Disparate roles of retinoid acid signaling molecules in kidney disease

Retinoic acid (RA) exerts pleotropic cellular effects, including induction of cell differentiation while inhibiting proliferation and inflammation. These effects are mediated by both RA responsive element-dependent or -independent pathways. In kidneys, RA confers renoprotection by signaling through podocyte RA receptor (RAR)α and activation of cAMP/PKA/Kruppel-like factor 15 pathway to promote podocyte differentiation. Nevertheless, in kidney disease settings, RA can also promote podocyte apoptosis and loss through downstream expression of RAR responder protein 1, a recently described risk factor for glomerular disease progression. These disparate roles of RA underscore the complexity of its effects in kidney homeostasis and disease, and a need to target specific RA-mediated pathways for effective therapeutic treatments against kidney disease progression.

Intracellular alpha-fetoprotein interferes with all-trans retinoic acid induced ATG7 expression and autophagy in hepatocellular carcinoma cells

Retinoic acid and retinoid acid receptor (RA-RAR) signaling exhibits suppressive functions in the progression of hepatocellular carcinoma (HCC) through multiple mechanisms. However, whether RA-RAR signaling induces autophagy that contributes its anti-tumor activity in HCC remains elusive. In the current study, the effects of RA-RAR pathway on autophagy were investigated in two HCC cell lines: alpha-fetoprotein (AFP) positive PLC/PRF/5 and AFP negative HLE cells. Cell autophagy was analyzed with western blot for detection of LC3 conversion and p62/SQSTM1 degradation while autophagy flux was assayed using the mRFP-GFP-LC3 reporter. Cell apoptosis and viability were analyzed by caspase-3 activity, TdT-mediated dUTP nick end labeling (TUNEL) assay, and Cell Counting Kit (CCK)-8, respectively. Chromatin immunoprecipitation (ChIP) was employed to detect the binding of RAR onto the promoter of autophagy-relevant 7 (ATG7), and co-immunoprecipitation (CoIP) was used to analyze the interaction of AFP and RAR. The results showed that ATRA dosage and time-dependently induced high levels of cell autophagy in both the PLC/PRF/5 and HLE cells, which was accompanied with up-regulation of ATG7. ChIP assay showed that RAR was able to bind to its responsive elements on ATG7 promoter. Impairment of ATG7 induction or blockade of autophagy with chloroquine aggravated ATRA induced apoptosis of HCC cells. Furthermore, intracellular AFP was able to complex with RAR in PLC/PRF/5 cells. Knockdown of AFP in PLC/PRF/5 cells augmented the up-regulation of ATG7 by ATRA while overexpression of AFP in HLE cells attenuated ATRA induced ATG7 expression and autophagy. Thus, ATRA induced ATG7 and autophagy participated in its cytotoxicity on HCC cells and AFP interfere with the induction of ATG7 and autophagy through forming complex with RAR.

Peretinoin, an Acyclic Retinoid, for the Secondary Prevention of Hepatocellular Carcinoma

The high rates of hepatocellular carcinoma (HCC) recurrence after initially successful curative therapy emphasize ongoing unmet needs to prevent or reduce HCC recurrence. Retinoid acid (RA), a metabolite of vitamin A and its related analogues (termed retinoids) has been suggested as a promising chemotherapeutic agent in cancer treatment. The synthetic oral retinoid peretinoin is the only agent for the secondary chemoprevention of HCC after curative therapy that is currently well applied into clinical development. Here we present an updated summary of the molecular pathogenesis of HCC and of preclinical and clinical findings with peretinoin, including its clinical characteristics, safety and tolerability profile and future perspectives for clinical use.

Differentiation of Mesenchymal Stem Cells Derived From Human Adipose Tissue Into Cholinergic-like Cells; in vitro

Cholinergic associated diseases currently are major cause of neurological and neurodegenerative disabilities. As the drugs are not efficient in improving the suffered tissues, stem cell treatment is considered as an effective strategy for substituting the lost cells. In the current study, we set out to investigate the differentiation properties of human adipose-derived mensenchymal stem cells (AD-MSCs) into cholinergic-like cells by two morphogens; including retinoid acid (RA) and Sonic hedgehog (Shh) using a three- step in vitro procedure. The results were evaluated using Real-time PCR, Flowcytometry and Immunocytochemistry for two weeks. Our data showed that the cells could express cholinergic specific markers; including Islet-1, AChE, SMI-32 and Nestin at the level of mRNA and protein. We could also quantitatively evaluate the expression of Islet-1, AChE and Nestin at 14 days post- induction using flowcytometry. It is concluded that human AD-MSCs are potent type cell to differentiate into cholinergic like cells in the presence of RA and Shh through a three- step protocol; thus it could be a suitable cell candidate for regeneration of cholinergic associated diseases; however, more functional and electrophysiological analysis are needed.

Trastuzumab treatment in human breast cancer is associated with over-expression of the retinoic acid receptor alpha (RARA).

Treatment with trastuzumab has been associated with an increased risk of central nervous system metastasis in patients with human breast cancer (1-5). We performed unbiased transcriptome profiling of primary tumors of patients treated with trastuzumab using published microarray and multiplexed gene expression datasets (6, 7) to understand the transcriptional makeup of breast tumors in the trastuzumab-treated patients. We found that the retinoid acid receptor alpha was among the genes most differentially expressed in the primary tumors of patients treated with trastuzumab; retinoid acid receptor alpha was expressed at significantly higher levels in tumors from patients with trastuzumab as compared to those not treated with trastuzumab. Increased retinoic acid receptor alpha expression is known to confer tamoxifen resistance to human breast cancers (8), and RARA expression is higher in tumors with higher proliferative capacity (9), suggesting that trastuzumab could contribute to resistance to endocrine therapy.

Picornavirus 3C proteins inhibit RIG-I-mediated innate immune responses by reducing TRIM25 expression

Background：Enterovirus (EV) 3C proteins suppress type I interferon (IFN) responses mediated by retinoid acid-inducible gene I (RIG-I). An E3 ubiquitin ligase, tripartite motif protein 25 (TRIM25)-mediated RIG-I ubiquitination is essential for RIG-I antiviral activity. However, whether the effect of EV 3C on RIG-I is associated with TRIM25 remains unknown.Methods：In this study，luciferase reporter assays was used to detected the activity of IFN-β. Western Blot was used to detected the expression of proteins. Real-time PCR are used to detect that the mRNAs expression. And the co-immunoprecipitation assay was used to detect the interaction between TRIM25 and 3C protein.Results：Here, we demonstrated that 3C proteins of EV71 and CVB3 reduced the expression of RIG-I and TRIM25 through protease cleavage activities. Overexpression of TRIM25 restored RIG-I expression and IFN production reduced by 3C proteins. Further investigation confirmed that the two amino acids in TRIM25 required for RIG-I ubiquitination and structural conformation of TRIM25 were essential for RIG-I recovery. Moreover, we observed that TRIM25 could rescue RIG-I expression reduced by CVA6and EVD68 but not CVA16 3C.Conclusions：Our findings provide an insightful interpretation of 3C protein-mediated host innate immune suppression and support TRIM25 as an attractive target against EV infection.