Genetic association-based functional analysis detects HOGA1 as a potential gene involved in fat accumulation.

Although there are a number of discoveries from genome-wide association studies (GWAS) for obesity, it has not been successful in linking GWAS results to biology. We sought to discover causal genes for obesity by conducting functional studies on genes detected from genetic association analysis. Gene-based association analysis of 917 individual exome sequences showed that HOGA1 attains exome-wide significance (p-value < 2.7 × 10-6) for body mass index (BMI). The mRNA expression of HOGA1 is significantly increased in human adipose tissues from obese individuals in the Genotype-Tissue Expression (GTEx) dataset, which supports the genetic association of HOGA1 with BMI. Functional analyses employing cell- and animal model-based approaches were performed to gain insights into the functional relevance of Hoga1 in obesity. Adipogenesis was retarded when Hoga1 was knocked down by siRNA treatment in a mouse 3T3-L1 cell line and a similar inhibitory effect was confirmed in mice with down-regulated Hoga1. Hoga1 antisense oligonucleotide (ASO) treatment reduced body weight, blood lipid level, blood glucose, and adipocyte size in high-fat diet-induced mice. In addition, several lipogenic genes including Srebf1, Scd1, Lp1, and Acaca were down-regulated, while lipolytic genes Cpt1l, Ppara, and Ucp1 were up-regulated. Taken together, HOGA1 is a potential causal gene for obesity as it plays a role in excess body fat development.

Identification and functional validation of HLA-C as a potential gene involved in colorectal cancer in the Korean population.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide and is influenced by environmental and genetic factors. Although numerous genetic loci for CRC have been identified, the overall understanding of the genetic factors is yet to be elucidated. We sought to discover new genes involved in CRC applying genetic association analysis and functional study. RESULTS: We conducted exome array analysis on 194 CRC and 600 control subjects for discovering new candidate CRC genes. Fisher's exact test detected one exome-wide significant functional locus for CRC on SMCO1 (P < 10-6) and two suggestive functional loci on HLA-C and NUTM1 (10-6 ≤ P < 10-4). To evaluate the biological role of three candidate CRC genes, the differential expression of these genes between CRC and non-cancer colorectal cells was analyzed using qRT-PCR and publicly available gene expression data. Of three genes, HLA-C consistently revealed the significant down-regulation in CRC cells. In addition, we detected a reduction in cell viability in the HLA-C overexpression CRC cell line, implying the functional relevance of HLA-C in CRC. To understand the underlying mechanism exerted by HLA-C in CRC development, we conducted RNA sequencing analyses of HLA-C overexpression CRC cells and non-cancer colorectal cells. Pathway analysis detected that significantly down-regulated genes in HLA-C overexpression CRC cells were highly enriched in cancer-related signaling pathways such as JAK/STAT, ErbB, and Hedgehog signaling pathways. CONCLUSIONS: Exome array CRC case-control analysis followed by functional validation demonstrated that HLA-C likely exerts its influence on CRC development via cancer-related signaling pathways.

The effect of pH and transition metal ions on cysteine-assisted gold aggregation for a distinct colorimetric response.

Colorimetric detection is a promising sensing strategy that is applicable to qualitative and quantitative determination of an analyte by monitoring visually detectable color changes with the naked eye. This study explored the cysteine (Cys)-induced aggregation of gold nanoparticles (AuNPs) in order to develop a sensitive colorimetric detection method for Cys. For this purpose, we systematically investigated the colorimetric response of AuNPs to Cys with varying particle sizes and concentrations. The AuNPs with various diameters ranging from 26.5 nm to 58.2 nm were synthesized by the citrate reduction method. When dispersed in water to have the same surface area per unit volume, the smaller AuNPs (26.5 nm) exhibited a more sensitive response to Cys compared to a larger counterpart (46.3 nm). We also examined the effect of divalent first-row transition metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+) on the Cys-induced aggregation of AuNPs. Among the tested metal ions, the addition of Cu2+ provided the highest enhancement in sensitivity to Cys regardless of pH between 3.5 and 7. The significant increase in the sensitivity caused by Cu2+ could be attributed to the capability of Cu2+ to form a highly stable chelate complex with surface-immobilized Cys, facilitating the aggregation of AuNPs. For the AuNPs-Cu2+ system at pH 7, the detection limit for Cys was determined to be 5 nM using UV-vis spectroscopy. The reported strategy showed the potential to be used for a rapid and sensitive detection of Cys and also metal ions that can facilitate Cys-mediated aggregation of AuNPs.

Erratum: The effect of pH and transition metal ions on cysteine-assisted gold aggregation for a distinct colorimetric response.

[This corrects the article DOI: 10.1039/D1RA00013F.].

Comparative release kinetics of small drugs (ibuprofen and acetaminophen) from multifunctional mesoporous silica nanoparticles.

Multifunctional mesoporous silica nanoparticles (MSNs) can confer dynamically varied release kinetics depending on the intermolecular interactions between model drugs and functional decorations on the MSNs. Herein, brush-like fluorescent conjugates were grafted on the pore walls of pristine MSNs for high drug loading and to impart fluorescence properties. The fluorescent MSNs (FMSNs) were further coated with polydopamine (PDA) and graphene oxide (GO) double layer, designated FMSNs@PDA and FMSNs@PDA@GO, respectively. The FMSNs@PDA@GO exhibited highly consistent drug release over one week (∼7 days) because of the consolidated PDA/GO double layer at neutral pH (7.4). However, the release rate of FMSN-Ibu@PDA@GO was increased at acidic pH (5.5) because the PDA/GO double layer was partially disrupted due to weakened π-π stacking and electrostatic interactions. The release kinetics of the FMSNs-based NPs (FMSNs, FMSNs@PDA, and FMSNs@PDA@GO) were systematically investigated using negatively charged hydrophobic ibuprofen and neutral hydrophilic acetaminophen at pH 7.4. In the FMSN-drug system, the release rate of acetaminophen was higher than that of ibuprofen because of the higher solubility of acetaminophen in aqueous solution. In addition, ibuprofen has a bulky molecular structure compared to acetaminophen, leading to its slower transmission through the porous channels of FMSNs. In the FMSNs-drug@PDA system, acetaminophen exhibited a slower release rate than ibuprofen, owing to the π-π stacking interactions in the transmission of neutral acetaminophen by the PDA coating layer. On the other hand, the FMSNs-drug@PDA@GO exhibited a slower ibuprofen release rate than acetaminophen, owing to the electrostatic repulsion effect of the negative GO layer. Our drug delivery system was demonstrated as an advanced delivery platform, in which the transmission rate is controlled by intermolecular interactions between the diffusing drugs and functional decorations on the nanocarrier.