Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine–metabolic disorder in which reproductive dysfunction coexists with insulin resistance, chronic low-grade inflammation, and heightened oxidative stress (OS). Increasing evidence indicates that these abnormalities are not independent phenomena but components of a self-perpetuating redox-endocrine network that sustains hyperandrogenism, anovulation, and metabolic impairment. This review critically synthesizes experimental, translational, and clinical data to examine whether vitamin D, myo-inositol, and melatonin, three widely used but often studied in isolation bioactives, can act synergistically as a mechanistically coherent ‘bioactive cocktail’ in PCOS. Vitamin D modulates inflammatory tone and steroidogenic signaling through vitamin D receptor-dependent transcription and immune–metabolic crosstalk; myo-inositol restores insulin signaling via inositolphosphoglycan second-messenger pathways, thereby attenuating hyperinsulinemia-driven androgen excess; and melatonin exerts pleiotropic effects on mitochondrial function, circadian regulation, and redox balance. Therefore, these agents converge on shared molecular hubs, including NF-κB, Nrf2, PI3K/Akt, and AMPK, linking OS reduction with endocrine and metabolic recalibration. The review further integrates emerging insights into gut microbiota-adipokineinteractions, highlighting how dysbiosis and altered adipokine profiles amplify oxidative and hormonal disturbances, and how these bioactives may counteract such system-level disruptions. While existing clinical trials report improvements in ovulatory function, insulin resistance indices, and OS biomarkers, outcomes remain heterogeneous due to differences in dosing, duration, and phenotype stratification. We propose a redox-guided, phenotype-aware framework for future trials, emphasizing biomarker-anchored outcomes and systems-level integration. If validated, combined vitamin D, myo-inositol, and melatonin supplementation may represent a precision nutraceutical strategy that targets the pathogenic core of PCOS rather than its isolated clinical manifestations.

Long-term recurrent exposure to petroleum fumes poses a substantial occupational risk, specifically among individuals in gasoline stations. They are routinely exposed to the inherent toxic constituents of petrol and diesel, such as hydrocarbons, VOCs, and trace elements, during their routine activities, including fuel dispensing, handling, storage, transport, and refining processes. Due to inadequate safety measures allow these toxicants into the lungs, cross the pulmonary barrier, enter the circulation and subsequently reach the brain through disrupting the lung-brain axis (LBA). The present study aims to investigate the sub-chronic effects of petrol and diesel fumes on respiratory and neurocognitive functions, along with therapeutic efficacy of saffron-derived bioactive constituent, crocin (10 mg/kg, i.p.), as a potential neuroprotective agent. The pulmonary dysfunctions were estimated by cytokine analysis in the broncho-alveolar lavage fluid (BALF), antioxidant activity, Evans blue dye (EBD) extravasation for microvascular airway leakage and histology analysis. Neurocognitive impairments were elucidated by behavioural paradigm, along with determination of acetylcholinesterase activity (AChE), antioxidant levels, protein biomarkers and EBD vascular permeability assay for blood-brain-barrier (BBB) permeability, neuronal count and histopathological examination. Intraperitoneal administration of crocin was found to attenuate anxiety-like behaviour and improve associative memory following intoxication with petroleum fumes. These effects are accompanied by enhanced antioxidant defence (SOD, GSH, CAT) and reduced lipid peroxidation in both lungs and brain tissues. Additionally, crocin downregulates the expression of amyloid precursor protein (APP) (p < 0.05) in DE animals, thereby preserving capillary barrier integrity and BBB permeability. Histopathology results confirmed that crocin can prevent alveolar damage and inflammatory cell infiltration, while improve neuronal integrity and increasing neuronal density in the hippocampus. These findings indicate partial protection of the pulmonary and neurological systems with crocin. However, no significant effects were observed on the spatial memory, cytokine levels and APP expression at the tested dose. Therefore, future studies are warranted to optimise the dosing regimen of crocin for preventing petroleum product-induced pulmonary and neurological complications.

Complex progressive neurodegenerative Alzheimer’s disease is characterized by cognitive decline, memory impairment, and accumulation of amyloid and tau pathologies, along with aggravation of neuroinflammatory and oxidative stress pathways. In our previous studies, the potential of azilsartan, a widely used angiotensin receptor blocker (ARB), was demonstrated to possess neuroprotective action when administered through intranasal route, improving memory and cognition through modulation of central renin-angiotensin signalling in a demented animal model. With the intranasal administration, azilsartan nanoemulgel offers the ability to bypass the BBB due to the use of the olfactory and trigeminal neural pathways, achieving direct brain targeting of the therapeutics. In the present study, the neuroprotective effect of azilsartan (5 mg/kg via intranasal route consequently for 45 days) was further validated in an AlCl3-induced murine model of Alzheimer’s dementia through investigation of mechanistic pathways. The results demonstrated that intranasal delivery of azilsartan significantly ameliorated cognitive decline when compared to standard drug donepezil, as evidenced from the behavioural tests, restored hippocampal oxidative balance (SOD, GSH, CAT), reduced lipid peroxidation (2.6-fold reduction in MDA levels compared to the AlCl3-intoxicated group), and increased neuronal count. The biomarker study revealed suppression of inflammatory markers, reduction of Alzheimer’s specific pathological markers, and significant restoration of neurotrophic pathways. To validate these findings, in silico molecular docking and dynamics simulations were conducted on the key markers TNFα, IL1β, PPARγ, BDNF, APP, and p-Tau, which showed strong and stable binding interactions with BDNF and PPARγ and moderate but persistent stabilization with APP and p-Tau, aligning with in vivo experimental outcomes. Therefore, the integrated computational and experimental evidence thus demonstrates that azilsartan exhibits neuroprotection, highlighting its potential as a therapeutic candidate for repurposing in Alzheimer’s disease.

Type-II diabetes mellitus and insulin resistance emerged as a significant health challenge, contributing to progressive neuronal loss and memory decline. The present study focuses on developing and optimizing oleanolic acid (OA) loaded chitosan-coated nanoemulsion (CN-NE) for targeted intranasal delivery to overcome poor bioavailability and BBB permeability issues of the phytoconstituent. The optimized formulation demonstrated superior attributes for intranasal administration, exhibiting an optimum pH, droplet size, polydispersity index, surface charge, and optimal viscosity at physiological temperatures. Additionally, the formulation achieved a high cumulative release of the entrapped drug within 8 h, along with the maximum cumulative permeation as assessed through goat nasal mucosa, indicating the greater efficacy to permeate through the nasal mucosal cells. The safety of the formulation was ensured by biocompatibility through in vitro HaCaT cell lines and ex vivo histopathological evaluation. In vivo behavioural assessments exhibited increased cognitive capabilities. At the same time, biochemical evaluations revealed higher antioxidant enzyme activities (SOD, GSH, CAT), lower malondialdehyde levels, reduced acetylcholinesterase levels, and a substantial increase in neuronal count in brain histopathological examinations. These data imply that intranasal OA-loaded CN-NE could be a safe and effective tool for alleviating insulin resistance-induced cognitive impairment and related neurodegenerations. Collectively, these findings highlight that this system may be a potential candidate for clinical translation as a targeted therapeutic approach for metabolic and neurodegenerative disorders.

Microplastics (MPs) are emerging environmental contaminants increasingly implicated in intestinal dysfunction and neuroinflammatory alterations through gut-brain axis (GBA) dysregulation. However, the mechanistic involvement of polyethylene (PE) and polypropylene (PP) MPs in GBA-associated neurotoxicity remains insufficiently understood. Therefore, the present study aimed to evaluate the impact of PE- and PP-MPs on intestinal barrier integrity, oxidative stress, neuroinflammation, and synaptic dysfunction. Following physicochemical characterization, experimental animals were orally exposed to PE- and PP-MPs (10 and 100 mg/kg BW) for 45 consecutive days. MP exposure significantly disrupted intestinal barrier integrity, reduced zonula occludens-1 expression, and altered short-chain fatty acid profiles, indicating impaired gut microbial metabolic activity. Concurrently, oxidative stress and inflammatory responses were evidenced by reduced antioxidant defence, increased lipid peroxidation, elevated inflammatory mediators, and altered neurochemical markers in small intestine and brain tissues. Behavioral abnormalities, increased amyloid precursor protein (APP) expression, tau-associated pathological alterations, and histopathological changes further indicated GBA impairment following MP exposure. Notably, PE-MPs produced comparatively greater toxicological effects than PP-MPs, particularly at higher dose. Overall, the findings demonstrate that chronic exposure to environmentally relevant PE- and PP-MPs disrupts intestinal homeostasis and promotes neuroinflammatory toxicity through GBA dysregulation.

Being established as an important natural component for wound healing, acacia honey (AH) in combination with ascorbic acid (AA) was evaluated for its tissue regenerative properties to establish a synergistic effect. A thermosensitive hydrogel formulation was developed and characterized for viscosity, mucoadhesion, moisture retention, pH, and morphology, where the parameters were found to be favourable for topical application and longer retention. The porosity and swelling of the hydrogel matrix allow for prolonged and sustained release of AH and AA. The release patterns of AH and AA from the gel matrix followed the Korsmeyer-Peppas and Michaelis-Menten patterns, respectively, indicating sustained release. The optimized formulation revealed antimicrobial properties, as evidenced by the significant increase (p < 0.05) in the diameter of the zone of inhibition. Scratch wound assay using HaCaT cell line showed wound healing potential of 90.6±4.5% for the co-loaded formulation. Furthermore, the wound healing potential of the co-loaded hydrogel in the excision wound model in experimental rats could be linked to increased vascularization due to the daily application of the formulation at the wound site. The antioxidant capacity was demonstrated by decreased IC50 values of 53.75±5.9 and 72.71±6.63 µg/mL against ABTS and DPPH, respectively, which additionally supported the wound healing potential. Lastly, the synergistic role of AH and AA facilitates fibroblast proliferation, collagen production, and glycosaminoglycan deposition, which could be correlated with a significant increase in hexosamine and hexuronic acid to 153.3±9.49 and 48.91±6.84 µg/40 mg of wound tissue, respectively. Overall, the co-loaded hydrogel could be an effective alternative for the treatment of acute dermal injuries.

Dementia, a progressive neurodegenerative disorder, is a primary cause of disability and dependence in the elderly. It has become prevalent worldwide, affecting more than 55 million people. This increasing epidemiological and mechanistic evidence indicates that neuroinflammation, mitochondrial dysfunction, oxidative stress, and neurotransmitter levels are solely related to the disease pathophysiology. Essential micronutrients, such as lipid and water-soluble vitamins, have been identified as potential neuroprotective substances due to their multiple important biochemical roles in maintaining the integrity and functioning of neurons. These oil and water-soluble vitamins (Vitamin A-K) support several important activities of the central nervous system, including the synthesis of neurotransmitters, antioxidant activity, neuroprotective role, and regulation of inflammation, lipid metabolism, and gene expression, all of which are essential in maintaining brain function and neural plasticity. Therefore, the purpose of this review is to critically evaluate the molecular mechanisms by which these vitamins provide neuroprotection as evident in the literature, in both preclinical models and clinical studies. Additionally, this review examines whether these potential vitamins have an adjunctive role in delaying or preventing neurodegenerative disease. Conclusively, optimizing vitamin levels in the body may present a promising, multifaceted role for the management of dementia and related CNS disorders.

The pervasive distribution of micro- and nanoplastics (M/NPs) across ecosystems necessitates a mechanistic investigation into their toxicological consequences. Chronic exposure to M/NPs through combined intestinal uptake and branchial contact in aquatic animals disrupts epithelial barrier integrity, alters gastric secretions and luminal pH, and induces microbial dysbiosis, evidenced by the depletion of commensal taxa and expansion of pathogenic strains. These local perturbations trigger systemic sequelae, including neurotoxicity and cardiotoxicity. Consequences on cross-species analyses demonstrate translational concordance, as human studies similarly link M/NP bioaccumulation with inflammatory bowel disease, cognitive decline, and cardiovascular dysfunction. Integrative multi-omics approaches, encompassing transcriptomic, metabolomic, and microbiome analyses, have begun to elucidate the molecular cascades underpinning M/NP toxicity, providing high-resolution insights into host-microbe-environment interactions. Notwithstanding these advances, critical gaps remain in chronic exposure modelling, capturing particle heterogeneity, and ensuring ecological realism. In this context, zebrafish (Danio rerio) provide a uniquely tractable system for gnotobiotic rearing, microbial transplantation, and live imaging, thereby enabling causal inference and functional validation in real-time. Collectively, this review establishes zebrafish as a pivotal model for elucidating M/NP-induced gut dysbiosis, neurotoxicity, and cardiotoxicity. Multi-omics analyses and translational evidence reveal systemic inflammation, immune-metabolic disruptions, and mechanistic links to human health, providing a foundation for targeted research, regulatory frameworks, and interventions to mitigate environmental M/NP exposure.

Rapid blood clotting is essential for controlling traumatic hemorrhage to save the lives of sufferers. For this purpose, hemostatic cubosomal nanoparticles loaded with thymoquinone (TQ) were formulated. The concentrations of the constituents of thymoquinone-loaded cubosomes (TQCs), i.e., the concentrations of glyceryl monooleate (GMO), Poloxamer 188 (P188), and polyvinyl alcohol (PVA), were optimized using a response-surface methodology, considering the optimum values of the polydispersity index (PDI), zeta potential (ζ), entrapment efficiency (EE), and in vitro blood clotting efficiency. The optimized TQC exhibited a PDI of 0.214 ± 0.044, a ζ potential of 68.75 ± 2.01 mV, an EE of 73.61% ± 16.75%, and an in vitro clotting time of 150.22 ± 16.21 s. The particles were found to be highly stable, exhibiting a burst release pattern consistent with the Gallagher-Corrigan pattern. Optimized drug-loaded cubosomes, due to their highly positive ζ potential, led to platelet aggregation, and the released TQ from the TQC was shown to induce platelet activation. This phenomenon ultimately led to a stable, firm blood clot, as observed in surface morphological studies. This effect was further validated using the rat tail injury model, showing a blood loss of 48.07 ± 6.22 mg in the TQC-treated group, which was significantly (p < 0.0001) lower than that in the standard treatment group (273.4 ± 19.70 mg). Additionally, the optimized TQC demonstrated an optimum antimicrobial activity, especially against Staphylococcus aureus, as well as potent in ovo angiogenic activity, supporting their application in open wounds as a potent hemostatic agent with additional advantages for wound healing.

Modulation of coagulation activity by thymoquinone (TQ), a 1,4-benzoquinone derivative of Nigella sativa, prompted the identification and validation of a molecular mechanism for hemostasis. Consequently, this research utilizes network pharmacology, molecular docking, and dynamics approaches to investigate the role of TQ for improved hemostasis. Initially, protein targets related to hemostasis and TQ were extracted, where the common targets were subjected to KEGG pathway enrichment and gene ontology analysis to determine the top pathways responsible for inducing hemostasis. The key protein targets from the identified pathways were selected for molecular docking and MM-GBSA calculations, where the targets with the highest absolute Glide docking and ΔGbind scores were further considered for molecular dynamics simulation. The results indicated that TQ exerts potential effects on hemostasis by modulating cMet, PDGFR, and PI3KA proteins involved in the EGFR-TKIR pathway. The nontoxic concentration of TQ was determined using the MTT assay, which revealed a safe concentration (< 2.5 µM) of TQ for biological applications. In practice, TQ was found to induce the formation of stable fibrin clots in platelet-poor plasma, confirming its hemostatic potential. Finally, in vivo studies in a rat tail hemorrhage model confirmed its clotting activity, where modulation of cMet and PDGFR indicates the potential of TQ in inducing rapid hemostasis. Thus, this study integrated in silico, in vitro, and in vivo approaches to investigate the role of TQ in hemostasis through the EGFR-TKIR pathway, a mechanism that remains largely unexplored in blood clotting.

Despite advancements in healthcare settings in developed countries, the early detection and higher mortality rate associated with amyotrophic lateral sclerosis (ALS), a fatal motor neuronal disorder, remain challenging. Recently, quantum dots (QDs) have emerged as a promising nanocarrier in the prognosis and treatment of ALS owing to their unique multifunctional properties. QDs, through their photoluminescence properties upon excitation, can facilitate the identification and real-time monitoring of disease biomarkers. They also act as a nanocarrier for the targeted delivery of therapeutics, avoiding accumulation at the non-targeted sites and minimising toxicity. QDs can be fabricated to conjugate with protein biomarkers linked to ALS, such as specific proteins, nucleic acids, or genetic variants, for the diagnosis of the disease. Such fabrication could lead to enhanced identification and diagnostic patterns of ALS, thereby contributing to improved therapeutic intervention strategies. Furthermore, these tiny structures could be applied in combined biosensor formats to identify ALS-associated biomarkers in body fluids, which would be a highly sensitive diagnostic system. Subsequently, comprehensive multiomics techniques have demonstrated improved identification of newer protein targets associated with neurological complications. Overall, QDs can be explored as a potential tool to identify biomarkers relevant to ALS, diagnose the disease at its early stages, and track the effectiveness of the treatment. The integration of QD with omic-based strategies and network analysis can potentially catalyse a breakthrough in the management of ALS. Therefore, this review aims to explore the application of QDs in ALS diagnosis and management, advancements in research, clinical trials, and patents.

Wound healing is one of the growing concerns, which, when worsened, can lead to amputation of the limbs and even loss of life. Flavonoids, a potent group of polyphenols, possess significant wound-healing potential due to their antioxidant, anti-inflammatory, antimicrobial, angiogenic-promoting, and diabetes-regulating actions. Naringenin, a citrus flavanone within the broad flavonoid family with the above-mentioned potential, has been selected for targeting wound healing. To deliver naringenin to the specific site, the present study aims to develop a transferosome-encapsulated gel for enhanced wound healing performance compared with control in a rat excision model. In due course, a 3-factor 3-level Box-Behnken design was employed to develop an optimized transferosome for loading naringenin, with phospholipid (

Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, affecting approximately 50 million individuals globally with significant impose in health and financial burdens. Despite extensive research, no current treatment effectively halts the progression of AD, primarily due to its complex pathophysiology of the disease and the limitations of available therapeutic approaches. In this context, stem cell transplantation has emerged as a promising treatment strategy, harnessing the regenerative capabilities of various stem cell types, including neural stem cells (NSCs), embryonic stem cells (ESCs), and mesenchymal stem cells (MSCs). This review explores the potential of stem cell-based therapies in AD, emphasizing the necessity for continued innovation to overcome existing challenges and enhance therapeutic efficacy. Briefly, NSCs have shown potential in improving cognitive function and reducing AD pathology through targeted transplantation and neuroprotection; however, challenges such as optimizing transplantation protocols and ensuring effective cell integration persist. Concurrently, ESCs, with their pluripotent nature, present opportunities for modulating AD and generating therapeutic neurons, but ethical concerns and immunogenicity present significant obstacles to clinical application. Moreover, MSCs have demonstrated potential in ameliorating AD-related pathology and promoting neurogenesis, offering a more accessible alternative with fewer ethical constraints. The review concludes that the combinatory approaches of different stem cells may provide synergistic benefits in addressing AD-related pathophysiology, warranting further exploration in future research.

Neurodegenerative disorders, such as cognitive disabilities and dementia, have nowadays become a global burden, distressing millions of elderly people worldwide. It is characterized by progressive loss of neurons in the central nervous system, affecting higher cortical centers and ultimately impacting the social life of the patients. Conventional treatment approaches to such neurological complications primarily involve systemic drug delivery through either oral or parenteral routes of administration. However, limited brain bioavailability due to the restrictive properties of the blood-brain barrier, systemic side effects, biotransformation of the drug, and limited ability to maintain therapeutic concentrations in the CNS pose a challenge in targeted therapy. In recent years, cubosomes, nanostructured lipid-based carriers of an internally bi-continuous cubic phase, have emerged as a novel drug delivery system capable of encapsulating both hydrophilic and lipophilic drugs. These unique structured nanocarriers possess favourable physical properties, including high surface area and thermodynamic stability, which make them a potential tool for controlled and targeted drug delivery systems. With intranasal administration, cubosomes offer the ability to bypass the BBB due to the use of the olfactory and trigeminal neural pathways, achieving direct brain targeting of the therapeutics. Thus, this review aims to provide an overview of the nose-to-brain transport mechanisms, based on the anatomical and physiological basis following intranasal delivery of cubosomes integrated into thermoresponsive in situ gels. The review also focuses on the absorption mechanisms of cubosomes and their potential therapeutic applications in the treatment of neurodegenerative diseases. In addition, the review also presents formulation challenges and strategies to address them, providing insight into the future possibilities of cubosome-based gels as a new non-invasive brain-targeted therapy.