODS We produced mice deficient in TNF-α, globally in BM and selectively in PI-BMDCs only, by gene targeting and BM transplantation, and induced diabetes by streptozotocin. Motor and sensory nerve conduction velocities were used to gauge nerve dysfunction. Immunocytochemistry, fluorescence in situ hybridisation (FISH) and PCR analysis of dorsal root ganglia (DRG) were employed to monitor outcome. RESULTS We found that loss of TNF-α in BM only protected mice from DPN. We developed a strategy to delete TNF-α specifically in PI-BMDCs, and found that PI-BMDC-specific loss of TNF-α protected against DPN as robustly as loss of total BM TNF-α. Selective loss of PI-BMDC-derived TNF-α downregulated TUNEL-positive DRG neurons. FISH revealed PI-BMDC-neuron fusion cells in the DRG in mice with DPN; fusion cells were undetectable in non-diabetic mice or diabetic mice that had lost TNF-α expression selectively in the PI-BMDC subpopulation. CONCLUSIONS/INTERPRETATION BMDC-specific TNF-α is essential for DPN development; its selective removal from a small PI-BMDC subpopulation protects against DPN. The pathogenicity of PI-BMDC-derived TNF-α may have important therapeutic implications.
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Affiliation(s)
- Hiroshi Urabe
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza (MS: BCM185), Houston, TX, 77030, USA
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Kallestrup M, Møller HJ, Tankisi H, Andersen H. Soluble CD163 levels are elevated in cerebrospinal fluid and serum in people with Type 2 diabetes mellitus and are associated with impaired peripheral nerve function. Diabet Med 2015; 32:54-61. [PMID: 25156085 DOI: 10.1111/dme.12568] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 06/26/2014] [Accepted: 08/20/2014] [Indexed: 12/13/2022]
Abstract
AIMS To measure soluble CD163 levels in the cerebrospinal fluid and serum of people with Type 2 diabetes, with and without polyneuropathy, and to relate the findings to peripheral nerve function. METHODS A total of 22 people with Type 2 diabetes and 12 control subjects without diabetes were included in this case-control study. Participants with diabetes were divided into those with neuropathy (n = 8) and those without neuropathy (n = 14) based on clinical examination, vibratory perception thresholds and nerve conduction studies. Serum and cerebrospinal fluid soluble CD163 levels were analysed using an enzyme-linked immunosorbent assay. RESULTS Soluble CD163 levels were significantly higher in the cerebrospinal fluid and serum of the participants with Type 2 diabetes compared with the control participants [cerebrospinal fluid: median (range) 107 (70-190) vs 84 (54-115) μg/l, P < 0.01 and serum: 2305 (920-7060) vs 1420 (780-2740) μg/l, P < 0.01). Cerebrospinal fluid soluble CD163 was positively related to impaired peripheral nerve conduction (nerve conduction study rank score: r = 0.42; P = 0.0497) and there was a trend for higher levels of soluble CD163 in the cerebrospinal fluid and serum in participants with neuropathy than in those without neuropathy [cerebrospinal fluid: median (range) 131 (86-173) vs 101 (70-190) μg/l, P = 0.08 and serum: 3725 (920-7060) vs 2220 (1130-4780), P = 0.06). CONCLUSIONS Cerebrospinal fluid soluble CD163 level is associated with impaired peripheral nerve function. Higher levels of soluble CD163 in people with diabetic polyneuropathy suggest that inflammation plays a role in the development of neural impairment. The relationship between cerebrospinal fluid soluble CD163 level and peripheral nerve conduction indicates that soluble CD163 may be a potential biomarker for the severity of diabetic polyneuropathy.
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MESH Headings
- Adult
- Aged
- Antigens, CD/blood
- Antigens, CD/cerebrospinal fluid
- Antigens, Differentiation, Myelomonocytic/blood
- Antigens, Differentiation, Myelomonocytic/cerebrospinal fluid
- Biomarkers/blood
- Biomarkers/cerebrospinal fluid
- Body Mass Index
- Case-Control Studies
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/cerebrospinal fluid
- Diabetes Mellitus, Type 2/physiopathology
- Diabetic Neuropathies/blood
- Diabetic Neuropathies/cerebrospinal fluid
- Diabetic Neuropathies/physiopathology
- Enzyme-Linked Immunosorbent Assay
- Female
- Humans
- Inflammation/blood
- Inflammation/cerebrospinal fluid
- Inflammation/physiopathology
- Male
- Middle Aged
- Neural Conduction
- Receptors, Cell Surface/blood
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Affiliation(s)
- M Kallestrup
- Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
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Differential gene expression of cytokines and neurotrophic factors in nerve and skin of patients with peripheral neuropathies. J Neurol 2014; 262:203-12. [PMID: 25371017 DOI: 10.1007/s00415-014-7556-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/17/2014] [Accepted: 10/21/2014] [Indexed: 12/18/2022]
Abstract
Pathophysiologically relevant alterations in cytokine and neurotrophic factor levels have been reported in neuropathy subtypes. We characterized gene expression profiles of pro- and anti-inflammatory cytokines and neurotrophic factors in nerve and skin samples of patients with neuropathies of different etiologies. We prospectively studied 133 patients with neuropathies and compared data between subtypes and with healthy controls. All patients underwent sural nerve and/or skin punch biopsy at the lateral thigh and lower leg; controls received skin punch biopsies. Gene expression of pro- and anti-inflammatory cytokines (IL-1β, IL-2, IL-6, TNF, IL-10), neurotrophic factors (BDNF, NGF, NT3, TrkA), and erythropoietin with the erythropoietin receptor (Epo, EpoR) was analyzed. Sural nerve gene expression of the investigated cytokines and neurotrophic factors did not differ between neuropathies of different etiologies; however, IL-6 (p < 0.01) and IL-10 (p < 0.05) expression was higher in painful compared to painless neuropathies. Skin IL-6 and IL-10 gene expression was increased in patients compared to controls (p < 0.05), and IL-10 expression was higher in lower leg skin of patients with non-inflammatory neuropathies compared to inflammatory neuropathies (p < 0.05). Proximal and distal skin neurotrophic factor and Epo gene expression of patients with neuropathies was reduced compared to controls (NGF, NT3, Epo; p < 0.05). Neuropathies are associated with an increase in cytokine expression and a decrease in neurotrophic factor expression including nerve and skin.
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Ahlawat A, Rana A, Goyal N, Sharma S. Potential role of nitric oxide synthase isoforms in pathophysiology of neuropathic pain. Inflammopharmacology 2014; 22:269-78. [PMID: 25095760 DOI: 10.1007/s10787-014-0213-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 07/15/2014] [Indexed: 12/11/2022]
Abstract
Neuropathic pain triggers a cascade of events in the sensory neurons. It is the main complication of diabetes after cardiovascular disease. Nitric oxide (NO) produced from nitric oxide synthases (NOS) is an important signaling molecule which is crucial for many physiological processes such as synaptic plasticity, neuronal survival, vasodilation, vascular homeostasis, immune regulation. Overproduction of NO due to changes in NOS isoforms level involves pathological processes such as neurotoxicity, septic shock and neuropathic pain. All three isoforms of NOS as well as their end product, NO have modulatory effect on neuropathic pain. Overactivation of the N-Methyl-D-Aspartate receptor and peroxynitrite formation results in high levels of neuronal NOS (nNOS) and endothelial NOS (eNOS) which suggest that nNOS and eNOS are critical for pain hypersensitivity. Inducible NOS induced in glia by inflammation due to activation of Tumor Necrosis Factor α, Calcitonin Gene Regulating Peptide, Mitogen Activated Protein Kinases, Extracellular signal Regulated Kinase, c-Jun N-terminal kinases can induce neuronal death. This review focuses on different nitric oxide synthases and their role in pathophysiology of neuropathic pain considering NOS as an important therapeutic target.
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Abstract
Neuropathy is the most common complication of diabetes. As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end‐products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors. Although these metabolic aberrations are deemed as the main stream for the pathogenesis of diabetic microvascular complications, organ‐specific histological and biochemical characteristics constitute distinct mechanistic processes of neuropathy different from retinopathy or nephropathy. Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults. Sparse vascular supply with impaired autoregulation is likely to cause hypoxic damage in the nerve. Such dual influences exerted by long‐term hyperglycemia are critical for peripheral nerve damage, resulting in distal‐predominant nerve fiber degeneration. More recently, cellular factors derived from the bone marrow also appear to have a strong impact on the development of peripheral nerve pathology. As evident from such complicated processes, inhibition of single metabolic factors might not be sufficient for the treatment of neuropathy, but a combination of several inhibitors might be a promising approach to overcome this serious disorder. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00070.x, 2010)
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Affiliation(s)
| | | | - Kazuhiro Sugimoto
- Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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Petrova NL, Shanahan CM. Neuropathy and the vascular-bone axis in diabetes: lessons from Charcot osteoarthropathy. Osteoporos Int 2014; 25:1197-207. [PMID: 24091593 DOI: 10.1007/s00198-013-2511-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 09/09/2013] [Indexed: 10/26/2022]
Abstract
Emerging evidence from the last two decades has shown that vascular calcification (VC) is a regulated, cell-mediated process orchestrated by vascular smooth muscle cells (VSMCs) and that this process bears many similarities to bone mineralization. While many of the mechanisms driving VSMC calcification have been well established, it remains unclear what factors in specific disease states act to promote vascular calcification and in parallel, bone loss. Diabetes is a condition most commonly associated with VC and bone abnormalities. In this review, we describe how factors associated with the diabetic milieu impact on VSMCs, focusing on the role of oxidative stress, inflammation, impairment of the advanced glycation end product (AGE)/receptor for AGE system and, importantly, diabetic neuropathy. We also explore the link between bone and VC in diabetes with a specific emphasis on the receptor activator of nuclear factor κβ ligand/osteoprotegerin system. Finally, we describe what insights can be gleaned from studying Charcot osteoarthropathy, a rare complication of diabetic neuropathy, in which the occurrence of VC is frequent and where bone lysis is extreme.
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Affiliation(s)
- N L Petrova
- Diabetic Foot Clinic, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
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Sikka R, Raina P, Matharoo K, Bandesh K, Bhatia R, Chakrabarti S, Bhanwer AJS. TNF-α (g.-308 G > A) and ADIPOQ (g. + 45 T > G) gene polymorphisms in type 2 diabetes and microvascular complications in the region of Punjab (North-West India). Curr Eye Res 2014; 39:1042-51. [PMID: 24655058 DOI: 10.3109/02713683.2014.892998] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AIMS The present study aims to examine the association of tumor necrosis factor-α (TNF-α) g.-308 G > A and adiponectin (ADIPOQ) g. + 45 T > G gene polymorphisms in type 2 diabetes (T2D) and its microvascular complications diabetic retinopathy (DR) and diabetic nephropathy (DN). MATERIALS AND METHODS A total of 672 individuals were analysed from the North-West population of Punjab. Genotyping was accomplished by a combination of allele specific amplification refractory mutation system and restriction digestion for TNF-α g. - 308 G > A and ADIPOQ g. + 45 T > G polymorphisms, respectively. Further, in silico modeling was done to predict secondary structure of mRNA for g. + 45 T > G polymorphism in the ADIPOQ gene by RNA fold. RESULTS The minor allele frequency observed in the controls for the TNF-α G > A and ADIPOQ T > G polymorphisms were 0.07 and 0.10, respectively. The results show no significant association with TNF-α g. - 308 G > A polymorphism in T2D as well as in any of the microvascular complication. However, the ADIPOQ g. + 45 T > G polymorphism shows significant association in T2D (p = 0.048) and DR (p = 0.001) but in DN patients, no association was observed. Interactive analysis revealed that the two polymorphisms jointly conferred a 1.45-fold risk towards the occurrence of T2D [p = 0.031; OR = 1.45 (1.03-2.05)]. In the secondary structure of mRNA, slight free energy change was observed between the wild ( - 1370.28 kcal/mol) and variant allele (-1369.08 kcal/mol). CONCLUSIONS Our results indicated a higher risk of T2D and DR in the background of ADIPOQ TT genotype. Further, the ADIPOQ g. + 45 T > G and TNF-α g. - 308 G > A polymorphisms jointly give 1.45-fold risk towards T2D.
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Affiliation(s)
- Ruhi Sikka
- Department of Human Genetics, Guru Nanak Dev University , Amritsar, Punjab , India
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