Exome sequence analysis of rare frequency variants in Late-Onset Alzheimer Disease.

Alzheimer disease (AD) is a leading cause of dementia in elderly patients who continue to live between 3 and 11 years of diagnosis. A steep rise in AD incidents is observed in the elderly population in East-Asian countries. The disease progresses through several changes, including memory loss, behavioural issues, and cognitive impairment. The etiology of AD is hard to determine because of its complex nature. The whole exome sequences of late-onset AD (LOAD) patients of Korean origin are investigated to identify rare genetic variants that may influence the complex disorder. Computational annotation was performed to assess the function of candidate variants in LOAD. The in silico pathogenicity prediction tools such as SIFT, Polyphen-2, Mutation Taster, CADD, LRT, PROVEAN, DANN, VEST3, fathmm-MKL, GERP + + , SiPhy, phastCons, and phyloP identified around 17 genes harbouring deleterious variants. The variants in the ALDH3A2 and RAD54B genes were pathogenic, while in 15 other genes were predicted to be variants of unknown significance. These variants can be potential risk candidates contributing to AD. In silico computational techniques such as molecular docking, molecular dynamic simulation and steered molecular dynamics were carried out to understand the structural insights of RAD54B with ATP. The simulation of mutant (T459N) RAD54B with ATP revealed reduced binding strength of ATP at its binding site. In addition, lower binding free energy was observed when compared to the wild-type RAD54B. Our study shows that the identified uncommon variants are linked to AD and could be probable predisposing genetic factors of LOAD.

Conformational insights into the inhibitory mechanism of phyto-compounds against Src kinase family members implicated in psoriasis.

Psoriasis is a chronic immune mediated disorder of the skin. There is growing evidence that the Src family tyrosine kinases (SFK) are highly upregulated in psoriasis. The SFK are the key components of the signaling pathways triggering cell growth and differentiation in addition to the immune cascades. In the current work, the interactions between SFK and selective phyto-compounds were studied using molecular docking approach. Based on the results of docking and binding energy calculations quercetin was identified as potential lead compound. To get a deeper insight into the binding of quercetin with the SFK, a combined molecular dynamics and binding free energy calculations were performed. The binding of quercetin disrupted the intra-molecular contacts making the SFK compact except Src kinase. The MM/PBSA free energy decomposition analysis highlighted the significance of hydrophobic and polar residues which are involved in the binding of quercetin. An experimental validation was carried out against the activated forms of Fyn, Lyn and Src kinases, the top three proteins which showed high preference for quercetin. The flow cytometry analysis showed that the expression levels of Fyn, Lyn and Src kinases were dramatically increased in HaCaT cells. However, the treatment of quercetin at the concentration of 51.65 µM for 24 h markedly decreased their expression in HaCaT cells. Besides, similar results were also observed when the HaCaT cells were treated with the kinase inhibitor Ponitinib (1.43 µM) for 24 h.Communicated by Ramaswamy H. Sarma.

Genetic characterization of Chikungunya virus 2009 isolates from South India.

Chikungunya Virus (CHIKV) is a single stranded positive sense enveloped RNA virus. Re-emergence of CHIKV caused a massive outbreak with severe clinical manifestation affecting multiple organs. The genetic diversity of CHIKV, which caused recurring outbreaks in India, was studied. Blood samples were collected from suspected human cases of CHIKV infection in Chennai, Tamil Nadu and three Northern districts of Kerala in Southern India during the CHIKV outbreak in 2009. A partial E2 gene segment was amplified by RT-PCR. Among 119 samples 37 samples were positive for CHIKV by RT-PCR. Phylogenetic analysis revealed that the isolated sequences belonged to Indian Ocean Lineage (IOL) of ECSA genotype. The mutational analysis revealed the presence of substitutions such as S299N, T312M, A344T, S375T, V386G, W339R and S375P in the current study. In addition, a novel mutation V386G was observed in all the sequences. Two isolates found with unique substitutions W339R and S375P are reported. The structural analysis of the wild type and mutant proteins revealed that the structural changes are accompanied by modification in the intraprotein interactions.

Deciphering the Mechanism of Action of Wrightia tinctoria for Psoriasis Based on Systems Pharmacology Approach.

OBJECTIVE: Psoriasis is a chronic immune-mediated disorder of the skin. The disease manifests itself with red or silvery scaly plaques distributing over the lower back, scalp, and extensor aspects of limbs. Several medications are available for the treatment of psoriasis; however, high rates of remission and side-effects still persist as a major concern. Siddha, one of the traditional systems of Indian medicine offers cure to many dermatological conditions, including psoriasis. The oil prepared from the leaves of Wrightia tinctoria is prescribed by many healers for the treatment of psoriasis. This work aims to decipher the mechanism of action of the W. tinctoria in curing psoriasis and its associated comorbidities. DESIGN: The work integrates various pharmacology approaches such as drug-likeness evaluation, oral bioavailability predictions, and network pharmacology approaches to understand the roles of various bioactive components of the herb. RESULTS: This work identified 67 compounds of W. tinctoria interacting with 238 protein targets. The compounds were found to act through synergistic mechanism in reviving the disrupted process in the diseased state. CONCLUSION: The results of this work not only shed light on the pharmacological action of the herb but also validate the usage of safe herbal drugs.

A systems pharmacology perspective to decipher the mechanism of action of Parangichakkai chooranam, a Siddha formulation for the treatment of psoriasis.

Psoriasis is a chronic relapsing immune mediated disorder of the skin. The disease presents itself with well featured clinical and histological characteristics however the aetiology of the disease still remains obscure. The current systemic therapies aim to eliminate the symptoms of disease rather than offering a complete cure. Parangichakkai chooranam (PC), a Siddha oral herbal formulation has been widely prescribed for the treatment of psoriasis. Though the medication is highly prescribed by the Siddha healers the mechanism of PC for the treatment of psoriasis remains to be elucidated. The current study utilizes an integrated systems pharmacology approach to decipher the mechanism of action of PC. The comprehensive network pharmacological approach resulted in the construction of a Compound-Target network which encloses 155 compounds and 583 protein targets. A Disease-Target network was constructed by assembling disease proteins and their partners. When the compound targets were mapped to the network their involvement as controllers of the disease and triggers of disease associated comorbidities were identified. A Target-Pathway network raised from the pathway enrichment analysis not only identified disease specific pathways but also the pathways mediating secondary complications such as skin hemostasis, wound healing, desquamation and itch. The present work sheds light on the mechanism of action of PC in treating psoriasis. This work not only highlights the pharmacological action of the formulation but also emphasis on safe herbal remedies offered by the Siddha medicinal system.

Weighted gene co-expression based biomarker discovery for psoriasis detection.

Psoriasis is a chronic inflammatory disease of the skin with an unknown aetiology. The disease manifests itself as red and silvery scaly plaques distributed over the scalp, lower back and extensor aspects of the limbs. After receiving scant consideration for quite a few years, psoriasis has now become a prominent focus for new drug development. A group of closely connected and differentially co-expressed genes may act in a network and may serve as molecular signatures for an underlying phenotype. A weighted gene coexpression network analysis (WGCNA), a system biology approach has been utilized for identification of new molecular targets for psoriasis. Gene coexpression relationships were investigated in 58 psoriatic lesional samples resulting in five gene modules, clustered based on the gene coexpression patterns. The coexpression pattern was validated using three psoriatic datasets. 10 highly connected and informative genes from each module was selected and termed as psoriasis specific hub signatures. A random forest based binary classifier built using the expression profiles of signature genes robustly distinguished psoriatic samples from the normal samples in the validation set with an accuracy of 0.95 to 1. These signature genes may serve as potential candidates for biomarker discovery leading to new therapeutic targets. WGCNA, the network based approach has provided an alternative path to mine out key controllers and drivers of psoriasis. The study principle from the current work can be extended to other pathological conditions.

Comorbidities of Psoriasis - Exploring the Links by Network Approach.

Increasing epidemiological studies in patients with psoriasis report the frequent occurrence of one or more associated disorders. Psoriasis is associated with multiple comorbidities including autoimmune disease, neurological disorders, cardiometabolic diseases and inflammatory-bowel disease. An integrated system biology approach is utilized to decipher the molecular alliance of psoriasis with its comorbidities. An unbiased integrative network medicine methodology is adopted for the investigation of diseasome, biological process and pathways of five most common psoriasis associated comorbidities. A significant overlap was observed between genes acting in similar direction in psoriasis and its comorbidities proving the mandatory occurrence of either one of its comorbidities. The biological processes involved in inflammatory response and cell signaling formed a common basis between psoriasis and its associated comorbidities. The pathway analysis revealed the presence of few common pathways such as angiogenesis and few uncommon pathways which includes CCKR signaling map and gonadotrophin-realising hormone receptor pathway overlapping in all the comorbidities. The work shed light on few common genes and pathways that were previously overlooked. These fruitful targets may serve as a starting point for diagnosis and/or treatment of psoriasis comorbidities. The current research provides an evidence for the existence of shared component hypothesis between psoriasis and its comorbidities.

Computational evaluation of phytocompounds for combating drug resistant tuberculosis by multi-targeted therapy.

The cell wall of Mycobacterium tuberculosis interacts with the host counterpart during the pathogenesis of tuberculosis. L-rhamnosyl (L-Rha) residue, a linker connects the arabinogalactan and peptidoglycan moieties in the bacterial cell wall. The biosynthesis of L-rhamnose utilizes four successive enzymes RmlA, RmlB, RmlC and RmlD. Neither rhamnose nor the genes responsible for its synthesis are observed in humans. Thus, drugs inhibiting enzymes of this pathway are unlikely to interfere with metabolic pathways in humans. The adverse drug effects of first and second line drugs along with the development of multi-drug resistance tuberculosis have stimulated the research in search of new therapeutic drugs. Thus, it is attractive to hypothesize that inhibition of the biosynthesis of L-Rha would be lethal to the mycobacteria. Nature provides innumerable secondary metabolites with novel structural architectures with reported activity against M. tuberculosis. Combination of structure based virtual screening with physicochemical and pharmacokinetic studies against rhamnose pathway enzymes identified potential leads. The crucial screening studies recognized four phytocompounds butein, diospyrin, indicanine, and rumexneposide A with good binding affinity towards the rhamnose pathway proteins. Furthermore, the high throughput screening methods recognized butein, a secondary metabolite from Butea monosperma with strong anti-tubercular bioactive spectrum. Butein displayed promising anti-mycobacterial activity which is validated by Microplate alamar blue assay (MABA). The focus on novel agents like these phytocompounds which exhibit preference toward the successive enzymes of a single pathway can prevent the development of bacterial resistance.

Insights into protein interaction networks reveal non-receptor kinases as significant druggable targets for psoriasis.

Psoriasis is a chronic disease of the skin characterized by hyper proliferation and inflammation of the epidermis and dermal components of the skin. T-cell-dependent inflammatory process in skin governs the pathogenesis of psoriasis. An in-silico search strategy was utilized to identify psoriatic therapeutic drug targets. The gene expression profiling of psoriatic skin identified a total of 427 differentially expressed genes (DEGs). Gene ontology investigation of DEGs identified genes involved in calcium binding, apoptosis, keratinisation, lipid transportation and homeostasis apart from immune mediated processes. The protein interaction networks identified proteins involved in various signaling mechanisms with high degree of interconnections. The gene modules derived from the main network were enriched with rich kinome. These sub-networks were dominated by the presence of non-receptor kinase family members which are major signal transmitters in immune response. The computational approach has aided in the identification of non-receptor kinases as potential targets for psoriasis drug development.