ETS1 regulates NDRG1 to promote the proliferation, migration, and invasion of OSCC.

OBJECTIVE: The aim of this study was to investigate the molecular mechanism by which the transcription factor ETS1 regulates N-myc downstream regulatory gene 1 (NDRG1) to provide a new theoretical basis for the study of oral squamous cell carcinoma (OSCC). METHODS: In this study, eight human OSCC and paraneoplastic samples were collected. The expressions of NDRG1, ETS1, and Ki67 were detected by immunohistochemistry; apoptosis was detected by tdt-mediated dUTP notched end labeling; cell migration and invasion were detected by Transwell; quantitative real-time PCR was performed to detect the expression of NDRG1; RNA-binding protein immunoprecipitation (RIP) assays detected NDRG1 expression; immunofluorescence assays detected ETS1 expression. RESULTS: NDRG1 and ETS1 expression was significantly upregulated in cancer tissues and CAL-27 and SCC-6 cells. Knockdown of NDRG1 and ETS1 inhibited cell proliferation, migration, invasion, cloning, and EMT while promoting apoptosis and inhibited tumor development; ETS1 positively regulated NDRG1 expression; Finally, overexpression of NDRG1 in vivo and in vitro reversed the effect of ETS1 knockdown on CAL-27 and SCC-6 cells. CONCLUSIONS: ETS1 positively regulates the expression of NDRG1 and promotes OSCC. Therefore, ETS1 may serve as a new target for the clinical diagnosis and treatment of OSCC.

Bag-1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience.

Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.

Screening of CXC chemokines in the microenvironment of ovarian cancer and the biological function of CXCL10.

BACKGROUND: This study aims to screen and identify the biological functions and prognostic value of CXC chemokines in ovarian cancer (OC) through bioinformatics and molecular biology methods, and to provide data support for the selection of biomarkers and prognostic analysis of OC. METHODS: In this study, GEO, ONCOMINE, GEPIA, cBioPortal, GeneMANIA, Metascape, STRING, TRRUST, and TIMER databases were used to study CXC chemokines. Angiogenesis and T cell killing assay were used to detect the effect of CXCL10 on tumor cell immunity and angiogenesis. Real-time quantitative PCR (qRT-PCR), immunoblotting, and ectopic tumor formation experiments were used to verify the effect of CXCL10 on ovarian cancer tumors. RESULTS: We found that CXCL1, CXCL10, CXCL11, CXCL13, and CXCL14 were significantly upregulated in OC samples compared with normal tissues. Our data showed that there was a relationship between the expression of CXC chemokines and the infiltration of six types of immune cells significant correlation. In vitro assay confirmed that overexpression of CXCL10 could enhance the killing effect of T cells and inhibit angiogenesis. Further in vivo assay had shown that CXCL10 could affect the progression of ovarian cancer by increasing the expression of cytotoxic T cells and inhibiting angiogenesis. CONCLUSION: In conclusion, we hope that our data will provide new insights into the development of immunotherapy and the selection of prognostic markers for patients with OC.

Adenosine A2A Receptor Agonist PSB-0777 Modulates Synaptic Proteins and AMPA Receptor Expression in a Dose- and Time-Dependent Manner in Rat Primary Cortical Neurons.

Regulating synaptic formation and transmission is critical for the physiology and pathology of psychiatric disorders. The adenosine A2A receptor subtype has attracted widespread attention as a key regulator of neuropsychiatric activity, neuroprotection and injury. In this study, we systematically investigated the regulatory effects of a novel A2A receptor agonist, PSB-0777, on the expression of synaptic proteins and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPA receptors) at the cellular level in a time- and dose-dependent manner. After 30 min of high-dose PSB-0777 stimulation, the expression of Synapsin-1 (Syn-1), postsynaptic density protein 95 (PSD95), and AMPA receptors and the number of synapses were rapidly and significantly increased in rat primary cortical neurons compared with the control. Sustained elevation was found in the low and medium-dose groups after 24 h and 3 d of treatment. In contrast, after stimulation with PSB-0777 for 3 consecutive days, the expression of Syn-1 was decreased, and PSD95, AMPA receptors and the number of synapses were no longer increased in the high-dose group. Our study focuses on the detailed and systematic regulation of synaptic proteins and AMPA receptors by an A2A receptor agonist, PSB-0777, which may result in both beneficial and detrimental effects on neurotransmission and neuroprotection and may contribute to the pathophysiology of psychiatric disorders related to A2A receptors. These experimental data may contribute to understanding of the mechanisms for neuroprotective and therapeutic effect of A2A receptor agonists.

Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer.

In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In our study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target.

Contrasting effects of acute and long-term corticosterone treatment on amyloid-ß, beta-secretase 1 expression, and nuclear factor kappa B nuclear translocation.

Regulation of neuroinflammation is critical to control the detrimental impact of chronic stress in the central nervous system. Neuroinflammation occurs in response to chronic stress, leading to enhanced neuronal damage in the brain. We investigated the regulatory effects of stress hormone corticosterone on neuroinflammation regulator, as well as amyloid-ß and Beta-secretase 1 related signaling. We demonstrate that corticosterone can both positively and negatively regulate amyloid-ß expression, which may be related to the ratio of neuroinflammation regulator and Beta-secretase 1 signaling in rat primary cortical neurons. Thirty minutes of treatment with 1 µM corticosterone significantly decreased the nuclear translocation of neuroinflammation mediator neuroinflammation regulator (Western Blot: P < 0.05, Immunofluorescence: P < 0.001) and production of Beta-secretase 1 enzyme (P < 0.01), which was accompanied by a reduction in amyloid-ß1-42 levels (P < 0.01). In contrast, 1 µM corticosterone treatment over 3 days increased nuclear neuroinflammation regulator localization (P < 0.001), followed by the upregulation of Beta-secretase 1 (P < 0.01) and amyloid-ß1-42 (P < 0.05) expression. This work is the first to demonstrate that the duration of corticosterone exposure can promote or inhibit amyloid-ß production, and to link this effect with Beta-secretase 1 / neuroinflammation regulator signaling, together with providing valuable insight into the mechanisms of neuroinflammation and neuroprotection.

Downregulation of N-Acetylglucosaminyltransferase GCNT3 by miR-302b-3p Decreases Non-Small Cell Lung Cancer (NSCLC) Cell Proliferation, Migration and Invasion.

BACKGROUND/AIMS: GCNT3 is a member of N-acetylglucosaminyltransferase family involved with mucin biosynthesis. GCNT3 aberrant expression is known to promote the progression of several human cancers. However, its role in tumorigenesis and the progression of non-small cell lung cancer (NSCLC) has not been well-characterized. Our study investigated the functional mechanisms of GCNT3 regulated by microRNAs (miRNAs) in NSCLC. METHODS: The differential expression of mRNAs in NSCLC tissues and matched adjacent non-cancerous lung tissues from patients in Xuanwei, Yunnan province, China, was screened via mRNA microarray. The expression of GCNT3 and its correlation with NSCLC progression was measured in 92 paired tumor tissues and adjacent normal tissues. The functions of GCNT3 in NSCLC cells and its underlying mechanisms were measured using siRNA and GCNT3-expression vectors. The miRNA immunoprecipitation (miRIP) method was used to identify the miRNAs targeting GCNT3. The protein were measured using western blot assay, and the mRNAs were measured by quantitative real-time PCR (qRT-PCR) assay. Cell proliferation was measured using Cell Counting Kit-8 (CCK-8) and a colony forming assays; cell migration and invasion assays were performed using 24-well Transwell chambers with 8-µm pores filter, and analyses of the cell cycle and apoptosis were performed via flow cytometric analysis. The dual luciferase reporter assay was performed to confirm whether GCNT3 gene was a direct target of miR-302b-3p. RESULTS: GCNT3 was found to be highly expressed in both NSCLC tissues and cell lines, and higher expression correlated significantly with advanced tumor-node-metastasis (TNM) stage, positive lymph node metastasis, and poor overall survival. Knockdown of GCNT3 inhibited the proliferation, migration and invasion ability of NSCLC cells, while overexpression facilitated these activities. Further mechanistic experiments using miRIP and dual luciferase reporter assays revealed that GCNT3 was a direct target of miR-302b-3p. Low expression of miR-302b-3p was found in NSCLC cells and negatively correlated with GCNT3 levels, while miR-302b-3p overexpression inhibited the proliferation, migration and invasion of NSCLC cells. Co-transfection with miR-302b-3p and the expression vector of GCNT3 abrogated the effects of mir-302b-3p, confirming that miR-302b-3p inhibited NSCLC progression by targeting GCNT3. Western blotting revealed that E-cadherin, N-cadherin, vimentin, p-Erk and cyclin D1 were downstream molecules of miR-302b-3p/GCNT3 pathway. CONCLUSION: miR-302b-3p/GCNT3 axis regulated cell proliferation, migration, and invasion by activating the Erk signaling pathway and epithelial-mesenchymal transition (EMT), which was identified as a potential therapeutic target for NSCLC.

Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR-126/SLC7A5 axis in lung cancer.

Dysregulated long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. The lncRNA plasmacytoma variant translocation 1 (PVT1) is reported to be an oncogene in a variety of cancers. However, the roles of PVT1-5 and its related miRNAs in lung cancer are poorly understood. In this study, we found that PVT1-5 expression was significantly increased in lung cancer tissues and cell lines. By using biotin-labeled lncRNA-PVT1-5 probe for miRNA in vivo precipitation (miRIP) in lung cancer cells and dual-luciferase reporterassays, we identified that miR-126 was associated with lncRNA-PVT1-5. Furthermore, knockdown of lncRNA-PVT1-5 in cells could down-regulate the expression of SLC7A5, the target of oncogenic miR-126, resulting in the cell proliferation. Conversely, inhibiting the expression of miR-126 markedly increased the expression of SLC7A5 and alleviated cell proliferation inhibition. Thus, our results indicated that lncRNA-PVT1-5 may function as a competing endogenous RNA (ceRNA) for miR-126 to promote cell proliferation by regulating the miR-126/SLC7A5 pathway, suggesting that lncRNA-PVT1-5 plays a crucial role in lung cancer progression and lncRNA-PVT1-5/miR-126/SLC7A5 regulatory network may shed light on tumorigenesis in lung cancer.

[Association of single nucleotide polymorphisms of CDH13 gene with metabolic syndrome among ethnic Han Chinese].

OBJECTIVE To assess the association of single nucleotide polymorphisms (SNPs) of the T-cadherin (CDH13) gene with metabolic syndrome (MS) among ethnic Han Chinese.METHODS Genotypes of 6 SNPs(rs11646213, rs12596316, rs3865188, rs12444338, rs12051272, and rs7195409) of the CDH13 gene among 453 patients with MS and 526 controls were determined with a TaqMan method, and their association with MS was assessed. RESULTS For 5 SNPs (rs11646213, rs3865188, rs12444338, rs12051272, and rs7195409), no difference was found in allelic and genotypic frequencies of the CDH13 gene between the two groups. Comparing with rs12596316 (AA+GG) genotype, rs12596316 AG genotype has significantly increased the risk of MS(P = 0.01,OR = 1.38,95%CI: 1.07-1.78), though no association was found between particular alleles of the rs12596316 with MS.There was no difference in the frequencies of rs11646213-rs12596316-rs3865188-rs12444338-rs12051272 haplotype between the two groups(P > 0.05). CONCLUSION No association was found between the five SNPs (rs11646213, rs3865188, rs12444338, rs12051272 and rs7195409) of the CDH13 gene with the MS, while the rs12596316AG genotype of the CDH13 gene is associated with the susceptibility to MS among ethnic Han Chinese.

Association of CYP17A1 Genetic Polymorphisms and Susceptibility to Essential Hypertension in the Southwest Han Chinese Population.

BACKGROUND The CYP17A1 gene encodes for cytochrome P450 enzyme CYP17A1, which is involved with the steroidogenic pathway including mineralocorticoids. The CYP17A1 polymorphisms might affect enzyme activity, then leading to a state of mineralocorticoid 11-deoxycorticosterone excess characterized by hypertension, suppressed plasma renin activity, and low aldosterone concentrations. The aim of this study was to investigate the contribution of CYP17A1 polymorphisms in inducing the susceptibility to essential hypertension among the Southwest Han Chinese population. MATERIAL AND METHODS Eight single nucleotide polymorphisms of CYP17A1 were genotyped in a case-control study for samples by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS The polymorphisms rs11191548 and rs4919687 were significantly associated with hypertension risk, which was confirmed by systolic and diastolic blood pressure distribution analyses between different genotype groups, and these two polymorphisms were found in linkage disequilibrium. The rs4919687 polymorphism was estimated to cause the destruction of exonic splicing silencer (ESR and Motif 3) sites and to transform the transcription factor AREB6 binding site, respectively, in the bioinformatics analyses. The haplotypes rs4919686A-rs3740397G -rs4919687C-rs743572C-rs11191548C and rs4919686A-rs3740397G-rs4919687T-rs743572C- rs11191548T were found to be susceptible to essential hypertension. CONCLUSIONS Our findings suggest that the CYP17A1 polymorphisms could be a genetic risk factor for essential hypertension among the Yunnan Han Chinese population, which would have implications for the treatment of this complex disorder.

Griflola frondosa (GF) produces significant antidepressant effects involving AMPA receptor activation in mice.

CONTEXT: Griflola frondosa (Fr) S.F. Gray (Meripilaceae) (GF) is a medical mushroom, and its regulation of the immune system is of interest for the treatment of mood disorders. α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors are the central mediator for the treatment of depression. OBJECTIVE: This study examines the antidepressant effects of GF and the role of AMPA in these antidepressant effects. MATERIALS AND METHODS: The CD-1 mice were fed with GF- or Pleurotus ostreatus [(Jacq.: Fr) Kumm (Pleurotaceae)] (PO)-containing food for 1 day or 5 days. The antidepressant effects was determined in the tail suspension test (TST), forced swim test (FST), and open field test (OFT). The involvement of AMPA receptors was determined by the application of the AMPA-specific blocker GYKI 52466. RESULTS: Treatments with 20%, 33% or 50% of GF-containing food significantly decreased the immobility time (63.6, 56.9, and 52.0% in TST; and 50.8, 43.2, and 38.2% in FST) after 1 day and (62.3, 51.8, and 52.8% in TST; and 49.5, 45.1, and 40.3% in FST) after 5 days. GF-containing food did not cause hyperactive effects in the OFT. The antidepressant effects of the 33% of GF-containing food (down-to 51.3% in 1-day TST and 46.8% in 5-day FST) were significantly stronger than that of the 33% of PO-containing food (down-to 85.5% in 1-day TST and 82.0% in 5-day FST). AMPA-specific blocker GYKI 52466 was able to block the antidepressant effects of the GF-containing food. CONCLUSION: GF demonstrated the potential as a safe medical food supplement for the patient with depression.

3'-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway.

BACKGROUND: The development of rapid and safe antidepressants for the treatment of major depression is in urgent demand. Converging evidence suggests that glutamatergic signaling seems to play important roles in the pathophysiology of depression. METHODS: We studied the antidepressant effects of 3(')-deoxyadenosine (3'-dA, Cordycepin) and the critical role of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in male CD-1 mice via behavioral and biochemical experiments. After 3'-dA treatment, the phosphorylation and synaptic localization of the AMPA receptors GluR1 and GluR2 were determined in the prefrontal cortex (PFC) and hippocampus (HIP). The traditional antidepressant imipramine was applied as a positive control. RESULTS: We found that an injection of 3'-dA led to a rapid and robust antidepressant effect, which was significantly faster and stronger than imipramine, after 45min in tail suspension and forced swim tests. This antidepressant effect remained after 5 days of treatment with 3'-dA. Unlike the psycho-stimulants, 3'-dA did not show a hyperactive effect in the open field test. After 45min or 5 days of treatment, 3'-dA enhanced GluR1 S845 phosphorylation in both the PFC and HIP. In addition, after 45min of treatment, 3'-dA significantly up-regulated GluR1 S845 phosphorylation and GluR1, but not GluR2 levels, at the synapses in the PFC. After 5 days of treatment, 3'-dA significantly enhanced GluR1 S845 phosphorylation and GluR1, but not GluR2, at the synapses in the PFC and HIP. Moreover, the AMPA-specific antagonist GYKI 52466 was able to block the rapid antidepressant effects of 3'-dA. CONCLUSION: This study identified 3'-dA as a novel rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the prefrontal AMPA receptor signaling pathway.

The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors.

Numerous studies have linked severe stress to the development of major depressive disorder (MDD) and suicidal behaviors. Furthermore, recent preclinical studies from our laboratory and others have demonstrated that in rodents, chronic stress and the stress hormone cortisol cause oxidative damage to mitochondrial function and membrane lipids in the brain. Mitochondria play a key role in synaptic neurotransmitter signaling by providing adenosine triphosphate (ATP), mediating lipid and protein synthesis, buffering intracellular calcium, and regulating apoptotic and resilience pathways. Membrane lipids are similarly essential to central nervous system (CNS) function because cholesterol, polyunsaturated fatty acids, and sphingolipids form a lipid raft region, a special lipid region on the membrane that mediates neurotransmitter signaling through G-protein-coupled receptors and ion channels. Low serum cholesterol levels, low antioxidant capacity, and abnormal early morning cortisol levels are biomarkers consistently associated with both depression and suicidal behaviors. In this review, we summarize the manner in which nutrients can protect against oxidative damage to mitochondria and lipids in the neuronal circuits associated with cognitive and affective behaviors. These nutrients include ω3 fatty acids, antioxidants (vitamin C and zinc), members of the vitamin B family (Vitamin B12 and folic acid), and magnesium. Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors. A growing body of studies suggests the intriguing possibility that regular consumption of these nutrients may help prevent the onset of mood disorders and suicidal behaviors in vulnerable individuals, or significantly augment the therapeutic effect of available antidepressants. These findings have important implications for the health of both military and civilian populations.

Overexpression of miR-30a in lung adenocarcinoma A549 cell line inhibits migration and invasion via targeting EYA2.

MicroRNAs (miRNAs) are a class of small non-coding RNAs and closely related to the pathogenesis of cancers. Increasing evidence indicates that miR-30a plays a profound role during the development of cancers. However, the functions of miR-30a in non-small-cell lung cancer (NSCLC) are still ambiguous. Here we found that miR-30a was decreased in lung adenocarcinoma A549 cells and in tissue samples from 14 patients by qRT-PCR, and also found that overexpression of miR-30a in A549 cells inhibited migration and invasion but not cell proliferation and cell cycle progression by wound-healing assay, matrigel invasion assay, MTS-based cell proliferation assay, and flow cytometry-based cell cycle analysis, respectively. We further explored the potential mechanism of miR-30a-mediated gene regulation in lung adenocarcinoma cell lines. EYA2 is a predicted target of miR-30a, and it has been found that EYA2 expression is inhibited by miR-30a in breast cancer cells. We demonstrated that EYA2 is a direct target of miR-30a by using the dual-luciferase reporter assay in A549 cells and showed that EYA2 protein levels are inversely correlated with miR-30a expression in A549 and BEAS-2B cells. In addition, we also confirmed the rescue effects of EYA2 overexpression in A549 cells by cotransfection with EYA2 expression vector and miR-30a mimics. Taken together, our results demonstrate that overexpression of miR-30a in lung adenocarcinoma A549 cells can inhibit cell migration and invasion, which is partially attributed to the decrease of EYA2 expression. Our findings suggest that miR-30a may be used as a new potential target for the treatment of lung adenocarcinoma in the future.

Association study of ARL15 and CDH13 with T2DM in a Han Chinese population.

Several studies indicate that plasma adiponectin levels are associated with the risk of type 2 diabetes mellitus (T2DM) or T2DM risk factors in diverse populations. In addition to the adiponectin gene, several other genes have been postulated to influence plasma adiponectin levels. In this study, we investigated two single nucleotide polymorphisms (SNPs), rs4311394 and rs4783244, located intronically in the ADP-ribosylation factor-like protein 15 (ARL15) and the T-cadherin (CDH13) genes, respectively. These SNPs were detected in a Han Chinese population using a TaqMan assay and evaluated for association with T2DM as well as with individual metabolic traits. Allele frequencies for rs4311394 were significantly different in T2DM and nondiabetes (NDM) groups (χ² = 4.49, P = 0.034). However, neither allele nor genotype frequencies for rs4783244 were associated with T2DM (χ² = 0.33, P = 0.56 and χ² = 2.35, P = 0.31 respectively). The SNPs did not exhibit significant association with individual metabolic traits in the T2DM and NDM groups. Our results indicated that the G allele of the rs4311394 might be a susceptibility factor for T2DM in the Han Chinese population (odds ratio: 1.20; 95% confidence interval: 1.01-1.41).

[Association of CMA1 gene tag single nucleotide polymorphisms with essential hypertension in Yi population from Yunnan].

OBJECTIVE: To assess the association of tag single nucleotide polymorphisms (tag SNPs) of chymase gene (CMA1) with essential hypertension in Yi population from Yunnan, China. METHODS: A case-control study was carried out. Four tag SNPs(rs1956921, rs1800876, rs5244 and rs1885108) were genotyped in 303 patients with essential hypertension and 312 healthy controls using polymerase chain reaction - restriction fragment length polymorphism(PCR-RFLP) method. RESULTS: No significant difference in genotypic and allelic distributions of the four polymorphisms was detected between the two groups(P>0.05), and the same results existed in the females. The frequencies of rs1956921 C allele and a C-T haplotype constructed with rs1956921 and rs5244 were greater in male patients compared with male controls(P<0.01). CONCLUSION: The rs1956921 C allele of the CMA1 gene and the C-T haplotype constructed with rs1956921 and rs5244 may be risk factors for essential hypertension in ethnic Yi males from Yunnan.

A single-cell pan-cancer analysis to show the variability of tumor-infiltrating myeloid cells in immune checkpoint blockade.

Myeloid cells are vital components of the immune system and have pivotal functions in orchestrating immune responses. Understanding their functions within the tumor microenvironment and their interactions with tumor-infiltrating lymphocytes presents formidable challenges across diverse cancer types, particularly with regards to cancer immunotherapies. Here, we explore tumor-infiltrating myeloid cells (TIMs) by conducting a pan-cancer analysis using single-cell transcriptomics across eight distinct cancer types, encompassing a total of 192 tumor samples from 129 patients. By examining gene expression patterns and transcriptional activities of TIMs in different cancer types, we discern notable alterations in abundance of TIMs and kinetic behaviors prior to and following immunotherapy. We also identify specific cell-cell interaction targets in immunotherapy; unique and shared regulatory profiles critical for treatment response; and TIMs associated with survival outcomes. Overall, our study illuminates the heterogeneity of TIMs and improves our understanding of tissue-specific and cancer-specific myeloid subsets within the context of tumor immunotherapies.

Association between HLA-B*46 allele and Graves disease in Asian populations: a meta-analysis.

Graves' disease (GD) is a leading cause of hyperthyroidism, which affects 1.0-1.6% of the general population. Previous studies reported a higher GD prevalence in Asian populations compared to Caucasian populations. The etiology of GD involves complex interactions between predisposing genes and environmental triggers. Genetic studies have shown that the human leukocyte antigen (HLA) is an important candidate genetic region associated with GD in Asian populations. However, the results were inconsistent and inconclusive. Here, we performed a meta-analysis to evaluate the role of the HLA-B*46 allele in GD in Asian populations. A total of 14 case-controlled studies on the association of the HLA-B*46 allele in 1743 GD patients and 5689 controls were included. Our results showed a trend toward an increased risk of GD in HLA-B*46-positive subjects compared to those HLA-B*46-negative (OR = 2.48; 95% CI = 1.96-3.13, P < 0.01). However, there were some limitations to the current meta-analysis, such as heterogeneity (P(heterogeneity )< 0.01 and I(2 )= 68.0%) or the different typing methods (serological and genotyping methods). The meta-analysis indicated that the HLA-B*46 allele is a risk factor for GD in Asian populations. Future studies on the role of the HLA-B*46 allele in GD should consider complications such as periodic paralysis, ophthalmopathy and recurrence.

Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis in Chinese Han population.

Toll-like receptor4 (TLR4) plays an important role in the induction and regulation of the innate or adaptive immune responses. Thus, the genetic variation in TLR4 gene may influence the development of autoimmune diseases such as rheumatoid arthritis (RA). Several studies have investigated the roles of genetic polymorphisms of TLR4 gene in RA, but most of these studies were restricted to two cosegregating functional missense polymorphisms Asp299Gly and Thr399Ile. To determine whether non-missense genetic polymorphisms located in regulatory region of TLR4 are related to RA in a Chinese Han population, four single nucleotide polymorphisms (SNPs) situated on 3' untranslating region (UTR) and 5' UTR were genotyped in 213 RA patients and 247 unrelated ethnically matched controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing techniques. Significant genetic associations were observed with the 3' UTR SNP rs41426344 and rs7873784. The minor allele C and homozygotic variant genotype CC of rs41426344 and minor allele C of rs7873784 were identified to be risk factors for the development of RA in Chinese Han people. Furthermore, by comparing the variation allele frequencies to other populations, prevalent genetic ethnic specificity was observed in all the four SNPs. Our study suggested that the effect of non-missense polymorphisms located in regulatory region would not be neglected in disease association analysis.

[Current status and implication of research on Bardet-Biedl syndrome].

OBJECTIVE: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disease initially reported by Bardet and Biedl in the 1920s. BBS is a pleiotropic and genetically heterogeneous disorder characterized by retinopathy, obesity, polydactyly, renal malformations and functional abnormalities, learning disabilities and hypogenitalism. BBS patients are also prone to diabetes mellitus, hypertension and congenital heart disease. To date, 16 BBS genes (BBS1-BBS16) have been identified. However, the molecular etiology of BBS is not yet entirely clear. In this article, we have reviewed recent research on BBS and discussed its implications for understanding of ciliopathology.