MicroRNA-29b-3p degenerates terminally differentiated dopaminergic SH-SY5Y cells by perturbation of mitochondrial functions.

Mitochondrial dysfunction is the main cause of gradual deterioration of structure and function of neuronal cells, eventually resulting in neurodegeneration. Studies have revealed a complex interrelationship between neurotoxicant exposure, mitochondrial dysfunction, and neurodegenerative diseases. Alteration in the expression of microRNAs (miRNAs) has also been linked with disruption in mitochondrial homeostasis and bioenergetics. In our recent research (Cellular and Molecular Neurobiology (2023) https://doi.org/10.1007/s10571-023-01362-4), we have identified miR-29b-3p as one of the most significantly up-regulated miRNAs in the blood of Parkinson's patients. The findings of the present study revealed that neurotoxicants of two different natures, that is, arsenic or rotenone, dramatically increased miR-29b-3p expression (18.63-fold and 12.85-fold, respectively) in differentiated dopaminergic SH-SY5Y cells. This dysregulation of miR-29b-3p intricately modulated mitochondrial morphology, induced oxidative stress, and perturbed mitochondrial membrane potential, collectively contributing to the degeneration of dopaminergic cells. Additionally, using assays for mitochondrial bioenergetics in live and differentiated SH-SY5Y cells, a reduction in oxygen consumption rate (OCR), maximal respiration, basal respiration, and non-mitochondrial respiration was observed in cells transfected with mimics of miR-29b-3p. Inhibition of miR-29b-3p by transfecting inhibitor of miR-29b-3p prior to exposure to neurotoxicants significantly restored OCR and other respiration parameters. Furthermore, we observed that induction of miR-29b-3p activates neuronal apoptosis via sirtuin-1(SIRT-1)/YinYang-1(YY-1)/peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α)-regulated Bcl-2 interacting protein 3-like-dependent mechanism. Collectively, our studies have shown the role of miR-29b-3p in dysregulation of mitochondrial bioenergetics during degeneration of dopaminergic neurons via regulating SIRT-1/YY-1/PGC-1α axis.

Transcriptome sequencing of medical herb Salvia Rosmarinus (Rosemary) revealed the phenylpropanoid biosynthesis pathway genes and their phylogenetic relationships.

BACKGROUND: The Salvia rosmarinus spenn. (rosemary) is considered an economically important ornamental and medicinal plant and is widely utilized in culinary and for treating several diseases. However, the procedure behind synthesizing secondary metabolites-based bioactive compounds at the molecular level in S. rosmarinus is not explored completely. METHODS AND RESULTS: We performed transcriptomic sequencing of the pooled sample from leaf and stem tissues on the Illumina HiSeqTM X10 platform. The transcriptomics analysis led to the generation of 29,523,608 raw reads, followed by data pre-processing which generated 23,208,592 clean reads, and de novo assembly of S. rosmarinus obtained 166,849 unigenes. Among them, nearly 75.1% of unigenes i.e., 28,757 were interpreted against a non-redundant protein database. The gene ontology-based annotation classified them into 3 main categories and 55 sub-categories, and clusters of orthologous genes annotation categorized them into 23 functional categories. The Kyoto Encyclopedia of Genes and Genomes database-based pathway analysis confirmed the involvement of 13,402 unigenes in 183 biochemical pathways, among these unigenes, 1,186 are involved in the 17 secondary metabolite production pathways. Several key enzymes involved in producing aromatic amino acids and phenylpropanoids were identified from the transcriptome database. Among the identified 48 families of transcription factors from coding unigenes, bHLH, MYB, WRKYs, NAC, C2H2, C3H, and ERF are involved in flavonoids and other secondary metabolites biosynthesis. CONCLUSION: The phylogenetic analysis revealed the evolutionary relationship between the phenylpropanoid pathway genes of rosemary with other members of Lamiaceae. Our work reveals a new molecular mechanism behind the biosynthesis of phenylpropanoids and their regulation in rosemary plants.

Repurposing of Drugs for Cardiometabolic Disorders: An Out and Out Cumulation.

Cardiometabolic disorders (CMD) is a constellation of metabolic predisposing factors for atherosclerosis such as insulin resistance (IR) or diabetes mellitus (DM), systemic hypertension, central obesity, and dyslipidemia. Cardiometabolic diseases (CMDs) continue to be the leading cause of mortality in both developed and developing nations, accounting for over 32% of all fatalities globally each year. Furthermore, dyslipidemia, angina, arrhythmia, heart failure, myocardial infarction (MI), and diabetes mellitus are the major causes of death, accounting for an estimated 19 million deaths in 2012. CVDs will kill more than 23 million individuals each year by 2030. Nonetheless, new drug development (NDD) in CMDs has been increasingly difficult in recent decades due to increased costs and a lower success rate. Drug repositioning in CMDs looks promising in this scenario for launching current medicines for new therapeutic indications. Repositioning is an ancient method that dates back to the 1960s and is mostly based on coincidental findings during medication trials. One significant advantage of repositioning is that the drug's safety profile is well known, lowering the odds of failure owing to undesirable toxic effects. Furthermore, repositioning takes less time and money than NDD. Given these facts, pharmaceutical corporations are becoming more interested in medication repositioning. In this follow-up, we discussed the notion of repositioning and provided some examples of repositioned medications in cardiometabolic disorders.

Applications of some advanced sequencing, analytical, and computational approaches in medicinal plant research: a review.

The potential active chemicals found in medicinal plants, which have long been employed as natural medicines, are abundant. Exploring the genes responsible for producing these compounds has given new insights into medicinal plant research. Previously, the authentication of medicinal plants was done via DNA marker sequencing. With the advancement of sequencing technology, several new techniques like next-generation sequencing, single molecule sequencing, and fourth-generation sequencing have emerged. These techniques enshrined the role of molecular approaches for medicinal plants because all the genes involved in the biosynthesis of medicinal compound(s) could be identified through RNA-seq analysis. In several research insights, transcriptome data have also been used for the identification of biosynthesis pathways. miRNAs in several medicinal plants and their role in the biosynthesis pathway as well as regulation of the disease-causing genes were also identified. In several research articles, an in silico study was also found to be effective in identifying the inhibitory effect of medicinal plant-based compounds against virus' gene(s). The use of advanced analytical methods like spectroscopy and chromatography in metabolite proofing of secondary metabolites has also been reported in several recent research findings. Furthermore, advancement in molecular and analytic methods will give new insight into studying the traditionally important medicinal plants that are still unexplored.

Post-periodontal surgery propounds early repair salivary biomarkers by 1H NMR based metabolomics.

INTRODUCTION: Oral microflora is a well-orchestrated and acts as a sequential defense mechanism for any infection related to oral disease. Chronic periodontitis is a disease of a microbial challenge to symbiosis and homeostasis. Periodontal surgery is the most promising cure with repair process during periodontal regeneration. It has an encouraging outcome in terms of early recovery biomarkers. OBJECTIVE: Saliva of periodontal surgery subjects with the chronic periodontitis have been evaluated by 1H NMR spectroscopy in search of possible early metabolic differences that could be obtained in order to see the eradication of disease which favours the symbiotic condition. METHOD: The study employed 1H NMR spectroscopy on 176 human saliva samples in search of distinctive differences and their spectral data were further subjected to multivariate and quantitative analysis. RESULT: The 1H NMR study of periodontal surgery samples shows clear demarcation and profound metabolic differences when compared with the diseased condition. Several metabolites such as lactate, ethanol, succinate, and glutamate were found to be of higher significance in periodontal surgery in contrast to chronic periodontitis subjects. The PLS-DA model of the studied group resulted in R2 of 0.83 and Q2 of 0.70. CONCLUSION: Significant metabolites could be considered as early repair markers for chronic periodontitis disease as they are being restored to achieve symbiosis. The study, therefore, concluded the early recovery process of the diseased subjects with the restoration of possible metabolomic profile similar to the healthy controls.

Multidrug ABC transporter Cdr1 of Candida albicans harbors specific and overlapping binding sites for human steroid hormones transport.

The present study examines the kinetics of steroids efflux mediated by the Candida drug resistance protein 1 (Cdr1p) and evaluates their interaction with the protein. We exploited our in-house mutant library for targeting the 252 residues forming the twelve transmembrane helices (TMHs) of Cdr1p. The screening revealed 65 and 58 residues critical for ß-estradiol and corticosterone transport, respectively. Notably, up to 83% critical residues for corticosterone face the lipid interface compared to 54% for ß-estradiol. Molecular docking identified a possible peripheral corticosterone-binding site made of 8/14 critical/non-critical residues between TMHs 3, 4 and 6. ß-estradiol transport was severely hampered by alanine replacements of Cdr1p core residues involving TMHs 2, 5 and 8, in a binding site made of 10/14 critical residues mainly shared with rhodamine 6G with which it competes. By contrast, TMH11 was poorly impacted, although being part of the core domain. Finally, we observed the presence of several contiguous stretches of 3-5 critical residues in TMHs 2, 5 and 10 that points to a rotation motion of these helices during the substrate transport cycle. The selective structural arrangement of the steroid-binding pockets in the core region and at the lipid-TMD interface, which was never reported before, together with the possible rotation of some TMHs may be the structural basis of the drug-transport mechanism achieved by these type II ABC transporters.

Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes.

Deltamethrin (DLM), a synthetic pyrethroid insecticide, is used all over the world for indoor and field pest management. In the present study, we investigated the elicited pathogenesis of DLM-induced hepatotoxicity in rat primary hepatocytes. DLM-induced cell death was accompanied with increased ROS generation, decreased mitochondrial membrane potential and G2/M arrest. Pre-treatment with N-acetyl cysteine/butylated hydroxyanisole/IM54 could partly rescue hepatocytes suggesting that ROS might play a role in DLM-induced toxicity. Interestingly, DLM treatment resulted in a caspase-independent but non-apoptotic cell death. Pre-treatment with pan-caspase inhibitor (ZVAD-FMK) could not rescue hepatocytes. Unaltered caspase-3 activity and absence of cleaved caspase-3 also corroborated our findings. Further, LDH release and Transmission electron microscopy (TEM) analysis demonstrated that DLM incites membrane disintegrity and necrotic damage. Immunochemical staining revealed an increased expression of inflammatory markers (TNFα, NFκB, iNOS, COX-2) following DLM treatment. Moreover, the enhanced RIPK3 expression in DLM treated groups and prominent rescue from cell death by GSK-872 indicated that DLM exposure could induce programmed necrosis in hepatocytes. The present study demonstrates that DLM could induce hepatotoxicity via non-apoptotic mode of cell death.

Cypermethrin induces astrocyte damage: role of aberrant Ca(2+), ROS, JNK, P38, matrix metalloproteinase 2 and migration related reelin protein.

Cypermethrin is a synthetic type II pyrethroid, derived from a natural pyrethrin of the chrysanthemum plant. Cypermethrin-mediated neurotoxicity is well studied; however, relatively less is known of its effect on astrocyte development and migration. Astrocytes are the major components of blood brain barrier (BBB), and astrocyte damage along with BBB dysfunction impair the tight junction (TJ) proteins resulting in altered cell migration and neurodegeneration. Here, we studied the mechanism of cypermethin mediated rat astrocyte damage and BBB disruption, and determined any change in expression of proteins associated with cell migration. Through MTT assay we found that cypermethrin reduced viability of cultured rat astrocytes. Immunolabelling with astrocyte marker, glial fibrillary acidic protein, revealed alteration in astrocyte morphology. The astrocytes demonstrated an enhanced release of intracellular Ca(++) and ROS, and up-regulation in p-JNK and p-P38 levels in a time-dependent manner. Cypermethrin disrupted the BBB (in vivo) in developing rats and attenuated the expression of the extracellular matrix molecule (ECM) and claudin-5 in cultured astrocytes. We further observed an augmentation in the levels of matrix metalloproteinase 2 (MMP2), known to modulate cellular migration and disrupt the developmental ECM and BBB. We observed an increase in the levels of reelin, involved in cell migration, in cultured rat astrocytes. The reelin receptor, α3ß1integrin, and a mammalian cytosolic protein Disabled1 (Dab1) were also up-regulated. Overall, our study demonstrates that cypermethrin induces astrocyte injury via modulation in Ca(++), ROS, JNK and P38 pathways, which may alter MMP expression and reelin dependent astrocyte migration during brain development.

From Hypertension to Beyond: Unraveling the Diverse Mechanisms of Olmesartan in Disease Modulation.

Olmesartan, originally known for its antihypertensive properties, exhibits promising potential in addressing inflammation-mediated diseases. As an angiotensin II receptor blocker (ARB), Olmesartan influences pivotal pathways, including reactive oxygen species, cytokines, NF-κB, TNF-α, and MAPK. This suggests a viable opportunity for repurposing the drug in conditions such as ulcerative colitis, neuropathy, nephropathy, and cancer, as supported by multiple preclinical studies. Ongoing clinical trials, particularly in cardiomyopathy and nephropathy, suggest a broader therapeutic scope for Olmesartan. Repurposing efforts would entail comprehensive investigations using disease-specific preclinical models and dedicated clinical studies. The drug's established safety profile, wide availability, and well-understood ARB mechanism of action offer distinct advantages that could facilitate a streamlined repurposing process. In summary, Olmesartan's versatile impact on inflammation-related pathways positions it as a promising candidate for repurposing across various diseases. Ongoing clinical trials and the drug's favorable attributes enhance its appeal for further exploration and potential application in diverse medical contexts.

Detection of IDH1 Mutation in cfDNA and Tissue of Adult Diffuse Glioma with Allele-Specific qPCR.

BACKGROUND: The World Health Organization (WHO) classification of central nervous system (CNS) tumors necessitates testing of isocitrate dehydrogenase (IDH) 1/2 gene mutation in patients with adult-type diffuse glioma (ADG) for better disease management. In clinical practice, the testing of IDH1 is primarily achieved using immunohistochemistry (IHC) specific to IDH1-R132, which carries a sensitivity of 80% and specificity of 100%. However, in some cases, non-specific background staining or regional heterogeneity in the protein expression of IDH1 may necessitate confirmatory genetic analysis. Robust and reliable assays are needed for IDH1/2 mutation testing. The aim of the current study was to detect IDH1 mutation in cfDNA and tissue of adult-type diffuse glioma with allele-specific qPCR. MATERIALS AND METHODS: In the current study, IDH1-R132H mutation was analyzed in tumor tissue with paired cell-free DNA (cfDNA) in patients with ADG (n = 45) using IHC and competitive allele-specific Taqman PCR (CAST-PCR). Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue and matched serum for cfDNA using commercially available kits. CAST-PCR with IHC for the detection of IDH1-R132H mutation was also compared. RESULTS: The IDH1-R132H mutation was detected in 46.67% (21/45) cases and 57.78% (26/45) cases using IHC and allele-specific CAST-PCR. In cfDNA of matched IDH1-mutant FFPE tissue DNA, IDH1-R132H mutation was detected in 11.54% (3/26) using CAST-PCR. The concordance rate for IDH1-R132Hmutation between IHC and CAST-PCR was 80.77% (21/26). CONCLUSION: The CAST-PCR assay is more precise and sensitive for  IDH1-R132Hdetection than traditional IHC, and IDH1-R132H mutation detection using cfDNA may add to the current methods of glioma genomic characterization.

Clinical Manifestation of AGE-RAGE Axis in Neurodegenerative and Cognitive Impairment Disorders.

The receptor of Advanced Glycation Endproducts (RAGE) and Advanced Glycation Endproducts (AGE) have multiple functions in our body and their restraint are being observed in neurodegenerative and memory impairment disorders. The review of different pathways allows an understanding of the probable mechanism of neurodegeneration and memory impairment involving RAGE and AGE. Commonly we observe AGE accumulation in neural cells and tissues but the extent of accumulation increases with the presence of memory impairment disorder. The presence of AGEs can also be seen in morbid accumulation, pathological structures in the form of amyloid clots, and nervous fibrillary tangles in Alzheimer's Disease (AD) and memory impairment disease.Many neuropathological and biochemical aspects of AD are explained by AGEs, including widespread protein crosslinking, glial activation of oxidative stress, and neuronal cell death. Oxidative stress is due to different reasons and glycation end products set in motion and form or define various actions which are normally due to AGE changes in a pathogenic cascade. By regulating the transit of ß-amyloid in and out of the brain or altering inflammatory pathways, AGE and it's ensnare receptor such as soluble RAGE may function as blockage or shield AD development. RAGE activates the transcription-controlling factor Necrosis Factor (NF-κB) and increases the protraction of cytokines, like a higher number of Tumor Necrosis Factor (TNF-α) and Interleukin (IL-I) by inducing several signal transduction cascades. Furthermore, binding to RAGE can pro-activate reactive oxygen species (ROS), which is popularly known to cause neuronal death.

NMR spectroscopy-based analysis of gallstones of cancerous and benign gallbladders from different geographical regions of the Indian subcontinent.

Analysis of the chemical composition of gallstones is vital for the etiopathogenesis of gallstone diseases that can ultimately help in the prevention of its formation. In the present study, gallstones from seven different regions of India were analyzed to highlight the major difference in their composition. Also, gallstones of different pathological conditions i.e., benign (chronic cholecystitis, CC) and malignant gallbladder disease (gallbladder cancer GBC) were characterized. The type of polymorphs of cholesterol molecules was also studied to provide insight into the structure of gallstones. 1H solution state NMR spectroscopy 1D experiments were performed on a total of 94 gallstone (GS) samples collected from seven different geographical regions of India. Solid-State NMR spectroscopy 13C cross-polarization magic angle spinning (CPMAS) experiments were done on the 20 CC GS samples and 20 GBC GS samples of two regions. 1H NMR spectra from the solution state NMR of all the stones reveal that cholesterol was a major component of the maximum stones of the north India region while in south Indian regions, GS had very less cholesterol. 13C CPMAS experiments reveal that the quantity of cholesterol was significantly more in the GS of CC in the Lucknow region compared with GBC stones of Lucknow and Chandigarh. Our study also revealed that GS of the Lucknow region of both malignant and benign gallbladder diseases belong to the monohydrate crystalline form of cholesterol while GS of Chandigarh region of both malignant and benign gallbladder diseases exists in both monohydrate crystalline form with the amorphous type and anhydrous form. Gallstones have a complicated and poorly understood etiology. Therefore, it is important to understand the composition of gallstones, which can be found in various forms and clinical conditions. Variations in dietary practices, environmental conditions, and genetic factors may influence and contribute to the formation of GS. Prevention of gallstone formation may help in decreasing the cases of gallbladder cancer.

Effectual Endeavors of Silk Protein Sericin against Isoproterenol Induced Cardiac Toxicity and Hypertrophy in Wistar Rats.

The silkworm cocoon has been used in the treatment of various ailments in different Asian countries. This research was designed to evaluate the effect of sericin on myocardial necrosis and hypertrophy in isoproterenol-challenged rats. The rats were administered with sericin (500 and 1000 mg/kg, p.o.) for 28 days, followed by administration of isoprenaline (85 mg/kg, s.c.) on the 29th and 30th days. The cardioprotective activity was assessed by various physical, enzymatic, and histopathological parameters along with apoptotic marker expression. The cardioprotective effect showed that pre-treatment of rats with sericin significantly increased the non-enzymatic antioxidants marker in serum and heart tissue (glutathione, vitamin E, and vitamin C). The results were the same in enzymatic antioxidant marker, mitochondrial enzymes, and protein. The grading of heart, heart/body weight ratio, gross morphology, cardiac markers, oxidative stress markers in serum and heart tissue, glucose, serum lipid profiling and Lysosomal hydrolases, heart apoptotic markers such as MHC expression by western blot, apoptosis by flow cytometry, total myocardial collagen content, fibrosis estimation, myocyte size were significantly decreased when compared with isoproterenol (ISG) group however histopathological studies showed normal architecture of heart in both control and treated rats. The pharmacological study reflects that sericin on both doses i.e., 500 mg/kg and 1000 mg/kg have potent cardioprotective action against the experimental model which was confirmed by various physical, biochemical, and histopathological parameters evaluated further research is required to examine the molecular mechanism of cardioprotective effect of sericin.

An in-Depth Analysis of Ovarian Cancer: Pathogenesis and Clinical Manifestation.

Ovarian cancer is characterized by the establishment of tolerance, the recurrence of disease, as well as a poor prognosis. Gene signatures in ovarian cancer cells enable cancer medicine research, therapy, prevention, & management problematic. Notwithstanding advances in tumor puncture surgery, novel combinations regimens, and abdominal radiation, which can provide outstanding reaction times, the bulk of gynecological tumor patients suffer from side effects & relapse. As a consequence, more therapy alternatives for individuals with ovarian cancer must always be studied to minimize side effects and improve progression-free and total response rates. The development of cancer medications is presently undergoing a renaissance in the quest for descriptive and prognostic ovarian cancer biomarkers. Nevertheless, abnormalities in the BRCA2 or BRCA1 genes, a variety of hereditary predispositions, unexplained onset and progression, molecular tumor diversity, and illness staging can all compromise the responsiveness and accuracy of such indicators. As a result, current ovarian cancer treatments must be supplemented with broad-spectrum & customized targeted therapeutic approaches. The objective of this review is to highlight recent contributions to the knowledge of the interrelations between selected ovarian tumor markers, various perception signs, and biochemical and molecular signaling processes, as well as one's interpretation of much more targeted and effective treatment interventions.

Dynamics of cell-free DNA in predicting response in adult diffuse glioma on chemoradiotherapy.

BACKGROUND: Adult diffuse glioma (ADG) is a heterogeneous primary brain tumor with a variable prognosis and treatment response. Tissue biomarkers and molecular genetic profiling form an integral part of diagnosis and prognostication. However, obtaining tissue in inoperable locations and diagnosis of recurrence can be an issue. Cell-free DNA (cfDNA) may help to meet these challenges in the management of ADG. OBJECTIVES: The study aimed to serially quantify cfDNA in ADG on chemoradiation and to correlate mutational profiling of the cfDNA with biopsy. MATERIAL AND METHODS: The study group comprised of histopathological confirmed ADG (n = 50), including grade II, III and IV glioma, and controls (n = 25). Serum cfDNA was extracted using ChargeSwitch gDNA 1 mL Serum Kit (Invitrogen, USA) and quantified using SYBR based quantitative polymerase chain reaction (qPCR). Next-generation sequencing (NGS) was performed in 07 pre-operative and 05 post-operative cfDNA and tumor biopsy DNA on an Ion personal genome machine (IonPGM) with an in-house designed NGS panel (including TP53, ATRX, and IDH1 and IDH2). RESULTS: In patients with ADG, the pre-radiotherapy cfDNA level was significantly higher (Median; 113.46 ng/mL) than normal controls (Median; 74.37 ng/mL), (p = 0.048). Non-responders had significantly higher cfDNA levels (Median; 184.4 ng/mL), than responders (Median; 68.12 ng/mL), (p = 0.023). TP53 gene mutation was most common in both pre-operative and post-operative cfDNA samples. CONCLUSION: Pre-radiotherapy cfDNA levels are associated with clinical outcomes independent of other prognostic factors. Targeted NGS in pre-operative cfDNA matches the results of IHC analysis with high concordance, and it may be helpful in inoperable cases or ADG recurrence.

Hydroxychloroquine in COVID-19: therapeutic promises, current status, and environmental implications.

The outbreak of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the entire world with its infectious spread and mortality rate. The severe cases of coronavirus disease 2019 (COVID-19) are characterized by hypoxia and acute respiratory distress syndrome. In the absence of any specific treatment, just the preventive and supportive care options are available. Therefore, much focus is given to assess the available therapeutic options not only to avoid acute respiratory failure and hypoxia but also to reduce the viral load to control the severity of the disease. The antimalarial drug hydroxychloroquine (HCQ) is among the much-discussed drugs for the treatment and management of COVID-19 patients. This article reviews the therapeutic potential of HCQ in the treatment of COVID-19 based on the available in vitro and clinical evidence, current status of registered HCQ-based clinical trials investigating therapeutic options for COVID-19, and environmental implications of HCQ.

A deep neural network-based approach for prediction of mutagenicity of compounds.

We are exposed to various chemical compounds present in the environment, cosmetics, and drugs almost every day. Mutagenicity is a valuable property that plays a significant role in establishing a chemical compound's safety. Exposure and handling of mutagenic chemicals in the environment pose a high health risk; therefore, identification and screening of these chemicals are essential. Considering the time constraints and the pressure to avoid laboratory animals' use, the shift to alternative methodologies that can establish a rapid and cost-effective detection without undue over-conservation seems critical. In this regard, computational detection and identification of the mutagens in environmental samples like drugs, pesticides, dyes, reagents, wastewater, cosmetics, and other substances is vital. From the last two decades, there have been numerous efforts to develop the prediction models for mutagenicity, and by far, machine learning methods have demonstrated some noteworthy performance and reliability. However, the accuracy of such prediction models has always been one of the major concerns for the researchers working in this area. The mutagenicity prediction models were developed using deep neural network (DNN), support vector machine, k-nearest neighbor, and random forest. The developed classifiers were based on 3039 compounds and validated on 1014 compounds; each of them encoded with 1597 molecular feature vectors. DNN-based prediction model yielded highest prediction accuracy of 92.95% and 83.81% with the training and test data, respectively. The area under the receiver's operating curve and precision-recall curve values were found to be 0.894 and 0.838, respectively. The DNN-based classifier not only fits the data with better performance as compared to traditional machine learning algorithms, viz., support vector machine, k-nearest neighbor, and random forest (with and without feature reduction) but also yields better performance metrics. In current work, we propose a DNN-based model to predict mutagenicity of compounds.

Metabolomics: An emerging potential approach to decipher critical illnesses.

Critical illnesses contribute to the maximum morbidity and mortality of hospitalized patients. Acute respiratory distress syndrome (ARDS) and sepsis/septic shock are the two most common acute illnesses associated with intensive care unit (ICU) admission. Once triggered, both have an identical underlying mechanism, portrayed by inflammation and endothelial dysfunction. The diagnosis of ARDS is based on clinical findings, laboratory tests, and radiological imaging. Blood cultures remain the gold standard for the diagnosis of sepsis, with the limitation of time delay and low positive yield. A combination of biomarkers has been proposed to diagnose and prognosticate these acute disorders with strengths and limitations, but still, the gold standard has been elusive to clinicians. In this review article, we illustrate the potential of metabolomics to unravel biomarkers that can be clinically utilized as a rapid prognostic and diagnostic tool associated with specific patient populations (ARDS and sepsis/septic shock) based on the available scientific data.

Diligent profiling of preclinical safety of the silk protein sericin.

BACKGROUND: Sericin is a widely used protein in the pharmaceutical industry derived from the silkworm, Bombyx mori, and used for the treatment of various diseases and pathological conditions. It is the main ingredient of the Unani preparation khameera abresham. The study was conducted to evaluate the preclinical toxicity of the silk protein sericin in mice. METHODS: In the acute toxicity study, sericin was administered once orally to different groups of animals at doses of 500, 1000, and 2000 mg/kg. Animals were observed for 14 days. In the sub-acute toxicity study, sericin was administered in mice for 4 weeks in the toxic group at doses of 500, 1000, and 2000 mg/kg, while in the recovery group it was administered for 4 weeks at doses of 500 and 2000 mg/kg followed by 2 weeks of distilled water administration. RESULTS: In the acute toxicity study, the observed parameters showed no significant difference, and no mortality was reported. In the sub-acute toxicity study, there were no toxicological effects in any of the estimated parameters, while histopathological analysis showed inflammation in vital organs at the dose of 2000 mg/kg. CONCLUSIONS: Results of our acute toxicity study suggest that sericin is safe at all administered doses, while the sub-acute study suggests that the NOAEL (no-observed-adverse-effect level) of sericin is below 2000 mg/kg, at which it can be considered safe.

Available Compounds With Therapeutic Potential Against COVID-19: Antimicrobial Therapies, Supportive Care, and Probable Vaccines.

The recent outbreak of the COVID-2019 (coronavirus disease 2019) due to the infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has realized the requirement of alternative therapeutics to mitigate and alleviate this lethal infection. These alternative therapies are effective when they are started at the initial stage of the infection. Some drugs that were used in previous other related infections SARS-CoV-2003 and Middle East respiratory syndrome coronavirus (MERS-CoV)-2012 could be potentially active against currently emerging SARS-CoV-2. This fact imparts some rationale of current interventions, in the absence of any specific therapeutics for SARS-CoV-2. It is imperative to focus on the available antimicrobial and adjunct therapies during the current emergency state and overcome the challenges associated with the absence of robust controlled studies. There is no established set of drugs to manage SARS-CoV-2 infected patients. However, closely following patients' conditions and responding with the dosage guidelines of available drugs may significantly impact our ability to slow down the infection. Of note, it depends upon the condition of the patients and associated comorbid; therefore, the health workers need to choose the drug combinations judiciously until COVID-19 specific drug or vaccine is developed with the collective scientific rigor. In this article, we reviewed the available antimicrobial drug, supportive therapies, and probable high importance vaccines for the COVID-19 treatment.