Innate immunity is mediated by a variety of cell types, including microglia, macrophages, and neutrophils, and serves as the immune system's first line of defense. There are numerous pathways involved in innate immunity, including the interferon (IFN) pathway, TRK pathway, mitogen-activated protein kinase (MAPK) pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, interleukin (IL) pathways, chemokine pathways (CCR5), GSK signaling, and Fas signaling. JAK/STAT is one of these important signaling pathways and this review focused on JAK/STAT signaling pathway only. The overactivation of microglia and astrocytes influences JAK/STAT's role in neuroinflammatory disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and ultimately constraining inflammatory and immunological responses. The JAK/STAT signaling pathway is one of the critical factors that promotes neuroinflammation in neurodegenerative diseases. Given the importance of the JAK/STAT pathway in neurodegenerative disease, this review discussed the feasibility of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative diseases in near future.

Polyphenols as “sensitizers” together with cytotoxic drugs as “inducers” cooperate to trigger apoptosis in various cancer cells. Hence, their combination having similar mode of mechanism may be a novel approach to enhance the efficacy of inducers. Additionally, this will also enable to achieve the physiological concentrations facilitating significant increase in the activity at concentrations which the compound can individually provide. Here we propose that polyphenols (Resveratrol (RES) and Curcumin (CUR)) pre-treatment may sensitize MCF-7/MDA MB-231 (Human Breast Cancer Cells, HBCCs) to Centchroman (CC, antineoplastic agent). 6 h pre-treated cells with 10 µM RES/CUR and 100 µM RES/30 µM CUR doses, followed by 10 µM CC for 18 h were investigated for Ser-167 ER-phosphorylation, cell cycle arrest, redox homeostasis, stress activated protein kinase (SAPKs: JNK and p38 MAPK) pathways and downstream apoptosis effectors. Low dose RES/CUR enhances the CC action through ROS mediated JNK/p38 as well as mitochondrial pathway in MCF-7 cells. However, RES/CUR sensitization enhanced apoptosis in p53 mutant MDA MB-231 cells without/with involvement of ROS mediated JNK/p38 adjunct to Caspase-9. Contrarily, through high dose sensitization in CC treated cells, the parameters remained unaltered as in polyphenols alone. We conclude that differential sensitization of HBCCs with low dose polyphenol augments apoptotic efficacy of CC. This may offer a novel approach to achieve enhanced action of CC with concomitant reduction of side effects enabling improved management of hormone-dependent breast cancer.

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Previously, it has been stated that the BCR-ABL fusion-protein is sufficient to induce Chronic Myeloid Leukemia (CML), but additional genomic-changes are required for disease progression. Hence, we profiled control and tyrosine kinase inhibitors (TKI) alone or in combination with other drug-treated CML-samples in different phases, categorized as drug-sensitive and drug-resistant on the basis of BCR-ABL transcripts, the marker of major molecular-response. Molecular-profiling was done using the molecular-inversion probe-based-array, Human Transcriptomics-Array2.0, and Axiom-Biobank genotyping-arrays. At the transcript-level, clusters of control, TKI-resistant and TKI-sensitive cases were correlated with BCR-ABL transcript-levels. Both at the gene- and exon-levels, up-regulation of MPO, TPX2, and TYMS and down-regulation of STAT6, FOS, TGFBR2, and ITK lead up-regulation of the cell-cycle, DNA-replication, DNA-repair pathways and down-regulation of the immune-system, chemokine- and interleukin-signaling, TCR, TGF beta and MAPK signaling pathways. A comparison between TKI-sensitive and TKI-resistant cases revealed up-regulation of LAPTM4B, HLTF, PIEZO2, CFH, CD109, ANGPT1 in CML-resistant cases, leading to up-regulation of autophagy-, protein-ubiquitination-, stem-cell-, complement-, TGFβ- and homeostasis-pathways with specific involvement of the Tie2 and Basigin signaling-pathway. Dysregulated pathways were accompanied with low CNVs in CP-new and CP-UT-TKI-sensitive-cases with undetectable BCR-ABL-copies. High CNVs (previously reported gain of 9q34) were observed in BCR-ABL-independent and -dependent TKI, non-sensitive-CP-UT/AP-UT/B-UT and B-new samples. Further, genotyping CML-CP-UT cases with BCR-ABL 0-to-77.02%-copies, the identified, rsID239798 and rsID9475077, were associated with FAM83B, a candidate for therapeutic resistance. The presence of BCR-ABL, additional genetic-events, dysregulated-signaling-pathways and rsIDs associated with FAM83B in TKI-resistant-cases can be used to develop a signature-profile that may help in monitoring therapy.

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Highly keratinized oral squamous cell carcinoma (OSCC) exhibits an improved response to treatment and prognosis compared with weakly keratinized OSCC. Therefore, we aimed to develop gene transcript signature and to identify novel full-length isoforms, fusion transcript and non-coding RNA to differentiate welldifferentiated (WD) with Moderately Differentiated (MD)/Poorly Differentiated (PD)/WD-lymphadenopathy OSCC through, HTA, Isoform sequencing, and NanoString. Additionally, specific copy number gain and loss were also identify in WD keratinized OSCC through Oncoscan array and validated through Realtime PCR in histopathologically characterized FFPE-WD keratinized OSCC. Threehundred-thirty-eight (338) differentially expressed full-length (FL) transcript isoforms (317 upregulated and 21 down-regulated in OSCC) were identified through Isoform Sequencing using the PacBio platform. Thirty-four (34) highly upregulated differentially expressed transcripts from IsoSeq data were also correlated with HTA2.0 and validated in 42 OSCC samples. We were able to identify 18 differentially expressed transcripts, 12 fusion transcripts, and two long noncoding RNAs. These transcripts were involved in increased cell proliferation, dysregulated metabolic reprogramming, oxidative stress, and immune system markers with enhanced immune Research Paper Oncotarget 3228 www.oncotarget.com rearrangements, suggesting a cancerous nature. However, an increase in proteasomal activity and hemidesmosome proteins suggested an improved prognosis and tumor cell stability in keratinized OSCC and helped to characterize WD with MD/PD/WD with lymphadenopathy OSCC. Additionally, novel isoforms of IL37, NAA10, UCHL3, SPAG7, and RAB24 were identified while in silico functionally validated SPAG7 represented the premalignant phenotype of keratinized (K4) OSCC. Most importantly we found copy number gain and overexpression of EGFR suggest that TKIs may also be used as therapeutics in WD-OSCCs.

Smoking has been associated with increased risk of periodontitis. The aim of the present study was to compare the periodontal disease severity among smokers and nonsmokers which may help in better understanding of predisposition to this chronic inflammation mediated diseases. We selected deep-seated infected granulation tissue removed during periodontal flap surgery procedures for identification and differential abundance of residential bacterial species among smokers and nonsmokers through long-read sequencing technology targeting full-length 16S rRNA gene. A total of 8 phyla were identified among which Firmicutes and Bacteroidetes were most dominating. Differential abundance analysis of OTUs through PICRUST showed significant (p>0.05) abundance of Phyla-Fusobacteria (Streptobacillus moniliformis); Phyla-Firmicutes (Streptococcus equi), and Phyla Proteobacteria (Enhydrobacter aerosaccus) in nonsmokers compared to smokers. The differential abundance of oral metagenomes in smokers showed significant enrichment of host genes modulating pathways involving primary immunodeficiency, citrate cycle, streptomycin biosynthesis, vitamin B6 metabolism, butanoate metabolism, glycine, serine, and threonine metabolism pathways. While thiamine metabolism, amino acid metabolism, homologous recombination, epithelial cell signaling, aminoacyl-tRNA biosynthesis, phosphonate/phosphinate metabolism, polycyclic aromatic hydrocarbon degradation, synthesis and degradation of ketone bodies, translation factors, Ascorbate and aldarate metabolism, and DNA replication pathways were significantly enriched in nonsmokers, modulation of these pathways in oral cavities due to differential enrichment of metagenomes in smokers may lead to an increased susceptibility to infections and/or higher formation of DNA adducts, which may increase the risk of carcinogenesis.