Divergent effects of acute and chronic PPT1 inhibition in melanoma.

Macroautophagy/autophagy-lysosome function promotes growth and survival of cancer cells, making them attractive targets for cancer therapy. One intriguing lysosomal target is PPT1 (palmitoyl-protein thioesterase 1). PPT1 inhibitors derived from chloroquine block autophagy, have significant antitumor activity in preclinical models and are being developed for clinical trials. However, the role of PPT1 in tumorigenesis remains poorly understood. Here we report that in melanoma cells, acute siRNA or pharmacological PPT1 inhibition led to increased ferroptosis sensitivity and significant loss of viability, whereas chronic PPT1 knockout using CRISPR-Cas9 produced blunted ferroptosis that led to sustained viability and growth. Each mode of PPT1 inhibition produced lysosome-autophagy inhibition but distinct proteomic changes, demonstrating the complexity of cellular adaptation mechanisms. To determine whether total genetic loss of Ppt1 would affect tumorigenesis in vivo, we developed a Ppt1 conditional knockout mouse model. We then crossed it into the BrafCA, PtenloxP, Tyr:CreERT2 melanoma mouse model to investigate the impact of Ppt1 loss on tumorigenesis. Loss of Ppt1 had no impact on melanoma histology, time to tumor initiation, or survival of tumor-bearing mice. These results suggest that chemical PPT1 inhibitors produce different adaptations than genetic PPT1 inhibition, and additional studies are warranted to fully understand the mechanism of chloroquine derivatives that target PPT1 in cancer.Abbreviations: 4-HT: 4-hydroxytamoxifen; BRAF: B-Raf proto-oncogene, serine/threonine kinase; cKO: conditional knockout; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9; DC661: A specific PPT1 inhibitor; DMSO: dimethyl sulfoxide; Dox; doxycycline hyclate; Easi-CRISPR: efficient additions with ssDNA inserts-CRISPR; GNS561/ezurpimtrostat: A PPT1 inhibitor; Hug: human guide; iCas: inducible CRISPR-Cas9; KO: knockout; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; LDLR: low density lipoprotein receptor; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NT: non-target; PTEN: phosphatase and tensin homolog; PPT1: palmitoyl-protein thioesterase 1; RSL3: RAS-selective lethal small molecule 3; SCRIB/SCRB1: scribble planar cell polarity protein; Tyr:CreERT2: tyrosinase-driven Cre recombinase fused with the tamoxifen-inducible mutant ligand binding domain of the human estrogen receptor; UGCG: UDP-glucose ceramide glucosyltransferase; WT: wild-type.

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.

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.

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.

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 pre-clinical and clinical levels, with discussion on the opportunities and challenges in pre-clinical and clinical cancer studies.

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.

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.

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.

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.

Lysosomal lipid peroxidation regulates tumor immunity.

Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.

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.

Identification and characterization of forced degradation products of sertraline hydrochloride using UPLC, ultra-high-performance liquid Chromatography-Quadrupole-Time of flight mass spectrometry (UHPLC-Q-TOF/MS/MS) and NMR.

The present study focused on the forced degradation behavior of sertraline hydrochloride (SRT), selective serotonin reuptake inhibitor (SSRI). The drug was exposed to different stressed conditions (hydrolytic, oxidative, thermal and photolytic) according to ICH Q1A (R2) guidelines. The study revealed that SRT was stable in hydrolytic (acidic, basic and neutral) and thermal degradation conditions. In contrast, five degradation products (DPs) were formed under oxidative and photolytic degradation conditions. The chromatographic separation of drug substance and its DPs was achieved on an Acquity HSS T3 column (100 × 2.1 mm, 1.7 µ) using 0.1% formic acid and acetonitrile as the mobile phase in gradient mode using a UHPLC-DAD system. The DPs were identified and characterized by high-resolution LC/MS and LC/MS/MS in ESI positive mode. Two DPs (DP-I and DP-II) were formed when SRT was exposed to oxidative degradation conditions. Three DPs formed (DP III-V) when exposed to photolytic degradation conditions. All the five major DPs were isolated using Preparative HPLC. The structures of major DPs formed were further confirmed using NMR technique (1D and 2D). The proposed mechanism for the formation of the SRT DPs via the photolytic/oxidative stress degradation pathway are discussed and outlined.

GSTO1 confers drug resistance in HCT­116 colon cancer cells through an interaction with TNFαIP3/A20.

The aim of the present study was to decipher the mechanism of glutathione­S­transferase Ω­1 (GSTO1)­induced drug resistance in colon cancer cells. Cisplatin is used widely as a therapeutic drug in cancer, but colon cancer is the most susceptible to acquired drug resistance. Autophagy is recognized as one of the contributors to drug resistance in cancers. Phase II detoxifying enzymes, such as GSTO1, serve important roles in autophagy­apoptosis cross talk. The present study revealed a novel interaction between GSTO1 and TNFα­induced protein 3/zinc­finger protein A20 (TNFαIP3/A20) as a prime target for cisplatin sensitization in drug­resistant cells. GSTO1 and ATP­binding cassette subfamily B member 1 (ABCB1) were both expressed at higher levels in multidrug­resistant (MDR) HCT­116 cells compared with the wild­type (WT) HCT­116 cells, suggesting they may serve vital roles in multidrug resistance. MDR cells showed autophagy induction, which is dependent on calcium signaling­dependent endoplasmic stress. In WT cells, the mitochondria­dependent pathway leads to apoptosis, which was not observed in MDR cells. The MDR conditions were mimicked by transfecting WT cells with the GSTO1­activation CRISPR plasmid, which induced autophagy. Similarly, MDR cells with GSTO1­knockdown (KD) CRISPR/Cas9 transfection showed reduced autophagy with increased apoptosis. These data revealed a potentially important role of GSTO1 in drug resistance. A GSTO1 pull­down assay detected TNFαIP3/A20 as a binding partner in MDR cells. The data suggested that the expression of TNFαIP3/A20 may be dependent on GSTO1 expression in MDR cells. Targeting either GSTO1 or TNFαIP3/A20 by CRISPR/Cas9 sensitized the MDR cells to cisplatin. GSTO1 and TNFαIP3/A20 dual­KD cells were more sensitive to cisplatin compared with single­gene KD cells. These data highlight the importance of the GSTO1­TNFαIP3/A20 interaction during drug resistance.

Expression of IL-6, TNF-α, and hs-CRP in the serum of patients undergoing single-sitting and multiple-sitting root canal treatment: A comparative study.

Background: In recent times, single-sitting root canal therapy has gained momentum over multiple-sitting root canal therapy due to its superior clinical outcome and less time required for treating the patient. Aim: Thus, the aim of current study was to compare the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) in the serum of patients undergoing single-sitting and multiple-sitting root canal treatment. Materials and Methods: This cross-sectional experimental study was conducted on 300 subjects who were indicated for root canal treatment. Subjects were categorized into Group I (single visit) and Group II (multiple visits).Clinical data was obtained and serum samples were collected both before and after 1 week of treatment completion. Inclusion criteria were those patients (a) over 18 years of age, (b) without any disease of inflammatory etiology, and (c) who had not previously received endodontic treatment or any related therapeutic treatment. Exclusion criteria were those (a) without a complete clinical history, (b) with greater than one indicated tooth, (c) who did not complete their treatment, and (d) with any periodontal disease. Chi-square and Student's t-test were applied. Results: It was found that in single-sitting root canal treatment, there was a statistically significant reduction in these inflammatory biomarkers, although no difference in clinical efficacy was observed. Conclusion: Single-visit root canal treatment is a better option for treatment of pulpitis compared to multiple-sitting treatment.

Ni-catalyzed domino transformation of enopyranoses and 2-iodo phenols/anilines to pyrano cis fused dihydro-benzofurans/indoles.

A Ni-catalyzed direct access to various pyrano cis-fused dihydro benzofurans and indoles from unsaturated enopyranoses and o-iodo phenols/anilines is developed. The domino synthesis of pyrano C2-C1 and C3-C2 cis-fused heteroarynes were achieved both from glycals and pseudo glycals in which heteroatoms are linked at C2 and C3 positions, respectively, with excellent chemo-selectivity.

Current Developments in the Pyran-Based Analogues as Anticancer Agents.

Heterocyclic compounds offer an enormous area for new lead molecules for drug discovery. Till today, efforts are being continuously made to find appropriate treatment for the management of the deadly disease of cancer. Amongst the large number of heterocycles that are found in nature, heterocycles having oxygen obtained noteworthy attention due to their distinctive and pharmacological activities.'Pyran' is one of the most significant non-aromatic, sixmembered ring composed of one oxygen atom and five carbon atoms. It is considered a privileged structure since pyran and its related derivatives exhibit a wide spectrum of biological activities. Pyran derivatives are found to have excellent anti-cancer properties against various types of cancer. The present review focussed on the current advances in different types of pyran-based derivatives as anti-cancer agents. Various in vitro (cell based testing), in vivo (animal based testing) models as well as molecular docking along with results are also covered. A subsection describing briefly natural pyran containing anticancer compounds is also incorporated in the review.