Exploring the role of miR-200 family in regulating CX3CR1 and CXCR1 in lung adenocarcinoma tumor microenvironment: implications for therapeutic intervention.

Lung adenocarcinoma (LUAD) is the most common malignant subtype of lung cancer (LC). miR-200 family is one of the prime miR regulators of epithelial-mesenchymal transition (EMT) and worst overall survival (OS) in LC patients. The study aimed to identify and validate the key differentially expressed immune-related genes (DEIRGs) regulated by miR-200 family which may serve for therapeutic aspects in LUAD tumor microenvironment (TME) by affecting cancer progression, invasion, and metastasis. The study identified differentially expressed miRNAs (DEMs) in LUAD, consisting of hsa-miR-200a-3p and hsa-miR-141-5p, respectively. Two highest-degree subnetwork motifs identified from 3-node miRNA FFL were: (i) miR-200a-3p-CX3CR1-SPIB and (ii) miR-141-5p-CXCR1-TBX21. TIMER analysis showed that the expression levels of CX3CR1 and CXCR1 were significantly positively correlated with infiltrating levels of M0-M2 macrophages and natural killer T (NKT) cells. The OS of LUAD patients was significantly affected by lower expression levels of hsa-miR-200a-3p, CX3CR1 and SPIB. These DEIRGs were validated using the human protein atlas (HPA) web server. Further, we validated the regulatory role of hsa-miR-200a-3p in an in-vitro indirect co-culture model using conditioned media from M0, M1 and M2 polarized macrophages (THP-1) and LUAD cell lines (A549 and H1299 cells). The results pointed out the essential role of hsa-miR-200a-3p regulated CX3CL1 and CX3CR1 expression in progression of LC TME. Thus, the study augments a comprehensive understanding and new strategies for LUAD treatment where miR-200 family regulated immune-related genes, especially chemokine receptors, which regulate the metastasis and invasion of LUAD, leading to the worst associated OS.

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.

Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-ß signaling molecules.

Cyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP (in vitro), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection (in vivo). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study's outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1ß (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the in vivo study when treated with NERO 400 and compared with CP 200. In Vitro study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-ß-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-ß1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson's' trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide.

Comprehensive multiomics and in silico approach uncovers prognostic, immunological, and therapeutic roles of ANLN in lung adenocarcinoma.

The anillin actin-binding protein (ANLN) is immensely overexpressed in cancers, including lung cancer (LC). Phytocompounds have gained interest due to their broader potential and reduced unwanted effects. Screening numerous compounds presents a challenge, but in silico molecular docking is pragmatic. The present study aims to identify the role of ANLN in lung adenocarcinoma (LUAD), along with identification and interaction analysis of anticancer and ANLN inhibitory phytocompounds followed by molecular dynamics (MD) simulation. Using a systematic approach, we found that ANLN is significantly overexpressed in LUAD and mutated with a frequency of 3.73%. It is linked with advanced stages, clinicopathological parameters, worsening of relapse-free survival (RFS), and overall survival (OS), pinpointing its oncogenic and prognostic potential. High-throughput screening and molecular docking of phytocompounds revealed that kaempferol (flavonoid aglycone) interacts strongly with the active site of ANLN protein via hydrogen bonds, Vander Waals interactions, and acts as a potent inhibitor. Furthermore, we discovered that ANLN expression was found to be significantly higher (p) in LC cells compared to normal cells. This is a propitious and first study to demonstrate ANLN and kaempferol interactions, which might eventually lead to removal of rout from cell cycle regulation posed by ANLN overexpression and allow it to resume normal processes of proliferation. Overall, this approach suggested a plausible biomarker role of ANLN and the combination of molecular docking subsequently led to the identification of contemporary phytocompounds, bearing symbolic anticancer effects. The findings would be advantageous for pharmaceutics but require validation using in vitro and in vivo methods. HIGHLIGHTS: • ANLN is significantly overexpressed in LUAD. • ANLN is implicated in the infiltration of TAMs and altering plasticity of TME. • Kaempferol (potential ANLN inhibitor) shows important interactions with ANLN which could remove the alterations in cell cycle regulation, imposed by ANLN overexpression eventually leading to normal process of cell proliferation.

Unravelling hub genes as potential therapeutic targets in lung cancer using integrated transcriptomic meta-analysis and in silico approach.

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Smoking has been identified as the main contributing cause of the disease's development. The study aimed to identify the key genes in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the two major types of LC. Meta-analysis was performed with two datasets GSE74706 and GSE149507 obtained from Gene Expression Omnibus (GEO). Both the datasets comprised samples from cancerous and adjacent non-cancerous tissues. Initially, 633 differentially expressed genes (DEGs) were identified. To understand the underlying molecular mechanism of the identified genes, pathway enrichment, gene ontology (GO) and protein-protein interaction (PPI) analyses were done. A total of 9 hub genes were identified which were subjected to mutation study analysis in LC patients using cBioPortal. These  9 genes (i.e. AURKA, AURKB, KIF23, RACGAP1, KIF2C, KIF20A, CENPE, TPX2 and PRC1) have shown overexpression in LC patients and can be explored as potential candidates for prognostic biomarkers. TPX2 reported a maximum mutation of 4%. This was followed with high throughput screening and docking analysis to identify the potential drug candidates following competitive inhibition of the AURKA-TPX2 complex. Four compounds, CHEMBL431482, CHEMBL2263042, CHEMBL2385714, and CHEMBL1206617 were identified. The results signify that the selected 9 genes can be explored as biomarkers in disease prognosis and targeted therapy. Also, the identified 4 compounds can be further analyzed as promising therapeutic candidates.Communicated by Ramaswamy H. Sarma.

miR-495-3p regulates sphingolipid metabolic reprogramming to induce Sphk1/ceramide mediated mitophagy and apoptosis in NSCLC.

Sphingolipid metabolism is the forefront area of cancer research, but the underlying mechanisms are not fully explored yet. Sphingolipid metabolites [ceramide, sphingosine-1-phosphate (S1P)] are critical players in cell growth and apoptosis. Sphk1 is a key enzyme, catalyzing the phosphorylation of sphingosine to S1P, favoring cell proliferation and survival. Contrarily, ceramide induces cell cycle arrest and apoptosis. Sphk1 also exerts regulatory roles in numerous cellular processes, wherein microRNAs (miRNAs) play a momentous role. However, miR-mediated regulation of Sphk1 in Non-small cell lung cancer (NSCLC), continues to be elusive. miR-495 is highly downregulated and worsens NSCLC prognosis. The present study demonstrates Sphk1 upregulation and poor prognosis in NSCLC. However, miR-495-3p directly targets Sphk1, and possesses tumor-suppressive roles by decreasing cell proliferation, wound healing, colony formation, LDH-A activity, and inducing G0/G1 phase cell cycle arrest upon restoration. Besides, we also found ceramide accretion upon Sphk1 inhibition, leading to mitochondrial dysregulation. We found a cogent upregulation of Drp-1, PARK2 and LC3ß, along with degradation of PINK1 and Mfn2, demonstrating an imbalance in mitochondrial fission/fusion and induction of mitophagy, even during PINK1 deficiency. Later, we found a reduction in mitochondrial energy homeostasis, mitochondrial membrane potential, increased ROS generation and ultimately initiation of apoptosis, upon miR-495-3p overexpression. Overall, we showed that miR-495-3p reprograms sphingolipid rheostat towards ceramide by targeting Sphk1 and induces lethal mitophagy to suppress NSCLC tumorigenesis. The study identified a miR-mediated mechanism of sphingolipid reprogramming that could be beneficial in designing novel therapeutic strategies for NSCLC.

miR-16-5p regulates aerobic glycolysis and tumorigenesis of NSCLC cells via LDH-A/lactate/NF-κB signaling.

BACKGROUND AND AIM: Cancer cells exhibit Warburg effect, characterized by increased glycolysis followed by fermentative conversion of pyruvate to lactate. Upregulation of Lactate Dehydrogenase-A (LDH-A) is elucidated to be a dominant molecular mediator of the phenomenon. Also, microRNA (miRNA) dysregulation participates in malignant progression and dissemination in several cancers. miR-16-5p is considerably reduced in lung cancers (LC), suggesting its tumor-suppressive role. However, its role in the regulation of aerobic glycolysis remains unknown. Our study aims to identify the regulatory roles of miR-16-5p/LDH-A in Non-small cell lung cancer (NSCLC). MAIN METHODS: We evaluated the differential expression of LDH-A and its prognostic potential in NSCLC tissues using online databases. We performed Tissue analysis using Immunohistochemistry (IHC); In-vitro cellular analysis including transient transfection, cellular proliferation, migration, and colony forming analysis. We also performed cell survival, metabolic, cell cycle, apoptotic, ROS generation and Immunocytochemistry (ICC) analyses to identify the role of miR-16-5p/LDH-A in aerobic glycolysis and tumorigenesis of NSCLC. KEY FINDINGS: We have identified that miR-16-5p directly targets LDH-A by binding to the complementary binding regions present in its 3'-UTR region, leading to degradation, sequentially leading to reduced lactate accumulation, glucose uptake and ATP levels. Our study also demonstrated the role of lactate accumulation in promoting NSCLC tumorigenesis via activation of NF-κB signaling pathway. However, miR-16-5p mediated targeting of LDH-A downregulates the expression of NF-κB associated genes, along with increased ROS generation, apoptosis, and cell cycle arrest. SIGNIFICANCE: In conclusion, our findings identify miR-16-5p/LDH-A/lactate/NF-κB as an important link between metabolism and NSCLC cells tumorigenesis.

Integration of chemokine signaling with non-coding RNAs in tumor microenvironment and heterogeneity in different cancers.

Chemokines are small secreted proteins that regulate the immune system by signaling through chemokine receptors to induce immune cell migration, motility, and infiltration into the tissue. Altered chemokine/receptor expression is associated with numerous inflammatory diseases, and more recently in non-immune cell diseases like cancer. Emerging new studies demonstrate that chemokines can directly modulate the tumor microenvironment (TME) to assist tumorigenesis by regulating proinflammatory signaling, immune cell infiltration,and metastasis. However, the diversity and complexity in the regulation of chemokine expression and how chemokine receptor signaling influences TME needs comprehensive understanding. One mechanistic pathway that has shown promising early results in targeting tumor progression is the non-coding RNAs (ncRNAs). These are widely expressed and designated as prime gene regulatory factors in tumors and the immune system. Notably, ncRNAs have been implicated in regulating chromatin stability, translation of cytoplasmic mRNAs, and the functional regulation of membrane-less nuclear bodies, which are significant pathways implicated in tumorigenesis. Tissue-specific patterns of expression of ncRNAs have suggested their role as potential cancer biomarkers, providing a suitable rationale for targeting them clinically. In this review, we discuss the recent findings which demonstrate the role of differential expression of chemokines and ncRNA in modulating TME during tumor progression. We also discuss the communication between tumor and immune effector cells via chemokine/ncRNAs and identify their potential as novel therapeutic targets.

Carbonic anhydrase IX: A tumor acidification switch in heterogeneity and chemokine regulation.

The primary physiological process of respiration produces carbon dioxide (CO2) that reacts with water molecules which subsequently liberates bicarbonate (HCO-3) and protons. Carbonic anhydrases (CAs) are the primary catalyst involved in this conversion. More than 16 isoforms of human CAs show organ or subcellular specific activity. Dysregulation of each CA is associated with multiple pathologies. Out of these members, the overexpression of membrane-bound carbonic anhydrase IX (CAIX) is associated explicitly with hypoxic tumors or various solid cancers. CAIX helps tumors deal with higher CO2 by sequestering it with bicarbonate ions and helping cancer cells to grow in a comparatively hypoxic or acidic environment, thus acting as a pH adaptation switch. CAIX-mediated adaptations in cancer cells include angiogenesis, metabolic alterations, tumor heterogeneity, drug resistance, and regulation of cancer-specific chemokines. This review comprehensively collects and describe the cancer-specific expression mechanism and role of CAIX in cancer growth, progression, heterogeneity, and its structural insight to develop future combinatorial targeted cancer therapies.

Integrative multiomics and in silico analysis revealed the role of ARHGEF1 and its screened antagonist in mild and severe COVID-19 patients.

COVID-19 is a sneaking deadly disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid increase in the number of infected patients worldwide enhances the exigency for medicines. However, precise therapeutic drugs are not available for COVID-19; thus, exhaustive research is critically required to unscramble the pathogenic tools and probable therapeutic targets for the development of effective therapy. This study utilizes a chemogenomics strategy, including computational tools for the identification of viral-associated differentially expressed genes (DEGs), and molecular docking of potential chemical compounds available in antiviral, anticancer, and natural product-based libraries against these DEGs. We scrutinized the messenger RNA expression profile of SARS-CoV-2 patients, publicly available on the National Center for Biotechnology Information-Gene Expression Omnibus database, stratified them into different groups based on the severity of infection, superseded by identification of overlapping mild and severe infectious (MSI)-DEGs. The profoundly expressed MSI-DEGs were then subjected to trait-linked weighted co-expression network construction and hub module detection. The hub module MSI-DEGs were then exposed to enrichment (gene ontology + pathway) and protein-protein interaction network analyses where Rho guanine nucleotide exchange factor 1 (ARHGEF1) gene conjectured in all groups and could be a probable target of therapy. Finally, we used the molecular docking and molecular dynamics method to identify inherent hits against the ARHGEF1 gene from antiviral, anticancer, and natural product-based libraries. Although the study has an identified significant association of the ARHGEF1 gene in COVID19; and probable compounds targeting it, using in silico methods, these targets need to be validated by both in vitro and in vivo methods to effectively determine their therapeutic efficacy against the devastating virus.

Deciphering Key Genes and miRNAs Associated With Hepatocellular Carcinoma via Network-Based Approach.

Hepatocellular carcinoma (HCC)is a common type of liver cancer and has a high mortality world-widely. The diagnosis, prognoses, and therapeutics are very poor due to the unclear molecular mechanism of progression of the disease. To unveil the molecular mechanism of progression of HCC, we extract a large sample of mRNA expression levels from the GEO database where a total of 167 samples were used for study, and out of them, 115 samples were from HCC tumor tissue. This study aims to investigate the module of differentially expressed genes (DEGs)which are co-expressed only in HCC sample data but not in normal tissue samples. Thereafter, we identified the highly significant module of significant co-expressed genes and formed a PPI network for these genes. There were only six genes (namely, MSH3, DMC1, ALPP, IL10, ZNF223, and HSD17B7)obtained after analysis of the PPI network. Out of six only MSH3, DMC1, HSD17B7, and IL10 were found enriched in GO Term & Pathway enrichment analysis and these candidate genes were mainly involved in cellular process, metabolic and catalytic activity, which promote the development & progression of HCC. Lastly, the composite 3-node FFL reveals the driver miRNAs and TFs associated with our key genes.

Long non-coding RNAs regulated NF-κB signaling in cancer metastasis: Micromanaging by not so small non-coding RNAs.

Cancer metastasis is a major reason for the cancer-associated deaths and a role of long non-coding RNAs (lncRNAs) in cancer metastasis is increasingly being realized. Among the many oncogenic pathways, NF-κB signalling's involvement in cancer metastasis as a key inflammation-regulatory transcription factor has been a subject of interest for long time. Accumulating data from in vitro as well as in vivo studies along with analysis of clinical cancer tissues points to regulation of NF-κB signalling by lncRNAs with implications toward the onset of cancer metastasis. LncRNAs FOXD2-AS1, KRT19P3 and the NF-κB interacting lncRNA (NKILA) associate with lymph node metastasis and poor prognosis of individual cancers. The role of epithelial-mesenchymal transition (EMT) in cancer metastasis is well known. EMT is regulated by NF-κB and regulation of NF-κB/EMT-induced metastasis by lncRNAs remains a hot topic of research with indications for such roles of lncRNAs MALAT1, SNHG15, CRNDE and AC007271.3. Among the many lncRNAs, NKILA stands out as the most investigated lncRNA for its regulation of NF-κB. This tumor suppressive lncRNA has been reported downregulated in clinical samples representing different human cancers. Mechanistically, NKILA has been consistently shown to inhibit NF-κB activation via inhibition of IκBα phosphorylation and the resulting suppression of EMT. NKILA is also a target of natural anticancer compounds. Given the importance of NF-κB as a master regulatory transcription factor, lncRNAs, as the modulators of NF-κB signaling, can provide alternate targets for metastatic cancers with constitutively active NF-κB.

Natural Bioactive as a Potential Therapeutic Approach for the Management of Cyclophosphamide-induced Cardiotoxicity.

Cyclophosphamide (CP) is an extensively used anticancer drug, but its cardiotoxic manifestation is a major concern for its widespread clinical use. The observed cardiotoxic attributes have been reported at the therapeutic dose and often result into a high mortality rate and poor clinical outcome. Fall in the level of antioxidant enzymes catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD) generation of reactive oxygen species (ROS), inflammatory cytokines nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL- 1ß), apoptotic proteins (caspases) and direct damage to myocardial tissue (histological and ultrastructural damage) are some of the reported manifestations of cardiotoxicity. The observed clinical attributes of CP-induced cardiotoxicity are myocarditis, hemorrhage, thrombosis, myocardial infarction (MI), reduced ejection fraction, altered electrocardiogram (ECG) reading and heart failure. However, unlike Daxarazasone (an adjuvant to reduce doxorubicin-induced cardiotoxicity), no approved adjuvant is available to mitigate CPinduced cardiotoxicity. Thus, various natural bioactives have been explored for the possible cardioprotective effect against CP-induced cardiotoxicity. In the current manuscript, we have discussed the clinical and preclinical aspects of CP-induced cardiotoxicity, its clinically used combination with other anticancer drugs, and the available therapeutic regimen to mitigate this cardiotoxicity. Further, we discussed the limitations of available synthetic drugs used as an adjuvant and discussed various natural bioactive and their experimental details. This manuscript's overall goal is to throw light on CP-induced cardiotoxicity and summarize all the experimental data so that researchers working in this field may scientifically get up-to-date information in one place.

Mitochondrial dynamics and mitophagy in lung disorders.

Mitochondria are biosynthetic, bioenergetic, and signaling organelles which are critical for physiological adaptations and cellular stress responses to the environment. Various endogenous and environmental stress affects critical processes in mitochondrial homeostasis such as oxidative phosphorylation, biogenesis, mitochondrial redox system which leads to the formation of reactive oxygen species (ROS) and free radicals. The state of function of the mitochondrion is particularly dependent on the dynamic balance between mitochondrial biogenesis, fusion and fission, and degradation of damaged mitochondria by mitophagy. Increasing evidence has suggested a prominent role of mitochondrial dysfunction in the onset and progression of various lung pathologies, ranging from acute to chronic disorders. In this comprehensive review, we discuss the emerging findings of multifaceted regulations of mitochondrial dynamics and mitophagy in normal lung homeostasis as well as the prominence of mitochondrial dysfunction as a determining factor in different lung disorders such as lung cancer, COPD, IPF, ALI/ARDS, BPD, and asthma. The review will contribute to the existing understanding of critical molecular machinery regulating mitochondrial dynamic state during these pathological states. Furthermore, we have also highlighted various molecular checkpoints involved in mitochondrial dynamics, which may serve as hopeful therapeutic targets for the development of potential therapies for these lung disorders.

Comprehensive Integrative Analysis Reveals the Association of KLF4 with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment.

Macrophage polarization and infiltration to the tumor microenvironment (TME) is a critical determining factor for tumor progression. Macrophages are polarized into two states-M1 (pro-inflammatory, anti-tumorigenic and stimulated by LPS or IFN-γ) and M2 (anti-inflammatory pro-tumorigenic and stimulated by IL-4) phenotypes. Specifically, M2 macrophages enhance tumor cell growth and survival. Recent evidences suggest the pivotal role of microRNAs in macrophage polarization during the development of Non-small cell lung cancer (NSCLC), thus proposing a new therapeutic option to target lung cancer. In silico analysis determined cogent upregulation of KLF4, downregulation of IL-1ß and miR-34a-5p in NSCLC tissues, consequently worsening the overall survival of NSCLC patients. We observed a significant association of KLF4 with macrophage infiltration and polarization in NSCLC. We found that KLF4 is critically implicated in M2 polarization of macrophages, which, in turn, promotes tumorigenesis. KLF4 expression correlated with miR-34a-5p and IL-1ß in a feed-forward loop (FFL), both of which are implicated in immune regulation. Mechanistic overexpression of miR-34a-5p in macrophages (IL-4 stimulated) inhibits KLF4, along with downregulation of ARG1, REL-1MB (M2 macrophage specific markers), and upregulation of IL-1ß, IL-6, (M1 macrophage specific markers), demonstrating macrophage polarization switch from M2 to M1 phenotype. Moreover, co-culture of these macrophages with NSCLC cells reduces their proliferation, wound healing, clonogenic capacity and enhanced NO-mediated apoptosis. Further, transfection of miR-34a-5p in NSCLC cells, also degrades KLF4, but enhances the expression of KLF4 regulated genes-IL-1ß, IL-6 (pro-inflammatory mediators), which is further enhanced upon co-culture with IL-4 stimulated macrophages. Additionally, we observed a significant increase in i-NOS/NO content upon co-culture, suggesting polarization reversion of macrophages from M2 to M1, and eventually leading to anti-tumor effects. Our findings thus show a significant role of KLF4 in tumorigenesis and TAM polarization of NSCLC. However, miR-34a-5p mediated targeting of these molecular networks will provide a better therapeutic intervention for NSCLC.

Long non-coding RNA: An immune cells perspective.

Long non-coding RNAs (lncRNAs) were considered as accumulated genetic waste until they were found to be gene expression regulators by highly sensitive modern genomics platforms. It is a huge class of non-coding transcripts with an arbitrary length of >200 nucleotides, which has gained much attention in the past few years. Increasing evidence from several experimental studies unraveled the expression of lncRNA linked to immune response and disease progression. However, only a small number of lncRNAs have robust evidence of their function. Differential expression of lncRNAs in different immune cells is also evident. In this review, we focused on how lncRNAs expression assist in shaping immune cells (Macrophages, Dendritic cells, NK cells, T cells, B cells, eosinophils, neutrophils, and microglial cells) function and their response to the diseased conditions. Emerging evidence revealed lncRNAs may serve as key regulators in the innate and adaptive immune response system. So, the molecular mechanism insight into the function of lncRNAs in immune response may contribute to the development of potential therapeutic targets for various disease treatments. Therefore, it is imperative to explore the expression of lncRNAs and understand its relevance associated with the immune system.

Vitamin D and its therapeutic relevance in pulmonary diseases.

Vitamin D is customarily involved in maintaining bone and calcium homeostasis. However, contemporary studies have identified the implication of vitamin D in several cellular processes including cellular proliferation, differentiation, wound healing, repair and regulatory systems inclusive of host defence, immunity, and inflammation. Multiple studies have indicated corelations between low serum levels of vitamin D, perturbed pulmonary functions and enhanced incidences of inflammatory diseases. Almost all of the pulmonary diseases including acute lung injury, cystic fibrosis, asthma, COPD, Pneumonia and Tuberculosis, all are inflammatory in nature. Studies have displayed strong inter-relations with vitamin D deficiency and progression of lung disorders; however, the underlying mechanism is still unknown. Vitamin D has emerged to possess inhibiting effects on pulmonary inflammation while exaggerating innate immune defenses by strongly influencing functions of inflammatory cells including dendritic cells, monocyte/macrophages, T cells, and B cells along with structural epithelial cells. This review dissects the effects of vitamin D on the inflammatory cells and their therapeutic relevance in pulmonary diseases. Although, the data obtained is very limited and needs further corroboration but presents an exciting area of further research. This is because of its ease of supplementation and development of personalized medicine which could lead us to an effective adjunct and cost-effective method of therapeutic modality for highly fatal pulmonary diseases.

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer.

BACKGROUND: Curcumin, an active compound of turmeric spice, is one of the most-studied natural compounds and has been widely recognized as a chemopreventive agent. Several molecular mechanisms have proven that curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as in the inhibition of the carcinogenesis process. OBJECTIVE: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. METHODS: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed Central, and Google scholar for the implication of curcumin in cancer management, along with a special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com, and www.freshpatents.com. RESULT: Recent studies based on cancer cells have proven that curcumin has potential effects against cancer cells as it prevents the growth of cancer and acts as a cancer therapeutic agent. Besides, curcumin exerted anti-cancer effects by inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion, and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. CONCLUSION: Accumulating evidences suggest that curcumin has the potential to inhibit cancer growth, induce apoptosis, and modulate various cell signaling pathway molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy, and safe dose in the management of various cancers.

Identification and Validation of Potential miRNAs, as Biomarkers for Sepsis and Associated Lung Injury: A Network-Based Approach.

Sepsis is a dysregulated immune response disease affecting millions worldwide. Delayed diagnosis, poor prognosis, and disease heterogeneity make its treatment ineffective. miRNAs are imposingly involved in personalized medicine such as therapeutics, due to their high sensitivity and accuracy. Our study aimed to reveal the biomarkers that may be involved in the dysregulated immune response in sepsis and lung injury using a computational approach and in vivo validation studies. A sepsis miRNA Gene Expression Omnibus (GEO) dataset based on the former analysis of blood samples was used to identify differentially expressed miRNAs (DEMs) and associated hub genes. Sepsis-associated genes from the Comparative Toxicogenomics Database (CTD) that overlapped with identified DEM targets were utilized for network construction. In total, 317 genes were found to be regulated by 10 DEMs (three upregulated, namely miR-4634, miR-4638-5p, and miR-4769-5p, and seven downregulated, namely miR-4299, miR-451a, miR181a-2-3p, miR-16-5p, miR-5704, miR-144-3p, and miR-1290). Overall hub genes (HIP1, GJC1, MDM4, IL6R, and ERC1) and for miR-16-5p (SYNRG, TNRC6B, and LAMTOR3) were identified based on centrality measures (degree, betweenness, and closeness). In vivo validation of miRNAs in lung tissue showed significantly downregulated expression of miR-16-5p corroborating with our computational findings, whereas expression of miR-181a-2-3p and miR-451a were found to be upregulated in contrast to the computational approach. In conclusion, the differential expression pattern of miRNAs and hub genes reported in this study may help to unravel many unexplored regulatory pathways, leading to the identification of critical molecular targets for increased prognosis, diagnosis, and drug efficacy in sepsis and associated organ injuries.