The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.
Objectives To investigated the clinical characteristics and prognosis of hypothyroid myopathy Methods The clinical characteristics were analyzed in 10 patients diagnosed with polymyositis-like hypothyroid myopathy. Symptoms and indicators at baseline and after levothyroxine replacement therapy were compared. The correlations of muscle enzyme levels with thyroid function were analyzed. Results A total of 10 patients, including 3 males and 7 females, were enrolled. The average onset age was 46.1 ± 10.3 years and duration of disease was 2.1 ± 0.9 months. The first manifestation comprised proximal muscle weakness and myalgia or arthralgia. Liver dysfunction, hyperlipidemia, muscle enzyme increased, pericardial effusion, pleural effusion, and fatty liver was common. All patients were Hashimoto's thyroiditis and negative for myositis antibodies. Pathological muscle biopsies revealed myxoid degeneration and muscle atrophy. The proportion of patients who experienced proximal muscle weakness, myalgia, and/or arthralgia, ALT increased, AST increased, CHOL increased, TG increased, CK increased , CK-MB increased, LDH increased, fT3 decreased, and fT4 decreased were significantly lower after treatment(all P<0.05). Levels of ALT, AST, CHOL, CK, CK-MB, LDH, and TSH were significantly lower while levels of fT3 and fT4 were significantly higher after treatment(all P<0.05). CK, CK-MB, and LDH levels negatively correlated with fT3 and fT4, but positively correlated with TSH (all P<0.05). Conclusion Hypothyroid myopathy was more common in female. Most patients had liver dysfunction, hyperlipidemia and abnormal muscle enzyme levels, serous cavity effusion and fatty liver. Electromyography and muscle pathology had no specific alterations. The prognosis was well after levothyroxine replacement therapy.
Observation ECA's treatment effects in Adjuvant arthritis rats and relative mechanisms. The rat model of arthritis was established by subcutaneous injection of 0.2 mL Freund's complete adjuvant. After model success, giving different ECA concentrations (25 mg/kg, 50 mg/kg and 100 mg/kg) to rats by ig methods and continued to 28 days. Measuring thymus and spleen index; observation histopathological morphology of rat joint by HE and Masson staining, and Inflammatory cells, synovial hyperplasia, oochas score and degree of fibrosis were detected semi quantitatively. The relative gene and protein expressions were measured by RT-PCR and Western blot. Compared with Normal group, Inflammatory cells, synovial hyperplasia, fibrosis and oochas score increased significantly in Model group (P<0.01, respectively); COX-1, COX-2, TNF-α, IL-1β, IL-6 and IL-17 mRNA expression were significantly up-regulation (P<0.01); AMPK, Beclin1 and ATG12 mRNA and protein expressions were significantly down-regulation (P<0.01, respectively). Compared with Model group, The inflammatory cells, the degree of fibrosis, the proliferation of synovial tissue and OOCHAS score decreased significantly in Middle and High groups (P<0.01, respectively); Thymus index significantly depressed in Low, Middle and High groups (P<0.01, respectively); spleen index were significantly down-regulation in Middle and High groups (P<0.05 or P<0.01); COX-2, TNF-α and IL-17 mRNA expression was significantly down-regulation (P<0.05), IL-1βand IL-6 mRNA expression were significantly depressed in Middle and High groups (P<0.05 or P<0.01); AMPK, Beclin1, LC3-II, ATG5 and ATG7 mRNA expressions were significantly up-regulation in Middle and High groups (P<0.05 or P<0.01); mTOR gene expression was significantly down-regulation (P<0.05), ATG12 mRNA expression was significantly up-regulation (P<0.01) in High group; AMPK, Beclin1, LC3-II, ATG5 and ATG7 protein expressions were significantly increased in High group (P<0.05 or P<0.01), mTOR protein expression were significantly down-regulation and ATG12 protein expression were significantly up-regulation in Low, Middle and High groups (P<0.05 or P<0.01, respectively). ECA can inhibit the inflammatory response in adjuvant arthritis rats, and its mechanism may be related to promoting autophagy of synovial cells.
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