Viral infection and host immune response in diabetes.

Diabetes, a chronic metabolic disorder disrupting blood sugar regulation, has emerged as a prominent silent pandemic. Uncontrolled diabetes predisposes an individual to develop fatal complications like cardiovascular disorders, kidney damage, and neuropathies and aggravates the severity of treatable infections. Escalating cases of Type 1 and Type 2 diabetes correlate with a global upswing in diabetes-linked mortality. As a growing global concern with limited preventive interventions, diabetes necessitates extensive research to mitigate its healthcare burden and assist ailing patients. An altered immune system exacerbated by chronic hyperinflammation heightens the susceptibility of diabetic individuals to microbial infections, including notable viruses like SARS-CoV-2, dengue, and influenza. Given such a scenario, we scrutinized the literature and compiled molecular pathways and signaling cascades related to immune compartments in diabetics that escalate the severity associated with the above-mentioned viral infections in them as compared to healthy individuals. The pathogenesis of these viral infections that trigger diabetes compromises both innate and adaptive immune functions and pre-existing diabetes also leads to heightened disease severity. Lastly, this review succinctly outlines available treatments for diabetics, which may hold promise as preventive or supportive measures to effectively combat these viral infections in the former.

siRNA-Based Novel Therapeutic Strategies to Improve Effectiveness of Antivirals: An Insight.

Since the ground-breaking discovery of RNA interference (RNAi), scientists have made significant progress in the field of small interfering RNA (siRNA) treatments. Due to severe barriers to the therapeutic application of siRNA, nanoparticle technologies for siRNA delivery have been designed. For pathological circumstances such as viral infection, toxic RNA abnormalities, malignancies, and hereditary diseases, siRNAs are potential therapeutic agents. However, systemic administration of siRNAs in vivo remains a substantial issue due to a lack of "drug-likeness" (siRNA are relatively larger than drugs and have low hydrophobicity), physiological obstacles, and possible toxicities. This write-up covers important accomplishment in the field of clinical trials and patents specially based of siRNAs using targeting viruses. Furthermore, it offers deep insight of nanoparticle applied for siRNA delivery and strategies to improve the effectiveness of antivirals.

Nano-strategies as Oral Drug Delivery Platforms for Treatment of Cancer: Challenges and Future Perspectives.

Oral drug administration is the oldest and widely used method for drug administration. The objectives behind developing an oral drug delivery for the treatment of cancer are to achieve low cost treatment by utilizing novel techniques to target cancer through gut-associated lymphoid tissue (GALT) and to enhance patient comfort and compliance through a hospital-free treatment leading to "Chemotherapy at Home." Unfortunately, due to the physiological environment of the GIT and physicochemical properties of drug candidate, the efficacy of oral drug delivery methods is limited in the treatment of cancer. Due to their low hydrophilicity, high P-gp efflux and restricted intestinal permeability most of the anti-cancer drugs fail to achieve oral bioavailability. The review focuses on the efforts, challenges, opportunities and studies conducted by scientists worldwide on the oral administration of anticancer medications via nanocarriers such as liposomes, SLNs and dendrimers, because of their potential to overcome the epithelial barrier associated with GALT, as well as the applications of different polymers in targeting the cancer. The oral delivery can set newer horizons in cancer therapy to make it more patient friendly.

A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome.

BACKGROUND: The treatment of primary CNS lymphoma (PCNSL) comprises high dose methotrexate (HDMTX) based chemotherapy followed by whole brain radiotherapy (WBRT), the major drawback of which is long term neurotoxicity. We intended to assess the feasibility of response adapted WBRT in PCNSL in the Indian setting. METHODS: We screened 32 patients and enrolled 22 eligible patients with PCNSL from 2015 to 2017 in a prospective phase II trial. The patients underwent five 2-weekly cycles of induction chemotherapy with rituximab, methotrexate, vincristine, procarbazine. Patients with complete response(CR) to induction chemotherapy were given reduced dose WBRT 23.4 Gy/13 fractions/2.5 weeks while those with partial response (PR), stable or progressive disease (SD or PD) were given standard dose WBRT 45 Gy/25 fractions/5 weeks. Thereafter two cycles of consolidation chemotherapy with cytarabine were given. The primary endpoints of the study were assessment of response rate (RR) and progression free survival (PFS). The secondary endpoints of the study were assessment of overall survival (OS), toxicity profile of treatment and serial changes in quality of life and neuropsychological parameters. RESULTS: Out of 19 patients who completed HDMTX based chemotherapy, 10 (52.63%) patients achieved CR, 8 (42.11%) patients had PR and 1 patient had PD. After a median follow-up period of 11.25 months, the estimated median OS was 19 months. The actuarial rates of PFS and OS were respectively 94.1 and 68.2% at 1 year and 50.2 and 48.5% at 2 years. Three patients in reduced dose WBRT arm had recurrence and two of them died of progressive disease, whereas there was no recurrence or disease related death in standard dose WBRT arm. On univariate analysis of PFS, age ≤ 50 years and use of standard dose WBRT (45 Gy) led to significantly improved outcome (p value 0.03 and 0.02 respectively). CONCLUSION: In patients with PCNSL, reduced dose WBRT after CR to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression and early death. Trial Registration No CTRI/2015/10/006268.

Small interfering RNA (siRNA) as a potential gene silencing strategy for diabetes and associated complications: challenges and future perspectives.

Objective: This article critically reviews the recent search on the use of Small Interfering RNA (siRNA) in the process of gene regulation that has been harnessed to silence specific genes in various cell types, including those involved in diabetes complications. Significance: Diabetes, a prevalent and severe condition, poses life-threatening risks due to elevated blood glucose levels. It results from inadequate insulin production by the pancreas or ineffective insulin utilization by the body. Recent research suggests siRNA could hold promise in addressing diabetes complications. Methods: In this review, we discussed several subjects, including diabetes; its function, and common treatment options. An in-depth analysis of gene silencing method for siRNA and role of siRNA in diabetes, focusing on its impact on glucose homeostasis, diabetic retinopathy, wound healing, diabetic nephropathy and peripheral neuropathy, diabetic foot ulcers, diabetic atherosclerosis, and diabetic cardiomyopathy. Result: siRNA-based treatment has the potential to target specific genes without disrupting several other endogenous pathways, which decreases the risk of off-target effects. In addition, siRNA has the capability to provide long-term efficacy with a single dose which will reduce treatment options and enhance patient compliance. Conclusion: In the context of diabetic complications, siRNA has been explored as a potential therapeutic tool to modulate the expression of genes involved in various processes associated with diabetes-related issues such as Diabetic Retinopathy, Neuropathy, Nephropathy, wound healing. The use of siRNA in these contexts is still largely experimental, and challenges such as delivery to specific tissues, potential off-target effects, and long-term safety need to be addressed. Additionally, the development of siRNA-based therapies for clinical use in diabetic complications is an active area of research. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-024-01405-7.

Development of fucoidan/polyethyleneimine based sorafenib-loaded self-assembled nanoparticles with machine learning and DoE-ANN implementation: Optimization, characterization, and in-vitro assessment for the anticancer drug delivery.

This study aims to develop sorafenib-loaded self-assembled nanoparticles (SFB-SANPs) using the combined approach of artificial neural network and design of experiments (ANN-DoE) and to compare it with other machine learning (ML) models. The central composite design (CCD) and ML algorithms were used to screen the effects of concentrations of both the polymers (polyethyleneimine and fucoidan) on the outcome responses, i.e., particle size and entrapment efficiency with defined constraints. The prediction from different ML models (bootstrap forest, K-nearest neighbors, artificial neural network, generalized regression-lasso and support vector machines) were compared with ANN-DoE model. The ANN-DoE model showed better accuracy and predictability and outperformed all the other models. This depicted that the concept of using ANN and DoE combination approach provided the best, uncomplicated and cost-effective way to optimized the nanoformulations. The optimized formulation generated from the ANN-DoE combined model was further evaluated for characterization and anticancer activity. The optimized SFB-SANPs were prepared using the polyelectrolyte complexation method with Polyethyleneimine (PEI) as a cationic polymer and fucoidan (FCD) as an anionic. The SFB-SANPs were nanometric in size (280.4 ± 0.089 nm) and slightly anionic in nature (zeta potential = -6.03 ± 0.92 mV) with an encapsulation efficiency of 95.56 ± 0.30 %. The drug release from SFB-SANPs was controlled and sustained in the cancer microenvironment (pH 5.0). The SFB-SANPs were compatible with red blood cells (RBCs), and the % hemolysis was found to be <5.0 %. The anticancer activity of the SFB-SANPs exhibited an IC50 at 2.017 ± 0.516 µM against MDMB-231 cells, showing a significantly high inhibitory effect on breast cancer cell lines. Therefore, the nanocarriers developed using various ML tools inherit a huge promise in anticancer drug delivery.

Inhibition of cellular activation induced by platelet factor 4 via the CXCR3 pathway ameliorates Japanese encephalitis and dengue viral infections.

BACKGROUND: Activated platelets secrete platelet factor 4 (PF4), which contributes to viral pathogenesis. Recently, we reported the proviral role of PF4 in replication of closely related flaviviruses, Japanese encephalitis virus (JEV) and dengue virus (DENV). OBJECTIVES: This study aimed to investigate the detailed mechanism of PF4-mediated virus replication. METHODS: PF4-/- or wild-type (WT) mice were infected with JEV, and host defense mechanisms, including autophagic/interferon (IFN) responses, were assessed. WT mice were pretreated with the CXCR3 antagonist AMG487 that inhibits PF4:CXCR3 pathway. This pathway was tested in PF4-/- monocytes infected with DENV or in monocytes isolated from patients with DENV infection. RESULTS: PF4-/- mice infected with JEV showed reduced viral load and improved brain inflammation and survival. PF4-/- mice synthesized more IFN-α/ß with higher expression of phosphorylated IRF3 in the brain. PF4 treatment decreased IRF-3/7/9 and IFN-α/ß expression and suppressed autophagic LC3-II flux and lysosomal degradation of viral proteins in JEV-infected cells. PF4 increased the expression of P-mTOR, P-p38, and P-ULK1Ser757 and decreased expression of LC3-II. Decreased autophagosome-lysosome fusion in turn promoted DENV2 replication. The above processes were reversed by AMG487. Uninfected PF4-/- monocytes showed elevated LC3-II and autophagosome-lysosome fusion. Microglia of JEV-infected PF4-/- mice exhibited elevated LC3-II inversely related to viral load. Similarly, monocytes from PF4-/- mice showed reduced infection by DENV2. In patients with DENV infection, higher plasma PF4 and viral load were inversely correlated with LC3-II, LAMP-1, and lysosomal degradation of DENV-NS1 in monocytes during the febrile phase. CONCLUSION: These studies suggest that PF4 deficiency or inhibition of the PF4:CXCR3 pathway prevents JEV and DENV infection. The studies also highlight the PF4:CXCR3 axis as a potential target to develop treatment regimens against flaviviruses.

Chitosan based mucoadhesive nanoparticles of ketoconazole for bioavailability enhancement: formulation, optimization, in vitro and ex vivo evaluation.

PURPOSE: The conventional dosage form of Ketoconazole (KZ) shows poor absorption due to rapid gastric emptying. Chitosan based mucoadhesive nanoparticles (NPs) of KZ were developed to efficiently release drug at its absorption window i.e. stomach and the site of action i.e. esophagus. METHOD: The NPs were prepared by ionic gelation method. Concentration of polymer, cross-linking agent and ratio of drug/polymer as well as polymer/cross linking agent were optimized. RESULTS: NPs had 69.16 ± 5.91% mucin binding efficiency, particle size of 382.6 ± 2.384 nm, ζ potential of +48.1 mv and entrapment efficiency of 59.84 ± 1.088%. DSC thermogram indicated absence of any drug polymer interaction. The drug release was by controlled, non-fickian diffusion mechanism. Ex vivo diffusion studies were performed by emptying the stomach contents after 2 h to simulate in vivo gastric emptying. The results showed that drug diffusion from the solution across stomach mucosa stopped after emptying whereas that from the NPs continued upto 5 h. Hence we could conclude that the NPs must have adhered to the stomach mucosa and thereby would have been retained at this absorption site even after gastric emptying. CONCLUSION: The orally delivered KZ loaded mucoadhesive NPs can be used as an efficient carrier for delivering drug at its absorption window i.e. the stomach and the site of action i.e. esophagus even after gastric emptying.

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization, in vitro and in vivo pharmacokinetic studies.

OBJECTIVES: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS). METHODS: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3(2) factorial design was done using Polyox WSR 303 (X1) and HPMC K4M (X2) as independent variables and cumulative percentage drug released at 6 h (Q6h) as dependent variable. RESULTS: Optimized formulation showed floating lag time of 4-5 s, floated for more than 12 h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6 h. In vivo pharmacokinetic studies in rabbits showed Cmax of 189.96 ± 13.04 ng/mL and Tmax of 4 ± 0.35 h for GFDDS. The difference for AUC(0-T) and AUC(0-∞) between the test and reference formulation was statistically significant (p > 0.05). AUC(0-T) and AUC(0-∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively. CONCLUSION: GFDDS provided prolonged gastric residence and showed significant increase in bioavailability of baclofen.

Gene therapy: an alternative to treat Alzheimer's disease.

Alzheimer's disease (AD), a neuro-degenerative disease that primarily affects the elderly, is a worldwide phenomenon. Loss of memory, cognitive decline, behavioural changes, and many other signs are used to classify it. Various hypotheses that may contribute to Alzheimer's disease have been found during decades of survey, including tau theory, the amyloid theory, the cholinergic hypothesis, and the oxidative stress hypothesis. According to some theories, the two leading causes of AD are the accumulation of amyloid beta plaque and development of NFTs in the brain. The hippocampus and cerebral cortex are the primary sites where amyloid beta plaques gather in the body. NFT formation in the brain impairs the brain's neurons' potential of signalling. According to the age at which it manifests in a person, there are two subtypes of AD: 'LOAD (Late Onset Alzheimer's Disease)' and 'EOAD (Early Onset Alzheimer's Disease)'. Long-term research into AD treatment has resulted in the introduction of some medications that provided symptomatic relief to patients but did not alter the disease's pathophysiology, like cholinesterase inhibitors, inhibitors of tau aggregation, and monoclonal antibodies to Aß aggregation. Even though the medications did not halt the progression of AD, researchers did not discontinue their work, which lead to the introduction of gene therapy - a recently created cutting-edge method of delivering genes to target sites where they can express the intended functionalities. Viral or non-viral vectors could be used to deliver the gene, each with advantages and limitations of their own. Gene therapy is proven to be a potential disease-modifying treatment for AD. This article discusses about gene therapy, its merits and demerits and the various ways of gene delivery. Additionally, it focuses on AD as the target for treatment through gene therapy, the pathophysiology of AD, and the multiple targets for gene therapy in the treatment of AD.

Tracking Plasmacytoid Dendritic Cell Response to Physical Contact with Infected Cells.

Dendritic cells (DCs) are key regulators of both innate and adaptive immunity via varied functions, including cytokine production and antigen presentation. Plasmacytoid DC (pDC) is a DC subset specialized in the production of type I and III interferons (IFNs). They are thus pivotal players of the host antiviral response during the acute phase of infection by genetically distant viruses. The pDC response is primarily triggered by the endolysosomal sensors Toll-like receptors, which recognize nucleic acids from pathogens. In some pathologic contexts, pDC response can also be triggered by host nucleic acids, hereby contributing to the pathogenesis of autoimmune diseases, such as, e.g., systemic lupus erythematosus. Importantly, recent in vitro studies from our laboratory and others uncovered that pDCs sense viral infections when a physical contact is established with infected cells. This specialized synapse-like feature enables a robust type I and III IFN secretion at the infected site. Therefore, this concentrated and confined response likely limits the correlated deleterious impacts of excessive cytokine production to the host, notably due to tissue damages. Here we provide a pipeline of methods for ex vivo studies of pDC antiviral functions, designed to address how pDC activation is regulated by cell-cell contact with virally infected cells and the current approaches enabling to decipher the underlying molecular events leading to an efficient antiviral response.

Toxicity evaluation of iron oxide nanoparticles to freshwater cyanobacteria Nostoc ellipsosporum.

The extensive usage of iron oxide nanoparticles (FeO NPs) in commercial and biomedical applications raises the risk of releasing their remains into the aquatic ecosystems and this could possibly cause cytotoxic effects on aquatic organisms. Thus, the toxicity assessment of FeO NPs on cyanobacteria, which are primary producers at the bottom of food chain in aquatic ecosystems, is essential to gain information about the potential ecotoxicological threat on aquatic biota. The present study investigated the cytotoxic effects of FeO NPs on Nostoc ellipsosporum using different concentrations (0, 10, 25, 50 and 100 mg L-1) to track the time-dependent and dose-dependent effects and compared with its bulk equivalent. In addition, the impacts of FeO NPs and bulk counterpart on cyanobacterial cells were assessed under nitrogen as well as nitrogen-deficient conditions, because of ecological role of cyanobacteria in nitrogen fixation. The study revealed that the highest protein content was observed in the control in both types of BG-11 media compared to treatments of nano and bulk particles of Fe2O3. A 23% reduction in protein in nanoparticle treatment and a 14% reduction in bulk treatment at 100 mg L-1 was observed in BG-11 medium. At same concentration, in BG-110 media, this decline was even more intense with 54% reduction in nanoparticle and a 26% reduction in bulk. Catalytic activity of catalase and superoxide dismutase was found to be linearly correlated with the dose concentration for nano and bulk form in BG-11 as well as BG-110 media. The increased levels of lactate dehydrogenase act as biomarker of the cytotoxicity brought on by nanoparticles. Optical, scanning electron, and transmission electron microscopy all demonstrated the cell entrapment, nanoparticle deposition on the cell surface, cell wall collapse and membrane degradation. A cause for concern is that nanoform was found to be more hazardous than bulk form.

Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2.

Type I and III interferons (IFN-I/λ) are important antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDC) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely via a local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to develop this response could be important to understand severe cases of COVID-19.

Formulation and Characterization of Febuxostat Loaded Nanostructured Lipid Carriers (NLCs) - Gel for Topical Treatment of Gout.

BACKGROUND: The aim of the present study was to formulate and characterize Nano- Structured Lipid Carriers (NLCs) of Febuxostat (FB) incorporated in the gel for the treatment of Gout. FB is a Xanthine Oxidase (XO) inhibitor drug used for chronic Gout and hyperuricemia. FB is a BCS class II drug, therefore, water solubility is very poor, and due to its poor solubility and wettability, it leads to poor dissolution. The hot high-pressure homogenization technique was used in this study to improve the physicochemical property of FB. METHODS: The carbopol 934 was used to prepare NLCs gel of FB. The NLCs of FB was prepared in different drug: polymer ratios w/w (2:1), (1:1), (1:2), (1:3) and (1:4) with solid lipid (Stearic Acid) and liquid lipid (Oleic acid). The preformulation study of FB included FTIR study melting point, standard calibration curves, and drug-polymer interaction study. RESULTS: The NLCs (1:3) showed high entrapment and drug content. The NLCs gel formulation was 87% released within 6 hours in a controlled manner. CONCLUSION: NLCs gel modifies the drug release, increases the bioavailability, and reduces side effects of FB. The prepared gel is the efficient formulation for the better treatment of chronic gout and hyperuricemia. The research findings have shown the undesirable side effects associated with the oral route that can be reduced by the use of NLCs formulation through the transdermal route in an effective manner.

In vitro and in cellulae methods for determining the target protein SUMOylation.

Post-translational modifications (PTMs) provide a critical means of calibrating the functional proteome and, thus, are extensively utilized by the eukaryotes to exert spatio-temporal regulation on the cellular machinery rapidly. Ubiquitination and phosphorylation are examples of the well-documented PTMs. SUMOylation, the reversible conjugation of the Small Ubiquitin-related MOdifier (SUMO) at a specific lysine residue on a target protein, bears striking similarity with ubiquitination and follows an enzymatic cascade for the attachment of SUMO to the target protein. Unlike Ubiquitination, SUMOylation can modulate the target protein's structure, stability, activity, localization, and interaction. Thus, SUMOylation regulates cellular events such as signal transduction, cell-cycle progression, transcription, nucleocytoplasmic transport, and stress responses. Accordingly, deregulation of SUMOylation is an avenue for diseases, which makes the investigation of SUMO and its substrates within the cell essential. However, the low extent of SUMOylation has posed a significant challenge in detecting SUMO modification within the cell. Bioinformatics tools can help predict SUMOylation, and mass-spectrometric analysis can identify a pool of cellular protein SUMOylome. Nevertheless, the biochemical methods for observing the enhanced level of in vitro SUMOylation help validate protein SUMOylation, critical lysine(s) utilized in the process, and its effect on substrate protein function. This chapter provides a detailed account of biochemical methods commonly utilized to detect SUMOylated proteins that are central for understanding the biological functions and mechanism of regulation of SUMO targets.

SARS-CoV-2 spike E156G/Δ157-158 mutations contribute to increased infectivity and immune escape.

Breakthrough infections by emerging SARS-CoV-2 variants raise significant concerns. Here, we sequence-characterized the spike gene from breakthrough infections that corresponded to B.1.617 sublineage. Delineating the functional impact of spike mutations revealed that N-terminal domain (NTD)-specific E156G/Δ157-158 contributed to increased infectivity and reduced sensitivity to vaccine-induced antibodies. A six-nucleotide deletion (467-472) in the spike-coding region introduced this change in the NTD. We confirmed the presence of E156G/Δ157-158 from cases concurrently screened, in addition to other circulating spike (S1) mutations such as T19R, T95I, L452R, E484Q, and D614G. Notably, E156G/Δ157-158 was present in more than 90% of the sequences reported from the USA and UK in October 2021. The spike-pseudotyped viruses bearing a combination of E156G/Δ157-158 and L452R exhibited higher infectivity and reduced sensitivity to neutralization. Notwithstanding, the post-recovery plasma robustly neutralized viral particles bearing the mutant spike. When the spike harbored E156G/Δ157-158 along with L452R and E484Q, increased cell-to-cell fusion was also observed, suggesting a combinatorial effect of these mutations. Our study underscores the importance of non-RBD changes in determining infectivity and immune escape.

Road map to the treatment of neglected tropical diseases: Nanocarriers interventions.

Neglected tropical disease (NTD) is a set of 20 deadliest endemic diseases which shows its presence in most of the developing countries worldwide. Nearly 1 billion of the population are affected by it and suffered from poverty yearly. These diseases offer their own unique challenges and limitations towards effective prevention and treatment methods. Neglected tropical diseases are severe infections they may not kill the patient but debilitate the patient by causing severe skin deformities, disfigurement and horrible risks for several infections. Existing therapies for neglected diseases suffer from the loopholes like high degree of toxicity, side effects, low bioavailability, improper targeting and problematic application for affected populations. Progress in the field of nanotechnology in last decades suggested the intervention of nanocarriers to take over and drive the research and development to the next level by incorporating established drugs into the nanocarriers rather than discovering the newer drugs which is an expensive affair. These nanocarriers are believed to be a sure shot technique to fight infections at root level by virtue of its nanosize and ability to reach at cellular level. This article highlights the recent advances, rationale, targets and the challenges that are being faced to fight against NTDs and how the novel therapy tactics are able to contribute to its importance in prevention and treatment of NTDs.

SUMO and SUMOylation Pathway at the Forefront of Host Immune Response.

Pathogens pose a continuous challenge for the survival of the host species. In response to the pathogens, the host immune system mounts orchestrated defense responses initiating various mechanisms both at the cellular and molecular levels, including multiple post-translational modifications (PTMs) leading to the initiation of signaling pathways. The network of such pathways results in the recruitment of various innate immune components and cells at the site of infection and activation of the adaptive immune cells, which work in synergy to combat the pathogens. Ubiquitination is one of the most commonly used PTMs. Host cells utilize ubiquitination for both temporal and spatial regulation of immune response pathways. Over the last decade, ubiquitin family proteins, particularly small ubiquitin-related modifiers (SUMO), have been widely implicated in host immune response. SUMOs are ubiquitin-like (Ubl) proteins transiently conjugated to a wide variety of proteins through SUMOylation. SUMOs primarily exert their effect on target proteins by covalently modifying them. However, SUMO also engages in a non-covalent interaction with the SUMO-interacting motif (SIM) in target proteins. Unlike ubiquitination, SUMOylation alters localization, interactions, functions, or stability of target proteins. This review provides an overview of the interplay of SUMOylation and immune signaling and development pathways in general. Additionally, we discuss in detail the regulation exerted by covalent SUMO modifications of target proteins, and SIM mediated non-covalent interactions with several effector proteins. In addition, we provide a comprehensive review of the literature on the importance of the SUMO pathway in the development and maintenance of a robust immune system network of the host. We also summarize how pathogens modulate the host SUMO cycle to sustain infectability. Studies dealing mainly with SUMO pathway proteins in the immune system are still in infancy. We anticipate that the field will see a thorough and more directed analysis of the SUMO pathway in regulating different cells and pathways of the immune system. Our current understanding of the importance of the SUMO pathway in the immune system necessitates an urgent need to synthesize specific inhibitors, bioactive regulatory molecules, as novel therapeutic targets.

Enhancing Quality of Life in Indian Parkinson's Disease Patients with Improved Measurement of Psychological Domains: A Perspective.

Parkinson's disease (PD) is the second most common progressive neuro-degenerative disorder. Research in PD is gradually increasing in India due to increased clinical cases, which could double by 2030 worldwide. Although its prevalence is low in India as compared to other countries, the total burden is much higher due to the large population size. PD is progressively debilitating, with pronounced motor and nonmotor symptoms (NMSs) that severely affect the quality of life (QoL) of patients and their caregivers. The progressive nature of the disease lays great emphasis on doctors to focus on the patients' QoL. As a consequence, Health-related QoL (HRQoL) has gradually become one of the main indicators for assessing health-related outcome. There is a growing need to pay attention to the NMSs and a pressing need to look at the QoL of Indian patients with PD through a culture and value specific lens. Research into the holistic QoL assessment with emphasis on psychological domains may allow for the early evaluation and intervention of depressive and cognitive symptoms in PD. This could result into increased productivity, reduced morbidity, and healthcare cost, which would in turn result into better QoL of Indian PD patients.

Preparation and Surface Modification of Polymeric Nanoparticles for Drug Delivery: State of the Art.

Nanotechnology is one of the emerging fields in drug delivery for targeting the drug to the site of action. The polymeric nanoparticles as drug delivery systems have gained importance for the last few decades. They offer advantages over liposomes, dendrimers, emulsions etc. Surface engineering of polymeric nanoparticles is widely utilized to effectively target the cells in various diseases such as cancer, HIV infection. Surface modified nanoparticles offer various advantages such as targeted drug delivery, reduction in side effects, dose reduction and improved therapeutic efficacy. Moreover, they can aid in improving physical and biochemical properties, pharmacokinetic and pharmacodynamic profiles of the drug. Surface modified polymeric nanoparticles can provide targeted delivery of drugs into specific cells, especially when targets are intracellularly localized. This approach of surface modification would be more advantageous for the delivery of various anticancer, anti-inflammatory, anti-HIV drugs for more effective therapy. This review focuses on the techniques used for the fabrication of polymeric nanoparticles, the material used for surface modification and their applications.