Nanotherapeutics targeting autophagy regulation for improved cancer therapy

The clinical efficacy of current cancer therapies falls short,and there is a pressing demand to integrate new targets with conventional therapies.Autophagy,a highly conserved self-degradation process,has received considerable attention as an emerging therapeutic target for cancer.With the rapid development of nanomedicine,nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance.Hence,considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy,we outline the latest advances in autophagy-based nanotherapeutics.Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression,the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated.Further,emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways,including modulation of the mammalian target of rapamycin(mTOR)pathway,autophagy-related(ATG)and its complex expression,reactive oxygen species(ROS)and mitophagy,interference with autophagosome-lysosome fusion,and inhibition of hypoxia-mediated autophagy.In addition,combination therapies in which nano-autophagy modulation is combined with chemotherapy,phototherapy,and immunotherapy are also described.Finally,the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.

An overview of autophagy in the differentiation of dental stem cells

Dental stem cells(DSCs)have attracted significant interest as autologous stem cells since they are easily accessible and give a minimal immune response.These properties and their ability to both maintain self-renewal and undergo multi-lineage differentiation establish them as key players in regenerative medicine.While many regulatory factors determine the differentiation trajectory of DSCs,prior research has predominantly been based on genetic,epigenetic,and molecular aspects.Recent evidence suggests that DSC differentiation can also be influenced by autophagy,a highly conserved cellular process responsible for maintaining cellular and tissue homeostasis under various stress conditions.This comprehensive review endeavors to elucidate the intricate regulatory mechanism and relationship between autophagy and DSC differentiation.To achieve this goal,we dissect the intricacies of autophagy and its mechanisms.Subsequently,we elucidate its pivotal roles in impacting DSC differentiation,including osteo/odontogenic,neurogenic,and angiogenic trajectories.Furthermore,we reveal the regulatory factors that govern autophagy in DSC lineage commitment,including scaffold materials,pharmaceutical cues,and the extrinsic milieu.The implications of this review are far-reaching,underpinning the potential to wield autophagy as a regulatory tool to expedite DSC-directed differentiation and thereby promote the application of DSCs within the realm of regenerative medicine.

Low Level of Cystic Fibrosis Transmembrane Conductance Regulator Is Associated with Human Sperm Autophagy and Vitality

Low sperm motility is one of the main causes of male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR, an anion channel protein) is related to the progressive motility of sperm. CFTR disruptor CFTRinh-172 or forskolin (FSK) in this study were used to treat human sperm separately, and the rates of sperm autophagy and progressive motility, mitochondrial membrane potential (MMP) and ATP concentration, and the expression levels of related factors were detected to explore their relationship. It was showed that sperms treated with CFTRinh-172 or FSK reduced the levels of cAMP, CFTR and PKA, but increased sperm autophagy rate, expression levels of AMPK and LC3B. However, reactive oxygen species content had no significant difference. It was indicated that low level of CFTR performed with cAMP and its downstream effectors such as PKA and AMPK to regulate mitochondrial structure and function, leading to increased autophagy rate and reduced vitality of sperm.

Dynamic Imaging of Autophagy-lysosomal Pathway and Autophagy Function Following Pulmonary Hypoxia/Reoxygenation In Vitro

Alterations of the autophagy-lysosomal pathway（ALP） and autophagy have been involved in lung ischemia-reperfusion（I/R） injury. However, dynamic imaging of ALP function under lung I/R injury particularly is not fully understood. Here we depicted the live-cell fluorescence imaging of autophagosome to monitor ALP activation and autophagy function. The p As Red2-N1-LC3 vectors were transfected into CRL-2192 NR8383（an alveolar macrophage cell line） and CCL149（an alveolar epithelial cell line） successfully. 0-h, 2-h, 4-h, and 6-h hypoxia/0-h, 2-h, 4-h, and 6-h reoxygenation were then induced with an ALP inhibitor（3-MA） or activator（rapamycin） in the culture of transfected cells separately. ALP activation was conformed by up-regulating AMPK and beclin1 expression. Apoptosis was not obvious in 2-h hypoxia/2-h reoxygenation. p As Red2-N1-LC3 CCL149 and p As Red2-N1-LC3 NR8383 cells revealed gradually enhanced As Red2 from 2-h to 6-h hypoxia/reoxygenation. As Red2 varied sensitively to 3-MA and rapamycin interventions during 2-h hypoxia/reoxygenation. Our data provides a simple method of autophagosome imaging to monitor ALP activation and autophagy function in lung I/R injury.

Drug discovery by targeting the protein–protein interactions involved in autophagy

Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation.Protein–protein interactions(PPIs)play a crucial role at many stages of autophagy,which present formidable but attainable targets for autophagy regulation.Moreover,selective regulation of PPIs tends to have a lower risk in causing undesired off-target effects in the context of a complicated biological network.Thus,small-molecule regulators,including peptides and peptidomimetics,targeting the critical PPIs involved in autophagy provide a new opportunity for innovative drug discovery.This article provides general background knowledge of the critical PPIs involved in autophagy and reviews a range of successful attempts on discovering regulators targeting those PPIs.Successful strategies and existing limitations in this field are also discussed.