Objective
Scavenger receptor BI (SR-BI) is an HDL receptor. Recent studies revealed that SR-BI protects against sepsis via modulating innate immunity. However, its role in adaptive immunity is unclear.
Methods and Results
SR-BI null mice exhibited impaired lymphocyte homeostasis as shown by splenomegaly and imbalanced expansion of T and B lymphocytes in the spleens. Importantly, the activated T and B lymphocytes were increased 3–4-fold, indicating a heightened active status of T and B lymphocytes. More importantly, in line with the accumulation of the activated T and B lymphocytes, SR-BI null mice developed systemic autoimmune disorders characterized by the presence of autoantibodies in circulation, the deposition of immune complexes in glomeruli, and the leukocyte infiltration in kidney. Further analyses revealed that SR-BI deficiency enhances lymphocyte proliferation, causes imbalanced IFN-g and IL-4 production in lymphocytes and elevated inflammatory cytokine production in macrophages. Furthermore, HDL from SR-BI null mice exhibited less capability of suppressing lymphocyte proliferation.
Conclusions
SR-BI regulates lymphocyte homeostasis likely through its roles in modulating the proliferation of lymphocytes, the cytokine production by lymphocytes and macrophages, and the function of HDL. Its deficiency leads to impaired lymphocyte homeostasis and autoimmune disorders. Our findings reveal a previously unrecognized role of SR-BI in adaptive immunity.
Selective modulation of the heterotrimeric G protein α S subunit–coupled prostaglandin E2 (PGE2) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo–electron microscopy structure of the EP2-Gs complex with its endogenous agonist PGE2 and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W6.48 “toggle switch” and coupling to Gs via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE2 signaling system.
By incorporating an anthracene moiety into a framework, a multiresponsive luminescent metal–organic framework (1) has been synthesized, which exhibits both direct chemiluminescence (CL) and dual tunable photoluminescence. By utilizing the CL, 1 has been explored as a selective visual sensor for hydrogen peroxide. Moreover, 1 also exhibits tunable fluorescence response toward different analytes. For electron‐rich aromatics, “turn‐on” and “turn‐off” responses can be simply switched by varying the excitation wavelength. For nitroaromatics, 1 exhibits novel linear quantitative quenching response. Density functional theory (DFT) calculations and experiments have been carried out to study the unique fluorescence response. The multiple luminescence properties and dual tunable sensing response indicate that incorporating anthracene moieties into frameworks should be a promising strategy to develop unprecedented luminescent materials with remarkable sensing properties.
Hjm and Hel308a are novel, RecQ-like DNA helicases recently identified in the euryarchaeotes Pyrococcus furiosus and Methanothermobacter thermautotrophicus, respectively. In this study, an Hjm/Hel308 homologue (designated StoHjm) from Sulfolobus tokodaii, a hyperthermophilic archaeon belonging to the Crenarchaeota subdomain of archaea, was cloned, purified, and characterized. Unlike Hjm and Hel308a, which unwind DNA in a 3-to-5 direction, StoHjm unwound DNA in both 3-to-5 and 5-to-3 directions. Remarkably, StoHjm exhibited structure-specific single-stranded-DNA-annealing and fork regression activities in vitro. In addition, gel filtration, affinity pulldown, and yeast two-hybrid analyses revealed that StoHjm physically interacted with StoHjc, the Holliday junction-specific endonuclease from S. tokodaii. This interaction may have functional significance, because the unwinding activity of StoHjm was inhibited by StoHjc in vitro. These results may suggest that the Hjm/Hel308 family helicases, in association with Hjc endonucleases, are involved in processing of stalled replication forks.
Lung cancer is the most common malignancy and leads to around one-quarter of all cancer deaths. Great advances have been achieved in the treatment of lung cancer with novel anticancer agents and improved technology. However, morbidity and mortality rates remain extremely high, calling for an urgent need to develop novel anti–lung cancer agents. 1,2,3-Triazole could be readily interact with diverse enzymes and receptors in organisms through weak interaction. 1,2,3-Triazole can not only be acted as a linker to tether different pharmacophores but also serve as a pharmacophore. This review aims to summarize the recent advances in 1,2,3-triazole–containing compounds with anti–lung cancer potential, and their structure–activity relationship (SAR) together with mechanisms of action is also discussed to pave the way for the further rational development of novel anti–lung cancer candidates.
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