Lumacaftor as a potential repurposed drug in targeting breast cancer stem cells: insights from in silico study.

CONTEXT: Breast cancer stem cells (BCSCs) are a small subset of cells within breast tumors with characteristics similar to normal stem cells. Despite advancements in chemotherapy and targeted therapy for breast cancer, the prognosis for breast cancer patients has remained poor due to drug resistance, reoccurrence, and metastasis. Growing evidence suggests that deregulation of the self-renewal pathways, like the Wnt signaling pathway mediated by ß-catenin, plays a crucial role in the survival of breast cancer stem cells. Targeting the Wnt signaling pathway in breast cancer stem cells offers a promising avenue for developing effective therapeutic strategies targeting these cells, potentially leading to improved patient outcomes and reduced tumor recurrence. METHODS: For this purpose, we have screened a 1615 FDA-approved drug library against our target protein, ß-catenin, which is involved in the Wnt signaling pathway using molecular docking analysis, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. RESULTS: Molecular docking studies showed that the Lumacaftor- ß-catenin complex had the lowest docking score of - 8.7 kcal/mol towards ß-catenin protein than the reference inhibitor. Molecular dynamic simulations and MM/PBSA calculations were also performed for the Lumacaftor-ß-catenin complex to establish the stability of the interactions involved. Considering its promising attributes and encouraging results, Lumacaftor holds significant potential as a novel therapeutic option to target BCSCs. This study opens avenues for further investigation and may pave the way for developing therapeutic potential in breast cancer treatment. Further confirmation is warranted through in vitro and clinical studies to validate the findings of this study.

Exploring progress in iron supplement formulation approaches for treating iron deficiency anemia through bibliometric and thematic analysis.

Anemia is a severe health issue that affects around one-third of the global population. Therefore, the present study aims to conduct a bibliometric analysis to investigate the research trends regarding advancements on iron formulations in treating iron deficiency anemia via oral or parenteral route. This study adopts thematic and bibliometric methods on existing research on novel iron formulations. It also provides perspective into the existing understanding on treatment strategies for iron deficiency anemia. This study is conducted on 543 papers on various ferrous and ferric formulations used in the treatment of iron deficiency anemia. The study period is from 1977 to 2022, and the papers are identified from the Scopus database. The bibliometric analysis was carried out using the R tool's Bibliometrix package. The study discusses performance analysis, including annual publications, geographic analysis, relevant affiliations, journal analysis, and citation analysis. In addition, the conceptual structure, including the co-occurrence network, thematic map, thematic evolution, intellectual structure highlighting co-citation analysis, and social structure depicting the collaboration network and collaboration world map, are presented. The results showed increased research on formulation strategies for the treatment of iron deficiency anemia from 2010 onwards. The top 5 contributing countries are the USA, Italy, India, Germany, and the UK, and peer-reviewed journals from the area of nutrition. The most trending areas of study are iron deficiency anemia in pregnancy, chronic kidney diseases, inflammatory bowel diseases, and various intravenous formulations used in its treatment. The authors from Europe collaborate the most with authors from other countries. The study concludes that a safer and more effective iron formulation is needed to reduce the prevalence of anemia. The findings of the study are helpful in advancing research on innovative formulations for treating iron deficiency anemia. The insights from the study are helpful to policymakers in designing specific health policies and investing more in research and development of novel formulations for the treatment of iron deficiency anemia.

ECG based apnea detection by multirate processing hybrid of wavelet-empirical decomposition Hjorth features extraction and neural networks.

Sleep Apnea (SA) can cause health complications including heart stroke and neurological disorders. The Polysomnography (PSG) test can detect the severity of sleep disturbance. However, it is expensive and requires a dedicated sleep laboratory and expertise to examine the patients. Therefore, it is not available to a large population in developing countries. This leads to the development of cost-effective and automated patient examination methods for the detection of sleep apnea. This study suggests an approach of using the ECG signals to categorize sleep apnea. In this work, we have devised an original technique of feature space designing by intelligently hybridizing the multirate processing, a mix of wavelet-empirical mode decomposition (W-EMD), modes-based Hjorth features extraction, and Adam-based optimized Multilayer perceptron neural network (MLPNN) for automated categorization of apnea. A publicly available ECG dataset is used for evaluating the performance of the suggested approach. Experiments are performed for four different sub-bands of the considered ECG signals. For each selected sub-band, five "Intrinsic Mode Functions" (IMFs) are extracted. Onward, three Hjorth features: complexity, activity, and mobility are mined from each IMF. In this way, four feature sets are formed based on wavelet-driven selected sub-bands. The performance of optimized MLPNN, for the apnea categorization, is compared for each feature set. Five different evaluation parameters are used to assess the performance. For the same dataset, a systematic comparison with current state-of-the-artwork has been done. Results have shown a classification accuracy of 98.12%.

Postpartum depression: aetiology, pathogenesis and the role of nutrients and dietary supplements in prevention and management.

Postpartum depression (PPD) is a challenging psychological disorder faced by 10-30% of mothers across the globe. In India, it occurs among 22% of mothers. Its aetiology and pathophysiology aren't fully understood as of today but multiple theories on the interplay of hormones, neurotransmitters, genetics, epigenetics, nutrients, socio-environmental factors, etc. exist. Nutrients are not only essential for the synthesis of neurotransmitters, but they may also indirectly influence genomic pathways that methylate DNA, and there is evidence for molecular associations between nutritional quality and psychological well-being. Increased behavioural disorders have been attributed to macro- and micronutrient deficiencies, and dietary supplementation has been effective in treating several neuropsychiatric illnesses. Nutritional deficiencies occur frequently in women, especially during pregnancy and breastfeeding. The aim of this study was to perform a comprehensive literature review of evidence-based research in order to identify, gather and summarize existing knowledge on PPD's aetiology, pathophysiology, and the role of nutrients in its prevention as well as management. The possible mechanisms of action of nutrients are also presented here. Study findings show that the risk of depression increases when omega-3 fatty acid levels are low. Both fish oil and folic acid supplements have been used to effectively treat depression. Antidepressant efficacy is lowered by folate insufficiency. Folate, vitamin B12, iron, etc. deficiencies are more prevalent in depressed people than in non-depressed people. Serum cholesterol levels and plasma tryptophan levels are found to be inversely correlated with PPD. Serum vitamin D levels were associated inversely with perinatal depression. These findings highlight the importance of adequate nutrition in the antepartum period. Given that nutritional therapies can be affordable, safe, simple to use, and are typically well-accepted by patients, more focus should be placed on dietary variables in PPD.

A pharmacological review on SIRT 1 and SIRT 2 proteins, activators, and inhibitors: Call for further research.

Sirtuins or Sir (Silent information regulator) are NAD+-dependent enzymes playing an important part in the pathogenesis and treatment of various disorders. They have ubiquitously expressed protein deacetylases. They are implicated in several cellular activities like DNA repair, cellular metabolism, mitochondrial function, and inflammation. Deletion of sirtuin protein, SIRT1 in the organs like brain, heart, liver and pancreas can cause inflammation and increases the level of free radical ions causing oxidative stress. Inflammation and oxidative stress are closely associated with pathophysiological events in many chronic diseases, like diabetes, cancer, cardiovascular, osteoporosis, and neurodegenerative diseases. Modulation of SIRT1 gene expression might help in preventing the progression of chronic diseases related to the brain, heart, liver, and pancreas. SIRT2 proteins play an essential role in tumorigenesis, including tumor-suppressing and tumor-promoting functions. Sirtuin activators are molecules that upregulate the activity of Sirtuins in the body. Their multifaceted uses have surprised the global scientific community. They are found to control obesity, lower cardiac risks, battle cancer, etc. This article provides an update on the pharmacological effect of SIRT1 and SIRT 2 proteins, their activators and inhibitors, and their molecular mechanism. It provides novel insights for future research in targeted therapy and drug development.

Investigation of Trends in the Research on Transferrin Receptor-Mediated Drug Delivery via a Bibliometric and Thematic Analysis.

This study systematically reviews and characterizes the existing literature on transferrin/transferrin receptor-mediated drug delivery. Transferrin is an iron-binding protein. It can be used as a ligand to deliver various proteins, genes, ions, and drugs to the target site via transferrin receptors for therapeutic or diagnostic purposes via transferrin receptors. This study is based on a cross-sectional bibliometric analysis of 583 papers limited to the subject areas of pharmacology, toxicology, and pharmaceutics as extracted from the Scopus database in mid-September 2022. The data were analyzed, and we carried out a performance analysis and science mapping. There was a significant increase in research from 2018 onward. The countries that contributed the most were the USA and China, and most of the existing research was found to be from single-country publications. Research studies on transferrin/transferrin receptor-mediated drug delivery focus on drug delivery across the blood-brain barrier in the form of nanoparticles. The thematic analysis revealed four themes: transferrin/transferrin receptor-mediated drug delivery to the brain, cancer cells, gene therapy, nanoparticles, and liposomes as drug delivery systems. This study is relevant to academics, practitioners, and decision makers interested in targeted and site-specific drug delivery.

Degradation of Xenobiotic Pollutants: An Environmentally Sustainable Approach.

The ability of microorganisms to detoxify xenobiotic compounds allows them to thrive in a toxic environment using carbon, phosphorus, sulfur, and nitrogen from the available sources. Biotransformation is the most effective and useful metabolic process to degrade xenobiotic compounds. Microorganisms have an exceptional ability due to particular genes, enzymes, and degradative mechanisms. Microorganisms such as bacteria and fungi have unique properties that enable them to partially or completely metabolize the xenobiotic substances in various ecosystems.There are many cutting-edge approaches available to understand the molecular mechanism of degradative processes and pathways to decontaminate or change the core structure of xenobiotics in nature. These methods examine microorganisms, their metabolic machinery, novel proteins, and catabolic genes. This article addresses recent advances and current trends to characterize the catabolic genes, enzymes and the techniques involved in combating the threat of xenobiotic compounds using an eco-friendly approach.

Dysregulation of multiple signaling pathways: A possible cause of cerebral palsy.

Cerebral palsy (CP) is a lifelong disability characterized by the impairment of brain functions that result in improper posture and abnormal motor patterns. Understanding this brain abnormality and the role of genetic, epigenetic, and non-genetic factors such as signaling pathway dysregulation and cytokine dysregulation in the pathogenesis of CP is a complex process. Hypoxic-ischemic injury and prematurity are two well-known contributors of CP. Like in the case of other neurodevelopmental disorders such as intellectual disability and autism, the genomic constituents in CP are highly complex. The neuroinflammation that is triggered by maternal cytokine response plays a critical role in the pathogenesis of fetal inflammation response, which is one of the contributing factors of CP, and it continues even after the birth of children suffering from CP. Canonical Wnt signaling pathway is important for the development of mammalian fetal brain and it regulates distinct processes including neurogenesis. The glycogen synthase kinase-3 (GSK-3) antagonistic activity in the Wnt signaling pathway plays a crucial role in neurogenesis and neural development. In this review, we investigated several genetic and non-genetic pathways that are involved in the pathogenesis of CP and their regulation, impairment, and implications for causing CP during embryonic growth and developmental period. Investigating the role of these pathways help to develop novel therapeutic interventions and biomarkers for early diagnosis and treatment. This review also helps us to comprehend the mechanical approach of various signaling pathways, as well as their consequences and relevance in the understanding of CP.

In vivo wound-healing and antioxidant activity of aqueous extract of Roylea elegans leaves against physically induced burn model in Wistar albino rats.

Roylea elegans Wall. ex Benth. is a lemon-scented hoary shrub belonging to the mint family (Lamiaceae). Traditionally, a local tribe of the Himalayan region uses leaves for scabs and skin infections. The aerial parts and leaves are widely used to cure various skin ailments. The plant is well known for two furanoid diterpenes, royeleganin and royelegafuran. The aqueous extract of Roylea elegans (AERE) leaves was investigated for wound-healing effects in rats using a physically induced burn model by assessing different parameters. Animals were divided into four groups (six rats in each group). Group I animals were considered as disease control and topically given base cream. Group II was considered as standard control and treated topically with Framycetin sulphate cream (1% w/w). Group III and IV animals were treated topically with creams containing 5 or 10% of AERE, respectively. Several parameters such as wound contraction rate, epithelialization period, and enzymatic and non-enzymatic antioxidant markers along with pro- and anti-inflammatory cytokines were studied followed by histopathological studies. The animals treated with AERE cream exhibited significant declination in the wound area and increased collagen content as compared to the disease control group. The results showed that the lower dose (5%) of AERE produced a significant decrease in the epithelialization period, wound contraction rate, and collagen content. Increased levels of cytokine production may be one of the mechanisms in accelerating the wound-healing process. The study established the traditional claim as an antioxidant and wound-healing potential of Roylea elegans by promoting the accelerated wound-healing activity against the physically induced burn model.

Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder.

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like "novel drugs for ASD" and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD.

Experimental Rodent Models of Vascular Dementia: A Systematic Review.

Vascular Dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of Vascular Cognitive Impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small Vessel Disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Cerebral Amyloid Angiopathy (CAA), which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as Diabetes Mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

Novel ß-Coronavirus (SARS-CoV-2): Current and future aspects of pharmacological treatments.

The novel coronavirus outbreak has reported to be rapidly spreading across the countries and becomes a foremost community health alarm. At present, no vaccine or specific drug is on hand for the treatment of this infectious disease. This review investigates the drugs, which are being evaluated and found to be effective against nCOVID-19 infection. A thorough literature search was performedon the recently published research papers in between January 2020 to May 2020, through various databases like "Science Direct", "Google Scholar", "PubMed","Medline", "Web of Science", and "World Health Organization (WHO)". We reviewed and documented the information related with the current and future aspects for the management and cure of COVID-19. As of 21st July 2020 a total of 14,562,550 confirmed cases of coronavirus and 607,781 deaths have been reported world-wide. The main clinical feature of COVID-19 ranges from asymptomatic disease to mild lower respiratory tract illness to severe pneumonia, acute lung injury, acute respiratory distress syndrome (ARDS), multiple organ dysfunction, and death. The drugs at present used in COVID-19 patients and ongoing clinical trials focusing on drug repurposing of various therapeutic classes of drug e.g. antiviral, anti-inflammatory and/or immunomodulatory drugs along with adjuvant/supportive care. Many drugs on clinical trials shows effective results on preliminary scale and now used currently in patients. Adjuvant/supportive care therapy are used in patients to get the best results in order to minimize the short and long-term complications. However, further studies and clinical trials are needed on large scale of population to reach any firm conclusion in terms of its efficacy and safety.

Cerebral palsy: Aetiology, pathophysiology and therapeutic interventions.

Cerebral palsy (CP) is the most common non-progressive neurodevelopmental disorder in which the impairment of motor and posture functions occurs. This condition may be present in many different clinical spectra. Various aetiological and risk factors play a crucial role in the causation of CP. In various cases, the causes of CP may not be apparent. Interruption in the supply of oxygen to the fetus or brain asphyxia was considered to be the main causative factor explaining CP. Antenatal, perinatal, and postnatal factors could be involved in the origin of CP. Understanding its pathophysiology is also crucial for developing preventive and protective strategies. A major advancement in the brain stimulation techniques has emerged as a promising status in diagnostic and interventional approaches. This review provides a brief explanation about the various aetiological factors, pathophysiology, and recent therapeutic approaches in the treatment of cerebral palsy.

Role of inflammatory markers in corona virus disease (COVID-19) patients: A review.

IMPACT STATEMENT: In late 2019, a novel virus called SARS-CoV-2, expanded globally from Wuhan, China and was declared a pandemic on 11 March 2020 by the WHO. The mechanism of virus entry inside the host cell depends upon the cellular proteases including cathepsins, HAT, and TMPRSS2, which splits up the spike protein and causes further penetration. MERS coronavirus uses DPP4, while coronavirus HCoV-NL63 and SARS-CoV and SARS-CoV-2 employ ACE-2 as the key receptor. Cytokine storm syndrome was analyzed in critically ill nCOVID-19 patients and it is presented with high inflammatory mediators, systemic inflammation, and multiple organ failure. Among various inflammatory mediators, the level of interleukins (IL-2, IL-7, IL-10), G-CSF, MIP1A, MCP1, and TNF-α was reported to be higher in critically ill patients. Understanding this molecular mechanism of ILs, T cells, and dendritic cells will be helpful to design immunotherapy and novel drugs for the treatment of nCOVID-19 infection.

Biomarker responses (serum biochemistry) in pregnant female wistar rats and histopathology of their neonates exposed prenatally to pesticides

Experiments were conducted to investigate the effects on health of pregnant female rats exposed to pesticides glyphosate and carbendazim. Glyphosate is used as herbicide and carbendazim as a fungicide; all are commercially available readily for various agricultural and domestic purposes. The hypothesis tested in this investigation is that pesticide exposure during pregnancy causes changes in biomarker responses like serum glucose level, total protein, total cholesterol, triglycerides, SGOT, SGPT, and billirubin level. Significant changes were observed in all above biomarker responses, when compared with the reference. Histopathology of skin and kidney of rat neonates showed marked damage. Degenerative changes and vacuolization with eroded capsule were observed in kidney sample and thinning of epidermis in skin sample was seen in pesticides exposed neonates of rats. The serum biochemistry and histopathological findings are valuable markers for observing the changes caused by pesticide exposure.

Transcriptional regulation of osmotic stress tolerance in wheat (Triticum aestivum L.).

KEY MESSAGE: The current review provides an updated, new insights into the regulation of transcription mediated underlying mechanisms of wheat plants to osmotic stress perturbations. Osmotic stress tolerance mechanisms being complex are governed by multiple factors at physiological, biochemical and at the molecular level, hence approaches like "OMICS" that can underpin mechanisms behind osmotic tolerance in wheat is of paramount importance. The transcription factors (TFs) are a class of molecular proteins, which are involved in regulation, modulation and orchestrating the responses of plants to a variety of environmental stresses. Recent reports have provided novel insights on the role of TFs in osmotic stress tolerance via direct molecular links. However, our knowledge on the regulatory role TFs during osmotic stress tolerance in wheat remains limited. The present review in its first part sheds light on the importance of studying the role of osmotic stress tolerance in wheat plants and second aims to decipher molecular mechanisms of TFs belonging to several classes, including DREB, NAC, MYB, WRKY and bHLH, which have been reported to engage in osmotic stress mediated gene expression in wheat and third part covers the systems biology approaches to understand the transcriptional regulation of osmotic stress and the role of long non-coding RNAs in response to osmotic stress with special emphasis on wheat. The current concept may lead to an understanding in molecular regulation and signalling interaction of TFs under osmotic stress to clarify challenges and problems for devising potential strategies to improve complex regulatory events involved in plant tolerance to osmotic stress adaptive pathways in wheat.

Anastomotic leak in colorectal surgery: are 75 % preventable?

INTRODUCTION: Anastomotic leak (AL) is a significant cause of morbidity and mortality associated with complications of colorectal surgery. Furthermore, AL results in prolonged hospital stays and significant increase in costs of medical resources. MATERIALS AND METHODS: In this study, we investigated the impact of anastomosis technique on the rate of anastomotic leak. The rate of leak was compared between two groups performing end-to-end (E-E) vs. side-to-end (S-E) anastomosis. The impact of various risk factors was also compared between the two groups. RESULTS: There were 382 E-E and 363 S-E anastomoses after left colectomy or rectal resections. The anastomotic leak rate was 8.64 % using E-E compared to 1.93 % using S-E anastomosis technique (p < 0.001). CONCLUSIONS: These results indicate that the rate of anastomotic leak after left colon and rectum resections could be significantly reduced utilizing S-E anastomosis technique.

High pressure vaginography to diagnose vaginal ureteral ectopia in patients with continuous urinary incontinence.

INTRODUCTION: Continuous urinary incontinence in female patients can be a diagnostic dilemma if traditional imaging fails to identify a source. Vaginography has been used to diagnose vaginal ectopic ureters in the past with mixed results. MATERIALS AND METHODS: Institutional review board approval was obtained for a retrospective review. Five teenage females with continuous incontinence and prior negative imaging work ups underwent high pressure vaginography. Their findings and treatment outcomes are reviewed. RESULTS: A vaginal ectopic ureter was diagnosed in each of the five patients at a mean age 15.8 years. Each had undergone prior magnetic resonance urography that was non-diagnostic. Four of the five were managed surgically with resolution of their incontinence. One was lost to follow up. CONCLUSION: High pressure vaginogram should be considered during the work up of female patients with continuous urinary incontinence, especially when other imaging modalities fail to identify an etiology.

Minimally invasive surgical approach to excision of symptomatic ectopic inverted-Y ureteral duplications.

Inverted-Y ureteral duplications are a rare duplication anomaly with few cases reported in the literature. We report a novel minimally invasive approach to managing inverted-Y duplications in two females who presented with continuous urinary incontinence and were found to have an ectopic insertion of the duplicated ureter. The ectopic segment was excised laparoscopically without complication in the outpatient setting with resultant cure of the continuous incontinence. This represents the first report of a laparoscopic approach to this rare anomaly.