Babar Murtaza

Neuropathic pain is an unpleasant condition that involves neuroinflammation and oxidative stress following injury to peripheral nerves. Recently, P2 × 7R, an ATP-gated channel, has been shown to play a role in the pathogenesis of neuropathic pain. Hence, we investigated the role of a potent and selective P2 × 7R antagonist in the amelioration of neuropathic pain in a mouse model of chronic constriction injury (CCI). Mice were randomly divided into five groups, namely: sham, CCI, CCI + P2 × 7R antagonist (2.5 mg/kg), CCI + P2 × 7R antagonist (0.5 mg/kg), and CCI + pregabalin (5 mg/kg). Behavioral assessments included the open field test for locomotor activity, von Frey filaments, and hot-plate tests for assessment of mechanical and thermal hyperalgesia, respectively. Sciatic nerve and spinal cord tissue samples were analyzed for inflammatory cytokines (TNF-α, IL-1β, IL-6, NF-κB), oxidative stress markers (catalase, GSH, GST, LPO), and histopathology. It was observed that the CCI group demonstrated significantly reduced locomotor activity along with reduced thresholds for mechanical and thermal hyperalgesia compared with control animals. This was also associated with a marked increase in the expression of the pro-inflammatory cytokines, including TNF-α, IL1β, IL-6, and NF-κB in these tissues. Interestingly, repeated treatment with P2 × 7R antagonist and pregabalin significantly reversed pain behavior, along with suppression of neuroinflammation, dose- dependently. Further, P2 × 7R antagonist treatment restored BDNF, PPAR-γ levels, antioxidant defenses, and histological degenerations in sciatic nerve and spinal cord tissues. Together, these findings demonstrate that pharmacological antagonism of P2 × 7R effectively alleviates neuropathic pain related behavior while exerting potent anti-inflammatory, antioxidative, and neuroprotective actions in the CCI model.

Implication de la signalisation Ca2 + dans la perception du goût du gras : modulation par plante triterpénoïdes et un agoniste chimique du GPR120: En dépit des efforts déployés, l'incidence de l'obésité est en augmentation dans le monde entier où la consommation d‘aliments moins coûteux et hyperénergétiquesriches en matières grasses, représente la principale cause. Des études récentes ont révélé l'existence d'un goût de gras et que l'envie de le satisfaire pourrait être responsable de l‘excès des prises alimentaires et de l'attirance pour les aliments riches en gras. Différentes stratégies ont été utilisées pour réduire la teneur engraisse des aliments ou pour la remplacer par des mimétiques et des substituts de graisse. Dans cette thèse, nous avons non seulement exploré des mécanismes de signalisation tels que le rôle des canaux TRPC3 Ca2+ dans les cellules du bourgeon gustatif, mais nous avons également tenté de rechercher de nouvelles classes de molécules artificielles et naturelles, d‘origines végétales, qui pourraient agir comme exhausteurs de goût ou comme activateurs du goût. Sur la base des résultats obtenus par des études biochimiques et comportementales au cours de la thèse actuelle, nous proposons que Zizyphine purifié à partir de Zizyphus lotus, d‘acide oléanolique et de TUG891 (un agoniste chimique de GPR120) puissent être un candidat novateur et prometteur pour le traitement et la prévention de l'obésité et du syndrome métabolique qui lui est associé.

Background: Migraine is a neurological disorder and major cause of disability globally, especially in women and young adults. This study aimed to investigate the beneficial effects of polydatin (PD), a natural compound, against nitroglycerin (NTG) induced migraine like headache in mice. Materials and methods: Behavioural paradigms included Von Frey filament test, tail flick test, light aversion test and assessment of migraine-associated pain like behaviour. In addition, biochemical investigations were undertaken to determine the effect of PD on migraine associated markers including oxidative stress, nitric oxide (NO) and calcitonin gene related peptide (CGRP). Integrated in vivo, in silico, and network pharmacology approaches were employed to evaluate PD’s antimigraine effects. Statistical significance was set at p < 0.05. Results: Treatment with PD attenuated NTG-induced migraine like headache and related behavioural changes. PD-subjected animals exhibited enhanced levels of catalase, glutathione-S-transferase, and glutathione, as well as reduced lipid peroxidation, compared to NTG-only treated animals. Reduction in CGRP and nitrite levels along with reduced expression of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) was also observed in mouse cortex and trigeminal nucleus caudalis (TNc) after treatment with PD compared with disease controls. Histological sections from PD treated animals from these regions resembled closely with those of controls with improved cell viability. Molecular docking studies suggested that PD docked in the similar binding pocket as that of CGRP, Rimegepant (a CGRP receptor blocker) and Sumatriptan. Network pharmacology revealed potential interaction of hub genes with PD, with proteins like NOS1 (nNOS), NOS2 (iNOS), NOS3, PDE5A, GATM, ARG1 and ARG2 having significant role in network functionality and the potential mediation of PD therapeutic effect. Conclusion: PD ameliorated NTG-induced migraine like headache through modulation of NO, CGRP and oxidative stress dependant mechanisms.

Sucrose provides both sweetness and energy by binding to both Venus flytrap domains (VFD) of the heterodimeric sweet taste receptor (T1R2/T1R3). In contrast, non-caloric sweeteners such as sucralose and aspartame only bind to one specific domain (VFD2) of T1R2, resulting in high-intensity sweetness. In this study, we investigate the binding mechanism of various steviol glycosides, artificial sweeteners, and a negative allosteric modulator (lactisole) at four distinct binding sites: VFD2, VFD3, transmembrane domain 2 (TMD2), and TMD3 through binding experiments and computational docking studies. Our docking results reveal multiple binding sites for the tested ligands, including the radiolabeled ligands. Our experimental evidence demonstrates that the C20 carboxy terminus of the Gα protein can bind to the intracellular region of either TMD2 or TMD3, altering GPCR affinity to the high-affinity state for steviol glycosides. These findings provide a mechanistic understanding of the structure and function of this heterodimeric sweet taste receptor.

Background: Migraine is one of the most common neurological disorders occurring globally and its treatment is currently based on synthetic drugs. Due to undesired effects associated with these agents, some of the patients might prefer natural compounds-based therapies that are cost-effective, efficacious, have more patient compliance and less adverse effects. Hence, this systematic review was conducted to evaluate the effects of natural compounds (single/combination) used for the prophylaxis or acute treatment of migraine. Method: Five electronic databases (PubMed, Scopus, Cochrane Library, Cumulated Index to Nursing and Allied Health Literature (CINAHL) library and Web of Science) were searched from 1 March 2020–31 January 2024. We included studies that evaluated the effects of natural compounds on migraine through randomized clinical trials (RCTs) that reported the duration of migraine headache, severity and frequency of attacks as primary outcomes. Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist was used to report the study while Cochrane Collaboration's Risk of Bias (ROB) 2 tool was used to assess the ROB in included studies. The review protocol was registered on PROSPERO (CRD42023454998). Results: Twelve RCTs with 889 participants were included. Seven RCTs had low ROB and two RCTs had high ROB, while three RCTs expressed “some concerns”. It was observed that natural compounds including curcumin, topical basil, cinnamon, ginger, Vitamin D3 (Vit D3), zinc (Zn), magnesium (Mg) and cobalamin significantly reduced the severity of migraine headache. In addition, the duration of migraine attacks was significantly decreased by curcumin, cinnamon, ginger, Vit D3, Mg and cobalamin. Further, curcumin, topical basil, cinnamon, Vit D3, Zn, Mg and cobalamin exhibited significant beneficial effect on migraine frequency. In contrast, nanocurcumin and jodeungsan showed no significant results. Conclusion: The current findings suggest that natural compounds including cinnamon, Vit D3, Zn, Mg and cobalamin might mitigate migraine attacks and serve as interesting alternate therapies. Nonetheless, further large scale studies are highly desired.

Sucrose provide sweetness and energy when it binds to both the Venus fly trap domains (VFD) of heterodimeric sweet taste receptor (T1R2/T1R3),1 while non-caloric sweeteners (Sucralose, Aspartame, Neotame, Saccharin, Acesulfame-K (Ace-K), Suosan, SC-45647, Fructose, and D-Tryptophan) bind only at the VFD of T1R2 (VFD2) to provide high-intensity sweetness.2 Here, we address the binding mechanism of various steviol glycosides (Rebaudioside B (RebB), RebM, RebD, Rubusoside (Rubu), RebC), artificial sweeteners (Neohesperidin dihydrochalcone (NHDC), acesulfame K, S-819, Amiloride, and Perillartine), and negative allosteric modulator (Lactisole) at four distinct binding sites, VFD2, VFD3, transmembrane domain 2 (TMD2) and TMD3 by performing binding experiments and computational docking studies. Our docking results find multiple binding sites for the tested ligands including the radio labelled ligands, which provides an explanation of the mixed data of the radio-ligand binding experiments. We predict different preferred binding sites depending on ligand modifications of steviol glycosides. Thus, Rubu binds best at VFD3, while RebB binds best at TMD3, while the others prefer VFD2. We also observed G protein-coupled receptor (GPCR) allostery using the label free Frequency Locking Optical Whispering Evanescent Resonator (FLOWER) method. We show experimentally that the C20 carboxy terminus of the Gα protein can bind to the intracellular region of either TMD2 or TMD3, which can alter GPCR affinity to the high-affinity state for steviol glycosides. These studies provide a mechanistic understanding of the structure and function of this heterodimeric sweet taste receptor that can guide rational structure-based design of novel non-caloric sweeteners aimed at enabling lower sugar usage levels while retaining the sweet taste. This may provide the basis for novel therapeutic applications for treatment of obesity and related metabolic dysfunctions such as diabetes.

Drug addiction is a devastating condition that poses a serious burden on the society. The use of some drugs like morphine for their tremendous analgesic properties is also accompanied with developing tolerance, dependence and the withdrawal symptoms. These symptoms are frequently severe enough to reinforce the person in recovery to start over the use of drug again and hinder the clinical use of drugs like morphine for chronic pain. Research into opioid receptors and related molecular pathways has seen resurgence in the wake of the growing opioid epidemic. The current study provides a comprehensive scientific exploration of the molecular mechanisms and underlying signalling in morphine tolerance and dependence. It also critically evaluates current therapeutic approaches, shedding light on their efficacy and limitations, and future prospects. Graphical Abstract The graphical abstract depicts an overview of the pathways involved in the emergence of morphine-related tolerance and dependence including NMDA, Nitric oxide, and PPAR, as well as behavioural sensitization along with present and future innovative treatment strategies including stem cell therapy that have been discussed in the current manuscript.

2-Mercaptobenzothiazole and its derivatives are widely known for their diverse biological activities, particularly antimicrobial and anticancer potential. In the present study, a series of new hybrid compounds consisting of 2-mercaptobenzothiazole and different aryl amines 2(a-j) were synthesized and characterized by Fourier transform infrared (FTIR), ¹H NMR, and ¹³C NMR spectral data. The synthesized compounds were screened for in vitro antibacterial activities through agar well diffusion assay. Among the series, 2b, 2c, and 2i exhibited significant antibacterial activity comparable to the standard drug levofloxacin. Based on their antibacterial potential, these compounds were further tested for their antibiofilm activity. All of the three compounds showed promising antibiofilm potential, even better than the standard drug cefadroxil at 100 μg/100 μL concentration. Molecular docking studies were performed to explore the antibacterial mechanism of these compounds. Strikingly, the molecule 2i shared the same hydrophobic pockets as those of levofloxacin in case of bacterial kinases and DNA gyrases. In addition, 2i exhibited satisfactory antibiofilm activity in comparison to the standard. Our study therefore suggested that the synthetic compound 2i possesses remarkable antibacterial activity and may serve as a lead molecule for the discovery of potent antibacterial agents.