Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling.

Peroxisome proliferator-activated receptor α (PPARα), a ligand-activated nuclear receptor critical for systemic lipid homeostasis, has been shown closely related to cardiac remodeling. However, the roles of cardiomyocyte PPARα in pressure overload-induced cardiac remodeling remains unclear because of lacking a cardiomyocyte-specific Ppara-deficient (PparaΔCM) mouse model. This study aimed to determine the specific role of cardiomyocyte PPARα in transverse aortic constriction (TAC)-induced cardiac remodeling using an inducible PparaΔCM mouse model. PparaΔCM and Pparafl/fl mice were randomly subjected to sham or TAC for 2 weeks. Cardiomyocyte PPARα deficiency accelerated TAC-induced cardiac hypertrophy and fibrosis. Transcriptome analysis showed that genes related to fatty acid metabolism were dramatically downregulated, but genes critical for glycolysis were markedly upregulated in PparaΔCM hearts. Moreover, the hypertrophy-related genes, including genes involved in extracellular matrix (ECM) remodeling, cell adhesion, and cell migration, were upregulated in hypertrophic PparaΔCM hearts. Western blot analyses demonstrated an increased HIF1α protein level in hypertrophic PparaΔCM hearts. PET/CT analyses showed an enhanced glucose uptake in hypertrophic PparaΔCM hearts. Bioenergetic analyses further revealed that both basal and maximal oxygen consumption rates and ATP production were significantly increased in hypertrophic Pparafl/fl hearts; however, these increases were markedly blunted in PparaΔCM hearts. In contrast, hypertrophic PparaΔCM hearts exhibited enhanced extracellular acidification rate (ECAR) capacity, as reflected by increased basal ECAR and glycolysis but decreased glycolytic reserve. These results suggest that cardiomyocyte PPARα is crucial for the homeostasis of both energy metabolism and ECM during TAC-induced cardiac remodeling, thus providing new insights into potential therapeutics of cardiac remodeling-related diseases.

Efficacy of extracorporeal shock wave therapy for knee tendinopathies and other soft tissue disorders: a meta-analysis of randomized controlled trials.

BACKGROUND: Extracorporeal shock-wave therapy (ESWT), which can be divided into radial shock-wave therapy (RaSWT) and focused shock-wave therapy (FoSWT), has been widely used in clinical practice for managing orthopedic conditions. The aim of this study was to determine the clinical efficacy of ESWT for knee soft tissue disorders (KSTDs) and compare the efficacy of different shock-wave types, energy levels, and intervention durations. METHODS: We performed a comprehensive search of online databases and search engines without restrictions on the publication year or language. We selected randomized controlled trials (RCTs) reporting the efficacy of ESWT for KSTDs and included them in a meta-analysis and risk of bias assessment. The pooled effect sizes of ESWT were estimated by computing odds ratios (ORs) with 95% confidence intervals (CIs) for the treatment success rate (TSR) and standardized mean differences (SMDs) with 95% CIs for pain reduction (i.e., the difference in pain relief, which was the change in pain from baseline to the end of RCTs between treatment and control groups) and for restoration of knee range of motion (ROM). RESULTS: We included 19 RCTs, all of which were of high or medium methodological quality and had a Physiotherapy Evidence Database score of ≥5/10. In general, ESWT had overall significant effects on the TSR (OR: 3.36, 95% CI: 1.84-6.12, P < 0.0001), pain reduction (SMD: - 1.49, 95% CI: - 2.11 to - 0.87, P < 0.00001), and ROM restoration (SMD: 1.76, 95% CI: 1.43-2.09, P < 0.00001). Subgroup analyses revealed that FoSWT and RaSWT applied for a long period (≥1 month) had significant effects on pain reduction, with the corresponding SMDs being - 3.13 (95% CI: - 5.70 to - 0.56; P = 0.02) and - 1.80 (95% CI: - 2.52 to - 1.08; P < 0.00001), respectively. Low-energy FoSWT may have greater efficacy for the TSR than high-energy FoSWT, whereas the inverse result was observed for RaSWT. CONCLUSIONS: The ESWT exerts an overall effect on the TSR, pain reduction, and ROM restoration in patients with KSTDs. Shock-wave types and application levels have different contributions to treatment efficacy for KSTDs, which must be investigated further for optimizing these treatments in clinical practice.

High Engraftment and Metastatic Rates in Orthotopic Xenograft Models of Gastric Cancer via Direct Implantation of Tumor Cell Suspensions.

Although the implantation of intact tumor fragments is a common practice to generate orthotopic xenografts to study tumor invasion and metastasis, the direct implantation of tumor cell suspensions is necessary when prior manipulations of tumor cells are required. However, the establishment of orthotopic xenografts using tumor cell suspensions is not mature, and a comparative study directly comparing their engraftment and metastatic capabilities is lacking. It is unclear whether tumor fragments are superior to cell suspensions for successful engraftment and metastasis. In this study, we employed three GC cell lines with varying metastatic capacities to stably express firefly luciferase for monitoring tumor progression in real time. We successfully minimized the risk of cell leakage during the orthotopic injection of tumor cell suspensions without Corning Matrigel by systematically optimizing the surgical procedure, injection volume, and needle size options. Comparable high engraftment and metastatic rates between these two methods were demonstrated using MKN-45 cells with a strong metastatic ability. Importantly, our approach can adjust the rate of tumor progression flexibly and cuts the experimental timeline from 10-12 weeks (for tumor fragments) to 4-5 weeks. Collectively, we provided a highly reproducible procedure with a shortened experimental timeline and low cost for establishing orthotopic GC xenografts via the direct implantation of tumor cell suspensions.