Enniatin B1 induces damage to Leydig cells via inhibition of the Nrf2/HO-1 and JAK/STAT3 signaling pathways.

Enniatin B1 (ENN B1) is a mycotoxin that can be found in various foods. However, whether ENN B1 is hazardous to the reproductive system is still elusive. Leydig cells are testosterone-generating cells that reside in the interstitial compartment between seminiferous tubules. Dysfunction of Leydig cells could result in male infertility. This study aimed to examine the toxicological effects of ENN B1 against TM3 Leydig cells. ENN B1 significantly inhibited cell viability in a dose-dependent manner. ENN B1 treatment also decreased the expression of functional genes in Leydig cells. Moreover, ENN B1 induced Leydig cells apoptosis and oxidative stress. Mechanistically, ENN B1 leads to the upregulation of Bax and downregulation of Bcl-2 in Leydig cells. In addition, ENN B1 inhibited the Nrf2/HO-1 pathway, which is critical for the induction of oxidative stress. Additionally, ENN B1 treatment repressed the JAK/STAT3 signaling pathway in Leydig cells. Rescue experiments showed that activation of STAT3 resulted in alleviation of ENN B1-induced damage in Leydig cells. Collectively, our study demonstrated that ENN B1 induced Leydig cell dysfunction via multiple mechanisms.

BNIP3 as a potential biomarker for the identification of prognosis and diagnosis in solid tumours.

BACKGROUND: Traditional radiotherapy and chemotherapy have been intensively studied for their role in the treatment of tumours. However, these therapies often cause side effects for patients, which calls for the development of novel treatment options for tumours. B-cell lymphoma-2 (Bcl-2)/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) reportedly apoptosis-inducing effects in tumour cells and is associated with the progression and treatment of multiple tumours. Nevertheless, little is known about its potential role in tumour diagnosis and targeted therapy. FINDINGS: The results of the study demonstrated that the interaction of BNIP3 with HDAC1 may affect the progression of breast invasive cancer (BRCA), sarcoma (SARC), kidney renal clear cell carcinoma (KIRC), and low-grade glioma (LGG). BNIP3 seemed to exert its effects in BRCA and SARC primarily through gene silencing and integrator complex, and in KIRC and LGG, mainly by affecting olfactory function, suggesting that targeted therapy can be developed based on the above signalling pathway and downstream molecules. INTERPRETATION: BNIP3 has emerged as a promising therapeutic and diagnostic target for BRCA, SARC, KIRC, and LGG, providing new insights into tumour molecular therapies in the clinic.

Clinical Characteristics and Risk Factors for Allergic Rhinitis in Children with Epistaxis.

Background: Epistaxis is frequently observed in children with allergic rhinitis. However, few studies have addressed the clinical characteristics and risk factors for allergic rhinitis in children with epistaxis. This study aimed to describe the factors associated with allergic rhinitis in children with epistaxis. Methods: In total, we recruited 80 children (aged 3-14 years) who presented with epistaxis at a tertiary hospital between January 2014 and January 2022. The follow-up duration was at least 3 months, and we performed a multivariate logistic regression analysis to identify the risk factors for allergic rhinitis. Results: Among the 80 children examined, 57 (71.25%) had allergic rhinitis. Epistaxis mainly occurred in autumn in children with allergic rhinitis; in contrast, it mostly occurred in summer in children without it (P = 0.029). Mites are common allergens for allergic rhinitis in children with epistaxis; the univariate analysis revealed significant differences between allergic-rhinitis group and nonallergic-rhinitis group in the number of allergens (P < 0.001) and total IgE (P < 0.001). The difference in severity of nasal symptoms between the two groups was statistically significant and included nasal obstruction (P < 0.001), rhinorrhea (P < 0.001), sneezing (P < 0.001), and nasal itching (P < 0.001). After adjusting for potential confounders, the severity of rhinorrhea symptoms was found to be associated with an increased risk of allergic rhinitis in children with epistaxis (odds ratio: 3.86; 95% confidence interval: 1.61-9.26; P = 0.003). Conclusions: Observing the onset season, number of allergens, total IgE, and nasal symptoms in cases of epistaxis could suggest the presence of associated allergic rhinitis and reduce the number of missed diagnoses; antiallergic drugs could help control epistaxis in these cases.

[Exploring the mechanisms of ferroptosis in non-obstructive azoospermia based on bioinformatics and machine learning].

OBJECTIVE: To explor the potential mechanisms of ferroptosis involvement in non-obstructive azoospermia based on bioinformatics and machine learning methods. METHODS: To obtain disease-related datasets and ferroptosis-related genes, we utilized the GEO database and FerrDb database, respectively. Using the R software, the disease dataset was subjected to normalization, differential analysis, and GO and KEGG enrichment analysis. The differentially expressed genes from the disease dataset were then intersected with the ferroptosis-related genes to identify common genes. Core genes were selected using three machine learning algorithms, namely LASSO, SVM-RFE, and random forest. Further analysis included exploring immune infiltration correlation, predicting target drugs, and conducting molecular docking simulations. RESULTS: The differential analysis of the GSE45885 dataset yielded 1751 differentially expressed genes, while the GSE145467 dataset yielded 4358 differentially expressed genes. The intersection of these two gene sets resulted in a disease-related gene set consisting of 508 genes. Taking the intersection of the disease-related gene set and the ferroptosis-related gene set, we obtained 17 disease-related ferroptosis genes. After machine learning-based screening, three core genes were identified: GPX4, HSF1, and KLHDC3. CONCLUSION: The mechanism underlying the involvement of ferroptosis in non-obstructive azoospermia may be linked to the downregulation of GPX4, HSF1, and KLHDC3 expression. This finding provides a basis for subsequent in-depth mechanistic and therapeutic studies.

Predictive value of serum bile acids as metabolite biomarkers for liver cirrhosis: a systematic review and meta-analysis.

INTRODUCTION: A large number of studies have explored the potential biomarkers for detecting liver cirrhosis in an early stage, yet consistent conclusions are still warranted. OBJECTIVES: To conduct a review and a meta-analysis of the existing studies that test the serum level of bile acids in cirrhosis as the potential biomarkers to predict cirrhosis. METHODS: Six databases had been searched from inception date to April 12, 2021. Screening and selection of the records were based on the inclusion criteria. The risk of bias was assessed with the Newcastle-Ottawa quality assessment scale (NOS). Mean difference (MD) and confidence intervals 95% (95% CI) were calculated by using the random effect model for the concentrations of bile acids in the meta-analysis, and I2 statistic was used to measure studies heterogeneity. This study was registered on PROSPERO. RESULTS: A total of 1583 records were identified and 31 studies with 2679 participants (1263 in the cirrhosis group, 1416 in the healthy control group) were included. The quality of included studies was generally high, with 25 studies (80.6%) rated over 7 stars. A total of 45 bile acids or their ratios in included studies were extracted. 36 increased in the cirrhosis group compared with those of the healthy controls by a qualitative summary, 5 decreased and 4 presented with mixing results. The result of meta-analysis among 12 studies showed that 13 bile acids increased, among which four primary conjugated bile acids showed the most significant elevation in the cirrhosis group: GCDCA (MD = 11.38 µmol/L, 95% CI 8.21-14.55, P < 0.0001), GCA (MD = 5.72 µmol/L, 95% CI 3.47-7.97, P < 0.0001), TCDCA (MD = 3.57 µmol/L, 95% CI 2.64-4.49, P < 0.0001) and TCA (MD = 2.14 µmol/L, 95% CI 1.56-2.72, P < 0.0001). No significant differences were found between the two groups in terms of DCA (MD = - 0.1 µmol/L, 95% CI - 0.18 to - 0.01, P < 0.0001) and LCA (MD = - 0.01 µmol/L, 95% CI - 0.01 to - 0.02, P < 0.0001), UDCA (MD = - 0.14 µmol/L, 95% CI - 0.04 to - 0.32, P < 0.0001), and TLCA (MD = 0 µmol/L, 95% CI 0-0.01, P < 0.0001). Subgroup analysis in patients with hepatitis B cirrhosis showed similar results. CONCLUSION: Altered serum bile acids profile seems to be associated with cirrhosis. Some specific bile acids (GCA, GCDCA, TCA, and TCDCA) may increase with the development of cirrhosis, which possibly underlay their potential role as predictive biomarkers for cirrhosis. Yet this predictive value still needs further investigation and validation in larger prospective cohort studies.

Endotherapy for the proximal migration of pancreatic stents: A systematic review.

OBJECTIVES: Proximal migration is one of the complications after pancreatic duct stenting. This study aimed to determine the incidence of proximal migration and to analyze the rescue methods. METHODS: A search was performed in MEDLINE/EMBASE database. The literatures included were reviewed and analyzed. Retrieval tools were classified into 3 classes: Class A works by indirectly contacting the outer surface of the stent. Class B works by directly contacting the outer surface. Class C works by directly contacting the inner surface. RESULTS: 416 literatures were retrieved from 1983 to 2021. 15 literatures were included. The incidence of proximal migration of pancreatic stents was 4.7% (106/2246). The success rate of endotherapy was 86.6% (214/247), and the surgical conversion rate of it was 9.3%. Among the 214 cases in which the displaced stents were successfully removed under endoscopy, 49 cases (22.9%) used Class A methods, 154 cases (72.0%) used Class B methods and 11 cases (5.1%) used Class C methods. The overall rate of postoperative complication was 12.1%, including postprocedure pancreatitis (9.1%, 18/247), followed by bleeding (1.5%), perforation (1.0%) and biliary infection (0.5%). CONCLUSIONS: Endoscopy is an effective method for the treatment of proximal displacement of pancreatic stents with acceptable complication rate.

Hexafluoropropylene oxide trimer acid (HFPO-TA) exerts cytotoxic effects on leydig cells via the ER stress/JNK/ß-trcp/mcl-1 axis.

Hexafluoropropylene oxide trimer acid (HFPO-TA) is an alternative to perfluorooctanoic acid (PFOA) and is widely used in various industries. The effects of HFPO-TA on the male reproductive system and the underlying mechanisms are still not fully understood. In this study, TM3 mouse Leydig cells were used as the main model to evaluate the cytotoxicity of HFPO-TA in vitro. HFPO-TA inhibited the viability and expression of multiple biomarkers of Leydig cells. HFPO-TA also induced Leydig cell apoptosis in a caspase-dependent manner. Moreover, HFPO-TA induced the ubiquitination and degradation of Mcl-1 in a ß-TrCP-dependent manner. Further investigations showed that HFPO-TA treatment led to the upregulation of ROS, which activated the ER stress/JNK/ß-TrCP axis in Leydig cells. Overall, our study provides novel insights into the cytotoxic effects of HFPO-TA on the male reproductive system.

Innovative Biomaterials for Bone Tumor Treatment and Regeneration: Tackling Postoperative Challenges and Charting the Path Forward.

Surgical resection of bone tumors is the primary approach employed in the treatment of bone cancer. Simultaneously, perioperative interventions, particularly postoperative adjuvant anticancer strategies, play a crucial role in achieving satisfactory therapeutic outcomes. However, the occurrence of postoperative bone tumor recurrence, metastasis, extensive bone defects, and infection are significant risks that can result in unfavorable prognoses or even treatment failure. In recent years, there has been significant progress in the development of biomaterials, leading to the emergence of new treatment options for bone tumor therapy and bone regeneration. This progress report aims to comprehensively analyze the strategic development of unique therapeutic biomaterials with inherent healing properties and bioactive capabilities for bone tissue regeneration. These composite biomaterials, classified into metallic, inorganic non-metallic, and organic types, are thoroughly investigated for their responses to external stimuli such as light or magnetic fields, internal interventions including chemotherapy or catalytic therapy, and combination therapy, as well as their role in bone regeneration. Additionally, an overview of self-healing materials for osteogenesis is provided and their potential applications in combating osteosarcoma and promoting bone formation are explored. Furthermore, the safety concerns of integrated materials and current limitations are addressed, while also discussing the challenges and future prospects.

Scoparone induces both apoptosis and ferroptosis via multiple mechanisms in non-small-cell lung cancer cells.

The present study investigated the anti-tumour effects of scoparone, also known as 6,7-dimethoxycoumarin, in non-small-cell-lung cancer (NSCLC) cells. It was discovered that scoparone inhibited the proliferation and induced cell death of NSCLC cells. Scoparone induced both apoptosis and ferroptosis in NSCLC cells. Mechanically, scoparone treatment led to the FBW7-mediated ubiquitination and downregulation of Mcl-1. Moreover, scopaone induced Bax activation in a reactive oxygen species (ROS)-dependent manner. Interestingly, scoparone also triggered ferroptosis, a novel form of cell death, as evidenced by upregulation of lipid peroxidation, ROS, and iron levels. The mechanism investigation showed that scoparone activated the ROS/JNK/SP1/ACSL4 axis to trigger ferroptosis in NSCLC cells. Overall, our data suggest that scoparone is a promising agent for the treatment of NSCLC.

Effect of sleep deprivation plus existing therapies on depression: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUNDS: Depression is the most common mental disorder in the world. Sleep deprivation (SD) is a well-known antidepressant. Several recombination protocols (including medications, bright light treatment [BLT], cognitive-behavioral therapy, sleep phrase advance/sleep phrase delay [SPA/SPD], and repetitive transcranial magnetic stimulation [rTMS]) have been developed to improve and maintain the effect of SD. However, relapse after recovery sleep has been reported, and different recombination protocols result in different outcomes. METHODS: The Embase, Cochrane, PubMed, CBM, Web of Science, and CINAHL databases were searched for clinical trials assessing depression and SD. Three independent reviewers classified forty-three abstracts. The Hamilton Depression Rating Scale was used to assess the outcomes. RESULTS: Compared with existing therapy, patients receiving SD displayed a significant improvement in clinician-rated depressive symptoms (MD -1.48 [95 % CI -2.60, -0.37], p < 0.05). A significant decrease was found in the subgroups of SD plus SPA/SPD (odds ratio 3.90 [95 % CI 1.66, 9.17], p < 0.05), total sleep deprivation[TSD] plus BLT (MD -3.28 [95 % CI -5.06, -1.50], p < 0.05), and partial sleep deprivation[PSD] plus rTMS (MD -7.94 [95 % CI -11.44, -4.45], p < 0.05). No significant differences were observed in the other subgroups. CONCLUSIONS: Adding SD to existing therapies showed a positive outcome in improving depression treatment, which provides evidence for the use of SD in treating depression. Further studies are needed to determine the precise effects of SD plus other interventions.

Endoscopic retrieval of a migrated pancreatic stent stuck at both ends: A case report.

Background: Endoscopic pancreatic stenting is an effective way to relieve the stricture of the pancreatic duct. However, proximal stent migration presents a threat to the patient and a challenge to the doctor. The limited space in the pancreatic duct often prevents the operation of suitable devices for stent removal. Case presentation: A 34-year-old man with painful chronic pancreatitis received endoscopic retrograde cholangiopancreatography (ERCP) and insertion of a pancreatic plastic stent, with 8.5 Fr in diameter and 12 cm in length. A year later, radiography revealed that the proximal end of the stent rested in the pancreatic tail while the distal end rested in the branch duct. Both balloon and rat-tooth forceps were used but failed to retrieve the stent. A week later, a second ERCP was performed. After dilation with a 10-mm balloon, a small amount of bleeding was noticed and a crack appeared in the wall of the branch duct. Consequently, the distal end of the stent was released. Then, rat-tooth forceps was used to grasp the distal end, and the stent was pulled out successfully. Conclusions: For a proximally migrated pancreatic stent stuck at both ends, a strategy of maximum dilation can be used cautiously to retrieve the stent.

RNAi-mediated ADAM9 gene silencing inhibits metastasis of adenoid cystic carcinoma cells.

A disintegrin and metalloproteinase 9 (ADAM9) is a type I transmembrane protein that has been associated with cancer development and metastases. Here, we show that ADAM9 is highly expressed in metastatic cancer tissues and in an adenoid cystic carcinoma cell line with a high metastatic potential. Using RNA interference for gene silencing, we show that ADAM9 is essential for in vitro cancer cell proliferation and invasion as well as in vivo cancer metastasis in an experimental murine model of lung metastases. These data indicate that ADAM9 is potentially an important new therapeutic target for the prevention of tumor metastases in adenoid cystic carcinoma.

Classification of Early-Onset and Late-Onset Idiopathic Chronic Pancreatitis Needs Reconsideration.

Bimodal classification of idiopathic chronic pancreatitis (ICP) into early-onset (<35 years) and late-onset (>35 years) ICP was proposed in 1994 based on a study of 66 patients. However, bimodal distribution wasn't sufficiently demonstrated. Our objective was to examine the validity and relevance of the age-based bimodal classification of ICP. We analyzed the distribution of age at onset of ICP in our cohort of 1633 patients admitted to our center from January 2000 to December 2013. Classify ICP patients into early-onset ICP(a) and late-onset ICP(a) according to different cut-off values (cut-off value, a = 15, 25, 35, 45, 55, 65 years old) for age at onset. Compare clinical characteristics of early-onset ICP(a) and late-onset ICP(a). We found slightly right skewed distribution of age at onset for ICP in our cohort. There were differences between early-onset and late-onset ICP with respect to basic clinical characteristics and development of key clinical events regardless of the cut off age at onset i.e. 15, 25, 35, 45 or even higher. The validity of the bimodal classification of early-onset and late-onset ICP could not be established in our large patient cohort and therefore such a classification needs to be reconsidered.

Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma.

Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2/day 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC.

Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma.

PURPOSE: To evaluate induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) followed by surgery and postoperative radiotherapy versus up-front surgery and postoperative radiotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). PATIENTS AND METHODS: A prospective open-label phase III trial was conducted. Eligibility criteria included untreated stage III or IVA locally advanced resectable OSCC. Patients received two cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by radical surgery and postoperative radiotherapy (54 to 66 Gy) versus up-front radical surgery and postoperative radiotherapy. The primary end point was overall survival (OS). Secondary end points included local control and safety. RESULTS: Of the 256 patients enrolled onto this trial, 222 completed the full treatment protocol. There were no unexpected toxicities, and induction chemotherapy did not increase perioperative morbidity. The clinical response rate to induction chemotherapy was 80.6%. After a median follow-up of 30 months, there was no significant difference in OS (hazard ratio [HR], 0.977; 95% CI, 0.634 to 1.507; P = .918) or disease-free survival (HR, 0.974; 95% CI, 0.654 to 1.45; P = .897) between patients treated with and without TPF induction. Patients in the induction chemotherapy arm with a clinical response or favorable pathologic response (≤ 10% viable tumor cells) had superior OS and locoregional and distant control. CONCLUSION: Our study failed to demonstrate that TPF induction chemotherapy improves survival compared with up-front surgery in patients with resectable stage III or IVA OSCC.

[The effect of MAB225 on radiosensitivity of salivary gland adenoid cystic carcinoma].

PURPOSE: To observe the effect of epidermal growth factor receptor's monoclonal antibody(MAB225) on radiosensitivity of salivary gland adenoid cystic carcinoma cell. METHODS: Bi-fluorescence stain ,MTT test and fluorescence flow cytometry(FCM) were used to observe the apoptosis rate and radiosensitizing effect for MAB225 on ACC-2 cell.SPSS11.0 software package was used for data analysis. RESULTS: Through bi-fluorescence stain, MTT test and fluorescence flow cytometry(FCM),it was found that MAB225 combined with radiation treatment produced a 3-fold induction of apoptosis rate, whereas exposure to radiation alone induced apoptosis only 1 fold, compared to the control group. CONCLUSION: MAB225 enhanced radiosensitivity and decreased survival rates of ACC-2 cell in vitro after radiation.

[The mechanism of MAb225 regulating radiosensitivity of Tca8113 cell].

PURPOSE: The objective of this study was to investigate the mechanism of MAb225 regulating radiosensitivity of Tca8113 cells. METHODS: Tca8113 cells were treated with MAb225 of different concentrations. The apoptosis rate was analysed by FCM and bi-fluorescence stain, the repair of DNA damage after radiation was analysed by single cell gel electrophoresis, cells redistribution in each phase of cell cycle was analysed by FCM, and GSH level of cell were assessed by spectrophotometer. RESULTS: Radiation alone (6 Gy) and MAb225 alone (0.5 microg/ml) produced a 2-fold induction of apoptosis respectively, whereas exposure to MAb225 (0.5 microg/ml) combination with 6 Gy of radiation induced apoptosis 5-6 fold, compared to untreated controls (F test). The length of comet tail of cells which treated with MAb225 was significantly longer than that of the control cells (t test, P<0.05). The percentage of cells in S phase was significantly decreased in MAb225 treated cells. Intracellular GSH level of MAb225 treated cells was significantly lower than that of untreated cells (t test, P<0.05). CONCLUSION: MAb225 increased the radiosensitivity of Tca8113 cells by enhancing radiation-induced apoptosis, downregulating S phase percentage, inhibiting DNA repair after radiation and decreasing GSH level.

[Effect of MAb225 on radiosensitivity of Tca8113 tongue squamous cell carcinoma].

OBJECTIVE: The purpose of this study was to invest the effect of epidermal growth factor receptor monoclonal antibody MAb225 on radiosensitivity of tongue squamous cell carcinoma cell Tca8113. METHODS: Tca8113 cells were treated with different concentrations of MAb225. Radiation dose survival curve was generated from clonogenic survival assay. SERPD0 and survival faction (SF2) was analysed by single hit multi-target (SHMT) radiobiological model using RADMEDIC software. Nude mice with Tca8113 tumor xenografts were treated with MAb225, radiation treatment or both of them. Tumor responses were assessed by tumor growth delay, and t test was used for statistical analysis. RESULTS: MAb225 enhanced the radiosensitivity of Tca8113 cells. SERD0 of Tca8113 cells treated with 0.5 mg/L MAb225 was 1.23. The survival fraction of cells treated with MAb225 was significantly decreased. Tumor radioresponse could be enhanced by MAb225 (P < 0.05). CONCLUSION: MAb225 could enhance radiosensitivity of tongue squamous cell carcinoma cell.