Current Molecular Pharmacology - Volume 14, Issue 3, 2021

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age, which include impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity, and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% of the patients live for more than 10 years. The limited intervention of pharmacologically active compounds, that are used clinically, is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models, where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB, is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, this current review specially targeted the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with the up-regulation of intracellular adenyl cyclase/cAMP/ CREB and activation of mitochondrial-ETC coenzyme-Q10 as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.

Background: Vulvovaginal candidiasis (VVC) is a common vaginal infection caused by candida species, affecting 70% of the women. It may occur due to the imbalance in the vaginal micro- biodata, pregnancy, diabetes, use of antibiotics, frequent sexual activities or AIDS. Aim: The main aim of this review is to provide overview about different vaginal delivery systems for the administration of antifungal agents like conventional, mucoadhesive and muco-penetrating delivery systems. Method: The conventional delivery systems available have limited efficacy due to the less residence time and adverse effects. In order to overcome these issues, a delivery system with mucoadhesive and muco-penetrating properties is required. Mucoadhesive polymers have excellent binding properties with mucin and thus increasing residence time. On the other hand, muco-penetrating polymers transport the antifungal agents across the mucus layer. Results: This review summarizes the pathophysiology of VVC along with novel delivery systems for the treatment of infection through mucoadhesive and muco-penetrating approaches. Surface modifications of nano/ microparticles with mucoadhesive or muco-penetrating particles may provide delivery systems with improved therapeutic efficacy. Conclusion: Based on the available data, conventional and mucoadhesive drug delivery systems have some limitations, they still require improvement/ development for safe and effective delivery of antifungal agents.

Cancer continues to be one of the deadliest diseases that adversely impacts the large population of the world. A stack of scientific documents reflects a huge number of potent plant-based anticancer drugs such as curcumin (CUR), podophyllotoxin, camptothecin (CPT), vincristine, vinblastine, paclitaxel (PTX), etc. that have been integrated into the modern practice of cancer treatment. The demand for natural products raises exponentially as they are generally considered to be safe, and devoid of critical toxic effects at the therapeutic dose when compared to their synthetic counterparts. Despite rising interest towards the potent phytoconstituents, formulation developer faces various challenges in drug development processes such as poor water solubility, low bioavailability, marginal permeability, and nonspecific drug delivery at the target site, etc. Further, adverse drug reaction and multidrug resistance are other critical issues that need to be addressed. Nanomedicines owing to their unique structural and functional attributes help to fix the above challenges for improved translational outcomes. This review summarises the prospects and challenges of a nanotechnology-based drug delivery approach for the delivery of plant-based anticancer drugs.

Background: Vitiligo is an auto-immune disease with white-coloured disfiguring patches or spots on the skin surface. It is highly prevalent in several corners of the world. This disease spreads in different age groups. Aim: The main aim of this review is to provide an overview of pathophysiology and lipid-based nano-carriers for the treatment of vitiligo. Methods: The conventional delivery systems available have limited efficacy due to less retention of the drug in the epidermal layer where melanocytes reside. In order to overcome these issues, an advanced delivery system with lipid-based nano-carriers for the treatment of vitiligo was proven to be better as per the literature explored. Results: This review summarizes the pathophysiology along with novel lipid-based nano-carriers for the treatment of vitiligo. Conclusion: Though various treatment regimens are present for the disease, nano-lipid carrier systems are significantly gaining importance nowadays, due to their high effectivity in topically acting on the target site. Nano-lipid carrier systems such as liposomes, ethosomes, transethosomes and transferosomes can be said to be at the top of the list in acting effectively against vitiligo or several other tropical diseases.

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

Asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are major inflammatory respiratory diseases. Current mainstay therapy for asthma, and chronic obstructive pulmonary disease are corticosteroids, which have well-established side effect profiles. Phospholipids (PLs) are ubiquitous, diverse compounds with varying functions such as their structural role in the cell membrane, energy storage, and cell signaling. Recent advances in understanding PLs role as inflammatory mediators in the body as well as their widespread long-standing use as carrier molecules in drug delivery demonstrate the potential application of PLs in modulating inflammatory conditions. This review briefly explains the main mechanisms of inflammation in chronic respiratory diseases, current anti-inflammatory treatments and areas of unmet need. The structural features, roles of endogenous and exogenous phospholipids, including their use as pharmaceutical excipients, are reviewed. Current research on the immunomodulatory properties of PLs and their potential application in inflammatory diseases is the major section of this review. Considering the roles of PLs as inflammatory mediators and their safety profile established in pharmaceutical formulations, these small molecules demonstrate great potential as candidates in respiratory inflammation. Future studies need to focus on the immunomodulatory properties and the underlying mechanisms of PLs in respiratory inflammatory diseases.

Cancer is one of the most serious health concerns in the 21st century whose prevalence is beyond boundaries and can affect any organ of the human body. The conventional chemotherapeutic treatment strategies lack specificity to tumors and are associated with toxic effects on the immune system and other organ systems. In the past decades, there has been continuous progress in the development of smart nanocarrier systems for target-specific delivery of drugs against a variety of tumors, including intracellular gene-specific targeting. These nanocarriers are able to recognize the tumor cells and deliver the therapeutic agent in fixed proportions, causing no or very less harm to healthy cells. Nanosystems have modified physicochemical properties, improved bioavailability, and long retention in blood, which enhances their potency. A huge number of nanocarrier based formulations have been developed and are in clinical trials. Nanocarrier systems include polymeric micelles, liposomes, dendrimers, carbon nanotubes, gold nanoparticles, etc. Recent advancements in nanocarrier systems include mesoporous silica nanoparticles (MSNs), metal organic frameworks, and quantum dots. In the present review, various nanocarrier based drug delivery systems, along with their applications in the management of cancer, have been described with special emphasis on MSNs.

Aim: Formulation, optimization and anticancer activity of spray-dried Doxorubicin loaded folic acid conjugated Gelatin nanoparticles (DOX-FA-GN). Methods: Doxorubicin loaded gelatin nanoparticles (DOX-GN) were prepared by the Coacervation phase separation method, optimized using DoE and then conjugated with folic acid by covalent coupling to formulate Doxorubicin loaded folic acid conjugated nanoparticles (DOX-FA-GN). The formulated nanoparticles were characterized to evaluate its physicochemical properties. Cellular uptake and cell viability studies were carried out using MTT assay and biodistribution studies were carried out in Wistar rats. Results: Particle size, PDI and entrapment efficiency for optimized DOX-GN were found to be 152.3 ± 9.3 nm 0.294 ± 0.1 and 86.9± 3.4% while for DOX-FA-GN, 193.9 ± 12.3 nm 0.247 ± 0.2 and 84 ± 3.6%. The cytotoxic studies showed a cell viability of 75.1% for DOX-GN and 29.5% DOX-FA-GN. Biodistribution studies were found to be statistically insignificant for conjugated nanoparticles with excellent flow properties. Significantly higher DOX distribution in the lungs was observed in the case of DOX-FA-GN. Conclusion: There was a higher uptake of DOX on HeLa cells with DOX-FA-GN compared to DOX-GN. Also, the biodistribution of Dox in the lungs of Wistar rats was higher in conjugated nanoparticles as compared to unconjugated nanoparticles.

Background: The existing parenteral treatment of cervical cancer has high toxicity and poor distribution of drugs at the targeted site. Purpose: To formulate localized mucoadhesive cisplatin loaded microparticles based formulation to treat cervical cancer so that enhanced therapeutics benefits with low toxicity could be achieved. Methods: Cisplatin loaded chitosan coated spray-dried microparticles were prepared by ionotropic gelation technique and optimized by Central Composite Design. The spray-dried uncoated and chitosan- coated microparticles were characterized for various parameters (Particle size, Morphology, Drug entrapment efficiency). In vitro drug release study was carried out in simulated vaginal fluids by dialysis membrane method. Ex vivo studies were carried out to evaluate the cytotoxic potential of the developed formulation by the MTT assay. A drug permeability study was performed by Franz diffusion cell using the vaginal tissue of Swiss Albino Mice. Results: All in vitro characterization parameters were found to be optimum. The in vitro release studies indicated a controlled release following the Higuchi model. The chitosan-coated microparticles were found to be more cytotoxic than uncoated microparticles and plain cisplatin solution. The chitosan-coated microparticles were found to be more permeable than uncoated microparticles. Finally, in vivo tumor regression and histopathological studies confirmed the significant decrease in tumor volume at different time intervals. Conclusion: Thus, it can be concluded that mucoadhesive spray-dried microparticles could provide a favorable approach for localized delivery of the anticancer drug via vaginal route against cervical cancer with its enhanced effectiveness.

Background: Psoriasis is an autoimmune disease of the skin with lapsing episodes of hyperkeratosis, irritation, and inflammation. Numerous traditional and novel drug delivery systems have been used for better penetration through psoriatic barrier cells and also for retention in the skin. As there is no effective remedy for better penetration, and retention is there because of the absence of an ideal carrier for effective and safe delivery of antipsoriatic drugs. Objectives: The main objective of this project is to develop a Squalene integrated NLC based carbopol 940 gel to create a local drug depot in the skin for improved efficacy against psoriasis. Methods: Homogenization method is used for the formulation of Nanostructured Lipid Carrier, which was characterized on the basis of size, entrapment efficiency, polydispersity index (PDI), viscosity, spreadability, DSC, zeta potential, % in vitro release, in vitro skin permeation and retention studies, physical storage stability studies. In vivo studies can use other alternative models for induction of psoriasis by severe redness, swelling macroscopically, and microvascular dilation edema lasting for 10 days. Furthermore, histopathology study was done to asses changes in the skin. Conclusion: The optimized formulation of nanostructured lipid carrier-based gel has shown significant and sustained release of clobetasol propionate. Furthermore, this formulation has also shown retention in skin because of squalene as it is a sebum derived lipid, which shows an affinity towards the sebaceous gland.

Objective: The aim of the current research is to formulate a nano delivery system for effective delivery of primaquine for liver targeting to achieve the potential anti-malarial activity. Another objective of current development is to formulate a lactobionic acid conjugated polyphosphazene based nano delivery of primaquine for liver targeting to distinguish anti-malarial activity. Method: The particle size, entrapment efficiency, in-vitro drug release pattern, hepatotoxicity, MTT assay, erythrocyte toxicity assay, histopathology study, HepG2 cell uptake study, anti-- malarial study, and organ-distribution was also carried out to estimate the activity and potential features of a nanoparticle system. Results: The results obtained from the above analysis justify the efficiency and effectiveness of the system. The NMR studies confirm the conjugation pattern and the TEM represents the spherical morphological features of nanoparticles. The controlled release pattern from the in-vitro release study was observed and found to be 73.25% of drug release in 20 hrs and in the nano-size range (61.6± 1.56 nm) by particle size analysis.SGOT level, SGPT, ALP, and Parasitemia level of optimized drug-loaded PEGylated lactobionic acid conjugated polyphosphazene derivatized nanoparticles (FF) was found to lie in the safe range, showing that the formulation is non-toxic to the liver. Primaquine drug-loaded PEGylated lactobionic acid conjugated polyphosphazene polymeric nanoparticles showed higher cell uptake on HepG2 cell lines as compared to the drug-loaded in PEGylated polyphosphazene polymeric nanoparticles and plain drug.Percentage cell viability of drugloaded PEGylated lactobionic acid conjugated polyphosphazene derivatized nanoparticles was decreased by enhancing the concentration of prepared nanoparticle system accessed by MTT assay. Conclusion: From the studies, it can be concluded that the optimized formulation of drug-loaded PEGylated lactobionic acid conjugated polyphosphazene derivatized nanoparticles showed high liver targeting, least toxicity to the liver, controlled release of the drug, higher anti-malarial activity against hepatocytes at a low dose, more effectiveness, and can be treated as a potential candidate for anti-malarial therapy.

Background: Neurodegenerative diseases have become an increasing cause of various disabilities worldwide, followed by aging, including Parkinson’s disease (PD). Parkinson’s disease is a degenerative brain disorder distinguished by growing motor & non-motor failure due to the degeneration of medium-sized spiked neurons in the striatum region. Rotenone is often employed to originate the animal model of PD. It is a powerful blocker of mitochondrial complex-I, mitochondrial electron transport chain that reliably produces Parkinsonism-like symptoms in rats. Rice bran (RB) is very rich in polyunsaturated fatty acids (PUFA) and nutritionally beneficial compounds, such as γ-oryzanol, tocopherols, and tocotrienols and sterols are believed to have favorable outcomes on oxidative stress & mitochondrial function. Objective: The present study has been designed to explore RB extract’s effect against rotenone-induced neurotoxicity in rats. Methods: In the present study, Rotenone (2 mg/kg, s.c) was administered systemically for 28 days. The hexane extract of RB was prepared using Soxhlation. Hexane extract (250 & 500 mg/kg) was administered per oral for 28 days in rotenone-treated groups. Behavioral parameters (grip strength, motor coordination, locomotion, and catalepsy) were conducted on the 7th, 14th, 21st, and 28th day. Animals were sacrificed on the 29th day for biochemical estimation in the striatum and cortex. Results: This study demonstrates significant alteration in behavioral parameters, oxidative burden (increased lipid peroxidation, nitrite concentration, and decreased glutathione, catalase, SOD) in rotenone-treated animals. Administration of hexane extract of RB prevented the behavioral, biochemical alterations induced by rotenone. The current research has been sketched to inspect RB extract’s effect against rotenone-developed neurotoxicity in rats. Conclusion: The findings support that PD is associated with impairments in motor activity. The results also suggest that the nutraceutical rice bran that contains γ-oryzanol, Vitamin-E, ferulic acid etc., may underlie the adjuvant susceptibility towards rotenone-induced PD in experimental rats.

Background: Olanzapine belongs to a new class of dual spectrum antipsychotic agents. It is known to show promise in managing both the positive and negative symptoms of schizophrenia. Drug delivery systems based on nanostructured lipid carriers (NLC) are expected to provide rapid nose-to-brain transport of this drug and improved distribution into and within the brain. Objective: The present study deals with the preparation and evaluation of olanzapine loaded NLC via the intranasal route for schizophrenia. Methods: Olanzapine-NLC were formulated through the solvent injection method using isopropyl alcohol as the solvent, stearic acid as solid lipid, and oleic acid as liquid lipid, chitosan as a coating agent, and Poloxamer 407 as a surfactant. NLC were characterized for particle size, polydispersity index, entrapment efficiency, pH, viscosity, X-ray diffraction studies, in-vitro mucoadhesion study, in- vitro release and ex-vivo permeation studies. The shape and surface morphology of the prepared NLC was determined through transmission electron microscopy. To detect the interaction of the drug with carriers, compatibility studies were also carried out. Results: Average size and polydispersity index of developed formulation S6 was 227.0±6.3 nm and 0.460, respectively. The encapsulation efficiency of formulation S6 was found to be 87.25%. The pH, viscosity, in-vitro mucoadhesion study, and in- vitro release of optimized olanzapine loaded NLC were recorded as 5.7 ± 0.05, 78 centipoise, 15±2 min, and 91.96%, respectively. In ex-vivo permeation studies, the percent drug permeated after 210 min was found to be 84.03%. Conclusion: These results reveal the potential application of novel olanzapine-NLC in intranasal drug delivery system for the treatment of Schizophrenia.

Objective: The aim of present study was to formulate chitosan microspheres loaded with ethanolic extract of Lens culinaris Medikus (L.culinaris) seeds (ME) and to explore its anticancer potential against lung cancer (A549) cell line. Methods: Central composite design was applied to prepare and optimise the chitosan microspheres. The prepared microspheres were evaluated for its physicochemical characterisation, in vitro drug release and anti-cancer potential in vitro. Results: L.culinaris loaded chitosan microspheres were prepared successfully with suitable particle size, entrapment efficiency and drug release. The developed ME were spherical shaped with the particle size of 2.08 μm. The drug entrapment efficiency and cumulative drug release was found 1.58±0.02% and 81.95±0.35%, respectively. Differential scanning calorimetry studies revealed no interaction between drugs and polymers used. The cytotoxic effect of the optimised formulation revealed a significant response as compared to the ethanolic extract of L.culinaris seeds (IC50: 22.56 μg/ml vs. 63.58 μg/ml), which was comparable to that of reference drug, doxorubicin (22 μg/ml). These observations demonstrate that the optimised microspheres are effective against lung cancer (A549) cells. Conclusion: The significant cytotoxic response of the developed microspheres may be attributed due to its low particle size, high entrapment efficiency and prolonged drug release profile.

Background: In photoaging, the accumulation of ultraviolet (UV)-induced oxidative damage leads to the characteristic hallmarks of aging. Here arises the importance of autophagy as a cellular degradation process that cleans the cells of defective or aged organelles and macromolecules, thus maintaining cellular homeostasis. In spite of this, the exact impact of autophagy in photoaging is still elusive. Objective: To evaluate the protective effects of resveratrol and/or co-enzyme-Q10 against the UVA-induced alterations and to explore the role of autophagy in their proposed benefits. Methods: Sixty female mice were randomly divided into normal control, untreated UVA-exposed, resveratrol (50mg/kg), co-enzyme-Q10 (100mg/kg), and resveratrol/co-enzyme-Q10-treated UVA-- exposed groups. Clinical signs of photoaging were evaluated using a modified grading score and the pinch test. Skin malondialdehyde and reduced glutathione were assessed as markers of oxidative stress. Tissues were examined for histopathological signs of photodamage, and autophagic changes were determined by immunohistochemical detection of LC3 and P62 in the different cells of the skin. Results: UVA-exposure increased the oxidative stress with subsequent epidermal and dermal injury. This was associated with the stimulation of autophagy in the keratinocytes and inhibition of autophagic flux in the fibroblasts and infiltrating macrophages. Both drugs corrected the impaired pinch test, macro–and microscopic changes, and exhibited distinct staining patterns with anti-LC3 and P62 in the different cell types denoting autophagic modulation. Conclusion: Changes in autophagic flux are strongly implicated in photoaging associated skin damage and the differential modulation of autophagy by resveratrol and, to a lesser extent by Co-enzyme- Q10, is partially involved in their therapeutic benefits.