FoxO1, a member of the Forkhead transcription factor family subgroup O (FoxO), is expressed in a range of cell types and is crucial for various pathophysiological processes, such as apoptosis and inflammation. While FoxO1’s roles in multiple diseases have been recognized, the target has remained largely unexplored due to the absence of cost-effective and efficient inhibitors. Therefore, there is a need for natural FoxO1 inhibitors with minimal adverse effects. In this study, docking, MMGBSA, and ADMET analyses were performed to identify natural compounds that exhibit strong binding affinity to FoxO1. The top candidates were then subjected to molecular dynamics (MD) simulations. A natural product library was screened for interaction with FoxO1 (PDB ID-3CO6) using the Glide module of the Schrödinger suite. In Silico ADMET profiling was conducted using SwissADME and pkCSM web servers. Binding free energies of the selected compounds were assessed with the Prime-MMGBSA module, while the dynamics of the top hits were analyzed using the Desmond module of the Schrödinger suite. Several natural products demonstrated high docking scores with FoxO1, indicating their potential as FoxO1 inhibitors. Specifically, the docking scores of neochlorogenic acid and fraxin were both below -6.0. These compounds also exhibit favorable drug-like properties, and a 25 ns MD study revealed a stable interaction between fraxin and FoxO1. Our findings highlight the potential of various natural products, particularly fraxin, as effective FoxO1 inhibitors with strong binding affinity, dynamic stability, and suitable ADMET profiles.

Objective: Statins play a key role in the management of atherosclerotic cardiovascular disease for both primary and secondary prevention. However, their increasing usage has correspondingly led to a higher incidence of adverse effects, with muscle symptoms being the most common. An intriguing drug interaction exists between ticagrelor and high-intensity statins, which may exacerbate the adverse effects of statin-induced rhabdomyolysis, leading to significant consequences. This study was conducted to examine the profile of patients who have experienced statin-induced rhabdomyolysis while undergoing percutaneous transluminal coronary angioplasty (PTCA). Methods: This was an observational study that included 1,862 patients who underwent PTCA at our institute over the course of 1 year. Results: Over a 1-year period, we encountered four patients who were being treated with high-intensity statin therapy following acute coronary syndrome. These patients presented with muscle weakness and kidney injury. A notable commonality among all patients was the co-prescription of ticagrelor. Two patients died, while the other 2 were successfully managed through hydration, electrolyte balance, dialysis, and alternative lipid management drugs. Conclusion The concomitant use of ticagrelor and high-intensity statins should be carefully considered due to the additional risk of rhabdomyolysis and kidney injury. Future pharmacokinetic studies are needed to establish a causal relationship and predict potential drug interactions, which, if not avoided, could be fatal.

Emergence of radioresistance in prostate cancer (PCa) cells is a major obstacle in cancer therapy and contributes to the relapse of the disease. EGF receptor (EGFR) signaling plays an important role in the development of radioresistance. Herein, we have assessed the modulatory effects of silibinin on radiation-induced resistance via DNA repair pathways in EGFR-knockdown DU145 cells. shRNA-based silencing of EGFR was done in radioresistant human PCa DU145 cells and effects of ionizing radiation (IR) and silibinin were assessed using clonogenic and trypan blue assays. Furthermore, radiosensitizing effects of silibinin on PCa in context with EGFR were analyzed using flow cytometry, comet assay, and immunoblotting. Silibinin decreased the colony formation ability with an increased death of DU145 cells exposed to IR (5 Gray), with a concomitant decrease in Rad51 protein expression. Silibinin (25 μM) augmented the IR-induced cytotoxic effect in EGFR-knockdown PCa cells, along with induction of G2/M phase cell cycle arrest. Further, we studied homologous recombination (HR) and non-homologous end joining (NHEJ) pathways in silibinin-induced DNA double-strand breaks in EGFR-knockdown DU145 cells. Silibinin down-regulated the expression of Rad51 and DNA-dependent protein kinase proteins without any considerable effect on Ku70 and Ku80 in IR-exposed EGFR-knockdown PCa cells. The pro-survival signaling proteins, phospho-extracellular signal-regulated kinases (ERK)1/2, phospho-Akt and phospho-STAT3 were decreased by silibinin in EGFR-deficient PCa cells. These findings suggest a novel mechanism of silibinin-induced radiosensitization of PCa cells by targeting DNA repair pathways, HR and NHEJ, and suppressing the pro-survival signaling pathways, ERK1/2, Akt and STAT3, in EGFR-knockdown PCa cells.

Background: The efficacy of local anesthesia decreases in patients with symptomatic irreversible pulpitis. Therefore, it was proposed that the use of premedication with an anti-inflammatory drug might increase the success rate of pulpal anesthesia in mandibular posterior teeth with vital inflamed pulp. Methods: One hundred thirty-four patients who were actively experiencing pain willingly participated in this study. The Heft Parker (HP) visual analog scale (VAS) was used to record the initial pain intensity. Patients were randomly allocated to receive a placebo, 10 mg of ketorolac, and 650 mg of paracetamol. The standard inferior alveolar nerve block (IANB) was administered to all patients using 2% lidocaine with 1:200,000 adrenaline after one hour of medication. After 15 min, the patient was instructed to rate the discomfort during each step of the treatment procedure, such as access to remaining dentin, access to the pulp chamber, and during canal instrumentation on the HP VAS. IANB was considered successful if the patient reported no or mild pain during access preparation and instrumentation. Moderate or severe pain was classified as a failure of IANB and another method of anesthesia was used before continuing the treatment. Results: The rate of successful anesthesia in the placebo, paracetamol, and ketorolac groups was 29%, 33%, and 43%, respectively, and no statistically significant difference was found between the groups. Conclusion Preoperative administration of paracetamol or ketorolac did not significantly affect the success rate of IANB in patients with irreversible pulpitis. No significant difference was observed between the paracetamol and ketorolac groups.

Celiac disease (CeD) is a systemic, immune-mediated enteropathy, which is triggered by gluten protein in genetically susceptible individuals. CeD, once thought to be an uncommon disease, is now recognized to affect approximately 40-60 million people globally.While CeD is now well reported from a few Asian countries such as India, China, Pakistan, and Middle Eastern countries; it is still believed to be uncommon in the rest of Asia. Gluten-related diseases other than CeD, like non-celiac gluten sensitivity (NCGS) are also emerging globally. CeD and NCGS may present with either intestinal or extra-intestinal symptoms, and a proportion of them have overlapping symptoms with irritable bowel syndrome. Hence, many of them are misdiagnosed as having irritable bowel syndrome in clinical practice. In this review, we discuss the emergence of CeD and other gluten-related disorders, both globally and in Asia, the overlapping manifestations between gluten-related disorders and irritable bowel syndrome, and the challenges associated with diagnosis and management of CeD in Asia.

Background/Aims: Gluten-free diet has an excess of fats and simple sugars and puts patients with celiac disease at risk of metabolic complications including metabolic syndrome and fatty liver. We assessed prevalence of metabolic syndrome and fatty liver in two cohorts of celiac disease. Methods: Study was done in 2 groups. In group 1, 54 treatment naïve patients with celiac disease were recruited. Of them, 44 returned after 1-year of gluten-free diet and were reassessed. In group 2, 130 celiac disease patients on gluten-free diet for ≥1 year were recruited. All patients were assessed for anthropometric and metabolic parameters and fatty liver. Metabolic syndrome was defined as per consensus definition for Asian Indians. Fatty liver was defined as controlled attenuation parameter value >263 decibels by FibroScan. Results: In group 1, of 44 treatment naïve patients with celiac disease, metabolic syndrome was present in 5 patients (11.4%) at baseline and 9 (18.2%) after 1 year of gluten-free diet. Patients having fatty liver increased from 6 patients (14.3%) at baseline to 13 (29.5%) after 1year of gluten-free diet (P=0.002). In group 2, of 130 patients with celiac disease on gluten-free diet for a median duration of 4 years, 30 out of 114 (26.3%) and 30 out of 130 patients (23%) had metabolic syndrome and fatty liver, respectively. Conclusions Patients with celiac disease are at high risk of developing metabolic syndrome and fatty liver, which increases further with gluten-free diet. These patients should be assessed for nutritional and metabolic features and counseled about balanced diet and physical activity regularly.

Introduction: Bicondylar tibial plateau fractures account for 10-30% of tibial plateau fractures. Despite recent advancements in the management of unstable bicondylar tibial plateau fractures, the outcomes are often poor. The present study aimed to evaluate the functional outcomes and complications of internal fixation of bicondylar tibial plateau fractures with the dual plating using two incisions. Materials and methods: The present study included 30 patients (26 males; 4 females, mean age 35.6 years; range, 19 to 65 years) with bicondylar tibial plateau fractures who were treated with dual plating between January 2017 to August 2019. Out of 30 patients, 5 patients had Schatzker type (V) and 25 patients had Schatzker type (VI) bicondylar tibial plateau fracture. All patients were treated with dual plating using two incisions. In all patient’s similar standard physical rehabilitation therapy was followed. All complications including intra and post-operative were assessed and recorded. The patients were followed-up for over 24 months. Functional outcomes were assessed with Rasmussen’s functional grading system, Oxford knee score, and range of motion of knee joint. Radiological outcomes were evaluated using Rasmussen’s radiological scoring system. Result: All fractures united with a mean time of 18 weeks. The average knee range of motion was 1.5° - 130° (range: 0° - 10° for extension lag, range: 100° -135° for flexion). Mean Rasmussen's functional grading score at the final follow-up was 26.75. All patients showed excellent or good radiographic results according to Rasmussen’s radiological scoring with a mean score of 8.5 (range 6-10). The postoperative radiographs showed mean MPTA was 84.3° and the mean PPTA was 6.2°. In the present study, complications were encountered in five patients. However, there were no cases of secondary loss of reduction, failure of the implant, malunion, or non-union. Conclusion: The surgical treatment of bicondylar tibial plateau fractures with dual locking represents a significant treatment option and provides rigid fixation in these fractures with good functional and radiological outcomes.