Potential Therapeutic Molecules Research Articles

Cytomorphology and Gene Expression Signatures of Anchorage-independent Aggregations of Oral Cancer Cells.

Cancer cells with high anchorage independence can survive and proliferate in the absence of adhesion to the extracellular matrix. Under anchorage-independent conditions, cancer cells adhere to each other and form aggregates to overcome various stresses. In this study, we investigated the cytomorphology and gene expression signatures of oral cancer cell aggregates. Two oral cancer-derived cell lines, SAS and HSC-3 cells, were cultured in a low-attachment plate and their cytomorphologies were observed. The transcriptome between attached and detached SAS cells was examined using gene expression microarrays. Subsequently, gene enrichment analysis and Ingenuity Pathway Analysis were performed. Gene expression changes under attached, detached, and re-attached conditions were measured via RT-qPCR. While SAS cells formed multiple round-shaped aggregates, HSC-3 cells, which had lower anchorage independence, did not form aggregates efficiently. Each SAS cell in the aggregate was linked by desmosomes and tight junctions. Comparative transcriptomic analysis revealed 1,698 differentially expressed genes (DEGs) between attached and detached SAS cells. The DEGs were associated with various functions and processes, including cell adhesion. Moreover, under the detached condition, the expression of some epithelial genes (DSC3, DSP, CLDN1 and OCLN) were up-regulated. The changes in both cytomorphology and epithelial gene expression under the detached condition overall returned to their original ones when cells re-attached. The results suggest specific cytomorphological and gene expression changes in oral cancer cell aggregates. Our findings provide insights into the mechanisms underlying anchorage-independent oral cancer cell aggregation and reveal previously unknown potential diagnostic and therapeutic molecules.

Cardioprotective Effects of 6-Gingerol against Alcohol-Induced ROS-Mediated Tissue Injury and Apoptosis in Rats.

The present study investigated the cardioprotective properties of 6-gingerol against alcohol-induced ROS-mediated cardiac tissue damage in rats. Experiments were conducted on 4 groups of rats, orally treated with control, 6-gingerol (10 mg/kg body weight), alcohol (6 g/kg body weight) and combination of 6-gingerol plus alcohol for two-month. In the results, we found 6-ginger treatment to alcohol-fed rats substantially suppressed ROS production in cardiac tissue. Alcohol-induced elevated 8-OHDG and protein carbonyls which represent oxidative modification of DNA and proteins were completely reversed by 6-gingerol. This was further endorsed by restored superoxide dismutase and catalase activities with 6-gingerol against alcohol-induced loss. The elevated cardiac biomarkers (CK-MB, cTn-T, cTn-I) and dyslipidemia in alcohol-intoxicated rats was significantly reversed by 6-gingerol. Furthermore, alcohol-induced apoptosis characterized by overexpression of cytochrome C, caspase-8 and caspase-9 was diminished with 6-gingerol treatment. Transmission electron microscope images conferred the cardioprotective properties of 6-gingerol as we have seen less structural derangements in mitochondria and reappearance of myofilaments. Our findings conclude that 6-ginger effectively protect alcohol-induced ROS-mediated cardiac tissue damage, which may be due to its potent antioxidant efficacy. Therefore, 6-gingerol could be a potential therapeutic molecule that can be used in the treatment of alcohol-induced myocardial injury.

Rational design of metal-free fluorescent probe for tracking CO-releasing molecule-3 in vitro and in vivo

Carbon monoxide (CO), a potential therapeutic gaseous molecule for the treatment of inflammation-related diseases, is difficult to deliver directly into the body. CO-releasing molecule (CORM)− 3 is an alternative molecule for in vivo delivery of CO. To track the distribution of CORM-3 in vitro and in vivo, we reasonably designed and synthesized a series of coumarin-pyridine dyads (1−3) by DFT calculation. Applying the 4-nitrobenzyl group as the recognition site, two new metal-free fluorescent probes (MFP-1/2) were used for CORM-3 detection. As expected, probe MFP-1/2 showed an obvious off-on fluorescent response after the reaction with CORM-3. Meanwhile, probe MFP-2 exhibited good selectivity and sensitivity to CORM-3 in PBS. With the aid of its large stock shift and red emitting wavelength, MFP-2 was successfully applied to track the distribution of CORM-3 in living cells and in mice.

Identification of potential molecular players and therapeutic drug molecules in Melphalan resistant Multiple myeloma by integrated bioinformatics analysis

Multiple myeloma (MM), second most common haematological malignancy, still remains incurable with the acquiring of drug resistance. Melphalan therapy which has been used as one of the key therapies against MM, is impeded by the occurrence of Melphalan resistance. The precise underlying mechanism of this acquired Melphalan resistance in MM is not yet well deciphered. Therefore, this present study was aimed to identify the differentially expressed genes (DEGs) associated micro RNAs (miRNAs) and transcription factors (TFs) from the microarray dataset of Melphalan resistant and Melphalan sensitive MM cell lines, obtained from Gene Expression Omnibus (GEO) database. DEGs were analysed using GEO2R tool from the dataset. Then the gene ontology (GO) and pathway enrichment analysis were executed by using DAVID database. Protein-protein interaction (PPI) network of DEGs was constructed and analysed by using STRING database and Cytoscape tool. Genetic alterations in DEGs were studied through COSMIC database. Network of interaction of DEGs and miRNAs as well as TFs was constructed and analysed by using mirDIP, TRRUST and miRNet tools. Drug gene interaction was examined to identify potential drug molecules by DGIdb tool. Various DEGs that might play pivotal role in Melphalan resistant MM, were detected and selected for further analysis. miRNA analysis detected hsa-mir- 21-3p, hsa-mir-27a-5p, hsa-mir-129-2-3p that could interact with maximum target DEGs. One TF, STAT1 was found to regulate the expression of selected DEGs. The whole study may give a better understanding about the Melphalan resistance in MM.

Inhibitor Assessment against the LpxC Enzyme of Antibiotic-resistant Acinetobacter baumannii Using Virtual Screening, Dynamics Simulation, and in vitro Assays.

Bacterial resistance is currently a significant global public health problem. Acinetobacter baumannii has been ranked in the list of the World Health Organization as the most critical and priority pathogen for which new antibiotics are urgently needed. In this context, computational methods play a central role in the modern drug discovery process. The purpose of the current study was to identify new potential therapeutic molecules to neutralize MDR A. baumannii bacteria. A total of 3686 proteins retrieved from the A. baumannii proteome were subjected to subtractive proteomic analysis to narrow down the spectrum of drug targets. The SWISS-MODEL server was used to perform a 3D homology model of the selected target protein. The SAVES server was used to evaluate the overall quality of the model. A dataset of 74500 analogues retrieved from the PubChem database was docked with LpxC using the AutoDock software. In this study, we predicted a putative new inhibitor for the Lpxc enzyme of A. baumannii. The LpxC enzyme was selected as the most appropriate drug target for A. baumannii. According to the virtual screening results, N-[(2S)-3-amino-1-(hydroxyamino)-1-oxopropan-2-yl]-4-(4-bromophenyl) benzamide (CS250) could be a promising drug candidate targeting the LpxC enzyme. This molecule shows polar interactions with six amino acids and non-polar interactions with eight other residues. In vitro experimental validation was performed through the inhibition assay. To the best of our knowledge, this is the first study that suggests CS250 as a promising inhibitory molecule that can be exploited to target this gram-negative pathogen.

Development of a Novel HTLV-1 Protease: Human Fcγ1 Recombinant Fusion Molecule in the CHO Eukaryotic Expression System.

Human T-cell leukaemia virus type 1 (HTLV-1) is the causative agent of two life-threatening diseases, adult T cell leukaemia/lymphoma (ATLL), and HTLV-1-associated myelopathy/tropical spastic (HAM/TSP). HTLV-1 protease (HTLV-1-PR) is an aspartic protease that represents a promising target for therapeutic purposes like human immunodeficiency virus-PR inhibitors (HIV-PR). Therefore, in this study, the human Fc fusion recombinant-PR (HTLV-1-PR:hFcγ1) was designed and expressed for two applications, finding a blocking substrate as a potential therapeutic or a potential subunit peptide vaccine. The PCR amplified DNA sequences encoding the HTLV-1-PR from the MT2-cell line using specific primers with restriction enzyme sites of Not1 and Xba1. The construct was then cloned to pTZ57R/T TA plasmid and, after confirming the PR sequence, subcloned into the pDR2ΔEF1α Fc-expression vector to create pDR2ΔEF1α.HTLV-1-PR:hFcγ1. The integrity of recombinant DNA was confirmed by sequencing to ensure that the engineered construct was in the frame. The recombinant fusion protein was then produced in the Chinese hamster ovary cell (CHO) system and was purified from its supernatant using HiTrap-rPA column affinity chromatography. Then, the immunofluorescence assay (IFA) co-localisation method showed that HTLV-1-PR:hFc recombinant fusion protein has appropriate folding as it binds to the anti-Fcγ antibody; the Fcγ1 tag participates to have HTLV-1-PR:hFcγ1 as a dimeric secretory protein. The development and production of HTLV-1-PR can be used to find a blocking substrate as a potential therapeutic molecule and apply it in an animal model to assess its immunogenicity and potential protection against HTLV-1 infection.

Repositioning of anti-dengue compounds against SARS-CoV-2 as viral polyprotein processing inhibitor.

A therapy for COVID-19 (Coronavirus Disease 19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) remains elusive due to the lack of an effective antiviral therapeutic molecule. The SARS-CoV-2 main protease (Mpro), which plays a vital role in the viral life cycle, is one of the most studied and validated drug targets. In Several prior studies, numerous possible chemical entities were proposed as potential Mpro inhibitors; however, most failed at various stages of drug discovery. Repositioning of existing antiviral compounds accelerates the discovery and development of potent therapeutic molecules. Hence, this study examines the applicability of anti-dengue compounds against the substrate binding site of Mpro for disrupting its polyprotein processing mechanism. An in-silico structure-based virtual screening approach is applied to screen 330 experimentally validated anti-dengue compounds to determine their affinity to the substrate binding site of Mpro. This study identified the top five compounds (CHEMBL1940602, CHEMBL2036486, CHEMBL3628485, CHEMBL200972, CHEMBL2036488) that showed a high affinity to Mpro with a docking score > -10.0 kcal/mol. The best-docked pose of these compounds with Mpro was subjected to 100 ns molecular dynamic (MD) simulation followed by MM/GBSA binding energy. This showed the maximum stability and comparable ΔG binding energy against the reference compound (X77 inhibitor). Overall, we repurposed the reported anti-dengue compounds against SARS-CoV-2-Mpro to impede its polyprotein processing for inhibiting SARS-CoV-2 infection.

Identification and in-vitro analysis of potential proteasome inhibitors targeting PSMβ5 for multiple myeloma

The proteasome subunit β5 (PSMβ5) is a chief target of proteasome inhibitors (PIs) for treatment of multiple myeloma (MM). The relevance of PSMβ5 mutations and their functional impact on the development of resistance to PIs have been demonstrated recently. Therefore, this present study deals with an in-depth E-pharmacophore based screening and repurposing of FDA-approved drugs that could target PSMβ5 for MM. Our molecular docking-based investigation revealed risedronate and zoledronate as potential alternative therapeutic molecules for targeting the PSMβ5 gene. Risedronate and zoledronate displayed high binding affinity (−9.51 and −8.56 kcal/mol respectively) to PSMβ5. Moreover, 100 ns molecular dynamics simulation analysis of docking complexes revealed risedronate and zoledronate with a superior binding free energies and stable interactions with PSMβ5. The RMSD plot shows that the risedronate-PSMβ5 (mean: 0.24 nm) and zoledronate-PSMβ5 (mean: 0.25 nm) complexes are identical and stays stable until 100 ns. We further validated the activity of zoledronate in MM cell lines RPMI8226 and U266 where zoledronate showed significant anti-proliferative and apoptotic activity. Importantly, zoledronate showed an enhanced anti-proliferative activity when combined with bortezomib in MM cell lines. Thus, this study demonstrates that combining bortezomib with zoledronate could have a significant impact on reducing MM cell growth and can be an alternative strategy for treating MM.

Antiviral Potential of Plants against COVID-19 during Outbreaks-An Update.

Several human diseases are caused by viruses, including cancer, Type I diabetes, Alzheimer's disease, and hepatocellular carcinoma. In the past, people have suffered greatly from viral diseases such as polio, mumps, measles, dengue fever, SARS, MERS, AIDS, chikungunya fever, encephalitis, and influenza. Recently, COVID-19 has become a pandemic in most parts of the world. Although vaccines are available to fight the infection, their safety and clinical trial data are still questionable. Social distancing, isolation, the use of sanitizer, and personal productive strategies have been implemented to prevent the spread of the virus. Moreover, the search for a potential therapeutic molecule is ongoing. Based on experiences with outbreaks of SARS and MERS, many research studies reveal the potential of medicinal herbs/plants or chemical compounds extracted from them to counteract the effects of these viral diseases. COVID-19's current status includes a decrease in infection rates as a result of large-scale vaccination program implementation by several countries. But it is still very close and needs to boost people's natural immunity in a cost-effective way through phytomedicines because many underdeveloped countries do not have their own vaccination facilities. In this article, phytomedicines as plant parts or plant-derived metabolites that can affect the entry of a virus or its infectiousness inside hosts are described. Finally, it is concluded that the therapeutic potential of medicinal plants must be analyzed and evaluated entirely in the control of COVID-19 in cases of uncontrollable SARS infection.

Systematic Analysis of Immune Infiltration and Predicting Prognosis in Clear Cell Renal Cell Carcinoma Based on the Inflammation Signature.

Clear cell renal cell carcinoma (ccRCC) is the most frequent kind of kidney malignancy. Inflammation is a physiological response of the immune system to harmful stimuli. Notably, the role inflammation plays in ccRCC is still unknown. In this study, consensus clustering analysis sorted the ccRCC specimens from the TCGA dataset into C1 and C2 clusters. The C2 cluster comprised ccRCC specimens with a high TNM stage and tumor grade. These specimens were characterized by the activation of the inflammatory response and an immunosuppressive microenvironment. A seven-gene inflammation-related risk signature was designed employing the LASSO and Cox regression analyses for the inflammation-related genes. The ccRCC specimens were classified into two groups with high and low risk by calculating the risk scores. The specimens in the group with high risk showed a poor prognosis and were positively correlated with immune inhibitory factors. Moreover, a nomogram was created by incorporating inflammation-related risk signatures and clinical characteristics. The ROC and DCA curves indicated a satisfactory efficiency of the nomogram for predicting the survival outcomes. Furthermore, we identified the potential therapeutic drug molecules through CMap analysis. The findings of our study may act as a guide for further research on new prognostic biomarkers and therapies.

Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson's disease.

Parkinson's disease (PD) is the second most popular age-associated neurodegenerative disorder after Alzheimer's disease. The degeneration of dopaminergic neurons, aggregation of α-synuclein (α-syn), and locomotor defects are the main characteristic features of PD. The main cause of a familial form of PD is associated with a mutation in genes such as SNCA, PINK1, Parkin, DJ-1, LRKK2, and others. Recent advances have uncovered the different underlying mechanisms of PD but the treatment of PD is still unknown due to the unavailability of effective therapies and preventive medicines in the current scenario. The pathophysiology and genetics of PD have been strongly associated with mitochondria in disease etiology. Several studies have investigated a complex molecular mechanism governing the identification and clearance of dysfunctional mitochondria from the cell, a mitochondrial quality control mechanism called mitophagy. Reduced mitophagy and mitochondrial impairment are found in both sporadic and familial PD. Pharmacologically modulating mitophagy and accelerating the removal of defective mitochondria are of common interest in developing a therapy for PD. However, despite the extensive understanding of the mitochondrial quality control pathway and its underlying mechanism, the therapeutic potential of targeting mitophagy modulation and its role in PD remains to be explored. Thus, targeting mitophagy using chemical agents and naturally occurring phytochemicals could be an emerging therapeutic strategy in PD prevention and treatment. We discuss the current research on understanding the role of mitophagy modulators in PD using Drosophila melanogaster as a model. We further explore the contribution of Drosophila in the pathophysiology of PD, and discuss comprehensive genetic analysis in flies and pharmacological drug screening to develop potential therapeutic molecules for PD.

Multicellular 3D Models for the Study of Cardiac Fibrosis

Ex vivo modelling systems for cardiovascular research are becoming increasingly important in reducing lab animal use and boosting personalized medicine approaches. Integrating multiple cell types in complex setups adds a higher level of significance to the models, simulating the intricate intercellular communication of the microenvironment in vivo. Cardiac fibrosis represents a key pathogenetic step in multiple cardiovascular diseases, such as ischemic and diabetic cardiomyopathies. Indeed, allowing inter-cellular interactions between cardiac stromal cells, endothelial cells, cardiomyocytes, and/or immune cells in dedicated systems could make ex vivo models of cardiac fibrosis even more relevant. Moreover, culture systems with 3D architectures further enrich the physiological significance of such in vitro models. In this review, we provide a summary of the multicellular 3D models for the study of cardiac fibrosis described in the literature, such as spontaneous microtissues, bioprinted constructs, engineered tissues, and organs-on-chip, discussing their advantages and limitations. Important discoveries on the physiopathology of cardiac fibrosis, as well as the screening of novel potential therapeutic molecules, have been reported thanks to these systems. Future developments will certainly increase their translational impact for understanding and modulating mechanisms of cardiac fibrosis even further.

GPR35, ally of the anti-ischemic ATPIF1-ATP synthase interaction

Mitochondrial ATP synthase synthesizes ATP for cellular functions; however, under various conditions, including ischemia, it hydrolyzes ATP, primarily to re-energize the mitochondria. ATP synthase inhibitory factor 1 (ATPIF1) inhibits hydrolysis of ATP by ATP synthase. Wyant and colleagues recently demonstrated that G-protein-coupled receptor 35 (GPR35) is involved in this process. This finding provides an additional framework for the novel discovery of potential therapeutic molecules against ischemia/reperfusion (I/R) injury.

Characterization of exogenous αSN response genes and their relation to Parkinson's disease using network analyses.

Despite extensive research, the molecular mechanisms underlying the toxicity of αSN in Parkinson’s disease (PD) pathology are still poorly understood. To address this, we used a microarray dataset to identify genes that are induced and differentially expressed after exposure to toxic αSN aggregates, which we call exogenous αSN response (EASR) genes. Using systems biology approaches, we then determined, at multiple levels of analysis, how these EASR genes could be related to PD pathology. A key result was the identification of functional connections between EASR genes and previously identified PD-related genes by employing the proteins’ interactions networks and 9 brain region-specific co-expression networks. In each brain region, co-expression modules of EASR genes were enriched for gene sets whose expression are altered by SARS-CoV-2 infection, leading to the hypothesis that EASR co-expression genes may explain the observed links between COVID-19 and PD. An examination of the expression pattern of EASR genes in different non-neurological healthy brain regions revealed that regions with lower mean expression of the upregulated EASR genes, such as substantia nigra, are more vulnerable to αSN aggregates and lose their neurological functions during PD progression. Gene Set Enrichment Analysis of healthy and PD samples from substantia nigra revealed that a specific co-expression network, “TNF-α signaling via NF-κB”, is an upregulated pathway associated with the PD phenotype. Inhibitors of the “TNF-α signaling via NF-κB” pathway may, therefore, decrease the activity level of this pathway and thereby provide therapeutic benefits for PD patients. We virtually screened FDA-approved drugs against these upregulated genes (NR4A1, DUSP1, and FOS) using docking-based drug discovery and identified several promising drugs. Altogether, our study provides a better understanding of αSN toxicity mechanisms in PD and identifies potential therapeutic targets and small molecules for treatment of PD.

In vitro chemo-protective effect of Eisenia foetida coelomic fluid against histone deacetylase inhibitor-induced oxidative toxicity in breast cancer cells

ABSTRACT Developing new drugs from natural products is important for therapeutic effects to minimise tissue toxicity of drugs used in cancer treatment. Eisenia foetida is a worm with a double transport system consisting of coelomic fluid (ECF) that can be used as alternative medicine. It is important to eliminate or reduce the high cytotoxicity of sodium butyrate (NaBu), a chemotherapeutic agent used in breast cancer treatment, for both neoplastic and normal cells. We aimed to evaluate the effect of ECF on the oxidative toxicity induced by NaBu in MCF-7 cells, changes in ROS production levels and expression of cell death and ROS-related genes. It was determined that the expression levels of Bax and Bcl-2 genes remained unchanged, while the amount of ROS decreased significantly in MCF-7 cells exposed to NaBu with ECF. Thus, ECF may be a potential therapeutic molecule with fewer side effects in cancer treatment in the future.

Long non-coding RNAs as biomarkers and therapeutic targets for ischemic stroke.

BackgroundThe problem of ischemic stroke (IS) has become increasingly important in recent years, as it ranks first in the structure of disability and mortality, crowding out other vascular diseases. In this regard, the study of this pathology and the search for new therapeutic and diagnostic tools remains an urgent problem of modern medical science and practice. Long non-coding RNAs (lncRNAs)-based therapeutics and diagnostic tools offer a very attractive area of study. Therefore, this systematic review aims at summarizing current knowledge on promising lncRNAs as biomarkers and therapeutic targets for IS exploring original articles and literature reviews on in vivo, in vitro and ex vivo experiments.MethodsThe current systematic review was performed according to PRISMA guidelines. PubMed, MEDLINE and Google Scholar databases were comprehensively explored to perform the article search.Results34 eligible studies were included and analyzed: 25 focused on lncRNAs-based therapeutics and 9 on lncRNAs-based diagnosis. We found 31 different lncRNAs tested as potential therapeutic and diagnostic molecules in cells and animal model experiments. Among all founded lncRNA-based therapeutics and non-invasive diagnostic tools, nuclear enriched abundant transcript 1 (NEAT1) emerged to be the most investigated and proposed as a potential molecule for IS diagnosis and treatment.ConclusionsOur analysis provides a snapshot of the current scenario regarding the lncRNAs as therapeutic molecules and biomarkers in IS. Different lncRNAs are differently expressed in IS, and some of them can be further evaluated as therapeutic targets and biomarkers for early diagnosis and prognosis or treatment response. However, despite many efforts, none of the selected studies go beyond preclinical studies, and their translation into clinical practice seems to be very premature.

Integrated Microarray Analysis to Identify Genes and Small-Molecule Drugs Associated with Stroke Progression.

Several blood biomarkers are now considered increasingly important for stratifying risk, monitoring disease progression, and evaluating the response to therapy in ischemic stroke. The purpose of the present study was to identify the key genes associated with ischemic stroke progression and elucidate the potential therapeutic small molecules. Microarray datasets related to stroke for GSE58294, GSE22255, and GSE16561 were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were filtered using the Limma package. DAVID was then searched to perform gene ontology (GO) and pathway enrichment analyses. Based on the DEGs, a protein-protein interaction (PPI) network was developed using Cytoscape, and MCODE was applied to conduct module analysis. Finally, to identify the potential drugs for ischemic stroke, the connectivity map (CMap) database was used. Sixty DEGs were identified after analyzing the three datasets. The GO data analysis revealed that the DEGs were significantly associated with biological processes, including positive regulation of programmed cell death, protein localization in organelles, and positive regulation of apoptosis. KEGG analysis showed that the DEGs were particularly enriched in the Fc epsilon RI signaling pathway, MAPK signaling pathway, and Huntington's disease. We selected five DEGs with high connectivity (CYBB, SYK, DUSP1, TNF, and SP1) that significantly predicted stroke progression. In addition, CMap prediction showed ten small molecules that could be used as adjuvants when treating ischemic stroke. The outcomes of the present study indicated that the five genes mentioned above can be considered potential targets for developing new medications that can modify the ischemic stroke process, and mycophenolic acid was the most promising small molecule to treat ischemic stroke.

Phytovid19: a compilation of phytochemicals research in coronavirus.

The COVID-19 pandemic has immensely impacted global health causing colossal damage. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has increased the quest to explore phytochemicals as treatment options. We summarize phytochemicals with activity against various coronaviruses including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). We compiled 705 phytochemical compounds through text mining of 893 PubMed articles. The physicochemical properties including molecular weight, lipophilicity, and the number of hydrogen bond donors and acceptors were determined from the structures of these compounds. A structure-based evaluation of these properties with respect to drug likeness showed that most compounds have a positive score of drug likeness. QSAR analysis showed that 5 descriptors, namely polar surface area, relative polar surface area, number of hydrogen bond donors, solubility, and lipophilicity, are significantly related to IC50. We envisage that these phytochemicals could be further explored for developing new potential therapeutic molecules for COVID-19.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11224-022-02035-6.

Oxidative Stress in Amyotrophic Lateral Sclerosis: Synergy of Genetic and Environmental Factors.

Amyotrophic lateral sclerosis (ALS) is a grievous neurodegenerative disease whose survival is limited to only a few years. In spite of intensive research to discover the underlying mechanisms, the results are fairly inconclusive. Multiple hypotheses have been regarded, including genetic, molecular, and cellular processes. Notably, oxidative stress has been demonstrated to play a crucial role in ALS pathogenesis. In addition to already recognized and exhaustively studied genetic mutations involved in oxidative stress production, exposure to various environmental factors (e.g., electromagnetic fields, solvents, pesticides, heavy metals) has been suggested to enhance oxidative damage. This review aims to describe the main processes influenced by the most frequent genetic mutations and environmental factors concurring in oxidative stress occurrence in ALS and the potential therapeutic molecules capable of diminishing the ALS related pro-oxidative status.

Fucose as a potential therapeutic molecule against the immune-mediated inflammation in IgA nepharopathy: An unrevealed link.

BackgroundIgA nephropathy (IgAN) is an autoimmune disease that affects people of any age and is an important cause of end-stage renal disease. However, the pathogenesis and pathophysiology of IgAN is not clear. This article aimed to explore the immune-mediated inflammation and genetic mechanisms in IgAN.MethodsThe transcriptome sequencing data of IgAN glomeruli in the Gene Expression Omnibus database were downloaded. Single-sample gene set enrichment analysis was used to estimate the immune microenvironment of the merged microarray data and GSE141295. IgAN samples were divided into two clusters by cluster analysis. “limma” and “DEseq2” package in R were used to identify differentially expressed genes (DEGs). The weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules related to inflammation in IgAN. R software package “clusterProfiler” was used for enrichment analysis, whereas Short Time-Series Expression Miner (STEM) analysis was used to identify the trend of gene expression. Machine-learn (ML) was performed using the shiny app. Finally, Drug Signatures Database (DSigDB) was used to identify potential molecules for treating IgAN.ResultsThe infiltration of macrophages in IgAN glomeruli was increased, whereas CD4+ T cells, especially inducedregulatory T cells (iTregs) were decreased. A total of 1,104 common DEGs were identified from the merged data and GSE141295. Brown module was identified to have the highest inflammatory correlation with IgAN using WGCNA, and 15 hub genes were screened from this module. Among these 15 hub genes, 14 increased with the severity of IgAN inflammation based on STEM analysis. Neural network (nnet) is considered as the best model to predict the severity of IgAN. Fucose identified from DSigDB has a potential biological activity to treat IgAN.ConclusionThe increase of macrophages and the decrease of iTregs in glomeruli represent the immune-mediated inflammation of IgAN, and fucose may be a potential therapeutic molecule against IgAN because it affects genes involved in the severe inflammation of IgAN.