Increased Expression of Receptor Activator of Nuclear Factor-κB Ligand in Osteoblasts from Adolescent Idiopathic Scoliosis Patients with Low Bone Mineral Density

Persistent generalized low bone mineral density (BMD) has been reported in patients with adolescent idiopathic scoliosis (AIS).However,the exact mechanisms and causes of the low BMD in AIS patients are largely unknown.The purpose of this study was to examine the relationship between the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) levels in osteoblasts (OBs) from AIS patients with low BMD and with comparison made between the patients and controls.Twenty AIS patients and eight age-matched controls were included in the present study.The BMD of lumbar spine and proximal femur was measured in all subjects.OBs from the cancellous bone of each subject was harvested and primarily cultured.The mRNA and protein expression of RANKL and OPG in OBs was detected by RT-PCR and Western blotting.The results showed BMD was lower in AIS patients than in controls.A significantly higher mRNA and protein expression of RANKL was observed in OBs from AIS patients,while no significant difference was found in the expression of OPG between AIS patients and controls.As a result,RANKL/OPG ratio in patients with AIS was remarkably higher than controls.Our study preliminarily demonstrated expression of RANKL was higher in OBs from AIS patients with low BMD as compared with controls,suggesting the unbalanced RANKL/OPG ratio caused by an over-expression of RANKL in OBs may be responsible for the low BMD in AIS patients.

Effect of Triptolide on Expression of Receptor Activator of Nuclear Factor-κB Ligand in Rat Adjuvant Induced Arthritis

The effect of triptolide （TP） on the expression of receptor activator of nuclear factor-κB ligand （RANKL） and osteoprotegerin （OPG） was explored in rat adjuvant induced arthritis （AA）. AA was induced in Wistar rats. Arthritis rats were treated with TP and methotrexate （MTX） at the onset （day 9） of arthritis. On the peak of arthritis （day 24）, the expression of RANKL and OPG protein in the joints and RANKL mRNA in peripheral blood mononuclear cells （PBMC） was detected. TNF-α and IL-1β levels in peripheral blood were determined. Bone erosion scores were also evaluated. The results showed that bone erosion scores in TP and MTX groups were lower than in AA group （.P〈0.01） ; The expression levels of RANKL in the synovium （P〈0.01） and bone （P〈0.05）, and OPG level in synovium （P〈0.05） were lower in TP group than in AA group （P〈0.05）. In TP group, the expression levels of RANKL mRNA and TNF-α, IL-1β in PBMC were lower than in AA group （all P〈0.01）. It was concluded that TP could inhibit rat adjuvant arthritis bone erosion by suppressing the expression of RANKL.

Influence of baicalin on the expression of receptor activator of nuclear factor-κB ligand and osteoprotegerin in human periodontal ligament cells

Objective To study the effect of baicalin on the expression of receptor activator of nuclear factor-κB ligand(RANKL)and osteoprotegerin(OPG)in cultured human periodontal ligament(HPDL)cells.Methods Small interfering RNA(siRNA)eukaryotic expression vector targeted transforming growth factor βⅡ receptor(TGF-β RⅡ)was constructed and transfected into T cells.HPDL cells with T cells transfected with siRNA or not were placed in the culture medium that had been added with lipopolysaccharide(LPS)and baicalin.The obtained solution was divided into six groups according to the components(group Ⅰ:HPDL cells+LPS+T cells transfected with siRNA1+baicalin;group Ⅱ:HPDL cells+LPS+T cells transfected with siRNA1;group Ⅲ:HPDL cells+LPS+T cells+baicalin;group Ⅳ:HPDL cells+LPS+T cells;group Ⅴ:HPDL cells+baicalin;group Ⅵ:HPDL cells)and was cultured for 48 hours.RT-PCR was used to observe the effect of baicalin on the expression of OPG-RANKL in HPDL cells.Results The ratio of RANKL/OPG in group Ⅰ was lower than that in group Ⅱ(P<0.01)and higher than that in group Ⅲ(P<0.01);The ratio of RANKL/OPG in group Ⅲ was lower than that in group Ⅳ(P<0.01);the ratio of RANKL/OPG in group Ⅳ was higher than that in group Ⅵ(P<0.01);the ratio of RANKL/OPG in group Ⅴ was lower than that in group Ⅵ(P<0.05).Conclusion ① Baicalin could decrease the ratio of RANKL/OPG in HPDL cells.② The TGF-β signaling transduction plays an important role in the effect of baicalin on the RANKL/OPG ratio in HPDL cells.③ Baicalin acts not only through TGF-β to regulate RANKL/OPG in HPDL cells,but also through other pathways.

Role of osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand axis in nonalcoholic fatty liver disease

Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome(Met S), like insulin resistance(IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, Met S, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin(OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesityrelated comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of Met S as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.

Receptor activator of nuclear factorκB ligand/osteoprotegerin axis and vascular calcifications in patients with chronic kidney disease

Vascular calcifications are commonly observed in patients with chronic kidney disease （CKD） and contri-bute to the excessive cardiovascular morbidity and mortality rates observed in these patients populations. Although the pathogenetic mechanisms are not yet fully elucidated, recent evidence suggests a link between bone metabolism and the development and progression of vascular calcifications. Moreover, accumulating data indicate that receptor activator of nuclear factor κB ligand/osteoprotegerin axis which plays essential roles in the regulation of bone metabolism is also involved in extra-osseous bone formation. Further studies are required to establish the prognostic significance of the above biomarkers as predictors of the presence and severity of vascular calcifications in CKD patients and of cardiovascular morbidity and mortality. Moreover, randomized clinical trials are needed to clarify whether inhibition of osteoclast activity will protect from vascular calcifcations.

Apigenin ameliorates imiquimod-induced psoriasis in C57BL/6J mice by inactivating STAT3 and NF-κB

Psoriasis is a chronic autoimmune disease featured by patches on the skin.It is caused by malfunction of immune cells and keratinocytes with inflammation as one of its key features.Apigenin(API)is a natural flavonoid with anti-inflammatory and immunoregulatory properties.Therefore,we speculated that API can ameliorate psoriasis,and determined its effect on the development of psoriasis by using imiquimod(IMQ)-induced psoriasis mouse model.Our results showed that API attenuated IMQ-induced phenotypic changes,such as erythema,scaling and epidermal thickening,and improved splenic hyperplasia.Abnormal differentiation of immune cells was restored in API-treated mice.Mechanistically,we revealed that API is a key regulator of signal transducer activator of transcription 3(STAT3).API regulated immune responses by reducing interleukin-23(IL-23)/STAT3/IL-17A axis.Moreover,it suppressed IMQ-caused cell hyperproliferation by inactivating STAT3 through regulation of extracellular signal-regulated kinase 1/2 and nuclear factor-κB(NF-κB)pathway.Furthermore,API reduced expression of inflammatory cytokines through inactivation of NF-κB.Taken together,our study demonstrates that API can ameliorate psoriasis and may be considered as a strategy for psoriasis treatment.

Effects of ω-3 fatty acids on toll-like receptor 4 and nuclear factor-κB p56 in lungs of rats with severe acute pancreatitis

AIM To determine the effects of ω-3 fatty acids(ω-3FA) on the toll-like receptor 4(TLR4)/nuclear factor κB p56(NF-κBp56) signal pathway in the lungs of rats with severe acute pancreatitis(SAP).METHODS A total of 56 Sprague-Dawley rats were randomly divided into 4 groups: control group, SAP-saline group, SAP-soybean oil group and SAP-ω-3FA group. SAP was induced by the retrograde infusion of sodium taurocholate into the pancreatic duct. The expression of TLR4 and NF-κBp56 in the lungs was evaluated by immunohistochemistry and Western blot analysis. The levels of inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in the lungs were measured by enzyme-linked immunosorbent assay. RESULTS The expression of TLR4 and NF-κBp56 in lungs and of inflammatory cytokines in serum significantly increased in the SAP group compared with the control group(P < 0.05), but was significantly decreased in the ω-3FA group compared with the soybean oil group at 12 and 24 h(P < 0.05).CONCLUSION During the initial stage of SAP, ω-3FA can efficiently lower the inflammatory response and reduce lung injury by triggering the TLR4/NF-κBp56 signal pathway.

Glycine Attenuates Myocardial Fibrosis in Myocardial Infarction in Rats Partly through Modulating Signal Transducer and Activator of Transcription 3/Nuclear Factor-κB/Transforming Growth Factor-β axis

Objective: Inflammation and fibrosis are strongly associated with each other. Glycine is present in various traditional Chinese medicines and exhibits anti-inflammatory activity. However, the effects of glycine on myocardial fibrosis(MF) in rats with myocardial infarction(MI) have not been reported. The purpose of this study is to investigate the effects of glycine therapy on MF and comprehend its underlying mechanisms. Materials and Methods: Left anterior descending artery ligation-induced MI in Sprague Dawley rats was leveraged to assess the therapeutic effects of Glycine. Rats received either normal saline or glycine(0.5 mg/g bodyweight) for 7 days. Results: Glycine upregulated cardiac ejection fraction and fractional shortening to improve cardiac function, as evaluated by echocardiography. Histological and immunohistochemical analyses demonstrated that glycine could decrease inflammatory cell infiltration and alleviate collagen deposition. Western blotting revealed that nuclear factor-κB(NF-κB)-mediated inflammatory signaling was also downregulated by glycine treatment. The expression of signal transducer and activator of transcription 3(STAT3), tumor necrosis factor-α, and transforming growth factor-β(TGF-β) was decreased significantly in the glycine-treated group compared to the model group. Thus, glycine plays a protective role against myocardial ischemia and subsequent MF. Conclusion: The protective effects of glycine were achieved partly through STAT3/NF-κB/TGF-β signaling pathway.

Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes

Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.

骨保护素/核因子κB受体活化因子/核因子κB受体活化因子配体调节骨代谢及其靶向治疗在口腔领域的应用

背景:骨保护素/核因子κB受体活化因子/核因子κB受体活化因子配体是偶联破骨细胞、成骨细胞分化和活化的重要细胞因子,是调节骨代谢的关键因子,影响着免疫系统、骨的再生和重塑,与牙槽骨的生理性及病理性改建密切相关。目的:分析总结骨保护素/核因子κB受体活化因子/核因子κB受体活化因子配体信号通路对牙槽骨改建的影响及其靶向治疗在口腔领域应用研究中的进展。方法:检索中国知网及PubMed数据库收录的相关文献。中文检索词为“骨保护素,抗RANKL抗体,核因子κB受体活化因子配体,牙周炎,正畸牙移动,种植,牙齿萌出,根尖周病变,牙槽骨吸收”,英文检索词为“OPG,anti-RANKL antibody,RANKL,periodontitis,orthodontic tooth movement,implant,tooth eruption,periapical lesion,alveolar bone resorption”,最终纳入63篇文献进行归纳总结。结果与结论:①抗核因子κB受体活化因子配体通过靶向抑制破骨细胞形成和牙槽骨吸收来治疗口腔疾病;②局部和全身抗核因子κB受体活化因子配体治疗可以抑制牙周炎、种植体周围炎、根尖周病变的进展,且其在预防正畸后复发、增强正畸支抗和种植体骨结合方面也发挥重要作用;③核因子κB受体活化因子配体通过靶向促进破骨细胞分化来治疗口腔疾病;④核因子κB受体活化因子配体治疗可以加速正畸牙移动、缩短治疗周期、减少正畸并发症的发生;⑤虽然抗核因子κB受体活化因子配体治疗存在局限性,但是可以通过合理应用如应用前排除危险因素,应用期间定期口腔维护、避免创伤性牙槽手术等措施来规避。

骨保护素/核因子кB受体活化因子配体、小泛素样修饰蛋白特异性蛋白酶1、脂蛋白相关磷脂酶A2与阻塞性睡眠呼吸暂停低通气综合征病情程度的关系及其预测心血管事件价值分析

目的分析骨保护素(OPG)/核因子кB受体活化因子配体(RANKL)、小泛素样修饰蛋白特异性蛋白酶1(SENP-1)、脂蛋白相关磷脂酶A2(Lp-PLA2)与阻塞性睡眠呼吸暂停低通气综合征(OSAHS)病情程度的关系及各指标预测心血管事件(CVE)价值。方法纳入2021年9月至2022年9月于河北省胸科医院接受治疗的120例OSAHS患者,根据病情分为轻度组、中度组、重度组,比较三组患者的基线资料,采用多元logistics回归分析OPG/RANKL、SENP-1、Lp-PLA2与阻塞性OSAHS病情程度的关系。随访1年,记录120例患者随访期间心血管事件(CVE)的发生情况,将发生CVE的患者纳入CVE组,将未发生CVE的患者纳入非CVE组,比较两组入院时OPG/RANKL、SENP-1、Lp-PLA2水平;采用受试者操作特性(ROC)曲线评估OPG/RANKL、SENP-1、Lp-PLA2预测OSAHS患者CVE发生风险的价值。结果重度组体重指数、颈围、腰围、臀围、RANK、SENP-1、Lp-PLA2高于中度组、轻度组,中度组高于轻度组(P<0.05),OPG、OPG/RANK低于中度组、轻度组,中度组低于轻度组(P<0.05)。多元logistics回归分析结果显示,颈围、颈围、腰围、RANKL、SENP-1、Lp-PLA2高水平是OSAHS患者病情加重的危险因素(OR>1,P<0.05)。OPG、OPG/RANKL高水平是OSAHS患者病情加重的保护因素(OR<1,P<0.05)。CVE组OPG、OPG/RANKL低于非CVE组,RANKL、SENP-1、Lp-PLA2高于非CVE组(P<0.05)。ROC曲线分析结果显示,OPG/RANKL、SENP-1、Lp-PLA2单一及联合检测预测OSAHS患者发生CVE的曲线下面积均>0.70,具有较好预测效能,且联合检测预测效能更高。结论OPG/RANKL、SENP-1、Lp-PLA2水平与OSAHS患者病情严重程度密切相关,并可有效预测OSAHS患者发生CVE的风险。

基于核因子κB受体活化因子配体信号通路激活破骨细胞治疗骨结核的研究进展

骨结核是一种严重危害人体健康的骨科感染性疾病,其病灶组织破坏的最大特点是骨质的吸收及破坏,其中破骨细胞是骨吸收的主要细胞。破骨细胞是由造血干细胞分化而来的多核细胞,通常是由核因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand,RANKL)与核因子κB受体活化因子(receptor activator for nuclear factor-κB,RANK)调控产生。结核分枝杆菌可以通过RANKL信号通路激活破骨细胞生成转录因子,以增强破骨细胞对骨质的吸收。笔者通过综述RANKL信号通路的结构及破骨细胞的研究进展,以及它们在骨结核临床治疗中可能发挥的潜在作用,为该领域的研究提供新的思路。

Suppressing high mobility group box-1 release alleviates morphine tolerance via the adenosine5'-monophosphate-activated protein kinase/heme oxygenase-1 pathway

Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.

Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Class B. These are targets of imaging probes for positron emission tomography (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Difficulties in development of non-peptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large N-terminal?ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most small-molecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential small-molecule lead structures suitable for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide structures with affinities in nM-range have been proposed as non-peptide ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been classified as non-competitive related to the orthosteric binding site of endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been identified hydrazide compounds for which an inhibitory and potentially competitive mechanism of receptor binding has been postulated based on molecular docking studies.

N-acetylserotonin alleviates retinal ischemia-reperfusion injury via HMGB1/RAGE/NF-κB pathway in rats

AIM:To observe the effects of N-acetylserotonin(NAS)administration on retinal ischemia-reperfusion(RIR)injury in rats and explore the underlying mechanisms involving the high mobility group box 1(HMGB1)/receptor for advanced glycation end-products(RAGE)/nuclear factor-kappa B(NF-κB)signaling pathway.METHODS:A rat model of RIR was developed by increasing the pressure of the anterior chamber of the eye.Eighty male Sprague Dawley were randomly divided into five groups:sham group(n=8),RIR group(n=28),RIR+NAS group(n=28),RIR+FPS-ZM1 group(n=8)and RIR+NAS+FPS-ZM1 group(n=8).The therapeutic effects of NAS were examined by hematoxylin-eosin(H&E)staining,and retinal ganglion cells(RGCs)counting.The expression of interleukin 1 beta(IL-1β),HMGB1,RAGE,and nod-like receptor 3(NLRP3)proteins and the phosphorylation of nuclear factorkappa B(p-NF-κB)were analyzed by immunohistochemistry staining and Western blot analysis.The expression of HMGB1 protein was also detected by enzyme-linked immunosorbent assay(ELISA).RESULTS:H&E staining results showed that NAS significantly reduced retinal edema and increased the number of RGCs in RIR rats.With NAS therapy,the HMGB1 and RAGE expression decreased significantly,and the activation of the NF-κB/NLRP3 pathway was antagonized along with the inhibition of p-NF-κB and NLRP3 protein expression.Additionally,NAS exhibited an anti-inflammatory effect by reducing IL-1βexpression.The inhibitory of RAGE binding to HMGB1 by RAGE inhibitor FPS-ZM1 led to a significant decrease of p-NF-κB and NLRP3 expression,so as to the IL-1βexpression and retinal edema,accompanied by an increase of RGCs in RIR rats.CONCLUSION:NAS may exhibit a neuroprotective effect against RIR via the HMGB1/RAGE/NF-κB signaling pathway,which may be a useful therapeutic target for retinal disease.

miR-338-3p靶向核因子κB受体活化因子配体影响牙槽骨成骨细胞增殖及凋亡

背景:miR-338-3p能够抑制破骨细胞分化,下调核因子κB受体活化因子配体水平能够促进骨形成。然而miR-338-3p是否通过调控核因子κB受体活化因子配体表达影响牙槽骨成骨细胞增殖、凋亡尚不清楚。目的:探究miR-338-3p靶向核因子κB受体活化因子配体对牙槽骨成骨细胞增殖、凋亡的影响及机制。方法:分离人牙槽骨成骨细胞,对其进行细胞转染及Wnt-C59(Wnt/β-catenin通路抑制剂)处理,分为转染对照组、miR-338-3p组、miR-338-3p+对照组、miR-338-3p+核因子κB受体活化因子配体组和miR-338-3p+Wnt-C59组。双荧光素酶实验验证miR-338-3p对核因子κB受体活化因子配体的调控作用;CCK-8、EdU染色检测细胞增殖水平;流式细胞术检测细胞周期和凋亡水平;RT-qPCR检测细胞miR-338-3p、核因子κB受体活化因子配体、Wnt-3a、β-catenin、糖原合酶激酶3βmRNA表达水平;Western Blot检测细胞核因子κB受体活化因子配体、增殖细胞核抗原、Ki67、细胞周期蛋白D1、Bcl-2、Bax、天冬氨酸半胱氨酸蛋白酶3、Wnt-3a、β-catenin、糖原合酶激酶3β蛋白表达水平。结果与结论:①miR-338-3p靶向调控核因子κB受体活化因子配体;②过表达miR-338-3p后,细胞存活率、EdU阳性细胞率、S期细胞比例升高,细胞凋亡率降低,miR-338-3p、增殖细胞核抗原、Ki67、细胞周期蛋白D1、Bcl-2、Wnt-3a、β-catenin mRNA和蛋白水平升高,Bax、天冬氨酸半胱氨酸蛋白酶3、核因子κB受体活化因子配体、糖原合酶激酶3βmRNA和蛋白水平降低(均P<0.05);③过表达核因子κB受体活化因子配体或Wnt-C59处理能够减弱过表达miR-338-3p对细胞增殖、凋亡的影响(均P<0.05);④结果表明,miR-338-3p靶向核因子κB受体活化因子配体表达可促进牙槽骨成骨细胞增殖,并抑制细胞凋亡,其可能通过激活Wnt/β-catenin信号通路发挥作用。

Imbalance of osteoprotegerin/receptor activator of nuclear factor-κB ligand and oxidative stress in patients with obstructive sleep apnea-hypopnea syndrome

Background:Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with a higher prevalence of osteoporosis.However,the underlying mechanisms linking OSAHS with bone loss are still unclear.The aim of this study was to investigate the changes of receptor activator of nuclear factor-κB ligand (RANKL,an osteoclastogenesis-promoting factor) and osteoprotegerin (OPG,the decoy receptor for RANKL),oxidative stress and bone metabolism markers in OSAHS,in order to understand the potential mechanisms underlying bone loss in OSAHS patients.Methods:Forty-eight male patients with OSAHS,confirmed by polysomnography (PSG) study,were enrolled.Twenty male subjects who were confirmed as not having OSAHS served as the controls.The subjects’bone mineral density (BMD) was assessed in lumbar spine and femoral neck using dual-energy X-ray absorptiometry (DXA).Blood samples were collected from all subjects for measurement of RANKL,OPG,the bone formation marker bone-specific alkaline phosphatase (BAP),the bone resorption marker tartrate-resistant acid phosphatase 5b (TRAP-5b),and total antioxidant capacity (TAOC).Results:The BMD and the T-score of the femoral neck and the lumbar spine were significantly lower in OSAHS patients as compared to the control group (P< 0.05).The serum level of BAP was significantly decreased in the OSAHS group (15.62 ± 5.20 μg/L) as compared to the control group (18.83 ± 5.50 μg/L,t= -2.235,P< 0.05),while the levels of TRAP-5b did not differ between the two groups (t= -1.447,P> 0.05).The serum level of OPG and the OPG/RANKL ratio were lower in the OSAHS group compared to the control group (bothP< 0.05).TAOC level was also decreased significantly in the OSAHS group (P< 0.05).Correlation analysis showed that the TAOC level was positively correlated with BAP in the OSAHS group (r= 0.248,P= 0.04),but there were no correlations between TAOC and the BMD or the T-scores.The correlations between the level of OPG (or the OPG/RANKL ratio) and BMD or TAOC did not reach significance.Conclusion:In OSAHS patients,lower levels of TAOC were associated with decreased bone formation,suggesting a role of oxidative stress in bone loss,while the role of OPG/RANKL imbalance in bone metabolism in OSAHS needs further evaluation .

核因子κB受体活化因子信号转导机制与破骨细胞的活化

背景:破骨细胞是目前已知的唯一一种骨吸收细胞,其生命活动对骨骼的正常发育和骨骼损伤修复至关重要。在绝大多数骨病中,破骨细胞均显示出异常增殖分化和骨吸收活性增加,而核因子κB受体活化因子信号是调控破骨细胞生命过程的关键信号通路。目的:总结对破骨细胞核因子κB受体活化因子信号下游靶点及DNA转录因子的最新研究进展,为相关疾病的研究和治疗提供依据。方法:文献检索数据库包括中国知网、万方、维普数据库、PubMed、Embase及Web of Science数据库,中文检索词为“破骨细胞,破骨前体细胞,骨质疏松症,骨代谢,发病机制,表观遗传学,信号通路,信号传导,转录因子,组织工程”,英文检索词为“osteoclasts,osteoclast precursor cells,osteoporosis,bone metabolism,pathogenesis,epigenetics,signaling pathway,signal transduction,transcription factors,tissue engineering”,时间设置为2017-2021年,根据纳入和排除标准共筛选52篇文献。结果与结论:核因子κB受体活化因子的特殊结构决定了其信号传导需要与肿瘤坏死因子受体激活因子6结合来募集多种蛋白、活性酶以及细胞因子,形成具有内在酶活性的核因子κB受体活化因子复合物;该复合物通过激活核因子κB、丝裂原活化蛋白激酶等信号通路的传导,最终调控破骨细胞分化、增殖、骨吸收等生命过程。

基于TLR4/NF-κB信号通路及血清CXCL16、ACA评价依达拉奉右莰醇对ACI神经功能的保护作用

目的基于Toll样受体(TLR)4/核因子κB(NF-κB)信号通路及血清CXC型趋化因子配体16(CXCL16)、抗心磷脂抗体(ACA)评价依达拉奉右莰醇治疗急性脑梗死(ACI)的疗效及神经功能保护作用。方法将102例ACI患者根据是否使用依达拉奉右莰醇分为两组:观察组(n=54)均在常规治疗基础上接受依达拉奉右莰醇治疗,对照组(n=48)未用依达拉奉治疗。对比两组治疗前及治疗7d、14d、30d后神经功能缺损量表(NIHSS),治疗前及治疗14d检测血清TLR4、NF-κB、白介素1β(IL-1β)、白介素6(IL-6)、肿瘤坏死因子α(TNF-α)、CXCL16、ACA,随访3个月采用改良Rankin量表(mRS)评价预后。结果治疗后7d、14d、30d,两组NIHSS评分均下降,而观察组明显低于对照组(P<0.05)。治疗14d后,两组血清TLR4、NF-κB、IL-1β、IL-6、TNF-α、CXCL16、ACA水平均下降,且观察组明显低于对照组(P<0.05)。随访3个月,观察组mRS均分低于对照组(P<0.05),但两组预后差异无统计学意义(79.63%vs 68.75%,P>0.05)。结论依达拉奉右莰醇用于ACI的治疗可保护神经功能,其机制可能与调节TLR4/NF-κB信号通路及血清CXCL16、ACA表达有关。

2型糖尿病患者骨保护素和NF-κB受体活化因子配体与左室舒张功能障碍的相关研究

【目的】探讨2型糖尿病(T2DM)患者血清骨保护素(OPG)和可溶性NF-κB受体活化因子配体(sRANKL)水平与可能左室舒张功能障碍(LADD)的相关性。【方法】本研究纳入68例T2DM患者和37例健康对照者,利用ELISA方法测定血清OPG和sRANKL水平,同时利用心脏彩超测定T2DM患者左室舒张功能,E/A<1定义为LADD。进一步将T2DM患者分为E/A≥1和E/A<1两个亚组。采用Spearman相关性分析、logistics回归分析和ROC曲线评估血清OPG和sRANKL与T2DM患者可能LADD的相关性。【结果】与健康对照者相比,T2DM患者血清OPG水平明显升高,差异有统计意义(P<0.01),而sRANKL水平降低,但无统计学意义(P=0.032)。亚组分析则显示E/A<1组的OPG水平较E/A≥1组升高(P<0.01),而sRANKL降低(P<0.01)。Spearman相关性分析显示,血清OPG水平与E/A比值呈负相关,而sRANKL则与E/A比值呈正相关。单因素logistics回归分析显示,血清OPG水平[OR(95%CI)=1.068(1.031,1.106),P<0.001]和sRANKL水平[OR(95%CI)=0.976(0.959,0.992),P=0.003]与T2DM患者可能LVDD显著相关。ROC曲线分析显示,联合OPG与sRANKL诊断糖尿病患者可能LADD的敏感性为78.13%,特异性为88.3%(曲线下面积:0.857;95%CI=(0.768,0.946);P<0.001)。【结论】T2DM患者血清中升高的OPG和降低的sRANKL水平提示其可能与LADD相关。