Network pharmacology-based and molecular docking-based analysis of You-Gui-Yin for the treatment of osteonecrosis of the femoral head.

You-Gui-Yin (YGY) is a classic prescription for warming up kidney-Yang and filling in kidney essence in traditional Chinese medicine, and has been used to treat osteonecrosis of the femoral head (ONFH) effectively. However, the underlying mechanisms are still unknown. This study is aimed at exploring the possible mechanisms of action of the YGY in the treatment of ONFH based on network pharmacology and molecular docking. TCMSP was used to screen the active components and targets of YGY. The disease targets of ONFH were collected in several public databases. The protein-protein interaction (PPI) Network was constructed using the STRING platform. The Metascape database platform was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The key active components and core target proteins of YGY in the treatment of ONFH were verified by the molecular docking. 120 active components were obtained from YGY, among which 73 components were hit by the 117 drug-disease intersection targets. Key effective components included quercetin, kaempferol, beta-sitosterol, glycitein, beta-carotene, and so on. Core target proteins included ALB, AKT1, TNF, IL6, TP53, and so on. According to GO and KEGG analyses, there were 1762 biological processes, 94 cellular component, 138 molecular function and 187 signaling pathways involved. we selected the top 20 biological processes (BP), cellular components (CC), molecular functions (MF) and signaling pathways to draw the heat maps, showing that Lipid and atherosclerosis signaling pathway, IL-17 signaling pathway, HIF-1 signaling pathway, relaxin signaling pathway and MAPK signaling pathway and other pathways may play a key role in the treatment of ONFH by YGY. The results of molecular docking showed that key effective components and corresponding core target proteins exhibited the good binding activity. YGY can treat ONFH through multicomponents, multitargets, and multipathways, which provides a reference for the subsequent research, development of targeted drugs and clinical application.

[Ultrasound-guided closed reduction and kirschner wires internal fixation for the treatment of Kilfoyleâ ¡and â ¢ medial condylar fracture of humerus in children].

OBJECTIVE: To explore clinical effectiveness and safety of ultrasound-guided closed reduction and K-wires internal fixation in treating of Kilfoyle Ⅱand Ⅲ medial condylar fracture of humerus in children. METHODS: Clinical data of 32 children with medial condylar fracture of humerus treated with closed reduction and internal fixation with K-wires under the guidance of ultrasound were retrospectively analyzed from January 2014 to August 2019, including 23 males and 9 females, age ranged from 3.2 to 12.8 years old with an average of (8.3±2.1) years old;According to classification of Kilfoyle, 12 patients classified to typeⅡ and 20 patients were type Ⅲ;5 patients combined with elbow dislocation;the time from injury to operation ranged from 1 to 5 days with an average of (3.1±1.3) days. Radiological evaluation of treatment results and complications were observed. At the final follow up, Mayo elbow performance score(MEPS) was used to evaluate elbow function. And humerus-ulna angle on the affect side and healthy side were measured and compared. RESULTS: All patients were followed up from 8 to 26 months with an average of(19.3±5.5) months. All fractures were healed well, the healing time ranged from 4 to 6 weeks with an average of (4.5±0.5) weeks. No infection, vascular and nerve injury, bone nonunion, trochlear necrosis, cubitus varus or valgus deformity were occurred. According to Mayo scoring, all patients were assessed as excellent. There was no significant difference in angle of humerus-ulna between affectedside (9.5±3.6)° and healthy side (9.1±3.5)°, and no difference in MEPS scores between affected side(95.3±2.5) and healthy side(96.3±2.2)(P>0.05). CONCLUSION: For Kilfoyle typeⅡand Ⅲ medial condylar fracture of humerus in children, closed reduction and internal fixation with K-wire under ultrasound guidance is a safe and effective method, and could promote in further.

Interleukin-34 Synovial Fluid Was Associated with Knee Osteoarthritis Severity: A Cross-Sectional Study in Knee Osteoarthritis Patients in Different Radiographic Stages.

BACKGROUND: Inflammation might play a crucial role in the pathogenesis of osteoarthritis (OA). Interleukin-34 (IL-34) is a well-known proinflammatory cytokine. OBJECTIVE: The objective of this study was to detect IL-34 levels in serum and synovial fluid (SF) of patients with OA and to investigate their correlation with radiographic and symptomatic severity. METHODS: One hundred and eighty-two OA patients and 69 controls were recruited. IL-34 levels were measured by enzyme-linked immunosorbent assay (ELISA). Radiographic and symptomatic severity of OA was reflected by Kellgren-Lawrence (KL) grades and Western Ontario McMaster University Osteoarthritis Index (WOMAC) scores, respectively. RESULTS: SF IL-34 levels were independently associated with the KL grade (B = 0.273, 95% CI: 0.150-0.395; P < 0.001). SF IL-34 levels were significantly correlated with WOMAC scores (r = 0.265, 95% CI: 0.123-0.399; P < 0.001). The correlation between SF IL-34 levels and WOMAC scores was still significant after adjusting for confounding factors (B = 0.020, 95% CI: 0.001-0.038; P = 0.035) in OA patients. CONCLUSIONS: We found that IL-34 levels in SF were significantly associated with the radiographic and symptomatic severity of knee OA.

Naringin inhibits vascular endothelial cell apoptosis via endoplasmic reticulum stress­ and mitochondrial­mediated pathways and promotes intraosseous angiogenesis in ovariectomized rats.

In this study, to investigate the effects of naringin on vascular endothelial cell (VEC) function, proliferation, apoptosis, and angiogenesis, rat VECs were cultured in vitro and randomly divided into four groups: control, serum­starved, low­concentration naringin treatment, and high­concentration naringin treatment. MTT assay was used to detect cell proliferation while Hoechst 33258 staining and flow cytometry were used to detect apoptosis. Changes in the expression of apoptosis­associated proteins [GRP78, CHOP, caspase­12, and cytochrome c (Cyt.c)] were detected using western blotting. JC­1 staining was employed to detect changes in mitochondrial membrane potential. Intracellular caspase­3, ­8, and ­9 activity was determined by spectrophotometry. ELISA was used to detect endothelin (ET), and a Griess assay was used to detect changes in the expression of nitric oxide (NO) in culture medium. The study further divided an ovariectomized (OVX) rat model of osteoporosis randomly into four groups: OVX, sham­operated, low­concentration naringin treatment (100 mg/kg), and high­concentration naringin treatment (200 mg/kg). After 3 months of treatment, changes in serum ET and NO expression, bone mineral density (BMD), and microvessel density of the distal femur (using CD34 labeling of VECs) were determined. At each concentration, naringin promoted VEC proliferation in a time­ and dose­dependent manner. Naringin also significantly reduced serum starvation­induced apoptosis in endothelial cells, inhibited the expression of GRP78, CHOP, caspase­12, and Cyt.c proteins, and reduced mitochondrial membrane potential as well as reduced the activities of caspase­3 and ­9. Furthermore, naringin suppressed ET in vitro and in vivo while enhancing NO synthesis. Distal femoral microvascular density assessment showed that the naringin treatment groups had a significantly higher number of microvessels than the OVX group, and that microvascular density was positively correlated with BMD. In summary, naringin inhibits apoptosis in VECs by blocking the endoplasmic reticulum (ER) stress­ and mitochondrial­mediated pathways. Naringin also regulates endothelial cell function and promotes angiogenesis to exert its anti­osteoporotic effect.

Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo.

Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment.

Fibroblast growth factor-21 concentration in serum and synovial fluid is associated with radiographic bone loss of knee osteoarthritis.

We aimed to evaluate whether FGF-21 concentration in serum and synovial fluid (SF) is associated with radiographic bone loss of knee osteoarthritis (OA). A total of 186 OA patients and 108 controls were recruited. The radiographic bone loss of knee OA was assessed by the Ahlbäck grading scale. FGF-21 concentration in serum and SF was measured by enzyme-linked immunosorbent assay (ELISA). We demonstrated that OA patients had significantly higher serum FGF-21 concentration compared with controls (204.30 [range 158.25-279.16] ng/L vs. 130.72 [range 94.93-218.03] ng/L, p < 0.01). FGF-21 concentration in serum was well correlated with that in paired SF samples (r = 0.668, p < 0.001). In OA patients, those with a higher Ahlbäck grade had significantly higher serum and SF FGF-21 concentration (p < 0.001 for both). FGF-21 concentration in serum and SF was significantly and independently associated with the Ahlbäck grade (r = 0.403, p < 0.001 and r = 0.410, p < 0.001; respectively). These findings indicated that FGF-21 might be a potential biomarker for predicting bone loss of OA. Therapeutic interventions by blocking FGF-21 signaling pathways to delay the degenerative process of OA warrants further investigations.

Functional annotation of rheumatoid arthritis and osteoarthritis associated genes by integrative genome-wide gene expression profiling analysis.

BACKGROUND: Rheumatoid arthritis (RA) and osteoarthritis (OA) are two major types of joint diseases that share multiple common symptoms. However, their pathological mechanism remains largely unknown. The aim of our study is to identify RA and OA related-genes and gain an insight into the underlying genetic basis of these diseases. METHODS: We collected 11 whole genome-wide expression profiling datasets from RA and OA cohorts and performed a meta-analysis to comprehensively investigate their expression signatures. This method can avoid some pitfalls of single dataset analyses. RESULTS AND CONCLUSION: We found that several biological pathways (i.e., the immunity, inflammation and apoptosis related pathways) are commonly involved in the development of both RA and OA. Whereas several other pathways (i.e., vasopressin-related pathway, regulation of autophagy, endocytosis, calcium transport and endoplasmic reticulum stress related pathways) present significant difference between RA and OA. This study provides novel insights into the molecular mechanisms underlying this disease, thereby aiding the diagnosis and treatment of the disease.

A human ICAM-1 antibody isolated by a function-first approach has potent macrophage-dependent antimyeloma activity in vivo.

We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.

Serum fetuin-A levels are inversely associated with clinical severity in patients with primary knee osteoarthritis.

The present study aimed to detect serum fetuin-A levels in knee osteoarthritis (OA) patients and to investigate their correlation with clinical severity. We enrolled 215 knee OA patients and 76 healthy controls. We measured serum fetuin-A levels by enzyme-linked immunosorbent assay and assessed the correlation between serum fetuin-A levels and Kellgren-Lawrence grades as well as Western Ontario and McMaster Universities Arthritis Index scores in OA patients. Our results demonstrated that serum fetuin-A levels were independently and negatively correlated with greater clinical severity in OA patients.

Difference in subchondral cancellous bone between postmenopausal women with hip osteoarthritis and osteoporotic fracture: implication for fatigue microdamage, bone microarchitecture, and biomechanical properties.

OBJECTIVE: Osteoarthritis (OA) and osteoporosis (OP) of the hip rarely occur in the same patient. The purpose of this study was to determine whether this difference might be attributable to the different quantity and quality of subchondral cancellous bone in the two conditions. METHODS: Subchondral cancellous bone from the femoral head was obtained at the time of hip arthroplasty from 60 postmenopausal women, 30 with OA and 30 with OP. In each group, 10 specimens were subjected to compressive fatigue loading and 20 were left nonloaded. Specimens were examined by compressive mechanical testing, micro-computed tomography scanning, fluorescence microscopy, and nanoindentation techniques. RESULTS: Both the ultimate stress and the elastic modulus of cancellous bone from OA patients were significantly higher than those of cancellous bone from OP patients (P < 0.05). Compared to cancellous bone from OP patients, the bone volume fraction and trabecular thickness were significantly increased, but bone matrix mineralization was significantly decreased, in cancellous bone from OA patients (P < 0.05 for each comparison). The microcrack density was significantly higher in OP cancellous bone than in OA cancellous bone (P < 0.001), irrespective of fatigue loading. In addition, fatigue loading resulted in a significant increase in microcrack density in both OA and OP cancellous bone (P < 0.001). There was no significant difference in nanoindentation elastic modulus and hardness between cancellous bone from OA and OP patients, as well as between bones with and without fatigue loading. CONCLUSION: The difference in mechanical properties between OA and OP cancellous bone is attributed to different bone mass and bone structure. OP cancellous bone is susceptible to fatigue damage due to insufficient structure. However, increased bone volume and plate-like structure provide OA cancellous bone a superior capacity to resist fatigue damage.

Correlation of synovial fluid HMGB-1 levels with radiographic severity of knee osteoarthritis.

PURPOSE: This study measured high-mobility group box 1 (HMGB-1) levels in serum and synovial fluid (SF) in patients with primary knee osteoarthritis (OA) and correlated these levels with radiographic disease severity. METHODS: Seventy-eight OA patients and 30 controls were enrolled in this study. All OA patients were scored according to the Kellgren-Lawrence (KL) grading system. HMGB-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: SF HMGB-1 levels were significantly higher in knee OA patients, compared with controls (P < 0.01). Moreover, SF HMGB-1 levels were positively associated with KL scores (P < 0.01). Multinomial logistic regression demonstrated that the SF HMGB-1 level was an independent factor for radiographic severity of OA (P=0.002); however, serum HMGB-1 levels did not differ significantly between OA patients and controls and did not correlate with KL scores (P > 0.05). CONCLUSION: These results demonstrate that HMGB-1 levels in SF of knee OA patients are independently associated with radiographic disease severity.

Small-animal PET/CT assessment of bone microdamage in ovariectomized rats.

UNLABELLED: Microdamage in bone contributes to bone fragility in postmenopausal women. Therefore, it is important to find a noninvasive method to detect microdamage in living bone. PET with (18)F-fluoride has been used for skeletal imaging in clinical studies. However, few studies are undertaken to investigate bone microdamage associated with osteoporosis in vivo using noninvasive means. The aim of our study was to analyze the impact of osteoporosis due to estrogen deficiency on the occurrence of microdamage by observing the change in the uptake of (18)F-fluoride in the tibiae of ovariectomized rats after fatigue loading with small-animal PET/CT. We also explored the feasibility of noninvasive detection of bone microdamage in vivo using a small-animal PET/CT scanner specially designed for rodent study. METHODS: Rats were randomized into 2 groups: ovariectomy and sham surgery. These rats were imaged using a dedicated small-animal PET scanner with (18)F-fluoride after the left tibiae were loaded cyclically under the axial compression. The fluoride uptake values were quantified in the tibial mid shafts, and the tibia was obtained for histomorphometric measurements of bone microdamage and osteocyte density. Bone mineral density at the fourth lumbar vertebra and right femur were measured using dual-energy x-ray absorptiometry. RESULTS: PET image intensity was significantly increased (P < 0.05) in the loaded tibia of the ovariectomy group, compared with that of the sham group. Histomorphometry showed that both crack density and crack length in the loaded tibia were significantly higher (P < 0.05) in ovariectomized rats than in sham rats. The PET image intensity in the loaded tibia was significantly positively correlated with crack length and crack density (which show in histomorphometric measurement) (P < 0.05). CONCLUSION: Both small-animal PET/CT and histomorphometric measurement provided evidence that bone microdamage is significantly increased after estrogen depletion. The strong correlation between these 2 measurements suggests that small-animal PET/CT is a useful noninvasive means to detect bone microdamage in vivo.

Surgical treatment of scoliosis associated with Marfan syndrome by using posterior-only instrumentation.

Surgical treatment of scoliosis associated with Marfan syndrome poses a challenge to spine surgeons. This retrospective study was undertaken to determine whether posterior-only surgery with instrumented fixation and fusion addresses the correction of scoliosis and maintains curve correction. Twelve consecutive patients with Marfan syndrome were treated between 2002 and 2007 for scoliosis by posterior segmental instrumentation using pedicle screws or hybrid thoracic-hook and lumbar-screw constructs. Their preoperative Cobb angle averaged 66 ± 10° (range: 55-90°). The average operation time was 252 ± 36 min (range: 200-300 min) and the average blood loss was 690 ± 117 ml (range: 550-920 ml). No significant complications were found. All the patients were followed for a minimum of 2 years (range: 2.4-6.8 years). The average Cobb angle was corrected to 23 ± 8° (range: 13-35°) immediately after surgery and 28 ± 9° (range: 14-43°) with a correction rate of 58 ± 13% at final follow-up. The results indicate that posterior-only surgery with instrumented fixation and fusion is effective and safe for the treatment of scoliosis in selected patients with Marfan syndrome.

Identification of the target for therapeutic recombinant anti-apoB-100 peptide antibodies in human atherosclerotic lesions.

PURPOSE: Accumulation of oxidized LDL in the arterial wall is believed to play a key role in the development of atherosclerosis. Experimental studies have identified the presence of immune responses against epitopes in oxidized LDL that protects against atherosclerosis. We have produced human recombinant IgG against one of these epitopes (aldehyde-modified apoB-100 amino acids 661-680) and demonstrated that treatment with this human IgG1 2D03 antibody markedly reduces atherosclerosis in hypercholesterolemic mice. METHODS: In the present study, we screened a panel of 25 carotid plaques associated with clinical symptoms and 26 clinically silent plaques obtained at surgery for presence of the aldehyde-modified apoB-100 peptide defined by the 2D03 antibody and compared the expression of this epitope with other plaque constituents, plasma lipoproteins levels, plasma oxidized LDL and autoantibodies against apoB-100 peptides. RESULTS: We demonstrated that the epitope is commonly expressed in human atherosclerotic plaques and that plaques associated with clinical symptoms have an almost three-fold higher content of this epitope (8.6+/-4.9% versus 22.1+/-12.2% immunostaining of total plaque area, p<0.0005). There was also a significant association between 2D03 epitope staining and the plaque content of cholesterol esters (r=0.43, p<0.05), whereas there was no association with plasma oxidized LDL and autoantibodies against apoB-100 peptides. CONCLUSIONS: By demonstrating the presence of the 2D03 epitope in human atherosclerotic lesions our findings support the possibility that treatment with this antibody may have beneficial effects also in humans. Furthermore, they suggest the possibility to use these or other similar antibodies for diagnostic imaging of atherosclerotic plaques in humans.