scholarly journals Design, Synthesis and In Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

2018 ◽  
Author(s):  
Blanca Colín-Lozano ◽  
Samuel Estrada-Soto ◽  
Fabiola Chávez-Silva ◽  
Abraham Gutiérrez-Hernández ◽  
Litzia Cerón-Romero ◽  
...  
Keyword(s):  
Single Molecule ◽  
Insulin Dependent Diabetes Mellitus ◽  
Binding Mode ◽  
Docking Studies ◽  
Dependent Diabetes Mellitus ◽  
Mice Model ◽  
Glut 4 ◽  
Small Series

We synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids using an easy and short step synthetic route. All compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: GPR40, aldose reductase (AKR1B1), PPARγ and GLUT-4. Compound 1 displayed an EC50 value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 μM. Compounds 2 and 3 behave as AKR1B1 inhibitors, GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active compounds on these targets. Compounds 1-3 were tested in vivo at 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non insulin-dependent diabetes mellitus mice model. Compounds 2 and 3 showed robust in vitro and in vivo efficacy, and could be considered as promising multitarget antidiabetic drug candidates. This is the first report of a single molecule with these four polypharmacological target action.

scholarly journals Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases?

2004 ◽  
Vol 50 (11) ◽  
pp. 2136-2140 ◽  
Author(s):  
Marie Bennermo ◽  
Claes Held ◽  
Sten Stemme ◽  
Carl-Göran Ericsson ◽  
Angela Silveira ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Promoter Region ◽  
Insulin Dependent Diabetes Mellitus ◽  
Juvenile Chronic Arthritis ◽  
In Vivo Studies ◽  
Dependent Diabetes Mellitus ◽  
Tnf Α

Abstract Background: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position −174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the −174 SNP for the induction of IL-6 in vivo. Methods: We vaccinated 20 and 18 healthy individuals homozygous for the −174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were measured in the blood at baseline and up to 24 h after vaccination. Results: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1β and TNF-α before or after vaccination. Conclusions: The −174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

Hyperglycemic athymic nude mice: factors affecting in vitro insulin secretion

1992 ◽  
Vol 263 (6) ◽  
pp. E1131-E1133
Author(s):  
A. Zeidler ◽  
P. Edwards ◽  
J. Goldman ◽  
S. Kort ◽  
W. P. Meehan ◽  
...  
Keyword(s):  
Animal Model ◽  
Insulin Secretion ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Factors Affecting ◽  
In Vitro Insulin Secretion ◽  
Insulin Secretion In Vitro ◽  
And Control

The strain of athymic nude male mice (ANM) developed at the University of Southern California (USC) exhibits spontaneous hyperglycemia and relative hypoinsulinemia in vivo. To investigate factors that influence insulin secretion in this animal model of non-insulin-dependent diabetes mellitus, we utilized the isolated perfused mouse pancreas of the ANM-USC and control BALB/c mice. We compared in vitro glucose-induced insulin secretion in ANM-USC and control mice, inhibition of secretion by somatostatin, and variability of insulin secretion over the two-year period it took to complete these experiments. Glucose-induced insulin secretion from the isolated pancreas was biphasic in both ANM-USC and controls. Insulin secretion was quantitatively equal to or greater than control mice, depending on the phase of secretion analyzed and the source of the control mice. In contrast to pancreases of control mice, insulin secretion from ANM-USC pancreases was relatively resistant to inhibition of insulin secretion by somatostatin. Variability in insulin secretion over the two years in which these experiments were performed was greater from pancreases of control than that observed from pancreases of the ANM-USC. The hyperglycemic ANM-USC mouse does not demonstrate diminished insulin secretion in vitro yet is relatively hypoinsulinemic in vivo. Thus circulating factors other than somatostatin might contribute to the insulinopenic stage in this animal model.

Metabolic effects of vanadyl sulfate in humans with non—insulin-dependent diabetes mellitus: In vivo and in vitro studies

Metabolism ◽  
2000 ◽  
Vol 49 (3) ◽  
pp. 400-410 ◽  
Author(s):  
Allison B. Goldfine ◽  
Mary-Elizabeth Patti ◽  
Lubna Zuberi ◽  
Barry J. Goldstein ◽  
Raeann LeBlanc ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Dependent Diabetes Mellitus ◽  
In Vitro Studies ◽  
Insulin Dependent Diabetes ◽  
Vanadyl Sulfate ◽  
Metabolic Effects ◽  
Dependent Diabetes Mellitus ◽  
Insulin Dependent

scholarly journals Structural Insights into Novel 15-Prostaglandin Dehydrogenase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5903
Author(s):  
Prema L. Mallipeddi ◽  
Yongyou Zhang ◽  
Hongyun Li ◽  
Sanford D. Markowitz ◽  
Bruce Posner
Keyword(s):  
Binding Mode ◽  
Marrow Transplant ◽  
Docking Studies ◽  
Binding Interactions ◽  
Prostaglandin Dehydrogenase ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Structural Insights

We discovered SW033291 in a high throughput chemical screen aimed at identifying 15-prostaglandin dehydrogenase (15-PGDH) modulators. The compound exhibited inhibitory activity in in vitro biochemical and cell-based assays of 15-PGDH activity. We subsequently demonstrated that this compound, and several analogs thereof, are effective in in vivo mouse models of bone marrow transplant, colitis, and liver regeneration, where increased levels of PGE2 positively potentiate tissue regeneration. To better understand the binding of SW033291, we carried out docking studies for both the substrate, PGE2, and an inhibitor, SW033291, to 15-PGDH. Our models suggest similarities in the ways that PGE2 and SW033291 interact with key residues in the 15-PGDH-NAD+ complex. We carried out molecular dynamics simulations (MD) of SW033291 bound to this complex, in order to understand the dynamics of the binding interactions for this compound. The butyl side chain (including the sulfoxide) of SW033291 participates in crucial binding interactions that are similar to those observed for the C15-OH and the C16-C20 alkyl chain of PGE2. In addition, interactions with residues Ser138, Tyr151, and Gln148 play key roles in orienting and stabilizing SW033291 in the binding site and lead to enantioselectivity for the R-enantiomer. Finally, we compare the binding mode of (R)-S(O)-SW033291 with the binding interactions of published 15-PGDH inhibitors.

Decreased expression of glucose transporter in muscle from insulin-resistant patients

1991 ◽  
Vol 260 (3) ◽  
pp. E459-E463 ◽  
Author(s):  
G. L. Dohm ◽  
C. W. Elton ◽  
J. E. Friedman ◽  
P. F. Pilch ◽  
W. J. Pories ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Glucose Transporter ◽  
Vastus Lateralis ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Obese Patients ◽  
Insulin Resistant ◽  
Glut 4 ◽  
Obesity And Diabetes

We have observed that in vitro incubated human muscle fiber strips from obese patients with or without non-insulin-dependent diabetes mellitus (NIDDM) have reduced insulin-stimulated glucose transport rates compared with nonobese control patients. To investigate if the decrease in glucose transport is associated with a depletion of glucose transport protein, we performed Western blot analysis of muscle samples from nonobese control, obese nondiabetic, and obese NIDDM patients to measure the levels of the muscle-adipose tissue glucose transporter (GLUT-4) protein. Glucose transporter protein was depressed by 23% in the obese nondiabetic and 18% in the obese NIDDM group. The results were essentially the same in the rectus abdominus and vastus lateralis muscles. These data suggest that the decreased glucose transport rate observed in muscle of these obese patients with or without NIDDM may be due, at least in part, to a decreased expression of the "insulin-sensitive" (GLUT-4) glucose transporter. This alteration may play a role in the insulin resistance seen in obesity and diabetes.

scholarly journals ETHYLCELLULOSE FLOATING MICROSPHERES OF ANTIDIABETIC AGENT: IN VITRO AND IN VIVO EVALUATION

2016 ◽  
Vol 9 (1) ◽  
pp. 44 ◽  
Author(s):  
Seema Kohli ◽  
Megha Sharma ◽  
Abhisek Pal
Keyword(s):  
Average Particle Size ◽  
Insulin Dependent Diabetes Mellitus ◽  
Treated Group ◽  
Antidiabetic Activity ◽  
Dependent Diabetes Mellitus ◽  
Average Particle ◽  
In Vivo Evaluation ◽  
Gastro Retentive

Objective: To develop and evaluate floating type gastro-retentive dosage form, appropriate for controlled release of repaglinide (RG) having a narrow therapeutic window.Methods: Repaglinide loaded microspheres (MS) using biological macromolecule ethylcellulose (EC) was prepared by a solvent diffusion-evaporation technique using polyvinyl alcohol (PVA) emulsifier. Compatibility of drug and polymer was studied by Fourier-transform infrared spectroscopy (FTIR). During formulation, various process optimisation parameters studied were stirring speed, the concentration of drug, polymer and emulsifier. Characterization and in vitro evaluation was performed. In vivo antidiabetic activity was performed on alloxan induced diabetic rats followed by histopathological screening.Results: The average particle size was in the range of 174-243 µm. Yield, entrapment and buoyancy of microspheres were 68.4­­-79.8, 58.6-73.1 and 71.8-84.1% respectively. 65.1% release of drug from optimised formulation was obtained which follows first-order kinetics (r2 = 0.989). Optimised formulation treated group shows significant (p<0.01) decrease in glucose level of blood as compared to pure drug treated group during the later hours of study with satisfactory results of histology.Conclusion: The investigation revealed the promising potential of gastro retentive microspheres for delivering RG for the treatment of non-insulin dependent diabetes mellitus (NIDDM).

Repeated intraperitoneal injections of interleukin 1β induce glucose intolerance in normal rats

1991 ◽  
Vol 124 (5) ◽  
pp. 470-478 ◽  
Author(s):  
Lise Wogensen ◽  
Jesper Reimers ◽  
Thomas Mandrup-Poulsen ◽  
Jørn Nerup
Keyword(s):  
Blood Glucose ◽  
Glucose Tolerance ◽  
Single Injection ◽  
Interleukin 1 ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Mild Depression ◽  
Wistar Kyoto

Abstract. Previous in vitro findings suggest the involvement of interleukin 1 (IL-1) in the pathogenesis of insulin-dependent diabetes mellitus. The aims of the present study were to investigate the effects of single or repeated ip injections of recombinant IL-1β on blood glucose and glucose tolerance in vivo. Normal Wistar Kyoto rats were injected ip with a single injection of 4 μg/kg of the mature form of recombinant IL-1β (amino acids 117-269) or once daily on 5 consecutive days. Control rats were given vehicle and were fed ad libitum or pair-fed together with the rIL-1β treated rats. An ip glucose tolerance test (0.2 g D-glucose/100 g) was performed 2 h after injection of rIL-1β. A single injection of rIL-1β caused a mild depression in blood glucose and an improved glucose tolerance. Multiple injections of rIL-1 β induced a diminished weight gain, a 24-28% reduction in food intake, a lasting mild depression of blood glucose (7 days) and a transiently impaired glucose tolerance on day 5. We conclude that systemic IL-1 should be considered an important regulator of glucose homeostasis in vivo.

Improved Functional Survival of Human Islets of Langerhans in Three-Dimensional Matrix Culture

1994 ◽  
Vol 3 (5) ◽  
pp. 427-435 ◽  
Author(s):  
Mathias D. Brendel ◽  
Shen Shen Kong ◽  
Rodolfo Alejandro ◽  
Daniel H. Mintz
Keyword(s):  
Culture Media ◽  
Three Dimensional ◽  
Culture Method ◽  
Threshold Level ◽  
Insulin Dependent Diabetes Mellitus ◽  
Absolute Number ◽  
Human Islets ◽  
Dependent Diabetes Mellitus

The current study evaluates functional survival of human islets maintained in tissue culture for up to 4 wk in suspension media (CMRL-1066 with supplements) and contrasts these results with immobilizing three-dimensional matrices (agarose or alginate). The absolute number and volume of islets retrieved from agarose is significantly higher after two and four wk of culture compared to conventional free-floating media. In vitro function of islets, assessed by insulin/DNA content, insulin secretion into the culture media over 24 h and glucose-theophylline stimulated insulin release in a dynamic perifusion system, was not significantly different between free-floating and matrix preserved islets. In vivo islet function was evaluated by the effectiveness for reversal of insulin-dependent diabetes mellitus by transplantation of the islets under the kidney capsule of nude mice. Although adequate insulin responses to glucose were seen after culture in conventional or matrix media, only agarose embedded islets were consistently able to induce normoglycemia in diabetic recipients after 14 days of culture. Additional transplantation experiments defined the threshold level required to reverse diabetes to be between 1,000 and 1,500 agarose preserved islets. Our data suggest improved engraftment of human islets after agarose culture. This culture method may be of benefit for the accumulation of functionally competent human islets, thus facilitating the implementation of clinical protocols that utilize freshly isolated islets from multiple donors without the need for cryopreservation.

scholarly journals From Design to in Vivo Active Organometallic-Containing Antimycotic Agents

2020 ◽  
Author(s):  
Riccardo Rubbiani ◽  
Tobias Weil ◽  
Noemi Tocci ◽  
Luciano Mastrobuoni ◽  
Severin Jeger ◽  
...  
Keyword(s):  
Rational Design ◽  
Fungal Infections ◽  
Binding Mode ◽  
Fungal Species ◽  
Antifungal Drugs ◽  
Hospital Environment ◽  
Ros Generation ◽  
Mice Model

Fungal infections are an alarming global problem, most importantly for immunocompromised patients in a hospital environment. The appearance of multidrug resistance in several fungal species is a strong indication that alternative treatments are required. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this work, by rational design, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (<b>1a-4a</b>). All compounds showed excellent <i>in vitro</i> activity against the yeast <i>C. robusta</i>, clearly surpassing the progenitor organic drug fluconazole. As anticipated, due to the presence of the ferrocenyl moiety in <b>1a-4a</b>, a modest increase in ROS generation was observed on <i>C. robusta</i> upon treatment. Very importantly, enzyme inhibition and chemogenetic profiling demonstrated that lanosterol 14α-demethylase was the main target of the most active compound of the series, (<i>N</i>-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, <b>2a</b>). Transmission electron microscopy (TEM) studies suggested that <b>2a</b> induced a loss in wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of <b>2a</b> was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, <b>2a </b>showed activity towards azole-resistant strains. This finding is very interesting since the target of <b>2a</b> is primarily the same as that of fluconazole, emphasizing the role played by the organometallic moiety. <i>In vivo</i> experiments conducted with <b>2a</b> at a dose of 10 mg/Kg in mice model of <i>Candida</i> infections, while not decreasing fungal burden in the kidney, reduced distal distribution to liver and brain and greatly improved the inflammatory pathology in the kidney and colon, compared to untreated mice.<br>

scholarly journals From Design to in Vivo Active Organometallic-Containing Antimycotic Agents

2020 ◽  
Author(s):  
Riccardo Rubbiani ◽  
Tobias Weil ◽  
Noemi Tocci ◽  
Luciano Mastrobuoni ◽  
Severin Jeger ◽  
...  
Keyword(s):  
Rational Design ◽  
Fungal Infections ◽  
Binding Mode ◽  
Fungal Species ◽  
Antifungal Drugs ◽  
Hospital Environment ◽  
Ros Generation ◽  
Mice Model

Fungal infections are an alarming global problem, most importantly for immunocompromised patients in a hospital environment. The appearance of multidrug resistance in several fungal species is a strong indication that alternative treatments are required. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this work, by rational design, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (<b>1a-4a</b>). All compounds showed excellent <i>in vitro</i> activity against the yeast <i>C. robusta</i>, clearly surpassing the progenitor organic drug fluconazole. As anticipated, due to the presence of the ferrocenyl moiety in <b>1a-4a</b>, a modest increase in ROS generation was observed on <i>C. robusta</i> upon treatment. Very importantly, enzyme inhibition and chemogenetic profiling demonstrated that lanosterol 14α-demethylase was the main target of the most active compound of the series, (<i>N</i>-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, <b>2a</b>). Transmission electron microscopy (TEM) studies suggested that <b>2a</b> induced a loss in wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of <b>2a</b> was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, <b>2a </b>showed activity towards azole-resistant strains. This finding is very interesting since the target of <b>2a</b> is primarily the same as that of fluconazole, emphasizing the role played by the organometallic moiety. <i>In vivo</i> experiments conducted with <b>2a</b> at a dose of 10 mg/Kg in mice model of <i>Candida</i> infections, while not decreasing fungal burden in the kidney, reduced distal distribution to liver and brain and greatly improved the inflammatory pathology in the kidney and colon, compared to untreated mice.<br>

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