Implementing high-dose rate surface mould brachytherapy for carcinoma of eyelid: a practical approach and weekly review.

Surface mould brachytherapy is a conformal radiotherapy technique that can deliver high dose to the target while sparing nearby normal structures, Here, we aim to describe the procedurals details for high-dose rate (HDR) surface mould brachytherapy in sebaceous carcinoma of eyelid in a 54-year old lady. She was hesitant for surgery and any form of invasive intervention like interstitial brachytherapy. So, she was treated with surface mould HDR brachytherapy to a total dose of 52 Gy in 13 fractions at a dose of 4 Gy per fraction delivered twice daily using Iridium-192 isotope with no acute side effects. She was evaluated on a weekly basis for any radiation side effects and now she is disease-free for 6 months post-treatment with only mild dry eye. A detailed step-by-step procedure of surface mould technique, simulation procedure, dose prescription, planning, plan evaluation and treatment has been described in this paper. Surface mould HDR brachytherapy can be safely used as organ preserving modality of treatment for eyelid carcinoma.

Breed and timepoint-based analysis of chicken harderian gland transcriptome during Newcastle disease virus challenge.

Introduction: Newcastle disease is a highly infectious disease caused by the Newcastle Disease Virus (NDV) and has a devastating financial impact on the global chicken industry. It was previously established that Leghorn and Fayoumi breeds of chicken exhibit variable resistance against NDV infection. The harderian gland is the less studied tissue of the chicken, known to play an essential role in the immune response. Methods: Our previous study, we reported differential gene expression and long noncoding RNAs (lncRNAs) between challenged and non-challenged chickens in the Harderian gland transcriptomic data. Now, we report the analysis of the same data studying the differential expression patterns between Leghorn and Fayoumi and between different timepoints during disease. First, the pipeline FHSpipe was used for identification of lncRNAs, followed by differential expression analysis by edgeR (GLM), functional annotation by OmicsBox, co-expression analysis using WGCNA and finally validation of selected lncRNAs and co-expressing genes using qRT-PCR. Results: Here, we observed that Leghorn showed a higher number of upregulated immune-related genes than Fayoumi in timepoint-based analysis, especially during the initial stages. Surprisingly, Fayoumi, being comparatively resistant, showed little difference between challenged and non-challenged conditions and different time points of the challenge. The breed-based analysis, which compared Leghorn with Fayoumi in both challenged and non-challenged conditions separately, identified several immune-related genes and positive co-expressing cis lncRNAs to be upregulated in Fayoumi when compared to Leghorn in both challenged and non-challenged conditions. Discussion: The current study shows that Leghorn, being comparatively more susceptible to NDV than Fayoumi, showed several immune-related genes and positive co-expressing cis lncRNAs upregulated in challenged Leghorn when compared to non-challenged Leghorn and also in different timepoints during challenge. While, breed-based analysis showed that there were more upregulated immune genes and positive cis-lncRNAs in Fayoumi than Leghorn. This result clearly shows that the differences in the expression of genes annotated with immune-related GO terms and pathways, i.e., immune-related genes and the co-expressing cis-lncRNAs between Leghorn and Fayoumi, and their role in the presence of differences in the resistance of Leghorn and Fayoumi chicken against NDV. Conclusion: These immune-genes and cis-lncRNAs could play a role in Fayoumi being comparatively more resistant to NDV than Leghorn. Our study elucidated the importance of lncRNAs during the host defense against NDV infection, paving the way for future research on the mechanisms governing the genetic improvement of chicken breeds.

Understanding the role of transmembrane 9 superfamily member 1 in bladder cancer pathogenesis.

In this editorial we comment on the article by Wei et al, published in the recent issue of the World Journal of Clinical Oncology. The authors investigated the role of Transmembrane 9 superfamily member 1 (TM9SF1) protein in bladder cancer (BC) carcinogenesis. Lentiviral vectors were used to achieve silencing or overexpression of TM9SF1 gene in three BC cell lines. These cell lines were then subject to cell counting kit 8, wound-healing assay, transwell assay, and flow cytometry. Proliferation, migration, and invasion of BC cells were increased in cell lines subjected to TM9SF1 overexpression. TM9SF1 silencing inhibited proliferation, migration and invasion of BC cells. The authors conclude that TM9SF1 may be an oncogene in bladder cancer pathogenesis.

A novel hierarchical framework for plant leaf disease detection using residual vision transformer.

Early detection of plant leaf diseases accurately and promptly is very crucial for safeguarding agricultural crop productivity and ensuring food security. During their life cycle, plant leaves get diseased because of multiple factors like bacteria, fungi, weather conditions, etc. In this work, the authors propose a model that aids in the early detection of leaf diseases using a novel hierarchical residual vision transformer using improved Vision Transformer and ResNet9 models. The proposed model can extract more meaningful and discriminating details by reducing the number of trainable parameters with a smaller number of computations. The proposed method is evaluated on the Local Crop dataset, Plant Village dataset, and Extended Plant Village Dataset with 13, 38, and 51 different leaf disease classes. The proposed model is trained using the best trail parameters of Improved Vision Transformer and classified the features using ResNet 9. Performance evaluation is carried out on a wide aspects over the aforementioned datasets and results revealed that the proposed model outperforms other models such as InceptionV3, MobileNetV2, and ResNet50.

Living in Syn: T Cell Antigen Identification Based on Synapse Sequencing.

The pivotal role of T cell responses has been well studied in both protective and destructive scenarios. T cells recognize peptide epitopes presented on Human Leukocyte Antigens (HLA) through their surface T cell receptors (TCR). Advances in single-cell RNA sequencing have identified millions of TCRs, but only a minuscule fraction of them have known epitopes. Recently, cell-based T cell antigen discovery platforms have emerged onto the landscape. Here, Jin and colleagues, report a novel antigen discovery platform called Tsyn-seq that relies on sequencing TCR-peptide-HLA-induced synapses for genome-wide epitope screening. See related article by Jin et al., p. 530 (3).

De novo identification of CD4+ T cell epitopes.

CD4+ T cells recognize peptide antigens presented on class II major histocompatibility complex (MHC-II) molecules to carry out their function. The remarkable diversity of T cell receptor sequences and lack of antigen discovery approaches for MHC-II make profiling the specificities of CD4+ T cells challenging. We have expanded our platform of signaling and antigen-presenting bifunctional receptors to encode MHC-II molecules presenting covalently linked peptides (SABR-IIs) for CD4+ T cell antigen discovery. SABR-IIs can present epitopes to CD4+ T cells and induce signaling upon their recognition, allowing a readable output. Furthermore, the SABR-II design is modular in signaling and deployment to T cells and B cells. Here, we demonstrate that SABR-IIs libraries presenting endogenous and non-contiguous epitopes can be used for antigen discovery in the context of type 1 diabetes. SABR-II libraries provide a rapid, flexible, scalable and versatile approach for de novo identification of CD4+ T cell ligands from single-cell RNA sequencing data using experimental and computational approaches.

Mechanistic Modeling of In Vitro Biopharmaceutic Data for a Weak Acid Drug: A Pathway Towards Deriving Fundamental Parameters for Physiologically Based Biopharmaceutic Modeling.

Mechanistic modeling of in vitro experiments using metabolic enzyme systems enables the extrapolation of metabolic clearance for in vitro-in vivo predictions. This is particularly important for successful clearance predictions using physiologically based pharmacokinetic (PBPK) modeling. The concept of mechanistic modeling can also be extended to biopharmaceutics, where in vitro data is used to predict the in vivo pharmacokinetic profile of the drug. This approach further allows for the identification of parameters that are critical for oral drug absorption in vivo. However, the routine use of this analysis approach has been hindered by the lack of an integrated analysis workflow. The objective of this tutorial is to (1) review processes and parameters contributing to oral drug absorption in increasing levels of complexity, (2) outline a general physiologically based biopharmaceutic modeling workflow for weak acids, and (3) illustrate the outlined concepts via an ibuprofen (i.e., a weak, poorly soluble acid) case example in order to provide practical guidance on how to integrate biopharmaceutic and physiological data to better understand oral drug absorption. In the future, we plan to explore the usefulness of this tutorial/roadmap to inform the development of PBPK models for BCS 2 weak bases, by expanding the stepwise modeling approach to accommodate more intricate scenarios, including the presence of diprotic basic compounds and acidifying agents within the formulation.

Environmentally friendly and efficient TBHP-mediated catalytic reaction for the synthesis of substituted benzimidazole-2-ones: In-silico approach to pharmaceutical applications.

A novel method was used to synthesize benzimidazole-2-ones from the corresponding benzimidazolium salts. These salts were subsequently reacted with potassium tertiary butoxide (KOtBu), followed by oxidation using tertiary butyl hydrogen peroxide (TBHP) at room temperature in tetrahydrofuran (THF) to obtain the desired products in 1 h with excellent yields. After optimizing the reaction conditions, the study focused on preparing benzimidazole-2-ones with diverse substituents at N1 and N3 positions, including benzyl, 2',4',6'-trimethyl benzyl groups, and long-chain aliphatic substituents (hexyl, octyl, decyl, and dodecyl). The compounds were characterized by 1H and 13C NMR spectra, of which compound 2a is supported by single crystal XRD. Benzimidazole-2-one compounds exhibited promising anti-inflammatory and anti-cancer properties. The inhibition of mitochondrial Heat Shock Protein 60 (HSP60) of title compounds was also explored. Computational simulations were employed to assess anti-cancer properties of 19 benzimidazole-2-one derivatives (potential drugs). In-silico docking studies demonstrated promising binding interactions with HSP60, and these results were supported by molecular dynamics simulations. Notably, molecules 2b and 2d exhibited high affinity for HSP60 protein, highlighting their potential efficacy. The developed ligands were viable for the treatment of hepatocellular carcinoma (HCC). The findings provide valuable initial evidence supporting the efficacy of benzimidazole-2-ones as HSP60 inhibitors and lay the foundation for subsequent studies, including in-vitro assays.

Therapeutic Implications of Dietary Polyphenols-Loaded Nanoemulsions in Cancer Therapy.

Cancer is one of the major causes of death worldwide, even the second foremost cause related to non-communicable diseases. Cancer cells typically possess several cellular and biological processes including, persistence, propagation, differentiation, cellular death, and expression of cellular-type specific functions. The molecular picture of carcinogenesis and progression is unwinding, and it appears to be a tangled combination of processes occurring within and between cancer cells and their surrounding tissue matrix. Polyphenols are plant secondary metabolites abundant in fruits, vegetables, cereals, and other natural plant sources. Natural polyphenols have implicated potential anticancer activity by various mechanisms involved in their antitumor action, including modulation of signaling pathways majorly related to cellular proliferation, differentiation, relocation, angiogenesis, metastatic processes, and cell death. The applications of polyphenols have been limited due to the hydrophobic nature and lower oral bioavailability that could be possibly overcome through encapsulating them into nanocarrier-mediated delivery systems, leading to improved anticancer activity. Nanoemulsions (NEs) possess diverse feasible properties, including greater surface area, modifiable surficial charge, higher half-life, site-specific targeting, and formulation imaging capability necessary to create a practical therapeutic impact, and have drawn increased attention in cancer therapy research. This review has summarized and discussed the basic concepts, classification, delivery approaches, and anticancer mechanism of various polyphenols and polyphenols-encapsulated nanoemulsions with improved cancer therapy.

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study.

The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein-ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from -84.22 to -76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research.

Homochiral antiferromagnetic merons, antimerons and bimerons realized in synthetic antiferromagnets.

The ever-growing demand for device miniaturization and energy efficiency in data storage and computing technology has prompted a shift towards antiferromagnetic topological spin textures as information carriers. This shift is primarily owing to their negligible stray fields, leading to higher possible device density and potentially ultrafast dynamics. We realize in this work such chiral in-plane topological antiferromagnetic spin textures namely merons, antimerons, and bimerons in synthetic antiferromagnets by concurrently engineering the effective perpendicular magnetic anisotropy, the interlayer exchange coupling, and the magnetic compensation ratio. We demonstrate multimodal vector imaging of the three-dimensional Néel order parameter, revealing the topology of those spin textures and a globally well-defined chirality, which is a crucial requirement for controlled current-induced dynamics. Our analysis reveals that the interplay between interlayer exchange and interlayer magnetic dipolar interactions plays a key role to significantly reduce the critical strength of the Dzyaloshinskii-Moriya interaction required to stabilize topological spin textures, such as antiferromagnetic merons, in synthetic antiferromagnets, making them a promising platform for next-generation spintronics applications.

Protective role of Pleurotus florida against streptozotocin-induced hyperglycemia in rats: A preclinical study.

Pleurotus florida (Mont.) Singer is a mushroom species known to be an antioxidant, immunomodulatory, and diuretic agent, reducing blood pressure and cholesterol. The aim of this study was to evaluate the in vivo potency of P. florida's anti-diabetic properties in rats affected by hyperglycemia induced by Streptozotocin (STZ) at 55 mg/kg (i.p.), characterized by oxidative stress impairment, and changes in insulin levels and lipid profile. After inducing hyperglycemia in the rats, they were treated with P. florida acetone and methanol extracts, orally administered for 28 days at doses of 200 mg/kg and 400 mg/kg body weight. The hyperglycemic control (DC) group showed significant increases (P < 0.05) in mean blood sugar, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, blood urea nitrogen, lipid hydroperoxides, and malondialdehyde, compared to the normal control (NC) group The high-density lipoprotein cholesterol, serum insulin, superoxide dismutase, catalase, glutathione disulfide, glutathione peroxidase, reduced glutathione, guaiacol peroxidase, and vitamin E and C levels showed a significant decrease (P < 0.05) in DC group, compared to the NC group. Blood glucose levels, lipid profiles, and insulin levels improved significantly after 28 days of treatment, in the group treated with glibenclamide (an oral hypoglycemic drug, used as positive control), and in the groups treated with P. florida extracts. In DC group, the treatment with P. florida was found to prevent diabetes, according to histopathological studies of the kidneys, pancreas, and liver of rats. In conclusion, this study has shown that the treatment with P. florida decreased oxidative stress and glucose levels in the blood, as well as restoring changes in lipid profiles.

Integrated analysis of genes and long non-coding RNAs in trachea transcriptome to decipher the host response during Newcastle disease challenge in different breeds of chicken.

Newcastle disease is a highly infectious economically devastating disease caused by Newcastle disease Virus in Chicken (Gallus gallus). Leghorn and Fayoumi are two breeds which show differential resistance patterns towards NDV. This study aims to identify the differentially expressed genes and lncRNAs during NDV challenge which could play a potential role in this differential resistance pattern. A total of 552 genes and 1580 lncRNAs were found to be differentially expressing. Of them, 52 genes were annotated with both Immune related pathways and Gene ontologies. We found that most of these genes were upregulated in Leghorn between normal and challenged chicken but several were down regulated between different timepoints after NDV challenge, while Fayoumi showed no such downregulation. We also observed that higher number of positively correlating lncRNAs was found to be downregulated along with these genes. This shows that although Leghorn is showing higher number of differentially expressed genes in challenged than in non-challenged, most of them were downregulated during the disease between different timepoints. With this we hypothesize that the downregulation of immune related genes and co-expressing lncRNAs could play a significant role behind the Leghorn being comparatively susceptible breed than Fayoumi. The computational pipeline is available at https://github.com/Venky2804/FHSpipe.

Five-year outcomes of off and on-pump CABG: Insights from PROMOTE Patency Trial.

BACKGROUND: There are limited studies reporting follow-up outcome data comparing of off-pump coronary artery bypass (OPCAB) with on-pump (ONCAB) technique. The aim of the study was to report the 5-year clinical outcomes of OPCAB and ONCAB in a post hoc analysis of the PROMOTE patency trial. METHODS: From March 2016 through March 2017, a total of 321 patients undergoing coronary artery bypass grafting (CABG) were randomised to either the off-pump or the on-pump technique. Data on all-cause mortality, myocardial infarction (MI), cerebrovascular accident (CVA), repeat revascularisation and need for renal replacement therapy (RRT) were recorded. The composite and each of these individual outcomes are reported at 5-year interval. RESULTS: The mean follow-up period was 65.9 months (±3.39). A total of 275 (85.93%) patients followed up at the 5-year interval who underwent CABG by the off-pump (n = 158) and the on-pump (n = 162) technique. The all-cause mortality was 8.9% and 5.7% in ONCAB and OPCAB, respectively (hazard ratio [HR] = 0.62; 95% confidence interval [CI] 0.25-1.57, p = 0.31). The composite of all-cause mortality, non-fatal MI, non-fatal CVA, RRT and need for repeat revascularisation was comparable in both groups (7.1% vs. 11.9%, HR = 0.57; 95% CI 0.25-1.31, p = 0.18 in OPCAB and ONCAB, respectively). The rates of 5-year non-fatal MI (p = 0.2), non-fatal CVA (p = 0.36) and need for repeat revascularisation (p = 1) were similar in both groups. A sub-group analysis did not show any significant interaction or effect modification with either of the techniques. CONCLUSIONS: The 5-year clinical outcomes of OPCAB are comparable to ONCAB in low-risk patients undergoing CABG. Off-pump coronary artery bypass had no additional benefit in any subgroup.

Early intervention with double balloon enteroscopy for higher yield for inpatient overt obscure gastrointestinal bleeding: A propensity matched analysis.

Background and Aim: Overt obscure gastrointestinal bleeding (OOGIB) is defined as continued bleeding with unknown source despite esophagogastroduodenoscopy (EGD) and colonoscopy evaluation. Small bowel evaluation through video capsule endoscopy (VCE) or double balloon enteroscopy (DBE) is often warranted. We studied the timing of DBE in hospitalized OOGIB patients regarding diagnostic yield, therapeutic yield, and GI rebleeding. Methods: We performed a retrospective review of DBEs performed at a tertiary medical center between November 2012 and December 2020. The inclusion criterion was first admission for OOGIB undergoing DBE. Those without previous EGD or colonoscopy were excluded. Patients were stratified into two groups: DBE performed within 72 h of OOGIB (emergent) and beyond 72 h of OOGIB (nonemergent). Propensity score matching was used to adjust for the difference in patients in the two groups. Logistic regression analysis was used to assess factors associated with diagnostic and therapeutic yield. Kaplan-Meir survival curve showed GI bleed-free survival following initial bleed and was compared using the log rank test. Results: A total of 154 patients met the inclusion criterion, of which 62 had emergent DBE and 92 had nonemergent DBE. The propensity-score-matched sample consisted of 112 patients, with 56 patients each in the emergent and nonemergent groups. Univariate and multivariable logistic regression analysis showed a significant association between VCE and emergent DBE and diagnostic and therapeutic yield (P < 0.05). Emergent DBE patients had increased GI bleed-free survival compared to those in the nonemergent group (P = 0.009). Conclusion: Our data demonstrate that emergent DBE during inpatient OOGIB can impact the overall diagnostic yield, therapeutic yield, and GI rebleeding post DBE.

Feasibility and Utility of Routine Point-of-Care Gastric Ultrasonography in Patients Undergoing Upper Gastrointestinal Endoscopy Procedures: A Prospective Cohort Study.

OBJECTIVES: Previous studies have indicated that point-of-care ultrasonography (POCUS) of the gastric antrum can predict the adequacy of fasting before surgery and anesthesia. The aim of this study was to evaluate the utility of gastric POCUS in patients undergoing upper gastrointestinal (GI) endoscopy procedures. METHODS: We performed a single-center cohort study in patients undergoing upper GI endoscopy. Consenting patient's gastric antrum was scanned before anesthetic care for endoscopy to determine the cross-sectional area (CSA) and qualitatively determine safe and unsafe contents. Further, an estimate of residual gastric volume was determined using the formula and the nomogram methods. Subsequently, gastric secretions aspirated during endoscopy were quantified and further correlated with nomogram and formula-based assessments. No patient required a change in the primary anesthetic plan except for using rapid sequence induction in those with unsafe contents on POCUS scans. RESULTS: Qualitative ultrasound measurements consistently determined safe and unsafe gastric residual contents in 83 patients enrolled in the study. Unsafe contents were determined by qualitative scans in 4 out of 83 cases (5%) despite adequate fasting status. Quantitatively, only a moderate correlation was demonstrated between measured gastric volumes and nomogram (r = .40, 95% CI: 0.20, 0.57; P = .0002) or formula-based (r = .38, 95% CI: 0.17, 0.55; P = .0004) determinations of residual gastric volumes. CONCLUSION: In daily clinical practice, qualitative POCUS determination of residual gastric content is a feasible and useful technique to identify patients at risk of aspiration before upper GI endoscopy procedures.

Nerve conduction studies through landmark based recording and effects of hand length.

As per existing guidelines, the distance between stimulator and recording electrodes in nerve conduction studies (NCS) should be the same (fixed) in all the subjects, i.e., it should not be based on anatomical landmarks. However, there are no studies comparing fixed distance recordings with landmark based NCS. We postulated that hand length can influence the NCS parameters in fixed distance recordings and this can be nullified using landmark based recordings. To test this theory, we performed NCS in 48 normal subjects as per standard guidelines (standard protocol) and then compared it to NCS with ulnar styloid as the landmark (modified protocol). NCS were performed on median and ulnar nerves of the right upper limb. Three motor NCS parameters including distal latency, compound muscle action potential (CMAP) amplitudes and nerve conduction velocities were measured. Sensory nerve action potential (SNAP) amplitudes and conduction velocities were the two sensory parameters measured. On analysis, ulnar motor conduction velocity was the only parameter affected by hand length in both standard and modified protocols. Modified protocol did not have any additional advantage to the standard protocol advised by NDTF. We conclude that the NDTF guidelines are therefore reasonable when considering the effects of hand length. Possible reasons for this result including anatomical and anthropometric explanations are discussed.

Reversal of uniocular blindness with corticosteroids in a solid organ transplant recipient with cryptococcal meningitis and immune reconstitution syndrome (IRIS): A case report.

Cryptococcal meningitis is a life-threatening infection commonly seen in patients with advanced HIV infection and solid organ transplant recipients. We report a case of cryptococcal meningitis with immune reconstitution syndrome (IRIS) who presented to us with a headache and complete loss of vision in the left eye. He was managed with antifungals and a short course of steroids, and he regained vision completely. In the hospital, he developed complications including tacrolimus toxicity, fluconazole-induced QT prolongation, and flucytosine-induced thrombocytopenia. Our case demonstrates the importance of a multidisciplinary approach in the management of complex cases like cryptococcal meningitis in solid organ transplant recipients.

A minor metabolite from Curcuma longa effective against metabolic syndrome: results from a randomized, double-blind, placebo-controlled clinical study.

Metabolic syndrome (MetS) is characterized by the presence of at least three interrelated risk factors, including central obesity, hypertension, elevated serum triglycerides, low serum high-density lipoproteins, and insulin resistance. Abdominal obesity is considered a predominant risk factor. Lifestyle changes with medications to lower cholesterol, blood sugar, and hypertension are the general treatment approaches. Functional foods and bioactive food ingredients represent versatile tools for addressing different aspects of MetS. In a randomized placebo-controlled clinical study, we evaluated the effect of Calebin A, a minor bioactive phytochemical from Curcuma longa, on metabolic syndrome in obese adults (N = 100), and 94 individuals completed the study (N = 47 in both groups). They were subjected to Calebin A supplementation for 90 days, which resulted in a statistically significant reduction in their body weight, waist circumference, body mass index, low-density lipoprotein-cholesterol, and triglyceride levels compared to those with the placebo. A small but significant increase in high-density lipoprotein-cholesterol levels was also observed in these individuals. Furthermore, Calebin A showed a positive effect on adipokines by reducing circulating leptin levels. Finally, C-reactive protein levels were significantly reduced in Calebin A-supplemented individuals, suggesting a beneficial impact on managing MetS-induced inflammation. Blood glucose levels, insulin resistance, and blood pressure levels were not affected by Calebin A. In conclusion, Calebin A may be an effective supplement for managing abdominal obesity, dyslipidemia, and systemic inflammation in individuals with metabolic syndrome. This study was prospectively registered on the Clinical Trial Registry of India (CTRI) with the registration number CTRI/2021/09/036495. https://ctri.nic.in/Clinicaltrials/advancesearchmain.php.

Retinoic acid and evernyl-based menadione-triazole hybrid cooperate to induce differentiation of neuroblastoma cells.

Neuroblastoma arises when immature neural precursor cells do not mature into specialized cells. Although retinoic acid (RA), a pro-differentiation agent, improves the survival of low-grade neuroblastoma, resistance to retinoic acid is found in high-grade neuroblastoma patients. Histone deacetylases (HDAC) inhibitors induce differentiation and arrest the growth of cancer cells; however, HDAC inhibitors are FDA-approved mostly for liquid tumors. Therefore, combining histone deacetylase (HDAC) inhibitors and retinoic acid can be explored as a strategy to trigger the differentiation of neuroblastoma cells and to overcome resistance to retinoic acid. Based on this rationale, in this study, we linked evernyl group and menadione-triazole motifs to synthesize evernyl-based menadione-triazole hybrids and asked if the hybrids cooperate with retinoic acid to trigger the differentiation of neuroblastoma cells. To answer this question, we treated neuroblastoma cells using evernyl-based menadione-triazole hybrids (6a-6i) or RA or both and examined the differentiation of neuroblastoma cells. Among the hybrids, we found that compound 6b inhibits class-I HDAC activity, induces differentiation, and RA co-treatments increase 6b-induced differentiation of neuroblastoma cells. In addition, 6b reduces cell proliferation, induces expression of differentiation-specific microRNAs leading to N-Myc downregulation, and RA co-treatments enhance the 6b-induced effects. We observed that 6b and RA trigger a switch from glycolysis to oxidative phosphorylation, maintain mitochondrial polarization, and increase oxygen consumption rate. We conclude that in evernyl-based menadione-triazole hybrid, 6b cooperates with RA to induce differentiation of neuroblastoma cells. Based on our results, we suggest that combining RA and 6b can be pursued as therapy for neuroblastoma. Schematic representation of RA and 6b in inducing differentiation of neuroblastoma cells.