Porcine Reproductive and Respiratory Syndrome Virus Engineered by Serine Substitution on the 44th Amino Acid of GP5 Resulted in a Potential Vaccine Candidate with the Ability to Produce High Levels of Neutralizing Antibody.

N-linked glycans covering GP5 neutralizing epitopes of porcine reproductive and respiratory syndrome virus (PRRSV) have been proposed to act as a sheath blocking the production of neutralizing antibodies. Herein, we genetically engineered PRRSV with serine (S) substitution on the 44th asparagine (N) on the GP5 ectodomain of PRRSV-2 lineage-1. To evaluate the recombinant PRRSV, in vivo experiments were performed in piglets. The recombinant virus group showed no viremia until 42 days post-inoculation (dpi), and the rectal temperature and average daily weight gain were in the normal range at the same time point as the negative control group. On the 42 dpi, both groups were challenged with the wild-type virus. The recombinant PRRSV group showed lower rectal temperature, viremia, and the lung lesions than that of the negative control group for 19 days post-challenge (dpc). Additionally, the recombinant virus induced 4.50 ± 3.00 (log2) and 8.25 ± 0.96 (log2) of neutralizing antibody before and after challenge, respectively. Taken together, this study confirmed that N44S substitution can create an infectious PRRSV that strongly induces neutralizing antibodies. In addition, the vCSL1-GP5-N44S mutant that we produced was confirmed to have potential as a vaccine candidate, showing good safety and protective effects in pigs.

Prospective longitudinal analysis of antibody response after standard and booster doses of SARS-COV2 vaccination in patients with early breast cancer.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants brought waves of pandemics with breakthrough infections in vaccinated individuals. We analyzed the antibody responses after primary and booster vaccination in healthy controls (HC) and patients with early breast cancer (BC). Methods: In this prospective longitudinal cohort study, the binding activity of serum antibody level against spike proteins and antigens of SARS-CoV-2 variants was measured within 21 days after each vaccination in the BC group and HC group. Results: All participants, 40 in the BC and 20 in the HC group, had increased antibody response after vaccination. BC group, however, had weaker humoral responses than the HC group (IgG: 1.5, 2.3, 2.5-folds in BC vs. 1.9, 3.6, 4.0-folds in HC after each dose; IgA: 2.1, 3.0, 3.6-folds in BC vs. 4.2, 10.4, 5.2-folds in HC after each dose, respectively). Those under concurrent cytotoxic chemotherapy had weaker antibody response than the non-cytotoxic treatment group and HC. Adjunct use of steroids and age were not significant risk factors. The levels of binding antibody against the Delta and the Omicron (BA1) variants were lower than the wild-type, especially in BC. Conclusion: In the waves of new sub-variants, our study suggests that an additional dose of vaccinations should be recommended according to the anti-cancer treatment modality in patients with BC who had received booster vaccination.

Recombinant African Swine Fever Virus Arm/07/CBM/c2 Lacking CD2v and A238L Is Attenuated and Protects Pigs against Virulent Korean Paju Strain.

African swine fever (ASF) is an obligated declaration swine disease, provoking farm isolation measures and the closing of affected country boarders. ASF virus (ASFV) is currently the cause of a pandemic across China and Eurasia. By the end of 2019, ASF was detected in nine EU Member States: Bulgaria, Romania, Slovakia, Estonia, Hungary, Latvia, Lithuania, Poland and Belgium. The affected area of the EU extended progressively, moving mostly in a southwestern direction (EFSA). Inactivated and/or subunit vaccines have proven to fail since certain virus replication is needed for protection. LAVs are thus the most realistic option, which must be safe, effective and industrially scalable. We here generated a vaccine prototype from the Arm/07/CBM/c2 genotype II strain, in which we have deleted the EP402R (CD2v) and A238L genes by CRISPR/Cas9 in COS-1 cells, without detectable further genetic changes. The successful immunization of pigs has proven this vaccine to be safe and fully protective against the circulating Korean Paju genotype II strain, opening the possibility of a new vaccine on the market in the near future.

Chronic Disease Management for People With Hypertension.

Objectives: To assess the effectiveness of continuity of care policies by identifying the impact of a chronic disease management program on the continuity of care in patients with hypertension in South Korea. Methods: The propensity score matching method was used to control selection bias, and the difference-in-differences method was used to compare the impact on the treatment and control groups according to the policy intervention. Results: The continuity of care index of hypertensive patients using the difference-in-differences analysis outcome of the chronic disease management program was higher than that of the non-participating hypertensive patients. Conclusion: Continuous treatment is vital for chronic diseases such as hypertension. However, the proportion of those participating in the intervention was low. Encouraging more hypertensive patients to participate in policy intervention through continuous research and expanding the policy to appropriately reflect the increasing number of chronic diseases is necessary.

Development of a Chimeric Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)-2 Vaccine Candidate Expressing Hypo-Glycosylated Glycoprotein-5 Ectodomain of Korean Lineage-1 Strain.

Vaccination is a practical method to provide protection against porcine reproductive and respiratory syndrome virus (PRRSV), but current PRRSV vaccines show limited efficacy against divergent field strains. Lineage 1 PRRSV includes virulent strains such as NADC30 and MN184 and now has become one of the most prevalent viruses in Korea. Accordingly, there is an urgent need to develop a new vaccine for Korean lineage-1 strains. In this study, a vaccine candidate against Korean lineage-1 PRRSV, vCSL1-GP5-N33D, was developed by reverse genetics technology. vCSL1-GP5-N33D was designed as a hypo-glycosylated chimeric virus containing the glycoprotein 5 ectodomain region of the Korean lineage-1 wild-type strain. An inactivated vaccine of vCSL1-GP5-N33D was applied to a PRRS-endemic farm and elicited high serum virus neutralization (SVN) antibody titers. The vaccinated group induced SVN antibody titers of 4.40 (log2) ± 2.46, which were approximately 2-fold higher than those of the negative control at 8-weeks post-vaccination. Moreover, 60% of pigs in the vaccinated group displayed SVN antibody titers of ≥5 (log2), while none of the pigs in the negative control exhibited SVN antibody titers of ≥5 (log2). The overall results of the animal experiment suggest that the vCSL1-GP5-N33D inactivated vaccine is a promising vaccine candidate.

Acute and chronic health risk assessment for inhalation and ingestion exposure in acrylic acid leak accidents.

We established a hypothetical acrylic acid leak accident scenario, conducted a health risk assessment of local residents, and compared an actual accident case to the hypothetical scenario. The exposed subjects were divided into four age groups, and a noncarcinogenic health risk assessment was conducted for inhalation and soil ingestion. In the hypothetical scenario, 40 tons of acrylic acid was leaked in Ulsan for 1 h from midnight on January 1, 2017. In the actual accident case, 3 L of acrylic acid was leaked in Hwaseong, Gyeonggi Province, for 1 h from 11:00 am on March 5, 2020. The environmental concentration of acrylic acid was calculated using the dynamic multimedia environmental model. Noncarcinogenic assessment of the hypothetical scenario showed the hazard quotient exceeded 1 across all age groups, suggesting that a health risk is likely to occur due to inhalation exposure to acrylic acid resulting from a chemical accident. In addition, Hazardacute exceeded 1 until 2 h after the accident under the hypothetical scenario, indicating the likelihood of a health risk. Thus, we propose a methodology that can assess changing concentrations in a hazardous chemical leak from a chemical accident based on the time, place, the chemical's behaviors in different environmental media, and the health risk posed by the exposure of the chemical to local residents in the area affected by the accident.

A chimeric porcine reproductive and respiratory syndrome virus (PRRSV)-2 vaccine is safe under international guidelines and effective both in experimental and field conditions.

Vaccination is currently the most effective strategy to control porcine reproductive and respiratory syndrome (PRRS). New-generation PRRS vaccines are required to be safe and broadly cross-protective. We have recently created the chimeric PRRS virus K418DM which proved to be a good vaccine candidate under field conditions. In the present study, we designed safety and efficacy tests under experimental and field conditions for further evaluation of K418DM1.1, a plaque-purified K418DM. In the homologous challenge study, K418DM1.1 induced high serum virus neutralization (SVN) antibody titers (i.e., 4.2 log2 ± 1.7) at 21 days post-challenge (dpc) and provided protection as demonstrated by the significantly lower levels of viremia at 3 and 7 dpc and significantly lower microscopic lung lesion scores compared to the unvaccinated group. K418DM1.1 was also protective in the heterologous challenge study, with vaccinated pigs showing significantly lower levels of viremia at 14 dpc compared to the unvaccinated pigs. A field study was performed to evaluate the efficacy of K418DM1.1 against heterologous exposure and vaccinated pigs presented significantly lower viremia than unvaccinated pigs. According to the safety test for the examination of virulence reversion, no infectivity was observed in tissue homogenate filtrate both in the vaccinated and comingled groups. Thus, the risk of virulence, as well as transmission, appeared negligible. These overall results indicate that K418DM1.1 is a good vaccine candidate based on its safety and protective efficacy.

5-year oncological outcomes of targeted axillary sampling in pT1-2N1 breast cancer.

BACKGROUND: axillary lymph nodes dissection (ALND) has been a standard treatment in breast cancer with positive sentinel LNs. However, various short- and long-term postoperative morbidities have been reported after conventional ALND. To define the concept of targeted axillary sampling (AS) and to assess its oncological feasibility for breast cancer. We compared the oncological outcomes in the axillary area between conventional ALND and targeted AS with or without radiotherapy. METHODS: One hundred and twenty-nine female patients with cT1-2N1 breast cancer underwent breast and axillary surgery. We defined the concept of targeted AS in clinical and pathological terms, and the oncological outcomes were compared between ALND and AS, and between AS with and without radiotherapy. RESULTS: There were no significant differences in oncological outcomes in the axilla between conventional ALND and AS, or between AS with radiotherapy and AS alone. CONCLUSIONS: The 5-year oncological outcomes of targeted AS were not inferior to those of conventional ALND, regardless of whether radiotherapy was added.

Race- and Isolate-specific Molecular Marker Development through Genome-Realignment Enables Detection of Korean Plasmodiophora brassicae Isolates, Causal agents of Clubroot Disease.

Clubroot is one of the most economically important diseases of the Brassicaceae family. Clubroot disease is caused by the obligate parasite Plasmodiophora brassicae, which is difficult to study because it is non-culturable in the laboratory and its races are genetically variable worldwide. In Korea, there are at least five races that belongs to four pathotype groups. A recent study conducted in Korea attempted to develop molecular markers based on ribosomal DNA polymorphism to detect P. brassicae isolates, but none of those markers was either race-specific or pathotype-specific. Our current study aimed to develop race- and isolate-specific markers by exploiting genomic sequence variations. A total of 119 markers were developed based on unique variation exists in genomic sequences of each of the races. Only 12 markers were able to detect P. brassicae strains of each isolate or race. Ycheon14 markers was specific to isolates of race 2, Yeoncheon and Hoengseong. Ycheon9 and Ycheon10 markers were specific to Yeoncheon isolate (race 2, pathotype 3), ZJ1-3, ZJ1-4 and ZJ1-5 markers were specific to Haenam2 (race 4) isolate, ZJ1-35, ZJ1-40, ZJ1-41 and ZJ1-49 markers were specific to Hoengseong isolate and ZJ1-56 and ZJ1-64 markers were specific to Pyeongchang isolate (race 4, pathotype 3). The PCR-based sequence characterized amplified region (SCAR) markers developed in this study are able to detect five Korean isolates of P. brassicae. These markers can be utilized in identifying four Korean P. brassicae isolates from different regions. Additional effort is required to develop race- and isolate-specific markers for the remaining Korean isolates.

Evaluation and optimization of a conventional SPCE for FMD post-vaccination monitoring.

BACKGROUND: Foot-and-mouth disease (FMD) can be controlled by either stamping out or vaccination, a choice which depends on both the economic importance of the livestock sector as well as the disease status. In FMD-free countries with vaccination, such as Korea, vaccination programs should guarantee prevention against transmission of FMD. Monitoring of vaccination programs is also essential for ensuring sufficient coverage that will limit the transmission of FMDV. There are several methods to screen FMD virus (FMDV) structural protein (SP) antibodies including SPCE (Solid-phase competitive ELISA), LPBE (Liquid-phase blocking ELISA), and VNT (Virus neutralization test). Among these, SPCE is widely used for serological monitoring since VNT-the gold standard method-has certain practical limitations, such as high costs in terms of time and labor. However, whether SPCE can ensure the vaccination status of individual animals and whole farms is unclear. In this study, SPCE, LPBE and VNT were compared with respect to correlation with each other and sensitivity at commercial pig farms. RESULTS: The positive results obtained by PrioCHECK SPCE differed from those obtained by LPBE and VNT. The sensitivity of SPCE relative to those of the other tests was fairly low. The raw data of SPCE were most highly correlated with those of VNT with XJ strain, while their positivity and negativity were most highly correlated with LPBE. The results of ROC analysis proposed new cut-off for PrioCHECK SPCE higher than the previous 50% inhibition. CONCLUSIONS: The high false positive rate of PrioCHECK SPCE suggested that high seropositivity by SPCE may not guarantee a true vaccination coverage. Adjusting the cut-off percentage (%) inhibition value for SPCE is needed to address this problem, and it is highly recommended that routine FMDV serological monitoring programs using PrioCHECK SPCE should be combined with alternative methods such as LPBE or VNT.

Cadaver skin allograft may improve mortality rate for burns involving over 30% of total body surface area: a propensity score analysis of data from four burn centers.

Cadaver skin is used for temporary wound covering, but there is insufficient evidence regarding its clinical usefulness in patients with major burns. We aimed to analyze the effect of cadaveric skin allograft on mortality rates in patients with burns involving > 30% of total body surface area (TBSA). Our study included 1282 patients with > 30% of TBSA burned admitted to four hospitals in Korea between June 1, 2008 and December 31, 2016. Of these, 698 patients underwent cadaver skin allograft (cadaver group), and 584 were treated with conventional treatment (non-cadaver group). We corrected the differences between the two groups using propensity score matching, and generated 474 propensity score-matched pairs. Overall 90-day in-hospital mortality rate among all patients was 35.3% (453/1282). There was a significant difference in 90-day in-hospital mortality between the two groups for both unmatched [cadaver vs. conventional, 31.7 vs. 39.7%; difference, 8.0; 95% confidence interval (CI) 2.8-13.3] and propensity-matched groups (37.8 vs. 47.3%; difference, 9.5; 95% CI 3.2-15.8). Logistic regression analyses showed a significant association between cadaver skin allograft and lower 90-day in-hospital mortality in the propensity-matched groups (odds ratio, 0.42; 95% CI 0.29-0.62). Patients with major burns who underwent cadaver skin allograft had a lower mortality rate compared to those who did not. Cadaver skin allograft may improve the survival of patients with major burns, especially in the early phase of injury.

Specific capture, recovery and culture of cancer cells using oriented antibody-modified polystyrene chips coated with agarose film.

Agarose gel can be used for three dimensional (3D) cell culture because it prevents cell attachment. The dried agarose film coated on a culture plate also protected cell attachment and allowed 3D growth of cancer cells. We developed an efficient method for agarose film coating on an oxygen-plasma treated micropost polystyrene chip prepared by an injection molding process. The agarose film was modified to maleimide or Ni-NTA groups for covalent or cleavable attachment of photoactivatable Fc-specific antibody binding proteins (PFcBPs) via their N-terminal cysteine residues or 6xHis tag, respectively. The antibodies photocrosslinked onto the PFcBP-modified chips specifically captured the target cells without nonspecific binding, and the captured cells grew 3D modes on the chips. The captured cells on the cleavable antibody-modified chips were easily recovered by treatment of commercial trypsin-EDTA solution. Under fluidic conditions using an antibody-modified micropost chip, the cells were mainly captured on the micropost walls of the chip rather than on the bottom of it. The presented method will also be applicable for immobilization of oriented antibodies on various microfluidic chips with different structures.

Covalent and Oriented Surface Immobilization of Antibody Using Photoactivatable Antibody Fc-Binding Protein Expressed in Escherichia coli.

Fc-specific antibody binding proteins (FcBPs) with the minimal domain of protein G are widely used for immobilization of well-oriented antibodies onto solid surfaces, but the noncovalently bound antibodies to FcBPs are unstable in sera containing large amounts of antibodies. Here we report novel photoactivatable FcBPs with photomethionine (pMet) expressed in E. coli, which induce Fc-specific photo-cross-linking with antibodies upon UV irradiation. Unfortunately, pMet did not support protein expression in the native E. coli system, and therefore we also developed an engineered methionyl tRNA synthetase (MRS5m). Coexpression of MRS5m proteins successfully induced photoactivatable FcBP overexpression in methionine-auxotroph E. coli cells. The photoactivatable FcBPs could be easily immobilized on beads and slides via their N-terminal cysteine residues and 6xHis tag. The antibodies photo-cross-linked onto the photoactivatable FcBP-beads were resistant from serum-antibody mediated dissociation and efficiently captured antigens in human sera. Furthermore, photo-cross-linked antibody arrays prepared using this system allowed sensitive detection of antigens in human sera by sandwich immunoassay. The photoactivatable FcBPs will be widely applicable for well-oriented antibody immobilization on various surfaces of microfluidic chips, glass slides, and nanobeads, which are required for development of sensitive immunosensors.

Effect of a Brown Rice Based Vegan Diet and Conventional Diabetic Diet on Glycemic Control of Patients with Type 2 Diabetes: A 12-Week Randomized Clinical Trial.

OBJECTIVE: Several intervention studies have suggested that vegetarian or vegan diets have clinical benefits, particularly in terms of glycemic control, in patients with type 2 diabetes (T2D); however, no randomized controlled trial has been conducted in Asians who more commonly depend on plant-based foods, as compared to Western populations. Here, we aimed to compare the effect of a vegan diet and conventional diabetic diet on glycemic control among Korean individuals. MATERIALS AND METHODS: Participants diagnosed with T2D were randomly assigned to follow either a vegan diet (excluding animal-based food including fish; n = 46) or a conventional diet recommended by the Korean Diabetes Association 2011 (n = 47) for 12 weeks. HbA1c levels were measured at weeks 0, 4, and 12, and the primary study endpoint was the change in HbA1c levels over 12 weeks. RESULTS: The mean HbA1c levels at weeks 0, 4, and 12 were 7.7%, 7.2%, and 7.1% in the vegan group, and 7.4%, 7.2%, and 7.2% in the conventional group, respectively. Although both groups showed significant reductions in HbA1C levels, the reductions were larger in the vegan group than in the conventional group (-0.5% vs. -0.2%; p-for-interaction = 0.017). When only considering participants with high compliance, the difference in HbA1c level reduction between the groups was found to be larger (-0.9% vs. -0.3%). The beneficial effect of vegan diets was noted even after adjusting for changes in total energy intake or waist circumference over the 12 weeks. CONCLUSION: Both diets led to reductions in HbA1c levels; however, glycemic control was better with the vegan diet than with the conventional diet. Thus, the dietary guidelines for patients with T2D should include a vegan diet for the better management and treatment. However, further studies are needed to evaluate the long-term effects of a vegan diet, and to identify potential explanations of the underlying mechanisms. TRIAL REGISTRATION: CRiS KCT0001771.

Changes in Ultrastructure and Sensory Characteristics on Electro-magnetic and Air Blast Freezing of Beef during Frozen Storage.

The ultrastructure in the beef muscle of the electro-magnetic resonance and air blast freezing during the frozen storage, and the changes in the quality characteristics after thawing were evaluated. The size of ice crystal was small and evenly formed in the initial freezing period, and it showed that the size was increased as the storage period was elapsed (p<0.05). The beef stored by the electro-magnetic resonance freezing showed the size of ice crystal with a lower rate of increase than the air blast freezing during the frozen storage. The thawing loss of beef stored by the electro-magnetic resonance freezing was significantly lower than the air blast freezing during frozen storage (p<0.05), and it showed that the thawing loss of the round was higher than the loin. Water holding capacity decreased as the storage period became longer while the electro-magnetic resonance freezing was higher than the air blast on 8 month (p<0.05). As a result of sensory evaluation, the beef stored by the electro-magnetic resonance freezing did not show the difference until 4 months, and it showed higher acceptability in comparison with the beef stored by the air blast freezing. Thus, it is considered that the freezing method has an effect on the change in the ultrastructure and quality characteristics of the beef.

Activation of Nrf2 by dimethyl fumarate improves vascular calcification.

Dimethyl fumarate (DMF) has several pharmacological benefits including immunomodulation and prevention of fibrosis, which are dependent on the NF-E2-related factor 2 (Nrf2) antioxidant pathways. Therefore, we hypothesized that DMF could attenuate vascular calcification via Nrf2 activation. Vascular calcification induced by hyperphosphataemia was significantly inhibited by DMF in vascular smooth muscle cells (VSMCs) in a dose-dependent manner. DMF-mediated Nrf2 upregulation was accompanied by the reduced expressions of genes related with osteoblast-like phenotype based on promoter activity, mRNA and protein expression, and von Kossa staining. Likewise, Nrf2 overexpression significantly decreased the formation of calcium deposit similar to the level of osteogenic staining in VSMCs, and DMF with Nrf2 knockdown failed to attenuate hyperphosphatemia induced vascular calcification. Furthermore, DMF significantly attenuated the calcification of ex vivo ring culture from both rat common carotid artery and mouse thoracic aorta as well as in vivo mouse model of Vitamin D3-induced calcification consistent with the increased Nrf2 protein levels in early stage of calcification by DMF. In conclusion, our data support that DMF stimulates Nrf2 activity to attenuate hyperphosphatamia in vitro or Vitamin D3-induced in vivo vascular calcification, which would be a beneficial effect on vascular diseases induced by oxidative stress such as vascular calcification.

Serum irisin levels in new-onset type 2 diabetes.

AIMS: Irisin has been identified as a novel myokine that drives brown-fat-like conversion of white adipose tissue. In this cross-sectional study, we investigated whether serum irisin levels are decreased in patients with type 2 diabetes (T2D) compared with control subjects with normal glucose tolerance (NGT), and assessed the association between serum irisin levels and various metabolic parameters. METHODS: The study population was selected from a population-based study and included 104 subjects with NGT and 104 subjects with new-onset T2D. Serum irisin and adiponectin levels and metabolic parameters were measured. Multivariate logistic regression analysis was performed to assess the association between irisin levels and newly diagnosed T2D. RESULTS: Serum irisin levels were significantly decreased in the new-onset T2D group compared with the NGT control group (p=0.003). In a multivariable model adjusted for various metabolic parameters, increased irisin levels were associated with reduced odds (OR 0.64, 95% CI 0.47-0.88, p=0.006) of prevalent newly diagnosed T2D. Furthermore, multiple regression analysis showed that 2 h plasma glucose was an independent variable influencing serum irisin levels (p=0.004). CONCLUSION: In the present study, we found that serum irisin levels were decreased in T2D patients and inversely associated with newly diagnosed T2D, suggesting that irisin may play a crucial role in glucose intolerance and T2D.

A large cohort of consecutive patients confirmed frequent HER2 positivity in gastric carcinomas with advanced stages.

BACKGROUND: Trastuzumab in association with systemic cytotoxic chemotherapy is the standard of care for patients with advanced HER2-positive gastric carcinoma (GC). However, HER2 as a prognostic factor in GC remains controversial. METHODS: HER2 overexpression and amplification was evaluated by immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 2,798 GCs obtained from 2,727 gastrectomy and 71 open/laparoscopic biopsy specimens from patients with peritoneal seeding. Regional heterogeneity was defined as the proportion of tumor cells showing membranous staining in 10-70 % of tumor cells. Genetic heterogeneity was determined by the existence of HER2/CEP17 ratio higher than 2.0 in >5 to <50 % of tumor cells. RESULTS: In IHC, 184 cases (6.6 %) were 3+ and 44 cases (1.6 %) were 2+. Of 44 HER2 2+ cases, SISH showed HER2 gene amplification in 21 cases (47.7 %), chromosome 17 polysomy in six cases (13.6 %), and genetic heterogeneity in five cases (11.4 %). HER2 positivity found in 7.3 % of GCs was significantly associated with older age, male gender, intestinal histology, upper third in location, higher lymph node stage (p < .002), and advanced AJCC stage (p = .033). Regional heterogeneity of HER2 was closely associated with 2+ (70.5 vs 42.9 % in 3+, p = .001) and diffuse or mixed histologic type (p = .005). CONCLUSIONS: Regional heterogeneity of HER2 expression was closely associated with weak HER2 overexpression (2+) and with diffuse or mixed histology. Polysomy of chromosome 17 would be an important cause of HER2 2+ in IHC. Frequent HER2 positivity observed in GCs with advanced stages suggests that HER2 may be involved in tumor progression and poor prognosis.

Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-ß/Smad signaling.

TGF-ß plays a key role in the development of renal fibrosis. Suppressing the TGF-ß signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-ß signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-ß signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (α-SMA), fibronectin and type 1 collagen expression in TGF-ß-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-ß-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-ß-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and α-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-ß/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis.

Association of the DDAH2 gene polymorphism with type 2 diabetes and hypertension.

AIMS: The aim of this study was to investigate whether the polymorphism of DDAH2 is associated with type 2 diabetes and hypertension in Korean population. METHODS: Total 605 subjects were included in this study: 403 patients with type 2 diabetes and 202 non-diabetic control subjects. The SNP rs805304 and rs2272592 in DDAH2 were analyzed. We examined the association of SNP rs805304 and rs2272592 in DDAH2 with type 2 diabetes and hypertension. RESULTS: SNP rs2272592 was significantly associated with type 2 diabetes (P<0.001) while SNP rs805304 was not (P=0.716). We observed that the prevalence of the AG+GG genotypes were significantly greater than AA homozygotes in type 2 diabetes (AA vs AG+GG; OR 20.74, 95% CI 6.48-66.35, P<0.001). Significance was maintained after adjusting for age, sex, BMI, DBP and BUN (OR 21.03, 95% CI 2.83-151.14, P=0.003). Both SNP rs805304 and rs2272592 in DDAH2 were not significantly associated with hypertension. CONCLUSIONS: In the present study, we found that SNP rs2272592 in DDAH2 is associated with type 2 diabetes but SNP rs805304 in DDAH2 is not. DDAH2 SNP rs2272592 AG+GG genotypes are associated with genetic susceptibility to type 2 diabetes in Korean population.