BA.1, BA.2 and BA.2.75 variants show comparable replication kinetics, reduced impact on epithelial barrier and elicit cross-neutralizing antibodies.

The Omicron variant of SARS-CoV-2 is capable of infecting unvaccinated, vaccinated and previously-infected individuals due to its ability to evade neutralization by antibodies. With multiple sub-lineages of Omicron emerging in the last 12 months, there is inadequate information on the quantitative antibody response generated upon natural infection with Omicron variant and whether these antibodies offer cross-protection against other sub-lineages of Omicron variant. In this study, we characterized the growth kinetics of Kappa, Delta and Omicron variants of SARS-CoV-2 in Calu-3 cells. Relatively higher amounts infectious virus titers, cytopathic effect and disruption of epithelial barrier functions was observed with Delta variant whereas infection with Omicron sub-lineages led to a more robust induction of interferon pathway, lower level of virus replication and mild effect on epithelial barrier. The replication kinetics of BA.1, BA.2 and BA.2.75 sub-lineages of the Omicron variant were comparable in cell culture and natural infection in a subset of individuals led to a significant increase in binding and neutralizing antibodies to the Delta variant and all the three sub-lineages of Omicron but the level of neutralizing antibodies were lowest against the BA.2.75 variant. Finally, we show that Cu2+, Zn2+ and Fe2+ salts inhibited in vitro RdRp activity but only Cu2+ and Fe2+ inhibited both the Delta and Omicron variants in cell culture. Thus, our results suggest that high levels of interferons induced upon infection with Omicron variant may counter virus replication and spread. Waning neutralizing antibody titers rendered subjects susceptible to infection by Omicron variants and natural Omicron infection elicits neutralizing antibodies that can cross-react with other sub-lineages of Omicron and other variants of concern.

Regio and Stereoselective One-Pot Synthesis of 2-Deoxy-3-thio Pyranoses and Their O-Glycosides from Glycals.

A reaction of glycals with two different types of nucleophiles in the presence of SnCl4 enabled one-pot rapid access to 2-deoxy-3-thio pyranoses and their O-glycosides. The process involves thioaryl substitution at C-3 with stereoretention and α-selective O-glycosylation at C-1 from d-glycals, thus combining two reactions with three interventions. The present methodology features an attractive three-component coupling (1:1.2:1.5 ratio) with operational simplicity at 0 °C in 10-20 min. This stereoselective one-pot 1,3-difunctionalization approach of glycals is compatible with wide range of primary and secondary alcohols affording products in good to excellent yields. This methodology was successfully extended toward disaccharide synthesis. Several control experiments suggested a plausible reaction mechanism and rationale behind regio and stereoselectivity. The reaction strategy possesses an intrinsic ability for the synthesis of various natural products and drug molecules.

Regulation of autophagy by canonical and non-canonical ER stress responses.

Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic reticulum (ER) stress, which can be counterbalanced by triggering the unfolded protein response (UPR) which is considered the canonical ER stress response. The UPR is characterized by three major proteins that lead to specific changes in transcriptional and translational programs in stressed cells. Activation of the UPR can induce apoptosis, but also can induce cytoprotective programs such as autophagy. There is increasing appreciation for the role that UPR-induced autophagy plays in supporting tumorigenesis and cancer therapy resistance. More recently several new pathways that connect cell stresses, components of the UPR and autophagy have been reported, which together can be viewed as non-canonical ER stress responses. Here we review recent findings on the molecular mechanisms by which canonical and non-canonical ER stress responses can activate cytoprotective autophagy and contribute to tumor growth and therapy resistance. Autophagy has been identified as a druggable pathway, however the components of autophagy (ATG genes) have proven difficult to drug. It may be the case that targeting the UPR or non-canonical ER stress programs can more effectively block cytoprotective autophagy to enhance cancer therapy. A deeper understanding of these pathways could provide new therapeutic targets in cancer.

Anticancer properties of bisaminoquinolines with modified linkers.

We have previously reported the unique features of dimeric bisaminoquinolines as anticancer agents and have identified their cellular target as PPT1, a protein palmitoyl-thioesterase. We now report a systematic study on the role of the linker in these constructs, both with respect to the distance between the heterocycles, the linker hydrophobicity and the methylation status (primary vs. secondary vs. tertiary) of the central nitrogen atom on the observed biological activity.

A Review on Obesity Management through Natural Compounds and a Green Nanomedicine-Based Approach.

Obesity is a serious health complication in almost every corner of the world. Excessive weight gain results in the onset of several other health issues such as type II diabetes, cancer, respiratory diseases, musculoskeletal disorders (especially osteoarthritis), and cardiovascular diseases. As allopathic medications and derived pharmaceuticals are partially successful in overcoming this health complication, there is an incessant need to develop new alternative anti-obesity strategies with long term efficacy and less side effects. Plants harbor secondary metabolites such as phenolics, flavonoids, terpenoids and other specific compounds that have been shown to have effective anti-obesity properties. Nanoencapsulation of these secondary metabolites enhances the anti-obesity efficacy of these natural compounds due to their speculated property of target specificity and enhanced efficiency. These nanoencapsulated and naive secondary metabolites show anti-obesity properties mainly by inhibiting the lipid and carbohydrate metabolizing enzymes, suppression of adipogenesis and appetite, and enhancing energy metabolism. This review focuses on the plants and their secondary metabolites, along with their nanoencapsulation, that have anti-obesity effects, with their possible acting mechanisms, for better human health.

Urease Inhibitory Kinetic Studies of Various Extracts and Pure Compounds from Cinnamomum Genus.

Urease is an enzyme that plays a significant role in the hydrolysis of urea into carbonic acid and ammonia via the carbamic acid formation. The resultant increase in pH leads to the onset of various pathologies such as gastric cancer, urolithiasis, hepatic coma, hepatic encephalopathy, duodenal ulcers and peptic ulcers. Urease inhibitors can reduce the urea hydrolysis rate and development of various diseases. The Cinnamomum genus is used in a large number of traditional medicines. It is well established that stem bark of Cinnamomum cassia exhibits antiulcerogenic potential. The present study evaluated the inhibitory effect of seven extracts of Cinnamomum camphora, Cinnamomum verum and two pure compounds Camphene and Cuminaldehyde on urease enzyme. Kinetic studies of potential inhibitors were carried out. Methanol extract (IC50 980 µg/mL) of C. camphora and a monoterpene Camphene (IC50 0.147 µg/mL) possess significant inhibitory activity. The Lineweaver Burk plot analysis suggested the competitive inhibition by methanol extract, hexane fraction and Camphene. The Gas Chromatography-Mass Spectroscopy (GC-MS) analysis of hexane fraction revealed the contribution of various terpenes. The present study targets terpenes as a new class of inhibitors that have potential therapeutic value for further development as novel drugs.

Synthesis of aryl ethers of carbohydrates via reaction with arynes: selective O-arylation of trans-vicinal dihydroxyl groups in carbohydrates.

A new method for the O-arylation of carbohydrates under metal-free conditions using arynes as an aryl source has been developed. This approach works well with mono, di and trihydroxy compounds. Preferential O-arylation takes place at primary over secondary and equatorial over axial. Site-selective O-arylation was achieved with the substrate having trans vicinal diequatorial hydroxyls.

Epidemiology of carbapenem-resistant Escherichia coli and first report of blaVIM carbapenemases gene in calves from India.

A cross-sectional study on six dairy farms was conducted to ascertain the occurrence of carbapenem-resistant Escherichia coli in calves. Two-hundred and seventy-nine isolates of E. coli were recovered from 90 faecal samples from apparently healthy (45) and diarrhoeal (45) calves. The isolates were screened for phenotypic susceptibility to carbapenems and production of metallo ß-lactamase, as well as five carbapenemase resistance genes by PCR, and overexpression of efflux pumps. Eighty-one isolates (29.03%) were resistant to at least one of three carbapenem antibiotics [meropenem (23.30%), imipenem (2.15%) and ertapenem (1.43%)], and one isolate was positive for the blaVIM gene which was located on an Incl1 plasmid of a novel sequence type (ST 297) by multilocus sequence typing. The majority (83.95%) of isolates had an active efflux pump. Calves housed on concrete floors were approximately seven times more likely to acquire meropenem-resistant isolates than those housed on earthen floors (95% CI 1.27-41.54). In India, carbapenem drugs are not used in food animal treatment, hence carbapenem-resistant strains in calves possibly originate from the natural environment or human contact and is of public health importance. To our knowledge, this is the first report of blaVIM carbapenemases gene in calves from India.

Eukaryotic translation initiation factor eIF5 promotes the accuracy of start codon recognition by regulating Pi release and conformational transitions of the preinitiation complex.

eIF5 is the GTPase activating protein (GAP) for the eIF2 · GTP · Met-tRNAi (Met) ternary complex with a critical role in initiation codon selection. Previous work suggested that the eIF5 mutation G31R/SUI5 elevates initiation at UUG codons by increasing GAP function. Subsequent work implicated eIF5 in rearrangement of the preinitiation complex (PIC) from an open, scanning conformation to a closed state at AUG codons, from which Pi is released from eIF2 · GDP · Pi. To identify eIF5 functions crucial for accurate initiation, we investigated the consequences of G31R on GTP hydrolysis and Pi release, and the effects of intragenic G31R suppressors on these reactions, and on the partitioning of PICs between open and closed states. eIF5-G31R altered regulation of Pi release, accelerating it at UUG while decreasing it at AUG codons, consistent with its ability to stabilize the closed complex at UUG. Suppressor G62S mitigates both defects of G31R, accounting for its efficient suppression of UUG initiation in G31R,G62S cells; however suppressor M18V impairs GTP hydrolysis with little effect on PIC conformation. The strong defect in GTP hydrolysis conferred by M18V likely explains its broad suppression of Sui(-) mutations in numerous factors. We conclude that both of eIF5's functions, regulating Pi release and stabilizing the closed PIC conformation, contribute to stringent AUG selection in vivo.

The gut-liver axis: emerging mechanisms and therapeutic approaches for nonalcoholic fatty liver disease and type 2 diabetes mellitus.

Nonalcoholic fatty liver disease (NAFLD), more appropriately known as metabolic (dysfunction) associated fatty liver disease (MAFLD), a prevalent condition in type 2 diabetes mellitus (T2DM) patients, is a complex condition involving hepatic lipid accumulation, inflammation, and liver fibrosis. The gut-liver axis is closely linked to metabolic dysfunction, insulin resistance, inflammation, and oxidative stress that are leading to the cooccurrence of MAFLD and T2DM cardiovascular diseases (CVDs). The purpose of this review is to raise awareness about the role of the gut-liver axis in the progression of MAFLD, T2DM and CVDs with a critical analysis of available treatment options for T2DM and MAFLD and their impact on cardiovascular health. This study analysed over 100 articles on this topic, using online searches and predefined keywords, to understand and summarise published research. Numerous studies have shown a strong correlation between gut dysfunction, particularly the gut microbiota and its metabolites, and the occurrence and progression of MAFLD and type 2 diabetes mellitus (T2DM). Herein, this article also examines the impact of the gut-liver axis on MAFLD, T2DM, and related complications, focusing on the role of gut microbiota dysbiosis in insulin resistance, T2DM and obesity-related cardiovascular complications. The study suggests potential treatment targets for MAFLD linked to T2DM, focusing on cardiovascular outcomes and the molecular mechanism of the gut-liver axis, as gut microbiota dysbiosis contributes to obesity-related metabolic abnormalities.

Comparative study on phytochemical screening of polyphenol rich extracts of Euphorbia tithymaloidesL. with special emphasis on antiglycation and anti-diabetic potential.

The present study evaluated a range of biological activities of Euphorbia tithymaloides L. (Family: Euphorbiaceae) in relation to diabetes and associated complications. This plant has antioxidant and anti-inflammatory properties, but its potential for the management of hyperglycaemia and subsequently, the inhibition and reversal of advanced glycation end products has not yet been pinpointed. The objectives of this work centred around comparative iv-vitro phytochemical screening of different plant parts, followed by antidiabetic, antiglycation and glycation-reversing activities of Euphorbia tithymaloides. Rutin and luteolin, two main bioactive compounds with significant antiglycation potentials, were also quantified using a recently developed and validated HPLC-PDA method. Leaf extract showed significantly higher potency than root and stem extracts in terms of antioxidant, anti-inflammatory, antidiabetic and antiglycation activity. A combination of enzymatic inhibition and HPLC phytochemical screening provided additional evidence to consider this plant a promising source for deepening the investigation on antidiabetic plant agents.

Development and Validation of Fast and Sensitive RP-HPLC Stability-Indicating Method for Quantification of Piroxicam in Bulk Drug.

A simple, rapid, sensitive, and cost-effective green solvent-assisted reverse-phase high-performance liquid chromatographic technique, coupled with a photodiode array detector, was developed and validated for the estimation of piroxicam (PRXM). The chromatographic separation was achieved by using a C-18 (250 × 4.6) mm, 5-µm stationary phase and a mobile phase consisting of methanol and 0.1% ortho-phosphoric acid in water in a ratio of (80:20) v/v at a flow rate of 1 ml/min. The detection was carried out at a wavelength of 254 nm with a constant injection volume of 10 µL throughout the analysis. The calibration curve was observed to be linear over the optimum concentration range of 50-300 µg mL-1, with an R2 value of 0.9995. The developed method was validated as per the International Council for Harmonisation (ICH) Q2 (R1) guideline. Various parameters like selectivity/specificity, accuracy/recovery, linearity, precision, detection limit, quantitation limit, robustness and stability of analyte in solution were performed for the method validation. The PRXM was evaluated under stressed conditions, including acidic, basic, oxidative, thermal and photolytic, as per ICH Q1 (R2) guidelines. Significant degradation was observed in acidic and basic degradation conditions. Conversely, the drug substance showed stability when exposed to oxidative, photolytic and thermal degradation conditions.

Corrections to "Phytochemical Screening and Antidiabetic Efficacy of Balanites aegyptiaca Seed Extract and Their Silver Nanoparticles on Muscle and Pancreatic Cell Lines".

[This corrects the article DOI: 10.1021/acsomega.4c00327.].

Phytochemical Screening and Antidiabetic Efficacy of Balanites aegyptiaca Seed Extract and Their Silver Nanoparticles on Muscle and Pancreatic Cell Lines.

Balanites aegyptiaca (L.) Delile, a member of the Zygophyllaceae family, is commonly known as the desert date. This tree is famous for yielding edible fruits and is esteemed for its nutritional richness and diverse health advantages. The primary aim of this research was to assess the potential antidiabetic and cytotoxic effects of seed extracts from B. aegyptiaca and its AgNPs for the first time on C2C12 and MIN6 cells, focusing on glucose uptake and insulin secretion, respectively. Additionally, the seed extracts underwent column chromatography through different solvent systems, resulting in the isolation of five distinct fractions with a mixture of methanol and water as an eluting solvent in different ratios. Comprehensive characterization of the aqueous seed extract was carried out using GC-MS and UPLC-MS. The study determined that the aqueous seed extract exhibited no toxicity at any tested concentration (6.25-100 µg/mL) on both cell types. The calculated IC50 values were 206.00 and 140.44 µg/mL for C2C12 and MIN6 cells, respectively, for seeds of AgNPs. Additionally, the aqueous seed extract and their AgNPs significantly increased glucose uptake by 150.45% and 156.00% of the control in C2C12 cells at a concentration of 100 µg/mL. Insulin secretion was also notably enhanced by 3.47- and 3.92-fold of the control after administering seed extracts and AgNPs, respectively, at 100 µg/mL. GC-MS and UPLC-MS analyses identified various compounds across different categories. Notably, the F2 fraction (methanol and water in ratio of 80:20 as eluting solvent) exhibited the highest glucose uptake activity (156.81% of control), while the F3 fraction (methanol and water in ratio of 70:30 as eluting solvent) fraction demonstrated the highest insulin secretion activity (3.70 folds of the control) among all fractions at 100 µg/mL. GC-MS analysis was employed to characterize both fractions, aiming to identify the compounds contributing to their antidiabetic potential. The study's findings concluded that both seed extracts and their AgNPs possess significant antidiabetic properties, with elevated activity observed in the case of AgNPs in both assays. Various compounds, including diosgenin, oleic acid, linoleic acid and palmitic acid esters were detected in the seed extracts, known for their reported antidiabetic and hypoglycemic effects.

Emerging Applications of Plant Antimicrobials in the Food Industry.

Food safety is a global concern with significant public health implications. Improper food handling can harbor a wide range of pathogenic organisms. Antimicrobial agents are crucial for controlling microbes and ensuring food safety and human health. The growing demand for natural, safe, and sustainable food preservation methods has driven research into using plant antimicrobials as alternatives to synthetic preservatives. The food industry is now exploring innovative approaches that combine various physical methods with multiple natural antimicrobials. This review aims to outline the evolving applications of plant antimicrobials in the food industry. It discusses strategies for managing bacteria and categorizes different plant antimicrobials, providing insights into their mechanisms of action and structures. This review offers a comprehensive overview of antimicrobial peptides (AMPs), detailing their structural characteristics, mechanisms of action, various types, and applications in food packaging fabrication and explaining how they contribute to food preservation. It highlights the synergistic and additive benefits of plant antimicrobials and their successful integration with food technologies like nanotechnology, which enhances the hurdle effect, improving food safety and extending shelf life. The review also emphasizes the importance of antimicrobial peptides and the need for further research in this area. Safety assessment and regulatory considerations are discussed as well. By addressing these gaps, plant antimicrobials have the potential to pave the way for more effective, safe, and sustainable food preservation strategies in the future.

Phytotherapeutics in Cancer: From Potential Drug Candidates to Clinical Translation.

Annually, a significant number of individuals succumb to cancer, an anomalous cellular condition characterized by uncontrolled cellular proliferation and the emergence of highly perilous tumors. Identifying underlying molecular mechanism(s) driving disease progression has led to various inventive therapeutic approaches, many of which are presently under pre-clinical and/or clinical trials. Over the recent years, numerous alternative strategies for addressing cancer have also been proposed and put into practice. This article delineates the modern therapeutic drugs employed in cancer treatment and their associated toxicity. Due to inherent drug toxicity associated with most modern treatments, demand rises for alternative therapies and phytochemicals with minimal side effects and proven efficacy against cancer. Analogs of taxol, Vinca alkaloids like vincristine and vinblastine, and podophyllotoxin represent a few illustrative examples in this context. The phytochemicals often work by modifying the activity of molecular pathways that are thought to be involved in the onset and progression of cancer. The principal objective of this study is to provide an overview of our current understanding regarding the pharmacologic effects and molecular targets of the active compounds found in natural products for cancer treatment and collate information about the recent advancements in this realm. The authors' interest in advancing the field of phytochemical research stems from both the potential of these compounds for use as drugs as well as their scientific validity. Accordingly, the significance of herbal formulations is underscored, shedding light on anticancer phytochemicals that are sought after at both preclinical and clinical levels, with discussion on the opportunities and challenges in pre-clinical and clinical cancer studies.

Piperidine Nucleus as a Promising Scaffold for Alzheimer's Disease: Current Landscape and Future Perspective.

Heterocycles and their derivatives hold an important place in medicinal chemistry due to their vast therapeutic and pharmacological significance and wider implications in drug design and development. Piperidine is a nitrogen-containing heterocyclic moiety that exhibits an array of pharmacological properties. This review discusses the potential of piperidine derivatives against the neurodegenerative disease Alzheimer's. The incidences of Alzheimer's disease are increasing nowadays, and constant efforts are being made to develop a medicinal agent for this disease. We have highlighted the advancement in developing piperidine-based anti-neuronal disease compounds and the profound activities of some major piperidine-bearing drug molecules with their important target site. This review focuses on advancements in the field of natural and synthetic occurring piperidines active against Alzheimer's disease, with emphasis on the past 6 years. The discussion also includes the structure-activity relationship, the structures of the most promising molecules, and their biological activities against Alzheimer's disease. The promising activities revealed by these piperidinebased scaffolds undoubtedly place them at the forefront of discovering prospective drug candidates. Thus, it would be of great interest to researchers working on synthesizing neuroprotective drug candidates.

Development and Validation of Robust, Highly Sensitive and Stability-Indicating RP-HPLC Method for Estimation of Deferasirox and its Degradation Products.

A rapid, simple and highly sensitive stability-indicating reverse-phase high-performance liquid chromatographic technique, coupled with a photodiode array detector, was developed and validated for the estimation of Deferasirox (DFS). The chromatographic separation was achieved using a C-18 (250 × 4.6 mm, 5 µm) stationary phase and a mobile phase composed of 0.1% orthophosphoric acid and acetonitrile at a flow rate of 1 mL/min. The detection was carried out at a wavelength of 245 nm with a constant injection volume of 10 µL throughout the analysis. With an R2 value of 0.9996, the calibration curve was determined to be linear over an appropriate concentration range of 50-500 ng/mL. According to the International Conference on Harmonization (ICH) Q1 (R2) guideline, DFS was evaluated under stress conditions that included hydrolytic (acid, alkali and neutral), oxidative and thermal degradation. The findings demonstrated that significant degradation was observed in acidic degradation conditions, whereas drug substance was found to be stable when exposed to neutral, basic, oxidative and thermal degradation. The developed method was validated as per ICH guidelines. The developed method was employed successfully to estimate the amount of DFS in bulk and pharmaceutical formulation.

Protective NaSICON Interlayer between a Sodium-Tin Alloy Anode and Sulfide-Based Solid Electrolytes for All-Solid-State Sodium Batteries.

This paper presents a suitable combination of different sodium solid electrolytes to surpass the challenge of highly reactive cell components in sodium batteries. The focus is laid on the introduction of ceramic Na3.4Zr2Si2.4P0.6O12 serving as a protective layer for sulfide-based separator electrolytes to avoid the high reactivity with the sodium metal anode. The chemical instability of the anode|sulfide solid electrolyte interface is demonstrated by impedance spectroscopy, X-ray photoelectron spectroscopy, and scanning electron microscopy. The Na3.4Zr2Si2.4P0.6O12 disk shows chemical stability with the sodium metal anode as well as the sulfide solid electrolyte. Impedance analysis suggests an electrochemically stable interface. Electron microscopy points to a reaction at the Na3.4Zr2Si2.4P0.6O12 surface toward the sulfide solid electrolyte, which does not seem to affect the performance negatively. The results presented prove the chemical stabilization of the anode-separator interface using a Na3.4Zr2Si2.4P0.6O12 interlayer, which is an important step toward a sodium all-solid-state battery. Due to the applied pressure that is mandatory for battery cells with sulfide-based cathode composite, the use of a brittle ceramic in such cells remains challenging.

Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition.

Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. Although UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted. SIGNIFICANCE: We discovered UGCG-dependent lipid remodeling drives resistance to LAI. Targeting UGCG with a drug approved for a lysosomal storage disorder enhanced LAI antitumor activity without toxicity. LAI and UGCG inhibition could be tested clinically in multiple cancers. This article is highlighted in the In This Issue feature, p. 247.