Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx.

To date, several molecules have been found to facilitate iron influx, while the types of iron influx channels remain to be elucidated. Here, Piezo1 channel was identified as a key iron transporter in response to mechanical stress. Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells (NPCs). Importantly, Piezo1-induced iron influx was independent of the transferrin receptor (TFRC), a well-recognized iron gatekeeper. Furthermore, pharmacological inactivation of Piezo1 profoundly reduced iron accumulation, alleviated mitochondrial ROS, and suppressed ferroptotic alterations in stimulation of mechanical stress. Moreover, conditional knockout of Piezo1 (Col2a1-CreERT Piezo1flox/flox) attenuated the mechanical injury-induced intervertebral disc degeneration (IVDD). Notably, the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout (cDKO) mice (Col2a1-CreERT Piezo1flox/flox/Gpx4flox/flox). These findings suggest that Piezo1 is a potential determinant of iron influx, indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.

Cortistatin prevents glucocorticoid-associated osteonecrosis of the femoral head via the GHSR1a/Akt pathway.

Long-term use of glucocorticoids (GCs) is known to be a predominant cause of osteonecrosis of the femoral head (ONFH). Moreover, GCs can mediate apoptosis of various cell types by exaggerating oxidative stress. We have previously found that Cortistatin (CST) antagonizes oxidative stress and improves cell apoptosis in several conditions. In this study, we detected that the CST expression levels were diminished in patients with ONFH compared with femoral neck fracture (FNF). In addition, a GC-induced rat ONFH model was established, which impaired bone quality in the femoral head. Then, administration of CST attenuated these ONFH phenotypes. Furthermore, osteoblast and endothelial cells were cultured and stimulated with dexamethasone (Dex) in the presence or absence of recombinant CST. As a result, Dex induced impaired anabolic metabolism of osteoblasts and suppressed tube formation in endothelial cells, while additional treatment with CST reversed this damage to the cells. Moreover, blocking GHSR1a, a well-accepted receptor of CST, or blocking the AKT signaling pathway largely abolished the protective function of CST in Dex-induced disorder of the cells. Taken together, we indicate that CST has the capability to prevent GC-induced apoptosis and metabolic disorder of osteoblasts in the pathogenesis of ONFH via the GHSR1a/AKT signaling pathway.

Selenomethionine against titanium particle-induced osteolysis by regulating the ROS-dependent NLRP3 inflammasome activation via the ß-catenin signaling pathway.

Wear debris-induced osteolysis, especially titanium (Ti) particles-induced osteolysis, is the most common cause of arthroplasty failure with no effective therapy. Previous studies have suggested that inflammation and impaired osteogenesis are associated with Ti particles -induced osteolysis. Selenium (Se) is an essential trace element in the human body, which forms selenomethionine (Se-Met) in nature, and selenoproteins has strong anti-inflammatory and antioxidant stress effects. In this study, the effects of Se-Met on Ti particles-induced osteolysis were observed and the potential mechanism was explored. We found that exogenous Se-Met relieved osteolysis induced by Ti particles in two animal models and MC3T3-E1 cells. We found that the addition of Se-Met effectively inhibited Ti particle-induced inflammation by regulating reactive oxygen species-dependent (ROS-dependent) NOD-like receptor protein 3 (NLRP3) inflammasome activation. These therapeutic effects were abrogated in MC3T3-E1 cells that had received a ß-catenin antagonist, suggesting that Se-Met alleviates inflammatory osteolysis via the ß-catenin signaling pathway. Collectively, these findings indicated that Se-Met may serve as a potential therapeutic agent for treating Ti particle-induced osteolysis.

Efficacy and safety of long-term use of a positive expiratory pressure device in chronic obstructive pulmonary disease patients, a randomized controlled trial.

BACKGROUND: Exercise intolerance is among the most common symptoms experienced by patients with chronic obstructive pulmonary disease (COPD), which is associated with lung dynamic hyperinflation (DH). There was evidence that positive expiratory pressure (PEP), which could be offered by less costly devices, could reduce DH. The purpose of this study was to evaluate the efficacy and safety of long-term domiciliary use of PEP device in subjects with COPD. METHODS: A randomized controlled trial was conducted and 25 Pre-COPD or mild-to-very severe subjects with COPD were randomized to intervention group (PEP device, PEP = 5 cmH2O, n = 13) and control group (Sham-PEP device, PEP = 0 cmH2O, n = 12). PEP device was a spring-loaded resistor face mask. Subjects were treated 4 h per day for a total of 2 months. Six-minute walk test (6MWT), pulmonary function, the Modified British Medical Research Council score, and partial pressure of end-tidal carbon dioxide were evaluated at baseline and after two months. RESULTS: The 6MWD (- 71.67 ± 8.70 m, P < 0.001), end-dyspnea (P = 0.002), and end-fatigue (P = 0.022) improved significantly in the intervention group when compared with the control group. All subjects in the intervention group reported that 4 h of daily use of the PEP device was well tolerated and accepted and there were no adverse events. CONCLUSION: Regular daily use of PEP device is safe and may improve exercise capacity in subjects with COPD or pre-COPD. PEP device could be used as an add-on to pulmonary rehabilitation programs due to its efficacy, safety, and low cost. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT04742114).

Effect of heated humidified high-flow nasal cannula (HFNC) oxygen therapy in dyspnea patients with advanced cancer, a randomized controlled clinical trial.

PURPOSE: Heated humidified high-flow nasal cannula (HFNC) oxygen therapy is one of the most important oxygen therapy methods, which are commonly applied to relieve dyspnea in advanced cancer patients. Our study aims to observe the efficacy and safety of HFNC oxygen therapy on dyspnea patients with advanced cancer and explore the clinical application. METHODS: Sixty subjects with advanced cancer requiring oxygen therapy from a grade 3, class A hospital in China were recruited and randomized (1:1) to traditional nasal catheter oxygen therapy or HFNC. Primary outcomes were dyspnea, oral dryness, and sleep condition, which were recorded after 72-h treatment. Secondary outcomes were heart rate (HR), respiration rate (RR), SpO2, PaO2, and PaCO2, which were recorded after 2, 6, 24, and 72 h treatment. RESULTS: Seventy-two hours after treatment, there were significant improvements in all primary outcomes (P < 0.001). PaO2 and RR were statistically changed 2 h after HFNC treatment (P < 0.001). PaCO2 and HR were statistically changed 24 h after HFNC treatment (P < 0.001). CONCLUSION: HFNC oxygen therapy has good effect, high safety, and is easy to be accepted by dyspnea patients with advanced cancer. It can be used as the first choice of oxygen therapy for these patients and has broad clinical prospects. TRIAL REGISTRATION: This work was retrospectively registered in the Chinese Clinical Trials Registry (ChiCTR2100049582) on August 4, 2021.

Factors affecting abnormal triggering with non-invasive ventilators: A before-and-after study.

INTRODUCTION: Abnormal triggering of non-invasive ventilator (NIV) is the main reason for increasing the possibility of patient intolerance and directly affecting the treatment effect. OBJECTIVE: To investigate factors that affect abnormal triggering of NIV. METHODS: Thirty health volunteers from August 2018 to August 2019 were recruited. Two kinds of NIVs, Curative Flexo ST30 and Resmed Stellar™ 150, were selected, with S/T mode, respiratory rate of 10 bpm and inspiration time of 1.0 s. Every volunteer received ventilation in two ventilators, five oxygen flows (5/10/15/20/25 L/min), five support pressures (independent inspired positive airway pressure/expired positive airway pressure [IPAP/EPAP]: 8/4; 10/4; 12/4; 16/6; 20/8 cm H2 O), two oxygen injection sites (proximal to the mask or the ventilator) and three masks (Curative: Bestfit™; Resmed: Mirage Quattro Full Face Mask™; Zhongshan: ZS-MZ-A™) for 60 min, respectively. RESULTS: All factors mentioned above affected normal triggering. With the increase of oxygen flow and support pressure, the frequency of auto-triggering and ineffective-triggering increased (P < 0.05). For Curative Flexo ST30 ventilator, when the oxygen injection site was proximal to the ventilator, the frequency of auto-triggering and ineffective-triggering is significantly lower than when it was proximal to the mask, whereas the result in Resmed Stellar™ 150 is totally different (P < 0.05). CONCLUSION: When using Curative Flexo ST30 ventilator, the oxygen injection site should be proximal to the ventilator, whereas Resmed Stellar™ 150 ventilator is just the opposite. Attention should be paid to the effectiveness of ventilators when oxygen flow and support pressure settings are high, as abnormal triggers occur more frequently. Choosing the suitable mask is also important.

Fractionation of 50kGy electron beam irradiation: effects on biomechanics of human flexor digitorum superficialis tendons treated with ascorbate.

The electron beam (Ebeam) irradiation has begun to be considered as an efficient alternative to gamma irradiation in the sterilization of allografts in the reconstruction of anterior cruciate ligament. The purpose of this study was to evaluate the biomechanical properties of human tendons after exposure to electron beam and free radical scavenger ascorbate. Forty human flexor digitorum superficialis tendons were prepared from five fresh cadavers and divided randomly into four groups: A, fresh (0kGy); B, 50kGy Ebeam irradiation; C, fractionated 50kGy Ebeam irradiation; D, fractionated 50kGy Ebeam on ascorbate-treated tendons. The fractionation of 50kGy was achieved by repeated irradiation of 2.5kGy for 20 repetitions. Biomechanical properties were analyzed during load-to-failure testing. The fresh tendons were found to be significant different in ultimate load, ultimate elongation relative to tendons in group B. Statistical differences were found between group B and C in ultimate load. No differences were detected between group A and C in all the parameters. Compare tendons in group C and D, significant differences were found in ultimate load and ultimate stress. It is recommended that fractionated 50kGy electron beam irradiation and free radical scavenger ascorbate should be applied in the sterilization of allografts tendons.