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Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro , SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling. [ABSTRACT FROM AUTHOR]

Objective Growing evidence indicates that microRNAs (miRNA) play a critical role in the pathogenesis of OA, and overexpressing or silencing miRNA expression in OA models can contribute to the development of miRNA-based therapeutics. The objective of this study was to determine whether intra-articular injection of miRNA can inhibit OA progression. Methods The miRNA expression profile was determined in OA cartilage tissues and controls. Functional analysis of the miRNAs on extracellular matrix degradation was performed after miRNA mimic or inhibitor transfection. Luciferase reporter assays and western blotting were employed to determine miRNA targets. To investigate the functional mechanism of miR-21-5p in OA development, miR-21-5pfl/flCol2a1-CreER and wild-type mice were subject to surgical destabilization of the medial meniscus. Therapeutically, wild-type mice undergoing surgical destabilization of the medial meniscus were treated with intra-articular injection of agomir- and antagomir-21-5p. Results We found that expression of miR-21-5p was significantly up-regulated in OA cartilage tissues. The articular cartilage degradation of miR-21-5p conditional knockout mice was significantly alleviated compared with that of wild-type mice in spontaneous and destabilization of the medial meniscus models. Through gain-of-function and loss-of-function studies, miR-21-5p was shown to significantly affect matrix synthesis genes expression, and chondrocyte proliferation and apoptosis. Further, fibroblast growth factor 18 (FGF18) was identified as a target of miR-21-5p. Intra-articular injection of antagomir-21-5p significantly attenuated the severity of experimental OA. Clinically, FGF18 expression level was correlated with miR-21-5p expression and a modified Mankin scale. Conclusion Our findings reveal a miRNA functional pathway important for OA development, highlighting miRNA-21-5p silencing as an attractive therapeutic regimen in future clinical trials involving patients with OA. [ABSTRACT FROM AUTHOR]

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Chemical investigation of the roots of Croton crassifolius led to the isolation of five pyran-2-one derivatives, including two brand new compounds ( 1 – 2 ), one new natural product ( 3 ) and two known compounds ( 4 – 5 ). Their structures and absolute configurations were established by spectroscopic analyses as well as comparison between the calculated optical rotation (OR) values with the experimental data. Interestingly, the new compound 1 showed an unusual negative chemical shift at H-11. It is well known that negative chemical shift values of 1 H NMR spectrum are extremely rare in natural products. Such a negative chemical shift of 1 H NMR spectrum was reproduced by density functional theory (DFT) calculations and explained by the shielding effect from the pyran-2-one ring over the hydrogen atom in the 3D conformations. Then, MTT assay was applied to evaluate the cytotoxicity of the isolated compounds ( 1 – 5 ) against two liver cancer cell lines (HepG2 and MHCC97H). The results suggested that compound 1 displayed the highest cytotoxicity with an IC 50 value of 9.8 μM against HepG2 cells. Moreover, there was no obvious cytotoxicity of compounds 1 – 5 on normal liver cell line LO2. Furthermore, the mechanism of apoptosis induction in compound 1 -treated HepG2 cells was investigated. The results showed that compound 1 could induce apoptosis via p53-mediated Ras/Raf/ERK suppression in HepG2 cells. [ABSTRACT FROM AUTHOR]

Intrafibrillar silicified collagen scaffold (SCS) is a promising biomaterial for bone regeneration because it promotes cell homing and angiogenesis in bone defects via monocyte modulation. In the present study, a rat femoral defect model was used to examine the contribution of monocyte signaling pathways to SCS modulation. Activation of the monocyte p38 signaling pathway by SCS resulted in monocyte differentiation into TRAP-positive mononuclear cells. These cells demonstrated increased secretion of SDF-1α, VEGFa and PDGF-BB, which, in turn, promoted homing of bone marrow stromal cells (BMSCs) and endothelial progenitor cells (EPCs), as well as local vascularization. Monocyte differentiation and secretion were blocked after inhibition of the p38 pathway, which resulted in reduction in cell homing and angiogenesis. Taken together, these novel findings indicate that the p38 signaling pathway is crucial in SCS-modulated monocyte differentiation and secretion, which has a direct impact on SCS-induced bone regeneration. Statement of significance Intrafibrillar silicified collagen scaffold (SCS) is a promising biomaterial for bone regeneration. The present work demonstrates that SCS possesses favorable bone regeneration potential in a rat femoral defect model. The degrading scaffold modulates monocyte differentiation and release of certain cytokines to recruit MSCs and EPCs, as well as enhances local vascularization by activating the p38 MAPK signaling pathway. These findings indicate that SCS contributes to bone defect regeneration by stimulating host cell homing and promoting local angiogenesis and osteogenesis without the need for loading cytokines or xenogenous stem cells. [ABSTRACT FROM AUTHOR]

Delphinidin, a flavonoid polyphenolic compound, is widely found in nature and is used as a food supplement due to its pharmacological activity. The aims of the present study were to examine the anti-inflammatory effect of delphinidin in alleviating spinal cord injury (SCI)-induced inflammation in a rat model and to determine the underlying mechanisms in SCI. The Basso, Beattie, Bresnahan (BBB) scores of rats were assessed to evaluate the effect of delphinidin on the recovery of motor function. ELISA kits were also used to analyze the activities of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and caspase-3. In addition, the protein expression levels of nuclear factor (NF)-κB, activator protein 1 (AP-1) and p38-MAPK protein expression were measured using western blot analysis. Treatment with delphinidin significantly increased the BBB scores, as well as inhibited the intramedullary spinal pressure in SCI rats. Delphinidin treatment also significantly suppressed the levels of inflammatory factors and NF-κB protein expression in SCI rats. Finally, treatment with delphinidin significantly inhibited NF-κB stimulation, COX-2 activity, PGE2 production, and AP-1 and p38-MAPK protein expression in SCI rats. These results suggest that the anti-inflammatory effect of delphinidin alleviated inflammation in the SCI rat model via alleviation of the intramedullary spinal pressure through the NF-κB and p38-MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

Exposure to stress could facilitate or inhibit pain responses (stress-induced hyperalgesia or hypoalgesia, respectively). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor antidepressant. There have been contradictory reports on whether fluoxetine produces antinociceptive effects. The purpose of this study was to elucidate changes in pain sensitivity after chronic stress exposure, and the effects of fluoxetine on these changes. We measured thermal, mechanical, and formalin-induced acute and inflammatory pain by using the tail-flick, von Frey, and formalin tests respectively. The results showed that rats exposed to chronic stress exhibited thermal and formalin-induced acute and inflammatory hypoalgesia and transient mechanical hyperalgesia. Furthermore, fluoxetine promoted hypoalgesia in thermal and inflammatory pain and induced mechanical hyperalgesia. Our results indicate that the 5-HT system could be involved in hypoalgesia of thermal and inflammatory pain and induce transient mechanical hyperalgesia after stress exposure. [ABSTRACT FROM AUTHOR]

Glaucoma is a progressive neurodegenerative disease, characterized by retinal ganglion cells (RGCs) and axon degeneration. The development of neuroprotective drug is required for improving the efficiency of glaucoma treatment. Eucommia ulmoides Oliv. has been used as a source of traditional medicine and as a beneficial health food. Lignans is one of the main bioactive components of Eucommia ulmoides. Here, we show that lignans protects RGCs against oxidative stress-induced injury in vitro. Moreover, lignans exerts neuroprotective effect on glaucoma-associated optic neuropathy in glaucomatous rats. Lignans treatment could improve oxidative stress response in RGCs and retinas of glaucomatous rats. Lignans plays an anti-oxidative stress role via the activation of AMPK signaling. This study provides evidence that lignans possesses protective effect on glaucoma-associated optic neuropathy. Lignans might be an alternative for the prevention and treatment of glaucomatous neurodegeneration. [ABSTRACT FROM AUTHOR]

Despite the intense efforts in searching for stroke therapies, an urgent need still exists to explore novel neuroprotective agents for ischemic stroke that have high efficacy and wide therapeutic time-window. Here, we provide the first demonstration that 28 -O-caffeoyl betulin (B- CA), a novel derivative of naturally occurring caffeoyl triterpene, could significantly alleviate brain infarction and neurological deficit when given as late as 6 h after transient middle cerebral artery occlusion in the rat. Moreover, post-ischemia B- CA administration exhibited long-term (14 days post stroke) protective effects on both brain infarction and functional (i.e., motor and sensory) deficits. Protective B- CA effects correlated with decreased inflammatory responses as indicated by inhibition of microglia and astrocyte activation [stained with ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) antibody, respectively], as well as suppression of tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2 overproduction in the ipsilateral cortex of ischemic rat. B- CA administration caused significant hypothermia in the focal cerebral ischemic rat, which may contribute to its ameliorative effects on brain damage and inflammation. In view of its potency in wide therapeutic time-window, robust anti-inflammatory and hypothermic effects, this novel caffeoyl triterpene derivative may lead toward the development of effective therapeutic strategies for the treatment of ischemic stroke. [ABSTRACT FROM AUTHOR]

Introduction: The timing of definitive aneurysm treatment (coiling or clipping) in poor-grade (Hunt-Hess IV or V) subarachnoid haemorrhage (SAH) patients has been a controversial topic. The purpose of this retrospective study was to analyse whether ultra-early coiling of ruptured intracranial aneurysms improves the clinical outcomes of poor-grade SAH patients. Methods: The records of patients with aneurysmal SAH who were treated with endovascular coiling were retrieved. The patients were classified into two groups: group A (patients coiled within 24 h of SAH) and group B (patients coiled ≥ 24 h after SAH). For each group, the patient demographics, Fisher grade, aneurysm characteristics and clinical outcomes were recorded. Outcomes were measured at 6 months using the modified Rankin Scale (mRS). Results: Thirty-one patients were coiled within 24 h of SAH (group A), and fourteen patients were coiled ≥24 h after SAH (group B). Groups A and B had similar clinical and angiographic characteristics. The clinical outcomes showed that a total of 58.1 % of the patients (18 of 31) in group A were independent (mRS 0-2) compared with 21.4 % of the patients (3 of 14) in group B ( P = .028). Univariate analysis demonstrated that ultra-early coiling ( P = .028) proved to be an independent predictor of better clinical outcomes (mRS 0-2). Conclusions: Ultra-early (<24 h after SAH) coiling of ruptured aneurysms was associated with improved clinical outcomes compared to coiling at ≥24 h in poor-grade SAH patients. Larger, prospective studies are required to adequately assess the outcome differences between these two groups. [ABSTRACT FROM AUTHOR]

Abstract: Cadmium (Cd) is one of the most toxic metal compounds released into the environment. It was well known that Cd induced hepatotoxicity in animal models. However, little is known about the negative effects of Cd toxicity in the liver of birds. To investigate the Cd hepatotoxicity in birds and the protective effects of selenium (Se) against subchronic exposure to dietary Cd, 100-day-old cocks received either Se (as 10mg Na2SeO3 per kg of diet), Cd (as 150mg CdCl2 per kg of diet) or Cd+Se in their diets for 60 days. Histological and ultrastructural changes in the liver, the concentrations of Cd and Se, the lipid peroxidation (LPO) and nitric oxide (NO) production, the activities of the antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx), nitric oxide synthase (NOS) activities and apoptosis were determined. Exposure to Cd significantly reduced SOD and GPx activity, Se content in the liver tissue. It increased the LPO and NO production, the numbers of apoptotic cells and Cd concentration and caused obvious histopathological changes in the liver. Concurrent treatment with Se reduced the Cd-induced liver histopathological changes, oxidative stress, overexpression of NO and apoptosis, suggesting that the toxic effects of Cd on the liver is partly ameliorated by inorganic Se. Se supplementation also modified the distribution of Cd in the liver. [Copyright &y& Elsevier]

Oral propranolol is the first-line therapy for infantile hemangioma (IH), but its mechanism of action remains unclear. The aim of this study was to evaluate the change in serum vascular endothelial growth factor (VEGF) levels in patients with IH who underwent propranolol treatment. The study included 22 patients with IH receiving propranolol treatment. At three time points-before treatment and 1 and 3 months after treatment-blood samples were examined by enzyme-linked immunosorbent assay for serum VEGF expression. The mean serum VEGF concentration in children with proliferative hemangiomas was 395.0 ± 176.7 pg/mL, approximately twice as high as in patients with venous malformations (mean 170.7 pg/mL) and in healthy controls (204.8 pg/mL, p = 0.006). After 1 month of propranolol treatment, the level had fallen 21.6% (p = 0.003), although the downward trend was less obvious after 3 months of treatment (18.0%, p = 0.63). VEGF expression correlated significantly with the lesion size (correlation coefficient [ R] = 0.43, p = 0.046), whereas no correlation was observed with age ( R = 0.13, p = 0.56). Serum VEGF levels were higher in patients with IH and fell after 1 month of oral propranolol treatment. Similar results, although less pronounced, were found after 3 months of treatment. Lesion volume and serum level of VEGF were significantly correlated. [ABSTRACT FROM AUTHOR]

Background: This study was performed to investigate whether ginseng has a protective effect in an experimental mouse model of cyclosporine-induced pancreatic injury. Methods: Mice were treated with cyclosporine (30 mg/kg/day, subcutaneously) and Korean red ginseng extract (0.2 or 0.4 g/kg/day, oral gavage) for 4 weeks while on a 0.01% salt diet. The effect of ginseng on cyclosporine-induced pancreatic islet dysfunction was investigated by an intraperitoneal glucose tolerance test and measurements of serum insulin level, β cell area, macrophage infiltration, and apoptosis. Using an in vitro model, we further examined the effect of ginseng on a cyclosporine-treated insulin-secreting cell line. Oxidative stress was measured by the concentration of 8-hydroxy-2′-deoxyguanosine in serum, tissue sections, and culture media. Results: Four weeks of cyclosporine treatment increased blood glucose levels and decreased insulin levels, but cotreatment with ginseng ameliorated the cyclosporine-induced glucose intolerance and hyperglycemia. Pancreatic β cell area was also greater with ginseng cotreatment compared with cyclosporine monotherapy. The production of proinflammatory molecules, such as induced nitric oxide synthase and cytokines, and the level of apoptotic cell death also decreased in pancreatic β cell with ginseng treatment. Consistent with the in vivo results, the in vitro study showed that the addition of ginseng protected against cyclosporine-induced cytotoxicity, inflammation, and apoptotic cell death. These in vivo and in vitro changes were accompanied by decreases in the levels of 8-hydroxy-2′-deoxyguanosine in pancreatic β cell in tissue section, serum, and culture media during cotreatment of ginseng with cyclosporine. Conclusions: The results of our in vivo and in vitro studies demonstrate that ginseng has a protective effect against cyclosporine-induced pancreatic β cell injury via reducing oxidative stress. [ABSTRACT FROM AUTHOR]

Aim:Gemcitabine has been increasingly prescribed for the treatment of gallbladder cancer. However, the response rate is low. The aim of this study is to determine whether icariin, a flavonoid isolated from Epimedi herba, could potentiate the antitumor activity of gemcitabine in gallbladder cancer.Methods:Human gallbladder carcinoma cell lines GBC-SD and SGC-996 were tested. Cell proliferation and apoptosis were analyzed using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related molecules was detected with Western blotting. Caspase-3 activity was analyzed using colorimetric assay, and NF-κB activity was measured with ELISA. A gallbladder cancer xenograft model was established in female BALB/c (nu/nu) mice. The mice were intraperitoneally administered gemcitabine (125 mg/kg) in combination with icariin (40 mg/kg) for 2 weeks.Results:Icariin (40-160 μg/mL) dose-dependently suppressed cell proliferation and induced apoptosis in both GBC-SD and SGC-996 cells, with SGC-996 cells being less sensitive to the drug. Icariin (40 μg/mL) significantly enhanced the antitumor activity of gemcitabine (0.5 μmol/L) in both GBC-SD and SGC-996 cells. The mice bearing gallbladder cancer xenograft treated with gemcitabine in combination with icariin exhibited significantly smaller tumor size than the mice treated with either drug alone. In GBC-SD cells, icariin significantly inhibited both the constitutive and gemcitabine-induced NF-κB activity, enhanced caspase-3 activity, induced G0-G1 phase arrest, and suppressed the expression of Bcl-2, Bcl-xL and surviving proteins.Conclusion:Icariin, by suppressing NF-κB activity, exerts antitumor activity, and potentiates the antitumor activity of gemcitabine in gallbladder cancer. Combined administration of gemcitabine and icariin may offer a better therapeutic option for the patients with gallbladder cancer. [ABSTRACT FROM AUTHOR]

Background. Osteoporosis is a major health problem for the elderly population. Chinese herb may be beneficial to osteoporosis due to its capability. Objectives. This study was designed to evaluate the effectiveness of Chinese medicine treatment on the patients with osteoporosis. Search Methods. Randomized controlled trials were retrieved from different 9 databases. Results. This meta analysis included 12 RCTs involving 1816 patients to compare Chinese herbs with placebo or standard anti-osteoporotic therapy in the treatment of bone loss. The pooled data showed that the percent change of increased BMD in the spine is higher with Chinese herb compared to placebo (lumber spine: WMD = 0.07, 95% CI: 0.01-0.04). In the femoral, Chinese herb showed significantly higher increments of BMD compared to placebo (femoral neck: WMD = 0.06, 95% CI: -0.02-0.13). Compared to the other standard anti-osteoporotic drugs, Chinese herbs also show advantage in BMD change (lumber spine: WMD = 0.03, 95% CI: -0.01-0.08; femoral: WMD = 0.01, 95% CI: -0.01-0.02). Conclusions. Our results demonstrated that Chinese herb significantly increased lumbar spine BMD as compared to the placebo or other standard anti-osteoporotic drugs. [ABSTRACT FROM AUTHOR]

Abstract: A 41-year-old man received an electrophysiological study (EPS) and radiofrequency catheter ablation (RFCA) for atrioventricular reentrant tachycardia (AVRT) in our hospital. Massive pulmonary embolism (PE) with hypotension developed 9 hours after these procedures. After emergent pulmonary angiography and catheter-directed intrathrombus urokinase infusion and clot breaking, the patient recovered well. This case suggests that life-threatening PE may occur in patients who receive EPS, RFCA, or both. An adequate observation time after RFCA and clinical alertness are necessary for immediate diagnosis and treatment. Emergent catheter-directed therapy may be of benefit in some patients with acute massive PE. [Copyright &y& Elsevier]

Abstract: The worldwide outbreak of pandemic influenza A (H1N1 influenza) infection in 2009 caused numerous hospitalizations and deaths resulting from severe complications such as pneumonia, sepsis, and acute respiratory distress syndrome. Fulminant myocarditis caused by H1N1 infection has been reported in children but rarely in adults. We present an adult who contracted H1N1 infection followed by fulminant myocarditis. Early implementation of extra-corporeal membrane oxygenation support in conjunction with a specific anti-influenza viral medication (Oseltamivir) led to the patient’s complete recovery from cardiogenic shock in 2 weeks. [Copyright &y& Elsevier]

In this paper, we addressed the immune adjuvant effects of interleukin(IL)-21 on DNA vaccine constructs expressing mycobacterium tuberculosis (TB) Ag85A and compared immune responses induced in mice inoculated DNA vaccine constructs expressing Ag85A and IL-21 with mice inoculated DNA vaccine constructs expressing Ag85A alone or Bacillus Galmette-Guérin(BCG.). In this experiment, the gene of IL-21 was firstly amplified from plasmid pcDNA3.1-mIL21 by PCR and cloned into the plasmid pRSC, forming recombinant plasmid pRSC-IL21. Then, the gene of Ag85A was amplified from the plasmid pIRES-Ag85A by PCR and cloned into the recombinant pRSC-IL21 again, finally forming co-expression DNA vaccine constructs pRSC-IL21-Ag85A. It was identified by the analysis of endonuclease digestion, DNA sequencing, the IL-21 and Ag85A expression in SP2/0 cells. Mice were i.m. immunized with BCG, DNA vaccine constructs pRSC-Ag85A or pRSC-IL21-Ag85A respectively, and the immune responses induced in mice was compared with other vaccines. The results showed that the DNA vaccine constructs pRSC-IL21-Ag85A was successfully constructed since the Ag85A and IL-21 was correctly expressed in SP2/0 cells respectively, and it elicited stronger immune responses in Balb/c mice than that of mice immunized with pRSC-Ag85A and the efficiency was as BCG did. We concluded that the IL-21 was a promising immune adjunctive modality to enhance immunigenicity of DNA vaccine containing Ag85A and the study provided the possibility of further development of immune accessory effect of IL-21 on DNA vaccine against TB. [ABSTRACT FROM AUTHOR]

Background: The transseptal technique has been widely used for diagnostic and therapeutic left-sided heart catheterization. However, its differential immediate and late outcomes among patients with various valvular and arrhythmic diseases are not yet determined. Methods: Beginning from 1993, all patients undergoing transseptal procedures were screened and categorized into diagnosis, arrhythmia, and valvuloplasty groups according to the purposes of the catheterization. Incidences of transseptum-related acute major events (cardiac perforation, embolic stroke, and bradyarrhythmia during the procedure) and late complications (residual atrial septal defect [ASD], embolic stroke, bradyarrhythmia, and death up to 18 months) were analyzed and compared between groups. Results: From January 1993 to May 2003, a total of 176 patients underwent 184 transseptal procedures for diagnosis of valvular heart diseases (n = 8), catheter ablation of arrhythmogenic foci (n = 29), and mitral valvuloplasty (n = 147). The immediate outcome was similar among the 3 groups, with an overall acute complication incidence of 3.8%. At follow-up, the incidences of bradyarrhythmia, embolic stroke, and death were not different among the 3 groups. Patients undergoing valvuloplasty had a significantly higher prevalence of residual ASD, especially for those with more severe mitral stenosis and less valvuloplasty success. However, presence of ASD did not impose disadvantage over the 1.5-year prognosis. Conclusion: Transseptal left-sided heart catheterization can be safely applied to patients with different categories of cardiac diseases with comparably good immediate and late outcomes. Although patients undergoing percutaneous valvuloplasty have a higher chance of permanent ASD creation, their prognosis is not influenced. [Copyright &y& Elsevier]

Background: Cilastatin (CL) is an inhibitor of dehydropeptidase-I, which is safely used in clinical practice to prevent nephrotoxicity of antibiotics. Tacrolimus (TAC) is the most important immunosuppressant in renal transplantation, but it causes considerable nephrotoxicity. We evaluated the protective effects of CL against chronic TAC-induced nephropathy.Methods: Chronic nephropathy was induced by administering TAC (1.5 mg/kg/ day, subcutaneous injection) to rats on a low-salt diet for 4 weeks. CL (75 or 150 mg/kg/day, intraperitoneal injection) was concomitantly treated with TAC. Human proximal tubular cells were exposed to TAC (50 μg/mL) with or without CL (250 μg/mL). We investigated the effects of CL on TAC-induced injury in terms of renal function, tubulointerstitial fibrosis, and inflammation. The effects of CL on oxidative stress and apoptosis were evaluated in both in vivo and in vitro models of TAC nephrotoxicity.Results: CL treatment improved TAC-induced renal dysfunction and decreased renal interstitial fibrosis (reduced expression of e-cadherin and TGFβ-1) and interstitial inflammation (decreased infiltration of ED-1-positive and osteopontin-positive cells). Compared to TAC treatment alone, CL co-treatment reduced oxidative stress (serum 8-OHdG level and immunoreactivity of 8-OHdG and 4-HHE in renal tissue) and increased renal expression of anti-oxidant enzyme, manganese superoxide dismutase. CL treatment decreased apoptotic cell death (decreased TUNEL-positive cells and reduced expression of active caspase-3) in TAC-treated kidney. In vitro CL treatment prevented tubular cell death from TAC treatment and decreased number of annexin V-positive cells were observed in cilastatin-cotreated cells.Conclusion: CL has protective effects against chronic TAC-induced nephrotoxicity owing to its anti-oxidative and anti-apoptotic properties. [ABSTRACT FROM AUTHOR]

Objective Osteosarcoma is an aggressive malignant neoplasm, which commonly afflicts patients of 20–30 years of age, and its morbidity has increased markedly in recent years. Certain genes and signal pathways have been identified to exert key roles in osteosarcoma progression. Here, we set out to characterize in more detail of the role of HIF-1/AKT/Cyclin D1 pathway in the progression of osteosarcoma. Methods Immunohistochemistry, western blot and qPCR were used to test the protein or mRNA levels of HIF-1 in osteosarcoma tissues or adjacent nontumor tissues. MTT, clone formation, wound healing, Transwell, in vivo tumorigenesis, flow cytometry and western blot analysis were used to determine cell proliferation, clone formation ability, migration, invasion, tumorigenesis, and cell apoptosis in MG63 and U2OS cells, respectively. Immunoprecipitation and immunofluorescence assays were performed to investigate the protein-protein interaction between HIF-1α and proteins related to signal pathways. Results HIF-1 was overexpressed in osteosarcoma tissues and cell lines, which promoted cell proliferation, clone formation, migration, invasion and inhibited cell apoptosis. Results also demonstrated that HIF-1 combined with AKT, and there might be a positive loop between the two proteins of HIF-1 and AKT, then the protein-protein interaction up-regulated the expression of Cyclin D1 in protein level, but not mRNA level, made Cyclin D1 protein more stable, triggered cell proliferation, clone formation, tumorigenesis, but inhibited cell apoptosis. Conclusions The present study showed that HIF-1 modulated Cyclin D1 expression might through shaping a positive loop with AKT proteins. Additionally, HIF-1α promoted the tumor cells growth, migration and invasion in osteosarcoma through the activation of the AKT/Cyclin D1 signal cascade. We proposed that HIF-1 could be served as a marker for distinguishing osteosarcoma and an effective therapeutic target for osteosarcoma. [ABSTRACT FROM AUTHOR]

A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by coupling with building block 6 or 32 . The corresponding targets 7a–n , 33b , and 33e were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides, compounds 33b and 33e , displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens. [ABSTRACT FROM AUTHOR]

• Discusses several different pathways for NETs formation. • Examine the antimicrobial properties of NETs. • Discusses the relationship between NETs and fibrosis. • Discusses the physiological clearance of NETs and related pharmacological interventions. Neutrophils are a major subset of leukocytes in human circulating blood. In some circumstances, neutrophils release neutrophil extracellular traps (NETs). lnitially, NETs were considered to have a strong antibacterial capacity. However, currently, NETs have been shown to have a pivotal impact on various diseases. Different stimulators induce the production of different types of NETs, and their biological functions and modes of clearance do not appear to be the same. In this review, we will discuss several important issues related to NETs in order to better understand the relationship between NETs and diseases, as well as how to utilize the characteristics of NETs for disease treatment. [ABSTRACT FROM AUTHOR]

The burden and morbidity of environmental nephrosis is increasing globally. Atrazine (ATR) and degradation products in the environment are considered key determinants of nephrosis. However, the lack of highly effective treatments for environmental nephrosis creates an urgent need to better understand the preventive strategies and mechanisms. This study aimed to highlight the mechanism of ATR-induced environmental nephrosis and the chemoprotective potential of lycopene (LYC) against the renal injury and nephrosis. Male mice were treated with LYC (5 mg/kg) and/or ATR (50 mg/kg or 200 mg/kg) by gavage administration for 21 days. Histopathological changes and biochemical function, cytochrome P450 enzymes system (CYP450s), nuclear xenobiotic receptors (NXRs) response and the transcription of CYP isoforms (CYPs) were detected. ATR exposure caused the changes of the histopathological and biochemical function, activated the NXR response and disturbed the CYP450s homeostasis. Supplementary LYC significantly prevented ATR-induced nephrotoxicity and alleviated the alternation of histopathological and biochemical function via modulating the CYP450s homeostasis and the NXR response. The results demonstrated AHR, CAR, PXR, PPAR (α, γ), CYP1, CYP2, CYP3 and CYP4 superfamily play a vital role in LYC-ATR interaction. Our findings provide new evidence that ATR exposure can cause the environmental nephrosis via inducing the kidney injury. Supplementary LYC showed significant chemoprotective potential against ATR-induced renal injury and environmental nephrosis via regulating the NXR response and the CYP450s homeostasis. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a ubiquitously distributed trace metal and environmental pollutant that is highly toxic to liver. Selenium (Se) may provide chemoprotection against Cd-induced cytotoxicity by augmenting the cellular antioxidant capacity. However, the mechanism of Se chemoprotection against Cd-induced hepatotoxicity is unclear. The present study evaluated the ameliorative properties of Se against Cd-induced cytotoxicity in hepatocytes. Primary cells were exposed to 5 μM Cd and/or 1 μM Se for 24 h. Cellular morphology and function, antioxidant status, activation of Nrf2 pathway, autophagy and apoptosis were determined. These results indicated that Se ameliorated the cytotoxicity of Cd by recovering hepatocyte morphology and function, inhibiting reactive oxygen species (ROS) and malondialdehyde (MDA) production, reducing intracellular LDH release, autophagy and apoptosis, and increasing the major antioxidative activities (Total antioxidant capacity (T-AOC) and superoxide dismutase (SOD). In summary, Cd is a hepatotoxin that causes hepatocytes damage by inducing oxidative stress, excessive autophagy and apoptosis as a mechanism of toxicity. Moreover, Se supplement ameliorated these effects by enhancing antioxidant systems, decreasing excessive autophagy and apoptosis. These results suggested that Se triggers Nrf2-mediated protection as the mechanism of Se chemoprotection against Cd-induced autophagy and apoptosis. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a leading cause of mortality and permanent disability in adults worldwide. Neurogenesis triggered by ischemia in the adult mammalian brain may provide insights into stroke treatment. Morroniside is an active component of sarcocarp of C. officinalis that have shown neuroprotective effects. The aim of the present study is to test whether morroniside promotes neurogenesis via Wnt/β-catenin signaling pathway for brain recovery in a rat model of focal cerebral ischemia. Morroniside was administered intragastrically once daily at the concentrations of 30, 90 and 270 mg/kg for 7 days post-ischemia. Neurological functions were detected by Ludmila Belayev score tests. Endogenous neural stem cells responses were investigated with immunofluorescence staining of Ki-67 and Nestin to identify the neurogenesis in the subventricular zone (SVZ). The expression of proteins involved in and related to Wnt/β-catenin signaling pathway was detected by western blotting analysis. Morroniside significantly promoted neurogenesis for brain recovery 7 days post-ischemia. Increased expression of Wnt 3a, β-catenin and T-cell transcription factor-4 (Tcf-4), along with activation of downstream transcription factors Pax6 and neurogenin2 (Ngn2), indicated that the neurorestorative effects of morroniside may be associated with Wnt/β-catenin signaling pathway. These data provide support for understanding the mechanisms of morroniside in neurorestorative effects and suggest a potential new strategy for ischemic stroke treatment. [ABSTRACT FROM AUTHOR]

Cortex Juglandis Mandshuricae (CJM) is the dry branch or stem bark of the Juglans mandshurica Maxim. and is widely used as a traditional Chinese medicine in Asia and Africa. Its use was first recorded in Kaibao Bencao. The present review provides a deeper insight, better awareness and detailed knowledge of phytochemistry, pharmacology, quality control, along with clinical applications of Cortex Juglandis Mandshuricae. The relevant information of Cortex Juglandis Mandshuricae was obtained from several databases including Web of Science, PubMed, and CNKI. The medical books, PhD and MSc dissertations in Chinese were also used to perform this work. CJM has been traditionally used against a wide range of diseases, including dysentery, acute conjunctivitis, bacterial infections, and cancer. A total of 249 compounds have been isolated from CJM; they mainly include quinones and their derivatives, flavonoids, tannins, diarylheptanoids, triterpenoids, coumarins, phenylpropanoids, and volatile oils. These compounds exert anti-tumor, anti-oxidant, anti-inflammatory, bacteriostatic, anti-complement, immunomodulatory, anti-parasitic activities. Specifically, the effects of juglone, alkaloids and unsaturated fatty acid CJM components against hepatic cancer occur through exertion of apoptosis through a mitochondria-dependent pathway. In addition, taxifolin and several tannins have been found to have anti-HIV activity, and (±)-juglanaloid A and (±)-juglanaloid B target Alzheimer disease. Quality control is monitored through identification of juglone, quercetin, and volatile oils. A clinical preparation of CJM, Compound Muji Granules, is used in the treatment of various liver diseases with good therapeutic effect. While CJM has been used extensively as a folk medicine, the relationships between structure and activity remain unclear. More in vivo models are needed to study the pharmacological mechanisms of action and to assess potential toxic components, in addition to which the evidence used to demonstrate the quality standards of medicinal materials is clearly inadequate. Therefore, more in-depth research is needed to provide a reasonable scientific basis improve its clinical utilization. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Background: Signal averaged electrocardiogram (SAECG) is a specific and non-invasive tool useful for arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis. However, its role in risk stratification of patients with ARVC remains largely undefined. Methods: Sixty-four patients fulfilling Task Force ARVC criteria (mean age: 47±14years-old, 56% male, 50% definite ARVC) were enrolled. The baseline demographic, electrocardiographic, structural, and electrophysiological characteristics were collected. Patients with SAECG fulfilling all 3 Task Force criteria (3+ SAECG) were categorized into group 1, and those fulfilled 2 or less criterion were categorized into group 2. The study endpoints were unstable ventricular arrhythmia (VA), device detectable sustained fast VA (cycle lengths <240ms) and cardiovascular death. Results: During a mean follow-up of 21±20months, 15 primary endpoints including 12 unstable VAs and 3 device-detected fast VAs were met. One patient died of electrical storm, and one patient underwent heart transplantation. The presence of 3+ SAECG predicted malignant events in all patients with definite and non-definite ARVC (p <0.01, OR=30.5, 95% CI=2.5–373.7) and in patients with definite ARVC alone (p =0.03, OR=11.1, 95% CI=1.3–93.9). Patients diagnosed with non-definite ARVC without 3+ SAECG were free from malignant events. Conclusions: SAECG fulfilling all 3 Task Force criteria was an independent risk predictor of malignant events in ARVC patients. SAECG may play a valuable role in ARVC risk stratification. [Copyright &y& Elsevier]