Soluble thrombomodulin alleviates Diquat-induced acute kidney injury by inhibiting the HMGB1/IκBα/NF-κB signalling pathway.

Our research aimed to investigate whether soluble thrombomodulin (sTM) relieved Diquat (DQ)-induced acute kidney injury (AKI) via HMGB1/IκBα/NF-κB signaling pathways. An AKI rat model was constructed using DQ. Pathological changes in renal tissue were detected by HE and Masson staining. Gene expression was determined using qRT-PCR, IHC, and western blotting. Cell activity and apoptosis were analysed using CCK-8 and Flow cytometry, respectively. An abnormal kidney structure was observed in DQ rats. The levels of blood urea nitrogen (BUN), creatinine (CRE), uric acid (UA), oxidative stress, and inflammatory responses in the DQ group increased on the 7th day but decreased on the 14th day, compared with the control group. Additionally, HMGB1, sTM, and NF-kappaB (NF-κB) expression had increased in the DQ group compared with the control group, while the IκKα and IκB-α levels had decreased. In addition, sTM relieved the damaging effects of diquat on renal tubular epithelial cell viability, apoptosis, and the inflammatory response. The levels of HMGB1, TM, and NF-κB mRNA and protein were significantly decreased in the DQ + sTM group compared with the DQ group. These findings indicated that sTM could relieve Diquat-induced AKI through HMGB1/IκBα/NF-κB signaling pathways, which provides a treatment strategy for Diquat-induced AKI.

TSC2/PKD1 contiguous deletion syndrome in a pregnant woman: A case report.

TSC2/PKD1 contiguous gene deletion syndrome is a disease caused by the deletions of the TSC2 and PKD1 genes. This is a rare contiguous genomic disease with clinical manifestations of tuberous sclerosis and polycystic kidney disease. To our knowledge, this case report is the first known case of TSC2/PKD1 contiguous gene deletions in a pregnant woman. The patient had multiple renal cysts, angiomyolipoma, hypomelanotic macules, shagreen patch, subependymal giant cell astrocytoma, multiple cortical tubers, and subependymal nodules. The patient underwent genetic testing. To exclude genetic defects in the fetus, prenatal fetal genetic testing was performed after obtaining the patient's consent. We found an increasing trend in the size of renal cysts and renal angiomyolipomas in patients with polycystic kidney with tuberous sclerosis during pregnancy. Through enhanced clinical monitoring of patients and prenatal genetic testing of the fetus, timely and effective clinical intervention for the mother may be achieved, thus obtaining the best possible outcome for both mother and fetus.

An immune genes signature for predicting mortality in sepsis patients.

A growing body of evidence indicates that the immune system plays a central role in sepsis. By analyzing immune genes, we sought to establish a robust gene signature and develop a nomogram that could predict mortality in patients with sepsis. Herein, data were extracted from the Gene Expression Omnibus and Biological Information Database of Sepsis (BIDOS) databases. We enrolled 479 participants with complete survival data using the GSE65682 dataset, and grouped them randomly into training (n = 240) and internal validation (n = 239) sets based on a 1:1 proportion. GSE95233 was set as the external validation dataset (n=51). We validated the expression and prognostic value of the immune genes using the BIDOS database. We established a prognostic immune genes signature (including ADRB2, CTSG, CX3CR1, CXCR6, IL4R, LTB, and TMSB10) via LASSO and Cox regression analyses in the training set. Based on the training and validation sets, the Receiver Operating Characteristic curves and Kaplan-Meier analysis revealed that the immune risk signature has good predictive power in predicting sepsis mortality risk. The external validation cases also showed that mortality rates in the high-risk group were higher than those in the low-risk group. Subsequently, a nomogram integrating the combined immune risk score and other clinical features was developed. Finally, a web-based calculator was built to facilitate a convenient clinical application of the nomogram. In summary, the signature based on the immune gene holds potential as a novel prognostic predictor for sepsis.

Maternal anaemia and birth weight: a cross-sectional study from Jiangxi Province, China.

BACKGROUND: Association between maternal haemoglobin (Hb) and low birth weight (LBW) remains a controversial topic, and data in China were sparse. AIMS: We aimed to investigate the association between maternal Hb and LBW among pregnant women in Jiangxi Province, China. METHODS: In this cross-sectional study, 1,029 participants were enrolled. Anaemia was classified according to World Health Organization's definition of anaemia in pregnancy. Logistic regression analysis was performed to evaluate the association between maternal Hb and LBW. Generalized additive model and smooth curve fitting (penalized spline method) were conducted to explore the exact shape of curve between them. RESULTS: The overall prevalence of anaemia was 58.2% in our study. A significantly higher risk of LBW was found in moderate anaemia subjects (odds ratio [OR] = 2.93; 95% confidence interval [CI]: 1.16-5.31) and severe anaemia subjects (OR = 63.86; 95% CI: 25.66-158.90) compared with maternal Hb concentration >100 g/L. The fully adjusted smooth curve fitting presented an L-shaped association between the maternal Hb and LBW, with a turning point at about 110 g/L. Subgroup analyses showed that stronger associations between maternal Hb and LBW were detected in pregnant women with high education, long duration of gestation and multiple antenatal visits (all P for interaction <0.05). CONCLUSIONS: Anaemia in delivering women was associated with an elevated risk of LBW and the risk increased with the severity of anaemia, especially among pregnant women with high education, long duration of gestation and multiple antenatal visits from Jiangxi Province, China.

Global DNA and protein interactomes of FLT1P1 (Fms-related tyrosine kinase 1 pseudogene 1) revealed its molecular regulatory functions associated with preeclampsia.

BACKGROUND: Preeclampsia (PE) is one of the most serious pregnancy complications with unknown pathogenesis. Emerging evidence has demonstrated that Fms-related tyrosine kinase 1 (FLT1) is highly involved in PE development. As a pseudogene of FLT1, FLT1P1 increased in PE samples. However, its functions remain largely unknown. METHODS AND RESULTS: In this study, co-expression analysis was performed to identify the potential target genes of FTL1P1. Then chromatin isolation using RNA purification (ChIRP) method was employed to explore the interactomes of FLT1P1, including interacting with DNA fragments and proteins. We found that in PE samples, both FLT1P1 and FLT1 were highly expressed and closely correlated. ChIRP-protein data revealed that FLT1P1 interacts with translation- and transcription-related proteins, including 4 transcription factors (TFs). ChIRP-DNA analysis revealed that FLT1P1 preferentially interacted with DNA fragments downstream of transcription start sites (TSSs). Functional analysis of its interacting genes revealed that they were enriched in transcriptional regulation and apoptosis-related pathways. Twenty-six TFs, including CREB1 and SRF, were extracted from the potential FLT1P1-interacting gene sets and were potential targets of FLT1P1. CREB1 could bind to FLT1 promoter, and was negatively correlated with FLT1 at the expression level, making it a potential regulator of FLT1. CONCLUSIONS: Our study extensively investigated the interactome profiles of FLT1P1, especially the prompter region of TF gene CREB1, and revealed the potential molecular regulatory mechanisms of FLT1 expression in PE samples. Our results provide a novel view of PE pathogenesis, and suggest that FLT1P1 could serve as a potential therapeutic target in PE diagnosis and treatment.

Sodium Danshensu protects against oxygen glucose deprivation/reoxygenation-induced astrocytes injury through regulating NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome and tuberous sclerosis complex-2 (TSC2)/mammalian target of rapamycin (mTOR) pathways.

Background: Cerebral ischemic stroke is a serious condition with high incidence, mortality, and associated disability. Currently, effective therapeutic options are available for ischemic stroke are limited. Accumulating evidence indicates that sodium Danshensu, mono sodium compound derived from Salvia miltiorrhiza, plays protective roles in ischemic stroke. However, the underlying protective mechanism of sodium Danshensu in cerebral ischemic stroke remains unknown. Methods: In the current study, we explored the role and mechanism of sodium Danshensu on astrocytes exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), which mimics the process of ischemia-reperfusion. The impact of sodium Danshensu on cell viability and apoptosis after OGD/R were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-dophenyl tetrazolium bromide (MTT) assay and flow cytometry. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were used to detect the expression of target messenger RNA (mRNA) and proteins associated with apoptosis and autophagy. The release of lactate dehydrogenase (LDH) was determined, and the production of proinflammatory cytokines were detected using enzyme-linked immunosorbent assay (ELISA) kits. Results: It was found that sodium Danshensu could significantly increase cell viability and decrease LDH release and apoptosis. Besides, it inhibited the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6. Sodium Danshensu also dose-dependently decreased protein and mRNA levels of nucleotide binding oligomerization NOD-like receptor pyrin domain containing 3 (NLRP3) and high mobility group box 1 (HMGB1), which play a crucial role in promoting ischemic stroke-induced cell injury. Moreover, sodium Danshensu dose-dependently upregulated Beclin 1 expression, downregulated P62 protein expression, and further increased LC3B-II/LC3B-I ratio through inducing autophagy in astrocytes. Additionally, we noticed that sodium Danshensu dose-dependently increased tuberous sclerosis complex-2 (TSC2) protein expression, while significantly reduced the levels of mammalian target of rapamycin (mTOR) in the presence of OGD/R insult. Conclusions: These findings suggest that sodium Danshensu protects against OGD/R-induced injury by modulating the NLRP3 inflammasome and TSC2/mTOR pathways.

Subitizing, unlike estimation, does not process sets in parallel.

Enumeration of very small quantities is a common task that we perform everyday. Much research has highlighted that in these conditions humans display fast, near errorless performance, a phenomenon dubbed subitizing. It has been suggested that this regime has a pivotal role in numerosity perception. Here we asked if this system can process multiple sets of items in parallel. At odds with what happens for moderate numerosities, we found a strong impairment caused already by the introduction of a second group of items marked by a different color. Adding shape as a cue provided no benefit. The only case in which subitizing was possible was when the target and distractor group were held constant through the experimental block. These results show the surprising fact that whilst being rapid and errorless, subitizing does not have the capability to disentangle multiple groups of items and deals only with coarse stimulus statistics.

[Protective effect of recombinant TM-N and recombinant soluble RAGE in a mouse model of acute hepatic failure].

OBJECTIVE: To evaluate the roles of N-terminal lectin-like domain of thrombomodulin (TM-N) and receptor for advanced glycation end products (RAGE) in acute hepatic failure using a mouse model system. METHODS: Acute hepatic failure was induced in Kunming mice by intraperitoneal injection of D-galactosamine (D-Galn at 600 mg/kg) and lipopolysaccharide (LPS at 5 mug/kg) and mice were divided into groups for injection with saline, recombinant (r)TM-N protein, or recombinant soluble (rs)RAGE protein. Unmanipulated model mice served as the negative controls. Effects on liver expression of high mobility group box-1 (HMGB1) were detected by immunohistochemistry and real time RT-PCR. Effects on serum levels of tumor necrosis factor-alpha (TNFa) and interleukin-1 beta (IL)-1b were quantified by ELISA. RESULTS: Treatment with rTM-N and rsRAGE both alleviated the acute liver damage induced by D-Galn/LPS exposure, and decreased the hepatic expression of HMGB1 as well as the serum levels of TNFa and IL-1b. CONCLUSION: Intraperitoneal delivery of rTM-N and rsRAGE can alleviate acute liver damage by modulating the expression of necrosis- and inflammation-related factors.

Recombinant human histidine triad nucleotide-binding protein 1 attenuates liver fibrosis induced by carbon tetrachloride in rats.

It is currently thought that the transforming growth factor-ß (TGF-ß)/Smad signaling pathway acts as a central pathway leading to liver fibrosis, and that the aberrant Wnt/ß-catenin signaling pathway also plays a vital role in the development of liver fibrosis. There is evidence that the histidine triad nucleotide-binding protein 1 (Hint1) was capable of inhibiting these two pathways. However, little data regarding the effects of Hint1 on liver fibrosis exists. Thus, we sought to investigate whether the recombinant human Hint1 protein (rhHint1) was capable of attenuating liver fibrosis induced by carbon tetrachloride (CCl4) in rats and the possible underlying mechanism(s) of action. In the present study, purified rhHint1 was obtained using genetic engineering technology. Liver fibrosis was induced in male Sprague-Dawley (SD) rats by the subcutaneous injection of CCl4. The rats were randomly divided into the normal control, the liver fibrosis model and the rhHint1 (doses, 50 and 100 µg/kg)­treated groups. Following four weeks of treatment, the rhHint1-treated rats exhibited significantly reduced liver fibrosis upon histopathological analysis and lower levels of hydroxyproline. Furthermore, rhHint1 inhibited the expression of α-smooth muscle actin (α-SMA) in the liver tissues. Additionally, rhHint1 lowered the gene expression levels of TGF-ß1/Smad3 and ß-catenin/cyclin D1, whereas it increased the gene expression levels of Smad7. In conclusion, the results of this study indicated that rhHint1 is capable of attenuating CCl4-induced liver fibrosis by simultaneously targeting multiple pathogenic pathways, which may be developed as a new treatment for liver fibrosis.