RESUMO
Background: Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically. Methods: First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated. Results: Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P<0.05), alongside mitigated podocyte injury (P<0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1ß, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway. Conclusion: Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside's efficacy in DKD treatment, providing a foundation for further basic and clinical research.
Assuntos
Diabetes Mellitus Experimental, Nefropatias Diabéticas, Glucosídeos, Simulação de Acoplamento Molecular, Farmacologia em Rede, Fenóis, Polifenóis, Estreptozocina, Nefropatias Diabéticas/tratamento farmacológico, Nefropatias Diabéticas/metabolismo, Animais, Ratos, Glucosídeos/farmacologia, Glucosídeos/química, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/metabolismo, Masculino, Fenóis/farmacologia, Fenóis/química, Ratos Sprague-DawleyRESUMO
This study is aimed at assessing the impact of soluble dietary fiber inulin on the treatment of diabetes-related chronic inflammation and kidney injury in mice with type 2 diabetes (T2DM). The T2DM model was created by feeding the Institute of Cancer Research (ICR) mice a high-fat diet and intraperitoneally injecting them with streptozotocin (50 mg/kg for 5 consecutive days). The thirty-six ICR mice were divided into three dietary groups: the normal control (NC) group, the T2DM (DM) group, and the DM + inulin diet (INU) group. The INU group mice were given inulin at the dose of 500 mg/kg gavage daily until the end of the 12th week. After 12 weeks, the administration of inulin resulted in decreased serum levels of fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), blood urea nitrogen (BUN), and creatinine (CRE). The administration of inulin not only ameliorated renal injury but also resulted in a reduction in the mRNA expressions of inflammatory factors in the spleen and serum oxidative stress levels, when compared to the DM group. Additionally, inulin treatment in mice with a T2DM model led to a significant increase in the concentrations of three primary short-chain fatty acids (SCFAs) (acetic acid, propionic acid, and butyric acid), while the concentration of advanced glycation end products (AGEs), a prominent inflammatory factor in diabetes, exhibited a significant decrease. The results of untargeted metabolomics indicate that inulin has the potential to alleviate inflammatory response and kidney damage in diabetic mice. This beneficial effect is attributed to its impact on various metabolic pathways, including glycerophospholipid metabolism, taurine and hypotaurine metabolism, arginine biosynthesis, and tryptophan metabolism. Consequently, oral inulin emerges as a promising treatment option for diabetes and kidney injury.
Assuntos
Glicemia, Diabetes Mellitus Experimental, Diabetes Mellitus Tipo 2, Inflamação, Inulina, Rim, Metabolômica, Camundongos Endogâmicos ICR, Estresse Oxidativo, Animais, Inulina/farmacologia, Diabetes Mellitus Tipo 2/complicações, Diabetes Mellitus Tipo 2/sangue, Diabetes Mellitus Tipo 2/tratamento farmacológico, Diabetes Mellitus Tipo 2/metabolismo, Diabetes Mellitus Experimental/sangue, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/complicações, Diabetes Mellitus Experimental/metabolismo, Camundongos, Masculino, Glicemia/metabolismo, Glicemia/efeitos dos fármacos, Rim/efeitos dos fármacos, Rim/metabolismo, Rim/patologia, Estresse Oxidativo/efeitos dos fármacos, Nefropatias Diabéticas/tratamento farmacológico, Nefropatias Diabéticas/metabolismo, Nefropatias Diabéticas/sangue, Nefropatias Diabéticas/patologia, Ácidos Graxos Voláteis/metabolismo, Dieta Hiperlipídica, Nitrogênio da Ureia SanguíneaRESUMO
Diabetes mellitus (DM) is a collection of metabolic disorder that is characterized by chronic hyperglycemia. Recent studies have demonstrated the crucial involvement of oxidative stress (OS) and inflammatory reactions in the development of DM. Curcumin (CUR), a natural compound derived from turmeric, exerts beneficial effects on diabetes mellitus through its interaction with the nuclear factor kappa B (NF-κB) pathway. Research indicates that CUR targets inflammatory mediators in diabetes, including tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), by modulating the NF-κB signaling pathway. By reducing the expression of these inflammatory factors, CUR demonstrates protective effects in DM by improving pancreatic ß-cells function, normalizing inflammatory cytokines, reducing OS and enhancing insulin sensitivity. The findings reveal that CUR administration effectively lowered blood glucose elevation, reinstated diminished serum insulin levels, and enhanced body weight in Streptozotocin -induced diabetic rats. CUR exerts its beneficial effects in management of diabetic complications through regulation of signaling pathways, such as calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII), peroxisome proliferator-activated receptor gamma (PPAR-γ), NF-κB, and transforming growth factor ß1 (TGFB1). Moreover, CUR reversed the heightened expression of inflammatory cytokines (TNF-α, Interleukin-1 beta (IL-1ß), IL-6) and chemokines like MCP-1 in diabetic specimens, vindicating its anti-inflammatory potency in counteracting hyperglycemia-induced alterations. CUR diminishes OS, avert structural kidney damage linked to diabetic nephropathy, and suppress NF-κB activity. Furthermore, CUR exhibited a protective effect against diabetic cardiomyopathy, lung injury, and diabetic gastroparesis. Conclusively, the study posits that CUR could potentially offer therapeutic benefits in relieving diabetic complications through its influence on the NF-κB pathway.
Assuntos
Curcumina, Inflamação, NF-kappa B, Estresse Oxidativo, Transdução de Sinais, Curcumina/farmacologia, Curcumina/uso terapêutico, Estresse Oxidativo/efeitos dos fármacos, NF-kappa B/metabolismo, Animais, Inflamação/tratamento farmacológico, Inflamação/metabolismo, Transdução de Sinais/efeitos dos fármacos, Humanos, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/metabolismo, RatosRESUMO
Type 2 diabetes mellitus is a worldwide public health issue. In the globe, Egypt has the ninth-highest incidence of diabetes. Due to its crucial role in preserving cellular homeostasis, the autophagy process has drawn a lot of attention in recent years, Therefore, the purpose of this study was to evaluate the traditional medication metformin with the novel therapeutic effects of cinnamondehyde on adipocyte and hepatic autophagy in a model of high-fat diet/streptozotocin-diabetic rats. The study was conducted on 40 male albino rats, classified into 2 main groups, the control group and the diabetic group, which was subdivided into 4 subgroups (8 rats each): untreated diabetic rats, diabetic rats received oral cinnamaldehyde 40 mg/kg/day, diabetic rats received oral metformin 200 mg/kg/day and diabetic rats received a combination of both cinnamaldehyde and metformin daily for 4 weeks. The outcomes demonstrated that cinnamaldehyde enhanced the lipid profile and glucose homeostasis. Moreover, Cinnamaldehyde had the opposite effects on autophagy in both tissues; by altering the expression of genes that control autophagy, such as miRNA 30a and mammalian target of rapamycin (mTOR), it reduced autophagy in adipocytes and stimulated it in hepatic tissues. It may be inferred that by increasing the treatment efficacy of metformin and lowering its side effects, cinnamaldehyde could be utilized as an adjuvant therapy with metformin for the treatment of type 2 diabetes.
Assuntos
Acroleína, Acroleína/análogos & derivados, Adipócitos, Autofagia, Diabetes Mellitus Experimental, Fígado, Metformina, Animais, Acroleína/farmacologia, Acroleína/uso terapêutico, Autofagia/efeitos dos fármacos, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/metabolismo, Fígado/efeitos dos fármacos, Fígado/metabolismo, Fígado/patologia, Masculino, Ratos, Adipócitos/efeitos dos fármacos, Adipócitos/metabolismo, Metformina/farmacologia, Dieta Hiperlipídica/efeitos adversos, Diabetes Mellitus Tipo 2/tratamento farmacológico, Diabetes Mellitus Tipo 2/metabolismo, MicroRNAs/metabolismo, MicroRNAs/genética, Hipoglicemiantes/farmacologia, Hipoglicemiantes/uso terapêutico, Estreptozocina, Glicemia/metabolismo, Serina-Treonina Quinases TOR/metabolismoRESUMO
Diabetic nephropathy (DN), a micro vascular complication of diabetes, is the main cause of end-stage renal disease, with a morbidity over 40% of diabetes. High glucose and lipid metabolism dysfunction are the leading cause of the development of DN. Previous study demonstrated that increased expression or activation of SREBPs in models of DN. Leonuride (LE), as an active constituent of Leonurus japonicus Houttuyn, has multiple biological activities, including antioxidant and anti-inflammatory effects. Previous studies showed that increasing the degradation of mature SREBPs is a robust way of lowering lipids and improve lipid metabolism dysfunction. However, effective regulation method of SREBPs degradation are still lacking. Herein, this study indicated that LE can effectively improve glucose and lipid metabolism disorders. In addition, the kidney function was also improved by inhibition of SREBPs activities in streptozocin (STZ)-induced type II diabetic mice. To our knowledge, this is the first time to describe the detailed mechanism of LE on the inhibition of precursor SREBPs, which would present a new direction for diabetic nephropathy treatment.
Assuntos
Diabetes Mellitus Experimental, Nefropatias Diabéticas, Nefropatias Diabéticas/tratamento farmacológico, Nefropatias Diabéticas/metabolismo, Nefropatias Diabéticas/prevenção & controle, Animais, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/complicações, Masculino, Camundongos, Metabolismo dos Lipídeos/efeitos dos fármacos, Glicemia/efeitos dos fármacos, Glicemia/metabolismo, Rim/efeitos dos fármacos, Rim/metabolismo, Rim/patologia, Transdução de Sinais/efeitos dos fármacos, Camundongos Endogâmicos C57BL, Diabetes Mellitus Tipo 2/tratamento farmacológico, Diabetes Mellitus Tipo 2/complicaçõesRESUMO
Vanadyl sulfate (VS), is a component of some food supplements and experimental drugs. This study was carried out to present a novel method for induction of Type 2 diabetes in rats, then for the first time in literature, for evaluating the effect of VS on metabolic parameters and gene expression, simultaneously. 40 male wistar rats were distributed between the four groups, equally. High fat diet and fructose were used for diabetes induction. Diabetic rats treated by two different dose of VS for 12 weeks. Metabolic profiles were evaluated by commercial available kits and gene expression were assayed by real time-PCR. Compared to controls, in non-treated diabetic rats, weight, glucose, triglyceride, total cholesterol, insulin and insulin resistance were increased significantly (p-value <0.05) that indicated induction of type 2 diabetes. Further, the results showed that VS significantly reduced weight, insulin secretion, Tumor Necrosis Factor-alpha (TNF-α) genes expression, lipid profiles except HDL that we couldn't find any significant change and increased Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) gene expression in VS-treated diabetic animals in comparison with the non-treated diabetics. Our study demonstrated that vanadyl supplementation in diabetic rats had advantageous effects on metabolic profiles and related gene expression.
Assuntos
Glicemia, Diabetes Mellitus Experimental, Diabetes Mellitus Tipo 2, PPAR gama, Ratos Wistar, Fator de Necrose Tumoral alfa, Compostos de Vanádio, Animais, Masculino, Fator de Necrose Tumoral alfa/genética, Fator de Necrose Tumoral alfa/metabolismo, PPAR gama/metabolismo, PPAR gama/genética, Diabetes Mellitus Tipo 2/tratamento farmacológico, Diabetes Mellitus Tipo 2/metabolismo, Diabetes Mellitus Tipo 2/genética, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/metabolismo, Diabetes Mellitus Experimental/genética, Glicemia/efeitos dos fármacos, Glicemia/metabolismo, Compostos de Vanádio/farmacologia, Resistência à Insulina, Ratos, Insulina/sangue, Hipoglicemiantes/farmacologia, Dieta Hiperlipídica/efeitos adversos, Regulação da Expressão Gênica/efeitos dos fármacosRESUMO
Diabetes mellitus, recognized by elevated glucose level in the body fluids is commonly caused by less insulin production or its action. To overcome the complications of diabetes, chemical drugs are never preferred over herbal medicines. Present study was designed to find out the anti-diabetic and health-promoting effects of ethanolic leaf extracts of Cucumis melo and Citrullus lanatus in induced-diabetic albino rats. Thirty male albino rats were bought from the animal house of the university and divided randomly into five feeding groups (n=6). Diabetes was induced in rats of groups A, B, C & D by a single dose of intra-peritoneal injection of streptozotocin (55 mg/Kg), whereas, the rats of group E were considered as control. The rats of groups A, B & C were fed basal diet supplemented with plant extracts (150mg/Kg body weight), whereas; only basal diet was offered to rats of groups D & E. After 28 days of the experiment, blood was collected for biochemical analysis. Results revealed that body weight, glucose, AST, ALB, GGT, HDL, cholesterol, triglyceride, urea and creatinine level differed significantly among treatment groups. It was therefore concluded that ethanolic leaf extracts of Cucumis melo and Citrullus lanatus can be used separately or in combination for the management of diabetes.
Assuntos
Glicemia, Citrullus, Cucumis melo, Diabetes Mellitus Experimental, Hipoglicemiantes, Lipídeos, Extratos Vegetais, Animais, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/sangue, Extratos Vegetais/farmacologia, Cucumis melo/química, Masculino, Glicemia/efeitos dos fármacos, Glicemia/metabolismo, Citrullus/química, Ratos, Hipoglicemiantes/farmacologia, Hipoglicemiantes/isolamento & purificação, Lipídeos/sangue, Folhas de Planta/química, Rim/efeitos dos fármacos, Rim/metabolismo, Fígado/efeitos dos fármacos, Fígado/metabolismo, EstreptozocinaRESUMO
Medicinal plants contain a wide variety of bioactive phytoconstituents which can serve as new therapeutic agents for several diseases. This study examines the antidiabetic potential of Aitchisonia rosea in alloxan-induced diabetic rats and identifies its bioactive phytoconstituents using GC-MS. In vitro, antidiabetic potential was established using the α-amylase inhibition assay. In vivo, antidiabetic potential was investigated by employing the oral glucose tolerance test (OGTT). GC-MS analysis was used to identify the bioactive phytoconstituents. The in vitro and in vivo tests showed that the aqueous extract of A. rosea possesses better antidiabetic potential. The α-amylase inhibition assay highlighted an IC50 value of 134.87µg/ml. In an oral glucose tolerance test, rats given an aqueous A. rosea extract significantly lowered their blood sugar levels significant reduction in the blood glucose concentration was observed in the oral glucose tolerance test in rats treated with the aqueous A. rosea extract. GC-MS investigation revealed many phytoconstituents, with serverogenin acetate and cycloheptasiloxane tetradecamethyl being important antidiabetic agents. This study found anti-diabetic properties in A. rosea extract. The phytochemical and GC-MS investigation also found serverogenin acetate and cycloheptasiloxane tetradecamethyl, which could be used to develop new antidiabetic drugs.
Assuntos
Glicemia, Diabetes Mellitus Experimental, Cromatografia Gasosa-Espectrometria de Massas, Hipoglicemiantes, Componentes Aéreos da Planta, Extratos Vegetais, Animais, Hipoglicemiantes/farmacologia, Hipoglicemiantes/isolamento & purificação, Hipoglicemiantes/química, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/sangue, Diabetes Mellitus Experimental/induzido quimicamente, Componentes Aéreos da Planta/química, Masculino, Glicemia/efeitos dos fármacos, Ratos, Teste de Tolerância a Glucose, alfa-Amilases/antagonistas & inibidores, alfa-Amilases/metabolismo, Ratos Wistar, Compostos Fitoquímicos/farmacologia, Compostos Fitoquímicos/análise, AloxanoRESUMO
Insulin is the cornerstone of treatment in type 1 diabetes mellitus. However, because of its protein structure, insulin has to be administered via injection, and many attempts have been made to create oral formulations, especially using nanoparticles (NPs). The aim of this study was to compare the hypoglycemic effect of insulin-loaded NPs to that of subcutaneous insulin in an in vivo rat model of diabetes. We used biodegradable D-α-tocopherol polyethylene glycol succinate-emulsified, chitosan-capped poly(lactic-co-glycolic acid) NPs loaded with soluble human insulin in a dose of 20 IU/kg body weight, and examined the physical characteristics of NPs in vivo and in vitro. Serum glucose levels were reduced after 6 h, but the difference was not significant compared to subcutaneous insulin; at 12 h and 24 h, insulin levels were significantly higher in rats treated with NPs than in rats treated with subcutaneous insulin. There was no significant difference in serum insulin levels at 12 h and 24 h compared to non-diabetic rats. Our findings suggest that chitosan-based NPs are able to maintain good glycemic control for up to 24 h and can be considered a potential carrier for oral insulin delivery.
Assuntos
Diabetes Mellitus Experimental, Hiperglicemia, Insulina, Nanopartículas, Estreptozocina, Animais, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/sangue, Insulina/sangue, Insulina/administração & dosagem, Ratos, Administração Oral, Masculino, Hiperglicemia/tratamento farmacológico, Quitosana/química, Glicemia, Hipoglicemiantes/administração & dosagem, Hipoglicemiantes/farmacologia, Hipoglicemiantes/uso terapêutico, Modelos Animais de Doenças, Ratos Sprague-DawleyRESUMO
Vascular lesions frequently arise as complication in patients diagnosed with diabetes mellitus (DM). Presently, percutaneous coronary intervention (PCI) and antithrombotic therapy serve as primary treatments. However, in-stent restenosis persists as a challenging clinical issue following PCI, lacking sustained and effective treatment. Linarin (LN) exhibits diverse pharmacological activities and is regarded as a potential drug for treating various diseases, including DM. But its specific role in restenosis after vascular injury in DM patients remains unclear. A rat model of diabetes-related restenosis was established to evaluate the role of LN on neointimal hyperplasia. Vascular smooth muscle cells (VSMCs) stimulated by high glucose (HG, 30 mM) underwent LN treatment. Additionally, an overexpression plasmid of A disintegrin and metalloproteinases (ADAM10) was constructed to transfect VSMCs. We employed CCK-8, Brdu, wound-healing scratch, and transwell migration assays to evaluate the proliferation and migration of VSMCs. Furthermore, western blot and immunofluorescence assays were utilized to investigate the expressions of ADAM10 and the downstream Notch signaling pathway in vivo and in vitro models. LN notably alleviated intimal hyperplasia after vascular injury in DM rats and reduced the protein expression of ADAM10, alongside its downstream Notch1 signaling pathway-related proteins (Notch1, NICD and Hes1) in rat carotid artery tissues. LN effectively suppressed the proliferation and migration of VSMCs induced by HG, downregulating the protein expression of ADAM10, Notch1, NICD and Hes1. Moreover, our findings indicated that ADAM10 overexpression significantly reversed LN's effects on proliferation, migration, and the expression of Notch1 signaling pathway-related proteins in HG-treated VSMCs. LN demonstrates potential therapeutic efficacy in addressing restenosis after diabetic-related vascular injury, with the ADAM10 mediated Notch signaling pathway playing a pivotal role.
Assuntos
Proteína ADAM10, Secretases da Proteína Precursora do Amiloide, Lesões das Artérias Carótidas, Movimento Celular, Proliferação de Células, Diabetes Mellitus Experimental, Proteínas de Membrana, Músculo Liso Vascular, Miócitos de Músculo Liso, Neointima, Ratos Sprague-Dawley, Transdução de Sinais, Animais, Proteína ADAM10/metabolismo, Músculo Liso Vascular/metabolismo, Músculo Liso Vascular/efeitos dos fármacos, Músculo Liso Vascular/patologia, Músculo Liso Vascular/enzimologia, Movimento Celular/efeitos dos fármacos, Miócitos de Músculo Liso/efeitos dos fármacos, Miócitos de Músculo Liso/patologia, Miócitos de Músculo Liso/metabolismo, Miócitos de Músculo Liso/enzimologia, Proliferação de Células/efeitos dos fármacos, Masculino, Proteínas de Membrana/metabolismo, Proteínas de Membrana/genética, Secretases da Proteína Precursora do Amiloide/metabolismo, Células Cultivadas, Lesões das Artérias Carótidas/patologia, Lesões das Artérias Carótidas/metabolismo, Lesões das Artérias Carótidas/tratamento farmacológico, Lesões das Artérias Carótidas/enzimologia, Diabetes Mellitus Experimental/complicações, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Tipo 2/complicações, Diabetes Mellitus Tipo 2/metabolismo, Hiperplasia, Receptores Notch/metabolismo, Receptor Notch1/metabolismo, Fatores de Transcrição HES-1/metabolismo, Fatores de Transcrição HES-1/genética, Modelos Animais de Doenças, Ratos, Reestenose Coronária/patologia, Reestenose Coronária/etiologia, Reestenose Coronária/metabolismo, Reestenose Coronária/prevenção & controleRESUMO
The anti-diabetic effect of Ficus carica (Fig) seed oil was investigated. 4 groups with 6 rats in each group were used in the experiment as control, diabetes (45 mg/kg streptozotocin), fig seed oil (FSO) (6 mL/ kg/day/rat by gavage) and diabetes+FSO groups. Glucose, urea, creatinine, ALT, AST, GSH, AOPP and MDA analyses were done. Pancreatic tissues were examined histopathologically. When fig seed oil was given to the diabetic group, the blood glucose level decreased. In the diabetes+FSO group, serum urea, creatinine, AOPP, MDA levels and ALT and AST activities decreased statistically significantly compared to the diabetes group, while GSH levels increased significantly, histopathological, immunohistochemical, and immunofluorescent improvements were observed. It has been shown for the first time that FSO has positive effects on blood glucose level and pancreatic health. It can be said that the protective effect of fig seed oil on tissues may be due to its antioxidant activity.
Assuntos
Antioxidantes, Glicemia, Diabetes Mellitus Experimental, Ficus, Hipoglicemiantes, Pâncreas, Óleos de Plantas, Sementes, Estreptozocina, Animais, Ficus/química, Diabetes Mellitus Experimental/tratamento farmacológico, Óleos de Plantas/farmacologia, Óleos de Plantas/isolamento & purificação, Sementes/química, Hipoglicemiantes/farmacologia, Hipoglicemiantes/isolamento & purificação, Glicemia/metabolismo, Masculino, Pâncreas/efeitos dos fármacos, Pâncreas/patologia, Pâncreas/metabolismo, Antioxidantes/farmacologia, Ratos, Ratos Wistar, Creatinina/sangueRESUMO
INTRODUCTION: There has been increasing evidence that the gut microbiota is closely related to type 2 diabetes (T2D). Metformin (Met) is often used in combination with saxagliptin (Sax) and repaglinide (Rep) for the treatment of T2D. However, little is known about the effects of these combination agents on gut microbiota in T2D. RESEARCH DESIGN AND METHODS: A T2D mouse model induced by a high-fat diet (HFD) and streptozotocin (STZ) was employed. The T2D mice were randomly divided into six groups, including sham, Met, Sax, Rep, Met+Sax and Met+Rep, for 4 weeks. Fasting blood glucose level, serum biochemical index, H&E staining of liver, Oil red O staining of liver and microbiota analysis by 16s sequencing were used to access the microbiota in the fecal samples. RESULTS: These antidiabetics effectively prevented the development of HFD/STZ-induced high blood glucose, and the combination treatment had a better effect in inhibiting lipid accumulation. All these dosing regimens restored the decreasing ratio of the phylum Bacteroidetes: Firmicutes, and increasing abundance of phylum Desulfobacterota, expect for Met. At the genus level, the antidiabetics restored the decreasing abundance of Muribaculaceae in T2D mice, but when Met was combined with Rep or Sax, the abundance of Muribaculaceae was decreased. The combined treatment could restore the reduced abundance of Prevotellaceae_UCG-001, while Met monotherapy had no such effect. In addition, the reduced Lachnospiraceae_NK4A136_group was well restored in the combination treatment groups, and the effect was much greater than that in the corresponding monotherapy group. Therefore, these dosing regimens exerted different effects on the composition of gut microbiota, which might be associated with the effect on T2D. CONCLUSIONS: Supplementation with specific probiotics may further improve the hypoglycemic effects of antidiabetics and be helpful for the development of new therapeutic drugs for T2D.
Assuntos
Adamantano, Glicemia, Carbamatos, Diabetes Mellitus Experimental, Diabetes Mellitus Tipo 2, Dieta Hiperlipídica, Dipeptídeos, Microbioma Gastrointestinal, Hipoglicemiantes, Metformina, Piperidinas, Animais, Microbioma Gastrointestinal/efeitos dos fármacos, Metformina/farmacologia, Metformina/uso terapêutico, Camundongos, Dieta Hiperlipídica/efeitos adversos, Diabetes Mellitus Tipo 2/tratamento farmacológico, Diabetes Mellitus Tipo 2/microbiologia, Hipoglicemiantes/farmacologia, Hipoglicemiantes/uso terapêutico, Diabetes Mellitus Experimental/tratamento farmacológico, Carbamatos/farmacologia, Dipeptídeos/farmacologia, Masculino, Adamantano/análogos & derivados, Adamantano/farmacologia, Adamantano/uso terapêutico, Piperidinas/farmacologia, Piperidinas/uso terapêutico, Glicemia/análise, Glicemia/efeitos dos fármacos, Camundongos Endogâmicos C57BL, Quimioterapia Combinada, EstreptozocinaRESUMO
BACKGROUND: One of the main causes of diabetic nephropathy is oxidative stress induced by hyperglycemia. Apelin inhibits insulin secretion. Besides, renal expression of TGF-ß is increased in diabetes mellitus (DM). The preventive effect of quercetin (Q) against renal functional disorders and tissue damage developed by DM in rats was assessed. METHODS: Forty male Wistar rats were grouped into normal control (NC), normal + quercetin (NQ: quercetin, 50 mg/kg/day by gavage), diabetic control (DC: streptozotocin, 65 mg/kg, i.p.), diabetic + quercetin pretreatment (D + Qpre), and diabetic + quercetin post-treatment (D + Qpost). All samples (24-hour urine, plasma, pancreatic, and renal tissues) were obtained at the terminal of the experiment. RESULTS: Compared to NC and NQ groups, DM ended in elevated plasma and glucose levels, decreased plasma insulin level, kidney dysfunction, augmented levels of malondialdehyde, decreased level of reduced glutathione, reduced enzymatic activities of superoxide dismutase and catalase, elevated gene expression levels of apelin and TGF-ß, also renal and pancreatic histological damages. Quercetin administration diminished entire the changes. However, the measure of improvement in the D + Qpre group was higher than that of the D + Qpost group. CONCLUSION: Quercetin prevents renal dysfunction induced by DM, which might be related to the diminution of lipid peroxidation, strengthening of antioxidant systems, and prevention of the apelin/ TGF-ß signaling pathway.
Assuntos
Apelina, Diabetes Mellitus Experimental, Nefropatias Diabéticas, Rim, Estresse Oxidativo, Quercetina, Ratos Wistar, Fator de Crescimento Transformador beta, Animais, Quercetina/farmacologia, Ratos, Masculino, Fator de Crescimento Transformador beta/metabolismo, Diabetes Mellitus Experimental/metabolismo, Diabetes Mellitus Experimental/tratamento farmacológico, Rim/efeitos dos fármacos, Rim/metabolismo, Rim/patologia, Nefropatias Diabéticas/metabolismo, Nefropatias Diabéticas/prevenção & controle, Nefropatias Diabéticas/tratamento farmacológico, Apelina/metabolismo, Estresse Oxidativo/efeitos dos fármacos, Glicemia/metabolismo, Glicemia/efeitos dos fármacos, Antioxidantes/farmacologia, Antioxidantes/metabolismo, Insulina/metabolismo, Insulina/sangue, Diabetes Mellitus Tipo 1/metabolismo, Regulação da Expressão Gênica/efeitos dos fármacosRESUMO
We aimed to delve into the mechanisms underpinning Jiawei Shengjiang San's (JWSJS) action in treating diabetic nephropathy and deploying network pharmacology. Employing network pharmacology and molecular docking techniques, we predicted the active components and targets of JWSJS and constructed a meticulous "drug-component-target" network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were utilized to discern the therapeutic pathways and targets of JWSJS. Autodock Vina 1.2.0 was deployed for molecular docking verification, and a 100-ns molecular dynamics simulation was conducted to affirm the docking results, followed by in vivo animal verification. The findings revealed that JWSJS shared 227 intersecting targets with diabetic nephropathy, constructing a protein-protein interaction network topology. KEGG enrichment analysis denoted that JWSJS mitigates diabetic nephropathy by modulating lipids and atherosclerosis, the PI3K-Akt signaling pathway, apoptosis, and the HIF-1 signaling pathway, with mitogen-activated protein kinase 1 (MAPK1), MAPK3, epidermal growth factor receptor (EGFR), and serine/threonine-protein kinase 1 (AKT1) identified as collective targets of multiple pathways. Molecular docking asserted that the core components of JWSJS (quercetin, palmitoleic acid, and luteolin) could stabilize conformation with three pivotal targets (MAPK1, MAPK3, and EGFR) through hydrogen bonding. In vivo examinations indicated notable augmentation in body weight and reductions in glycated serum protein (GSP), low-density lipoprotein cholesterol (LDL-C), uridine triphosphate (UTP), and fasting blood glucose (FBG) levels due to JWSJS. Electron microscopy coupled with hematoxylin and eosin (HE) and Periodic acid-Schiff (PAS) staining highlighted the potential of each treatment group in alleviating kidney damage to diverse extents, exhibiting varied declines in p-EGFR, p-MAPK3/1, and BAX, and increments in BCL-2 expression in the kidney tissues of the treated rats. Conclusively, these insights suggest that the protective efficacy of JWSJS on diabetic nephropathy might be associated with suppressing the activation of the EGFR/MAPK3/1 signaling pathway and alleviating renal cell apoptosis.
Assuntos
Diabetes Mellitus Experimental, Nefropatias Diabéticas, Medicamentos de Ervas Chinesas, Receptores ErbB, Simulação de Acoplamento Molecular, Transdução de Sinais, Nefropatias Diabéticas/metabolismo, Nefropatias Diabéticas/tratamento farmacológico, Animais, Ratos, Receptores ErbB/metabolismo, Medicamentos de Ervas Chinesas/farmacologia, Medicamentos de Ervas Chinesas/química, Diabetes Mellitus Experimental/metabolismo, Diabetes Mellitus Experimental/tratamento farmacológico, Transdução de Sinais/efeitos dos fármacos, Proteína Quinase 3 Ativada por Mitógeno/metabolismo, Masculino, Sistema de Sinalização das MAP Quinases/efeitos dos fármacos, Ratos Sprague-Dawley, Proteína Quinase 1 Ativada por Mitógeno/metabolismo, Farmacologia em Rede/métodos, Modelos Animais de DoençasRESUMO
OBJECTIVE: Diabetic osteoporosis (DOP) belongs to the group of diabetes-induced secondary osteoporosis and is the main cause of bone fragility and fractures in many patients with diabetes. The aim of this study was to determine whether Ziyin Bushen Fang (ZYBSF) can improve DOP by inhibiting autophagy and oxidative stress. METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats using a high-fat high-sugar diet combined with streptozotocin. Micro-CT scanning was used to quantitatively observe changes in the bone microstructure in each group. Changes in the serum metabolites of DOP rats were analyzed using UHPLC-QTOF-MS. The DOP mouse embryonic osteoblast precursor cell model (MC3T3-E1) was induced using high glucose levels. RESULTS: After ZYBSF treatment, bone microstructure significantly improved. The bone mineral density, trabecular number, and trabecular thickness in the ZYBSF-M and ZYBSF-H groups significantly increased. After ZYBSF treatment, the femur structure of the rats was relatively intact, collagen fibers were significantly increased, and osteoporosis was significantly improved. A total of 1239 metabolites were upregulated and 1527 were downregulated in the serum of T1DM and ZYBSF-treated rats. A total of 20 metabolic pathways were identified. In cellular experiments, ZYBSF reduced ROS levels and inhibited the protein expression of LC3II / I, Beclin-1, and p-ERK. CONCLUSION: ZYBSF may improve DOP by inhibiting the ROS/ERK-induced autophagy signaling pathway.
Assuntos
Autofagia, Medicamentos de Ervas Chinesas, Osteoporose, Estresse Oxidativo, Animais, Autofagia/efeitos dos fármacos, Estresse Oxidativo/efeitos dos fármacos, Osteoporose/tratamento farmacológico, Osteoporose/metabolismo, Ratos, Medicamentos de Ervas Chinesas/farmacologia, Medicamentos de Ervas Chinesas/química, Camundongos, Diabetes Mellitus Experimental/tratamento farmacológico, Masculino, Ratos Sprague-Dawley, Estreptozocina, Diabetes Mellitus Tipo 1/tratamento farmacológico, Diabetes Mellitus Tipo 1/complicações, Densidade Óssea/efeitos dos fármacosRESUMO
Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal sensitivity. The impact of diabetes on the lacrimal functional unit (LFU) and the structures responsible for maintaining tear homeostasis, is not completely known. It has been shown that the Opioid Growth Factor Receptor (OGFr), and its ligand, Opioid Growth Factor (OGF), is dysregulated in the ocular surface of diabetic rats leading to overproduction of the inhibitory growth peptide OGF. The opioid antagonist naltrexone hydrochloride (NTX) blocks the OGF-OGFr pathway, and complete blockade following systemic or topical treatment with NTX restores the rate of re-epithelialization of corneal epithelial wounds, normalizes corneal sensitivity, and reverses dry eye in diabetic animal models. These effects occur rapidly and within days of initiating treatment. The present study was designed to understand mechanisms related to the fast reversal (<5 days) of dry eye by NTX in type 1 diabetes (T1D) by investigating dysregulation of the LFU. The approach involved examination of the morphology of the LFU before and after NTX treatment. Male and female adult Sprague-Dawley rats were rendered hyperglycemic with streptozotocin, and after 6 weeks rats were considered to be a T1D model. Rats received topical NTX twice daily to one eye for 10 days. During the period of treatment, tear production and corneal sensitivity were recorded. On day 11, animals were euthanized and orbital tissues including conjunctiva, eyelids, and lacrimal glands, were removed and processed for histologic examination including immunohistochemistry. Male and female T1D rats had significantly decreased tear production and corneal insensitivity, significantly decreased number and size of lacrimal gland acini, decreased expression of aquaporin-5 (AQP5) protein and decreased goblet cell size. Thus, 10 days of NTX treatment restored tear production and corneal sensitivity to normal values, increased AQP5 expression, and restored the surface area of goblet cells to normal. NTX had no effect on the number of lacrimal gland acini or the number of conjunctival goblet cells. In summary, blockade of the OGF-OGFr pathway with NTX reversed corneal and lacrimal gland complications and restored some components of tear homeostasis confirming the efficacy of topical NTX as a treatment for ocular defects in diabetes.
Assuntos
Aquaporina 5, Diabetes Mellitus Experimental, Aparelho Lacrimal, Naltrexona, Ratos Sprague-Dawley, Lágrimas, Animais, Aparelho Lacrimal/metabolismo, Aparelho Lacrimal/efeitos dos fármacos, Aparelho Lacrimal/patologia, Lágrimas/metabolismo, Lágrimas/efeitos dos fármacos, Naltrexona/farmacologia, Masculino, Diabetes Mellitus Experimental/tratamento farmacológico, Diabetes Mellitus Experimental/metabolismo, Diabetes Mellitus Experimental/patologia, Ratos, Aquaporina 5/metabolismo, Administração Tópica, Síndromes do Olho Seco/tratamento farmacológico, Síndromes do Olho Seco/patologia, Síndromes do Olho Seco/metabolismoRESUMO
Background: Ducrosia anethifolia is an aromatic desert plant used in Saudi folk medicine to treat skin infections. It is widely found in Middle Eastern countries. Methods: A methanolic extract of the plant was prepared, and its phytoconstituents were determined using LC-MS. In-vitro and in-vivo antibacterial and antibiofilm activities of the methanolic extract were evaluated against multidrug-resistant bacteria. The cytotoxic effect was assessed using HaCaT cell lines in-vitro. Diabetic mice were used to study the in-vivo antibiofilm and wound healing activity using the excision wound method. Results: More than 50 phytoconstituents were found in the extract after LC-MS analysis. The extract exhibited antibacterial activity against both the tested pathogens. The extract was free of irritant effects on mice skin, and no cytotoxicity was observed on HaCaT cells with an IC50 value of 1381 µg/ml. The ointment formulation of the extract increased the healing of diabetic wounds. The microbial load of both pathogens in the wounded tissue was also reduced after the treatment. The extract was more effective against methicillin-resistant Staphylococcus aureus (MRSA) than MDR-P. aeruginosa in both in vitro and in vivo experiments. Further, skin regeneration was also observed in histological studies. Conclusions: The results showed that D. anethifolia methanol extract supports wound healing in infected wounds in diabetic mice through antibacterial, antibiofilm, and wound healing activities.
Assuntos
Antibacterianos, Biofilmes, Diabetes Mellitus Experimental, Staphylococcus aureus Resistente à Meticilina, Extratos Vegetais, Pseudomonas aeruginosa, Cicatrização, Animais, Biofilmes/efeitos dos fármacos, Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Camundongos, Antibacterianos/farmacologia, Cicatrização/efeitos dos fármacos, Pseudomonas aeruginosa/efeitos dos fármacos, Humanos, Diabetes Mellitus Experimental/tratamento farmacológico, Testes de Sensibilidade Microbiana, Infecções por Pseudomonas/tratamento farmacológico, Infecções por Pseudomonas/microbiologia, Linhagem Celular, Células HaCaT, Masculino, Infecção dos Ferimentos/tratamento farmacológico, Infecção dos Ferimentos/microbiologia, Modelos Animais de Doenças, Infecções Estafilocócicas/tratamento farmacológico, Infecções Estafilocócicas/microbiologiaRESUMO
Mangiferin, a key bioactive constituent in Gentiana rhodantha, has a favorable impact on reducing blood sugar. A selective and sensitive UPLC MS/MS approach was developed for determining mangiferin in diabetic rats. Employing acetonitrile protein precipitation, chromatographic separation utilized a 2.1×50 mm, 3.5µm C18 column with a mobile phase of 0.1% formic acid aqueous and 5mM ammonium acetate (A, 45%) and acetonitrile (B, 55%) at a 0.5mL min-1 flow rate. Quantification, employing the multiple reaction monitoring (MRM) mode, focused on precursor-to-product ion transitions at m/z 447.1â271.1 for baicalin m/z and 421.0â301.0 for mangiferin. Calibration curves demonstrated linearity in the 1.00~100ng/mL range, with a lower quantification limit for rat plasma set at 1.00ng/mL. Inter- and intra-day accuracies spanned -9.1% to 8.5% and mangiferin mean recovery varied from 82.3% to 86.7%. The adeptly utilized UPLC-MS/MS approach facilitated the exploration of mangiferin pharmacokinetics in diabetic rats.
Assuntos
Diabetes Mellitus Experimental, Gentiana, Extratos Vegetais, Espectrometria de Massas em Tandem, Xantonas, Animais, Xantonas/farmacocinética, Xantonas/sangue, Xantonas/administração & dosagem, Diabetes Mellitus Experimental/sangue, Diabetes Mellitus Experimental/tratamento farmacológico, Espectrometria de Massas em Tandem/métodos, Masculino, Cromatografia Líquida de Alta Pressão/métodos, Extratos Vegetais/farmacocinética, Extratos Vegetais/administração & dosagem, Extratos Vegetais/sangue, Administração Oral, Ratos, Gentiana/química, Ratos Sprague-Dawley, Estreptozocina, Reprodutibilidade dos Testes, Espectrometria de Massa com Cromatografia LíquidaRESUMO
The present study was designed to assess Tradescantia spathacea's antidiabetic ability, as well as the antiulcer activity of the entire plant extract. The diabetic condition was evaluated using Streptozotocin's oral glucose tolerance test, diabetes-alloxan and diabetes-models. Antiulcer activities were observed in rats where gastric ulcers were either caused by oral administration of ethanol, or pyloric ligation. Standards include ranitidine, glibenclamide and sucralfate. In all models, the blood glucose levels of animals treated with the test extract were found to be significantly lower compared to diabetic care. Similarly, in all models, the ulcer index in the animals treated with the test extract was found to be significantly lower relative to the animals under vehicle supervision. Our findings say T. Spathacea extract has essential anti-diabetic properties, as well as antiulcer properties.
Assuntos
Antiulcerosos, Glicemia, Diabetes Mellitus Experimental, Hipoglicemiantes, Extratos Vegetais, Ratos Wistar, Úlcera Gástrica, Animais, Hipoglicemiantes/farmacologia, Hipoglicemiantes/isolamento & purificação, Extratos Vegetais/farmacologia, Extratos Vegetais/isolamento & purificação, Antiulcerosos/farmacologia, Antiulcerosos/isolamento & purificação, Diabetes Mellitus Experimental/tratamento farmacológico, Úlcera Gástrica/tratamento farmacológico, Úlcera Gástrica/prevenção & controle, Úlcera Gástrica/patologia, Úlcera Gástrica/induzido quimicamente, Masculino, Ratos, Glicemia/efeitos dos fármacos, Glicemia/metabolismo, Metanol/química, Teste de Tolerância a Glucose, Solventes/química, FitoterapiaRESUMO
Heart failure is a condition in which the heart's one or both ventricles are unable to either receive an adequate amount of blood or eject an adequate amount of blood. Diabetes is considered one of the major risk factors for cardiovascular diseases. The current research is designed to evaluate the cardioprotective effects of dapagliflozin in streptozotocin and isoproterenol-induced comorbid rats. The COX-2, TNF-α, NF-ÐB, NLRP3, PPAR-γ, CKMB, TROP-I, AR, GP and SGLT were docked against dapagliflozin, propranolol and metformin. Dapagliflozin restored adequate blood flow and halted myofibril damage. Moreover, it's evident from this study that dapagliflozin significantly decreased serum concentration of various blood markers, decreased relative growth rate and QT interval prolongation, as compared to the negative control group. However, it improved the ventricular ejection fraction in rats of the treatment group. The GST, GSH and CAT levels were increased, as compared to normal. On the contrary, a decrease in LPO concentrations was observed. Evaluation of the coronal section of heart tissues showed the anti-inflammatory expressions evaluated through H & E staining and immunohistochemical techniques and with ELISA and PCR. In a nutshell, dapagliflozin reverses myocardial necrosis and apoptosis.
