β-Glucuronidase (GLU) as a vital factor in enterohepatic circulation and drug-inducing enteropathy has been given more and more attention in recent years. In this study, an off-on near-infrared (NIR) fluorescent probe (DDAO-glu) for selectively and sensitively sensing GLU was developed on the basis of its substrate preference. DDAO-glu can rapidly and selectively respond to bacterial GLU under physiological conditions for detecting the real-time intestinal GLU bioactivity of complex biological systems such as human feces in clinic. Meantime, DDAO-glu has been successfully applied for visualization of endogenous GLU in bacterial biofilm, thallus, and even in vivo. Using this NIR probe, we successfully visualized the real distribution of intestinal GLU in the enterohepatic circulation. Furthermore, a high-throughput screening method was successfully established by our probe, and a potent natural inhibitor of GLU was identified as (-)-epicatechin-3-gallate (ECG) for effectively preventing NSAIDs-inducing enteropathy in vivo. DDAO-glu could serve as a powerful tool for exploring real physical functions of intestinal GLU in enterohepatic circulation, under physiological and pathological contexts, and developing the novel inhibitors of GLU to therapy acute drug-inducing enteropathy in clinic.
The tumor microenvironment (TME) enhances regulatory T (T
reg
) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as T
reg
fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying T
reg
fitness. We demonstrate that TME-specific stressors including transforming growth factor–β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 (
Usp22
) and
Usp21
, by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain T
reg
fitness. Simultaneous deletion of both USPs in T
reg
cells largely diminishes TME-induced Foxp3 up-regulation, alters T
reg
metabolic signatures, impairs T
reg
-suppressive function, and alleviates T
reg
suppression on cytotoxic CD8
+
T cells. Furthermore, we developed the first
Usp22
-specific small-molecule inhibitor, which dramatically reduced intratumoral T
reg
Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying T
reg
fitness and identify
Usp22
as an antitumor therapeutic target that inhibits T
reg
adaptability in the TME.
The recent emerged SARS-CoV-2 may first transmit to intermediate animal host from bats before the spread to humans. The receptor recognition of ACE2 protein by SARS-CoVs or bat-originated coronaviruses is one of the most important determinant factors for the cross-species transmission and human-to-human transmission. To explore the hypothesis of possible intermediate animal host, we employed molecular dynamics simulation and free energy calculation to examine the binding of bat coronavirus with ACE2 proteins of 47 representing animal species collected from public databases. Our results suggest that intermediate animal host may exist for the zoonotic transmission of SARS-CoV-2. Furthermore, we found that tree shrew and ferret may be two putative intermediate hosts for the zoonotic spread of SARS-CoV-2. Collectively, the continuous surveillance of pneumonia in human and suspicious animal hosts are crucial to control the zoonotic transmission events caused by SARS-CoV-2.
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