Current Molecular Medicine - Volume 23, Issue 3, 2023

The cancers of the cervix, endometrium, ovary, and breast are great threats to women’s health. Cancer is characterized by the uncontrolled proliferation of cells and deregulated cell cycle progression is one of the main causes of malignancy. Agents targeting cell cycle regulators may have potential anti-tumor effects. CDC20 (cell division cycle 20 homologue) is a co-activator of the anaphase-promoting complex/cyclosome (APC/C) and thus acts as a mitotic regulator. In addition, CDC20 serves as a subunit of the mitotic checkpoint complex (MCC) whose function is to inhibit APC/C. Recently, higher expression of CDC20 has been reported in these cancers and was closely associated with their clinicopathological parameters, indicating CDC20 a potential target for cancer treatment that is worth further study. In the present review, we summarized current progress and put forward perspectives of CDC20 in female reproductive cancers.

Hypoxia is a classical function of the tumor's microenvironment with a substantial effect on the development and therapeutic response of cancer. When put in hypoxic environments, cells undergo several biological reactions, including activation of signaling pathways that control proliferation, angiogenesis, and death. These pathways have been adapted by cancer cells to allow tumors to survive and even develop in hypoxic conditions, and poor prognosis is associated with tumor hypoxia. The most relevant transcriptional regulator in response to hypoxia, Hypoxia-inducible factor-1 alpha (HIF-1α), has been shown to modulate hypoxic gene expression and signaling transduction networks significantly. The significance of non-coding RNAs in hypoxic tumor regions has been revealed in an increasing number of studies over the past few decades. In regulating hypoxic gene expression, these hypoxia-responsive ncRNAs play pivotal roles. Hypoxia, a general characteristic of the tumor's microenvironment, significantly affects the expression of genes and is closely associated with the development of cancer. Indeed, the number of known hypoxia-associated lncRNAs has increased dramatically, demonstrating the growing role of lncRNAs in cascades and responses to hypoxia signaling. Decades of research have helped us create an image of the shift in hypoxic cancer cells' DNA repair capabilities. Emerging evidence suggests that hypoxia can trigger genetic instability in cancer cells because of microenvironmental tumor stress. Researchers have found that critical genes' expression is coordinately repressed by hypoxia within the DNA damage and repair pathways. In this study, we include an update of current knowledge on the presentation, participation, and potential clinical effect of ncRNAs in tumor hypoxia, DNA damage reactions, and genomic instability, with a specific emphasis on their unusual cascade of molecular regulation and malignant progression induced by hypoxia.

The liver is exposed to several harmful substances that bear the potential to cause excessive liver damage ranging from hepatitis and non-alcoholic fatty liver disease to extreme cases of liver cirrhosis and hepatocellular carcinoma. Liver ailments have been effectively treated from very old times with Chinese medicinal herbal formulations and later also applied by controlled trials in Japan. However, these traditional practices have been hardly well characterized in the past till in the last decades when more qualified studies have been carried out. Modern advances have given rise to specific molecular targets which are specifically good candidates for affecting the intricate mechanisms that play a role at the molecular level. These therapeutic regimens that mainly affect the progression of the disease by inhibiting the gene expression levels or by blocking essential molecular pathways or releasing cytokines may prove to play a vital role in minimizing the tissue damage. This review, therefore, tries to throw light upon the variation in the therapies for the treatment of benign and malignant liver disease from ancient times to the current date. Nonetheless, clinical research exploring the effectiveness of herbal medicines in the treatment of benign chronic liver diseases as well as prevention and treatment of HCC is still warranted.

Myocardial cell injury and following sequelae are the primary reasons for death globally. Unfortunately, myocardiocytes in adults have limited regeneration capacity. Therefore, the generation of neo myocardiocytes from non-myocardial cells is a surrogate strategy. Transcription factors (TFs) can be recruited to achieve this tremendous goal. Transcriptomic analyses have suggested that GATA, Mef2c, and Tbx5 (GMT cocktail) are master TFs to transdifferentiate/reprogram cell linage of fibroblasts, somatic cells, mesodermal cells into myocardiocytes. However, adding MESP1, MYOCD, ESRRG, and ZFPM2 TFs induces the generation of more efficient and physiomorphological features for induced myocardiocytes. Moreover, the same cocktail of transcription factors can induce the proliferation and differentiation of induced/pluripotent stem cells into myocardial cells. Amelioration of impaired myocardial cells involves the activation of healing transcription factors, which are induced by inflammation mediators; IL6, tumor growth factor β, and IL22. Transcription factors regulate the cellular and subcellular physiology of myocardiocytes to include mitotic cell cycling regulation, karyokinesis and cytokinesis, hypertrophic growth, adult sarcomeric contractile protein gene expression, fatty acid metabolism, and mitochondrial biogenesis and maturation. Cell therapy by transcription factors can be applied to cardiogenesis and ameliorating impaired cardiocytes. Transcription factors are the cornerstone in cell differentiation.

Aims: Due to a large number of identified hub-genes encoding key molecular regulators, which are involved in signal transduction and metabolic pathways in cancers, it is relevant to systemize and update these findings. Background: Colorectal cancer (CRC) is the third leading cause of cancer death in the world, with high metastatic potential. Elucidating the pathogenic mechanisms and selection of novel biomarkers in CRC is of great clinical significance. Objective: This analytical review aims at the systematization of bioinformatics and experimental identification of hub-genes associated with CRC for a more consolidated understanding of common features in networks and pathways in CRC progression as well as hub-genes selection. Results: In total, 301 hub-genes were derived from 40 articles. The “core” consisted of 28 hub-genes (CCNB1, LPAR1, BGN, CXCL3, COL1A2, UBE2C, NMU, COL1A1, CXCL2, CXCL11, CDK1, TOP2A, AURKA, SST, CXCL5, MMP3, CCND1, TIMP1, CXCL8, CXCL1, CXCL12, MYC, CCNA2, GCG, GUCA2A, PAICS, PYY and THBS2) mentioned in not less than three articles and having clinical significance in cancerassociated pathways. Of them, there were two discrete clusters enriched in chemokine signaling and cell cycle regulatory genes. High expression levels of BGN and TIMP1 and low expression levels of CCNB1, CXCL3, CXCL2, CXCL2 and PAICS were associated with unfavorable overall survival of patients with CRC. Differently expressed genes such as LPAR1, SST, CXCL12, GUCA2A, and PYY were shown as down regulated, whereas BGN, CXCL3, UBE2C, NMU, CXCL11, CDK1, TOP2A, AURKA, MMP3, CCND1, CXCL1, MYC, CCNA2, PAICS were up regulated genes in CRC. It was also found that MMP3, THBS2, TIMP1 and CXCL12 genes were associated with metastatic CRC. Network analysis in ONCO.IO showed that upstream master regulators RELA, STAT3, SOX2, FOXM1, SMAD3 and NF-kB were connected with “core” hub-genes. Conclusión: Results obtained are of useful fundamental information on revealing the mechanism of pathogenicity, cellular target selection for optimization of therapeutic interventions, as well as transcriptomics prognostic and predictive biomarkers development.

Background: Diabetes is a major global health concern, manifesting the symptoms of chronic hyperglycemia. Either insufficient or excessive angiogenesis is generally involved in the pathogenesis of diabetes and its complications. Objective: Given that macronutrients are important dietary players in global health issues, we aimed to review the role of macronutrients, including carbohydrates and proteins, to manage diabetes via angiogenesis modulation. Methods: Sixteen studies regarding the effects of macronutrients, including carbohydrates and proteins derived from plants, fungus, bacteria, and their derivatives, on angiogenesis in diabetes were included in our study. Results: Reviewing these studies suggests that carbohydrates, including low molecular weight fucoidan (LMWF), Astragalus polysaccharide (APS), and Ganoderma lucidum polysaccharide (Gl-PS), as well as oligopeptides, like sea cucumber-isolated small molecule oligopeptides (SCCOPs), can induce angiogenesis in the process of wound healing. Considering retinopathy, carbohydrates, including Diphlorethohydroxycarmalol (DPHC), Lyciumbarbarum (LBP), Sulfated K5 Escherichia coli polysaccharide (K5-N, OS (H)), and carnosine suppressed retinal angiogenesis. Furthermore, rice bran protein (RBP) ameliorated angiogenesis in diabetic nephropathy. Carbohydrates, including DPHC, Anoectochilus roxburghii polysaccharide (ARP), and LMWF, showed beneficial effects on endothelial cell dysfunction. Conclusion: In conclusion, data suggest that a number of macronutrients, including proteins and carbohydrates, could have protective effects against complications of diabetes via modulation of angiogenesis.

Background: DNA methylation was considered as prognostic information in some hematological malignancies. Previous studies have reported the in vitro and in vivo biology role of mesenchymal stem cells (MSCs) on leukemic cells. The aim of this study was to investigate the effect of MSCs on the promoter methylation status of hTERT as a catalytic subunit of telomerase enzyme. Methods: In the experimental study, the Molt-4 leukemic cells were co-cultured with MSCs for 7 days. At the end of the co-culture period, the Molt-4 cells were collected, DNA and protein were extracted. Then methylation specific-PCR and western blotting were done for evaluating the hTERT gene promoter methylation status and cyclin D1 and hTERT protein expression, respectively. In the following, the flow cytometry was done for cell cycle distribution assay. Results: It was found that MSCs resulted in a significant decrease in the cyclin D1 and hTERT protein expression levels. Also, MSCs caused changes in the methylation status of the CpG islands in the hTERT gene promoter region. The following results showed that MSCs caused a significant increase in the number of cells at G0/G1 phase and arrest the G0/G1 phase as well as decrease in the cell proliferation of Molt-4 cells. Conclusion: It is concluded that co-culture of MSCs with Molt-4 cells could be involved in changing the methylation status of hTERT gene promoter, cell cycle and hTERT protein expression; it could be potentially beneficial for further investigations regarding the cell transplantation and cell-based therapy.

Objective: Mounting studies have clarified the link between long non-coding RNAs (lncRNAs) and pneumonia. This research aims to probe the function and regulatory mechanism of lncRNA H19 in lipopolysaccharide (LPS)-induced cell models of pneumonia. Methods: WI-38 cells were exposed to LPS for 12 h to mimic cell models of pneumonia. The relative expression of H19, miR-140-5p, and toll-like receptor 4 (TLR4) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability was detected by MTT assay. The protein expression of apoptosis-associated proteins (Bax and Bcl-2) and TLR4 were determined by western blot. Moreover, the content of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay (ELISA). The target relationship between miR- 140-5p and H19/ TLR4 was confirmed by Dual luciferase reporter (DLR) assay. Results: LncRNA H19 and TLR4 were up-regulated, while miR-140-5p was downregulated in peripheral blood of patients with pneumonia and LPS-treated WI-38 cells compared with their controls. Silencing of H19 or miR-140-5p mimics facilitated cell viability, whereas repressed apoptosis and reduced content of TNF-α, IL-6, and IL-1β in LPS-induced WI-38 cells. H19 targeted miR-140-5p and it inversely regulated miR-140- 5p expression. MiR-140-5p targeted TLR4 and it inversely regulated TLR4 expression. H19 positively regulated TLR4 expression. Moreover, inhibition of miR-140-5p or overexpression of TLR4 reversed the effects of H19 silencing on cell viability, inflammation, and apoptosis in LPS-induced WI-38 cells. Conclusion: Silencing of H19 inhibited apoptosis and inflammation by miR-140- 5p/TLR4 pathway in LPS-induced WI-38 cells.