GSDMD mediated pyroptosis induced inflammation of Graves' orbitopathy via the NF-κB/ AIM2/ Caspase-1 pathway.

Gasdermin D (GSDMD) is a key executor which triggers pyroptosis as well as an attractive checkpoint in various inflammatory and autoimmune diseases but it has yet to prove its function in Graves'orbitopathy (GO). Our aim was to investigate GSDMD levels in orbital connective tissue and serum of GO patients and then assess the association between serum levels and patients' clinical activity score (CAS). Further, GSDMD-mediated pyroptosis and the underlying mechanism in inflammatory pathogenesis in the cultured orbital fibroblasts (OFs) of GO patients were examined. OFs were collected after tumor necrosis factor (TNF)-α or interferon (IFN)-γ treatment or combination treatment at different times, and the expression of GSDMD and related molecular mechanisms were analyzed. Then, we constructed the GSDMD knockout system with siRNA and the system was further exposed to the medium with or without IFN-γ and TNF-α for a specified time. Finally, we evaluated the production of interleukin (IL)-1ß and IL-18. We found that serum GSDMD levels were elevated and positively correlated with the CAS in GO patients. Meanwhile, the expression of GSDMD and N-terminal domain (NT-GSDMD) in orbital connective tissue of GO patients was augmented. Also, increased expression of GSDMD and related pyroptosis factors was observed in vitro model of GO. We further demonstrated that GSDMD-mediated pyroptosis induced inflammation via the nuclear factor kB (NF-κB)/absent in melanoma-2 (AIM-2)/caspase-1 pathway. In addition, blocking GSDMD suppressed proinflammatory cytokine production in GO. We concluded that GSDMD may be a biomarker as well as a potential target for the evaluation and treatment of inflammation related with GO.

Computer-Aided Diagnosis of Laryngeal Cancer Based on Deep Learning with Laryngoscopic Images.

Laryngeal cancer poses a significant global health burden, with late-stage diagnoses contributing to reduced survival rates. This study explores the application of deep convolutional neural networks (DCNNs), specifically the Densenet201 architecture, in the computer-aided diagnosis of laryngeal cancer using laryngoscopic images. Our dataset comprised images from two medical centers, including benign and malignant cases, and was divided into training, internal validation, and external validation groups. We compared the performance of Densenet201 with other commonly used DCNN models and clinical assessments by experienced clinicians. Densenet201 exhibited outstanding performance, with an accuracy of 98.5% in the training cohort, 92.0% in the internal validation cohort, and 86.3% in the external validation cohort. The area under the curve (AUC) values consistently exceeded 92%, signifying robust discriminatory ability. Remarkably, Densenet201 achieved high sensitivity (98.9%) and specificity (98.2%) in the training cohort, ensuring accurate detection of both positive and negative cases. In contrast, other DCNN models displayed varying degrees of performance degradation in the external validation cohort, indicating the superiority of Densenet201. Moreover, Densenet201's performance was comparable to that of an experienced clinician (Clinician A) and outperformed another clinician (Clinician B), particularly in the external validation cohort. Statistical analysis, including the DeLong test, confirmed the significance of these performance differences. Our study demonstrates that Densenet201 is a highly accurate and reliable tool for the computer-aided diagnosis of laryngeal cancer based on laryngoscopic images. The findings underscore the potential of deep learning as a complementary tool for clinicians and the importance of incorporating advanced technology in improving diagnostic accuracy and patient care in laryngeal cancer diagnosis. Future work will involve expanding the dataset and further optimizing the deep learning model.

B lymphocytes transdifferentiate into immunosuppressive erythroblast-like cells.

Recent studies have demonstrated that a particular group of nucleated cells that exhibit erythroid markers (TER119 in mice and CD235a in humans) possess the ability to suppress the immune system and promote tumor growth. These cells are known as CD45+ erythroid progenitor cells (EPCs). According to our study, it appears that a subset of these CD45+ EPCs originate from B lymphocytes. Under conditions of hypoxia, mouse B lymphoma cells are capable of converting to erythroblast-like cells, which display phenotypes of CD45+TER119+ cells, including immunosuppressive effects on CD8 T cells. Furthermore, non-neoplastic B cells have similar differentiation abilities and exert the same immunosuppressive effect under anemia or tumor conditions in mice. Similar B cells exist in neonatal mice, which provides an explanation for the potential origin of immunosuppressive erythroid cells in newborns. Additionally, CD19+CD235a+ double-positive cells can be identified in the peripheral blood of patients with chronic lymphocytic leukemia. These findings indicate that some CD45+ EPCs are transdifferentiated from a selective population of CD19+ B lymphocytes in response to environmental stresses, highlighting the plasticity of B lymphocytes. We anticipate a potential therapeutic implication, in that targeting a specific set of B cells instead of erythroid cells should be expected to restore adaptive immunity and delay cancer progression.

Plant commensal type VII secretion system causes iron leakage from roots to promote colonization.

Competition for iron is an important factor for microbial niche establishment in the rhizosphere. Pathogenic and beneficial symbiotic bacteria use various secretion systems to interact with their hosts and acquire limited resources from the environment. Bacillus spp. are important plant commensals that encode a type VII secretion system (T7SS). However, the function of this secretion system in rhizobacteria-plant interactions is unclear. Here we use the beneficial rhizobacterium Bacillus velezensis SQR9 to show that the T7SS and the major secreted protein YukE are critical for root colonization. In planta experiments and liposome-based experiments demonstrate that secreted YukE inserts into the plant plasma membrane and causes root iron leakage in the early stage of inoculation. The increased availability of iron promotes root colonization by SQR9. Overall, our work reveals a previously undescribed role of the T7SS in a beneficial rhizobacterium to promote colonization and thus plant-microbe interactions.

m6A mRNA modification promotes chilling tolerance and modulates gene translation efficiency in Arabidopsis.

N 6-methyladenosine (m6A), the most prevalent mRNA modification in eukaryotes, is an emerging player of gene regulation at transcriptional and translational levels. Here, we explored the role of m6A modification in response to low temperature in Arabidopsis (Arabidopsis thaliana). Knocking down mRNA adenosine methylase A (MTA), a key component of the modification complex, by RNA interference (RNAi) led to drastically reduced growth at low temperature, indicating a critical role of m6A modification in the chilling response. Cold treatment reduced the overall m6A modification level of mRNAs especially at the 3' untranslated region. Joint analysis of the m6A methylome, transcriptome and translatome of the wild type (WT) and the MTA RNAi line revealed that m6A-containing mRNAs generally had higher abundance and translation efficiency than non-m6A-containing mRNAs under normal and low temperatures. In addition, reduction of m6A modification by MTA RNAi only moderately altered the gene expression response to low temperature but led to dysregulation of translation efficiencies of one third of the genes of the genome in response to cold. We tested the function of the m6A-modified cold-responsive gene ACYL-COA:DIACYLGLYCEROL ACYLTRANSFERASE 1 (DGAT1) whose translation efficiency but not transcript level was reduced in the chilling-susceptible MTA RNAi plant. The dgat1 loss-of-function mutant exhibited reduced growth under cold stress. These results reveal a critical role of m6A modification in regulating growth under low temperature and suggest an involvement of translational control in chilling responses in Arabidopsis.

Elevated serum uric acid level is associated with adverse reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles: a retrospective cohort study.

BACKGROUND: Serum uric acid levels are elevated in polycystic ovary syndrome, however, the relationship between serum uric acid level and reproductive outcomes in women with polycystic ovary syndrome remains unclear. OBJECTIVE: This study aimed to investigate the association between serum uric acid level and the reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles. STUDY DESIGN: This was a retrospective cohort study performed at a university-affiliated reproductive medicine center. A total of 1903 women with polycystic ovary syndrome undergoing their first in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles between January 2010 and January 2021 were initially included. The trends for reproductive outcomes in polycystic ovary syndrome across quartiles of serum uric acid levels were assessed. A logistic regression analysis was performed to obtain the odds ratios for in vitro fertilization outcomes based on the quartiles of serum uric acid with or without adjusting for potential confounding variables. Using generalized additive models, serum uric acid was further treated as its original continuous property to visualize its nonlinear relationship with in vitro fertilization outcomes. The live birth rate was the main outcome. RESULTS: After exclusions, a total of 883 women with polycystic ovary syndrome with their first fresh-embryo transfer cycles were included. In quartiles of serum uric acid levels, there was a significant decreasing trend in the live birth rate from the lowest quartile (Q1: 61.8%) to the highest (Q4: 45.9%) (Ptrend=.002). The percentage of low birthweight increased from Q1 (22.3%) to Q4 (31.7%) (Ptrend=.049). Compared with those in Q1, women in Q4 showed a significant lower probability of live birth and clinical pregnancy and a higher risk for low birthweight (all P<.05). Both the unadjusted and adjusted generalized additive models indicated that as the serum uric acid level increased, the probability of clinical pregnancy and the live birth rate exhibited an overall decreasing profile, and the risk for low birthweight showed an increasing profile. CONCLUSION: An elevated serum uric acid level is associated with decreased probabilities of live birth and clinical pregnancy and an increased risk for low birthweight in women with polycystic ovary syndrome. However, these associations may be confounded by other factors and more well-designed studies are needed to confirm these findings in the future.

Molecular mechanism of di-n-butyl phthalate promotion of bladder cancer development.

PURPOSE: To determine whether di-n-butyl phthalate (DBP) promotes the occurrence of bladder cancer (BCa) and explore the action of DBP acts on BCa cells at the cellular and molecular levels. METHODS: MTT and Transwell assays were used to investigate the tumorigenic actions of DBP on BCa cells. Second-generation sequencing was used to identify differences in gene expression before and after DBP treatment. Differential gene expression was verified by q-PCR and analyzed using bioinformatics. Cells were transfected to overexpress genes of interest and proliferation and migration were measured using MTT and Transwell assays, respectively. RESULTS: DBP treatment stimulated both proliferation and invasion in BCa cells. Second-generation sequencing identified differences in the expression of FOSB, JUND, ATP6V1C2, and RHOQ before and after DBP treatment. FOSB expression was confirmed by q-PCR and bioinformatic analyses. FOSB overexpression increased both proliferation and invasion in BCa cells. CONCLUSION: DBP promoted BCa tumorigenesis by inducing changes in gene expression.

Metformin Attenuates Inflammation and Fibrosis in Thyroid-Associated Ophthalmopathy.

The pathogenesis of thyroid-associated ophthalmopathy (TAO) is still unclear, and therapeutic drugs have great limitations. As metformin has multiple therapeutic effects in many autoimmune diseases, we explored the effects of metformin on TAO in an in vitro fibroblast model. We used orbital connective tissues and fibroblasts that were obtained from TAO patients and normal controls. The activity of adenosine monophosphate-activated protein kinase (AMPK) and the levels of inflammatory or fibrotic factors were examined by immunofluorescence (IF) and immunohistochemistry (IHC). Quantitative real-time polymerase chain reaction (qPCR), cytokine quantification by enzyme-linked immunosorbent sssay (ELISA), IF, and western blotting (WB) were used to measure the expression of factors related to inflammation, fibrosis, and autophagy. To determine the anti-inflammatory and antifibrotic mechanisms of metformin, we pretreated cells with metformin, 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR, an AMPK activator) or compound C (CC, an AMPK inhibitor) for 24 h and used WB to verify the changes in protein levels in the AMPK/mammalian target of rapamycin (mTOR) pathway. We determined that the low activity of AMPK in the periorbital tissue of TAO patients may be closely related to the occurrence and development of inflammation and fibrosis, and metformin exerts multiple effects by activating AMPK in TAO. Furthermore, we suggest that AMPK may be a potential target of TAO therapy.

A Multi-Center, Randomized, Blind, Controlled Clinical Trial of the Safety and Efficacy of Micro Radio Frequency Therapy System for the Treatment of Overactive Bladder.

Purpose: The purpose of this study was to evaluate the efficacy and safety of low power micro radiofrequency (RF) therapy (µRFthera®) through urethra in the treatment of overactive bladders (OAB) through a prospective, single-blind, placebo-controlled, multi-center clinical protocol. Materials and Methods: One hundred and fourteen patients with refractory OAB were randomized at 2:1 ratio, treatment to control undergoing same procedures except only the micro-RF treatment group at turned "on" setting in energy. Bladder diaries recorded during the screening period (3 days before enrollment) and during follow-up period on week 1, 3, and 7, respectively. The patients in control could choose receiving an energized treatment during extension stage. Results: The treatment efficacy was 76.1%. There was 49.80% rate improvement compared to control (95%CL 32.48%, 67.13%). The crude rate ration (RR) was 2.89, 95% CI (1.67-5.01) with p < 0.001 in uni-variate analysis, while the RR became 2.94, 95% CI (1.67-5.16) with p < 0.001 after adjusted potential confounding factors in multi-variate analysis. Statistically significant improvements have been demonstrated in the frequency of urination, urgency, nocturia, and quality of life (QoL) scores. Conclusions: Micro RF therapy is safe and effective for the treatment of OAB. The main treatment-related complications were catheterization related complications. Clinical Trial Registration: Zhejiang Device Registration Certificate No. 202090909, www.chictr.org.cn, Clinical Trial Accession Number: ChiCTR2100050096.

Reference interval for urinary neutrophil gelatinase-associated lipocalin in healthy adults in Jiangsu region in Eastern China: a multicenter study.

Aim: We explored the concentrations of urinary neutrophil gelatinase-associated lipocalin (NGAL) in healthy adults in the Jiangsu region in Eastern China and established a reference interval using latex-enhanced immunoturbidimetry to provide important guidelines for the interpretation and application of urinary NGAL in clinical practice. Methods: In total, 1970 eligible subjects from four regions were included in this study. The urinary NGAL levels were measured using an AU5800 automatic biochemical analyzer with its matched reagents. The urinary NGAL reference interval was established using the one-sided percentile method (95th percentile). Results: The urinary NGAL data were non-normally distributed. The urinary NGAL levels were not significantly different by sex or age. Therefore, the urinary NGAL reference interval in healthy adults in the Jiangsu region in Eastern China was <87.5 ng/ml (95th percentile of the upper limit). Conclusion: Urinary NGAL reference interval will play an important role in promoting the clinical value of urinary NGAL.

A Novel Standardized Method of Renal Biopsy in Mice.

INTRODUCTION: In animal models, it can be difficult to confirm therapeutic effects due to technical inconsistencies and other reasons. Although renal biopsy is widely used in clinical diagnosis, it is rarely used in animal experimental models, especially in mice, because the problems of surgery-induced renal injury and bleeding have not been solved. METHODS: We developed an easy-to-use method of renal biopsy in mice and evaluated whether 3 consecutive renal biopsies can be performed in the same kidney in a standardized manner. This method was verified using 2 mouse models, a healthy mouse model and a unilateral ureteral obstruction (UUO) mouse model, and evaluated based on renal function and histological changes. RESULTS: There were no perioperative complications in any of the model mice. There was no significant difference in serum Cr, 24-h urine protein, or kidney/body weight ratio between the biopsy and control groups. Each biopsy sample contained sufficient renal tissue. The damage to the operated tissue was limited to the tissue near the biopsy site. Compared with renal tissues in the corresponding control group, the renal tissues obtained from the 3 biopsies (healthy model days 0, 4, and 7 and UUO model days 3, 7, and 10) and the remnant renal tissues after the biopsy showed no significant difference in the glomerular sclerosis index, degree of renal tubular damage, inflammatory response and renal fibrosis in these 2 models. CONCLUSIONS: Our new standardized method of renal biopsy in mice is a safe and cost-saving approach that allows repeated renal biopsies and ensures minimal trauma and sufficient sample size to quality in experimental disease models.

The characteristics and risk factors of healthcare-seeking men with lower urinary tract symptoms in China: Initial report from the POInT group.

AIMS: To investigate the clinical characteristics of health care-seeking men presenting with lower urinary tract symptoms (LUTS) in China and to reveal risk factors for symptom severity. METHODS: This multicenter, hospital-based, cross-sectional study recruited 1477 eligible male subjects, who were at least 45 years, seeking health care at 9 participating hospitals across the mainland China. The general medical information and subjective symptoms were recorded, followed by the measurement of prostate volume, urodynamic indices, and laboratory tests for kidney function, plus glucose/lipid metabolism. Univariate and multivariate linear regression were employed for the detection of risk factors for symptom severity. RESULTS: The proportion of mild, moderate, and severe LUTS was 14.6%, 32.6%, and 52.8%, respectively, with 62.2% reporting the triple combination of storage, voiding, and postmicturition symptoms. Median prostate volume was 44.6 ml, and 71.1% were experiencing comorbidities. Thirteen independent risk factors for LUTS severity were identified, namely, nocturnal voiding episodes and the presence of straining and weak steam; the triple combination of symptom subtypes; general and nocturia quality of life; Qmax and bladder outlet obstruction index; and numbers of comorbidities, hypertension, estimated glomerular filtration rate, and cholesterol and glycosylated hemoglobin. CONCLUSIONS: The majority of health care-seeking LUTS men present with moderate-to-severe and overlapping symptoms, with a high prevalence of both lower urinary tract dysfunction and systemic comorbidities. The evidence from both urological and nonurological independent risk factors demonstrate the multifactorial nature of LUTS, for which a multidisciplinary management is essential.

Porphyrin Iron-Grafted Mesoporous Silica Composites for Drug Delivery, Dye Degradation and Colorimetric Detection of Hydrogen Peroxide.

Porphyrin iron molecules (hemin) were successfully grafted on the channeled mesoporous silica of SBA-15 (FeIX-SBA-15), in which attached hemin molecules acted as the enzyme mimic for catalyzing oxidation reactions. In the presence of H2O2, the prepared FeIX-SBA-15 composite effectively degraded industrial dye Orange II and catalyzed tetramethylbenzidine hydrochloride (TMB) both in the solution and on the membrane, from which the colorimetric H2O2 detection was achieved. Moreover, the hemin-grafted composites showed high loading content of anticancer drug of doxorubicin hydrochloride (DOX) displaying the sustained releasing behavior as monitored by real-time cell analysis, which resulted in improved inhibitory effect on cancer cells growth compared with that DOX/SBA-15. The hemin-modified mesoporous silica nanocomposite provides an integrated nanoplatform with promising biomedical applications.

Silencing circSLC19A1 Inhibits Prostate Cancer Cell Proliferation, Migration and Invasion Through Regulating miR-326/MAPK1 Axis.

BACKGROUND: Emerging evidence indicates that circular RNAs (circRNAs), which form as covalently closed loops, play a regulatory role in various types of cancer, including prostate cancer (PCa). CircSLC19A1, one kind of circRNA, was subjected to the study and its role in PCa was explored. METHODS: Expressions of circSLC19A1, miR-326 and MAPK1 in PCa tissues and cells were assessed by qRT-PCR. CircSLC19A1 was identified by RNase R treatment. The binding relations between circSLC19A1 and miR-326 and between miR-326 and MAPK1 were predicted by RegRNA2.0 or Targetscan7.2 and further confirmed by dual-luciferase reporter assay. Pearson correlation analysis of the correlation among circSLC19A1, miR-326 and MAPK1 was performed. CCK-8, cell colony formation, wound healing and Transwell assays were used to assess PCa cell viability, proliferation, migration and invasion, respectively. RESULTS: CircSLC19A1 expression was up-regulated in PCa tissue and cell cytoplasm. Silencing circSLC19A1 inhibited PCa cell viability, proliferation, migration, invasion and miR-326 expression. MiR-326 inhibitor promoted the luciferase activities of circSLC19A1 and MAPK1, increased MAPK1 expression and facilitated PCa cell progression. MiR-326 expression was down-regulated in PCa tissue and there was a negative correlation between miR-326 and circSLC19A1 expressions. MAPK1 expression was up-regulated in PCa tissue. There was a negative correlation between MAPK1 and miR-326 expressions as well as a positive correlation between MAPK1 and circSLC19A1 expressions. Silencing MAPK1 promoted the viability, proliferation, migration, and invasion of PCa cells co-transfected with siRNA-circSLC19A1a and miR-326 inhibitor. CONCLUSION: CircSLC19A1 silencing inhibited PCa cell proliferation, migration and invasion through regulating miR-326/MAPK1 axis.

Influence of patient sex on the effectiveness of sacral neuromodulation: A cohort study from China.

BACKGROUND: Sacral neuromodulation (SNM) has been widely used to treat lower urinary tract dysfunction. Studies have shown a higher conversion rate among female patients than among male patients. However, the influence of gender on the clinical effectiveness of SNM remains unclear. We aimed to confirm whether patients of both genders show similar benefits after SNM treatment. MATERIALS AND METHODS: Clinical data of patients with lower urinary tract symptoms associated with pelvic floor dysfunction (overactive bladder, neurogenic bladder, interstitial cystitis/painful bladder syndrome, idiopathic urinary retention) treated with SNM in 10 medical centres in China between January 2012 and December 2016 were retrospectively collected. The patients were classified by gender. Variations in objective (voiding diary) and subjective scores in the baseline, testing, and last follow-up periods were compared. Data were analysed using statistical measures. RESULTS: The study included 203 patients (93 males, 110 females). There were no statistical differences in baseline information between the two groups, both groups showed improvement over time. Unsatisfactory improvement was observed in the quality of life and sexual life scores of both groups over the entire treatment period (all p＞0.05). Although there was a difference in the maximum voiding volume between the groups at baseline, no difference was observed at the last follow-up (p = 0.004, p = 0.044, p = 0.124), unlike in the average volume where a difference was noted at the last follow-up (p = 0.085, p = 0.964, p = 0.031). While there were no differences in quality of life, sexual life, or pelvic pain and urinary urgency frequency scores at baseline, a significant difference was observed at the last follow-up, and the degree of improvement was less among female patients (p = 0.836, p = 0.131, p = 0.015; p = 0.294, p = 0.265, p = 0.013; p = 0.299, p = 0.087, p = 0.015). CONCLUSION: SNM treatment elicited a similar effect on patients of both gender; however, a significant difference was observed regarding patient satisfaction with the treatment. Further preoperative patient education, especially, for female patients with interstitial cystitis/painful bladder syndrome may improve patient satisfaction.

MiR-338-3p inhibits cell migration and invasion in human hypopharyngeal cancer via downregulation of ADAM17.

Studies have confirmed that microRNAs play important roles in the development and progression of cancer. Therefore, to identify the differentially expressed microRNAs between the cancer and the normal tissues, microRNAs will provide new clues for exploring the molecular mechanisms of cancer development and potential targeted therapies. In the present study, we found that miR-338-3p was downregulated in hypopharyngeal carcinoma and inversely correlated with the pathological grade. When the miR-338-3p was further downregulated, the migration and invasion ability of the FaDu hypopharyngeal carcinoma cells were enhanced, and these functions were inhibited when the miR-338-3p was upregulated. In addition, we demonstrated that ADAM17 was a target of miR-338-3p, and that ADAM17 directly activated the wnt/ß-catenin signaling pathway and promoted the expression of its target gene MMP2, Nanog and SOX2, which affected the growth, migration and invasion of hypopharyngeal carcinoma cells. In conclusion, our results demonstrate for the first time that miR-338-3p targets ADAM17 and blocks the development of hypopharyngeal carcinoma involving the wnt/ß-catenin signaling pathway, which may be a new target for clinical intervention in human cancer.

Ginkgolide B inhibits hydrogen peroxide­induced apoptosis and attenuates cytotoxicity via activating the PI3K/Akt/mTOR signaling pathway in H9c2 cells.

Ginkgolide B (GB) is a diterpene lactone found in the leaves of the traditional Chinese medicinal plant Ginkgo that has been shown to have various pharmacological effects. However, the anti­apoptotic properties of GB in cardiovascular disease remain poorly understood. The present study aimed to investigate the effect of GB on hydrogen peroxide­induced cell injury in cardiac H9c2 cells, and to further clarify its protective mechanism of action. An in vitro hydrogen peroxide­treated H9c2 cell model was used in order to mimic myocardial ischemia­reperfusion (I/R) injury. Cell viability was assessed by the Cell Counting Kit­8 assay. The induction of apoptosis was determined by flow cytometry and staining was performed using Hoechst 33342. In addition, the effect of GB on the expression levels of apoptosis­associated proteins was evaluated by western blot analysis. The present study demonstrated that GB protected against hydrogen peroxide­induced cytotoxicity and cell apoptosis in H9c2 cardiac cells. GB upregulated the expression level of the anti­apoptotic protein Bcl­2 and downregulated the expression levels of the pro­apoptotic proteins cleaved caspase­3 and Bax in hydrogen peroxide­treated H9c2 cells. The molecular mechanism underlying the anti­apoptotic effects of GB was subsequently detected. GB pretreatment activated the PI3K/Akt/mTOR signaling pathway and caused an increase in the phosphorylation levels of Akt and mTOR in hydrogen peroxide­treated H9c2 cells. These results revealed that GB inhibited hydrogen peroxide­induced apoptosis in H9c2 cells via activation of the PI3K/Akt/mTOR signaling pathway. These findings indicate the potential therapeutic benefits of GB in the treatment of myocardial I/R injury.

Dual-Responsive Dual-Drug-Loaded Bioinspired Polydopamine Nanospheres as an Efficient Therapeutic Nanoplatform against Drug-Resistant Cancer Cells.

Multidrug resistance evoked by overusing pharmaceuticals of poor water solubility has posed a serious threat to public health, which urges the development of safe and efficacious therapeutic formulations. In this study, biomimetic nanospherical polydopamine (PDA) formed under mild conditions was modified using methoxypolyethylene glycol amine (m-PEG-NH2) to produce a polydopamine-based drug delivery platform. As characterized by various physicochemical methods, the PEGylated PDA with a uniform size distribution showed superior biocompatibility and efficient load capability for two hydrophobic anticancer drugs of paclitaxel and phytochemical curcumin, which exhibited synergistic cytotoxicity and a pH/ROS-responsive release behavior. Significantly, an enhanced effect of the encapsulated paclitaxel and curcumin was identified toward the drug-resistant A549/TAX cancer cells, which was correlated with the improved cellular internalization of hyperbranched PDA composites and distinctive cell cycle arrest of loaded drugs. The dual-drug-loaded spherical PDA nanocomposites hold enormous potential to tackle drug resistance from a chemotherapy perspective.

Antibiotic Bacillomycin D Affects Iron Acquisition and Biofilm Formation in Bacillus velezensis through a Btr-Mediated FeuABC-Dependent Pathway.

Bacillus spp. produce a wide range of secondary metabolites, including antibiotics, which have been well studied for their antibacterial properties but less so as signaling molecules. Previous results indicated that the lipopeptide bacillomycin D is a signal that promotes biofilm development of Bacillus velezensis SQR9. However, the mechanism behind this signaling is still unknown. Here, we show that bacillomycin D promotes biofilm development by promoting the acquisition of iron. Bacillomycin D promotes the transcription of the iron ABC transporter FeuABC by binding to its transcription factor, Btr. These actions increase intracellular iron concentration and activate the KinB-Spo0A-SinI-SinR-dependent synthesis of biofilm matrix components. We demonstrate that this strategy is beneficial for biofilm development and competition with the Pseudomonas fluorescens PF-5. Our results unravel an antibiotic-dependent signaling mechanism that links iron acquisition to biofilm development and ecological competition.