Capsaicin mitigates ventilator-induced lung injury by suppressing ferroptosis and maintaining mitochondrial redox homeostasis through SIRT3-dependent mechanisms.

BACKGROUND: Ventilator-induced lung injury (VILI) is one of the severe complications in the clinic concerning mechanical ventilation (MV). Capsaicin (CAP) has anti-inflammatory and inhibitory effects on oxidative stress, which is a significant element causing cellular ferroptosis. Nevertheless, the specific role and potential mechanistic pathways through which CAP modulates ferroptosis in VILI remain elusive. METHODS: VILI was established in vivo, and the pulmonary epithelial cell injury model induced by circulation stretching (CS) was established in vitro. Both mice and cells were pretreated with CAP. Transmission electron microscopy, ELISA, Western blot, immunofluorescence, RT-PCR, fluorescent probes, and other experimental methods were used to clarify the relationship between iron death and VILI in alveolar epithelial cells, and whether capsaicin alleviates VILI by inhibiting iron death and its specific mechanism. RESULTS: Ferroptosis was involved in VILI by utilizing in vivo models. CAP inhibited ferroptosis and alleviated VILI's lung damage and inflammation, and this protective effect of CAP was dependent on maintaining mitochondrial redox system through SITR3 signaling. In the CS-caused lung epithelial cell injury models, CAP reduced pathological CS-caused ferroptosis and cell injury. Knockdown SIRT3 reversed the role of CAP on the maintaining mitochondria dysfunction under pathological CS and eliminated its subsequent advantageous impacts for ferroptosis against overstretching cells. CONCLUSION: The outcomes showed that CAP alleviated ferroptosis in VILI via improving the activity of SITR3 to suppressing mitochondrial oxidative damage and maintaining mitochondrial redox homeostasis, illustrating its possibility as a novel therapeutic goal for VILI.

Fe(III)/peroxymonosulfate oxidation system for the degradation of rhein, a toxic component abundance in rhubarb residue.

Rhubarb is widely used in health care, but causing a great amount of rhein-containing herbal residue. Rhein with several toxicities might pollute environment, damage ecology and even hazard human health if left untreated. In this study, the degradation effects of bisulfite- (BS) and peroxymonosulfate- (PMS) based oxidation systems on rhein in rhubarb residue were compared and investigated. The effects of BS and PMS with two valence states of ferric ion (Fe) on the degradation of rhein in rhubarb residue were optimized for the selection of optimal oxidation system. The influences of reaction temperature, reaction time and initial pH on the removal of rhein under the optimal oxidation system were evaluated. The chemical profiles of rhubarb residue with and without oxidation process were compared by UPLC-QTOF-MS/MS, and the degradation effects were investigated by PLS-DA and S plot/OPLS-DA analysis. The results manifested that PMS showed relative higher efficiency than BS on the degradation of rhein. Moreover, Fe(III) promoted the degradation effect of PMS, demonstrated that Fe(III)/PMS is the optimal oxidation system to degrade rhein in rhubarb residue. Further studies indicated that the degradation of rhein by the Fe(III)/PMS oxidation system was accelerated with the prolong of reaction time and the elevation of reaction temperature, and also affected by the initial pH. More importantly, Fe(III)/PMS oxidation system could degrade rhein in rhubarb residue completely under the optimal conditions. In conclusion, Fe(III)/PMS oxidation system is a feasible method to treat rhein in rhubarb residue.

Delirium in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: a multicentre randomised trial.

BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).

Long-term survival in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: follow-up of a multicentre randomised trial.

BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.

Necrostatin-1 attenuates Caspase-1-dependent pyroptosis induced by the RIPK1/ZBP1 pathway in ventilator-induced lung injury.

BACKGROUND: Ventilator-induced lung injury (VILI) is a complex pathophysiological process leading to acute respiratory distress syndrome (ARDS) and poor outcomes in affected patients. As a form of programmed cell death, pyroptosis is proposed to play an important role in the development of ARDS. Here we investigated whether treating mice with the specific RIPK1 inhibitor Necrostatin-1 (Nec-1) before mechanical ventilation could inhibit pyroptosis and alleviate lung injury in a mouse model. METHODOLOGYS: Anesthetized C57BL/6J mice received a transtracheal injection of Nec-1 (5 mg/kg) or vehicle (DMSO) 30 min before the experiment which was ventilated for up to 4 h. Lung damage was assessed macroscopically and histologically with oedema measured as the wet/dry ratio of lung tissues. The release of inflammatory mediators into bronchoalveolar lavage fluid (BALF) was assessed by ELISA measurements of TNF-α,interleukin-1ß (IL-1ß), and IL-6. The expression of RIPK1, ZBP1, caspase-1, and activated (cleaved) caspase-1 were analyzed using western blot and immunohistochemistry, and the levels of gasdermin-D (GSDMD) and IL-1ß were analyzed by immunofluorescence staining. RESULTS: High tidal ventilation produced time-dependent inflammation and lung injury in mice which could be significantly reduced by pretreatment with Nec-1. Notably, Nec-1 reduced the expression of key pyroptosis mediator proteins in lung tissues exposed to mechanical ventilation, including caspase-1, cleaved caspase-1, and GSDMD together with inhibiting the release of inflammatory cytokines. CONCLUSION: Nec-1 pretreatment alleviates pulmonary inflammatory responses and protects the lung from mechanical ventilation damage. The beneficial effects were mediated at least in part by inhibiting caspase-1-dependent pyroptosis through the RIPK1/ZBP1 pathway.

Arecoline promotes proliferation and migration of human HepG2 cells through activation of the PI3K/AKT/mTOR pathway.

BACKGROUND: Arecoline is a well-known risk factor for oral submucosal fibrosis and cancer. However, the mechanistic correlation between arecoline and hepatocellular cancer remains elusive. Here, we investigated the effect of arecoline on the proliferation and migration of human HepG2 hepatoma cells and its potential oncogenic mechanisms. METHODS: Bioinformatic technologies were used to identify the deferentially expressed miRNAs (DE-miRNAs) and hub target genes of arecoline-induced cancers. These DE-miRNAs, hub genes and pathway were proved in arecoline-treated HepG2 cells. RESULTS: A total of 86 DE-miRNAs and 460 target genes were identified. These target genes are associated with DNA-templated regulation of transcription and other biological processes. Significant molecular functions were protein binding, calcium ion binding, and enrichment in the nucleus and cytoplasm. These genes are involved in the PI3K-AKT pathway. CDK1, CCND1, RAF1, CDKN1B and BTRC were defined as the top 5 hub target genes, and patients with high expression of CDK1 showed poor prognosis. Compared with control group, 2.5 µM arecoline treatment increased the proliferation and migration ability of the HepG2 cells. Treatment with 2.5 µM arecoline increased the levels of miR-21-3p, miR-21-5p and miR-1267, upregulated the expression of PI3K-AKT pathway factors, CDK1, CCND1 but decreased RAF1 expression. CONCLUSION: A low concentration arecoline can induce the proliferation and migration of HepG2 cells, with the potential mechanism of action linked to high levels of exosomal miR-21 and miR-1267, activation of the PI3K-AKT pathway, upregulation of CDK1 and CCND1, and downregulation of RAF1.

Toll-like receptor 2 activation and up-regulation by high mobility group box-1 contribute to post-operative neuroinflammation and cognitive dysfunction in mice.

Post-operative cognitive dysfunction (POCD) is common and is associated with poor clinical outcome. Toll-like receptor (TLR) 3 and 4 have been implied in the development of POCD. The role of TLR2, a major brain TLR, in POCD is not clear. High mobility group box-1 (HMGB1) is a delayed inflammatory mediator and may play a role in POCD. The interaction between HMGB1 and TLRs in the perioperative period is not known. We hypothesize that TLR2 contributes to the development of POCD and that HMGB1 regulates TLR2 for this effect. To test these hypotheses, 6- to 8-week old male mice were subjected to right carotid artery exposure under isoflurane anesthesia. CU-CPT22, a TLR1/TLR2 inhibitor, at 3 mg/kg was injected intraperitoneally 30 min before surgery and 1 day after surgery. Glycyrrhizin, a HMGB1 antagonist, at 200 mg/kg was injected intraperitoneally 30 min before surgery. Mice were subjected to Barnes maze and fear conditioning tests from 1 week after surgery. Hippocampus and cerebral cortex were harvested 6 hr or 12 hr after the surgery for Western blotting, ELISA, immunofluorescent staining, and chromatin immunoprecipitation. There were neuroinflammation and impairment of learning and memory in mice with surgery. Surgery increased the expression of TLR2 and TLR4 but not TLR9 in the brain of CD-1 male mice. CU-CPT22 attenuated surgery-induced neuroinflammation and cognitive impairment. Similarly, surgery induced neuroinflammation and cognitive dysfunction in C57BL/6J mice but not in TLR2-/- mice. TLR2 staining appeared in neurons and microglia. Surgery increased HMGB1 in the cell nuclei of the cerebral cortex and hippocampus. Glycyrrhizin ameliorated this increase and the increase of TLR2 in the hippocampus after surgery. Surgery also increased the amount of tlr2 DNA precipitated by an anti-HMGB1 antibody in the hippocampus. Our results suggest that TLR2 contributes to surgery-induced neuroinflammation and cognitive impairment. HMGB1 up-regulates TLR2 expression in the hippocampus after surgery to facilitate this contribution. Thus, TLR2 and HMGB1 are potential targets for reducing POCD.

Impact of Sevoflurane Versus Propofol Anesthesia on Post-Operative Cognitive Dysfunction in Elderly Cancer Patients: A Double-Blinded Randomized Controlled Trial.

BACKGROUND Research on the clinical outcomes of surgical patients anaesthetized with sevoflurane and the association of sevoflurane with post-operative cognitive dysfunction (POCD) is scarce. We evaluated whether sevoflurane-based anesthesia increased the incidence of POCD and worsened prognosis compared to propofol-based anesthesia in elderly cancer patients. MATERIAL AND METHODS This single-center, prospective, double-blind randomized controlled trial included 234 patients aged 65 to 86 years undergoing tumor resection who received sevoflurane-based (Group S) or propofol-based (Group P) anesthesia during surgery. A series of neuropsychological tests was performed to evaluate cognitive function before surgery and at 7 days and 3 months post-operation, and the results were compared to those of healthy controls. RESULTS At 7 days post-operation there were no significant differences in the incidence of POCD between patients who received sevoflurane-based or propofol-based anesthesia during surgery: Group S was at 29.1% (32 out of 110 patients) versus Group P at 27.3% (30 out of 110), P=0.764. At 3 months, Group S was at 11.3% (12 out of 106 patients) versus Group P at 9.2% (10 out of 109), P=0.604. During the first 2 days post-operation, the QoR-40 global score was significantly lower in Group S compared to Group P [POD 1: P=0.004; POD 2: P=0.001]. There were no significant differences in in-hospital post-operative complications, post-operative length of hospital stay, all-cause mortality at 30 days, and 3 months post-operation, or post-operative quality of life at 3 months between patients in Group S and Group P. CONCLUSIONS Sevoflurane-based anesthesia did not increase the incidence of POCD compared to propofol-based anesthesia at 7 days or 3 months post-operation or impact short-term post-operative prognosis.

Cancer-Related Anemia Is a Risk Factor for Medium-Term Postoperative Cognitive Dysfunction in Laparoscopic Surgery Patients: An Observational Prospective Study.

Anemia in the elderly may impair cognitive function. Our primary objective was to determine whether cancer-related anemia was associated with postoperative cognitive dysfunction (POCD) in nonelderly patients. We conducted an observational prospective study of 177 patients scheduled for laparoscopic surgery. Patients aged 18-64 were divided into two groups according to whether they were anemic due to cancer or not. The cognitive function was assessed by the Mini-Mental State Examination (MMSE) 1 day before and 1 week after operation. The cognitive function of the patients was evaluated by using the Telephone Interview for Cognitive Status-Modified (TICS-M) 3 months after operation. The quality of life of patients was evaluated after operation. The hemoglobin level and other clinical data were recorded before operation. Of the 170 patients, 100 without anemia and 70 anemia patients had been evaluated 1 week after operation. POCD was detected in 43 cases (25.3% of 170 cases) at 1 week and 30 cases (19% of 158 cases) at 3 months postoperatively. Anemia was an independent risk factor for 3-month POCD occurrence (P = 0.034). The education level of the patients who had POCD at 1 week and 3 months after operation was lower (P < 0.001, P = 0.011, respectively). Age was independently associated with the incidence of POCD at 3 months (P = 0.011). In general, these findings suggested that anemia may increase the incidence of medium-term POCD in cancer patients undergoing laparoscopic surgery.

Celecoxib Inhibits Hepatocellular Carcinoma Cell Growth and Migration by Targeting PNO1.

BACKGROUND Celecoxib has shown anti-tumor activities against several types of cancer. Although the majority of research focuses on its mechanism via cyclooxygenase-2 (COX-2) enzyme inhibition, we identified a distinct mechanism behind celecoxib anti-cancer abilities. MATERIAL AND METHODS We treated hepatocellular carcinoma (HCC) Huh-7 cells and tumor xenograft mice models with celecoxib to test its effects on the tumor. Using gene chip method to identify the differential expressed genes after celecoxib treatment and using pathway enrichment analysis to predict the potential pathways for further study. We transfected cells with lentiviral shRNA to detect the effect of RNA binding gene partner of NOB1 (PNO1) on tumor growth in vitro and in vivo. Further we performed western blot to detect the effect of PNO1 on the protein kinase B (AKT) pathway. RESULTS Celecoxib inhibited HCC cell growth in vitro and in vivo, and gene chip and pathway enrichment analysis revealed that PNO1 may be the potential target of celecoxib in HCC cells. Celecoxib significantly reduced levels of PNO1 in tumor tissue. Knockdown of PNO1 remarkably suppressed tumor growth and metastasis in vitro and in vivo. Disruption of PNO1 expression significantly reduced protein kinase B (AKT)/rapamycin (mTOR) signaling, indicating that this pathway may be involved in PNO1-mediated tumorigenic activity. CONCLUSIONS Celecoxib may exert its anti-tumor activity by inhibiting PNO1, and that AKT/mTOR signaling helps mediate the oncogenic effects of PNO1. This work offers the first evidence for a role of PNO1 as an HCC oncogene, which may open new avenues for prevention and treatment of HCC.

Subclassification of patients with solitary hepatocellular carcinoma based on post-hepatectomy survival: a large retrospective study.

Official guidelines group together all cases of solitary hepatocellular carcinoma (HCC) without macroscopic vascular invasion, regardless of tumor size. Here, we examined whether this is justified based on overall survival (OS) after hepatic resection (HR). Patients with newly diagnosed solitary HCC treated by initial HR from January 2004 to October 2013 were classified into six groups based on tumor size (in 2-cm increments). Combining adjacent categories with similar OS led to three groups: ≤5 cm (n = 426), >5 and ≤8 cm (n = 229), and >8 cm (n = 202). Among all patients, median survival time was 62 months, and OS was 95 % at 1 year, 73 % at 3 years, and 54 % at 5 years. Patients in the ≤5 cm group showed significantly higher OS (P < 0.001) and lower tumor recurrence (P = 0.004) than those in the >5 and ≤8 cm group, who in turn showed significantly higher OS (P = 0.003) and lower tumor recurrence (P = 0.021) than those in the >8 cm group. Our results suggest that patients with solitary HCC should be subclassified based on tumor size for more accurate prognosis. We propose defining solitary HCC tumors >5 and ≤8 cm as "large" and tumors >8 cm as "huge".

Efficacy of triclosan-coated sutures for reducing risk of surgical site infection in adults: a meta-analysis of randomized clinical trials.

BACKGROUND: Surgical site infection (SSI) is the third most frequent type of nosocomial infections. Triclosan-coated sutures are often used to reduce the risk of SSI, but studies examining this have given conflicting results. Therefore, this meta-analysis was performed to assess the efficacy of triclosan-coated sutures for reducing risk of SSI in adults. METHODS: PubMed, EMBASE, Google Scholar, and ClinicalTrials.gov were searched to identify randomized clinical trials evaluating triclosan-coated sutures for preventing SSI on patients 18 y or older. RESULTS: Thirteen randomized clinical trials involving 5256 participants were included. Triclosan-coated sutures were associated with lower risk of SSI than uncoated sutures across all surgeries (risk ratio [RR] 0.76, 95% confidence interval [CI] 0.65-0.88, P < 0.001). Similar proportions of patients experienced wound dehiscence with either type of suture (RR 0.97, 95% CI 0.49-1.89, P = 0.92). Subgroup analysis showed lower risk of SSI with triclosan-coated sutures in abdominal surgeries (RR 0.70, 95% CI 0.50-0.99, P = 0.04) and group with prophylactic antibiotic (RR 0.79, 95% CI 0.63-0.99, P = 0.04). However, such risk reduction was not observed in cardiac surgeries, breast surgeries, or group without prophylactic antibiotic. CONCLUSIONS: Triclosan-coated sutures can decrease the incidence of SSI in abdominal surgeries and might not interfere with wound healing process. Nevertheless, further studies are needed to examine whether triclosan-coated sutures are effective at preventing SSI in non-abdominal surgeries and to further study the interaction of antibiotic prophylaxis with triclosan-coated sutures.

Effects of a simulated CO2 pneumoperitoneum environment on the proliferation, apoptosis, and metastasis of cervical cancer cells in vitro.

BACKGROUND: This study aimed to investigate the growth curve, cell colony formation, cell cycle, apoptosis, anti-anoikis, and ability of invasion, adhesion, and migration of cervical cancer cells after exposure to a model of a simulated CO2 pneumoperitoneum environment with different pressures and at different times. MATERIAL AND METHODS: The cervical cancer cells were cultured in groups with 8 and 16 mmHg of 100% CO2 for 1, 2, 3, and 4 h in a model of a simulated environment of CO2 pneumoperitoneum. The cells in the control group were cultured in a standard environment. The growth curve was drawn through constant survival cell counts for 7 days, and the group with most obvious change was selected for subsequent experiments to detect cell colony formation, cell cycle apoptosis, and anti-anoikis, and the ability of invasion, adhesion, and migration. RESULTS: After a brief inhibition, the proliferation of cervical cancer cells was markedly increased and had no relationship with different CO2 pressures. Compared with the control group, the early apoptosis rate in the experimental group was higher, and the ability of invasion, migration, and adhesion decreased significantly. CONCLUSIONS: Cervical cancer cells stimulated by a CO2 pneumoperitoneum environment in vitro have an increased the ability to proliferate after a short period of inhibition and have reduced abilities of invasion, migration, and adhesion.

Oxymatrine and Gut Microbiota Modulation: A Potential Therapeutic Strategy for Bone Cancer Pain Management.

Chronic pain often coincides with changes in gut microbiota composition. Yet, the role of gut microbiota in bone cancer pain (BCP) is still not fully understood. This study investigated the role of gut microbiota in BCP and the effect of oxymatrine (OMT) on gut microbiota in BCP. A BCP mice model was developed to assess gut microbiota composition, serum and brain tissue butyric acid levels, and blood-brain barrier (BBB) permeability. Microbiota transplantation was used to restore gut microbiota, and the effect of Clostridium butyricum or sodium butyrate (NaB) supplementation on pain-related behaviors and BBB integrity was evaluated. The potential benefits of OMT on gut microbiota composition, peroxisome proliferator-activated receptor gamma (PPARγ)/cyclooxygenase-2 (COX-2) signaling, BBB integrity, and pain-related behaviors were also explored. BCP significantly altered gut microbiota composition and reduced serum and brain tissue butyric acid levels. Additionally, BBB permeability increased considerably in the BCP group compared with sham and control mice. Microbiota transplantation, as well as C butyricum or NaB supplementation, ameliorated pain-related behaviors and BBB integrity; the supplementation of C butyricum or NaB boosted brain-tight-junction protein expression, potentially through modulating PPARγ/COX-2 signaling. OMT influenced gut microbiota composition and regulated PPARγ/COX-2 signaling in the BCP model, improving pain-related behaviors and BBB integrity. BCP affects gut microbiota composition and butyric acid levels. Modulating gut microbiota and butyric acid levels through transplantation or supplementation may alleviate BCP. OMT shows potential as a treatment by altering gut microbiota composition and regulating PPARγ/COX-2 signaling. These findings provide new insights into BCP pathophysiology and possible treatments. PERSPECTIVE: This study explores the impact of gut microbiota on BCP. Microbiota transplantation alleviates BCP and enhances BBB integrity. Also, C butyricum or NaB improves BBB via PPARγ/COX-2. OMT, a BCP treatment, modifies microbiota by regulating PPARγ/COX-2, in turn improving pain and BBB integrity. These findings suggest a therapeutic approach, emphasizing clinical relevance in targeting gut microbiota and restoring butyric acid levels.

Effects of dexmedetomidine on early postoperative cognitive function and postoperative inflammatory response: a systematic review and network meta-analysis.

Background: Dexmedetomidine (DEX) has demonstrated potential as an effective agent for enhancing early postoperative cognitive function. However, there is ongoing debate regarding its optimal dosage and impact on early postoperative inflammatory response. This study aimed to assess and prioritize the effects of varying doses of DEX on early postoperative cognitive function and inflammatory response, in order to identify the most effective intervention dosage. Methods: Randomised controlled trials (RCTs) and retrospective cohort studies (RCS) from PubMed, Embase, and Cochrane Library up to January 28, 2024, were included. The Mini-Mental State Examination (MMSE) was utilized to assess the impact of varying doses of DEX on cognitive function during the early postoperative period as the primary outcome, peripheral blood levels of IL-6 and TNF-α were considered as secondary outcomes. Meta-analysis and Bayesian Network Meta-Analysis (NMA) were conducted using R. Funnel plots were generated using Stata 15.0. Results: A total of 29 studies involving 2,807 patients and 25 different doses of DEX were included. DEX was given at a loading dose of 0.3-1.0 µg/kg followed by a maintenance dose of 0.1-0.5 µg/kg/h, or at a uniform intraoperative dose of 0.4-0.7 µg/kg/h. Network meta-analysis revealed most doses of DEX were significantly more effective than normal saline (NS) in improving postoperative MMSE scores (on days 1, 3, and 7) and lowering IL-6 and TNF-α levels. Probability results showed that a 1 µg/kg loading dose followed by a 0.6 µg/kg/h maintenance dose was the best dosing regimen for improving MMSE scores on postoperative days 1 (97.3%), 3 (100%), and 7 (99.9%), as well as for reducing postoperative blood IL-6 levels (1.3%). On the other hand, 0.3 µg/kg followed by 0.2 µg/kg/h was the optimal dosing regimen for reducing postoperative blood TNF-α levels (6.6%). Conclusion: Compared with NS, intraoperative intravenous DEX improved early postoperative cognitive function and postoperative inflammatory response in patients undergoing elective surgery. In particular, a 1 µg/kg loading dose and a 0.6 µg/kg/h maintenance dose resulted in the best improvement in postoperative MMSE scores and blood IL-6 levels, while a 0.3 µg/kg loading dose followed by a 0.2 µg/kg/h maintenance dose is the optimal regimen for lowering postoperative blood TNF-α levels.Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=433932, identifier CRD42023433932.

HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review.

Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.

Transforming growth factor-ß1 is associated with inflammatory resolution via regulating macrophage polarization in lung injury model mice.

OBJECTIVE: Ventilation is the main respiratory support therapy for acute respiratory distress syndrome, which triggers acute lung injury (ALI). Macrophage polarization is vital for the resolution of inflammation and tissue injury. We hypothesized that transforming growth factor (TGF)-ß1 may attenuate inflammation and ventilator-induced ALI by promoting M2 macrophage polarization. METHODS: C57BL/6 mice received 4-hour ventilation and extubation to observe the resolution of lung injury and inflammation. Lung vascular permeability, inflammation, and histological changes in the lungs were evaluated by bronchoalveolar lavage analysis, enzyme linked immunosorbent assay, hematoxylin and eosin staining, as well as transmission electron microscope. TGF-ß1 cellular production and macrophage subsets were analyzed by flow cytometry. The relative expressions of targeted proteins and genes were measured by immunofuorescence staining, Western blot, and quantitative polymerase chain reaction. RESULTS: High tidal volume-induced injury and inflammation were resolved at 3 days of post-ventilation (PV3d) to PV10d, with increased elastic fibers, proteoglycans, and collagen content, as well as higher TGF-ß1 levels. M1 macrophages were increased in the acute phase, whereas M2a macrophages began to increase from PV1d to PV3d, as well as increased M2c macrophages from PV3d to PV7d. A single dose of rTGF-ß1 attenuated lung injury and inflammation at end of ventilation with polymorphonuclear leukocyte apoptosis, while nTAb pretreatment induced the abnormal elevation of TGF-ß1 that aggravated lung injury and inflammation due to the significant inhibition of M1 macrophages polarized to M2a, M2b, and M2c macrophages. CONCLUSIONS: Precise secretion of TGF-ß1-mediated macrophage polarization plays a crucial role in the resolution of ventilator-induced inflammatory lung injury.

Zoledronate for metastatic bone disease and pain: a meta-analysis of randomized clinical trials.

BACKGROUND: Randomized controlled trials (RCTs) have reported different results when using zoledronate to treat skeletal-related events (SREs) and bone pain in patients with metastatic bone disease (MBD), and few have looked at the risks and benefits of long-term use of the drug. This meta-analysis aimed to investigate the efficacy and safety of zoledronate to treat MBD in the short and long-term. METHODS: PubMed, EMBASE, and the Cochrane Library were searched to identify RCTs evaluating zoledronate for MBD. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Twelve RCTs involving 4,450 patients were included in the meta-analysis. Zoledronate decreased the risk of developing SREs compared with placebo (RR 0.75, 95% CI 0.69 to 0.81, P < 0.001). Zoledronate consistently reduced the brief pain inventory (BPI) below baseline compared with placebo at 3, 12, and 24 months. In addition, the likelihood of experiencing a bone pain event was significantly lower in the zoledronate group than in the placebo group (RR 0.83, 95% CI 0.76 to 0.89, P < 0.001). While the two groups did not differ significantly in the incidence of nausea(RR = 1.07, 95% CI 0.96 to 1.19, P = 0.250), emesis (RR 0.94, 95% CI 0.81 to 1.09, P = 0.420), or adverse renal events (RR 1.41, 95% CI 0.94 to 2.11, P = 0.09), the zoledronate group showed a significantly higher relative risk of pyrexia (RR 1.43, 95% CI 1.20 to 1.70, P < 0.001), fatigue (RR 1.26, 95% CI 1.10 to 1.43, P < 0.001), and anemia (RR 1.33, 95% CI 1.14 to 1.55, P < 0.001). CONCLUSION: Compared to placebo, zoledronate significantly reduced the incidence of bone pain and SREs in patients with MBD for periods as long as 24 months. In addition, zoledronate is generally well tolerated over this long period.

Effects of dexmedetomidine as an adjuvant to ropivacaine or ropivacaine alone on duration of postoperative analgesia: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Ropivacaine is a long-acting local anesthetic that is used to treat postoperative pain. Adjuvant use of dexmedetomidine in regional anesthesia may prolong the duration of analgesia. The objective of this systematic review and meta-analysis was to investigate the duration and effect of ropivacaine alone vs. ropivacaine in combination with dexmedetomidine for postoperative analgesia. METHODS: The PubMed, EMBASE, Web of Science, and Google Scholar databases were searched for randomized controlled trials (RCTs) of ropivacaine alone or ropivacaine in combination with dexmedetomidine for regional anesthesia. The primary outcome was duration of analgesia, defined as the time from onset of the block to the time of the first analgesic request or initial pain report. Secondary outcomes were duration of sensory block, duration of motor block, consumption of sufentanil for analgesia, length of hospital stay, and incidence of postoperative nausea and vomiting. RESULTS: Eighteen studies with 1148 patients were included. Overall quality of the RCTs, as assessed by the Jadad scale, was high. The meta-analysis demonstrated that ropivacaine combined with dexmedetomidine significantly prolonged the duration of postoperative analgesia from local anesthetics compared to ropivacaine alone (WMD: 4.14h; 95%CI: 3.29~5.0h; P<0.00001; I2 = 99%). There was evidence of high heterogeneity between studies. The duration of sensory and motor block was significantly increased, and consumption of sufentanil for analgesia and the incidence of postoperative nausea and vomiting were significantly reduced in patients who received ropivacaine combined with dexmedetomidine compared to ropivacaine alone. There was no significant difference in length of hospital stay. CONCLUSIONS: Compared to ropivacaine alone, ropivacaine combined with dexmedetomidine significantly prolonged the duration of postoperative analgesia and sensory and motor block, and reduced consumption of sufentanil for analgesia and the incidence of postoperative nausea and vomiting, across an array of surgeries.