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The plant, Curcuma angustifolia Roxb., belonging to the family Zingiberaceae was subjected to a pot experiment to study the effects of arbuscular mycorrhizal fungi (AMF) on its metabolome. The experiment consisted of two treatments: Mycorrhizal (M), C. angustifolia plants inoculated with a consortium of AMF and non-mycorrhizal control plants (NM), plants not inoculated with AMF. GC-MS analyses revealed that AMF colonization modulated the composition and concentration of metabolites in different plant parts, leaves, rhizomes and roots as compared to their respective NM counterparts. However, n-hexadecanoic acid, 5-Hydroxymethylfurfural, 9, 12-octadecadienoic acid and terpineol were observed in all the parts in higher percentages. Cis-vaccenic acid was found in the highest concentration in rhizomes while roots showed a high concentration of coronarin E. These metabolites were found to possess good characteristics of being therapeutic drugs and their predicted targets are involved in different diseases such as obesity, diabetes mellitus, hypertension, cancers, etc. They also have many structurally similar compounds to the metabolites which are active against various protein targets involved in different diseases. Among them, terpineol has the Androgen receptor (AR) as the highest probable target whose roles have been reported in several cancers, especially prostate cancer. AR showed a thermodynamically favourable binding affinity with terpineol (ΔG = -6.2 kcal/mol). Similarly, other metabolites also showed binding affinities with their predicted targets. Thus, in the study, we report various metabolites of C. angustifolia and their potential characteristic drug-like properties, which may serve as a green alternative for better health care to mankind. [ABSTRACT FROM AUTHOR]

Complex disease networks can be studied successfully using network theoretical approach which helps in finding key disease genes and associated disease modules. We studied prostate cancer (PCa) protein-protein interaction (PPI) network constructed from patients' gene expression datasets and found that the network exhibits hierarchical scale free topology which lacks centrality lethality rule. Knockout experiments of the sets of leading hubs from the network leads to transition from hierarchical (HN) to scale free (SF) topology affecting network integration and organization. This transition, HN → SF , due to removal of significant number of the highest degree hubs, leads to relatively decrease in information processing efficiency, cost effectiveness of signal propagation, compactness, clustering of nodes and energy distributions. A systematic transition from a diassortative PCa PPI network to assortative networks after the removal of top 50 hubs then again reverting to disassortativity nature on further removal of the hubs was also observed indicating the dominance of the largest hubs in PCa network intergration. Further, functional classification of the hubs done by using within module degrees and participation coefficients for PCa network, and leading hubs knockout experiments indicated that kinless hubs serve as the basis of establishing links among constituting modules and heterogeneous nodes to maintain network stabilization. We, then, checked the essentiality of the hubs in the knockout experiment by performing Fisher's exact test on the hubs, and showed that removal of kinless hubs corresponded to maximum lethality in the network. However, excess removal of these hubs essentially may cause network breakdown. • The study showed that the PCa PPI network follows hierarchical scale free network topology lacking centrality lethality rule. • From knockout experiment, the removing of leading hubs results in a systemic transition from a hierarchical scale free network to scale free topology and then to Network breakdown regime on excessive removal of hubs. • The network topology transition behavior corresponded with losing its self organization and compactness. • The classification of the hubs to modular kinless, connector and peripheral hubs on their participation ratios (P i) and within module degree z score (Z i) showed that the kinless hubs take major responsibility to regulate the PCa PPI network and their removal corresponded with maximum lethality on the network. • Top 100 hubs of the PCa PPI network had the maximum percentage of essential genes with maximum kinless hubs are essential genes important for survival and the kinless hubs can be good targets for drug development against PCa. [ABSTRACT FROM AUTHOR]

Sporadic cases of breast cancer being more prevalent than the hereditary cases, can be largely attributed to environmental pollutants like polycyclic aromatic hydrocarbons (PAHs). The aim of the present study was to identify gene dysregulations and the associations in DMBA (a PAH) induced breast cancer. A breast cancer model was developed in Wistar rats (n = 40), using DMBA. Serum proteomics (2D electrophoresis and MALDI-TOF MS) followed by relative gene expression analysis in mammary glands were conducted to reach to the differential gene signatures. The candidate genes were subjected to survival analysis (by GEPIA2 and KM plotter) and infiltration analysis (by ImmuCellAI) for correlating gene expression with patient survival and immune cell infiltration respectively. Further, the regulatory network investigation (by Cytoscape) was performed to find out the transcription factors (TFs) and miRNAs of the concerned genes. A gene trio (ANXA5, MTG1, PPP2R5B), expressing differentially in early mammary carcinogenesis at 4 months (precancerous stage) till full-fledged cancerous stage (post 6 months) was identified. The altered gene expression was associated with less survival among breast cancer patients (n = 4019). The dysregulated expression also has a correlation with enhanced mammary infiltration of immune cells. Moreover, a regulatory network (comprising of 77 transcription factors and 50 miRNAs) involved in the regulation of candidate genes was also deciphered. The deregulated target genes can therefore be explored for reregulation via identified TFs and miRNAs, and survival thereby improved. • ANXA5, MTG1, and PPP2R5B genes are deregulated in mammary carcinogenesis. • This alteration is correlated with immune dysregulation, and low patient survival. • The gene trio in question is regulated by 77 transcription factors and 50 miRNAs. [ABSTRACT FROM AUTHOR]

Abstract: Globally only 5–10% of people encountering Mycobacterium tuberculosis have a lifetime risk of active disease indicating a strong host genetic bias towards development of tuberculosis. In the current study we investigated genotype variants pertaining to five cytokine genes namely IFNG, TNFA, IL4, IL10 and IL12 in the north Indian population with active pulmonary tuberculosis (APTB) and correlated the serum cytokine levels with the corresponding genotypes. Twenty five single nucleotide polymorphisms (SNPs) including six loci examined for the first time in tuberculosis were selected for genotyping in 108 patients with APTB from north India and 48 healthy regional controls (HC). Applying exclusion criteria 12 SNPs passed all the filters and were analysed further. The serum cytokine concentrations were measured by ELISA. Compared to HC mean serum IFN-γ, IL-12, IL-4, and IL-10 levels were higher in APTB (p =0.3661, p =0.0186, p =0.003, p =0.7, respectively). In contrast the mean serum TNF-α level was higher in HC (p =0.007). Comparison of genotypes and serum levels of the corresponding cytokine genes reveal that though IFN-γ and IL-4 levels were higher in APTB the genotype variants showed no difference between HC and APTB. In contrast the genotypes of the selected rsIDs in the TNFA, IL12 and IL10 genes showed significant association with the varying serum levels of corresponding cytokines. The variant of the TNFA gene at rs3093662, the IL12 gene at rs3213094 and rs3212220 and the IL10 gene at rs3024498 did show a strong indication to be of relevance to the immunity to tuberculosis. To our knowledge this is the first report from this region relating genotypes and serum cytokine levels in north Indian population. [Copyright &y& Elsevier]

Network medicine provides network theoretical tools, methods and properties to study underlying laws governing human interactome to identify disease states and disease complexity leading to drug discovery. Within this framework, we investigated the topological properties of ovarian cancer network (OCN) and the roles of hubs to understand OCN organization to address disease states and complexity. The OCN constructed from the experimentally verified genes exhibits fractal nature in the topological properties with deeply rooted functional communities indicating self-organizing behavior. The network properties at all levels of organization obey one parameter scaling law which lacks centrality lethality rule. We showed that |$\langle k\rangle $| can be taken as a scaling parameter, where, power law exponent can be estimated from the ratio of network diameters. The betweenness centrality |$C_B$| shows two distinct behaviors one shown by high degree hubs and the other by segregated low degree nodes. The |$C_B$| power law exponent is found to connect the exponents of distributions of high and low degree nodes. OCN showed the absence of rich-club formation which leads to the missing of a number of attractors in the network causing formation of weakly tied diverse functional modules to keep optimal network efficiency. In OCN, provincial and connector hubs, which includes identified key regulators, take major responsibility to keep the OCN integrity and organization. Further, most of the key regulators are found to be over expressed and positively correlated with immune infiltrates. Finally, few potential drugs are identified related to the key regulators. [ABSTRACT FROM AUTHOR]

Identification of key regulators and regulatory pathways is an important step in the discovery of genes involved in cancer. Here, we propose a method to identify key regulators in prostate cancer (PCa) from a network constructed from gene expression datasets of PCa patients. Overexpressed genes were identified using BioXpress, having a mutational status according to COSMIC, followed by the construction of PCa Interactome network using the curated genes. The topological parameters of the network exhibited power law nature indicating hierarchical scale-free properties and five levels of organization. Highest degree hubs (k ≥ 65) were selected from the PCa network, traced, and 19 of them was identified as novel key regulators, as they participated at all network levels serving as backbone. Of the 19 hubs, some have been reported in literature to be associated with PCa and other cancers. Based on participation coefficient values most of these are connector or kinless hubs suggesting significant roles in modular linkage. The observation of non-monotonicity in the rich club formation suggested the importance of intermediate hubs in network integration, and they may play crucial roles in network stabilization. The network was self-organized as evident from fractal nature in topological parameters of it and lacked a central control mechanism. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) poses a significant global health challenge due to its highly aggressive nature and invasive characteristics. Dysregulation of the Hippo pathway, a key regulator of various biological processes, is observed in TNBC, and its inhibition holds promise for impeding cancer growth. This in-silico analysis investigates the role of Transcriptional Enhanced Associate Domain 4 (TEAD4) in TNBC and its interaction with Yes Associated Protein (YAP) in cancer progression. Our results demonstrate that TEAD4 upregulation is linked to poor prognosis in TNBC, emphasizing its critical role in the disease. Moreover, we identify CID44521006, an analog of Flufenamic acid, as a potential therapeutic compound capable of disrupting the TEAD4-YAP interaction by binding to the YAP-binding domain of TEAD4. These findings underscore the significance of TEAD4 in TNBC and propose CID44521006 as a promising candidate for therapeutic intervention. The study contributes valuable insights to advance treatment options for TNBC, offering a potential avenue for the development of targeted therapies against this aggressive form of breast cancer. [ABSTRACT FROM AUTHOR]

Dicranella pseudosubulata Müll Hal. ex Gangulee is a moss species and a member of the Dicranaceae family, which is known to harbour many secondary metabolites of therapeutic importance. A gas chromatography-mass spectrometry (GC-MS) analysis of the methanolic extract of D. pseudosubulata was obtained to determine the metabolites of the moss. The chromatogram revealed 48 compounds, of which four compounds showed the highest concentrations, constituting 73.86% of all the bioactive chemicals detected. The compound d-Glucitol, 1-O-heptyl-showed the highest area percentage of 45.70 per cent. Other compounds with high concentrations are 9,12-Octadecadienoic acid (Z, Z)-, TMS derivative (13.35%); Palmitic acid, TMS derivative (9.46%) and Butanoic acid, 4-[(trimethylsilyl)oxy]-, trimethylsilyl ester (5.35%). These metabolites were then examined for their drug-like characteristics using SwissADME and predicted for potential target proteins using SwissTargetPrediction tools. Molecular docking analyses with the most probable targets of d-Glucitol, 1-O-heptyl-;9,12-octadecadienoic acid; Palmitic acid, TMS derivative and Butanoic acid, 4-[(trimethylsilyl)oxy]-, trimethylsilyl ester with Beta-glucocerebrosidase (GBA), Peroxisome proliferator-activated receptor gamma (PPARG), fatty acid binding protein (FABP4) and Thymidylate synthase (TYMS), respectively, showed thermodynamically favourable bindings. The target proteins have been reported to be associated with various ailments and their inhibition by these compounds is necessary to control and maintain cell growth in several cancers as well as in treating malaria and leishmania, obesity, lipidosis, kidney necrosis, liver carcinoma, insulin resistance etc. Some of the compounds have been reported to exhibit antimicrobial, antioxidant, and hepatoprotective activities. Thus, the finding suggests that D. pseudosubulata could serve as a potential therapeutic drug against various diseases. [ABSTRACT FROM AUTHOR]