Transcriptional Repressor BCL11A in Erythroid Cells.

BCL11A, a zinc finger repressor, is a stage-specific transcription factor that controls the switch from fetal (HbF, α2γ2) to adult (HbA, α2ß2) hemoglobin in erythroid cells. While BCL11A was known as a factor critical for B-lymphoid cell development, its relationship to erythroid cells and HbF arose through genome-wide association studies (GWAS). Subsequent work validated its role as a silencer of γ-globin gene expression in cultured cells and mice. Erythroid-specific loss of BCL11A rescues the phenotype of engineered sickle cell disease (SCD) mice, thereby suggesting that downregulation of BCL11A expression might be beneficial in patients with SCD and ß-thalassemia. Common genetic variation in GWAS resides in an erythroid-specific enhancer within the BCL11A gene that is required for its own expression. CRISPR/Cas9 gene editing of the enhancer revealed a GATA-binding site that confers a large portion of its regulatory function. Disruption of the GATA site leads to robust HbF reactivation. Advancement of a guide RNA targeting the GATA-binding site in clinical trials has recently led to approval of first-in-man use of ex vivo CRISPR editing of hematopoietic stem/progenitor cells (HSPCs) as therapy of SCD and ß-thalassemia. Future challenges include expanding access and infrastructure for delivery of genetic therapy to eligible patients, reducing potential toxicity and costs, exploring prospects for in vivo targeting of hematopoietic stem cells (HSCs), and developing small molecule drugs that impair function of BCL11A protein as an alternative option.

TNF-α-positive patients with recurrent pregnancy loss: The etiology and management.

BACKGROUND: Elevated levels of tumor necrosis factor-alpha (TNF-α) have been associated with adverse pregnancy outcomes, specifically recurrent pregnancy loss (RPL). These elevated levels may be associated with the presence of autoantibodies. Although TNF-α inhibitors have shown promise in improving pregnancy rates, further research is needed to comprehend their impact and mechanisms in RPL patients. OBJECTIVE: This study aims to investigate the association between elevated TNF-α levels and autoantibodies in RPL patients, as well as evaluate the effect of TNF-α inhibition on pregnancy outcomes. METHODS: A total of 249 RPL patients were included in this study. Serum levels of TNF-α, autoantibodies, and complement were measured and monitored. Among these patients, 138 tested positive for TNF-α, while 111 tested negative. The medical records of these patients were retrospectively evaluated. Additionally, 102 patients with elevated TNF-α levels were treated with TNF-α inhibitors, and their pregnancy outcomes were assessed. RESULTS: TNF-α-positive RPL patients had higher levels of complement C1q, anti-cardiolipin (ACL)-IgA, ACL-IgM ,ACL-IgG, thyroglobulin antibody, and Anti-phosphatidylserine/prothrombin IgM antibody, as well as a higher positive rate of antinuclear antibodies compared to TNF-α-negative patients (23.19% vs. 12.6%, P< 0.05). Conversely, complement C3 were lower in TNF-α-positive patients (t test, P< 0.05). The use of TNF-α inhibitors led to a reduction in the early abortion rate (13.7% vs. 44.4%, P< 0.001) and an improvement in term delivery rate (52.0% vs. 27.8%, P= 0.012). Furthermore, patients who used TNF-α inhibitors before 5 weeks of pregnancy had a lower early abortion rate (7.7% vs. 24.3%, P= 0.033) and a higher term delivery rate (69.2% vs. 48.6%, P= 0.033). CONCLUSION: TNF-α plays a role in the occurrence and development of RPL, and its expression is closely associated with autoantibodies and complements. TNF-α inhibitors increase the term delivery rate in TNF-α-positive RPL patients, and their use before 5 weeks of pregnancy may more beneficial.

Sexual orientation disparities in the prevalence of suicidal ideation among U.S adults aged 20 to 59 years: Results from NHANES 2005-2016.

Existing studies have been limited in providing nationally representative data on the relationship between sexual orientation and suicidal ideation (SI) among adults in the U.S. particularly in terms of gender and racial differences. To fill this research gap, we conducted a study using data from the NHANES conducted between 2005 and 2016. Survey-weighted logistic regression models were used to investigate the relationship between sexual orientation and SI risk. Additionally, we performed further analysis by stratifying the data based on demographic variables and performed sensitivity analysis to ensure the reliability of our findings. This study included a weighted sample of 16,564 adults, representing a noninstitutionalized U.S population of 840.1 million. The overall age-adjusted prevalence of SI was found to be 3.5 %. After adjusting for relevant covariates, the study revealed that individuals who identified as something else, homosexual, and bisexual had a higher prevalence risk of suicidal ideation (SI) compared to heterosexual participants. Additionally, the study found that heterosexual participants were 74.4 % less likely to experience SI compared to bisexual individuals. These findings highlight the urgent requirement for inclusive and supportive prevention strategies to effectively address SI among adult sexual minorities in the U.S.

Influential Factors and Academic Significance of the Construction of Clinical Chinese Materia Medica in the Period of the Republic of China / 中医杂志

The Republic of China period （1912—1949） was an important stage of transition from traditional herbalism to clinical Chinese materia medica. The clinical application of Chinese materia medica became the focus of academic attention. During the Republic of China period， the research objectives， methods， and content of clinical Chinese materia medica were clarified， and the basic framework of Chinese materia medica was established through efficacy classification and item description. Based on the historical background at that time， striving for survival in adversity were the internal factors driving the construction of clinical Chinese materia medica， and the rise of academic education and the popularity of traditional Chinese medicine journals provided favorable conditions for the development of clinical Chinese materia medica. The clinical Chinese materia medica during the Republic of China period gradually formed a theoretical structure and core content that was distinctly different from that of traditional herbal medicine， which was integrated with the scientific research of Chinese materia medica and promoted the continuous development of Chinese materia medica together with other subdisciplines， presenting distinctive characteristics of the times and important academic significance.

Metabolic reprogramming induced by DCA enhances cisplatin sensitivity through increasing mitochondrial oxidative stress in cholangiocarcinoma.

Background: Cholangiocarcinoma has obvious primary multidrug resistance and is generally resistant to cisplatin and other chemotherapy drugs and high glycolytic levels may be associated with chemotherapy resistance of cholangiocarcinoma cells. Dichloroacetate (DCA) is a specific inhibitor of PDK, which can promote mitochondrial aerobic oxidation process by activating PDH. In the past few years, there have been an increasing number of studies supporting the action of DCA against cancer, which also provided evidence for targeting metabolism to enhance the efficacy of cholangiocarcinoma chemotherapy. Methods: Glucose uptake and lactic acid secretion were used to detect cell metabolism level. Cell apoptosis and cell cycle were detected to confirm cell fate induced by cisplatin combined with DCA. Mito-TEMPO was used to inhibit mtROS to explore the relationship between oxidative stress and cell cycle arrest induced by DCA under cisplatin stress. Finally, PCR array and autophagy inhibitor CQ were used to explore the potential protective mechanism under cell stress. Results: DCA changed the metabolic model from glycolysis to aerobic oxidation in cholangiocarcinoma cells under cisplatin stress. This metabolic reprogramming increased mitochondrial reactive oxygen species (mtROS) levels, which promoted cell cycle arrest, increased the expression of antioxidant genes and activated autophagy. Inhibition of autophagy further increased the synergistic effect of DCA and cisplatin. Conclusion: DCA increased cisplatin sensitivity in cholangiocarcinoma cells via increasing the mitochondria oxidative stress and cell growth inhibition. Synergistic effects of DCA and CQ were observed in cholangiocarcinoma cells, which further increased the cisplatin sensitivity via both metabolic reprogramming and inhibition of the stress response autophagy.

The impact of pension insurance types on the health of older adults in China: a study based on the 2018 CHARLS data.

Introduction: Pension insurance is an essential safeguard for the quality of life and health of older adults because it provides a stable and dependable source of income after retirement. China has constructed a multi-level social security system to accommodate the diverse needs of older adults, and offers various levels of pension insurance to maximize their interests. Methods: This study uses propensity score matching and ordinary least squares techniques to analyze 7,359 data from the 2018 China Health and Retirement Longitudinal Study (CHARLS) in order to explore the relationship between different pension insurance categories and the health of older individuals. Results: The research findings reveal that advanced insurances greatly benefit the health of older adults more than basic pension insurances, and the findings pass the robustness test. In addition, the effect was found to be heterogeneous, depending on the location of retirement and the marital status of older adults.Our findings suggest that both material and non-material consumption may be potential mechanisms by which pension insurance affects the health of older adults, providing new evidence for the causal mechanism between pension insurance and the health of older adults. Discussion: This study expands the scope of research on the health effects of pension insurance by covering a large representative sample across the country. The results show the important impact of the level of pension insurance on the health of older adults and can contribute to the development of social policies to promote the physical and mental health of older adults.

MUC1 induces the accumulation of Foxp3+ Treg cells in the tumor microenvironment to promote the growth and metastasis of cholangiocarcinoma through the EGFR/PI3K/Akt signaling pathway.

Tumor microenvironment (TME) plays an important role in the progression of cholangiocarcinoma. This study aims to explore whether Mucin 1 (MUC1) regulates Foxp3+ Treg cells in the TME of cholangiocarcinoma through the epidermal growth factor receptor (EGFR)/phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. High-throughput sequencing dataset in the GEO database combined with GeneCards and Phenolyzer databases was used to obtain key genes in cholangiocarcinoma, followed by downstream pathway prediction. The relationship among MUC1, EGFR, and PI3K/Akt signaling pathway was explored. CD4+ T cells extracted from peripheral blood were induced to differentiate into Treg cells, followed by co-culture with cholangiocarcinoma cells. A mouse model was constructed to detect the role of MUC1 in the accumulation of Foxp3+ Treg cells, malignant phenotypes of cholangiocarcinoma, and tumorigenesis in vivo. MUC1, highly expressed in cholangiocarcinoma, might be involved in cholangiocarcinoma development. MUC1 interacted with the EGFR to activate the EGFR/PI3K/Akt signaling pathway. MUC1 overexpression could activate the EGFR/PI3K/Akt signaling pathway, which promoted the accumulation of Foxp3+ Treg cells in the TME and the malignant phenotypes of cholangiocarcinoma cells both in vitro and in vivo and enhanced tumorigenesis in vivo. MUC1 may interact with EGFR to activate the EGFR/PI3K/Akt signaling pathway, which induces the accumulation of Foxp3+ Treg cells, enhancing the malignant phenotypes of cholangiocarcinoma cells and tumorigenesis in vivo and ultimately augmenting cholangiocarcinoma growth and metastasis.

Evolution of nanobodies specific for BCL11A.

Transcription factors (TFs) control numerous genes that are directly relevant to many human disorders. However, developing specific reagents targeting TFs within intact cells is challenging due to the presence of highly disordered regions within these proteins. Intracellular antibodies offer opportunities to probe protein function and validate therapeutic targets. Here, we describe the optimization of nanobodies specific for BCL11A, a validated target for the treatment of hemoglobin disorders. We obtained first-generation nanobodies directed to a region of BCL11A comprising zinc fingers 4 to 6 (ZF456) from a synthetic yeast surface display library, and employed error-prone mutagenesis, structural determination, and molecular modeling to enhance binding affinity. Engineered nanobodies recognized ZF6 and mediated targeted protein degradation (TPD) of BCL11A protein in erythroid cells, leading to the anticipated reactivation of fetal hemoglobin (HbF) expression. Evolved nanobodies distinguished BCL11A from its close paralog BCL11B, which shares an identical DNA-binding specificity. Given the ease of manipulation of nanobodies and their exquisite specificity, nanobody-mediated TPD of TFs should be suitable for dissecting regulatory relationships of TFs and gene targets and validating therapeutic potential of proteins of interest.

Clinical Analysis of Pulmonary Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To study the clinical, imaging, and pathological features of pulmonary lymphoma.@*METHODS@#Patients with pulmonary lymphoma diagnosed by lung biopsy in Zhongda Hospital Affiliated to Southeast University from November 2013 to December 2020 were collected and divided into secondary pulmonary lymphoma (SPL) group and primary pulmonary lymphoma (PPL) group according to the primary site of lymphoma. The clinical characteristics, stages, imaging features, diagnostic methods and pathological types of the two groups were analyzed.@*RESULTS@#A total of 22 patients were included, 10 cases were PPL and 12 cases were SPL. The main symptoms of the two groups were cough, dyspnea and chest pain. The proportion of stage III/IV patients and international prognostic index (IPI) in SPL group were significantly higher than those in PPL group (P<0.05). Chest high-resolution computed tomography (HRCT) mainly showed masses, nodules and consolidation in both groups. The proportions of single mass and air bronchial sign in PPL group were significantly higher than those in SPL group, while the proportions of multiple nodules, mediastinal/hilar lymphadenopathy and pleural effusion were significantly lower (P<0.05). The max standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in PPL group were lower than those in SPL group, but the differences were not statistically significant (P>0.05). In PPL group, 8 cases were diagnosed by transbronchial lung biopsy (TBLB) and 2 cases by percutaneous lung puncture. In SPL group, 4 cases were diagnosed by TBLB, 7 cases by percutaneous lung puncture, and 1 case by surgery. 95.5% patients were diagnosed by non-surgical methods. The main pathological type of PPL was mucosa-associated lymphoid tissue (MALT) lymphoma, while that of SPL was diffuse large B-cell lymphoma (P<0.05).@*CONCLUSION@#The clinical symptoms of pulmonary lymphoma are nonspecific, but the chest HRCT has characteristic manifestations, which can also help to distinguish between SPL and PPL. 18F-FDG PET/CT is also a potential method to distinguish between SPL and PPL. TBLB and percutaneous lung puncture biopsy are reliable methods for the diagnosis of lung lymphoma. The main pathological type of PPL is MALT lymphoma, while that of SPL is diffuse large B-cell lymphoma.

Association between exposure patterns of adverse childhood experiences and anxiety symptom trajectories in medical college students / 中华预防医学杂志

Objective: To analyze the association between exposure patterns of adverse childhood experiences (ACEs) and anxiety symptom trajectories in medical college students. Methods: A survey was conducted on first-year students from Anhui Medical College and Anqing Medical College, using the Childhood Abuse Questionnaire, Family Disability Questionnaire, Childhood Adverse Social Experience Item, and Anxiety Self Rating Scale. The baseline survey was conducted from November to December 2019, and two follow-up visits were conducted once every six months until November to December 2020. The latent class analysis (LCA) was used to analyze the exposure patterns of ACEs. The latent class growth analysis (LCGA) was used to analyze the development trajectory of anxiety symptoms. The multiple logistic regression model was used to analyze the correlation between different exposure patterns of ACEs and the trajectory of anxiety symptom trajectories. Results: A total of 3 662 college students aged (19.2±1.0) were surveyed. The LCA showed that the exposure patterns of ACEs could be divided into the "high ACEs" group (13.4%), "high neglect/emotional abuse" group (25.7%), "high family dysfunction" group (6.9%), "high neglect" group (27.1%), and "low ACEs" group (26.3%). The LCGA divided anxiety trajectories into four groups: "high anxiety decline" (7.1%),"anxiety increase "(4.1%), "moderate anxiety"(52.9%), and "low anxiety"(35.9%). Using the low ACEs group as a reference group, compared with the low anxiety trajectory, the high ACEs group, high neglect/emotional abuse group, high family dysfunction group, high neglect group, and medium to high-level anxiety trajectory were all associated with an increased risk (P<0.05). Conclusion: There is heterogeneity in ACEs exposure patterns among medical college students, and ACEs exposure patterns are important influencing factors for anxiety symptom trajectories.

Does Migration Distance Affect Happiness? Evidence From Internal Migrants in China.

Background: Happiness is a complex concept involving many subjects such as society, psychology, and ethics. How will migration distance affect migrants' happiness under the new trend of migration in China? The goal of this paper is to analyze the influence and transmission mechanism of migration distance on happiness of migrant individuals, and the heterogeneity of this effect on urban and rural migrants. Methods: Employing data of 129,803 observations from the 2012 China Migrants Dynamic Survey, we first estimate the effects of migration distance on happiness by the ordinal logistic regression and propensity score matching (PSM) method. Second, we examine the heterogeneity of effect by splitting the sample into the urban and rural migrants. Finally, we analyze the transmission mechanism of migration distance on happiness by mediating effect model. Results: The migration distance of internal migrants in China has a significant negative impact on happiness. Urban migrant individuals show a stronger response to migration distance compared to rural counterparts. Social integration is proved as the potential mechanism through which the effect of migration distance on happiness. Conclusion: The results emphasize happiness of internal migrant and other mental health problems. Moreover, particular attention should be paid to social integration on happiness, such as strengthening the cultural exchange in different areas, narrowing the income gap between urban and rural areas, promoting rational migrant decision of individual, and enhancing the happiness of them.

Education, Income, and Happiness: Evidence From China.

Happiness is the continuous joy that people experience when they are satisfied with their lives long term, and is the ultimate goal pursued by all citizens. In this study, we investigate the relationship between education, income, and happiness in the migrant population in China. Using 1,31,186 individuals in the 2012 China Migrants Dynamic Survey (CMDS) as research samples, the estimated results of ordinal logistic regression show that education, including secondary education and higher education, has a significant and direct impact on individual happiness, and that the impact of education on happiness can also be mediated by income as an intermediary mechanism. In addition, factors such as gender, flow distance, flow time, employment status, type of housing, number of children, degree of preference for the city, and degree of discrimination by locals have obvious effects on happiness. This work provides important insights for countries seeking to implement an active education policy in order to increase economic income and thus achieve the development goal of universal happiness among their citizens.

Advances in Renal Cell Carcinoma Drug Resistance Models.

Renal cell carcinoma (RCC) is the most common form of kidney cancer. Systemic therapy is the preferred method to eliminate residual cancer cells after surgery and prolong the survival of patients with inoperable RCC. A variety of molecular targeted and immunological therapies have been developed to improve the survival rate and prognosis of RCC patients based on their chemotherapy-resistant properties. However, owing to tumor heterogeneity and drug resistance, targeted and immunological therapies lack complete and durable anti-tumor responses; therefore, understanding the mechanisms of systemic therapy resistance and improving clinical curative effects in the treatment of RCC remain challenging. In vitro models with traditional RCC cell lines or primary cell culture, as well as in vivo models with cell or patient-derived xenografts, are used to explore the drug resistance mechanisms of RCC and screen new targeted therapeutic drugs. Here, we review the established methods and applications of in vivo and in vitro RCC drug resistance models, with the aim of improving our understanding of its resistance mechanisms, increasing the efficacy of combination medications, and providing a theoretical foundation for the development and application of new drugs, drug screening, and treatment guidelines for RCC patients.

A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin.

Proximity-based strategies to degrade proteins have enormous therapeutic potential in medicine, but the technologies are limited to proteins for which small molecule ligands exist. The identification of such ligands for therapeutically relevant but "undruggable" proteins remains challenging. Herein, we employed yeast surface display of synthetic nanobodies to identify a protein ligand selective for BCL11A, a critical repressor of fetal globin gene transcription. Fusion of the nanobody to a cell-permeant miniature protein and an E3 adaptor creates a degrader that depletes cellular BCL11A in differentiated primary erythroid precursor cells, thereby inducing the expression of fetal hemoglobin, a modifier of clinical severity of sickle cell disease and ß-thalassemia. Our strategy provides a means of fetal hemoglobin induction through reversible, temporal modulation of BCL11A. Additionally, it establishes a new paradigm for the targeted degradation of previously intractable proteins.

Adrenal intravascular large B-cell lymphoma: report of 1 case and review of literature / 白血病·淋巴瘤

Objective:To investigate the diagnosis and treatment of intravascular large B-cell lymphoma (IVLBCL).Methods:The clinical data of 1 patient with adrenal IVLBCL in Zhongda Hospital Southeast University in May 2020 were retrospectively analyzed, and the relevant literature was reviewed.Results:The patient was an elderly male with recurrent fever of unknown cause at initial stage, and was finally diagnosed as adrenal IVLBCL based on the results of laboratory, imaging and adrenal biopsy at different stages. After multiple courses of R-COP in combination with Bruton tyrosine kinase (BTK) inhibitor, the patient achieved complete remission.Conclusions:IVLBCL is rare and it lacks specific clinical symptoms. PET-CT and pathological biopsy can help in the diagnosis of it. R-COP combined with BTK inhibitor is effective in the treatment of biphenotype IVLBCL.

Clinical and Cytogenetical Characteristics in Acute Myeloid Leukemia with Myelodysplasia-Related Changes / 中国实验血液学杂志

OBJECTIVE@#To explore the clinical and cytogenetic characteristics of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) based on morphology define.@*METHODS@#A total of 180 newly diagnosed acute myeloid leukemia (AML) patients were enrolled and retrospectively analyzed, and marrow cell morphology of 126 patients were re-evaluated. The clinical and cytogenetic characteristics, including ages, sex, WBC count, HGB level, PLT count, blasts percentage, abnormal karyotype detection rate of the patients in AML with multilineage dysplasia (AML-MRC-1), secondary AML from myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) (AML-MRC-2), and AML not otherwise specified (AML-NOS) groups were investigated.@*RESULTS@#There was no significant differences between the patients in three groups in terms of sex, age and platelet count (P=0.898, P=0.365, P=0.853), but AML-MRC-2 group (73.2%) was higher than AML-MRC-1 (60.0%) and AML-NOS (56.4%) in the percentages of patients over 60 years old (P=0.228); there were statistically significant differences on WBC count, HGB level, and blasts percentage (P=0.000, P=0.022, P=0.000, AML-MRC-2

Methylprednisolone alleviates multiple sclerosis by expanding myeloid-derived suppressor cells via glucocorticoid receptor ß and S100A8/9 up-regulation.

Methylprednisolone is an effective drug in the treatment of autoimmune disease, such as multiple sclerosis (MS), due to long-acting anti-inflammatory, antiallergic and immunosuppressant. Previous studies have noted the importance of myeloid-derived suppressor cells (MDSC) in MS progression. However, it is still not known whether methylprednisolone could influence the ratio and function of MDSC during MS treatment. In the current study, we found an increased ratio of MDSC at the onset of EAE in mice model; but methylprednisolone pulse therapy (MPPT) did not alter the percentage and suppressive function of MDSC during disease attenuation. However, the percentage of G-MDSC in PBMC significantly increased in patients with MS. Surprisingly, relapsing MS patients showed a significant increase in both M-MDSC and G-MDSC after MPPT. The disease remission positively correlated expansion of MDSC and expression of arginase-1. Additionally, MPPT reduced the expression of inhibitory glucocorticoid (GCs) receptor ß subunit on MDSC while elevating serum levels of immune regulatory S100A8/A9 heterodimer. Thus, MDSC dynamics and function in mouse EAE differ from those in human MS during MPPT. Our study suggested that GCs treatment may help relieve the acute phase of MS by expanding MDSC through up-regulating of GR signalling and S100A8/A9 heterodimers.

Biologically active 1,25-dihydroxyvitamin D3 protects against experimental sepsis by negatively regulating the Toll-like receptor 4/myeloid differentiation primary response gene 88/Toll-IL-1 resistance-domain-containing adapter-inducing interferon-ß signaling pathway.

The hormonally active form of vitamin D (VD), 1,25­dihydroxyvitamin D3, has been reported to be a key immunoregulator in the reduction of inflammation. In this study, we investigated the effects of VD in an experimental sepsis cell model, and the underlying mechanisms. The sepsis cell model was first established in monocytes, isolated from newborns and healthy adults, which were stimulation with lipopolysaccharide (LPS). We observed that cell viability was significantly impaired in the monocytes after LPS stimulation, using a Cell Counting Kit­8 and trypan blue assays. Additionally, ELISA revealed that LPS stimulation significantly elevated the expression of interleukin 6 (IL­6), IL­10 and tumor necrosis factor­α (TNF­α). The expression levels of Toll­like receptor (TLR4), myeloid differentiation primary response gene 88 (MyD88), and Toll­IL­1 resistance­domain­containing adapter­inducing interferon­ß (TRIF) mRNA were also significantly elevated under LPS stimulation using reverse transcription­quantitative PCR and western blot analysis. VD treatment could significantly suppress the effects of LPS simulation on monocytes by negatively regulating inflammatory cytokines and TLR4/MyD88/TRIF signaling. Furthermore, a regulatory feedback mechanism was proposed to involve TLR4, MyD88 and TRIF in the sepsis cell model. In conclusion, VD may effectively decrease the release of inflammatory cytokines by inhibiting the TLR4/MyD88/TRIF signaling pathway, could be considered as a potential therapeutic agent for the treatment of sepsis.

Association between indel polymorphism (rs145204276) in the promoter region of lncRNA GAS5 and the risk of febrile convulsion.

BACKGROUND: This study aimed to explore the regulatory relationship between growth arrest special 5 (GAS5) and interleukin-1ß (IL-1ß) implicated in the development of febrile seizure (FS). METHOD: The presence of FS and the genotype of GAS5 were used as two different indicators to divide the 50 newborn babies, recruited in this study, into different groups. The potential regulatory relationship among GAS5, miR-21, and IL-1ß was identified by measuring their expression using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry assays among different sample groups. Computational analyses and luciferase assays were also conducted to verify the interaction between GAS5, miR-21, and IL-1ß. RESULT: GAS5 and IL-1ß expression was upregulated in cells collected from FS patients or genotyped as INS/DEL and DEL/DEL, whereas the expression of miR-21 was decreased in above samples, indicating a negative relationship between miR-21 and GAS5/IL-1ß. Results of the computational analysis showed that miR-21 directly bound to and increased the expression of GAS5, whereas the expression of IL-1ß was suppressed by miR-21. In the presence of GAS5, the expression of miR-21 was lowered, whereas the expression of IL-1ß was increased. CONCLUSION: The results obtained in this study supported the conclusion that GAS5 negatively regulated the expression of miR-21, which in turn negatively regulated the expression IL-1ß. Therefore, the overexpression of GAS5 could decrease the magnitude of FS.

Identification of the association between rs41274221 polymorphism in the seed sequence of microRNA-25 and the risk of neonate sepsis.

BACKGROUND: Many studies have investigated the role of microRNA-25 (miR-25) in the initiation and progression of sepsis in newborns. In this study, we aim to explore how rs41274221 polymorphism in miR-25 compromises the interaction between miR-25 and CD69, so as to understand the mechanisms involved in the control of sepsis in newborns. METHODS: Computational analysis, luciferase assay, real-time polymerase chain reaction (PCR), and western blot analysis were performed in this study. RESULTS: The luciferase assays results showed that CD69 was a target gene of miR-25, because the luciferase activity in cells transfected with wild type CD69 was much lower than that in the cells transfected with mutant CD69 or the scramble control. Real-time PCR and western blot analysis results showed that the expression of miR-25 in sepsis patients was significantly upregulated as compared with that in the normal control group, and the CD69 position ratio as well as the messenger RNA (mRNA) and protein level of CD69 in sepsis patients was much higher than those in the normal control group. As compared with the scramble control, miR-25 mimics, and CD69 small interfering RNA (siRNA) downregulated the mRNA and protein expression of CD69, whereas the expression of CD69 mRNA and protein in cells transfected with miR-25 inhibitors was significantly higher as compared with that in the scramble control. In addition, interferonγ production was significantly downregulated in cells transfected with miR-25 inhibitors but notably upregulated in cells transfected with miR-25 mimics or CD69 siRNA. CONCLUSION: The single-nucleotide polymorphism (SNP; rs41274221) in miR-25 is associated with the risk of sepsis in newborns.