CDH1 overexpression sensitizes TRAIL resistant breast cancer cells towards rhTRAIL induced apoptosis.

PURPOSE: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is well known for its unique ability to induce apoptosis in cancer cells but not normal cells. However, a subpopulation of cancer cells exist that does not respond to toxic doses of TRAIL. In this study, we aimed to identify key factors regulating TRAIL resistance in breast cancer. METHODS: rhTRAIL (recombinant human TRAIL) resistant cells (TR) isolated from TRAIL sensitive MDA-MB-231 parental cells (TS) were confirmed using trypan blue assay, cell viability assay and AO/EtBr (acridine orange/ethidium bromide) staining. Microarray was performed followed by analysis using DAVID and Cytoscape bioinformatics software to identify the candidate hub gene. Gene expression of the candidate gene was confirmed using real-time PCR and western blot. Candidate gene was overexpressed via transient transfection to identify its significance in the context of rhTRAIL. Breast cancer patient data was obtained from The Cancer Genome Atlas (TCGA) database. RESULTS: Whole transcriptome analysis identified 4907 differentially expressed genes (DEGs) between TS and TR cells. CDH1 was identified as the candidate hub gene, with 18-degree centrality. We further observed CDH1 protein to be downregulated, overexpression of which increased apoptosis in TR cells after rhTRAIL treatment. TCGA patient data analysis also showed CDH1 mRNA to be low in TRAIL resistant patient group compared to TRAIL sensitive group. CONCLUSION: CDH1 overexpression sensitizes TR cells towards rhTRAIL induced apoptosis. Therefore, we can hypothesize that CDH1 expression should be taken into account while performing TRAIL therapy in breast cancer.

Morpho-physiological traits and SSR markers-based analysis of relationships and genetic diversity among fodder maize landraces in India.

BACKGROUND: Maize is an excellent fodder crop due to its high biomass, better palatability, succulency, and nutrition. Studies on morpho-physiological and biochemical characterization of fodder maize are limited. The present study aimed to explore the genetic variation in fodder maize landraces for various morpho-physiological traits and estimation of genetic relationship and population structure. METHODS AND RESULTS: The study on 47 fodder maize landraces revealed significant variation for all morpho-physiological traits except leaf-stem ratio. Plant height, stem girth, leaf-width and number of leaves showed positive correlation with green fodder yield. Morpho-physiological traits-based clustering grouped the landraces into three major clusters, whereas neighbour joining cluster and population structure analysis using 40 SSR markers revealed four and five major groups, respectively. Most landraces of Northern Himalaya-Kashmir and Ludhiana fall into a single group, whereas rest groups mainly had landraces from North-Eastern Himalaya. A total of 101 alleles were generated with mean polymorphic information content value of 0.36 and major allele frequency of 0.68. The pair wise genetic dissimilarity between genotypes ranged from 0.21 to 0.67. Mantel test revealed weak but significant correlation between morphological and molecular distance. Biochemical characterisation of superior landraces revealed significant variation for neutral detergent fibre, acid detergent fibre, cellulose and lignin content. CONCLUSION: Interestingly, significant, and positive correlation of SPAD with lignin content can be explored to bypass the costly affair of invitro quality assessment for digestibility parameters. The study identified superior landraces and demonstrated the use of molecular markers in genetic diversity assessment and grouping of genotypes for fodder maize improvement.

Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma.

Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.

Narrowing down molecular targets for improving phosphorus-use efficiency in maize (Zea mays L.).

Conventional agricultural practices rely heavily on chemical fertilizers to boost production. Among the fertilizers, phosphatic fertilizers are copiously used to ameliorate low-phosphate availability in the soil. However, phosphorus-use efficiency (PUE) for major cereals, including maize, is less than 30%; resulting in more than half of the applied phosphate being lost to the environment. Rock phosphate reserves are finite and predicted to exhaust in near future with the current rate of consumption. Thus, the dependence of modern agriculture on phosphatic fertilizers poses major food security and sustainability challenges. Strategies to optimize and improve PUE, like genetic interventions to develop high PUE cultivars, could have a major impact in this area. Here, we present the current understanding and recent advances in the biological phenomenon of phosphate uptake, translocation, and adaptive responses of plants under phosphate deficiency, with special reference to maize. Maize is one of the most important cereal crops that is cultivated globally under diverse agro-climatic conditions. It is an industrial, feed and food crop with multifarious uses and a fast-rising global demand and consumption. The interesting aspects of diversity in the root system architecture traits, the interplay between signaling pathways contributing to PUE, and an in-depth discussion on promising candidate genes for improving PUE in maize are elaborated.

NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas.

Adipose tissue is an important source of adipokines involved in anti- and pro-inflammatory effects. Their involvement in certain cancers such as breast and colon cancer is known but in gliomas it remains unexplored till date. The aim of this study was to assess the status of adipokines as prognostic markers of gliomas (low grade gliomas [LGG] and glioblastoma mutiforme [GBM]). Expression status (messenger RNA [mRNA]), overall survival (OS) and disease-free survival (DFS) was identified using gene expression profiling interactive analysis server. Clinicopathological analysis and correlation between different adipokines was performed using Xena server. Protein expression status was analyzed using tissue sections from the Human Protein Atlas. Out of 11 adipokines studied visfatin (NAMPT), apelin (APLN), granulin (GRN), serpin peptidase inhibitor/plasminogen activator inhibitor type 1 (PAI-1) member 1 (SERPINE1), and chemokine (C-C motif) ligand 2 (CCL2) mRNA levels were significantly upregulated in both LGG and GBM. Interleukin 6 (IL6) mRNA was found be significantly upregulated only in GBM. NAMPT, GRN, SERPINE1, and IL6 showed reduced OS as well as worst DFS for patients having higher mRNA expression in LGG. Increased expression of CCL2 showed worst OS in LGG patients while resistin (RETN) and GRN showed the worst OS in GBM patients. Higher expression of RETN, GRN, IL6, SERPINE1, and CCL2 were found to be positively correlated with shorter DFS in GBM. In the clinicopathological analysis, NAMPT, GRN, IL6, SERPINE1, and CCL2 expressions were significantly associated between the neoplasm histological G2 and G3 grades. Furthermore, expression of NAMPT, GRN, tumor necrosis factor, IL6, SERPINE1, and CCL2 were significantly associated with histological type in LGG patients. NAMPT, GRN, SERPINE1, CCL2, and RETN expression were found to be correlated with each other in gliomas. Finally, NAMPT, GRN, and SERPINE1 were also found to be upregulated using immunohistochemistry in a lower grade and high grade gliomas as compared to normal cells. In conclusion, we have identified key adipokines, namely NAMPT, GRN, and SERPINE1 as potential diagnostic and prognostic markers that might be instrumental in the development and progression of gliomas.

Environmental impact of phytic acid in Maize (Zea mays. L) genotypes for the identification of stable inbreds for low phytic acid.

Phytic acid is a ubiquitous compound that chelates the micronutrients in food and hinder their absorption. Hence, breeding for low phytate content for producing stable low phytic acid (lpa) hybrids is essential. Phytic acid content in maize grains has been found to vary across environments and its stable expression has yet to be explored. In a view of this, forty inbreds were screened with two checks viz., CO-6 and CO-H(M)-8 across three locations. Twenty morphological and three quality traits were observed to identify the stable lines for low phytic acid with higher free inorganic phosphorous and starch. Among all the lines, UMI-467, LPA-2-285, LPA-2-395 and UMI-447 recorded a stable performance in both AMMI and GGE biplot analysis for low phytic acid (2.52-3.32 mg/g). These lines also had a higher free inorganic phosphorous, ensuring its bioavailability (1.78-1.88 mg/g). There were perturbations in yield, starch and seed characteristics of the stable low phytic acid lines due to their lower phytic acid concentrations. This stated the role of phytic acid in plant physiology and established the constraints to be faced in breeding for low phytic acid in maize. Among the lpa lines, LPA-2-285 (57.83%) and UMI-447 (55.78%) had the highest average starch content. The lowest stable phytic acid content was observed in UMI-467 (2.52 mg/g) and this line had severe reductions in yield parameters. Considering the seed and yield characteristics, LPA-2-285, LPA-2-395 and UMI-447 performed better than UMI-467. Although these four stable lines were poor in their adaptability among all the genotypes, they could be utilised as promising stable donors to facilitate the development of stable lpa hybrids.

Assessment of epigenetic alterations and in silico analysis of mutation affecting PTEN expression among Indian cervical cancer patients.

Genetic and epigenetic anomalies accountable for genetic dysregulation are the most common aberrations that determine the underlying heterogeneity of the tumor cells. Currently, phosphatase and tensin homolog (PTEN) incongruity has emerged as potent and persuasive malfunctioning in varied human malignancies. In this study, we have analysed the promoter hypermethylation and expression status of PTEN. We identified different mutations in the exonic region of PTEN. Functional consequences of these mutations were explored using in silico techniques. Promoter hypermethylation of PTEN was detected using methylation-specific polymerase chain reaction (MS-PCR), expression analysis was performed with immunohistochemistry (IHC) and mutation by direct sequencing in a total of 168 uterine cervix tumor cases. The findings were statistically correlated with the clinical parameters. In addition, the effect of nonsynonymous mutations was studied with molecular dynamics simulations. PTEN promoter hypermethylation (45.8%) was found to be significantly associated with the of PTEN loss (57.14%, P < 0.0001). Tumor stages, tumor size, lymph node (LN) were found to be significantly correlated with both PTEN promoter hypermethylation and PTEN loss. Histological grade, however, showed a significant association with only PTEN loss. In total, 11.76% of tumors exhibited mutations in exon 5 and 7, out of which E150K of exon 5 showed the highest deviations in the crystal structure of PTEN by in silico analysis. This study provides valuable insights into oncology and paves the path in the development of efficient biomarker and/or imperative therapeutic tool for cervical cancer treatment.

Genetic and epigenetic alterations affecting PARK-2 expression in cervical neoplasm among North Indian patients.

The recent investigation on PARK-2, a putative tumor suppressor gene, has found that it has been altered in multiple human malignancies. However, the clinical impact of PARK-2 alteration in uterine cervix carcinoma has not yet been studied. Therefore, we aimed to examine mutations, promoter hypermethylation, and protein expression of PARK-2 among the North Indian patients and their association with clinical parameters to evaluate the implication of PARK-2 in the genesis of cervical cancer. A total of 168 patient samples were processed for mutational analysis by single-strand conformation polymorphism, sequencing, and further in silico analysis of the identified mutations. Promoter hypermethylation by methylation-specific polymerase chain reaction and expression of PARK-2 were performed using immunohistochemistry. Statistical correlation between molecular findings and the clinicopathological parameters was taken to figure out the meaningful outcome. As per our findings, 3.5% (6/168) tumors showed novel missense mutations in exon 11 of PARK-2. In silico analysis showed high structural deviations manifested by mutations, A398D and Y391N, in both mutant proteins as compared to wild type. Promoter hypermethylation was observed in total of 29% of (48/168) tumor samples. Furthermore, 46.43% tumors (78/168) exhibited loss of PARK-2 expression in cervical carcinoma. The loss of expression of PARK-2 when correlated with clinical parameters resulted in significant association with tumor stage (p = 0.002) and with histological grade (p = 0.025). However, only clinical stage remained significant after Bonferroni correction (p < 0.007). A trend was observed between PARK-2 promoter hypermethylation and its protein expression. Our study provided sufficient information and insight for investigation of PARK-2 and highlighted its role as a tumor suppressor gene in cervical cancer in North Indian population.

Association of mitochondrial copy number variation and T16189C polymorphism with colorectal cancer in North Indian population.

Globally, colorectal cancer is the third most common type of cancer. Genetic instability leading to cancer development is one of the major causes for development of cancer. Alterations in mitochondrial genome, that is, mutations, single-nucleotide polymorphisms, and copy number variations are known to contribute in cancer development. The aim of our study was to investigate association of mitochondrial T16189C polymorphism and copy number variation with colorectal cancer in North Indian population. DNA isolated from peripheral blood of 126 colorectal cancer patients and 114 healthy North Indian subjects was analyzed for T16189C polymorphism and half of them for mitochondrial copy number variation. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism, and copy number variation was estimated using real-time polymerase chain reaction, numbers of mitochondrial copies and found to be significantly higher in colorectal cancer patients than healthy controls (88 (58-154), p = 0.001). In the regression analysis, increased mitochondrial copy number variation was associated with risk of colorectal cancer (odds ratio = 2.885, 95% confidence interval = 1.3-6.358). However, T16189C polymorphism was found to be significantly associated with the risk of rectal cancer (odds ratio = 5.213, p = 0.001) and non-significantly with colon cancer (odds ratio = 0.867, p = 0.791). Also, false-positive report probability analysis was done to validate the significant findings. Our results here indicate that mitochondrial copy number variation may be playing an important role in the development of colorectal cancer, and detection of mitochondrial copy number variation can be used as a biomarker for predicting the risk of colorectal cancer in North Indian subjects.

Mapping of PARK2 and PACRG overlapping regulatory region reveals LD structure and functional variants in association with leprosy in unrelated indian population groups.

Leprosy is a chronic infectious disease caused by Mycobacterium Leprae, where the host genetic background plays an important role toward the disease pathogenesis. Various studies have identified a number of human genes in association with leprosy or its clinical forms. However, non-replication of results has hinted at the heterogeneity among associations between different population groups, which could be due to differently evolved LD structures and differential frequencies of SNPs within the studied regions of the genome. A need for systematic and saturated mapping of the associated regions with the disease is warranted to unravel the observed heterogeneity in different populations. Mapping of the PARK2 and PACRG gene regulatory region with 96 SNPs, with a resolution of 1 SNP per 1 Kb for PARK2 gene regulatory region in a North Indian population, showed an involvement of 11 SNPs in determining the susceptibility towards leprosy. The association was replicated in a geographically distinct and unrelated population from Orissa in eastern India. In vitro reporter assays revealed that the two significantly associated SNPs, located 63.8 kb upstream of PARK2 gene and represented in a single BIN of 8 SNPs, influenced the gene expression. A comparison of BINs between Indian and Vietnamese populations revealed differences in the BIN structures, explaining the heterogeneity and also the reason for non-replication of the associated genomic region in different populations.

Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner.

The present study was designed to examine the functional relevance of two heterozygous mutations (H391Y and K422R), observed earlier by us in the Bloom syndrome condition. Cells stably expressing exogenous wild-type or mutant PKM2 (K422R or H391Y) or co-expressing both wild type and mutant (PKM2-K422R or PKM2-H391Y) were assessed for cancer metabolism and tumorigenic potential. Interestingly, cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism as compared with cells expressing either wild-type or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation, and tumor growth. These observations signify the dominant negative nature of mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; this study demonstrates for the first time the possible predisposition of Bloom syndrome patients with impaired PKM2 activity to cancer and the importance of studying genetic variations in PKM2 in the future to understand their relevance in cancer in general.

Mapping of yellow mosaic virus (YMV) resistance in soybean (Glycine max L. Merr.) through association mapping approach.

Yellow Mosaic Virus (YMV) is a serious disease of soybean. Resistance to YMV was mapped in 180 soybean genotypes through association mapping approach using 121 simple sequence repeats (SSR) and four resistance gene analogue (RGA)-based markers. The association mapping population (AMP) (96 genotypes) and confirmation population (CP) (84 genotypes) was tested for resistance to YMV at hot-spot consecutively for 3 years (2007-2009). The genotypes exhibited significant variability for YMV resistance (P < 0.01). Molecular genotyping and population structure analysis with 'admixture' co-ancestry model detected seven optimal sub-populations in the AMP. Linkage disequilibrium (LD) between the markers extended up to 35 and 10 cM with r2 > 0.15, and >0.25, respectively. The 4 RGA-based markers showed no association with YMV resistance. Two SSR markers, Satt301 and GMHSP179 on chromosome 17 were found to be in significant LD with YMV resistance. Contingency Chi-square test confirmed the association (P < 0.01) and the utility of the markers was validated in the CP. It would pave the way for marker assisted selection for YMV resistance in soybean. This is the first report of its kind in soybean.

Moderate DNA damage promotes metabolic flux into PPP via PKM2 Y-105 phosphorylation: a feature that favours cancer cells.

Pyruvate kinase M2, an important metabolic enzyme, promotes aerobic glycolysis (Warburg effect) to facilitate cancer cell proliferation. Unravelling the status of this important glycolytic pathway enzyme under sub-lethal doses of etoposide, a commonly used anti-proliferative genotoxic drug to induce mild/moderate DNA damage in HeLa cells as a model system and discern its effect on: PKM2 expression, phosphorylation, dimer: tetramer ratio, activity and associated effects, was pertinent. Protein expression and phosphorylation of PKM2 from HeLa cells was estimated using Western blotting. Same protein lysate was also used to estimate total pyruvate kinase activity and the total dimer: tetramer content evaluated using glycerol gradient ultra-centrifugation. Intracellular PEP was estimated manually using standard curve; while NADPH was assessed by NADPH estimation kit. Unpaired t test and two-way-ANOVA was used for statistical analysis. A relative decrease in PKM2 expression and a subsequent dose and time dependent increase in Y105-phosphorylation were observed. A concomitant increase in PKM2 dimer content and Y105-phosphorylation responsible for reduced PKM2 activity promoted PEP accumulation and NADPH production, representing increased metabolic flux into PPP, a feature that favours cancer cells. It was apparent that the sub-lethal doses of etoposide induced inadequate damage to DNA in cancer cells in culture promoted pro-survival conditions due to Y105-phosphorylation of PKM2, its stable dimerization and inactivation, a unique association not known earlier, indicating what might happen in tumour revivals or recurrences.

Multilocus functional characterization of indigenous and exotic inbreds for dgat1-2, fatb, ge2 and wri1a genes affecting kernel oil and fatty acid profile in maize.

Demand for maize oil is progressively increasing due to its diverse industrial applications, aside from its primary role in human nutrition and animal feed. Oil content and composition are two crucial determinants of maize oil in the international market. As kernel oil in maize is a complex quantitative trait, improving this trait presents a challenge for plant breeders and biotechnologists. Here, we characterized a set of 292 diverse maize inbreds of both indigenous and exotic origin by exploiting functional polymorphism of the dgat1-2, fatb, ge2, and wri1a genes governing kernel oil in maize. Genotyping using gene-based functional markers revealed a lower frequencies of dgat1-2 (0.15) and fatb (0.12) mutant alleles and a higher frequencies of wild-type alleles (Dgat1-2: 0.85; fatB: 0.88). The favorable wri1a allele was conserved across genotypes, while its wild-type allele (WRI1a) was not detected. In contrast, none of the genotypes possessed the ge2 favorable allele. The frequency of favorable alleles of both dgat1-2 and fatb decreased to 0.03 when considered together. Furthermore, pairwise protein-protein interactions among target gene products were conducted to understand the effect of one protein on another and their responses to kernel oil through functional enrichments. Thus, the identified maize genotypes with dgat1-2, fatb, and wri1a favourable alleles, along with insights gained through the protein-protein association network, serve as prominent and unique genetic resources for high-oil maize breeding programs. This is the first comprehensive report on the functional characterization of diverse genotypes at the molecular and protein levels.

Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2.

BACKGROUND: Insulin is tightly associated with cancer progression; however, mechanistic insights into such observations are poorly understood. Recent studies show that metabolic transformation is critical to cancer cell proliferation. Here, we attempt to understand the role of insulin in promotion of cancer metabolism. To this end, the role of insulin in regulating glycolytic enzyme pyruvate kinase M2 (PKM2) was examined. RESULTS: We observed that insulin up-regulated PKM2 expression, through PI3K/mTOR mediated HIF1α induction, but significantly reduced PKM2 activity independent of this pathway. Drop in PKM2 activity was attributed to subunit dissociation leading to formation of low activity PKM2 oligomers, as assessed by density gradient centrifugation. However, tyrosine 105 phosphorylation of PKM2, known for inhibiting PKM2 activity, remained unaffected on insulin treatment. Interestingly, insulin-induced ROS was found responsible for PKM2 activity reduction. The observed changes in PKM2 status led to augmented cancer metabolism. Insulin-induced PKM2 up-regulation resulted in enhanced aerobic glycolysis as confirmed by PKM2 knockdown studies. Further, PKM2 activity reduction led to characteristic pooling of glycolytic intermediates and increased accumulation of NADPH; suggesting diversion of glucose flux towards macromolecular synthesis, necessary for cancer cell growth. CONCLUSION: The study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin's role in cancer.

Integrative multiomics and weighted network approach reveals the prognostic role of RPS7 in lung squamous cell carcinoma pathogenesis.

Lung cancer is one of the most commonly occurring malignant cancers with the highest rate of mortality globally. Difference between lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) and their treatment strategies according to genetic markers may be helpful in reducing the cancer progression and increasing the overall survival (OS) in patients. LUSC is known for comparatively less typical onco-drivers, target therapy resistance, marked genomic complexity, and a reasonably higher mutation rate. The mRNA-seq data and clinical information of LUAD and LUSC cohorts from UCSC Xena comprising 437 and 379 patient samples were extracted. Differential expression and weighted network analyses revealed 47 and 18 hub differentially expressed genes (DEGs) corresponding to LUAD and LUSC cohorts. These hub DEGs were further subjected to protein-protein interaction network (PPIN) and OS analyses. Lower mRNA expression levels of both RPS15A and RPS7 worsened the OS of LUSC patients. Additionally, both these prognostic biomarkers were validated via external sources such as UALCAN, cBioPortal, TIMER, and HPA. RPS7 had higher mutation frequency compared to RPS15A and showed significant negative correlations with infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, and macrophages. Our findings provided novel insights into biomarker discovery and the critical role of ribosomal biogenesis especially smaller ribosomal subunit in pathogenesis of LUSC.

Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.

Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies.

Brønsted acid catalyzed mechanochemical domino multicomponent reactions by employing liquid assisted grindstone chemistry.

Here, we have demonstrated a metal-free energy-efficient mechanochemical approach for expedient access to a diverse set of 2-amino-3-cyano-aryl/heteroaryl-4H-chromenes, tetrahydrospiro[chromene-3,4'-indoline], 2,2'-aryl/heteroarylmethylene-bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) as well as tetrahydro-1H-xanthen-1-one by employing the reactivity of 5,5-dimethylcyclohexane-1,3-dione/cyclohexane-1,3-dione with TsOH⋅H2O as Brønsted acid catalyst under water-assisted grinding conditions at ambient temperature. The ability to accomplish multiple C-C, C=C, C-O, and C-N bonds from readily available starting materials via a domino multicomponent strategy in the absence of metal-catalyst as well as volatile organic solvents with an immediate reduction in the cost of the transformation without necessitates complex operational procedures, features the significant highlights of this approach. The excellent yield of the products, broad functional group tolerances, easy set-up, column-free, scalable synthesis with ultralow catalyst loading, short reaction time, waste-free, ligand-free, and toxic-free, are other notable advantages of this approach. The greenness and sustainability of the protocol were also established by demonstrating several green metrics parameters.

Investigating the link between miR-34a-5p and TLR6 signaling in sepsis-induced ARDS.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are lung complications diagnosed by impaired gaseous exchanges leading to mortality. From the diverse etiologies, sepsis is a prominent contributor to ALI/ARDS. In the present study, we retrieved sepsis-induced ARDS mRNA expression profile and identified 883 differentially expressed genes (DEGs). Next, we established an ARDS-specific weighted gene co-expression network (WGCN) and picked the blue module as our hub module based on highly correlated network properties. Later we subjected all hub module DEGs to form an ARDS-specific 3-node feed-forward loop (FFL) whose highest-order subnetwork motif revealed one TF (STAT6), one miRNA (miR-34a-5p), and one mRNA (TLR6). Thereafter, we screened a natural product library and identified three lead molecules that showed promising binding affinity against TLR6. We then performed molecular dynamics simulations to evaluate the stability and binding free energy of the TLR6-lead molecule complexes. Our results suggest these lead molecules may be potential therapeutic candidates for treating sepsis-induced ALI/ARDS. In-silico studies on clinical datasets for sepsis-induced ARDS indicate a possible positive interaction between miR-34a and TLR6 and an antagonizing effect on STAT6 to promote inflammation. Also, the translational study on septic mice lungs by IHC staining reveals a hike in the expression of TLR6. We report here that miR-34a actively augments the effect of sepsis on lung epithelial cell apoptosis. This study suggests that miR-34a promotes TLR6 to heighten inflammation in sepsis-induced ALI/ARDS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03700-1.

Direct Michael addition/decarboxylation reaction catalyzed by a composite of copper ferrite nanoparticles immobilized on microcrystalline cellulose: an eco-friendly approach for constructing 3,4-dihydrocoumarin frameworks.

A composite of copper ferrite oxide nanoparticles immobilized on microcrystalline cellulose (CuFe2O4@MCC) was synthesized. The synthesized composite was characterized by FESEM with EDS-Mapping, TEM, P-XRD, TEM, and BET analysis and investigated for its catalytic activity toward Tandem Michael addition and decarboxylation of coumarin-3-carboxylic acid with cyclic 1,3-diketones to obtain novel 3,4-dihydrocoumarin derivatives. This protocol was established with wide substrate scope and significant yield. The significant characteristics of this methodology are mild reaction conditions, easy setup procedure, non-toxic, and cost-effectiveness. A gram-scale synthesis with low catalyst loading was also demonstrated.