HSK3486 Inhibits Colorectal Cancer Growth by Promoting Oxidative Stress and ATPase Inhibitory Factor 1 Activation.

BACKGROUND: HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown. AIMS: This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation. METHODS: Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells. RESULTS: Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486. CONCLUSION: Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.

Fasting-Mimicking Diet Drives Antitumor Immunity against Colorectal Cancer by Reducing IgA-Producing Cells.

As a safe, feasible, and inexpensive dietary intervention, fasting-mimicking diet (FMD) exhibits excellent antitumor efficacy by regulating metabolism and boosting antitumor immunity. A better understanding of the specific mechanisms underlying the immunoregulatory functions of FMD could help improve and expand the clinical application of FMD-mediated immunotherapeutic strategies. In this study, we aimed to elucidate the role of metabolic reprogramming induced by FMD in activation of antitumor immunity against colorectal cancer. Single-cell RNA sequencing analysis of intratumoral immune cells revealed that tumor-infiltrating IgA+ B cells were significantly reduced by FMD treatment, leading to the activation of antitumor immunity and tumor regression in murine colorectal cancer models. Mechanistically, FMD delayed tumor growth by repressing B-cell class switching to IgA. Therefore, FMD-induced reduction of IgA+ B cells overcame the suppression of CD8+ T cells. The immunoregulatory and antitumor effects of FMD intervention were reversed by IgA+ B-cell transfer. Moreover, FMD boosted fatty acid oxidation (FAO) to trigger RUNX3 acetylation, thus inactivating Cα gene transcription and IgA class switching. IgA+ B-cell expansion was also impeded in patients placed on FMD, while B-cell expression of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme of FAO, was increased. Furthermore, CPT1A expression was negatively correlated with both IgA+ B cells and IgA secretion within colorectal cancer. Together, these results highlight that FMD holds great promise for treating colorectal cancer. Furthermore, the degree of IgA+ B cell infiltration and FAO-associated metabolic status are potential biomarkers for evaluating FMD efficacy. SIGNIFICANCE: Metabolic reprogramming of B cells induced by fasting-mimicking diet suppresses IgA class switching and production to activate antitumor immunity and inhibit tumor growth. See related commentary by Bush and Perry, p. 3493.

Psychological Impact and Workload of COVID-19 on Healthcare Workers in China During the Early Time of the Pandemic: A Cross-sectional Study.

OBJECTIVE: This study aimed to investigate the organization, workload, and psychological impact of COVID-19 on healthcare workers from the domestic Medical Aid Teams (MATs) sent to Wuhan in China. METHODS: Leaders and members of MATs involved in the care for COVID-19 patients were invited to participate in a study by completing 2 separate self-report questionnaires from April 1 to 24, 2020. RESULTS: A total of 9 MAT leaders were involved and 464 valid questionnaires were collected from 140 doctors and 324 nurses. Mean age of the doctors and nurses were 39.34 ± 6.70 (26∼58 years old) and 31.88 ± 5.29 (21∼52 years old), with 72 (15.5%) being males. Nurses were identified as an independent risk factor (HR 1.898; P = 0.001) for a day working time in the multivariate analysis. The proportions of psychological consulting received among nurses were higher than those among doctors (49.7 vs 30.0%, P < 0.001). More than 50% of the anesthetists and emergency doctors who have received psychological consulting thought that it was effective according to self-evaluation. CONCLUSIONS: This study focused on healthcare workers' situation during the early period of the pandemic. Nurses worked longer than doctors. The effectiveness of psychological consulting depends on the physicians' specialties and the working conditions of the nurses and psychological consulting targeting different specialties need to be improved.

The Role of Ferroptosis in Acute Respiratory Distress Syndrome.

Ferroptosis is a newly discovered type of regulated cell death that is different from apoptosis, necrosis and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation, which induces cell death. Iron, lipid and amino acid metabolism is associated with ferroptosis. Ferroptosis is involved in the pathological development of various diseases, such as neurological diseases and cancer. Recent studies have shown that ferroptosis is also closely related to acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS), suggesting that it can be a novel therapeutic target. This article mainly introduces the metabolic mechanism related to ferroptosis and discusses its role in ALI/ARDS to provide new ideas for the treatment of these diseases.

The Effect of Epidural Nalbuphine Combined With Ropivacaine on Epidural Analgesia During Labor: A Multicenter, Randomized, Double-blind, Controlled Study.

OBJECTIVES: The addition of a small dose of opioids during epidural labor analgesia can enhance the local analgesic effect, reduce the dose of local anaesthetic required, and minimize motor blockade. For the treatment of visceral pain, studies have shown that κ-opioid receptor agonist are more effective than µ-receptor agonists. This study compared the effectiveness of epidural nalbuphine and sufentanil in combination with ropivacaine for labor analgesia, respectively. MATERIALS AND METHODS: We conducted a prospective, randomized, double-blind, multicentre clinical trial. Parturients who requested labor pain relief were randomly assigned to either the nalbuphine group or sufentanil group. After 5 minutes of initial dose, parturients in nalbuphine group received 10 mL 0.1% ropivacaine plus 0.3 mg/mL nalbuphine solution. The sufentanil group received the same ropivacaine dose plus 0.3 µg/mL sufentanil. The primary outcome was the duration of analgesia (the time to the first requirement for additional medication). Secondary outcomes included the ropivacaine dose per hour, and adverse reactions. RESULTS: Between November 2018 and February 2019, 180 parturients were recruited for the study. The study showed that the duration of analgesia was shorter in the nalbuphine group as compared with the sufentanil group (P=0.040). The ropivacaine dose per hour in nalbuphine group 9.3 (2.4) mg was significantly greater versus sufentanil group 8.4 (2.5) mg (P=0.024). No serious adverse events directly associated with the analgesics were observed. DISCUSSION: The analgesia effects of 0.3 mg/mL nalbuphine with ropivacaine are inferior to 0.3 µg/mL sufentanil with ropivacaine in labor analgesia. No serious side effects, either in the mother or in the fetus, were observed.

Impact of anesthesia methods on perioperative systemic inflammation and long-term outcomes in patients undergoing surgery for hepatocellular carcinoma: a propensity score-matched analysis.

BACKGROUND: Recent studies have shown regional anesthesia might improve the survival of cancer patients. We hypothesized that general-epidural anesthesia (GEA) was associated with longer survival than general anesthesia (GA) in patients undergoing hepatocellular carcinoma (HCC) resections. METHODS: A retrospective study included patients who received curative resection for HCC between January 2014 to December 2017. Patients were grouped in GEA vs. GA. After propensity score matching, perioperative inflammatory scores were calculated. Grade of postoperative complications, length of stay (LOS), dosage of sufentanil used and times of patients requiring rescue analgesia in both groups were compared for intraoperative and postoperative parameter. Survival curves were constructed from the date of surgery to death, univariable and multivariable Cox regression models were used to compare hazard ratios for death. RESULTS: A total of 772 patients were included in the study. With 386 patients in GA group and 386 patients in GEA group. After propensity score matching, the demographic and baseline biomarkers in the two groups were similar. Patients in GEA group showed significantly lower inflammatory scores. Grade of postoperative complications, LOS, opioid use, and times of patients requiring rescue analgesia was significantly lower in the GEA group. The overall survival (OS) and disease-free survival (DFS) rate was significantly lower in the GA group (54.2% vs. 62.3%, 41.2% vs. 52.5%, P<0.001). The multivariate analysis indicated the GA was associated with shorter OS (HR: 1.28, 95% CI: 1.07-2.02, P<0.001) and DFS (HR: 1.06, 95% CI: 1.03-1.71, P<0.001). CONCLUSIONS: GA combined with epidural anesthesia is associated with lower levels of inflammation, and longer survival in patients undergoing hepatectomy.

Effects of sevoflurane and propofol on the optic nerve sheath diameter in patients undergoing laparoscopic gynecological surgery: a randomized controlled clinical studies.

BACKGROUND: The results of studies on changes in intracranial pressure in patients undergoing laparoscopic surgery are inconsistent. Meanwhile, previous neurosurgery studies have suggested that propofol and sevoflurane have inconsistent effects on cerebral blood flow and cerebrovascular self-regulation. The purpose of this study is to compare changes in the optic nerve sheath diameter in patients undergoing laparoscopic gynecological surgery under anesthetic maintenance with propofol versus sevoflurane. METHODS: This study included 110 patients undergoing laparoscopic gynecological surgery with an estimated operative time of more than 2 h under general anesthesia. The study was a randomized controlled study. The optic nerve sheath diameter (ONSD) at various time points was measured by ultrasound, including when the patients entered the operating room (Tawake), after successful anesthesia induction and endotracheal intubation (Tinduction), when the body position was adjusted to the Trendelenburg position and the CO2 pneumoperitoneum pressure reached 14 mmHg, which was recorded as T0. Then, measurements were conducted every 15 min for the first 1 h and then once every hour until the end of the surgery (T15, T30, T45, T1h, T2h …), after the end of surgery and the tracheal tube was removed (Tend), and before the patients were transferred to the ward (Tpacu). RESULTS: A significant difference in optic nerve sheath diameter was found between two groups at T15, T30, T45 (4.64 ± 0.48 mm and 4.50 ± 0.29 mm, respectively, p = 0.031;4.77 ± 0.45 mm and 4.62 ± 0.28 mm, respectively, p = 0.036;4.84 ± 0.46 mm and 4.65 ± 0.30 mm, respectively, p = 0.012), while there was no significant difference at Tawake and other time points. CONCLUSION: During laparoscopic gynecological surgery lasting more than 2 h, the optic nerve sheath diameter was slightly larger in the propofol group than that in the sevoflurane group in the first 45 min. No significant difference was observed between the two groups 1 h after surgery. TRIAL REGISTRATION: clinicaltrials.gov, NCT03498235 . Retrospectively registered 1 March 2018. The manuscript adheres to CONSORT guidelines.

Interaction of Analgesic Effects of Dezocine and Sufentanil for Relief of Postoperative Pain: A Pilot Study.

PURPOSE: The combination of dezocine and sufentanil is often used for postoperative analgesia in China and other areas, but the interaction of both two drugs is still unclear. The purpose of this study was to evaluate the interaction of the analgesic effects of dezocine and sufentanil in the patients after gynecological laparoscopic surgery. PATIENTS AND METHODS: We conducted a prospective, randomized, double-blinded clinical trial. A total of 150 patients were divided into 5 groups (30 in each group) in the post-anesthesia care unit, namely, dezocine group (Group D), sufentanil group (Group S) and dezocine mixed sufentanil groups (Group DS1-3). In group D and S, the initial dose of dezocine or sufentanil was 5mg and 5µg intravenously, respectively. In Group DS1, the initial dose was dezocine 5mg × 3/4 and sufentanil 5µg × 1/4. In Group DS2, the initial dose was dezocine 5mg × 1/2 and sufentanil 5µg × 1/2. In Group DS3, the initial dose was dezocine 5mg × 1/4 and sufentanil 5µg × 3/4. RESULTS: The median effective dose (ED50) of dezocine and sufentanil alone was 3.92 (95% confidence interval (CI) 3.01~4.64) mg and 3.71 (95% CI 2.78~4.39) µg, respectively. The isobolographic analysis showed that the combination of dezocine and sufentanil at 1:3, 1:1 or 3:1 appeared in the additive line. CONCLUSION: In conclusion, when simultaneously administered intravenously, combined dezocine and sufentanil produce an additive effect for relieving the acute nociception after gynecological laparoscopic surgery.

Dezocine regulates the malignant potential and aerobic glycolysis of liver cancer targeting Akt1/GSK-3ß pathway.

BACKGROUND: Due to the "ceiling effect" of respiratory depression and the non-addictiveness, the consumption of dezocine is increasing quickly in the cancer surgery perioperative period for security and comfort reasons in China. Former studies find dezocine inhibits the norepinephrine transporters (NET) and serotonin transporters (SERT) and sigma-1opioid receptors. Given the complexity of the molecular mechanism, the effect of dezocine on tumor cells need to be studied. In this study, we investigated the effect of dezocine on HepG2 and Hep 3B liver cancer cell lines growth and glycolysis, and the molecular mechanisms behind. METHODS: HepG2 and Hep 3B cells viability and migration were measured by CCK8, Wound healing and transwell assay, Extracellular acidification rate (ECAR) was used to index the aerobic glycolysis of liver cancer cells and western blot analysis showed protein expression levels in the cells. SC79, an agonist of Akt, and the siRNA silence of Akt1 aimed to regulate Akt1 activity and expression in the reverse experiments. RESULTS: Dezocine played opposite roles in HepG2 and Hep 3B cells viability and migration in a concentration-dependent manner (P<0.01). Dezocine has diverse effects on aerobic glycolysis and adjusts the serine/threonine kinase 1 (Akt1)-glycogen synthase kinase-3ß (GSK-3ß) pathway. The effects of SC79 and the siRNA silence of Akt1 could reverse the effects of dezocine on HepG2 and Hep 3B cells. CONCLUSIONS: As an analgesic drug widely used in clinical practice, dezocine play reversed roles on HepG2 and Hep 3B cells viability and migration targeting Akt1/GSK-3ß pathway then the glycolysis in a concentration-dependent manner.

Effect of different anesthetic methods on cellular immune functioning and the prognosis of patients with ovarian cancer undergoing oophorectomy.

The present study aimed to explore the effects of different anesthetic methods on cellular immune function and prognosis of patients with ovarian cancer (OC) undergoing oophorectomy. A total of 167 patients who received general anesthesia (GA) treatment (GA group) and 154 patients who received combined general/epidural anesthesia (GEA) treatment (GEA group) were collected retrospectively. Each group selected 124 patients that met the inclusion and exclusion criteria for further study. ELISA and radioimmunoassay were employed to detect levels of IL-2, TNF-α, and CA-125. The rates of tumor-red cell rosette (RTRR), red cell immune complex rosette (RRICR), and red cell C3b receptor rosette (RRCR) were also measured. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were determined by hemodynamics. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-2 decreased at 1 h intraoperation (T2), but increased 24-h post surgery (T3). The levels of TNF-α and IL-2 were recovered faster in the GEA group than in the GA group. The GA group exhibited greater levels of CA-125 expression than in the GEA group. The levels of RTRR, RRICR, and RRCR; ratios of CD3+, CD4+, CD4+/CD8+, CD16+, and CD56+ at 30 min after anesthesia (T1), T2, T3 and 48 h after the operation (T4) and levels of SBP, DBP, and HR at T1, T2, and T3 displayed increased levels in the GEA group than in the GA group. At 72-h post surgery (T5), the 5-year survival rate significantly increased in the GEA group compared with the GA group. GEA to be more suitable than GA for surgery on OC patients.

Effect of preloading epidural space with normal saline on the incidence of complications of epidural catheter placement and spinal anesthesia for cesarean section.

To evaluate the effect of preloading the epidural space with normal saline (NS) on the incidence of complications of epidural catheter placement and spinal anesthesia for cesarean section. Two hundred and ninety parturients at full term, who were scheduled for cesarean section under combined spinal-epidural anesthesia were randomly divided into two groups: group control (I) and group NS (II). The epidural puncture was performed at the estimated L3-4 interspace with a Tuohy needle attached to a 5 ml syringe. Loss of resistance to air was used to identify the epidural space. In group I no fluid was injected into the epidural space before insertion of the catheter; while in group II NS 5 ml was injected into the epidural space before catheter insertion. The incidence of blood vessel trauma and paraesthesia were evaluated. The effect of spinal anesthesia was evaluated. Blood vessel trauma in group II was significantly lower than in group I, P < 0.05. However, the incidence of paraesthesia was similar between the two groups, P > 0.05. Preloading the epidural space with NS can decrease the incidence of clinically apparent injury to blood vessels during epidural catheter placement, and can improve the effects of spinal analgesia, but does not reduce the incidence of paraesthesia.