Epigenetics in osteoarthritis: Novel spotlight

Osteoarthritis (OA) is the most common type of arthritis and no longer is considered as an absolute consequence of joint mechanical use (wear and tear); rather recent data demonstrate the pivotal role of inflammatory mediators in the development and progression of this disease. This multifactorial disease results from several environmental and inherited factors. Genetic cannot solely explain all the contribution share of inheritance and, this way, it is speculated that epigenetics can play a role, too. Moreover, environmental factors can induce local epigenetic changes. The epigenetic contribution to OA pathogenesis occurs at all of its levels, DNA methylation, histone modification, microRNA, and long noncoding RNA. In fact, during early phases of OA pathogenesis, environmental factors employ epigenetic mechanisms to provide a positive feedback for the OA-related pathogenic mechanisms and pathways with an ultimate outcome of a well-established clinical OA. These epigenetic changes stay during clinical disease and prevent the body natural healing and regenerative processes to work properly, resulting in an incurable disease condition. In this review article, we aimed to have an overview on the studies performed with regard to understanding the role of epigenetics in the etiopathogenesis of OA and highlighted the importance of such kind of regulatory mechanisms within this context.     

Exosomes in tuberculosis: Still terra incognita?

Today, diagnosis, vaccination, and treatment of tuberculosis (TB) remain major clinical challenges. Therefore, an introduction of new diagnostic measures and biomarkers is necessary to improve infection control. The ideal biomarker for TB infection can be defined as a host or pathogen-derived biomolecule, which is potent for identifying infection and determining its clinical stage. Exosomes, defined as cell-derived nanovesicles released into biological fluids, are involved in cell–cell communication and immune modulation. These vesicles have emerged as a new platform for improving the clinical diagnosis and prognosis of different infectious diseases and cancers. The role of these nanovehicles, as alternative biomarkers for the improvement of TB diagnosis and treatment, has been demonstrated in a significant body of literature. In this review, we summarized recent progress in the clinical application of exosome-based biomarkers in TB infection.     

PNU-74654 enhances the antiproliferative effects of 5-FU in breast cancer and antagonizes thrombin-induced cell growth via the Wnt pathway

The Wnt/β-catenin pathway is one of the most common pathways dysregulated in breast cancer, and may, therefore, be a potential-therapeutic target. We have investigated the effects of PNU-74654 in breast cancer, as a Wnt/β-catenin inhibitor, either alone or in combination with fluorouracil (5-FU). PNU-74654 suppressed cell growth at an IC ₅₀ of 122 ± 0.4 μmol/L and synergistically enhanced the antiproliferative activity of gemcitabine by modulating the Wnt pathway. Using a 3D cell culture model, we found that the PNU-74654 caused tumor shrinkage. It reduced the migration of MCF-7 cells (by an 18% reduction in invasive behavior) after the treatment with PNU-74654 through perturbation of E-cadherin and MMP3/9. PNU-74654/5-FU combination enhanced the percentages of cells in S-phase and significantly increased apoptosis. Moreover, our data showed that this agent was able to inhibit the growth of tumor in a xenograft model, although this effect was more pronounced in the animals treated with PNU-74654 plus 5-FU. These data show the ability of PNU-74654 to specifically target Wnt pathway, interfere with cell proliferation, induce-apoptosis, reduce-migration, and synergistically interact with 5-FU, supporting further studies on this novel therapeutic-approach for breast cancer.     

The role of HSP27 in the development of drug resistance of gastrointestinal malignancies: Current status and perspectives

Heat-shock protein 27 (HSP27) is a chaperone molecule that plays a critical role in the refolding and activity of several proteins responsible for cancer cell drug toxicity. Upregulation of HSP27 is associated with decreased drug sensitivity as well as poorer survival in gastrointestinal (GI) malignancies. It is, therefore, possible that HSP27 may be of value in the assessment of prognostic and therapeutic efficacy in the treatment of GI cancers. Pharmacological and biological inhibitors of HSP27 enhance tumor cell chemosensitivity. This review summarizes the potential role of HSP27 in chemotherapy drug resistance and the therapeutic potential of HSP27 inhibitors as a novel strategy in the treatment of GI cancers.     

Herbal medicine as an auspicious therapeutic approach for the eradication of Helicobacter pylori infection: A concise review

Helicobacter pylori (H. pylori) causes gastric mucosa inflammation and gastric cancer mostly via several virulence factors. Induction of proinflammatory pathways plays a crucial role in chronic inflammation, gastric carcinoma, and H. pylori pathogenesis. Herbal medicines (HMs) are nontoxic, inexpensive, and mostly anti-inflammatory reminding meticulous emphasis on the elimination of H. pylori and gastric cancer. Several HM has exerted paramount anti-H. pylori traits. In addition, they exert anti-inflammatory effects through several cellular circuits such as inhibition of 5′-adenosine monophosphate-activated protein kinase, nuclear factor-κB, and activator protein-1 pathway activation leading to the inhibition of proinflammatory cytokines (interleukin 1α [IL-1α], IL-1β, IL-6, IL-8, IL-12, interferon γ, and tumor necrosis factor-α) expression. Furthermore, they inhibit nitrous oxide release and COX-2 and iNOS activity. The apoptosis induction in Th1 and Th17-polarized lymphocytes and M2-macrophagic polarization and STAT6 activation has also been exhibited. Thus, their exact consumable amount has not been revealed, and clinical trials are needed to achieve optimal concentration and their pharmacokinetics. In the aspect of bioavailability, solubility, absorption, and metabolism of herbal compounds, nanocarriers such as poly lactideco-glycolide-based loading and related formulations are helpful. Noticeably, combined therapies accompanied by probiotics can also be examined for better clearance of gastric mucosa. In addition, downregulation of inflammatory microRNAs (miRNAs) by HMs and upregulation of those anti-inflammatory miRNAs is proposed to protect the gastric mucosa. Thus there is anticipation that in near future HM-based formulations and proper delivery systems are possibly applicable against gastric cancer or other ailments because of H. pylori.     

Wnt pathway targeting reduces triple-negative breast cancer aggressiveness through miRNA regulation in vitro and in vivo

Triple-negative breast cancer, devoid of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is deprived of commonly used targeted therapies. MicroRNAs (miRNAs) are undergoing a revolution in terms of potentially diagnostic or therapeutic elements. Combining computational approaches, we enriched miRNA binding motifs of Wnt pathway-associated upregulated genes. Our in-depth bioinformatics, in vitro and in vivo analyses indicated that miR-381 targets main genes of the Wnt signaling pathway including CTNNB1, RhoA, ROCK1, and c-MYC genes. The expression level of miR-381 and target genes was assessed by quantitative real-time polymerase chain reaction (RT-qPCR) in MCF-7, MDA-MB-231, and MCF-10A as well as 20 breast cancer samples and normal tissues. Luciferase reporter assay was performed. Lentiviral particles containing miR-381 were used to evaluate the effect of miR-381 restoration on cell proliferation, migration, and invasion of the invasive triple-negative MDA-MB-231 cell line and also in a mouse model of breast cancer. The expression of miR-381 was lower than that of normal cells, especially in TNBC cell line and breast tissues. Luciferase assay results confirmed that miR-381 targets all the predicted 3′-untranslated regions (3′-UTRs). Upon miR-381 overexpression, the expression of target genes declined, and the migration and invasion potential of miR-381-receiving MDA-MB-231 cells decreased. In a mouse model of triple-negative breast cancer, miR-381 re-expression inhibited the invasion of cancer cells to lung and liver and prolonged the survival time of cancer cell-bearing mice. Therefore, miR-381 is a regulator of Wnt signaling and its re-expression provides a potentially effective strategy for inhibition of TNBC.     

Stem cell therapy: A novel approach for myocardial infarction

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Until recently, it was thought that myocardium was not able to repair itself, but studies have now shown that resident cardiac stem cells have regenerative capacity, and stem cell therapy may be a novel approach for cardiac muscle repair and regeneration. Stem cell-derived paracrine factors have been shown to regulate ventricular remodeling, inflammation, apoptosis, cardiomyocytes regeneration, and neovascularization in regions of infarcted cardiac tissue. In this review, we summarize the evidence from cellular, animal, and clinical studies supporting the potential clinical significance of stem cell therapy as a novel therapeutic approach for the treatment of MI.     

Survivin a pivotal antiapoptotic protein in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease, pathologically characterized by lymphocyte infiltration of the synovial membrane that leads to chronic inflammation and progressive joint damage. RA develops as a result of increased cell infiltration and cell proliferation as well as impaired cell death. Activated cells in joints including lymphocytes and fibroblast-like synoviocytes (FLS) survive for a long time as a consequence of compromised apoptosis, but the mechanism underlying cell survival in synovium remains to be firmly established. Inhibition of apoptosis by survivin, as a critical antiapoptotic protein, contributes to both the persistence of autoreactive T lymphocytes and tumor-like phenotype of FLS in RA. In addition to the antiapoptotic role, survivin also has prognostic relevance in RA prodromal phase. Hence, this review provides an overview of the current knowledge regarding the involvement of survivin protein in the pathogenesis of RA.     

Therapeutic potency of Wnt signaling antagonists in the pathogenesis of prostate cancer,current status and perspectives

Prostate cancer is a major cause of cancer-related death in males. Wnt/β-catenin signaling plays a critical role in the pathogenesis of this disease by regulating angiogenesis, drug resistance, cell proliferation, and apoptosis. Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease.