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Abstract Background Here, we investigated the predictive efficiency of a newly developed model based on single nucleotide polymorphisms (SNPs) and laboratory data for intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) in a Chinese population. Methods Data relating to children with KD were acquired from a single center between December 2015 and August 2019 and used to screen target SNPs. We then developed a predictive model of IVIG resistance using previous laboratory parameters. We then validated our model using data acquired from children with KD attending a second center between January and December 2019. Results Analysis showed that rs10056474 GG, rs746994GG, rs76863441GT, rs16944 (CT/TT), and rs1143627 (CT/CC), increased the risk of IVIG-resistance in KD patients (odds ratio, OR > 1). The new predictive model, which combined SNP data with a previous model derived from laboratory data, significantly increased the area under the receiver-operator-characteristic curves (AUC) (0.832, 95% CI: 0.776-0.878 vs 0.793, 95%CI:0.734-0.844, P

Abstract Antibiotics affect gut microbial composition, leading to Gut–Brain-Axis imbalance and neurobehavioral changes. However, the intestinal dysbacteriosis associated behavior changes are not consistently reported. It is not clear whether these changes are transient or permanent. The neuroprotective effect of probiotics against intestinal dysbacteriosis induced alternations needs to be determined either. In the present study, oral antibiotic mixture including Ampicillin, Streptomycin, and Clindamycin was utilized to induce intestinal dysbacteriosis in mice. Antibiotics application triggered mechanical allodynia in von frey test and spontaneous pain in open field test. It also resulted in increased anxiety and depressive-like behaviors and damaged spatial memory performance. After application of probiotics, the mechanical allodynia and spontaneous pain were alleviated significantly. The anxiety behaviors, depressive-like behaviors and recognitive performance were ameliorative as well. By using Fos protein as a marker, it is found that the sensory, emotion and memory related brain regions were activated in mice with intestinal dysbacteriosis. Our study is not only helpful for enriching our basic knowledge for understanding the changed pain responses and related brain disorders in antibiotics-induced dysbacteriosis mice, but also beneficial for providing a more comprehensive mechanistic explanation for the regulation of antibiotics and probiotics on gut microbiota and relevant alternations in animal neurological behaviors.

Abstract Background Oral squamous cell carcinoma (OSCC), a form of head and neck squamous cell carcinoma (HNSCC) has a poor 5-year survival rate. OSCC patients are often treated with cisplatin but resistance to chemotherapy is often observed. This makes it important identification of alternative therapeutic targets which will result in more favorable outcome in OSCC patients. The plant homeodomain (PHD)-containing protein Inhibitor of Growth family of tumor suppressor proteins (p33ING1b) has been indicated as a tumor suppressor in different cancers including OSCC. This protein has been shown to function by modulating transcriptional activity of p53; however, the exact mechanism(s) are not well defined. Methods Expression of total and acetylated p53 and p33ING1b protein was determined in OSCC cell lines YD-9, YD-8, and YD-38 by immunoblot analysis. Effect of modulation of p33ING1b protein expression on acetylation of p53 and cell proliferation was determined by immunoblot and MTT assay. Effect of modulation of p33ING1b protein expression on transactivation of p53 was assessed by heterologous promoter-based reporter and chromatin immunoprecipitation. Effect of modulation of expression of p33ING1b on SIR2 mRNA and protein was determined by quantitative real-time PCR and immunoblot analyses. Impact of modulation of p33ING1b alone or in combination with SIR2 on chemosensitivity of YD-9 and YD-8 cells to cisplatin was determined in time and dose-dependent cell proliferation assays. Results Here, using a panel of OSCC cell lines with wild type or mutant p53, we show that p33ING1b expression is correlated to acetylation of p53 at lysine 382 residue. Increased acetylation of p53 following overexpression of p33ING1b was associated with increased expression of the pro-apoptotic proteins BAX, p21, and cleaved-Caspase 3, and decreased cell proliferation. Reporter assays with p21 and BAX promoters showed that p33ING1b expression levels directly correlated to promoter activity of these 2 genes. Chromatin immunoprecipitation assay showed that transcriptional regulation of p21 and BAX by acetylated p53 is dependent on expression level of p33ING1b. Differential acetylation of p53 following modulation of p33ING1b expression was indirect. Expression of p33ING1b was found to be inversely correlated to the NAD-dependent deacetylase silent information regulator 2 (SIR2). SIR2 was transcriptionally regulated by p33ING1b. Relative expression of p33ING1b was found to dictate chemosensitivity of OSCC cell lines to cisplatin treatment. Concomitant overexpression of p33ING1b and knockdown of SIR2 had a synergistic effect on chemosensitivity of OSCC cell lines to cisplatin, compared to either overexpression of p33ING1b or knockdown of SIR2 alone. Conclusions The results from the current study thus elucidate that p33ING1b regulates p53 acetylation irrespective of p53 mutation and subsequent transactivation by transcriptional regulation of SIR2 expression. The results also indicate that p33ING1b and SIR2 are potentially attractive therapeutic targets.

Abstract Background To investigate the relationships of plasma renin, angiotensin, and aldosterone levels to blood pressure variability and target organ damage in children with essential hypertension. Methods A case-control study was conducted on 132 children diagnosed with essential hypertension (103 males and 29 females with the mean age of 11.8 ± 2.4 years). The plasma RAAS levels were measured using the enhanced chemiluminescence method, the ambulatory blood pressure was monitored for 24 h, and then the average real variability (ARV) was calculated. Data on indicators were used for assessing cardiac and renal damages. The correlations of plasma renin, angiotensin, and aldosterone (RAAS) levels to blood pressure variability (BPV) and target organ damage (TOD) were studied. A comparison between the groups was conducted using SPSS 20. Results Among the 132 children, 55 cases had target organ damage. The 24-h ARV and the daytime ARV of the systolic blood pressure of the high angiotensin II (AT II) group was significantly higher than that of the normal AT II group (t = 2.175, P = 0.031; t = 2.672, P = 0.009). Plasma AT II and aldosterone levels were significantly associated with the left ventricular mass index (r = 0.329, P = 0.0001; r = 0.175, P = 0.045). Linear regression analysis showed that AT II [β ± s.e. = 0.025 ± 0.006, 95% CI (0.013–0.038), P = 0.0001] and aldosterone [β ± s.e. = 0.021 ± 0.007, 95% CI (0.008–0.034), P = 0.002] were risk factors for LVH. Conclusions The AT II level in children with essential hypertension affected the variability of the 24-h and the daytime SBP. Plasma AT II and aldosterone levels were associated with cardiac damage. Results from this study indicated that AT II and aldosterone are risk factors for LVH in childhood hypertension and are of great significance for improving the clinical prognosis of pediatric patients with hypertension.

Abstract Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. This study was designed to examine the role of anterior insular cortex (aIC) in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). Abdomen hyperalgesia and anxiety were assessed by von Frey filament and open field tests, respectively. Two weeks after surgery, the activation of aIC was indicated by FOS immunohistochemical staining and electrophysiological recordings. Expressions of VGluT1, NMDAR subunit NR2B and AMPAR subunit GluR1 were analyzed by immunoblottings. The regulatory roles of aIC in hyperalgesia and pain-related anxiety were detected via pharmacological approach and chemogenetics in CP rats. Our results showed that TNBS treatment resulted in long-term hyperalgesia and anxiety-like behavior in rats. CP rats exhibited increased FOS expression and potentiated excitatory synaptic transmission within aIC. CP rats also showed up-regulated expression of VGluT1, and increased membrane trafficking and phosphorylation of NR2B and GluR1 within aIC. Blocking excitatory synaptic transmission significantly attenuated abdomen mechanical hyperalgesia. Specifically inhibiting the excitability of insular pyramidal cells reduced both abdomen hyperalgesia and pain-related anxiety. In conclusion, our findings emphasize a key role for aIC in hyperalgesia and anxiety of painful CP, providing a novel insight into cortical modulation of painful CP and shedding light on aIC as a potential target for neuromodulation interventions in the treatment of CP.

Abstract Background Yeast strains that are tolerant to multiple environmental stresses are highly desired for various industrial applications. Despite great efforts in identifying key genes involved in stress tolerance of budding yeast Saccharomyces cerevisiae, the effects of de novo purine biosynthesis genes on yeast stress tolerance are still not well explored. Our previous studies showed that zinc sulfate addition improved yeast acetic acid tolerance, and key genes involved in yeast stress tolerance were further investigated in this study. Results Three genes involved in de novo purine biosynthesis, namely, ADE1, ADE13, and ADE17, showed significantly increased transcription levels by zinc sulfate supplementation under acetic acid stress, and overexpression of these genes in S. cerevisiae BY4741 enhanced cell growth under various stress conditions. Meanwhile, ethanol productivity was also improved by overexpression of the three ADE genes under stress conditions, among which the highest improvement attained 158.39% by ADE17 overexpression in the presence of inhibitor mixtures derived from lignocellulosic biomass. Elevated levels of adenine-nucleotide pool “AXP” ([ATP] + [ADP] + [AMP]) and ATP content were observed by overexpression of ADE17, both under control condition and under acetic acid stress, and is consistent with the better growth of the recombinant yeast strain. The global intracellular amino acid profiles were also changed by overexpression of the ADE genes. Among the changed amino acids, significant increase of the stress protectant γ-aminobutyric acid (GABA) was revealed by overexpression of the ADE genes under acetic acid stress, suggesting that overexpression of the ADE genes exerts control on both purine biosynthesis and amino acid biosynthesis to protect yeast cells against the stress. Conclusion We proved that the de novo purine biosynthesis genes are useful targets for metabolic engineering of yeast stress tolerance. The engineered strains developed in this study with improved tolerance against multiple inhibitors can be employed for efficient lignocellulosic biorefinery to produce biofuels and biochemicals.

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