A neoteric annotation on the advances in combination therapy for Parkinson's disease: nanocarrier-based combination approach and future anticipation. Part II: nanocarrier design and development in focus.

INTRODUCTION: The current treatment modalities available for Parkinson's disease (PD) prove inadequate due to the inherent constraints in effectively transporting bioactive compounds across the blood-brain barrier. The utilization of synergistic combinations of multiple drugs in conjunction with advanced nanotechnology, emerges as a promising avenue for the treatment of PD, offering potential breakthroughs in treatment efficacy, targeted therapy, and personalized medicine. AREAS COVERED: This review provides a comprehensive analysis of the efficacy of multifactorial interventions for PD, simultaneously addressing the primary challenges of conventional therapies and highlighting how advanced technologies can help overcome these limitations. Part II focuses on the effectiveness of nanotechnology for improving pharmacokinetics of conventional therapies, through the synergistic use of dual or multiple therapeutic agents into a single nanoformulation. Significant emphasis is laid on the advancements toward innovative integrations, such as CRISPR/Cas9 with neuroprotective agents and stem cells, all effectively synergized with nanocarriers. EXPERT OPINION: By using drug combinations, we can leverage their combined effects to enhance treatment efficacy and mitigate side effects through lower dosages. This article is meant to give nanocarrier-mediated co-delivery of drugs and the strategic incorporation of CRISPR/Cas9, either as an independent intervention or synergized with a neuroprotective agent.

A neoteric annotation on the advances in combination therapy for Parkinson's disease: nanocarrier-based combination approach and future anticipation. Part I: exploring theoretical insights and pharmacological advances.

INTRODUCTION: Parkinson's disease (PD) is a neurological condition defined by a substantial reduction in dopamine-containing cells in the substantia nigra. Levodopa (L-Dopa) is considered the gold standard in treatment. Recent research has clearly shown that resistance to existing therapies can develop. Moreover, the involvement of multiple pathways in the nigrostriatal dopaminergic neuronal loss suggests that modifying the treatment strategy could effectively reduce this degeneration. AREAS COVERED: This review summarizes the key concerns with treating PD patients and the combinations, aimed at effectively managing PD. Part I focuses on the clinical diagnosis at every stage of the disease as well as the pharmacological treatment strategies that are applied throughout its course. It methodically elucidates the potency of multifactorial interventions in attenuating the disease trajectory, substantiating the rationale for co-administration of dual or multiple therapeutic agents. Significant emphasis is laid on evidence-based pharmacological combinations for PD management. EXPERT OPINION: By utilizing multiple drugs in a combination fashion, this approach can leverage the additive or synergistic effects of these agents, amplify the spectrum of treatment, and curtail the risk of side effects by reducing the dose of each drug, demonstrating significantly greater efficacy.

Signalling Pathways Involved in Microglial Activation in Alzheimer's Disease and Potential Neuroprotective Role of Phytoconstituents.

Alzheimer's disease (AD) is a commonly reported neurodegenerative disorder associated with dementia and cognitive impairment. The pathophysiology of AD comprises Aß, hyperphosphorylated tau protein formation, abrupt cholinergic cascade, oxidative stress, neuronal apoptosis, and neuroinflammation. Recent findings have established the profound role of immunological dysfunction and microglial activation in the pathogenesis of AD. Microglial activation is a multifactorial cascade encompassing various signalling molecules and pathways such as Nrf2/NLRP3/NF-kB/p38 MAPKs/ GSK-3ß. Additionally, deposited Aß or tau protein triggers microglial activation and accelerates its pathogenesis. Currently, the FDA-approved therapeutic regimens are based on the modulation of the cholinergic system, and recently, one more drug, aducanumab, has been approved by the FDA. On the one hand, these drugs only offer symptomatic relief and not a cure for AD. Additionally, no targeted-based microglial medicines are available for treating and managing AD. On the other hand, various natural products have been explored for the possible anti-Alzheimer effect via targeting microglial activation or different targets of microglial activation. Therefore, the present review focuses on exploring the mechanism and associated signalling related to microglial activation and a detailed description of various natural products that have previously been reported with anti-Alzheimer's effect via mitigation of microglial activation. Additionally, we have discussed the various patents and clinical trials related to managing and treating AD.

A technical note on emerging combination approach involved in the onconanotherapeutics.

Cancer is the second cause of mortality worldwide, and the currently available conventional treatment approach is associated with serious side effects and poor clinical outcomes. Based on the outcome of the exploratory preclinical and clinical studies, it was found that therapeutic response increases multiple folds when anticancer drugs are used in combination. However, the conventional combination of anticancer drugs was associated with various limitations such as increased cost of treatment, systemic toxicity, drug resistance, and reduced pharmacokinetic attributes. Hence, attempts were made to formulate nanocarrier fabricated combinatorial drugs (NFCDs) to effectively manage and treat cancer. This approach offers several advantages, such as improved stability, lower drug exposure, targeted drug delivery, low side effects, and improved clinical outcome. Hence, in this review, first time, we have discussed the recent advancement and various types of nano carrier-based combinatorial drug delivery systems in a different type of cancer and highlighted the personalized combinatorial theranostic medicine as a futuristic anticancer treatment approach.

Pathogenic mechanisms and therapeutic promise of phytochemicals and nanocarriers based drug delivery against radiotherapy-induced neurotoxic manifestations.

Radiotherapy is one of the extensively used therapeutic modalities in glioblastoma and other types of cancers. Radiotherapy is either used as a first-line approach or combined with pharmacotherapy or surgery to manage and treat cancer. Although the use of radiotherapy significantly increased the survival time of patients, but its use has been reported with marked neuroinflammation and cognitive dysfunction that eventually reduced the quality of life of patients. Based on the preclinical and clinical investigations, the profound role of increased oxidative stress, nuclear translocation of NF-kB, production of proinflammatory cytokines such as TNF-α, IL-6, IL-ß, increased level of MMPs, increased apoptosis, reduced angiogenesis, neurogenesis, and histological aberrations in CA1, CA2, CA3 and DG region of the hippocampus have been reported. Various pharmacotherapeutic drugs are being used as an adjuvant to counteract this neurotoxic manifestation. Still, most of these drugs suffer from systemic adverse effect, causes interference to ongoing chemotherapy, and exhibit pharmacokinetic limitations in crossing the blood-brain barrier. Therefore, various phytoconstituents, their nano carrier-based drug delivery systems and miRNAs have been explored to overcome the aforementioned limitations. The present review is focused on the mechanism and evidence of radiotherapy-induced neuroinflammation and cognitive dysfunction, pathological and molecular changes in the brain homeostasis, available adjuvants, their limitations. Additionally, the potential role and mechanism of neuroprotection of various nanocarrier based natural products and miRNAs have been discussed.

An Overview and Therapeutic Promise of Nutraceuticals Against Sports-Related Brain Injury.

Sports-related traumatic brain injury (TBI) is one of the common neurological maladies experienced by athletes. Earlier, the term 'punch drunk syndrome' was used in the case TBI of boxers and now this term is replaced by chronic traumatic encephalopathy (CTE). Sports-related brain injury can either be short-term or long-term. A common instance of brain injury encompasses subdural hematoma, concussion, cognitive dysfunction, amnesia, headache, vision issue, axonopathy, or even death, if it remains undiagnosed or untreated. Further, chronic TBI may lead to pathogenesis of neuroinflammation and neurodegeneration via tauopathy, the formation of neurofibrillary tangles, and damage to the blood-brain barrier, microglial, and astrocyte activation. Thus, altered pathological, neurochemical, and neurometabolic attributes lead to the modulation of multiple signaling pathways and cause neurological dysfunction. Available pharmaceutical interventions are based on one drug one target hypothesis and are thereby unable to cover altered multiple signaling pathways. However, in recent times, pharmacological intervention of nutrients and nutraceuticals have been explored as they exert a multifactorial mode of action and maintain over homeostasis of the body. There are various reports available showing the positive therapeutic effect of nutraceuticals in sport-related brain injury. Therefore, in the current article, we have discussed the pathology, neurological consequence, sequelae, and perpetuation of sports-related brain injury. Further, we have discussed various nutraceutical supplements as well as available animal models to explore the neuroprotective effect/ upshots of these nutraceuticals in sports-related brain injury.

Nutraceuticals and their Derived Nano-Formulations for the Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the common chronic neurological disorders and associated with cognitive dysfunction, depression and progressive dementia. The presence of ß-amyloid or senile plaques, hyper-phosphorylated tau proteins, neurofibrillary tangle, oxidative-nitrative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation and derailed neurotransmitter status are the hallmarks of AD. Currently, donepezil, memantine, rivastigmine and galantamine are approved by the FDA for symptomatic management. It is well-known that these approved drugs only exert symptomatic relief and possess poor patient-compliance. Additionally, various published evidence showed the neuroprotective potential of various nutraceuticals via their antioxidant, anti-inflammatory and anti-apoptotic effects in the preclinical and clinical studies. These nutraceuticals possess a significant neuroprotective potential and hence, can be a future pharmacotherapeutic for the management and treatment of AD. However, nutraceuticals suffer from certain major limitations such as poor solubility, low bioavailability, low stability, fast hepatic- metabolism and larger particle size. These pharmacokinetic attributes restrict their entry into the brain via the blood-brain barrier. Therefore, to overcome such issues, various nanoformulations of nutraceuticals have been developed, that allow their effective delivery into the brain owing to reduced particle size, increased lipophilicity, increased bioavailability and avoidance of fast hepatic metabolism. Thus, in this review, we have discussed the etiology of AD, focusing on the pharmacotherapeutics of nutraceuticals with preclinical and clinical evidence, discussed pharmaceutical limitations and regulatory aspects of nutraceuticals to ensure safety and efficacy. We have further explored various nanoformulations of nutraceuticals as a novel approach to overcome the existing pharmaceutical limitations and for effective delivery into the brain.

Compendium of Conventional and Targeted Drug Delivery Formulation Used for the Treatment and Management of the Wound Healing.

Wound healing is a complex and dynamic phenomenon that involves the restoration of normal physiology and functioning of injured tissue. The process of wound healing is primarily regulated by various cytokines, inflammatory mediators, and growth factors at the molecular level. Any intervention in the normal wound healing process leads to further tissue damage, which in turn leads to delayed wound healing. Several natural, synthetic drugs and their combinations were used to restore and accelerate the wound healing process. However, the conventional delivery carriers were not much effective, and thus, nowadays, nanocarriers are gaining much popularity since they are playing a pivotal role in drug delivery. Since nanocarriers have their own applicability and benefits (enhance the bioavailability, site-specific targeting) so, they can accelerate wound healing more efficiently. This review briefly discussed about the various events that take place during the wound healing process with emphasis on various natural, synthetic, and combination drug therapy used for accelerating wound healing and the role of nanotechnology-based approaches in chronic wound healing.

Recent Advancement of Pyrazole Scaffold Based Neuroprotective Agents: A Review.

As a source of therapeutic agents, heterocyclic nitrogen-containing compounds and their derivatives are still interesting and essential. Pyrazole, a five-member heteroaromatic ring with two nitrogen atoms, has a major impact in chemical industries as well as pharmaceutical industries. Due to its wide range of biological activities against various diseases, it has been identified as a biologically important heterocyclic scaffold. The treatment of neurological disorders has always been a difficult task in both the past and present. Therefore, identifying therapeutically effective molecules for neurological conditions remains an open challenge in biomedical research and development. For developing novel entities as neuroprotective agents, recently, pyrazole scaffold has attracted medicinal chemists worldwide. The major focus of research in this area is discovering novel molecules as neuroprotective agents with minimal adverse effects and better effectiveness in improving the neurological condition. This review mainly covers recent developments in the neuropharmacological role of pyrazole incorporated compounds, including their structural-activity relationship (SAR), which also further includes IC50 values (in mM as well as in µM), recent patents, and a brief history as neuroprotective agents.

Current Insight into the Therapeutic Potential of Phytocompounds and their Nanoparticle-Based Systems for Effective Management of Lung Cancer.

Lung cancer is the second most common cancer and the primary cause of cancer-related death in both men and women worldwide. Due to diagnosis at an advanced stage, it is associated with high mortality in the majority of patients. At present, various treatment approaches are available, such as chemotherapy, surgery, and radiotherapy, but all these approaches usually cause serious side effects like degeneration of normal cells, bone marrow depression, alopecia, extensive vomiting, etc. To overcome the aforementioned problems, researchers have focused on the alternative therapeutic approach in which various natural compounds are reported, which possessed anti-lung cancer activity. Phytocompounds exhibit their anti lung cancer activity via targeting various cell-signaling pathways, apoptosis and cell cycle arrest, and by regulating antioxidant status and detoxification. Apart from the excellent anti-cancer activity, clinical administration of phytocompounds is confined because of their high lipophilicity and low bioavailability. Therefore, researchers show their concern in the development of a stable, safe and effective approach of treatment with minimal side effects by the development of nanoparticle-based delivery of these phytocompounds to the target site. Targeted delivery of phytocompound through nanoparticles overcomes the aforementioned problems. In this article, the molecular mechanism of phytocompounds, their emerging combination therapy, and their nanoparticles-based delivery systems in the treatment of lung cancer have been discussed.

miRNAs in the Regulation of Cancer Immune Response: Effect of miRNAs on Cancer Immunotherapy.

In the last few decades, carcinogenesis has been extensively explored and substantial research has identified immunogenic involvement in various types of cancers. As a result, immune checkpoint blockers and other immune-based therapies were developed as novel immunotherapeutic strategies. However, despite being a promising therapeutic option, immunotherapy has significant constraints such as a high cost of treatment, unpredictable toxicity, and clinical outcomes. miRNAs are non-coding, small RNAs actively involved in modulating the immune system's multiple signalling pathways by binding to the 3'-UTR of target genes. miRNAs possess a unique advantage in modulating multiple targets of either the same or different signalling pathways. Therefore, miRNA follows a 'one drug multiple target' hypothesis. Attempts are made to explore the therapeutic promise of miRNAs in cancer so that it can be transported from bench to bedside for successful immunotherapeutic results. Therefore, in the current manuscript, we discussed, in detail, the mechanism and role of miRNAs in different types of cancers relating to the immune system, its diagnostic and therapeutic aspect, the effect on immune escape, immune-checkpoint molecules, and the tumour microenvironment. We have also discussed the existing limitations, clinical success and the prospective use of miRNAs in cancer.

Signaling Pathway Inhibitors, miRNA, and Nanocarrier-Based Pharmacotherapeutics for the Treatment of Lung Cancer: A Review.

Lung cancer is one of the most commonly diagnosed cancers and is responsible for a large number of deaths worldwide. The pathogenic mechanism of lung cancer is complex and multifactorial in origin. Thus, various signaling pathways as targets for therapy are being examined, and many new drugs are in the pipeline. However, both conventional and target-based drugs have been reported to present significant adverse effects, and both types of drugs can affect the clinical outcome in addition to patient quality of life. Recently, miRNA has been identified as a promising target for lung cancer treatment. Therefore, miRNA mimics, oncomiRs, or miRNA suppressors have been developed and studied for possible anticancer effects. However, these miRNAs also suffer from the limitations of low stability, biodegradation, thermal instability, and other issues. Thus, nanocarrier-based drug delivery for the chemotherapeutic drug delivery in addition to miRNA-based systems have been developed so that existing limitations can be resolved, and enhanced therapeutic outcomes can be achieved. Thus, this review discusses lung cancer's molecular mechanism, currently approved drugs, and their adverse effects. We also discuss miRNA biosynthesis and pathogenetic role, highlight pre-clinical and clinical evidence for use of miRNA in cancer therapy, and discussed limitations of this therapy. Furthermore, nanocarrier-based drug delivery systems to deliver chemotherapeutic drugs and miRNAs are described in detail. In brief, the present review describes the mechanism and up-to-date possible therapeutic approaches for lung cancer treatment and emphasizes future prospects to bring these novel approaches from bench to bedside.

Determination of in vivo virtue of dermal targeted combinatorial lipid nanocolloidal based formulation of 5-fluorouracil and resveratrol against skin cancer.

The current study has been designed to appraise the efficacy of developed combinatorial lipid-nanosystem-based gel (linogel) of 5-fluorouracil and resveratrol for skin cancer treatment. Initially, linogel was prepared and characterized for different parameters, namely pH, texture, drug content uniformity, occlusiveness, etc. Then in vivo efficacy studies (tumor number, area, and volume, histopathology, ultrastructural and immunohistochemical analysis) of linogel were determined over-developed skin tumors. Developed linogel possessed significantly (p < 0.05) better texture and occlusiveness than conventional gel formulation. Decreased tumor number, area, and volume showed significant results (p < 0.05) in favor of linogel. Histopathological and ultrastructural analysis confirmed superior efficacy of linogel in terms of marked improvement in the nucleus and subcellular structures in photomicrographs. The antioxidants and anti-inflammatory analysis findings showed a significantly (p < 0.05) potent effectiveness of linogel. The apoptotic and anti-proliferation activity of linogel was confirmed by analysis of caspase-3 and ki-67, which showed significant (p < 0.05) elevation in the level of cleaved caspase-3 and reduction in the level of ki-67 than untreated and conventional gel formulation treated tumors, indicating antitumor effect due to cancerous cell death. Thus, developed linogel fulfilled all the criteria of dermal application and exhibited efficacious therapeutic results, which could be a beneficial therapeutic approach against skin cancer.

Combinatorial lipid-nanosystem for dermal delivery of 5-fluorouracil and resveratrol against skin cancer: Delineation of improved dermatokinetics and epidermal drug deposition enhancement analysis.

In the present study, combinatorial nanostructured lipid carrier gel of 5-fluorouracil and resveratrol was formulated, optimized and characterized to enhance permeation in between epidermis and dermis layers of the skin to obtain a synergistic effect against skin cancer. After extensive trials, a newly modified emulsiosonication method was developed and additionally, for the first time, stability studies were done in the beginning to optimize formulation technique, which exhibited two major benefits simultaneously; first, it provided best-optimized technique for preparation of combinatorial lipid-nanosystem, and secondly, it also demonstrated a detailed report card of durability of formulations. In vitro release study showed a significantly improved, slow and prolonged release of drugs from the optimized lipid-nanosystem (***p < 0.05), which followed non-Fickian Higuchi kinetics. Besides, mechanism of skin permeation enhancement study, dermatokinetic assessment, and depth analysis of optimized formulation on skin exhibited improved permeation and well distribution of drugs up to the dermis layer of skin. Moreover, combinatorial linogel possessed significantly greater efficacy (**p < 0.01) on the A431 cell line, as compared to the conventional formulation. Thus, findings revealed that modified method of preparation for dual drug-loaded lipid-nanosystem lead to the production of a stable formulation that also improved the retention of both 5-fluorouracil and resveratrol in between the epidermis and dermis region of skin thereby helping in the management and treatment of skin cancer.

COVID-19 and cardiovascular complications: an update from the underlying mechanism to consequences and possible clinical intervention.

Introduction: The novel coronavirus has caused significant mortality worldwide and is primarily associated with severe acute respiratory distress syndrome (ARDS). Apart from ARDS, clinical reports have shown noticeable cardiovascular complications among the patients of COVID-19. Infection from virus, stimulation of cytokine storm, altered immune response, and damage to myocardial tissue are some of the proposed mechanisms of cardiovascular complications in COVID-19.Areas covered: Based on the clinical reports of CVDs among COVID-19 patients, we have discussed the molecular mechanisms involved in cardiovascular pathogenesis, its prevalence, and association with COVID-19, and various available therapeutic modality for the treatment.Expert opinion: Seeing the cardiovascular complications in COVID-19 patients and its association with the existing drug, risk-benefit ratio of treatment paradigm, as well as the level of cardiac injury biomarkers must be monitored regularly. Additionally, a well-designed clinical trial should be conducted where head to head comparison can be made with anti-COVID-19 drugs and cardioprotective anti-inflammatory drugs. Nevertheless, vaccines are the best-suited approach, but until then, sanitization, social distancing, and active lifestyle are the best ways to beat this global pandemic situation.

Current Quest in Natural Bioactive Compounds for Alzheimer's Disease: Multi-Targeted-Designed-Ligand Based Approach with Preclinical and Clinical Based Evidence.

Alzheimer's disease is a common and most chronic neurological disorder (NDs) associated with cognitive dysfunction. Pathologically, Alzheimer's disease (AD) is characterized by the presence of ß-amyloid (Aß) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, however, persistence oxidative-nitrative stress, endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory cytokines, pro-apoptotic proteins along with altered neurotransmitters level are common etiological attributes in its pathogenesis. Rivastigmine, memantine, galantamine, and donepezil are FDA approved drugs for symptomatic management of AD, whereas tacrine has been withdrawn because of hepatotoxic profile. These approved drugs only exert symptomatic relief and exhibit poor patient compliance. In the current scenario, the number of published evidence shows the neuroprotective potential of naturally occurring bioactive molecules via their antioxidant, anti-inflammatory, antiapoptotic and neurotransmitter modulatory properties. Despite their potent therapeutic implications, concerns have arisen in context to their efficacy and probable clinical outcome. Thus, to overcome these glitches, many heterocyclic and cyclic hydrocarbon compounds inspired by natural sources have been synthesized and showed improved therapeutic activity. Computational studies (molecular docking) have been used to predict the binding affinity of these natural bioactive as well as synthetic compounds derived from natural sources for the acetylcholine esterase, α/ß secretase Nuclear Factor kappa- light-chain-enhancer of activated B cells (NF-kB), Nuclear factor erythroid 2-related factor 2(Nrf2) and other neurological targets. Thus, in this review, we have discussed the molecular etiology of AD, focused on the pharmacotherapeutics of natural products, chemical and pharmacological aspects and multi-targeted designed ligands (MTDLs) of synthetic and semisynthetic molecules derived from the natural sources along with some important on-going clinical trials.

Targeted Delivery of Natural Bioactives and Lipid-nanocargos against Signaling Pathways Involved in Skin Cancer.

At present, skin cancer is considered a widespread malignancy in human beings. Among diverse population types, Caucasian populations are much more prone to this malignancy in comparison to darker skin populations due to the lack of skin pigmentation. Skin cancer is divided into malignant and non-melanoma skin cancer, which is further categorized as basal and squamous cell carcinoma. Exposure to ultraviolet radiation, chemical carcinogen (polycyclic aromatic hydrocarbons, arsenic, tar, etc.), and viruses (herpes virus, human papillomavirus, and human T-cell leukemia virus type-1) are major contributing factors to skin cancer. There are distinct pathways available through which skin cancer develops, such as the JAK-STAT pathway, Akt pathway, MAPKs signaling pathway, Wnt signaling pathway, to name a few. Currently, several targeted treatments are available, such as monoclonal antibodies, which have dramatically changed the line of treatment of this disease but possess major therapeutic limitations. Thus, many phytochemicals have been evaluated either alone or in combination with the existing synthetic drugs to overcome their limitations and have been found to play a promising role in the prevention and treatment. In this review, a complete overview of skin cancer, starting from the signaling pathways involved, newer developed drugs with their targets and limitations, along with the emerging role of natural products alone or in combination as potent anticancer agents and their molecular mechanism involved has been discussed. Apart from this, various nano-cargos have also been mentioned here, which can play a significant role in the management and treatment of different types of skin cancer.

Nano-engineered nerolidol loaded lipid carrier delivery system attenuates cyclophosphamide neurotoxicity - Probable role of NLRP3 inflammasome and caspase-1.

Neuroinflammation is one of the most common etiology in various neurological disorders and responsible for multi-array neurotoxic manifestations such as neurodegeneration, neurotransmitters alteration and cognitive dysfunction. NR (Nerolidol) is a natural bioactive molecule which possesses significant antioxidant and anti-inflammatory potential, but suffers from glitches of low solubility, low bioavailability and fast hepatic metabolism. In the current study, we fabricated nano-engineered lipid carrier of nerolidol (NR-NLC) for its effective delivery into the brain and explored its effect on neuroinflammation, neurotransmitters level and on dysfunctional behavioral attributes induced by CYC (cyclophosphamide). The binding affinity of nerolidol with NLRP3 and TLR-4 was performed which showed stong interaction between them. NR-NLC was prepared by the ultrasonication methods and particle size was determined by Zeta-sizer. Swiss Albino mice were divided into 5 groups (n = 6), assessed for behavioral dysfunction, and sacrificed on the fifteenth day following cyclophosphamide treatment. Brains were then removed and used for biochemical, histopathological, immunohistochemical and fluorescence microscopic analysis. Biochemical analysis showed increased levels of MDA, TNF-α, IL-6, IL-1ß, acetylcholine esterase, BDNF, 5-HT and dopamine, and reduced levels of SOD, CAT, GSH, IL-10, along with significant behavioral dysfunction in cyclophosphamide-treated animals. Significant neuronal damage was also observed in the histological study. Immunohistochemical analysis demonstrated increased expression of NLRP3 and caspase-1. Fluorescence microscopic analysis showed significant availability of NR-NLC in the hippocampus and cortex region. In contrast, treatment with NR-NLC effectively mitigated the aforementioned neurotoxic manifestation as compared to NR suspension. Our results showed potent neuroprotective effect of NR-NLC via modulation of oxidative stress, NLRP3 inflammasome, caspase-1 and neurotransmitter status.

Environmental neurotoxic pollutants: review.

Environmental pollutants are recognized as one of the major concerns for public health and responsible for various forms of neurological disorders. Some of the common sources of environmental pollutants related to neurotoxic manifestations are industrial waste, pesticides, automobile exhaust, laboratory waste, and burning of terrestrial waste. Among various environmental pollutants, particulate matter, ultrafine particulate matter, nanoparticles, and lipophilic vaporized toxicant (acrolein) easily cross the blood-brain barrier, activate innate immune responses in the astrocytes, microglia, and neurons, and exert neurotoxicity. Growing shreds of evidence from human epidemiological studies have correlated the environmental pollutants with neuroinflammation, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, myelin sheath disruption, and alterations in the blood-brain barrier anatomy leading to cognitive dysfunction and poor quality of life. These environmental pollutants also considerably cause developmental neurotoxicity, exhibit teratogenic effect and mental growth retardance, and reduce IQ level. Until now, the exact mechanism of pollutant-induced neurotoxicity is not known, but studies have shown interference of pollutants with the endogenous antioxidant defense system, inflammatory pathway (Nrf2/NF-kB, MAPKs/PI3K, and Akt/GSK3ß), modulation of neurotransmitters, and reduction in long-term potentiation. In the current review, various sources of pollutants and exposure to the human population, developmental neurotoxicity, and molecular mechanism of different pollutants involved in the pathogenesis of different neurological disorders have been discussed.

Topical nanostructured lipid carrier gel of quercetin and resveratrol: Formulation, optimization, in vitro and ex vivo study for the treatment of skin cancer.

The objective of this investigation was to develop dual drug-loaded nanostructured lipid carrier (NLC) gel of quercetin and resveratrol to enhance their disposition in dermal and epidermal layers. The optimization of the lipidic phase, i.e., liquid lipid and solid lipid was done on the basis of the solubility of quercetin & resveratrol in lipids in the preformulation stage. NLC formulation was optimized by central composite rotatable design (CCRD). The NLC formulation contained lipid binary mixture (1.0% w/w) and Cremophor RH40 (5% w/v) as a surfactant and had a particle size of 191 nm ± 5.20, polydispersity index (PDI) of 0.33 ± 0.01, zeta potential (ZP) of -10.00 mV ± 0.30 and entrapment efficiency (EE) of 92.85 ± 0.25% (quercetin), 89.05 ± 0.18% (resveratrol) respectively. The flux and permeability coefficient of quercetin and resveratrol from NLC gel were found to be 14.09 µg/cm2/h, 3.70 µg/cm2/h and 7.21 × 10-2 cm/h, 4.69 × 10-2 cm/h respectively. Dermatokinetic studies revealed that there was a significant increase in the CSkin max and AUC0-8 h in skin treated with NLC gel as compared to skin treated with conventional gel, which was prepared using carbopol 934 (1.5% w/w). Further, all claims of dermatokinetic studies were proved by confocal microscopic (CLMS) studies, which revealed that the disposition of combinatorial NLC gel was higher (~3 folds) as compared to the conventional gel. Furthermore, skin treated with NLC gel and untreated skin were analysed by FTIR and DSC spectra to understand the permeation dynamics of NLC gel. The cytotoxic effect of combinatorial NLC gel and the conventional gel assessed in human epidermoid carcinoma (A431) cell line by MTT assay, revealed that IC50 of NLC gel and the conventional gel was 86.50 µM and 123.64 µM respectively. Thus, these results disclosed that NLC gel could be used as a potential carrier for the delivery of quercetin & resveratrol into deeper layers of the skin and can serve as a promising formulation for treatment of skin cancer.