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BackgroundThe human microbiome may influence prostate cancer initiation and/or progression through both direct and indirect interactions. To date, the majority of studies have focused on direct interactions including the influence of prostate infections on prostate cancer risk and, more recently, on the composition of the urinary microbiome in relation to prostate cancer. Less well understood are indirect interactions of the microbiome with prostate cancer, such as the influence of the gastrointestinal or oral microbiota on pro- or anti-carcinogenic xenobiotic metabolism, and treatment response.MethodsWe review the literature to date on direct and indirect interactions of the microbiome with prostate inflammation and prostate cancer.ResultsEmerging studies indicate that the microbiome can influence prostate inflammation in relation to benign prostate conditions such as prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia, as well as in prostate cancer. We provide evidence that the human microbiome present at multiple anatomic sites (urinary tract, gastrointestinal tract, oral cavity, etc.) may play an important role in prostate health and disease.ConclusionsIn health, the microbiome encourages homeostasis and helps educate the immune system. In dysbiosis, a systemic inflammatory state may be induced, predisposing remote anatomical sites to disease, including cancer. The microbiome’s ability to affect systemic hormone levels may also be important, particularly in a disease such as prostate cancer that is dually affected by estrogen and androgen levels. Due to the complexity of the potential interconnectedness between prostate cancer and the microbiome, it is vital to further explore and understand the relationships that are involved.

P53 is a transcription factor that regulates many signaling pathways like apoptosis, cell cycle, DNA repair, and cellular stress responses. P53 is involved in inflammatory responses through the regulation of inflammatory signaling pathways, induction of cytokines, and matrix metalloproteinase expression. Also, p53 regulates immune responses through modulating Toll-like receptors expression and innate and adaptive immune cell differentiation and maturation. P53 is a modulator of the apoptosis and proliferation processes through regulating multiple anti and pro-apoptotic genes. Rheumatoid arthritis (RA) is categorized as an invasive inflammatory autoimmune disease with irreversible deformity of joints and bone resorption. Different immune and non-immune cells contribute to RA pathogenesis. Fibroblast-like synoviocytes (FLSs) have been recently introduced as a key player in the pathogenesis of RA. These cells in RA synovium produce inflammatory cytokines and matrix metalloproteinases which results in synovitis and joint destruction. Besides, hyper proliferation and apoptosis resistance of FLSs lead to synovial hyperplasia and bone and cartilage destruction. Given the critical role of p53 in inflammation, apoptosis, and cell proliferation, lack of p53 function (due to mutation or low expression) exerts a prominent role for this gene in the pathogenesis of RA. This review focuses on the role of p53 in different mechanisms and cells (specially FLSs) that involved in RA pathogenesis.

Benign prostatic hyperplasia (BPH) is a common issue among older men. Diagnosis of BPH currently relies on imaging tests and assessment of urinary flow rate due to the absence of definitive diagnostic markers. Developing more accurate markers is crucial to improve BPH diagnosis. The BPH dataset utilized in this study was sourced from the Gene Expression Omnibus (GEO). Initially, differential expression and functional analyses were conducted, followed by the application of multiple machine learning techniques to identify key diagnostic markers. Subsequent investigations have focused on elucidating the functions and mechanisms associated with these markers. The ssGSEA method was employed to evaluate immune cell scores in BPH samples, facilitating the exploration of the relationship between key diagnostic markers and immune cells. Additionally, molecular docking was performed to assess the binding affinity of these key markers to therapeutic drugs for BPH. Tissue samples from BPH patients were collected for experimental validation of the expression differences of the aforementioned genes. A total of 185 differential genes were identified, comprising 67 up-regulated and 118 down-regulated genes. These genes are implicated in pathways that regulate extracellular matrix tissue composition and cellular responses to transforming growth factor beta stimulation, as well as critical signaling pathways such as AMPK and mTOR. Through the application of various machine learning techniques, DACH1, CACNA1D, STARD13, and RUNDC3B were identified as key diagnostic markers. The ssGSEA algorithm further corroborated the association of these diagnostic genes with diverse immune cells. Moreover, molecular docking analysis revealed strong binding affinities of these markers to tamsulosin and finasteride, suggesting their potential as drug targets. Finally, experimental validation confirmed the expression differences of DACH1, CACNA1D, STARD13, and RUNDC3B in BPH tissues. This study introduces novel immune-related diagnostic markers for BPH and highlights their promise as new drug targets, providing a valuable approach for predictive diagnosis and targeted therapy of BPH.

We discovered T-cell clonal expansions in benign prostatic hyperplasia, indicative of a specific adaptive immune response and with implications for disease pathogenesis and new treatments.

NF-κB is constitutively activated in psoriatic epidermis. However, how activated NF-κB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. Here we report that the NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA (miRNA) miR-31, one of the most dynamic miRNAs identified in the skin of psoriatic patients and mouse models. The genetic deficiency of miR-31 in keratinocytes inhibits their hyperproliferation, decreases acanthosis and reduces the disease severity in psoriasis mouse models. Furthermore, protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. The inhibition of ppp6c is functionally important for miR-31-mediated biological effects. Moreover, NF-κB activation inhibits ppp6c expression directly through the induction of miR-31, and enhances keratinocyte proliferation. Thus, our data identify NF-κB-induced miR-31 and its target, ppp6c, as critical factors for the hyperproliferation of epidermis in psoriasis. Psoriasis is accompanied by NF-κB activation and hyperplasia. Here the authors show that NF-κB transcriptionally activates miR-31, which downregulates a negative cell cycle regulator protein phosphatase 6, and that this is critical for NF-κB to drive keratinocyte hyperproliferation.

Senescent cells accumulate with age in all tissues. Although senescent cells undergo cell-cycle arrest, these cells remain metabolically active and their secretome — known as the senescence-associated secretory phenotype — is responsible for a systemic pro-inflammatory state, which contributes to an inflammatory microenvironment. Senescent cells can be found in the ageing prostate and the senescence-associated secretory phenotype and can be linked to BPH and prostate cancer. Indeed, a number of signalling pathways provide biological plausibility for the role of senescence in both BPH and prostate cancer, although proving causality is difficult. The theory of senescence as a mechanism for prostate disease has a number of clinical implications and could offer opportunities for targeting in the future.Senescent cells and their secretome — the senescence-associated secretory phenotype (SASP) — cause a systemic pro-inflammatory state, contributing to an inflammatory microenvironment. In this article, the authors discuss the presence of senescent cells and the SASP in the ageing prostate and the evidence for a role of senescence in BPH and prostate cancer, as well as possible therapeutic targeting of these pathways in the future.

Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity.

Vascular intimal hyperplasia (VIH) is an important stage of atherosclerosis (AS), in which macrophages not only play a critical role in local inflammation, but also transform into foam cells to participate into plaque formation, where they appear to be heterogeneous. Recently, it was shown that CD11c+ macrophages were more associated with active plaque progression. However, the molecular regulation of phenotypic changes of plaque macrophages during VIH has not been clarified and thus addressed in the current study. Since CD11c- cells were M2a-polarized anti-inflammatory macrophages, while CD11c+ cells were M1/M2b-polarized pro-inflammatory macrophages, we used bioinformatics tools to analyze the CD11c+ versus CD11c- plaque macrophages, aiming to detect the differential genes associated with M1/M2 macrophage polarization. We obtained 122 differential genes that were significantly altered in CD11c+ versus CD11c- plaque macrophages, regardless of CD11b expression. Next, hub genes were predicted in these 122 genes, from which we detected 3 candidates, interleukin 6 (Il6), Decorin (Dcn) and Tissue inhibitor matrix metalloproteinase 1 (Timp1). The effects of these 3 genes on CD11c expression as well as on the macrophage polarization were assessed in vitro , showing that only expression of Il6, but not expression of Dcn or Timp1, induced M1/M2b-like polarization in M2a macrophages. Moreover, only suppression of Il6, but not suppression of either of Dcn or Timp1, induced M2a-like polarization in M1/M2b macrophages. Furthermore, pharmaceutical suppression of Il6 attenuated VIH formation and progression of AS in a mouse model that co-applied apolipoprotein E-knockout and high-fat diet. Together, our data suggest that formation of VIH can be controlled through modulating macrophage polarization, as a promising therapeutic approach for prevent AS.

Leptin-deficient ob/ob mice are overweight, develop insulin resistance, and serve as a model for type 2 diabetes (T2D). Studies suggest that inflammatory pathways are linked to the development of insulin resistance and T2D both in animals and humans. We asked whether the induction of regulatory T cells (Tregs) could alleviate the pathological and metabolic abnormalities in ob/ob mice. We induced TGF-β-dependent CD4⁺ latency-associated peptide (LAP)-positive Tregs by oral administration of anti-CD3 antibody plus β-glucosylceramide. We found a decrease in pancreatic islet cell hyperplasia, fat accumulation in the liver, and inflammation in adipose tissue, accompanied by lower blood glucose and liver enzymes. In addition, treated animals had decreased CD11b⁺F4/80⁺ macrophages and TNF-α in adipose tissue. Adoptive transfer of orally induced CD4⁺LAP⁺ Tregs ameliorated metabolic and cytokine abnormalities. Our results demonstrate the importance of inflammation in T2D and identify a unique immunological approach for treatment of T2D by the induction of Tregs.

To confirm that neoplastic monocyte-derived collagen- and fibronectin-producing fibrocytes induce bone marrow (BM) fibrosis in primary myelofibrosis (PMF), we injected PMF BM-derived fibrocyte-precursor CD14+/CD34- monocytes into the tail vein of NOD-SCID-γ (NSG) mice. PMF BM-derived CD14+/CD34- monocytes engrafted and induced a PMF-like phenotype with splenomegaly, myeloid hyperplasia with clusters of atypical megakaryocytes, persistence of the JAK2V617F mutation, and BM and spleen fibrosis. As control we used normal human BM-derived CD14+/CD34- monocytes. These monocytes also engrafted and gave rise to normal megakaryocytes that, like PMF CD14+/CD34--derived megakaryocytes, expressed HLA-ABC and human CD42b antigens. Using 2 clonogenic assays we confirmed that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte colony-forming cells, suggesting that a subpopulation BM monocytes harbors megakaryocyte progenitor capacity. Taken together, our data suggest that PMF monocytes induce myelofibrosis-like phenotype in immunodeficient mice and that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte progenitor cells.