Cereblon (CRBN) deletion reverses streptozotocin induced diabetic osteoporosis in mice.

Diabetes mellitus is a major cause to induce osteoporosis. Though the pathogenesis of osteoporosis progression has been well investigated, its still not fully understood. Recently, cereblon (CRBN) was considered as a negative modulator of adenosine monophosphate-activated protein kinase (AMPK) in vitro and in vivo. Here, we presented results indicating that CRBN could effectively regulate osteoporosis development. In STZ-induced wild type (WT) mice with diabetes, the osteoclasts were highly increased along with the deterioration of bone structure. However, CRBN knockout (KO) reduced blood glucose the levels and attenuated insulin resistance. What's more, CRBN ablation suppressed osteoclast differentiation and rescued diabetic bone loss in vivo, accompanied with decreased receptor activator of NF-kB ligand (RANKL), RANKL/osteoprotegerin (OPG), and tartrate-resistant acid phosphatase (TRAP) levels, as well as improved AMP-activated kinase (AMPK) α/acetyl-CoA carboxylase (ACC)αactivation. In vitro, suppressing CRBN expression could reduce RANKL-induced osteoclastogenesis, supported by the reduction of TRAP-positive cells. CRBN knockdown (KD) obviously reduced RANKL-induced activity of IκBα/nuclear factor-κB (NF-κB) pathway. In addition, osteoclast-specific genes expression levels stimulated by RANKL were also decreased by CRBN silence. More importantly, CRBN blockage increased phosphorylated AMPK-α and ACC-α expressions in RANKL-incubated cells. However, these processes could be abolished by suppressing AMPK-α with its inhibitor, Compound C. Collectively, our data suggested that CRBN is a potential treatment option against diabetes-induced osteolytic bone disease.

A network meta-analysis of short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma.

The network meta-analysis was conducted to compare the short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma (RCC). We initially searched databases for randomized controlled trials (RCTs) on different single-drug targeted therapies in treating RCC. The meta-analysis combined the direct and indirect evidence to calculate the pooled odds ratios (OR) and draw surface under the cumulative ranking curves (SUCRA). A total of 14 eligible RCTs were ultimately selected. The partial response (PR) of Cabozantinib in the treatment of RCC was better than Sunitinib (OR = 2.7, 95%CI = 1.0-7.8), Everolimus (OR = 8.1, 95%CI = 3.1-25.0), and Temsirolimus (OR = 4.8, 95%CI = 1.0-31.0); the overall response rate (ORR) of Cabozantinib was better than Sorafenib, Sunitinib, Everolimus, and Temsirolimus (OR = 5.5, 95%CI = 1.1-27.0; OR = 2.6, 95%CI = 1.1-6.6; OR = 8.3, 95%CI = 3.5-20.0; OR = 5.7, 95%CI = 1.3-28.0 respectively). In addition, as for complete response (CR), PR, stable disease (SD), progressive disease (PD), ORR, and disease control rate (DCR), Cabozantinib had the best short-term efficacy among nine single-drug targeted therapies in the treatment of RCC (CR: 50.3%; PR: 93.6%; SD: 75.1%; PD: 68.0%; ORR: 95.5%; DCR: 73.2%); while Everolimus had the worst short-term efficacy (CR: 33.6%; PR: 22.3%; SD: 78.0%; PD: 35.9%; ORR: 22.9%; DCR: 19.9%). Our network meta-analysis indicated that Cabozantinib might have better short-term efficacy than other regimens in the treatment of RCC, while Everolimus might have poor short-term efficacy.

Neuroprotective Effect of Matrine in Mouse Model of Vincristine-Induced Neuropathic Pain.

Chemotherapy drugs such as vincristine (VCR) can cause neuropathic pain, and there is still lack of ideal strategy to treat it. The current study was designed to investigate effect of matrine (MT) on VCR-induced neuropathic pain in animal model. VCR (75 µg/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy model in mice. MT (15, 30 and 60 mg/kg, i.p.) and pregabalin (10 mg/kg, i.p.) were administered for 11 consecutive days. Various tests were performed to assess the degree of pain at different days (1, 6, 11, 16, and 21). Von Frey hair, hot plate, cold-plate and paw pressure tests were conducted to assess the degree of mechanical allodynia, thermal hyperalgesia, cold allodynia and mechanical hyperalgesia in the hind paw respectively. The electrophysiological and histopathological changes were also analyzed. Furthermore, tissue malondialdehyde (MDA), total antioxidant capacity (T-AOC),superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total calcium (TCA), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10) were measured to investigate possible involvement of MT in inflammation and oxidative stress. Administration of MT attenuated the VCR-induced behavioral alterations as well as electrophysiological and histopathological changes in a dose dependent manner. Further, MT also attenuated the VCR-induced oxidative stress (MDA, T-AOC, GSH-Px, SOD and TCA) and inflammation (MPO, TNF-α, IL-6 and IL-10). Taken together, MT ameliorated VCR-induced painful neuropathy, which might be attributed to neuroprotective effects by subsequent reduction in oxidative stress and anti-inflammatory actions.

Resveratrol inhibits oligomeric Aß-induced microglial activation via NADPH oxidase.

Microglia­mediated neuroinflammation is key in the pathogenesis of Alzheimer's disease (AD). Several studies have suggested that NADPH oxidase contributes to microglia­mediated neuroinflammation. Resveratrol, which is a natural polyphenolic compound, exerts neuroprotective effects in AD due to its anti­inflammatory properties. The present study aimed to investigate the effects of resveratrol on the activation of oligomeric amyloid ß (oAß)­induced BV­2 microglia, and to determine the role of NADPH oxidase in these effects. Microglial proliferation was measured by high­content screening cell counting and using a bromodeoxyuridine incorporation assay. In addition, the levels of reactive oxygen species (ROS), nitric oxide (NO), tumor necrosis factor (TNF)­α and interleukin (IL)­1ß were assessed. The results of the present study demonstrated that resveratrol inhibited the proliferation of oAß­induced microglia and the production of pro­inflammatory factors, including ROS, NO, TNF­α and IL­1ß. Subsequent mechanistic investigations demonstrated that resveratrol inhibited the oAß­induced mRNA and protein expression levels of p47phox and gp91phox. These results suggested that NADPH oxidase may be a potential target for AD treatment, and resveratrol may be a valuable natural product possessing therapeutic potential against AD.

Oxymatrine attenuated hypoxic-ischemic brain damage in neonatal rats via improving antioxidant enzyme activities and inhibiting cell death.

Oxymatrine (OMT), an active constituent of Chinese herb Sophora flavescens Ait, has been proved to possess anti-tumor, anti-oxidant, anti-inflammatory, and anti-apoptotic activities. Previous study has demonstrated that OMT had protective roles on multiple in vitro and in vivo brain injury models including regulation of apoptosis-related proteins caspase-3, Bax and Bcl-2. In this study, we investigated whether this protective effect could apply to neonatal hypoxic-ischemic brain damage. Seven-day-old Sprague-Dawley rats were treated with the left carotid artery ligation followed by exposure to 8% oxygen (balanced with nitrogen) for 2.5 h at 37 °C. In sham group rats, neither ligation nor hypoxia was performed. After two successive days intraperitoneal injection with OMT (30, 60 and 120 mg/kg), Nimodipine (1 mg/kg), and saline, brain infarct volume was estimated, histomorphology changes were performed by hematoxylin-eosin (HE) staining as well as electron microscopy. In addition, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC), as well as production of malondialdehyde (MDA) were assayed in ipsilateral hemisphere homogenates to evaluate the redox status after hypoxic-ischemic. Expression of apoptosis-related proteins Caspase-3, Bax and Bcl-2 in brain were analyzed by western-blot analysis and immunofluorescence. Administration of OMT significantly decreased brain infarct volume and the percentage of injured cells, and ameliorated histopathology and morphological injury as well. Furthermore, OMT obviously increased the activities of SOD, GSH-Px, CAT and T-AOC, and decreased MDA content. Western-blot analysis showed a marked decrease in Caspase-3 expression and increase in the ratio of Bcl-2/Bax after OMT (120 mg/kg) post-treatment as compared with hypoxic-ischemic group. These results suggest that OMT exerts a neuroprotective effect against hypoxic-ischemic brain damage in neonatal rats, which is likely to be mediated through increasing anti-oxidant enzyme activities and inhibiting cell death.

Occupational safety training and education for needlestick injuries among nursing students in China: intervention study.

OBJECTIVES: To confirm the effect of occupational safety training and education programs (OSTEP) on needlestick injuries (NSIs) among nursing students in China. METHODS: Compare the rates and the nature of NSIs before and after OSTEP among the nursing students in China. Firstly, questionnaires were delivered to 248 randomly selected nursing students from seven training hospitals to obtain basic information concerning relevant occupational NSIs. Then regular intervention measures through OSTEP on 246 nursing students had been introduced for four years. And the resultant information concerning relevant occupational NSIs was obtained afterwards. Finally, the data analysis was performed using SPSS software, version 11.5. RESULTS: The rate of NSIs among these nursing students was relatively high before the OSTEP in China (average, 4.65 events/nurse). However, it decreased rapidly to 0.16 events/nurse average after the OSTEP. Occupational safety awareness and behavior in handling NSIs was improved in China. There was a significant difference in the results of Chi-square value (P<0.005). CONCLUSIONS: NSIs are common in nursing students in China. The OSTEP can reduce NSIs and change practical behavior markedly among nursing students in China. We should perform OSTEP on nurse students before and during the clinical practice. We must also provide effective preventive measures to reduce this kind of problem in future.

[Preparation method of polystyrene core-poly (acrylamide-acrylic acid) shell fluorescent microspheres].

OBJECTIVE: To investigate the preparation method of polystyrene core-poly (acrylamide-acrylic acid) shell fluorescent microspheres. METHODS: The polystyrene core-poly (acrylamide-acrylic acid) shell (P-(St-co-AAM)) fluorescent microspheres were prepared using fluorescent microspheres as the core and acrylamide/acrylic as polymerization monomer. Reaction conditions affecting the morphology of core-shell structure including feeding mode, initiator, cross linker, pH, concentration and swelling were studied. RESULT: Fluorescent microscopy showed that the relatively uniform particle sizes were distributed in a range of 7-8 µm. Fourier transform infra-red spectroscopy (FT-IR) proved the existence of poly (acrylamide-acrylic acid) shell and amide group on the surface. The optimal conditions for seeding polymerization: azobisisobutyronitrile was used as the initiator in the absence of cross linker, after a 40 h swelling treatment by using alcohol with the appropriate reaction temperature (70 degree), reaction time (3 h) and pH(6-7). The average dispersion and stability were 25.14 % and 90.21%, respectively. The fluorescein release percentage was kept stable at approximately 30% after 40 h. CONCLUSION: The fluorescent microspheres prepared by this method have core-shell structure and satisfactory fluorescence properties with good dispersion and stability.

Needlestick injuries among nursing students in China.

OBJECTIVES: To describe and characterize the rates and the nature of needlestick injuries among nursing students in China. METHODS: A questionnaire was delivered to 248 randomly selected nursing students from seven training hospitals to obtain information relevant occupational needlestick injuries. RESULTS: A total of 1144 incidents of needlestick injuries were reported among the 246 nurses during the time period of internship. The overall rate of needlestick injuries among these nurses was 100%, according to this survey. Insufficient awareness of occupational safety and limited work experience with handling needlestick injuries in these nurse students were significantly reported. In addition, when stratified by departments, the highest rate of needlestick injuries was seen in the surgery department. The occurrence of needlestick injuries is significantly related to clinical practice behaviors. CONCLUSIONS: Needlestick injuries are commonly reported in nursing students in China. Enhanced awareness of occupational safety in nursing students is expected to reduce the risk of needlestick injuries.