DNA-induced 2'3'-cGAMP enhances haplotype-specific human STING cleavage by dengue protease.

The cytosolic DNA sensor cGMP-AMP synthase (cGAS) synthesizes the noncanonical cyclic dinucleotide 2'3'-cGAMP to activate the adaptor protein stimulator of IFN genes (STING), thus awakening host immunity in response to DNA pathogen infection. However, dengue virus (DENV), an RNA virus without a DNA stage in its life cycle, also manipulates cGAS-STING-mediated innate immunity by proteolytic degradation of STING. Here, we found that the sensitivity of STING to DENV protease varied with different human STING haplotypes. Exogenous DNA further enhanced DENV protease's ability to interact and cleave protease-sensitive STING. DNA-enhanced STING cleavage was reduced in cGAS-knockdown cells and triggered by the cGAS product 2'3'-cGAMP. The source of DNA may not be endogenous mitochondrial DNA but rather exogenous reactivated viral DNA. Cells producing 2'3'-cGAMP by overexpressing cGAS or with DNA virus reactivation enhanced STING cleavage in neighboring cells harboring DENV protease. DENV infection reduced host innate immunity in cells with the protease-sensitive STING haplotype, whose homozygote genotype frequency was found significantly reduced in Taiwanese people with dengue fever. Therefore, the human STING genetic background and DNA pathogen coinfection may be the missing links contributing to DENV pathogenesis.

Integrated Medicine for Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of typical chemotherapeutics among cancer survivors. Despite the recent progress, the effective prevention and treatment strategies for CIPN remain limited. Better understanding of the pathogenesis of CIPN may provide new niches for developing a new ideal therapeutic strategy. This review summarizes the current understanding of CIPN and current recommendations along with completed/active clinical trials and aims to foster translational research to improve the development of effective strategies for managing CIPN.

Single nucleotide polymorphisms at the PRR3, ABCF1, and GNL1 genes in the HLA class I region are associated with Graves' ophthalmopathy in a gender-dependent manner.

OBJECTIVE: To investigate whether a conserved HLA class I region influenced the development of Graves' ophthalmopathy (GO) in patients with Graves' disease (GD) in a Taiwan-Chinese population. DESIGN: Case-control study. PARTICIPANTS: Four hundred sixty-eight Taiwan-Chinese patients with GD; 200 of these patients had GO, whereas 268 patients did not. METHODS: Five single nucleotide polymorphisms (SNPs) between the HLA-A and HLA-C loci were genotyped. MAIN OUTCOME MEASURES: The Mann-Whitney U test and chi-square test with Bonferroni correction were used. The odds ratios (ORs) were estimated by applying unconditional logistic regression with a 95% confidence intervals (CIs). RESULTS: Strong gender effects on the distribution of the SNPs were apparent: male GD patients carrying an A allele at rs2074503 in the PRR3 gene tended to avoid demonstrating GO (P = 0.008; OR, 0.450; 95% CI, 0.248-0.819), whereas female patients tended to show GO (P = 0.01; OR, 1.486; 95% CI, 1.098-2.012). In addition, only the female GD patients with a T allele at rs1264439 in the ABCF-1 gene tended to demonstrate GO (P = 0.005; OR, 1.539; 95% CI, 1.139-2.081). Analysis of the haplotype blocks of the SNPs rs2074505 (GNL1) and rs2074503 (PRR3) showed that haplotype HA1 was underrepresented in male GO patients (P = 0.004; OR, 0.418; 95% CI, 0.228-0.767), whereas HA-4 was underrepresented in female GO patients (P = 0.007; OR, 0.660; 95% CI, 0.490-0.895). CONCLUSIONS: The results suggested that SNPs at PRR3 and ABCF1 genes and the haplotype composed by SNPs at GNL1 and PRR3 between the HLA-A and HLA-C genes tended to predict GO in a gender-dependent manner in patients with GD in Taiwan.

Sex difference, proteostasis and mitochondrial function impact stroke-related sarcopenia-A systematic review and meta-analysis.

BACKGROUND: The prevalence of stroke-related sarcopenia has been noted; however, epidemiological data and interventions that increase or reduce the incidence of stroke-related sarcopenia remain lacking. METHODS: Studies on stroke-related sarcopenia were included in association or interventional analyses. All analyses were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two evaluators independently extracted the data. RESULTS: Female stroke patients had a higher preference for sarcopenia than male patients (pooled odds ratio [OR] = 0.670, 95 % CI 0.533-0.842, p = 0.001). Although stroke patients without drug use have improved skeletal muscle mass index (SMI) (MD = 0.272, 95 % CI 0.087-0.457, p = 0.004), handgrip strength (HGS) was not significantly altered (MD = -0.068, 95 % CI -0.221-0.076, p = 0.354). Stroke patients with nutrient interventions have improved SMI (MD = -0.354, 95 % CI -0.635- -0.073, p = 0.014) and HGS (MD = -0.394, 95 % CI -0.678- -0.111, p = 0.006); the synergistic effect of rehabilitation exercise has not been ruled out. Whether a sex difference exists in these interventions remains to be investigated. The underlying pathological mechanisms and potential therapeutic strategies for this disease are discussed. CONCLUSION: Sex difference, proteostasis, and mitochondrial function may impact the incidence of stroke-related sarcopenia. Understanding the underlying pathological mechanisms and potential therapeutic targets for this disease will provide new insights into disease treatment, prevention, and drug development.

Thymic stromal lymphopoietin gene promoter polymorphisms and expression levels in Graves' disease and Graves' ophthalmopathy.

BACKGROUND: Graves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. In the present study, we investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation. METHODS: In this study, we genotyped 470 patients with GD at 3 single nucleotide polymorphisms (SNPs) in TSLP. In addition, the serum concentrations of TSLP were determined in 432 patients and 272 controls. Ten patients and controls each were further screened using in vitro Th17 differentiation assays. The SNPs were genotyped using ABI TaqMan® SNP genotyping assays. For the Th17 differentiation assays, peripheral blood mononuclear cells (PBMCs) isolated from the patients and controls were placed into Th17 differentiation media, and interleukin 17 expression levels were determined. RESULTS: Haplotype analysis indicated that patients with the Ht3 (TCC) haplotype have a 3.28-fold higher risk of developing GD (p = 0.007), whereas those with the Ht5 (TCG) haplotype had a 0.03-fold, reduced risk of developing GD (p = 1 × 10-14). SNP rs3806933 (p = 0.007) was associated with female Graves ophthalmopathy (GO). TSLP expression levels were higher in GD patients than in control subjects, and TLSP was also shown to promote the differentiation of Th17 cells in GD patients. CONCLUSIONS: These results suggest that polymorphisms in TSLP may be used as genetic markers for the diagnosis and prognosis of GD. Furthermore, TLSP may be a target for treating GD.

Association of IL12B polymorphisms with susceptibility to Graves ophthalmopathy in a Taiwan Chinese population.

BACKGROUND: Interleukin 12B (IL12B) gene polymorphisms have been linked to several inflammatory diseases, but their role in the development of Graves ophthalmopathy (GO) in Graves disease (GD) patients is unclear. The purpose of this study was to investigate the disease association of IL12B single nucleotide polymorphisms (SNPs). METHODS: A Taiwan Chinese population comprising 200 GD patients with GO and 271 GD patients without GO was genotyped using an allele-specific extension and ligation method. Hardy-Weinberg equilibrium was estimated using the chi-square test. Allele and genotype frequencies were compared between GD patients with and without GO using the chi-square test. RESULTS: The genotype and allele frequencies of examined SNPs did not differ between GD patients with and without GO. Although the genotype distribution remained nonsignificant in the sex-stratified analyses, the frequency of the T allele at SNP rs1003199 was significantly higher in patients with GO in the male cohort (P = 6.00 × 10(-3)). In addition, haplotypes of IL12B may be used to predict the risk of GO (P = 1.70 × 10(-2)); however, we could not prove the statistical significance of analysis after applying the Bonferroni correction. CONCLUSIONS: Our results provide new information that the examined IL12B gene polymorphisms may be associated with susceptibility to GO in the Taiwan Chinese population in a sex-specific manner. This conclusion requires further investigation.

Involvement of prohibitin upregulation in abrin-triggered apoptosis.

Abrin (ABR), a protein purified from the seeds of Abrus precatorius, induces apoptosis in various types of cancer cells. However, the detailed mechanism remains largely uncharacterized. By using a cDNA microarray platform, we determined that prohibitin (PHB), a tumor suppressor protein, is significantly upregulated in ABR-triggered apoptosis. ABR-induced upregulation of PHB is mediated by the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway, as demonstrated by chemical inhibitors. In addition, ABR significantly induced the expression of Bax as well as the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP) in Jurkat T cells, whereas the reduction of PHB by specific RNA interference delayed ABR-triggered apoptosis through the proapoptotic genes examined. Moreover, our results also indicated that nuclear translocation of the PHB-p53 complex may play a role in the transcription of Bax. Collectively, our data show that PHB plays a role in ABR-induced apoptosis, which may be helpful for the development of diagnostic or therapeutic agents.

Aqueous Extract of Paeonia suffruticosa Inhibits Migration and Metastasis of Renal Cell Carcinoma Cells via Suppressing VEGFR-3 Pathway.

Renal cell carcinoma (RCC) cells are characterized by strong drug resistance and high metastatic incidence. In this study, the effects of ten kinds of Chinese herbs on RCC cell migration and proliferation were examined. Aqueous extract of Paeonia suffruticosa (PS-A) exerted strong inhibitory effects on cancer cell migration, mobility, and invasion. The results of mouse xenograft experiments showed that the treatment of PS-A significantly suppressed tumor growth and pulmonary metastasis. We further found that PS-A markedly decreased expression of VEGF receptor-3 (VEGFR-3) and phosphorylation of FAK in RCC cells. Moreover, the activation of Rac-1, a modulator of cytoskeletal dynamics, was remarkably reduced by PS-A. Additionally, PS-A suppressed polymerization of actin filament as demonstrated by confocal microscopy analysis and decreased the ratio of F-actin to G-actin in RCC cells, suggesting that PS-A inhibits RCC cell migration through modulating VEGFR-3/FAK/Rac-1 pathway to disrupt actin filament polymerization. In conclusion, this research elucidates the effects and molecular mechanism for antimigration of PS-A on RCC cells and suggests PS-A to be a therapeutic or adjuvant strategy for the patients with aggressive RCC.

Effects of a Chinese Herbal Medicine, Guan-Jen-Huang (Aeginetia indica Linn.), on Renal Cancer Cell Growth and Metastasis.

Aeginetia indica Linn. (Guan-Jen-Huang, GJH), a traditional Chinese herb, has the potential to be an immunomodulatory agent. The purpose of this study was to explore the effect of GJH in the treatment of renal cancer. Concentration-effect curves for the influence of GJH on cellular proliferation showed a biphasic shape. Besides, GJH had a synergistic effect on cytotoxicity when combined with 5-fluorouracil (5-FU)which may be due to the alternation of the chemotherapeutic agent resistance-related genes and due to the synergistic effects on apoptosis. In addition, treatment with GJH extract markedly reduced 786-O cell adherence to human umbilical vein endothelial cells (HUVECs) and decreased 786-O cell migration and invasion. In a xenograft animal model, GJH extract had an inhibitory effect on tumor cell-induced metastasis. Moreover, western blot analysis showed that the expression of intercellular adhesion molecule-1 (ICAM-1) in 786-O cells was significantly decreased by treatment with GJH extract through inactivation of nuclear factor-κB (NF-κB). These results suggest that GJH extract has a synergistic effect on apoptosis induced by chemotherapeutic agents and an inhibitory effect on cell adhesion, migration, and invasion, providing evidence for the use of water-based extracts of GJH as novel alternative therapeutic agents in the treatment of human renal cancer.

Interplays of glucose metabolism and KRAS mutation in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide. The primary reasons for this are the lack of early detection methods and targeted therapy. Emerging evidence highlights the metabolic addiction of cancer cells as a potential target to combat PDAC. Oncogenic mutations of KRAS are the most common triggers that drive glucose uptake and utilization via metabolic reprogramming to support PDAC growth. Conversely, high glucose levels in the pancreatic microenvironment trigger genome instability and de novo mutations, including KRASG12D, in pancreatic cells through metabolic reprogramming. Here, we review convergent and diverse metabolic networks related to oncogenic KRAS mutations between PDAC initiation and progression, emphasizing the interplay among oncogenic mutations, glucose metabolic reprogramming, and the tumor microenvironment. Recognizing cancer-related glucose metabolism will provide a better strategy to prevent and treat the high risk PDAC population.

Oral administration of processed Cassia obtusifolia L. seed powder May reduce body weight and cholesterol in overweight patients with schizophrenia: A 36-week randomized, double-blind, controlled trial of high and low doses.

ETHNOPHARMACOLOGICAL RELEVANCE: Obesity in patients with schizophrenia is related to antipsychotic drug use, hypertension, diabetes, and dyslipidemia, which are critical risk factors for cardiovascular disease. Cassia seed is a traditional Chinese medicine that can be used to treat various eye disorders. Anthraquinone-containing Cassia seed were used to lower serum levels of fat and cholesterol. AIM OF STUDY: The effects of Cassia seed powder on body weight and lipids were investigated in overweight or obese patients with schizophrenia. METHODS: The present study was designed as a double-blind, randomized, controlled trial. Ninety-four patients with schizophrenia who were overweight or obese were assigned to a control group (CG, 47 patients) and treatment group (TG, 47 patients) that received low dose Cassia seed power (0.3 g once daily) and Cassia seed powder (3.0 g once daily), respectively, for 36 weeks. The main outcome was the change in body mass index and waist circumference (WC). The secondary outcome was the change in serum lipids, C-reactive protein, interleukin-6, and glycated hemoglobin. RESULTS: Seventy-four patients completed the study (n = 36, CG; n = 38, TG). WC was significantly lower at the second (24 weeks, 98.63 ± 9.44 vs 95.80 ± 10.26 cm, p = 0.023), third (36 weeks, 98.35 ± 9.46 vs 95.05 ± 10.07 cm, p = 0.002), and fourth (48 weeks, 98.78 ± 9.48 vs 93.73 ± 10.28 cm, p < 0.001) follow-ups than at baseline in the TG, but only significantly lower than baseline at the fourth follow-up (100.78 ± 13.98 vs 94.03 ± 9.74 cm, p = 0.006); no significant difference in CG was observed at both the second (101.03 ± 13.62 vs 97.35 ± 8,29 cm, p = 0.08) and third (100.55 ± 13.69 vs 96.55 ± 8.29 cm, p = 0.066) follow-up. The difference in serum total cholesterol and low-density lipoprotein levels between the baseline and the third follow-up was greater in the TG than in the CG (149.68 ± 34.85 vs 179.08 ± 75.87 mg/dL, p = 0.033; 84.40 ± 28.06 vs102.08 ± 34.12 mg/dL, p = 0.015, respectively). CONCLUSION: In patients with schizophrenia who were overweight or obese, oral administration of Cassia seed powder (3.0 g) for 24 weeks and 36 weeks reduced WC, and oral administration of Cassia seed powder for 36 weeks reduced total cholesterol and low-density lipoprotein levels, suggesting that Cassia seed powder aids the management of patients with schizophrenia who are overweight or obese. However, these results are preliminary, and future studies should use larger sample sizes, multiple testing centers, and multiple dosing.

The association between polymorphisms of B7 molecules (CD80 and CD86) and Graves' ophthalmopathy in a Taiwanese population.

OBJECTIVE: This study evaluates whether B7 molecules (CD80 and CD86) could be used as genetic markers for the development of Graves' ophthalmopathy (GO). DESIGN: Cross-sectional study. PARTICIPANTS: We included 471 patients with Graves' disease (GD; 200 patients with GO and 271 patients without GO) in a Chinese population in Taiwan. METHODS: An endocrinologist with substantial experience in thyroid diseases identified GO. Blood samples were taken for DNA extraction from GD subjects. The gene polymorphism of CD80 and CD86 was genotyped by polymerase chain reaction in each patient. MAIN OUTCOME MEASURES: Genotypes of CD80 and CD86 polymorphism. RESULTS: We found that the frequency of C allele at position rs_9831894 of the CD86 gene is different in patients with GD (with and without GO; chi-square test, P = 0.0017). In addition, the multifactor dimensionality reduction method was used to identify the best gene-gene interaction to predict the risk of GO. We identified an interaction between CD80_rs9289131 and CD86_rs9872483 (sign test, P = 0.0010). Moreover, the G-A haplotype was shown to have a protective effect in the development of ophthalmopathy among patients with GD (odds ratio, 0.63; 95% confidence interval, 0.44-0.90). Moreover, among patients with GO, the patients carrying the G-A haplotype had a lower level of free thyroxine T(4) than those not carrying the G-A haplotype (P = 0.0001). CONCLUSIONS: These results suggest that the polymorphisms of the CD86 gene may be used as genetic markers for making the diagnosis and prognosis of GO. Therefore, GO could be a disease with complex genetic factors, resulting from the existing gene-gene interaction found in the present study.

Association between copy number variation of complement component C4 and Graves' disease.

BACKGROUND: Gene copy number of complement component C4, which varies among individuals, may determine the intrinsic strength of the classical complement pathway. Presuming a major role of complement as an effecter in peptide-mediated inflammation and phagocytosis, we hypothesized that C4 genetic diversity may partially explain the development of Graves' disease (GD) and the variation in its outcomes. METHODS: A case-control study including 624 patients with GD and 160 healthy individuals were enrolled. CNV of C4 isotypes (C4A and C4B) genes were performed by quantitative real-time polymerase chain reaction analysis. Statistical comparison and identification of CNV of total C4, C4 isotypes (C4A and C4B) and C4 polymorphisms were estimated according to the occurrence of GD and its associated clinical features. RESULTS: Individuals with 4, 2, and 2 copies of C4, C4A and C4B genes, especially those with A2B2 polymorphism may associate with the development of GD (p = 0.001, OR = 10.994, 95% CI: 6.277-19.255; p = 0.008, OR = 1.732, 95% CI: 1.190-2.520; p = 2.420 × 10-5, OR = 2.621, 95% CI: 1.791-3.835; and p = 1.395 × 10-4, OR = 2.671, 95% CI: 1.761-4.052, respectively). Although the distribution of copy number for total C4, C4 isotypes as well as C4 polymorphisms did not associate with the occurrence of goiter, nodular hyperplasia, GO and myxedema, <2 copies of C4A may associate with high risk toward vitiligo in patients with GD (p = 0.001, OR = 5.579, 95% CI: 1.659-18.763). CONCLUSIONS: These results may be further estimated for its clinical application on GD and the vitiligo in patients with GD.

Yoga versus massage in the treatment of aromatase inhibitor-associated knee joint pain in breast cancer survivors: a randomized controlled trial.

Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with oestrogen receptor-positive, early-stage, and metastatic breast cancer. Although effective, the risk of falls due to AI-associated knee joint pain significantly increased. The aim of this study was to evaluate the therapeutic effects of yoga and massage on AI-associated knee joint pain. Breast cancer survivors were randomly assigned to a 6-week yoga intervention-2-week rest-6-week massage exposure (Yoga first, n = 30) or a 6-week massage intervention-2-week rest-6-week yoga exposure (Massage first, n = 30). Evaluations of the treatment efficacy were made at baseline, post-intervention, and post-exposure using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, plasma cytokine levels, and changes in meridian energy. The results showed that yoga, superior to massage intervention, significantly reduced AI-associated knee joint pain, as demonstrated by the WOMAC pain score. The yoga intervention improvements were also associated with changes in plasma cytokine levels and meridian energy changes. In conclusion, this study provides scientific evidence that yoga was more effective than massage for reducing AI-associated knee joint pain. Meridian energy changes may provide another scientific, objective, non-invasive way to monitor the therapeutic effects of yoga and investigate another alternative, complementary medicine.

Toll-like receptor gene polymorphisms are associated with susceptibility to Graves' ophthalmopathy in Taiwan males.

BACKGROUND: Toll-like receptors (TLRs) are a family of pattern-recognition receptors, which plays a role in eliciting innate/adaptive immune responses and developing chronic inflammation. The polymorphisms of TLRs have been associated with the risk of various autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis and rheumatorid arthritis. The aim of this study was to evaluate whether TLR genes could be used as genetic markers for the development of Graves' ophthalmopathy (GO). METHODS: 6 TLR-4 and 2 TLR-9 gene polymorphisms in 471 GD patients (200 patients with GO and 271 patients without GO) from a Taiwan Chinese population were evaluated. RESULTS: No statistically significant difference was observed in the genotypic and allelic frequencies of TLR-4 and TLR-9 gene polymorphisms between the GD patients with and without GO. However, sex-stratified analyses showed that the association between TLR-9 gene polymorphism and GO phenotype was more pronounced in the male patients. The odds ratios (ORs) was 2.11 (95% confidence interval [CI] = 1.14-3.91) for rs187084 AàG polymorphism and 1.97 (95% CI = 1.07-3.62) for rs352140 AàG polymorphism among the male patients. Increasing one G allele of rs287084 and one A allele of rs352140 increased the risk of GO (p values for trend tests were 0.0195 and 0.0345, respectively). Further, in haplotype analyses, the male patients carrying the GA haplotype had a higher risk of GO (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.09-3.73) than those not carrying the GA haplotype. CONCLUSION: The present data suggest that TLR-9 gene polymorphisms were significantly associated with increased susceptibility of ophthalmopathy in male GD patients.

Disease association of the CD103 polymorphisms in Taiwan Chinese Graves' ophthalmopathy patients.

OBJECTIVE: To evaluate whether variations in the CD103 gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease. DESIGN: Case-control study. PARTICIPANTS: A total of 484 Chinese patients with Graves' disease in Taiwan, including 203 patients with GO and 281 patients without GO, were enrolled. METHODS: Five single nucleotide polymorphisms (SNPs) in CD103 were genotyped using an assay-on-demand allelic discrimination assay and detection system according to the manufacturer's instructions. MAIN OUTCOME MEASURES: Association of SNPs in CD103 with the development of GO. RESULTS: The CD103 SNP rs11652878 was associated with GO, which may decrease the risk of GO by 1.57-fold (P = 0.029). The Ht5-GCGCG haplotype, composed of 5 SNPs in the CD103 gene (rs1716, rs3744679, rs11652878, rs16953477, and rs9905739), were protective haplotypes (P = 0.010). Moreover, the heterozygous genotype (Ht5/non-Ht5) was correlated with a reduced risk of GO and high grades of goiter as compared with the non-Ht5/non-Ht5 genotype (P = 0.006 and P = 0.048, respectively). Logistic analysis confirmed the contribution of CD103 rs11652878 to the protection of GO. CONCLUSIONS: These data suggest that patients with Graves' disease in the presence of the G allele of SNP rs11652878, especially Ht5-GCGCG, in CD103 are less susceptible toward the development of GO.

Association of phospholipase A2 receptor 1 polymorphisms with idiopathic membranous nephropathy in Chinese patients in Taiwan.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is one of the most common forms of autoimmune nephritic syndrome in adults. The purpose of this study is to evaluate whether polymorphisms of PLA2R1 affect the development of IMN. METHODS: Taiwanese-Chinese individuals (129 patients with IMN and 106 healthy controls) were enrolled in this study. The selected single nucleotide polymorphisms (SNPs) in PLA2R1 were genotyped by real-time polymerase chain reaction using TaqMan fluorescent probes, and were further confirmed by polymerase chain reaction-restriction fragment length polymorphism. The roles of the SNPs in disease progression were analyzed. RESULTS: Genotype distribution was significantly different between patients with IMN and controls for PLA2R1 SNP rs35771982 (p = 0.015). The frequency of G allele at rs35771982 was significantly higher in patients with IMN as compared with controls (p = 0.005). In addition, haplotypes of PLA2R1 may be used to predict the risk of IMN (p = 0.004). Haplotype H1 plays a role in an increased risk of IMN while haplotype H3 plays a protective role against this disease. None of these polymorphisms showed a significant and independent influence on the progression of IMN and the risk of end-stage renal failure and death (ESRF/death). High disease progression in patients having C/T genotype at rs6757188 and C/G genotype at rs35771982 were associated with a low rate of remission. CONCLUSIONS: Our results provide new evidence that genetic polymorphisms of PLA2R1 may be the underlying cause of IMN, and the polymorphisms revealed by this study warrant further investigation.

Up-regulation of vascular endothelial growth factor-D expression in clear cell renal cell carcinoma by CD74: a critical role in cancer cell tumorigenesis.

Elevation of CD74 is associated with a number of human cancers, including clear cell renal cell carcinoma (ccRCC). To understand the role of CD74 in the oncogenic process of ccRCC, we ectopically expressed CD74 in human embryonic kidney 293 cells (HEK/CD74) and evaluated its oncogenic potential. Through overexpression of CD74 in HEK293 and Caki-2 cells and down-regulation of CD74 in Caki-1 cells, we show that vascular endothelial growth factor-D (VEGF-D) expression is modified accordingly. A significant, positive correlation between CD74 and VEGF-D is found in human ccRCC tissues (Pearson's correlation, r = 0.65, p < 0.001). In HEK/CD74 xenograft mice, CD74 significantly induced the formation of tumor masses, increased tumor-induced angiogenesis, and promoted cancer cell metastasis. Blockage of VEGF-D expression by small interference RNA resulted in a decrease in cell proliferation, invasion, and cancer cell-induced HUVEC migration enhanced by CD74. Furthermore, we provide evidence that the intracellular signaling cascade responsible for VEGF-D up-regulation by CD74 is both PI3K/AKT- and MEK/ERK-dependent, both of which are associated with NF-kappaB nuclear translocation and DNA-binding activity. These results suggest that VEGF-D is crucial for CD74-induced human renal carcinoma cancer cell tumorigenesis.

Association of variant on the promoter of cluster of differentiation 74 in graves disease and graves ophthalmopathy.

The macrophage migration inhibitory factor (MIF)/cluster of differentiation 74 (CD74) plays a role in immunological functions. The present study aims to investigate whether single-nucleotide polymorphisms (SNPs) in the MIF and CD74 are risk factors for developing Graves ophthalmopathy (GO) in patients with Graves disease (GD). A case-control study enrolled 484 patients with GD (203 with and 281 without GO) and 1000 healthy individuals. SNPs were discriminated using real-time polymerase chain reaction. Hardy-Weinberg equilibrium, as well as frequencies of allele and genotype between GD patients with and without GO, were estimated using the Chi-square test. The effects of CD74 on adipocyte proliferation and differentiation were evaluated using 3T3-L1 preadipocytes. Quantitative DNA-immunoprecipitation was used to detect the binding capacity of NR3C1 and FOXP3 to A/G oligonucleotides. The results showed that individuals carrying the GG genotype at rs2569103 in the CD74 had a decreased risk of developing GD (P=3.390 × 10-11, odds ratio (OR) = 0.021, 95% confidence interval (CI) = 0.003-0.154); however, patients with GD carrying the AG genotype at rs2569103 in the CD74 had an increased risk of developing GO (P=0.009, OR = 1.707, 95% CI = 1.168-2.495). The knockdown of CD74 reduced adipocyte proliferation and differentiation. NR3C1 had a higher affinity for A, whereas FOXP3 had a higher affinity for G of rs2569103. The results suggested the existence of a link between the genetic variation of CD74 promoter and the risk for developing GD and GO, which should be considered in clinical practice.

Involvement of prohibitin 1 and prohibitin 2 upregulation in cBSA-induced podocyte cytotoxicity.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, when not effectively treated. The aim of this study was to discover new targets for the diagnosis and treatment of MN. A reliable mouse model of MN was used by the administration of cationic bovine serum albumin (cBSA). Mice with MN exhibited proteinuria, histopathological changes, and accumulation of immune complexes in the glomerular basement membrane. Label-free proteomics analysis was performed to identify changes in protein expression, and the overexpressed proteins were evaluated. There were 273 proteins that showed significantly different expression in mice with MN, as compared to the controls. String analysis showed that functions related to cellular catabolic processes were downregulated in MN. Among the differentially expressed proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2) were upregulated in the kidneys of mice with MN, as demonstrated by immunohistochemistry (IHC), and this upregulation was observed in both the tubular cells and glomeruli. Both shRNA-mediated knockdown of PHB1 or PHB2 inhibited tumor suppressor p53 expression and significantly promoted podocyte proliferation. In addition, both PHB1 and PHB2 were responsible for cBSA-induced cytotoxicity. Microarray analysis further revealed that the upregulation of PHB1 and PHB2 may be due to a blockage of proteasome activity. These data demonstrate that the upregulation of PHB2 is involved in cBSA-mediated podocyte cytotoxicity, which may lead to MN development.