TBC1D5 reverses the capability of HIF-2α in tumor progression and lipid metabolism in clear cell renal cell carcinoma by regulating the autophagy.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is known for abnormal lipid metabolism and widespread activation of HIF-2α. Recently, the importance of autophagy in ccRCC has been focused, and it has potential connections with HIF-2α and lipid metabolism. However, the specific regulatory mechanism between HIF-2α, autophagy, and lipid metabolism in ccRCC is still unclear. METHODS: In this study, Bioinformatics Analysis and Sequencing of the whole transcriptome were used to screen our target. The expression of TBC1D5 in renal clear cell carcinoma was confirmed by database analysis, immunohistochemistry, PCR and Western blot. The effects of TBC1D5 on tumor cell growth, migration, invasion and lipid metabolism were examined by CCK8, Transwell and oil red staining, and the mechanism of TBC1D5 on autophagy was investigated by Western blot, fluorescence microscopy and electron microscopy. Chloroquine and rapamycin were used to verified the key role of autophagy in effects of TBC1D5 on tumor cell. The regulatory mechanism of TBC1D5 in renal clear cell carcinoma (RCC) was investigated by shhif-2α, shTBC1D5, mimic, inhibitor, ChIP and Luciferase experiments. The animal model of ccRCC was used to evaluate the biological function of TBC1D5 in vivo. RESULTS: In this study, TBC1D5 was found to be an important bridge between autophagy and HIF-2α. Specifically, TBC1D5 is significantly underexpressed in ccRCC, serving as a tumor suppressor which inhibits tumor progression and lipid accumulation, and is negatively regulated by HIF-2α. Further research has found that TBC1D5 regulates the autophagy pathway to reverse the biological function of HIF-2α in ccRCC. Mechanism studies have shown that HIF-2α regulates TBC1D5 through hsa-miR-7-5p in ccRCC, thereby affecting tumor progression and lipid metabolism through autophagy. CONCLUSIONS: Our research reveals a completely new pathway, HIF-2α/hsa-miR-7-5p/TBC1D5 pathway affects ccRCC progression and lipid metabolism by regulating autophagy.

Medium- and long-chain triglyceride propofol reduces the activity of acetyl-coenzyme A carboxylase in hepatic lipid metabolism in HepG2 and Huh7 cells.

Medium- and long-chain triglyceride (MCT/LCT) propofol is widely used as an intravenous anesthetic, especially in the intensive care unit. The present study aimed to assess whether MCT/LCT propofol is safe in the hyperlipidemic population for long-term use. Free fatty acids (FFAs) were used to establish high-fat stimulation of HepG2 and Huh7 cells. Subsequently, these cells were treated with propofol at the concentration of 0, 4, or 8 µg/ml for 24 and 48 h. The results indicated that the cell viability was notably decreased when the cells were stimulated with 2 mmol/L FFAs and treated with 12 µg/ml MCT/LCT propofol. Accordingly, we chose 2 mmol/L FFAs along with 4 and 8 µg/ml MCT/LCT propofol for the subsequent experiments. Four and 8 µg/ml MCT/LCT propofol inhibited FFA-induced lipid accumulation in the cells and significantly reversed acetyl coenzyme A carboxylase (ACC) activity. In addition, MCT/LCT propofol not only significantly promoted the phosphorylation of AMPK and ACC, but also reversed the FFA-induced decreased phosphorylation of AMPK and ACC. In conclusion, MCT/LCT propofol reverses the negative effects caused by FFAs in HepG2 and Huh7 cells, indicating that MCT/LCT propofol might positively regulate lipid metabolism.

Comparison of dexmedetomidine and opioids as local anesthetic adjuvants in patient controlled epidural analgesia: a meta-analysis.

BACKGROUND: Data on the efficacy and incidence of adverse effects associated with dexmedetomidine (DEX) as a local anesthetic adjuvant for patient-controlled epidural analgesia (PCEA) are inconclusive. This meta-analysis assessed the efficacy and risks of DEX for PCEA using opioids as a reference. METHODS: Two researchers independently searched PubMed, Embase, Cochrane Library, and China Biology Medicine for randomized controlled trials comparing DEX and opioids as local anesthetic adjuvants in PCEA. RESULTS: In total, 636 patients from seven studies were included in this meta-analysis. Postoperative patients who received DEX had lower visual analog scale (VAS) scores than those who received opioids at 4-8 h (mean difference [MD]: 0.61, 95% CI [0.45, 0.76], P < 0.001, I2 = 0%), 12 h (MD: 0.85, 95% CI [0.61, 1.09], P < 0.001, I2 = 0%), 24 h (MD: 0.59, 95% CI [0.06, 1.12], P = 0.030, I2 = 82%), and 48 h (MD: 0.54, 95% CI [0.05, 1.02], P = 0.030, I2 = 91%). Additionally, patients who received DEX had a lower incidence of itching (odds ratio [OR]: 2.86, 95% CI [1.18, 6.95], P = 0.020, I2 = 0%) and nausea and vomiting (OR: 6.83, 95% CI [3.63, 12.84], P < 0.001, I2 = 24%). In labor analgesia, no significant differences in neonatal (pH and PaO2 of cord blood, fetal heart rate) or maternal outcomes (duration of labor stage, mode of delivery) were found between the DEX and opioid groups. CONCLUSIONS: Compared with opioids, using DEX as a local anesthetic adjuvant in PCEA improved postoperative analgesia and reduced the incidence of itching and nausea and vomiting without increasing the incidence of adverse events.

Comparison of different methods of obturator nerve block in transurethral resection of bladder tumors: A systematic review and network meta-analysis.

BACKGROUND: Bladder cancer is the most common malignancy of the urinary system, and accounts for 3% of newly diagnosed tumors. Transurethral resection of bladder tumor plays a key role in treating bladder cancer, among which one of the most serious complications is bladder perforation caused by obturator nerve reflex. Obturator nerve reflex can be prevented by inducing obturator nerve block after lumbar anesthesia. However, No study so far has compared the inhibitory effect of different obturator nerve block approaches on intraoperative obturator nerve reflex and bladder perforation. METHOD: In this study, we conducted a network meta-analysis (NMA) of studies comparing the efficacy of different obturator nerve block approaches performed after lumbar anesthesia in operation. RESULT: The distal obturator nerve block guided by peripheral nerve stimulator is the best approach for preventing obturator reflex. The proximal obturator nerve block guided by ultrasound is the best approach for preventing bladder perforation. CONCLUSION: Spinal anesthesia combined with the distal obturator nerve block guided by peripheral nerve stimulator is the most optimal approach to prevent the obturator nerve reflex. But the doctor should choose the appropriate anesthesia method according to the patient's general condition, tumor location, and doctor's proficiency in puncture techniques.

Analysis of the Preventive Action of Rivaroxaban against Lower Extremity Deep Venous Thrombosis in Patients after Laparoscopic Radical Gastrectomy.

Background: Gastric carcinoma (GC) is a common lethal cancer in the world. Patients are prone to develop lower extremity deep venous thrombosis (LEDVT) after laparoscopic radical gastrectomy (LRG), which threatens their life and health. Purpose: This research is to clarify the preventive action of rivaroxaban (Riv) against LEDVT in patients undergoing LRG. Methods: A retrospective study was conducted on 70 patients with GC admitted for LRG between January 2019 and January 2022, including 40 patients (observation group) receiving Riv treatment and 30 patients (conventional group) treated with air wave pressure therapy apparatus. Quality of life, coagulation function, LEDVT formation, and complications were compared between groups. Results: The observation group had better recovery of life quality than the control group, along with more effective inhibition of coagulation disorders, less DVT formation, and fewer complications. Conclusions: Compared with air wave pressure therapy apparatus, Riv has better preventive action against LEDVT in GC patients after LRG.

Melatonin postconditioning ameliorates anoxia/reoxygenation injury by regulating mitophagy and mitochondrial dynamics in a SIRT3-dependent manner.

Ischaemia/reperfusion (I/R) injury is accompanied by excessive mitochondrial autophagy (mitophagy) and an imbalance in mitochondrial dynamics. Melatonin has been reported to alleviate I/R injury by regulating mitophagy and mitochondrial dynamics. However, the underlying mechanism associated with this activity is not fully understood. The goal of the present study was to investigate whether and how melatonin administration at the beginning of reoxygenation exerts protective effects by regulating mitophagy and mitochondrial dynamics. H9c2 cells were transfected with sirtuin 3 (SIRT3)-targeting siRNA and then subjected to anoxia/reoxygenation (A/R) injury, with melatonin (150 µM) administered at the onset of reoxygenation. Biomarkers related to cellular apoptosis, oxidative stress, mitochondrial function, mitophagy and mitochondrial dynamics were assessed, and the expression and activity of SIRT3 was also measured. Mitochondrial fission and mitophagy were activated after A/R injury and were accompanied by cellular apoptosis, oxidative stress, and mitochondrial dysfunction. However, melatonin postconditioning inhibited excessive mitochondrial fission and mitophagy, promoted mitochondrial fusion, restored mitochondrial function and reduced cellular apoptosis, and the mitophagy inhibitor 3-methyladenine (3-MA) also attenuated A/R-induced apoptosis. Moreover, the A/R-induced decreases in SIRT3 and manganese superoxide dismutase (SOD2) activities were ameliorated by melatonin. However, SIRT3 silencing abolished the beneficial effects of melatonin, eliminated the inhibitory effects of melatonin on mitochondrial fission and mitophagy, and reversed the melatonin-induced increase in SOD2 activity. These results indicate that melatonin postconditioning protects H9c2 cells from A/R injury by inhibiting excessive mitophagy and maintaining the balance of mitochondrial fission and fusion in a SIRT3-dependent manner.

Melatonin Attenuates Anoxia/Reoxygenation Injury by Inhibiting Excessive Mitophagy Through the MT2/SIRT3/FoxO3a Signaling Pathway in H9c2 Cells.

PURPOSE: Autophagy caused by ischemia/reperfusion (I/R) increases the extent of cardiomyocyte damage. Melatonin (Mel) diminishes cardiac injury through regulating autophagy and mitochondrial dynamics. However, illustrating the specific role of mitophagy in the cardioprotective effects of melatonin remains a challenge. The aim of our research was to investigate the impact and underlying mechanisms of melatonin in connection with mitophagy during anoxia/reoxygenation (A/R) injury in H9c2 cells. METHODS: H9c2 cells were pretreated with melatonin with or without the melatonin membrane receptor 2 (MT2) antagonist 4-P-PDOT, the MT2 agonist IIK7 and the sirtuin 3 (SIRT3) inhibitor 3-TYP for 4 hours and then subjected to A/R injury. Cell viability, cellular apoptosis, necrosis levels and oxidative markers were assessed. The expression of SIRT3 and forkhead box O3a (FoxO3a), mitochondrial function and the levels of mitophagy-related proteins were also evaluated. RESULTS: A/R injury provoked enhanced mitophagy in H9c2 myocytes. In addition, increased mitophagy was correlated with decreased cellular viability, increased oxidative stress and mitochondrial dysfunction in H9c2 cells. However, melatonin pretreatment notably increased cell survival and decreased cell apoptosis and oxidative response after A/R injury, accompanied by restored mitochondrial function. The inhibition of excessive mitophagy is involved in the cardioprotective effects of melatonin, as shown by the decreased expression of the mitophagy-related molecules Parkin, Beclin1, and BCL2-interacting protein 3-like (BNIP3L, best known as NIX) and decreased light chain 3 II/light chain 3 I (LC3 II/LC3 I) ratio and upregulation of p62 expression. Moreover, the decreased expression of SIRT3 and FoxO3a in A/R-injured H9c2 cells was abrogated by melatonin, but these beneficial effects were attenuated by the MT2 antagonist 4-P-PDOT or the SIRT3 inhibitor 3-TYP and enhanced by the MT2 agonist IIK7. CONCLUSION: These results indicate that melatonin protects H9c2 cells during A/R injury through suppressing excessive mitophagy by activating the MT2/SIRT3/FoxO3a pathway. Melatonin may be a useful candidate for alleviating myocardial ischemia/reperfusion (MI/R) injury in the future, and the MT2 receptor might become a therapeutic target.

Pleiotropic effects and pharmacological properties of penehyclidine hydrochloride.

BACKGROUND: Penehyclidine hydrochloride (PHC) is an anticholinergic drug manufactured in China. It is used widely in clinics as a reversal agent in cases of organic phosphorus poisoning and as a preanesthetic medication. Compared with other anticholinergic agents, PHC confers substantial advantages. Here, in this review, we focus on its important clinical effects for organic phosphorus poisoning, preanesthetic medication, and the protective effects on certain visceral organs. MATERIALS AND METHODS: Our bibliographic sources include the PubMed and China National Knowledge Infrastructure (CNKI) databases, updated in March 2018. To assess the data in detail, we used the search terms "penehyclidine hydrochloride," "preanesthetic medication," and "organic phosphorus." Papers were restricted to those published in the English and Chinese languages, and to "paper" and "review" as the document type. RESULTS: PHC can effectively antagonize the symptoms of central and peripheral poisoning caused by organophosphorus poisoning. As a preanesthetic medication, it can not only effectively reduce mucus secretion and vascular infiltration but can also relax airway smooth muscles, dilate bronchioles in pulmonary conditions such as bronchiectasis, and increase pulmonary dynamic compliance. It can also prevent reflexive actions of the vagus nerve caused by excessive acetylcholine release such as abnormal airway contraction. Furthermore, it can strengthen sedation, bidirectionally regulate heart rate, and effectively inhibit respiratory secretions. In recent studies, PHC was shown to also have protective effects on various organs, such as the heart, lungs, brain, kidneys, intestines, and liver. CONCLUSION: PHC has beneficial pharmacological properties used in the treatment of organophosphorus poisoning and as a preanesthetic medication for its few side effects. It also has protective effects on multiple organs, suggesting that PHC has extensive clinical application value which is worth further research. This review should be of help to those intending to research these topics further.

Penehyclidine hydrochloride preconditioning provides pulmonary and systemic protection in a rat model of lung ischaemia reperfusion injury.

Penehyclidine hydrochloride (PHC) is a new anticholinergic agent that provides protective effects in experimental models of heart and brain ischaemia as well as reperfusion (I/R) injury. In this study, we tested the hypothesis that PHC can alleviate lung ischaemia-reperfusion injury and improve pulmonary and systemic function in rats. PHC was administered intravenously at various doses (d= 0.1, 0.3, 1, 3 mg/kg) to I/R rats. We used six indicators, including lung function, histologic examination, pulmonary oedema, oxidative stress, inflammatory responses, and apoptosis staining to quantify the pulmonary and systemic protective effects of PHC. Haematoxylin and eosin staining was used for pulmonary histologic examination. The expression of Toll-like receptor (TLR) 4, phospho-inhibitor of NF-κB (p-IκB) and nuclear factor-kappa B (NF-κB) was analysed using western blotting. ELISA was conducted to detect inflammatory mediators. Oxidative stress markers as well as myeloperoxidase (MPO) were determined using an assay kit. PHC preconditioning (with concentrations ranging from 0.3 mg/kg to 3 mg/kg 30 min before the onset of I/R) significantly reduced lung histopathological changes, down regulated TLR4, p-IκB and NF-κB expression, and decreased inflammatory mediators as well as the total number of leukocytes and neutrophils in bronchoalveolar lavage (BAL) fluid and plasma. The lung tissue contents of reactive oxygen species (ROS), malondialdehyde (MDA), and MPO as well as pulmonary oedema formation decreased, while SOD (superoxide dismutase) activity was significantly upregulated. PHC preconditioning (with concentrations ranging from 1 mg/kg to 3 mg/kg) significantly improved the lung function and attenuated the apoptotic rate. The probable mechanism for this finding is the inhibition of proinflammatory mediators via the suppression of reactive oxygen species production and the TLR4/NF-κB signalling pathway.