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.

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.

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.

Receptor activator of nuclear factor kappa B ligand and osteoprotegerin expression in chronic apical periodontitis：possible association with inflammatory cells

Background Receptor activator of nuclear factor kappa B （NF-κB） ligand （RANKL） and osteoprotegerin （OPG） have been recently shown to play important roles in bone resorption. The aim of this study was to investigate the possible association between the expression of bone resorption regulators （RANKL and OPG） and inflammatory cell infiltration in chronic apical periodontitis.Methods The samples of chronic periapical lesions （n=40） and healthy periapical tissues （n=10） were examined for immunohistochemical analysis of RANKL and OPG. Lesion samples were further analyzed for the inflammatory infiltration condition. The inflammatory cell infiltration was scored in relation to immunohistochemical reactivity for CD3, CD20 and CD68.Results The number of RANKL-positive cells and the ratio of RANKL/OPG in chronic apical periodontitis were significantly higher than those in healthy periapical tissues （P＜0.001）. The number of RANKL-positive cells was higher in lesions with severe inflammatory infiltration than in those with light inflammatory infiltration （P＜0.05）. Significantly increased RANKL expression was found with T lymphocytes （CD3＋）, macrophages （CD68＋） and B lymphocytes （CD20＋）infiltration （P＜0.05）. No association was found between the ratio of RANKL/OPG and inflammatory cell infiltration.Conclusions RANKL expression was increased with T, B lymphocytes and macrophages infiltration, respectively in chronic periapical lesions. RANKL appears to be closely related to periapical inflammatory infiltrates. The relative ratio of RANKL/OPG may be a key determinant of RANKL-mediated bone resorption.

Effect of Wenhua Juanbi Recipe(温化蠲痹方) on Expression of Receptor Activator of Nuclear Factor Kappa B Ligand,Osteoprotegerin,and Tumor Necrosis Factor Receptor Superfamily Member 14 in Rats with Collagen-Induced Arthritis

Objective： To study the effect of Wenhua Juanbi Recipe（温化蠲痹方, WJR） on expression of receptor activator of nuclear factor kappa B ligand（RANKL）, osteoprotegerin（OPG）, and tumor necrosis factor receptor superfamily member 14（TNFRSF14, also known as LIGHT） in rats with collagen-induced arthritis（CIA）. Methods： CIA rats were generated by subcutaneous injection of bovine collagen type-Ⅱ at the tail base. Sixty CIA rats were randomly assigned（10 animals/group） to： model, methotrexate（MTX）-treated（0.78 mg/kg body weight）, and WJR-treated（22.9 g/kg） groups. Healthy normal rats（n=10） were used as the normal control. Treatments or saline were administered once daily by oral gavage. Rats were sacrificed at day 28 post-treatment and knee synovium and peripheral blood serum were collected. Toe swelling degree and expression of RANKL, OPG, and LIGHT were determined by Western blot and immunohistochemistry. Results： Compared with the normal group, toe swelling degree was significantly increased in the model group（P〈0.01）. After treatment, toe swelling degree decreased significantly in the WJR and MTX groups compared with the model group（P〈0.01）. Compared with the normal group, expression of RANKL and LIGHT were significantly increased and OPG significantly decreased in peripheral blood and synovium of the model group（P〈0.01）. Conversely, RANKL and LIGHT expression were significantly reduced and OPG increased in the WJR and MTX groups compared with the model group（P〈0.01）. No statistically significant difference existed between WJR and MTX groups. Conclusion： WJR likely acts by reducing RANKL expression and increasing OPG expression, thus inhibiting RANKL/RANK interaction and reducing LIGHT expression, thereby inhibiting osteoclast formation/activation to block bone erosion.

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。

Cannabinoid receptor-2 selective antagonist negatively regulates receptor activator of nuclear factor kappa B ligand mediated osteoclastogenesis

Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK） ligand （RANKL）induced osteoclast differentiation and the underlying signaling pathway using a monocyte-macrophage cell line-RAW264.7.Methods RAW264.7 was cultured with RANKL for 6 days and then treated with AM630 for 24 hours. Mature osteoclasts were measured by tartrate-resistant acid phosphatase （TRAP） staining using a commercial kit. Total ribonucleic acid （RNA）was isolated and real-time reverse transcriptase-polymerase chain reaction （RT-PCR） was done to examine the expression of RANK, cathepsin K （CPK） and nuclear factor kappa B （NF-κB）. The extracellular signal-regulated kinase （ERK）,phosphorylation of ERK （P-ERK） and NF-κB production were tested by Western blotting. The effect of AM630 on RAW264.7 viability was determined using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazoliumbromide （MTT） assay.Results AM630 did not affect the viability of RAW264.7. However, this CB2 selective antagonist markedly inhibited osteoclast formation and the inhibition rate was dose-dependent. The dose of 〉100 nmol/L could reduce TRAP positive cells to the levels that were significantly lower than the control. AM630 suppressed the expression of genes associated with osteoclast differentiation and activation, such as RANK and CPK. An analysis of a signaling pathway showed that AM630 inhibited the RANKL-induced activation of ERK, but not NF-κB.Conclusion AM630 could inhibit the osteoclastogenesis from RAW264.7 induced with RANKL.

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。

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。

正畸保持期龈沟液骨保护素/核因子kappa B受体活化因子配体水平对牙槽骨改建状态的意义

目的:探讨正畸保持期牙周龈沟液中骨保护素(osteoprotegerin,OPG)和核因子kappa B受体活化因子配体水平(receptor activator of nuclear factor kappa B ligand,RANKL)的变化及相应牙周组织OPG和RANKL表达的变化,为预测保持期牙周骨组织状态是否稳定提供依据。方法:选择6周龄雄性Wista大鼠15只,按时间点(T1:基线,T2:加力14 d,T3:停止加力14 d)分为3组,每组5只。在每个时间点先采集龈沟液样本,应用酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)检测OPG和sRANKL(soluble receptor activator of nuclear factor kappaB ligand)浓度,然后处死大鼠,采用免疫组织化学检测牙周组织中OPG和RANKL表达。结果:龈沟液中sRANKL浓度在T2期明显上升(P<0.05),T3期则显著下降(P<0.05),与T1期几乎相当。龈沟液中OPG浓度在3个时间点的变化差异均无统计学意义(P>0.05);龈沟液中sRANKL/OPG的比值和牙周组织RANKL/OPG的比值变化近似,均在T2期明显增大(P<0.05和P<0.01),在T3期显著减小(P<0.05)。结论:在正畸加力至保持期,龈沟液中sRANKL/OPG的比值可以在一定程度上反映牙周组织中骨改建的状态。

Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway

Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae （Gegen）, has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that anti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic anti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be involved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment （intravenous injection） re- duced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-a in brain tissue. Pretreatment with puerarin （intravenous injection） attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 （JAK2） and signal transducers and activators of transcription 3 （STAT3） activation and nuclear factor kappa B （NF-KB） inhibition. These observa- tions were inhibited by the alpha7 nicotinic acetylcholine receptor （a7nAchR） antagonist a-bungarotoxin （a-BGT）. In addition, puerarin pretreatment increased the expression of a7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory re- sponse. Our results also indicated that the anti-inflammatory effect of puerarin may partly be medi- ated through the activation of the cholinergic anti-inflammatory pathway.

低能量激光对人牙周膜细胞白细胞介素-6、肿瘤坏死因子-α、骨保护素、核因子-κB受体活化因子配体表达的影响

目的通过观察高糖环境下低能量激光(LLL)对受静压力刺激的人牙周膜细胞(HPDLC)白细胞介素-6(IL-6)、肿瘤坏死因子(TNF)-α、骨保护素(OPG)、核因子-κB受体活化因子配体(RANKL)表达的影响,以期探究LLL对糖尿病患者牙周组织炎症及正畸治疗过程中骨改建调控的分子生物学机制。方法体外培养HPDLC,模拟正畸加力,结合LLL照射,将所培养细胞随机分为4组:低糖型杜氏改良Eagle培养基(DMEM)+压力刺激(A组),高糖型DMEM+压力刺激(B组),低糖型DMEM+LLL照射+压力刺激(C组),高糖型DMEM+LLL照射+压力刺激(D组),其中C、D组根据给予的激光能量密度值不同又分C1、D1组(能量密度值:3.75 J/cm2)和C2、D2组(能量密度值:5.625 J/cm2)。根据已有分组,对A、B、C、D组细胞进行加力,对C、D组细胞在细胞加力前进行LLL照射。分别观察0、12、24、48、72 h,定时提取各组细胞培养上清液,采用酶联免疫吸附(ELISA)法检测各组不同时段IL-6、TNF-α、OPG、RANKL的蛋白表达。结果1)在持续静压力刺激下,HPDLC分泌的IL-6、TNF-α浓度随时间逐渐上升;12 h后IL-6、TNF-α的浓度在A组与B、C1、C2组组间两两比较的差异均有统计学意义(P<0.05),B组与D1、D2组组间两两比较的差异也均有统计学意义(P<0.01)。2)OPG蛋白浓度在24h之前呈现出上升趋势,24h后随时间出现下降趋势;RANKL蛋白浓度随时间呈上升趋势;OPG/RANKL比值随时间呈下降趋势;持续静压力刺激12h后,A组与B、C1、C2组,B组与D1、D2组组间两两比较的OPG、RANKL及OPG/RANKL的比值的差异均具有统计学意义(P<0.05)。结论1)在高糖环境持续静压力刺激下,HPDLC分泌的IL-6、TNF-α浓度随时间呈现上升趋势;OPG的表达水平降低,RANKL的表达水平增加,OPG/RANKL的比值减小,提示高糖环境会促进骨吸收反应的发生;给予LLL照射干预后发现,IL-6、TNF-α的浓度出现下降,表明其可拮抗高糖环境所致的炎症因子水平的升高,并且能上调人HPDLC中OPG的表达,下调HPDLC中RANKL的表达,从而上调OPG/RANKL的比值,逆转高糖所致的骨代谢失衡。2)在3.75~5.625J/cm2这一能量密度范围内,随着给予的激光能量密度值的增大,其表现出的降低炎症因子及对HPDLC骨代谢的调控作用增强,提示在一定范围内,LLL调节骨改建的能力随剂量增加而增强。

Anluohuaxianwan Alleviates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats through Upregulation of Peroxisome Proliferator-Activated Receptor-Gamma and Downregulation of Nuclear Factor-Kappa B/IκBα Signaling Pathway

Objective:The aim of this study was to investigate the effects of traditional Chinese medicine Anluohuaxianwan(ALHXW)on peroxisome proliferator-activated receptor-gamma(PPARγ)and nuclear factor-kappa B(NF-κB)signaling pathways using a rat model of carbon model groups were gavaged with saline for 6 weeks.Liver function was measured,and liver fibrosis and necroinflammation were assessed.Protein and messenger RNA expression levels of PPARγ,NF-κB,and Inhibitorαof NF-κB(IκBα)were analyzed by Western blot and reverse transcription–quantitative polymerase chain reaction.Results:ALHXW markedly alleviated liver injury compared with the model group,as indicated by the improvements in disease status,the morphology of liver and spleen,the liver and spleen indexes,and liver function.The extent of liver fibrosis was improved,hepatic stellate cell activation was inhibited,the expression of PPARγand IκBαwas significantly higher,and the expression of NF-κB was significantly lower in the treatment group as compared with the model group.Conclusions:ALHXW treatment can alleviate CCl4-induced liver fibrosis in rats, and the potential antifibrogenic mechanisms may occur through the upregulation of PPARγ expression and downregulation of NF-κB/IκBα signaling pathway.

核因子κB受体活化因子配体抑制剂地舒单抗在肺癌骨转移中的应用

目前,随着基因靶向治疗和免疫治疗在肺癌领域中取得巨大突破,晚期肺癌患者总生存期(OS)显著延长,但发生远处骨转移及骨相关事件(SRE),如骨痛、病理性骨折、脊髓压迫、高钙血症等风险也随之增大,严重影响了患者的生活质量。因此,在全身治疗基础上应积极预防和治疗骨转移及SRE治疗。临床研究表明,核因子κB受体活化因子(RANK)配体(RANKL)/RANK/骨保护素信号通路在肿瘤骨转移中发挥着重要作用,阻断该通路能有效预防和治疗SRE。RANKL抑制剂地舒单抗(商品名:安加维)是一种人免疫球蛋白G2单克隆抗体,可特异性结合RANKL而阻断破骨细胞参与的RANKL/RANK/骨保护素信号通路激活,最终发挥预防骨转移及SRE的作用。与双磷酸盐类药物比较,地舒单抗疗效显著,能明显延长患者OS和SRE的发生时间。同时,地舒单抗还具有抗肿瘤作用。该文就地舒单抗的作用机制、临床研究及安全性等方面的最新研究进行了阐述,以期为临床医生提供参考。

Efficacy of recombinant human osteoprotegerin combined with tinidazole in the treatment of periodontitis mice and its correlation with serum RANKL and MCP-1 levels

Objective: To investigate the effect of recombinant human osteoprotegerin combined with tinidazole on mice with periodontitis and the effect on serum RANKL and MCP-1 levels. Methods: 80 SPF-cleaned mice were randomly divided into 4 groups, 20 each, model group, tinidazole group and recombinant human osteoprotegerin group were modeled by Kimura et al., and tinidazole group received tinidazole. After intragastric administration, the recombinant human osteoprotegerin group was injected with recombinant human osteoprotegerin in the periodontal pocket according to the tinidazole group. The periodontal changes of the four groups of mice were observed and recorded, and the gingival rating was performed. Epithelial tissue morphology was observed by hematoxylin-eosin (HE) staining. Serum levels of IL-4, IL-6, RANKL and MCP-1 were measured by enzyme-linked immunosorbent assay. Results:After the intervention, the model group developed severe inflammatory reactions, including redness, hemorrhage, and deep periodontal pockets. The teeth were significantly loosened. The mice in the tinidazole group and the recombinant human osteoprotegerin group recovered substantially, and the gingival rating of the recombinant human osteoprotegerin group was better than that. The tinidazole group and the model group (P<0.05). The results of HE staining showed that the model group had edema, vasodilation and a large amount of inflammatory infiltration. The epithelial structure of the mice in the tinidazole group and the recombinant human osteoprotegerin group was intact and arranged closely and orderly. After intervention, the IL-4 in the tinidazole group and the recombinant human osteoprotegerin group was significantly higher than the model group and IL-6 was significantly lower than the model group (P<0.05), and the recombinant human osteoprotegerin group IL-4 was significantly higher after the intervention. IL-6 was significantly lower in the tinidazole group than in the tinidazole group (P<0.05). After the intervention, the tinidazole group and the recombinant human osteoprotegerin group were significantly reduced, and the recombinant human osteoprotegerin group RAKNL and MCP-1 were significantly lower than the model group (P>0.05). Conclusion: Recombinant human osteoprotegerin combined with tinidazole has a better therapeutic effect on gums and teeth in mice with periodontitis, and can lower the levels of RAKNL and MCP-1 in serum, inhibit bone resorption and protect teeth.

基于骨免疫学论中医药抑制类风湿关节炎骨破坏的研究进展

类风湿关节炎(RA)是一种以滑膜炎、软骨与骨破坏为主要病理表现的自身免疫性疾病,致残率较高。RA免疫及炎症反应与骨细胞代谢互为影响,其核心环节为破坏机体核因子κB受体活化因子配体/核因子κB受体活化因子/骨保护素(RANKL/RANK/OPG)信号通路的平衡,导致成骨细胞减少,以及破骨细胞凋亡减退及异常活化。西药目前以抑制炎症反应及相关细胞因子分泌,减缓疾病进展,但长期使用其不良反应难以忽视。中医药在防治骨破坏中研究逐步深入,但在基础及临床研究方面仍存在一定局限性。

丹参酮ⅡA调节骨关节炎小鼠骨代谢的作用机制

目的探讨丹参酮ⅡA(TanⅡA)通过介导Yes激酶相关蛋白(Yes-associated protein,YAP)、核因子-κB受体活化因子配基(receptor activator of nuclear factor-κB ligand,RANKL)/核因子κB受体活化因子(eceptor activator of nuclear factor-κB,RANK)/骨保护蛋白(osteoprotegerin,OPG)调节骨关节炎小鼠骨代谢的作用机制。方法建立骨关节炎小鼠模型,将60只小鼠随机分成假手术组、模型组、TanⅡA低剂量组和TanⅡA高剂量组,每组15只,造模成功后灌胃给药,连续4周。HE和番红O固绿染色观察软骨组织病理损伤并进行Mankin评分。酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)检测血清骨碱性磷酸酶(bone alkaline phosphatase,BALP)、骨钙素(osteocalcin,OC)、Ⅰ型胶原交联羧基末端肽(C-telopeptide of typeⅠcollagen,CTX)、白细胞介素(interleukin,IL)-1β、IL-6、IL-8和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)。蛋白质印迹法(Western blotting)检测基质金属蛋白酶(matrix metalloproteinases,MMPs)、YAP、RANK、RANKL和OPG蛋白。结果TanⅡA可改善小鼠软骨组织病理变化并降低Mankin评分。与假手术组比较,模型组BALP、OC水平下降,CTX、TNF-α、IL-6、IL-1β、IL-8、MMP1、MMP3和MMP13水平升高(P<0.05)。与模型组比较,TanⅡA低剂量组、TanⅡA高剂量组BALP、OC水平升高,CTX、TNF-α、IL-6、IL-1β、IL-8、MMP1、MMP3和MMP13水平降低(P<0.05)。与假手术组比较,模型组小鼠软骨组织中YAP、OPG和RANK蛋白水平下降,RANKL蛋白水平升高(P<0.05);与模型组比较,TanⅡA 2组小鼠软骨组织中YAP、OPG和RANK蛋白水平上升,RANKL蛋白水平下降(P<0.05)。结论TanⅡA可能通过介导YAP、RANK/RANKL/OPG信号通路调控骨关节炎。