Dexmedetomidine Attenuates Inflammation in Elderly Patients Following Major Hepatobiliary and Pancreatic Surgery: A Randomized Clinical Trial.

Background: Dexmedetomidine (Dex) may have anti-inflammatory properties and potentially reduce the incidence of postoperative organ injury. Objective: To investigate whether Dex protects pulmonary and renal function via its anti-inflammatory effects in elderly patients undergoing prolonged major hepatobiliary and pancreatic surgery. Design and Setting: Between October 2019 and December 2020, this randomized controlled trial was carried out at a tertiary hospital in Chongqing, China. Patients: 86 patients aged 60-75 who underwent long-duration (> 4 hrs) hepatobiliary and pancreatic surgery without significant comorbidities were enrolled and randomly assigned into two groups at a 1:1 ratio. Interventions: Patients were given either Dex or an equivalent volume of 0.9% saline (Placebo) with a loading dose of 1 µg kg-1 for 10 min, followed by 0.5 µg kg-1 hr-1 for maintenance until the end of surgery. Main Outcome Measures: The changes in serum concentrations of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were primary outcomes. Results: At one hour postoperatively, serum IL-6 displayed a nine-fold increase (P<0.05) in the Placebo group. Administration of Dex decreased IL-6 to 278.09 ± 45.43 pg/mL (95% CI: 187.75 to 368.43) compared to the Placebo group (P=0.019; 432.16 ± 45.43 pg/mL, 95% CI: 341.82 to 522.50). However, no significant differences in TNF-α were observed between the two groups. The incidence of postoperative acute kidney injury was twice as high in the Placebo group (9.30%) compared to the Dex group (4.65%), and the incidence of postoperative acute lung injury was 23.26% in the Dex group, lower than that in the Placebo group (30.23%), although there was no statistical significance between the two groups. Conclusion: Dex administration in elderly patients undergoing major hepatobiliary and pancreatic surgery reduces inflammation and potentially protects kidneys and lungs. Registration: Chinese Clinical Trials Registry, identifier: ChiCTR1900024162, on 28 June 2019.

Cuproptosis in glioblastoma: unveiling a novel prognostic model and therapeutic potential.

Glioblastoma, a notably aggressive brain tumor, is characterized by a brief survival period and resistance to conventional therapeutic approaches. With the recent identification of "Cuproptosis," a copper-dependent apoptosis mechanism, this study aimed to explore its role in glioblastoma prognosis and potential therapeutic implications. A comprehensive methodology was employed, starting with the identification and analysis of 65 cuproptosis-related genes. These genes were subjected to differential expression analyses between glioblastoma tissues and normal counterparts. A novel metric, the "CP-score," was devised to quantify the cuproptosis response in glioblastoma patients. Building on this, a prognostic model, the CP-model, was developed using Cox regression techniques, designed to operate on both bulk and single-cell data. The differential expression analysis revealed 31 genes with distinct expression patterns in glioblastoma. The CP-score was markedly elevated in glioblastoma patients, suggesting an intensified cuproptosis response. The CP-model adeptly stratified patients into distinct risk categories, unveiling intricate associations between glioblastoma prognosis, immune response pathways, and the tumor's immunological environment. Further analyses indicated that high-risk patients, as per the CP-model, exhibited heightened expression of certain immune checkpoints, suggesting potential therapeutic targets. Additionally, the model hinted at the possibility of personalized therapeutic strategies, with certain drugs showing increased efficacy in high-risk patients. The CP-model offers a promising tool for glioblastoma prognosis and therapeutic strategy development, emphasizing the potential of Cuproptosis in cancer treatment.

Effect of different analgesic treatments on the pulmonary function in elderly hip fracture patients: A prospective study.

BACKGROUND: To investigate the effect of different analgesic methods on lungs in elderly patients with hip fractures. METHODS: A prospective study was conducted on 78 elderly hip fracture patients undergoing spinal anesthesia for surgery, where 3 analgesic methods were used: postoperative Patient-controlled intravenous analgesia pump (PCIA) (group I), pre and postoperative PCIA (group II), and preoperative fascia iliaca compartment block (FICB) + postoperative PCIA (group III). The following indicators were monitored at admission (T1), on the day of surgery before anesthesia (T2), and 7 days after surgery (T3): heart rate (HR), respiratory rate (RR), forced expiratory volume during the first second, arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2), C-reactive protein (CRP), and interleukin 6 (IL-6). Pulmonary complications such as pulmonary atelectasis and respiratory insufficiency were analyzed. RESULTS: The HR, RR, forced expiratory volume during the first second, PaO2, PaCO2, IL-6, and CRP levels at T1 after fracture did not significantly differ among the 3 groups (P > .05). After different analgesic treatments post-admission, all indicators at T2 were significantly higher in group I than in groups II and III (P < .05), while there was no significant difference between groups II and III (P > .05). At T3, there were no significant differences in RR, HR, PaO2, PaCO2, and CRP levels among the groups (P > .05), but IL-6 levels at T3 were significantly higher in group I than in groups II and III (P < .05). CONCLUSION: The use of effective pain relief during surgery can help protect the lung function of elderly patients with hip fractures. When using PCIA with FICB before surgery, respiratory performance may be better protected compared to using unsustained analgesia. This could be due to a decrease in the levels of inflammatory markers such as CRP and interleukin-6.

Effects of Remifentanil and Sufentanil Anesthesia on Cardiac Function and Serological Parameters in Congenital Heart Surgery.

In this study, we have investigated feasibility of remifentanil and sufentanil anesthesia in children with congenital heart disease surgery and its effects on cardiac function and serological parameters. For this purpose, a retrospective study was conducted on 120 children with congenital heart disease who underwent repair of ventricular septum or atrial septum in our hospital, specifically from January 2016 to January 2018, and 60 patients in each group were randomly divided into the control and treatment groups, respectively. The control group was anesthetized with sufentanil, and the treatment group was anesthetized with remifentanil. The heart function, serological indexes, and adverse reactions were observed and compared. We have observed that there was no significant difference in HR levels between these groups (P > 0.05), but SDP and DBP values of the two groups were decreased after anesthetic induction (P < 0.05). ACH, cortisol, and lactic acid in the treatment group were significantly lower than those in the control group, and the difference was statistically significant (P < 0.05). The incidence of bradycardia, nausea and vomiting, hypotension, muscle rigidity, and respiratory depression in the treatment group was 16.67% lower than that in the control group (P < 0.05). Remifentanil has less influence on hemodynamics and a better analgesic effect than fentanyl in inhibiting stress response in congenital heart surgery, which provides reference and basis for children congenital heart surgery.

Establishment and validation of an immune-based prognostic score model in glioblastoma.

BACKGROUND: Immune escape is one of the landmark features of glioblastoma (GBM). Immunotherapy is undoubtedly a revolution in the field of tumor treatment, especially the application of immune checkpoint inhibitors and CAR-T cells, which have achieved amazing results in fighting against cancer. This study aimed to establish a TP53-related immune-based score model to improve the prognostic of GBM by investigating the gene mutations and the immune landscape of GBM. METHODS: Data were obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed genes (DEGs) analysis between the TP53 mutated (TP53MUT) and wild-type (TP53WT) GBM patients was conducted. The CIBERSORT algorithm was applied to evaluate the proportion of immune cell types and RNA sequencing (RNA-seq) data from the TCGA and CGGA were used as discovery and validation cohorts, respectively, to build and validate an immune-related prognostic model (IPM). Genes in the IPM model were first screened by univariate Cox analysis, then filtered by the least absolute shrinkage and selection operator (LASSO) Cox regression method to eliminate collinearity among DEGs. A nomogram was finally established and evaluated by combining both the IPM and other clinical factors. RESULTS: PTEN was the top most mutated gene in GBM patients (118/393), followed by TP53 (116/393). 332 immune-related genes were identified and the immune response in the TP53WT group was remarkably greater than in the TP53MUT group. The final IPM model composed three immune-related genes: IPM risk score = (0.392 × S100A8 expression) + (0.174 × CXCL1 expression) + (0.368 × IGLL5 expression), significantly correlated with the overall survival (OS) of GBM in the stratified TP53 status subgroups and was an independent prognostic variate for GBM. By integrating the IPM and clinical characteristics, a nomogram was generated to facilitate clinical utilization, with the results suggesting that it has better predictive performance for GBM prognosis than the IPM. CONCLUSIONS: The IPM model can identify patients at high-risk and can be combined with other clinical factors to estimate the OS of GBM patients, demonstrating that it is a promising biomarker to optimize the prognosis of GBM.

Geniposide exhibits anticancer activity to medulloblastoma cells by downregulating microRNA-373.

BACKGROUND: Medulloblastoma is a common tumor originates from central nervous system in children with metastatic potential. Geniposide is the major active ingredient separated from the fruit of Gardenia jasminoides Ellis. Herein, we tested the possible anticancer activity of geniposide on human medulloblastoma cells, as well as the potential underlying molecular mechanisms. METHODS: Firstly, followed by geniposide incubation, cell viability, proliferation, apoptosis, migration, and invasion of medulloblastoma Daoy cells, along with microRNA-373 (miR-373) expression were tested, respectively. Then, the influences of miR-373 overexpression in the reduction of medulloblastoma cell proliferation, migration, and invasion and the elevation of apoptosis, triggered by geniposide treatment, were re-investigated. Finally, the Ras/Raf/MEK/ERK pathway activity was analyzed. RESULTS: Geniposide treatment inhibited medulloblastoma cell viability, proliferation, migration, and invasion, but promoted cell apoptosis. Surprisingly, miR-373 expression in medulloblastoma cells was obviously downregulated by geniposide treatment. miR-373 overexpression reversed the effects of geniposide on Daoy cells. Furthermore, geniposide hindered the Ras/Raf/MEK/ERK pathway by downregulating miR-373 expression. CONCLUSION: Geniposide exhibited anticancer activity on human medulloblastoma cells and blocked Ras/Raf/MEK/ERK pathway by downregulating miR-373 expression.

Intracerebral schwannoma: A case report and literature review.

Intracranial schwannoma accounts for between 5 and 8% of intracranial tumors, whereas intracerebral schwannoma, a rare disease, accounts for <1% of intracranial schwannomas. In addition to the present case report, a total of 84 cases reported within China and elsewhere were reviewed and summarized, and the age of the tumor onset, the site of disease, imaging results, clinical presentation, pathological classification and prognosis were analyzed. The present case report described a 12-year-old female with an intracerebral schwannoma in the brainstem, who was followed-up for 5 years using magnetic resonance imaging after a surgical resection without recurrence, and clinical symptoms were reported to have completely resolved. The incidence of intracerebral schwannoma was low among cases, and the correct diagnosis was not able to be made preoperatively, and the majority of cases were diagnosed on the basis of postoperative pathology. The majority of cases analyzed were supratentorial, occurring at an age ≤40 according to previous literature. In addition, 33% of patients presented with subtentorial schwannoma, occurring at an age >40. The prognosis was classified as good (patient can live independently) for the majority of patients if surgery was able to completely resect the lesion.

Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis.

Cardiokines play an essential role in maintaining normal cardiac functions and responding to acute myocardial injury. Studies have demonstrated the heart itself is a significant source of C1q/TNF-related protein 9 (CTRP9). However, the biological role of cardiac-derived CTRP9 remains unclear. We hypothesize cardiac-derived CTRP9 responds to acute myocardial ischemia/reperfusion (MI/R) injury as a cardiokine. We explored the role of cardiac-derived CTRP9 in MI/R injury via genetic manipulation and a CTRP9-knockout (CTRP9-KO) animal model. Inhibition of cardiac CTRP9 exacerbated, whereas its overexpression ameliorated, left ventricular dysfunction and myocardial apoptosis. Endothelial CTRP9 expression was unchanged while cardiomyocyte CTRP9 levels decreased after simulated ischemia/`reperfusion (SI/R) in vitro. Cardiomyocyte CTRP9 overexpression inhibited SI/R-induced apoptosis, an effect abrogated by CTRP9 antibody. Mechanistically, cardiac-derived CTRP9 activated anti-apoptotic signaling pathways and inhibited endoplasmic reticulum (ER) stress-related apoptosis in MI/R injury. Notably, CTRP9 interacted with the ER molecular chaperone calreticulin (CRT) located on the cell surface and in the cytoplasm of cardiomyocytes. The CTRP9-CRT interaction activated the protein kinase A-cAMP response element binding protein (PKA-CREB) signaling pathway, blocked by functional neutralization of the autocrine CTRP9. Inhibition of either CRT or PKA blunted cardiac-derived CTRP9's anti-apoptotic actions against MI/R injury. We further confirmed these findings in CTRP9-KO rats. Together, these results demonstrate that autocrine CTRP9 of cardiomyocyte origin protects against MI/R injury via CRT association, activation of the PKA-CREB pathway, ultimately inhibiting cardiomyocyte apoptosis.

MiR-199a targeting ROCK1 to affect kidney cell proliferation, invasion and apoptosis.

Renal cell carcinoma (RCC) is one of the three most common cancers of urinary tract cancer, accounting for 2-3% of all systemic cancers. Recent studies have found that miR-199a is lowly expressed in RCC, may act as a tumour suppressor gene to induce the occurrence of kidney cancer. In the present study, we investigated the role of miR-199a in the progression and metastasis of RCC. The results showed that miR-199a significantly downregulated in RCC and cell lines. Overexpression of miR-199a in RCC cell lines significantly inhibited cell proliferation, migration and invasion. Furthermore, the qRT-PCR and western blot results showed that miR-199a overexpression significantly downregulated ROCK-1 mRNA and protein levels. ROCK1 was identified as a target of miR-199a, and ectopic expression of miR-199a downregulated ROCK1 by direct binding to its 3' untranslated region. Together, these findings indicate that miR-199a acts as a tumour suppressor and its downregulation in tumour tissues may contribute to the progression and metastasis of RCC through a mechanism involving ROCK1, suggesting miR-199a as a potential new diagnostic and therapeutic target for the treatment of RCC.

Tumor Microenvironment in Treatment of Glioma.

Glioma is one of the most malignant and fatal tumors in adults. Researchers and physicians endeavor to improve clinical efficacy towards it but made little achievement. In recent years, people have made advances in understanding characteristics and functions of tumor microenvironment and its role in different processes of tumor. In this paper, we describe the effects of tumor microenvironment on glioma proliferation, invasion and treatments. By explaining underlying mechanisms and enumerating new therapy strategies employing tumor microenvironment, we aim to provide novel ideas to improve clinical outcomes of glioma.

Pterostilbene exerts anticancer activity on non-small-cell lung cancer via activating endoplasmic reticulum stress.

Pterostilbene (PT), the natural dimethylated analog of resveratrol (RSV), is a potent anticarcinogen for non-small-cell lung cancer (NSCLC), but its anti-NSCLC mechanisms remain unclear. In this study, we show that PT treatment time- and dose-dependently enhanced the endoplasmic reticulum stress (ERS) signaling (i.e., p-PERK, IRE1, ATF4, CHOP), thus decreasing the cell viability and inducing apoptosis in human PC9 and A549 NSCLC cell lines. Moreover, the decreased migratory and adhesive abilities, downregulation of intracellular glutathione (GSH) level, enhanced reactive oxygen species (ROS) generation, Caspase 3 activity and mitochondrial membrane depolarization were observed in NSCLC cells treated with PT. These effects were reversed by CHOP siRNA which inhibited the ERS signaling pathway, but were promoted by thapsigargin (a classical ERS inducer) in vitro. Besides, in vivo studies also verify that PT exerted anticancer activity by mobilizing ERS signaling and apoptosis-related proteins, and these effects were enhanced by thapsigargin. Therefore, ERS activation may represent a new mechanism of anti-NSCLC action by PT, and a novel therapeutic intervention for lung cancer.

Effect of estrogen administration on middle cerebral arterial viscoelastic properties in aged female rats.

PURPOSE:: To develop a model for studying cerebrovascular disease prevention in elderly women. METHODS:: Sixty 18-month-old Sprague Dawley (SD) rats were randomly divided into an estrogen administration group (EA, n=30) and a non-administration group (NA, n=30); thirty 4-month-old SD rats were allocated to a control group. The EA group received estradiol benzoate starting on the 5th day of a 34-day breeding period, and the serum levels of estradiol (E2), estrogen receptor (ER), and malondialdehyde (MDA) were measured. The MCA of each group was then sampled for viscoelastic experiments. RESULTS:: The serum levels of E2 and MDA in the EA group showed significant differences compared to those in the control group (p<0.05), while the difference in ER between the EA and control groups was not significant (p>0.05). The decrease in MCA stress at 7,200 s and the increase in strain at 7,200 s in the EA group showed no significant differences compared to the control group (p>0.05). CONCLUSION:: Estradiol administration inhibited the formation of lipid peroxidation products and restored middle cerebral arterial viscoelasticity in aged female rats.

Effect of estrogen administration on middle cerebral arterial viscoelastic properties in aged female rats

ABSTRACT PURPOSE: To develop a model for studying cerebrovascular disease prevention in elderly women. METHODS: Sixty 18-month-old Sprague Dawley (SD) rats were randomly divided into an estrogen administration group (EA, n=30) and a non-administration group (NA, n=30); thirty 4-month-old SD rats were allocated to a control group. The EA group received estradiol benzoate starting on the 5th day of a 34-day breeding period, and the serum levels of estradiol (E2), estrogen receptor (ER), and malondialdehyde (MDA) were measured. The MCA of each group was then sampled for viscoelastic experiments. RESULTS: The serum levels of E2 and MDA in the EA group showed significant differences compared to those in the control group (p<0.05), while the difference in ER between the EA and control groups was not significant (p>0.05). The decrease in MCA stress at 7,200 s and the increase in strain at 7,200 s in the EA group showed no significant differences compared to the control group (p>0.05). CONCLUSION: Estradiol administration inhibited the formation of lipid peroxidation products and restored middle cerebral arterial viscoelasticity in aged female rats.

Acellular allogeneic nerve grafting combined with bone marrow mesenchymal stem cell transplantation for the repair of long-segment sciatic nerve defects: biomechanics and validation of mathematical models.

We hypothesized that a chemically extracted acellular allogeneic nerve graft used in combination with bone marrow mesenchymal stem cell transplantation would be an effective treatment for long-segment sciatic nerve defects. To test this, we established rabbit models of 30 mm sciatic nerve defects, and treated them using either an autograft or a chemically decellularized allogeneic nerve graft with or without simultaneous transplantation of bone marrow mesenchymal stem cells. We compared the tensile properties, electrophysiological function and morphology of the damaged nerve in each group. Sciatic nerves repaired by the allogeneic nerve graft combined with stem cell transplantation showed better recovery than those repaired by the acellular allogeneic nerve graft alone, and produced similar results to those observed with the autograft. These findings confirm that a chemically extracted acellular allogeneic nerve graft combined with transplantation of bone marrow mesenchymal stem cells is an effective method of repairing long-segment sciatic nerve defects.

Adiponectin enhances bone marrow mesenchymal stem cell resistance to flow shear stress through AMP-activated protein kinase signaling.

Adiponectin has been demonstrated to protect the cardiovascular system and bone marrow mesenchymal stem cells (BMSCs). However, it is unclear whether adiponectin can protect BMSCs against flow shear stress (FSS). In this study, our aim was to explore the effects of adiponectin on BMSCs and to explore the role of AMP-activated protein kinase (AMPK) signaling in this process. Shear stress significantly inhibits the survival and increases the apoptosis of BMSCs in an intensity-dependent manner. The expression levels of TGF-ß, bFGF, VEGF, PDGF, and Bcl2 are simultaneously reduced, and the phosphorylation levels of AMPK and ACC, as well as the expression level of Bax, are increased. Supplementation with adiponectin promotes the survival of BMSCs; reverses the changes in the expression levels of TGF-ß, bFGF, VEGF, PDGF, Bcl2, and Bax; and further amplifies the phosphorylation of AMPK and ACC. Furthermore, the protective effects of adiponectin can be partially neutralized by AMPK siRNA. In summary, we have demonstrated for the first time that adiponectin can effectively protect BMSCs from FSS and that this effect depends, at least in part, on the activation of AMPK signaling.

Melatonin reverses flow shear stress-induced injury in bone marrow mesenchymal stem cells via activation of AMP-activated protein kinase signaling.

Tissue-engineered heart valves (TEHVs) are a promising treatment for valvular heart disease, although their application is limited by high flow shear stress (FSS). Melatonin has a wide range of physiological functions and is currently under clinical investigation for expanded applications; moreover, extensive protective effects on the cardiovascular system have been reported. In this study, we investigated the protection conferred by melatonin supplementation against FSS-induced injury in bone marrow mesenchymal stem cells (BMSCs) and elucidated the potential mechanism in this process. Melatonin markedly reduced BMSC apoptotic death in a concentration-dependent manner while increasing the levels of transforming growth factor ß (TGF-ß), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and B-cell lymphoma 2 (Bcl2), and decreasing those of Bcl-2-associated X protein (Bax), p53 upregulated modulator of apoptosis (PUMA), and caspase 3. Notably, melatonin exerted its protective effects by upregulating the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), which promotes acetyl-CoA carboxylase (ACC) phosphorylation. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked the anti-FSS injury (anti-FSSI) effects of melatonin. Inhibition of AMPK by Compound C also counteracted the protective effects of melatonin, suggesting that melatonin reverses FSSI in BMSCs through the AMPK-dependent pathway. Overall, our findings indicate that melatonin contributes to the amelioration of FSS-induced BMSC injury by activating melatonin receptors and AMPK/ACC signaling. Our findings may provide a basis for the design of more effective strategies that promote the use of TEHCs in patients.