Hydromorphone hydrochloride preconditioning combined with postconditioning attenuates myocardial ischemia/reperfusion injury in rats by improving mitochondrial function and activating the PI3K/Akt signaling pathway.

Thrombolytic therapy or percutaneous coronary intervention for myocardial infarction often cause myocardial ischemia/reperfusion injury (MIRI) and poor prognosis of patients. This study aimed to explore the protective effect and potential mechanism of hydromorphone hydrochloride (HH) on MIRI. Fifty Sprague-Dawley male rats were randomly divided into Sham group, I/R group, HH-pre group, HH-post group, and HH-pre + post group. Except Sham group, MIRI models were established by ligating and relaxing the left anterior descending coronary artery, followed by tail vein injection of HH (0.3 µmol/L) 10 min before ligation (HH-pre group), 10 min after reperfusion (HH-post group), and twice at the above two time points (HH-pre + post group). After intervention, the cardiac function of rats was evaluated by echocardiography, and the levels of myocardial injury markers, oxidative stress indicators, and mitochondrial function indicators were detected. Next, the myocardial infarction area was evaluated by 2,3,5-triphenyltetrazolium chloride staining, mitochondrial biogenesis, and phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway by western blot. Compared with the I/R group, HH intervention improved cardiac function, decreased myocardial infarction area, reduced serum myocardial injury markers, alleviated oxidative stress, improved mitochondrial function, up-regulated mitochondrial biogenesis, and activated PI3K/Akt signaling pathway. Moreover, the HH-pre + post group was superior to the HH-pre and HH-post groups in the above aspects. Collectively, HH had protective effect on MIRI rats, and HH preconditioning combined with postconditioning showed optimal efficacy. Such efficacy may be achieved by promoting mitochondrial biogenesis to improve mitochondrial function and reduce oxidative stress, and activating the PI3K/Akt signaling pathway.

Potential Role of Bmal1 in Lipopolysaccharide-Induced Depression-Like Behavior and its Associated "Inflammatory Storm".

Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an "inflammatory storm" in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic-pituitary-adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.

Co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia predict prognosis and immunotherapy response in glioblastoma.

OBJECTIVES: Anesthetic drugs had been reported may impact the bio-behavior of the tumor. Propofol and sevoflurane are common anesthetics in the operation for glioblastoma (GBM). This study aims to establish a co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia to predict prognosis and immunotherapy response in GBM. METHOD: GPM tissues with different anesthetics gene expression profiles (GSE179004) were obtained from the Gene Expression Omnibus (GEO) database. Core modules and central genes associated with propofol and sevoflurane anesthesia were identified by weighted gene coexpression network analysis (WGCNA) and establish a risk score prognostic model. Immune cell signature analysis in TCGA datasets was predicted via CIBERSORT. At last, serum methylation level of O6-methylguanine-DNA methyltransferase (MGMT) promoter was detected in GPM patient in different time during perioperative period. RESULTS: The burlywood1 group screened was significantly associated with sevoflurane-treated GBM tissue. 22 independent prognostic differential genes were construct a prognostic-related genes risk score in GBM, and showed good predictive ability. The risk score was strongly correlated with the age of the patients, but not with the sex of the patients. In addition, the differential responses to immunotherapy in high and low risk groups were analyzed, indicating that sevoflurane signature genes were consistent in the classification of gliomas. High-risk patients have high T-cell damage score and are less sensitive to immunotherapy. At last, serum methylation level of MGMT promoter was decreased in GBM patients during propofol and sevoflurane anesthesia. CONCLUSIONS: Propofol and sevoflurane anesthesia associated impact on the gene expression of GBM, included the methylation level of MGMT promoter. Propofol and sevoflurane anesthesia-based risk score prognostic model, which has good prognostic power and is an independent prognostic factor in GBM patients. Therefore, this model can be used as a new biomarker for judging the prognosis of GBM patients.KEY MESSAGESPropofol and sevoflurane anesthesia-based risk score prognostic model has good prognostic power and is an independent prognostic factor in GBM patients.High Propofol and sevoflurane anesthesia-based risk score GBM patients have high T-cell damage scores and are less sensitive to immunotherapy.Serum methylation level of MGMT promoter decrease during propofol and sevoflurane anesthesia in GBM patients.

Postoperative analgesic effect of dexmedetomidine combined with TPVB applied to open gastrectomy for gastric cancer.

OBJECTIVES: This study is aimed to investigate the analgesic effect of combined dexmedetomidine and thoracic paravertebral nerve block (TPVB) on gastric cancer (GC) patients undergoing open gastrectomy. METHODS: From May 2019 to Nov 2020, a total of 80 GC patients preparing for open gastrectomy were enrolled in our hospital and were divided into the ropivacaine (RO) group and the ropivacaine + dexmedetomidine (RD) group ad libitum. All of the patients underwent TPVB. The characteristics, usage of patient-controlled analgesia (PCA), adverse events, visual analogue scale (VAS) scores, inflammatory cytokines, and T cell subgroups between the two groups were compared. RESULTS: Patients in the RD group showed the decreased occurrence rate of postoperative adverse events and VAS scores and improved anti-inflammation and immune function. These findings implied that the application of dexmedetomidine in combination with RO in TPVB has a good postoperative analgesic effect, as well as anti-inflammatory and immune-enhancing effects. CONCLUSIONS: Dexmedetomidine as an adjunct analgesic may be potentially applied in clinical practice for GC patients undergoing open gastrectomy.

Protective Effect of Sufentanil on Myocardial Ischemia-Reperfusion Injury in Rats by Inhibiting Endoplasmic Reticulum Stress.

Objective: Sufentanil is the most common drug in clinical practice for the treatment of ischemic heart disease. This study is to investigate the protective mechanism of sufentanil on rat myocardial ischemia-reperfusion (I/R) injury. Methods: A rat I/R model was established by ligating the left anterior descending coronary artery. A total of 24 SD male rats were enrolled and divided randomly into the control group, I/R group, sufentanil group (SUF; 3 µg/kg), and diltiazem group (DLZ; 20 mg/kg; positive control). The rat hearts were subjected to 30 min of ischemia followed by 120 min of reperfusion. Subsequently, hemodynamics, pathological changes of myocardial tissue, serum biochemical parameters, oxidative stress factors, the level of serum inducible nitric oxide synthases (iNOS), interleukin-6 (IL-6), and other bioactive factors were analyzed in the rats. Result: Compared with the I/R group, sufentanil significantly improved cardiac action, myocardial fiber, and cardiomyocyte morphology and reduced inflammatory cell infiltration in rats in the SUF group. And the level of creatine kinase isoenzyme (CK-MB), troponin (cTn), lactate dehydrogenase (LDH), malondialdehyde (MDA), iNOS, and IL-6 was significantly declined in the serum of SUF group, while the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were significantly activated in the myocardial tissues. In addition, sufentanil also significantly decreased the protein expression of GRP78, CHOP, Caspase 12, and ATF6 in the myocardial tissue of the SUF group. Conclusion: Sufentanil has a significant protective activity on myocardial I/R injury in rats, the mechanism of which may be associated with the inhibition of endoplasmic reticulum stress and oxidative stress.

Propofol ameliorates neuropathic pain and neuroinflammation through PPAR γ up-regulation to block Wnt/ß-catenin pathway.

OBJECTIVE: As an intravenous anesthetic, propofol has been exhibited to provide excellent clinical analgesia. Whether propofol has amelioration property for NP and neuroinflammation remains unexplored. The present study was arranged to probe the role of propofol in the mitigation of NP and neuroinflammation in rats and underlying mechanisms. METHODS: Rats were randomly classified into the following groups: Model, Sham, Control, Propofol, GW9662, and Saline groups. The radiant heat stimulation was used to measure paw withdrawal latency (PWL), and mechanical stimulation was employed to detect paw withdrawal threshold (PWT). Subsequently, the expression of GFAP was assessed by immunofluorescence to reflect the activation of astrocyte. qRT-PCR and Western blot were utilized for the performance of mRNA and protein expression levels of PPAR γ as well as inflammation factors (TNF-α, IL-1ß, and IL-6). RESULTS: Pentobarbital sodium anesthesia significantly shortened the PWL and PWT, suppressed PPAR γ expression in rats in addition to elevating astrocyte activation and inflammation response. Propofol treatment attenuated the NP of rats as evidenced by restrained astrocyte activation level and inflammation factor levels. Rats treated with propofol had markedly heightened PPAR γ expression. PPAR γ exposure ameliorated NP and inflammation degree, which demonstrated by elevated astrocyte activation and inflammation levels as well as suppressed PWL and PWT in rats injected with PPAR γ inhibitor. Besides, PPAR γ decreased the expression level of ß-catenin. CONCLUSION: Propofol ameliorates NP and neuroinflammation of rats by up-regulating PPAR γ expression to block the Wnt/ß-catenin pathway.

Chrysin protects human osteoarthritis chondrocytes by inhibiting inflammatory mediator expression via HMGB1 suppression.

High­mobility group box chromosomal protein (HMGB­1) contributes to osteoarthritis (OA) by modulating various oxidative, inflammatory and apoptotic signaling pathways. The effect of chrysin (CH), a natural plant flavonoid, and its functional interaction with HMGB­1, was investigated in a chondrocyte model of OA. Human chondrocytes were pre­treated with CH, and then subsequently treated with IL­1ß to induce the formation of chondrocytes similar to those found in OA joints. Next, the expression level of HMGB­1 was determined by immunofluorescence and western blot analysis. Additionally, inflammatory factor expression was measured by ELISA, and cell apoptosis was analyzed with flow cytometry. To further explore the effects of CH, HMGB­1 expression was silenced following CH treatment with small interfering (si)RNA. The results demonstrated that CH inhibited cell apoptosis, dose­dependently reduced matrix metalloproteinase (MMP) 13, collagenase and IL­6 expression, and increased collagen α­1 (II) chain (COL2A1) expression in human osteoarthritis chondrocytes. These effects of CH were accompanied by decreased HMGB­1 expression. Additionally, the expression of MMP13, collagenase, IL­6 and COL2A1, as well as apoptosis, was significantly reduced by HMGB­1 siRNA. These results demonstrated that HMGB­1 is critical for the protective effect of CH on human osteoarthritis chondrocytes, including cell apoptosis and inflammatory factor inhibition, which suggests that CH may have potential therapeutic effect in treating OA by protecting human osteoarthritis chondrocytes via HMGB1 suppression.

Modified classification and single-stage microsurgical repair of posttraumatic infected massive bone defects in lower extremities.

Posttraumatic infected massive bone defects in lower extremities are difficult to repair because they frequently exhibit massive bone and/or soft tissue defects, serious bone infection, and excessive scar proliferation. This study aimed to determine whether these defects could be classified and repaired at a single stage. A total of 51 cases of posttraumatic infected massive bone defect in lower extremity were included in this study. They were classified into four types on the basis of the conditions of the bone defects, soft tissue defects, and injured limb length, including Type A (without soft tissue defects), Type B (with soft tissue defects of 10 × 20 cm or less), Type C (with soft tissue defects of 10 × 20 cm or more), and Type D (with the limb shortening of 3 cm or more). Four types of single-stage microsurgical repair protocols were planned accordingly and implemented respectively. These protocols included the following: Protocol A, where vascularized fibular graft was implemented for Type A; Protocol B, where vascularized fibular osteoseptocutaneous graft was implemented for Type B; Protocol C, where vascularized fibular graft and anterior lateral thigh flap were used for Type C; and Protocol D, where limb lengthening and Protocols A, B, or C were used for Type D. There were 12, 33, 4, and 2 cases of Types A, B, C, and D, respectively, according to this classification. During the surgery, three cases of planned Protocol B had to be shifted into Protocol C; however, all microsurgical repairs were completed. With reference to Johner-Wruhs evaluation method, the total percentage of excellent and good results was 82.35% after 6 to 41 months of follow-up. It was concluded that posttraumatic massive bone defects could be accurately classified into four types on the basis of the conditions of bone defects, soft tissue coverage, and injured limb length, and successfully repaired with the single-stage repair protocols after thorough debridement.

Effects of gene­activated matrix on autograft healing of anterior cruciate ligament.

The aim of the present study was to observe the effects of gene­activated matrix (GAM) on autograft healing of the anterior cruciate ligament. Forty­eight rabbits were randomly divided into groups A and B. Rabbits were used to construct models of anterior cruciate ligament reconstruction. In group A, transforming growth factor (TGF)­ß1 was locally injected into the bone tunnel, while in group B, empty vector was administered. Tendons were removed to observe histology and ultrastructure and to evaluate biomechanics at postoperative months 1, 3 and 6. Optical microscopy revealed increased numbers of fibroblasts and collagen fibers in group A at each time­point compared with B. Electron microscopy identified increased mitosis and abundance of fibroblasts, endoplasmic reticulum and mitochondria in group A at each time­point compared with B. No significant difference was identified in the biomechanical parameters between the 2 groups at postoperative month 1. At postoperative months 3 and 6, maximum force and elastic modulus were greater in group A compared with group B (P<0.0.5). No significant differences in other biochemical parameters were observed at these time­points. The healing ligament graft transfected with TGF­ß1 by GAM was observed to have improved tissue structure and biomechanical characteristics. The results of the current study may provide a theoretical basis for GAM application in ligament repair.

[Treatment of displaced humeral supracondylar fractures in children with external fixation using plaster or splint].

OBJECTIVE: To investigate the therapeutic effects of closed reduction and external fixation (plaster or splint) for the treatment of displaced humeral supracondylar fractures in children. METHODS: From March 2007 to September 2009,33 children (15 female and 18 male) with humeral supracondylar fractures treated in our hospital, ranging from 3 to 12 years old with an average of 6.4 years old. All the fractures were extension-type injuries, the flexion injures were excluded in our study. The humeral supracondylar fractures were classified according to Gartland classification. There were 21 Type H and 12 type III. In the initial treatment, all the patients were treated with closed reduction and external immobilization. The blood supply of the damaged upper extremity was evaluated before and after treatment. Clinical assessment was obtained at final follow-up using Flynn criteria, and radiologic assessment was obtained using Baumann and lateral humerocapitellar angles. RESULTS: All the children were treated successfully with closed reduction in the initial time; 24 children maintained limb alignment by external immobilization. Nine patients lost position due to the swelling around the elbow which affected unstable external fixation during the follow-up, 5 of which were treated with a repeated closed reduction and internal fixation with Kirschner wires, 4 of which were treated with traction. Thirty-one patients had a satisfactory outcome and 2 patients had an unsatisfactory outcome according to the Flynn criteria at the latest follows-up. CONCLUSION: Closed reduction and external stabilization is an important method for the treatment of displaced humeral supracondylar fractures in children. Making regular follow-up visits after closed reduction and casting is important for patients to maintain acceptable alignment, avoid complications and diagnose any loss of reduction.

The applications of arthroscopy on malleolus fractures.

It was well known that in 1918 Takagi performed the first arthroscopic inspection of a cadaver's knee in Japan.(1) His interest in this area laid the foundation for arthroscopy and facilitated the development of arthroscope. In 1931, Burman reported an experimental study on the arthroscopic exploration of cadaveric joints, but he believed that the ankle joint was unsuitable for such techniques because it was too narrow to pass through the posterior puncture.(2) Unexpectedly, several years later Takagi described a routine method for arthroscopic examination of the ankle.(1) Since 1970's, ankle arthroscopy had made some significant progress after almost four decades of silence. In 1972, Watanabe reported 28 cases adopting his newly-developed fiberoptic arthroscope and described the anteromedial, anterolateral and posterior approaches.(3) Then, in 1976, Chen reviewed his experience with ankle arthroscopy on 67 patients and 17 cadavers. He elaborately analyzed the various compartments within the ankle and described their anatomy in detail.(4) Subsequently, many authors reported their experiences and techniques in this field.(5-9) In 2000, Hintermann addressed his experience of the arthroscopic application in acute fractures of the ankle.(10) Meanwhile, with rich knowledge about the anatomic portals, some advanced technologies, including video camera, fiberoptic light transmission, joint distraction by invasive or non-invasive means and instruments for small joints, make it possible to perform diagnostic and operative arthroscopy in the ankle.

Nerve transfer for treatment of brachial plexus injury: comparison study between the transfer of partial median and ulnar nerves and that of phrenic and spinal accessary nerves.

OBJECTIVE: To compare the effect of using partial median and ulnar nerves for treatment of C(5-6) or C(5-7) avulsion of the brachial plexus with that of using phrenic and spinal accessary nerves. METHODS: The patients were divided into 2 groups randomly according to different surgical procedures. Twelve cases were involved in the first group. The phrenic nerve was transferred to the musculocutaneous nerve or through a sural nerve graft, and the spinal accessary nerve was to the suprascapular nerve. Eleven cases were classified into the second group. A part of the fascicles of median nerve was transferred to be coapted with the motor fascicle of musculocutaneous nerve and a part of fascicles of ulnar nerve was transferred to the axillary nerve. The cases were followed up from 1 to 3 years and the clinical outcome was compared between the two groups. RESULTS: There were 2 cases (16.6%) who got the recovery of M4 strength of biceps muscle in the first group but 7 cases (63.6%) in the second group, and the difference was statistically significant (P<0.025). However, it was not statistically different in the recovery of shoulder function between the two groups. CONCLUSIONS: Partial median and ulnar nerve transfer, phrenic and spinal accessary nerve transfer were all effective for the reconstruction of elbow or shoulder function in brachial plexus injury, but the neurotization using a part of median nerve could obtain more powerful biceps muscle strength than that of phrenic nerve transfer procedure.