Current Molecular Medicine - Volume 18, Issue 1, 2018

Background: Vascular network formation induced by angiogenesis plays an important role in many physiological and pathological processes. However, the role of blood flow and underlying mechanisms in vascular network formation, for example for the development of the caudal vein plexus (CVP), is poorly understood. Objective: The aim of this study was to explore the role of ERK5-klf2a-nos2b signaling in the CVP angiogenesis. Method and Results: In this study on tnnt2a-MO injection and chemical blood flow modulator treatment in zebrafish embryos, we demonstrated that decreased blood flow disrupted CVP formation. The hemodynamic force was quantitatively analyzed. Furthermore, CVP angiogenesis in zebrafish embryos was inhibited by disruption of the blood flow downstream effectors ERK5, klf2a, and nos2b in response to treatment with the ERK5 specific inhibitor and to injection of klf2a-MO, nos2b-MO. Overexpression of klf2a mRNA or nos2b mRNA restored vascular defects in tnnt2a or klf2a morphants. The data suggest that flow-induced ERK5-klf2a-nos2b signaling is involved in CVP angiogenesis in zebrafish embryos. Conclusion: We have demonstrated that blood flow is essential for vascular network formation, specifically for CVP angiogenesis in zebrafish. A novel genetic and mechanical mechanism was discovered in which ERK5 facilitates the integration of blood flow with the downstream klf2a-nos2b signaling for CVP angiogenesis.

Background: Hesperetin, a natural component of citrus fruits, is indicated to have beneficial anti-inflammatory effects on injury and various cancers as a transforming growth factor beta (TGF-β) inhibitor. However, little evidence associates hesperetin with liver fibrosis. Objective: Work from our laboratory aims at finding the mechanism by which hesperetin attenuates liver fibrosis. Methods: Bile duct ligation (BDL) was used to induce liver fibrosis in mice and the findings were determined using enzyme-linked immunosorbent assay, quantitative realtime polymerase chain reaction, western blotting and immunohistochemical staining. Results: Data from Immunohistochemical staining and injury score indicated that pathological lesions were reduced by hesperetin treatment. Decreasing levels of several serum parameters including cytokines tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), liver enzyme alanine aminotransferase (ALT) and aspartate aminotransferase (AST), fibrosis indicators laminin (LN), hyaluronic acid (HA) and hydroxylproline (Hyp) suggested similar results to the immunohistochemical. In addition, our data verified hesperetin could suppress the formation of extracellular matrix and hepatocyte apoptosis in vitro, together with promoting hepatic stellate cell death in vivo, which was considered to be associated with the inhibition of TGF-β1/Smad pathways. Conclusion: In the present study, the favorable role of hesperetin extracted from citrus peels was verified to prevent the progression of BDL-induced liver fibrosis via inhibiting TGF-β1/Smad pathway-mediated extracellular matrix progression and apoptosis.

Background: Loss of heterozygosity (LOH) of 12p12-13 has been frequently found in various types of cancer. LOH12CR1 is one of the seven critical genes located within the 12p12-13 region. The protein encoded by LOH12CR1 is involved in the function of lysosomes and its other functions are still unclear. Objective: The aim of this study is to investigate the potential roles of LOH12CR1 in the development of colorectal cancer. Methods: A total of 174 colorectal cancer tissues were used to examine the protein level of LOH12CR1 by immunohistochemistry staining. The correlation between LOH12CR1 expression and the patient prognosis was further investigated through retrospective study. The tumor suppression capacity was examined by knockdown or overexpression of LOH12CR1 in four colorectal cancer cell lines and one normal cell line. Results: Significant decrease of LOH12CR1 protein was observed in colorectal cancerous tissues (P<0.001). Knockdown of LOH12CR1 promoted colorectal cancer cell proliferation, colony formation, and accelerated G1/S cell cycle transition through downregulation of p16^INK4a and p21^WAF1/CIP1, while ectopic expression of LOH12CR1 displayed the opposite effects. The protein level of LOH12CR1 was well correlated with the expression of p16^INK4a and p21^WAF1/CIP1. Most importantly, the protein level of LOH12CR1 negatively correlated with clinical prognosis of colorectal carcinomas. Conclusion: The present results suggest that LOH12CR1 might function as a tumor suppressor. Thus, loss of function of LOH12CR1 might be a potential driver in the development of colorectal carcinoma. Detection of LOH12CR1 could be used as a method for diagnosis and therapeutic assessment of patients with colorectal cancer.

Background: Ranolazine is generally used to treat anginal symptoms for patients with symptomatic chronic stable angina pectoris. By improving ischemiareperfusion, ranolazine is also observed to have protective effects on myocardial ischemic injury in animal models. It is noteworthy to find interventions that can decrease adverse effects of this drug and thereby increase its clinical application. Methods: In this report, we used a rat model of chronic ischemic heart failure (CHF) to examine if vagal stimulation can strengthen the effects of ranolazine on worsened cardiac function in CHF. Plasma norepinephrine (NE) and brain natriuretic peptide [BNP, termed B-type natriuretic peptide-45 (BNP-45) in rats] are regulated by sympathetic nerve activity. Because NE and BNP are considered as neurohormones indicating heart failure progression, we also determined the levels of plasma NE and BNP-45 besides cardiac function. Moreover, we examined the role of sympathetic pro-inflammatory cytokines in engagement of vagal activation. Results: Our data show that ranolazine intraperitoneally improved the impaired left ventricular function, and attenuated the exaggerated NE/BNP-45 and cytokines (such as IL-1β, IL-6 and TNF-α) after development of CHF. Particularly, our results show that vagal activation largely amplified the effects of ranolazine on cardiac function in CHF. Conclusion: Our data indicate that: 1) ranolazine alleviates sympathetic nerve activity thereby leading to improvement of the worsened cardiac function in CHF; and 2) vagal stimulation augments the effect of ranolazine. Accordingly, results of this study have implications for the role played by a combination of vagal stimulation and ranolazine in improving cardiac function in CHF.

Cancer remains a deadly disease for effective treatment. Although anomalous tumor microenvironment is now widely exploited for targeted chemotherapy, safe and efficacious drug delivery to tumor cells is not still warranted. Liposomes are promising biodegradable and biocompatible nanocarriers having potential amenability for surface and internal modifications, and extraordinary capability to carry both hydrophilic as well as hydrophobhic drugs. Meticulous fabrication of liposomes with tumor selective ligand(s) and PEGylation reduces immunogenicity and increase target-specificity. This review focuses on critical developmental aspects of liposomes to target cancer cells exploiting Enhanced Permeability and Retention (EPR) effect and tumor-selective ligands such as folate, transferrin, peptides etc. Moreover, stimuli-responsive smart liposomes (triggers: pH, temperature, enzymes, magnetic field, ultrasound, and redox potential etc.) are also investigated for enhancement of drug delivery to tumors. This review summarizes advances in tumor-targeted liposomes via various means of targeting. This knowledgeable assemblage of advances in liposomal approaches will render new insights to formulators and budding scientists to design cancer targeted liposomes.

Generation of patient-specific stem cells has been a long-held aim of many developmental biologists. Apart from providing a source for stem cell therapies, these cells have the potential to be utilized in a number of scenarios like disease modeling, drug screening and studying normal development. Various approaches have been used to reprogram terminally differentiated cells to a pluripotent state with varying efficiencies and limitations. The nuclear transfer had been the most successful method for reprogramming until recently. Shinya Yamanaka in 2006 published a seminal study wherein, by using a cocktail of stem cell transcription factors famously called Yamanaka factors, the differentiated cells were reprogrammed to a pluripotent state. These cells, called induced pluripotent stem (iPS) cells, were later generated by various laboratories using a different combination of molecules. Importantly, induced pluripotency is a state that is achieved in a stepwise manner with landmark steps. Various molecules including microRNAs (miRNAs) are activated or repressed at these steps to ensure a successful transition to pluripotency. The precise regulation of miRNAs is important as they collectively regulate myriads of mRNAs representing specific pathways important for steering cellular fate towards stemness. Owing to their significance, miRNAs have been constituents of cocktails used for iPSCs generation. This review aims at discussing the stepwise regulation of miRNAs and their significance along the path to reprogramming.

Background: Dopamine physiological functions make dopaminergic genes suitable candidates for association studies in eating disorders (ED). A Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene, which is involved in dopamine degradation, has been studied in relation to ED. Objective: We aimed to analyze the association between this polymorphism and general psychopathological symptoms that are often coupled to these disorders. Method: A total of 303 ED patients, diagnosed according to DSM-5 criteria, completed the SCL-90R questionnaire and were genotyped for the Val158Met polymorphism. Results: There were significant differences in the global indices of the SCL-90R inventory between the three ED groups (Anorexia Nervosa (AN), Bulimia Nervosa (BN) and binge-eating disorder; ANOVA-p < 0.05). Females with BN showed the highest scores (worse symptomatology) of all participants. In this group, a gene-dose effect was observed on the psychometric evaluation of the patients, as Val/Val carriers displayed the highest scores for all the SCL-90R scales, followed by Val/Met and then Met/Met carriers. Significant differences between genotypes were observed in the Obsessive- Compulsive (p = 0.018), Paranoid Ideation (p = 0.0005) and Psychoticism (p = 0.039) scales, as well as in the PSDI (p = 0.014) general index. Conclusion: The results taken together suggest that COMT genetic variability may contribute to general psychopathological symptoms in patients with BN.