Modulating activity of PVN neurons prevents atrial fibrillation induced circulation dysfunction by electroacupuncture at BL15.

BACKGROUND: Circulation dysfunction is a major contributing factor to thrombosis in patients with atrial fibrillation (AF) for which effective interventions are lacking. Growing evidence indicates that regulating the paraventricular nucleus (PVN), an autonomic control center, could offer a novel strategy for treating cardiovascular and circulatory diseases. Concurrently, electroacupuncture (EA) at Xinshu (BL15), a form of peripheral nerve stimulation, has shown efficacy in treating several cardiovascular conditions, although its specific mechanism remains unclear. This study aimed to assess the impact of EA at BL15 on circulatory dysfunction in a rat AF model and investigate the pivotal role of PVN neuronal activity. METHODS: To mimic the onset of AF, male SD rats received tail intravenous injection of ACh-CaCl2 and were then subjected to EA at BL15, sham EA, or EA at Shenshu (BL23). Macro- and micro-circulation function were evaluated using in vivo ultrasound imaging and laser doppler testing, respectively. Vasomotricity was assessed by measuring dimension changes during vascular relaxation and contraction. Vascular endothelial function was measured using myograph, and the activation of the autonomic nerve system was evaluated through nerve activity signals. Additionally, chemogenetic manipulation was used to block PVN neuronal activation to further elucidate the role of PVN activation in the prevention of AF-induced blood circulation dysfunction through EA treatment. RESULTS: Our data demonstrate that EA at BL15, but not BL23 or sham EA, effectively prevented AF-induced macro- and micro-circulation dysfunction. Furthermore, EA at BL15 restored AF-induced vasomotricity impairment. Additionally, EA treatment prevented abnormal activation of the autonomic nerve system induced by AF, although it did not address vascular endothelial dysfunction. Importantly, excessive activation of PVN neurons negated the protective effects of EA treatment on AF-induced circulation dysfunction in rats. CONCLUSION: These results indicate that EA treatment at BL15 modulates PVN neuronal activity and provides protection against AF-induced circulatory dysfunction.

Restoring the Autonomic Balance in an Atrial Fibrillation Rat Model by Electroacupuncture at the Neiguan Point.

OBJECTIVES: Autonomic nervous activity imbalance plays an important role in atrial fibrillation (AF). AF can be treated by acupuncture at the Neiguan point (PC6), but the mechanism remains elusive. Here, we investigated autonomic nervous system activity in electroacupuncture (EA) at PC6 in a rat AF model. MATERIAL AND METHODS: In this study, we established a rat AF model via tail vein injection with ACh-CaCl2 for ten consecutive days with or without EA at PC6. AF inducibility and heart rate variability (HRV) were assessed by electrocardiogram. Next, we completed in vivo recording of the activity of cervical sympathetic and vagal nerves, respectively. Finally, the activities of brain regions related to autonomic nerve regulation were assessed by c-Fos immunofluorescence and multichannel recording. RESULTS: EA at PC6 decreased AF inducibility and prevented changes in HRV caused by ACh-CaCl2 injection. Meanwhile, EA at PC6 reversed the increased sympathetic and decreased vagal nerve activity in AF rats. Furthermore, EA treatment downregulated increased c-Fos expression in brain regions, including paraventricular nucleus, rostral ventrolateral medulla, and dorsal motor nucleus of the vagus in AF, while c-Fos expression in nucleus ambiguus was upregulated with EA. CONCLUSION: The protective effect of EA at PC6 on AF is associated with balance between sympathetic and vagal nerve activities.

HDAC inhibitor quisinostat prevents estrogen deficiency-induced bone loss by suppressing bone resorption and promoting bone formation in mice.

Postmenopausal osteoporosis (PMOP) is a metabolic skeletal disorder characterized by reduced bone mass and impaired bone microarchitecture resulting in increased bone fragility and fracture risk. PMOP is primarily caused by excessive osteoclastogenesis induced by estrogen deficiency. Quisinostat (Qst) is a potent hydroxamate-based second-generation inhibitor of histone deacetylases (HDACs) that can inhibit osteoclast differentiation in vitro, and protect mice from titanium particle-induced osteolysis in vivo. However, whether Qst has therapeutic potential against PMOP remains unclear. In the present study, we evaluated the therapeutic efficacy of Qst on PMOP, using a murine model of ovariectomy (OVX)-induced osteoporosis. We examined the body weight, femur length, and histology of major organs, and showed that Qst did not cause obvious toxicity in mice. Micro-computed tomography and histological analyses revealed that Qst treatment prevented OVX-induced trabecular bone loss both in femurs and vertebrae. Moreover, ELISA showed that Qst decreased the serum levels of the osteoclastic bone resorption marker CTX-1, whereas increased the levels of the osteoblastic bone formation marker Osteocalcin in OVX mice. Consistent with the CTX-1 results, TRAP staining showed that Qst suppressed OVX-induced osteoclastogenesis. Mechanistically, we showed that Qst suppressed RANKL-induced osteoclast differentiation in part by inhibiting p65 nuclear translocation. Collectively, our results demonstrated that Qst can ameliorate estrogen deficiency-induced osteoporosis by inhibiting bone resorption and promoting bone formation in vivo. In summary, our study provided the first preclinical evidence to support Qst as a potential therapeutic agent for PMOP prevention and treatment.

Gold nanorods modified by endogenous protein with light-irradiation enhance bone repair via multiple osteogenic signal pathways.

Fracture is one of the most common clinical diseases that reduce the quality of patients' lives significantly. In this study, we prepared gold nanorods modified by endogenous proteins which collected from the autologous blood of individual mice for enhanced photothermal therapy (PTT) to treat fracture. Due to the outermost layer being endogenous proteins, we find that GNRs neither activate the immune cells in vitro nor cause any rejection immune responses after entering the body as compared with PEG modification. In addition, the internal bleeding and edema of the fracture site result in a rapid enrichment of GNRs after intravenous injection. Under near infrared (NIR) light irradiation, the mild photothermal effect of the accumulated GNRs can effectively promote healing of fracture in mice. The molecular mechanism of osteogenic capability is revealed by transcriptome sequencing and subsequent confirmatory experiments, indicating enhanced two key osteogenic signal transduction (MAPK, PI3K-Akt) and multiple key osteogenesis related factors expression following the treatment. Our strategy offers an alternative way to promote bone regeneration following a fracture.

Comparison of the TightRope system versus hook plate in acute acromioclavicular joint dislocations: a retrospective analysis.

This study compared the results of the minimally invasive coracoclavicular (CC) fixation with a single TightRope (MITR) procedure and the hook plate (HP) procedure for acute acromioclavicular (AC) joint dislocation treatment. Sixteen patients with a mean age of 44.9 ± 11 years were treated with the MITR procedure. Nineteen patients with a mean age of 40.2 ± 8.7 years were treated using the HP procedure. Clinical outcomes were evaluated with the Visual Analog Scale (VAS) for pain, Constant-Murley Score (CMS), and University of California at Los Angeles (UCLA) Shoulder score. Vertical displacement of the clavicle with reference to the height of the acromion was measured in standard anteroposterior radiographs. The mean follow-up was 27 months in the MITR group and 30 months in the HP group. No statistically significant differences were found between the MITR group and the HR group in terms of VAS score (0.4 ± 0.6 vs 0.7 ± 0.6, P = 0.138), UCLA Shoulder score (33.9 ± 2.5 vs 33.7 ± 1.5, P = 0.843), or CMS (95.7 ± 7.3 vs 93.7 ± 6.6, P = 0.400). No redislocation was identified in the HP group, while redislocation occurred in 1 of 16 (6.3%) patients in the MITR group. One patient in the HP group (5.3%) had acromial osteolysis, while no acromial osteolysis was found in the MITR group. No other adverse events, such as infections, tunnel widening, fractures, or implant-related complications, were observed. Both procedures provided satisfactory results. The HP procedure provided better reduction, while the MITR procedure provided a slightly lower tendency of pain. Long-term follow-up is needed to investigate the clinical outcomes and radiological outcomes of both groups.

Inhibition of osteoclastogenesis by histone deacetylase inhibitor Quisinostat protects mice against titanium particle-induced bone loss.

Periprosthetic osteolysis (PPO) and subsequent aseptic loosening are major long-term complications after total joint arthroplasty and have become the first causes for further revision surgery. Since PPO is primarily caused by excessive bone resorption stimulated by released wear particles, osteoclast-targeted therapy is considered to be of great potential for PPO prevention and treatment. Accumulating evidences indicated that inhibition of histone deacetylases (HDACs) may represent a novel approach to suppress osteoclast differentiation. However, different inhibitors of HDACs were shown to exhibit distinct safety profiles and efficacy in inhibiting osteoclastogenesis. Quisinostat (Qst) is a hydroxamate-based histone deacetylase inhibitor, and exerts potent anti-cancer activity. However, its effect on osteoclastogenesis and its therapeutic potential in preventing PPO are still unclear. In this study, we found that Qst suppressed RANKL-induced production of TRAP-positive mature osteoclasts, expression of osteoclast-specific genes, formation of F-actin rings, and bone resorption activity at a nanomolar concentration as low as 2 nM in vitro. Furthermore, we found that as low as 30 µg/kg of Qst was sufficient to exert preventive effect on titanium particle-induced osteolysis in the murine calvarial osteolysis model. Mechanistically, we found that Qst suppressed osteoclastogenesis by interfering with NF-κB and c-Fos/NFATc1 pathways. Thus, our study revealed that Qst may serve as a potential therapeutic agent for prevention and treatment of PPO and other osteoclast-mediated diseases.

Protection against Doxorubicin-Induced Cardiotoxicity through Modulating iNOS/ARG 2 Balance by Electroacupuncture at PC6.

BACKGROUND: Doxorubicin (DOX) is a commonly used chemotherapeutic drug but is limited in clinical applications by its cardiotoxicity. Neiguan acupoint (PC6) is a well-recognized acupoint for the treatment of cardiothoracic disease. However, whether acupuncture at PC6 could be effective in preventing DOX-induced cardiotoxicity is still unknown. METHODS: A set of experiments were performed with myocardial cells, wild type, inducible nitric oxide synthase knockout (iNOS-/-), and myocardial-specific ablation arginase 2 (Myh6-ARG 2-/-) mice. We investigated the protective effect and the underlying mechanisms for electroacupuncture (EA) against DOX-induced cardiotoxicity by echocardiography, immunostaining, biochemical analysis, and molecular biotechnology in vivo and in vitro analysis. RESULTS: We found that DOX-mediated nitric oxide (NO) production was positively correlated with the iNOS level but has a negative correlation with the arginase 2 (ARG 2) level in both myocardial cells and tissues. Meanwhile, EA at PC6 alleviated cardiac dysfunction and cardiac hypertrophy in DOX-treated mice. EA at PC6 blocked the upregulation of NO production in accompanied with the downregulated iNOS and upregulated ARG 2 levels in myocardial tissue induced by DOX. Furthermore, knockout iNOS prevented cardiotoxicity and EA treatment did not cause the further improvement of cardiac function in iNOS-/- mice treated by DOX. In contrast, deficiency of myocardial ARG 2 aggravated DOX-induced cardiotoxicity and reduced EA protective effect. CONCLUSION: These results suggest that EA treatment at PC6 can prevent DOX-induced cardiotoxicity through modulating NO production by modulating the iNOS/ARG 2 balance in myocardial cells.

Krüppel-like factor 17 upregulates uterine corin expression and promotes spiral artery remodeling in pregnancy.

Spiral artery remodeling is an important physiological process in the pregnant uterus which increases blood flow to the fetus. Impaired spiral artery remodeling contributes to preeclampsia, a major disease in pregnancy. Corin, a transmembrane serine protease, is up-regulated in the pregnant uterus to promote spiral artery remodeling. To date, the mechanism underlying uterine corin up-regulation remains unknown. Here we show that Krüppel-like factor (KLF) 17 is a key transcription factor for uterine corin expression in pregnancy. In cultured human uterine endometrial cells, KLF17 binds to the CORIN promoter and enhances the promoter activity. Disruption of the KLF17 gene in the endometrial cells abolishes CORIN expression. In mice, Klf17 is up-regulated in the pregnant uterus. Klf17 deficiency prevents uterine Corin expression in pregnancy. Moreover, Klf17-deficient mice have poorly remodeled uterine spiral arteries and develop gestational hypertension and proteinuria. Together, our results reveal an important function of KLF17 in regulating Corin expression and uterine physiology in pregnancy.

The role of fucosylation in the promotion of endothelial progenitor cells in neovascularization and bone repair.

Bone marrow-derived endothelial progenitor cells (EPCs) are being tested as a therapy to treat a variety of ischemic diseases. Poor homing to targeted tissues is one of the major factors limiting the therapeutic efficacy of EPCs. Here, we show that human cord blood-derived EPCs expressed little sialyl Lewis X (sLe(x)) antigen that is necessary for selectin-mediated cell-cell interactions. Expression of α1,3-fucosyltransferase VI (FucT VI) in the EPCs enhanced sLe(x) synthesis, E- and P-selectin-binding, and EPC adhesion to tumor necrosis factor-α-stimulated human umbilical vein endothelial cells in culture. In a mouse model of hind limb ischemia, in which EPCs were injected intravenously, FucT VI expression increased EPC homing, neovascularization, and blood flow in ischemic muscles. In another mouse model of femoral fracture, FucT VI-expressing EPCs were more efficient than control EPCs in targeting to peri-fracture tissues to enhance angiogenesis, blood flow and bone repair. These results indicate that fucosylated EPCs may be used to as an improved cellular source to treat ischemic diseases.

[EFFECTIVENESS OF ANTERIOR APPROACH FOR TREATING ANTEROMEDIAL FACET FRACTURES OF U LNAR CORONOID PROCESS].

OBJECTIVE: To explore the effectiveness of non-absorbable suture or suture anchor fixation by anterior approach in the treatment of anteromedial facet fractures of the ulnar coronoid process. METHODS: Between February 2007 and February 2012, 16 cases of anteromedial facet fractures of the ulnar coronoid process were treated with operation. There were 9 males and 7 females, aged 20-80 years (mean, 43.5 years). The causes of injury were traffic accident injury in 7 cases, tumble injury in 5 cases, and falling injury from height in 4 cases. The time from injury to operation was 6.8 days on average (range, 2-8 days). All cases had closed fractures. According to O'Driscoll classification, there were 4 cases of type II a, 7 cases of type II b, and 5 cases of type II c. Among 16 patients, 7 had simple anteromedial facet fractures of the ulnar coronoid process, and 9 had associated injury, including terrible triad in 3, Monteggia fractures in 4, and olecranon fractures in 2. All fractures were fixed with non-absorbable suture in 10 cases, and with suture anchor in 6 cases. The Mayo Elbow Performance Score (MEPS), range of motion (ROM), and complications were used to assess the elbow function. RESULTS: The incisions all healed by first intension, without neurovascular injury. Fifteen patients were followed up 10-48 months (mean, 25.3 months). The X-ray films showed that all fractures healed, with the mean healing time of 17.5 weeks (range, 11-30 weeks). At last follow-up, the mean MEPS score was 88.5 (range, 55-100); the results were excellent in 10 cases, good in 3 cases, fair in 1 case, and poor in 1 case, with an excellent and good rate of 86.7%. The mean ROM of flexion and extension was 118° (range, 35-145°), and the mean ROM of forearm rotation was 138° (range, 85-165°). One case had elbow instability, and 3 had slight pain. No heterotopic ossification and traumatic arthritis occurred during the follow-up. CONCLUSION: The anteromedial facet fractures of the ulnar coronoid process can be clearly exposed through anterior approach, and the fracture fixation using non-absorbable suture and suture anchor fixation usually can restore the elbow function.

[Effect of aspirin on function of human umbilical cord blood-derived late endothelial progenitor cells].

This study was aimed to investigate whether aspirin has effect on function of late endothelial progenitor cells (EPC). Cord blood CD34(+) cells were purified using the ficoll density gradient centrifugation and human CD34 positive selection kit, then the cells were inoculated on fibronectin-coated culture plate. After culture for 2 weeks, adherent cells were identified as EPC by flow cytometry, immunofluorescence, RT-PCR, uptake of Dil-Ac-LDL and matrigel tube formation assay. EPC were treated with different concentrations of aspirin (0.1, 1, 10, 100, 1 000, 10 000 µmol/L) for 24 h, then the proliferation, adhesion and migration ability of these cells were analyzed by CCK-8 assay and transwell methods. The results indicated that the low concentrations of aspirin (0.1 and 1 000 µmol/L) promoted late EPC adhesive and migratory capacity, but no obvious effect on proliferation of late EPC were observed. On the other hand, the high concentrations of aspirin (10 000 µmol/L) inhibited proliferation and migratory capacity of EPC, but had no obvious effect on adhesive ability of EPC. It is concluded that low concentration of aspirin promotes migration and adhesion of late EPC, while the high concentration of aspirin decreases EPC proliferation and migratory capacity of EPC.