Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency.

BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

Revealing novel genomic insights and therapeutic targets for juvenile idiopathic arthritis through omics.

BACKGROUND: The genetic architecture of JIA remains only partially comprehended. There is a clear imperative for continued endeavours to uncover insights into the underlying causes of JIA. METHODS: This study encompassed a comprehensive spectrum of endeavours, including conducting a JIA genome-wide association study (GWAS) meta-analysis that incorporated data from 4550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritizing target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. RESULTS: Fourteen genome-wide significant non-HLA loci were identified, including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and BMD traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for the affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized. CONCLUSIONS: Our identification of four novel JIA-associated genes, CD247, RHOH, COLEC10 and IRF8, broadens the novel potential drug repositioning opportunities. We established a new genetic link between COLEC10, TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms.

Prevalence and Clinical Significance of Low T3 Syndrome in Non-Dialysis Patients with Chronic Kidney Disease.

BACKGROUND There are few data on the prevalence of low T3 (triiodothyronine) syndrome in patients with non-dialysis chronic kidney disease (CKD) and it is unclear whether low T3 can be used to predict the progression of CKD. MATERIAL AND METHODS We retrospectively studied 279 patients who had been definitively diagnosed with CKD, without needing maintenance dialysis. Thyroid function was analyzed in all enrolled subjects and the incidence of thyroid dysfunction (low T3 syndrome, low T4 syndrome, and subclinical hypothyroidism) in patients at different stages of CKD was determined. RESULTS Glomerular filtration rate (GFR) of CKD patients was estimated as follows: 145 subjects (52%) had GFR <60 ml/min per 1.73 m2; 47 subjects (16.8%) had GFR between 30 and 59 ml/min per 1.73 m2, and 98 subjects (35.1%) had GFR <30 ml/min per 1.73 m2. Among all enrolled subjects, 4.7% (n=13) had subclinical hypothyroidism, 5.4% (n=15) had low T4 syndrome, and 47% (n=131) had low T3 syndrome. In 114 CKD patients in stages 3-5, serum T3 was positively related to protein metabolism (STP, PA, and ALB) and anemia indicators (Hb and RBC), and negatively related to inflammatory status (CRP and IL-6). CONCLUSIONS A high prevalence of low T3 syndrome was observed in CKD patients without dialysis, even in early stages (1 and 2). The increasing prevalence of low T3 as CKD progresses indicates its value as a predictor of worsening CKD. Furthermore, low T3 syndrome is closely associated with both malnutrition-inflammation complex syndrome (MICS) and anemia.

Processed Polygonatum cyrtonema Hua attenuates postpartum depression in rat model by regulating monoamines and hormones.

Background: Polygonatum cyrtonema Hua is a traditional Chinese medicinal food herb which can regulate the liver and Qi, nourish the heart and blood, moisten the lungs and nourish the kidneys with the potential to treat emotional diseases. However, few studies have explored the effects of Polygonatum cyrtonema Hua on postpartum depression. Therefore, we investigated whether processed Polygonatum cyrtonema Hua could improve postpartum depression in rat models by regulating monoamines and hormones. Methods: Female Sprague-Dawley rats were randomized into normal control (0.9%Nacl), Sham operation (0.9%Nacl), postpartum depression model (0.9%Nacl), fluoxetine (2.5 mg/kg Fluoxetine), low, medium and high dose of processed Polygonatum cyrtonema Hua (2.5 g/kg, 5 g/kg, 10 g/kg) groups. Rats in these groups received drug intervention, and then subjected to Open-field test and Forced swimming test. Brain tissues and serum samples were collected and used to quantify levels of monoamines, hypothalamic-pituitary-adrenal axis and serum Estradiol. The status of neuronal cells in hippocampus 1 region was examined through hematoxylin-eosin staining, whereas expression of estrogen receptor α and ß was detected by immunohistochemistry. Results: Rats in the model group showed decreased mobility time, the disorder of neuronal cells in hippocampus 1 area, and decreased concentration of 5-hydroxytryptamine and dopamine in brain tissue, norepinephrine and estradiol in serum as well as estrogen receptor α and ß expression. They also exhibited increased adrenocorticotropic hormone, corticosterone and corticotropin releasing hormone in serum. However, the treatment with processed Polygonatum cyrtonem Hua or fluoxetine reversed the above abnormalities. Conclusion: The H group showed significant improvement in postpartum depression in rats, and processed Polygonatum cyrtonema Hua can be used as a developing drug for the prevention or treatment of depression.

Hesperetin affects osteoclast differentiation via MAPK signaling pathway.

BACKGROUND: The number and activity of osteoblasts and osteoclasts play an important role in skeletal biology, especially in bone reconstruction. Scientific and rational regulation of osteoclast formation and activity has become a critical strategy aimed at inhibiting the loss of bone mass in the body and alleviating the occurrence of bone diseases. Currently, there are only a few reports related to hesperetin-regulated osteoclast differentiation. OBJECTIVES: To investigate the influence of hesperetin on osteoclast-like cell differentiation and formation, and determine whether the MAPK signaling pathway is involved in the differentiation process. MATERIAL AND METHODS: The RAW264.7 cells were induced and cultured in vitro to promote their differentiation into osteoclast-like cells. Tetrazolium bromide was utilized to determine the effects of different concentrations (100, 200, 400, and 600 µM) of hesperetin on the proliferation of osteoclast-like cell precursors. Osteoclast-like cell differentiation was conducted using tartrate-resistant acid phosphatase (TRAP) staining assay. The status of nuclei and actin filaments of differentiated osteoclast-like cells was observed with the use of 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) and actin-tracker green staining experiments. Changes in key proteins of the MAPK signaling pathway were detected using western blot. RESULTS: The results of TRAP staining experiments showed that the number of osteoclast-like cells decreased with the increase in hesperetin concentration. The DAPI and actin-tracker green staining demonstrated that the nuclei of differentiated osteoclast-like cells reduced in size with the increase in hesperetin concentration, and the osteoclast-like cells became smaller. Western blot for key MAPK signaling pathway proteins revealed that phospho-ERK and phospho-p38 protein levels were not significantly inhibited, but phospho-JNK protein levels were reduced. CONCLUSIONS: Hesperetin inhibits the differentiation of osteoclast-like cells. Further studies revealed that hesperetin also affects the activation level of phospho-JNK, a key signaling protein of the MAPK signaling pathway, in the induced differentiation of osteoclast-like cells.

Tuberculostearic acid incorporated predictive model contributes to the clinical diagnosis of tuberculous meningitis.

The conventional confirmation tests of tuberculous meningitis (TBM) are usually low in sensitivity, leading to high TBM mortality. Hence, sensitive methods for indicating the presence of bacilli are required. Tuberculostearic acid (TBSA), a constituent from Mycobacterium tuberculosis had been evaluated as a promising marker, but fails to demonstrate consistent results for definite TBM. This study retrospectively reviewed medical records of 113 TBM suspects, constructing a TBSA-combined scoring system based on multiple factors, which show sensitivity and specificity of 0.8148 and 0.8814, respectively, and the area under the receiver operating characteristic curve of 0.9010. Multivariate analyses revealed four co-predictive factors strongly associated with TBSA: extra-neural tuberculosis, basal meningeal enhancement, CSF glucose/Serum glucose <0.595, and coinfection in CNS (Total). The subsequent machine learning-based validation showed correspondent importance to factors in the TBSA model. This study demonstrates a simple scoring system to facilitate TBM prediction, yield reliable diagnoses and allow timely treatment initiation.

MicroRNA-193b-3p reduces oxidative stress and mitochondrial damage in rats with cerebral ischemia-reperfusion injury via the seven in absentia homolog 1/Jun N-terminal kinase pathway.

Ischemic stroke is one of the major causes of death and disability among adults. This study sought to explore the mechanism of microRNA (miR)-193b-3p in rats with cerebral ischemia-reperfusion (I/R) injury. The cerebral I/R injury models of rats were established using the suture-occluded method. The pathological changes were observed, and oxidative stress (OS) and mitochondrial function indexes in rat brain tissue were examined. The levels of miR-193b-3p and seven in absentia homolog 1 (SIAH1) were detected. miR-193b-3p agomir or antagomir was injected into the lateral ventricle of I/R rats to overexpress or inhibit miR-193b-3p expression. The targeting relationship between miR-193b-3p and SIAH1 was verified. The effect of SIAH1 overexpression on brain injury in I/R rats was investigated by injecting the lentivirus vector into the lateral ventricle. The phosphorylation level of Jun N-terminal kinase (JNK) was identified. miR-193b-3p was lowly expressed in I/R rats. Overexpression of miR-193b-3p alleviated the pathological damage of I/R rats and limited the OS and mitochondrial damage. miR-193b-3p targeted SIAH1. Overexpression of SIAH1 partially reversed the protection of miR-193b-3p overexpression against cerebral I/R injury. p-JNK was up-regulated in I/R rats and overexpression of miR-193b-3p inhibited p-JNK. Overall, overexpression of miR-193b-3p targeted SIAH1 to inhibit the activation of the JNK pathway and protect rats against cerebral I/R injury.

MANCR drives esophageal carcinoma progression by targeting PDE4D.

PURPOSE: To explore the role of lncRNA MANCR in regulating in vitro proliferation and apoptosis in esophageal carcinoma cells and in vivo growth of esophageal carcinoma in nude mice. METHODS: MANCR levels in 15 pairs of esophageal carcinomas and non-tumoral tissues were detected by qRT-PCR. In vitro regulations of MANCR on proliferative and apoptotic potentials in TE-1 and EC-109 cells were explored by CCK-8, colony formation assay and flow cytometry. In addition, dual-luciferase reporter assay and rescue experiments were conducted to clarify the potential mechanisms of MANCR on regulating PDE4D. Finally, in vivo role of MANCR in mediating esophageal carcinoma growth was determined in nude mice implanted with EC-109 cells. RESULTS: MANCR was highly expressed in esophageal carcinomas tissues than non-tumoral ones. MANCR promoted proliferative ability and inhibited apoptosis in TE-1 and EC-109 cells. In nude mice with xenografted esophageal carcinoma, knockdown of MANCR markedly slowed down tumor growth. PDE4D was the target gene binding MANCR, which was downregulated in esophageal carcinoma tissues. Its level was negatively regulated by MANCR. Importantly, PDE4D could abolish the role of MANCR in stimulating the malignant progression of esophageal carcinoma. CONCLUSIONS: LncRNA MANCR is upregulated in esophageal carcinoma cases. Through negatively regulating PDE4D level, MANCR stimulates proliferative ability and inhibits apoptosis in esophageal carcinoma, thus driving the malignant progression.