Unveiling the Influence of Glutathione in Suppressing the Conversion of Aspirin to Salicylic Acid: A Fluorescence and DFT Study.

Aspirin is a commonly used nonsteroidal anti-inflammatory drug, associated with many adverse effects. The adverse effects of aspirin such as tinnitus, Reye's syndrome and gastrointestinal bleeding are caused due to conversion of aspirin into its active metabolite salicylic acid after oral intake. Glutathione is a naturally occurring antioxidant produced by the liver and nerve cells in the central nervous system. It helps to metabolize toxins, break down free radicles, and support immune function. This study aims to investigate and explore the possibility of inhibiting aspirin to salicylic acid conversion in presence of glutathione at a molecular level using spectroscopic techniques such as UV-Visible absorption, time-Resolved and time-dependent fluorescence and theoretical DFT/ TD-DFT calculations. The results of steady state fluorescence spectroscopy and time-dependent fluorescence indicated that the aspirin to salicylic acid conversion is considerably inhibited in presence of glutathione. Further, the results presented here might have significant clinical implications for individuals with variations in glutathione level.

Comparison of Acute Physiology and Chronic Health Evaluation (APACHE) II and American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) scoring system in predicting postoperative mortality in patients undergoing emergency laparotomy: A retrospective study.

Background and Aims: There is paucity of studies on preoperative risk assessment tools in patients undergoing emergency surgery. The present study evaluated the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) II, American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) surgical risk calculator and American Society of Anesthesiologists (ASA) physical status (PS) classification system in patients undergoing emergency exploratory laparotomy. Methods: This retrospective study included 60 adult patients who underwent emergency exploratory laparotomy for perforation peritonitis. The clinical details, ASA PS classification, laboratory investigations and postoperative course of patients were retrieved from their medical records. Based on these details, APACHE II and ACS-NSQIP were calculated for the patients. The study's primary outcome was the accuracy of the preoperative APACHE II, ACS-NSQIP risk calculator and ASA PS class in predicting the postoperative 30-day mortality of patients. Results: The area under the curve (AUC) of APACHE II, ACS-NSQIP score, and ASA PS classification for mortality 30 days after surgery was 0.737, 0.694 and 0.601, respectively. The P value for the Hosmer-Lemeshow (H-L) test of scoring systems was 0.05, 0.25 and 0.05, respectively. AUC for postoperative complications was 0.799 for APACHE II, 0.683 for ACS-NSQIP and 0.601 for ASA PS classification. H-L test of these scoring systems for complications after surgery revealed P values of 0.62, 0.36 and 0.53, respectively. Conclusion: Compared to the ACS-NSQIP and ASA PS classification system, the APACHE II score has a better discriminative ability for postoperative complications and mortality in adult patients undergoing emergency exploratory laparotomy.

Unravelling the role of long non-coding RNAs in modulating the Hedgehog pathway in cancer.

Cancer is a multifactorial pathological condition characterized by uncontrolled cellular proliferation, genomic instability, and evasion of regulatory mechanisms. It arises from the accumulation of genetic mutations confer selective growth advantages, leading to malignant transformation and tumor formation. The intricate interplay between LncRNAs and the Hedgehog pathway has emerged as a captivating frontier in cancer research. The Hedgehog pathway, known for its fundamental roles in embryonic development and tissue homeostasis, is frequently dysregulated in various cancers, contributing to aberrant cellular proliferation, survival, and differentiation. The Hh pathway is crucial in organizing growth and maturation processes in multicellular organisms. It plays a pivotal role in the initiation of tumors as well as in conferring resistance to conventional therapeutic approaches. The crosstalk among the Hh pathway and lncRNAs affects the expression of Hh signaling components through various transcriptional and post-transcriptional processes. Numerous pathogenic processes, including both non-malignant and malignant illnesses, have been identified to be induced by this interaction. The dysregulation of lncRNAs has been associated with the activation or inhibition of the Hh pathway, making it a potential therapeutic target against tumorigenesis. Insights into the functional significance of LncRNAs in Hedgehog pathway modulation provide promising avenues for diagnostic and therapeutic interventions. The dysregulation of LncRNAs in various cancer types underscores their potential as biomarkers for early detection and prognostication. Additionally, targeting LncRNAs associated with the Hedgehog pathway presents an innovative strategy for developing precision therapeutics to restore pathway homeostasis and impede cancer progression. This review aims to elucidate the complex regulatory network orchestrated by LncRNAs, unravelling their pivotal roles in modulating the Hedgehog pathway and influencing cancer progression.

MicroRNA-21's role in PTEN suppression and PI3K/AKT activation: Implications for cancer biology.

MicroRNA-21 (miR-21) was recognized as a key figure in the intricate web of tumor biology, with a prominent role in regulating the PTEN tumor suppressor gene and the PI3K/AKT cascade. This review elucidates the multifaceted interactions between miR-21, PTEN, and the PI3K/AKT signaling, shedding light on their profound implications in cancer initiation, progression, and therapeutic strategies. The core of this review delves into the mechanical intricacies of miR-21-mediated PTEN suppression and its consequent impact on PI3K/AKT pathway activation. It explores how miR-21, as an oncogenic miRNA, targets PTEN directly or indirectly, resulting in uncontrolled activation of PI3K/AKT, fostering cancerous cell survival, proliferation, and evasion of apoptosis. Furthermore, the abstract emphasizes the clinical relevance of these molecular interactions, discussing their implications in various cancer types, prognostic significance, and potential as therapeutic targets. The review provides insights into ongoing research efforts to develop miR-21 inhibitors and strategies to restore PTEN function, offering new avenues for cancer treatment. This article illuminates the critical function of miR-21 in PTEN suppression and PI3K/AKT activation, offering profound insights into its implications for cancer biology and the potential for targeted interventions.

New drug discovery of cardiac anti-arrhythmic drugs: insights in animal models.

Cardiac rhythm regulated by micro-macroscopic structures of heart. Pacemaker abnormalities or disruptions in electrical conduction, lead to arrhythmic disorders may be benign, typical, threatening, ultimately fatal, occurs in clinical practice, patients on digitalis, anaesthesia or acute myocardial infarction. Both traditional and genetic animal models are: In-vitro: Isolated ventricular Myocytes, Guinea pig papillary muscles, Patch-Clamp Experiments, Porcine Atrial Myocytes, Guinea pig ventricular myocytes, Guinea pig papillary muscle: action potential and refractory period, Langendorff technique, Arrhythmia by acetylcholine or potassium. Acquired arrhythmia disorders: Transverse Aortic Constriction, Myocardial Ischemia, Complete Heart Block and AV Node Ablation, Chronic Tachypacing, Inflammation, Metabolic and Drug-Induced Arrhythmia. In-Vivo: Chemically induced arrhythmia: Aconitine antagonism, Digoxin-induced arrhythmia, Strophanthin/ouabain-induced arrhythmia, Adrenaline-induced arrhythmia, and Calcium-induced arrhythmia. Electrically induced arrhythmia: Ventricular fibrillation electrical threshold, Arrhythmia through programmed electrical stimulation, sudden coronary death in dogs, Exercise ventricular fibrillation. Genetic Arrhythmia: Channelopathies, Calcium Release Deficiency Syndrome, Long QT Syndrome, Short QT Syndrome, Brugada Syndrome. Genetic with Structural Heart Disease: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia, Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, Atrial Fibrillation, Sick Sinus Syndrome, Atrioventricular Block, Preexcitation Syndrome. Arrhythmia in Pluripotent Stem Cell Cardiomyocytes. Conclusion: Both traditional and genetic, experimental models of cardiac arrhythmias' characteristics and significance help in development of new antiarrhythmic drugs.

Unlocking new approaches to Urolithiasis management via Nutraceutical.

Urolithiasis, commonly known as kidney stones, is characterized by the formation of hard deposits in the urinary tract. These stones can cause severe pain and discomfort, and their management typically involves a combination of medical interventions and lifestyle modifications. According to the literature, 30% and 50% of urolithiasis cases recur. Between 9 and 12% of persons in industrialised countries are predicted to have urolithiasis at some time. Due to the high frequency of stone formation, recurrent nature, and prevalence in adults, it has a significant impact on society, the person, and the health care system. Adopting the best prophylactic measures is crucial in light of these developments to decrease the impact of urolithiasis on individuals and society. In recent years, there has been growing interest in the potential role of nutraceuticals in the management of urolithiasis. Nutraceuticals, such as herbal extracts, vitamins, minerals, and probiotics, have gained recognition for their potential in promoting urinary health and reducing the risk of urolithiasis. These compounds can aid in various ways, including inhibiting crystal formation, enhancing urine pH balance, reducing urinary calcium excretion, and supporting kidney function. Additionally, nutraceuticals can help alleviate symptoms associated with urolithiasis, such as pain and inflammation. While medical interventions remain crucial, incorporating nutraceuticals into a comprehensive management plan can offer a holistic approach to urolithiasis, improving patient outcomes and quality of life. Therefore, nutraceuticals may be a desirable choice for treating and avoiding recurring urolithiasis for patients and medical professionals. Therefore, the present study has focused on nutraceuticals' role in preventing urolithiasis.

Tumoral cutaneous rhinosporidiosis: Case report and review of literature.

Rhinosporidiosis is a chronic granulomatous disease caused by Rhinosporidium seeberi commonly affecting nasal mucosa, conjunctiva, and urethra. Subcutaneous tumor nodule presentation is rare and often mimics as sarcoma. Such tumoral rhinosporidiosis has been reported rarely. This report describes a 60-year male who presented with a solitary, firm, nontender swelling in posterior aspect of right leg with an ulcer and mimicking clinically as soft tissue sarcoma. Histopathology was diagnostic. Surgical excision was found to be useful.

Differential Expression of Non-Coding RNAs in Stem Cell Development and Therapeutics of Bone Disorders.

Stem cells' self-renewal and multi-lineage differentiation are regulated by a complex network consisting of signaling factors, chromatin regulators, transcription factors, and non-coding RNAs (ncRNAs). Diverse role of ncRNAs in stem cell development and maintenance of bone homeostasis have been discovered recently. The ncRNAs, such as long non-coding RNAs, micro RNAs, circular RNAs, small interfering RNA, Piwi-interacting RNAs, etc., are not translated into proteins but act as essential epigenetic regulators in stem cells' self-renewal and differentiation. Different signaling pathways are monitored efficiently by the differential expression of ncRNAs, which function as regulatory elements in determining the fate of stem cells. In addition, several species of ncRNAs could serve as potential molecular biomarkers in early diagnosis of bone diseases, including osteoporosis, osteoarthritis, and bone cancers, ultimately leading to the development of new therapeutic strategies. This review aims to explore the specific roles of ncRNAs and their effective molecular mechanisms in the growth and development of stem cells, and in the regulation of osteoblast and osteoclast activities. Furthermore, we focus on and explore the association of altered ncRNA expression with stem cells and bone turnover.

Angioleiomyoma of the uterus presenting as an endometrial polyp: An uncommon occurrence of two cases with a literature review.

ABSTRACT: Angioleiomyoma is a benign neoplasm that arises from vascular smooth muscle cells. Angioleiomyoma of the endometrium is very uncommon. The differential diagnoses of this entity are myopericytoma, angiomyofibroblastoma, endometrial stromal tumor, and perivascular epithelioid cell tumor. 31-year-old and 45-year-old patients presented with heavy menstrual bleeding, lower abdomen pain, and dysmenorrhea. Perspeculum and radiological investigations showed an endometrial polyp. They underwent diagnostic hysteroscopy, polypectomy, and endometrial biopsy. Polypectomy specimens of both cases revealed polypoidal lesions lined by the endometrium. The core of the polyp was arranged in long intersecting bundles of spindle cells and interconnecting anastomotic patterns with many intervening thick-walled blood vessels. These spindle cells have oval and cigar-shaped nuclei, fine chromatin, and a moderate amount of eosinophilic cytoplasm, resembling smooth muscle cells. These smooth muscle cells of the vessel wall were merging with the adjacent walls of the blood vessel. There was no nuclear atypia or necrosis. The mitotic rate was 0-1/10 HPF. Focal areas of hyalinization and adipocytic components were noted in one case. The endometrial glands did not show intraepithelial or invasive neoplasia. On immunohistochemistry (IHC), these spindle cells were diffuse and strongly immunopositive for SMA and Desmin. CD34 highlighted the endothelial lining of the prominent thick-walled blood vessels. By correlating with histomorphology and IHC positivity, a diagnosis of angioleiomyomatous polyp of endometrium was rendered. We report two uncommon cases of angioleiomyoma of the endometrium and discuss the differential diagnosis and literature review.

Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.

Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.

Proteo-Molecular Investigation of Cultivated Rice, Wild Rice, and Barley Provides Clues of Defense Responses against Rhizoctonia solani Infection.

Rhizoctonia solani is a soil-borne fungus causing sheath blight disease in cereal crops including rice. Genetic resistance to sheath blight disease in cereal crops is not well understood in most of the host(s). Aside from this, a comparative study on the different hosts at the biochemical and proteomic level upon R. solani infection was not reported earlier. Here, we performed proteomic based analysis and studied defense pathways among cultivated rice (cv. Pusa Basmati-1), wild rice accession (Oryza grandiglumis), and barley (cv. NDB-1445) after inoculation with R. solani. Increased levels of phenol, peroxidase, and ß-1, 3-glucanase were observed in infected tissue as compared to the control in all of the hosts. Wild rice accession O. grandiglumis showed a higher level of biochemical signals than barley cv. NDB 1445 and cultivated rice cv. Pusa Basmati-1. Using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry (MS), differently expressed proteins were also studied in control and after inoculation with R. solani. Wild rice accession O. grandiglumis induced a cysteine protease inhibitor and zinc finger proteins, which have defense functions and resistance against fungal pathogens. On the other hand, barley cv. NDB-1445 and cultivated rice cv. Pusa Basmati-1 mainly induce energy metabolism-related proteins/signals after inoculation with R. solani in comparison to wild rice accession O. grandiglumis. The present comprehensive study of R. solani interaction using three hosts, namely, Pusa Basmati-1 (cultivated rice), O. grandiglumis (wild rice), and NDB-1445 (barley) would interpret wider possibilities in the dissection of the protein(s) induced during the infection process. These proteins may further be correlated to the gene(s) and other related molecular tools that will help for the marker-assisted breeding and/or gene editing for this distressing disease among the major cereal crops.

Inhibition of the endosomal recycling pathway downregulates HER2 activation and overcomes resistance to tyrosine kinase inhibitors in HER2-positive breast cancer.

The development of HER2-targeted therapies has led to a dramatic improvement in outcomes for breast cancer patients. However, nearly all patients with metastatic HER2-positive breast cancer will eventually progress on these therapies due to innate or acquired resistance. Recent evidence suggests that the endosomal recycling of HER2 plays an important role in regulating its oncogenic signalling. Here we report that the expression of Rab coupling protein (RCP), a key regulator of endosomal recycling, positively correlates with that of HER2 and HER3 in breast tumours, and high RCP expression is predictive of poor relapse-free and overall survival in patients with HER2-amplified breast cancer. Chemical and genetic inhibition of endosomal recycling leads to a reduction in the total cellular levels of HER2 and HER3 and inhibits the activation of their downstream signalling pathways. We find that HER2 and HER3 that have been internalised from the plasma membrane are diverted to lysosomes for degradation when endosomal recycling is blocked. Primaquine (PQ), a small molecule inhibitor of the endosomal recycling pathway, synergises with HER2-targeting tyrosine kinase inhibitors and overcomes innate and acquired resistance to these TKIs. Moreover, TKI-induced drug tolerant persister cells are vulnerable to endosomal recycling inhibitors. These findings suggest that inhibition of endosomal recycling represents a promising therapeutic strategy for treating drug resistant HER2-positive breast cancer.

Retraction of "Anticancer Effect of Rosiglitazone, a PPAR-γ Agonist against Diethylnitrosamine-Induced Lung Carcinogenesis".

[This retracts the article DOI: 10.1021/acsomega.9b04357.].

Retinoic Acid-Inducible Gene I-Like Receptors Activate Snail To Limit RNA Viral Infections.

Retinoic acid-inducible gene I-like receptors (RLRs) are important cytosolic pattern recognition receptors (PRRs) that sense viral RNA before mounting a response leading to the activation of type I IFNs. Several viral infections induce epithelial-mesenchymal transition (EMT), even as its significance remains unclear. Here, we show that EMT or an EMT-like process is a general response to viral infections. Our studies identify a previously unknown mechanism of regulation of an important EMT-transcription factor (EMT-TF) Snail during RNA viral infections and describe its possible implication. RNA viral infections, poly(I·C) transfection, and ectopic expression of RLR components induced Snail levels, indicating that RLR pathway could regulate its expression. Detailed examination using mitochondrial antiviral signaling protein knockout (MAVS-KO) cells established that MAVS is essential in this regulation. We identified two interferon-stimulated response elements (ISREs) in the SNAI1 promoter region and demonstrated that they are important in its transcriptional activation by phosphorylated IRF3. Increasing the levels of Snail activated RLR pathway and dramatically limited replication of the RNA viruses dengue virus, Japanese encephalitis virus (JEV), and vesicular stomatitis virus, pointing to their antiviral functions. Knockdown of Snail resulted in a considerable increase in the JEV titer, validating its antiviral functions. Finally, transforming growth factor ß-mediated IFNB activation was dependent on Snail levels, confirming its important role in type I IFN activation. Thus, EMT-TF Snail is transcriptionally coregulated with type I IFN by RLRs and, in turn, promotes the RLR pathway, further strengthening the antiviral state in the cell. Our work identified an interesting mechanism of regulation of Snail that demonstrates potential coregulation of multiple innate antiviral pathways triggered by RLRs. Identification of antiviral functions of Snail also provides an opportunity to expand the sphere of RLR signaling. IMPORTANCE RLRs sense viral genomic RNA or the double-stranded RNA intermediates and trigger the activation of type I IFNs. Snail transcription factor, commonly associated with epithelial-mesenchymal transition (EMT), has been reported to facilitate EMT in several viral infections. Many of these reports are based on oncoviruses, leading to the speculation that EMT induced during infection is an important factor in the oncogenesis triggered by these infections. However, our studies reveal that EMT or EMT-like processes during viral infections have important functions in antiviral response. We have characterized a new mechanism of transcriptional regulation of Snail by IRF3 through interferon-stimulated response elements in their promoters, and this finding could have importance in nonviral contexts as well. We also identify that EMT-TF Snail promotes antiviral status of the infected cells through the RLR pathway. This study characterizes a new regulatory mechanism of activation of Snail and establishes its unidentified function in antiviral response.

Role of intra-abdominal pressure in the outcomes of perforation peritonitis: A prospective observational study.

OBJECTIVES: Intra-abdominal pressure (IAP) has been investigated for its role in causing morbidity and mortality, with various studies showing different degrees of correlation. There remains paucity of literature on this subject, applied to patients of perforation peritonitis, especially in the Indian subcontinent. MATERIAL AND METHODS: It is a prospective observational study involving 40 patients of perforation peritonitis undergoing exploratory laparotomy. IAP was measured as per WSACS (World Society of Abdominal Compartment Syndrome) guidelines. APACHE II (Acute Physiology And Chronic Health Evaluation- II) and SOFA (Sequential Organ Failure Assessment) were calculated. Data was collected regarding occurrence of prolonged ileus, burst abdomen, duration of hospital stay, 30 day mortality, and was statistically analyzed to correlate with IAP. RESULTS: At admission, mean IAP was 13.37 mmHg, and the incidence of IAH was 65%. IAH was seen in 17.9% and 7.6% at 24 h and 48 h post-operatively. Incidence of prolonged ileus and burst abdomen were 7.7% and 22.5% respectively. Mortality rate was 17.5%. Mean duration of hospital stay was 13.45 days. Post-operative IAP correlated with mortality (p: 0.014) and post-operative SOFA score (p <0.05). Statistically significant correlation was also seen with the occurrence of prolonged ileus (p: 0.006). IAP did not significantly correlate with APACHE II score, occurrence of burst abdomen, and duration of hospital stay. CONCLUSION: Rise in IAP correlates with deterioration of SOFA score, and also with the occurrence of prolonged ileus. IAP is also a predictor of mortality. IAP measured post-operatively (24 and 48 hours) had a better correlation with these outcomes than the value measured at admission. No statistically significant correlation of IAP with the occurrence of burst abdomen and duration of hospital stay could be found, which warrants further studies with a larger population.

Triantennary GalNAc Molecular Imaging Probes for Monitoring Hepatocyte Function in a Rat Model of Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease that can lead to irreversible liver cirrhosis and cancer. Early diagnosis of NASH is vital to detect disease before it becomes life-threatening, yet noninvasively differentiating NASH from simple steatosis is challenging. Herein, bifunctional probes have been developed that target the hepatocyte-specific asialoglycoprotein receptor (ASGPR), the expression of which decreases during NASH progression. The results show that the probes allow longitudinal, noninvasive monitoring of ASGPR levels by positron emission tomography in the newly developed rat model of NASH. The probes open new possibilities for research into early diagnosis of NASH and development of drugs to slow or reverse its progression.