Dynamic endocannabinoid-mediated neuromodulation of retinal circadian circuitry.

Circadian rhythms are biological rhythms that originate from the "master circadian clock," called the suprachiasmatic nucleus (SCN). SCN orchestrates the circadian rhythms using light as a chief zeitgeber, enabling humans to synchronize their daily physio-behavioral activities with the Earth's light-dark cycle. However, chronic/ irregular photic disturbances from the retina via the retinohypothalamic tract (RHT) can disrupt the amplitude and the expression of clock genes, such as the period circadian clock 2, causing circadian rhythm disruption (CRd) and associated neuropathologies. The present review discusses neuromodulation across the RHT originating from retinal photic inputs and modulation offered by endocannabinoids as a function of mitigation of the CRd and associated neuro-dysfunction. Literature indicates that cannabinoid agonists alleviate the SCN's ability to get entrained to light by modulating the activity of its chief neurotransmitter, i.e., γ-aminobutyric acid, thus preventing light-induced disruption of activity rhythms in laboratory animals. In the retina, endocannabinoid signaling modulates the overall gain of the retinal ganglion cells by regulating the membrane currents (Ca2+, K+, and Cl- channels) and glutamatergic neurotransmission of photoreceptors and bipolar cells. Additionally, endocannabinoids signalling also regulate the high-voltage-activated Ca2+ channels to mitigate the retinal ganglion cells and intrinsically photosensitive retinal ganglion cells-mediated glutamate release in the SCN, thus regulating the RHT-mediated light stimulation of SCN neurons to prevent excitotoxicity. As per the literature, cannabinoid receptors 1 and 2 are becoming newer targets in drug discovery paradigms, and the involvement of endocannabinoids in light-induced CRd through the RHT may possibly mitigate severe neuropathologies.

Novel Gene Therapy Approaches for Targeting Neurodegenerative Disorders: Focusing on Delivering Neurotrophic Genes.

Neurodegenerative illnesses (NDDs) like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington's disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.

Pharmacokinetics and toxicity considerations for antibody-drug conjugates: an overview.

Antibody-drug conjugates (ADCs) is one of the fastest-growing drug-delivery systems. It involves a monoclonal antibody conjugated with payload via a ligand that directly targets the expressive protein of diseased cell. Hence, it reduces systemic exposure and provides site-specific delivery along with reduced toxicity. Because of this advantage, researchers have gained interest in this novel system. ADCs have displayed great promise in drug delivery and biomedical applications. However, a lack of understanding exists on their mechanisms of biodistribution, metabolism and side effects. To gain a better understanding of the therapeutics, careful consideration of the pharmacokinetics and toxicity needs to be undertaken. In this review, different pharmacokinetics parameters including distribution, bioanalysis and heterogeneity are discussed for developing novel therapeutics.

Brain insulin resistance linked Alzheimer's and Parkinson's disease pathology: An undying implication of epigenetic and autophagy modulation.

In metabolic syndrome, dysregulated signalling activity of the insulin receptor pathway in the brain due to persistent insulin resistance (IR) condition in the periphery may lead to brain IR (BIR) development. BIR causes an upsurge in the activity of glycogen synthase kinase-3 beta, increased amyloid beta (Aß) accumulation, hyperphosphorylation of tau, aggravated formation of Aß oligomers and simultaneously neurofibrillary tangle formation, all of which are believed to be direct contributors in Alzheimer's Disease (AD) pathology. Likewise, for Parkinson's Disease (PD), BIR is associated with alpha-synuclein alterations, dopamine loss in brain areas which ultimately succumbs towards the appearance of classical motor symptoms corresponding to the typical PD phenotype. Modulation of the autophagy process for clearing misfolded proteins and alteration in histone proteins to alleviate disease progression in BIR-linked AD and PD have recently evolved as a research hotspot, as the majority of the autophagy-related proteins are believed to be regulated by histone posttranslational modifications. Hence, this review will provide a timely update on the possible mechanism(s) converging towards BIR induce AD and PD. Further, emphasis on the potential epigenetic regulation of autophagy that can be effectively targeted for devising a complete therapeutic cure for BIR-induced AD and PD will also be reviewed.

Design and biological evaluation of Repaglinide loaded polymeric nanocarriers for diabetes linked neurodegenerative disorder: QbD-driven optimization, in situ, in vitro and in vivo investigation.

Diabetes mellitus is a metabolic disorder characterized by inadequate insulin secretion and signaling dysfunction, leading to a vast spectrum of systemic complications. These complications trigger cascades of events that result in amyloid-beta plaque formation and lead to neurodegenerative disorders such as Alzheimer's. Repaglinide (REP) an insulinotropic agent, suppresses the down regulatory element antagonist modulator (DREAM) and enhances the ATF6 expression to provide neuroprotection following the DREAM/ATF6/apoptotic pathway. However, oral administration of REP for brain delivery becomes more complicated due to its physicochemical characteristics (high protein binding (>98%), low permeability, short half-life (∼1 h), low bioavailability). Therefore, to circumvent these problems, we develop a polymeric nanocarrier system (PNPs) by in-house synthesized di-block copolymer (PEG-PCL). PNPs were optimized using quality by design approach response surface methodology and characterized by particle size (112.53 ± 5.91 nm), PDI (0.157 ± 0.08), and zeta potential (-6.20 ± 0.82 mV). In vitro release study revealed that PNPs (∼70% in 48 h) followed the Korsmeyer-Peppas model with a Fickian diffusion release pattern, and in intestinal absorption assay PNPs showed increment of ∼1.3 folds compared of REP. Moreover, cellular studies confirmed that REP-loaded PNPs significantly enhance the cellular viability, uptake and reduce the peroxide-induced stress in neuroblastoma SHSY-5Y cells. Further, pharmacokinetic parameters of PNPs showed an increment in tmax (2.46-fold), and Cmax (1.25-fold) associated with REP. In the brain biodistribution study, REP loaded PNPs was sustained for 24 h whereas free REP sustained only for12 h. In DM induced neurodegenerative murine model, a significantly (p < 0.01) enhanced pharmacodynamic was observed in PNP treated group by estimating biochemical and behavioral parameters. Hence, oral administration of REP-loaded PNPs promotes efficient brain uptake and improved efficacy of REP in the diseased model.

Comprehensive Review on Potential Signaling Pathways Involving the Transfer of α-Synuclein from the Gut to the Brain That Leads to Parkinson's Disease.

Parkinson's disease is the second most prevalent neurological disease after Alzheimer's. Primarily, old age males are more affected than females. The aggregates of oligomeric forms of α-synuclein cause the loss of dopaminergic neurons in the substantia nigra pars compacta. Further, it leads to dopamine shortage in the striatum region. According to recent preclinical studies, environmental factors like pesticides, food supplements, pathogens, etc. enter the body through the mouth or nose and ultimately reach the gut. Further, these factors get accumulated in enteric nervous system which leads to misfolding of α-synuclein gene, and aggregation of this gene results in Lewy pathology in the gut and reaches to the brain through the vagus nerve. This evidence showed a strong bidirectional connection between the gut and the brain, which leads to gastrointestinal problems in Parkinson patients. Moreover, several studies reveal that patients with Parkinson experience more gastrointestinal issues in the early stages of the disease, such as constipation, increased motility, gut inflammation, etc. This review article focuses on the transmission of α-synuclein and the mechanisms involved in the link between the gut and the brain in Parkinson's disease. Also, this review explores the various pathways involved in Parkinson and current therapeutic approaches for the improvement of Parkinson's disease.

Recent Advances in Targeted Nanocarriers for the Management of Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a life-threatening form of breast cancer which has been found to account for 15% of all the subtypes of breast cancer. Currently available treatments are significantly less effective in TNBC management because of several factors such as poor bioavailability, low specificity, multidrug resistance, poor cellular uptake, and unwanted side effects being the major ones. As a rapidly growing field, nano-therapeutics offers promising alternatives for breast cancer treatment. This platform provides a suitable pathway for crossing biological barriers and allowing sustained systemic circulation time and an improved pharmacokinetic profile of the drug. Apart from this, it also provides an optimized target-specific drug delivery system and improves drug accumulation in tumor cells. This review provides insights into the molecular mechanisms associated with the pathogenesis of TNBC, along with summarizing the conventional therapy and recent advances of different nano-carriers for the management of TNBC.

Exploring the Epigenetic Regulated Modulation of Fibroblast Growth Factor 21 Involvement in High-Fat Diet Associated Parkinson's Disease in Rats.

Imbalance in brain glucose metabolism and epigenetic modulation during the disease course of insulin resistance (IR) associated with Parkinson's disease (PD) risk remains a prime concern. Fibroblast growth factor 21 (FGF21), the metabolic hormone, improves insulin sensitivity and elicits anti-diabetic properties. Chronic stress during brain IR may modulate the FGF21 expression and its dynamic release via epigenetic modifications. Metformin regulates and increases the expression of FGF21 which can be modulating in obesity, diabetes, and IR. Hence, this study was designed to investigate the FGF21 expression modulation via an epigenetic mechanism in PD and whether metformin (MF), an autophagy activator, and sodium butyrate (NaB), a pan histone deacetylase inhibitor, alone and in combination, exert any therapeutic benefit in PD pathology exacerbated by high-fat diet (HFD). Our results portray that the combination treatment with MF and NaB potentially attenuated the abnormal lipid profile and increased motor performance for the rats fed with HFD for 8 weeks followed by intrastriatal 6-hydroxy dopamine administration. The enzyme-linked immunosorbent assay (ELISA) estimations of C-reactive protein, tumor necrosis factor-α, interleukin-1 beta and 6, and FGF21 exhibited extensive downregulation after treatment with the combination. Lastly, mRNA, western blot, histological, and cresyl violet staining depicted that the combination treatment can restore degenerated neuronal density and increase the protein level compared to the disease group. The findings from the study effectively conclude that the epigenetic mechanism involved in FGF21 mediated functional abnormalities in IR-linked PD pathology. Hence, combined treatment with MF and NaB may prove to be a novel combination in ameliorating IR-associated PD in rats, probably via the upregulation of FGF21 expression.

Age-related changes in gonadotropin-releasing hormone (GnRH) splice variants in mouse brain.

Gonadotropin-releasing hormone (GnRH) is the primary regulator of the mammalian reproductive axis. We investigated the spatiotemporal expression of GnRH splice variants (V1, V2, and V3) and splicing factors (Srsf7, Srsf9, and Tra-2) in the male mice brain. Further, using in silico tools, we predicted protein structure and the reason for the low translational efficiency of V2 and V3. Messenger RNA levels of GnRH variants and splicing factors were quantified using real-time reverse transcription-polymerase chain reaction at different age groups. Our data show that expression of almost all the variants alters with aging in all the brain regions studied; even in comparison to the hypothalamus, several brain areas were found to have higher expression of these variants. Hypothalamic expression of splicing factors such as Srsf7, Srsf9, and Tra-2 also change with aging. Computational studies have translation repressors site on the V3, which probably reduces its translation efficiency. Also, V2 is an intrinsically disordered protein that might have a regulatory or signaling function. In conclusion, this study provides novel crucial information and multiple starting points for future analysis of GnRH splice variants in the brain.

Chronic Light-Distorted Glutamate-Cortisol Signaling, Behavioral and Histological Markers, and Induced Oxidative Stress and Dementia: An Amelioration by Melatonin.

The present work aimed to investigate the induction of circadian rhythm dysfunction and dementia upon chronic exposure to light-light and its reversal by melatonin in Wistar rats. Animals underwent different light-dark conditions, viz., light/dark (LD), light/light (LL), and dark/dark (DD) in respective groups for 4 months. Melatonin 0.5 mg/kg s.c., dextromethorphan 50 µg/100 g s.c., and mifepristone 25 µg/100 g s.c. were given once a day. Chronic LL and DD conditions significantly increased brain glutamate and cortisol levels. The LL period caused a deficit in spatial memory, working memory, decision making, and exploration of novel objects, compared to LD animals. A significant (p < 0.05) change in neuropathological observations in the hippocampus, CA1, CA2, and CA3; cortex; and cerebellum regions (40×, 100×, and 400×) was observed in the histological study. Induced oxidative stress in brain tissue was also observed by estimating tissue glutathione and TBARS levels. Dextromethorphan (NMDA antagonist), mifepristone (corticosterone antagonist), and melatonin significantly (p < 0.05) reversed the pathological states caused due to LL. The histological features in the hippocampus, cortex, and cerebellum region revealed inflammatory cells, vacuolation, and pyknotic cells, which were significantly rescued by antagonizing NMDA or cortisol or melatonin treatment. It may be concluded that continuous exposure to light-light conditions produced an imbalance between neuronal excitation and stress hormone, leading to poor cognitive abilities and neuropathology.

Nanocarrier mediated drug delivery as an impeccable therapeutic approach against Alzheimer's disease.

For the past several years, dementia, is one of the predominantly observed groups of symptoms in a geriatric population. Alzheimer's disease (AD) is a progressive memory related neurodegenerative disease, for which the current Food and drug administration approved therapeutics are only meant for a symptomatic management rather than targeting the root cause of AD. These therapeutics belong to two classes, Acetylcholine Esterase inhibitors and N-methyl D-aspartate antagonist. Furthermore, to facilitate neuroprotective action in AD, the drugs are majorly expected to reach the specific target area in the brain for the desired efficacy. Thus, there is a huge requirement for drug discovery and development for facilitating the entry of drugs more in brain to exert a specific action. The very first line of defense and the major limitation for the entry of drugs into the brain is the Blood Brain Barrier, followed by Blood-Cerebrospinal Fluid Barrier. More than a barrier, these mainly act as selectively permeable membranes, which allows entry of specific molecules into the brain. Furthermore, specific enzymes result in the degradation of xenobiotics. All these mechanisms pose as hurdles in the way of effective drug delivery in the brain. Thus, novel techniques need to be harbored for the facilitation of the delivery of such drugs into the brain. Nanocarriers are advantageous for facilitating the specific targeted drug treatment in AD. As nanomedicines are one of the novels and most useful approaches for AD, thus the present review mainly focuses on understanding the advanced use of nanocarriers for targeted drug delivery in the management of AD.

Neuroprotective Effect of Lentivirus-Mediated FGF21 Gene Delivery in Experimental Alzheimer's Disease is Augmented when Concerted with Rapamycin.

Alzheimer type of dementia is accompanied with progressive loss of cognitive function that directly correlates with accumulation of amyloid beta plaques. It is known that Fibroblast growth factor 21 (FGF21), a metabolic hormone, with strong neuroprotective potential, is induced during oxidative stress in Alzheimer's disease. Interestingly, FGF21 cross-talks with autophagy, a mechanism involved in the clearance of abnormal protein aggregate. Moreover, autophagy activation by Rapamycin delivers neuroprotective role in Alzheimer's disease. However, the synergistic neuroprotective efficacy of overexpressed FGF21 along with Rapamycin is not yet investigated. Therefore, the present study examined whether overexpressed FGF21 along with autophagy activation ameliorated neurodegenerative pathology in Alzheimer's disease. We found that cognitive deficits in rats with intracerebroventricular injection of Amyloid beta1-42 oligomers were restored when injected with FGF21-expressing lentiviral vector combined with Rapamycin. Furthermore, overexpression of FGF21 along with Rapamycin downregulated protein levels of Amyloid beta1-42 and phosphorylated tau and expression of major autophagy proteins along with stabilization of oxidative stress. Moreover, FGF21 overexpressed rats treated with Rapamycin revamped the neuronal density as confirmed by histochemical, cresyl violet and immunofluorescence analysis. These results generate compelling evidence that Alzheimer's disease pathology exacerbated by oligomeric amyloid beta may be restored by FGF21 supplementation combined with Rapamycin and thus present an appropriate treatment paradigm for people affected with Alzheimer's disease.

Epigenetic regulation and autophagy modulation debilitates insulin resistance associated Alzheimer's disease condition in rats.

Insulin resistance (IR) and accumulation of amyloid beta (Aß) oligomers are potential causative factor for Alzheimer's Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin (rapa) and vorinostat (vori) in-vitro and in-vivo. Aß1-42 treated SH-SY5Y cells were exposed to rapa (20 µM) and vori (4 µM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3), lysosome-associated membrane protein 2 (LAMP2) and microtubule associated protein 2 (MAP2). In order to develop IR condition, rats were fed a high fat diet (HFD) for 8 weeks and then subjected to intracerebroventricular Aß1-42 administration. Subsequently, their treatment was initiated with rapa (1 mg/kg, i.p.) and vori (50 mg/kg, i.p.) once daily for 28 days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent mRNA, biochemical, western blot and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aß1-42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.

Orchestration of the circadian clock and its association with Alzheimer's disease: Role of endocannabinoid signaling.

Circadian rhythms are 24-hour natural rhythms regulated by the suprachiasmatic nucleus, also known as the "master clock". The retino-hypothalamic tract entrains suprachiasmatic nucleus with photic information to synchronise endogenous circadian rhythms with the Earth's light-dark cycle. However, despite the robustness of circadian rhythms, an unhealthy lifestyle and chronic photic disturbances cause circadian rhythm disruption in the suprachiasmatic nucleus's TTFL loops via affecting glutamate and γ-aminobutyric acid-mediated neurotransmission in the suprachiasmatic nucleus. Recently, considerable evidence has been shown correlating CRd with the incidence of Alzheimer's disease. The present review aims to identify the existence and signalling of endocannabinoids in CRd induced Alzheimer's disease through retino-hypothalamic tract- suprachiasmatic nucleus-cortex. Immunohistochemistry has confirmed the expression of cannabinoid receptor 1 in the suprachiasmatic nucleus to modulate the circadian phases of the master clock. Literature also suggests that cannabinoids may alter activity of suprachiasmatic nucleus by influencing the activity of their major neurotransmitter γ-aminobutyric acid or by interacting indirectly with the suprachiasmatic nucleus's two other major inputs i.e., the geniculo-hypothalamic tract-mediated release of neuropeptide Y and serotonergic inputs from the dorsal raphe nuclei. Besides, the expression of cannabinoid receptor 2 ameliorates cognitive deficits via reduction of tauopathy and microglial activation. In conclusion, endocannabinoids may be identified as a putative target for correcting CRd and decelerating Alzheimer's disease.

Recent advances in nanocarriers for nutrient delivery.

For the past few years, there has been a surge in the use of nutraceuticals. The global nutraceuticals market in 2020 was USD 417.66 billion, and the market value is expected to increase by 8.9% compound annual growth rate from 2020 to 2028. This is because nutraceuticals are used to treat and prevent various diseases such as cancer, skin disorders, gastrointestinal, ophthalmic, diabetes, obesity, and central nervous system-related diseases. Nutritious food provides the required amount of nutrition to the human body through diet, whereas most of the bioactive agents present in the nutrients are highly lipophilic, with low aqueous solubility leading to poor dissolution and oral bioavailability. Also, the nutraceuticals like curcumin, carotenoids, anthocyanins, omega-3 fatty acids, vitamins C, vitamin B12, and quercetin have limitations such as poor solubility, chemical instability, bitter taste, and an unpleasant odor. Additionally, the presence of gastrointestinal (GIT) membrane barriers, varied pH, and reaction with GIT enzymes cause the degradation of some of the nutraceuticals. Nanotechnology-based nutrient delivery systems can be used to improve oral bioavailability by increasing nutraceutical stability in foods and GIT, increasing nutraceutical solubility in intestinal fluids, and decreasing first-pass metabolism in the gut and liver. This article has compiled the properties and applications of various nanocarriers such as polymeric nanoparticles, micelles, liposomes, niosomes, solid lipid nanocarriers, nanostructured lipid carrier, microemulsion, nanoemulsion, dendrimers in organic nanoparticles, and nanocomposites for effective delivery of bioactive molecules.

A novel UPLC-MS/MS method for simultaneous quantification of trigonelline, 4-hydroxyisoleucine, and diosgenin from Trigonella foenum-graecum extract: Application to pharmacokinetic study in healthy and type 2 diabetic rats.

Trigonelline (TR), 4-hydroxyisoleucine (4-HI), and diosgenin (DG) are the main bioactives of the purified standardized extract of the popular plant Trigonella foenum-graecum L. (TFG), and it has been proven effective for the treatment of various diseases. However, to the best of our knowledge, no study has investigated the pharmacokinetic parameters of purified standardized T. foenum-graecum extract in normal and diabetic Wistar rats. The present study has developed and validated a rapid, reliable, and sensitive simultaneous ultra-performance liquid chromatography MS method to estimate these bioactives. The chromatographic separation was achieved using methanol, acetonitrile, and 0.1% formic acid with the ideal gradient flow system on a BEH Shield RP 18 column. A positive electrospray ionization mode was selected to estimate m/z values of TR (138.14 > 94.63), 4-HI (148.19 > 74.08), and DG (415.54 > 271.33). The method was robust and reproducible over the linearity range of 60-5000, 6-5000, and 15-5000 ng/mL for TR, 4-HI, and DG, respectively. Using this novel validated method, we investigated the pharmacokinetic parameters of bioactives using Phoenix WinNonlin version 8.0 (Certera) in normal and diabetic rats. The assay was successfully applied for the estimation of pharmacokinetic parameters using noncompartmental analysis. This investigation shows that the absorption rate increased, whereas distribution and elimination processes slowed down in diabetic rats compared with normal rats.

Advances in Antibody-Based Therapeutics for Cerebral Ischemia.

Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are activated, comprising necrosis, apoptosis, and autophagy as well as glial activation and white matter injury, which leads to neuronal cell death. Current treatments for strokes include challenging mechanical thrombectomy or tissue plasminogen activator, which increase the danger of cerebral bleeding, brain edema, and cerebral damage, limiting their usage in clinical settings. Monoclonal antibody therapy has proven to be effective and safe in the treatment of a variety of neurological disorders. In contrast, the evidence for stroke therapy is minimal. Recently, Clone MTS510 antibody targeting toll-like receptor-4 (TLR4) protein, ASC06-IgG1 antibody targeting acid sensing ion channel-1a (ASIC1a) protein, Anti-GluN1 antibodies targeting N-methyl-D-aspartate (NMDA) receptor associated calcium influx, GSK249320 antibody targeting myelin-associated glycoprotein (MAG), anti-High Mobility Group Box-1 antibody targeting high mobility group box-1 (HMGB1) are currently under clinical trials for cerebral ischemia treatment. In this article, we review the current antibody-based pharmaceuticals for neurological diseases, the use of antibody drugs in stroke, strategies to improve the efficacy of antibody therapeutics in cerebral ischemia, and the recent advancement of antibody drugs in clinical practice. Overall, we highlight the need of enhancing blood-brain barrier (BBB) penetration for the improvement of antibody-based therapeutics in the brain, which could greatly enhance the antibody medications for cerebral ischemia in clinical practice.

Surface engineered nanocarriers for the management of breast cancer.

Breast cancer is commonly known life-threatening malignancy in women after lung cancer. The standard of care (SOC) treatment for breast cancer primarily includes surgery, radiotherapy, hormonal therapy, and chemotherapy. However, the effectiveness of conventional chemotherapy is restricted by several limitations such as poor targeting, drug resistance, poor drug delivery, and high toxicity. Nanoparticulate drug delivery systems have gained a lot of interest in the scientific community because of its unique features and promising potential in breast cancer diagnosis and treatment. The unique physicochemical and biological properties of the nanoparticulate drug delivery systems promotes the drug accumulation, Pharmacokinetic profile towards the tumor site and thereby, reduces the cytotoxicity towards healthy cells. In addition, to improve tumor-specific drug delivery, researchers have focused on surface engineered nanocarrier system with targeting molecules/ligands that are specific to overexpressed receptors present on cancer cells. In this review, we have summarized the different biological ligands and surface-engineered nanoparticles, enlightening the physicochemical characteristics, toxic effects, and regulatory considerations of nanoparticles involved in treatment of breast cancer.

Solid Lipid Nanoparticles (SLNs): An Advanced Drug Delivery System Targeting Brain through BBB.

The blood-brain barrier (BBB) plays a vital role in the protection and maintenance of homeostasis in the brain. In this way, it is an interesting target as an interface for various types of drug delivery, specifically in the context of the treatment of several neuropathological conditions where the therapeutic agents cannot cross the BBB. Drug toxicity and on-target specificity are among some of the limitations associated with current neurotherapeutics. In recent years, advances in nanodrug delivery have enabled the carrier system containing the active therapeutic drug to target the signaling pathways and pathophysiology that are closely linked to central nervous system (CNS) disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), brain tumor, epilepsy, ischemic stroke, and neurodegeneration. At present, among the nano formulations, solid lipid nanoparticles (SLNs) have emerged as a putative drug carrier system that can deliver the active therapeutics (drug-loaded SLNs) across the BBB at the target site of the brain, offering a novel approach with controlled drug delivery, longer circulation time, target specificity, and higher efficacy, and more importantly, reducing toxicity in a biomimetic way. This paper highlights the synthesis and application of SLNs as a novel nontoxic formulation strategy to carry CNS drugs across the BBB to improve the use of therapeutics agents in treating major neurological disorders in future clinics.

Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations.

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the most recent coronaviruses, which has infected humans, and caused the disease COVID-19. The World Health Organization has declared COVID-19 as a pandemic in March 2020. The SARS-CoV-2 enters human hosts majorly via the respiratory tract, affecting the lungs first. In few critical cases, the infection progresses to failure of the respiratory system known as acute respiratory distress syndrome acute respiratory distress syndrome may be further associated with multi-organ failure and vasoplegic shock. Currently, the treatment of COVID-19 involves use of antiviral and anti-cytokine drugs. However, both the drugs have low efficacy because they cannot inhibit the production of free radicals and cytokines at the same time. Recently, some researchers have reported the use of methylene blue (MB) in COVID-19 management. MB has been used since a long time as a therapeutic agent, and has been approved by the US FDA for the treatment of other diseases. The additional advantage of MB is its low cost. MB is a safe drug when used in the dose of < 2 mg/kg. In this review, the applicability of MB in COVID-19 and its mechanistic aspects have been explored and compiled. The clinical studies have been explained in great detail. Thus, the potential of MB in the management of COVID-19 has been examined.