Targeting ROCK2 isoform with its widely used inhibitors for faster post-stroke recovery

Recovery after ischemic stroke is slow and highly variable. Activated ROCK (Rho-associated coiled-coil kinase) pathway hampers recovery of impaired neurons. Though inhibiting ROCK pathway has shown therapeutic effects in vitro, the selectivity of most of the ROCK inhibitors is still not investigated. Present study aims to investigate the binding affinity in silico of nine widely used ROCK inhibitors with brainspecific ROCK2 isoform. Three-dimensional structures of ROCK2 and eight drugs were taken from Protein Data Bank and PubChem Chemical Compound Database, respectively, whereas, FSD-C10 structure was generated based on Xin et al., 2015. In docking, ROCK2 was set to be rigid and drugs were free to rotate. All simulations were carried out using AutoDock 4.2. This study demonstrated strong complexation between all ligands and ROCK2. All ROCK inhibitors, except FSD-C10, were able to bind to ROCK2 more strongly [Binding constant (Ka) between 2.6 – 36.7 × 105 M−1] than fasudil (Ka = 2.5 × 105 M−1). SLx-2119 (KD-025) had the highest binding constant (Ka = 36.7 × 105 M−1) thus succeeding as a better ROCK2 specific inhibitor. Selectivity of ROCK inhibitors (in silico) towards ROCK2 can be an indicative measure to estimate therapeutic benefits or adverse effects prior to in vitro study

Management of glaucoma in pregnancy: risks or choices, a dilemma?

The treatment of glaucoma in and around pregnancy offers the unique challenge of balancing the risk of vision loss to the mother as against the potential harm to the fetus or newborn. Most anti-glaucoma drugs (i.e. beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors topical and systemic, cholinergics, anticholinesterases, and apraclonidine) are considered category C agents and ophthalmologists are usually limited to treating patients with the category B drugs of brimonidine and dipivefrin. Brimonidine is generally the preferred first-line drug in the first, second and early third trimester. Late in the third trimester, brimonidine should be discontinued because it can induce central nervous system depression in newborns wherein topical carbonic anhydrase inhibitors may be the optimal choice. Glaucoma surgery can be performed with caution in second and third trimester if the patients have a strong indication for the procedure. However, anesthetics, sedative agents, and antimetabolites still have potential risk for the fetus. Argon laser trabeculoplasty (ALT) or selective laser trabeculoplasty (SLT) is an alternative treatment that can be performed in all trimesters. Carbonic anhydrase inhibitors and β-blockers are certified by the American Academy of Pediatrics for use during nursing. However, low doses of these medications should be considered when used in the breast feeding period. Optimum treatment for glaucoma in pregnancy must not be withheld so as to prevent any further deterioration in progressive vision loss and quality of life

Taxonomic relationships and breeding possibilities of species of Abelmoschus related to okra (A. esculentus)

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Differentially Expressed Genes and Their Clinical Significance in Ischaemic Stroke: An In-Silico Study

International audienc

Genome-wide expression reveals potential biomarkers in breast cancer bone metastasis

International audienceBreast cancer metastases are most commonly found in bone, an indication of poor prognosis. Pathway-based biomarkers identification may help elucidate the cellular signature of breast cancer metastasis in bone, further characterizing the etiology and promoting new therapeutic approaches. We extracted gene expression profiles from mouse macrophages from the GEO dataset, GSE152795 using the GEO2R webtool. The differentially expressed genes (DEGs) were filtered by log2 fold-change with threshold 1.5 (FDR < 0.05). STRING database and Enrichr were used for GO-term analysis, miRNA and TF analysis associated with DEGs. Autodock Vienna was exploited to investigate interaction of anti-cancer drugs, Actinomycin-D and Adriamycin. Sensitivity and specificity of DEGs was assessed using receiver operating characteristic (ROC) analyses. A total of 61 DEGs, included 27 down-regulated and 34 up-regulated, were found to be significant in breast cancer bone metastasis. Major DEGs were associated with lipid metabolism and immunological response of tumor tissue. Crucial DEGs, Bcl3, ADGRG7, FABP4, VCAN, and IRF4 were regulated by miRNAs, miR-497, miR-574, miR-138 and TFs, CCDN1, STAT6, IRF8. Docking analysis showed that these genes possessed strong binding with the drugs. ROC analysis demonstrated Bcl3 is specific to metastasis. DEGs Bcl3, ADGRG7, FABP4, IRF4, their regulating miRNAs and TFs have strong impact on proliferation and metastasis of breast cancer in bone tissues. In conclusion, present study revealed that DEGs are directly involved in of breast tumor metastasis in bone tissues. Identified genes, miRNAs, and TFs can be possible drug targets that may be used for the therapeutics. However, further experimental validation is necessary

Differential Transcriptome Profiling Unveils Novel Deregulated Gene Signatures Involved in Pathogenesis of Alzheimer&rsquo;s Disease

Alzheimer&rsquo;s disease (AD) is a neurodegenerative disorder that is characterized by a progressive loss of cognitive functions at a higher level than normal aging. Although the apolipoprotein (APOE) gene is a major risk factor in developing AD, other genes have also been reported to be linked with complex phenotypes. Therefore, this genome-wide expression study explored differentially expressed genes as possible novel biomarkers involved in AD. The mRNA expression dataset, GSE28146, containing 15 sample data composed of 7 AD cases from the hippocampus region with age-matched control (n = 8, &gt;80 years), was analyzed. Using &ldquo;affy&rdquo; R-package, mRNA expression was calculated, while pathway enrichment analysis was performed to determine related biological processes. Of 58 differentially expressed genes, 44 downregulated and 14 upregulated genes were found to be significantly (p &lt; 0.001) altered. The pathway enrichment analysis revealed two altered genes, i.e., dynein light chain 1 (DYNLL1) and kalirin (KLRN), associated with AD in the elderly population. The majority of genes were associated with retrograde endocannabinoid as well as vascular endothelial growth factors affecting the complex phenotypes. The DYNLL1 and KLRN genes may be involved with AD and Huntington&rsquo;s disease (HD) phenotypes and represent a common genetic basis of these diseases. However, the hallmark of AD is dementia, while the classic motor sign of HD includes chorea. Our data warrant further investigation to identify the role of these genes in disease pathogenesis

Transcriptomic Profiling Unravels Novel Deregulated Gene Signatures Associated with Acute Myocardial Infarction: A Bioinformatics Approach

Acute myocardial infarction (AMI) is a severe disease with elevated morbidity and mortality rate worldwide. This is attributed to great losses of cardiomyocytes, which can trigger the alteration of gene expression patterns. Although several attempts have been made to assess the AMI biomarkers, to date their role in rescuing myocardial injury remains unclear. Therefore, the current study investigated three independent microarray-based gene expression datasets from AMI patients (n = 85) and their age&ndash;sex-matched healthy controls (n = 70), to identify novel gene signatures that might be involved in cardioprotection. The differentially expressed genes (DEGs) were analyzed using &lsquo;GEO2R&rsquo;, and weighted gene correlation network analysis (WGCNA) was performed to identify biomarkers/modules. We found 91 DEGs, of which the number of upregulated and downregulated genes were 22 and 5, respectively. Specifically, we found that the deregulated genes such as ADOR-A3, BMP6, VPS8, and GPx3, may be associated with AMI. WGCNA revealed four highly preserved modules among all datasets. The &lsquo;Enrichr&rsquo; unveiled the presence of miR-660 and STAT1, which is known to affect AMI severity. Conclusively, these genes and miRNA might play a crucial role the rescue of cardiomyocytes from severe damage, which could be helpful in developing appropriate therapeutic strategies for the management of AMI