Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective cure. GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD. A key pathological feature of C9orf72 related ALS/FTD is the presence of abnormal dipeptide repeat proteins translated from GGGGCC repeat expansion, including poly Glycine-Arginine (GR). In this study, we observed that (GR)50 conferred significant mitochondria damage and cytotoxicity. Metformin, the most widely used clinical drug, successfully relieved (GR)50 induced mitochondrial damage and inhibited (GR)50 related cytotoxicity. Further research revealed metformin effectively restored mitochondrial function by upregulating AKT phosphorylation in (GR)50 expressed cells. Taken together, our results indicated restoring mitochondrial function with metformin may be a rational therapeutic strategy to reduce poly(GR) toxicity in C9orf72 ALS/FTD patients.

Surmounting Cancer Drug Resistance: New Perspective on RNA-Binding Proteins.

RNA-binding proteins (RBPs), being pivotal elements in both physiological and pathological processes, possess the ability to directly impact RNA, thereby exerting a profound influence on cellular life. Furthermore, the dysregulation of RBPs not only induces alterations in the expression levels of genes associated with cancer but also impairs the occurrence of post-transcriptional regulatory mechanisms. Consequently, these circumstances can give rise to aberrations in cellular processes, ultimately resulting in alterations within the proteome. An aberrant proteome can disrupt the equilibrium between oncogenes and tumor suppressor genes, promoting cancer progression. Given their significant role in modulating gene expression and post-transcriptional regulation, directing therapeutic interventions towards RBPs represents a viable strategy for combating drug resistance in cancer treatment. RBPs possess significant potential as diagnostic and prognostic markers for diverse cancer types. Gaining comprehensive insights into the structure and functionality of RBPs, along with delving deeper into the molecular mechanisms underlying RBPs in tumor drug resistance, can enhance cancer treatment strategies and augment the prognostic outcomes for individuals afflicted with cancer.

HHEX suppresses advanced thyroid cancer by interacting with TLE3.

Haematopoietically Expressed Homeobox (HHEX) gene is highly expressed in the thyroid gland and plays critical roles in the development and differentiation of the thyroid gland. While it has been indicated to be downregulated in thyroid cancer, its function and the underlying mechanism remain unclear. Herein, we observed low expression and aberrant cytoplasmic localization of HHEX in thyroid cancer cell lines. Knockdown of HHEX significantly enhanced cell proliferation, migration and invasion, while overexpression of HHEX showed the opposite effects in vitro and in vivo. These data provide evidence that HHEX is a tumor suppressor in thyroid cancer. Additionally, our results showed that HHEX overexpression upregulated the expression of sodium iodine symporter (NIS) mRNA and also enhanced NIS promoter activity, suggesting a favorable effect of HHEX in promoting thyroid cancer differentiation. Mechanistically, HHEX exerted a regulatory effect on the expression of transducin-like enhancer of split 3 (TLE3) protein, which inhibited the Wnt/ß-catenin signaling pathway. Nuclear localized HHEX bound to and upregulated TLE3 expression by preventing TLE3 protein from being distributed to the cytoplasm and being ubiquitinated. In conclusion, our study suggested that restoring HHEX expression has the potential to be a new strategy in the treatment of advanced thyroid cancer.

Exploring the molecular mechanism of Gan Shuang granules for the treatment of non-alcoholic steatohepatitis using network pharmacology, molecular docking, and experimental verification.

Background: With the gradual increase in prevalence in recent years, non-alcoholic steatohepatitis (NASH) has become one of the significant health problems that urgently needs to be addressed worldwide. GanShuang Granules (GSG) is derived from the classical Chinese formula Xiaoyao San and mainly used in the clinical treatment of chronic liver diseases. Objective: In this study, we aim to gain a deeper insight into the inhibiting effects of GSG on non-alcoholic fatty liver disease (NAFLD) rats and preliminarily elucidate the underlying intervention mechanisms. Methods: First, High performance liquid chromatography (UHPLC-Q/Orbitrap-MS/MS) was used for the active compounds prediction in GSG. Then the data was mapped to mzCloud database. The targets corresponding to GSG compounds were collected from public databases, along with disease genes for NAFLD. The core targets and molecular mechanisms of GSG for NAFLD treatment were predicted by protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Molecular docking of the core target-component interactions was simulated using AutoDock Vina software. The effect of GSG on NASH rats was evaluated by pathological staining and analysis of various index results. Finally, the candidate targets were further validated by ELISA and western blot (WB) analyses. Results: Combining UHPLC-Q/Orbitrap-MS/MS data analysis and public database data, a total of 346 cross-targets were obtained, corresponding to 81 compounds. The subnetwork with an MCODE score of 53.623 is a potential core target group for this study. GO and KEGG enrichment analyses showed that the targets of GSG in NAFLD were mostly related to oxidative stress, the NF-κB signaling pathway, and the apoptosis signaling pathway. By integrating the results of network pharmacology analysis, the core objectives of this study mainly include AKT1, CASP9, TNF, and CASP8. The core ingredients are related to resveratrol and fisetin. The molecular docking results indicated key binding activity between AKT1-fisetin, AKT1-Resveratrol, and CASP8-fisetin. Moreover, GSG could improve the inflammatory status and restore the abnormal lipid accumulation of NAFLD/NASH liver, and these levels are further verified by pathological staining and detection of related indicators. Mechanistically, GSG could regulate protein expression levels in the liver for P65, p-P65, IKB, p-IKB, IKK, caspase-3, -8, -9, and cytochrome C, etc. It reflects the inhibitory effect of GSG on the NF-κB/IκB signaling pathway. Conclusion: Our results suggested that GSG demonstrated therapeutic effects on NAFLD/NASH rats, and these may be mainly reflected in the inhibitory effects on the NF-κB/IκB signaling pathway and its downstream inflammation and apoptosis signals.

Exosomes from human urine-derived stem cells carry NRF1 to alleviate bladder fibrosis via regulating miR-301b-3p/TGFßR1 pathway.

Bladder outlet obstruction (BOO) is a common disease that always make the bladder develops from inflammation to fibrosis. This study was to investigate the effect of exosomes from human urine-derived stem cells (hUSCs) on bladder fibrosis after BOO and the underlying mechanism. The BOO mouse model was established by inserting a transurethral catheter, ligation of periurethral wire, and removal of the catheter. Mouse primary bladder smooth muscle cells (BSMCs) were isolated and treated with TGFß1 to mimic the bladder fibrosis model in vitro. Exosomes from hUSCs (hUSC-Exos) were injected into the bladder of BOO mice and added into the culture of TGFß1-induced BSMCs. The associated factors in mouse bladder tissues and BSMCs were detected. It was confirmed that the treatment of hUSC-Exos alleviated mouse bladder fibrosis and down-regulated fibrotic markers (a-SMA and collagen III) in bladder tissues and TGFß1-induced BSMCs. Overexpression of NRF1 in hUSC-Exos further improved the effects of hUSC-Exos on bladder fibrosis both in vivo and in vitro. TGFßR1 was a target of NRF1 and miR-301b-3p, and miR-301b-3p was a target of NRF1. It was next characterized that hUSC-Exos carried NRF1 to up-regulate miR-301B-3p, thereby reducing TGFßR1level. Our results illustrated that hUSC-Exos carried NRF1 to alleviate bladder fibrosis through regulating miR-301b-3p/TGFßR1 pathway.

Study on Detection and Recognition of Traffic Lights Based on Improved YOLOv4.

To resolve the issues of a deep backbone network, a large model, slow reasoning speed on a mobile terminal, low detection accuracy for small targets and difficulties detecting and recognizing traffic lights in real time and accurately with YOLOv4, a traffic lights recognition method based on improved YOLOv4 is proposed. The lightweight ShuffleNetv2 network is utilized to replace the CSPDarkNet53 network of YOLOv4 to satisfy the requirements of a mobile terminal. The reformed k-means clustering algorithm is applied to generate anchor boxes for avoiding the sensitivity issue of outliers and initial values. A novel attention mechanism named CS2A is added to enhance the extraction capability of effective features. Multiple data augmentation methods are combined to improve the generalization ability of the model. Ultimately, the detection and recognition of traffic lights can be realized. The S2TLD dataset is selected for training and testing, and it can be proved that the recognition accuracy and model size are greatly optimized. Meanwhile, a self-made dataset is selected for training and testing. Compared with the conventional YOLOv4, the recognition accuracy of the proposed algorithm for traffic lights' state information increases by 1.79%, and the model size decreases by 81.97%. Appropriate scenes are selected for real-vehicle testing and the results demonstrate that the detection speed of the presented algorithm increases by 16%, and the recognition effect for small targets increases by 37% in comparison with conventional YOLOv4.

Clinical analysis of tracheobronchial foreign body aspiration in children: a focus on external and intrinsic factors.

BACKGROUND: Tracheobronchial foreign body aspiration (TFBA) is a critical disease in children and is extremely dangerous, even life-threatening. The factors affecting the occurrence and prognosis of TFBA are complex. The purpose of this study is to examine the external and intrinsic factors affecting clinical features of TFBA in West China and propose potential effective intervention measures. METHODS: We retrospectively analyzed the clinical data of pediatric patients diagnosed with TFBA with foreign bodies (FBs) removed by rigid bronchoscopy under general anesthesia at the otolaryngology department from December 2017 to November 2018. The data included age, sex, clinical symptoms, type and location of FB, guardians, prehospital duration and residence of these pediatric patients. RESULTS: The ratio of males (72) to females (53) was 1.4:1. Children aged from 1 to 3 years accounted for 76% (95/125) of patients. Cough, continuous fever and dyspnea were the primary symptoms. The right primary bronchus was the most common location of FB detection by rigid bronchoscopy (67 cases, 53.6%). Organic FBs were most common in our study. Guardians of patients significantly differed in the rural (parents 16, grandparents 31) and urban (parents 52, grandparents 26) groups (χ2 = 12.583, p = 0.000). More children in the rural group than in the urban group had a treatment delay longer than 72 h. More children in the group with no history of FB aspiration (12, 25%) than in the group with prior FB aspiration had a treatment delay longer than 72 h. CONCLUSION: Pediatric TFBA is a common emergency in otolaryngology. Age, sex, tracheobronchial anatomy and other physiological elements were defined as intrinsic factors, while guardians, residence, FB species and prehospital time were defined as external factors of TFBA. External and intrinsic factors both influence the occurrence and progression of TFBA. It is extremely important to take effective measures to control external factors, which can decrease morbidity and mortality.

A CARE-compliant article: Lymphangiomatous polyps of the palatine tonsils in a miner: A case report.

RATIONALE: Lymphangiomatous polyps of the palatine tonsils are benign tumors that are rare in both adults and children. Most patients suffering from this disease present with nonspecific symptoms similar to those of chronic tonsillitis. PATIENT CONCERN: We report a case of a 21-year-old male miner who presented with a chronic history of a foreign body sensation in the oropharynx and an intermittently sore throat. DIAGNOSIS: The patient was preoperatively diagnosed with the palatine tonsils neoplasm. INTERVENTIONS: The neoplasm with palatine tonsils was completely resected under general anesthesia. The tissue was sent for histological examination, and the diagnosis was lymphangiomatous polyps of the palatine tonsils. OUTCOME: The surgical outcome was good, and no surgical site infection was recorded. After 12 months of follow-up, the miner was asymptomatic with no recurrence. LESSONS: Tonsillectomy is a curative method to address lymphangiomatous polyps (LAPs) of the tonsils which resulted in no recurrence during the clinical follow-up period. The etiology of this rare disorder and potential pathogenesis should be studied in the future, which would help prevent its occurrence.