Explore the vast range of titles available.

Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and dementia. It has been documented that 80–90% of the patients with MERRF syndrome are caused by the A8344G mutation in the tRNA Lys gene of mitochondrial DNA (mtDNA). We and other investigators have reported that the mtDNA mutation results in not only inefficient generation of adenosine triphosphate but also increased production of reactive oxygen species (ROS) in cultured cells harboring A8344G mutation of mtDNA. In addition, we found an imbalance in the gene expression of antioxidant enzymes in the skin fibroblasts of MERRF patients. The mRNA, protein, and enzyme activity levels of manganese-superoxide dismutase were increased, but those of Cu,Zn-SOD, catalase, and glutathione peroxidase did not show significant changes. Recently, we showed that the excess ROS could damage voltage-dependent anion channel, prohibitin, Lon protease, and aconitase in the MERRF cells. Moreover, there was a dramatic increase in the gene expression and activity of matrix metalloproteinase 1, which may contribute to the cytoskeleton remodeling involved in the weakness and atrophy of muscle commonly seen in MERRF patients. Taken together, we suggest that mtDNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression are involved in the pathogenesis and progression of MERRF syndrome.

Zika virus (ZIKV) is primarily transmitted by Aedes mosquitoes in the subgenus Stegomyia but can also be transmitted sexually and vertically in humans. STAT1 is an important downstream factor that mediates type I and II interferon signaling. In the current study, we showed that mice with STAT1 knockout (Stat1-/-) were highly susceptible to ZIKV infection. As low as 5 plaque-forming units of ZIKV could cause viremia and death in Stat1-/- mice. ZIKV replication was initially detected in the spleen but subsequently spread to the brain with concomitant reduction of the virus in the spleen in the infected mice. Furthermore, ZIKV could be transmitted from mosquitoes to Stat1-/- mice back to mosquitoes and then to naïve Stat1-/- mice. The 50% mosquito infectious dose of viremic Stat1-/- mouse blood was close to 810 focus-forming units (ffu)/ml. Our further studies indicated that the activation of macrophages and conventional dendritic cells were likely critical for the resolution of ZIKV infection. The newly developed mouse and mosquito transmission models for ZIKV infection will be useful for the evaluation of antiviral drugs targeting the virus, vector, and host.

Background The role of interleukin (IL) 17A in chronic liver diseases had been extensively studied, but the function of IL-17F, which shares a high degree of homology with IL-17A, in the progression of chronic hepatic diseases is poorly understood. The aim of the study was to evaluate the association between IL-17F and liver diseases including, fibrosis and hepatocellular carcinoma (HCC). Methods Hepatic tumor samples from both hepatitis C virus (HCV) positive and negative patients (without HBV and HCV, NBNC) were examined with quantitative PCR and immunohistochemistry staining for inflammatory cytokine genes expression. In addition, 250 HCV patients naïve for interferon treatment were also subjected to enzyme-linked immunosorbent Assay (ELISA) for their serum cytokine concentrations. Results Serum IL-17F concentrations were significantly elevated in HCV patients with severe fibrosis stages. In accordance with serum data, IL-17F expression was also found higher in HCV-associated HCC tissues compared with NBNC HCC tissues at both the mRNA and protein levels. Conclusions Our data suggest that IL-17F might be used as a valuable biological marker than IL-17A during chronic fibrosis progression and HCC development in HCV patients.

Typhoid fever was rare in Taiwan but approximately two-thirds of the cases were indigenous. The transmission source of the indigenous cases and the relatedness to the imported cases remained unknown. Patients with any site culture positive for Salmonella enterica serovar Typhi were identified in a teaching hospital during 2001–2014. The isolates were determined for antibiotic susceptibilities, pulsed-field gel electrophoresis (PFGE) types and single nucleotide polymorphisms (SNP) types. A total of 64 typhoid episodes were identified in 63 patients. Seventeen episodes (26.6%) were imported and a majority (10, 58.8%) of them were from Indonesia. The clinical manifestations, outcomes of patients and antibiograms of isolates were similar between indigenous and imported cases. 63.3% of the isolates were ciprofloxacin-resistant. The distributions of PFGE and SNP types did not differ significantly between indigenous and imported isolates, either (P = 0.191 and 0.124, respectively). Identical PFGE pattern could be identified in indigenous isolates appearing at certain time frames, indicating outbreaks due to local transmission of certain Typhi strains. The imported cases of typhoid fever from Southeast Asia were the major sources of indigenous S. Typhi infections in Taiwan. Small-scale outbreaks occurred due to local transmission of the strains after their importation.

KMUP‐1 (1, 3, 5 mg kg−1, i.v.), a xanthine derivative, produced dose‐dependent sustained hypotensive and short‐acting bradycardiac effects in anaesthetized rats. This hypotensive effect was inhibited by pretreatment with glibenclamide (5 mg kg−1, i.v.). In endothelium‐intact or denuded aortic rings preconstricted with phenylephrine, KMUP‐1 caused a concentration‐dependent relaxation. This relaxation was reduced by endothelium removal, the presence of NOS inhibitor L‐NAME (100 μM) and sGC inhibitors methylene blue (10 μM) and ODQ (1 μM). The vasorelaxant effects of KMUP‐1 was attenuated by pretreatment with various K+ channel blockers TEA (10 mM), glibenclamide (1 μM), 4‐AP (100 μM), apamin (1 μM) and charybdotoxin (ChTX, 0.1 μM). Increased extracellular potassium levels (30 – 80 mM) caused a concentration‐related reduction of KMUP‐1‐induced vasorelaxations. Preincubation with KMUP‐1 (1, 10, 100 nM) increased the ACh‐induced maximal vasorelaxations mediated by endogenous NO release, and enhanced the potency of exogenous NO‐donor SNP. The vasorelaxant responses of KMUP‐1 (0.01, 0.05, 0.1 μM) together with a PDE inhibitor IBMX (0.5 μM) had an additive action. Additionally, KMUP‐1 (100 μM) affected cyclic GMP metabolism since it inhibited the activity of PDE in human platelets. KMUP‐1 induced a dose‐related increase in intracellular cyclic GMP levels in rat A10 vascular smooth muscle (VSM) cells, but not cyclic AMP. The increase in cyclic GMP content of KMUP‐1 (0.1 – 100 μM) was almost completely abolished in the presence of methylene blue (10 μM), ODQ (10 μM), and L‐NAME (100 μM). In conclusion, these results indicate that KMUP‐1 possesses the following merits: (1) stimulation of NO/sGC/cyclic GMP pathway and subsequent elevation of cyclic GMP, (2) K+ channels opening, and (3) inhibition of PDE or cyclic GMP breakdown. Increased cyclic GMP display a prominent role in KMUP‐1‐induced VSM relaxations. British Journal of Pharmacology (2001) 134, 265–274; doi:10.1038/sj.bjp.0704231

Dry-eye syndrome (DES) is a general eye disease. Eye drops are the common ophthalmological medication. However, the ocular barrier makes it difficult to attain high drug bioavailability. Nanomedicine is a promising alternative treatment for ocular diseases and may increase drug content in the affected eye. To explore this potential, we constructed nanoparticles (NPs) containing an anti-inflammatory agent for DES treatment. The NPs were made of gelatin-epigallocatechin gallate (EGCG) with surface decoration by hyaluronic acid (HA) and designated \"GEH\". The particle size, surface charge, and morphology were evaluated. The in vitro biocompatibility and anti-inflammation effect of nanoparticles were assayed via culturing with human corneal epithelium cells (HCECs) and in vivo therapeutic effect was examined in a DES rabbit's model. The synthesized GEH NPs had a diameter of approximately 250 nm and were positively charged. A coculture experiment revealed that 20 µg/mL GEH was not cytotoxic to HCECs and that an EGCG concentration of 0.2 µg/mL downregulated the gene expression of and in inflamed HCECs. Large amounts of GEH NPs accumulated in the cytoplasm of HCECs and the ocular surfaces of rats and rabbits, indicating the advantage of GEH NPs for ocular delivery of medication. Twice-daily topical treatment with GEH NPs was performed in a rabbit model of DES. The ocular surface of GEH-treated rabbits displayed normal corneal architecture with no notable changes in inflammatory cytokine levels in the cornea lysate. The treatment improved associated clinical signs, such as tear secretion, and fluorescein staining recovered. We successfully produced GEH NPs with high affinity for HCECs and animal eyes. The treatment can be delivered as eye drops, which retain the drug on the ocular surface for a longer time. Ocular inflammation was effectively inhibited in DES rabbits. Therefore, GEH NPs are potentially valuable as a new therapeutic agent delivered in eye drops for treating DES.

Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.