Leprosy in Post-elimination Era: A Study Conducted in Rural Tertiary Settings in North India.

Background Leprosy is an age-old disease caused by Mycobacterium leprae. The disease was declared eradicated in India in 2005. Many new cases are still being identified in the outdoor patient department. This study was undertaken to understand the epidemiological, clinical, and social aspects of leprosy among new patients, and assess the current situation regarding caseload and presentation. Material and methods This study was designed as an observational study. It was carried out in people newly diagnosed with leprosy attending the outpatient department of Dermatology, Venereology, and Leprology in the tertiary care hospital in Uttar Pradesh University of Medical Sciences from July 2022 to January 2024. A total of 231 people afflicted with leprosy were included in the study. The data collected was statistically analyzed to identify demographic and social patterns, clinical presentations, and features associated with leprosy. Result Out of these 231 patients, 139 (60.17%) were male and 92 (39.83%) were female. Most cases belonged to the age group 40-59 years 87 (37.66%). History of close contact with an afflicted person was present in 34 (14.71%). Clinically, most patients belong to the borderline tuberculoid (BT) type. Only 24 (10.4%) patients were found positive for M. leprae by slit-skin smear examination. The ulnar nerve was the most common nerve involved in 63 (27.27%) cases. Trophic ulcers were the predominant deformity in 34 (14.7%), followed by foot drop in 13 (5.62 %). Conclusion The present study provides an overview of the prevailing trends of Leprosy within a specific region in the post-elimination era. The findings underscore the significance of the ongoing National Leprosy Eradication Program (NLEP) program and stress the importance of aligning them with the common goal of eliminating the burden and stigma of Leprosy from society.

Asparagus officinalis Herb-Derived Carbon Quantum Dots: Luminescent Probe for Medical Diagnostics.

The utilization of natural materials for the synthesis of highly fluorescent carbon quantum dots (CQDs) presents a sustainable approach to overcome the challenges associated with traditional chemical precursors. Here, we report the synthesis of novel S,N-self-doped CQDs (S,N@CQDs) derived from asparagus officinalis herb. These S,N@CQDs exhibit 16.7 % fluorescence quantum yield, demonstrating their potential in medical diagnostics. We demonstrate the efficacy of S,N@CQDs as luminescent probes for the detection of anti-pathogenic medications metronidazole (MTZ) and nitazoxanide (NTZ) over concentration ranges of 0.0-180.0 µM (with a limit of detection (LOD) of 0.064 µM) and 0.25-40.0 µM (LOD of 0.05 µM), respectively. The probes were successfully applied to determine MTZ and NTZ in medicinal samples, real samples, and spiked human plasma, with excellent recovery rates ranging from 99.82 % to 103.03 %. Additionally, S,N@CQDs demonstrate exceptional efficacy as diagnostic luminescent probes for hemoglobin (Hb) detection over a concentration range of 0-900 nM, with a minimal detectability of 9.24 nM, comparable to commercially available medical laboratory diagnostic tests. The eco-friendly synthesis and precise detection limits of S,N@CQDs meet necessary analytical requirements and hold promise for advancing diagnostic capabilities in clinical settings. This research signifies a significant step towards sustainable and efficient fluorescence-based medical diagnostics.

Expanding roles of cross-talk between hydrogen sulfide and nitric oxide under abiotic stress in plants.

Abiotic stress such as salt, heavy metals, drought, temperature, and others can affect plants from seed germination to seedling growth to reproductive maturity. Abiotic stress increases reactive oxygen species and lowers antioxidant enzymes in plants resulted the plant tolerance ability against stress conditions decrease. Hydrogen sulfide (H2S) and nitric oxide (NO) are important gasotransmitters involved in seed germination, photosynthesis, growth and development, metabolism, different physiological processes and functions in plants. In plants, various enzymes are responsible for the biosynthesis of both H2S and NO via both enzymatic and non-enzymatic pathways. They also mediate post-translation modification, such as persulfidation, and nitrosylation, which are protective mechanisms against oxidative damage. They also regulate some cellular signalling pathways in response to various abiotic stress. H2S and NO also stimulate biochemical reactions in plants, including cytosolic osmoprotectant accumulation, reactive oxygen species regulation, antioxidant system activation, K+ uptake, and Na+ cell extrusion or vacuolar compartmentation. In this review, we summarize how H2S and NO interact with each other, the function of both H2S and NO, the mechanism of biosynthesis, and post-translational modification under different abiotic stress. Our main emphasis was to find the cross-talk between NO and H2S and how they regulate genes in plants under abiotic stress.

Nickel-doped magnetic carbon aerogel derived from xanthan gum: a competent catalyst for the degradation of single and binary dye-based water pollutants.

Toxic organic dyes (colorants) are one of the main causes of water pollution that releases destructive effluents in the environment. To overcome this issue, a fundamental need to produce a novel, efficient catalyst for the degradation and mineralization of dye mixtures has arisen. The objective of this research is to develop an eminent Ni-doped magnetic carbon aerogel (Ni-MCA) catalyst using graft co-polymerization method having xanthan gum as backbone doped with Ni-magnetic nanoparticles (Ni-MNPs), that do not show agglomeration and easy to separate. The examination revealed that Ni-MCA provided exceptional magnetic characteristics (Ms = 52.75 emu/g) and potent catalytic activity for the degradation of mono- as well as binary-dye solutions of Congo red (CR) and methyl green (MG) dyes. The formation was verified by various characterization techniques such as FTIR, VSM, XRD, XPS, SEM, TEM, and EDX mapping. Interestingly, Ni-MCA shows faster result on anionic dye CR up to 97% with degradation rate of 5.647 × 10-1 min-1, and MG dye shows degradation of 95.7% with the degradation rate of 2.169 × 10-1 min-1, while dye mixture is showing 90% degradation with rate of 2.159 × 10-1 min-1.

A comprehensive review on anaerobic digestion with focus on potential feedstocks, limitations associated and recent advances for biogas production.

With the escalating energy demand to accommodate the growing population and its needs along with the responsibility to mitigate climate change and its consequences, anaerobic digestion (AD) has become the potential approach to sustainably fulfil our demands and tackle environmental issues. Notably, a lot of attention has been drawn in recent years towards the production of biogas around the world in waste-to-energy perspective. Nevertheless, the progress of AD is hindered by several factors such as operating parameters, designing and the performance of AD reactors. Furthermore, the full potential of this approach is not fully realised yet due the dependence on people's acceptance and government policies. This article focuses on the different types of feedstocks and their biogas production potential. The feedstock selection is the basic and most important step for accessing the biogas yield. Furthermore, different stages of the AD process, design and the configuration of the biogas digester/reactors have been discussed to get better insight into process. The important aspect to talk about this process is its limitations associated which have been focused upon in detail. Biogas is considered to attain the sustainable development goals (SDG) proposed by United Nations. Therefore, the huge focus should be drawn towards its improvements to counter the limitation and makes it available to all the rural communities in developing countries and set-up the pilot scale AD plants in both developing and developed countries. In this regard, this article talks about the improvements and futures perspective related to the AD process and biogas enhancement.

An Evaluation of Variations in the Carpal Tunnel Dimensions of Adult Subjects in a Hospital-Based Population: An Ultrasonographic Cross-Sectional Study.

Background The carpal tunnel is a groove that spans the palm as a 'U.' The ulnar and radial sides of the wrist are made up of the scaphoid tubercle and trapezium while the palmar aspect is made up of carpal bones. Our study aimed to see whether there were differences in carpal tunnel size between men and women. Material and methods The study was conducted on 65 healthy adults, 13 (20%) were males and 52 (80%) were females (both non-pregnant and pregnant). Inclusion criteria were healthy adults and bilaterally symmetrical limbs. Exclusion criteria were chronic disease, diabetes, hypertension, immunological disorders, any visible abnormalities, and a history of upper extremity pain on either side. A high-resolution ultrasound machine with a linear transducer was used to perform an ultrasound scan of the carpal tunnel. The anteroposterior dimension was measured at the midline, or along the axis of the middle finger, and the transverse diameter was measured at the midpoint of the flexor retinaculum. The cross-sectional area of the tunnel was measured at its largest diameter within the carpal tunnel. All the dimensions were measured in centimeters. Results The mean transverse diameter of the right side was 1.824 ± 0.223 cm (p-value 0.002) and of the left side was 1.742 ± 0.197 cm (p-value 0.004). The mean cross-sectional area of the carpal tunnel on the right side was 1.417 ± 0.379 cm2 (p-value 0.008) and on the left side was 1.306 ± 0.303 cm2 (p-value 0.004), respectively. Age, sex, weight, and BMI were discussed. The carpal tunnels of females were found to be comparatively squarer and smaller than those of males. Conclusion The transverse diameter and cross-sectional area of the carpal tunnel and their correlation with carpal tunnel syndrome are predicted by age, sex, weight, and BMI. Both sexes had the same wrist ratio.

Phyto-therapeutic potential of Withania somnifera: Molecular mechanism and health implications.

Withania somnifera, the plant named Indian ginseng, Ashwagandha, or winter cherry, has been used since ancient times to cure various health ailments. Withania somnifera is rich in constituents belonging to chemical classes like alkaloids, saponins, flavonoids, phenolic acids, and withanolides. Several chemotypes were identified based on their phytochemical composition and credited for their multiple bioactivities. Besides, exhibiting neuroprotective, immunomodulatory, adaptogenic, anti-stress, bone health, plant has shown promising anti-cancer properties. Several withanolides have been reported to play a crucial role in cancer; they target cancer cells by different mechanisms such as modulating the expression of tumor suppressor genes, apoptosis, telomerase expression, and regulating cell signaling pathway. Though, many treatments are available for cancer; however, to date, no assured reliable cure for cancer is made available. Additionally, synthetic drugs may lead to development of resistance in time; therefore, focus on new and natural drugs for cancer therapeutics may prove a longtime effective alternative. This current report is a comprehensive combined analysis upto 2023 with articles focused on bio-activities of plant Withania somnifera from various sources, including national and international government sources. This review focuses on understanding of various mechanisms and pathways to inhibit uncontrolled cell growth by W. somnifera bioactives, as reported in literature. This review provides a recent updated status of the W. somnifera on pharmacological properties in general and anti-cancer in particular and may provide a guiding resource for researchers associated with natural product-based cancer research and healthcare management.

Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations.

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.Communicated by Ramaswamy H. Sarma.

Biaryl carboxamide-based peptidomimetics analogs as potential pancreatic lipase inhibitors for treating obesity.

A series of 1,1'-biphenyl-3-carboxamide and furan-phenyl-carboxamide analogs were synthesized using an optimized scheme and confirmed by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry techniques. The synthesized peptidomimetics analogs were screened in vitro to understand the inhibitory potential of pancreatic lipase (PL). Analogs were assessed for the PL inhibitory activity based on interactions, geometric complementarity, and docking score. Among the synthesized analogs, 9, 29, and 24 were found to have the most potent PL inhibitory activity with IC50 values of 3.87, 4.95, and 5.34 µM, respectively, compared to that of the standard drug, that is, orlistat, which inhibits PL with an IC50 value of 0.99 µM. The most potent analog, 9, exhibited a competitive-type inhibition with an inhibition constant (Ki) of 2.72 µM. In silico molecular docking of analog 9 with the PL (PDB ID:1LPB) showed a docking score of -11.00 kcal/mol. Analog 9 formed crucial hydrogen bond interaction with Ser152, His263, π-cation interaction with Asp79, Arg256, and π-π stacking with Phe77, Tyr114 at the protein's active site. The molecular dynamic simulation confirmed that analog 9 forms stable interactions with PL at the end of 200 ns with root mean square deviation values of 2.5 and 6 Å. No toxicity was observed for analog 9 (concentration range of 1-20 µM) when tested by MTT assay in RAW 264.7 cells.

Harnessing fluorescent carbon quantum dots from natural resource for advancing sweat latent fingerprint recognition with machine learning algorithms for enhanced human identification.

Nowadays, it is fascinating to engineer waste biomass into functional valuable nanomaterials. We investigate the production of hetero-atom doped carbon quantum dots (N-S@MCDs) to address the adaptability constraint in green precursors concerning the contents of the green precursors i.e., Tagetes erecta (marigold extract). The successful formation of N-S@MCDs as described has been validated by distinct analytical characterizations. As synthesized N-S@MCDs successfully incorporated on corn-starch powder, providing a nano-carbogenic fingerprint powder composition (N-S@MCDs/corn-starch phosphors). N-S@MCDs imparts astounding color-tunability which enables highly fluorescent fingerprint pattern developed on different non-porous surfaces along with immediate visual enhancement under UV-light, revealing a bright sharp fingerprint, along with long-time preservation of developed fingerprints. The creation and comparison of latent fingerprints (LFPs) are two key research in the recognition and detection of LFPs, respectively. In this work, developed fingerprints are regulated with an artificial intelligence program. The optimum sample has a very high degree of similarity with the standard control, as shown by the program's good matching score (86.94%) for the optimal sample. Hence, our results far outperform the benchmark attained using the conventional method, making the N-S@MCDs/corn-starch phosphors and the digital processing program suitable for use in real-world scenarios.

Pancreatic lipase and its related proteins: where are we now?

Obesity is a disease of epidemic proportions, with a worrisome upward trend. The high consumption of lipids, a major energy source, leads to obesity because of their high calorific value. Pancreatic lipase (PTL), produced by pancreatic acinar cells, hydrolyzes 50-70% of triacylglycerol (TAG) from food. PTL-related protein 1 (PLRP1) and 2 (PLRP2) are also produced by these cells. In vertebrates, PLRP1 has relatively less lipolytic activity, whereas PLRP2 has an essential role in lipid digestion, especially in infants. In this review, we summarize the structure and function of PTL, PLRP1, and PLRP2, and the metabolic fate of PTL inhibitors. We also discuss the current status of clinical trials on orlistat and its combinations for obesity treatment.

Synthesis, molecular modelling and pharmacological evaluation of novel indole-thiazolidinedione based hybrid analogues as potential pancreatic lipase inhibitors.

A series of novel indole-thiazolidinedione hybrid analogues (7a to 7 u) were synthesised, characterised and evaluated for their potential Pancreatic Lipase (PL) inhibition. Amongst the screened analogues, 7r was found to be the most active PL inhibitor with an IC50 of 2.67 µM. Furthermore, enzyme inhibition kinetics study revealed a competitive mode of inhibition by the analogues. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking was performed using human PL (PDB ID: 1LPB) and were in agreement with the in vitro results (Pearson's r = 0.8355, p < 0.05). A molecular dynamics study (100 ns) indicated that 7r was stable in a dynamic environment. The analogue 7r exhibited potential antioxidant activity and was devoid of cytotoxic effect on RAW 264.7 cells. Based on the in-vitro profiles, 7r was selected for the in-vivo pharmacological evaluation. Oral triglyceride tolerance test highlighted effect of 7r on the inhibition of triglyceride absorption. A four-week treatment of 7r in the HFD feed mice provided information regarding its anti-obesity effect with respect to parameters such as body weight, triglycerides, total cholesterol and high-density lipids. Quantification of the faecal triglyceride contents inveterates the potential role of 7r in the PL inhibition. Overall, the synthesized analogue 7r exerted an anti-obesity effect comparable to orlistat. All these results demonstrated the potential role of the newly synthesised indole-thiazolidinedione hybrid analogues in PL inhibition and may be studied further to find potential drug candidates for treating obesity.Communicated by Ramaswamy H. Sarma.

Seroprotection With Three Dose vs Four Dose Schedule for Hepatitis B Vaccination in Children Living With Human Immunodeficiency Virus: Follow-up Data at 36-42 Months From a Randomized Controlled Trial.

OBJECTIVE: To compare the long-term seroprotection (anti-HBs ≥10 IU/L) in children living with HIV (CLHIV) receiving a 3- or 4-dose double-strength (20 µg) recombinant Hepatitis B virus (rHBV) vaccination. METHODS: We present anti-retroviral therapy (ART) clinic based follow-up data collected from January, 2021 to August, 2022, from CLHIV who had received either 3-dose or 4-dose double-strength (20 µg) rHBV vaccination, after 36-42 months and assessed for anti-HBs titres, naïve and memory T-helper lymphocytes, CD4 counts and HIV viral load. Children found unprotected after primary immunization, were administered a single double-strength rHBV vaccine booster dose (20 µg) and seroprotection was reassessed after 4 and 12 weeks. RESULTS: Out of 50 children initially vaccinated, 45 were followed up 36-42 months after primary immunization; median (IQR) anti-HBs titres (IU/L) were 230 (80.5 - 305.7) in the 3-dose group (n=23) and 263.5 (47.1-332.9) in the 4-dose group (n=22) (P=0.33). 19 and 20 children in the 3-dose and 4-dose group, respectively, were seroprotected (P=0.24). Anti-HBs titres at 36-42 months correlated with CD4 counts at baseline, anti-HBs titres at 1 and 6 months after completion of primary immunization and percentage of memory T-helper lymphocytes. All the five children (3-dose group: 4; 4-dose group: 1) who received rHBV vaccine booster dose attained seroprotection one-month later. CONCLUSION: Three-dose double strength rHBV vaccination schedule offers comparable seroprotection to a 4-dose double strength rHBV vaccination schedule in CLHIV receiving ART.

Triethyl phosphine decorated cerium oxide nanoparticles exhibit selective killing of the unicellular protozoan parasite Leishmania donovani.

Globally, Leishmaniasis affects underprivileged communities of the nations and chemotherapy remains one of the preferred treatment options. However, the cytotoxicity, side effects, and cost of the present chemotherapies limit their utilization. Auranofin [an organogold compound having significant structural similarity with triethyl-phosphine (TEP)] has been reported as an effective therapy for Leishmaniasis treatment. Considering the high cost of gold and the strong affinity of cerium oxide nanoparticles (CeNPs) to phosphine ligands, we designed TEP-decorated CeNPs (CeNPs-TEP) and used them as a novel antileishmanial agent. The hydrodynamic size of synthesized CeNPs and CeNPs-TEP was observed to be 22.2 ± 3.7 nm and 92.11 ± 6.2 nm, respectively. CeNPs-TEP provided aqueous stability to TEP as TEP alone is extremely unstable in water. Exposure of CeNPs-TEP showed ~ 60 and ~ 82% cell death in Leishmania donovani Ag83 promastigotes after 24 and 48 h, respectively. The same concentration of CeNPs-TEP did not affect the cellular viability of RAW 264.7 macrophage cells significantly. The oxidative stress and depolarization of the mitochondrial membrane were also observed after the treatment of CeNPs-TEP. Exposure of CeNPs-TEP induced a ~ 2.2-fold increase in ROS generation inside Leishmania donovani Ag83 cells. Dual staining with ethidium bromide and acridine orange reveals that these processes ultimately result in cell death. The results conclude that a combination of CeNPs and TEP could open the door for developing novel antileishmanial therapeutics in the future. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03813-7.

Xanthan gum-based copper nano-magnetite doped carbon aerogel: A promising candidate for environmentally friendly catalytic dye degradation.

In this work, a novel copper nano-magnetite doped carbon aerogel (CXMCA) was created utilizing a simple graft co-polymerization approach with xanthan gum (XG) as a template to tackle the agglomeration problem caused by magnetic nanoparticle magnetism. The results indicated that the XG based CXMCA exhibited outstanding magnetic properties (Ms = 36.52 emu/g) as well as strong catalytic activity for the degradation of cationic and anionic dyes. Among all organic dyes, methylene blue and crystal violet (MB, CV) as cationic dyes, as well as congo red and methyl orange (CR, and MO) as anionic dyes, CXMCA demonstrated an exceptional dye degradation rate (8.06 × 10-3 s-1-1.12 × 10-2 s-1) and was highly competent for cationic dyes with degradation (90 %-98 %) as compared to its unsupported magnetic nanoparticles. The formation of CXMCA catalyst is clearly confirmed by the FTIR, XRD, XPS, VSM, SEM & TEM analyses. We report a very effective xanthan gum-based copper nano-magnetite doped carbon aerogel dye scavenger with application in percentage dye degradation and kinetic investigations, as well as a remarkable reusability assay up to 7 repetition cycles. The findings suggested that using biological macromolecules like xanthan gum as a foundation to generate magnetic aerogels might be a good choice for evaluating environmental aspects.

Biocontrol Screening of Endophytes: Applications and Limitations.

The considerable loss of crop productivity each year due to plant disease or pathogen invasion during pre- or post-harvest storage conditions is one of the most severe challenges to achieving the goals of food security for the rising global population. Although chemical pesticides severally affect the food quality and health of consumers, a large population relies on them for plant disease management. But currently, endophytes have been considered one of the most suitable biocontrol agents due to better colonization and acclimatization potential. However, a very limited number of endophytes have been used commercially as biocontrol agents. Isolation of endophytes and their screening to represent potential characteristics as biocontrol agents are considered challenging by different procedures. Through a web search using the keywords "endophytes as biocontrol agents" or "biocontrol mechanism of endophytes," we have succinctly summarised the isolation strategies and different in vitro and in vivo biocontrol screening methods of endophytic biocontrol agents in the present review. In this paper, biocontrol mechanisms of endophytes and their potential application in plant disease management have also been discussed. Furthermore, the registration and regulatory mechanism of the endophytic biocontrol agents are also covered.

In-situ synthesis of ionic liquid-based-carbon quantum dots as fluorescence probe for hemoglobin detection.

Carbon quantum dots (CQDs) have emerged as a potential fluorescent probe in bio/analytical chemistry in the present decade. The optical characteristics of CQDs may be tuned by their functional groups, which can also be used to selectively produce stable bonds with target molecules. Along with them, ionic liquids (ILs) are now demonstrating their important relevance in the field of pharmaceuticals for the creation of potent therapeutics. In the article, we have discussed the use of high fluorescent ILs-decorated-CQDs (CQDs-IM@OTf) as a straightforward and quick-acting fluorescence probe for sensitive and precise hemoglobin (Hb) determination with minimum detectability of 6.7 nM. The proposed mechanism behind this involves static mode of quenching which leads to the formation of a ground state complex [CQDs-IM@OTf-Hb complex] between the Hb protein and the drug. Despite the fact that Hb can quench the fluorescence of CQDs due to the inner filter effect (IFE) of the protein, which effects both the excitation and emission spectra of the CQDs, the addition of H2O2 improved the sensitivity of Hb detection. The present assay predicated on Hb interaction with H2O2, which produces reactive oxygen species such as hydroxyl (OH.) and superoxide (O2.-) radicals under heme degradation and/or iron release from Hb. The subsequent reaction of hydroxyl radicals with CQDs, which acts as a strong oxidising agent, causes a high fluorescence quenching. The designed fluorescence probe was used to measure Hb in the concentration range of 3-90 nM with a precise detection limit of 0.33 nM. The quantification of hemoglobin (Hb) in diluted human blood samples is done using this observation.

Phosphine-catalysed denitrative rearomatising (3 + 2) annulation of α,ß-ynones and 3-nitroindoles.

We describe a metal-free strategy to access various α-arylidene cyclopenta[b]indoles via phosphine-catalysed (3 + 2) annulation of α,ß-ynones and 3-nitroindoles. For the first time, the rearomatisation of the indole nucleus was observed in such an annulative transformation. The method was extended to the synthesis of an antimalarial natural product, bruceolline E.

Molecular modelling, synthesis and in vitro evaluation of quinazolinone hybrid analogues as potential pancreatic lipase inhibitors.

Obesity is a multifactorial metabolic disorder, growing in an alarming rate across the world. Amongst the numerous targets explored for obesity management, inhibition of pancreatic lipase (PL) is considered as one of the promising approaches. Orlistat is the only PL inhibitory drug approved for long term treatment of obesity. However, it is reported to possess hepatotoxicity and nephrotoxicity. Thus, novel drug candidates that act through PL inhibition are considered the hour's need. Based on this aim, a series of quinazolinone hybrid analogues have been synthesized, characterized and evaluated for their PL inhibitory potential. The physicochemical properties and toxicity parameters suggested that these parameters are in an acceptable range for the screened analogues. Amongst the synthesised analogues, QH-25 exerted potential PL inhibition (IC50 = 16.99 ± 0.54 µM). Further, enzyme inhibition studies suggested a reversible competitive inhibition. Molecular docking of these analogues was in line with in vitro results, wherein the obtained MolDock scores exhibited a significant correlation with their inhibitory activity (Pearson's r = 0.6629). To further confirm the stability of the QH-25-PL complex in a dynamic environment, a molecular dynamics study (100 ns) was carried out and the results suggested that this complex is stable at dynamic conditions. Overall, these results shed light on the quinazolinone hybrids as potential PL inhibitors. Further structural modification may result in the development of potent anti-obesity agents which acts through PL inhibition.Communicated by Ramaswamy H. Sarma.

Inhibition of p21 activates Akt kinase to trigger ROS-induced autophagy and impacts on tumor growth rate.

Owing to its ability to induce cellular senescence, inhibit PCNA, and arrest cell division cycle by negatively regulating CDKs as well as being a primary target of p53, p21 is traditionally considered a tumor suppressor. Nonetheless, several reports in recent years demonstrated its pro-oncogenic activities such as apoptosis inhibition by cytosolic p21, stimulation of cell motility, and promoting assembly of cyclin D-CDK4/6 complex. These opposing effects of p21 on cell proliferation, supported by the observations of its inconsistent expression in human cancers, led to the emergence of the concept of "antagonistic duality" of p21 in cancer progression. Here we demonstrate that p21 negatively regulates basal autophagy at physiological concentration. Akt activation, upon p21 attenuation, driven ROS accumulation appears to be the major underlying mechanism in p21-mediated modulation of autophagy. We also find p21, as a physiological inhibitor of autophagy, to have oncogenic activity during early events of tumor development while its inhibition favors survival and growth of cancer cells in the established tumor. Our data, thereby, reveal the potential role of autophagy in antagonistic functional duality of p21 in cancer.