Potential Biomarker of Acute Anthracycline-induced Cardiotoxicity Among Children With Acute Lymphoblastic Leukemia: Cardiac Adriamycin-responsive Protein.

ABSTRACT: This study aimed to investigate whether serum cardiac adriamycin-responsive protein (CARP) can serve as a sensitive and specific biomarker of anthracyclines (ANT)-induced cardiotoxicity. Fifty-five children with acute lymphoblastic leukemia were recruited. Before and after the administration of ANT, serum levels of CARP, high-sensitivity troponin T, creatine kinase-MB, and electrocardiogram were measured. Postchemotherapeutic clinical manifestations of cardiotoxicity were also investigated. Adverse cardiac events (ACEs) were graded according to the Common Terminology Criteria for Adverse Events 4.0. Then, the CARP expression was statistically analyzed among different groups. The receiver operating characteristic curve was used to evaluate the efficacy of CARP in predicting acute ANT-induced cardiotoxicity. After ANT chemotherapy, the serum CARP concentration increased in the non-ACEs group but decreased in the ACEs group ( P < 0.05). In addition, not only the serum CARP levels (△CARP) was negatively correlated with the grade of ACEs (R=-0.754, P < 0.0001) but also the extent of QT interval corrected (QTc) prolongation (△QTc; R=-0.5592, P < 0.01). The area under the receiver operating characteristic curve of CARP was 90.94% ( P < 0.0001), and the sensitivity and specificity were 88.64% and 91.67%, respectively, all of which are superior to △high-sensitivity troponin T, △creatine kinase-MB, and △QTc. In conclusion, serum CARP could serve as a novel sensitive and specific biomarker of acute ANT-induced cardiotoxicity, which is negatively associated with ACE grade.

Genetic contribution of synapse-associated protein 97 to cerebellar functional connectivity changes in first-episode schizophrenia.

Our previous study data suggested that the synapse-associated protein 97 (SAP97) rs3915512 polymorphism is significantly related to clinical performance in schizophrenia. The cerebellum exhibits abundant expression of SAP97, which is involved with negative symptoms, cognition and emotion in schizophrenia. As functional dysconnectivity with the cortical-subcortical-cerebellar circuitry has been widely shown in patients with schizophrenia, cortical-subcortical-cerebellar dysconnectivity can therefore be considered a possible intermediate phenotype that connects risk genes with schizophrenia. In this study, resting-state functional magnetic resonance imaging (fMRI) was applied to evaluate whether the SAP97 rs3915512 polymorphism changes cortical/subcortical-cerebellar resting-state functional connectivity (RSFC) in 104 Han Chinese subjects (52 first-episode schizophrenia (FES) patients and 52 matched healthy controls (HCs)). To examine RSFC between cortical/subcortical regions and the cerebellum, a ROI (region of interest)-wise functional connectivity analysis was conducted. The association between abnormal cortical/subcortical-cerebellar connectivity and clinical manifestation was further assessed in FES patients with different genotypes. The interactive effect of disease and genotype on RSFC was found between the frontal gyrus (rectus) and cerebellum. A positive correlation was suggested between RSFC in the cerebellum and the hostility scores in FES patients with the A allele, and no correlation was found in FES patients with the TT genotype. The current findings identified that SAP97 may be involved in the process of mental symptoms in FES patients via cerebellar connectivity depending on the rs3915512 polymorphism genotype.

Direct targeting of DOCK4 by miRNA-181d in oxygen-glucose deprivation/reoxygenation-mediated neuronal injury.

The miRNA-181 (miR-181) family regulates neuronal persistence during cerebral ischemia/reperfusion injury (CI/RI). Since the effect of miR-181d on CI/RI has never been studied, the current work sought to determine the involvement of miR-181d in neuronal apoptosis after brain I/R injury. To replicate in vivo and in vitro CI/RI, a transient middle cerebral artery occlusion (tMCAO) model in rats and an oxygen-glucose deficiency/reoxygenation (OGD/R) model in neuro 2A cells were developed. In both in vivo and in vitro stroke models, the expression of miR-181d was considerably higher. miR-181d suppression reduced apoptosis and oxidative stress in OGD/R-treated neuroblastoma cells, but miR-181d overexpression increased both. Furthermore, it was observed that miR-181d has a direct target in dedicator of cytokinesis 4 (DOCK4). The overexpression of DOCK4 partially overcame cell apoptosis and oxidative stress induced by miR-181d upregulation and OGD/R injury. Furthermore, the DOCK4 rs2074130 mutation was related to lower DOCK4 levels in ischemic stroke (IS) peripheral blood and higher susceptibility to IS. These findings suggest that downregulating miR-181d protects neurons from ischemic damage by targeting DOCK4, implying that the miR-181d/DOCK4 axis might be a novel therapeutic target for IS.

miR-181a targets PTEN to mediate the neuronal injury caused by oxygen-glucose deprivation and reoxygenation.

Evidence suggests that the microRNA-181 (miR-181) family performs various roles in the pathophysiology of cerebral ischemia and reperfusion injury (CIRI). MiR-181a has been identified as a critical determinant of neuronal survival. Moreover, the significance of miR-181a in controlling neuronal death after CIRI has received little attention. The objective of this study was to assess the role of miR-181a in neuronal cell injury after CIRI. To mimic the in-vitro and in-vivo CIRI, we developed an oxygen-glucose deficiency/reoxygenation (OGD/R) model in SH-SY5Y cells and a transient middle cerebral artery occlusion model in rats. MiR-181a expression was significantly higher in both in-vivo and in-vitro CIRI models. The overexpression of miR-181a increased cell damage and oxidative stress caused by OGD/R, whereas inhibition of miR-181a reduced both. PTEN has also been found to be a direct miR-181a target. PTEN overexpression reduced cell apoptosis and oxidative stress induced by miR-181a upregulation under an OGD/R condition. Furthermore, we found that the rs322931 A allele was related to increased miR-181a levels in IS peripheral blood and higher susceptibility to IS. The current results offer new insights into the understanding of the molecular pathophysiology of CIRI, as well as possible new treatment candidates.

Isolated steroid-resistant nephrotic syndrome in a Chinese child carrying a de novo mutation in WT1 gene:a case report and literature review.

BACKGROUND: Isolated steroid-resistant nephrotic syndrome (ISRNS) is caused by mutations in the Wilms' tumor-1 (WT1) gene, which encodes glomerular podocytes and podocyte slit diaphragm.We report a novel 8-year-old female patient with ISRNS carrying a de novo missense mutation in WT1 gene and presenting a new type of pathology, have never been reported.We also systematically review previous reports of ISRNS in Chinese children. CASE PRESENTATION: A 8-year-old Chinese patient who had steroid-resistant nephrotic syndrome,responded poorly to immunosuppressant, and had no extrarenal manifestations. The patient had a female phenotype and karyotype of 46, XX. A new type of renal pathology, proliferative sclerosing glomerulonephritis (PSG),and a de novo missense mutation in WT1 gene, c.748C > T (p.R250W),which have not yet been reported, were identified. She was diagnosed with ISRNS.The patient progressed to end-stage renal disease at the age of 10 years,underwent dialysis and kidney transplant. Renal function and urine protein were normal during 4-year follow-up. CONCLUSIONS: WT1 gene testing should be performed to guide treatment for patients with steroid-resistant nephrotic syndrome, especially for isolated cases and female patients.

microRNA-186 alleviates oxygen-glucose deprivation/reoxygenation-induced injury by directly targeting hypoxia-inducible factor-1α.

Previous studies have suggested that microRNA-186 (miR-186) can be induced under hypoxic conditions, and is associated with apoptosis. This study was undertaken to explore the exact role of this microRNA (miRNA) in the apoptotic death of neurons during cerebral ischemic/reperfusion (I/R) injury. To model cerebral ischemia/reperfusion (I/R) injuries, we utilized a transient middle cerebral artery occlusion approach in rats, as well as a model of oxygen-glucose deprivation/reoxygenation (OGD/R) in Neuro2a cells. We found that in both in vitro and in vivo models of cerebral I/R injuries, levels of miR-186 were markedly decreased. When we overexpressed miR-186, this was associated with a reduction in the apoptotic death of neuroblastoma cells in the OGD/R model system, whereas the opposite was true when this miRNA was instead inhibited. We further found miR-186 to directly target hypoxia-inducible factor 1α (HIF-1α) by interacting with the 3'-untranslated region of this mRNA. When we knocked down HIF-1α, this partially overcame the apoptotic death of cells in response to OGD/R injury and associated miR-186 downregulation. Our findings indicate that miR-186 is able to reduce ischemic injury to neurons at least in part through downregulating HIF-1α, suggesting that the miR-186/HIF-1α axis is a potential therapeutic target for the treatment of ischemic stroke.

Association study of a genetic variant in the long intergenic noncoding RNA (linc01080) with schizophrenia in Han Chinese.

BACKGROUND: Schizophrenia is currently considered to be a polygene-related disease with unknown etiology. This research will verify whether the single nucleotide polymorphism (SNP) of the long intergenic noncoding RNA01080 (linc01080) contributes to the susceptibility and phenotypic heterogeneity of schizophrenia, with a view to providing data support for the prevention and individualized treatment of this disease. METHOD: The SNP rs7990916 in linc01080 were genotyped in 1139 schizophrenic and 1039 controls in a Southern Chinese Han population by the improved multiplex ligation detection reaction (imLDR) technique. Meanwhile, we assessed and analyzed the association between this SNP and schizophrenics' clinical symptoms, and the cognitive function. RESULT: There was no significant difference in genotype distribution, allele frequency distribution, gender stratification analysis between the two groups. However, the SNP of rs7990916 was significantly associated with the age of onset in patients with schizophrenia (P = 8.22E-07), patients with T allele had earlier onset age compared with CC genotype carriers. In terms of cognitive function, patients with T allele scored lower than CC genotype carriers in the Tower of London score and symbol coding score in the Brief assessment of Cognition (BACS), and the difference was statistically significant (P = 0.014, P = 0.022, respectively). CONCLUSION: Our data show for the first time that linc01080 polymorphism may affect the age of onset and neurocognitive function in patients with schizophrenia.

Cloning and expression profiling of muscle regulator ANKRD2 in domestic chicken Gallus gallus.

Striated muscle signaling protein and transcriptional regulator ANKRD2 participates in myogenesis, myogenic differentiation, muscle adaptation and stress response. It is preferentially expressed in slow, oxidative fibers of mammalian skeletal muscle. In this study, we report on characterization of chicken ANKRD2. The chicken ANKRD2 coding region contains 1002 bp and encodes a 334-amino acid protein which shares approximately 58% identity with human and mouse orthologs, mostly in the conserved region of ankyrin repeats. Comprehensive analysis of the ANKRD2 gene and protein expression in adult chicken demonstrated its predominant expression in red muscles of thigh and drumstick, compared to white muscle. It was not detected in heart and white pectoral muscle. Uneven expression of ANKRD2 in chicken skeletal muscles, observed by immunohistochemistry, was attributed to its selective expression in slow, oxidative, type I and fast, oxidative-glycolytic, type IIA myofibers. Association of chicken ANKRD2 with phenotypic differences between red and white muscles points to its potential role in the process of myofiber-type specification. In addition to expression in slow oxidative myofibers, as demonstrated for mammalian protein, chicken ANKRD2 was also detected in fast fibers with mixed oxidative and glycolytic metabolism. This finding suggests that ANKRD2 is responsive to metabolic differences between types of avian myofibers and orientates future studies towards investigation of its role in molecular mechanisms of myofiber-type-specific gene expression.

Protection of Fecal Microbiota Transplantation in a Mouse Model of Multiple Sclerosis.

Given the growing evidence of a link between gut microbiota (GM) dysbiosis and multiple sclerosis (MS), fecal microbiota transplantation (FMT), aimed at rebuilding GM, has been proposed as a new therapeutic approach to MS treatment. To evaluate the viability of FMT for MS treatment and its impact on MS pathology, we tested FMT in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We provide evidence that FMT can rectify altered GM to some extent with a therapeutic effect on EAE. We also found that FMT led to reduced activation of microglia and astrocytes and conferred protection on the blood-brain barrier (BBB), myelin, and axons in EAE. Taken together, our data suggest that FMT, as a GM-based therapy, has the potential to be an effective treatment for MS.

SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy.

D-serine is a predominant N-methyl-D-aspartate receptor co-agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L-serine to D-serine. In this study, we aimed to investigate the genetic roles of SRR and a neighbouring gene, nonsense-mediated mRNA decay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496 TLE patients and 528 healthy individuals were successfully genotyped for three SRR tag single nucleotide polymorphisms. The frequencies of the GG genotype at rs4523957 T > G were reduced in the TLE cases in the initial cohort (cohort 1) and were confirmed in the independent cohort (cohort 2). An analysis of all TLE cases in cohort 1 + 2 revealed that the seizure frequency and drug-resistant incidence were significantly decreased in carriers of the GG genotype at rs4523957. Intriguingly, the activity of the SMG6 promoter with the mutant allele at rs4523957 decreased by 22% in the dual-luciferase assay, and up-regulated expression of SMG6 was observed in an epilepsy rat model. This study provides the first demonstration that the GG genotype is a protective marker against TLE. In particular, variation at rs4523957 likely inhibits SMG6 transcription and plays a key role against susceptibility to and severity of TLE. The significance of SMG6 hyperfunction in epileptic seizures deserves to be investigated in future studies.

Association of Polymorphisms of the Matrix Metalloproteinase 9 Gene with Ischaemic Stroke in a Southern Chinese Population.

BACKGROUND/AIMS: Matrix metalloproteinase 9 (MMP9), a potent endopeptidase degrading extracellular matrix, plays a pivotal role in the pathogenesis of ischaemic stroke (IS). The present study was undertaken to determine the association of MMP9 gene polymorphisms and the risk of IS in a southern Chinese population. METHODS: A cohort of 1274 patients and 1258 age-matched healthy controls were genotyped to detect the four MMP9 polymorphisms (rs17156, rs3787268, rs3918241 and rs3918242) using SNaPshot. RESULTS: Our study demonstrated a significant difference in the genotype and allele frequencies of the MMP9 rs3918242 polymorphism between the IS patients and the controls (P = 0.012 for the genotype and P = 0.0092 for the allele). Stratification by smoking status showed statistically significant differences in the frequency and allele of the rs3918242 polymorphism between IS patients and the controls (P = 0.0052 for the genotype and P = 0.0019 for the allele). Further stratification by IS subtypes revealed that the presence of the T allele of the MMP9 rs3918242 polymorphism confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.017). Moreover, IS patients with the rs3918242 T allele of MMP9 presented with increased serum MMP9 production, and this increase was more significant in smokers with IS (P = 0.022). Patients carrying the variant T allele of the MMP9 rs3918242 polymorphism exhibited significantly higher infarct volumes than those with the major CC genotype (P = 0.036). CONCLUSION: Our study provides preliminary evidence that the MMP9 rs3918242 polymorphism is linked to a higher risk of IS, confirming the role of MMP9 in the pathophysiology of IS, with potentially important therapeutic implications.

Genetic association of MiR-146a with multiple sclerosis susceptibility in the Chinese population.

BACKGROUND: miR-146a polymorphisms have been involved in susceptibility to multiple diseases. The aim of the present study was to analyze the potential association between two functional miR-146a polymorphisms (rs2910164 and rs57095329) and multiple sclerosis (MS) in the Han Chinese population. METHODS: A cohort of 525 patients and 568 healthy controls were genotyped to detect the two polymorphisms by SNaPshot. RESULTS: No significant differences were detected in the distribution of the two miR-146a polymorphisms between the patients and controls (P > 0.05). However, stratification by gender showed a statistically significant difference in the frequency of the genotype rs2910164 between MS patients and control females (P=0.009). Further stratification analysis by subgroup revealed that the miR-146a rs2910164 C allele conferred a higher risk of developing relapsing-remitting MS (RRMS) (P=0.018). In addition, the rs2910164 C allele was significantly associated with increased expression of miR-146a in patients with RRMS (P=0.025). Moreover, patients with the rs2910164 C allele released more TNF-α and IFN-γ, but not IL-1ß, compared with individuals carrying the homozygous GG genotype (P < 0.05). CONCLUSIONS: Our results provide evidence that rs2910164 may play a role in MS susceptibility in females. The rs2910164 G>C variation may affect the expression of miR-146a and the release of proinflammatory cytokines.

An ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis.

INTRODUCTION: Although genetic variants of the A disintegrin and metalloproteinase 10 (ADAM10) gene have been shown to be associated with susceptibility to several inflammatory-related diseases, to date little is known about the clinical relationship in the development of sepsis. METHODS: Two genetic variants in the promoter of ADAM10 were selected to analyze the potential association with the risk of sepsis. A total of 440 sepsis patients and 450 matched healthy individuals in two independent Chinese Han population were enrolled. Pyrosequencing and polymerase chain reaction-length polymorphism was used to determine the genotypes of the rs514049 and rs653765. A real-time qPCR method was used to detect the mRNA level of ADAM10. Enzyme-linked immunosorbent assay was used to measure the expression levels of substrates CX3CL1, interleukin (IL)-6R, tumor necrosis factor alpha (TNF-α), and the pro-inflammatory cytokines IL-1ß and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10. RESULTS: No statistically significant differences between sepsis cases and controls in the genotype or allele frequencies were observed, suggesting that ADAM10 single nucleotide polymorphisms (SNPs) may not be risk factors for the occurrence of sepsis. A significant difference in the genotype and allele frequencies of the rs653765 SNP between patients with sepsis subtype and severe sepsis (P = 0.0014) or severe sepsis/sepsis shock (P = 0.0037) were observed. Moreover, the rs653765 CC genotype in severe sepsis showed a higher ADAM10 level compared to healthy groups, and the rs653765 CC polymorphism had a strong impact on the production of the ADAM10 substrates CX3CL1, IL-6R and TNF-α. Furthermore, the functional assay showed that ADAM10 C-A haplotype carriers exhibited significantly higher reporter activity compared with the T-A carriers and T-C carriers in human acute monocytic leukemia cell line. CONCLUSIONS: Our data initially indicated the ADAM10 rs653765 polymorphism was associated with the development of severe sepsis; the risk CC genotype could functionally affect the expression level of ADAM10 mRNA and was accompanied by the up-regulation of its substrates. Thus, ADAM10 might be clinically important and play a critical role in the pathogenesis of the development of sepsis, with potentially important therapeutic implications.

Increases in peripheral SIRT1: a new biological characteristic of asthma.

BACKGROUND AND OBJECTIVE: Silent information regulator 1 (SIRT1) is a class III histone deacetylase that exerts both anti-inflammatory and anti-aging effects. However, no data are available regarding SIRT1 expression in patients with asthma. Here, we studied SIRT1 levels in the serum of patients with asthma and analysed the distribution of SIRT1 in both the serum and the lungs in an asthmatic mouse model to determine its clinical significance. METHODS: Serum SIRT1 levels, total immunoglobulin E (IgE) levels and peripheral blood eosinophil percentages as well as pulmonary function were quantified in 97 patients with asthma and 118 healthy volunteers. BALB/c mice were sensitized and challenged using ovalbumin (OVA) to produce the asthmatic model, and SIRT1 levels in both the serum and the lung tissues were subsequently measured. RESULTS: The serum SIRT1 levels were significantly elevated in the patients with asthma compared with the controls. Serum SIRT1 levels positively correlated with total IgE levels and negatively correlated with pulmonary function. In the OVA-sensitized and challenged mice, an increased serum SIRT1 level was confirmed, whereas decreased SIRT1 expression was observed in the lung tissues. CONCLUSIONS: These data indicate that lung SIRT1 expression decreased while serum SIRT1 increased in the setting of asthma. Serum SIRT1 levels correlate positively with both IgE levels and negatively with pulmonary function, suggesting that increased peripheral SIRT1 levels represent a new biological characteristic of asthma. Increased serum SIRT1 may be an auxiliary index for the diagnosis of asthma and elevating lung SIRT1 levels may be a new strategy for asthma therapy.

Analysis of ADAM17 polymorphisms and susceptibility to sporadic abdominal aortic aneurysm.

BACKGROUND: Accumulating evidence suggests that the principal TNF-α converting enzyme, a disintegrin and metalloproteinase 17 (ADAM17), is involved in the development of human abdominal aortic aneurysm (AAA). However, the association between ADAM17 gene polymorphisms and AAA has not been explored. The present study was aimed to determine the association between ADAM17 promoter polymorphisms and AAA. METHODS: A total of 316 patients with AAA and 306 age-matched healthy controls were enrolled in this study. Two ADAM17 promoter polymorphisms (rs12692386 and rs1524668) were determind. Real-time PCR was employed to detect the expression of ADAM17. RESULTS: Overall, there was a significant difference in the frequency of the genotype rs12692386 between the AAA and control subjects (P=0.0096). Furthermore, men with the rs12692386 AG genotype conferred a higher risk of developing AAA (P=0.0058). Additionally, the rs12692386 mutated AG genotype of ADAM17 was significantly associated with increased ADAM17 expression (P=0.035) and TNF-α production (P=0.042) in AAA patients. In contrast, the allele frequency of rs1524668 was not statistically associated with AAA. CONCLUSIONS: Our findings indicate a positive association between the rs12692386 polymorphism of ADAM17 and AAA. This new knowledge about ADAM17 identifies a role for ADAM17 in the pathophysiology of AAA and has important clinical implications with regard to potential therapeutics.

Bayesian model selection for multiple QTLs mapping combining linkage disequilibrium and linkage.

Linkage disequilibrium (LD) mapping is able to localize quantitative trait loci (QTL) within a rather small region (e.g. 2 cM), which is much narrower than linkage analysis (LA, usually 20 cM). The multilocus LD method utilizes haplotype information around putative mutation and takes historical recombination events into account, and thus provides a powerful method for further fine mapping. However, sometimes there are more than one QTLs in the region being studied. In this study, the Bayesian model selection implemented via the Markov chain Monte Carlo (MCMC) method is developed for fine mapping of multiple QTLs using haplotype information in a small region. The method combines LD as well as linkage information. A series of simulation experiments were conducted to investigate the behavior of the method. The results showed that this new multiple QTLs method was more efficient in separating closely linked QTLs than single-marker association studies.

Association between polymorphisms in the flanking region of the TAFI gene and atherosclerotic cerebral infarction in a Chinese population.

BACKGROUND: Atherosclerosis is the leading etiologic factor of Atherosclerotic Cerebral Infarction (ACI). Previous studies have shown that thrombin activatable fibrinolysis inhibitor (TAFI) may play an important role in the occurrence of acute cerebral infarction, and the levels of TAFI are affected by several single nucleotide polymorphisms (SNPs) located in the regulatory and coding regions of the gene encoding TAFI. The present study aimed to determine whether polymorphisms (TAFI -2345 2G/1G, -1690 A/G, -438 A/G, +1583 A/T) of the TAFI gene were associated with ACI in a Han Chinese population. METHODS: The variant genotypes were identified by restriction fragment length polymorphism (RFLP) and allele-specific polymerase chain reactions (AS-PCR) in 225 patients with ACI and 184 age-matched healthy individuals. RESULTS: There was a significant difference in the genotype and allele frequencies of TAFI -2345 2G/1G and -1690 A/G polymorphisms between the ACI and control subjects. Further stratification analysis by gender revealed that the presence of the -438 AA genotype and the A allele conferred a higher risk of developing ACI in male patients (p < 0.05). Haplotype analysis demonstrated that four haplotypes of TAFI are significantly associated with ACI. CONCLUSIONS: Our study provides preliminary evidence that the TAFI -2345 2G/1G and -1690 A/G polymorphisms are associated with ACI susceptibility in a Han Chinese population.

The functional polymorphisms of miR-146a are associated with susceptibility to severe sepsis in the Chinese population.

MicroRNA-146a (miR-146a) acts as a pivotal regulatory molecule in immune response and various diseases, such as carcinoma and autoimmune diseases. Growing evidences have demonstrated the association of miR-146a gene single-nucleotide polymorphisms (SNPs) with risk of several diseases, but no genetic relevance studies of miR-146a gene polymorphisms to sepsis have been reported by now. Our study has analyzed the association of sepsis with two functional miR-146a gene SNPs rs2910164 G/C and rs57095329 A/G in a Chinese Han population (226 sepsis cases; 206 healthy controls). Our results indicated a higher prevalence of the miR-146a gene SNP rs2910164 C allele and CC genotype in patients with severe sepsis (rs2910164G versus rs2910164C: P = 0.0029, odds ratio (OR) = 1.664; GG+GC versus CC: P = 0.0045, OR = 1.947). Neither the genotype nor the allele in rs57095329 showed significant differences between the septic cases and the controls (P = 0.5901 and 0.3580, resp.), and no significant difference was observed in the subgroups. In addition, we confirmed that the two SNPs rs2910164 and rs57095329 could functionally affect the miR-146a expression levels and the reduction of miR146a was accompanied with the upregulation of the expression levels of TRAF-6 and IRAK-1 in severe sepsis patients. This present study might provide valuable clinical evidence that miR-146a gene polymorphism rs2910164 is associated with the risk of severe sepsis.

miR-137: a new player in schizophrenia.

Schizophrenia is a complex genetic disease and characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are critical to neurodevelopment and adult neuronal processes by modulating the activity of multiple genes within biological networks. MiR-137 as a brain-enriched microRNA, plays important roles in regulating embryonic neural stem cells (NSCs) fate determination, neuronal proliferation and differentiation, and synaptic maturation. Its dysregulation causes changes in the gene expression regulation network of the nervous system, thus inducing mental disorders. Recently, miR-137 has been confirmed as a gene related to schizophrenia susceptibility. In the following review, we summarize the expression pattern, epigenetic regulation and functions of miR-137. A more complete picture of the miR-137, which is dysregulated in psychiatric illness, may improve our understanding of the molecular mechanisms underlying schizophrenia.

Emerging roles of SIRT1 activator, SRT2104, in disease treatment.

Silent information regulator 1 (SIRT1) is a NAD+-dependent class III deacetylase that plays important roles in the pathogenesis of numerous diseases, positioning it as a prime candidate for therapeutic intervention. Among its modulators, SRT2104 emerges as the most specific small molecule activator of SIRT1, currently advancing into the clinical translation phase. The primary objective of this review is to evaluate the emerging roles of SRT2104, and to explore its potential as a therapeutic agent in various diseases. In the present review, we systematically summarized the findings from an extensive array of literature sources including the progress of its application in disease treatment and its potential molecular mechanisms by reviewing the literature published in databases such as PubMed, Web of Science, and the World Health Organization International Clinical Trials Registry Platform. We focuses on the strides made in employing SRT2104 for disease treatment, elucidating its potential molecular underpinnings based on preclinical and clinical research data. The findings reveal that SRT2104, as a potent SIRT1 activator, holds considerable therapeutic potential, particularly in modulating metabolic and longevity-related pathways. This review establishes SRT2104 as a leading SIRT1 activator with significant therapeutic promise.