Recent advancements and applications of ophthalmic gene therapy strategies: A breakthrough in ocular therapeutics.

Over the past twenty years, ocular gene therapy has primarily focused on addressing diseases linked to various genetic factors. The eye is an ideal candidate for gene therapy due to its unique characteristics, such as easy accessibility and the ability to target both corneal and retinal conditions, including retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), age-related macular degeneration (AMD), and Stargardt disease. Currently, literature documents 33 clinical trials in this field, with the most promising results emerging from trials focused on LCA. These successes have catalyzed further research into other ocular conditions such as glaucoma, AMD, RP, and choroideremia. The effectiveness of gene therapy relies on the efficient delivery of genetic material to specific cells, ensuring sustained and optimal gene expression over time. Viral vectors have been widely used for this purpose, although concerns about potential risks such as immune reactions and genetic mutations have led to the development of non-viral vector systems. Preliminary laboratory research and clinical investigations have shown a connection between vector dosage and the intensity of immune response and inflammation in the eye. The method of administration significantly influences these reactions, with subretinal delivery resulting in a milder humoral response compared to the intravitreal route. This review discusses various ophthalmic diseases, including both corneal and retinal conditions, and their underlying mechanisms, highlighting recent advances and applications in ocular gene therapies.

Polymeric micelle gel with luliconazole: in vivo efficacy against cutaneous candidiasis in Wistar rats.

The objective of this research was focused on the design and development of luliconazole-loaded polymeric micelle hydrogel (LUL-PM-CHG) using quality by design (QbD) principle to improve the penetration and retention of LUL in the skin. The optimization of the formulation involved the utilization of a Box-Behnken design with three factors and three levels. The impact of specific formulation variables, namely the ratio of poloxamer P123 and F127, sonication time, and the quantity of drug, was investigated in terms of particle size, micellar incorporation efficiency, and polydispersity index. The LUL-loaded P123/F127 mixed micelles involved the thin film hydration method for thin preparation. The characteristics of optimized formulation include a particle size of 226 ± 8.52 nm, a polydispersity index (PDI) of 0.153 ± 0.002, a zeta potential (ZP) of 30.15 ± 2.32 mV, and a micellar incorporation efficiency (MIE) of 88.38 ± 3.84%. In vitro release studies indicated a sustained release of LUL-PM-CHG for a duration of up to 8 h. The MIC, GI50, and GI90 of different formulations on Candida albicans were determined using both the microtiter broth dilution method and the plate method and showed that LUL-PM-CHG exhibited the highest antifungal activity compared to the other formulations, with MIC values of 3.25 ± 0.19 ng/mL, GI50 values of 37.11 ± 2.89, and GI90 values of 94.98 ± 3.41 The study also measured the % of inhibition activity and the generation of intracellular reactive oxygen species (ROS) using flow cytometry. LUL-PM-CHG showed the highest percentage of inhibition (75.5%) and ROS production (MFI-140951), indicating its enhanced activity compared to LUL-CHG and LUL. Fungal infection was induced in Wistar rats using immunosuppressant's treatment followed by exposure to C. albicans. Finally, in vivo fungal scaling and histopathological studies indicated a reduction in fungal infection in Wistar rat skin after treatment. The obtained results suggested that LUL-PM can serve as a promising formulation to enhance luliconazole antifungal activity and increase patient compliance.

Enhanced antichemobrain activity of amino acid assisted ferulic acid solid dispersion in adult zebrafish (Danio rerio).

Chemotherapy-induced cognitive impairment (CICI), also known as "chemobrain," is a common side effect of breast cancer therapy which causes oxidative stress and generation of reactive oxygen species (ROS). Ferulic acid (FA), a natural polyphenol, belongs to BCS class II is confirmed to have nootropic, neuroprotective and antioxidant effects. Here, we have developed FA solid dispersion (SD) in order to enhance its therapeutic potential against chemobrain. An amorphous ferulic acid loaded leucin solid dispersion (FA-Leu SD) was prepared by utilizing amino acid through spray-drying technique. The solid-state characterization was carried out via Fourier-transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and field emission scanning electron microscopy (FE-SEM). Additionally, in-vitro release studies and antioxidant assay were also performed along with in-vivo locomotor, biochemical and histopathological analysis. The physical properties showed that FA-Leu SD so formed exhibited spherical, irregular surface hollow cavity of along with broad melting endotherm as observed from FE-SEM and DSC results. The XRD spectra demonstrated absence of sharp and intense peaks in FA-Leu SD which evidenced for complete encapsulation of drug into carrier. Moreover, in-vitro drug release studies over a period of 5 h in PBS (pH 7.4) displayed a significant enhanced release in the first hr (68. 49 ± 5.39%) and in-vitro DPPH assay displayed greater antioxidant potential of FA in FA-Leu SD. Furthermore, the in-vivo behavioral findings of FA-Leu SD (equivalent to 150 mg/kg of free FA) exhibited positive results accompanied by in-vivo biochemical and molecular TNF-α showed a significant difference (p < 0.001) vis-à-vis DOX treated group upon DOX + FA-Leu SD. Additionally, histopathological analysis revealed neuroprotective effects of FA-Leu SD together with declined oxidative stress due to antioxidant potential of FA which was induced by anticancer drug doxorubicin (DOX). Overall, the above findings concluded that spray-dried FA-Leu SD could be useful for the treatment of chemotherapy induced cognitive impairment.

Recent Trends in Nanocarrier-Based Drug Delivery System for Prostate Cancer.

Prostate cancer remains a significant global health concern, requiring innovative approaches for improved therapeutic outcomes. In recent years, nanoparticle-based drug delivery systems have emerged as promising strategies to address the limitations of conventional cancer chemotherapy. The key trends include utilizing nanoparticles for enhancing drug delivery to prostate cancer cells. Nanoparticles have some advantages such as improved drug solubility, prolonged circulation time, and targeted delivery of drugs. Encapsulation of chemotherapeutic agents within nanoparticles allows for controlled release kinetics, reducing systemic toxicity while maintaining therapeutic efficacy. Additionally, site-specific accumulation within the prostate tumor microenvironment is made possible by the functionalization of nanocarrier with targeted ligands, improving therapeutic effectiveness. This article highlights the basics of prostate cancer, statistics of prostate cancer, mechanism of multidrug resistance, targeting approach, and different types of nanocarrier used for the treatment of prostate cancer. It also includes the applications of nanocarriers for the treatment of prostate cancer and clinical trial studies to validate the safety and efficacy of the innovative drug delivery systems. The article focused on developing nanocarrier-based drug delivery systems, with the goal of translating these advancements into clinical applications in the future.

GABA-transaminase: A Key Player and Potential Therapeutic Target for Neurological Disorders.

Neurological disorders such as epilepsy, autism, Huntington's disease, multiple sclerosis, and Alzheimer's disease alter brain functions like cognition, mood, movements, and language, severely compromising the well-being of persons, suffering from their negative effects. The neurotransmitters (GABA, glutamate, norepinephrine, dopamine) are found to be involved in neuronal signaling and neurotransmission. GABA, a "commanding neurotransmitter" is directly or indirectly associated with various neurological disorders. GABA is metabolized to succinic semialdehyde by a mitochondrial gamma-aminobutyric acid-transaminase (GABA-T) enzyme. Therefore, the alterations in the GABA performance in the distinct regions of the brain via GABA-T overstimulation or inhibition would play a vital role in the pathogenesis of various neurological disorders. This review emphasizes the leading participation of GABA-T in neurological disorders like Huntington's disease, epilepsy, autism, Alzheimer's disease, and multiple sclerosis. In Huntington's disease, epilepsy, and multiple sclerosis, the surfeited performance of GABA-T results in diminished levels of GABA, whereas in autism, the subsidence of GABA-T activity causes the elevation in GABA contents, which is responsible for behavioral changes in these disorders. Therefore, GABA-T inhibitors (in Huntington's disease, epilepsy, and multiple sclerosis) or agonists (in autism) can be used therapeutically. In the context of Alzheimer's disease, some researchers favor the stimulation of GABA-T activity whereas some disagree with it. Therefore, the activity of GABA-T concerning Alzheimer's disease is still unclear. In this way, studies of GABA-T enzymatic activity in contrast to neurological disorders could be undertaken to understand and be considered a therapeutic target for several GABA-ergic CNS diseases.

Quality by Design Assisted Development of Luliconazole Transethosomes in Gel for the Management of Candida albicans Infection.

The objective of this study was to develop and evaluate a novel vesicular formulation of luliconazole (LUL) for the management of Candida albicans infection through a topical route. LUL-loaded transethosomes (LUL-TE) were prepared by the film hydration method and various independent and dependent variables were optimized using the Box-Behnken design. Selected critical material attributes were the content of phospholipids (X1), concentration of ethanol (X2), and amount of sodium cholate (X3). Formulated LUL-TE were characterized for percent entrapment efficiency, percent drug loading, vesicle size, and polydispersity index (PDI) and were incorporated into the carbomer gel base and further evaluated for gel characterizations. The prepared transethosomal gel (LUL-TE-CHG) was evaluated for pH, spreadability, viscosity, antifungal activity, and in vitro study. From the observed results, it was evident that the prepared LUL-TE-CHG was in the desired pH (6.2 ± 0.45), spreadability [8.3 ± 0.42 g/(cm·s)], viscosity (236.1-19.2.26 mPa·s), nanovesicle size (252 ± 9.82), entrapment efficiency (85% ± 5.24%), zeta potential (-34.05 ± 3.52 mV), and PDI (0.233 ± 0.002). The zone of inhibition results suggested that the LUL-TE-CHG formulation has the highest antifungal activity, that is, 5.83 ± 0.15 mm3. The in vitro results showed that drug release within 2 h was 18.1% ± 2.0% and after that sustained release action, 83.2% ± 1.7% within 8 h. Finally, to confirm the therapeutic efficacy of the developed formulation, fungal infection was induced by using C. albicans in Wistar rats. In vivo, skin irritation study and histopathology studies were performed in the disease-induced model. Animal experiments revealed that LUL-TE-CHG has significantly improved the diseased condition in Wistar rats. The results observed from the skin permeation and skin deposition profile ensure that the prepared novel LUL-loaded TE system had a higher permeation rate and increased retention time compared with LUL-CHG. The hydrogel incorporated with LUL could be a novel approach with safe and effective fungal treatment.

Investigation of the anti-cancer potential of epoxyazadiradione in neuroblastoma: experimental assays and molecular analysis.

Neuroblastoma, the most common childhood solid tumor, originates from primitive sympathetic nervous system cells. Epoxyazadiradione (EAD) is a limonoid derived from Azadirachta indica, belonging to the family Meliaceae. In this study, we isolated the EAD from Azadirachta indica seed and studied the anti-cancer potential against neuroblastoma. Herein, EAD demonstrated significant efficacy against neuroblastoma by suppressing cell proliferation, enhancing the rate of apoptosis and cycle arrest at the SubG0 and G2/M phases. EAD enhanced the pro-apoptotic Caspase 3 and Caspase 9 and inhibited the NF-kß translocation in a dose-dependent manner. In order to identify the specific EAD target, a gel-free quantitative proteomics study on SH-SY5Y cells using Liquid Chromatography with tandem mass spectrometry was done in a dose-dependent manner, followed by detailed bioinformatics analysis to identify effects on protein. Proteomics data identified that Enolase1 and HSP90 were up-regulated in neuroblastoma. EAD inhibited the expression of Enolase1 and HSP90, validated by mRNA expression, immunoblotting, Enolase1 and HSP90 kit and flow-cytometry based bioassay. Molecular docking study, Molecular dynamic simulation, and along with molecular mechanics/Poisson-Boltzmann surface area analysis also suggested that EAD binds at the active site of the proteins and were stable throughout the 100 ns Molecular dynamic simulation study. Overall, this study suggested EAD exhibited anti-cancer activity against neuroblastoma by targeting Enolase1 and HSP90 pathways.Communicated by Ramaswamy H. Sarma.

Targeted Delivery of Doxorubicin as a Potential Chemotherapeutic Agent.

Cancer is the world's fifth-most significant cause of related death and the second most commonly diagnosed malignancy among women and men. Some of its types, like brain cancer, colon cancer, and breast cancer, are threatened and considered fatal. These cancers are more prevalent in developed and underdeveloped countries. Still, doxorubicin is considered a gold standard drug and the only molecule used in multiple types of cancer. However, the toxicity and biopharmaceutical hindrances like poor solubility, poor permeability, and high in vivo fate of drug cause low systematic circulation. The creation of a multifunctional nanocarrier for targeted medication delivery that can transport and accumulate drugs at cancer sites should help to lessen the likelihood of side effects. These nanocarriers improve the targetability of infected tissue and the therapeutic circulation of drugs. Hence, the present review focused on the improved targetability of doxorubicin using different nanocarriers and its possible outcomes in different types of cancer. Moreover, the prior art also discussed various challenges and prospects of improved doxorubicin delivery and its therapeutic outcomes.

Identifying novel putative ERK1/2 inhibitors via hybrid scaffold hopping -FBDD approach.

ERK inhibitors are continuously explored by the researchers due to their clinical significance in resistant tumor cell lines. Though many ERK1/2 inhibitors are reported, there is still need to identify novel hits to increase the number of molecules in clinical trials. Therefore, an urgent need is to examine the existing chemical space for ERK inhibitory potential with an aim to develop novel scaffolds which can act as potent ERKs inhibitors. In this study, Ulixertinib, a known ERK2 inhibitor was selected to perform scaffold hopping to discover new scaffolds with similar binding mode followed by molecular docking analysis of the hits with highest similarity score to determine, both the binding mode and affinity in the catalytic domain of ERK2. The top hit was then subjected to FBDD to identify side chains which could enhance the binding affinity in the catalytic domain of ERK2. Again, docking analysis was performed to validate and determine their binding affinity. Further the top hit identified after docking analysis was subjected to molecular dynamic simulations. Overall, 3 hits (ligand 6, 8 and 10) were found to possess optimum pharmacodynamic and pharmacokinetic profile, in-silico, to be claimed as putative ERK2 inhibitors. This study disclosed new lead molecules with putative ERK2 inhibitory potential which may be further validated via biological evaluation.

IL-23/Th17 Axis: A Potential Therapeutic Target of Psoriasis.

Psoriasis is an immune-mediated skin disease that leads to the initiation of abnormal production of inflammatory mediators and keratinocytes hyper-proliferation. Th-1 cell expressing cytokines such as IL-1ß and TNF-α have been the important hallmarks in the management of psoriasis. However, investigations carried out in the previous few years underline the involvement of another subset of T helper cells, i.e. Th-17 in psoriasis exacerbation, and hence have become the point of focus now. The immunopathogenesis of Th-17 is the result of the IL-23/Th-17 axis. It involves the release of IL-17 and IL-22 in response to the activated NF-kß dependent activation of IL-23. The function of human Th-17 cells, as well as the crucial role of IL-23/Th-17 axis in the exacerbation of psoriasis and treatment, have been well explored. Therefore, considering IL-23/Th17 axis as a pertinent therapeutic target in immune driven disorders, extensive investigations are now highlighting the utility of biopharmaceuticals and/or biological agents acting on these targets. Here, we review the IL-23/Th-17 axis based therapeutic targets, different types of active moieties based on their source of availability and most useful USFDA approved Mabs targeting the IL-23/Th17 axis in psoriasis for a better understanding of the future possibilities in this area.

Development and In Vivo Evaluation of Pectin Based Enteric Coated Microparticles Loaded with Mesalamine and Saccharomyces boulardii for Management of Ulcerative Colitis.

Mesalamine is the first-line choice of drug for ulcerative colitis management. However, due to the nontargeted delivery of mesalamine, it shows side effects. The possible impact of mesalamine can be improved by coated microparticles in combination with S. boulardii for targeted delivery to the colon with the prevention of unwanted side effects. In this work, pectin-based mesalamine and S. boulardii loaded microparticles were prepared by dehydration technique and coated by an oil-in-oil solvent evaporation method and characterized by Scanning electron microscopy (SEM), X-ray diffraction, and zeta analysis. 2, 4, 6-Trinitrobenzenesulfonic acid was used for the induction of colitis. The anti-inflammatory effects of coated microparticles on Caco-2 cells were assessed by the determination of interleukin (IL)-8 concentration. In addition, the impact of coated microparticles on the concentration of colonic enzymes, including myeloperoxidase (MPO), lipid peroxides, and glutathione (GSH), were also evaluated. Moreover, hematological parameters, including white blood cell (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), were assessed. SEM data revealed that all the prepared coated microparticles had an almost spherical shape. The X-ray powder diffraction analysis of uncoated and coated microparticles showed maximum stability without any interaction. The particle size of uncoated and coated microparticles was 9.14 and 15.61 µm, respectively. The zeta potential of uncoated and coated microparticles was observed to be -26.78 and -29.36 mV, respectively. The prepared coated microparticles decreased the levels of lipid peroxides, MPO, and GSH significantly in colitis. In the Caco-2 cell culture model, the concentration of IL-8 is decreased significantly. The hematological observations confirmed that the prepared formulation showed a promising decrease in the levels of WBC, CRP, and ESR in diseased animals. Animal experiments revealed that cellulose acetate phthalate coated microparticles of mesalamine and S. boulardii significantly improved the colitis disease conditions of Wistar rats. Hence, cellulose acetate phthalate-coated microparticles of mesalamine and S. boulardii could be recommended as adjuvant therapy to achieve a synergistic effect in the management of UC. Lay summary Mesalamine is the drug of choice for the management of ulcerative colitis (UC), which inhibits mediators responsible for inflammation. We investigated the in vivo effects of cellulose acetate phthalate-coated microparticles of mesalamine with Saccharomyces boulardii (probiotic) for their efficacy against UC. Our findings evidenced that the combination of mesalamine with S. boulardii showed a synergistic effect in the 2,4,6- trinitrobenzene sulfonic acid-induced colitis model by reducing the inflammation and maintains the macroscopic features. From the observed results, it can be concluded that S. boulardii can be used to enhance the individual drug's effect in the therapeutic management of UC.

Development and characterisation of clobetasol propionate loaded Squarticles as a lipid nanocarrier for treatment of plaque psoriasis.

Aim: The aim of this project is to improve the therapeutic effectiveness, permeation and retention of clobetasol propionate in sebaceous glands by reporting the use of Squarticles as lipidic nanosystem.Methods: Homogenisation method is used for the formulation of Squarticles (nanoemulgel) which was characterised on the basis of size, polydispersity index (PDI), viscosity, spreadability, DSC, % in vitro release, in vitro skin permeation deposition studies, and in vivo studies, scanning electron microscopic (SEM) and physical storage stability studies were done at different temperature conditions, i.e. 4 ± 2 °C, 25 ± 2 °C and 45 ± 2 °C for a period of 6 months for drug and formulation.Result: The morphological characterisation of prepared nanoemulsion shows small spherical shape and uniform size distribution as observed in the Scanning electron microscopic (SEM), having mean size (240.5 ± 9.2) and mean size distribution (0.282 ± 0.03) and zeta potential (-51.21). The drug release from optimised nanoemulsion (F2) in PBS (pH 5.5) was approximately 84.24 ± 1.35%, nanoemulgel formulations showed the release of 66.83 ± 2.05% while marketed gel showed the release of 57.67 ± 1.63% after 24 h. The cumulative percentage retention of clobetasol propionate loaded nanoemulgel was 63 ± 1.28% which was more than the marketed formulation (23.12% ±0.54). Physical stability studies show that formulation is more stable in cold condition. Further, the stability of active ingredient in gel formulation was determined using HPLC which shows around 15 ± 0.84% of loss in its activity.Conclusion: The present work has demonstrated the use of Squarticles as a novel carrier for treatment of plaque psoriasis by enhancing the better permeation, increasing skin retention, and enhances the effect of drug. The study also shows that the formulation is more stable in cold condition.

Role of sulphur-heterocycles in medicinal chemistry: An update.

From many decades, S-heterocycles have maintained their status as an important part and core of FDA approved drugs and medicinally active compounds. With exhaustive exploration of nitrogen heterocycles in medicinal chemistry, researchers have shifted their interest towards other heterocycles, especially, S-heterocycles. Thus several attempts have been made to synthesize a variety of new sulphur containing compounds with high medicinal value and low toxicity profile, in comparison to previous N-heterocycles. Till today, S-heterocycle containing compounds have been largely reported as anticancer, antidiabetic, antimicrobial, antihypertension, antivral, antinflammatory etc. In this review, the authors have tried to provide a critical analysis of synthesis and medicinal attributes of sulphur containing heterocycles such as thiirane, thiophene, thiazole, thiopyran, thiazolidine etc reported within last five years to emphasize the significance and usefulness of these S-heterocycles in the drug discovery process.