Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury

Naturally occurring compounds polyphenols are secondary metabolites of plants, comprised several categories, namely, flavonoids, phenolic acids, lignans and stilbenes. The biological aging process is driven by a series of interrelated mechanisms, including oxidative stress, inflammation status, and autophagy function, through diverse signaling pathways. Moreover, the crucial role of gut microbiota in regulating aging and health status was widely demonstrated. In recent years, the potential anti-aging benefits of polyphenols have been gaining increasing scientific interest due to their capability to modulate oxidative damage, inflammation, autophagy, and gut microbiota. This review highlights the influence of polyphenols in preventing aging disorders and augmenting lifespan based on the influence of oxidative stress, inflammation, autophagy, and gut microbiota, and encourages research on novel polyphenol-based strategies and clinical trials to develop a nutrition-oriented holistic anti-aging therapy.

Potential Implications of Polyphenols on Aging Considering Oxidative Stress, Inflammation, Autophagy, and Gut Microbiota

Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly inhibitors, has been the mainstream in drug development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells' own destruction machinery. In addition to PROTAC, many different targeted protein degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC), are emerging. These technologies have not only greatly expanded the scope of TPD, but also provided fresh insights into drug discovery. Here, we summarize recent advances of major TPD technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field. 

/pdf/targeted-protein-degradation-mechanisms-strategies-and-1wijifzl.pdf

Targeted protein degradation: mechanisms, strategies and application

Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs' modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small-molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.

Death-associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes.

Gene therapy for neurodegenerative disorders: advances, insights and prospects

Targeting autophagy-related protein kinases for potential therapeutic purpose.

Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones and nonhistone proteins via tandem bromodomains and regulate chromatin dynamics, cellular processes, and disease procession. Thus targeting BET proteins is a promising strategy for treating various diseases, especially malignant tumors and chronic inflammation. Many pan-BET small-molecule inhibitors have been described, and some of them are in clinical evaluation. Nevertheless, the limited clinical efficacy of the current BET inhibitors is also evident and has inspired the development of new technologies to improve their clinical outcomes and minimize unwanted side effects. In this Review, we summarize the latest protein characteristics and biological functions of BRD4 as an example of BET proteins, analyze the clinical development status and preclinical resistance mechanisms, and discuss recent advances in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis targeting chimera degraders, and protein-protein interaction inhibitors.

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy

A series of tools for targeted protein degradation are inspiring scientists to develop new drugs with advantages over traditional small-molecule drugs. Among these tools, proteolysis-targeting chimeras (PROTACs) are most representative of the technology based on proteasomes. However, the proteasome has little degradation effect on certain macromolecular proteins or aggregates, extracellular proteins, and organelles, which limits the application of PROTACs. Additionally, lysosomes play an important role in protein degradation. Therefore, lysosome-induced protein degradation drugs can directly regulate protein levels in vivo, achieve the goal of treating diseases, and provide new strategies for drug discovery. Lysosome-based degradation technology has the potential for clinical translation. In this review, strategies targeting lysosomal pathways and lysosome-based degradation techniques are summarized. In addition, lysosome-based degrading drugs are described, and the advantages and challenges are listed. Our efforts will certainly promote the design, discovery, and clinical application of drugs associated with this technology.

Targeting Lysosomal Degradation Pathways: New Strategies and Techniques for Drug Discovery.

Epidermal growth factor receptor (EGFR), the receptor for members of the epidermal growth factor family, regulates cell proliferation and signal transduction; moreover, EGFR is related to the inhibition of tumor cell proliferation, angiogenesis, invasion, metastasis, and apoptosis. Therefore, EGFR has become an important target for the treatment of cancer, including non-small cell lung cancer, head and neck cancer, breast cancer, glioma, cervical cancer, and bladder cancer. First- to third-generation EGFR inhibitors have shown considerable efficacy and have significantly improved disease prognosis. However, most patients develop drug resistance after treatment. The challenge of overcoming intrinsic and acquired resistance in primary and recurrent cancer mediated by EGFR mutations is thus driving the search for alternative strategies in the design of new therapeutic agents. In view of resistance to third-generation inhibitors, understanding the intricate mechanisms of resistance will offer insight for the development of more advanced targeted therapies. In this review, we discuss the molecular mechanisms of resistance to third-generation EGFR inhibitors and review recent strategies for overcoming resistance, new challenges, and future development directions. 

/pdf/emerging-strategies-to-overcome-resistance-to-third-17ki1qra.pdf

Jifa Zhang

Papers

Targeting autophagy-related protein kinases for potential therapeutic purpose.

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy

Targeting Lysosomal Degradation Pathways: New Strategies and Techniques for Drug Discovery.

Emerging strategies to overcome resistance to third-generation EGFR inhibitors