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Age-related macular degeneration (AMD) is the main cause of blindness in elderly individuals. As a metabolic regulator, fibroblast growth factor 21 (FGF-21) has been proven indicated to have an effect on wet AMD, but whether this cytokine has a therapeutic effect on dry AMD is unclear. The current study aimed to evaluate the preventive effects of FGF-21 against retinal degeneration in mice and provide mechanistic insights. FGF-21−/− mice were raised to 10 months of age. Then, the morphological changes in the retinal pigment epithelium (RPE)/choroid of the mice were observed by transmission electron microscopy (TEM), and iTRAQ was used to detect the variations in the protein profile. Next, FGF-21−/− and wild-type mice of the same age were fed hydroquinone to generate a dry AMD mouse model to examine whether exogenous FGF-21 can interfere with the occurrence and development of dry AMD. In vivo studies revealed that following FGF-21 knockout, there was an increase in the expression of complement in the RPE/choroid concomitant with the occurrence of dry AMD-like pathological changes. Furthermore, exogenous FGF-21 administration effectively reversed this phenomenon. FGF-21 also demonstrated strong anti-inflammatory effects in the RPE/choroid by inhibiting the NF-κB pathway. In conclusion, the present study demonstrates that FGF-21 treatment presents a novel therapeutic approach for the prevention and development of dry AMD by reducing complement. • Fibroblast Growth Factor 21 Deficiency Induces Dry AMD in Mice by Elevating Complement in the Eye. • FGF-21 has a novel therapeutic approach for the prevention of dry AMD development via reducing inflammatory process induced by NF-kB pathway. [ABSTRACT FROM AUTHOR]

Abstract: Neuronal cell death in HD is believed to be largely a dominant cell-autonomous effect of the mutant huntingtin protein. We previously developed an inducible PC12 cell model which expresses an N-terminal huntingtin fragment with an expanded poly Q repeat (N63-148Q) under the control of the tet-off system. In order to evaluate the ability of compounds to protect against mutant huntingtin toxicity in our model, we measured LDH released by dead cells into the medium. We have now screened the library of 1040 compounds from the NINDS Custom Collection as part of a National Institute of Neurological Disorders and Stroke (NINDS) collaborative project. Each positive compound was tested at 3–8 concentrations. Five compounds significantly attenuated mutant huntingtin (htt)-induced LDH release without affecting the expression level of huntingtin and independent of effect on aggregates. We also tested a broad spectrum caspase inhibitor Z-VAD-fmk and previously proposed candidate compounds. This cell model can provide a method to screen potential therapeutic compounds for treating Huntington''s disease. [Copyright &y& Elsevier]

• IL17A polymorphism (rs8193036) is associated with susceptibility to TB. • rs8193036 is a functional SNP that could regulate IL17A gene expression. • Treatments targeting to the IL17A pathway could be a new therapy strategy to TB. Th17 cells play a key role in immunity against Mycobacterium tuberculosis, our previous research showed that reduced Th17 responses were associated with the severe outcome of Mtb infection. The associations between IL17A polymorphisms and susceptibility of TB has been reported, but the results are inconsistent and the underlying mechanisms is unknown. In this study, we identified a genetic variation (rs8193036) in the promoter region of IL17A is associated with susceptibility to TB. The minor allele T frequency of rs8193036 was significantly different between patients with active TB (29.7%) and healthy controls (32.3%) (OR = 0.81; 95%CI, 0.71–0.93; P = 0.0026). Peripheral blood mononuclear cells from individuals carrying rs8193036CC genotypes produced significantly lower amount of IL17A upon CD3/28 stimulation compared to the individuals carrying rs8193036TT genotypes. Functional assay by reporter luciferase activity and EMSA demonstrated that rs8193036C exhibited significantly lower promotor transcription activities. In conclusion, our study confirmed that IL17A (rs8193036) is a functional SNP that could regulate gene expression though influencing transcription factor binding activity. [ABSTRACT FROM AUTHOR]

A CDR3 mutant library was constructed from a previously isolated anti-HBV neutralizing Homo sapiens scFv-31 template by random mutant primers PCR. Then the library was displayed on the inner membrane surface in Escherichia coli periplasmic space. Seven scFv clones were isolated from the mutant library through three rounds of screening by flow cytometry. Competition ELISA assay indicates that isolated scFv fragments show more efficient binding ability to HBV PreS1 compared with parental scFv-31. HBV neutralization assay indicated that two clones (scFv-3 and 59) show higher neutralizing activity by blocking the HBV infection to Chang liver cells. Our method provides a new strategy for rapid screening of mutant antibody library for affinity-enhanced scFv clones and the neutralizing scFvs obtained from this study provide a potential alternative of Hepatitis B immune globulin. [ABSTRACT FROM AUTHOR]

Abstract: Huntington''s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, incoordination, and shortened life-span, and by huntingtin inclusions and neurodegeneration. We previously screened the 1040 FDA-approved compounds from the NINDS compound library and found that a compound, nipecotic acid, significantly reduced mutant huntingtin aggregations and blocked cell toxicity in an inducible cell model of HD. Because nipecotic acid does not cross the blood–brain barrier (BBB), we studied its analogue, tiagabine, which is able to cross the BBB, in both N171-82Q and R6/2 transgenic mouse models of HD. Tiagabine was administered intraperitoneally at 2 and 5 mg/kg daily in HD mice. We found that tiagabine extended survival, improved motor performance, and attenuated brain atrophy and neurodegeneration in N171-82Q HD mice. These beneficial effects were further confirmed in R6/2 HD mice. The levels of tiagabine at effective doses in mouse serum are comparable to the levels in human patients treated with tiagabine. These results suggest that tiagabine may have beneficial effects in the treatment of HD. Because tiagabine is an FDA-approved drug, it may be a promising candidate for future clinical trials for the treatment of HD. [Copyright &y& Elsevier]

The pentacyclic triterpenoid quinone methide celastrol (CS) from Tripterygium wilfordii Hook. F. effectively ameliorates inflammation with potential as therapeutics for inflammatory diseases. However, the molecular mechanisms underlying the anti-inflammatory and inflammation-resolving features of CS are incompletely understood. Here we demonstrate that CS potently inhibits the activity of human 5-lipoxygenase (5-LOX), the key enzyme in pro-inflammatory leukotriene (LT) formation, in cell-free assays with IC 50 = 0.19–0.49 µM. Employing metabololipidomics using ultra-performance liquid chromatography coupled to tandem mass spectrometry in activated human polymorphonuclear leukocytes or M1 macrophages we found that CS (1 µM) potently suppresses 5-LOX-derived products without impairing the formation of lipid mediators (LM) formed by 12-/15-LOXs as well as fatty acid substrate release. Intriguingly, CS induced the generation of 12-/15-LOX-derived LM including the specialized pro-resolving mediator (SPM) resolvin D5 in human M2 macrophages. Finally, intraperitoneal pre-treatment of mice with 10 mg/kg CS strongly impaired zymosan-induced LT formation and simultaneously elevated the levels of SPM and related 12-/15-LOX-derived LM in peritoneal exudates, spleen and plasma in vivo. Conclusively, CS promotes a switch from LT biosynthesis to formation of SPM which may underlie the anti-inflammatory and inflammation-resolving effects of CS, representing an interesting pharmacological strategy for intervention with inflammatory disorders. [Display omitted] • 5-LOX is a high affinity target for celastrol (CS) with IC 50 of 0.19–0.49 µM. • CS blocks 5-LOX-derived leukotriene formation in PMNL and M1 macrophages. • in M2 macrophages CS elicits specialized pro-resolving mediator (SPM) formation. • CS impairs the levels of leukotrienes but elevates SPM in murine peritonitis. [ABSTRACT FROM AUTHOR]