Beneficial Effect of Rapamycin on Liver Fibrosis in a Mouse Model (C57bl/6 Mouse).

BACKGROUND: Liver fibrosis is a chronic inflammatory disease that progresses and has a high mortality rate. This study was performed to investigate the protective effect of rapamycin on experimentally induced chronic liver injury in mice models using both biochemical parameters of liver function enzymes. METHODS: Twenty-four mice were divided randomly into 4 equal groups: [1] the normal group, n = 6; [2] the liver fibrosis (LF) group, n = 6; [3] the LF with the treatment of rapamycin group, n = 6; [4] the LF with the treatment of silimaryn, n = 6. RESULTS: In the group receiving oral administration of rapamycin, aspartate aminotransferase, alanine aminotransferase, urea, and creatinine were found to significantly decrease compared to the liver fibrosis group. Rapamycin, in the orally administered group, demonstrated a statistically significant decrease in the expression of interleukin (IL) 10, IL-1B, inducible nitric oxide synthase, and tumor necrosis factor alpha compared to the liver fibrosis group. CONCLUSIONS: In this study, we explored the potential therapeutic effects of rapamycin on liver fibrosis in an animal model.

Protective Effects of Repetitive Transcranial Magnetic Stimulation Against Streptozotocin-Induced Alzheimer's Disease.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation under investigation for treatment of a wide range of neurological disorders. In particular, the therapeutic application of rTMS for neurodegenerative diseases such as Alzheimer's disease (AD) is attracting attention. However, the mechanisms underlying the therapeutic efficacy of rTMS have not yet been elucidated, and few studies have systematically analyzed the stimulation parameters. In this study, we found that treatment with rTMS contributed to restoration of memory deficits by activating genes involved in synaptic plasticity and long-term memory. We evaluated changes in several intracellular signaling pathways in response to rTMS stimulation; rTMS treatment activated STAT, MAPK, Akt/p70S6K, and CREB signaling. We also systematically investigated the influence of rTMS parameters. We found an effective range of applications for rTMS and determined the optimal combination to achieve the highest efficiency. Moreover, application of rTMS inhibited the increase in cell death induced by hydrogen peroxide. These results suggest that rTMS treatment exerts a neuroprotective effect on cellular damage induced by oxidative stress, which plays an important role in the pathogenesis of neurological disorders. rTMS treatment attenuated streptozotocin (STZ)-mediated cell death and AD-like pathology in neuronal cells. In an animal model of sporadic AD caused by intracerebroventricular STZ injection, rTMS application improved cognitive decline and showed neuroprotective effects on hippocampal histology. Overall, this study will help in the design of stimulation protocols for rTMS application and presents a novel mechanism that may explain the therapeutic effects of rTMS in neurodegenerative diseases, including AD.

A Pilot Genome-Wide Association Study Identifies Novel Markers of Metabolic Syndrome in Patients with Psoriasis.

BACKGROUND: Recent studies have reported that psoriasis is associated with the development of metabolic syndrome. Genome-wide association studies have been used to discover gene variant markers that occur frequently in case group in relation to specific diseases. OBJECTIVE: The aim of the present study was to investigate the variants of specific genes involved in metabolic syndrome associated with psoriasis. METHODS: A total of 95 psoriasis patients were recruited and divided into two groups: one with metabolic syndrome (38 patients) and the other without (57 patients). After genotyping, imputation, and quality checking, the association between the several single nucleotide polymorphisms and metabolic syndrome in psoriasis was tested, followed by gene set enrichment analysis. RESULTS: We found 76 gene polymorphisms that conferred an increased risk for metabolic syndrome in patients with psoriasis. Four single nucleotide polymorphisms (rs17154774 of FRMD4A, rs77498336 of GPR116, rs75949580 and rs187682251 of MAPK4) showed the strongest association between metabolic syndrome and psoriasis. The epidermal growth factor receptor protein was located at the center of the protein interactions for the gene polymorphisms. CONCLUSION: This study identified several previously unknown polymorphisms associated with metabolic syndrome in psoriasis. These results highlight the potential for future genetic studies to elucidate the development, and ultimately prevent the onset, of metabolic syndrome in patients with psoriasis.

Bisphenol A release from commercially available 3-dimensionally printed resins and human cell apoptosis to bisphenol A: an in-vitro study.

Bisphenol A (BPA) from dental materials may be linked to children's health issues. This study aimed to assess the release of BPA from commercially available 3-dimensional (3D)-printed resin materials and evaluate BPA-related apoptotic effects on human periodontal ligament cells and gingival fibroblasts. Commercially available 3D-printed resin materials for prosthodontic use were selected as follows: NextDent C&B MFH (3D Systems, Rock Hill, SC, USA), DIOnavi-P. MAX (Dio Co., Busan, Korea), and DIOnavi-Denture02 (Dio Co., Busan, Korea). Identical cuboidal samples (1 cm × 1 cm × 0.5 cm) were printed from the materials and cured. BPA release was assessed using liquid chromatography/mass spectrometry (LC/MS). In addition, human gingival fibroblasts and periodontal ligament cells were exposed to various BPA solutions based on the LC/MS results. Cell Counting kit-8 (CCK-8) and real-time polymerase chain reaction analyses were performed to evaluate BPA-related apoptotic effects. The LC/MS analysis confirmed that none of the 3D-printed resin materials released BPA after curing. Both human gingival fibroblasts and periodontal ligament cells showed lower viability after BPA exposure. Regarding apoptosis-related gene expression, Caspase10 (CASP10) expression in periodontal ligament cells was significantly different in the BPA solutions (p < 0.05). The expression of BAX and Capspase8 (CASP8) in gingival fibroblasts was significantly increased by BPA in a dose-dependent manner (p < 0.05). Within the limitations of this study, the 3D-printed resin materials were not found to release BPA. This finding implies that 3D-printed resin materials are not associated with potential BPA-related risks in children.

Anti-Apoptotic Effect of Chrysophanol Isolated from Cassia tora Seed Extract on Blue-Light-Induced A2E-Loaded Human Retinal Pigment Epithelial Cells.

The seeds of Cassia tora (C. tora) species mainly contain anthraquinone, anthraquinone glycoside, and naphthalene derivatives. We investigated the anti-apoptotic effects of C. tora seed extract and its isolated compounds on blue-light-induced lipofuscin (A2E)-loaded human retinal pigment epithelial (RPE) cells. For analysis of the C. tora extract, high-performance liquid chromatography method was used. A2E-loaded human retinal pigment epithelial cells and blue light were used to create excessive photo-oxidation to induce cell death. Lactate dehydrogenase (LDH) assay was used to measure cell cytotoxicity, and the mRNA expression of genes involved in apoptosis was examined to evaluate the mechanism of cell death. C. tora extract, n-hexane fraction, and chrysophanol were found to inhibit apoptotic cell death. Additionally, C. tora extract, n-hexane fraction, and chrysophanol reduced the mRNA expression of genes involved in the apoptosis pathway. C. tora and chrysophanol were considered to inhibit apoptosis and oxidative stress response. The major component of C. tora has a protective effect against apoptosis. The ingredients of C. tora can be used as therapeutic substances or to prevent diseases caused by the excessive oxidation of A2E substances in the retina, such as in age-related macular degeneration.

Whole Exome Sequencing of a Patient with a Milder Phenotype of Xeroderma Pigmentosum Group C.

A 17-year-old female Korean patient (XP115KO) was previously diagnosed with Xeroderma pigmentosum group C (XPC) by Direct Sanger sequencing, which revealed a homozygous nonsense mutation in the XPC gene (rs121965088: c.1735C > T, p.Arg579Ter). While rs121965088 is associated with a poor prognosis, our patient presented with a milder phenotype. Hence, we conducted whole-exome sequencing in the patient and her family members to detect coexisting mutations that may have resulted in a milder phenotype of rs121965088 through genetic interaction. Materials and Methods: the whole-exome sequencing analysis of samples obtained from the patient and her family members (father, mother, and brother) was performed. To identify the underlying genetic cause of XPC, the extracted DNA was analyzed using Agilent's SureSelect XT Human All Exon v5. The functional effects of the resultant variants were predicted using the SNPinfo web server, and structural changes in the XPC protein using the 3D protein modeling program SWISS-MODEL. Results: Eight biallelic variants, homozygous in the patient and heterozygous in her parents, were detected. Four were found in the XPC gene: one nonsense variant (rs121965088: c.1735C > T, p.Arg579Ter) and three silent variants (rs2227998: c.2061G > A, p. Arg687Arg; rs2279017: c.2251-6A > C, intron; rs2607775: c.-27G > C, 5'UTR). The remaining four variants were found in non-XP genes, including one frameshift variant [rs72452004 of olfactory receptor family 2 subfamily T member 35 (OR2T35)], three missense variants [rs202089462 of ALF transcription elongation factor 3 (AFF3), rs138027161 of TCR gamma alternate reading frame protein (TARP), and rs3750575 of annexin A7 (ANXA7)]. Conclusions: potential candidates for genetic interactions with rs121965088 were found. The rs2279017 and rs2607775 of XPC involved mutations in the intron region, which affected RNA splicing and protein translation. The genetic variants of AFF3, TARP, and ANXA7 are all frameshift or missense mutations, inevitably disturbing the translation and function of the resultant proteins. Further research on their functions in DNA repair pathways may reveal undiscovered cellular relationships within xeroderma pigmentosum.

Risk prediction of the metabolic syndrome using TyG Index and SNPs: a 10-year longitudinal prospective cohort study.

TyG (triglyceride and glucose) index using triglyceride and fasting blood glucose is recommended as a useful marker for insulin resistance. To clarify whether the TyG index is a marker for predicting metabolic syndrome (MetS) and to investigate the importance of single-nucleotide polymorphisms (SNPs) in MetS diagnosis. From 2001 to 2014, a longitudinal prospective cohort study of 3580 adults aged 40-70 years was conducted. The area under the receiver operating characteristic curves (AUROC) and Youden index (YI) was calculated to assess the diagnostic value. During the 14-year follow-up, 1270 subjects developed MetS. Five SNPs in four genes (BUD13 rs10790162, ZPR1 rs2075290, APOA5 rs2266788, APOA5 rs2075291, and MKL1 rs4507196) significantly correlated with susceptibility to MetS (p < 0.00005). The areas under the curve of TyG index and HOMA-IR were 0.854 (95% confidence interval [CI], 0.841-0.867) and 0.702 (95% CI, 0.684-0.721), respectively. Despite no statistical significance, AUROC and YI were increased when MetS was diagnosed using TyG index and the five SNPs. TyG index might be useful for identifying individuals at high risk of developing MetS. The combination of TyG index and SNPs showed better diagnostic accuracy than TyG index alone, indicating the potential value of novel SNPs for MetS diagnosis.

Association between exonic polymorphisms of human leukocyte antigen-G gene and non-segmental vitiligo in the Korean population.

Background Vitiligo is a pigmentary skin disorder characterised by a chronic and progressive loss of melanocytes. Although several theories have been suggested to the pathogenesis of vitiligo, an autoimmune process leading to melanocyte destruction appears most likely. Human leukocyte antigen-G is a non-classic, major histocompatibility complex Class I molecule that plays an important role in the suppression of the immune response. Several recent studies have provided evidences that polymorphisms in the human leukocyte antigen-G gene might be related with autoimmune diseases. Objectives The aim of this study was to decide whether exonic single nucleotide polymorphisms in human leukocyte antigen-G contribute to the risk of developing non-segmental vitiligo in the Korean population. Methods To evaluate the associations between exonic single nucleotide polymorphisms (rs1630223 [Ala5Ala] and rs12722477 [Leu134Ile]) of human leukocyte antigen-G and vitiligo, 244 patients with vitiligo and 398 healthy controls were recruited. Genotyping was performed using Fluidigm 192.24 Dynamic Array with EP1 (Fluidigm Corp., CA). The SNP type assay (Fluidigm Corp., CA), which employs allele-specifically designed fluorescences (FAM or VIC) primers and a common reverse primer was applied and the data were analysed using the EP1 single nucleotide polymorphisms genotyping analysis software to obtain genotype calls. Results Two exonic single nucleotide polymorphisms (rs1630223 and rs12722477) exhibited significant associations with susceptibility and remained a statistically significant association following Bonferroni correction. These two single nucleotide polymorphisms were located within a block of linkage disequilibrium. Haplotypes G-C and A-A comprising rs1630223 and rs12722477 demonstrated a significant association with non-segmental vitiligo. Limitations The protein expression level of patients with vitiligo and controls was not studied and a replication study of the genetic association in an independent group was not managed. Conclusion Our results suggest that exonic human leukocyte antigen-G polymorphisms (rs1630223 and rs12722477) are associated with the development of non-segmental vitiligo.

Serum 25-Hydroxy Vitamin D Levels and Association of Vitamin D Receptor Gene Polymorphisms in Vitiligo.

BACKGROUND: The role of vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms has been established in many autoimmune diseases, including vitiligo, but the result is still controversial. OBJECTIVES: The aim of this study was to investigate the serum vitamin D levels in vitiligo patients and to compare the association of VDR gene polymorphisms in vitiligo patients and healthy controls. METHODS: We collected the data of age, sex, serum 25-hydroxy vitamin D (25[OH]D) level, thyroid autoantibodies, disease duration, types of vitiligo, family history and the affected body surface area of vitiligo from 172 patients. And we analyzed the VDR gene polymorphisms in 130 vitiligo and 453 age-sex-matched control subjects. RESULTS: The mean serum level of 25(OH)D in 172 vitiligo patients was 18.75 ± 0.60 ng/mL, which had no significant difference with a mean serum value of 25(OH)D in the Korean population. However, there were significant differences according to the duration of the disease and family history. Also, there were no significant differences in the genotypic and allelic distributions of 37 examined SNPs of VDR gene between vitiligo patients and healthy controls. CONCLUSION: Serum level of 25(OH)D in vitiligo patients was not significantly different from the mean serum value of the Korean population. Also, there were no significant differences in the genotypic distributions of VDR gene between vitiligo patients and healthy controls.

Acute Kidney Injury: Biomarker-Guided Diagnosis and Management.

Acute kidney injury (AKI) is a common clinical syndrome that is characterized by abnormal renal function and structure. The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference in 2019 reviewed the stages of AKI and the definitions of AKI-related terminologies, and discussed the advances in the last decade. Along with serum creatinine level and urine output, more accurate novel biomarkers for predicting AKI are being applied for the early detection of renal dysfunction. A literature search was conducted in PubMed, Scopus, Medline, and ClinicalTrials.gov using the terms AKI and biomarker, combined with diagnosis, management, or prognosis. Because of the large volume of data (160 articles) published between 2005 and 2022, representative literature was chosen. A number of studies have demonstrated that new biomarkers are more sensitive in detecting AKI in certain populations than serum creatinine and urine output according to the recommendations from the Acute Disease Quality Initiative Consensus Conference. To be specific, there is a persistently unresolved need for earlier detection of patients with AKI before AKI progresses to a need for renal replacement therapy. Biomarker-guided management may help to identify a high-risk group of patients in progression to severe AKI, and decide the initiation time to renal replacement therapy and optimal follow-up period. However, limitations such as biased data to certain studied populations and absence of cutoff values need to be solved for worldwide clinical use of biomarkers in the future. Here, we provide a comprehensive review of biomarker-based AKI diagnosis and management and highlight recent developments.

Diabetes Mellitus Promotes Smooth Muscle Cell Proliferation in Mouse Ureteral Tissue through the P-ERK/P-JNK/VEGF/PKC Signaling Pathway.

Background and objectives: The aim of our study was to evaluate the role of diabetes mellitus (DM) as a significant factor affecting spontaneous stone expulsion, as suggested by previous research. Materials and methods: We investigated the influence of DM on the ureter using a murine model. The mouse-model arm of this study used 20 15 -week-old mice, including 10 normal (control) mice and 10 DM mice. We measured the proximal, middle and distal ureteral smooth muscle thickness in each mouse and the differences among ureteral sections were analyzed. Mouse ureteral specimens were also analyzed via western blotting to detect relative protein expression of phosphor-extracellular signal regulated kinases (P-ERK), phosphor-C-Jun N-terminal kinase (P-JNK), vascular endothelial growth factor (VEGF), and protein kinase C (PKC), which are representative factors involved in cell regulation. Results: We observed significant hyperproliferation of ureteral smooth muscle in DM mice compared to normal mice, which may provoke reduced peristalsis. The ureteral smooth muscle of DM mice was significantly thicker than that of normal mice in all ureteral tissues: proximal (p = 0.040), mid (p = 0.010), and distal (p = 0.028). The relative protein expression of P-ERK (p = 0.005) and P-JNK (p = 0.001) was higher in the diabetic group compared to the normal group. Additionally, protein expression of VEGF (p = 0.002) and PKC (p = 0.001) were remarkably up-regulated in DM mice. Conclusions: Hyperproliferation of ureteral smooth muscle was observed in DM mice, but not in normal mice. The pathways mediated by P-ERK, P-JNK, VEGF, and PKC may play an important role in pathological ureteral conditions.

Anti-Inflammatory and Anti-Oxidant Effects of Korean Ginseng Berry Extract in LPS-Activated RAW264.7 Macrophages.

Inflammatory macrophages stimulated by LPS disrupt homeostasis in the production of inflammatory cytokines and nitric oxide (NO). These are the causes of inflammation-related diseases and various cancers. The present study aimed to evaluate the protective effects of Korean ginseng berry extract (KGB) on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophage cells. NO and prostaglandin E2 (PGE[Formula: see text] production was elevated in response to LPS stimulation and was dose-dependently reduced by pretreatment with KGB. The expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein were also reduced by KGB treatment. KGB treatment significantly suppressed the LPS-induced gene expression and production of cytokines, including interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]. Furthermore, KGB inhibited the translocation of nuclear expression of nuclear factor-kappa B (NF-[Formula: see text]B) by preventing inhibitory factor-kappa B (I[Formula: see text]B[Formula: see text] phosphorylation and suppressing the phosphorylation of extracellular signal-related kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Additionally, decreased reactive oxygen species (ROS) generation and increased glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities were observed following KGB treatment. Taken together, these results indicated that KGB possesses anti-inflammatory and anti-oxidant effects, mediated by the inhibition of the mitogen-activated protein kinases (MAPKs) signaling pathway in LPS-induced RAW264.7 macrophages. KGB may represent a potential therapeutic agent for inflammatory and oxidative stress-related diseases.

Association of GZMB polymorphisms and susceptibility to non-segmental vitiligo in a Korean population.

Non-segmental vitiligo (NSV) is the most common type of vitiligo, which is characterized by chronic and progressive loss of melanocytes. Genetic factors have been shown to play a key role in NSV in association and family studies. Granzyme B is a serine protease found in the cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells that play an important role in inducing apoptotic changes of target cells. Several recent studies have provided evidence that polymorphism in the GZMB gene might be associated with autoimmune disease. A total of 249 NSV patients and 455 healthy controls were recruited to determine whether single nucleotide polymorphisms (SNPs) [rs2236337 (3' untranslated region, UTR), rs2236338 (Tyr247His), rs11539752 (Pro94Ala), rs10909625 (Lys80Lys), rs8192917 (Arg55Gln), and rs7144366 (5' near gene)] in GZMB gene contribute to the risk of developing NSV. Genotyping was performed using a single 192.24 Dynamic Array IFC. Data were analyzed using EP1 SNP Genotyping Analysis software to obtain genotype calls. Among the six SNPs tested, five SNPs (rs2236337, rs2236338, rs11539752, rs10909625, and rs8192917) showed significant association with NSV susceptibility. Among them, rs2236338, rs11539752, rs10909625, and rs8192917 remained a statistically significant association following multiple correction test. The five SNPs were located within a block of linkage disequilibrium. Haplotypes T-A-G-T-T and C-G-C-C-C consisting of rs2236337, rs2236338, rs11539752, rs10909625, and rs8192917 demonstrated significant association with NSV. Our results suggest that GZMB polymorphisms are associated with the development of NSV.

Effect of Glycyrrhizic Acid on Scopolamine-Induced Cognitive Impairment in Mice.

PURPOSE: Cognitive impairment is one of the main symptoms of Alzheimer disease and other dementias. Glycyrrhiza uralensis is a natural product that has a protective effect against cognitive impairment. In this study, we investigated whether glycyrrhizic acid, among the main bioactive components of Glycyrrhiza uralensis, has a neuroprotective effect on scopolamine-induced cognitive impairment. METHODS: Twenty-week-old male Institute of Cancer Research mice were used in this study. The scopolamine-induced cognitive impairment mice model was used. Glycyrrhizic acid was orally administered to mice once daily for 21 days, while scopolamine (1 mg/kg) treatment was delivered 30 minutes before behavioral tests. Donepezil (2 mg/kg) was used as a positive drug control. To evaluate the effect of glycyrrhizic acid, the following assessments were performed on hippocampal tissue: Y-maze test, acetylcholinesterase activity, antioxidant enzymes' activity (superoxide dismutase, catalase). Western blotting for phosphor-extracellular signal-regulated kinase, P38, and c-Jun NH2-terminal kinase was conducted. RESULTS: We found that glycyrrhizic acid administration significantly improved scopolamine-induced cognitive impairment in the Y-maze test. The acetylcholinesterase activity, superoxide dismutase, and catalase activity in the glycyrrhizic acid-treated group showed a significant reversal of cognitive impairment compared with the scopolamine-treated group. CONCLUSION: Our results suggest that glycyrrhizic acid has a neuroprotective effect on cognitive function in scopolamine-induced cognitive impairment.

Association of the Promoter Haplotype of IFN-γ-Inducible Protein 16 Gene with Schizophrenia in a Korean Population.

OBJECTIVE: Viral infections play an important role in the development of schizophrenia, inducing the faulty immunological responses and aberrant inflammation. IFN-γ-inducible protein 16 (IFI16) is an immunological DNA sensor against viral infections, triggering the inflammatory responses. In this study, we investigated an association between putative promoter single nucleotide polymorphisms (SNPs) and haplotypes of IFI16 and schizophrenia. METHODS: A total of 280 schizophrenia patients and 427 control subjects were recruited in this study. We genotyped three promoter SNPs (rs1465175, rs3754464, rs1417806) using direct sequencing. Associations of SNPs and haplotypes of IFI16 with schizophrenia were analyzed. The promoter activities on the haplotypes of IFI16 were measured. RESULTS: The T allele of rs1465175 and the C allele of rs1417806 were protectively associated with schizophrenia (p=0.021 on rs1465175; p=0.016 on rs1417806), whereas the G allele of rs3754464 was associated with an increased risk of schizophrenia (p=0.019). In haplotype analysis, a significant association between the GGA haplotype and schizophrenia was shown (p=0.013). Moreover, we found that the GGA haplotype elevated the promoter activity compared to the GAA haplotype, whereas the TAC haplotype reduced that. CONCLUSION: The promoter SNPs and haplotypes of IFI16 may contribute to the susceptibility of schizophrenia, affecting the promoter activity of IFI16.

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population.

Purpose: Epidermal growth factor (EGF) has been found to be associated with the development and repair mechanisms of several renal diseases. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in EGF or its receptor genes might have an association with end-stage renal disease (ESRD) or acute renal allograft rejection (AR) in a Korean population.Methods: Three-hundred and forty seven recipients of the first renal transplants for ESRD, including 63 AR patients along with 289 healthy adults were included in the study. Five EGF gene SNPs (rs11568835, rs11568943, rs2237051, rs11569017, and rs3756261) and four EGFR gene SNPs (rs1140475, rs2293347, rs1050171, and rs6965469) were analyzed. The genotypes of these SNPs were analyzed using the AxiomTM genome-wide human assay. Statistical analysis was performed using SNPStats and Haploview version 4.2 software. Multiple logistic regression models (codominant, dominant, recessive, and Log-additive) were used to estimate the odds ratio (OR), 95% confidence interval (CI), and P value.Results: One SNP (rs11569017) in the EGF gene showed significant association with ESRD but not with AR. Another SNP (rs11568835) in the EGF gene showed significant association with susceptibility to AR but not with ESRD. One SNP (rs1050171) in the EGFR gene showed significant association with susceptibility to AR but not with ESRD.Conclusion: Our findings suggest that SNPs in the EGF and EGFR gene may be associated with the risk of ESRD and AR development in the Korean population.

Association between MicroRNA-4669 Polymorphism and Ischemic Stroke in a Korean Population.

Recent studies have explored the association between single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) and ischemic stroke (IS). In particular, the associations of rs2910164 (miRNA-146A), rs11614913 (miRNA-196A2), and rs3746444 (miRNA-499A) were intensively studied in IS. In this study, we investigated the associations between SNPs in miRNAs and IS including rs2910164, rs11614913, and rs3746444 in a Korean population. For a pilot study, we selected 19 SNPs in pre-miRNA region (including mature miRNA region) and genotyped in 140 IS patients and 240 control subjects using the Fluidigm Dynamic Array. Our pilot study showed a weak association of rs79402775 in miRNA-933 (p = 0.044) and a relatively strong association of rs35196866 in miRNA-4669 (p = 0.016) with IS. From the pilot study, we selected rs79402775, rs35196866, and rs7202008 (miRNA-2117; p = 0.055) as candidate miRNA SNPs on IS and further genotyped these SNPs in 264 IS patients and 455 control subjects using direct sequencing. In addition, we further analyzed the associations of rs2910164, rs11614913, and rs3746444 that have been intensively studied in previous studies. In the further analysis, we found the significant association between rs35196866 and IS (p = 0.0014 in additive model and p = 0.00015 in dominant model; p = 0.00037 in allele frequency analysis). However, the association between rs2910164, rs11614913, rs3746444, rs79402775, and rs7202008 and IS was not shown. These results suggest that miRNA-4669 may be involved in the susceptibility of IS.

Protective Effect of Citric Acid Against Hepatic Ischemia Reperfusion Injury in Sprague-Dawley Rats.

OBJECTIVE: Hepatic ischemia reperfusion (I/R) injury is regarded as a serious concern in clinical practice. Citric acid reduces oxidative stress and inflammation during hypoxia and reoxygenation. Our objective was to investigate the protective effect of citric acid against hepatic I/R injury in rats. METHODS: We fed Sprague-Dawley rats either citric acid (100 mg/kg/d) or saline. One week later, ischemia was induced by clamping the rats' common hepatic artery and portal vein for 30 minutes. The rats were randomly divided into 3 major groups that were treated as follows: 1. the sham operated group; 2. the I/R group; and 3. the I/R-citric acid group. RESULTS: Compared to the sham group, the I/R group had higher expression of aspartate aminotransferase and alanine aminotransferase and lower expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, nitric oxide, and albumin. Compared to the I/R group, the I/R-citric acid group had higher expression of catalase, superoxide dismutase, antioxidants, and nitric oxide, and lower expression of aspartate aminotransferase and alanine aminotransferase. CONCLUSIONS: These results suggest that citric acid therapy has significant therapeutic potential in ischemic liver injury.

Hesperidin Shows Protective Effects on Renal Function in Ischemia-induced Acute Kidney Injury (Sprague-Dawley Rats).

OBJECTIVE: Hesperidin is a well-known flavanone glycoside copiously found in sweet orange and lemon, which was recently reported to possess significant anti-inflammatory, analgesic, antifungal, antiviral, antioxidant, and anticancer activities. Ischemia-reperfusion (I/R) injury is a major problem after renal transplantation. Furthermore, inflammatory responses to I/R exacerbate the resultant renal injury. In the present study, we investigated whether hesperidin exhibits renoprotective effects against I/R-induced acute kidney injury in a rat model. METHODS: We fed Sprague-Dawley rats either hesperidin (100 mg/kg/d) or saline. One week later, ischemia was induced by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion. The rats were randomly divided into 3 groups, which were treated as follows: 1. the sham operated group; 2. the I/R group; 3. the I/R-hesperidin group RESULTS: Compared to the sham group, the I/R group had higher expression of blood urea nitrogen and serum creatinine and lower expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidants, and nitric oxide. Compared to the I/R group, the I/R-hesperidin group had higher expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, and nitric oxide and lower expression of blood urea nitrogen and serum creatinine. CONCLUSIONS: Hesperidin improved acute renal I/R injury through its antioxidant effects. These findings suggest that hesperidin is a potential therapeutic agent for acute ischemia-induced renal damage.

Genome-wide association study identifies new susceptible loci of IgA nephropathy in Koreans.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent evidence suggests that genetic factors are related to the pathogenesis of IgAN. We conducted a genome-wide association study (GWAS) to identify novel genetic susceptibility loci for IgAN in a Korean population. METHODS: We enrolled 188 biopsy-confirmed IgAN cases and 455 healthy controls for the discovery stage and explored associations between IgAN and single nucleotide polymorphisms (SNPs) using a customized DNA chip. The significant SNPs from the discovery samples were then selected for replication in an independent cohort with 310 biopsy-confirmed IgAN cases and 438 healthy controls. RESULTS: In the first stage, two SNPs (rs10172700 in LOC105373592 and rs2296136 in ANKRD16) were selected for further association analysis in the next stage. In the replication cohort, rs2296136 in ANKRD16 was significantly associated with IgAN (odds ratio [OR] = 1.40, 95% confidence interval [CI] 0.99-1.98, p = 0.05 in log-additive model, OR = 1.55, 95% CI = 1.06--2.27, p = 0.02 in dominant model, and OR = 0.70, 95% CI = 0.17--2.84, p = 0.62 in recessive model). rs2296136 in ANKRD16 also showed a significant association with IgAN in the entire study population combining GWAS and replication study (p = 0.0045 in log-additive model, p = 0.0027 in dominant model, and p = 0.76 in recessive model). CONCLUSIONS: The SNPs identified in the present study could be good candidate markers for predicting IgAN in Koreans, although further experimental validation is needed.