An Open-Label, Investigator-Initiated, Single-Centre Pilot Study to Determine the Safety and Efficacy of Tofacitinib in Resistant Chronic Spontaneous Urticaria.

Background: Chronic spontaneous urticaria (CSU) is a distressing skin condition characterized by the recurrent appearance of itchy hives. A subset of CSU patients remains resistant to conventional treatment with high-dose antihistamines. Tofacitinib, a Janus kinase inhibitor, has shown promise in various inflammatory skin diseases. We aimed to evaluate the efficacy of oral tofacitinib in patients with CSU resistant to antihistamines. Methods: This study examined data retrospectively from seven patients who were diagnosed with CSU and were treated with tofacitinib for at least six months. These patients initially exhibited resistance to treatment with four-fold up-dosed antihistamines. One of the patients was already on omalizumab, and another was tried on cyclosporine. The patients were administered oral tofacitinib at a dosage of 5 mg twice daily for six months. Patients were followed up monthly for disease control and side effects. The response to treatment was evaluated using the urticaria activity score over 7 days (UAS7) and urticaria control test (UCT). Paired t-tests were conducted to determine the statistical significance of the results using SPSS version 25 software. Results: Six out of the seven patients demonstrated a significant improvement in both UAS7 and UCT scores after six months of treatment with oral tofacitinib. The mean UAS7 score decreased from 24.86 at baseline to 3.83 at the study endpoint (P < 0.0001). Similarly, the mean UCT score increased from 0.57 at baseline to 14 at the study endpoint (P < 0.0001). The standard deviations for both measures were 4.85 and 0.98 at baseline and 3.1 and 3.1 at the study endpoint for UAS7 and UCT, respectively. Conclusion: In this six-month follow-up study, oral tofacitinib demonstrated significant efficacy in treating CSU patients' resistant to high-dose antihistamines. Most patients experienced a remarkable reduction in urticaria activity and an improvement in disease control. These findings suggest that tofacitinib holds promise as a potential therapeutic option for this challenging subset of CSU patients. However, larger, randomized controlled trials are warranted to further investigate the long-term safety and effectiveness of tofacitinib in this population.

A comprehensive review on the recent trends in extractions, pretreatments and modifications of plant-based proteins.

Plant-based proteins offer sustainable and nutritious alternatives to animal proteins with their techno-functional attributes influencing product quality and designer food development. Due to the inherent complexities of plant proteins, proper extraction and modifications are vital for their effective utilization. This review highlights the emerging sources of plant-based proteins, and the recent statistics of the techniques employed for pretreatment, extraction, and modifications. The pretreatment, extraction and modification approach to modify plant proteins have been classified, addressed, and the recent applications of such methodologies are duly indicated. Furthermore, this study furnishes novel perspectives regarding the potential impacts of emerging technologies on the intricate dynamics of plant proteins. A thorough review of 100 articles (2018-2024) shows the researchers' keen interest in investigating novel plant proteins and how they can be used; seeds being the main source for protein extraction, followed by legumes. Use of by-products as a protein source is increasing rapidly, which is noteworthy. Protein studies still lack knowledge on protein fraction, antinutrients, and pretreatments. The use of physical methods and their combination with other techniques are increasing for effective and environmentally friendly extraction and modification of plant proteins. Several studies explore the effect of protein changes on their function and nutrition, especially with a goal of replacing ingredients with plant proteins that have improved or enhanced qualities. However, the next step is to investigate the sophisticated modification methods for deeper insights into food safety and toxicity.

Bilastine in Refractory Chronic Spontaneous Urticaria: Disease Control and Cytokine Modulation in an Open-label Prospective Study.

Introduction: The treatment options for chronic spontaneous urticaria (CSU) primarily include second generation non-sedative antihistamine (SGAHs). Bilastine is a newer, nonsedating SGAH approved for urticaria in February 2019 by the Drugs Controller General of India. Its major advantages are in terms of superior efficacy, lack of drug interactions and adverse effects, including sedation, compared to conventional SGAHs. The role of cytokines in the pathogenesis of CSU is well known. However, there is a shortage of data regarding the change in serum levels of proinflammatory cytokines following H1 antihistamines. We conducted this trial to evaluate the role of bilastine in cytokine modulation and autoimmunity, thereby explaining its role in modifying the disease process in CSU. Materials and Methods: This prospective study was conducted in a tertiary institute in Kolkata on patients aged 12 years and above with a CSU >6 months. These patients had an unsatisfactory response, as per the Urticaria Activity Score 7 (UAS7), to previous antihistamine therapies in standard doses. Treatment effectiveness was determined by comparing the UAS7 at baseline with that at weeks 4, 8 and 12. Also, baseline serum interleukin-6 (IL-6) and IL-17 were compared with those at the end of the study, that is, 12 weeks. Results: Thirty patients who matched the inclusion criteria and signed informed consent were included in the study. At the end of 12 weeks, 10% of patients (n = 3) achieved a complete treatment response (UAS = 0), whereas 43.33% of patients (n = 13) were labelled as having well-controlled urticaria (UAS <6). At 12 weeks, the mean UAS7 score (6.47 ± 4.45) was statistically significant compared to the baseline score (25.47 ± 7.74). The mean values of serum IL-6 (pg/ml) and IL-17 (pg/ml) at baseline were 5.96 ± 5.24 pg/ml and 6.96 ± 5.97 pg/ml, respectively. At the end of treatment, that is, 3 months, the mean values were reduced to 4.61 ± 4.56 pg/ml and 5.08 ± 3.87 pg/ml. The reduction was statistically significant for both serum IL-6 (P < 0.001) and IL-17 (P < 0.0001). Conclusion: We conclude that bilastine at a once-daily continuous dose of 40 mg for 3 months is safe and effective in CSU patients who are refractory to treatment at the standard doses of SGAHs. Improved symptomatic control with bilastine was also associated with better control over the inflammatory process, as suggested by the lowering of mean cytokine levels in our study.

A Cross-Sectional Study to Evaluate the Role of the Nuclear Factor Kappa B (Nf-κB) Pathway in Regulating the Cytokine Cascade and as a Potential Therapeutic Target in Leprosy.

Pattern recognition receptors (PRRs), which are found in microorganisms but not in hosts, allow Leprae bacilli to be recognized as foreign. Several kinds of pattern recognition receptors, such as toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-1-like receptors (RLRs), are present in the innate immune system. Sen and Baltimore (1986) discovered the transcription factor nuclear factor kappa-B (NF-B), employed by eukaryotic cells to regulate immunity, cell differentiation and proliferation. This study aimed to evaluate the role of the nuclear factor kappa B (NF-B) pathway in controlling the cytokine cascade in leprosy due to a lack of understanding of the link between cytokines and the severity of leprosy. Clinically suspected Hansen's patients were analysed for 4 years. Newly diagnosed leprosy patients were considered to have leprosy disease control (LDC). The cases with active or new lesions and an increase in BI by at least 2+, 12 months after completion of MDT were considered leprosy disease relapse (LDR) cases. Age- and sex-matched healthy individuals served as our control group (HC). An ELISA was performed to measure the concentration of five human cytokines. By qRT-PCR, the quantitative expression of receptor genes (NOD1 and NOD2), cytokine genes and the expression of the transcription factor NFκß were evaluated. This was followed by a transcription factor NFκß assay to see its expression in the monocytes of study subjects. Nuclear factor NF-κß was found to have a pronounced response in monocytes of HC and LDC patients and LDR cases when treated with NOD1 and NOD2 ligands. Our study concludes that the NF-kB pathway is involved in the induction and regulation of the cytokine cascade that contributes to chronic inflammation in leprosy.

Detection and molecular characterization of 'Candidatus Phytoplasma australasiaticum' in Aegle marmelos: a fruit of high medicinal values in India.

In surveys conducted from 2020 to 2022, five leaf samples each from symptomatic Agele marmelos trees and seedlings, along with five samples from asymptomatic trees and seedlings, were collected in Ayodhya, Uttar Pradesh, India. The DNA extraction from all the samples was subjected to nested PCR assays, using the universal phytoplasma-specific primers set (P1/P7 followed by R16F2n/R16R2). The resulting 1.2 kb amplified products were observed in all the symptomatic samples but not in the asymptomatic samples. Bael phytoplasma strain sequences from the trees and seedlings were found 100% identical within themselves and only two representative sequences (one each from tree and seedling) were deposited in GenBank (NCBI) as PP415872 (AmA-1) and PP415873 (AmA-2). BLASTn searches revealed the maximum (100%) sequence identity with a phytoplasma strain from murraya little leaf strain of Faizabad (GenBank Acc.no. OP984129) and lowest (99.84%) with arecanut crown choking of Shimoga (GenBank Acc. no. OM417502) from Karnataka. Phylogenetic analysis clustered the bael phytoplasma isolates with peanut witches' broom group phytoplasma strains. Virtual RFLP analysis confirmed their identity as 'Ca. P. australasiaticum', a 16SrII-D subgroup strain. This study presents the first identification of a phytoplasma strain in A. marmelos, emphasizing its potential threat to fruit crops and the need for vigilance in nursery practices to prevent further dissemination.

Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer's disease.

Cathepsin B is a cysteine protease lysosomal enzyme involved in several physiological functions. Overexpression of the enzyme enhances its proteolytic activity and causes the breakdown of amyloid precursor protein (APP) into neurotoxic amyloid ß (Aß), a characteristic hallmark of Alzheimer's disease (AD). Therefore, inhibition of the enzyme is a crucial therapeutic aspect for treating the disease. Combined structure and ligand-based drug design strategies were employed in the current study to identify the novel potential cathepsin B inhibitors. Five different pharmacophore models were developed and used for the screening of the ZINC-15 database. The obtained hits were analyzed for the presence of duplicates, interfering PAINS moieties, and structural similarities based on Tanimoto's coefficient. The molecular docking study was performed to screen hits with better target binding affinity. The top seven hits were selected and were further evaluated based on their predicted ADME properties. The resulting best hits, ZINC827855702, ZINC123282431, and ZINC95386847, were finally subjected to molecular dynamics simulation studies to determine the stability of the protein-ligand complex during the run. ZINC123282431 was obtained as the virtual lead compound for cathepsin B inhibition and may be a promising novel anti-Alzheimer agent.

Centella asiatica improves memory and executive function in middle-aged rats by controlling oxidative stress and cholinergic transmission.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (L.) Urban, is a medicinal herb with rich history of traditional use in Indian subcontinent. This herb has been valued for its diverse range of medicinal properties including memory booster, and also as a folk treatment for skin diseases, wound healing and mild diuretic. AIM OF STUDY: Aging is a gradual and continuous process of natural decay in the biological systems, including the brain. This work aims to evaluate the effectiveness of ethanolic extract of Centella asiatica (CAE) on age-associated cognitive impairments in rats, as well as the underlying mechanism. MATERIAL AND METHODS: Rats were allocated into five distinct groups of 5 animals each: Young rats (3 months old rats), middle-aged (m-aged) rats (13-14 months old), and the remaining three groups were comprised of m-aged rats treated with different concentrations of CAE, viz., 150, 300, and 450 mg/kg b. w., orally for 42 days. Y-maze, open field, novel object recognition, and elevated plus maze tests were used to assess animal behavior. The malondialdehyde (MDA), superoxide dismutase (SOD), and acetylcholinesterase (AChE) assays; and H&E staining were done in the rat brain to assess the biochemical and structural changes. CAE was also subjected to HPLC analysis, in vitro antioxidant and anti-cholinergic activity. The active compounds of CAE were docked with AChE and BuChE in molecular docking study. RESULTS: The results showed that CAE treatment improves behavioral performance; attenuates the age-associated increase in MDA content, SOD, and AChE activity; and reduces neuronal loss. In vitro study showed that CAE has concentration-dependent antioxidant and anti-AChE activity. Furthermore, the presence of Asiatic acid and Madecassic acid in CAE and their good binding with cholinergic enzymes (in silico) also suggest the anticholinergic effect of CAE. CONCLUSION: The findings of the current study show that the anticholinergic and antioxidant effects of CAE are attributable to the presence of Asiatic acid and Madecassic acid, which not only provide neuroprotection against age-associated cognitive decline but also reverse it.

Viscoelastic behavior, gelation properties and structural characterization of Deccan hemp seed (Hibiscus cannabinus) protein: Influence of protein and ionic concentrations, pH, and temperature.

This study investigates the viscoelastic behavior, gelling properties, and structural characteristics of Deccan hemp seed protein (DHSP) to overcome limitations in its application in food formulations. Small amplitude oscillatory shear measurements were employed to investigate the impact of protein concentration, pH, ionic concentration, and temperature on DHSP's rheological features. The study revealed that the 20 % protein dispersion had the highest storage modulus (G') and yield stress at 63.96 ± 0.23 Pa and 0.61 Pa, respectively. DHSP dispersion exhibited pseudo-plastic behavior across various conditions. The gelling performance was higher at pH 4 and 8 and at ionic concentration in the range of 0.1 M - 0.5 M. Gelation time and temperature were observed from the temperature ramp test. Structural characterizations, including fluorescence spectroscopy, circular dichroism spectra, FTIR spectra, SEM, AFM images, zeta potential analysis, and DSC, provided insights into DHSP's tertiary and secondary conformation, surface characteristics, and thermal properties. Notably, the study highlighted DHSP's exceptional rheological properties, making it a promising gelling material for the food and nutraceutical industries. The findings also offer new insights into DHSP's structural characteristics, suggesting potential applications in food packaging and product development within the food industry.

Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer's disease.

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), ß-secretase-1 (BACE-1), and inhibition of amyloid ß (Aß) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.

Preparation, Characterization, in-vitro and in-vivo Pharmacokinetic Evaluation of Thermostable Dimethyl Fumarate Cocrystals.

Dimethyl fumarate (DMF) is an FDA-approved drug for treating relapsing-remitting multiple sclerosis; but it is susceptible to sublimation leading to its loss during processing. Cocrystals can protect against thermal energy via the interaction of DMF with a coformer via weak forces of interaction. With this hypothesis, we have, for the first time, prepared DMF cocrystals using the solvent evaporation method using coformers like citric acid and succinic acid screened by in-silico predictions and hydrogen bonding properties. Analysis using infra-red (IR), powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and sublimation evaluation characterized cocrystals and their thermostability. Comparative analysis of the release profile has been done by dissolution and pharmacokinetic study of DMF and its cocrystals. The cocrystals have improved thermal stability and better pharmacological activities than DMF. In the safety and efficacy evaluation of the formulated cocrystals, they were found to be non-cytotoxic, antioxidant, and inhibiting IL-6 and TNF-α in PBMC induced by lipopolysaccharide (LPS). We have obtained cocrystals of DMF with improved thermal stability and better pharmacological activities than DMF.

Isolated cardiac cysticercosis of the right ventricle.

Cardiac cysticercosis is a rarely encountered form of cysticercosis, caused by the larval cyst of tapeworm (Taenia solium). It commonly affects the central nervous system; however, systematic involvement has been reported as well. We describe a case of isolated cardiac cysticercosis incidentally discovered in a 16-year-old female undergoing surgical closure of a ventricular septal defect (VSD), with no prior history of parasitic infestation. Our objective is to highlight the importance of cardiac cysticercosis as a differential finding in epicardial cystic masses which may be missed or misinterpreted on imagining modalities and to the limited literature on this particular rate manifestation of cysticercosis.

Survival Analysis for Cohort of Bhopal Gas Disaster Victims during 1985-2015.

Context: After the gas tragedy on the night of December 2/3, 1984, at Bhopal, the Indian Council of Medical Research (ICMR) started following up on four population cohorts with different levels of post-disaster mortality from December 3-6, 1984. Aims: The present study was undertaken to estimate the survival time of the cohort, and investigate the risk of mortality based on exposure, gender, and median age. Settings and Design: Survival analysis is generally used to evaluate factors associated with the time to an event of failure or death among any covered population. Methods and Materials: To know the cause of death and mortality rate, a retrospective cohort analysis was conducted on the outcomes of 92,320 individuals with an exposed and non-exposed group from 1985 to 2015 in Bhopal, India. Statistical Analysis Used: Basic survival analysis method, Kaplan-Meier method, and Cox proportional hazard regression model were used to analyze the mortality risk. Results: During the past 30 years, the survivability was 87.25%, and the mortality rate was 7.2% for the cohort population of Bhopal gas survivors. Cox regression analysis showed that exposed, males, and individuals above 21 years (at the time of the disaster) were at higher risk of mortality from 1985 to 2015. Conclusions: During the initial two phases, the mortality was higher in the exposed group, but over time, their survival turned out to be the same in both groups.

Physical, optoelectronic and thermoelectric characteristics of double perovskite (Sr2ScBiO6) for green energy technology using ab initio computations.

This work presents the investigation of physical characteristics including structural, electronic, elastic, optical and thermoelectric, of the double perovskite (DP) oxide Sr2ScBiO6 with the aid of the FP-LAPW method, dependent on DFT combined with BoltzTraP code. To incorporate the inclusion of exchange as well as correlation effects, approximations like LDA and three different forms of GGA [PBE-GGA, WC-GGA & PBEsol-GGA] are applied. The mBJ-GGA method including spin-orbital coupling (SOC) & not including SOC was utilised in this investigation and it was carried out in the WIEN2k code. In addition, the TB-mBJ exchange potential analysis classified Sr2ScBiO6 as having a p-type semiconducting nature with an indirect bandgap value of 3.327 eV. Additionally, the mechanical properties analysis and the related elastic constants demonstrate the anisotropic nature of Sr2ScBiO6 with decent mechanical stability. Apart from that, the Sr2ScBiO6 was considered a brittle non-central force solid with dominant covalent bonding. The varying optical parameter evaluations highlighted the potential use of Sr2ScBiO6 in visible-light (vis) and ultraviolet (UV)-based optoelectronic devices. Moreover, the semiconducting nature of Sr2ScBiO6 was verified through its thermoelectric response, which revealed that the charge carriers mostly consist of holes. Over a wide temperature range (100-1200 K), several transport metrics like the Seebeck coefficient (S), electrical conductivity (σ/τ), thermal conductivity (κ/τ), and power factor (PF) are investigated. An optimal value of figure of merit (ZT) ∼ 0.62 at T = 1200 K is accomplished. The extremely lower value of thermal conductivity as well as higher electrical conductivity leads to a higher figure of merit of the investigated system. The Sr2ScBiO6 verified a high ZT value, confirming that the material would be beneficial in renewable energy and thermoelectric (TE) applications.

Computational screening of coumarin derivatives as inhibitors of the NACHT domain of NLRP3 inflammasome for the treatment of Alzheimer's disease.

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), leucine-rich-repeat (LRR), and pyrin domain containing 3 (NLRP3) is one of the key players in neuroinflammation, which is a major pathological hallmark of Alzheimer's Disease (AD). Activated NLRP3 causes release of pro-inflammatory molecules that aggravate neurodegeneration. Thus, pharmacologically inhibiting the NLRP3 inflammasome has the potential to alleviate the inflammatory injury to the neurons. Coumarin is a multifunctional nucleus with potent anti-inflammatory properties and can be utilized to develop novel drugs for the treatment and management of AD. In the present study, we have explored the NLRP3-inhibitory activities of a library of coumarin derivatives through a computational drug discovery approach. Drug-like, PAINS free, and potentially BBB permeable compounds were screened out and subjected to molecular docking and in silico ADMET studies, resulting in three virtual hits, i.e. MolPort-050-872-358, MolPort-050-884-068, and MolPort-051-135-630. The hits exhibited better NLRP3-binding affinity than MCC950, a selective inhibitor of NLRP3. Further, molecular dynamics (MD) simulations, post-MD simulation analyses, and binding free energy calculations of the hits established their potential as promising virtual leads with a common coumarin scaffold for the inhibition of NLRP3 inflammasome.Communicated by Ramaswamy H. Sarma.

Effect of sulfonamide derivatives of phenylglycine on scopolamine-induced amnesia in rats.

Alzheimer's disease is a neurodegenerative disease responsible for dementia and other neuropsychiatric symptoms. In the present study, compounds 30 and 33, developed earlier in our laboratory as selective butyrylcholinesterase inhibitors, were tested against scopolamine-induced amnesia to evaluate their pharmacodynamic effect. The efficacy of the compounds was determined by behavioral experiments using the Y-maze and the Barnes maze and neurochemical testing. Both compounds reduced the effect of scopolamine treatment in the behavioral tasks at a dose of 20 mg/kg. The results of the neurochemical experiment indicated a reduction in cholinesterase activity in the prefrontal cortex and the hippocampus. The levels of antioxidant enzymes superoxide dismutase and catalase were restored compared to the scopolamine-treated groups. The docking study on rat butyrylcholinesterase (BChE) indicated tight binding, with free energies of -9.66 and -10.23 kcal/mol for compounds 30 and 33, respectively. The two aromatic amide derivatives of 2-phenyl-2-(phenylsulfonamido) acetic acid produced stable complexes with rat BChE in the molecular dynamics investigation.

Recent Advances in the Development of Near-Infrared Fluorescent Probes for the in Vivo Brain Imaging of Amyloid-ß Species in Alzheimer's Disease.

The deposition of ß-amyloid (Aß) plaques in the parenchymal and cortical regions of the brain of Alzheimer's disease (AD) patients is considered the foremost pathological hallmark of the disease. The early diagnosis of AD is paramount in order to effective management and treatment of the disease. Developing near-infrared fluorescence (NIRF) probes targeting Aß species is a potential and attractive approach suitable for the early and timely diagnosis of AD. The advantages of the NIRF probes over other tools include real-time detection, higher sensitivity, resolution, comparatively inexpensive experimental setup, and noninvasive nature. Currently, enormous progress is being observed in the development of NIRF probes for the in vivo imaging of Aß species. Several strategies, i.e., the classical push-pull approach, "turn-on" effect, aggregation-induced emission (AIE), and resonance energy transfer (RET), have been exploited for development. We have outlined and discussed the recently emerged NIRF probes with different design strategies targeting Aß species for ex vivo and in vivo imaging. We believe that understanding the recent development enables the prospect of the rational design of probes and will pave the way for developing future novel probes for early diagnosis of AD.

Prevalence of chronic kidney disease among severely gas-exposed survivors in Bhopal, India.

Background The survivors of the 1984 Bhopal gas disaster frequently express concern of them being at higher risk of developing chronic kidney disease (CKD) as a consequence of the long-term health effects of gas exposure. We aimed to estimate the prevalence of CKD among the survivors of severely gas-exposed cohort assembled in 1985 after the Bhopal gas disaster to study the long-term health consequences of gas exposure. Methods We did this cross-sectional study with a sample size of 215 systematically selected participants among the severely gas-exposed survivors in Bhopal to estimate the prevalence of CKD. Sociodemographic and relevant past medical history of the participants was obtained using a semi-structured questionnaire and their blood and urine samples were collected. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation. Those found with reduced e-GFR and proteinuria, suggestive of CKD, were further surveyed after 3 months to differentiate CKD from acute renal damage. Results The prevalence of CKD among the severely gas-exposed cohort survivors in Bhopal was 16.7%. Multiple logistic regression analysis revealed that body mass index and level of education were significant predictors of CKD. Conclusion The prevalence of CKD among the severely exposed survivors of Bhopal was at par with the national prevalence, putting at rest the apprehension of gas-exposed survivors of being at higher risk of developing CKD.

Discovery of Multitarget-Directed Ligands from Piperidine Alkaloid Piperine as a Cap Group for the Management of Alzheimer's Disease.

The naturally inspired multitarget-directed ligands (PC01-PC10 and PD01-PD26) were synthesized from piperine for the management of Alzheimer's disease (AD). The compound PD07 showed significant inhibitory activity on ChEs, BACE1, and Aß1-42 aggregation in in vitro studies. Further, compound PD07 effectively displaced the propidium iodide at the AChE PAS site. The compound PD07 exhibited significant lipophilicity in PAMPA studies. Additionally, PD07 demonstrated neuroprotective properties in the Aß1-42 induced SH-SY5Y cell line. Furthermore, DFT calculations were performed using B3LYP/6-311G(d,p) basis sets to explore the PD07 physical and chemical properties. The compound PD07 showed a similar binding interaction profile at active sites of AChE, BuChE, and BACE1 proteins as compared to reference ligands (donepezil, tacrine, and BSD) in molecular docking and dynamic simulation studies. In acute oral toxicity studies, compound PD07 exhibited no toxicity symptoms up to 300 mg/kg, po. The compound PD07 (10 mg/kg, po) improved memory and cognition in scopolamine-induced amnesia rats. Further, PD07 increased ACh levels in the brain by inhibiting the AChE activity. The results from in vitro, in silico, and in vivo studies suggested that compound PD07 is a potent multitarget-directed lead from piperine to overcome Alzheimer's disease.

Novel Gastroprotective and Thermostable Cocrystal of Dimethyl Fumarate: Its Preparation, Characterization, and In Vitro and In Vivo Evaluation.

Crystallization has revolutionized the field of solid-state formulations by modulating the physiochemical and release profile of active pharmaceutical ingredients (APIs). Dimethyl fumarate (DF), an FDA-approved first-line drug for relapsing-remitting multiple sclerosis, has a sublimation problem, leading to loss of the drug during its processing. To tackle this problem, DF cocrystal has been prepared by using solvent evaporation technique using nicotinamide as a coformer, which has been chosen based on in silico predictions and their ability to participate in hydrogen bonding. Fourier transform infrared (FT-IR), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and sublimation analysis have characterized the cocrystal and its thermostability. Comparative analysis of the release profile has been done by the dissolution and pharmacokinetic study of DF and its cocrystal. Formulated cocrystal is noncytotoxic, antioxidant and inhibits interleukin-6 and tissue necrosis factor-α in peripheral blood mononuclear cells induced by lipopolysaccharide. We have obtained a thermostable cocrystal of DF with a similar physicochemical and release profile to that of DF. The formulated cocrystal also provides a gastroprotective effect which helps counterbalance the adverse effects of DF by reducing lipid peroxidation and total nitrite levels.