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The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is activated constitutively in a wide array of human cancers. It is an appealing molecular target for novel therapy as it directly regulates expression of genes involved in cell proliferation, survival, angiogenesis, chemoresistance and immune responsiveness. In addition to these well-established oncogenic roles, STAT3 has also been found to mediate a wide array of functions in modulating cellular behavior. The transcriptional function of STAT3 is canonically regulated through tyrosine phosphorylation. However, STAT3 phosphorylated at a single serine residue can allow incorporation of this protein into the inner mitochondrial membrane to support oxidative phosphorylation (OXPHOS) and maximize the utility of glucose sources. Conflictingly, its canonical transcriptional activity suppresses OXPHOS and favors aerobic glycolysis to promote oncogenic behavior. Apart from mediating the energy metabolism and controversial effects on ATP production, STAT3 signaling modulates lipid metabolism of cancer cells. By mediating fatty acid synthesis and beta oxidation, STAT3 promotes employment of available resources and supports survival in the conditions of metabolic stress. Thus, the functions of STAT3 extend beyond regulation of oncogenic genes expression to pleiotropic effects on a spectrum of essential cellular processes. In this review, we dissect the current knowledge on activity and mechanisms of STAT3 involvement in transcriptional regulation, mitochondrial function, energy production and lipid metabolism of malignant cells, and its implications to cancer pathogenesis and therapy.

COVID-19 is the cause of a pandemic associated with substantial morbidity and mortality. As yet, there is no available approved drug to eradicate the virus. In this review article, we present an alternative study area that may contribute to the development of therapeutic targets for COVID-19. Growing evidence is revealing further pathophysiological mechanisms of COVID-19 related to the disregulation of inflammation pathways that seem to play a critical role toward COVID-19 complications. The NF-kB and JAK/STAT signaling pathways are highly activated in acute inflammation, and the excessive activity of these pathways in COVID-19 patients likely exacerbates the inflammatory responses of the host. A group of non-coding RNAs (miRNAs) manage certain features of the inflammatory process. In this study, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of COVID-19 disease. Furthermore, previous studies published in the online databases, namely web of science, MEDLINE (PubMed), and Scopus, were reviewed for the potential role of miRNAs in the inflammatory manifestations of COVID-19. Moreover, we disclosed the interactions of inflammatory genes using STRING DB and designed interactions between miRNAs and target genes using Cityscape software. Several miRNAs, particularly miR-9, miR-98, miR-223, and miR-214, play crucial roles in the regulation of NF-kB and JAK-STAT signaling pathways as inflammatory regulators. Therefore, this group of miRNAs that mitigate inflammatory pathways can be further regarded as potential targets for far-reaching-therapeutic strategies in COVID-19 diseases.

SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease.

Objective Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. Methods Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. Results Inguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = −0.413, p, Graphical abstract Image 1, Highlights • OSM is regulated under obesity and negatively correlates with UCP1 in WAT. • OSM suppresses isoproterenol-induced UCP1 in subcutaneous adipocytes. • OSM signals through the gp130-STAT3 pathway to lower UCP1 expression. • Obese mice lacking gp130 in adipocytes exhibit increased WAT browning.

Interleukin-6 (IL-6) is a cytokine implicated in proinflammatory as well as regenerative processes and acts via receptor complexes consisting of the ubiquitously expressed, signal-transducing receptor gp130 and the IL-6 receptor (IL-6R). The IL-6R is expressed only on hepatocytes and subsets of leukocytes, where it mediates specificity of the receptor complex to IL-6 as the subunit gp130 is shared with all other members of the IL-6 cytokine family such as IL-11 or IL-27. The amount of IL-6R at the cell surface thus determines the responsiveness of the cell to the cytokine and might therefore be decisive in the development of inflammatory disorders. However, how the expression levels of IL-6R and gp130 at the cell surface are controlled is largely unknown. Here, we show that IL-6R and gp130 are constitutively internalized independent of IL-6. This process depends on dynamin and clathrin and is temporally controlled by motifs within the intracellular region of gp130 and IL-6R. IL-6 binding and internalization of the receptors is a prerequisite for activation of the Jak/STAT signaling cascade. Targeting of gp130, but not of the IL-6R, to the lysosome for degradation depends on stimulation with IL-6. Furthermore, we show that after internalization and activation of signaling, both the IL-6R and gp130 are recycled back to the cell surface, a process that is enhanced by IL-6. These data reveal an important function of IL-6 beyond the pure activation of signaling.

Phosphorylation of STAT3 (signal transducer and activator of transcription 3) is critical for its nuclear import and transcriptional activity. Although a shorter STAT3β spliceform was initially described as a negative regulator of STAT3α, gene knockout studies have revealed that both forms play critical roles. We have expressed STAT3α and STAT3β at comparable levels to facilitate a direct comparison of their functional effects, and have shown their different cytokine-stimulated kinetics of phosphorylation and nuclear translocation. Notably, the sustained nuclear translocation and phosphorylation of STAT3β following cytokine exposure contrasted with a transient nuclear translocation and phosphorylation of STAT3α. Importantly, co-expression of the spliceforms revealed that STAT3β enhanced and prolonged the phosphorylation and nuclear retention of STAT3α, but a STAT3β R609L mutant, with a disrupted SH2 (Src homology 2) domain, was not tyrosine phosphorylated following cytokine stimulation and could not cross-regulate STAT3α. The physiological importance of prolonged phosphorylation and nuclear retention was indicated by transcriptome profiling of STAT3−/− cells expressing either STAT3α or STAT3β, revealing the complexity of genes that are up- and down-regulated by the STAT3 spliceforms, including a distinct set of STAT3β-specific genes regulated under basal conditions and after cytokine stimulation. These results highlight STAT3β as a significant transcriptional regulator in its own right, with additional actions to cross-regulate STAT3α phosphorylation and nuclear retention after cytokine stimulation.

Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to contribute to development of inflammatory bowel diseases (IBD). The single nucleotide polymorphism rs2228145 in IL6R associates with increased levels of soluble IL6R (s-IL6R), as well as reduced IL6R signaling and risk of inflammatory disorders; its effects are similar to those of a therapeutic monoclonal antibody that blocks IL6R signaling. We used the effect of rs2228145 on s-IL6R level as an indirect marker to investigate whether reduced IL6R signaling associates with risk of ulcerative colitis (UC) or Crohn’s disease (CD). In a genome-wide meta-analysis of 20,550 patients with CD, 17,647 patients with UC, and more than 40,000 individuals without IBD (controls), we found that rs2228145 (scaled to a 2-fold increase in s-IL6R) was associated with reduced risk of CD (odds ratio 0.876; 95% confidence interval 0.822–0.933; P = .00003) or UC (odds ratio 0.932; 95% confidence interval 0.875–0.996; P = .036). These findings indicate that therapeutics designed to block IL6R signaling might be effective in treatment of IBD.