The activation of HAMP promotes colorectal cancer cell proliferation through zinc-mediated upregulation of SMAD4 expression.

Background: Colorectal cancer (CRC) poses a significant challenge in digestive system diseases, and emerging evidence underscores the critical role of zinc metabolism in its progression. This study aimed to investigate the clinical implications of genes at the intersection of zinc metabolism and CRC. Methods: We downloaded CRC prognosis-related genes and zinc metabolism-related genes from public databases. Then, the overlapping genes were screened out, and bioinformatics analysis was performed to obtain the hub gene associated with CRC prognosis. Subsequently, in vitro assays were carried out to investigate the expression of this hub gene and its exact mechanism between zinc metabolism and CRC. Results: HAMP was identified as the hub CRC prognostic gene from overlapping zinc metabolism-related and CRC prognostic genes. In vitro analysis showed HAMP was over-expressed in CRC, and its knockdown inhibited RKO and HCT-116 cell invasion and migration significantly. ZnSO4 induced HAMP up-regulation to promote cell proliferation, while TPEN decreased HAMP expression to inhibit cell proliferation. Importantly, we further found that ZnSO4 enhanced SMAD4 expression to augment HAMP promoter activity and promote cell proliferation in CRC. Conclusions: HAMP stands out as an independent prognostic factor in CRC, representing a potential therapeutic target. Its intricate regulation by zinc, particularly through the modulation of SMAD4, unveils a novel avenue for understanding CRC biology. This study provides valuable insights into the interplay between zinc metabolism, HAMP, and CRC, offering promising clinical indicators for CRC patients. The findings present a compelling case for further exploration and development of targeted therapeutic strategies in CRC management.

IL1A regulates the inflammation in gout through the Toll-like receptors pathway.

Objective: Gout is a dangerous metabolic condition related to monosodium urate (MSU). Our aim is to study the molecular mechanisms underlying gout and to identify potential clinical biomarkers by bioinformatics analysis and experimental validation. Methods: In this study, we retrieved the overlapping genes between GSE199950-Differential Expressed Genes (DEGs) dataset and key module in Weighted Gene Co-Expression Network Analysis (WGCNA) on GSE199950. These genes were then analyzed by protein-protein interaction (PPI) network, expression and Gene Set Enrichment Analysis to identify the hub gene related to gout. Then, the gene was investigated by peripheral blood mononuclear cells (PBMCs), immunoassay and cell experiments like western blotting to uncover its underlying mechanism in gout cells. Results: From the turquoise module and 83 DEGs, we identified 62 overlapping genes, only 11 genes had mutual interactions in PPI network and these genes were highly expressed in MSU-treated samples. Then, it was found that the IL1A (interleukin 1 alpha) was the only one gene related to Toll-like receptor signaling pathway that was associated with the occurrence of gout. Thus, IL1A was determined as the hub gene in this study. In immunoassay, IL1A was significantly positively correlated with B cells and negatively correlated with macrophages. Moreover, IL1A is highly expressed in gout patients,it has a good clinical diagnostic value. Finally, the results of in vitro experiments showed that after knocking down IL1A, the expressions of pro-inflammatory cytokines and Toll-like receptor signaling pathway-related proteins (TLR2, TLR4, MyD88) were all reduced. Conclusion: It is confirmed that IL1A is a promoting gene in gout with a good diagnostic value, and specifically it affects the inflammation in gout through Toll-like receptor pathway. Our research offers fresh perspectives on the pathophysiology of gout and valuable directions for future diagnosis and treatment.

Large Phase-Transition Temperature Enhancement Achieved in a Layered Lead Iodide Hybrid Crystal by H/F Substitution.

Organic-inorganic hybrid metal halides with structural flexibility and solution processability have been widely investigated for different application scenarios. However, the effective construction of phase-transition materials with a high phase-transition temperature (Ttr) for potential practical applications remains a great challenge, and reports on the regulation of Ttr with significant enhancement have been rare. In this manuscript, we have realized a large Ttr increase of 148 K in a layered hybrid lead iodide crystal (4-FTMBA)4Pb3I10 (4-FTMBA = 4-fluoro-N,N,N-trimethylbenzenaminium) by the H/F substitution strategy. Compared to the parent (TMBA)4Pb3I10 (TMBA = N,N,N-trimethylbenzenaminium), H/F substitution preserves the structural framework and crystal symmetry in (4-FTMBA)4Pb3I10. The introduction of heavier fluorine will significantly increase the motion barrier for the order-disorder transition, resulting in the remarkably improved Ttr. Temperature-dependent crystal structures, Raman spectra, and dielectric analyses well support the phase-transition behavior. In addition, evident thermochromism with a tunable direct band gap in (4-FTMBA)4Pb3I10 has been observed using UV-vis spectra. To the best of our knowledge, the achieved Ttr enhancement of 148 K by H/F substitution is the highest among the organic-inorganic hybrid lead halide phase-transition materials. This finding would greatly inspire the rational design of functional materials with high performance.

Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome.

Background and Aims: The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies. Methods: Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors. Results: In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients. Conclusions: Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic.

Background: The purpose of this study was to characterize the novel sedative/hypnotic agent HSK3486, a 2,6-disubstituted alkylphenol analogue. Methods: The mechanism of action of HSK3486 was studied in competitive binding assays and whole-cell patch clamp assays. HSK3486 was administered by bolus intravenous injection to dogs and rats, and the loss of righting reflex as well as effects on the cardiovascular and respiratory systems were assessed. The in vitro metabolism of HSK3486 was analyzed by CYP450 genotyping and enzyme inhibition. Results: HSK3486 competed with t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) for binding to the gamma-aminobutyric acid type A (GABAA) receptor. HSK3486 potentiated GABA-evoked chloride currents at lower concentrations while activating GABAA receptor at higher concentrations. HSK3486 induced hypnosis in rats and dogs, and had a higher therapeutic index than propofol in rats. The hypnotic potency of HSK3486 was approximately 4-5 fold higher than that of propofol. HSK3486 exerted minimal effects on the cardiovascular system. Conclusions: HSK3486 is a positive allosteric regulator and direct agonist of GABAA receptor. It has a promising sedative/hypnotic effect and good in vivo pharmacokinetic properties, which justify further studies towards its clinical application.

Systematic review and meta-analysis of the efficacy of general anesthesia combined with a thoracic nerve block in modified breast cancer surgery.

BACKGROUND: Breast cancer is a malignant tumor disease that poses a significant threat to women's health. In recent years, the incidence of breast cancer in China has been increasing. This report aims to explore the effects of general anesthesia combined with a thoracic nerve block in modified breast cancer surgery. METHODS: A computer-based search of PubMed, Web of Science, Embase, and the Cochrane Library was performed to identify randomized controlled studies on breast cancer, general anesthesia combined with a thoracic nerve block, modified breast cancer surgery, and other breast cancer treatments. Further search criteria included postoperative pain score, postoperative morphine equivalents given 24 hours after surgery, and operation duration. After an initial selection process, the studies were evaluated using the Jadad scale and the Cochrane Handbook for Systematic Reviews of Interventions to assess their suitability for inclusion in the subsequent meta-analysis of the experimental data, which was carried out using RevMan 5.3. RESULTS: A total of 8 studies comprising a total of 624 patients were selected for inclusion in this report. According to the meta-analysis, the analytical structure of the thoracic nerve group and the control group had a mean difference (MD) of -1.27 [95% confidence interval (CI): -1.68 to -0.86], the structure of the statistical test was Z=6.08 (P<0.00001), the MD of the total analysis structure of morphine equivalents was -2.71 (95% CI: -4.98 to -0.44), and the statistical test structure was Z=2.34 (P=0.02). DISCUSSION: General anesthesia combined with a thoracic nerve block in breast cancer surgery may effectively improve postoperative pain in patients and reduce the need for analgesic drugs. However, the outcome indicators included in this study are not sufficient. It is necessary to increase both the sample size and the number of outcome indicators to provide further theoretical evidence for the subsequent application of thoracic nerve block in modified breast cancer surgery.

Anesthesia airway management for tracheal resection and reconstruction: a single-center case series.

BACKGROUND: Anesthesia airway management is challenging during tracheal resection and reconstruction as these surgical procedures involve the airway. This case series describes four approaches to airway management in patients undergoing tracheal resection and reconstruction and discusses their advantages and disadvantages. METHODS: Thirteen patients underwent 1 of the following 4 kinds of airway management techniques during tracheal resection and reconstruction between 2013 and 2019: intubation, intubation with high frequency jet ventilation (HFJV), non-intubation, and venovenous extracorporeal membrane oxygenation (VV-ECMO). Intraoperative variables and postoperative outcomes were compared for the techniques based on our institution's medical electronic database. RESULTS: Intraoperative oxygenation management involved VV-ECMO in 8 patients, intubation in 2 patients, intubation with HFJV in 2 patients, or non-intubation in 1 patient. The lowest peripheral oxygen saturation (SpO2) in 4 patients was below 90%. Three patients were extubated in the operation room after complete recovery of spontaneous respiration. Most patients were admitted to the intensive care unit for further postoperative treatment, except 1 patient who received laryngeal mask airway management without tracheal intubation during surgery. Two patients died, 1 due to severe anastomotic leakage and the other from acute respiratory distress syndrome. In addition, another patient showed complications with oozing from the wound. CONCLUSIONS: Our clinical experience suggests that there is no single airway strategy universally suitable for all tracheal surgeries. The choice of airway management strategy is best determined by multifactorial assessment of advantages and disadvantages according to preoperative comorbidities, unique features of the obstructive mass, surgical experience, and patient preference.