Inhibitory effect of tannic acid and its derivative (gallic acid) against cisplatin–induced thiobarbituric acid reactive substances (TBARS) production in rat kidney – in vitro

Increasing amounts of evidence suggests tannic acid (TA) and its derivative, gallic acid (GA) has beneficial effects against nephrotoxicity. The aim of this study was to investigate the effect of TA and GA (two structurally related phenolic acids) against cisplatin-induced thiobarbituric acid reactive substances (TBARS) production in rat kidney in vitro. The effect of both phenolic acids on kidney TBARS level in the presence of cisplatin, an antineoplastic drug used in the treatment of many solid-tissue cancers which has its chief side effect in nephrotoxicity, was assessed. Thereafter, the antioxidant properties were also determined. Incubation of the kidney tissue homogenate in the presence of cisplatin (1 mM) caused a significant (P<0.05) increase in the TBARS level. However, both phenolic acids caused a significant (P<0.05) decrease in the TBARS content of the kidney in a dose dependent manner (0 – 12.5 µM). Nevertheless, TA had a significantly higher (P<0.05) inhibitory effect on TBARS production than gallic acid judging by their IC50 value. Furthermore, TA possesses stronger antioxidant properties than GA as revealed by their scavenging, chelating and reducing ability. The inhibition of cisplatin–induced thiobarbituric acid reactive substances (TBARS) production in rat kidney by both TA and GA could be due to their antioxidant properties and this provide further insight into the mechanism of action for their nephroprotective properties from previous reported experimental studies. However, the study revealed that hydrolysis of TA reduces its potenc

Computational and preclinical prediction of the antimicrobial properties of an agent isolated from monodora myristica: A novel dna gyrase inhibitor

The African nutmeg (Monodora myristica) is a medically useful plant. We, herein, aimed to critically examine whether bioactive compounds identified in the extracted oil of Monodora myristica could act as antimicrobial agents. To this end, we employed the Schrödinger platform as the computational tool to screen bioactive compounds identified in the oil of Monodora myristica. Our lead compound displayed the highest potency when compared with levofloxacin based on its binding affinity. The hit molecule was further subjected to an Absorption, Distribution, Metabolism, Excretion (ADME) prediction, and a Molecular Dynamics (MD) simulation was carried out on molecules with PubChem IDs 529885 and 175002 and on three standards (levofloxacin, cephalexin, and novobiocin). The MD analysis results demonstrated that two molecules are highly compact when compared to the native protein; thereby, this suggests that they could affect the protein on a structural and a functional level. The employed computational approach demonstrates that conformational changes occur in DNA gyrase after the binding of inhibitors; thereby, this resulted in structural and functional changes. These findings expand our knowledge on the inhibition of bacterial DNA gyrase and could pave the way for the discovery of new drugs for the treatment of multi-resistant bacterial infections

Mitochondrial defects in pancreatic beta-cell dysfunction and neurodegenerative diseases: Pathogenesis and therapeutic applications

Financiaciado para publicación en acceso aberto: Universidade de Vigo/CISUGMitochondria malfunction is linked to the development of β-cell failure and a variety of neurodegenerative disorders. Pancreatic β-cells are normally configured to detect glucose and other food secretagogues in order to adjust insulin exocytosis and maintain glucose homeostasis. As a result of the increased glucose level, mitochondria metabolites and nucleotides are produced, which operate in concert with cytosolic Ca2+ to stimulate insulin secretion. Furthermore, mitochondria are the primary generators of adenosine triphosphate (ATP), reactive oxygen species (ROS), and apoptosis regulation. Mitochondria are concentrated in synapses, and any substantial changes in synaptic mitochondria location, shape, quantity, or function might cause oxidative stress, resulting in faulty synaptic transmission, a symptom of various degenerative disorders at an early stage. However, a greater understanding of the role of mitochondria in the etiology of β-cell dysfunction and neurodegenerative disorder should pave the way for a more effective approach to addressing these health issues. This review looks at the widespread occurrence of mitochondria depletion in humans, and its significance to mitochondria biogenesis in signaling and mitophagy. Proper understanding of the processes might be extremely beneficial in ameliorating the rising worries about mitochondria biogenesis and triggering mitophagy to remove depleted mitochondria, therefore reducing disease pathogenesi

Ameliorative potential of Aframomum melegueta extract in cadmiuminduced hepatic damage and oxidative stress in male Wistar rats

The present study was undertaken to explore the ameliorative potential of aqueous extract of Aframomum melegueta (AM) on cadmium-induced hepatic damage in rats. Toxicity was induced by daily administration of 200 mg/L cadmium: Cd (Cd as CdCl2) in the animals’ main drinking water for 21 days. Lipid peroxidation (LPO), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were determined in the liver while total protein, albumin, direct bilirubin and t otal bilirubin concentration as well as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were monitored in the serum and histological examination was carried out. Exposure to cadmium resulted in various alterations in all the evaluated parameters. Treatment with AM (200 or 400 mg/kg bw) extract showed a significant (P <0.05) reversal effect that mitigated the deleterious effect of cadmium. Results of the histological examination also support the above findings. The results suggest that aqueous extracts of A. melegueta when administered orally, could ameliorate cadmium-associated oxidative stress in male Wistar rats in a dose dependant manner via its free radical-scavenging mechanism which could be linked to the synergetic effects between the bioactive constituents present in the extract

Profiling the antidiabetic potential of compounds identified from fractionated extracts of Entada africana toward glucokinase stimulation: computational insight

Abstract: Glucokinase plays an important role in regulating the blood glucose level and serves as an essential therapeutic target in type 2 diabetes management. Entada africana is a medicinal plant and highly rich source of bioactive ligands with the potency to develop new target drugs for glucokinase such as diabetes and obesity. Therefore, the study explored a computational approach to predict identified compounds from Entada africana following its intermolecular interactions with the allosteric binding site of the enzymes. We retrieved the three-dimensional (3D) crystal structure of glucokinase (PDB ID: 4L3Q) from the online protein data bank and prepared it using the Maestro 13.5, Schrödinger Suite 2022-3. The compounds identified were subjected to ADME, docking analysis, pharmacophore modeling, and molecular simulation. The results show the binding potential of the identified ligands to the amino acid residues, thereby suggesting an interaction of the amino acids with the ligand at the binding site of the glucokinase activator through conventional chemical bonds such as hydrogen bonds and hydrophobic interactions. The compatibility of the molecules was highly observed when compared with the standard ligand, thereby leading to structural and functional changes. Therefore, the bioactive components from Entada africana could be a good driver of glucokinase, thereby paving the way for the discovery of therapeutic drugs for the treatment of diabetes and its related complications

U0126 Compound Triggers Thermogenic Differentiation in Preadipocytes via ERK-AMPK Signaling Axis

In recent years, thermogenic differentiation and activation in brown and white adipose tissues have been regarded as one of the major innovative and promising strategies for the treatment and amelioration of obesity. However, the pharmacological approach towards this process has had limited and insufficient commitments, which presents a greater challenge for obesity treatment. This research evaluates the effects of U0126 compound on the activation of thermogenic differentiation during adipogenesis. The results show that U0126 pretreatment primes both white and brown preadipocytes to upregulate thermogenic and mitochondrial genes as well as enhance functions during the differentiation process. We establish that U0126-mediated thermogenic differentiation induction occurs partially via AMPK activation signaling. The findings of this research suggest U0126 as a promising alternative ligand in pursuit of a pharmacological option to increase thermogenic adipocyte formation and improve energy expenditure. Thus it could pave the way for the discovery of therapeutic drugs for the treatment of obesity and its related complications

Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney

In this study, the effect of enzymes involved in degradation of renal adenosine and l-arginine was investigated in rats exposed to cadmium (Cd) and treated with curcumin, the principal active phytochemical in turmeric rhizome. Animals were divided into six groups (n = 6): saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. The results of this study revealed that the activities of renal adenosine deaminase and arginase were significantly increased in Cd-treated rats when compared with the control (p < 0.05). However, co-treatment with curcumin inhibits the activities of these enzymes compared with Cd-treated rats. Furthermore, Cd intoxication increased the levels of some renal biomarkers (serum urea, creatinine, and electrolytes) and malondialdehyde level with a concomitant decrease in functional sulfhydryl group and nitric oxide (NO). However, co-treatment with curcumin at 12.5 mg/kg and 25 mg/kg, respectively, increases the nonenzymatic antioxidant status and NO in the kidney, with a concomitant decrease in the levels of malondialdehyde and renal biomarkers. Therefore, our results reinforce the importance of adenosine deaminase and arginase activities in Cd poisoning conditions and suggest some possible mechanisms of action by which curcumin prevent Cd-induced renal toxicity in rats

Computational and Preclinical Prediction of the Antimicrobial Properties of an Agent Isolated from <i>Monodora myristica</i>: A Novel DNA Gyrase Inhibitor

The African nutmeg (Monodora myristica) is a medically useful plant. We, herein, aimed to critically examine whether bioactive compounds identified in the extracted oil of Monodora myristica could act as antimicrobial agents. To this end, we employed the Schrödinger platform as the computational tool to screen bioactive compounds identified in the oil of Monodora myristica. Our lead compound displayed the highest potency when compared with levofloxacin based on its binding affinity. The hit molecule was further subjected to an Absorption, Distribution, Metabolism, Excretion (ADME) prediction, and a Molecular Dynamics (MD) simulation was carried out on molecules with PubChem IDs 529885 and 175002 and on three standards (levofloxacin, cephalexin, and novobiocin). The MD analysis results demonstrated that two molecules are highly compact when compared to the native protein; thereby, this suggests that they could affect the protein on a structural and a functional level. The employed computational approach demonstrates that conformational changes occur in DNA gyrase after the binding of inhibitors; thereby, this resulted in structural and functional changes. These findings expand our knowledge on the inhibition of bacterial DNA gyrase and could pave the way for the discovery of new drugs for the treatment of multi-resistant bacterial infections

Computational and preclinical prediction of the antimicrobial properties of an agent isolated from Monodora myristica: a novel DNA gyrase inhibitor

The African nutmeg (Monodora myristica) is a medically useful plant. We, herein, aimed to critically examine whether bioactive compounds identified in the extracted oil of Monodora myristica could act as antimicrobial agents. To this end, we employed the Schrödinger platform as the com- putational tool to screen bioactive compounds identified in the oil of Monodora myristica. Our lead compound displayed the highest potency when compared with levofloxacin based on its binding affinity. The hit molecule was further subjected to an Absorption, Distribution, Metabolism, Excre- tion (ADME) prediction, and a Molecular Dynamics (MD) simulation was carried out on molecules with PubChem IDs 529885 and 175002 and on three standards (levofloxacin, cephalexin, and novo- biocin). The MD analysis results demonstrated that two molecules are highly compact when com- pared to the native protein; thereby, this suggests that they could affect the protein on a structural and a functional level. The employed computational approach demonstrates that conformational changes occur in DNA gyrase after the binding of inhibitors; thereby, this resulted in structural and functional changes. These findings expand our knowledge on the inhibition of bacterial DNA gy- rase and could pave the way for the discovery of new drugs for the treatment of multi-resistant bacterial infections

Computer-aided drug design in anti-cancer drug discovery: What have we learnt and what is the way forward?

The escalating prevalence of cancer on a global scale, coupled with the inadequacies of present-day therapies and the emergence of drug-resistant cancer strains, has necessitated the development of additional anticancer drugs. The traditional drug discovery process is long and complex, and the high failure rate of new drugs in clinical trials further highlights the need for computational approaches in anticancer drug discovery. Computer-aided drug design (CADD), including molecular docking, molecular dynamics simulations, QSAR analysis, and machine learning, are employed to predict the efficacy of potential drug compounds and pinpoint the most auspicious compounds for subsequent testing and advancement. This article provides an overview of contemporary computational approaches employed in the design of anti-cancer drugs. It highlights a range of small molecules that have been identified as capable of impeding cancer growth and migration through various mechanisms, including cell cycle arrest/apoptosis, signal transduction inhibition, angiogenesis, epigenetics, and the hedgehog pathway. It also examines the constraints of computational techniques and presents remedies to surmount these limitations in the development and identification of efficacious anticancer compounds