Intracerebroventricular (ICV) streptozotocin (STZ) deveops Alzheimer's disease (AD)-like conditions in rodents, which are characterized by insulin resistance, tau pathology, and neurodegeneration. Hentriacontane, a natural compound found in various sources, including beeswax, possesses anti-inflammatory and antioxidant properties. In the present investigation, we performed in silico molecular docking, molecular dynamics, MMGBSA, PCA, and FEL analysis of hentriacontane and rivastigmine with acetylcholinesterase (AchE). Further, we assessed the in vivo neuroprotective effects of hentriacontane in an ICV-STZ-induced AD-like condition in rats. STZ (3 mg/kg/ICV) was injected into male Sprague-Dawley rats. Cognitive functions were evaluated by Barnes-Maze (BM), novel object recognition test (NORT), and passive avoidance test (PAT). Hentriacontane (3 and 5 mg/kg) and rivastigmine (1 mg/kg) were given intraperitoneally for 14 days. Brain-derived neurotrophic factor (BDNF), AchE, oxidative stress parameters including GSH, MDA, SOD, and CAT, and proinflammatory cytokines including IL-6, TNF-α, IL-1β, and NF-ҡB were measured via ELISA. Further, we have also estimated the BACE1 and NO levels. Histopathological evaluation was conducted using hematoxylin and eosin staining. In silico molecular docking, dynamics, and post-dynamics data revealed promising binding affinities of hentriacontane for AchE. Further, hentriacontane attenuated ICV-STZ-induced cognitive deficit in BM, NORT, and PAT. Additionally, altered oxidative stress, proinflammatory, and cell signalling parameters were restored. Histopathology revealed that the hentriacontane-treated group showed significant restoration of the small pyramidal cells in the CA1 and CA2 regions of the brain. Hentriacontane demonstrated neuroprotective effects by modulation of AchE, leading to improved cognitive functions as evidenced by in silico and in vivo investigations.

AIM:The present study aimed to evaluate the therapeutic potential of the Unani formulation Ark-e-Kasni in alleviating the symptoms of polycystic ovary syndrome (PCOS). METHODS:In the present study, letrozole and a high-fat diet (HFD) were used to induce PCOS-like symptoms in rats. After induction, different groups were treated with varying doses of Ark-e-Kasni (5, 10, and 20 mL/kg), metformin, and finasteride. At the end of treatment, blood and ovaries were collected for biochemical and histological analysis. RESULTS:A significant weight gain and prolonged diestrous phase were observed in PCOS rats, accompanied by a considerable elevation in LH (42.52 ± 0.90 mIU/mL) and testosterone (8370 ± 122.18 pg/mL), and a low level of FSH (11.86 ± 0.43 mIU/mL). Moreover, an increase in insulin (14.31 ± 0.35 mIU/mL), TNF-α (358.81 ± 9.81 pg/mL), IL-1β (143.74 ± 3.39 pg/mL), and IL-6 (154.04 ± 2.04 pg/mL), and a reduction in SOD, CAT, and GSH were noticed. While the Ark-e-Kasni restored the levels of LH (30.97 ± 1.04 mIU/mL), testosterone (5651.83 ± 182.69 pg/mL), FSH (15.66 ± 0.56 mIU/mL), insulin (5.48 ± 0.23 mIU/mL), TNF-α (212.16 ± 8.66 pg/mL), IL-1β (78.79 ± 1.46 pg/mL), and IL-6 (74.53 ± 1.60 pg/mL), and lipid markers. Histological and microscopic analysis showed reduced cystic follicles and enhanced corpus luteum formation, improving ovarian morphology. CONCLUSION:The findings suggest that Ark-e-Kasni ameliorates PCOS through diverse molecular mechanisms. Ark-e-Kasni may modulate steroidogenic enzyme activity to reduce hyperandrogenism, enhance insulin sensitivity through the PI3K/Akt pathway, and inhibit the downstream inflammatory pathway of NF-κB.

Streptozotocin (STZ) is a commonly administered chemical via the intracerebroventricular (ICV) route in rodents to induce Alzheimer’s disease (AD)-like symptoms. Unfortunately, available research articles from different laboratories suggest inconsistency in doses, administration schedules, and target brain regions. For instance, ICV dose varies from 1.5 to 5 mg/kg either unilaterally or bilaterally, for 7 days to 21 days, as a single or multiple injections. Therefore, it is challenging for novice investigators to select the optimal doses, treatment durations, and targeted molecular pathways while employing STZ to induce AD-like conditions in experimental animals. In this background, the information related to the STZ-induced animal model of AD should be available on a single platform to aid researchers in selecting the suitable doses and regimens that suit their research objectives. The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as streptozotocin, intracerebroventricular, dosage optimization, Alzheimer’s disease, neuroinflammation, and oxidative stress. The present review highlights the articles published up to May 2025, with predefined inclusion (ICV-STZ model, cognitive/biochemical outcomes) and exclusion criteria (non-peer-reviewed papers, studies lacking behavioral or molecular endpoints, and studies older than 20 years). We have attempted to present the optimal dose, administration regimen, and biological process for inducing ICV-STZ AD models based on their advantages and limitations. According to the comparative quantitative evaluation of preclinical investigations, bilateral ICV administration of STZ at a cumulative dose of 3 mg/kg (1.5 mg/kg on days 1 and 3) displays the most reliable and physiologically relevant regimen. Studies also demonstrated that between 14 and 21 days after injection, this regimen reliably causes oxidative stress, neuroinflammation, cholinergic dysfunction, and progressive cognitive impairments, offering a balanced picture of physiological, histological, and behavioral alterations. However, unlike transgenic models, the ICV-STZ paradigm generally fails to develop extensive amyloid-beta plaque deposition or well-formed neurofibrillary tangles. Hence, more quantitative investigations are necessary to validate this optimization.

Menopause is a natural biological process in women driven by estrogen deficiency and is associated with multiple post-menopausal physiological and behavioral changes. Notably, menopause increases the risk of depression. However, the precise neural mechanisms by which estrogen deficiency contributes to depressive phenotypes remain poorly understood.Estrogen deficiency is known to activate transient receptor potential melastatin 3 (TRPM3) channels and promote neuroinflammation by inducing microglial activation and upregulating pro-inflammatory cytokines. Although the paraventricular nucleus of the hypothalamus (PVN) plays a central role in integrating the physiological response to stress, the role of TRPM3 channels in this region remains unexplored. We hypothesize that estrogen deficiency during menopause activates TRPM3 channels in the PVN, promoting neuroinflammation and disrupting medial prefrontal cortex (mPFC) function, thereby contributing to depressive-like phenotypes. Using a bilateral ovariectomy rat model, we demonstrate that estrogen loss induces robust depression-like behaviors, accompanied by increased TRPM3 expression and interleukin-1β levels in the PVN, as well as reduced dendritic complexity and serotonin levels in the mPFC. In the present study, retrograde DiI tracing confirmed direct PVN-mPFC connectivity, and immunofluorescence revealed co-expression of TRPM3 and the serotonin transporter in PVN neurons, implicating TRPM3 in serotonergic regulation. Notably, intraperitoneal administration of the selective TRPM3 inhibitor, naringenin reversed behavioral deficits, attenuated neuroinflammation, restored dendritic arborization, and normalized mPFC serotonin levels. These findings indicate that TRPM3-mediated PVN neuroinflammation disrupts mPFC serotonin signaling, contributing to menopause-associated depressive phenotypes and identifying TRPM3 as a potential therapeutic target.

Neurodegenerative diseases, such as Alzheimer’s disease (AD), are marked by gradual neuronal loss, frequently associated with mitochondrial dysfunction. Hentriacontane is a naturally occurring long-chain saturated hydrocarbon found in beeswax and certain herbal plants, and has antioxidant, anti-inflammatory and cytoprotective properties, suggesting its therapeutic potential in oxidative stress-associated neurodegeneration. Rotenone, a mitochondrial complex I inhibitor, induces oxidative stress and apoptosis, making it a widely used neurotoxic agent for investigating neurodegenerative disorders like AD. We initially performed in silico molecular docking, molecular dynamics, MM/GBSA, and ADMET pharmacokinetic analyses of hentriacontane against GSK3β to evaluate binding affinities and energies and assess the stability and dynamics of protein–ligand complexes. An in vitro drug safety assay was conducted using the MTT assay in SH-SY5Y cells. The cells were pretreated with 100 μM rotenone two hours before the assay. A 96-well tissue culture-grade microplate was prepared with 100 μL of cell suspension (1 × 104 cells/mL), and test compounds were added at concentrations of 20, 40, 60, 80, and 100 μg/mL. Biochemical assays were conducted on cell supernatant to evaluate oxidative stress, proinflammatory, and apoptotic markers. Hentriacontane exhibited a significant binding affinity, with lower RMSD, RMSF, and a more negative ΔG_bind. ADMET analyses indicated favorable pharmacokinetic features. In vitro studies demonstrated that hentriacontane significantly enhanced cell viability, reduced oxidative stress markers, suppressed apoptotic and pro-inflammatory markers, and GSK3β protein levels. The collaborative significance of in silico and in vitro investigations suggests that hentriacontane may serve as a promising therapeutic candidate for mitigating oxidative stress-induced neurotoxicity via modulation of the GSK3β pathway.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by motor impairment, but early-stages are dominated by non-motor symptoms such as olfactory dysfunction, anxiety, depression, and cognitive deficits, which are poorly replicated by currently studied animal models. In animal models of PD, stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the substantia nigra induces dopaminergic neurodegeneration, which consequently produces motor deficits; but inadequately representing early non-motor features. Emerging evidence suggests that transient receptor potential melastatin 3 (TRPM3)-associated neuroinflammation may contribute to early PD progression and non-motor symptoms. However, its role in early-stage PD, particularly in non-invasive models, remains unclear. Therefore, this study aimed to develop a novel non-invasive early-stage PD model and investigate TRPM3-associated neuroinflammation. Early-stage PD-like symptoms were induced in rats by intranasal 6-OHDA (5 mg/nostril) for 7 consecutive days and evaluated using the buried food, odor identification, open field, and elevated plus maze tests. Tyrosine hydroxylase (TH) immunoreactivity was quantified in the olfactory bulb, ventral striatum, and posterior ventral tegmental area (pVTA). TRPM3 immunoreactivity, neuroplastic changes in the pVTA and interleukin-1β (IL-1β) in the ventral striatum and pVTA were also assessed. 6-OHDA produced behavioral deficits, reduced TH immunoreactivity, increased TRPM3, elevated IL-1β, and impaired pVTA neuroplasticity. Intraperitoneal (i.p.) treatment of TRPM3 inhibitor primidone (2.5, 5, and 10 mg/kg) significantly reversed these alterations, and standard pramipexole (3 mg/kg, i.p.) also reduced behavioral deficits. Overall, the intranasal 6-OHDA model reproduces key features of early-stage PD, including non-motor deficits, dopaminergic dysfunction, TRPM3-associated neuroinflammation, and impaired neuroplasticity, providing a simple and clinically relevant platform for therapeutic evaluation.

INTRODUCTION:Neuropathic pain (NP), a chronic and debilitating condition resulting from nerve injury, remains a significant clinical challenge due to limited effective therapies. Ethyl gallate (EG), a natural ester of gallic acid, possesses potent antioxidant and antiinflammatory properties; however, its role in NP management has not been previously explored. METHODS:This study investigated the neuroprotective potential of EG in a chronic constriction injury (CCI)-induced NP model in rats. EG was administered intraperitoneally at doses of 10, 15, and 20 mg/kg/day for 14 days. Behavioral assessments, including thermal hyperalgesia, mechanical allodynia, and motor nerve conduction velocity (MNCV), were performed. Biochemical evaluations, such as oxidative stress markers (SOD, GSH, catalase, MDA) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) were conducted. Histopathological analysis of the sciatic nerve was performed to assess structural integrity. Additionally, molecular docking was employed to evaluate the binding interactions of EG with key redox and inflammatory regulators, Nrf2 and NF-κB, in comparison with the standard drug gabapentin (GBP). RESULTS:EG significantly alleviated CCI-induced pain behaviors, demonstrated by increased paw withdrawal latency, enhanced mechanical threshold, and improved MNCV. EG treatment restored antioxidant enzyme activities and reduced MDA levels, indicating decreased oxidative stress. Additionally, EG markedly lowered pro-inflammatory cytokine levels. Histological findings revealed preserved nerve fiber integrity and reduced structural damage in EG-treated groups. Molecular docking revealed stronger binding affinity of EG (-6.8 kcal/mol with Nrf2; -5.1 kcal/mol with NF-κB) compared to GBP (-5.9 kcal/mol and -4.3 kcal/mol, respectively), supporting its potential mechanistic role in modulating oxidative stress and inflammatory pathways. DISCUSSION:These results suggest that EG mitigates NP symptoms by modulating oxidative stress and inflammation. Its ability to enhance endogenous antioxidant defenses and suppress pro-inflammatory responses underlies its neuroprotective action. CONCLUSION:EG demonstrates promising therapeutic potential in the management of NP through its antioxidant, anti-inflammatory, and neuroprotective properties. Further molecular studies are warranted to elucidate its underlying mechanisms.

Introduction: DENV NS2B-NS3 protease inhibitors were designed based upon the reference molecule, 4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl) benzenesulfonamide, reported by our team with the aim to optimize lead compound via rational approach. Top five best scoring molecules with zinc ids ZINC23504872, ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613 bearing ‘pyrimidin-4(3H)-one’ basic scaffold have been identified as a promising candidate against DENV protease enzyme. Methods: The shape and electrostatic complementary between identified HITs and reference molecules were found to be Tanimotoshape 0.453, 0.690, 0.680, 0.685 & 0.672 respectively and Tanimotoelectrostatic 0.211, 0.211, 0.441, 0.442, 0.442 and 0.442 respectively. The molecular docking studies suggested that the identified HITs displayed the good interactions with active site residues and lower binding energies. The stability of docked complexes was assessed by MD simulations studies. The RMSD values of protein backbone (1.6779, 3.1563, 3.3634, 3.3893 & 3.0960 Å) and protein backbone RMSF values (1.0126, 1.0834, 1.0890, 0.9974 & 1.0080 Å respectively) for all top five HITs were stable and molecules did not fluctuate from the active pocket during entire 100ns MD run. Results: The druggability Dscore below 1 indicate the tightly binding of ligand at the active site. Dscore for ZINC23504872 was found to be 1.084 while for the second class of compounds ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613, 0.503, 0.484, 0.487 and 0.501 Dscores were observed. In-silico ADMET calculations suggested that all five HITs were possessed the drug likeliness properties and did not violate the Lipinski’s rule of five. Conclusion: Summing up, these in-silico generated data suggested that the identified molecules bearing pyrimidin-4(3H)-one would be promising scaffold for DENV protease inhibitors. However, experimental results are needed to prove the obtained results.

Currently, Diabetic Nephropathy (DN) stands as the predominant global cause of endstage renal disease. Many scientists believe that diabetes will eventually spread to pandemic levels due to the rising prevalence of the disease. While the primary factor leading to diabetic nephropathy is vascular dysfunction induced by hyperglycemia, several other pathological elements, such as fibrosis, inflammation, and oxidative stress, also contribute to the progression of the disease. The primary targets of current DN therapy approaches are the underlying abnormalities of hypertension and glucose. With several targets and fewer side effects, curcumin is a commonly utilized antioxidant in DN. The present study emphasizes the critical role of oxidative stress and inflammation in the development of diabetic nephropathy. It reveals how these factors induce damage in key kidney cell types, highlighting their potential as therapeutic targets for this disease. In addition, by concentrating on Nrf2, SIRT1, HMGB1, NF-κB, and NLRP3 of curcumin, has strong anti- inflammatory and antioxidant characteristics. This review describes the role of curcumin in the therapeutic application of diabetic nephropathy. In this attempt, we tried to elaborate on the bench-to-bedside aspects of curcumin in DN, including clinical and preclinical investigations. The rationales of curcumin's mechanisms in alleviating symptoms of the DN were discussed. Curcumin could serve as the potential therapeutic agent for the patient seeking to recover from DN.

Elevated peripheral inflammatory markers are associated with the development of several neurological disorders. Curcumin, a strong natural anti-inflammatory agent, has recently been identified as a potent agonist of the CB2 cannabinoid receptor. Since the function of CB2 receptors in neuropsychiatric illnesses is gaining increasing attention, the present study aimed to elucidate their involvement in the effects of curcumin on depressive phenotypes. The mice were inoculated with BCG and allowed 7 days to induce depression-like behavior. The animals were then administered curcumin alone or concomitantly with CB2 receptor agonist JWH133 or antagonist AM630, daily for 7 days, and subjected to the sucrose preference test, open field test, tail suspension test, and splash test. Further, the blood samples were analyzed for the TNF-α and IL-6 contents, and the brains were processed to estimate NF-κB and serotonin levels using the ELISA and HPLC techniques. The results showed a significant reversal of depressive episodes by curcumin in BCG-inoculated mice. The elevated plasma levels of TNF-α and IL-6 in depressed animals were associated with higher NF-κB and lower serotonin contents in the brain. The concentrations of these biochemical parameters were restored by curcumin treatment. Moreover, pre-treatment with JWH133 potentiated the effects of curcumin on behavioral and biochemical parameters, whereas AM630 attenuated the same. We suggest that curcumin, through its interaction with the CB2 receptor, may inhibit BCG-evoked activation of peripheral TNF-α and IL-6, which could prevent the stimulation of NF-κB in the brain, potentially leading to increased serotonin contents and alleviation of depressive phenotypes.

Increased nitric oxide activity in the medial prefrontal cortex (mPFC) and striatum plays a key role in the pathogenesis of obsessive-compulsive disorder (OCD) by lowering serotonin contents and triggering neurodegeneration. Since molecular docking analysis revealed plumbagin as a potent inhibitor of neuronal nitric oxide synthase (nNOS) enzyme, this study aims to investigate the ameliorative potential of plumbagin on mild traumatic brain injury (mTBI)-induced OCD-like behavior in mice. Following mTBI, the mice were administered with plumbagin (1 mg/kg, intraperitoneal) for 6 days. Animals were subjected to rotarod, open field and beam walk tests for studying neuromuscular functions, and marble-burying test for evaluating OCD phenotypes. Subsequently, the brains were processed for Golgi-Cox and crystal violet stainings to examine dendritic arborization and cell viability in the mPFC and striatum. Moreover, the contents of serotonin and nitric oxide in these regions were quantified using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA), respectively. Plumbagin improved neuromuscular functions and reduced marble-burying behavior. Also, dendritic arborization, cell viability, and serotonin levels in the mPFC and striatum were improved. However, concentrations of nitric oxide were significantly decreased in these brain regions. The data of this study suggest that plumbagin by inhibiting nNOS might reverse the mTBI-associated degenerative neuronal changes in the mPFC and striatum. Furthermore, neuronal survival might promote cortico-striatal serotonergic neurotransmission to mitigate OCD-like behavior. Thus, plumbagin seems to be a promising therapeutic candidate for the management of OCD associated with traumatic brain injuries.

INTRODUCTION:Achieving reliable anesthesia induction and rapid postoperative recovery are crucial aspects of animal research, particularly in small experimental animals. Thiopentone is still a widely used anesthetic drug, but its safety is a primary concern in delivering a safe dose to experimental animals. However, the use of thiopentone in combination with xylazine for surgical procedures in small experimental animals remains underexplored. Therefore, this study assesses the efficacy and safety of combining thiopentone and xylazine for inducing anesthesia and facilitating recovery in Sprague-Dawley rats (n = 6). METHODS:Several sedatives and anesthetic agents, with diazepam (A), thiopentone (B), and xylazine (C), were evaluated alone and in combinations (AB, AC, BC, ABC). Rectal temperature, pulse rate, onset of anesthesia, and sedation duration were recorded before and after the administration. RESULTS:Thiopentone (45 mg/kg) alone caused significant declines in vital parameters and mortality. However, the BC combination (thiopentone 35 mg/kg + xylazine 7 mg/kg) induced rapid and prolonged anesthesia without mortality, mitigating thiopentone-induced hypothermia, bradycardia, and respiratory depression. This combination was further validated in 24 rats undergoing stereotaxic surgery, demonstrating its effectiveness and safety. DISCUSSION:The results demonstrated that while thiopentone monotherapy led to significant adverse effects, including hypothermia, decreased pulse rate, and respiratory depression, the combination of thiopentone with xylazine, particularly at specific doses, showed promising outcomes in mitigating these side effects. CONCLUSION:The data obtained from the present study suggest that a combination of thiopentone (35 mg/kg) with xylazine (7 mg/kg) may represent the optimal surgical dose for inducing surgical anesthesia in rats.

INTRODUCTION:Doxorubicin (DOX), a widely used chemotherapeutic agent, is effective against various malignancies, but its clinical application is limited by cumulative dose-dependent cardiotoxicity. The objective of this review is to systematically explore the molecular mechanisms involved in DOX-induced cardiotoxicity (DIC) and evaluate the cardioprotective potential of plant-derived bioactive compounds. METHODS:A comprehensive literature search was conducted using databases, such as PubMed, Scopus, and Web of Science, focusing on studies published in the last two decades. Emphasis was placed on experimental and preclinical models that investigated molecular pathways of DIC and the therapeutic role of phytochemicals. RESULTS:DOX-induced cardiotoxicity is mediated through a cascade of molecular events, including excessive oxidative and nitrosative stress, mitochondrial damage, apoptosis, impaired autophagy, and altered activity of signaling pathways, such as AMPK, Nrf2, TGF-β1/Smad2, and HIF-1α. Epigenetic dysregulation also contributes to myocardial injury. Phytochemicals, such as flavonoids, polyphenols, and alkaloids, have shown significant cardioprotective effects. These compounds exert their actions by modulating redox homeostasis, preserving mitochondrial function, regulating apoptotic markers, and restoring signaling imbalances. DISCUSSION:The pleiotropic nature of phytocompounds enables them to target multiple pathological mechanisms associated with DIC. Despite promising in vitro and in vivo evidence, limitations, such as poor bioavailability, lack of standardized dosing, and inadequate clinical data, hinder their translational potential. Novel delivery systems and well-controlled clinical trials are necessary to overcome these challenges. CONCLUSION:Plant-derived bioactive compounds show potential in mitigating doxorubicin-induced cardiotoxicity, as supported by preclinical evidence. However, further translational studies are warranted to validate these findings, optimize pharmacokinetics, and evaluate their feasibility in clinical oncology settings.

Rheumatoid arthritis (RA) is an inflammatory immune-triggered disease that causes synovitis, cartilage degradation, and joint injury. In nanotechnology, conventional liposomes were extensively investigated for RA. However, they frequently undergo rapid clearance, reducing circulation time and therapeutic efficacy. Additionally, their stability in the bloodstream is often compromised, resulting in premature drug release. The current review explores the potential of targeted liposomal-based nanosystems in the treatment of RA. It highlights the pathophysiology of RA, explores selective targeting sites, and elucidates diverse mechanisms of novel liposomal types and their applications. Furthermore, the targeting strategies of pH-sensitive, flexible, surface-modified, PEGylated, acoustic, ROS-mediated, and biofunctionalized liposomes are addressed. Targeted nanoliposomes showed potential in precisely delivering drugs to CD44, SR-A, FR-β, FLS, and toll-like receptors through the high affinity of ligands. In vitro studies interpreted stable release profiles and improved stability. Ex vivo studies on skin demonstrated that ultradeformable and glycerol-conjugated liposomes enhanced drug penetrability. In vivo experiments for liposomal types in the arthritis rat model depicted remarkable efficacy in reducing joint swelling, pro-inflammatory cytokines, and synovial hyperplasia. In conclusion, these targeted liposomes represented a significant leap forward in drug delivery, offering effective therapeutic options for RA. In the future, integrating these advanced liposomes with artificial intelligence, immunotherapy, and precision medicine holds great promise.

Emerging research implicates systemic inflammation in the disruption of neuroimmune signaling, contributing to the pathogenesis of major depressive disorder. While ATP-citrate lyase (ACLY) is a key lipogenic enzyme that amplifies immune cell-mediated inflammatory responses, bempedoic acid (BA), a recently approved ACLY inhibitor for hypercholesterolemia, has demonstrated significant anti-inflammatory properties. Therefore, we investigated the antidepressant potential of BA in a mouse model of BCG-induced depression, focusing on its interaction with peripheral tumor necrosis factor-alpha (TNF-α) and the downstream modulation of brain NF-κB signaling and serotonin levels. Male Swiss Albino mice were inoculated with BCG to induce systemic inflammation-associated depressive phenotypes. BA was administered alone or with TNF-α inhibitor etanercept. Behavioral assessments included sucrose preference test (SPT), tail suspension test (TST), and locomotor activity (LMA). Levels of TNF-α in the serum, and NF-κB and serotonin contents in the brain were estimated using ELISA and HPLC techniques. BCG administration significantly reduced sucrose preference in SPT and increased immobility in TST, correlating with elevated TNF-α and NF-κB, and reduced serotonin contents. BA treatment significantly reversed these behavioral and biochemical abnormalities, and its combination with etanercept produced synergistic effects, without affecting the LMA. This study provides the first evidence of the antidepressant effect of BA, demonstrating that suppression of peripheral TNF-α by BA leads to downregulation of central NF-κB and restoration of serotonin levels. Further investigations in diverse animal models are warranted to confirm the broad-spectrum efficacy of BA, along with the evaluation of its translational potential for treating depression.

Ethanol intake activates the posterior ventral tegmental area (pVTA), enhancing dopamine synthesis in the nucleus accumbens shell (AcbSh) and contributing to Alcohol Use Disorder (AUD). Chronic adolescent ethanol exposure promotes neuroinflammation and disrupts reward pathways, increasing susceptibility to addiction. Although transient receptor potential melastatin 3 (TRPM3) activation promotes inflammation and contributes to psychiatric disorders, its role in reward mechanisms remains unclear. Current AUD treatments reduce cravings and promote alcohol aversion but are often limited by adverse effects, highlighting the need for safer, natural alternatives. Naringenin, a citrus flavonoid, exhibits anti-inflammatory and neuroprotective properties. This study investigates the involvement of TRPM3 in reward processing and whether naringenin modulates its activity to reduce ethanol-induced neuroinflammation and craving. The effect of intraperitoneal (i.p.) naringenin (50 mg/kg) was tested by administering it daily prior to ethanol (2 g/kg, 20% w/v, i.p.) in adolescent male Sprague-Dawley rats for 2 weeks. Reward behavior was assessed using the conditioned place preference and open field tests. The pVTA was examined for TRPM3 expression, biochemical and synaptic changes, while dopamine levels in the AcbSh. Ethanol increases preference scores (0.46±0.01), locomotion (84.4±2.13), TRPM3 expression (48.77±2.58%) and co-expression with tyrosine hydroxylase (27.70±1.29%), TNF-α (298.29±10.48 pg/mg protein) and IL-6 (198.29±9.31 pg/mg protein), dendritic length in the pVTA (887.31±21.07 µm), and dopamine contents in the AcbSh (387,126.1±10,390.04 AUC). Naringenin reversed these effects, suggesting its potential anti-addictive properties and supporting TRPM3 as a promising therapeutic target for AUD.

INTRODUCTION:Although Doxorubicin (DOX) is an effective anticancer agent, its cardiotoxicity limits clinical use. DOX-induced oxidative stress augments NF-κB expression, elevates inflammatory cytokines, and causes myocardial injury. Since the flavonoid Myricetin (MYR) has antioxidant, anti-inflammatory, and NF-κB-inhibitory properties, we investigated its potential to mitigate DOX-induced cardiotoxicity in rats. METHOD:Molecular docking of MYR was performed against NF-κB and proinflammatory cytokines (TNF-α, IL-1β, IL-6). After confirming binding affinities, DOX was administered to rats on days 1, 3, 5, 7, and 9, while MYR was given daily for 9 days. On day 10, hemodynamic parameters were recorded, and blood and heart tissues were collected. Serum transaminases (SGPT, SGOT) and cardiac markers (CK-MB, LDH) were measured. Oxidative stress markers (CAT, SOD, GSH, MDA), proinflammatory cytokines (TNF-α, IL-1β, IL-6), NO, NF-κB levels, and myocardial histopathology were assessed. RESULTS:MYR exhibited strong binding affinity to target proteins. In vivo, MYR significantly attenuated DOX-induced ECG (ST height) alterations and reduced serum SGPT, SGOT, CK-MB, and LDH levels. In cardiac tissue, MYR enhanced CAT, SOD, and GSH, while reducing MDA. MYR also decreased NF-κB, NO, TNF-α, IL-1β, and IL-6 levels, and improved histopathological features. DISCUSSION:These findings suggest that MYR effectively counteracts DOX-induced myocardial injury by suppressing NF-κB-mediated inflammatory pathways and oxidative stress, supporting its therapeutic potential in cardioprotection. CONCLUSION:MYR mitigates DOX-induced cardiotoxicity through antioxidant and antiinflammatory mechanisms involving inhibition of NF-κB signaling.

Polycystic ovary syndrome (PCOS) is a common health problem that can affect the reproductive health of women. A typical characteristic of PCOS is infertility, androgen excess, and anovulation. In addition, a disorder also accompanies other pathologies like obesity and hyperinsulinemia, with an increased threat of cardiovascular complications. Current treatment strategies focus on the reduction of PCOS symptoms primarily through pharmacological medications such as metformin, oral contraceptives, and anti-androgenic agents. Since these medications do not encompass all the outcomes of PCOS, there is a critical need for research to identify more effective treatments. Given the rising global prevalence of PCOS and its association with cardiovascular and metabolic risks, there is an urgent need for better therapeutic options with minimal adverse effects. This review integrates the current pharmacotherapies and emerging molecular and cellular targets, offering novel directions for comprehensive PCOS management. Additionally, this review explores various novel targets such as neuropeptides, inflammasome, anti-inflammatory agents, gene therapy/microRNA (miRNA) based therapies, adipokines-based therapies and stem cells-based therapy. Furthermore, we highlight key areas requiring further research to improve PCOS management.

Preclinical models are essential for understanding the pathophysiology of intermittent explosive disorder (IED) in rodents. However, current models fail to fully uncover the molecular mechanisms behind restraint stress-induced aggression. We introduced a restrainer combined with a biting rod to measure IED-associated symptoms in stressed rats. Activation of 5-HT3 receptors promotes aggression by increasing pro-inflammatory cytokines and nuclear factor kappa B (NF-κB) activity in the brain. NF-κB, in turn, upregulates indoleamine 2,3-dioxygenase 1 (Ido1), which converts tryptophan (a serotonin precursor) into kynurenine, depleting serotonin levels in the amygdala. We examined the roles of 5-HT3 receptors and Ido1 in driving aggression in restrained-stressed rats. Aggressive behavior of rats was assessed in a restrainer with a biting assembly after ondansetron (5-HT3 antagonist) and minocycline (kynurenine pathway inhibitor) treatments. Pro-inflammatory cytokines and NF-κB levels in the amygdala were measured using ELISA and immunohistochemistry. HPLC quantified kynurenine and tryptophan, while Golgi-Cox staining analyzed dendritic spines. Restraint stress induced extensive biting (aggression), elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and increased NF-κB expression in the amygdala. Elevated kynurenine and decreased tryptophan levels and dendritic spine density were also noticed. Blocking 5-HT3 receptors and inhibiting kynurenine pathway reduced cytokines, kynurenine, and restored tryptophan and spine density. Compared to existing methods, our model offers a more accurate assessment of restraint stress-induced aggression, incorporating molecular pathways and behavioral measures, enhancing understanding of IED. Moreover, stress-induced 5-HT3 signaling may activate NF-κB and kynurenine pathways in the amygdala, potentially contributing to the development of aggressive behavior in rodents.

INTRODUCTION:Drug targeting and drug discovery methodologies are advancing rapidly due to recent developments in molecular docking techniques. Molecular docking forecasts the interactions between a small molecule, such as a potential medicine, and a target protein or receptor. OBJECTIVES:This comprehensive review focuses on significant advances in molecular docking algorithms such as Vina, Glide, and AutoDock, including their enhanced accuracy and efficiency in predicting drug-target interactions. It also examines how novel features, such as fragment-based docking, covalent docking, and virtual screening, have expanded the significance of docking in modern pharmaceutical research. METHODS:The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as Molecular Docking, Lead-Optimization, Protein Flexibility, Fragment-Based Docking, Covalent Docking, and Virtual Screening. RESULTS:This present state-of-the-art review highlights recent advances in various docking methodologies and their significant applications in drug discovery, while also discussing the scoring functions of some well-established studies. Furthermore, by predicting the interactions between putative medications and protein residues involved in the creation of covalent bonds, covalent docking provides new opportunities for targeting difficult drug-resistant mutations. The efficiency and precision of these simulations have been increased by improved sampling techniques and sophisticated algorithms, enabling the investigation of conformational changes and protein flexibility throughout the drug-binding process. CONCLUSION:These approaches may hasten the course of emerging new remedies, increase the precision of hit-finding, and make it easier to find cutting-edge treatments for a variety of diseases. Molecular docking alone is insufficient to ensure the safety and efficacy of a pharmacological agent for commercialization. While it predicts binding affinity and interaction, it does not account for pharmacokinetics, toxicity, off-target effects, or in vivo behavior. Therefore, experimental validation through MD simulation, ADMET, in vitro, in vivo, and clinical studies is essential.