Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Profibrotic role of the SOX9-MMP10-ECM biosynthesis axis in the tracheal fibrosis after injury and repair.

Fibroblast activation and extracellular matrix (ECM) deposition play an important role in the tracheal abnormal repair process and fibrosis. As a transcription factor, SOX9 is involved in fibroblast activation and ECM deposition. However, the mechanism of how SOX9 regulates fibrosis after tracheal injury remains unclear. We investigated the role of SOX9 in TGF-ß1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast (RTF) cells. SOX9 overexpression adenovirus (Ad-SOX9) and siRNA were transfected into RTF cells. We found that SOX9 expression was up-regulated in RTF cells treated with TGF-ß1. SOX9 overexpression activated fibroblasts and promoted ECM deposition. Silencing SOX9 inhibited cell proliferation, migration, and ECM deposition, induced G2 arrest, and increased apoptosis in RTF cells. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) assays identified MMP10, a matrix metalloproteinase involved in ECM deposition, as a direct target of SOX9, which promotes ECM degradation by increasing MMP10 expression through the Wnt/ß-catenin signaling pathway. Furthermore, in vivo, SOX9 knockdown ameliorated granulation proliferation and tracheal fibrosis, as manifested by reduced tracheal stenosis. In conclusion, our findings indicate that SOX9 can drive fibroblast activation, cell proliferation, and apoptosis resistance in tracheal fibrosis via the Wnt/ß-catenin signaling pathway. The SOX9-MMP10-ECM biosynthesis axis plays an important role in tracheal injury and repair. Targeting SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.

Integrative omics analysis reveals insights into small colony variants of Staphylococcus aureus induced by sulfamethoxazole-trimethoprim.

BACKGROUND: Long-term treatment with trimethoprim-sulfamethoxazole (SXT) can lead to the formation of small-colony variants (SCVs) of Staphylococcus aureus. However, the mechanism behind SCVs formation remains poorly understood. In this study, we explored the phenotype and omics-based characterization of S. aureus SCVs induced by SXT and shed light on the potential causes of SCV formation. METHODS: Stable SCVs were obtained by continuously treating S. aureus isolates using 12/238 µg/ml of SXT, characterized by growth kinetics, antibiotic susceptibility testing, and auxotrophism test. Subsequently, a pair of representative strains (SCV and its parental strain) were selected for genomic, transcriptomic and metabolomic analysis. RESULTS: Three stable S. aureus SCVs were successfully screened and proven to be homologous to their corresponding parental strains. Phenotypic tests showed that all SCVs were non-classical mechanisms associated with impaired utilization of menadione, heme and thymine, and exhibited slower growth and higher antibiotic minimum inhibitory concentrations (MICs), compared to their corresponding parental strains. Genomic data revealed 15 missense mutations in 13 genes in the representative SCV, which were involved in adhesion, intramolecular phosphate transfer on ribose, transport pathways, and phage-encoded proteins. The combination analysis of transcriptome and metabolome identified 35 overlapping pathways possible associated with the phenotype switching of S. aureus. These pathways mainly included changes in metabolism, such as purine metabolism, pyruvate metabolism, amino acid metabolism, and ABC transporters, which could play a crucial role in promoting SCVs development by affecting nucleic acid synthesis and energy metabolism in bacteria. CONCLUSION: This study provides profound insights into the causes of S. aureus SCV formation induced by SXT. The findings may offer valuable clues for developing new strategies to combat S. aureus SCV infections.

Essential role of glycoprotein Ibα in platelet activation.

ABSTRACT: Glycoprotein Ibα (GPIbα), the ligand-binding subunit of platelet GPIb-IX complex, interacts with von Willebrand factor (VWF) exposed at the injured vessel wall, initiating platelet adhesion, activation, hemostasis, and thrombus formation. The cytoplasmic tail of GPIbα interacts with 14-3-3ζ, regulating the VWF-GPIbα-elicited signal transduction and VWF binding function of GPIbα. However, we unexpectedly found that the GPIbα-14-3-3ζ association, beyond VWF-dependent function, is essential for general platelet activation. We found that the myristoylated peptide of GPIbα C-terminus MPαC, a potential GPIbα inhibitor, by itself induced platelet aggregation, integrin αIIbß3 activation, granule secretion, and phosphatidylserine (PS) exposure. Conversely, the deletion of the cytoplasmic tail of GPIbα in mouse platelets (10aa-/-) decreased platelet aggregation, integrin αIIbß3 activation, granule secretion, and PS exposure induced by various physiological agonists. Phosphoproteome-based kinase activity profiling revealed significantly upregulated protein kinase C (PKC) activity in MPαC-treated platelets. MPαC-induced platelet activation was abolished by the pan-PKC inhibitor and PKCα deletion. Decreased PKC activity was observed in both resting and agonist-stimulated 10aa-/- platelets. GPIbα regulates PKCα activity by sequestering 14-3-3ζ from PKCα. In vivo, the deletion of the GPIbα cytoplasmic tail impaired mouse hemostasis and thrombus formation and protected against platelet-dependent pulmonary thromboembolism. Therefore, our findings demonstrate an essential role for the GPIbα cytoplasmic tail in regulating platelet general activation and thrombus formation beyond the VWF-GPIbα axis.

Cone-beam computed tomography of accessory canals of the canalis sinuosus and analysis of the related risk factors.

PURPOSE: Cone-beam computed tomography (CBCT) was used in this study for evaluating the diameter, prevalence, spatial location, and risk factors of the accessory canal (AC) of the canalis sinuosus. METHODS: A comprehensive assessment of the incidence rate, diameter, three-dimensional (3D) spatial location, and direction of travel of AC was performed on 1003 CBCT images. The CBCT data were used to reconstruct a 3D model of the maxilla to determine the alveolar bone volume. The obtained data were further analyzed and processed. RESULTS: AC was present in 50.1% of images. Male patients more frequently had ACs than female patients did (P < 0.01) and was positively correlated with the maxillary alveolar bone volume (P < 0.001, OR 1.532). Age or nasopalatine canal diameter were not significantly associated with the occurrence of AC (P > 0.05). Among the 502 patients with AC, AC was present on the left side, right side, and bilaterally in 189, 98, and 215, respectively. The maximum number of ACs observed per individual was eight. The average AC diameter was 0.89 ± 0.26 mm (minimum, 0.5 mm; maximum, 2.02 mm). CONCLUSIONS: As the prevalence of AC and its trajectory display considerable variation among individuals, surgeons must consider the possibility of the presence of AC when devising surgical plans involving the anterior maxillary region.

CYP1B1 affects the integrity of the blood-brain barrier and oxidative stress in the striatum: An investigation of manganese-induced neurotoxicity.

AIMS: Excessive influx of manganese (Mn) into the brain across the blood-brain barrier induces neurodegeneration. CYP1B1 is involved in the metabolism of arachidonic acid (AA) that affects vascular homeostasis. We aimed to investigate the effect of brain CYP1B1 on Mn-induced neurotoxicity. METHOD: Brain Mn concentrations and α-synuclein accumulation were measured in wild-type and CYP1B1 knockout mice treated with MnCl2 (30 mg/kg) and biotin (0.2 g/kg) for 21 continuous days. Tight junctions and oxidative stress were analyzed in hCMEC/D3 and SH-SY5Y cells after the treatment with MnCl2 (200 µM) and CYP1B1-derived AA metabolites (HETEs and EETs). RESULTS: Mn exposure inhibited brain CYP1B1, and CYP1B1 deficiency increased brain Mn concentrations and accelerated α-synuclein deposition in the striatum. CYP1B1 deficiency disrupted the integrity of the blood-brain barrier (BBB) and increased the ratio of 3, 4-dihydroxyphenylacetic acid (DOPAC) to dopamine in the striatum. HETEs attenuated Mn-induced inhibition of tight junctions by activating PPARγ in endothelial cells. Additionally, EETs attenuated Mn-induced up-regulation of the KLF/MAO-B axis and down-regulation of NRF2 in neuronal cells. Biotin up-regulated brain CYP1B1 and reduced Mn-induced neurotoxicity in mice. CONCLUSIONS: Brain CYP1B1 plays a critical role in both cerebrovascular and dopamine homeostasis, which might serve as a novel therapeutic target for the prevention of Mn-induced neurotoxicity.

Patterns of information literacy and their predictors among emergency department nurses: a latent profile analysis based on the person-context interaction theory.

BACKGROUND: With the development of information technology, information has been an important resource in clinical medicine, particularly within the emergency department. Given its role in patient rescue, the emergency department demands a high level of information literacy from nurses to effectively collect, analyze, and apply information due to the urgency and complexity of emergency nursing work. Although prior studies have investigated the information literacy of nursing staff, little has been undertaken in examining the patterns of information literacy and their predictors among emergency department nurses. AIM: To clarify the subtypes of information literacy among nurses in the emergency department and explore the factors affecting profile membership. METHODS: A cross-sectional study was conducted among a convenience sample of 2490 nurses in the emergency department from April to June 2023. The clinical nurses completed the online self-report questionnaires including the general demographic questionnaire, information literacy scale, self-efficacy scale and social support scale. Data analyses involved the latent profile analysis, variance analysis, Chi-square tests and multivariate logistic regression. RESULTS: Four latent profiles were identified: 'Low information literacy (Class 1)', 'Moderate information knowledge (Class 2)', 'High information knowledge and support (Class 3)' and 'High information literacy (Class 4)', accounting for 20.14%, 42.11%, 23.36% and 14.39%, respectively. Each profile displayed unique characteristics representative of different information literacy patterns. Age, years of work, place of residence, hospital grade, title, professional knowledge, using databases, reading medical literature, participating in information literacy training, self-efficacy, and social support significantly predicted information literacy profile membership. CONCLUSIONS: Information literacy exhibits different classification features among emergency department nurses, and over half of the nurses surveyed were at the lower or middle level. Identifying sociodemographic and internal-external predictors of profile membership can aid in developing targeted interventions tailored to the needs of emergency department nurses. Nursing managers should actively pay attention to nurses with low information literacy and provide support to improve their information literacy level. RELEVANCE TO CLINICAL PRACTICE: Insights from the current study of the latent profile analysis are beneficial to hospital managers in understanding the different types of emergency department nurses' information literacy. These insights serve as a reference for managers to enhance nurses' information literacy levels.

The Effect of Beautification Strategies on Mating Popularity Judged by Men from the People's Republic of China.

Contemporary women frequently employ beautification strategies. The impact of such strategies, such as plastic surgery, on mating popularity in different mate contexts remains unclear. To investigate this issue, the current study conducted two experiments. In Experiment 1, beautification strategies were manipulated using three images of the same female with different conditions (natural, makeup, and plastic surgery). The results indicated that when the beautification strategies were not informed, surgical-enhanced and makeup targets were perceived as significantly more attractive, loyal, and popular among potential mates than natural targets. However, when participants were informed of the beautification strategies, both natural and makeup targets showed a significant increase in perceived loyalty and mating popularity. In contrast, surgically enhanced targets saw a reduction in these dimensions. Experiment 2 aimed to reduce the confounding effect of facial attractiveness by using vignettes. The results indicated that the mating popularity of natural targets was significantly higher than that of makeup or surgically enhanced targets, with surgically enhanced targets being the least popular. Moreover, the results revealed the mediating role of perceived loyalty in the impact of beautification strategies on long-term mating popularity. This study sheds light on the potential stigmatization and negative bias toward beautification strategies in the mating market. Additionally, it provides guidance for women who intend to enhance their mate popularity through plastic surgery.

The application of a multi-component reaction peptide as a model regenerative active to enhance skin wound-healing postlaser procedure in a double-blinded placebo-controlled clinical trial.

INTRODUCTION: Esthetic procedures are currently among the most effective options for consumers seeking to correct aging signs such as fine lines, wrinkles, and skin tone unevenness. Currently, there is a scientific need for an adjunct active to be paired with esthetic procedures to encourage wound recovery and address postprocedure pigmentation concerns. OBJECTIVE: Toward that goal, this study assessed the efficacy of a peptide created from a multi-component reaction (multi-component peptide, MCP) as a model active for postprocedure care and evaluated its ability to promote skin healing in an ablative laser-induced wound model on the forearm. METHODS: The mechanism of action of MCP was investigated using tubo assays, 2D melanocyte, and fibroblast cultures, reconstructed skin equivalents, and ex vivo skin explants. The MCP formula and the clinical benchmark formula of Aquaphor were assessed head-to-head by applying the products topically in an ablative laser-induced wound model (n = 20 subjects). The promotion of wound healing was evaluated by the investigator assessment of epithelial confluence, crusting or scabbing, general wound appearance, erythema, and edema. RESULTS: MCP was determined to be beneficial to postprocedure skin recovery and healing by four main mechanisms of action: barrier repair as determined in an ex vivo tape-stripping model, reduction of inflammation and postinflammatory hyperpigmentation, reduction of elastase activity, and stimulation of fibroblast through the mTOR pathway. The formula containing 10% MCP enhanced the kinetics of epithelial confluence and improvement of the crusting or scabbing appearance of the laser-generated wounds in a laser-induced mini-zone wound healing study on the forearm. CONCLUSION: This study demonstrates the use of MCP as a proof of concept regenerative active that when incorporated into an optimized postprocedure skincare formula can improve skin healing and enhance the appearance of skin after injury with relevance to ablative aesthetic procedures.

Recombinant Slit2 attenuates tracheal fibroblast activation in benign central airway obstruction by inhibiting the TGF-ß1/Smad3 signaling pathway.

Airway fibrosis is among the pathological manifestations of benign central airway obstruction noted in the absence of effective treatments and requires new drug targets to be developed. Slit guidance ligand 2-roundabout guidance receptor 1 (Slit2-Robo1) is involved in fibrosis and organ development. However, its significance in airway fibrosis has not yet been reported. The study explored how the recombinant protein Slit2 functions in transforming growth factor-ß1 (TGF-ß1)-mediated airway fibrosis in vivo and in vitro. In this study, Slit2 expression initially increased in the tracheal granulation tissues of patients with tracheobronchial stenosis but decreased in the fibrotic tissue. In primary rat tracheal fibroblasts (RTFs), recombinant Slit2 inhibited the expression of extracellular matrices such as Timp1, α-SMA, and COL1A2, whereas recombinant TGF-ß1 promoted the expression of Robo1, α-SMA, and COL1A2. Slit2 and TGF-ß1 played a mutual inhibitory role in RTFs. Slit2 supplementation and Robo1 downregulation inhibited excessive extracellular matrix (ECM) deposition induced by TGF-ß1 in RTFs via the TGF-ß1/Smad3 pathway. Ultimately, exogenous Slit2 and Robo1 knockdown-mediated attenuation of airway fibrosis were validated in a trauma-induced rat airway obstruction model. These findings demonstrate that recombinant Slit2 alleviated pathologic tracheobronchial healing by attenuating excessive ECM deposition. Slit2-Robo1 is an attractive target for further exploring the mechanisms and treatment of benign central airway obstruction.

Exosomes in lung cancer metastasis, diagnosis, and immunologically relevant advances.

Lung cancer is a chronic wasting disease with insidious onset and long treatment cycle. Exosomes are specialized extracellular vesicles, at first exosomes were considered as a transporter of cellular metabolic wastes, but recently many studies have identified exosomes which contain a variety of biologically active substances that play a role in the regulation of cellular communication and physiological functions. Exosomes play an important role in the development of lung cancer and can promote metastasis through a variety of mechanisms. However, at the same time, researchers have also discovered that immune cells can also inhibit lung cancer through exosomes. In addition, researchers have discovered that some specific miRNAs in exosomes can be used as markers for early diagnosis of lung cancer. Engineering exosomes may be one of the strategies to enhance the clinical translational application of exosomes in the future, for example, strategies such as modifying exosomes to enhance targeting or utilizing exosomes as carriers for drug delivery have been explored. but more studies are needed to verify the safety and efficacy. This article reviews the latest research on exosomes in the field of lung cancer, from the mechanism of lung cancer development, the functions of immune cell-derived exosomes and tumor-derived exosomes, to the early diagnosis of lung cancer.

Novel Effective Photocatalytic Self-Cleaning Coatings: TiO2-Polyfluoroalkoxy Coatings Prepared by Suspension Plasma Spraying.

Photocatalytic coatings can degrade volatile organic compounds into non-toxic products, which has drawn the attention of scholars around the world. However, the pollution of dust on the coating adversely affects the photocatalytic efficiency and service life of the coating. Here, a series of TiO2-polyfluoroalkoxy (PFA) coatings with different contents of PFA were fabricated by suspension plasma spraying technology. The results demonstrate that the hybrid coatings contain a large number of circular and ellipsoidal nanoparticles and a porous micron-nano structure due to the inclusion of PFA. According to the optimized thermal spraying process parameters, TiO2 nanoparticles were partially melted to retain most of the anatase phases, whereas PFA did not undergo significant carbonization. As compared to the TiO2 coating, the static contact angle of the composite coating doped with 25 wt.% PFA increased from 28.2° to 134.1°. In addition, PFA strongly adsorbs methylene blue, resulting in a greater involvement of methylene blue molecules in the catalyst, where the catalytic rate of hybrid coatings is up to 95%. The presented nanocomposite coatings possess excellent photocatalytic and self-cleaning properties and are expected to find wider practical applications in the field of photocatalysis.

Relationship of sleep-quality and social-anxiety in patients with breast cancer: a network analysis.

BACKGROUND: There is a complex relationship between social anxiety and sleep quality. However, network analysis studies of associations between social anxiety and sleep quality are lacking, particularly among patients with breast cancer. The current study aimed to extend this research to a sample of patients with breast cancer and to examine symptom-level associations between social anxiety and sleep quality using network analysis. METHODS: Network analysis was conducted to explore their associations and identify bridge items of social anxiety and sleep quality. RESULTS: The network structure revealed 9 important edges between social anxiety and sleep quality. "Subjective sleep quality" had the highest EI value in the network. "Working difficulty under watching" and "Sleep disorders" had the highest BEI values in their own communities. CONCLUSION: There are complex pathological correlation pathways between social anxiety and sleep quality in breast cancer patients. "Subjective sleep quality", "Working difficulty under watching" and "Sleep disorders" have the potential to be intervention targets for sleep disorder-social anxiety comorbidity. Medical staff can take corresponding interventions according to the the centrality indices and bridge centrality indicators identified in this study, which is likely to effectively reduce the comorbidity of sleep disorders and social anxiety.

The efficacy of dexmedetomidine for septic shock: A meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of dexmedetomidine was elusive for septic shock. This meta-analysis aimed to explore the efficacy of dexmedetomidine for septic shock. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases have been searched through October 2022 and we included randomized controlled trials reporting the effect of dexmedetomidine in patients with septic shock. RESULTS: Five randomized controlled trials were included in the meta-analysis. Compared with control group for septic shock, dexmedetomidine treatment was able to substantially decrease Sequential Organ Failure Assessment score (mean difference [MD] = -0.99; 95% confidence interval [CI] = -1.14 to -0.84; P < .00001) and duration of mechanical ventilation (MD = -0.90; 95% CI = -1.27 to -0.54; P < .00001), but showed no obvious influence on morality at 28 days (odds ratio = 0.79; 95% CI = 0.38 to 1.66; P = 054), hospital mortality (odds ratio = 0.66; 95% CI = 0.35 to 1.24; P = .20) or intensive care unit length of stay (MD = -1.47; 95% CI = -4.60 to 1.66; P = .36). CONCLUSIONS: Dexmedetomidine administration may help treat patients with septic shock.

Impact of type 2 diabetes on surgical site infections and prognosis post orthopaedic surgery: A systematic review and meta-analysis.

BACKGROUND: The escalating prevalence of type 2 diabetes raises concerns about adverse postoperative outcomes like surgical site infections (SSIs) and deep vein thrombosis (DVT) in orthopaedic surgeries. This meta-analysis aims to resolve inconclusive evidence by systematically quantifying the risks in type 2 diabetic patients compared to non-diabetic individuals. METHODS: The meta-analysis was conducted adhering to the PRISMA guidelines and based on the PICO framework. Four primary databases were searched: PubMed, Embase, Web of Science and the Cochrane Library, with no temporal restrictions. Studies included were either prospective or retrospective cohort studies published in English or Chinese, which assessed orthopaedic surgical outcomes among adult type 2 diabetic and non-diabetic patients. The meta-analysis employed the Newcastle-Ottawa Scale for quality assessment and used both fixed-effect and random-effects models for statistical analysis based on the level of heterogeneity. RESULTS: Out of 951 identified articles, nine studies met the inclusion criteria. The odds ratio (OR) for developing postoperative SSIs among diabetic patients was 1.63 (95% CI: 1.19-2.22), indicating a significantly elevated risk compared to non-diabetic subjects. Conversely, no statistically significant difference in the risk of postoperative DVT was found between the two groups (OR: 0.82; 95% CI: 0.55-1.22). Sensitivity analysis confirmed the stability of these outcomes. CONCLUSIONS: Patients with type 2 diabetes are at a higher risk of developing SSIs post orthopaedic surgery compared to non-diabetic individuals. However, both groups demonstrated comparable risks for developing postoperative DVT.

Phenotypic Variation Analysis and Excellent Clone Selection of Alnus cremastogyne from Different Provenances.

Alnus cremastogyne is a rapidly growing broad-leaved tree species that is widely distributed in southwest China. It has a significant economic and ecological value. However, with the expansion of the planting area, the influence of phenotypic variation and differentiation on Alnus cremastogyne has increased, resulting in a continuous decline in its genetic quality. Therefore, it is crucial to investigate the phenotypic variation of Alnus cremastogyne and select excellent breeding materials for genetic improvement. Herein, four growth-related phenotypic traits (diameter at breast height, the height of trees, volume, height under the branches) and twelve reproductive-related phenotypic traits (fresh weight of single cone, dry weight of single cone, seed weight per plant, thousand kernel weight, cone length, cone width, cone length × cone width, fruit shape index, seed rate, germination rate, germination potential, germination index) of 40 clones from four provenances were measured and analyzed. The phenotypic variation was comprehensively evaluated by correlation analysis, principal component analysis and cluster analysis, and excellent clones were selected as breeding materials. The results revealed that there were abundant phenotypic traits variations among and within provenances. Most of the phenotypic traits were highly significant differences (p < 0.01) among provenances. The phenotypic variation among provenances (26.36%) was greater than that of within provenances clones (24.80%). The average phenotypic differentiation coefficient was accounted for 52.61% among provenances, indicating that the phenotypic variation mainly came from among provenances. The coefficient of variation ranged from 9.41% (fruit shape index) to 97.19% (seed weight per plant), and the repeatability ranged from 0.36 (volume) to 0.77 (cone width). Correlation analysis revealed a significantly positive correlation among most phenotypic traits. In principal component analysis, the cumulative contribution rate of the first three principal components was 79.18%, representing the main information on the measured phenotypic traits. The cluster analysis revealed four groups for the 40 clones. Group I and group II exhibited better performance phenotypic traits as compared with group III and group IV. In addition, the four groups are not clearly clustered following the distance from the provenance. Employing the multi-trait comprehensive evaluation method, 12 excellent clones were selected, and the average genetic gain for each phenotypic trait ranged from 4.78% (diameter at breast height) to 32.05% (dry weight of single cone). These selected excellent clones can serve as candidate materials for the improvement and transformation of Alnus cremastogyne seed orchards. In addition, this study can also provide a theoretical foundation for the genetic improvement, breeding, and clone selection of Alnus cremastogyne.

S100 Calcium-Binding Protein A8 Functions as a Tumor-Promoting Factor in Renal Cell Carcinoma via Activating NF-κB Signaling Pathway.

BACKGROUND: Renal cell carcinoma (RCC), arising from the renal tubular epithelium, is one of the most common types of genitourinary malignancies. Based on the Gene Expression Omnibus (GEO) database (GSE100666), S100 calcium-binding protein A8 (S100A8) was highly expressed in RCC tissues. S100A8, an inflammatory regulatory factor, has emerged as an important mediator associated with the occurrence and development of cancer. MATERIALS AND METHODS: The Gene Expression Omnibus (GEO) database was used to identify the key genes and investigate the main signaling pathways in RCC. Human RCC samples and corresponding adjacent normal tissues were collected in our hospital. The expression of S100A8 in human RCC samples was detected using western blotting and immunohistochemical analysis. S100A8 overexpression or knockdown was mediated by using Lipofectamine 3000 in human renal cell carcinoma cell line 786-O and ACHN cells. Basic experiments, including MTT and cell apoptosis assays, were utilized for investigating the function of S100A8 in RCC. Furthermore, the levels of inflammation were also evaluated in 786-O and ACHN cells. RESULTS: In the current study, we found that downregulation of S100A8 inhibited proliferation and promoted apoptosis in 786-O and ACHN RCC cells. Of note, S100A8 silencing downregulated the phosphorylation of NF-κB p65, thereby decreasing the levels of TNF-α, cleaved caspase1, and MMP9. By contrast, S100A8 upregulation could increase these expressions. CONCLUSION: Overall, S100A8 knockdown restrained RCC malignant biological properties, which was associated with the deactivation of the NF-κB signaling pathway. This present study demonstrates new insights that S100A8 may be a potential therapeutic target in RCC.

GATA6 promotes fibrotic repair of tracheal injury through NLRP3 inflammasome-mediated epithelial pyroptosis.

Tracheal injury is a challenging emergency condition that is characterized by the abnormal repair of the trachea. GATA6, a well-established transcription factor, plays a crucial role in tissue injury and epithelial regenerative repair. This study aims to evaluate the role of GATA6 in NF-κB-mediated NLRP3 inflammasome activation and pyroptosis after tracheal injury. Tracheal tissues and serum samples were collected from clinical patients and a rat model of tracheal injury. Upon GATA6 knockdown or overexpression, BEAS-2B and rat tracheal epithelial (RTE) cells were treated with lipopolysaccharides and nigericin before being co-cultured with primary tracheal fibroblasts. The changes of NLRP3 inflammasome activation and pyroptosis and their underlying mechanisms were detected. Additionally, the role of GATA6 downregulation in tracheal injury was verified in rats. GATA6 expression and NLRP3 inflammasome activation were upregulated following tracheal injury in the epithelium of granulation tissues. GATA6 silencing inhibited NLRP3 priming, NLRP3 inflammasome activation, and pyroptosis in BEAS-2B and RTE cells. Mechanistically, GATA6 was determined to have bound to the promoter region of NLRP3 and synergistically upregulated NLRP3 promoter activity with NF-κB. Furthermore, GATA6 overexpression promoted epithelial-mesenchymal transition via modulating the NF-κB/NLRP3 pathway. Epithelial NLRP3 inflammasome activation triggered ECM production in fibroblasts, which was suppressed by GATA6 knockdown and induced by GATA6 overexpression. Finally, the downregulation of GATA6 alleviated NLRP3 inflammasome-mediated pyroptosis induced by tracheal injury in rats, thereby reducing tracheal stenosis, inflammation, and fibrosis. GATA6 promotes fibrotic repair in tracheal injury through NLRP3 inflammasome-mediated epithelial pyroptosis, making it a potential biological therapeutic target for tracheal injury.

Characteristics of enzymolysis of silkworm pupa protein after tri-frequency ultrasonic pretreatment: kinetics, thermodynamics, structure and antioxidant changes.

As a by-product of the sericulture industry, the utilization rate of silkworm pupa resources is currently not high. Proteins are converted into bioactive peptides through enzymatic hydrolysis. Not only can it solve the utilization problem, but it also creates more valuable nutritional additives. Silkworm pupa protein (SPP) was pretreated with tri-frequency ultrasonic (22/28/40 kHz). Effects of ultrasonic pretreatment on enzymolysis kinetics, enzymolysis thermodynamics, hydrolysate structure as well as hydrolysate antioxidant of SPP were investigated. Ultrasonic pretreatment significantly increased the hydrolysis efficiency, showing a 6.369% decrease in k m and a 16.746% increase in k A after ultrasonic action (p < 0.05). The SPP enzymolysis reaction followed a second-order rate kinetics model. Evaluation of enzymolysis thermodynamics revealed that Ultrasonic pretreatment markedly enhanced the SPP enzymolysis, leading to a 21.943% decrease in E a. Besides, Ultrasonic pretreatment significantly increased SPP hydrolysate's surface hydrophobicity, thermal stability, crystallinity, and antioxidant activities (DPPH radical scavenging activity, Fe2+ chelation ability, and reducing power). This study indicated that tri-frequency ultrasonic pretreatment could be an efficient approach to enhancing the enzymolysis and improving the functional properties of SPP. Therefore, tri-frequency ultrasound technology can be applied industrially to enhance enzyme reaction process.