Development, characterization, and evaluation of withaferin-A and artesunate-loaded pH-responsive acetal-dextran polymeric nanoparticles for the management of malaria.

Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical challenge in malaria management. In the present study, we have proposed a combinatorial approach, utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria. The optimized WS-3 and Art Ac-Dex NPs demonstrated enhanced pH-responsive release profiles under parasitophorous mimetic conditions (pH 5.5). Computational molecular modeling reveals that Ac-Dex's polymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), preventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex NPs reveals a 1-1.5-fold reduction in IC50 values compared to pure drug against the 3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100 mg/kg) and Art Ac-Dex NPs (30 mg/kg) to Plasmodium berghei-infected mice resulted in 78.11 % and 100 % inhibition of parasitemia. Notably, the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications.

Development of Betulin-Loaded Nanostructured Lipid Carriers for the Management of Imiquimod-Induced Psoriasis.

Psoriasis is a complex and persistent autoimmune skin disease. The present research focused on the therapeutic evaluation of betulin-loaded nanostructured lipid carriers (BE-NLCs) towards managing psoriasis. The BE-NLCs were synthesized using the emulsification cum solidification method, exhibiting a spherical shape with a particle size of 183.5±1.82nm and a narrow size distribution window (PDI: 0.142±0.05). A high zeta potential -38.64±0.05mV signifies the relative stability of the nano-dispersion system. BE-NLCs show a drug loading and entrapment efficiency of 47.35±3.25% and 87.8±7.86%, respectively. In vitro release study, BE NLCs show a cumulative percentage release of 90.667±5.507% over BE-sol (57.334±5.03%) and BD-oint (42±4.58%) for 720min. In an ex vivo 24-h permeation study, % cumulative amount permeated per cm2 was found to be 55.667±3.33% from BE-NLCs and 32.012±3.26% from BE-sol, demonstrating a better permeability of 21.66% when compared to the standard formulation BD-oint. The in vivo anti-psoriatic activity in the IMQ-induced model shows topical application of BE-sol, BE-NLCs, and BD-oint resulted in recovery rates of 56%, 82%, and 65%, respectively, based on PASI (Psoriasis Area and Severity Index) score. Notably, BE-NLCs demonstrated a more significant reduction in spleen mass, indicating attenuation of the local innate immune system in psoriatic mice. Reductions in TNF-α, IL-6, and IL-17 levels were observed in both BE-sol and BE-NLCs groups compared to the disease control (DC) group, with BE-NLCs exhibiting superior outcomes (74.05%, 44.76%, and 49.26% reduction, respectively). Soy lecithin and squalene-based NLCs could be better carrier system for the improvement of the therapeutic potential of BE towards management of psoriasis.

Identification of starvation-mimetic bioactive phytocomponent from Withania somnifera using in-silico molecular modelling and flow cytometry-based analysis for the management of malaria.

Multidrug resistance episodes in malaria increased from 3.9% to 20% from 2015 to 2019. Synchronizing the clinical manifestation in chronological sequence led to a unique impression on glucose demand (increased up to 100-fold) by the parasite-infected RBCs. Hence, restriction in the glucose uptake to parasite-infected RBCs could be an alternative approach to conquer the global burden of malaria to a greater extent. A C28 steroidal lactone Withaferin A (WS-3) isolated from Withania somnifera leave extract shows better thermodynamically stable interactions with the glucose transporters (GLUT-1 and PfHT) to standard drugs metformin and lopinavir. MD simulations for a trajectory period of 100 ns reflect stable interactions with the interactive amino acid residues such as Pro141, Gln161, Gln282, Gln283, Trp388, Phe389, and Phe40, Asn48, Phe85, His168, Gln169, Asn311 which potentiating inhibitory activity of WS-3 against GLUT-1 and PfHT respectively. WS-3 was non-hemotoxic (%hemolysis <5%) for a high concentration of up to 1 mg/ml in the physiological milieu. However, the %hemolysis significantly increased up to 30.55 ± 0.929% in a parasitophorous simulated environment (pH 5.0). Increased hemolysis of WS-3 could be due to the production of ROS in an acidic environment. Further, the inhibitory activity of WS-3 against both glucose transporters was supported with flow cytometry-based analysis of parasite-infected RBCs. Results show that WS-3 has low mean fluorescence intensities for both target proteins compared to conventional drugs, suggesting a potential sugar transporter inhibitor against GLUT-1 and PfHT for managing malaria. Communicated by Ramaswamy H. Sarma.

Isolation and structure elucidation of a steroidal moiety from Withania somnifera and in silico evaluation of antimalarial efficacy against artemisinin resistance Plasmodium falciparum kelch 13 protein.

According to the 2021 Malaria report, 241 million clinical episodes with 627000 deaths penalty was estimated across the worldwide. However, mutation in the propeller domain of Plasmodium falciparum kelch 13 protein resulted in longer parasite clearance time following an artemisinin-based treatment and had a greater survival rate of ring-stage parasites even after a brief exposure to a high dose of artesunate. Clinical manifestations become more complex and worse with the emerging trend of drug resistance against artemisinin derivatives and the poor effectiveness of malaria vaccination drive. Steroidal lactone (withanolide) moiety (C-28) isolated from methanolic leaf extract Withania somnifera show a greater affinity towards Pfkelch 13 protein in comparison to the artemisinin derivatives (artesunate, artemether). The isolated compound was characterized to be withaferin A with a percentage yield of 29.01% w/w in chloroform fraction, 1.75% w/w in methanolic extract, and 0.29% w/w in raw leaf powder. Structure-based analysis shows that withaferin A (docking score -8.253, -9.802) has a higher affinity for two distinct binding pockets I and II of the Plasmodium falciparum kelch 13 protein than artesunate (docking score -4.470, -3.656). Further, Gibbs binding free energy signifies thermodynamic stability of the docked complex of withaferin A (-43.25, -43.76 Kcal/mol) in comparison to artesunate docked complex (-8.49, -5.75 Kcal/mol). The pharmacokinetic profile of withaferin A shows more drug-likeness characteristics without violating Jorgensen's rule of three, and Lipinski's rule of five. Hence above experimental findings suggest withaferin A could be a suitable therapeutic adjunct for preclinical evaluation of antimalarial potentiality in artemisinin-resistant malaria. HIGHLIGHTsMalaria is a life-threatening parasitic disease caused by Plasmodium species.The emerging trend of artemisinin resistance and severe side effects (CNS and cardiotoxicity) are the potential challenges faced by antimalarial therapeutics.Artemisinin-mimic potentiality (ROS-mediated antiparasitic activity) of withaferin A shows a strong affinity towards artemisinin resistance Plasmodium falciparum kelch 13 protein.The pharmacokinetic profiling of the withaferin A signifies its drug-likeness characteristics without violating Jorgensen's rule of three, and Lipinski's rule of five.Based on molecular docking and pharmacokinetic profiling, withaferin A could be a suitable therapeutic adjunct for preclinical investigation of antimalarial potentiality in artemisinin-resistant malaria.Communicated by Ramaswamy H. Sarma.

Phytochemical investigation, structural elucidation, in silico study and anti-psoriatic activity of potent bioactive from Betula utilis.

Psoriasis is a chronic autoimmune pathological condition characterized by hyperactivation of proinflammatory cytokines (IL-6, TNF-α, IL-17, IL-23, etc.). Severe drug-associated toxicities like hepatotoxicity and nephrotoxicity (Methotrexate), teratogenicity (Tazarotene), hypercholesterolemia (Cyclosporine) and hypercalcemia (tacalcitol), are the forefront challenges that demand an alternative approach for the treatment of psoriasis. In the present study, a natural lead molecule 'Betulin' (BE, lup-20(29)-ene-3b,28-diol) was isolated from Betula utilis and subsequently, structure-based molecular docking was employed to identify the molecular target for psoriasis. The computational analysis reflects better affinity of BE towards pro-inflammatory cytokine as compared to standard drugs. Apart from this BE shows a greater affinity towards the overexpressed Glut-1 receptor in comparison to standard drug Metformin (Met). Based on the in silico screening the isolated lead compound was further processed for the evaluation of anti-psoriatic activity via imiquimod (IMQ 5%) induced psoriasis-like skin inflammation model. In vivo screening models were characterized by different parameters (psoriasis area and severity index (PASI) scores, macroscopically and behavioral evaluation, splenomegaly, cytokine levels and histological changes) and compared among the experimental groups. The experimental finding reflects comparable results of PASI score, i.e., 57.14% and 61.9% recovery of test BE-solution (180 mg/kg) and standard Betamethasone di-propionate ointment (BD-oint.0.5 mg/g), respectively. Focusing on other parameters, BE shows relative results such as an enhanced macroscopically with behavioral conditions, reducing the expression of proinflammatory cytokine as well as restoring histological changes with that of BD. These findings suggest that BE-isolated phytoconstituents from Betula utilis could be a potential agent and a step closer to psoriasis treatment. HIGHLIGHTPsoriasis is a multifaceted, immunologically mediated disease consequences production of high levels of proinflammatory mediators and overexpression of Glut-1 transporters that trigger keratinocyte proliferation and inflammatory cascades.A Himalayan silver birch, Betula utilis (Bhojpatra) contains many steroidal terpenes which are responsible for various pharmacological activities that could be exploited in drug development in psoriasis.The computational analysis of BE reflects a better affinity toward the proinflammatory cytokines with their target receptors and indicates a satisfactory range with a slight deviation from Jorgensen and Lipinski's rule and possesses a significant drug choice for psoriasis.Preclinical findings of BE-solution (BE-sol) give a positive response towards IMQ-induced psoriasis-like skin inflammation model.[Figure: see text]Communicated by Ramaswamy H. Sarma.

Chitosan as a potential biomaterial for the management of oral mucositis, a common complication of cancer treatment.

Oral mucositis is a serious issue in patients receiving oncological therapies. Mucosal protectants considered to be one of the preferred choices used in the management of mucositis. However, the protective efficacy of currently available mucosal protectants has been significantly compromised due to poor retention, lack of lubrication, poor biodegradability, and inability to manage secondary complications. Chitosan is a promising material for mucosal applications due to its beneficial biomedical properties. Chitosan is also anti-inflammatory, anti-microbial, and capable of scavenging free radicals, makes it a good candidate for the treatment of oral mucositis. Additionally, chitosan's amino polysaccharide skeleton permits a number of chemical alterations with better bioactive performance. This article provides a summary of key biological properties of chitosan and its derivatives that are useful for treating oral mucositis. Current literature evidence shows that Chitosan has superior mucosal protective properties when utilised alone or as delivery systems for co-encapsulated drugs.

Metal nanoparticles against multi-drug-resistance bacteria.

Antimicrobial-resistant (AMR) bacterial infections remain a significant public health concern. The situation is exacerbated by the rapid development of bacterial resistance to currently available antimicrobials. Metal nanoparticles represent a new perspective in treating AMR due to their unique mechanisms, such as disrupting bacterial cell membrane potential and integrity, biofilm inhibition, reactive oxygen species (ROS) formation, enhancing host immune responses, and inhibiting RNA and protein synthesis by inducing intracellular processes. Metal nanoparticles (MNPs) properties such as size, shape, surface functionalization, surface charges, and co-encapsulated drug delivery capability all play a role in determining their potential against multidrug-resistant bacterial infections. Silver, gold, zinc oxide, selenium, copper, cobalt, and iron oxide nanoparticles have recently been studied extensively against multidrug-resistant bacterial infections. This review aims to provide insight into the size, shape, surface properties, and co-encapsulation of various MNPs in managing multidrug-resistant bacterial infections.

Trends in iron oxide nanoparticles: a nano-platform for theranostic application in breast cancer.

Breast cancer (BC) is the deadliest malignant disorder globally, with a significant mortality rate. The development of tolerance throughout cancer treatment and non-specific targeting limits the drug's response. Currently, nano therapy provides an interdisciplinary area for imaging, diagnosis, and targeted drug delivery for BC. Several overexpressed biomarkers, proteins, and receptors are identified in BC, which can be potentially targeted by using nanomaterial for drug/gene/immune/photo-responsive therapy and bio-imaging. In recent applications, magnetic iron oxide nanoparticles (IONs) have shown tremendous attention to the researcher because they combine selective drug delivery and imaging functionalities. IONs can be efficaciously functionalised for potential application in BC therapy and diagnosis. In this review, we explored the current application of IONs in chemotherapeutics delivery, gene delivery, immunotherapy, photo-responsive therapy, and bio-imaging for BC based on their molecular mechanism. In addition, we also highlighted the effect of IONs' size, shape, dimension, and functionalization on BC targeting and imaging. To better comprehend the functionalization potential of IONs, this paper provides an outline of BC cellular development. IONs for BC theranostic are also reviewed based on their clinical significance and future aspects.Graphical Abstract[Formula: see text].

Current Breast cancer treatment resists due to the development of drug tolerance throughout cancer treatment and non-specific drug targeting.Magnetic IONs are being utilised for the therapy and bio-imaging of breast cancer by targeting overexpressed biomarkers, proteins, and receptors in breast cancer progression.Physical properties of IONs, such as size, shape, and dimensions, also alter their therapeutic and imaging responses.Iron oxide nanoparticles can be efficaciously functionalised based on breast cancer molecular mechanisms for potential application in breast cancer drug delivery, gene delivery, immunotherapy, photo responsive therapy, and bio-imaging.

Clinical Interventions and Budding Applications of Probiotics in the Treatment and Prevention of Viral Infections.

Over the period, viral infections remain the utmost challenge in front of the scientific community. Continuous shifting and drafting of viral antigenic peptides are the main drivers in the development of antiviral drug resistance. The resurgence of disease, difficulties facing the development of an effective vaccine and undesirable immunological outcomes, foster to develop an alternative therapeutic approach to combat viral infections. Biomimetic nature of viral particles competent to invade the host cell by downregulating the expression of immune responsive cells. To revive from such complications, strengthening the innate immunity places first and foremost defense mechanisms to restrict viral infiltration. Variegated probiotic strains show antiviral activity by stimulating the macrophage and dendritic cell to secret the inflammation response mediated chemokines and cytokines, production of antimicrobial peptides, and biosurfactants, modulate the antiviral gens expression, alter the proportional functionality of CD4+CD25+Foxp3+ regulatory cells (Tregs), etc. With the appreciation for the antiviral activity and health benefits, however, the selectivity of specific probiotic strain from the diversified microbiome, the interactive molecular mechanism of probiotics, viability and sustainability of a specific number of a probiotic strain at the end of the shelf life, stability, selection of the formulation materials, identification and validation of the key process parameters have the major challenges for the development of an effective probiotic therapy against viral infections.

Recent Advancement in Topical Nanocarriers for the Treatment of Psoriasis.

Psoriasis is a life-threatening autoimmune inflammatory skin disease, triggered by T lymphocyte. Recently, the drugs most commonly used for the treatment of psoriasis include methotrexate (MTX), cyclosporine (CsA), acitretin, dexamethasone, and salicylic acid. However, conventional formulations due to poor absorptive capacity, inconsistent drug release characteristics, poor capability of selective targeting, poor retention of drug molecules in target tissue, and unintended skin reactions restrict the clinical efficacy of drugs. Advances in topical nanocarriers allow the development of prominent drug delivery platforms can be employed to address the critical issues associated with conventional formulations. Advances in nanocarriers design, nano-dimensional configuration, and surface functionalization allow formulation scientists to develop formulations for a more effective treatment of psoriasis. Moreover, interventions in the size distribution, shape, agglomeration/aggregation potential, and surface chemistry are the significant aspects need to be critically evaluated for better therapeutic results. This review attempted to explore the opportunities and challenges of current revelations in the nano carrier-based topical drug delivery approach used for the treatment of psoriasis.