Diketopiperazine and isoindolinone alkaloids from the endophytic fungus Aspergillus sp. HAB10R12.

Four previously undescribed alkaloids, aspergillinine A-D, and four known diterpene pyrones were isolated from the potato dextrose agar (PDA) culture of Aspergillus sp. HAB10R12. The chemical structures of the isolated compounds were elucidated based on a detailed analysis of their NMR and MS data. The absolute configuration of the isolated compounds was determined by Electronic Circular Dichroism analysis coupled with computational methods. Aspergillinine A represents the first example of a diketopiperazine dipeptide containing the unnatural amino acid N-methyl kynurenine. Its absolute configuration revealed that it adopts a rather unusual conformation. Aspergillinine B represents a previously unencountered skeleton containing an isoindolinone ring. Aspergillinine C and D were similar to previously isolated diketopiperazine alkaloids, namely, lumpidin and brevianamide F, respectively. The diterpene pyrones were isolated twice previously, once from a soil-derived Aspergillus species, and once from the liquid culture of Aspergillus sp. HAB10R12. The alkaloids isolated in this study showed no antiproliferative activity when tested against HepG2 and A549 cancer cell lines.

Palm tocotrienol rich fraction with palm kernel oil supplementation prevents development of liver steatosis in high fat diet ICR mice.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) in Asian countries is increasing at concerning level. Currently, no specific treatment available to prevent its oxidative stress and progression except for diet and lifestyle changes. Vitamin E such as tocotrienol-rich fraction (TRF) has a promising potential in preventing NAFLD progression. TRF is a potent antioxidant but has low bioavailability due to the use of long-chain triglycerides (LCT) as its carrier. Testing of potential therapeutic agents such as TRF are commonly carried out using animal models. These animal models are often costly due to limited access to the supply especially Asian countries and predisposed to high transportation cost. Lower expenditure of NAFLD model should be investigated without forfeiting the outcome of study. Therefore, this study addresses the gap by utilizing the ICR mice as NAFLD model through dietary modification and testing on the newly formulated TRF with combination of palm kernel oil (PKO) as a medium-chain triglycerides (MCT) carrier. METHODS: Fifteen ICR strain mice were randomly group into two control and one treatment group. Control groups received high-fat diet (HFD) only and standard diet while treatment group was given HFD with TRF (200 mg/kg/day). Study was carried out for 10 weeks. Weights were recorded twice a week. At the end of study, all mice were euthanized and data such weights, waist circumference and random blood glucose were recorded. Liver from each mouse were prepared for histology assessment. RESULTS: Mice mean weights and random blood sugar showed no difference between group (P>0.05) while significance waist circumference was larger in HFD and TRF groups compared to SD (P<0.05). Histology assessment showed steatosis in TRF group had lower severity compared to HFD group. NAFLD activity score (NAS) was lower in treatment group compared to HFD group. CONCLUSIONS: TRF showed promising potential as an agent to reduce NAFLD progression in ICR mice. Further study at gene and protein levels are required to fully elucidate the mechanism of this new TRF formulation in reducing NAFLD progression.

Understanding the Impact of Perfluorinated Compounds on Cardiovascular Diseases and Their Risk Factors: A Meta-Analysis Study.

Perfluorinated compounds (PFCs) are non-biodegradable synthetic chemical compounds that are widely used in manufacturing many household products. Many studies have reported the association between PFCs exposure with the risk of developing cardiovascular diseases (CVDs). However, those reports are still debatable, due to their findings. Thus, this review paper aimed to analyse the association of PFCs compound with CVDs and their risk factors in humans by systematic review and meta-analysis. Google Scholar, PubMed and ScienceDirect were searched for PFCs studies on CVDs and their risk from 2009 until present. The association of PFCs exposure with the prevalence of CVDs and their risk factors were assessed by calculating the quality criteria, odds ratios (ORs), and 95% confidence intervals (CIs). CVDs risk factors were divided into serum lipid profile (main risk factor) and other known risk factors. The meta-analysis was then used to derive a combined OR test for heterogeneity in findings between studies. Twenty-nine articles were included. Our meta-analysis indicated that PFCs exposure could be associated with CVDs (Test for overall effect: z = 2.2, p = 0.02; Test for heterogeneity: I2 = 91.6%, CI = 0.92-1.58, p < 0.0001) and their risk factors (Test for overall effect: z = 4.03, p < 0.0001; Test for heterogeneity: I2 = 85.8%, CI = 1.00-1.14, p < 0.0001). In serum lipids, total cholesterol levels are frequently reported associated with the exposure of PFCs. Among PFCs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) exposure increased the risk of CVDs than other types of PFCs. Although the risk of PFOA and PFOS were positively associated with CVDs and their risk factors, more observational studies shall be carried out to identify the long-term effects of these contaminants in premature CVDs development in patients.

The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.

RNA-binding proteins (RBPs) are increasingly identified as post-transcriptional drivers of cancer progression. The RBP LARP1 is an mRNA stability regulator, and elevated expression of the protein in hepatocellular and lung cancers is correlated with adverse prognosis. LARP1 associates with an mRNA interactome that is enriched for oncogenic transcripts. Here we explore the role of LARP1 in epithelial ovarian cancer, a disease characterized by the rapid acquisition of resistance to chemotherapy through the induction of pro-survival signalling. We show, using ovarian cell lines and xenografts, that LARP1 is required for cancer cell survival and chemotherapy resistance. LARP1 promotes tumour formation in vivo and maintains cancer stem cell-like populations. Using transcriptomic analysis following LARP1 knockdown, cross-referenced against the LARP1 interactome, we identify BCL2 and BIK as LARP1 mRNA targets. We demonstrate that, through an interaction with the 3' untranslated regions (3' UTRs) of BCL2 and BIK, LARP1 stabilizes BCL2 but destabilizes BIK with the net effect of resisting apoptosis. Together, our data indicate that by differentially regulating the stability of a selection of mRNAs, LARP1 promotes ovarian cancer progression and chemotherapy resistance.

The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration.

The RNA binding protein Larp1 was originally shown to be involved in spermatogenesis, embryogenesis and cell-cycle progression in Drosophila. Our data show that mammalian Larp1 is found in a complex with poly A binding protein and eukaryote initiation factor 4E and is associated with 60S and 80S ribosomal subunits. A reduction in Larp1 expression by siRNA inhibits global protein synthesis rates and results in mitotic arrest and delayed cell migration. Consistent with these data we show that Larp1 protein is present at the leading edge of migrating cells and interacts directly with cytoskeletal components. Taken together, these data suggest a role for Larp1 in facilitating the synthesis of proteins required for cellular remodelling and migration.