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1.
J Ethnopharmacol ; 318(Pt B): 117015, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37572932

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ardisia elliptica Thunb. (AE) (Primulaceae) is a medicinal plant found in the Malay Peninsula and has been traditionally used to treat diabetes. However, limited studies to date in providing scientific evidence to support the antidiabetic efficacy of this plant by in-vitro and in-vivo models. AIM OF THE STUDY: To investigate the anti-hyperglycemic potential of AE through in-vitro enzymatic activities and streptozotocin-nicotinamide (STZ-NA) induced diabetic rat models using proton-nuclear magnetic resonance (1H-NMR)-based metabolomics approach. MATERIALS AND METHODS: Anti-α-amylase and anti-α-glucosidase activities of the hydroethanolic extracts of AE were evaluated. The absolute quantification of bioactive constituents, using ultra-high performance liquid chromatography (UHPLC) was performed for the most active extract. Three different dosage levels of the AE extract were orally administered for 4 weeks consecutively in STZ-NA induced diabetic rats. Physical assessments, biochemical analysis, and an untargeted 1H-NMR-based metabolomics analysis of the urine and serum were carried out on the animal model. RESULTS: Type 2 diabetes mellitus (T2DM) rat model was successfully developed based on the clear separation observed between the STZ-NA induced diabetic and normal non-diabetic groups. Discriminating biomarkers included glucose, citrate, succinate, allantoin, hippurate, 2-oxoglutarate, and 3-hydroxybutyrate, as determined through an orthogonal partial least squares-discriminant analysis (OPLS-DA) model. A treatment dosage of 250 mg/kg body weight (BW) of standardized 70% ethanolic AE extract mitigated increase in serum glucose, creatinine, and urea levels, providing treatment levels comparable to that obtained using metformin, with flavonoids primarily contribute to the anti-hyperglycemic activities. Urinary metabolomics disclosed that the following disturbed metabolism pathways: the citrate cycle (TCA cycle), butanoate metabolism, glycolysis and gluconeogenesis, pyruvate metabolism, and synthesis and degradation of ketone bodies, were ameliorated after treatment with the standardized AE extract. CONCLUSIONS: This study demonstrated the first attempt at revealing the therapeutic effect of oral treatment with 250 mg/kg BW of standardized AE extract on chemically induced T2DM rats. The present study provides scientific evidence supporting the ethnomedicinal use of Ardisia elliptica and further advances the understanding of the fundamental molecular mechanisms affected by this herbal antidote.


Assuntos
Ardisia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estreptozocina/farmacologia , Ardisia/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Glicemia , Metabolômica/métodos , Espectroscopia de Ressonância Magnética , Glucose , Etanol/química
2.
J Ethnopharmacol ; 318(Pt A): 116843, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37414197

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, the causes of diabetic retinopathy (DR) are blood stasis and heat. Curcuma wenyujin Y. H. Chen & C. Ling and its extracts have the effects of promoting blood circulation to remove blood stasis, clearing the heart, and cooling the blood, and have been used in the treatment of DR. Elema-1,3,7 (11),8-tetraen-8,12-lactam (Ele), an N-containing sesquiterpene isolated from this plant. However, the anti-inflammatory and anti-angiogenic effects of Ele and its therapeutic potential in DR are still unknown. AIM OF THE STUDY: To evaluate the anti-inflammatory and anti-angiogenic effects of Ele and its therapeutic potential in DR. MATERIALS AND METHODS: In vitro, anti-inflammatory and anti-angiogenic effects were assessed using TNF-α or VEGF-stimulated HUVECs. Protein expression was analyzed using Western blotting. ICAM-1 and TNF-α mRNA expressions were analyzed using real-time quantitative RT-PCR. The therapeutic potential in DR was assessed using both animal models of STZ-induced diabetes and oxygen-induced retinopathy. The retinal vascular permeability was measured using Evans blue, and the quantitation of retinal leukostasis using FITC-coupled Con A. The retinal neovascular tufts were analyzed using fluorescein angiography and counting pre-retinal vascular lumens. RESULTS: Ele inhibited NF-κB pathway, and ICAM-1, TNF-α mRNA expression in TNF-α- stimulated HUVECs. It also inhibits the multistep process of angiogenesis by inhibiting the phosphorylation of VEGFR2 and its downstream signaling kinases Src, Erk1/2, Akt, and mTOR in VEGF-stimulated HUVECs. Intravitreal injection of Ele can significantly reduce retinal microvascular leakage, leukostasis, and expression of ICAM-1, TNF-α in diabetic rats and inhibits oxygen-induced retinal neovascularization and VEGFR2 phosphorylation in OIR mice. CONCLUSIONS: Ele has anti-inflammatory and anti-angiogenic effects through inhibiting NF-κB and VEGFR2 signaling pathways, and it may be a potential drug candidate for DR.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Leucostasia , Ratos , Camundongos , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , NF-kappa B/metabolismo , Curcuma , Molécula 1 de Adesão Intercelular/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Leucostasia/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de Necrose Tumoral alfa , Oxigênio , Anti-Inflamatórios/efeitos adversos , RNA Mensageiro
3.
Carbohydr Polym ; 323: 121425, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37940297

RESUMO

Islet transplantation to restore endogenous insulin secretion is a promising therapy for type 1 diabetes in clinic. However, host immune rejection seriously limits the survival of transplanted islets. Despite of the various encapsulation strategies and materials developed so far to provide immune isolation for transplanted islets, long-term blood glucose regulation is still difficult due to the inherent defects of the encapsulation materials. Herein, a novel islet-encapsulation composite material with low immunogenicity, good biocompatibility and excellent stability is reported. Specifically, chitosan (CS) microgels (diameter: ∼302 µm) are prepared via Michael addition reaction between maleimide grafted chitosan (CS-Mal) and thiol grafted chitosan (CS-NAC) in droplet-based microfluidic device, and then zwitterionic surface layer is constructed on CS microgel surface by covalent binding between maleimide groups on CS and thiol groups on thiol modified carboxymethyl cellulose (CMC-SH). The as-formed carboxymethyl cellulose coated chitosan (CS@CMC) microgels show not only long-term stability in vivo owing to the non-biodegradability of CMC, but also fantastic anti-adsorption and antifibrosis because of the stable zwitterionic surface layer. As a result, islets encapsulated in the CS@CMC microgels exhibit high viability and good insulin secretion function in vivo, and long-term blood glucose regulation is achieved for 180 days in diabetic mice post-transplantation.


Assuntos
Quitosana , Diabetes Mellitus Experimental , Ilhotas Pancreáticas , Microgéis , Camundongos , Animais , Glicemia/metabolismo , Quitosana/metabolismo , Carboximetilcelulose Sódica/metabolismo , Diabetes Mellitus Experimental/metabolismo , Maleimidas , Compostos de Sulfidrila , Ilhotas Pancreáticas/metabolismo
4.
J Ethnopharmacol ; 319(Pt 1): 117111, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37673199

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes and its complications have overwhelmed India's healthcare system. Current therapies are expensive and have adverse side effects, thus dietary changes and alternative treatments are needed. Lagenaria siceraria (Molina) Standl. Juice is used mainly for its nutritional and medicinal values, however toxicity of the juice and antidiabetic effects have been poorly characterized. AIM OF THE STUDY: To investigate the toxicity, anti-diabetic and anti-inflammatory efficacy of Lagenaria siceraria (Molina) Standl. (LS) juice. MATERIALS AND METHODS: In vitro antidiabetic (α-glucosidase, α-amylase and DPP-4 inhibitory) activities were screened using standard procedures. The glucose uptake test was carried out by using L6 rat skeletal muscle cell line. In vivo sub-acute toxicity of LS juice was assessed on Wistar rats. Wistar rats were induced with diabetes by a single intraperitoneal (I.P) injection of freshly prepared streptozotocin (55 mg/kg body weight). The animals were randomly divided into 6 groups: normal control, untreated diabetic control, diabetic rats. Different dose of 200 mg/kg, 400 mg/kg and 600 mg/kg body weight of LS juice were administered, one group of diabetic rats were administered with 2 IU/mL insulin. The rats were sacrificed on the 31st day of the experiment and various in vivo biochemical parameters were evaluated in the serum and tissue homogenates of diabetic rats. RESULTS: Significant dose-dependent inhibition of α-amylase (22.6%), α-glucosidase (50.13%), and DPP-4 (61.50%) activity was observed by LS juice. LS juice (10 µg/mL) increased insulin-mediated 2NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose) absorption in L6 cells. Animals treated with LS juice showed no toxicity or unfavorable pharmacological effects. Lagenaria siceraria (Molina) Standl. Juice improved glucose tolerance in diabetic rats with reduced fasting blood glucose. Lipopolysaccharide induced NF-κB, TNF-α and IL-1ß production was also decreased in rats fed with LS juice. CONCLUSION: Lagenaria siceraria (Molina) Standl. Juice has demonstrated promising anti-inflammatory properties as well as the capacity to inhibit the digestion enzymes glucosidase and amylase. Our findings thus open new avenues for further research into the antidiabetic potential of LS juice.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemiantes , Ratos , Animais , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/toxicidade , Ratos Wistar , Estreptozocina , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , alfa-Glucosidases , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Insulina , Frutas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/análise , alfa-Amilases , Peso Corporal , Glicemia/análise
5.
J Ethnopharmacol ; 319(Pt 1): 117135, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37689326

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is a neurovascular disease that causes blindness in adults and is the most serious and common complication of diabetes mellitus. Retinal inflammation is an early stage of DR, and it is believed to play a crucial role in the development of DR. Panax notoginseng saponins (PNS) are the major active constituent in the main root of P. notoginseng, and they exhibit various biological activities, including anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory functions. However, the protective effects and underlying mechanisms of PNS against DR remain unclear. AIM OF THE STUDY: This study aimed to investigate the alleviation effects of PNS on DR and the mechanisms involved. Furthermore, it intended to explore the major components that exert efficacy in vivo. MATERIALS AND METHODS: Streptozotocin (STZ) was administered intraperitoneally to Sprague Dawley rats, and PNS was administered orally for 1 month after 2 months of STZ injection. The morphological structure of the retina and retinal acellular capillaries were assessed via hematoxylin and eosin (H&E) staining assay. The disruption of the blood-retinal barrier (BRB) was detected through Evans blue dye leakage assay, and retinal leukocyte adhesion was achieved via fluorescein isothiocyanate-coupled concanavalin A lectin labeling assay. Immunofluorescence staining and Western blot assays were conducted to detect the expression of tight junction proteins, adhesion molecules, and the ionized calcium-binding adapter molecule-1 (Iba-1) in the retina. Enzyme-linked immunosorbent assay was performed to detect the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß in serum. In addition, the protein expression levels of nuclear factor (NF)-κB p65, phosphorylated IκB kinase (p-IKK), phosphorylated NF-κB inhibitor (p-IκB), and phosphorylated NF-κB p65 (p-p65) were measured using Western blot assay. The ocular tissue distribution of PNS in normal and diabetic rats was determined through ultra-performance liquid chromatography-tandem mass spectrometry. The in vitro anti-inflammatory effects of PNS, notoginsenoside (NGR1), ginsenoside Rg1, Re, Rb1, and Rd (GRg1, GRe, GRb1, and GRd) were evaluated on human Müller (MIO-M1) cells. RESULTS: PNS increased the reduction in retinal inner nuclear layer thickness, reduced the increase in retinal acellular capillaries, and attenuated elevated BRB disruption by upregulating the decrease in protein expression of claudin-1 and occludin. Furthermore, PNS significantly abrogated microglial cell activation and reversed the increase in leukocyte adhesion by downregulating the increase in the protein expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Moreover, PNS reduced the elevated levels of TNF-α, IL-6, and IL-1ß in serum and inhibited the increased protein expression of p-IKK, p-IκB, and p-p65, and the nuclear translocation of p65. The tissue distribution results revealed that NGR1, GRg1, GRe, GRb1, and GRd were detected in the ocular tissue, while GRg1 and GRb1 were found at the highest levels compared with the other components. The cellular results showed that PNS, NGR1, GRg1, GRe, GRb1, and GRd suppressed the development of cellular inflammatory responses by inhibiting the activation of the NF-κB signaling pathway in MIO-M1 cells and that their anti-inflammatory effects were comparable. CONCLUSION: PNS suppressed retinal inflammation by inhibiting the activation of the NF-κB signaling pathway, alleviating DR. GRg1 and GRb1 may be the primary components that exert anti-inflammatory effects in vivo.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Panax notoginseng , Saponinas , Ratos , Humanos , Animais , Retinopatia Diabética/patologia , NF-kappa B/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico , Saponinas/metabolismo , Panax notoginseng/química , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ratos Sprague-Dawley , Inflamação/patologia , Retina , Transdução de Sinais , Proteínas I-kappa B/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/metabolismo
6.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166900, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37778481

RESUMO

Diabetic cardiomyopathy (DCM) is a pathophysiological condition triggered by diabetes mellitus and can lead to heart failure. Doublecortin-like kinase protein 1 (DCLK1) is a multifunctional protein kinase involved in the regulation of cell proliferation, differentiation, survival, and migration. Current studies on DCLK1 mainly focus on cancer development; however, its role in non-tumor diseases such as DCM is yet to be deciphered. Our analysis revealed that DCLK1 was upregulated in cardiomyocytes of streptozotocin (STZ)-induced type 1 diabetic mouse, suggesting a correlation between DCLK1 and DCM progression. It was further demonstrated that either cardiomyocyte-specific DCLK1 knockout or pharmacological DCLK1 inhibitor DCLK1-IN-1 significantly alleviated cardiac hypertrophy and fibrosis in STZ-induced diabetic mice. RNA-seq analysis of heart tissues revealed that DCLK1 regulated the nuclear factor kappa B (NF-κB)-mediated inflammatory response in DCM. In vitro, DCLK1 activated NF-κB and the inflammatory response by inducing the IKKß phosphorylation in high-concentration glucose (HG)-challenged cardiomyocytes. DCLK1-IN-1 also prevented HG-induced IKKß/NF-κB activation and inflammatory injuries in cardiomyocytes. In conclusion, this study highlights the novel role of cardiomyocyte DCLK1 in regulating IKKß/NF-κB, which aggravates inflammation to promote the pathogenesis of DCM. DCLK1 may serve as a new target for DCM treatment.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Miocardite , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/metabolismo , Quinases Semelhantes a Duplacortina , Quinase I-kappa B/metabolismo , Inflamação/metabolismo , Miocardite/patologia , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Estreptozocina
7.
J Ethnopharmacol ; 319(Pt 2): 117252, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37777023

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xi Yang Shen (Panax quinquefolium L.) was originally recorded in "Ben Cao Cong Xin" edited by Wu Yiluo during the Qing Dynasty. Panax Quinquefolium Saponins (PQS) is the main component derived from Panax quinquefolium L, and has been wildly used in the treatment of coronary heart disease. AIM OF THE STUDY: This study aims to explore the potential role and underlying mechanisms of PQS in promoting angiogenesis in rats with diabetes and myocardial infarction. MATERIALS AND METHODS: Echocardiograms were used to assess cardiac function, while the heart weight to tibia length ratio was calculated to determine cardiac hypertrophy. Hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome staining were used to examine cardiac morphology, myocyte diameter, and myocardial fibrosis. Immunofluorescence staining was employed to evaluate arteriolar density. The transcriptomes were analyzed and bioinformatic analyses were conducted to predict the potential angiogenesis-promoting mechanism of PQS. In addition, RT-PCR and western blotting was utilized to examine the expression of genes and proteins influenced by PQS. RESULTS: PQS improved blood glucose, ameliorated cardiac function, reduced cardiac hypertrophy, and enhanced myocardial morphology in diabetic rats with myocardial infarction. PQS was also found to decrease myocyte diameter, curtail myocardial fibrosis, and increase arteriolar density. However, the effects of PQS were abolished following the deletion of protein kinase C δ (PKCδ). Molecular docking predicted strong interactions between the major blood components of PQS and PKCδ. Transcriptomic and bioinformatic analyses indicated that PQS may bolster angiogenesis by activating the VEGF/PI3K-Akt/eNOS pathway in rats with diabetes and myocardial infarction. Finally, the study demonstrated that PQS could inhibit the expression of PKCδ and stimulate the activation of the VEGF/PI3K-Akt/eNOS pathway. CONCLUSIONS: PQS improves blood glucose, enhances cardiac function, mitigates cardiac damage, and boosts arteriolar density. The angiogenic impact of PQS appears to be, at least partially, due to its modulation of the PKCδ-mediated VEGF/PI3K-Akt/eNOS signaling pathway in rats with diabetes and myocardial infarction.


Assuntos
Diabetes Mellitus Experimental , Infarto do Miocárdio , Panax , Saponinas , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases , Glicemia , Fator A de Crescimento do Endotélio Vascular , Diabetes Mellitus Experimental/tratamento farmacológico , Simulação de Acoplamento Molecular , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico , Cardiomegalia/tratamento farmacológico , Fibrose
8.
J Ethnopharmacol ; 319(Pt 2): 117254, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37778519

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Si Wei Jiang Huang Tang San (SWJHTS) is a traditional Tibetan medicine prescription for the treatment of urethritis, frequent urination, and urgency, composed of four traditional Chinese medicines: Curcumae longae rhizoma, Berberidis cortex, Tribuli fructus, and Phyllanthi fructus. However, whether SWJHTS exhibits hypoglycemic efficacy and its specific mechanism remain unclear. AIM OF THE STUDY: In this study, we aimed to investigate the anti-diabetic effects of SWJHTS and elucidate the underlying mechanism. MATERIALS AND METHODS: HPLC-MS method was used to identify the key components of four kinds of traditional Chinese medicine (Curcumae longae rhizoma, Berberidis cortex., Tribuli fructus, and Phyllanthi fructus) which composed SWJHTS and determine their structure. Normal mice and 145 mg/kg STZ-induced type 1 diabetic mice were treated with three doses of SWJTHS by oral gavage. Body weight, 24h food and water intake, fasting blood glucose, glucose tolerance and other indicators were measured to evaluate the hypoglycemic effect of SWJHTS. OMIM, Genecards and other databases were used to collect targets of diabetes, and HPLC-MS results and TCMSP database information were used to collect drug component targets. Bioinformatics methods such as pathway enrichment analysis and molecular docking were used to predict the key targets of SWJHTS. The gene and protein expressions of HIF1α and ERK signaling pathways in HepG2 cells treated with SWJHTS were detected by RT-PCR and Western blot. RESULTS: A total of 181 components were identified, including curcumin, palmatine, and berberine, etc. The in vivo studies showed that SWJHTS could significantly lower fasting blood glucose levels and improve the symptoms of polydipsia, polyphagia, and polyuria in diabetic mice. Furthermore, we identified HIF1α as the potential key target of SWJHTS against diabetes utilizing network pharmacology approach and in silico molecular docking. Subsequently, we experimentally confirmed that SWJHTS could suppress the high glucose-induced upregulation of HIF1α expression, which mediated the glucose consumption in HepG2 cells. The ERK signaling pathway was further found to be activated by the SWJHTS as the upstream of HIF1α. CONCLUSIONS: SWJHTS can improve glucose metabolism by targeting the ERK/HIF1α signaling pathway; hence might be a prospective anti-diabetic drug for diabetic patients as traditional Tibetan medicine.


Assuntos
Diabetes Mellitus Experimental , Medicamentos de Ervas Chinesas , Humanos , Animais , Camundongos , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Simulação de Acoplamento Molecular , Farmacologia em Rede , Transdução de Sinais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
9.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166890, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37734469

RESUMO

AIM: Progression of diabetic nephropathy (DN) is linked to the dysregulated increase of adenosine and altered signaling properties. A major contribution to the maintenance of physiological extracellular adenosine levels relies on cellular uptake activity through plasma membrane nucleoside transporters. Because kidney cells are responsive to insulin, this study aims to determine how DN affects insulin regulation of the equilibrative nucleoside transporter-2 (ENT2). METHODS: Human Podocytes and rat glomeruli were used to study ENT2 regulation. The effects of diabetes and insulin on ENT2 mediated transport activity were determined measuring the fraction of total adenosine uptake in sodium-free medium which is inhibitable by hypoxanthine. Alterations in ENT2 subcellular distribution were assessed in the kidney of people affected with DN and diabetic rats. The consequences of impaired ENT2 activity on the kidney were evaluated using dipyridamole in an animal model. RESULTS: Insulin upregulates ENT2 uptake activity by increasing the Vmax, thus counteracting decreased adenosine uptake due to high d-glucose and achieving extracellular adenosine homeostasis. Insulin promoted ENT2 translocation to the plasma membrane dependent on PI3-kinase/Akt signaling and actin cytoskeleton integrity. However, in diabetic rats, the insulin-mediated induction of ENT2 activity was lost. Additionally, reduced Akt activation in response to insulin correlated with decreased ENT2 distribution at the plasma membrane. Kidney tissues from diabetic rats and human DN biopsies showed ENT2 redistribution to an intracellular pattern, evidencing dysfunctional adenosine uptake. Through ENT inhibition, we evidenced increased proteinuria and induced alpha-smooth muscle actin as a result of profibrotic activation of cells in the kidney. CONCLUSION: Deficient insulin regulation of ENT2 activity contributes to chronically high adenosine levels and glomerular alterations that underline diabetic kidney disease progression.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ratos , Humanos , Animais , Adenosina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Membrana Transportadoras , Homeostase , Insulina/metabolismo , Proteínas de Transporte de Nucleosídeos
10.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166912, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37816397

RESUMO

Considering the effects of sodium-glucose cotransporter inhibitors and metformin on the kidneys, a combination of both agents is postulated to provide protection against diabetic nephropathy (DN). We examined the potential protective effects of dapagliflozin, metformin, and their combination on kidney injury in rats with type 2 diabetes. Diabetic (DM) rats were administered dapagliflozin (1.0 mg/kg/day), metformin (100 mg/kg/day), or a combination (dapagliflozin 0.5 mg/kg/day plus metformin 50 mg/kg/day) by oral gavage for 4 weeks. Dapagliflozin monotherapy or in combination with metformin was more effective than metformin monotherapy in attenuating renal dysfunction, improving renal organic anion transporter 3 expression, and activating renal autophagy by modulating the AMPK/mTOR/SIRT1 axis in DM rats. Interestingly, dapagliflozin monotherapy exhibited greater efficacy in suppressing renal oxidative stress in DM rats than metformin or the combination treatment. Renal and pancreatic injury scores decreased in all treatment groups. Apoptotic markers were predominantly reduced in dapagliflozin monotherapy and combination treatment groups. The low-dose combination treatment, through synergistic coordination, appeared to modulate oxidative, autophagic, and apoptotic signaling and confer significant renoprotective effects against DM-induced complications. In addition, a low dose of the combination might be beneficial to patients by avoiding the risk of side effects of the medication. Future clinical trials are necessary to study the nephroprotective effects of the combined treatment at a low dosage in patients with diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Metformina , Humanos , Ratos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse Oxidativo , Apoptose , Inflamação/tratamento farmacológico , Autofagia
11.
Psychoneuroendocrinology ; 159: 106412, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37898037

RESUMO

Chronic hyperglycemia can cause changes in synaptic plasticity of hippocampal cells, which has accelerated the pathological process of cognitive dysfunction. However, the heterogeneity of the hippocampal cell populations under long term high glucose statement remains largely unknown. To mimic chronic hyperglycemia induced cognitive function deficit in vivo, db-/- diabetic mice was selected and Novel Object Recognition(NOR) behavior tests were performed. Based on diabetic induced cognitive impairment(CI) animal model, single-cell RNA sequencing was performed in the hippocampus of CI group (21,379 cells) or control group (20,045 cells), and single cell RNA sequencing was applied, and then the single cell atlas of gene expression was profiled. The comprehensive analysis explicated 18 nerve cell clusters, including 9 distinct sub-clusters, More in-depth analysis of oligodendrocyte precursor cells(OPCs) showed five distinct OPCs sub-clusters including expressing marker gene Lingo2-OPCs, Kcnc1-OPCs, Sst-OPCs, Slc6a1-OPCs and Lhfpl3-OPCs, which seems to be able to proliferate, migrate, and finally differentiate into mature oligodendrocytes and produce myelin. To be noted, differentially expressed genes(DEGs) of the Sst-OPCs sub-cluster indicated that the genes participating in neuroactive ligand-receptor interaction, nervous system development and inflammatory process were up-regulated in diabetic induced cognitive impairment(DCI) groups compared to normal control groups. Integrating the data of neuroplasticity regulation, the 20th top-enriched biological process was associated with neuroplasticity regulation in CI groups compared to control groups. Among these neuroplasticity-related genes, the intersectional gene Sstr2 may play an important role in neuroplasticity regulation. Focused on neuroplasticity regulation and its related specific genes may provide potential new clues for the treatment of diabetes mellitus complicated with cognitive impairment. In summary, we showed the comprehensively transcriptional landscape of hippocampal cells in the db-/- diabetic mice with cognitive dysfunction, distinctive cell sub-clusters and the gene expression characteristics were identified, and also their special functions were proposed, which may give new clues and potential targets for diagnosis and treatment of diabetic encephalopathy.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Camundongos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Oligodendroglia/fisiologia , Hipocampo/metabolismo , Hiperglicemia/metabolismo
12.
J Ethnopharmacol ; 319(Pt 3): 117307, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37939911

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Phytochemicals have unique advantages in the treatment of diabetes due to their multi-target activity and low toxicity. Mulberry leaves, a traditional Chinese herbal medicine, have been used in the prevention and treatment of diabetes for centuries. The main active ingredients in mulberry leaves with regards to the hypoglycemic effect are 1-deoxynojirimycin, flavonoids, and polysaccharides. However, the combined hypoglycemic effects and mechanisms of mulberry leaf multi-components remain unclear. AIM OF THE STUDY: This study explored the anti-diabetic effects of mulberry leaf multi-components (MMC) and the role of the PI-3K/Akt insulin signalling pathway in improving insulin resistance. MATERIALS AND METHODS: The main chemical components of MMC were analyzed using the phenol-sulfuric acid method, aluminum nitrate-sodium nitrite method, and HPLC-ultraviolet/fluorescence detection method. The T2DM rat model was created via feeding a high-fat diet and peritoneal injection of streptozotocin. T2DM rats were divided into four groups: model, model plus metformin, model plus low-dose, and model plus high-dose MMC groups (100 and 200 mg/kg body weight/day, respectively), and plus normal group for a total of five groups. MMC was administered by oral gavage for six weeks. Fasting blood glucose and serum lipid profiles were measured using a glucometer and an automatic biochemistry analyzer, respectively. Serum insulin and adipocytokine levels were analyzed by ELISA. Hepatic glucose metabolizing enzyme activity was evaluated by ELISA and the double antibody sandwich method. Expression of PI-3K/Akt signalling pathway proteins was analyzed by RT-PCR and Western blotting. RESULTS: Extracted 1-deoxynojirimycin, flavonoid, and polysaccharide purity was 70.40%, 52.34%, and 32.60%, respectively. These components were then mixed at a ratio of 1:6:8 to form MMC. MMC significantly reduced serum glucose, insulin, and lipid levels. In diabetic rats, MMC enhanced insulin sensitivity and alleviated inflammatory and oxidative damage by lowing adipocytokine levels and increasing anti-oxidative enzyme activity. Insulin resistance was also mitigated. MMC regulated the activity of key downstream enzymes of hepatic glucose metabolism via activating the expression of PI-3K, Akt, PDX-1, and GLUT4 at the mRNA and protein levels, thereby correcting hepatic glucolipid metabolism disorders and exerting a hypoglycemic effect. CONCLUSION: MMC ameliorated hepatic glucolipid metabolism disorders and improved insulin resistance in T2DM rats by activating the PI-3K/Akt signaling pathway. These results highlight the multi-component, multi-target, and combined effects of MMC, and suggest it may be further developed as a hypoglycemic drug.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Morus , Ratos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , 1-Desoxinojirimicina/farmacologia , Glucose/metabolismo , Transdução de Sinais , Polissacarídeos/farmacologia , Folhas de Planta/metabolismo , Adipocinas , Lipídeos/farmacologia
13.
J Ethnopharmacol ; 319(Pt 2): 117249, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37806534

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cola nitida (Vent.) Schott & Endl. are among the common medicinal plants employed in traditional medicine for treating diabetes and its complications. AIM OF THE STUDY: The present study investigated the effect of Cola nitida infusion on the expression of key genes involved in insulin signaling vis-à-vis Insulin receptor substrate 1 (IRS-1), tumor protein P53 gene, glucose transporter type 4 (GLUT4), phosphoinositide 3-kinases (PI3K) and B-cell lymphoma-2 (BCL2) in skeletal muscles of type 2 diabetic (T2D) rats. METHODS: Type 2 diabetic rats were administered C. nitida infusion at low and high doses (150 and 300 mg/kg bodyweight, respectively), while a high dose of the infusion was also administered to a normal toxicological group. Metformin served as the standard antidiabetic drug. The rats were sacrificed at the end of the experimental period. Their psoas muscles were harvested and assayed for the expressions of IRS1, p53, GLUT4, PI3K and BCL2. The studied genes were further subjected to enrichment analysis using the ShinyGO 0.76 online software. RESULTS: Induction of T2D upregulated the expressions of IRS-1, p53, PI3K and BCL2 in psoas muscles, while concomitantly downregulating GLUT4 expression. These expressions were significantly reversed in type 2 diabetic rats treated with C. nitida infusion, and the results were statistically significant compared to metformin. Gene enrichment analysis revealed that the genes were linked to intrinsic pathways and biological processes involved in insulin resistance. The infusion further improved muscle glucose uptake, ex vivo. Molecular docking and molecular dynamics stimulation of C. nitida infusion phytoconstituents, caffeine and theobromine with IRS-1, p53, GLUT4, PI3K and BCL2 revealed a strong binding affinity as evident by the RMSD and RMSF values. CONCLUSION: These results indicate the potentials of C. nitida infusion to improve glucose homeostasis in skeletal muscles of type 2 diabetic rats.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Ratos , Animais , Cola/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Simulação de Acoplamento Molecular , Proteína Supressora de Tumor p53 , Insulina/metabolismo , Músculo Esquelético/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transportador de Glucose Tipo 4/genética
14.
Talanta ; 268(Pt 1): 125298, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37832452

RESUMO

Hypochlorous acid (HClO) is a key signaling molecule which involved in various pathological and physiological processes and the immune system. It had been proved that excess HClO in the organisms was closely associated with diabetes. In this paper, we constructed a series of BODIPY-based fluorophores modified with olefinic bond. With the assistance of theoretical calculations, the optimized near-infrared (NIR) dye BDP-ENE-S-Me, which possessed the longest wavelength (690 nm) and the best stability, was screened and synthesized. Based on BDP-ENE-S-Me, we further introduced N, N-dimethylcarbamate group to construct a NIR fluorescent probe BDP-ENE-ClO. BDP-ENE-ClO displayed excellent selectivity and sensitivity with a low detection limit (49 nM) towards HClO. Besides, the probe was successfully applied in monitoring concentration fluctuations of HClO in vitro and in vivo caused by various stimuli. Most importantly, the over-production of HClO in the type I, type II diabetes and diabetic liver disease mice models could be visualized and assessed precisely with the assistance of BDP-ENE-ClO. By comparing fluorescent intensity of diabetic mice models with that of diabetic liver disease mice models, the probe was competent to assess the progression of diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hepatopatias , Camundongos , Animais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Experimental/diagnóstico por imagem , Corantes Fluorescentes/química , Ácido Hipocloroso/química
15.
J Ethnopharmacol ; 319(Pt 2): 117167, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37716489

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: SiJunZi decoction (SJZD), one of the traditional Chinese medicine formulas, has been clinically and traditionally used to improve glucose and lipid metabolism and promote bone remodeling. AIM OF THE STUDY: To study the actions and mechanisms of SJZD on bone remodeling in a type 2 diabetes mouse model. MATERIALS AND METHODS: Diabetic mice generated with a high-fat diet (HFD) and streptozotocin (STZ) were subjected to SJZD treatment for 8 weeks. Blood glucose and lipid profile, redox status and bone metabolism were determined by ELISA or biochemical assays. Bone quality was evaluated by micro-CT, three-point bending assay and Fourier transform infrared spectrum (FTIR). Bone histomorphometry alterations were evaluated by Hematoxylin-Eosin (H&E), tartrate resistant acid phosphatase (TRAP) staining and Safranin O-fast green staining. The expressions of superoxide dismutase 1 (SOD1), advanced glycation end products (AGEs), receptor for advanced glycosylation end products (RAGE), phosphorylated nuclear factor kappa-B (p-NF-κB), NF-κB, cathepsin K, semaphorin 3A (Sema3A), insulin-like growth factor 1 (IGF1), p-GSK-3ß, (p)-ß-catenin, Runt-related transcription factor 2 (Runx2) and Cyclin D1 in the femurs and/or tibias were examined by Western blot or immunohistochemical staining. The main constituents in the SJZD aqueous extract were characterized by a HPLC/MS. RESULTS: SJZD intervention improved glucose and lipid metabolism and preserved bone quality in the diabetic mice, in particular glucose tolerance, lipid profile, bone microarchitecture, strength and material composition. SJZD administration to diabetic mice preserved redox homeostasis in serum and bone marrow, and prevented an increase in AGEs, RAGE, p-NF-κB/NF-κB, cathepsin K, p-GSK-3ß, p-ß-catenin expressions and a decrease in Sema3A, IGF1, ß-catenin, Runx2 and Cyclin D1 expressions in tibias and/or femurs. Thirteen compounds were identified in SJZD aqueous extract, including astilbin, liquiritin apioside, ononin, ginsenoside Re, Rg1, Rb1, Rb2, Ro, Rb3, Rd, notoginsenoside R2, glycyrrhizic acid, and licoricesaponin B2. CONCLUSIONS: SJZD ameliorates bone quality in diabetic mice possibly via maintaining redox homeostasis. The mechanism governing these alterations are possibly related to effects on the AGEs/RAGE and Wnt/ß-catenin signaling pathways. SJZD may offer a novel source of drug candidates for the prevention and treatment of type 2 diabetes and osteoporosis.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , NF-kappa B/metabolismo , Catepsina K/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Semaforina-3A/metabolismo , Glicemia , Produtos Finais de Glicação Avançada/metabolismo , Oxirredução , Homeostase , Lipídeos/farmacologia
16.
Eur J Med Chem ; 263: 115948, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37984299

RESUMO

Keeping in view the inhibitory potential of monoterpenes thymol and carvacrol as well as coumarin nucleus against α-glucosidase, novel series of thymol/carvacrol-coumarin hybrids was designed, synthesized and evaluated for α-glucosidase inhibitory potential. Among the series of hybrid molecules, AS14 with IC50 value of 4.32 ± 0.11 µM was selective α-glucosidase inhibitor over α-amylase (IC50 = 37.36 ± 0.84 µM). AS14 was non-toxic toward mouse normal fibroblast cells (L929: IC50 > 100 µM). Molecular docking and dynamic simulation studies confirmed desired interactions of AS14 with α-glucosidase responsible for the inhibition of its catalysis capabilities. Acute oral toxicity study confirmed AS14 as safer molecule for in vivo pharmacological investigations with LD50 value of 300 mg/kg. AS14 also showed acute hypoglycaemic effects [reduction in blood glucose levels at 1 h of administration in maltose loading test (at 10 and 20 mg/kg by 62.65 % and 70.12 %) and sucrose loading test (at 10 and 20 mg/kg by 59.65 % and 60.23 %), respectively] as well as long term (28 days) fasting blood glucose reduction (At day 28: 10 mg/kg = 54.69 % and 20 mg/kg = 62.23 % reduction in fasting blood glucose levels) capabilities in streptozotocin induced diabetic rats. Overall study represents, AS14 as potential α-glucosidase inhibitor with adequate efficacy and safety profile and act as an effective hit lead for the further development of potent and safer α-glucosidase inhibitors for the management of postprandial hyperglycemia in diabetic patients.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemiantes , Humanos , Camundongos , Ratos , Animais , Hipoglicemiantes/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Timol , Glicemia , Simulação de Acoplamento Molecular , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Triazóis/farmacologia , alfa-Glucosidases , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico
17.
J Ethnopharmacol ; 318(Pt A): 116963, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37495027

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Globally, 537 million individuals are estimated to have diabetes. The traditional use of herbs for ameliorating diabetes symptoms is a common practice in Pakistan and use of Loranthus pulverulentus Wall (L. pulverulentus) by local people in Azad Jammu and Kashmir has been reported. AIM OF THE STUDY: In the present study, the antidiabetic potential of standardized n-butanol fraction of leaves of L. pulverulentus Wall, which is a parasite of Dalbergia sisso Roxb was assessed in both alloxan (ALX) and streptozotocin (STZ) diabetic animal models. MATERIALS AND METHODS: Chemical characterization of BF was performed using HPLC, GCMS and UHPLC-MS. The effect of the fraction (250 mg/kg) on insulin, plasma free fatty acids, L-lactate, pyruvate, MDA, HbA1c and glycogen levels in ALX and STZ animal models was determined. Liver and renal profiles were analyzed in the STZ model. Toxicological studies were performed by hemolytic, Ames mutagenicity, DNA protection, and thrombolytic assays. Histopathological analysis of the pancreas, liver, and kidney was performed. RESULTS: BF demonstrated highly significant (p < 0.001) antidiabetic potential in both diabetic models. BF significantly (p < 0.05) improved OGTT results in alloxanized diabetic mice and blocked the absorption of glucose from the gut. A significant (p < 0.001) increase in insulin levels and glycogen content in liver tissue and a decrease in plasma FFA, MDA, HbA1c, L-lactate, and pyruvate levels in STZ-diabetic mice were recorded. GC-MS and chromatographic analysis showed the presence of catechin, eugenol, longifolene, caryophyllene, Ar-tumerone and Geranyl-alpha-terpinene. Various metabolites with antidiabetic potential, including 4-hydroxycinnamyl alcohol 4-D-glucoside, zingerone glucoside, trans-trismethoxy resveratrol-d4, epigallocatechin 3-O-cinnamate, and ß-glucogallin, were identified using UHPLC-MS. Animals treated with BF showed marked improvements in cellular structures of the pancreas, liver and kidneys. This fraction is non-mutagenic and protects the DNA. CONCLUSION: The experimental fraction contained potential antidiabetic bioactive compounds responsible for alleviating diabetes-associated biochemical dysregulation. The fraction increased insulin levels and enhanced glycogen storage in muscles and the liver. It blocked glucose absorption from the intestine and substantially decreased HbA1c, lactate, pyruvate, free fatty acids, lipid, liver and kidney damage. Therefore, the use of BF for the treatment of type-2 diabetes may be beneficial.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemiantes , Camundongos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , 1-Butanol , Hemoglobinas Glicadas , Diabetes Mellitus Experimental/metabolismo , Butanóis , Ácidos Graxos não Esterificados , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Glicemia , Insulina , Fígado , Glicogênio/metabolismo , Glucosídeos/farmacologia , Piruvatos/metabolismo , Piruvatos/farmacologia , Piruvatos/uso terapêutico , Estreptozocina/farmacologia
18.
J Ethnopharmacol ; 319(Pt 3): 117328, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37865275

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Huayuwendan decoction (HYWD) is a broad used traditional Chinese medicine and therapeutic effects against type 2 diabetes mellitus (T2DM). The mechanism of HYWD on the treatment of T2DM is still unclear. AIM OF THE STUDY: For this reason, this study was performed to uncover the effects and mechanism of action of HYWD on T2DM. MATERIALS AND METHODS: Male Wistar rats were chosen to set up the T2DM model. This study was randomly divided into six groups: CON (control), MOD (model), HYWDL (Huayuwendan decoction Low Dose), HYWDM (Huayuwendan decoction Middle Dose), HYWDH (Huayuwendan decoction High Dose), and MET (Metformin). Body weight gains were estimated. Using H&E staining, pathological alterations was explored. The serums of fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2 h PG) were detected by Roche blood glucose meter. LDL-C and HDL-C were analyzed by automatic biochemical analyzer. Network pharmacology analyzed the active ingredients, drug targets, and key pathways of HYWD in T2DM treatment. The islet function and inflammation related factors were determined by ELISA. NF-κB signaling pathway or IL-17 signaling pathway related proteins were analyzed by Western blotting. IL-17RA were determined by immunohistochemistry analyze. RESULTS: HYWD inhibited weight gain in T2DM rats. Histopathological results showed that HYWD inhibits liver injury. HYWD suppressed LDL-C and enhanced HDL-C in serum of T2DM rats. HYWD reduce FPG and 2 h PG, inhibit Fins, GSP and IRI, but enhance IAI in serum of T2DM rats. In addition, the network pharmacology results identified 292 chemical compounds in HYWD. 279 candidate targets were recognized, including IL-17A, IL-1ß, NFкB, stats, mmp3, and cxcl2. The pathways revealed that the possible target of HYWD related with the regulation of IL-17 signaling pathway and NF-κB pathway. Then in vivo study, HYWD reduced the levels of IL-6, TNF-α, IL-17 and IL-1ß in serum and inhibit the protein expression involved in IL-17/NF-κB signaling pathway. CONCLUSIONS: The study demonstrates that HYWD may improve T2DM by repressing with the IL-17/NF-κB signaling pathway, which offer encouraging support for using alternative medicine of type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Masculino , Ratos , Animais , NF-kappa B , Diabetes Mellitus Tipo 2/tratamento farmacológico , Interleucina-17 , Glicemia , LDL-Colesterol , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos Wistar , Transdução de Sinais , Inflamação/tratamento farmacológico
19.
J Ethnopharmacol ; 319(Pt 1): 117032, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37582477

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The polyherbal mixture made of Centaurium erythraea aerial parts and Cichorium intybus roots and Potentilla erecta rhizomes has been used for centuries to treat both the primary and secondary complications of diabetes. AIM OF THE STUDY: As a continuation of our search for the most effective herbal mixture used as an ethnopharmacological remedy for diabetes, this study aimed to compare the in vitro biological activities of this polyherbal mixture and its individual ingredients, and, most importantly, to validate the ethnopharmacological value of the herbal mixture through evaluation of its phytochemical composition, its potential in vivo toxicity and its effect on diabetes complications. MATERIALS AND METHODS: Phytochemical analysis was performed using HPLC-UV. Antioxidant activity was estimated via the DPPH test. Potential cytotoxicity/anticytotoxicity was assessed using an in vitro RBCs antihemolytic assay and an in vivo sub-chronic oral toxicity method. Antidiabetic activity was evaluated using an in vitro α-amylase inhibition assay and in vivo using a chemically induced diabetic rat model. RESULTS: The HPLC-UV analysis revealed the presence of p-hydroxybenzoic acid, p-hydroxybenzoic acid derivative, catechin, five catechin derivatives, epicatechin, isoquercetin, hyperoside, rutin, four quercetin derivatives, caffeic acid, and four caffeic acid derivatives in the polyherbal mixture decoction. Treatment with the decoction has shown no toxic effects. The antioxidant and cytoprotective activities of the polyherbal mixture were higher than the reference's ones. Its antidiabetic activity was high in both in vitro and in vivo studies. Fourteen days of treatment with the decoction (15 g/kg) completely normalized blood glucose levels of diabetic animals, while treatments with insulin and glimepiride only slightly lowered glycemic values. In addition, lipid status of treated animals as well as levels of serum AST, ALT, ALP, creatinine, urea and MDA were completely normalized. In addition, the polyherbal mixture completely restored the histopathological changes of the liver, kidneys and all four Cornu ammonis regions of the hippocampus. CONCLUSIONS: The polyherbal mixture was effective in the prevention of both primary and secondary diabetic complications such as hyperlipidemia, increased lipid peroxidation, non-alcoholic fatty liver disease, nephropathy and neurodegeneration.


Assuntos
Catequina , Centaurium , Chicória , Diabetes Mellitus Experimental , Potentilla , Ratos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Glicemia
20.
J Biomed Mater Res A ; 112(2): 288-295, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37776226

RESUMO

Immunoisolation of pancreatic islets in alginate microcapsules allows for transplantation in the absence of immunosuppression but graft survival time is still limited. This limited graft survival is caused by a combination of tissue responses to the encapsulating biomaterial and islets. A significant loss of islet cells occurs in the immediate period after transplantation and is caused by a high susceptibility of islet cells to inflammatory stress during this period. Here we investigated whether necrostatin-1 (Nec-1), a necroptosis inhibitor, can reduce the loss of islet cells under stress in vitro and in vivo. To this end, we developed a Nec-1 controlled-release system using poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) as the application of Nec-1 in vivo is limited by low stability and possible side effects. The PLGA NPs stably released Nec-1 for 6 days in vitro and protected beta cells against hypoxia-induced cell death in vitro. Treatment with these Nec-1 NPs at days 0, 6, and 12 post-islet transplantation in streptozotocin-diabetic mice confirmed the absence of side effects as graft survival was similar in encapsulated islet grafts in the absence and presence of Nec-1. However, we found no further prolongation of graft survival of encapsulated grafts which might be explained by the high biocompatibility of the alginate encapsulation system that provoked a very mild tissue response. We expect that the Nec-1-releasing NPs could find application to immunoisolation systems that elicit stronger inflammatory responses, such as macrodevices and vasculogenic biomaterials.


Assuntos
Diabetes Mellitus Experimental , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Camundongos , Animais , Diabetes Mellitus Experimental/terapia , Ilhotas Pancreáticas/metabolismo , Materiais Biocompatíveis/efeitos adversos , Alginatos/metabolismo
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