Current Molecular Medicine - Volume 20, Issue 4, 2020

Lifestyle factors, such as alcohol intake, have placed a substantial burden on public health. Alcohol consumption is increasing globally due to several factors including easy accessibility of this addictive substance besides its legal status and social acceptability. In the US, alcohol is the third leading preventable cause of death (after tobacco, poor diet and physical inactivity) with an estimated 88,000 people dying from alcohol-related causes annually, representing 1 in 10 deaths among working adults. Furthermore, the economic burden of excess drinking costs the US around $249 billion ($191.1 billion related to binge drinking). Although men likely drink more than women do, women are at much higher risk for alcohol-related problems. Alcohol use is also considered to be one of the most common non-communicable diseases, which affects reproductive health. This review article summarizes the current knowledge about alcohol-related pathogenesis of uterine fibroids (UFs) and highlights the molecular mechanisms that contribute to the development of UFs in response to alcohol consumption. Additionally, the effect of alcohol on the levels of various factors that are involved in UFs pathogenesis, such as steroid hormones, growth factors and cytokines, are summarized in this review. Animal studies of deleterious alcohol effect and future directions are discussed as well.

It is well-established that cardiovascular disease continues to represent a growing health problem and significant effort has been made to elucidate the underlying mechanisms. In this review, we report on past and recent high impact publications in the field of intracrine network signaling, focusing specifically on opioids and their interrelation with key modulators of the cardiovascular system and the onset of related disease. We present an overview of studies outlining the scope of cardiovascular and cerebrovascular processes that are affected by opioids, including heart function, ischemia, reperfusion, and blood flow. Specific emphasis is placed on the importance of dynorphin molecules in cerebrovascular and cardiovascular regulation. Evidence suggests that excessive or insufficient dynorphin could make an important contribution to cardiovascular physiology, yet numerous paradoxical observations frequently impede a clear understanding of the role of dynorphin. Thus, we argue that dynorphin-mediated signaling events for which an immediate regulatory effect is disputed should not be dismissed as unimportant, as they may play a role in cross-talk with other signaling networks. Finally, we consider the most recent evidence on the role of dynorphin during cardiovascular-related inflammation and on the potential value of endogenous and exogenous inhibitors of kappa-opioid receptor, a major dynorphin A receptor, to limit or prevent cardiovascular disease and its related sequelae.

Celiac Disease (CD) is a complex immunogenic disease mainly triggered by gluten intake in genetically susceptible individuals with a prevalence of 1 in 100-300. CD results from the interplay between genetic and environmental factors. Genetic susceptibility is believed to play a prominent role in the pathogenicity of CD, mainly due to human leukocyte antigen (HLA)-related class II genes. Although CD is wellrecognized among Arab populations, there are few studies on the genetic epidemiology and prevalence of CD in the Arab countries. Therefore, the aim of this review was to highlight the importance of studying this disease in the Arab world in the context of a global perspective. Within the few studies published so far, it was found that Arab populations have a distinctive susceptibility genetic profile from other ethnic groups with the DQ2.5 and DQ8 genotypes that are considered the major genotypes that confer susceptibility among Arab patients with CD. Our findings will pave the way to perform further epidemiological studies that will help identify potential therapeutic targets against CD among Arab patients that are diagnosed with CD.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the third leading cause of cancer-related death. It is a heterogeneous disease that develops through different genetic and epigenetic mechanisms. To date, no comprehensive systematic review investigating genetic risk factors for familial and sporadic CRC has been performed on the extended MENA (eMENA) region. Aims: This study aimed to systematically analyze genetic variations significantly associated with CRC in the eMENA region. Methods: We searched four literature databases (PubMed, Scopus, Science Direct, and Web of Science) from the time of inception until May 2019 using broad search terms to obtain all reported genetic data related to eMENA patients with CRC. Variants with an OR>1 that are associated with CRC were identified. Results: A total of 1,200 studies were obtained from our search method, 27 of which met the inclusion criteria for our systematic review, with a total of 8,230 CRC patients and 7,611 controls. Of these, 1,941 patients distributed throughout nine eMENA countries were found to carry 46 variants in 33 different genes. Interestingly, 19 variants were unique to CRC patients in the eMENA region. Interpretation: This is the first systematic review to capture the spectrum of variants significantly associated with CRC in the eMENA region. There appears to be a distinctive clinical picture for eMENA patients with CRC, and the range and distribution of variants among patients from the eMENA region differ from those noted in other ethnic groups.

Background: Previously, we first identified the human tripartite motifcontaining protein 45 (TRIM45) acts as a novel transcriptional repressor in mitogenactivated protein kinase (MAPK) signaling pathway. After that, the inhibitory role of TRIM45 in the development of tumor was gradually unveiled. However, the function of TRIM45 in the tumorigenesis of lung cancer has not been characterized. Methods and Results: In this study, we found that TRIM45 was up-regulated in earlystage human non-small-cell lung cancer (NSCLC) tissues. Overexpression of TRIM45 in lung cancer cells induces G1 arrest and promotes apoptosis, which accompanied by upregulated expression of RB, p16, p53, p27Kip1, and Caspase3 and down-regulated expression of CyclinE1 and CyclinE2. Further detection of the expression of the molecules in the MAPK signaling pathway revealed that overexpression of TRIM45 in lung cancer cells promotes phosphorylated p38 (p-p38) activation and inhibits phosphorylated ERK (p-ERK) activation. In accordance with this, p-p38 is increased while p-ERK is decreased in lung cancer tissues. Conclusion: These findings indicate that TRIM45 plays an inhibitory role in the tumorigenesis of lung cancer. High-level expression of TRIM45 in lung cancer tissue may promote cell apoptosis by activating p38 signal and inhibit proliferation by down-regulating p-ERK, which provides a new clue for understanding the tumorigenesis of lung cancer.

Background: Butyric acid (BT), a short-chain fatty acid, is the preferred colonocyte energy source. The effects of BT on the differentiation, proliferation, and apoptosis of small intestinal epithelial cells of piglets and its underlying mechanisms have not been fully elucidated. Methods: In this study, it was found that 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells. BT at 0.5 mM or higher concentrations significantly impaired cell viability in a dose- and time-dependent manner. In addition, BT at high concentrations inhibited the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase. Results: Our results demonstrated that BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production. BT at high concentrations inhibited cell autophagy associated with increased lysosome formation. It was found that BT-reduced IPEC-J2 cell viability could be attenuated by p38 MAPK inhibitor SB202190. Moreover, SB202190 attenuated BT-increased p38 MAPK target DDIT3 mRNA level and V-ATPase mRNA level that were responsible for normal acidic lysosomes. Conclusion: In conclusion, 1) at 0.2-0.4 mM, BT promotes the differentiation of IPEC-J2 cells; 2) BT at 0.5 mM or higher concentrations induces cell apoptosis via the p38 MAPK pathway; 3) BT inhibits cells autophagy and promotes lysosome formation at high concentrations.

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results: After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.