Effect of Antidepressants on Non-Alcoholic Fatty Liver Disease and their Underlying Mechanism.

INTRODUCTION: The high prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), a chronic progressive disease characterized by hepatic steatosis, poses a serious burden to human health. Depression and NAFLD share some common pathogenic mechanisms, and patients with depression are at an increased risk of NAFLD. The drug mirtazapine is commonly used in the treatment of depression, but it can also cause liver damage. However, whether mirtazapine induces or aggravates NAFLD remains uncertain. Thus, we evaluated the risk factors for NAFLD in patients with depression and the effects of mirtazapine on NAFLD in vitro. METHODS: Inpatients diagnosed with depression at the Second Xiangya Hospital of Central South University between 2019 and 2022 were included in this study, and NAFLD was determined using an abdominal ultrasound examination. The risk factors for the development of NAFLD in patients with depression were analyzed using logistic regression analysis. AML-12 and MIHA cell lines were used to observe the effects of mirtazapine on NAFLD using oil red O staining. RT-qPCR and western blotting were used to explore the molecular mechanism behind NAFLD development induced by mirtazapine. RESULTS: Logistic regression analysis showed that older age, use of mirtazapine or fluoxetine, longer duration of antidepressant use, and combined hyperlipidemia or T2DM were risk factors for NAFLD in patients with depression. in vitro experiments revealed a subsequent increase in the content of intracellular lipid droplets as mirtazapine concentration increased. Mechanistic studies showed that mirtazapine increased the expressions of TLR4, MyD88, IFN-γ, IL-1ß, IL-6, and TNF-α mRNA in hepatocytes. Moreover, the expressions of TLR4, MyD88, and p-NF-κB-p65 proteins increased in a dose-dependent manner. CONCLUSION: Age, antidepressant type, duration of antidepressant use, and comorbidities could be risk factors for NAFLD in patients with depression. Furthermore, mirtazapine can cause steatosis in both AML-12 and MIHA cell lines and may promote the development of NAFLD through the TLR4/MyD88/NF-κB signaling pathway. This study lays a solid foundation for further research on depression and NAFLD and can contribute to the prevention and treatment of these two diseases.

NEMF-mediated Listerin-independent mitochondrial translational surveillance by E3 ligase Pirh2 and mitochondrial protease ClpXP.

The ribosome-associated protein quality control (RQC) pathway acts as a translational surveillance mechanism to maintain proteostasis. In mammalian cells, the cytoplasmic RQC pathway involves nuclear export mediator factor (NEMF)-dependent recruitment of the E3 ligase Listerin to ubiquitinate ribosome-stalled nascent polypeptides on the lysine residue for degradation. However, the quality control of ribosome-stalled nuclear-encoded mitochondrial nascent polypeptides remains elusive, as these peptides can be partially imported into mitochondria through translocons, restricting accessibility to the lysine by Listerin. Here, we identify a Listerin-independent organelle-specific mitochondrial RQC pathway that acts on NEMF-mediated carboxy-terminal poly-alanine modification. In the pathway, mitochondrial proteins carrying C-end poly-Ala tails are recognized by the cytosolic E3 ligase Pirh2 and the ClpXP protease in the mitochondria, which coordinately clear ribosome-stalled mitochondrial nascent polypeptides. Defects in this elimination pathway result in NEMF-mediated aggregates and mitochondrial integrity failure, thus providing a potential molecular mechanism of the RQC pathway in mitochondrial-associated human diseases.

Endoscopic Submucosal Dissection for Treatment of Early-Stage Cancer or Precancerous Lesion in the Upper Gastrointestinal Tract in Patients with Liver Cirrhosis.

(1) Background: Endoscopic submucosal dissection (ESD) has been widely accepted as the standard method for treating early-stage cancer or precancerous lesions in the upper gastrointestinal tract; however, it may be difficult in patients with liver cirrhosis due to clinical challenges such as coagulation dysfunction, presence of gastroesophageal varices, etc. We aimed to demonstrate the safety and efficacy of ESD in these populations. (2) Methods: The clinical data of patients were retrospectively collected and analyzed. Inclusion criteria of the study were: a. patients with liver cirrhosis; b. patients who underwent ESD; c. patients who were diagnosed with early-stage cancer or precancerous lesions in the upper gastrointestinal tract. (3) Results: Eight patients were enrolled from April 2019 to April 2023, of whom three were male and five were female, with ages ranging from 43 to 70 years old. Seven lesions were located in the stomach and one other lesion was in the esophagus. ESD was performed successfully in all eight patients, and the resected lesion size ranged from 2 to 6 cm. Only one patient encountered postoperative complications, namely, chest pain and fever. No recurrence was noticed during a follow-up of 3 to 45 months. (4) Conclusions: ESD may serve as a safe and effective method for treating upper gastrointestinal early-stage cancer or precancerous lesions in patients with liver cirrhosis.

Role of Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA) in the Diagnosis of Suspicious Malignant Esophageal Strictures.

(1) Background: The accurate diagnosis of esophageal strictures is quite critical for optimizing medical intervention. However, the diagnosis of suspicious malignant esophageal strictures with intact mucosa appearance and negative biopsy results is challenging. This study aimed to evaluate the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the diagnosis of suspicious esophageal strictures. (2) Methods: We retrospectively analyzed the cases with suspicious malignant esophageal strictures that underwent EUS-FNA, with or without rapid on-site evaluation (ROSE), in our hospital from April 2017 to September 2022. Their clinical manifestations, imaging examinations, gastroscopic examinations, EUS-FNA results, and therapeutic strategies were retrospectively recorded and analyzed. (3) Results: A total of 23 patients (15 male and 8 female) were enrolled in this study. Based on EUS-FNA results, 18 patients were diagnosed with malignancies, including 16 cases of primary esophageal cancer (13 squamous carcinomas and 3 adenocarcinomas), 1 case of mediastinal cancer, and 1 case of metastatic esophageal cancer; 1 case of tuberculosis was also confirmed by EUS-FNA. Among 4 cases of ambiguous diagnosis with EUS-FNA, 1 was diagnosed with an esophageal glomus tumor after surgical removal, and 2 patients survived for several years without medical intervention, which hinted at the possibility of benign esophageal strictures. No major complications, including bleeding or perforation, were observed. (4) Conclusions: EUS-FNA may serve as a safe and effective diagnostic tool in suspicious malignant esophageal strictures with accurate specimen acquisition, especially for biopsy-negative cases.