Hypoxia-related signature to risk stratify patients for the benefit of immune checkpoint inhibitors therapy in head and neck squamous cell carcinoma: An experimental study.

BACKGROUND: Increasing evidence has shown that hypoxia is a biomarker of tumor proliferation and metastasis. This research aimed to identify a hypoxia-associated gene prognostic index (HAGPI) in head and neck squamous cell carcinoma (HNSCC) and based on HAGPI-defined subgroups to predict prognosis and response to immune checkpoint inhibitors therapy. METHODS: RNA-sequencing transcriptomic data for patients with HNSCC were downloaded from The Cancer Genome Atlas (TCGA). Protein-protein interaction network analysis was performed to select hypoxia-related hub genes. Univariate and multivariate cox regression analyses were used to identify hub genes to develop the HAGPI. Afterward expression data were imported into CIBERSORT to evaluate the relative proportion of 22 immune cells and compared the relative proportions of immune cells between the 2 HAGPI subgroups. The relationship between immunopheno score (IPS) and HAGPI was validated for immune checkpoint inhibitors (ICIs) response in TCGA cohorts. RESULTS: The HAGPI was constructed based on HS3ST1, HK1, PGK1, STC2, SERPINE1, PKLR genes. In high-HAGPI patients, the primary and secondary endpoint events in TCGA and GEO cohorts were significantly lower than low-HAGPI groups (P < .05). HAGPI-high patients exhibited a poorer prognosis than HAGPI-low patients did. The abundance of M2 macrophages and NK cell were significantly enhanced in the high-HAGPI while T cells regulatory and T cells CD8, were markedly elevated in the low-HAGPI. Meanwhile, patients in the low-HAGPI patients had higher levels of immunosuppressant expression and less aggressive phenotypes. Furthermore, IPS analysis showed that the low-HAGPI group with higher IPS represented a more immunogenic phenotype. CONCLUSION: The current study developed and verified a HAPGI model that can be considered as an independent prognostic biomarker and elucidated the tumor immune microenvironment of HNSCC.

Research Progress on Ferroptosis and Nanotechnology-Based Treatment in Triple-Negative Breast Cancer.

In recent years, more and more researches on cell death mode in breast cancer, including apoptosis, ferroptosis, etc. Ferroptosisis a regulated form of cell death characterized by iron-dependent accumulation of lipid peroxidation to lethal levels, and numerous studies have shown that ferroptosis is closely associated with tumor cells. Breast cancer is one of the malignant tumors with the highest incidence in women, and TNBC accounts for about 15-20% of all types of breast cancer. Due to the poor prognosis, strong aggressiveness, high drug resistance and lack of molecular targeting characteristics of TNBC, the treatment of TNBC faces many difficulties and great challenges. A large number of studies have shown that ferroptosis plays an important role in the occurrence and development of TNBC, tumor diagnosis, treatment and prognosis, among which the main mechanisms inducing ferroptosis include oxidative stress pathway, iron metabolism pathway and lipid metabolism pathway. Since TNBC is highly sensitive to oxidative stress pathways, intracellular GSH reduces reactive oxygen species under the action of GSH peroxidase (GPX), and when intracellular lipid peroxidase (LPO) accumulates to a certain level, ferroptosis will be induced, thus achieving the purpose of killing TNBC cells. In addition, lipid metabolism is highly consistent with the high lipid level of TNBC tumor cells. As a new therapeutic method, nanotechnology has added security to the treatment of cancer with its high safety and excellent biocompatibility. Therefore, the combination of nanotechnology with iron-based radiotherapy, chemotherapy, targeting and immunization has great research value for the treatment of TNBC In addition, the novel idea of treating TNBC with ethnopharmacology combined with ferroptosis is also involved. This article reviews the mechanism of ferroptosis and the recent research on the treatment prospects of TNBC based on ferroptosis and nanotechnology, hoping to provide references for the treatment of diseases based on ferroptosis.

Assessing the suitability of video-assisted anal fistula treatment for obese patients compared to conventional surgery: a question worth investigating.

BACKGROUND AND AIMS: Video-assisted anal fistula treatment (VAAFT) is an innovative surgical approach enabling the direct visualization of the fistula tract structure. This study aims to assess the efficacy of VAAFT in comparison with that of traditional surgical methods and explore potential risk factors contributing to fistula recurrence to provide new recommendations for surgical selection. MATERIALS AND METHODS: Information was collected from 100 patients with complex anal fistula (CAF) in our hospital who underwent surgical treatment from January 2021 to January 2023. We compared the baseline information and surgical outcomes of two groups, analyzed the risk factors for fistula recurrence by using logistic regression analysis, and conducted further exploration by using the body mass index. RESULTS: Equal numbers of patients underwent VAAFT and traditional surgeries, and no significant differences in baseline information were observed. Patients who received VAAFT experienced less intraoperative bleeding (15.5 (14.0-20.0) vs. 32.0 (25.0-36.0)), shorter hospital stays (2.0 (2.0-2.5) vs. 3.0 (3.0-3.5)), reduced postoperative pain and wound discharge, but longer operative times (43.3 ± 6.9 vs. 35.0 (31.5-40.0)) compared with patients who underwent traditional surgeries. No significant differences in recurrence rates were found three and six months after operation (the p-values were 0.790 and 0.806, respectively). However, the Wexner scores of the VAAFT group were significantly low in the first follow-up (0 (0-1.0) vs. 2.0 (1.0-2.0)). Postoperative recurrence of fistulas may be associated with obesity (p-value = 0.040), especially in patients undergoing traditional surgeries (p-value = 0.036). CONCLUSION: VAAFT offers advantages, such as less pain, less trauma, and faster recovery, compared with traditional surgical treatment. Obese patients with CAF are prone to recurrence, and we recommend that they undergo VAAFT treatment rather than traditional surgeries.

Lethal Immune-Related Pneumonitis after Durvalumab Therapy for Small Cell Lung Cancer: A First Case in China.

Introduction: Although programmed death ligand 1 (PD-L1) inhibitor plus chemotherapy regimen is a promising strategy for malignant tumors, it can induce significant immune-related adverse events, such as immune-related pneumonitis. Here, we report the first case of lethal immune-related pneumonitis in an Asian patient receiving anti-PD-L1 treatment. Case Presentation: A 68-year-old man was diagnosed with small cell lung cancer and interstitial pneumonia. After his pulmonary infection was relieved by comprehensive treatment, the patient received first-line treatment with durvalumab plus etoposide and carboplatin. Two weeks after starting durvalumab treatment, the patient had chest pain and shortness of breath. He was diagnosed with immune-induced pneumonia and treated with methylprednisolone, cefoperazone, and sulbactam, followed by oxygen and pirfenidone. Oxygen partial pressure decreased to 58 mm Hg within next the 4 days and laboratory assessment suggested cytokine storm. The patient underwent 2 plasma exchanges, one double filtration plasmapheresis and oxygen saturation decreased continuously. The patient died 1 month after durvalumab treatment. Conclusion: Immune-related pneumonitis induced by PD-L1 inhibitors is rare but life-threatening. Infection should be ruled out before starting immunotherapy.

Drug-eluting bead transarterial chemoembolization as neoadjuvant therapy pre-liver transplantation for advanced-stage hepatocellular carcinoma.

BACKGROUND: The objectives of this study were to assess the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) as neoadjuvant therapy before liver transplantation (LT) for advanced-stage hepatocellular carcinoma (HCC) and to analyze the prognostic factors. AIM: To determine whether DEB-TACE before LT is superior to LT for advanced-stage HCC. METHODS: A total of 99 individuals diagnosed with advanced HCC were studied retrospectively. The participants were categorized into the following two groups based on whether they had received DEB-TACE before LT: DEB-TACE group (n = 45) and control group (n = 54). The participants were further divided into two subgroups based on the presence or absence of segmental portal vein tumor thrombus (PVTT). The DEB-TACE group consisted of two subgroups: Group A (n = 31) without PVTT and group B (n = 14) with PVTT. The control group also had two subgroups: Group C (n = 37) without PVTT and group D (n = 17) with PVTT. Data on patient demographics, disease characteristics, therapy response, and adverse events (AEs) were collected. The overall survival (OS) and recurrence-free survival (RFS) rates were assessed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were conducted to determine the parameters that were independently related to OS and RFS. RESULTS: The DEB-TACE group exhibited an overall response rate of 86.6%. Following therapy, there was a significant decrease in the median alpha-fetoprotein (AFP) level (275.1 ng/mL vs 41.7 ng/mL, P < 0.001). The main AE was post-embolization syndrome. The 2-year rates of RFS and OS were significantly higher in the DEB-TACE group than in the control group (68.9% vs 38.9%, P = 0.003; 86.7% vs 63.0%, P = 0.008). Within the subgroups, group A had higher 2-year rates of RFS and OS compared to group C (71.0% vs 45.9%, P = 0.038; 83.8% vs 62.2%, P = 0.047). The 2-year RFS rate of group B was markedly superior to that of group D (64.3% vs 23.5%, P = 0.002). Results from multivariate analyses showed that pre-LT DEB-TACE [hazard ratio (HR) = 2.73, 95% confidence interval (CI): 1.44-5.14, P = 0.04], overall target tumor diameter ≤ 7 cm (HR = 1.98, 95%CI: 1.05-3.75, P = 0.035), and AFP level ≤ 400 ng/mL (HR = 2.34; 95%CI: 1.30-4.19, P = 0.009) were significant risk factors for RFS. Additionally, pre-LT DEB-TACE (HR = 3.15, 95%CI: 1.43-6.96, P = 0.004) was identified as a significant risk factor for OS. CONCLUSION: DEB-TACE is a safe and efficient therapy for advanced-stage HCC and also enhances patient survival after LT.

The relationship between obstructive sleep apnea and osteoarthritis: evidence from an observational and Mendelian randomization study.

Objectives: Obstructive sleep apnea (OSA) and osteoarthritis (OA) are common comorbidities that significantly impact individuals' quality of life. However, the relationship between OSA and OA remains unclear. This study aims to explore the connection between OSA and OA and evaluate causality using Mendelian randomization (MR). Methods: A total of 12,454 participants from the National Health and Nutrition Examination Survey (2009-2012) were included. OSA participants were identified based on self-reported interviews. The association between OA and OSA was assessed through multivariable logistic regression analysis. A two-sample MR was employed to investigate the relationship between OSA and OA, specifically hip OA and knee OA, utilizing the inverse variance-weighted (IVW) approach. Results: Based on the observational study, individuals with OSA exhibited a higher risk of OA (OR = 1.67, 95% CI = 1.40-1.98). IVW demonstrated that the risk of OA (OR = 1.13, 95% CI: 1.05-1.21, p = 0.001), hip OA (OR = 1.11, 95% CI: 1.04-1.18, p = 0.002), and knee OA (OR = 1.08, 95% CI: 1.02-1.14, p = 0.005) was significantly associated with OSA. Reverse MR analyses indicated no effect of OA on OSA. Additionally, body mass index (BMI) was found to mediate 36.9% (95% CI, 4.64-73.2%, p = 0.026) of the OSA effects on OA risk. Conclusion: The cross-sectional observational analysis unveiled noteworthy associations between OSA and OA. Meanwhile, findings from the MR study provide support for a causal role.

Prophylactic dose of rivaroxaban versus warfarin for the treatment of isolated calf muscle vein thrombosis: a retrospective propensity score-matched analysis.

BACKGROUND: Prophylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT), nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy. METHODS: A retrospective analysis of 472 ICMVT patients who received two different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching. RESULTS: 242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); No major bleeding events occurred in each group, and clinically relevant non-major bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); Complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619 to 3.347, P = 0.397) and clinically relevant non-major bleeding events (odds ratio 0.483, 95% confidence interval 0.161 to 1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the two groups (odds ratio 0.589, 95% confidence interval 0.375 to 0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm) and risk factors for VTE (non-surgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05). CONCLUSIONS: In this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR > 2.0 for >50% of the time); but it was not conducive to complete clot resolution.

Pyroptosis-related long-noncoding RNA signature predicting survival and immunotherapy efficacy in patients with lung squamous cell carcinoma.

Pyroptosis-related long-noncoding RNAs (PRlncRNAs) play an important role in cancer progression. However, their role in lung squamous cell carcinoma (LUSC) is unclear. A risk model was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis based on RNA sequencing data from The Cancer Genome Atlas database. The LUSC cohort was divided into high- and low-risk groups based on the median risk score. For the prognostic value of the model, the Kaplan-Meier analysis, log-rank test, and Cox regression analysis were performed. A nomogram was constructed to predict the prognosis of patients, using a risk score and clinical parameters such as age, sex, clinical stage, and tumor node metastasis classification (TNM) stage. Afterwards, six common algorithms were employed to assess the invasion of immune cells. The Gene Set Enrichment Analysis (GSEA) was conducted to identify differences between patients at high and low risk. Furthermore, the pRRophetic package was employed to forecast the half-maximal inhibitory doses of prevalent chemotherapeutic drugs, while the tumor immune dysfunction and exclusion score was computed to anticipate the response to immunotherapy. The expression levels of the seven PRlncRNAs were examined in both LUSC and normal lung epithelial cell lines using RT-qPCR. Proliferation, migration, and invasion assays were also carried out to investigate the role of MIR193BHG in LUSC cells. Patients in the low-risk group showed prolonged survival in the total cohort or subgroup analysis. The Cox regression analysis showed that the risk model could act as an independent prognostic factor for patients with LUSC. The results of GSEA analysis revealed that the high-risk group showed enrichment of cytokine pathways, Janus tyrosine kinase/signal transducer and activator of the transcription signalling pathway, and Toll-like receptor pathway. Conversely, the low-risk group showed enrichment of several gene repair pathways. Furthermore, the risk score was positively correlated with immune cell infiltration. Moreover, patients in the high-risk category showed reduced responsiveness to conventional chemotherapeutic medications and immunotherapy. The majority of the long noncoding RNAs in the risk model were confirmed to be overexpressed in LUSC cell lines compared to normal lung epithelial cell lines by in vitro tests. Further studies have shown that downregulating the expression of MIR193BHG may inhibit the growth, movement, and infiltration capabilities of LUSC cells, whereas increasing the expression of MIR193BHG could enhance these malignant tendencies. This study found that PRlncRNAs were linked to the prognosis of LUSC patients. The risk model, evaluated across various clinical parameters and treatment modalities, shows potential as a future reference for clinical applications.

N-terminal truncated trehalose-6-phosphate synthase 1 gene (△NIbTPS1) enhances the tolerance of sweet potato to abiotic stress.

Sweet potato [Ipomoea batatas (L.) Lam], the crop with the seventh highest annual production globally, is susceptible to various adverse environmental influences, and the study of stress-resistant genes is important for improving its tolerance to abiotic stress. The enzyme trehalose-6-phosphate synthase (TPS) is indispensable in the one pathway for synthesizing trehalose in plants. TPS is known to participate in stress response in plants, but information on TPS in sweet potato is limited. This study produced the N-terminal truncated IbTPS1 gene (△NIbTPS1) overexpression lines of Arabidopsis thaliana and sweet potato. Following salt and mannitol-induced drought treatment, the germination rate, root elongation, and fresh weight of the transgenic A. thaliana were significantly higher than that in the wild type. Overexpression of △NIbTPS1 elevated the photosynthetic efficiency (Fv/Fm) and the activity of superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase in sweet potato during drought and salt treatments, while reducing malondialdehyde and O2∙- contents, although expression of the trehalose-6-phosphate phosphatase gene IbTPP and trehalose concentrations were not affected. Thus, overexpressing the △NIbTPS1 gene can improve the stress tolerance of sweet potato to drought and salt by enhancing the photosynthetic efficiency and antioxidative enzyme system. These results will contribute to understand the functions of the △NIbTPS1 gene and trehalose in the response mechanism of higher plants to abiotic stress.

Heterogeneity of hepatocellular carcinoma that responds differently to combination therapy with TACE and Sorafenib as determined by digital spatial gene expression profiling.

BACKGROUND: The combination of Sorafenib and transcatheter arterial chemoembolization (TACE) exhibits limited efficacy in the treatment of certain advanced hepatocellular carcinomas (HCC), and the molecular mechanisms underlying resistance to this combination remain unclear. OBJECTIVE: This study aims to underscore the distinctive contribution of GeoMx DSP technology in elucidating the molecular intricacies of HCC resistance to the Sorafenib and TACE combination. METHODS: Patients with advanced HCC during the waiting period before liver transplantation were classified into sensitive and resistant groups based on their response to Sorafenib and TACE combination therapy. Employing GeoMx DSP technology for comprehensive gene expression profiling, we identified pivotal molecular targets linked to resistance against combination therapy. RESULTS: The investigation scrutinized intra-tumoral and inter-individual variances, unveiling a spectrum of crucial molecular targets, such as PLG, PLVAP, immunoglobulin genes, ORM1, and NR4A1, among others. Additionally, we explored signaling pathways associated with treatment responsiveness, including the PPAR signaling pathway. Notably, we emphasized the significance of the immune microenvironment characterized by heightened SPP1 expression in HCC resistance to combination therapy. In the resistant group, SPP1+ tumor-associated macrophage (TAM) infiltration was notably pronounced (p = 0.037), while T-cell depletion showed a mitigated presence (p = 0.013). CONCLUSION: The study reveals intra- and inter-individual heterogeneity in HCC that is differentially responsive to the combination of Sorafenib and TACE, highlighting multiple key molecular targets associated with treatment resistance. The immune microenvironment is important, and in particular, SPP1+ TAM infiltration may play a key role. Meanwhile, the introduction of immunotherapy in patients resistant to combination therapy may lead to positive results.

Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones.

Previous studies of hematopoietic stem cells (HSCs) primarily focused on single cell-based niche models, yielding fruitful but conflicting findings 1-5 . Here we report our investigation on the fetal liver (FL) as the primary fetal hematopoietic site using spatial transcriptomics. Our study reveals two distinct niches: the portal-vessel (PV) niche and the sinusoidal niche. The PV niche, composing N-cadherin (N-cad) Hi Pdgfrα + mesenchymal stromal cells (MSCs), endothelial cells (ECs), and N-cad Lo Albumin + hepatoblasts, maintains quiescent and multipotential FL-HSCs. Conversely, the sinusoidal niche, comprising ECs, hepatoblasts and hepatocytes, as well as potential macrophages and megakaryocytes, supports proliferative FL-HSCs biased towards myeloid lineages. Unlike prior reports on the role of Cxcl12, with its depletion from vessel-associated stromal cells leading to 80% of HSCs' reduction in the adult bone marrow (BM) 6,7 , depletion of Cxcl12 via Cdh2 CreERT (encoding N-cad) induces altered localization of HSCs from the PV to the sinusoidal niches, resulting in an increase of HSC number but with myeloid-bias. Similarly, we discovered that adult BM encompasses two niches within different zones, each composed of multi-cellular components: trabecular bone area (TBA, or metaphysis) supporting deep-quiescent HSCs, and central marrow (CM, or diaphysis) fostering heterogenous proliferative HSCs. This study transforms our understanding of niches by shifting from single cell-based to multicellular components within distinct zones, illuminating the intricate regulation of HSCs tailored to their different cycling states.

Multiple myeloma, IL6, and risk of schizophrenia: A Mendelian randomization, transcriptome, and Bayesian colocalization study.

Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome-wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment-resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation-relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein-coding region of HLA-DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA-DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin-6 (IL-6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA-DRB1 polymorphism, and enhanced IL-6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.

Polar Solvent-Induced Spontaneous Nanofoaming for Synthesizing Ultra-High-Performance Polyamide Nanofiltration Membranes.

Nanofiltration membranes with both high water permeance and selectivity are perpetually studied because of their applications in water purification. However, these two critical attributes are considered to be mutually exclusive. Here, we introduce a polar solvent, dichloromethane, in place of the apolar hexane used for decades as the organic phase for membrane interfacial polymerization synthesis to solve this dilemma. When a polar solvent as the organic phase is combined with a solvent-resistant aramid nanofibrous hydrogel film as the water phase, monomer enrichment in the reaction zone leads to a polyamide nanofiltration membrane with densely distributed nanobubble features, enhanced nanoporosity, and a loosened backbone. Benefiting from these structural features, the resulting membrane exhibits superior properties with a combination of high water permeance (52.7 L m-2 h-1 bar-1) and selectivity (water/Na2SO4, 36 bar-1; NaCl/Na2SO4, 357 bar-1), outperforming traditional nanofiltration membranes. We envision that this novel technology involving polar solvent systems and the water phase of nanofibrous hydrogel would provide new opportunities for membrane development for environmental engineering.

Nerve growth factor alleviates arsenic-induced testicular injury by enhancing the function of Sertoli cells.

Sertoli cells (SCs) maintain testicular homeostasis and promote spermatogenesis by forming the blood-testis barrier (BTB) and secreting growth factors. The pro-proliferative and anti-apoptotic effects of nerve growth factor (NGF) on SCs have been proved previously. It is still unclear whether the damage effect of arsenic on testis is related to the inhibition of NGF expression, and whether NGF can mitigate arsenic-induced testicular damage by decreasing the damage of SCs induced by arsenic. Here, the lower expression of NGF in testes of arsenic exposed mice (freely drinking water containing 15 mg/l of NaAsO2) was observed through detection of Western blot and Real-time PCR. Subsequently, hematoxylin and eosin (HE) staining, Evans blue staining and transmission electron microscopy were used to evaluate the pathology, BTB permeability and tight junction integrity in testes of control mice, arsenic exposed mice (freely drinking water containing 15 mg/l of NaAsO2) and arsenic + NGF treated mice (freely drinking water containing 15 mg/l of NaAsO2 + intraperitoneal injection with 30 µg/kg of NGF), respectively. Evidently, spermatogenic tubule epithelial cells in testis of arsenic exposed mice were disordered and the number of cell layers was reduced, accompanied by increased permeability and damaged integrity of the tight junction in BTB, but these changes were less obvious in testes of mice treated with arsenic + NGF. In addition, the sperm count, motility and malformation rate of mice treated with arsenic + NGF were also improved. On the basis of the above experiments, the viability and apoptosis of primary cultured SCs treated with arsenic (10 µM NaAsO2) or arsenic + NGF (10 µM NaAsO2 + 100 ng/mL NGF) were detected by Cell counting kit-8 (CCK8) and transferase-mediated DUTP-biotin nick end labeling (TUNEL) staining, respectively. It is found that NGF ameliorated the decline of growth activity and the increase of apoptosis in arsenic-induced SCs. This remarkable biological effect that NGF inhibited the increase of Bax expression and the decrease of Bcl-2 expression in arsenic-induced SCs was also determined by western blot and Real-time PCR. Moreover, the decrease in transmembrane resistance (TEER) and the expression of tight junction proteins ZO-1 and occludin was mitigated in SCs induced by arsenic due to NGF treatment. In conclusion, the above results confirmed that NGF could ameliorate the injury effects of arsenic on testis, which might be related to the function of NGF to inhibit arsenic-induced SCs injury.

Peroxysulfur species-mediated enhanced oxidation of micropollutants by ferrate(VI): Peroxymonosulfate versus peroxydisulfate.

Many studies have shown that Peroxymonosulfate (PMS) works synergistically with ferrate (Fe(VI)) to remove refractory organic compounds in a few minutes. However, little has been reported on the combined effects of peroxydisulfate (PDS) and Fe(VI). Since PDS is stable and cost effective, it is of practical significance to study the reaction mechanism and conditions of the PDS/Fe(VI) system. The results of the study indicate that the intermediate Fe(II) is formed during the decomposition of Fe(VI), which is then rapidly oxidized. Due to the asymmetry of the PMS molecular structure, PMS can rapidly trap Fe(II) (kPMS/Fe(II)= 3 × 104 M-1∙s-1), whereas PDS cannot (kPDS/Fe(II)= 26 M-1∙s-1). Hydroxylamine hydrochloride (HA) can reduce Fe(VI) and Fe(III) to Fe(II) to excite PDS to produce SO4•-. Acetate helps to detect Fe(II), but does not help PDS to trap Fe(II). Active species such as SO4•-, •OH, 1O2, and Fe(IV), Fe(V) are present in both systems, but in different amounts. In the PMS/Fe(Ⅵ) system, all these active species react with ibuprofen (IBP) and degrade IBP within several minutes. The effects of the initial pH, PMS or Fe(VI) dosage, and different amounts of IBP on the removal rate of IBP were investigated. According to the intermediates detected by the GC-MS, the degradation process of IBP includes hydroxylation, demethylation and single bond breakage. The degradation pathways of IBP were proposed. The degradation of IBP in tap water and Songhua River was also investigated. In actual water treatment, the dosage needs to be increased to achieve the same results. This study provides a basis and theoretical support for the application of PMS/Fe(Ⅵ) and PDS/Fe(VI) system in water treatment.

CircZfp644-205 inhibits osteoblast differentiation and induces apoptosis of pre-osteoblasts via sponging miR-455-3p and promoting SMAD2 expression.

BACKGROUND: Circular RNAs (circRNAs) are involved in the progression of osteoporosis; however, their impact on osteogenic differentiation has yet to be fully elucidated. In this study, we identified a novel circRNA known as circZfp644-205 and investigated its effect on osteogenic differentiation and apoptosis in osteoporosis. METHODS: CircZfp644-205, miR-445-3p, and SMAD2 levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). MC3T3-E1 cells were subjected to microgravity (MG) to establish a cell model. Osteogenic differentiation was assessed using qRT-PCR, Alizarin Red S staining, alkaline phosphatase staining, and western blot. The apoptosis was evaluated using flow cytometry. The relationship between miR-445-3p and circZfp644-205 or SMAD2 was determined using bioinformatics, RNA pull-down, and luciferase reporter assay. Moreover, a hindlimb unloading mouse model was generated to investigate the role of circZfp644-205 in vivo using Micro-CT. RESULTS: CircZfp644-205 expression was up-regulated significantly in HG-treated MC3T3-E1 cells. Further in vitro studies confirmed that circZfp644-205 knockdown inhibited the osteogenic differentiation and induced apoptosis of pre-osteoblasts. CircZfp644-205 acted as a sponge for miR-455-3p, which reversed the effects of circZfp644-205 on pre-osteoblasts. Moreover, miR-455-3p directly targeted SMAD2, thus inhibiting the expression of SMAD2 to regulate cellular behaviors. Moreover, circZfp644-205 alleviated the progression of osteoporosis in mice. CONCLUSIONS: This study provides a novel circRNA that may serve as a potential therapeutic target for osteoporosis and expands our understanding of the molecular mechanism underlying the progression of osteoporosis.

Ferulic Acid Inhibits Arsenic-Induced Colon Injury by Improving Intestinal Barrier Function.

The prolonged exposure to arsenic results in intestinal barrier dysfunction, which is strongly concerned with detrimental processes such as oxidative stress and the inflammatory response. Ferulic acid (FA), as a phenolic acid, possesses the capability to mitigate arsenic-induced liver damage and cardiotoxic effects dependent on inhibition of oxidative stress and inflammatory responses. FA can mitigate testicular tissue damage and alveolar epithelial dysfunction, the mechanism of which may rely on nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) activation and nuclear factor-kappa B (NF-κB) pathway blocking. Based on the antioxidant and anti-inflammatory properties of FA, we speculated that FA might have the potential to inhibit arsenic-induced intestinal damage. To confirm this scientific hypothesis, mice exposed to sodium arsenite were treated with FA to observe colonic histopathology and TJ protein levels, and oxidative stress and TJ protein levels in Caco-2 cells exposed to sodium arsenite were assessed after FA intervention. In addition, molecular levels of NF-κB and Nrf2/HO-1 pathway in colon and Caco-2 cells were also detected. As shown in our data, FA inhibited arsenic-induced colon injury, which was reflected in the improvement of mucosal integrity, the decrease of down-regulated expression of tight junction (TJ) proteins (Claudin-1, Occludin, and ZO-1) and the inhibition of oxidative stress. Similarly, treatment with FA attenuated the inhibitory effect of arsenic on TJ protein expression in Caco-2 cells. In addition to suppressing the activation of NF-κB pathway, FA retrieved the activation of Nrf2/HO-1 pathway in colon and intestinal epithelial cells induced by arsenic. In summary, our findings propose that FA has the potential to mitigate arsenic-induced intestinal damage by preserving the integrity of intestinal epithelial TJs and suppressing oxidative stress. These results lay the groundwork for the potential use of FA in treating colon injuries caused by arsenic.

Lactobacillus plantarum-Derived Extracellular Vesicles Modulate Macrophage Polarization and Gut Homeostasis for Alleviating Ulcerative Colitis.

Extracellular vesicles released by probiotics have been demonstrated to effectively alleviate intestinal inflammation, yet the precise underlying mechanisms remain unclear. In this research, for the first time, Lactobacillus plantarum UJS001 (LP-UJS) was isolated from fermented sauerkraut in Zhenjiang, China. Thereafter, the therapeutic effect of LP-UJS-derived extracellular vesicles (LP-UJS-EVs) on dextran sulfate sodium-induced ulcerative colitis (UC) in mice was analyzed to elucidate the immune mechanisms. According to our findings, LP-UJS-EVs played a pivotal role in restoring the intestinal barrier and alleviating intestinal inflammation. Notably, LP-UJS-EVs induced M2 polarization of macrophages, promoted the release of IL-10 and TGF-ß, inhibited the release of histamine, IL-6, and TNF-α, and exerted regulatory effects on intestinal microflora, as evidenced by the reduced abundances of Coprococcus, Parabacteroides, Staphylococcus, and Allobaculum, alongside the enhanced abundance of Prevotella. Furthermore, both LP-UJS and LP-UJS-EVs affected the lysine degradation pathway and significantly increased the abundance of related metabolites, especially oxoadipic acid. In summary, our results underscore the substantial therapeutic potential of LP-UJS and its secreted EVs in the treatment of UC.

IDEAL-IQ combined with intravoxel incoherent motion diffusion-weighted imaging for quantitative diagnosis of osteoporosis.

BACKGROUND: Osteoporosis (OP) is a common chronic metabolic bone disease characterized by decreased bone mineral content and microstructural damage, leading to increased fracture risk. Traditional methods for measuring bone density have limitations in accurately distinguishing vertebral bodies and are influenced by vertebral degeneration and surrounding tissues. Therefore, novel methods are needed to quantitatively assess changes in bone density and improve the accurate diagnosis of OP. METHODS: This study aimed to explore the applicative value of the iterative decomposition of water and fat with echo asymmetry and least-squares estimation-iron (IDEAL-IQ) sequence combined with intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for the diagnosis of osteoporosis. Data from 135 patients undergoing dual-energy X-ray absorptiometry (DXA), IDEAL-IQ, and IVIM-DWI were prospectively collected and analyzed. Various parameters obtained from IVIM-DWI and IDEAL-IQ sequences were compared, and their diagnostic efficacy was evaluated. RESULTS: Statistically significant differences were observed among the three groups for FF, R2*, f, D, DDC values, and BMD values. FF and f values exhibited negative correlations with BMD values, with r=-0.313 and - 0.274, respectively, while R2*, D, and DDC values showed positive correlations with BMD values, with r = 0.327, 0.532, and 0.390, respectively. Among these parameters, D demonstrated the highest diagnostic efficacy for osteoporosis (AUC = 0.826), followed by FF (AUC = 0.713). D* exhibited the lowest diagnostic performance for distinguishing the osteoporosis group from the other two groups. Only D showed a significant difference between genders. The AUCs for IDEAL-IQ, IVIM-DWI, and their combination were 0.74, 0.89, and 0.90, respectively. CONCLUSIONS: IDEAL-IQ combined with IVIM-DWI provides valuable information for the diagnosis of osteoporosis and offers evidence for clinical decisions. The superior diagnostic performance of IVIM-DWI, particularly the D value, suggests its potential as a more sensitive and accurate method for diagnosing osteoporosis compared to IDEAL-IQ. These findings underscore the importance of integrating advanced imaging techniques into clinical practice for improved osteoporosis management and highlight the need for further research to explore the full clinical implications of these imaging modalities.