PDGF-BB prevents destructive repair and promotes reparative osteogenesis of steroid-associated osteonecrosis of the femoral head in rabbits.

Destructive repair characterized by inadequate angiogenesis and osteogenesis is the main pathological progression in steroid-associated osteonecrosis of the femoral head (SONFH). Platelet-derived growth factor-BB (PDGF-BB) is an "angiogenesis and osteogenesis coupling" factor that has been used for the treatment of bone defects in clinic. This study was designed to analyze the ability of PDGF-BB for preventing destructive repair and promoting reparative osteogenesis in SONFH. Steroid-associated osteonecrosis (SAON) was induced and triggered destructive repair of the femoral head by repeated lipopolysaccharide (LPS) and methylprednisolone (MPS) injections in rabbits. At 2, 4, and 6 weeks after induction, recombinant human PDGF-BB, neutralizing PDGF-BB antibody, or saline was intramedullary injected into the proximal femora. At week 6 after SAON induction, the proximal femora were dissected for bone architecture and histological analysis. C3H10T1/2 cells and HUVECs were used for further mechanistic investigation. After PDGF-BB treatment, type H vessels and leptin receptor-positive (LepR+) mesenchymal stem cells (MSCs) increased in the affected femoral head, and more osteoblastic osteogenesis along the bone surfaces but scattered adipocytes in bone marrow tissue than that in the SAON group. PDGF-BB treatment prevented destructive repair progression and led to 50-70 % of osteonecrotic femoral heads undergoing reparative osteogenesis. In particular, we found that PDGF-BB could mediate MSC self-renewal and maintain their osteogenic potency by activating PDGFR/Akt/GSK3ß/CERB signaling in the presence of steroids. Moreover, PDGF-BB also stabled the newly formed vascular tubes by recruiting MSCs for improving intraosseous vascular integration. PDGF-BB may be a candidate for the promotion of reparative osteogenesis in SONFH.

Puerarin specifically disrupts osteoclast activation via blocking integrin-ß3 Pyk2/Src/Cbl signaling pathway.

OBJECTIVE: Given the limitations of current anti-resorption agents for postmenopausal osteoporosis, there is a need for alternatives without impairing coupling crosstalk between bone resorption and bone formation ie. osteoclastogenesis. Puerarin, a unique C-glycoside isoflavonoid, was found to be able to prevent bone loss by inhibiting bone resorption, but the underlying mechanism was controversial. In this study, we investigated the effects of puerarin on osteoclastic differentiation, activation and bone resorption and its underlying molecular mechanism in vitro, and then evaluated the effects of puerarin on bone metabolism using an ovariectomized (OVX) rat model. METHODS: In vitro, the effect of puerarin on osteoclastic cytotoxicity, differentiation, apoptosis, activation and function were studied in raw 264.7 â€‹cells and mouse BMMs. Mechanistically, osteoclast-related makers were determined by RT-PCR, western blot, immunofluorescence, and kinase activity assay. In vivo, Micro-CT, histology, serum bone biomarker, and mechanical testing were used to evaluate the effects of puerarin on preventing osteoporosis. RESULTS: Puerarin significantly inhibited osteoclast activation and bone resorption, without affecting osteoclastogenesis or apoptosis. In terms of mechanism, the expressions of protein of integrin-ß3 and phosphorylations of Src, Pyk2 and Cbl were lower in puerarin group than those in the control group. Oral administration of puerarin prevented OVX-induced trabecular bone loss and significantly improved bone strength in rats. Moreover, puerarin significantly decreased trap positive osteoclast numbers and serum TRAP-5b, CTx1, without affecting bone formation rate. CONCLUSIONS: Collectively, puerarin prevented the bone loss in OVX rat through suppression of osteoclast activation and bone resorption, by inhibiting integrin-ß3-Pyk2/Cbl/Src signaling pathway, without affecting osteoclasts formation or apoptosis. TRANSLATIONAL POTENTIAL OF THIS ARTICLE: These results demonstrate the unique mechanism of puerarin on bone metabolism and provide a novel agent for prevention of postmenopausal osteoporosis.

3D-bioprinted BMSC-laden biomimetic multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model.

Osteochondral defect repair in osteoarthritis (OA) remains an unsolved clinical problem due to the lack of enough seed cells in the defect and chronic inflammation in the joint. To address this clinical need, we designed a bone marrow-derived mesenchymal stem cell (BMSC)-laden 3D-bioprinted multilayer scaffold with methacrylated hyaluronic acid (MeHA)/polycaprolactone incorporating kartogenin and ß-TCP for osteochondral defect repair within each region. BMSC-laden MeHA was designed to actively introduce BMSCs in situ, and diclofenac sodium (DC)-incorporated matrix metalloproteinase-sensitive peptide-modified MeHA was induced on the BMSC-laden scaffold as an anti-inflammatory strategy. BMSCs in the scaffolds survived, proliferated, and produced large amounts of cartilage-specific extracellular matrix in vitro. The effect of BMSC-laden scaffolds on osteochondral defect repair was investigated in an animal model of medial meniscectomy-induced OA. BMSC-laden scaffolds facilitated chondrogenesis by promoting collagen II and suppressed interleukin 1ß in osteochondral defects of the femoral trochlea. Congruently, BMSC-laden scaffolds significantly improved joint function of the injured leg with respect to the ground support force, paw grip force, and walk gait parameters. Therefore, this research demonstrates the potential of 3D-bioprinted BMSC-laden scaffolds to simultaneously inhibit joint inflammation and promote cartilage defect repair in OA joints.

Dual-Depletion of Intratumoral Lactate and ATP with Radicals Generation for Cascade Metabolic-Chemodynamic Therapy.

Increasing evidence has demonstrated that lactate and adenosine triphosphate (ATP) both play important roles in regulating abnormal metabolism in the tumor microenvironment. Herein, an O2 self-supplying catalytic nanoagent, based on tannic acid (TA)-Fe(III) coordination complexes-coated perfluorooctyl bromide (PFOB) nanodroplets with lactate oxidases (LOX) loading (PFOB@TA-Fe(III)-LOX, PTFL), is designed for cascade metabolic-chemodynamic therapy (CDT) by dual-depletion of lactate and ATP with hydroxyl • OH radicals generation. Benefiting from the catalytic property of loaded LOX and O2 self-supplying of PFOB nanodroplets, PTFL nanoparticles (NPs) efficiently deplete tumoral lactate for down-regulation of vascular endothelial growth factor expression and supplement the insufficient endogenous H2 O2 . Simultaneously, TA-Fe(III) complexes release Fe(III) ions and TA in response to intracellular up-regulated ATP in tumor cells followed by TA-mediated Fe(III)/Fe(II) conversion, leading to the depletion of energy source ATP and the generation of cytotoxic • OH radicals from H2 O2 . Moreover, TA-Fe(III) complexes provide photoacoustic contrast as imaging guidance to enhance therapeutic accuracy. As a result, PTFL NPs efficiently accumulate in tumors for suppression of tumor growth and show evidence of anti-angiogenesis and anti-metastasis effects. This multifunctional nanoagent may provide new insight for targeting abnormal tumor metabolism with the combination of CDT to achieve a synergistic therapeutic effect.

Resection of the gastric submucosal tumor (G-SMT) originating from the muscularis propria layer: comparison of efficacy, patients' tolerability, and clinical outcomes between endoscopic full-thickness resection and surgical resection.

BACKGROUND AND AIMS: Endoscopic full-thickness resection (EFTR) has been increasingly applied in the treatment of gastric submucosal tumors (G-SMTs) with explorative intention. This study aimed to compare the efficacy, tolerability, and clinical outcomes of EFTR and surgical intervention for the management of muscularis propria (MP)-derived G-SMTs. METHODS: Between September 2011 and May 2019, the clinical records of patients with MP-derived G-SMTs undergoing EFTR at our endoscopic unit were collected. A cohort of people with primary MP-derived G-SMTs treated by surgery was matched in a 1:1 ratio to EFTR group with regard to patients' baseline characteristics, clinicopathologic features of the tumor and the procedure date. The perioperative outcomes and follow-up data were analyzed. RESULTS: In total, 62 and 62 patients were enrolled into the surgery and EFTR group, respectively, with median follow-up of 786 days. The size of G-SMTs (with ulceration) ranged from 10 to 90 mm. For patients with tumor smaller than 30 mm, surgery and EFTR group presented comparable procedural success rate (both were 100%), en bloc resection rate (100% vs. 94.7%), tumor capsule rupture rate (0% vs. 5.3%), and pathological R0 resection rate (both were 100%). EFTR had a statistically significant advantage over surgery for estimated blood loss (3.12 ± 5.20 vs. 46.97 ± 60.73 ml, p ≤ 0.001), discrepancy between the pre- and postprocedural hemoglobin level (5.18 ± 5.43 vs. 9.84 ± 8.25 g/L, p = 0.005), bowel function restoration [1 (0-5) vs. 3 (1-5) days, p ≤ 0.001], and hospital cost (28,617.09 ± 6720.78 vs. 33,963.10 ± 13,454.52 Yuan, p = 0.033). The patients with tumor larger than 30 mm showed roughly the same outcomes after comparison analysis of the two groups. However, the clinical data revealed lower en bloc resection rate (75.0% vs. 100%, p = 0.022) and higher tumor capsule rupture rate (25.0% vs. 0%, p = 0.022) for EFTR when compared to surgery. The procedure time, duration of postprocedural fasting and antibiotics usage, and hospital stay of the two groups were equivalent. The occurrence rate of adverse events within postoperative day 7 were 74.2% and 72.6% after EFTR and surgery, respectively (p = 1.000). No complications occurred during the follow-up. CONCLUSION: For treatment of MP-derived G-SMTs (with or without ulceration), our study showed the feasibility and safety of EFTR, which also provided better results in terms of procedural blood loss, the postoperative bowel function restoration and cost-effectiveness when compared to surgery, whereas the surgery was superior in en bloc resection rate for G-SMTs larger than 30 mm. The postprocedural clinical outcomes seemed to be equivalent in these two resection methods.

Blockage of ETS homologous factor inhibits the proliferation and invasion of gastric cancer cells through the c-Met pathway.

BACKGROUND: Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, but its exact pathogenesis has not been fully elucidated. ETS homologous factor (EHF) is an important member of the ETS family and contributes to the pathogenesis of multiple malignant tumors. To date, whether EHF participates in the development of GC via the c-Met signaling pathway remains unclear. AIM: To investigate the role and mechanism of EHF in the occurrence and development of GC. METHODS: The expression of EHF mRNA in GC tissues and cell lines was measured by quantitative PCR. Western blotting was performed to determine the protein expression of EHF, c-Met, and its downstream signal molecules. The EHF expression in GC tissues was further detected by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNA (siRNA) against EHF was transfected into GC cells. The cell proliferation of GC cells was determined by Cell Counting Kit-8 and colony formation assays. Flow cytometry was performed following Annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. Cell migration and invasion were assessed by transwell assays. RESULTS: The data showed that EHF was upregulated in GC tissues and cell lines in which increased expression of c-Met was also observed. Silencing of EHF by siRNA reduced the proliferation of GC cells. Inhibition of EHF induced significant apoptosis and cell cycle arrest in GC cells. Cell migration and invasion were significantly inhibited. EHF silencing led to c-Met downregulation and further blocked the Ras/c-Raf/extracellular signal-related kinase 1/2 (Erk1/2) pathway. Additionally, phosphatase and tensin homolog was upregulated and glycogen synthase kinase 3 beta was deactivated. Moreover, inactivation of signal transducer and activator of transcription 3 was detected following EHF inhibition, leading to inhibition of the epithelial-to-mesenchymal transition (EMT). CONCLUSION: These results suggest that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway. Therefore, EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.

Systematic review with network meta-analysis: dual therapy for high-risk bleeding peptic ulcers.

BACKGROUND: Adding a second endoscopic therapy to epinephrine injection might improve hemostatic efficacy in patients with high-risk bleeding ulcers but the optimum modality remains unknown. We aimed to estimate the comparative efficacy of different dual endoscopic therapies for the management of bleeding peptic ulcers through random-effects Bayesian network meta-analysis. METHODS: Different databases were searched for controlled trials comparing dual therapy versus epinephrine monotherapy or epinephrine combined with another second modality until September, 30 2016. We estimated the ORs for rebleeding, surgery and mortality among different treatments. Adverse events were also evaluated. RESULTS: Seventeen eligible articles were included in the network meta-analysis. The addition of mechanical therapy (OR 0.19, 95% CrI 0.07-0.52 and OR 0.10, 95% CrI 0.01-0.50, respectively) after epinephrine injection significantly reduced the probability of rebleeding and surgery. Similarly, patients who received epinephrine plus thermal therapy showed a significantly decreased rebleeding rate (OR 0.30, 95% CrI 0.10-0.91), as well as a non-significant reduction in surgery (OR 0.47, 95% CrI 0.16-1.20). Although differing, epinephrine plus mechanical therapy did not provide a significant reduction in rebleeding (OR 0.62, 95% CrI 0.19-2.22) and surgery (OR 0.21, 95% CrI 0.03-1.73) compared to epinephrine plus thermal therapy. Sclerosant failed to confer further benefits and was ranked highest among the 5 treatments in relation to adverse events. CONCLUSIONS: Mechanical therapy was the most appropriate modality to add to epinephrine injection. Epinephrine plus thermal coagulation was effective for controlling high risk bleeding ulcers. There was no further benefit with sclerosants with regard to rebleeding or surgery, and sclerosants were also associated with more adverse events than any other modality.

Prophylactic stenting for esophageal stricture prevention after endoscopic submucosal dissection.

Endoscopic submucosal dissection (ESD) of superficial esophageal cancer has been increasingly used as an alternative to surgery because it is minimally invasive and has a high rate of en bloc resection. However, a high rate of esophageal stricture is observed after ESD for large lesions, which can dramatically decrease the patient's quality of life. Stricture prevention is necessary to allow for endoscopic therapy to expand. We, herein, review the most recent evidence and discuss the role of the metallic self-expandable stent and the biodegradable stent in esophageal stricture prevention. Limited studies suggested that prophylactic stenting could reduce the stricture rate without increasing the number of complications. In addition, the number of bougie dilation procedures was significantly lower with stent placement. Esophageal stenting is a promising option for post-ESD stricture prevention. However, current evidence is too preliminary to formulate practice standards. Future studies are needed to further validate the efficacy and safety of prophylactic stenting and determine the best strategy for stricture prevention. Stent migration is the most common complication. A new stent that has advantages of a low migration rate and minimal tissue reaction will need to be developed. Therefore, randomized controlled trials with long-term follow-up periods are required before prophylactic stenting could be considered a valid option to prevent post-ESD stricture.