Current Molecular Medicine - Volume 16, Issue 9, 2016

Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein’s function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels.

Infection is the process of pathogen invasion, as well as the host reaction to the foreign agents. Proline-directed phosphorylation is a major regulatory mechanism that regulates the function of fundamental proteins involved in infection and infection-induced cancer. Recently, the identification of the phosphorylation-dependent prolyl isomerase Pin1 has uncovered a unique regulatory signaling mechanism controlling protein conformation and function after phosphorylation. Pin1 is the only proline isomerase that specifically recognizes certain Pro-directed Ser/Thr phosphorylation motifs. Pin1 has emerged as a major regulator of cancerrelated viral and bacterial infections notably via activating Toll-like receptor signaling and NF-ΚB pathways. This paper will specifically review recent findings on the role of Pin1 in cancer-related viral and bacterial infections and also discuss newly discovered Pin1 inhibitors as promising drugs for the prevention and treatment of viral and bacterial infections and associated tumorigenesis.

The structure and developmental mechanisms of vertebrate retina are highly conserved. One of the most distinctive events during retinogenesis is the temporally and spatially generation of seven types of retinal cells from the multipotent retinal progenitor cells. The importance and prevalence of SUMOylation in regulation of this process through modulation of gene expression and protein function diversity have been increasingly appreciated. Here, we review the biological significance of SUMOylation in retina development, examine how SUMOylation balances the proliferation and cell cycle exit of retinal progenitor cells, and finally discuss the molecular mechanisms mediating the specification of different retina neurons and photoreceptors through modulation of various transcription factors. The potential role of SUMOylation in normal retina function is illustrated by the abundant expression of key components of SUMOylation machinery in mouse retina, and is also exemplified by the highly conserved SUMOylation site on neurotransmission receptors in ganglion cells.

Kupffer cells (KCs) are vital innate immune system cells in the liver that participate in various metabolic states. Although several studies have directly evaluated the role of KCs in different metabolic situations in the liver, the definite characteristics of KCs remain unknown. KC depletion techniques are used to determine the functions of KCs under metabolic challenges; however, there is debate about their precise role even after successful ablation. While some KC ablation studies showed improvement in insulin resistance, fatty liver and metabolic parameters, other reports, under the similar conditions, have not. Some studies have rationalized the KCs dual actions in liver metabolic states by arguing their M1 and M2 biases. Activated M1 KCs secrete pro-inflammatory cytokines, growth factors and other mediators to create inflammatory stress which initiates inflammatory signalling in hepatocytes to disrupt the metabolic scenario. In contrast, M2 KCs generate anti-inflammatory cytokines and mediators which improve glucose and lipid metabolic states within the liver. Unfortunately, the M1/M2 bias does not provide reliable explanation as KCs depletion shows strikingly different results. Despite many investigational studies on this topic, a comprehensive review of these studies is lacking. This review attempts to address the issues related with the dichotomy of KCs effects in lipid metabolism. This review not only warns the future studies to carefully analyze the results that are drawn from KCs effects on lipid metabolism but also suggest to evaluate animal models and KCs depletion techniques as an equally important cofactor.

Background and Objective: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Genotoxic stress resistance in patients often contributes to poor clinical outcomes, and is intensively associated to the upregulation of Nrf2/ARE signaling pathway. In this study, we examined the connection between the anticancer activity of two novel indazolo[3,2-b]quinazolinone (IQ) derivatives, IQ-7 and IQ-12, and their effect on the Nrf2/ARE signaling pathway. Methods: We initially measured the cytotoxicity of IQ-7 and IQ-12 in Hep3B (human hepatoma cell) and HL-7702 (normal human liver cell) cell lines, then further detected their effects on Nrf2/ARE signaling pathway and apoptosis. Results: IQ-7 and IQ-12 downregulated the expression levels of Nrf2 and its downstream target genes, such as NQO1, HO-1 and Gclc. In Hep3B cells treated with IQ-7 or IQ-12, the mitochondrial membrane potential decreased dramatically while the expression level of the pro-apoptotic protein VDAC1 and anti-apoptotic protein Bcl-2 significantly increased and decreased, respectively. In addition, IQ-7 (but not IQ-12) also induced the activity of Caspase-3. Interestingly, IQ-7 appeared to selectively inhibit Hep3B cells while having rare adverse effect on HL-7702 cells. Conclusion: The two compounds were shown to induce apoptosis and inhibit the Nrf2/ARE signaling pathway in Hep3B cells, and IQ-7 was suggested a degree of specificity against cancer cells. The design of these compounds may therefore represent a new strategy for designing quinazoline derivatives that could selectively target carcinoma cells.

Purpose: Recently, a different type of microsatellite instability (MSI) instability designated ‘elevated microsatellite alterations at selected tetranucleotide repeats’ (EMAST) has been reported in several neoplasms, but its clinical implications remain unclear. We aimed to determine the relationships among EMAST, MSI and clinicopathologic characteristics, including oncologic outcomes, in colorectal cancer (CRC). Materials and Methods: We evaluated 100 sporadic CRC cases subjected to surgery using five markers (MYCL1, D9S242, D20S85, D8S321, and D20S82) for EMAST and the Bethesda panel for MSI status. Immunohistochemical detection of hMSH3, c-erbB2, EGFR and thymidylate synthase was performed. Clinical characteristics and prognostic relevance were assessed. Results: We identified 22 EMAST-positive tumors (22.0%) and 32 MSI-high (MSI-H) tumors (32.0%). EMAST was more frequent in colon cancer than rectal cancer (p=0.033), and associated with MSI-H phenotype (p<0.001), low expression of hMSH3 (p=0.004), and overexpression of thymidylate synthase (p=0.006). Among the 38 MSI-L tumors, only one (4.5%) showed EMAST. Long-term oncologic results in terms of overall and disease-free survival were similar between EMAST and non-EMAST tumors. Conclusion: EMAST is more closely related to MSI-H than MSI-L or MSS status. The clinical and molecular characteristics of EMAST were distinct in terms of tumor location, thymidylate synthase expression, MSI status and hMSH3 expression. Our preliminary findings support the utility of EMAST as a new potential classifier in CRC.

Background: Convergent evidence from genetics, symptomatology and psychopharmacology imply that there are intrinsic connections between schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD), for example, any two or even three of these disorders could co-exist in some families. Objective: To screen out the susceptibility genes on chromosome 6 comprehensively for SCZ, BPD and MDD in a relative homogenous population in China. Method: A total of 56.400 single nucleotide polymorphism (SNPs) on chromosome 6 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type- I), 177 MDD patients and 1000 controls. Results: Associated SNP loci on chromosome 6 were comprehensively revealed and outstanding susceptibility genes were identified including JARID2 (Homo sapiens jumonji, AT rich interactive domain 2) which plays an essential role in embryonic development and neural tube fusion process. Unexpectedly, flanking genes for all associated SNPs were replicated in an enlarged cohort of 986 SCZ patients. Conclusion: Considering all evidence, our results imply that both of bipolar disorder and major depressive disorder are subtypes of schizophrenia. Furthermore, JARID2 is an important psychosis gene in this population.