High-intensity interval training improves hypothalamic inflammation by suppressing HIF-1α signaling in microglia of male C57BL/6J mice.

Repeated bouts of high-intensity interval training (HIIT) induce an improvement in metabolism via plasticity of melanocortin circuits and attenuated hypothalamic inflammation. HIF-1α, which plays a vital role in hypothalamus-mediated regulation of peripheral metabolism, is enhanced in the hypothalamus by HIIT. This study aimed to investigate the effects of HIIT on hypothalamic HIF-1α expression and peripheral metabolism in obese mice and the underlying molecular mechanisms. By using a high-fat diet (HFD)-induced obesity mouse model, we determined the effect of HIIT on energy balance and the expression of the hypothalamic appetite-regulating neuropeptides, POMC and NPY. Moreover, hypothalamic HIF-1α signaling and its downstream glycolytic enzymes were explored after HIIT intervention. The state of microglia and microglial NF-κB signaling in the hypothalamus were also examined in vivo. In vitro by using an adenovirus carrying shRNA-HIF1ß, we explored the impact of HIF-1 signaling on glycolysis and NF-κB inflammatory signaling in BV2 cells. Food intake was suppressed and whole-body metabolism was improved in exercised DIO mice, accompanied by changes in the expression of POMC and NPY. Moreover, total and microglial HIF-1α signaling were obviously attenuated in the hypothalamus, consistent with the decreased levels of glycolytic enzymes. Both HFD-induced microglial activation and hypothalamic NF-κB signaling were significantly suppressed following HIIT in vivo. In BV2 cells, after HIF-1 complex knockdown, glycolysis and NF-κB inflammatory signaling were significantly attenuated. The data indicate that HIIT improves peripheral metabolism probably via attenuated HFD-induced microglial activation and microglial NF-κB signaling in the hypothalamus, which could be mediated by suppressed microglial HIF-1α signaling.

Postoperative Antiosteoporotic Treatment with Zoledronic Acid Improves Rotator Cuff Healing but Does Not Improve Outcomes in Female Patients with Postmenopausal Osteoporosis: A Prospective, Single-Blinded, Randomized Study.

PURPOSE: To investigate the effect of the antiosteoporotic agent zoledronic acid (ZA) on rotator cuff healing and clinical outcomes in patients with postmenopausal osteoporosis. METHODS: We prospectively enrolled 138 female patients with postmenopausal osteoporosis who were scheduled to undergo arthroscopic rotator cuff repair (ARCR) from March 2020 to March 2021. Patients were randomly allocated to the ZA group (ARCR followed by intravenous ZA infusions at postoperative Day 1 and 1 year later) and the control group (ARCR alone). All patients were followed up for 24 months. Tendon healing was evaluated by ultrasonography at 6 weeks and 24 months after surgery. The American Shoulder and Elbow Surgeons (ASES) score, Western Ontario Rotator Cuff (WORC) index, and Numeric Rating Scale (NRS) for pain were recorded at each follow-up, and the minimal clinically important difference (MCID) was calculated. RESULTS: A total of 124 patients were included in the final analysis, 61 in the ZA group and 63 in the control group. There was no statistically significant difference in participant characteristics between the 2 groups. The ZA group had a significantly higher tendon healing rate than the control group at 2 years after surgery (odds ratio = 5.0; 95% confidence interval [CI], 1.4-18.7; P = .014). Regarding clinical outcomes, 100% of patients exceeded the MCID in both groups, and no significant differences were found at 2 years after surgery between the 2 groups (ASES: 2.5 [95% CI, -2.2 to 7.2; P = .291]; WORC index: 4.5 [95% CI, -0.117 to 9.117; P = .056]; NRS: -0.1 [95% CI, -0.3 to 0.1; P = .394]). CONCLUSIONS: Antiosteoporotic treatment with ZA reduced the retear rate but did not significantly influence the clinical outcomes after ARCR in female patients with postmenopausal osteoporosis. Outcomes of ARCR showed good results in both groups and exceeded the MCID. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Ultrasonography Outperforms Magnetic Resonance Imaging in Diagnosing Partial-Thickness Subscapularis Tear.

PURPOSE: To evaluate the diagnostic reliability of ultrasonography (US) and magnetic resonance imaging (MRI) for subscapularis (SSC) tears with shoulder arthroscopy as the gold standard and to investigate the diagnostic value of 2 MRI signs (lesser tuberosity cysts and subcoracoid cysts) for SSC tears. METHODS: We consecutively enrolled 437 patients who were scheduled to undergo arthroscopic rotator cuff repair from January 2019 to December 2020. Patients with previous shoulder surgery or shoulder fracture, recurrent shoulder instability, and systemic inflammatory disease were excluded. Preoperative US and MRI of the shoulder were performed and interpreted with a standardized approach. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of US and MRI were calculated using arthroscopic findings as the gold standard. RESULTS: Of the 437 patients, 157 had SSC tears confirmed at the time of arthroscopy, 126 of whom had partial-thickness tears. US correctly diagnosed 122 of 157 patients with SSC tears, with an overall sensitivity of 77.7% (confidence interval [CI] 70.6%-83.5%), which was significantly greater than that of MRI (49.7%, CI 42.0%-57.4%, P < .001). For partial-thickness SSC tears, US correctly diagnosed 93 of 126 positive patients and 276 of 311 negative patients. This resulted in a sensitivity of 73.8% (CI 65.5%-80.7%), specificity of 88.7% (CI 84.8%-91.8%), and accuracy of 84.4% (CI 80.7%-87.5%). As with MRI, the sensitivity, specificity, and accuracy were 38.1% (CI 29.7%-47.2%), 86.5% (CI 82.3%-89.9%), and 72.5% (CI 68.2%-76.5%), respectively. Lesser tuberosity cysts and subcoracoid cysts were 2 MRI signs with high specificity (98.2% and 94.6%); however, their sensitivities were relatively low (19.8% and 33.8%). CONCLUSIONS: US is a reliable and accurate diagnostic method for SSC tears, especially in easily missed partial-thickness tears. Lesser tuberosity cyst and subcoracoid cyst are highly specific but insensitive MRI signs for SSC tear. LEVEL OF EVIDENCE: Level I, diagnostic, testing of previously developed diagnostic criteria.

Ultrasound shear wave elastography-derived tissue stiffness is positively correlated with rotator cuff tear size and muscular degeneration.

PURPOSE: The purpose of this study is to describe rotator cuff muscle stiffness in patients with different degrees of rotator cuff tear (RCT) severity and to assess its predictive ability for RCT reparability. METHODS: One hundred and thirty-three consecutive patients who were scheduled to undergo arthroscopic shoulder surgery were prospectively enrolled. Tendon retraction, fatty infiltration, and muscle atrophy were evaluated using magnetic resonance imaging. Shear modulus of supraspinatus (SSP) and infraspinatus (ISP) muscles were measured by ultrasound shear wave elastography (SWE). The tear size and reparability were determined intraoperatively. RESULTS: There were 97 patients in RCT group and 36 patients in control group. Bilateral shear modulus discrepancy (Δshear modulus) was used to represent rotator cuff stiffness. Severely fatty-infiltrated rotator cuff muscles possessed a significantly higher stiffness compared with their counterparts (SSP: CI 27.8-31.8 vs. 13.5-15.6 kPa, ISP: CI 33.2-38.1 vs. 8.8-11.2 kPa, p < 0.001). The same trend applied to muscles with distinct tendon retraction (SSP: CI 27.7-32.3 vs. 10.9-14.9 kPa, ISP: CI 33.2-38.6 vs. 6.5-11.0 kPa, p < 0.001) and obvious muscle atrophy (SSP: CI 27.9-32.1 vs. 13.6-15.8 kPa, ISP: CI 32.9-38.2 vs. 9.0-11.7 kPa, p < 0.001). Irreparable massive RCT (MRCT) patients had significantly stiffer SSP (CI 27.7-31.9 vs. 13.5-16.5 kPa, p < 0.001) and ISP (CI 33.5-37.8 vs. 10.3-14.8 kPa, p < 0.001) than reparable MRCT. The Δshear modulus of the ISP was a highly accurate predictor of RCT reparability. A cutoff value of 18.0 kPa had a sensitivity of 100% and specificity of 98.8% for irreparable MRCT. CONCLUSION: Ultrasound SWE-derived rotator cuff muscle stiffness is closely correlated with RCT size and severity. LEVEL OF EVIDENCE: I.

C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation.

OBJECTIVE: C1qTNF-related protein 4 (CTRP4) acts in the hypothalamus to modulate food intake in diet-induced obese mice and has been shown to exert an anti-inflammatory effect on macrophages. Since high-fat diet-induced microglial activation and hypothalamic inflammation impair leptin signaling and increase food intake, we aimed to explore the potential connection between the anorexigenic effect of CTRP4 and the suppression of hypothalamic inflammation in mice with DIO. METHODS: Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and the hypothalamic leptin signaling pathway in diet-induced obese mice. Furthermore, central and plasma proinflammatory cytokines, including TNF-α and IL-6, were measured by Western blotting and ELISA. Changes in the hypothalamic NF-κB signaling cascade and microglial activation were also examined in vivo. In addition, NF-κB signaling and proinflammatory factors were investigated in BV-2 cells after CTRP4 intervention. RESULTS: We found that food intake was decreased, while leptin signaling was significantly improved in mice with DIO after CTRP4 overexpression. Central and peripheral TNF-α and IL-6 levels were reduced by central Ad-CTRP4 administration. Hypothalamic NF-κB signaling and microglial activation were also significantly suppressed in vivo. In addition, NF-κB signaling was inhibited in BV-2 cells following CTRP4 intervention, which was consistent with the decreased production of TNF-α and IL-6. CONCLUSIONS: Our data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.

Bilateral coracohumeral distance discrepancy is associated with subscapularis tear in rotator cuff rupture patients.

PURPOSE: To describe the bilateral coracohumeral morphological discrepancy in rotator cuff rupture patients with and without subscapularis (SSC) involvement and to investigate its association with SSC tears. METHODS: Two hundred and thirteen consecutive patients who were scheduled to have arthroscopic rotator cuff repair were prospectively enrolled in the current study. Patients with acute traumatic rotator cuff rupture, glenohumeral osteoarthritis, bilateral rotator cuff rupture, recurrent shoulder instability, systemic inflammatory disease, and previous shoulder surgery history were excluded. Coracohumeral distance (CHD), coracoid overlap (CO), lesser tuberosity index (LTI) and acromiohumeral interval (AHI) were measured bilaterally using CT scans. Based on arthroscopic findings, patients were included in either the SSC tear group (n = 72) or the control group (n = 141). RESULTS: In the SSC tear group, the affected shoulder possessed a significantly smaller CHD [95% confidence interval (CI) 6.1-7.2 vs. 7.2-8.0 mm, p < 0.0001], larger LTI (95% CI 9.4-9.9 vs. 9.0-9.6 mm, p < 0.0001), and smaller AHI (95% CI 5.0-5.5 vs. 7.1-7.5 mm, p < 0.0001) than the contralateral normal shoulder. In the control group, there was no significant difference between bilateral CHD and CO, and the AHI bilateral discrepancy was less distinct. CO did not differ significantly in the bilateral comparison in either group. Among all evaluated parameters, bilateral CHD discrepancy was the best predictor of SSC tears, with an area under the curve (AUC) of 0.882. A cutoff value of 0.5 mm had a sensitivity of 76.4% and specificity of 99.3% for SSC tears. CONCLUSION: The CHD values are significantly different between affected and contralateral shoulders in SSC tear patients. Bilateral CHD discrepancy is closely associated with subcoracoid impingement and SSC tears, and its presence warrants specific intraoperative SSC inspection. LEVEL OF EVIDENCE: Level II.

Postoperative bone marrow edema lasts no more than 6 months after uncomplicated arthroscopic double-row rotator cuff repair with PEEK anchors.

PURPOSE: To assess the natural evolution of the osseous reaction following arthroscopic double-row rotator cuff repair with PEEK anchors and to analyze its correlation with clinical shoulder function. METHODS: Between 2015 and 2017, 159 patients received arthroscopic double-row rotator cuff repair with PEEK anchors and underwent serial clinical and radiological follow-up (3, 6, 12, and 24 months). Radiological results were analyzed by tendon integrity, bone marrow edema, and peri-implant osteolysis. Clinical shoulder function was evaluated with the Constant score. RESULTS: One-hundred and seventeen patients were enrolled; among them, 63% demonstrated bone marrow edema around the anchors on postoperative 3-month MRI. The edema area percentage was 41% ± 7%. At 6 months, edema was only seen in 12% of cases, with an area percentage of 18% ± 5%. At 12 and 24 months, edema was rarely present. Fluid signals around the anchor were observed in 17.6%, 42.7%, 33.3%, and 21.0% of patients at 3, 6, 12, and 24 months, respectively; the tunnel widening values were 1.1 ± 0.4 mm, 1.8 ± 0.5 mm, 2.3 ± 0.6 mm, and 2.2 ± 0.7 mm at each follow-up, respectively. The sign of osteolysis was significantly more obvious around the lateral anchor than around the medial anchor. The presence of an osseous reaction was not correlated with worse clinical outcome. CONCLUSION: Osseous reactions following arthroscopic rotator cuff repair are common and significant even with PEEK anchors. Bone marrow edema does not last more than 6 months in patients without complications. Peri-implant osteolysis is more evident around the lateral anchor than around the medial anchor and improves gradually over time. The sign of osteolysis is not correlated with clinical shoulder function. Based on these findings, surgeons should be cautious about bone marrow edema lasting more than 6 months following arthroscopic rotator cuff repair. LEVEL OF EVIDENCE: Level IV.

Effect and Safety of Transcutaneous Auricular Vagus Nerve Stimulation on Recovery of Upper Limb Motor Function in Subacute Ischemic Stroke Patients: A Randomized Pilot Study.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is regarded as a potential method for recovery in stroke. The effectiveness of taVNS in acute and subacute stroke should be further discussed as previously, only a few small-scale trials have focused on chronic stroke patients. The objective of this study is to investigate the effect and safety of taVNS on upper limb motor function in subacute ischemic stroke patients. Methods: Twenty-one subacute ischemia stroke patients with single upper limb motor function impairment were enrolled and randomly assigned to conventional rehabilitation training with real or sham taVNS, delivered for 15 consecutive days. Electrodes were fixed to the cymba conchae of the left ear with or without electrical stimulation. Conventional rehabilitation training was performed immediately after the end of real or sham taVNS by the same therapists. Baseline assessments were performed on day 0 of enrollment, and posttreatment evaluations were performed at 15 days, 4 weeks, and 12 weeks after the first intervention. The assessment included the upper limb Fugl-Meyer assessment (FMA-U), the Wolf motor function test (WMFT), the Functional Independence Measurement (FIM), and Brunnstrom stage. Heart rate (HR) and blood pressure (BP) were measured before and after each taVNS intervention. At the same time, any adverse effects were observed during the procedure. Outcomes were assessed by a blind evaluator. Results: There were no significant differences in FMA-U, WMFT, FIM, and Brunnstrom scores between the two groups at baseline (P > 0.05). At the endpoint, the FMA-U, WMFT, and FIM scores were significantly higher than before treatment (P < 0.05), and there was a significantly greater improvement of those measurements in taVNS group compared with sham-taVNS group (P < 0.05). Significant improvements in FMA-U score were found between groups at follow-up. Only one case of skin redness occurred during the study. Conclusions: This study revealed that taVNS appeared to be beneficial to the recovery of upper limb motor function in subacute ischemia stroke patients without obvious adverse effects. Trial registration. This trial is registered with ChiCTR1800019635 on 20 November 2018 (http://www.chictr.org.cn/showproj.aspx?proj=32961).

Long-term Effects of Extracorporeal Shock Wave Therapy on Poststroke Spasticity: A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this meta-analysis was to assess the long-term effects of extracorporeal shock wave therapy (ESWT) on post-stroke spasticity. DATA SOURCES: An electronic search of EMBASE, MEDLINE, and Cochrane Central Register of Controlled Trials (CENTRAL) with hand search of relevant papers were performed on 20 June 2019. REVIEW METHODS: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the literature for randomized controlled trials of ESWT in stroke patients with spasticity. The primary outcome was the Modified Ashworth Scale (MAS) grade, and the second outcomes were the Visual Analogue Scale (VAS), range of motion (ROM) of joint, the Fugl-Meyer assessment (FMA) grade and adverse events. Two authors independently extracted data, assessed trial eligibility and risk of bias. Meta-analyses were performed using RevMan 5.3 software. RESULTS: We extracted data from 8 randomized controlled trials (301 participants). At long-term follow-up, ESWT significantly reduced MAS (Weighted Mean Difference (WMD) = -.36, 95% confidence interval (CI) = -.53 to -.19, I2 = 68%; P < .001) and VAS (WMD = -.94, 95% CI = -1.51 to -.37, I2 = 15%; P = .001), enhanced ROM (WMD = 5.97, 95% CI = 2.76 to 9.18, I2 = 0%; P < .001) and FMA (WMD = 1.26, 95% CI = .29 to 2.24, I2 = 96%; P = .01). CONCLUSIONS: ESWT showed long-term effects in relieving spasticity, while reducing pain, enhancing ROM and motor function in stroke patients.

Effects of kinesiotape on pain and disability in individuals with chronic low back pain: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE:: To explore the effects of kinesiotape on pain and disability in individuals with chronic low back pain. DATA SOURCES:: PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched for English language publications from inception to 13 February 2018. REVIEW METHODS:: This study was registered in PROSPERO (CRD42018089831). Our key search terms were ((kinesio taping) OR (kinesiotaping) OR (kinesiotape)) AND (low back pain). Randomized controlled trials evaluating the effects of kinesiotape published in English language were included in this review. The reference lists of retrieved studies and relevant reviews were also searched. Quality of the included trials was assessed according to 2015 updated Cochrane Back and Neck Review Group 13-Item criteria. RESULTS:: A total of 10 articles were included in this meta-analysis. A total of 627 participants were involved, with 317 in the kinesiotape group and 310 in the control group. The effects of kinesiotape on pain and disability were explored. While kinesiotape was not superior to placebo taping in pain reduction, either alone ( P = 0.07) or in conjunction with physical therapy ( P = 0.08), it could significantly improve disability when compared to the placebo taping ( P < 0.05). CONCLUSION:: Since kinesiotape is convenient for application, it could be used for individuals with chronic low back pain in some cases, especially when the patients could not get other physical therapy.

Comparative effectiveness of glucosamine, chondroitin, acetaminophen or celecoxib for the treatment of knee and/or hip osteoarthritis: a network meta-analysis.

OBJECTIVES: To compare the efficacies of oral glucosamine, chondroitin, the combination of glucosamine and chondroitin, acetaminophen and celecoxib on the treatment of knee and/or hip osteoarthritis. METHODS: We searched electronic databases including PubMed, Embase, and Cochrane Library and the reference lists of relevant articles published from inception to October 23, 2017. A Bayesian hierarchical random effects model was used to examine the overall effect size among mixed multiple interventions. RESULTS: We identified 61 randomised controlled trials of patients with knee and/or hip osteoarthritis. There was no obvious difference in the results between the traditional meta-analysis and the network meta-analysis. The network meta-analysis demonstrated that celecoxib was most likely the best option (SMD, -0.32 [95% CI, -0.38 to -0.25]) for pain, followed by the combination of glucosamine and chondroitin. For physical function, all interventions were significantly superior to oral placebo except for acetaminophen. In terms of stiffness, glucosamine (SMD, -0.36 [95% CI, -0.67 to -0.06]) and celecoxib (SMD, -0.29 [95% CI, -0.51 to -0.08]) were significantly better compared to placebo. In view of safety, compared to placebo only, celecoxib and acetaminophen presented significant differences. CONCLUSIONS: Given the effectiveness of these non-steroidal anti-inflammatory drugs and symptomatic slow-acting drugs, oral celecoxib is more effective than placebo on relieving pain and improving physical function, followed by the combination of glucosamine and chondroitin. Acetaminophen is likely the least efficacious intervention option. This information, accompanied by the tolerability and economic costs of the included treatments, would be conducive to making decisions for clinicians.

Sagittal geometry of the middle and lower cervical endplates.

PURPOSE: Construct subsidence is a relatively common complication following anterior cervical fusion. Its occurrence has been revealed to be closely related to endplate-implant contact interface. But current literature focusing on the anatomy of cervical endplate is very scarce. The purpose of this morphometric study was to analyse the sagittal geometry, especially the concavity and slope, of vertebral endplates from C3 to C7 by employing data from CT scans. METHODS: Reformatted CT scans of 97 individuals were analyzed and endplate concavity depth, endplate concavity apex location, as well as endplate slope were measured in midsagittal plane. Those specific parameters were compared among different age and gender groups. Meanwhile, comparison between superior and inferior endplate of each vertebra was also performed. RESULTS: Age and gender did not influence endplate concavity depth, endplate concavity apex location, or endplate slope significantly (P > 0.05). Endplate concavity depths of superior endplates (range 0.9-1.2 mm) were significantly smaller than those of inferior endplates (range 2.1-2.7 mm). Endplate concavity apex was always located in the posterior half of the endplate, with the superior one ranged from 56 to 67% and the inferior one 52 to 57%. Average endplate slopes of superior endplates were between 4.5° and 9.0°, and average inferior endplate slopes ranged from 4.5° to 7.5°. Among all measured segments, C5 had the largest endplate slope values, while C7 the least. CONCLUSIONS: Superior endplate is more flat than its inferior counterpart in middle and lower cervical spine, and the concavity apex is always located in the posterior half of the endplate. Endplate slope is correlated with cervical curvature, greater slope implying more significant lordosis. These sagittal endplate geometrical parameters should be taken into consideration when investigating implant subsidence following anterior cervical fusion.

An Acute Bout of Exercise Suppresses Appetite via Central Lactate Metabolism.

Exercise has been reported to elicit a transient suppression of appetite. Plasma lactate, which is produced by exercising muscle, is believed to have a critical effect on exercise-induced appetite suppression. However, the underlying mechanisms and signaling steps of central lactate metabolism remain unexplored. After central oxamate administration, C57BL/6J male mice performed 10 high-intensity interval running at 90% Vmax for 4 minutes each, which separated by 2 minutes at 12 m/min. Food intake and the expression of hypothalamic appetite-regulating neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were investigated following exercise training. Janus kinase 2 (Jak2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway was also determined by Western blot. In addition, hypoxia-inducible factor-1α (HIF-1α) was investigated to explore the effect of central lactate metabolism following exercise. We found that central oxamate administration reversed exercise-induced suppression of food intake, and as well as changes in the expression of POMC and NPY. Moreover, acute exercise led to an increase in the phosphorylation of Jak2 and STAT3 in the hypothalamus, while central lactate inhibition significantly blunted this effect. In addition, HIF-1α expression increased obviously after exercise, while it was attenuated by central oxamate administration. Collectively, our data reveal that central lactate metabolism mediates exercise-induced suppression of appetite and changes in neuropeptides, possibly through enhanced Jak2-STAT3 signaling.

Lactate Mediates the Bone Anabolic Effect of High-Intensity Interval Training by Inducing Osteoblast Differentiation.

BACKGROUND: High-intensity interval training (HIIT) reportedly improves bone metabolism and increases bone mineral density (BMD). The purpose of the present study was to investigate whether lactate mediates the beneficial effects of exercise on BMD, bone microarchitecture, and biomechanical properties in an established osteoporotic animal model. In addition, we hypothesized that lactate-induced bone augmentation is achieved through enhanced osteoblast differentiation and mineralization. METHODS: A total of 50 female C57BL/6 mice were randomly allocated into 5 groups: the nonovariectomized group, the ovariectomized group (OVX), the HIIT group (OVX + HIIT), the HIIT with lactate transporter inhibition group (OVX + HIIT + INH), and the lactate subcutaneous injection group (OVX + LAC). After 7 weeks of intervention, bone mass, bone strength, and bone formation/resorption processes were evaluated via microcomputed tomography (micro-CT), biomechanical testing, histological analysis, and serum biochemical assays; in vitro studies were performed to explore the bone anabolic effect of lactate at the cellular level. RESULTS: Micro-CT revealed significantly increased BMD in both the OVX + HIIT group (mean difference, 41.03 mg hydroxyapatite [HA]/cm 3 [95% CI, 2.51 to 79.54 mg HA/cm 3 ]; p = 0.029) and the OVX + LAC group (mean difference, 40.40 mg HA/cm 3 [95% CI, 4.08 to 76.71 mg HA/cm 3 ]; p = 0.031) compared with the OVX group. Biomechanical testing demonstrated significantly improved mechanical properties in those 2 groups. However, the beneficial effects of exercise on bone microstructure and biomechanics were largely abolished by blocking the lactate transporter. Notably, histological and biochemical results indicated that increased bone formation was responsible for the bone augmentation effects of HIIT and lactate. Cell culture studies showed a marked increase in the expression of osteoblastic markers with lactate treatment, which could be eliminated by blocking the lactate transporter. CONCLUSIONS: Lactate may have mediated the bone anabolic effect of HIIT in osteoporotic mice, which may have resulted from enhanced osteoblast differentiation and mineralization. CLINICAL RELEVANCE: Lactate may mediate the bone anabolic effect of HIIT and serve as a potential inexpensive therapeutic strategy for bone augmentation.

Metformin improves fibroblast metabolism and ameliorates arthrofibrosis in rats.

Background: Emerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has beneficial effect on arthrofibrosis and its underlying mechanism. Methods: Articular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation. Results: We found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion (ROM) of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin. Conclusion: Metformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis.The translational potential of this article: The findings of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.

Tryptophan metabolism as bridge between gut microbiota and brain in chronic social defeat stress-induced depression mice.

Backgrounds: Gut microbiota plays a critical role in the onset and development of depression, but the underlying molecular mechanisms are unclear. This study was conducted to explore the relationships between gut microbiota and host's metabolism in depression. Methods: Chronic social defeat stress (CSDS) model of depression was established using C57BL/6 male mice. Fecal samples were collected from CSDS group and control group to measure gut microbiota and microbial metabolites. Meanwhile, tryptophan metabolism-related metabolites in hippocampus were also analyzed. Results: CSDS successfully induced depressive-like behaviors in CSDS group. The 24 differential bacterial taxa between the two groups were identified, and 14 (60.87%) differential bacterial taxa belonged to phylum Firmicutes. Functional analysis showed that tryptophan metabolism was significantly affected in CSDS mice. Meanwhile, 120 differential microbial metabolites were identified, and two key tryptophan metabolism-related metabolites (tryptophan and 5-hydroxytryptophan (5-HTP)) were significantly decreased in feces of CSDS mice. The correlation analysis found the significant relationships between tryptophan and differential bacterial taxa under Firmicutes, especially genus Lactobacillus (r=0.801, p=0.0002). In addition, the significantly decreased 5-hydroxytryptamine (5-HT) in hippocampus of depressed mice was also observed. Conclusions: Our results showed that tryptophan metabolism might have an important role in the crosstalk between gut microbioa and brain in depression, and phylum Firmicutes, especially genus Lactobacillus, might be involved in the onset of depression through regulating tryptophan metabolism.

A treatment combined prussian blue nanoparticles with low-intensity pulsed ultrasound alleviates cartilage damage in knee osteoarthritis by initiating PI3K/Akt/mTOR pathway.

Reactive oxidative stress (ROS) related apoptosis in chondrocytes and extracellular matrix (ECM) degradation play crucial roles in the process of osteoarthritis. Prussian blue nanoparticles are known to scavenge ROS in cellular. Low-intensity pulsed ultrasound has been used as a non-invasive modality for the is widely used in clinical rehabilitation management of OA. In this study, we aim to investigate the effects of PBNPs/LIPUS combined treatment on knee osteoarthritis (KOA) and to determine whether phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway mediates this process. Use LPS to process primary cells of knee joint cartilage to establish a cartilage knee arthritis model. After treated with LIPUS and PBNPs, cell viability was rated by CCK-8 and ROS levels were assessed by DCFH-DA. Articular pathological changes were observed by naked eyes, H&E, and Safranin O staining, then monitored by cartilage lesion grades and Mankin's score. Cellular ROS, apoptosis rate, and TUNEL staining of chondrocytes were fairly decreased in the PBNPs group and the LIPUS group but drastically down-regulated in the PBNPs/LIPUS combination treatment group when compared with the LPS group. Western blot results showed that the cleaved caspase-3, Bax, IL-1ß, MMP3 and MMP13 in the PBNPs and LIPUS groups slightly decreased, and Bcl2 increased slightly, while in the combination treatment group, the former was significantly decreased, and Bcl2 was Significantly increased. The PBNPs/LIPUS combination treatment reduced cellular ROS, apoptosis, and matrix metalloproteinases (MMPs), as a consequence, alleviated articular cartilage damage in KOA. Moreover, the PBNPs/LIPUS combination treatment suppressed the JNK/c-Jun signal pathway.

Effectiveness of exercise therapy versus occlusal splint therapy for the treatment of painful temporomandibular disorders: a systematic review and meta-analysis.

BACKGROUND: This systematic review of the literature was to compare the effects of exercise therapy and occlusal splint therapy on pain and mobility in individuals with painful temporomandibular disorders (TMD). METHODS: PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched for English publications from database root to March 1, 2020. Search terms were [("temporomandibular joint disorders" or "temporomandibular disorders" or "craniomandibular disorders" or "orofacial pain" or "myofascial pain" or "myofascial pain" or "facial pain") AND (exercise or "physical therapy modalities" or physiotherapy or "exercise therapy") AND ("splints" or "occlusal splints" or "stabilization splint" or "occlusal appliance" or "occlusal splint therapy")]. We included randomized controlled trials that evaluated the effects of therapeutic exercise therapy and occlusal splint therapy, and were published in English. Trial quality was assessed with the Physiotherapy Evidence Database scale. RESULTS: Six studies were included (498 patients: 251 occlusal splint therapy, 247 therapeutic exercise). The results revealed that exercise therapy was not superior to occlusal splint therapy for pain reduction in patients with painful TMD (P=0.08; weighted standardized mean difference -0.29; 95% CI, -0.62 to 0.04). The effectiveness of occlusal splint therapy and exercise therapy was found to be equivalent in the maximum mouth-opening range (P=0.51; weighted standardized mean difference 0.12; 95% CI, -0.24 to 0.48), right laterotrusion (P=0.99; weighted standardized mean difference -0.00; 95% CI, -0.31 to 0.31), left laterotrusion (P=0.32; weighted standardized mean difference 0.16; 95% CI, -0.16 to 0.48), and protrusion (P=0.77; weighted standardized mean difference 0.06; 95% CI, -0.32 to 0.43) for painful TMD patients. CONCLUSIONS: Given the limitations of the study, the small number of studies included in the sub-analysis for pain relief and the maximum mouth-opening range, and the small overall standardized mean difference for pain relief and mandibular movement observed, no high-quality evidence was found to distinguish the clinical effectiveness between occlusal splint therapy and exercise therapy for painful TMD patients. It appears that more randomized controlled trials comparing the effects of exercise therapy and occlusal splint therapy need to be implemented.

C1q/TNF-related Protein 4 Induces Signal Transducer and Activator of Transcription 3 Pathway and Modulates Food Intake.

C1q/TNF-related protein 4 (CTRP4) has been reported to decrease food intake and regulate energy homeostasis. However, its underlying mechanism and signaling pathway remain unknown. Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and signal transducer and activator of transcription 3 (STAT3) signaling pathway in normal chow-fed mice. Expressions of neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were studied in hypothalamus by Western blot and immunochemistry. STAT3 and suppressor of cytokine signaling 3 (SOCS3) were determined by Western blot. STAT3 signaling pathway was also investigated in Neuro 2A (N2a) cells after CTRP4 overexpression intervention. We found that food intake decreased significantly in mice under normal chow condition after CTRP4 overexpression. Both immunohistochemistry and Western blot demonstrated that POMC expression was significantly increased while NPY expression was significantly decreased. The changes of neuropeptides were accompanied by significant increased STAT3 phosphorylation and decreased SOCS3 levels. The same changes of neuropeptides and STAT3 signaling were also found in N2a cells after CTRP4 overexpression intervention. Collectively, our data reveals that CTRP4 induces the activation of STAT3 signaling and decreases food intake.

Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: a meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the symptomatic effectiveness and safety of oral symptomatic slow-acting drugs (SYSADOAs) on the treatment of knee and/or hip osteoarthritis, such as chondroitin, glucosamine, and combination treatment with chondroitin plus glucosamine. METHODS: We searched electronic database including PubMed, Embase, Cochrane Library, and the reference lists of relevant articles published from inception to May 22, 2018. An updated meta-analysis was performed to assess the effectiveness of these slow-acting drugs for osteoarthritis. RESULTS: Twenty-six articles describing 30 trials met our inclusion criteria and were included in the meta-analysis. The estimates between chondroitin and placebo showed that chondroitin could alleviate pain symptoms and improve function. Compared with placebo, glucosamine proved significant effect only on stiffness improvement. However, the combination therapy did not have enough evidence to be superior to placebo. Additionally, there was no significant difference in the incidence of AEs and discontinuations of AEs when compared with placebo. CONCLUSIONS: Given the effectiveness of these symptomatic slow-acting drugs, oral chondroitin is more effective than placebo on relieving pain and improving physical function. Glucosamine showed effect on stiffness outcome. Regarding on the limited number of combination therapy, further studies need to investigate the accurate effectiveness. This information accompanied with the tolerability and economic costs of included treatments would be conducive to making decisions for clinicians.