TSPO is a novel biomarker for prognosis that regulates cell proliferation through influencing mitochondrial functions in HCC.

The disorder of mitochondrial functions plays a key role in oncogenesis. It is known that TSPO (18-kDa translocator protein) lies in a peculiar location at the interface between the mitochondria and the cytosol. TSPO is found in many types of tissues and is associated with multiple cellular processes, including apoptosis, cell proliferation and the regulation of mitochondria. However, the involvement of TSPO in hepatocellular carcinoma (HCC) remains unclear. In this study, we found that TSPO is upregulated in HCC tissue and is associated with poor differentiation and poor survival. Multivariate analyses showed that TSPO was an independent predictive factor for poor prognosis in HCC patients. For the first time, we provided evidence that TSPO knockdown suppressed HCC cell proliferation in vitro. Hence, TSPO knockdown-induced apoptosis by disturbing mitochondrial function by enhancing the formation of reactive oxygen species (ROS) and decreasing the mitochondrial membrane potential (ΔΨm). An assay exploring the underlying mechanism revealed that TSPO knockdown modulated apoptotic regulatory proteins by regulating the ERK signaling pathway. Through a functional assay and an in vivo mouse model, the anti-cancer effect of PK11195, a specific ligand of TSPO, on HCC was revealed. In summary, TSPO may potentially serve as a prognostic biomarker, and TSPO might be a potential therapeutic target for HCC.

Effect of mindfulness-based intervention on endurance performance under pressure and performance-relevant mental attributes, an interdisciplinary perspective: Protocol for a Mindfulness-Based Peak Performance (MBPP) trial.

Performance under pressure is one of the primary features of competitive sports. Considering that increased competition levels are typically accompanied by elevated stress and anxiety, athletes' ability to cope with stress has gained even more importance in recent years. Accordingly, the current trial, entitled Mindfulness-based Peak Performance (MBPP), will take an interdisciplinary approach (e.g., sport psychology, sports training, and cognitive neuroscience), to more definitively examine whether a MBPP affects athletic performance under pressure and relevant mental attributes. This study is an 8-week, three-arm, randomized controlled trial (RCT). A total of 90 athletes, aged between 18 and 30 years will be recruited. Eligible participants will be randomly assigned into (1) an MBPP group, (2) a self-talk (ST) group, and (3) a wait-list control (WC) group. The MBPP and ST interventions consist of a 60-min session weekly for 8 weeks. Primary outcomes are endurance performance and performance-relevant mental attributes including behavior (i.e., stress response, emotion regulation, and engagement) and neurocognitive processes (e.g., attention, executive function, brain resting state), which will be assessed at baseline and post-intervention. Dispositional mindfulness and athletic psychological skills will be secondary outcomes, also assessed at baseline and post-intervention. The MBPP and ST are expected to improve performance under pressure, but MBPP is expected to show greater improvement than ST. Additionally, we expect the MBPP will improve the relevant mental attributes. The results from this trial might provide rigorous evidence and insight into MBI application in the sports context. ClinicalTrials.govregistration:NCT05612295.

Dexmedetomidine Protects Against Chemical Hypoxia-Induced Neurotoxicity in Differentiated PC12 Cells Via Inhibition of NADPH Oxidase 2-Mediated Oxidative Stress.

Dexmedetomidine (Dex) is a widely used sedative in anesthesia and critical care units, and it exhibits neuroprotective activity. However, the precise mechanism of Dex-exerted neuroprotection is not clear. Increased neuronal NADPH oxidase 2 (NOX2) contributes to oxidative stress and neuronal damage in various hypoxia-related neurodegenerative disorders. The present study investigated whether Dex regulated neuronal NOX2 to exert its protective effects under hypoxic conditions. Well-differentiated PC12 cells were exposed to cobalt chloride (CoCl2) to mimic a neuronal model of chemical hypoxia-mediated neurotoxicity. The data showed that Dex pretreatment of PC12 cells significantly suppressed CoCl2-induced neurotoxicity, as evidenced by the enhanced cell viability, restoration of cellular morphology, and reduction in apoptotic cells. Dex improved mitochondrial function and inhibited CoCl2-induced mitochondrial apoptotic pathways. We further demonstrated that Dex attenuated oxidative stress, downregulated NOX2 protein expression and activity, and inhibited intracellular calcium ([Ca2+]i) overload in CoCl2-treated PC12 cells. Moreover, knockdown of the NOX2 gene markedly improved mitochondrial function and attenuated apoptosis under hypoxic conditions. These results demonstrated that the protective effects of Dex against hypoxia-induced neurotoxicity in neural cells were mediated, at least partially, via inhibition of NOX2-mediated oxidative stress.

The Prognostic Value of Peripheral Benzodiazepine Receptor in Patients with Esophageal Squamous Cell Carcinoma.

Background: The peripheral benzodiazepine receptor (PBR) has previously been reported as an oncogene in prostate, breast and colorectal cancers, but its prognostic value, biological behavior and function in esophageal squamous cell carcinoma (ESCC) has not been investigated. Methods: qRT-PCR, western blotting and immunohistochemistry (IHC) were used to detect PBR expression in ESCC and matched non-cancerous tissues. Based on all of the significantly independent factors, a nomogram was established to predict the prognosis of ESCC patients. In addition, we performed comprehensive in vitro experiments to study the functions of PBR in cell growth, colony formation, and migration ability, as well as its relationship with epithelial-mesenchymal transition (EMT) related proteins in ESCC cells. Results: The mRNA and protein expression levels of PBR in ESCC were higher than those in adjacent non-tumor esophageal epithelial tissues. The IHC results demonstrated that PBR expression was an independent prognostic factor in ESCC survival, patients with higher PBR expression had a poorer survival than those with low expression, and PBR expression was significantly associated with lymphoid nodal status. Furthermore, a nomogram was established to reliably predict the probability of death in ESCC patients, with a Harrell's c-index of 0.696. In the vitro experiments, knocking down the expression of PBR inhibited proliferation, colony formation and migration of ESCC cells, and regulated EMT-associated proteins (up-regulation of E-cadherin, ZO-1 and ß-catenin and concomitant with down-regulation of Fibronectin and N-cadherin). Conclusions: PBR is an independent prognostic factor in ESCC, and it promotes ESCC progression and metastasis. Basing on PBR expression level, a nomogram is established and performs a well in predicting survival of ESCC patients.

Lidocaine Induces Apoptosis and Suppresses Tumor Growth in Human Hepatocellular Carcinoma Cells In Vitro and in a Xenograft Model In Vivo.

BACKGROUND: Recent epidemiologic studies have focused on the potential beneficial effects of regional anesthetics, and the differences in cancer prognosis may be the result of anesthetics on cancer biologic behavior. However, the function and underlying mechanisms of lidocaine in hepatocellular carcinoma both in vitro and in vivo have been poorly studied. METHODS: Human HepG2 cells were treated with lidocaine. Cell viability, colony formation, cell cycle, and apoptosis were assessed. The effects of lidocaine on apoptosis-related and mitogen-activated protein kinase protein expression were evaluated by Western blot analysis. The antitumor activity of lidocaine in hepatocellular carcinoma with or without cisplatin was investigated with in vitro experiments and also with animal experiments. RESULTS: Lidocaine inhibited the growth of HepG2 cells in a dose- and time-dependent manner. The authors also found that lidocaine arrested cells in the G0/G1 phase of the cell cycle (63.7 ± 1.7% vs. 72.4 ± 3.2%; P = 0.0143) and induced apoptosis (1.7 ± 0.3% vs. 5.0 ± 0.7%; P = 0.0009). Lidocaine may exert these functions by causing an increase in Bax protein and activated caspase-3 and a corresponding decrease in Bcl-2 protein through the extracellular signal-regulated kinase 1/2 and p38 pathways. More importantly, for the first time, xenograft experiments (n = 8 per group) indicated that lidocaine suppressed tumor development (P < 0.0001; lidocaine vs. control) and enhanced the sensitivity of cisplatin (P = 0.0008; lidocaine plus cisplatin vs. cisplatin). CONCLUSIONS: The authors' findings suggest that lidocaine may exert potent antitumor activity in hepatocellular carcinoma. Furthermore, combining lidocaine with cisplatin may be a novel treatment option for hepatocellular carcinoma.

Prognostic value of pre-operative serum uric acid levels in esophageal squamous cell carcinoma patients who undergo R0 esophagectomy.

BACKGROUND: The serum uric acid (SUA) is the end-product from the metabolic breakdown of purine nucleotides. It has been considered to be a prognostic factor for malignant tumor in several researches. However, its prognostic value in patients with esophageal squamous cell carcinoma (ESCC) has not been elucidated. METHODS: We retrospectively reviewed the records of 209 ESCC patients who underwent R0 esophagectomy. A receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off value for pre-operative SUA levels and to divide the ESCC patients into two groups. Furthermore, we analyzed the pre-operative serum uric acid (SUA) levels and its relationship with the clinicopathological parameters and the prognosis of 209 ESCC patients. RESULTS: Optimal cut-off value for pre-operative SUA in ROC analysis was 304.5 µ mol/l (sensitivity 67.46%, specificity 65.06%). SUA low- or high-levels were associated with gender (P< 0.001), smoking status (P< 0.001), pN statues (P= 0.003) and TNM stage (P= 0.010). SUA levels, tumor differentiation and pTNM stage were independent predictors of ESCC patient survival in a multivariate analysis. CONCLUSIONS: The pre-operative level of SUA is an independent prognostic predictor in ESCC patients who undergo R0 esophagectomy and patients with higher SUA level may have an unfavorable survival probability.

Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice.

Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided.