Dimethyl itaconate inhibits LPS-induced inflammatory release and apoptosis in alveolar type II epithelial and bronchial epithelial cells by activating pulmonary surfactant proteins A and D.

BACKGROUND: Injury to the lung is a common, clinically serious inflammatory disease. However, its pathogenesis remains unclear, and the existing treatments, including cytokine therapy, stem cell therapy, and hormone therapy, are not completely effective in treating this disease. Dimethyl itaconate (DMI) is a surfactant with important anti-inflammatory effects. OBJECTIVE: The present study used alveolar type II (AT II) and bronchial epithelial cells as models to determine the role of DMI in lung injury. MATERIAL AND METHODS: First, the effects of DMI were established on the survival, inflammatory release, and apoptosis in lipopolysaccharide (LPS)-induced AT II and bronchial epithelial cells. The association between DMI and Sirtuin1 (SIRT1) was assessed using molecular docking. Next, by constructing interference plasmids to inhibit surfactant protein (SP)-A and SP-D expressions, the effect of DMI was observed on inflammatory release and apoptosis. RESULTS: The results revealed that DMI increased the survival rate and expression levels of SP-A, SP-D, and SIRT1, and inhibited inflammatory factors as well as apoptosis in LPS-induced cells. Furthermore, DMI could bind to SIRT1 to regulate SP-A and SP-D expressions. After SP-A and SP-D expressions were inhibited, the inhibitory effect of DMI was reversed on inflammatory release and apoptosis. CONCLUSION: The findings of the present study revealed that DMI inhibited LPS-induced inflammatory release and apoptosis in cells by targeting SIRT1 and then activating SP-A and SP-D. This novel insight into the pharmacological mechanism of DMI lays the foundation for its later use for alleviating lung injury.

[Efficacy and safety of levetiracetam versus phenytoin as second-line drugs for the treatment of children with convulsive status epilepticus: a Meta analysis].

OBJECTIVE: To systematically evaluate the efficacy and safety of levetiracetam (LEV) versus phenytoin (PHT) as second-line drugs for the treatment of convulsive status epilepticus (CSE) in children. METHODS: English and Chinese electronic databases were searched for the randomized controlled trials comparing the efficacy and safety of LEV and PHT as second-line drugs for the treatment of childhood CSE. RevMan 5.3 software was used for data analysis. RESULTS: Seven studies with 1 434 children were included. The Meta analysis showed that compared with the PHT group, the LEV group achieved a significantly higher control rate of CSE (RR=1.12, 95%CI:1.00-1.24, P=0.05), but there was no significant difference between the two groups in the recurrence rate of epilepsy within 24 hours (RR=0.82, 95%CI:0.22-3.11, P=0.77) and the rate of further antiepileptic drug therapy (RR=0.97, 95%CI:0.64-1.45, P=0.87). There was no significant difference in the incidence rate of adverse events between the two groups (RR=0.77, 95%CI:0.55-1.09, P=0.15). CONCLUSIONS: LEV has a better clinical effect than PHT in the treatment of children with CSE and does not increase the incidence rate of adverse events.

Traditional Chinese medicine for neonatal hypoxic-ischemic encephalopathy: A Bayesian network meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Although therapeutic hypothermia is currently considered an effective treatment for neonatal hypoxic-ischemic encephalopathy (HIE), neonatal HIE is a disease requiring multiple therapeutic measures. Related Chinese herbal injections (CHIs) have been carried out in Chinese local hospitals for several years, and the outcomes all seem to show positive results. At the same time, other Traditional Chinese medicine (TCM) methods have also shown vigorous vitality. AIM OF THE STUDY: This study constructed a network meta-analysis (NMA) to investigate the efficacy of CHIs including Shenmai Injection (SMI), Compound musk injection (SXI), Ligustrazine injection (CXI), Compound danshen injection (DSI), Astragalus injection (HQI), Ginkgo biloba extract injection (YXI), and Puerarin injection (GGI) combined with traditional symptomatic treatment (TST) and TST alone in HIE. METHODS: A literature review was conducted in several databases from inception to 9 February 2023. The quality of the included studies was assessed by the Cochrane risk of bias tool. Data were analyzed by STATA 17.0 and R 4.2.2 software. Surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the examined treatments. Bayesian network meta-analysis was designed to access the effectiveness of different CHIs. RESULTS: A total of 46 eligible randomized controlled trials involving 3,448 patients and 7 CHIs were included. The results of the NMA showed that SMI, SXI, CXI, DSI, HQI, YXI, and GGI combined with TST significantly improved treatment performance compared to TST alone. SMI + TST had obvious superiorities in the clinical effective rate and the original reflection recovery time. SXI + TST was the most advantageous in the Cure rate and the Neonatal Behavioral Neurological Assessment (NBNA). CXI + TST was shown to reduce the incidence of sequelae best. All articles reported that there were no obvious adverse drug reactions/adverse drug events (ADRs/ADEs). CONCLUSION: This NMA showed that using CHIs in combination with TST improved treatment performance and could be beneficial for patients with HIE compared to using TST alone. Thereinto, SXI + TST showed a preferable improvement in patients with HIE when unified considering the clinical effective rate and other outcomes. As for safety, more evidence is needed to support this hypothesis.

RNA-seq Analysis Reveals Potential Molecular Mechanisms of ZNF580/ZFP580 Promoting Neuronal Survival and Inhibiting Apoptosis after Hypoxic-ischemic Brain damage.

Neonatal hypoxic-ischemic brain damage (HIBD) is one of the main causes of neonatal acute death and chronic nervous system impairment, but still lacks effective treatments. ZNF580/ZFP580, reported in our previous studies, may be a newly identified member of the Krüppel-like factor (KLF) family, and has anti-apoptotic effects during ischemic myocardial injury. In the present study, we showed that the expression levels of both ZFP580/ZNF580 mRNA and protein increased significantly in neonatal HIBD rats and oxygen-glucose deprivation (OGD) SH-SY5Y cell models. ZNF580 overexpression promoted neuron survival and suppressed neuron apoptosis after OGD in neuron-like SH-SY5Y cells, while interference with ZNF580 resulted in the opposite results. RNA-seq analysis identified 248 differentially-expressed genes (DEGs) between ZNF580 overexpression SH-SY5Y cells and interference-expressed SH-SY5Y cells. Gene Ontology functional enrichment analysis showed that these DEGs played significant roles in the growth, development, and regeneration of axons, DNA biosynthetic processes, DNA replication, and apoptosis. Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that these DEGs were found in some pathways, including ferroptosis, glutamatergic synapses, protein processing in the endoplasmic reticulum, estrogen signaling pathways, the TGF-beta signaling pathway, and the longevity regulating pathway. The qRT-PCR validation results were consistent with RNA-seq results, which showed that HSPA5, IGFBP3, NTN4, and KLF9 increased in ZNF580-overexpressed SH-SY5Y cells and decreased in interference-expressed SH-SY5Y cells, when compared with normal cells. Together, the results suggested that ZNF580 targeted these genes to inhibit neuronal apoptosis.

[Autoimmune regulator gene mutations in a Chinese family with autoimmune polyendocrinopathy syndrome type I].

OBJECTIVE: To identify the mutation of the autoimmune regulator gene (AIRE) in a Chinese family with autoimmune polyendocrinopathy syndrome type I (APS-I). METHODS: The AIRE gene mutations were detected using PCR and direct DNA sequencing. Restriction enzyme analysis was used to confirm the mutations and bioinformatic methods were used to predict the possible impact of the mutations on the structure and function of the AIRE protein. RESULTS: A compound heterozygous mutation of A19T/R257X was detected in the proband. Her father had the A19T mutation in exon 1, but this mutation was not detected in 100 unrelated healthy individuals. Her mother had the R257X mutation in exon 6. CONCLUSION: This is the first report about AIRE mutations in Chinese APS-I kindred. The A19T mutation identified in this study has not been reported in the human gene mutation database (HGMD); the R257X has not been reported in Asians.

Resveratrol reserved hypoxia-ischemia induced childhood hippocampal dysfunction and neurogenesis via improving mitochondrial dynamics.

Early life stress usually causes the abnormal brain development and results in the onset of cognitive and emotional disorders in later childhood. Neonatal hypoxic ischemia (HI) causes dramatic brain damage in early life and resulted in serious impairment to brain development. Hippocampal neurogenesis, as one of the key structural plasticity to mediate animal behaviors, can be impact by neonatal HI until child stage. In our study, we identified the natural product resveratrol (RES) as the potential alternative therapy to improve brain functions of childhood mice after underwent neonatal HI. Treatment of RES improved the spatial learning and memory in morris water maze and increased the recognize ability in objective recognition task. Moreover, RES also attenuate the depressive and anxiety like mood in child mice after experiencing neonatal HI. Brain morphological study showed RES promote the proliferation of neural stem cells and increase the neuronal differentiation in hippocampal dentate gyrus (DG) region. Our in vitro study in C17.2 neural stem cell line demonstrated RES could prevent the mitochondrial fragmentation induced by hypoxia. Moreover, same effect was also observed in primary cultural neurons. To summarize, RES could prevent the cognitive deficit and depressive/anxiety mood in childhood with experience of neonatal HI via promoting hippocampal neurogenesis. Improving mitochondrial dynamics could be one of the key biological mechanisms underlying such effects of RES.

[Levels of intracellular IL-6 and IFN-gamma in children with acute lymphoblastic leukemia].

OBJECTIVE: To study the changes of intracellular interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) expressions in children with acute lymphoblastic leukemia (ALL) at different stages, and to examine the correlation between IL-6 and IFN-gamma in ALL children. METHODS: The levels of intracellular IL-6 and IFN-gamma in venous blood lymphocytes were detected by flow cytometry in 42 children with ALL at diagnosis and at remission stage. Twenty healthy children were used as the controls. RESULTS: The intracellular IL-6 level in ALL children at diagnosis was 81.74+/-9.31, which was much higher than that in the Control group (5.67 +/- 0.96 ) (P < 0.01). The intracellular IFN-gamma level in ALL children (1.31 +/- 0.32) was significantly lower than that in the Control group (1.46 +/- 0.49) (P < 0.01). However, the intracellular IL-6 level (27.52 +/- 3.40) decreased remarkably in ALL patients at remission stage (P < 0.01), but was still higher than that in the Control group (P < 0.01). In contrast, the intracellular IFN-gamma level (1.97 +/- 0.72) increased noticeably in ALL patients at remission stage, which was higher than that at diagnosis and the Control group (P < 0.01). A negative correlation was found between the intracellular IL-6 and the IFN-gamma levels in ALL patients (r=-0.476, P < 0.05). CONCLUSIONS: Intracellular IL-6 and IFN-gamma levels may be used as the markers for monitoring the response to treatment in ALL patients. There is a negative correlation between intracellular IL-6 and IFN-gamma levels in ALL children.

[Localized expressing tendency of nuclear transcription factor kappa-B, pro-fibrosis genetic factors and fibronectin mRNA in renal tissues in proteinuria overload nephrotic young rats].

OBJECTIVE: Terminal stage renal failure is the final common fate of chronic nephropathies independent of the type of initial insult. Abnormally filtered proteins have an intrinsic renal toxicity linked to their over-reabsorption by proximal tubular cells and activation of tubular-dependent pathways of interstitial inflammation and fibrosis. The functional importance of tubulointerstitial events in progressive renal disease is supported by evidence that the severity of tubular interstitial damage strongly correlates with the risk of renal failure. The present study aimed to investigate the expressive tendency of some pro-fibrosis genetic factors mRNA, including thrombospondin-1 (TSP-1), transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and the major component of extracellular matrix-fibronectin (FN) in renal tissues at different time points during early stage of renal lesions caused by proteinuria in bovine serum albumin (BSA) injection-induced proteinuria overload nephrotic young rats and the significance of these factors on tubulointerstitial fibrosis development. METHODS: Female young Wistar rats aged 3-4 weeks with proteinuria overload nephrosis induced by BSA (1.0 g/d) injected intraperitoneally were used as experimental models. The 80 young rats were divided into control group (n = 40) and BSA injected group (n = 40). At different time points (weeks 1, 2, 3 and 4), the urinary protein was measured by Coomassie brilliant blue colorimetric assay; the renal tissues morphologic changes were evaluated after HE staining; the P(65)/Rel-A, TSP-1, TGF-beta1 and CTGF mRNA expression in renal tissues was determined by in situ hybridization method and the FN mRNA expression was detected by Northern blot. The experimental data were evaluated by statistics software SPSS10.0. RESULTS: (1) Three to four weeks after BSA injection, heavy proteinuria was observed in the rats of BSA group (week 3: 104.3 +/- 21.8 mg/24 h; week 4: 131.1 +/- 18.3 mg/24 h). The proteinuria deteriorated progressively afterwards. Histopathological examination revealed that inflammatory cells infiltrated into tubulointerstitial areas extensively, protein casts were seen in tubules and edema occurred in tubulointerstitial areas. (2) In situ hybridization showed that NF-kappaB (P(65)/Rel-A) mRNA expression was up-regulated progressively in nuclei of tubular epithelial cells, the semi-quantitative scores (at 1, 2, 3 and 4 weeks) were 2.33 +/- 0.20, 2.76 +/- 0.12, 2.96 +/- 0.19, and 3.76 +/- 0.18, respectively (F = 37.34, P < 0.01). (3) At 1 week after BSA injection, the TSP-1 mRNA expression appeared in glomeruli and increased, but was light in tubulointerstitial areas, its expressive peak was observed at week 2, and declined to mild after weeks 3 and 4. The semi-quantitative scores at different time points suggested that TSP-1 mRNA was expressed mainly in early stage of lesion in this model, then, this tendency turned to a flat roof smoothly. (4) TGF-beta1 and CTGF mRNA was up-regulated simultaneously in tubular epithelial cells (F = 8.80, P < 0.01 F = 19.41, P < 0.01). (5) Northern blotting showed that FN mRNA was considerably up-regulated at second week in the kidneys of rats in BSA group, 2.7-fold higher at week 4 than that at week 1 in BSA group rats, and was 3.6-fold higher than that of control group. CONCLUSION: The present study suggested that NF-kappaB (P(65)/Rel-A) mRNA expression and its activity was enhanced significantly by proteinuria-loading and synchronized with high expression of TSP-1, TGF-beta1, and CTGF mRNA in the kidney, at the same time, FN mRNA was up-regulated in renal tissues and an aggravating tendency in tubulointerstitial lesions was observed in nephrotic young rats with heavy proteinuria.