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Exosomes are vesicles secreted by a variety of cell types. They can release their cargo into the extracellular environment or transfer their contents to other cells, as a form of intercellular communication. Therefore, exosomes are vital to both physiological and pathological functions. Autophagy is a process of intracellular degradation of unnecessary or dysfunctional cellular components such as damaged organelles and misfolded proteins. It is initiated by various environmental stressors and mediated by lysosomes. Under physiological conditions, autophagy exists in cells at basal levels to support cellular metabolism and help maintain self-homeostasis. In other circumstances, autophagy can contribute to the initiation and progression of disease. Recent studies have revealed that exosomal and autophagic pathways can be regulated by each other and play important roles in health and disease. However, the cross-regulation between these pathways is highly intricate, and the effects on exosomal trafficking and autophagy are environment-dependent. Here, we summarize the recent advances in understanding the cross-regulation between the exosomal and autophagic pathways, and their involvement in multiple diseases, which can help develop novel strategies for their prevention and treatment. From the evidence summarized in this review, we conclude: 1) exosomal trafficking plays a beneficial or harmful role in disease through the regulation of autophagy; 2) autophagy is vital in disease by regulating the generation of exosomes; and 3) the cross-regulation between exosomal and autophagic pathways may be promising targets for disease prevention and treatment, while this needs to be clarified in future investigations.

Metabolic stress induces autophagy as a protective mechanism in tumorigenesis and development. Conversely, excessive autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. DT-13, the saponin monomer 13 of the Dwarf lilyturf tuber, inhibited tumor metastasis and angiogenesis in previous studies. However, there is scarcity of data regarding the effect of DT-13 on autophagy process. Here, we demonstrated that DT-13 induced autophagy in human cancer cell lines and caused significant cell apoptosis under nutrient starvation. We firstly showed that DT-13 increased the accumulation of GFP-LC3 puncta and induced the expression of LC3-II in a dose- and time-dependent manner. DT-13 also upregulated the expression of Beclin-1, Atg-3 and Atg-7, and induced autophagic flux in human gastric cancer BGC-823 cells. We next found that low-toxic concentrations of DT-13 significantly induced apoptosis under nutrient deprivation. We finally demonstrated that the PI3K/Akt/mTOR signal pathway was involved in the cytotoxic effect of DT-13. Our data indicated that DT-13 was a novel autophagy inducer and might be considered in future treatment of cancer., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Vitamin D3 is believed to be a contributing factor to innate immunity. Vitamin D receptor (VDR) has a positive effect on inhibiting nuclear factor κB (NF-κB)-mediated inflammation. The underlying molecular mechanisms remain unclear, particularly in mollusks. Consequently, this study will investigate the process of vitamin D3/VDR regulating NF-κB pathway and further explore their functions on inflammation, autophagy, and apoptosis in abalone Haliotis discus hannai. Results showed that knockdown of VDR by using siRNA and dsRNA of VDR in vitro and in vivo led to more intense response of NF-κB signaling to lipopolysaccharide and higher level of apoptosis and autophagy. In addition, 1,25(OH)2D3 stimulation after VDR silencing could partially alleviate apoptosis and induce autophagy. Overexpression of VDR restricted the K48-polyubiquitin chain-dependent inhibitor of κB (IκB) ubiquitination and apoptosis-associated speck-like protein containing CARD (ASC) oligomerization. Besides, VDR silencing resulted in increase of ASC speck formation. In further mechanistic studies, we showed that VDR can directly bind to IκB and IKK1 in vitro and in vivo. In the feeding trial, H&E staining, TUNEL, and electron microscope results showed that vitamin D3 deficiency (0 IU/kg) could recruit more basophilic cells and increase more TUNEL-positive apoptotic cells and lipid droplets (LDs) than vitamin D3 supplement (1000 IU/kg and 5000 IU/kg). In summary, abalone VDR plays a negative regulator role in NF-κB-mediated inflammation via interacting with IκB and inhibiting ubiquitin-dependent degradation of IκB. Vitamin D3 in combination with VDR is essential to establish a delicate balance between autophagy and apoptosis in response to inflammation. [ABSTRACT FROM AUTHOR]

Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e , encoded KWLX-12e , with good inhibitory activity against PARP1 (IC 50 = 6.89 nM) and EZH2 (IC 50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC 50 = 2.84 μM) and BT-549 cells (IC 50 = 0.91 μM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC. [Display omitted] • Novel dual-target PARP1/EZH2 inhibitors were designed and synthesized. • KWLX-12e showed potential inhibitory activity on PARP1/EZH2 and had no toxicity. • KWLX-12e increased sensitivity to PARP1 by inhibiting EZH2. • KWLX-12e could significantly inhibit tumor growth and proliferation. [ABSTRACT FROM AUTHOR]

CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily and expressed in both normal and malignant lymphoid cells. However, the role of CD30 in lymphopoiesis is not known. In this study, we showed CD30 was expressed both in T and B cells, but its deficiency in mice had no effect on T‐ and B‐cell development. In fact, CD30 deficiency attenuated B‐cell response to T‐cell‐dependent antigens. The impaired B cell response in CD30‐deficient mice is caused by the reduction of activation‐induced cytidine deaminase (AID) expression. Moreover, CD30‐deficient mice exhibited decreased TCR‐mediated T cell proliferation and slightly impaired TCR signaling. High‐throughput RNA sequencing analysis revealed that CD30 deficiency led to a decrease of FOXO‐autophagy axis in T cells upon TCR stimulation. Thus, CD30 positively regulates T‐cell‐dependent immune response and T cell proliferation. [ABSTRACT FROM AUTHOR]