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1.
Molecules ; 29(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38338442

RESUMO

(1) Background: The effect of Dendrobium nobile Lindl. (D. nobile) on hyperglycemic syndrome has only been recently known for several years. Materials of D. nobile were always collected from the plants cultivated in various growth ages. However, regarding the efficacy of D. nobile on hyperglycemic syndrome, it was still unknown as to which cultivation age would be selected. On the other hand, with the lack of quality markers, it is difficult to control the quality of D. nobile to treat hyperglycemic syndrome. (2) Methods: The effects of D. nobile cultivated at year 1 and year 3 were checked on alloxan-induced diabetic mice while their body weight, diet, water intake, and urinary output were monitored. Moreover, levels of glycosylated serum protein and insulin were measured using Elisa kits. The constituents of D. nobile were identified and analyzed by using UPLC-Q/trap. Quality markers were screened out by integrating the data from UPLC-Q/trap into a network pharmacology model. (3) Results: The D. nobile cultivated at both year 1 and year 3 showed a significant effect on hyperglycemic syndrome at the high dosage level; however, regarding the significant level, D. nobile from year 1 showed the better effect. In D. nobile, most of the metabolites were identified as alkaloids and sesquiterpene glycosides. Alkaloids, represented by dendrobine, were enriched in D. nobile from year 1, while sesquiterpene glycosides were enriched in D. nobile from year 3. Twenty one metabolites were differentially expressed between D. nobile from year 1 and year 3. The aforementioned 21 metabolites were enriched to 34 therapeutic targets directly related to diabetes. (4) Conclusions: Regarding the therapy for hyperglycemic syndrome, D. nobile cultivated at year 1 was more recommended than that at year 3. Alkaloids were recommended to be used as markers to control the quality of D. nobile for hyperglycemic syndrome treatment.


Assuntos
Alcaloides , Dendrobium , Diabetes Mellitus Experimental , Sesquiterpenos , Animais , Camundongos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Alcaloides/análise , Glicosídeos
2.
Molecules ; 29(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38338482

RESUMO

Phlorizin, as a flavonoid from a wide range of sources, is gradually becoming known for its biological activity. Phlorizin can exert antioxidant effects by regulating the IL-1ß/IKB-α/NF-KB signaling pathway. At the same time, it exerts its antibacterial activity by reducing intracellular DNA agglutination, reducing intracellular protein and energy synthesis, and destroying intracellular metabolism. In addition, phlorizin also has various pharmacological effects such as antiviral, antidiabetic, antitumor, and hepatoprotective effects. Based on domestic and foreign research reports, this article reviews the plant sources, extraction, and biological activities of phlorizin, providing a reference for improving the clinical application of phlorizin.


Assuntos
Glucosídeos , Florizina , Florizina/farmacologia , Florizina/metabolismo , Antioxidantes/farmacologia , Flavonoides , Hipoglicemiantes/farmacologia
3.
Sci Rep ; 14(1): 3823, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360784

RESUMO

Zebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.


Assuntos
Diabetes Mellitus , Hiperglicemia , Animais , Feminino , Masculino , Hipoglicemiantes/farmacologia , Limoneno , Peixe-Zebra/metabolismo , Glicemia/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Obesidade/metabolismo , Dieta Hiperlipídica , Hiperglicemia/complicações
4.
Front Endocrinol (Lausanne) ; 15: 1313597, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370354

RESUMO

Background: Metformin is a drug with a long history of providing benefits in diabetes management and beyond. The mechanisms of action of metformin are complex, and continue to be actively debated and investigated. The aim of this study is to identify metabolic signatures associated with metformin treatment, which may explain the pleiotropic mechanisms by which metformin works, and could lead to an improved treatment and expanded use. Methods: This is a cross-sectional study, in which clinical and metabolomic data for 146 patients with type 2 diabetes were retrieved from Qatar Biobank. Patients were categorized into: Metformin-treated, treatment naïve, and non-metformin treated. Orthogonal partial least square discriminate analysis and linear models were used to analyze differences in the level of metabolites between the metformin treated group with each of the other two groups. Results: Patients on metformin therapy showed, among other metabolites, a significant increase in 3-hydroxyoctanoate and 3-hydroxydecanoate, which may have substantial effects on metabolism. Conclusions: This is the first study to report an association between 3-hydroxy medium chain fatty acids with metformin therapy in patients with type 2 diabetes. This opens up new directions towards repurposing metformin by comprehensively understanding the role of these metabolites.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Diabetes Mellitus Tipo 2/complicações , Estudos Transversais , Hipoglicemiantes/farmacologia , Ácidos Graxos
5.
Cardiovasc Diabetol ; 23(1): 56, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38331780

RESUMO

BACKGROUND: SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other clinical parameters. METHODS: This is a multicenter, open-label, randomized, controlled trial. Patients with type 2 diabetes (20-74 years old) with HbA1c levels of 7.0-10.5% and serum triglyceride levels of 120-399 mg/dL (1.35-4.50 mmol/L) on diet and/or oral hypoglycemic agents were enrolled. Subjects were randomized to treatment with ipragliflozin (50 mg/day, n = 77) or sitagliptin (50 mg/day, n = 83). Laboratory measurements were performed at 0, 1, 3, and 6 months of treatment. RESULTS: Ipragliflozin and sitagliptin reduced fasting plasma glucose, glycoalbumin, and HbA1c almost equally. Ipragliflozin increased HDL-C and decreased apo E. Sitagliptin decreased TG, apo B48, CII, and CIII, but increased LDL-C. The between-treatment differences were significant for HDL-C (P = 0.02) and apo B48 (P = 0.006), and nearly significant for apo A1 (P = 0.06). In addition, ipragliflozin reduced body weight, blood pressure, serum liver enzymes, uric acid, and leptin, and increased serum ketones compared with sitagliptin. CONCLUSIONS: While ipragliflozin and sitagliptin showed similar effects on glycemic parameters, the effects on serum lipid and apolipoprotein profiles were different. Ipragliflozin may have an anti-atherogenic effect through modulation of HDL-C and apo E compared to sitagliptin through TG and apo B48, CII, and CIII in patients with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Glucosídeos , Fosfato de Sitagliptina , Tiofenos , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Apolipoproteínas , Apolipoproteínas E , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas , Hipoglicemiantes/farmacologia , Fosfato de Sitagliptina/farmacologia
6.
J Agric Food Chem ; 72(7): 3259-3276, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38308635

RESUMO

Polysaccharides are an important class of biomolecules derived from several sources. However, the inherent structure of polysaccharides prevents them from exhibiting favorable physicochemical properties, which restricts their development in agriculture, industry, food, and biomedicine. This paper systematically summarizes the changes in the primary and advanced structures of modified polysaccharides, and focuses on the effects of various modification methods on the hydrophobicity, rheological properties, emulsifying properties, antioxidant activity, hypoglycemic, and hypolipidemic activities of polysaccharides. Then there is a list the applications of modified polysaccharides in treating heavy metal pollutants, purifying water resources, improving beverage stability and bread quality, and precisely delivering the drug. When summarized and reviewed, the information above can shed further light on the relationship between polysaccharide structure and function. Determining the structure-activity relationship provides a scientific basis for the direction of molecular modifications of polysaccharides.


Assuntos
Hipoglicemiantes , Polissacarídeos , Relação Estrutura-Atividade , Hipoglicemiantes/farmacologia , Polissacarídeos/farmacologia , Polissacarídeos/química , Antioxidantes/farmacologia , Antioxidantes/química , Reologia
7.
ScientificWorldJournal ; 2024: 1998870, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38356989

RESUMO

The aims of this study were to determine the polyphenolic profile, to estimate the total phenolic and flavonoid contents, and to evaluate the antioxidant and antidiabetic activities of the extract of Pistacia lentiscus leaves, and the hydroacetonic mixture was employed as an alternative for common solvents in the extraction process. In order to explain the antidiabetic activity, molecular docking has been performed on the main constituents of the leaf extract. The characterization of the extract has been performed by high-performance liquid chromatography (HPLC) leading to the detection of 20 compounds of which gallic acid, ellagic acid, catechin, kaempferol, and quercetin 3-glucoside were identified using authentic standards. The total phenolic and flavonoid contents, assessed using the Folin-Ciocalteu and quercetin methods, were 394.5 ± 0.08 mg gallic acid equivalent/g dry extract (mg GAE/g DE) and 101.2 ± 0.095 mg quercetin equivalent/g dry extract (mg QE/g DE), respectively. On the other hand, the antioxidant activity of leaf extract, quantified by determining the ability to neutralize the free radical DPPH and ß-carotene/linoleate model system, reached the values of 0.0027 ± 0.002 mg/mL and 0.128 ± 0.04 mg/mL, respectively. Regarding the antidiabetic activity, based on the inhibition of pancreatic α-amylase activity, a significant inhibition of about 68.20% with an IC50 value of 0.266 mg/mL had been observed. This finding is consistent with the molecular docking study of the main phenolic compounds of the extracts, where a remarkable binding affinity against α-amylase was observed, with values of -7.631 (kcal/mol), -6.818 (kcal/mol), and -5.517 (kcal/mol) for the major compounds catechin, quercetin-3-glucoside, and gallic acid, respectively.


Assuntos
Catequina , Pistacia , Antioxidantes/química , Quercetina , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , Fenóis/análise , Extratos Vegetais/química , Flavonoides/análise , Ácido Gálico
8.
J Vis Exp ; (203)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38345259

RESUMO

Diabetes mellitus (DM) is caused by insufficient insulin release from the pancreatic ß-cells (Type1 DM) and insulin sensitivity in muscles, liver, and adipose tissues (Type2 DM). Insulin injection treats DM patients but leads to hypoglycemia as a side effect. Cortisol and catecholamines are released to activate glucose production from the liver to recover hypoglycemia, called counter-regulatory responses (CRR). In DM research using rodent models, glucose tolerance tests and 2-deoxy-glucose injection are used to measure insulin release and CRR, respectively. However, blood glucose concentrations change persistently during experiments, causing difficulties in assessing net insulin release and CRR. This article describes a method in which blood glucose is kept at 250 mg/dL or 50 mg/dL in conscious mice to compare the release of insulin and CRR hormones, respectively. Polyethylene tubing is implanted in the mice's carotid artery and jugular vein, and the mice are allowed to recover from the surgery. The jugular vein tubing is connected to a Hamilton syringe with a syringe pump to enable insulin or glucose infusion at a constant and variable rate. The carotid artery tubing is for blood collection. For the hyperglycemic clamp, 30% glucose is infused into the vein, and blood glucose levels are measured from the arterial blood every 5 min or 10 min. The infusion rate of 30% glucose is increased until the blood glucose level becomes 250 mg/dL. Blood is collected to measure insulin concentrations. For hypoglycemic clamp, 10 mU/kg/min insulin is infused together with 30% glucose, whose infusion rate is variable to maintain 50 mg/dL of blood glucose level. Blood is collected to measure counter-regulatory hormones when both glucose infusion and blood glucose reach a steady state. Both hyperglycemic and hypoglycemic clamps have the same surgical procedure and experimental setups. Thus, this method is useful for researchers of systemic glucose metabolism.


Assuntos
Diabetes Mellitus , Hipoglicemia , Humanos , Camundongos , Animais , Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Técnica Clamp de Glucose , Hipoglicemia/metabolismo , Insulina/metabolismo , Glucose/metabolismo
11.
Sci Rep ; 14(1): 4224, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378730

RESUMO

Biosimilar insulin analogues are increasing market access for diabetic patients globally. Scientific establishment of biosimilarity is cornerstone of this key change in the medical landscape. BGL-ASP is a biosimilar insulin aspart developed by BioGenomics Limited, India. BioGenomics has considered a stepwise approach in generating the totality of evidence required to establish similarity with reference product. Insulin aspart is a recombinant rapid-acting human insulin analogue utilised in the treatment of type-1 and type-2 diabetes mellitus. The single amino acid substitution at position B28 where proline is replaced with aspartic acid results in a decreased propensity to form hexamers, thus increasing the absorption rate on subcutaneous administration compared to native insulin. In order to establish the safety and efficacy of BGL-ASP, the critical quality attributes (CQAs) of BGL-ASP are identified based on the impact created on biological activity, pharmacokinetic/pharmacodynamic (PK/PD), immunogenicity and safety. The CQAs of insulin aspart are related to product structure, purity and functionality and are characterised using a series of state-of-the-art orthogonal analytical tools. The primary protein sequence, the secondary, tertiary and quaternary structure are found to be highly similar for BGL-ASP and reference product. The product related impurities of insulin aspart and the assay content are determined using high performance liquid chromatography (HPLC) based analysis and is similar for BGL-ASP and reference insulin aspart sourced from United States of America (US), Europe Union (EU) and India. The safety, efficacy and immunogenicity of BGL-ASP is also found to be comparable with reference product and is confirmed through the clinical trials conducted as recommended by International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) and European Medicines Agency (EMA) guidelines. The data encompassed in this study demonstrates that reference insulin aspart and BGL-ASP are highly similar in terms of structural, physicochemical, and biological properties, thus confirming its safety and efficacy for usage as potential alternative economical medicinal treatment for diabetes mellitus.


Assuntos
Medicamentos Biossimilares , Diabetes Mellitus Tipo 2 , Humanos , Medicamentos Biossimilares/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Índia , Insulina/uso terapêutico , Insulina Aspart/uso terapêutico , Estados Unidos
12.
Future Med Chem ; 16(4): 335-348, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38314616

RESUMO

Aim: Recently, thiadiazole-containing drugs have gained greater clinical relevance and are being explored for the development of new antidiabetic, antiurease and antimicrobial agents that target drug resistance. Methods & results: The authors disclose the synthesis of N-(5-[4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl)methanimine derivatives starting from 4-(trifluoromethyl)benzoic acid. All of the synthesized derivatives were evaluated for their biological potential in order to investigate the inhibitory activity against antidiabetic, antiurease and antibacterial profiles. Compounds 1, 2 and 9 showed excellent inhibitory activities due to the hydrogen bonding presence of -OH, -F and -CF3 substitutions attached with the phenyl ring. Conclusion: The present study provides potent antidiabetic, antiurease and antimicrobial agents that can be further optimized to discover novel antidiabetic, antiurease drugs.


Assuntos
Anti-Infecciosos , Tiadiazóis , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Bases de Schiff/farmacologia , Tiadiazóis/farmacologia , Anti-Infecciosos/farmacologia , Hipoglicemiantes/farmacologia , Estrutura Molecular
13.
BMC Complement Med Ther ; 24(1): 69, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302935

RESUMO

BACKGROUND: Litsea glutinosa (Lour.) C. B. Rob. belongs to the Litsea genus and is categorized under the family of Lauraceae. The study aimed to investigate the phytoconstituents and pharmacological properties of methanol extract of leaves of Litsea glutinosa, focusing on antidiabetic activity via in vivo and in silico techniques. METHODS: Extensive chromatographic and spectroscopic techniques were applied to isolate and characterize the constituents from the L. glutinosa plant species. The antidiabetic activity was studied in streptozotocin-induced diabetes mice, and the computational study of the isolated compounds was carried out by utilizing AutoDock Vina programs. In addition, the pharmacokinetic properties in terms of absorption, distribution, metabolism and excretion (ADME) and toxicological profiles of the isolated compounds were examined via in silico techniques. RESULTS: In the present study, two flavonoid glycosides 4΄-O-methyl (2 ̋,4 ̋-di-E-p-coumaroyl) afzelin (1) and quercetin 3-O-(2 ̋,4 ̋-di-E-p-coumaroyl)-α-L-rhamnopyranoside (2) were isolated from the leaves of L. glutinosa and characterized by 1H and 13C NMR, COSY, HSQC, HMBC, and mass spectral data. Although compounds 1 and 2 have been reported twice from Machilis litseifolia and Lindera akoensis, and Machilis litseifolia and Mammea longifolia, respectively, this is the first report of this isolation from a Litsea species. Administering the methanolic extract of L. glutinosa at doses of 300 and 500 mg/kg/day to mice with diabetes induced by streptozotocin led to a significant decrease in fasting blood glucose levels (p < 0.05) starting from the 7th day of treatment. Besides, the computational study and PASS analysis endorsed the current in vivo findings that the both isolated compounds exerted higher binding affinities to human pancreatic α-amylase and aldose reductase than the conventional drugs. The in silico ADMET analysis revealed that the both isolated compounds have a favorable pharmacokinetic and safety profile suitable for human consumption. CONCLUSION: According to the current outcomes obtained from in vivo and in silico techniques, the leaf extract of L. glutinosa could be a natural remedy for treating diabetes, and the isolated phytoconstituents could be applied against various illnesses, mainly hyperglycemia. However, more investigations are required for extensive phytochemical isolation and pharmacological activities of these phytoconstituents against broader targets with exact mechanisms of action.


Assuntos
Diabetes Mellitus , Litsea , Humanos , Animais , Camundongos , Flavonoides/química , Glicosídeos/farmacologia , Litsea/química , Hipoglicemiantes/farmacologia , Estreptozocina
14.
Bioorg Med Chem ; 100: 117630, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38330849

RESUMO

Tirzepatide, the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T1/2: 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans. This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Receptores dos Hormônios Gastrointestinais , Animais , Cães , Humanos , Camundongos , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/uso terapêutico
15.
Int J Mol Sci ; 25(3)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38338796

RESUMO

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from ß-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.


Assuntos
Diabetes Mellitus Tipo 2 , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia , Insulina/uso terapêutico , Obesidade/tratamento farmacológico , Glucose/uso terapêutico , Amiloide/fisiologia
16.
Bioorg Chem ; 144: 107132, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38241768

RESUMO

The pleiotropic effects of TGR5 make it an appealing target for intervention of metabolic and inflammatory disorders, but systemic activation of TGR5 faces challenges of on-target side effects, especially gallbladder filling. Gut-restricted agonists were proved to be sufficient to circumvent these side effects, but extremely low systemic exposure may not be effective in activating TGR5 since it is located on the basolateral membrane. Herein, to balance potency and physicochemical properties, a series of gut-restricted TGR5 agonists with diversified kinetophores had been designed and synthesized. Compound 22-Na exhibited significant antidiabetic effect, and showed favorable gallbladder safety after 7 days of oral administration in humanized TGR5H88Y mice, confirming that gut-restricted agonism of TGR5 is a viable strategy to alleviate systemic target-related effects.


Assuntos
Ácido Betulínico , Receptores Acoplados a Proteínas G , Camundongos , Animais , Receptores Acoplados a Proteínas G/metabolismo , Hipoglicemiantes/farmacologia , Vesícula Biliar/metabolismo
17.
Bioorg Chem ; 144: 107106, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244380

RESUMO

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with Ki = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health.


Assuntos
Diabetes Mellitus Tipo 2 , Nitroimidazóis , Ratos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , alfa-Glucosidases/metabolismo , Acarbose/farmacologia , Acarbose/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Simulação de Acoplamento Molecular , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Nitroimidazóis/uso terapêutico , Relação Estrutura-Atividade , Estrutura Molecular
18.
Bioorg Chem ; 143: 107085, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38183681

RESUMO

A green catalyst WELPSA-catalyzed three-component condensation (Biginelli) process involving an aldehyde, barbituric/thiobarbituric/1,3-dimethylbarbituric acid, and urea/thiourea/guanidine hydrochloride in a single pot in presence of a green solvent for the production of DHPM have been presented. The catalyst is reusable and this methodology is scalable. By using the in vitro experiments, the antidiabetic potentiality of synthesized compounds that inhibit α-amylase along with α-glucosidase efficiencies was assessed. All the synthesized compounds except for 4a and 4e, showed the most significant inhibition for α-amylase and α-glucosidase activities. Among the synthesized DHPM compounds, 4c and 4b exhibited significant inhibition profiles compared to the standard antidiabetic drug acarbose. Furthermore, synthesized substances' energy-minimized structures, 3D structures, and DFT calculations were performed using Gaussian 09 software, hybrid models, and MM2 force approaches. Strong hydrogen bonds with amino acid residues Arg-672, Arg-600, Trp-613, Asp-404, Asp-282, and Asp-616 indicate that an α-glucosidase-inhibitory peptide may have hypoglycemic efficacy confirmed by the molecular docking study of the synthesized DHPM.


Assuntos
Inibidores de Glicosídeo Hidrolases , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , alfa-Amilases/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Catálise
19.
Exp Neurol ; 373: 114689, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38199510

RESUMO

Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Inibidores da Dipeptidil Peptidase IV , Metformina , Camundongos , Animais , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Quimiocina CCL3/farmacologia , Microglia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , Inflamação
20.
Chemosphere ; 351: 141149, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38218233

RESUMO

This study utilizes the abundance of pharmacologically active compounds found in natural products and concentrates on the promising anticancer agent lupeol (LUP). The limited water solubility and bioavailability of lupeol have limited its therapeutic utility. To test their potential for treating diabetes and cancer, we synthesized lupeol@chitosan (LUP@CS) nanoparticles encapsulated in cellulose acetate (CA) membranes (LUP@CS/CA). Extensive characterization, including Scanning electron microscopy, Thermogravimetric analysis, X-ray photoelectron spectroscopy, and mechanical strength analysis, confirmed the membrane's structural integrity and drug release capacity. Notably, in vitro experiments utilizing A431 human skin cancer cells revealed remarkable anticancer activity, positioning the membrane as a potential novel therapeutic agent for the treatment of skin cancer. Inhibiting carbohydrate-digesting enzymes effectively, as evidenced by IC50 values as low as 54.56 mg/mL, the membrane also exhibited significant antidiabetic potential. These results demonstrate the multifarious potential of the membrane, which offers promise for both the treatment of skin cancer and the management of diabetes, and has significant implications for nano biological applications.


Assuntos
Celulose/análogos & derivados , Quitosana , Diabetes Mellitus , Lupanos , Nanopartículas , Neoplasias Cutâneas , Humanos , Quitosana/farmacologia , Quitosana/química , Hipoglicemiantes/farmacologia , Nanopartículas/química
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