Intermittent Fasting Targets Osteocyte Neuropeptide Y to Relieve Osteoarthritis.

Osteoarthritis is a highly prevalent progressive joint disease that still requires an optimal therapeutic approach. Intermittent fasting is an attractive dieting strategy for improving health. Here this study shows that intermittent fasting potently relieves medial meniscus (DMM)- or natural aging-induced osteoarthritic phenotypes. Osteocytes, the most abundant bone cells, secrete excess neuropeptide Y (NPY) during osteoarthritis, and this alteration can be altered by intermittent fasting. Both NPY and the NPY-abundant culture medium of osteocytes (OCY-CM) from osteoarthritic mice possess pro-inflammatory, pro-osteoclastic, and pro-neurite outgrowth effects, while OCY-CM from the intermittent fasting-treated osteoarthritic mice fails to induce significant stimulatory effects on inflammation, osteoclast formation, and neurite outgrowth. Depletion of osteocyte NPY significantly attenuates DMM-induced osteoarthritis and abolishes the benefits of intermittent fasting on osteoarthritis. This study suggests that osteocyte NPY is a key contributing factor in the pathogenesis of osteoarthritis and intermittent fasting represents a promising nonpharmacological antiosteoarthritis method by targeting osteocyte NPY.

Tenecteplase versus alteplase for patients with acute ischemic stroke: a meta-analysis of randomized controlled trials.

Tenecteplase (TNK), a newer fibrinolytic agent with greater fibrin specificity and longer half-life than alteplase, may has practical advantages over alteplase in acute ischemic stroke (AIS) thrombolysis. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare different doses of TNK (0.1, 0.25, 0.4 mg/kg) and alteplase in acute ischemic stroke patients. We systematically searched PubMed, Embase and https://clinicaltrials.gov/ for RCTs comparing TNK with alteplase in this population eligible for thrombolysis. The Cochrane Risk of Bias Tool was used to assess study quality. Random-effects or fixed-effects meta-analysis models were used for evaluating all outcomes. Total 10 RCTs with 5097 patients were included. Compared with alteplase, TNK at doses of 0.25 mg/kg may associated with the greatest odds to achieve 90-day excellent independence (mRS score ≤1), but there were no significant differences between other doses of TNK (0.1 mg/kg and 0.4 mg/kg) and alteplase. Among secondary outcomes, no significant differences were found in functional outcome (mRS score ≤2) and mortality at 90 days between any dose of TNK and alteplase. Compared with alteplase, TNK was effective at doses of 0.1 mg/kg and 0.25 mg/kg without increased risk of symptomatic intracerebral hemorrhage (sICH), but patients treated with TNK 0.4 mg/kg showed increased odds of sICH. In conclusion, compared with alteplase, intravenous thrombolysis with TNK at dose of 0.25 mg/kg has a better efficacy and similar safety profile and is a reasonable option for patients with AIS.

Ångstrom-scale silver particles ameliorate collagen-induced and K/BxN-transfer arthritis in mice via the suppression of inflammation and osteoclastogenesis.

OBJECTIVE: Nanoparticles (NPs) hold a great promise in combating rheumatoid arthritis, but are often compromised by their toxicities because the currently used NPs are usually synthesized by chemical methods. Our group has previously fabricated Ångstrom-scale silver particles (AgÅPs) and demonstrated the anti-tumor and anti-sepsis efficacy of fructose-coated AgÅPs (F-AgÅPs). This study aimed to uncover the efficacy and mechanisms of F-AgÅPs for arthritis therapy. METHODS: We evaluated the efficacy of F-AgÅPs in collagen-induced arthritis (CIA) mice. We also compared the capacities of F-AgÅPs, the commercial AgNPs, and the clinical drug methotrexate (MTX) in protecting against K/BxN serum-transfer arthritis (STA) mice. Moreover, we evaluated the effects of F-AgÅPs and AgNPs on inflammation, osteoclast formation, synoviocytes migration, and matrix metalloproteinases (MMPs) production in vitro and in vivo. Meanwhile, the toxicities of F-AgÅPs and AgNPs in vitro and in vivo were also tested. RESULTS: F-AgÅPs significantly prevented bone erosion, synovitis, and cartilage damage, attenuated rheumatic pain, and improved the impaired motor function in mouse models of CIA or STA, the anti-rheumatic effects of which were comparable or stronger than AgNPs and MTX. Further studies revealed that F-AgÅPs exhibited similar or greater inhibitory abilities than AgNPs to suppress inflammation, osteoclast formation, synoviocytes migration, and MMPs production. No obvious toxicities were observed in vitro and in vivo after F-AgÅPs treatment. CONCLUSIONS: F-AgÅPs can effectively alleviate arthritis without notable toxicities and their anti-arthritic effects are associated with the inhibition of inflammation, osteoclastogenesis, synoviocytes migration, and MMPs production. Our study suggests the prospect of F-AgÅPs as an efficient and low-toxicity agent for arthritis therapy.

Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression.

Due to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.

The Protective Effects of Osteocyte-Derived Extracellular Vesicles Against Alzheimer's Disease Diminished with Aging.

Both Alzheimer's disease (AD) and osteoporosis (OP) are common age-associated degenerative diseases and are strongly correlated with clinical epidemiology. However, there is a lack of clear pathological relationship between the brain and bone in the current understanding. Here, it is found that young osteocyte, the most abundant cells in bone, secretes extracellular vesicles (OCYYoung -EVs) to ameliorate cognitive impairment and the pathogenesis of AD in APP/PS1 mice and model cells. These benefits of OCYYoung -EVs are diminished in aged osteocyte-derived EVs (OCYAged -EVs). Based on the self-constructed OCY-EVs tracer transgenic mouse models and the in vivo fluorescent imaging system, OCY-EVs have been observed to be transported to the brain under physiological and pathological conditions. In the hippocampal administration of Aß40 induced young AD model mice, the intramedullary injection of Rab27a-shRNA adenovirus inhibits OCYYoung -EVs secretion from bone and aggravates cognitive impairment. Proteomic quantitative analysis reveals that OCYYoung -EVs, compared to OCYAged -EVs, enrich multiple protective factors of AD pathway. The study uncovers the role of OCY-EV as a regulator of brain health, suggesting a novel mechanism in bone-brain communication.

Direct Endovascular Thrombectomy or With Prior Intravenous Thrombolysis for Acute Ischemic Stroke: A Meta-Analysis.

Background and purpose: It is unclear whether endovascular thrombectomy alone compared with intravenous thrombolysis combination with endovascular thrombectomy can achieve similar neurological outcomes in patients with acute large vessel occlusion stroke. We aimed to perform a systematic review and meta-analysis of randomized controlled trials to compare endovascular thrombectomy alone or intravenous thrombolysis plus endovascular thrombectomy in this population. Methods: We systematically searched PubMed, Embase, and ClinicalTrials.gov. We restricted our search to randomized clinical trials that examined the clinical outcomes of endovascular thrombectomy alone vs. intravenous thrombolysis plus endovascular thrombectomy. The Cochrane risk of bias tool was used to assess study quality. Random-effects meta-analyses were used for evaluating all outcomes. Results: Total three randomized controlled trials with 1,092 individuals enrolled were included in the meta-analysis, including 543 (49.7%) who received endovascular thrombectomy alone and 549 (50.3%) who received intravenous thrombolysis plus endovascular thrombectomy. The primary outcome of 90-day functional independence (modified Rankin scale (mRS) score ≤ 2) was 44.6% (242/543) in the endovascular thrombectomy alone group vs. 42.8% (235/549) in the alteplase with endovascular thrombectomy group (odds ratio (OR), 1.08 [95% CI, 0.85-1.38]; P = 0.0539). Among pre-specified secondary outcomes, no significant between-group differences were found in excellent outcome (mRS score ≤ 1) (OR, 1.12 [95% CI, 0.85-1.47]; P = 0.418), mortality at 90 days (OR, 0.93 [95% CI, 0.68-1.29]; P = 0.673), successful reperfusion (thrombolysis in cerebral infarction 2b-3) (OR, 0.75 [95% CI, 0.54-1.05]; P = 0.099), and symptomatic intracranial hemorrhage (OR, 0.72 [95% CI, 0.45-1.15]; P = 0.171). Conclusions: Among patients with acute ischemic stroke in the anterior circulation within 4.5 h from the onset, endovascular thrombectomy alone was non-inferior to combined intravenous thrombolysis and endovascular thrombectomy.

Neuronal Induction of Bone-Fat Imbalance through Osteocyte Neuropeptide Y.

A differentiation switch of bone marrow mesenchymal stem/stromal cells (BMSCs) from osteoblasts to adipocytes contributes to age- and menopause-associated bone loss and marrow adiposity. Here it is found that osteocytes, the most abundant bone cells, promote adipogenesis and inhibit osteogenesis of BMSCs by secreting neuropeptide Y (NPY), whose expression increases with aging and osteoporosis. Deletion of NPY in osteocytes generates a high bone mass phenotype, and attenuates aging- and ovariectomy (OVX)-induced bone-fat imbalance in mice. Osteocyte NPY production is under the control of autonomic nervous system (ANS) and osteocyte NPY deletion blocks the ANS-induced regulation of BMSC fate and bone-fat balance. γ-Oryzanol, a clinically used ANS regulator, significantly increases bone formation and reverses aging- and OVX-induced osteocyte NPY overproduction and marrow adiposity in control mice, but not in mice lacking osteocyte NPY. The study suggests a new mode of neuronal control of bone metabolism through the ANS-induced regulation of osteocyte NPY.

Fructose-coated Ångstrom silver prevents sepsis by killing bacteria and attenuating bacterial toxin-induced injuries.

Serious infection caused by multi-drug-resistant bacteria is a major threat to human health. Bacteria can invade the host tissue and produce various toxins to damage or kill host cells, which may induce life-threatening sepsis. Here, we aimed to explore whether fructose-coated Ångstrom-scale silver particles (F-AgÅPs), which were prepared by our self-developed evaporation-condensation system and optimized coating approach, could kill bacteria and sequester bacterial toxins to attenuate fatal bacterial infections. Methods: A series of in vitro assays were conducted to test the anti-bacterial efficacy of F-AgÅPs, and to investigate whether F-AgÅPs could protect against multi-drug resistant Staphylococcus aureus (S. aureus)- and Escherichia coli (E. coli)-induced cell death, and suppress their toxins (S. aureus hemolysin and E. coli lipopolysaccharide)-induced cell injury or inflammation. The mouse models of cecal ligation and puncture (CLP)- or E. coli bloodstream infection-induced lethal sepsis were established to assess whether the intravenous administration of F-AgÅPs could decrease bacterial burden, inhibit inflammation, and improve the survival rates of mice. The levels of silver in urine and feces of mice were examined to evaluate the excretion of F-AgÅPs. Results: F-AgÅPs efficiently killed various bacteria that can cause lethal infections and also competed with host cells to bind with S. aureus α-hemolysin, thus blocking its cytotoxic activity. F-AgÅPs inhibited E. coli lipopolysaccharide-induced endothelial injury and macrophage inflammation, but not by directly binding to lipopolysaccharide. F-AgÅPs potently reduced bacterial burden, reversed dysregulated inflammation, and enhanced survival in mice with CLP- or E. coli bloodstream infection-induced sepsis, either alone or combined with antibiotic therapy. After three times injections within 48 h, 79.18% of F-AgÅPs were excreted via feces at the end of the 14-day observation period. Conclusion: This study suggests the prospect of F-AgÅPs as a promising intravenous agent for treating severe bacterial infections.

Extracellular Vesicles from Child Gut Microbiota Enter into Bone to Preserve Bone Mass and Strength.

Recently, the gut microbiota (GM) has been shown to be a regulator of bone homeostasis and the mechanisms by which GM modulates bone mass are still being investigated. Here, it is found that colonization with GM from children (CGM) but not from the elderly (EGM) prevents decreases in bone mass and bone strength in conventionally raised, ovariectomy (OVX)-induced osteoporotic mice. 16S rRNA gene sequencing reveals that CGM reverses the OVX-induced reduction of Akkermansia muciniphila (Akk). Direct replenishment of Akk is sufficient to correct the OVX-induced imbalanced bone metabolism and protect against osteoporosis. Mechanistic studies show that the secretion of extracellular vesicles (EVs) is required for the CGM- and Akk-induced bone protective effects and these nanovesicles can enter and accumulate into bone tissues to attenuate the OVX-induced osteoporotic phenotypes by augmenting osteogenic activity and inhibiting osteoclast formation. The study identifies that gut bacterium Akk mediates the CGM-induced anti-osteoporotic effects and presents a novel mechanism underlying the exchange of signals between GM and host bone.

Akkermansia muciniphila promotes type H vessel formation and bone fracture healing by reducing gut permeability and inflammation.

Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila, a gut probiotic, ameliorates systemic inflammation by tightening the intestinal barrier. In this study, fractured mice intragastrically administrated with A. muciniphila were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muciniphila at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis, and can be stimulated by PDGF-BB. Moreover, A. muciniphila treatment significantly reduced gut permeability and inflammation at the early stage. Dextran sulfate sodium (DSS) was used to disrupt the gut barrier to determine its role in fracture healing and whether A. muciniphila still can stimulate bone fracture healing. As expected, A. muciniphila evidently improved gut barrier, reduced inflammation and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muciniphila reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB+ preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidence for the involvement of type H vessels in fracture healing and suggests the potential of A. muciniphila as a promising strategy for bone healing.This article has an associated First Person interview with the first author of the paper.

SRT2104 attenuates chronic unpredictable mild stress-induced depressive-like behaviors and imbalance between microglial M1 and M2 phenotypes in the mice.

Although activated microglia-induced neuroinflammation link to the physiopathology of major depressive disorder, the homeostasis of switchable M1/M2 microglia in treating depression are unclear. Recent accumulating evidences suggest that Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, plays a key role in mood regulation, yet its role in the polarization of microglia acting on depressive behaviors remains unknown. Here, we intended to investigate whether activation of SIRT1 in hippocampus has antidepressant potential in relation to microglial phenotypic switch. Chronic unpredictable mild stress (CUMS) treatment was performed on C57BL/6 mice, followed by injecting with SRT2104, a selective SIRT1 agonists. We found that activation of SIRT1 in hippocampus ameliorate CUMS-induced depressive-like behaviors, as indicated by sucrose preference test, tail suspension test and forced swim test. Moreover, activation of SIRT1 abrogated the increased expression of M1 markers (IL-6, IL-1ß and iNOS,) and decreased expression of M2 markers (IL-10, TGF-ß and Arignase1) induced by CUMS. Notably, activation of SIRT1 shifted microglia polarization toward the M2 phenotype in CUMS-induced depressive-like behaviors of mice. In addition, SRT2104 treatment ameliorated CUMS-induced SIRT1 decreased expression in the hippocampus coincides with the up-regulation phosphorylation levels of GSK3ß and PTEN. Taken together, these findings indicated that activation of SIRT1 ameliorate CUMS-induced depressive-like behaviors via shifting microglial polarization toward the M2 phenotype, thereby providing a novel and beneficial therapeutic approach for depression that may be translatable to depression patients in the future.

Effect of General Anesthesia vs. Conscious Sedation on the Outcomes of Acute Ischemic Stroke Patients After Endovascular Therapy: A Meta-Analysis of Randomized Clinical Trials.

Background: Endovascular therapy is the standard treatment for acute ischemic stroke (AIS) patients caused by a large vessel occlusion in the anterior circulation, whereas the impacts of general anesthesia (GA) vs. conscious sedation (CS) for such procedures remained as a continued debate. Methods: We systematically searched PubMed, Embase, and ClinicalTrials.gov. We restricted our search to RCTs that examined the clinical outcomes of endovascular therapy with GA vs. CS. The Cochrane Risk of Bias Tool was used to assess study quality. Random-effects or fixed-effects meta-analyses were used for evaluating all outcomes. Results: A total of three randomized clinical trials met our inclusion criteria, with 368 individuals enrolled. Patients were randomized to receive GA or CS during endovascular therapy. In a meta-analysis of these trials, patients in the GA group were associated with favorable functional outcome (mRS score ≤ 2) compared with the CS group (pooled OR = 1.81, 95% CI: 1.17-2.79, P = 0.008). Besides, patients in the GA group had higher odds of successful reperfusion (pooled OR = 1.80, 95% CI: 1.05-3.08, P = 0.033), but no significant differences were seen in symptomatic intracranial hemorrhage (pooled OR = 0.54, 95% CI: 0.11-2.57, P = 0.308), vessel dissection or perforation (pooled OR = 1.38, 95% CI: 0.30-6.31, P = 0.679), migration of embolus to a new territory (pooled OR = 2.28, 95% CI: 0.89-5.87, P = 0.085), post-operative pneumonia (pooled OR = 1.74, 95% CI: 0.76-4.01, P = 0.149), and all-cause mortality at 90 days (pooled OR = 0.73, 95% CI: 0.43-1.26, P = 0.263) compared with the CS group. Conclusion: Performing endovascular therapy with GA, compared with CS, improves functional independence after 90 days significantly for patients with AIS caused by a large vessel occlusion in the anterior circulation. However, additional larger and multi-center randomized controlled trials to definitively confirm our findings are warranted for the limitation of the small sample size in this study.

Cardiovascular outcomes of liraglutide in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Liraglutide is a novel, long-acting glucagon-like peptide-1 (GLP-1) analogue used to treat type 2 diabetes mellitus. However, the cardiovascular safety and benefits of liraglutide treatment on type 2 diabetes patients remain in debate. In this study, we aimed to examine the overall cardiovascular outcomes of liraglutide in patients with type 2 diabetes. METHODS: In this systematic review and meta-analysis, we searched the PubMed, Embase, and Web of Knowledge databases up to September 1st, 2017 for randomized trials in which type 2 diabetes patients were assigned to liraglutide and placebo or other comparators groups. RESULTS: Eight studies fulfilled the eligibility criteria for inclusion and 14,608 patients were analyzed in this systematic review and meta-analysis. We found patients in the liraglutide group had a lower risk of major cardiovascular events (MACE) (RR = 0.89, 95% CI: 0.82-0.96, P = .002), acute myocardial infarction (AMI) (RR = 0.85, 95% CI: 0.74-0.99, P = .036), all-cause death (RR = 0.84, 95% CI: 0.74-0.96, P = .009), and cardiovascular death (RR = 0.77, 95% CI: 0.65-0.91, P = .002) than all comparator groups. However, liraglutide treatment did not decrease incidence of stroke (RR = 0.86, 95% CI: 0.70-1.04, P = .124). But among the MACE subgroups analysis, a significant reduction of MACE with liraglutide was only observed in placebo-controlled trials (RR = 0.89, 95% CI: 0.83-0.96, P = .004) but not in studies concerning other comparators (RR = 0.58, 95% CI: 0.29-1.16, P = .122). CONCLUSIONS: In conclusion, our results suggest that liraglutide treatment decreases the risk of MACE, AMI, all-cause death and cardiovascular death among patients with type 2 diabetes.

Outcomes of general anesthesia versus conscious sedation for Stroke undergoing endovascular treatment: a meta-analysis.

BACKGROUND: The impact of anesthesia strategy on the outcomes of acute ischemic stroke (AIS) patients undergoing endovascular treatment is currently controversy. Thus, we performed this meta-analysis to compare the differences of clinical and angiographic outcomes between general anesthesia (GA) and conscious sedation (CS). METHODS: A literature search in PubMed, Embase, and Web of Knowledge databases through February 2019 was conducted for related records on GA and CS of AIS undergoing endovascular treatment. The results of the studies were pooled and meta-analyzed with fixed- or random-effect model based on heterogeneity test in total and subgroup analyses. RESULTS: Twenty-three studies including 6703 patients were analyzed in this meta-analysis. We found that patients in the GA group have lower odds of favorable functional outcome (mRS scores ≤2) compared with the CS group (odds ratio [OR] = 0.62, 95% confidence interval [CI]: 0.49-0.77), and higher risk of mortality (OR = 1.68, 95% CI: 1.49-1.90), pneumonia (OR = 1.78, 95% CI: 1.40-2.26), symptomatic intracranial hemorrhage (OR = 1.64, 95% CI: 1.13-2.37). However, no significant differences were seen between the groups in the rate of recanalization (OR = 1.07, 95% CI: 0.89-1.28), vessel dissection or perforation (OR = 1.00, 95% CI: 0.98-1.03) and asymptomatic intracranial hemorrhage (OR = 1.19, 95% CI: 0.96-1.47). While in the RCT subgroup analysis, we found patients in the GA group does not show lower rate of favorable functional outcome compared with the CS group (OR = 1.84, 95% CI: 1.17-2.89). And there was no significant difference in the rate of mortality between GA and CS groups during RCT subgroup analysis (OR = 0.74, 95% CI: 0.43-1.27). CONCLUSIONS: AIS patients performed endovascular treatment under GA compared with CS was associated with worse functional outcome and increased rate of mortality, but differences in worsened outcomes do not exist when one looks into the GA vs. CS RCTs. Moreover, these findings are mainly based on the retrospective studies and additional multi-center randomized controlled trials to definitively address these issues is warranted.