Search

CYtochrome P450, family 51 (CYP51) is an important enzyme for de novo cholesterol synthesis in mammalian cells. In the present study, we found that the expression of CYP51 positively correlated with CD4+ T cell activation both in vivo and in vitro. The addition of ketoconazole, a pharmacological inhibitor of CYP51, prevented the proliferation and activation of anti-CD3/CD28-expanded mouse CD4+ T cells in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry indicated an increase in levels of lanosterol in T cells treated with ketoconazole during activation. Ketoconazole-induced blockade of the cholesterol synthesis pathway also caused Sterol regulatory element binding protein 2 (SREBP2) activation in CD4+ T cells. Additionally, ketoconazole treatment elicited an integrated stress response in T cells that up-regulated activating transcription factor 4 (ATF4) and DNA-damage inducible transcript 3 (DDIT3/CHOP) at the translational level. Furthermore, treatment with ketoconazole significantly decreased the amount of CD4+ T cells infiltrating lesions in the submandibular glands of NOD/Ltj mice. In summary, our results suggest that CYP51 plays an essential role in the proliferation and survival of CD4+ T cells, which makes ketoconazole an inhibitor of CD4+ T cell proliferation and of the SS-like autoimmune response through regulating the biosynthesis of cholesterol and inducing the integrated stress response. [ABSTRACT FROM AUTHOR]

Deep eutectic solvents (DESs) are a new class of green solvents analogous to ionic liquids due to their biodegradable capacity and low cost. However, the direct extractive desulfurization of diesel oil by DESs cannot meet the government’s standard. In this work, amphiphilic polyoxometalates were synthesized and characterized by FT-IR and mass spectrometry. The oxidative desulfurization results showed that benzothiophene (BT) could be completely removed by employing a [(C6H13)3P(C14H29)]3PMo12O40, DES (ChCl/2Ac) and H2O2 system. It was also found that the organic cation of catalysts played a positive role in oxidative desulfurization. The reaction conditions, such as reaction temperature and time, the amount of catalyst and DES and H2O2/S (O/S) molar ratio, were optimized. Different sulfides were tested to determine the desulfurization selectivity of the optimal reaction system, and it was found that 97.2% of dibenzothiophene (DBT) could be removed followed by 80.7% of 4-MDBT and 76.0% of 4,6-DMDBT. After reaction, the IR spectra showed that the catalyst [(C6H13)3P(C14H29)]3PMo12O40 was stable during the reaction process and the oxidative product was dibenzothiophene sulfone (DBTO2). Furthermore, the catalyst can be regenerated and recycled for four runs with little loss of activity. [ABSTRACT FROM AUTHOR]

Introduction: Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4 + T cells. Thus, interventions targeting abnormal activation of CD4 + T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4 + T-cell activation and SS pathophysiology. Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4 + T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy. Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4 + T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4 + T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice. Conclusion: These findings suggest that HUWE1 may regulate CD4 + T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DX declared a shared affiliation with the authors JY, JX, CC, XM, HZ, LX, BW, YS, CY, JF, and LZ to the handling editor at the time of review., (Copyright © 2023 Yin, Xu, Chen, Ma, Zhu, Xie, Wang, Shao, Zhao, Wei, Hu, Zheng, Yu, Fu and Zheng.)