Preoperative exercise training decreases complications of minimally invasive lung cancer surgery: A randomized controlled trial.

OBJECTIVE: Limited evidence exists regarding the efficacy of preoperative exercise in reducing short-term complications after minimally invasive surgery in patients with non-small cell lung cancer. This study aims to investigate the impact of preoperative exercise on short-term complications after minimally invasive lung resection. METHODS: In this prospective, open-label, randomized (1:1) controlled trial at Xiangya Hospital, China (September 2020 to February 2022), patients were randomly assigned to a preoperative exercise group with 16-day alternate supervised exercise or a control group. The primary outcome assessed was short-term postoperative complications, with a follow-up period of 30 days postsurgery. RESULTS: A total of 124 patients were recruited (preoperative exercise group n = 62; control n = 62). Finally, 101 patients (preoperative exercise group; n = 51 and control; n = 50) with a median age of 56 years (interquartile range, 50-62 years) completed the study. Compared with the control group, the preoperative exercise group showed fewer postoperative complications (preoperative exercise 3/51 vs control 10/50; odds ratio, 0.17; 95% CI, 0.04-0.86; P = .03) and shorter hospital stays (mean difference, -2; 95% CI, -3 to -1; P = .01). Preoperative exercise significantly improved depression, stress, functional capacity, and quality of life (all P < .05) before surgery. Furthermore, preoperative exercise demonstrated a significantly lower minimum blood pressure during surgery and lower increases in body temperature on day 2 after surgery, neutrophil-to-lymphocyte ratio, and neutrophil count after surgery (all P < .05). Exploratory research on lung tissue RNA sequencing (5 in each group) showed downregulation of the tumor necrosis factor signaling pathway in the preoperative exercise group compared with the control group. CONCLUSIONS: Preoperative exercise training decreased short-term postoperative complications in patients with non-small cell lung cancer.

Cardiorespiratory fitness and morbidity and mortality in patients with non-small cell lung cancer: a prospective study with propensity score weighting.

INTRODUCTION: This study aimed to investigate the association between cardiorespiratory fitness (CRF) and perioperative morbidity and long-term mortality in operable patients with early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This prospective study included consecutive patients with early-stage NSCLC who underwent presurgical cardiopulmonary exercise testing between November 2014 and December 2019 (registration number: ChiCTR2100048120). Logistic and Cox proportional hazards regression were applied to evaluate the correlation between CRF and perioperative complications and long-term mortality, respectively. Propensity score overlap weighting was used to adjust for the covariates. We performed sensitivity analyses to determine the stability of our results. RESULTS: A total of 895 patients were followed for a median of 40 months [interquartile range 25]. The median age of the patients was 59 years [range 26-83], and 62.5% were male. During the study period, 156 perioperative complications and 146 deaths were observed. Low CRF was associated with a higher risk of death (62.9 versus 33.6 per 1000 person-years; weighted incidence rate difference, 29.34 [95% CI, 0.32 to 58.36] per 1000 person-years) and perioperative morbidity (241.6 versus 141.9 per 1000 surgeries; weighted incidence rate difference, 99.72 [95% CI, 34.75 to 164.70] per 1000 surgeries). A CRF of ≤ 20 ml/kg/min was significantly associated with a high risk of long-term mortality (weighted hazard ratio, 1.98 [95% CI, 1.31 to 2.98], p < 0.001) and perioperative morbidity (weighted odds ratio, 1.93 [1.28 to 2.90], p = 0.002) compared to higher CRF. CONCLUSION: The study found that low CRF is significantly associated with increased perioperative morbidity and long-term mortality in operable patients with early-stage NSCLC.

Low cardiorespiratory fitness is significantly associated with increased perioperative morbidity and long-term mortality in operable patients with early-stage non-small cell lung cancer.Future research is recommended to investigate the potential prognostic role of integrating cardiorespiratory fitness into the currently used prognosis algorithm for patients with non-small cell lung cancer.

miR-135a-5p overexpression in peripheral blood-derived exosomes mediates vascular injury in type 2 diabetes patients.

Objective: Diabetes pathology relies on exosomes (Exos). This study investigated how peripheral blood Exo-containing microRNAs (miRNAs) cause vascular injury in type 2 diabetes (T2D). Methods: We removed DEmiRNA from T2D chip data from the GEO database. We isolated Exo from 15 peripheral blood samples from T2D patients and 15 healthy controls and measured Exo DEmiRNA levels. We employed the intersection of Geneards and mirWALK database queries to find T2D peripheral blood mRNA-related chip target genes. Next, we created a STRING database candidate target gene interaction network map. Next, we performed GO and KEGG enrichment analysis on T2D-related potential target genes using the ClusterProfiler R package. Finally, we selected T2D vascular damage core genes and signaling pathways using GSEA and PPI analysis. Finally, we used HEK293 cells for luciferase assays, co-cultured T2D peripheral blood-derived Exo with HVSMC, and detected HVSMC movement alterations. Results: We found 12 T2D-related DEmiRNAs in GEO. T2D patient-derived peripheral blood Exo exhibited significantly up-regulated miR-135a-3p by qRT-PCR. Next, we projected miR-135a-3p's downstream target mRNA and screened 715 DEmRNAs to create a regulatory network diagram. DEmRNAs regulated biological enzyme activity and vascular endothelial cells according to GO function and KEGG pathway analysis. ErbB signaling pathway differences stood out. PPI network study demonstrated that DEmRNA ATM genes regulate the ErbB signaling pathway. The luciferase experiment validated miR-135a-3p and ATM target-binding. Co-culture of T2D patient-derived peripheral blood Exo with HVSMC cells increases HVSMC migration, ErbB2, Bcl-2, and VEGF production, and decreases BAX and ATM. However, miR-135a-3p can reverse the production of the aforesaid functional proteins and impair HVSMC cell movement. Conclusion: T2D patient-derived peripheral blood Exo carrying miR-135a-3p enter HVSMC, possibly targeting and inhibiting ATM, activating the ErbB signaling pathway, promoting abnormal HVSMC proliferation and migration, and aggravating vascular damage.

Prognostic role of minute ventilation/carbon dioxide production slope for perioperative morbidity and long-term survival in resectable patients with nonsmall-cell lung cancer: a prospective study using propensity score overlap weighting.

BACKGROUND: The role of minute ventilation/carbon dioxide production ( / CO 2 ) slope, a ventilation efficiency marker, in predicting short-term and long-term health outcomes for patients with nonsmall-cell lung cancer (NSCLC) undergoing lung resection has not been well investigated. MATERIAL AND METHODS: This prospective cohort study consecutively enrolled NSCLC patients who underwent a presurgical cardiopulmonary exercise test from November 2014 to December 2019. The association of / CO 2 slope with relapse-free survival (RFS), overall survival (OS), and perioperative mortality was evaluated using the Cox proportional hazards and logistic models. Covariates were adjusted using propensity score overlap weighting. The optimal cut-off point of the E/ CO 2 slope was estimated using the receiver operating characteristics curve. Internal validation was completed through bootstrap resampling. RESULTS: A cohort of 895 patients [median age (interquartile range), 59 (13) years; 62.5% male] was followed for a median of 40 (range, 1-85) months. Throughout the study, there were 247 relapses or deaths and 156 perioperative complications. The incidence rates per 1000 person-years for relapses or deaths were 108.8 and 79.6 among patients with high and low E/ CO 2 slopes, respectively [weighted incidence rate difference per 1000 person-years, 29.21 (95% CI, 7.30-51.12)]. A E/ CO 2 slope of greater than or equal to 31 was associated with shorter RFS [hazard ratio for relapse or death, 1.38 (95% CI, 1.02-1.88), P =0.04] and poorer OS [hazard ratio for death, 1.69 (1.15-2.48), P =0.02] compared to a lower / CO 2 slope. A high E/ CO 2 slope increased the risk of perioperative morbidity compared with a low E/ CO 2 slope [odds ratio, 2.32 (1.54-3.49), P <0.001]. CONCLUSIONS: In patients with operable NSCLC, a high E/ CO 2 slope was significantly associated with elevated risks of poorer RFS, OS, and perioperative morbidity.

N6-methylation of RNA-bound adenosine regulator HNRNPC promotes vascular endothelial dysfunction in type 2 diabetes mellitus by activating the PSEN1-mediated Notch pathway.

AIM: The regulatory mechanism of m6A regulators in vascular endothelial function of type 2 diabetes mellitus (T2DM) remains largely unknown. We addressed this issue based on the data retrieved Gene Expression Omnibus (GEO) database and experimental validations. METHODS: Expression of m6A methylation regulators was evaluated in T2DM samples of GSE76894 dataset and GSE156341 dataset. Further analysis of candidate m6A methylation regulators was conducted in the thoracic aorta of db/db mice and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). Ectopic expression and depletion experiments were conducted to detect effects of m6A methylation regulators on vascular endothelial function in T2DM. RESULTS: It emerged that three m6A methylation regulators (HNRNPC, RBM15B, and ZC3H13) were highly expressed in T2DM, which were related to vascular EC function, showing diagnostic values for T2DM. HNRNPC expression in the thoracic aorta of db/db mice was higher than that in heterozygous db mice, and HNRNPC expression in HG-induced HUVECs was upregulated when compared with normal glucose-exposed HUVECs. Furthermore, HNRNPC activated PSEN1-dependent Notch pathway to induce eNOS inactivation and NO production decrease, thereby causing vascular endothelial dysfunction in T2DM. CONCLUSIONS: HNRNPC impaired vascular endothelial function to enhance the development of vascular complications in T2DM through PSEN1-mediated Notch signaling pathway.

Demethylation of miR-299-5p by aerobic exercise relieves insulin resistance in the vascular endothelium by repressing resistin.

AIMS: Insulin resistance (IR) is a critical marker underlying type 2 diabetes mellitus (T2DM). Exercise is reported to prevent IR, yet the mechanism of which is complicated and largely unknown. Here, the study aimed to ascertain whether and how aerobic exercise mediates IR in T2DM. METHODS: An in vivo model of high-fat diet (HFD)-induced IR and an in vitro model of high-glucose-induced IR were constructed. RESULTS: Aerobic exercise training in mice led to attenuation of IR in the vascular endothelium. microRNA-299-5p (miR-299-5p) expression was deficient in T2MD, which could be restored by aerobic exercise through modulating the DNA methylation modification enzymes. The expression of miR-299-5p enhanced by aerobic exercise consequently resulted in ameliorating the IR in vivo. Furthermore, increased levels of nitric oxide (NO), reduced levels of Angiotensin II (Ang II), vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in response to miR-299-5p elevation suggested the anti-IR role of miR-299-5p in IR-cell model. Dual-luciferase reporter and ChIP assays identified that miR-299-5p could bind to resistin and hence repressed the resistin level. CONCLUSION: The key observation of the study is that aerobic exercise stimulates miR-299-5p-targeted resistin inhibition through demethylation, which underlies the mechanism of reducing IR.

Rhodiola pre-conditioning reduces exhaustive exercise-induced myocardial injury of insulin resistant mice.

Myocardial injury reduction and recovery under acute cardiac stress are adversely impacted by insulin resistance (IR). We previously demonstrated that Rhodiola improved cardiac anti-stress capacity in mice. Thus, this study focuses on the preventive efficacy of Rhodiola on exhaustive exercise (EE)-induced myocardial injury of IR mice. An 8-week high-fat diet (HFD) model of IR mice was established. Rhodiola was administrated by garaging. After the 8-week intervention, half of the mice performed EE to simulate acute cardiac stress, and determine myocardial injury; The remaining mice were sacrificed following fasting to assess metabolic disorder. We found myocardial injury induced by EE in IR mice was worse and was alleviated by Rhodiola pre-conditioning. Further, the nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant system was impaired by HFD, while mitochondrial dynamic fusion and fission were activated by HFD as a physiological protective compensation. The Rhodiola administration rescued Nrf2 impairment and further facilitated mitochondrial fusion and fission. All these results indicate that Rhodiola is a potential treatment for the prevention of cardiac events in type 2 diabetes mellitus and metabolic syndrome patients, and the Nrf2-related antioxidant activity and mitochondrial dynamics are the proposed mechanisms.

Trimetazidine and exercise offer analogous improvements to the skeletal muscle insulin resistance of mice through Nrf2 signaling.

INTRODUCTION: Insulin resistance (IR) plays a key role in the pathogenesis and clinical course of patients with multiple metabolic diseases and diabetes. This study aimed to explore the effect of trimetazidine (TMZ) on skeletal muscle IR in mice fed a high-fat diet (HFD) and explore the possible underlying mechanism. RESEARCH DESIGN AND METHODS: In vivo, a HFD mouse IR model was adopted and TMZ and exercise were used to intervene. Postintervention the following were determined: blood levels of glucose and insulin, homeostasis model assessment of IR index, expression of skeletal muscle insulin signaling-related proteins phosphorylated insulin receptor substrate 1 (p-IRS1/IRS1) and phosphorylated protein kinase B (p-AKT/AKT), nuclear factor erythroid 2 related factor 2 (Nrf2) signaling pathway, and oxidative stress. In vitro, a palmitate-treated C2C12 myotube IR model was constructed. Cellular glucose uptake, p-IRS1/IRS1, and p-AKT/AKT were determined, and reactive oxygen species (ROS) production was analyzed based on treatments with specific small interfering RNA of Nrf2 with or without TMZ. Western blot was used to obtain the protein expression level and ROS production by functional analysis kits. RESULTS: In vivo, TMZ and exercise decreased the blood glucose and insulin levels and homeostasis model assessment of IR index, increased skeletal muscle insulin signaling-related protein ratios of p-IRS1/IRS1 and p-AKT/AKT, and both interventions activated Nrf2 signaling and reduced oxidative stress production in HFD mice. In vitro, TMZ reduced the oxidative stress reaction, increased the ratios of p-AKT/AKT and p-IRS1/IRS1, and attenuated the insulin stimulation of PA-induced glucose uptake. However, in the absence of Nrf2, TMZ failed to resist the effects of IR. CONCLUSIONS: This study showed that TMZ, like exercise, brought about marked improvements to HFD-induced skeletal muscle IR through TMZ, a common pathway with exercise in the form of Nrf2, regulating oxidative stress. We provide new evidence to support the use of TMZ for diabetes treatment.

Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control.

Obesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

The Treatment of Rhodiola Mimics Exercise to Resist High-Fat Diet-Induced Muscle Dysfunction via Sirtuin1-Dependent Mechanisms.

Muscle dysfunction is a complication of high-fat diet (HFD)-induced obesity that could be prevented by exercise, but patients did not get enough therapeutic efficacy from exercise due to multiple reasons. To explore alternative or supplementary approaches to prevent or treat muscle dysfunction in individuals with obesity, we investigated the effects of Rhodiola on muscle dysfunction as exercise pills. SIRT1 might suppress atrogenes expression and improve mitochondrial quality control, which could be a therapeutic target stimulated by exercise and Rhodiola, but further mechanisms remain unclear. We verified the lipid metabolism disorders and skeletal muscle dysfunction in HFD feeding mice. Moreover, exercise and Rhodiola were used to intervene mice with a HFD. Our results showed that exercise and Rhodiola prevented muscle atrophy and dysfunction in obese mice and activating the SIRT1 pathway, while atrogenes were suppressed and mitochondrial quality control was improved. EX-527, SIRT1 inhibitor, was used to validate the essential role of SIRT1 in salidroside benefit. Results of cell culture experiment showed that salidroside alleviated high palmitate-induced atrophy and mitochondrial quality control impairments, but these improvements of salidroside were inhibited by EX-527 in C2C12 myotubes. Overall, Rhodiola mimics exercise that activates SIRT1 signaling leading to improvement of HFD-induced muscle dysfunction.

Exercise combined with trimetazidine improves anti-fatal stress capacity through enhancing autophagy and heat shock protein 70 of myocardium in mice.

Background: Anti-stress capacity is important to resist the occurrence of adverse events. To observe the effects of exercise, trimetazidine alone or combined on the anti-stress capacity of mice, and further explore its potential mechanism. Methods: Forty-four C57BL/6 male mice aged 8 weeks were randomly divided into four groups (n=11 for each group): control group (group C), exercise group (group E), trimetazidine group (group T), exercise combined with trimetazidine group (group TE). After the intervention, each group was randomly subdivided into the exhaustive exercise (EE, n=6) and the non-EE (n=5) subgroups. The mice in the EE-subgroup underwent EE. Mice were sacrificed 12 hours later after EE. The myocardial ultrastructure and autophagosomes were observed under an electron microscope. The expression of autophagy-related proteins: BNIP3, LC3-II, and P62 were analyzed and the heat shock protein 70 mRNA transcription and protein expression were also investigated. Results: Exercise or trimetazidine increased the expression of BNIP3, LC3-II, and heat shock protein 70, decreased the expression of P62 pre- and post-EE while the combination has the synergistic effect. Conclusion: Exercise and trimetazidine, alone or combined enhanced the anti-stress capacity of mice significantly. The underlying mechanism may be associated with the promotion of autography and the expression of heat shock protein 70.

Characteristics and reference values for cardiopulmonary exercise testing in the adult Chinese population - The Xiangya hospital exercise testing project (the X-ET project).

BACKGROUND: Reference values of cardiopulmonary exercise testing (CPX) vary with race/ethnicity. Chinese Americans are the fastest-growing racial/ethnic group in the United States. However, there is limited information about the reference values of cardiopulmonary exercise testing (CPX) variables in the Chinese population. METHODS: As part of the Xiangya Hospital Exercise Testing project (the X-ET project), this cross-sectional study screened 20,696 consecutive CPXs performed by 17,802 unique individuals at Xiangya Hospital of Central South University, China, from January 1, 2002, to December 31, 2019. A total of 964 unique healthy adults/tests (42% female) aged 49 ± 12 who completed a maximal ramp incremental CPX with cycle ergometry were included in this study. The reference values of primary CPX variables were expressed as the lower limit or upper limit of normal. Stepwise linear regression was used to fit the equations of key CPX variables. Predictive accuracy analysis for the equations with a comparison between present and previous studies were performed. RESULTS: Peak oxygen consumption (V̇O2), carbon dioxide production, ventilation/min, work rate, and V̇O2 at the anaerobic threshold were regressed on age, height, weight, and sex. These predictive equations showed good in- and out-sample predictive accuracy. Comparison with prior research revealed that prediction equations of peak V̇O2 resultant from studies in which populations were entirely or primarily Caucasian had overestimated our subjects' actual values. CONCLUSION: The reference values and predicted equations of CPX variables in this study may provide a more appropriate framework to interpret the response to maximal ramp incremental cycle ergometry in the Chinese adult population.

Exercise improves lipid droplet metabolism disorder through activation of AMPK-mediated lipophagy in NAFLD.

AIM: To emphasize the mechanism of the effect of exercise on lipid droplet (LD) metabolism disorder in nonalcoholic fatty liver disease (NAFLD). MAIN METHODS: C57BL/6J mice were randomly divided into three groups: The first group was fed with a normal diet (CON), the second group was fed a high-fat diet (HF), and finally group with a high-fat diet intervention and swim training (HF-EX). The total intervention period was 16 weeks. RT-PCR and Western blot were performed to evaluate the effect of exercise on LDs metabolism and the AMPK pathway. Histopathological examinations and immunofluorescence were performed to evaluate the lipid deposition and lipophagy in the liver. KEY FINDINGS: Exercise reduced liver steatosis and insulin resistance along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of lipid metabolism. In addition, exercise increased the expression of autophagy marker and colocalization of LC3 and LAMP1 with LDs. SIGNIFICANCE: Exercise stimulated AMPK/SIRT1 and activated lipophagy in NAFLD. Enhancing lipophagy may be one of the key mechanisms of regulation and resolution of NAFLD by exercise.