Bergamottin (Ber) ameliorates the progression of osteoarthritis via the Sirt1/NF-κB pathway.

Osteoarthritis (OA) is a common chronic disease characterized by progressive cartilage degeneration and secondary synovial inflammation. Bergamottin (Ber) is an important natural derivative of the furanocoumarin compound, extracted from natural foods, such as the pulp of grapefruits and pomelos. Ber exhibits several characteristicsthat are beneficial to human health, such as anti-inflammation, antioxidant, and anti-cancer effects. However, the role of Ber in the treatment of OA has not been elucidated to date. Therefore, in the present study, in vitro experiments were conducted, which demonstrated that Ber reduces the secretion of inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) under the stimulation of interleukin-1ß (IL-1ß). Ber also reversed the IL-1 ß-mediated aggrecan and type II collagen degradation within the extracellular matrix (ECM). In addition, in vivo experiments were conducted, in which Ber ameliorated the progression of OA in mice. It was revealed that Ber exerted its cellular effect by activating the Sirt1/NF-kB pathways. In conclusion, the present study demonstrated the therapeutic potential of Ber in the context of OA.

Procyanidin B2 regulates the Sirt1/Nrf2 signaling pathway to improve random-pattern skin flap survival.

Random-pattern skin flaps have been widely used in the reconstruction of damaged tissues. Ischemia-reperfusion injury occurring in the distal regions of the flap is a common issue, which often leads to flap necrosis and restricts its clinical applications. Procyanidin B2 (PB2), a naturally occurring flavonoid in large quantities in various fruits, has been demonstrated to exhibit several significant pharmacological properties. However, the effect of PB2 on flap viability is not clearly known. Here, using Western blot analysis, immunohistochemistry, and immunofluorescence staining, we observed that PB2 significantly reduced oxidative stress and inflammation and enhanced angiogenesis. Mechanically, we provided evidence for the first time that the beneficial effects of PB2 occur through the activation of the Sirt1/Nrf2 signaling pathway. Moreover, co-administration of PB2 and EX527, a selective inhibitor of Sirt1, resulted in down-regulation of the expression of Sirt1, Nrf2, and downstream antioxidants. In summary, our study showed that PB2 might be a novel therapeutic strategy for improving the survival of random-pattern skin flaps.

ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death.

Rationale: The development of a highly effective and tumor-specific therapeutic strategy, which can act against the primary tumor and also condition the host immune system to eliminate distant tumors, remains a clinical challenge. Methods: Herein, we demonstrate a facile yet versatile ZnO-capping and Doxorubicin (DOX)-loaded multifunctional nanocomposite (AuNP@mSiO2@DOX-ZnO) that integrates photothermal properties of gold nanoparticles (NPs), pH-responsive properties and preferential selectivity to tumor cells of ZnO QDs and chemotherapeutic agent into a single NP. The photothermal performance, pH-triggered release and preferential phagocytic ability were assessed. The induced anti-tumor immunity was determined by analyzing immune cell profile in tumor in vivo and molecular mechanism were identified by detecting expression of immunogenic cell death (ICD) markers in vitro. Moreover, mice models of unilateral and bilateral subcutaneous melanoma and lung metastasis were established to evaluate the antitumor effects. Results: As an efficient drug carrier, ZnO-capped NPs guarantee a high DOX payload and an in vitro, efficient release of at pH 5.0. In murine melanoma models, the nanocomposite can significantly inhibit tumor growth for a short period upon low-power laser irradiation. Importantly, ZnO NPs not only demonstrate preferential selectivity for melanoma cells but can also induce ICD. Meanwhile, AuNP@mSiO2-based photothermal therapy (PTT) and DOX are directly cytotoxic towards cancer cells and demonstrate an elevated ICD effect. The induced ICD promotes maturation of dendritic cells, further stimulating the infiltration of effector T cells into tumor sites, preventing tumor growth and distant lung metastases. Conclusions: This study highlights the novel mechanism of ZnO-triggered anti-tumor immunity via inducing ICD. Additionally, we shed light on the multifunctionality of nanocomposites in delivering localized skin tumor therapy as well as inhibiting metastatic growth, which holds great promise in clinical applications.

Comparison between Percutaneous Screw Fixation and Plate Fixation via Sinus Tarsi Approach for Calcaneal Fractures: An 8-10-Year Follow-up Study.

OBJECTIVE: To assess the long-term outcomes after percutaneous reduction (PR) and screw fixation versus plate fixation via the sinus tarsi approach (STA) for displaced intra-articular calcaneal fractures (DIACF). METHODS: This retrospective study included a total of 150 patients (June 2008-August 2011), comprising 85 men and 65 women (mean age, 38.4 years), who were assigned to the PR group or the STA group. The inclusion criteria were DIACF (>2 mm) including Sanders type II and III, closed fracture, unilateral fracture, no history of smoking or no smoking during hospitalization and 3 months after surgery, and follow-up time not less than 8 years. The exclusion criteria were clear surgical contraindications (severe cardiovascular and cerebrovascular diseases), local or systemic infection symptoms, diagnosis with diabetes or lower extremity vascular disease, and Sanders type IV or open fractures. Outcomes were assessed by means of the American Orthopedic Foot and Ankle Society (AOFAS) hindfoot scores, radiographic images, and postoperative complications. RESULTS: The mean follow-up period was 8.7 years (range, 8.0-10.0 years). The AOFAS scores in the PR group during the follow-up period were 54.2 ± 5.1, 85.8 ± 4.0, 88.1 ± 3.8, 87.9 ± 3.6, 87.8 ± 3.9, 86.9 ± 3.9, respectively, and in the STA group were 55.0 ± 5.6, 84.5 ± 5.2, 87.1 ± 3.8, 86.9 ± 3.8, 87.7 ± 3.3, and 87.6 ± 2.8, respectively. There was no significant difference in AOFAS scores, Bohler's angle, Gissane's angle, calcaneal length, and height between the two groups (P > 0.05). The good to excellent rate of the PR group (80.8%) was less than that of the STA group (91.7%) (P = 0.055). For Sanders III fractures, the good to excellent rate of the PR group (33.3%) was less than that of the STA group (76.9%) (P = 0.029). For calcaneal width recovery, the STA group performed better than the PR group (P < 0.05). The incidence of postoperative complications in the PR group (12.8%) was lower than that in the STA group (27.8%) (P = 0.026), of which the incidence of wound complications was 3.8% in the PR group and 13.9% in the STA group (P = 0.041). In addition, there was no significant difference in other postoperative complications such as sural nerve injury, peroneus longus and brevis muscle injury, calcaneal valgus symptoms, lateral impingement symptoms, and subtalar arthritis (P > 0.05). CONCLUSION: From the 8-10-year follow-up results of PR and STA as surgical procedures for the treatment of DIACF, it was found that there was no significant difference in the overall efficacy between them. STA was found to be superior to the PR in terms of the recovery of calcaneal width, providing more stable fixation for Sanders III fractures. PR was found to be more effective in reducing wound complications.

A Comparative Study of Finger Pulp Reconstruction Using Free Distal Ulnar Artery Perforator Flaps and Reverse Dorsal Homodigital Island Flaps.

PURPOSE: This study aimed to compare and analyze the outcomes of finger reconstruction using free distal ulnar artery perforator (FDUAP) and reverse dorsal homodigital island (RDHI) flaps. METHODS: The study included 27 patients with finger pulp defects that were reconstructed using FDUAP or RDHI flaps. Standardized assessment of outcomes included objective sensory recovery, duration of operation, range of motion in the repaired fingers, pain at the reconstructed finger pulps and donor sites, and recovery time before returning to work. Subjective assessment of outcomes included the cold intolerance, aesthetic appearance, and functional recovery. RESULTS: All flaps in the series showed complete survival. The average surgical time for the RDHI flaps was significantly smaller than that for the FDUAP flaps. Sensory recovery was significantly better with FDUAP flaps than with RAHI flaps. No significant differences were detected between the 2 procedures regarding range of motion, cold intolerance, or pain of the injured finger pulps and donor sites. The outcomes of aesthetic result and functional recovery satisfied all patients. Optimal cosmetic satisfaction was obtained in the FDUAP flap group. CONCLUSIONS: Although both types of flaps offer a satisfactory approach for finger reconstruction with small-to-medium defects, FDUAP flaps are more suitable for such operations because of the better sensory reconstruction and aesthetic results.

Effects of adiponectin on random pattern skin flap survival in rats.

BACKGROUND: Random flaps are commonly used to repair wounds and improve the clinical appearance. However, flap necrosis is frequently encountered in the clinical setting. Adiponectin is a biologically active endogenous polypeptide secreted by adipocytes that can reduce oxidative stress, inflammation, and apoptosis. This study was performed to explore the effects of adiponectin on the survival of random flaps in rats. MATERIALS AND METHODS: Thirty-six healthy rats were divided into two groups, i.e., an adiponectin group and a control group. A modified McFarlane flap was created on the backs of the rats. The area of flap survival was gauged after sacrifice of the rats on day 7 after surgery, and the tissue samples were subjected to histological analysis. Angiogenesis was assessed by oxide-gelatin angiography, laser Doppler imaging, and immunohistochemistry. Pathological changes in the flaps were examined by hematoxylin and eosin staining. The level of oxidative stress was evaluated using malondialdehyde (MDA) and superoxide dismutase (SOD) kits. RESULTS: The adiponectin group had a larger tissue survival area and less edema compared with the control group. VEGF expression and SOD activity were markedly increased, but the MDA level was significantly decreased, in the adiponectin group. Histological analysis showed that adiponectin promoted angiogenesis and inhibited inflammation. CONCLUSIONS: Adiponectin is useful for improving random skin flap survival.

Apoptotic cell-mimicking gold nanocages loaded with LXR agonist for attenuating the progression of murine systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

Effects of curculigoside A on random skin flap survival in rats.

Necrosis in distal areas of random skin flaps remains a challenging issue. Curculigoside A (CA), one of the main bioactive phenolic compounds, has been reported to induce angiogenesis in vitro by increasing proliferation, tube formation, and migration. In addition, CA was shown to increase vascular endothelial growth factor (VEGF) expression. In this study, we investigated the potential use of CA as a novel candidate to enhance the viability of the ischemic skin flap. A modified McFarlane flap was used as a surgical model in Sprague-Dawley rats. Three groups of rats were treated as follows: the control group received 0.9% saline orally, while rats in the two treatment groups were administered 10 mg/kg or 20 mg/kg CA orally for 7 days, respectively. On day7, the mice were killed, and tissue samples were collected for hematoxylin and eosin staining and immunohistochemical examination, while laser Doppler imaging and oxide-gelatin angiography were performed to assess angiogenesis. Kits for the analysis of superoxide dismutase (SOD) and malondialdehyde (MDA) were used to verify the oxidative stress level. Treating animals with CA significantly increased the surviving portion of the flaps. VEGF and SOD expression and microvessel development were markedly increased, and the MDA level was reduced, in the CA treatment groups. Histological studies demonstrated that CA promoted angiogenesis and attenuated inflammatory cell numbers. These findings indicated that CA increases random skin flap survival.

Naringin improves random skin flap survival in rats.

BACKGROUND: Random-pattern flap transfer is commonly used to treat soft-tissue defects. However, flap necrosis remains a serious problem. Naringin accelerates angiogenesis by activating the expression of vascular endothelial growth factor (VEGF). In the present study, we investigated whether naringin improves the survival of random skin flaps. RESULTS: Compared with controls, the naringin-treated groups exhibited significantly larger mean areas of flap survival, significantly increased SOD activity and VEGF expression, and significantly reduced MDA level. Hematoxylin and eosin (HE) staining revealed that naringin promoted angiogenesis and inhibited inflammation. MATERIALS AND METHODS: "McFarlane flap" models were established in 90 male Sprague-Dawley (SD) rats divided into three groups: a 40 mg/kg control group (0.5 % sodium carboxymethylcellulose), a 40 mg/kg naringin-treated group, and an 80 mg/kg naringin-treated group. The extent of necrosis was measured 7 days later, and tissue samples were subjected to histological analysis. Angiogenesis was evaluated via lead oxide-gelatin angiography, immunohistochemistry, and laser Doppler imaging. Inflammation was evaluated by measurement of serum TNF-α (tumor necrosis factor-α) and IL-6 (interleukin-6) levels. Oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and the malondialdehyde (MDA) level. CONCLUSION: Naringin improved random skin flap survival.

Reciprocal negative feedback loop between EZH2 and miR-101-1 contributes to miR-101 deregulation in hepatocellular carcinoma.

Although the tumor suppressive role of miR-101 is well documented in hepatocellular carcinoma (HCC), how the expression of miR-101 itself is regulated remains elusive. In the present study, we demonstrated that the miR-101 precursor pre-miR-101-1 could be regulated by an important epigenetic regulator, the enhancer of zeste homolog 2 (EZH2). Reporter gene assays revealed that ectopic expression of EZH2 inhibited the transcriptional activities of miR-101-1 promoter. Subsequent analyses revealed that miR-101-1 directly represses the expression of EZH2, and miR-101-1 and EZH2 form a reciprocal negative feedback loop as indicated by the fact that ectopic mature miR-101 could induce endogenous pre-miR-101-1 expression. This mature miR-101-induced pre-miR-101 expression was specific to pre-miR-101-1 and depended on EZH2 activities. Moreover, our results also demonstrated that similar antitumor effects can be achieved either by ectopic miR-101 or EZH2 silencing in HCC cells. These findings show that elevated EZH2 contributes to miR-101 deregulation in HCC and highlight the coordinated role of miR-101 and EZH2 in hepatocarcinogenesis.