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Inflammatory responses mediated by activated microglia play a pivotal role in the pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders. Studies on identification of specific targets to control microglia activation and resultant neurotoxic activity are imperative. Increasing evidence indicate that voltage-gated K+ (Kv) channels are involved in the regulation of microglia functionality. In this study, we investigated Kv1.3 channels in the regulation of neurotoxic activity mediated by HIV-1 glycoprotein 120 (gp120)-stimulated rat microglia. Our results showed treatment of microglia with gp120 increased the expression levels of Kv1.3 mRNA and protein. In parallel, whole-cell patch-clamp studies revealed that gp120 enhanced microglia Kv1.3 current, which was blocked by margatoxin, a Kv1.3 blocker. The association of gp120 enhancement of Kv1.3 current with microglia neurotoxicity was demonstrated by experimental results that blocking microglia Kv1.3 attenuated gp120-associated microglia production of neurotoxins and neurotoxicity. Knockdown of Kv1.3 gene by transfection of microglia with Kv1.3-siRNA abrogated gp120-associated microglia neurotoxic activity. Further investigation unraveled an involvement of p38 MAPK in gp120 enhancement of microglia Kv1.3 expression and resultant neurotoxic activity. These results suggest not only a role Kv1.3 may have in gp120-associated microglia neurotoxic activity, but also a potential target for the development of therapeutic strategies. 相似文献
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《Journal of molecular biology》2021,433(22):167254
Tau is an intrinsically disordered protein implicated in many neurodegenerative diseases. The repeat domain fragment of tau, tau-K18, is known to undergo a disorder to order transition in the presence of lipid micelles and vesicles, in which helices form in each of the repeat domains. Here, the mechanism of helical structure formation, induced by a phospholipid mimetic, sodium dodecyl sulfate (SDS) at sub-micellar concentrations, has been studied using multiple biophysical probes. A study of the conformational dynamics of the disordered state, using photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS) has indicated the presence of an intermediate state, I, in equilibrium with the unfolded state, U. The cooperative binding of the ligand (L), SDS, to I has been shown to induce the formation of a compact, helical intermediate (IL5) within the dead time (∼37 µs) of a continuous flow mixer. Quantitative analysis of the PET-FCS data and the ensemble microsecond kinetic data, suggests that the mechanism of induction of helical structure can be described by a U ↔ I ↔ IL5 ↔ FL5 mechanism, in which the final helical state, FL5, forms from IL5 with a time constant of 50–200 µs. Finally, it has been shown that the helical conformation is an aggregation-competent state that can directly form amyloid fibrils. 相似文献
45.
Masayo Suzuki Hiroyuki Ishida Yukimasa Shiotsu Taisuke Nakata Shiro Akinaga Shigemitsu Takashima Toshiaki Utsumi Toshiaki Saeki Nobuhiro Harada 《The Journal of steroid biochemistry and molecular biology》2009,113(3-5):195-201
In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17β-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor β, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues. 相似文献
46.
《Journal of molecular biology》2021,433(21):167224
Retinoblastoma-binding protein 1 (RBBP1) is involved in gene regulation, epigenetic regulation, and disease processes. RBBP1 contains five domains with DNA-binding or histone-binding activities, but how RBBP1 specifically recognizes chromatin is still unknown. An AT-rich interaction domain (ARID) in RBBP1 was proposed to be the key region for DNA-binding and gene suppression. Here, we first determined the solution structure of a tandem PWWP-ARID domain mutant of RBBP1 after deletion of a long flexible acidic loop L12 in the ARID domain. NMR titration results indicated that the ARID domain interacts with DNA with no GC- or AT-rich preference. Surprisingly, we found that the loop L12 binds to the DNA-binding region of the ARID domain as a DNA mimic and inhibits DNA binding. The loop L12 can also bind weakly to the Tudor and chromobarrel domains of RBBP1, but binds more strongly to the DNA-binding region of the histone H2A-H2B heterodimer. Furthermore, both the loop L12 and DNA can enhance the binding of the chromobarrel domain to H3K4me3 and H4K20me3. Based on these results, we propose a model of chromatin recognition by RBBP1, which highlights the unexpected multiple key roles of the disordered acidic loop L12 in the specific binding of RBBP1 to chromatin. 相似文献
47.
Elucidation of the pathogenesis in respiratory chain diseases is of great importance for developing specific treatments. The limitations inherent to the use of patient material make studies of human tissues often difficult and the mouse has therefore emerged as a suitable model organism for studies of respiratory chain diseases. In this review, we present an overview of the field and discuss in depth a few examples of animal models reproducing pathology of human disease with primary and secondary respiratory chain involvement. 相似文献
48.
Bird specimens collected by 19th century explorer and ornithologist Prince Maximilian of Wied-Neuwied form one of the foundation collections of the American Museum of Natural History in New York. However, parts of his collection remained in Germany and came to the Museum Wiesbaden. Since Wied described numerous new species without designating types, some of these specimens might be type material. Here we present a catalog of the 30 Wiesbaden specimens associated with him and discuss their potential type status. We conclude that 17 individuals in 11 species are potential type specimens that should be considered in future taxonomic work. 相似文献
49.
The gorgoniid Eugorgia is exclusively an eastern Pacific genus. It has a wide geographic and bathymetric range of distribution, found from California to Perú and extends down to 65 m deep. Two new species are herein described. The morphological characters were analyzed and illustrated by light and scanning electron microscopy. Eugorgia beebei
sp. n. can be distinguished by its white, ascending, sparse colony growth. Eugorgia mutabilis
sp. n. can be distinguished by its white colony that changes color after collection, and the conspicuous sharp-crested disc sclerites. From a morphological point of view the new species are related to the daniana-group, the rubens-group and the siedenburgae-group of Eugorgia; their affiliations, and the proposal of a new group are discussed. These new species increases the number of species in the genus to 15, and contribute to the knowledge of the eastern Pacific octocoral biodiversity. 相似文献
50.