RESUMEN
Disturbances in copper (Cu) homeostasis have been observed in diabetes and associated complications. Cu is an essential micronutrient that plays important roles in various fundamental biological processes. For example, diabetic cardiomyopathy is associated with elevated levels of Cu in the serum and tissues. Therefore, targeting Cu may be a novel treatment strategy for diabetic complications. This review provides an overview of physiological Cu metabolism and homeostasis, followed by a discussion of Cu metabolism disorders observed during the occurrence and progression of diabetic complications. Finally, we discuss the recent therapeutic advances in the use of Cu coordination complexes as treatments for diabetic complications and their potential mechanisms of action. This review contributes to a complete understanding of the role of Cu in diabetic complications and demonstrates the broad application prospects of Cu-coordinated compounds as potential therapeutic agents.
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Cobre , Complicaciones de la Diabetes , Humanos , Cobre/metabolismo , Animales , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/tratamiento farmacológico , HomeostasisRESUMEN
AIMS: Prolonged high levels of cytokines, glucose, or free fatty acids are associated with diabetes, elevation of cytosolic Ca2+ concentration ([Ca2+]C), and depletion of Ca2+ concentration in the endoplasmic reticulum (ER) of pancreatic beta cells. This Ca2+ imbalance induces ER stress and apoptosis. Lupenone, a lupan-type triterpenoid, is beneficial in diabetes; however, its mechanism of action is yet to be clarified. This study evaluated the protective mechanism of lupenone against thapsigargin-induced ER stress and apoptosis in pancreatic beta cells. MATERIALS AND METHODS: MIN6, INS-1, and native mouse islet cells were used. Western blot for protein expressions, measurement of [Ca2+]C, and in vivo glucose tolerance test were mainly performed. KEY FINDINGS: Thapsigargin increased the protein levels of cleaved caspase 3, cleaved PARP, and the phosphorylated form of JNK, ATF4, and CHOP. Thapsigargin increased the interaction between stromal interaction molecule1 (Stim1) and Orai1, enhancing store-operated calcium entry (SOCE). SOCE is further activated by protein tyrosine kinase 2 (Pyk2), which is Ca2+-dependent and phosphorylates the tyrosine residue at Y361 in Stim1. Lupenone inhibited thapsigargin-mediated Pyk2 activation, suppressed [Ca2+]C, ER stress, and apoptosis. Lupenone restored impaired glucose-stimulated insulin secretion effectuated by thapsigargin and glucose intolerance in a low-dose streptozotocin-induced diabetic mouse model. SIGNIFICANCE: These results suggested that lupenone attenuated thapsigargin-induced ER stress and apoptosis by inhibiting SOCE; this may be due to the hindrance of Pyk2-mediated Stim1 tyrosine phosphorylation. In beta cells that are inevitably exposed to frequent [Ca2+]C elevation, the attenuation of abnormally high SOCE would be beneficial for their survival.
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Diabetes Mellitus , Células Secretoras de Insulina , Lupanos , Triterpenos , Animales , Ratones , Apoptosis , Calcio/metabolismo , Línea Celular , Diabetes Mellitus/metabolismo , Estrés del Retículo Endoplásmico , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 2 de Adhesión Focal/metabolismo , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Fosforilación , Tapsigargina/efectos adversos , Triterpenos/metabolismo , Tirosina/metabolismo , Lupanos/farmacologíaRESUMEN
Phenolipids are characteristic phytochemicals of Syzygium genus. However, the antidiabetic potential and underlying molecular mechanism of these components are not fully elucidated. Herein, we studied the anti-diabetic effects of jambone E (JE), a phenolipid from S. cumini, with in vitro and in vivo models. Data from current study showed that JE enhanced glucose consumption and uptake, promoted glycogen synthesis, and suppressed gluconeogenesis in insulin resistant (IR)-HepG2 cells and primary mouse hepatocytes. JE also attenuated streptozotocin-induced hyperglycemia and hyperlipidemia in type 1 diabetic (T1D) mice. Eleven metabolites (e.g. trimethylamine n-oxide, 4-pyridoxic acid, phosphatidylinositol 39:4, phenaceturic acid, and hippuric acid) were identified as potential serum biomarkers for JE's antidiabetic effects by an untargeted metabolomics approach. The further molecular mechanistic study revealed that JE up-regulated phosphorylation levels of protein kinase B (AKT), glycogen synthase kinase 3 beta, and forkhead box O1 (FoxO1), promoted nuclear exclusion of FoxO1 whilst decreased gene expression levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase in IR-HepG2 cells and T1D mice. Our data suggested that JE might be a potent activator for AKT-mediated insulin signaling pathway, which was confirmed by the usage of AKT inhibitor and AKT-target siRNA interference, as well as the cellular thermal shift assay. Findings from the current study shed light on the anti-diabetic effects of phenolipids in the Syzygium species, which supports the use of medicinal plants in the Syzygium genus for potential pharmaceutical applications.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hipoglucemiantes , Resistencia a la Insulina , Fitoquímicos , Syzygium , Animales , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Gluconeogénesis , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/química , Insulina/metabolismo , Hígado , Metaboloma , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Estreptozocina , Syzygium/química , Fitoquímicos/farmacología , Fitoquímicos/uso terapéuticoRESUMEN
The antidiabetic effect and potential mechanisms of the polysaccharides from the fruits of Lycium barbarum L. (LBPs) by the mouse model of high-fat diet/streptozotocin-induced diabetes were investigated. Six-week oral administration of LBPs (200 mg/kg/day) resulted in improvement in the levels of fasting blood glucose (13.51% decrease) and glycated hemoglobin and ß-cell function in diabetic mice, and simultaneously induced a 3.3-fold increment in one taxon belonging to genus Allobaculum in gut bacterial community. The experiments of fecal microbiota transplantation and antibiotics treatment confirmed that the LBPs-mediated gut microbiota participated in the glycemic control of the diabetes management. Moreover, LBPs intervention guarded the intestinal barrier function via upregulating the expression of zonula occludens 1 both in vivo (analyzing the gut permeability in diabetic mice) and in vitro (using intestinal-like Caco-2/RAW264.7 cells co-culture inflammation model). Collectively, our study showed that LBPs could confer anti-diabetic effect through modifying gut microbiota and intestinal barrier.
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Diabetes Mellitus Experimental , Microbioma Gastrointestinal , Lycium , Animales , Células CACO-2 , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Frutas , Humanos , Ratones , Polisacáridos/farmacología , Polisacáridos/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional polyherbal preparations have been utilized in Sri Lanka since ancient times and have gained a wide acceptance throughout the country. Although an extensive body of evidence supports the use of traditional herbal mixtures in the treatment of diabetes mellitus, only a few polyherbal mixtures have been subjected to systematic scientific investigations and their mechanisms for long-term glucose control remain unclear. In general, scientific evaluations of the effectiveness of antidiabetic formulations which are prescribed by traditional practitioners have received great attention, and therefore uncovering their mechanism of action would be beneficial. AIM: The aim of the present study was to investigate the therapeutic efficacy, in terms of antidiabetic and antihyperlipidaemic activities, of a well-known traditional polyherbal mixture composed of leaves of Murraya koenigii L., -cloves of Allium sativum L., - fruits of Garcinia quaesita Pierre and seeds of Piper nigrum L. in streptozotocin induced diabetic rats. MATERIALS AND METHODS: Equal amounts from each of the above plant parts (100 g) were mixed together and extracted into cold water, hot water (3 h, refluxed) and water-acetone (1:1) separately. Dose response study of cold water, hot water, and water-acetone extracts of the polyherbal mixture at three selected doses of 0.5 g/kg, 1.0 g/kg and 1.5 g/kg was conducted in streptozotocin (STZ) induced diabetic rats. Based on the dose response data, hot water and water-acetone extracts at the therapeutic dose of 1.0 g/kg were administered to STZ induced diabetic rats (n = 6/group) daily for 30 days in the long-term study. Glibenclamide (0.5 mg/kg) was used as the positive control. Glycaemic parameters, pancreatic ß cell restoration, and lipid profile were evaluated in diabetic rats treated with the plant extract mixture. HPLC fingerprints of hot water and water-acetone extracts of the polyherbal mixture were compared with those of extracts of individual plants with the respective solvents, in the standardisation protocol. RESULTS: The hot water and water-acetone extracts were shown to be active in the dose response study and 1.0 g/kg was selected for the long term study. Treatment with the hot water and water-acetone extracts of the polyherbal mixture and glibenclamide significantly lowered the glycated haemoglobin by 19%, 26%, and 43%, respectively, at the end of the intervention (p < 0.05). The serum insulin concentration was significantly increased (p < 0.05) upon the plant treatment, corroborating the evidence of ß-cell restoration in the pancreas of H and E stained sections. Moreover, the above extracts reported an impressive restoration of lipoproteins in diabetic rats compared to the diabetic control rats. The homeostatic assessment of ß-cell functions (HOMA-ß) was also improved in rats treated with the hot water and water-acetone extracts of the polyherbal mixture. The HPLC fingerprints of the polyherbal mixture and the individual plants showed shifts in some peaks and formation of new peaks. CONCLUSION: The results revealed that the aforementioned polyherbal mixture possesses potent antihyperglycaemic and antihyperlipidaemic effects with considerable restoration of pancreatic ß-cells, justifying the traditional use of the mixture in diabetes associated dyslipidaemia.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Lipoproteínas/sangre , Extractos Vegetales/farmacología , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/aislamiento & purificación , Hipolipemiantes/aislamiento & purificación , Células Secretoras de Insulina/metabolismo , Masculino , Medicina Tradicional , Extractos Vegetales/aislamiento & purificación , Ratas Wistar , Sri Lanka , EstreptozocinaRESUMEN
Angiogenesis is rapidly initiated in response to pathological conditions and is a key target for pharmaceutical intervention in various malignancies. Anti-angiogenic therapy has emerged as a potential and effective therapeutic strategy for treating cancer and cardiovascular-related diseases. Metformin, a first-line oral antidiabetic agent for type 2 diabetes mellitus (T2DM), not only reduces blood glucose levels and improves insulin sensitivity and exerts cardioprotective effects but also shows benefits against cancers, cardiovascular diseases, and other diverse diseases and regulates angiogenesis. MicroRNAs (miRNAs) are endogenous noncoding RNA molecules with a length of approximately 19-25 bases that are widely involved in controlling various human biological processes. A large number of miRNAs are involved in the regulation of cardiovascular cell function and angiogenesis, of which miR-21 not only regulates vascular cell proliferation, migration and apoptosis but also plays an important role in angiogenesis. The relationship between metformin and abnormal miRNA expression has gradually been revealed in the context of numerous diseases and has received increasing attention. This paper reviews the drug-target interactions and drug repositioning events of metformin that influences vascular cells and has benefits on angiogenesis-mediated effects. Furthermore, we use miR-21 as an example to explain the specific molecular mechanism underlying metformin-mediated regulation of the miRNA signaling pathway controlling angiogenesis and vascular protective effects. These findings may provide a new therapeutic target and theoretical basis for the clinical prevention and treatment of cardiovascular diseases.
Asunto(s)
Hipoglucemiantes/farmacología , Metformina/farmacología , MicroARNs , Neovascularización Patológica/genética , Animales , Reposicionamiento de Medicamentos , HumanosRESUMEN
Despite extensive efforts to develop efficacious therapeutic approaches, the treatment of skin wounds remains a considerable clinical challenge. Existing remedies cannot sufficiently meet current needs, so the discovery of novel pro-healing agents is of growing importance. In the current research, we identified a novel short peptide (named RL-QN15, primary sequence 'QNSYADLWCQFHYMC') from Rana limnocharis skin secretions, which accelerated wound healing in mice. Exploration of the underlying mechanisms showed that RL-QN15 activated the MAPK and Smad signaling pathways, and selectively modulated the secretion of cytokines from macrophages. This resulted in the proliferation and migration of skin cells and dynamic regulation of TGF-ß1 and TGF-ß3 in wounds, which accelerated re-epithelialization and granulation tissue formation and thus skin regeneration. Moreover, RL-QN15 showed significant therapeutic potency against chronic wounds, skin fibrosis, and oral ulcers. Our results highlight frog skin secretions as a potential treasure trove of bioactive peptides with healing activity. The novel peptide (RL-QN15) identified in this research shows considerable capacity as a candidate for the development of novel pro-healing agents.
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Úlceras Bucales/tratamiento farmacológico , Péptidos/uso terapéutico , Piel/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Fibrosis , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Péptidos/farmacología , Células RAW 264.7 , Ranidae , Piel/lesiones , Piel/metabolismo , Piel/patología , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta3/metabolismoRESUMEN
The dynamic and delicate interactions amongst intestinal microbiota, metabolome and metabolism dictates human health and disease. In recent years, our understanding of gut microbial regulation of intestinal immunometabolic and redox homeostasis have evolved mainly out of in vivo studies associated with high-fat feeding induced metabolic diseases. Techniques utilizing fecal transplantation and germ-free mice have been instrumental in reproducibly demonstrating how the gut microbiota affects disease pathogenesis. However, the pillars of modern drug discovery i.e. evidence-based pharmacological studies critically lack focus on intestinal microflora. This is primarily due to targeted in vitro molecular-approaches at cellular-level that largely overlook the etiology of disease pathogenesis from the physiological perspective. Thus, this review aims to provide a comprehensive understanding of the key notions of intestinal microbiota and dysbiosis, and highlight the microbiota-phytochemical bidirectional interactions that affects bioavailability and bioactivity of parent phytochemicals and their metabolites. Potentially by focusing on the three major aspects of gut microbiota i.e. microbial abundance, diversity, and functions, I will discuss phytochemical-microbiota reciprocal interactions, biotransformation of phytochemicals and plant-derived drugs, and pre-clinical and clinical efficacies of herbal medicine on dysbiosis. Additionally, in relation to phytochemical pharmacology, I will briefly discuss the role of dietary-patterns associated with changes in microbial profiles and review pharmacological study models considering possible microbial effects. This review therefore, emphasize on the timely and critically needed evidence-based phytochemical studies focusing on gut microbiota and will provide newer insights for future pre-clinical and clinical phytopharmacological interventions.
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Microbioma Gastrointestinal/efectos de los fármacos , Fitoquímicos/farmacología , Fitoterapia , Animales , Biotransformación , Dieta , Humanos , Fitoquímicos/farmacocinéticaRESUMEN
Estrogen is known to exhibit cardioprotective and antihyperlipidemic action. Valproic acid has been shown to upregulate estrogen receptors (ERs) in breast and prostate cancer tissues. No pharmacological evaluations for magnesium valproate (MgV) so far have been done for diabetic cadio-lipidemic complications. Based on the above context, current study was undertaken to evaluate the therapeutic effectiveness of MgV in cardiac complications associated with type-1 diabetes mellitus in rats wherein diabetes was induced by single tail vein injection of streptozotocin (STZ, 45mg/kg, IV) in female Sprague Dawley rats and treatment of MgV (210mg/kg, PO) was given for eight weeks to diabetic animals, after which, various biochemical and cardiac biomarkers, hypertrophic, hemodynamic and histological parameters along with immunohistochemistry of ERs in the left ventricle (LV) were estimated. MgV treatment significantly controlled hyperglycemia and dyslipidemia, reduced elevated cardiac biomarkers and C-reactive protein(CRP), significantly improved hemodynamic functions and increased the rate of pressure development and decay. MgV also significantly reduced left ventricular hypertrophy index and cardiac hypertrophy index, LV wall thickness, LV collagen, cardiomyocyte diameter and prevented the oxidative stress with significant increase in Na+-K+-ATPase activity in LV. Moreover, MgV reversed STZ-induced histological alterations and decreased glycogen content in LV and increased the ERß expressions in LV as evidenced by immunohistochemistry. The result indicated that MgV prevented disease progression in the early stage of diabetic cardiomyopathy which seems to be mediated by upregulation of estrogen receptors in LV tissue.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Ácido Valproico/farmacología , Animales , Cardiomegalia/etiología , Cardiomegalia/prevención & control , Diabetes Mellitus Tipo 1/complicaciones , Progresión de la Enfermedad , Dislipidemias/tratamiento farmacológico , Femenino , Hiperglucemia/tratamiento farmacológico , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Estreptozocina , Regulación hacia ArribaRESUMEN
An overactivation of Gαq dependent signaling pathway is crucial for development of metabolic and vascular abnormalities in diabetes. Therefore, our objective was to study effects of Gαq-RGS2 loop activator (1-(5-chloro-2-hydroxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one) on STZ induced diabetic complications in rats. Animals were divided into four groups; normal rats, diabetic rats (Streptozotocin, STZ, 60mg/kg, i.p.), Gαq-RGS2 loop activator (1mg/kg/d, i.p., 15 d, at 6 wk after citrate buffer or STZ administration, respectively) treated normal rats and diabetic rats. At the end of 8 wk, the metabolic parameters, hemodynamic parameters, in-vivo vascular reactivity and aortic anti-oxidant status were evaluated. A treatment of Gαq-RGS2 loop activator significantly decreased serum cholesterol (P < 0.001), triglyceride (P < 0.01), systolic/diastolic/mean arterial blood pressure (P < 0.001), lactate dehydrogenase (P < 0.001), cardiac selective creatinine kinase (P < 0.001), urea (P < 0.05), creatinine (P < 0.001), aortic superoxide dismutase (P < 0.05) and catalase(P < 0.05) in diabetic rats whereas increased basal (P < 0.05) and stimulated (acetylcholine (P < 0.01) and nitroglycerine (P < 0.05)) serum nitric oxide level without affecting elevated serum glucose level. The nitroglycerin stimulated NO production was significantly (P < 0.01) increased by Gαq-RGS2 loop activator administration in normal rats, too. Collectively, Gαq-RGS2 loop activator protects rats against streptozotocin induce hemodynamic and metabolic modulation without affecting elevated serum glucose level.
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Glucemia/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Proteínas RGS/metabolismo , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiopatología , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/fisiopatología , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Masculino , Ratas , Ratas Wistar , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
The objective of the present study was to formulate eprosartan mesylate loaded nano-bilosomes and investigates its potential for controlling streptozotocin induced diabetes nephropathy in Wistar rats. The eprosartan mesylate loaded nano-bilosomes comprising of various ratios of soybean phosphatidylcholine/sodium deoxycholate were prepared by thin film hydration technique. The prepared formulations were evaluated for vesicles size, polydispersity index, zeta potential and entrapment efficiency. Further the optimized formulation was characterized for vesicles morphology, and its efficacy for the management of diabetic nephropathy in Wistar rats. The optimized eprosartan mesylate loaded nano-bilosomes exhibited vesicles size, polydispersity index, zeta potential and entrapment efficiency of 63.88±3.46nm, 0.172±0.026, -30.40±2.75mV and 61.19±0.88% respectively. In vivo activity demonstrated that the prepared eprosartan mesylate loaded nano-bilosomes formulation demonstrated a nephro-protecting outcome as shown by the substantial decrease in serum creatinine, urea, lactate dehydrogenase, total albumin, and malondialdehyde. Additionally, an oral administration of eprosartan mesylate loaded nano-bilosomes decreases the raised expressions of Angiotensin II type 1 receptor, inducible nitric oxide synthase, and transforming growth factor-ß1 in Wistar rats. Further, histopathological examination established the nephro-protective effect of prepared formulation. In conclusion, the research work in the paper suggests that the prepared eprosartan mesylate loaded nano-bilosomes could serve as a practical oral formulation for diabetic nephropathy in future therapy and may offer potential benefits in cases with hypertension and renal disease.
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Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/prevención & control , Imidazoles/química , Imidazoles/farmacología , Tiofenos/química , Tiofenos/farmacología , Administración Oral , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Ácidos y Sales Biliares , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Liposomas , Masculino , Nanoestructuras , Tamaño de la Partícula , RatasRESUMEN
AIMS: Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. MAIN METHODS: Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. KEY FINDINGS: STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ-injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. SIGNIFICANCE: STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage.
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Enfermedad de Alzheimer/diagnóstico , Gliosis/patología , Hipocampo/patología , Resistencia a la Insulina , Insulina/metabolismo , Síntomas Prodrómicos , Estreptozocina/efectos adversos , Animales , Astrocitos/patología , Colina O-Acetiltransferasa/biosíntesis , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Gliosis/inducido químicamente , Infusiones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Neuronas/patología , Ratas , Receptor de Insulina/biosíntesis , Reconocimiento en Psicología/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Estreptozocina/administración & dosificación , Factores de Tiempo , Proteínas tau/biosíntesisRESUMEN
Diabetes can cause serious health complications, which can affect every organ of the body, including the skin. The molecular etiology has not yet been clarified for all diabetic skin conditions. Thus, this study aimed to investigate the changes of diabetes in skin compared to non-diabetic skin in rats. Fifteen days after establishing the diabetic status, skin samples from the dorsum-cervical region were harvested for subsequent analysis of alterations caused by diabetes. Our results demonstrate that diabetes stimulated higher inflammation and oxidative stress in skin, but antioxidant defense levels were lower compared to the non-diabetic group (p < 0.05). This could have been related to a decreased number of blood vessels and low expression of VEGF, eNOS and TGF-ß1. Finally, insulin signaling proteins IRS, Akt, Shc and ERK showed a low expression in the diabetic group. Thus, our study shows that the pathology of diabetes induced immunohistopathological and biochemical skin changes compared to non-diabetic skin in rats.
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Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Piel/metabolismo , Piel/patología , Animales , Diabetes Mellitus Experimental/inducido químicamente , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
BACKGROUND AND PURPOSE: NLX-112 (a.k.a. befiradol, F13640) is a drug candidate intended for the treatment of l-DOPA-induced dyskinesia. It is a highly selective serotonin 5-HT1A receptor full agonist which has been previously tested in a variety of models of CNS effects including analgesic activity in rat. Its activity in mouse models of pain has not been previously investigated. EXPERIMENTAL APPROACH: The activity of NLX-112 was tested in mouse models of acute pain (hot plate), tonic pain (intraplantar formalin test), in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin (STZ)-induced model of painful diabetic neuropathy. KEY RESULTS: The main findings indicate that (i) NLX-112 was markedly active in the formalin test with potent reduction of paw licking in both phases of the test (minimal effective dose (MED) 0.5 mg/kg i.p. and p.o. in acute phase, and 0.1 mg/kg i.p. and 1 mg/kg p.o. in late phase). The effects of NLX-112 in this test were completely abolished by the selective 5-HT1A receptor antagonist, WAY100635; (ii) NLX-112 was active in the hot plate test and in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy, but at markedly higher doses (MED 2.5 mg/kg i.p.); (iii) NLX-112 was least active in the STZ-induced model of painful diabetic neuropathy (MED 5 mg/kg i.p.); (iv) NLX-112 did not affect locomotor activity. CONCLUSIONS AND IMPLICATIONS: NLX-112 may have significant potential for treatment of tonic pain but may be less promising as a candidate for treatment of chemotherapy-induced or diabetic neuropathic pain.
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Analgésicos/farmacología , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Dolor Nociceptivo/tratamiento farmacológico , Piperidinas/farmacología , Piridinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Animales , Antineoplásicos/toxicidad , Ciclohexanos/farmacología , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Formaldehído , Calor , Hiperalgesia/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Neuralgia/metabolismo , Dolor Nociceptivo/metabolismo , Compuestos Organoplatinos/toxicidad , Oxaliplatino , Piperazinas/farmacología , Distribución Aleatoria , Receptor de Serotonina 5-HT1A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Estreptozocina , TactoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes mellitus (T2DM) is becoming a serious threat to human health. The fruit of Morus alba L. is widely used as a traditional Chinese medicine for the treatment of DM, dizziness, tinnitus, insomnia, and premature graying, as well as to protect the liver and kidneys. Several studies have demonstrated that the aqueous extracts of the roots bark, leaves, and ramuli of mulberry, which are known to contain polyphenols and polysaccharides, have antihyperglycemic and antihyperlipidemic activities. The aim of the present study was to further investigate the active polysaccharides from M. alba fruit by evaluating the antidiabetic activities of different fractions on T2DM rats and elucidate the mechanism underlying these activities. MATERIALS AND METHODS: Diabetic rats were treated with two fractions of M. alba fruit polysaccharides (MFP50 and MFP90). The disease models were induced by a high-fat diet and low dose injection of streptozotocin and were compared to normal rats and metformin-treated diabetic rats. After seven weeks, the fasting blood glucose (FBG), oral glucose tolerance test (OGTT), fasting serum insulin (FINS) levels, homeostasis model of assessment-insulin resistance (HOMA-IR), glycated serum protein (GSP), and serum alanine transaminase (ALT) levels, as well as serum lipid profiles and histopathological changes in the pancreas were measured. Next, the expressions of the insulin signaling pathway were measured by western blot analysis to elucidate the potential mechanism underlying these antidiabetic activities. RESULTS: After seven weeks of treatment, a significant reduction in the FBG levels, OGTT-area under the curve (OGTT-AUC), FINS, HOMA-IR, ALT, and triglyceride (TG) values of the MFP50 group was observed. On the other hand, in the MFP90 group, the FBG, OGTT-AUC, FINS, HOMA-IR, GSP, and TG levels were significantly reduced. The level of high-density lipoprotein cholesterol (HDL-c) and the proportion of HDL-c to total cholesterol (TC) significantly increased in the MFP50 group. Moreover, MFP50 and MFP90 induced repair of damaged pancreatic tissues of the diabetic rats. The hypoglycemic effect of MFP50 was more stable than MFP90, whereas the hypolipidemic effect of MFP90 was slightly better than MFP50. Moreover, the expression levels of InsR, IRS-2, Akt and GLUT4 in the MFP90 group significantly increased relative to that of the T2DM group. CONCLUSIONS: MFP50 and MFP90 have markedly antihyperglycemic and antihyperlipidemic effects and can clearly relieve diabetes symptoms in the T2DM rat model. The M. alba fruit polysaccharides may potentially be utilized as an effective treatment for T2DM. Further research into the structures of active M. alba fruit polysaccharides and their mechanisms in promoting antidiabetic effects are underway.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Frutas , Hipoglucemiantes/uso terapéutico , Morus , Polisacáridos/uso terapéutico , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Hipoglucemiantes/aislamiento & purificación , Masculino , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Polisacáridos/aislamiento & purificación , Ratas , Ratas Wistar , Estreptozocina , Resultado del TratamientoRESUMEN
Heracleum dissectum Ledeb. has long been used as a wild edible vegetable by local people in China. The purpose of this study is to investigate the antidiabetic potential of aerial part of H. dissectum methanol extract (HdME) and the chemical constituents. Ten compounds including eight coumarins were isolated and four of them were found from H. dissectum for the first time. HdME potently inhibited the elevation of plasma glucose after its oral administration to glucose-loaded mice, and its petroleum ether (PE) fraction exerted the greatest inhibitory activities. Meanwhile, HdME (125 and 250mg/kg) also significantly decreased the blood glucose level in STZ-induced diabetic mice, but had no effect in normoglycemic mice. Additionally, HdME showed weak inhibitory effects on α-glucosidase activity and DPPH free radicals scavenging. In conclusion, HdME has antidiabetic action and PE fraction is the active part where coumarins possibly play an important role in antidiabetic activity.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Heracleum/química , Hipoglucemiantes/química , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Animales , Masculino , RatonesRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The development of compounds able to improve metabolic syndrome and mitigate complications caused by inappropriate glycemic control in type 1 diabetes mellitus is challenging. The medicinal plant with established hypoglycemic properties Garcinia kola Heckel might have the potential to mitigate diabetes mellitus metabolic syndrome and complications. AIM OF THE STUDY: We have investigated the neuroprotective properties of a suspension of G. kola seeds in long-term type 1 diabetes mellitus rat model. MATERIALS AND METHODS: Wistar rats, made diabetic by single injection of streptozotocin were monitored for 8 months. Then, they were administered with distilled water or G. kola oral aqueous suspension daily for 30 days. Body weight and glycemia were determined before and after treatment. After sacrifice, cerebella were dissected out and processed for stereological quantification of Purkinje cells. Histopathological and immunohistochemical analyses of markers of neuroinflammation and neurodegeneration were performed. RESULTS: Purkinje cell counts were significantly increased, and histopathological signs of apoptosis and neuroinflammation decreased, in diabetic animals treated with G. kola compared to diabetic rats given distilled water. Glycemia was also markedly improved and body weight restored to non-diabetic control values, following G. kola treatment. CONCLUSIONS: These results suggest that G. kola treatment improved the general condition of long-term diabetic rats and protected Purkinje cells partly by improving the systemic glycemia and mitigating neuroinflammation.
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Enfermedades Cerebelosas/prevención & control , Cerebelo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Neuropatías Diabéticas/prevención & control , Garcinia kola/química , Hipoglucemiantes/farmacología , Degeneración Nerviosa , Fármacos Neuroprotectores/farmacología , Preparaciones de Plantas/farmacología , Animales , Apoptosis/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Enfermedades Cerebelosas/sangre , Enfermedades Cerebelosas/etiología , Enfermedades Cerebelosas/patología , Cerebelo/metabolismo , Cerebelo/patología , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/inducido químicamente , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/patología , Hipoglucemiantes/aislamiento & purificación , Neuroinmunomodulación/efectos de los fármacos , Fármacos Neuroprotectores/aislamiento & purificación , Fitoterapia , Preparaciones de Plantas/aislamiento & purificación , Plantas Medicinales , Células de Purkinje/efectos de los fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patología , Ratas Wistar , Estreptozocina , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo , Receptor fas/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (Lin Zhi) has been used to treat diabetes in Chinese folk for centuries. Our laboratory previously demonstrated that Ganoderma lucidum polysaccharides (GLPs) had hypoglycemic effects in diabetic mice. Our aim was to identify the main bioactives in GLPs and corresponding mechanism of action. MATERIALS AND METHODS: Four polysaccharide-enriched fraction were isolated from GLPs and the antidiabetic activities were evaluated by type 2 diabetic mice. Fasting serum glucose (FSG), fasting serum insulin (FSI) and epididymal fat/BW ratio were measured at the end of the experiment. In liver, the mRNA levels of hepatic glucose regulatory enzymes were determined by quantitative polymerase chain reaction (qPCR) and the protein levels of phospho-AMP-activated protein kinase (p-AMPK)/AMPK were determined by western blotting test. In epididymal fat tissue, the mRNA and protein levels GLUT4, resistin, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC1) were determined by qPCR and immuno-histochemistry. The structure of polysaccharide F31 was obtained from GPC, FTIR NMR and GC-MS spectroscopy, RESULTS: F31 significantly decreased FSG (P<0.05), FSI and epididymal fat/BW ratio (P<0.01). In liver, F31 decreased the mRNA levels of hepatic glucose regulatory enzymes, and up-regulated the ratio of phospho-AMP-activated protein kinase (p-AMPK)/AMPK. In epididymal fat tissue, F31 increased the mRNA levels of GLUT4 but decreased fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC1) and resistin. Immuno-histochemistry results revealed F31 increased the protein levels of GLUT4 and decreased resistin. CONCLUSION: Data suggested that the main bioactives in GLPs was F31, which was determined to be a ß-heteropolysaccharide with the weight-average molecular weight of 15.9kDa. The possible action mechanism of F31 may be associated with down-regulation of the hepatic glucose regulated enzyme mRNA levels via AMPK activation, improvement of insulin resistance and decrease of epididymal fat/BW ratio. These results strongly suggest that F31 has antidiabetic potential.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polisacáridos Fúngicos , Ganoderma , Hipoglucemiantes , Proteínas Quinasas Activadas por AMP/metabolismo , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Regulación hacia Abajo , Ayuno/sangre , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Cuerpos Fructíferos de los Hongos , Polisacáridos Fúngicos/farmacología , Polisacáridos Fúngicos/uso terapéutico , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , ARN Mensajero/metabolismoRESUMEN
Blunted cystathionine-γ lyase (CSE) activity (reduced endogenous H2S-level) is implicated in hypertension and myocardial dysfunction in diabetes. Here, we tested the hypothesis that CSE derived H2S mediates the cardiovascular protection conferred by the imidazoline I1 receptor agonist moxonidine in a diabetic rat model. We utilized streptozotocin (STZ; 55mg/kg i.p) to induce diabetes in male Wistar rats. Four weeks later, STZ-treated rats received vehicle, moxonidine (2 or 6mg/kg; gavage), CSE inhibitor DL-propargylglycine, (37.5mg/kg i.p) or DL-propargylglycine with moxonidine (6mg/kg) for 3 weeks. Moxonidine improved the glycemic state, and reversed myocardial hypertrophy, hypertension and baroreflex dysfunction in STZ-treated rats. Ex vivo studies revealed that STZ caused reductions in CSE expression/activity, H2S and nitric oxide (NO) levels and serum adiponectin and elevations in myocardial imidazoline I1 receptor expression, p38 and extracellular signal-regulated kinase, ERK1/2, phosphorylation and lipid peroxidation (expressed as malondialdehyde). Moxonidine reversed these biochemical responses, and suppressed the expression of death associated protein kinase-3. Finally, pharmacologic CSE inhibition (DL-propargylglycine) abrogated the favorable cardiovascular, glycemic and biochemical responses elicited by moxonidine. These findings present the first evidence for a mechanistic role for CSE derived H2S in the glycemic control and in the favorable cardiovascular effects conferred by imidazoline I1 receptor activation (moxonidine) in a diabetic rat model.
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Cardiotónicos/farmacología , Cistationina gamma-Liasa/metabolismo , Diabetes Mellitus Experimental/metabolismo , Sulfuro de Hidrógeno/metabolismo , Imidazoles/farmacología , Adiponectina/metabolismo , Alquinos/farmacología , Animales , Barorreflejo/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Cistationina gamma-Liasa/antagonistas & inhibidores , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glicina/análogos & derivados , Glicina/farmacología , Hipertrofia/prevención & control , Masculino , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Diabetes is associated with endothelial dysfunction, which is characterized by impaired endothelium-dependent relaxations. The present study aimed to examine the role of nitric oxide (NO), prostacyclin and endothelium-dependent hyperpolarization (EDH), in the relaxation of ventral tail arteries of rats under diabetic conditions. Relaxations of tail arteries of control and diabetic rats were studied in wire myograph. Western blotting and immunostaining were used to determine the presence of proteins. Acetylcholine-induced relaxations were significantly smaller in arteries of diabetic compared to control rats (Rmax; 70.81 ± 2.48% versus 85.05 ± 3.15%). Incubation with the combination of non-selective cyclooxygenase (COX) inhibitor, indomethacin and potassium channel blockers, TRAM 34 and UCL 1684, demonstrated that NO-mediated relaxation was attenuated significantly in diabetic compared to control rats (Rmax; 48.47 ± 5.84% versus 68.39 ± 6.34%). EDH-type (in the presence of indomethacin and NO synthase inhibitor, LNAME) and prostacyclin-mediated (in the presence of LNAME plus TRAM 34 and UCL 1684) relaxations were not significantly reduced in arteries of diabetic compared to control rats [Rmax: (EDH; 17.81 ± 6.74% versus 34.16 ± 4.59%) (prostacyclin; 15.85 ± 3.27% versus 17.23 ± 3.75%)]. Endothelium-independent relaxations to sodium nitroprusside, salbutamol and prostacyclin were comparable in the two types of preparations. Western blotting and immunostaining indicated that diabetes diminished the expression of endothelial NO synthase (eNOS), while increasing those of COX-1 and COX-2. Thus, since acetylcholine-induced NO-mediated relaxation was impaired in diabetes because of reduced eNOS protein expression, pharmacological intervention improving NO bioavailability could be useful in the management of diabetic endothelial dysfunction.