Signal Transduction and Targeted Therapy最新文献

Correction to: Signal Transduction and Targeted Therapy https://doi.org/10.1038/sigtrans.2017.13, published online 26 May 2017

Brincidofovir (BCV) and tecovirimat are the only two chemical drugs that have been approved to treat smallpox and can be requested for monkeypox (Mpox) treatment through a single-patient Emergency Investigational New Drug (EIND) application. Disappointedly, the efficacy of tecovirimat manifested in recent clinical trials is far from being satisfactory, while the clinical efficacy of BCV is still inconclusive. Given that monkeypox virus (MPXV), variola and other emerging orthopoxviruses are posing serious threats to global health, it is urgent to develop better therapeutics. In this study, we tested the antiviral effects of three novel prodrugs, which were designed based on previously reported parent drugs, either (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine ((S)-HPMPC, cidofovir) or (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA). We found that one of the (S)-HPMPA-based prodrugs, ODE-(S)-HPMPA formate, exhibited significantly better anti-orthopoxvirus activity than BCV both in vitro and in vivo, which also inhibited human adenovirus type 2 and type 21 more efficiently than BCV. Most strikingly, the EC₅₀ and EC₉₀ of ODE-(S)-HPMPA formate against MPXV were more than 40-fold lower than those of BCV. In contrast, we observed that the anti-herpes simplex virus type 1 (HSV-1) activities of the (S)-HPMPA-based prodrugs were less effective than those of the cidofovir-based prodrugs (BCV and BCV formate), especially in vivo. Moreover, we showed for the first time that cytidine and adenine analog combined therapies could provide mice with complete protection against lethal challenges of both vaccinia and HSV-1. Collectively, we propose that both the ODE-(S)-HPMPA formate and the BCV/ODE-(S)-HPMPA formate combination are worth further investigations for their potential clinical applications.

In a recent study published in Cancer Cell, Braun et al. introduced extracorporeal photopheresis (ECP) as a novel immunomodulatory approach to mitigate immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) without compromising anti-tumor immunity.¹ ECP suppressed Th1/Trm cell activation and neutrophil infiltration while enhancing an anti-inflammatory macrophage phenotype through adiponectin, facilitating the resolution of steroid-refractory irAEs.

Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). The goal of this work is to examine how AKAP12’s PKA-anchoring ability regulates outcomes of alcohol-associated steatosis. Crosslinking proteomics identified PKA and its lipogenic substrates as interacting partners of AKAP12. Alcohol exposure diminished AKAP12’s interaction with PKA regulatory subunits and PKA substrates, acetyl CoA carboxylase (ACC1), pyruvate dehydrogenase (PDHA) and adipose triglyceride lipase (ATGL). Alcohol inhibited PKA activity and increased triglyceride content in human hepatocytes. Forced expression of AKAP12 restored alcohol suppressed PKA activation and inhibited lipid accumulation, whereas silencing had the reverse effect. Since AKAP12 sustained PKA activity, we evaluated whether the AKAP12-PKA scaffold was important in lipid homeostasis. Inhibition of AKAP12-PKA interaction by CRISPR deletion of AKAP12’s PKA binding domain in cultured hepatocytes or in mouse models of ALD dramatically suppressed PKA activity, enhanced ACC1 activity demonstrated by reduced inhibitory phosphorylation, increased lipid accumulation and reduced FAO in hepatocytes. Overexpression of AKAP12 in mouse livers sustained PKA activation, diminished basal and alcohol potentiated triglyceride content, and regulated inflammatory signaling altered by alcohol. Mechanistically, we discovered that alcohol enhanced the inhibitory activity of a kinase, serine/threonine-protein kinase 25 (STK25) on PKA that regulated its interaction with AKAP12. In conclusion, the AKAP12-PKA scaffold controls lipogenic signaling, disruption of which favors steatosis during ALD.

A recent study published in Nature by Maya M. Arce and colleagues unveils the role of central gene circuits in governing the delicate balance between T cell rest and T cell activation.¹ This work bridges fundamental molecular biology with findings in preclinical models, providing insights into context-specific gene regulation and potential therapeutic targets for immune modulation.

Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events. However, effective strategies for preventing or treating advanced atherosclerosis and calcification are currently lacking. This study investigated the efficacy of DT-109 (Gly-Gly-Leu) in attenuating atherosclerosis and calcification in nonhuman primates, exploring its broader therapeutic potential. In this study, twenty male cynomolgus monkeys were administered a cholesterol-rich diet ad libitum for 10 months. Then, the animals were treated either orally with DT-109 (150 mg/kg/day) or a vehicle (H₂O) for 5 months while continuing on the same diet. Plasma lipid levels were measured monthly and at the end of the experiment, pathological examinations of the aortas and coronary arteries and RNA sequencing of the coronary arteries were performed. To explore possible molecular mechanisms, the effects of DT-109 on smooth muscle cells (SMCs) were examined in vitro. We found that DT-109 administration significantly suppressed atherosclerotic lesion formation in both the aorta and coronary arteries. Pathological examinations revealed that DT-109 treatment reduced lesional macrophage content and calcification. RNA sequencing analysis showed that DT-109 treatment significantly downregulated the pro-inflammatory factors NLRP3, AIM2, and CASP1, the oxidative stress factors NCF2 and NCF4, and the osteogenic factors RUNX2, COL1A1, MMP2, and MMP9, while simultaneously upregulating the expression of the SMCs contraction markers ACTA2, CNN1, and TAGLN. Furthermore, DT-109 inhibited SMC calcification and NLRP3 inflammasome activation in vitro. These results demonstrate that DT-109 effectively suppresses both atherosclerosis and calcification. These findings, in conjunction with insights from our previous studies, position DT-109 as a novel multifaceted therapeutic agent for cardiovascular diseases.

The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling’s involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.

Correction to: Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-020-00447-6, published online 19 February 2021