Flaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV), represent a substantial public health challenge as there are currently no approved treatments available. Here, we investigated the antiviral effects of bis-benzylisoquinoline alkaloids (BBAs) on flavivirus infections. We evaluated five specific BBAs-berbamine, tetrandrine, iso-tetrandrine, fangchinoline, and cepharanthine-and found that they effectively inhibited infections by ZIKV, DENV, or JEV by blocking virus entry and genome replication stages in the flavivirus life cycle.
View Article and Find Full Text PDF(1) Background: Bovine viral diarrhea virus (BVDV) causes calf diarrhea, bovine respiratory syndrome, and cow abortion, resulting in substantial economic losses in the cattle industry. Owing to its persistent infection mechanism, BVDV is a major challenge in the treatment of cattle. (2) Methods: To determine how metformin (Met) inhibits the interaction between BVDV and host cells, we treated BVDV-infected cells with Met.
View Article and Find Full Text PDFBackground: Many viruses enter host cells by hijacking endosomal trafficking. CapZ, a canonical actin capping protein, participates in endosomal trafficking, yet its precise role in endocytosis and virus infection remains elusive.
Results: Here, we showed that CapZ was transiently associated with early endosomes (EEs) and was subsequently released from the matured EEs after the fusion of two EEs, which was facilitated by PI(3)P to PI(3,5)P2 conversion.
We previously identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as one of the cyclic adenosine diphosphoribose (cADPR)'s binding proteins and found that GAPDH participates in cADPR-mediated Ca release from endoplasmic reticulum via ryanodine receptors (RyRs). Here, we aimed to chemically synthesise and pharmacologically characterise novel cADPR analogues. Based on the simulated cADPR-GAPDH complex structure, we performed the structure-based drug screening, identified several small chemicals with high docking scores to cADPR's binding pocket in GAPDH and showed that two of these compounds, C244 and C346, are potential cADPR antagonists.
View Article and Find Full Text PDFDespite the great success achieved by photoactivated chemotherapy, eradicating deep tumors using external sources with high tissue penetration depth remains a challenge. Here, we present cyaninplatin, a paradigm of Pt(IV) anticancer prodrug that can be activated by ultrasound in a precise and spatiotemporally controllable manner. Upon sono-activation, mitochondria-accumulated cyaninplatin exhibits strengthened mitochondrial DNA damage and cell killing efficiency, and the prodrug overcomes drug resistance as a consequence of combined effects from released Pt(II) chemotherapeutics, the depletion of intracellular reductants, and the burst of reactive oxygen species, which gives rise to a therapeutic approach, namely sono-sensitized chemotherapy (SSCT).
View Article and Find Full Text PDFDysfunctional autophagy is associated with various human diseases, e.g., cancer.
View Article and Find Full Text PDFThe aberrant regulation of PD-L1 in tumor cells remains poorly understood. Here, the authors systematically investigate the endosomal trafficking of plasma membrane PD-L1 in tumor cells. They show that plasma membrane PD-L1 is continuously internalized, and then trafficked from early endosomes to multivesicular bodies/late endosomes, recycling endosomes, lysosomes, and/or extracellular vesicles (EVs).
View Article and Find Full Text PDFBackground: Retinoic acid(RA), an embryonic morphogen, regulates cell differentiation. Endocytosis regulates receptor signaling that governs such RA-directed cellular processes. Vacuolin-1 is a small molecule that disrupts endocytosis, motivating interest in its effect on RA-induced differentiation/arrest.
View Article and Find Full Text PDFThe proper orientation of centrosome and spindle is essential for genome stability; however, the mechanism that governs these processes remains elusive. Here, we demonstrated that polo-like kinase 1 (Plk1), a key mitotic kinase, phosphorylates residue Thr76 in VCP/p97 (an AAA-ATPase), at the centrosome from prophase to anaphase. This phosphorylation process recruits VCP to the centrosome and in this way, it regulates centrosome orientation.
View Article and Find Full Text PDFActin filaments (F-actin) have been implicated in various steps of endosomal trafficking, and the length of F-actin is controlled by actin capping proteins, such as CapZ, which is a stable heterodimeric protein complex consisting of α and β subunits. However, the role of these capping proteins in endosomal trafficking remains elusive. Here, we found that CapZ docks to endocytic vesicles via its C-terminal actin-binding motif.
View Article and Find Full Text PDFMetformin is one of the most widely used drugs for type 2 diabetes and it also exhibits cardiovascular protective activity. However, the underlying mechanism of its action is not well understood. Here, we used an adult zebrafish model of heart cryoinjury, which mimics myocardial infarction in humans, and demonstrated that autophagy was significantly induced in the injured area.
View Article and Find Full Text PDFBackground: Lung cancer is a common kind of human malignancies. Lung squamous cell carcinoma (LUSC) is a key subtype of lung cancer. Cell cycle plays an important role in the development and occurrence of LUSC, however, there is still a lack of cell cycle-related genes in LUSC diagnosis and prediction of prognosis.
View Article and Find Full Text PDFJapanese encephalitis virus (JEV), a member of the genus, is an important pathogen that causes human and animal infectious diseases in Asia. So far, no effective antiviral agents are available to treat JEV infection. Here, we found that LDLR is a host factor required for JEV entry.
View Article and Find Full Text PDFJapanese encephalitis virus is absolutely dependent on their host cells and has evolved various strategies to manipulate the cellular secretory pathways for viral replication. However, how cellular secretory pathways are hijacked, and the origin of the viral vesicles remains elusive during JEV replication. Here we show how JEV manipulates multiple components of the cellular secretory pathway, including autophagic machinery, to generate a superior environment for genome replication.
View Article and Find Full Text PDFAutophagy, an evolutionarily conserved lysosomal degradation pathway, is known to regulate a variety of physiological and pathological processes. At present, the function and the precise mechanism of autophagy regulation in kidney and renal cells remain elusive. Here, we explored the role of ERK1 and ERK2 (referred as ERK1/2 hereafter) in autophagy regulation in renal cells in response to hypoglycemia.
View Article and Find Full Text PDFAutophagy
January 2021
Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo.
View Article and Find Full Text PDFAutophagy is a conserved lysosomal degradation process, and abnormal autophagy has been associated with various pathological processes, e.g., neurodegeneration, cancer, and pathogen infection.
View Article and Find Full Text PDFThe known collaboration between all-transretinoic acid and interferon motivates this study of the dependence of RA-induced leukemic cell differentiation on interferon regulatory factor-1 (IRF-1), a transcription factor that is the main mediator of interferon effects. In the HL-60 acute myeloid leukemia (AML) model that represents a rare RA-responsive subtype of AML, IRF-1 is not expressed until RA induces its prominent expression, and ectopic IRF-1 expression enhances RA-induced differentiation, motivating interest in how IRF-1 is putatively needed for RA response. Accordingly, we created CRISPR/Cas9-mediated IRF-1 knockout HL-60 cells.
View Article and Find Full Text PDFAll-trans retinoic acid (ATRA) is an anti-cancer differentiation therapy agent effective for acute promyelocytic leukemia (APL) but not acute myeloid leukemia (AML) in general. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation and G1/G0 cell cycle arrest, we now observe that c-Raf in the nucleus showed novel interactions with several prominent regulators of the cell cycle and cell differentiation. One is cyclin-dependent kinase 2 (Cdk2).
View Article and Find Full Text PDFOne of the critical regulatory mechanisms for cell cycle progression is the timely degradation of CDK inhibitors, including p21 and p27 . VCP/p97, an AAA-ATPase, is reported to be overexpressed in many types of cancers. Here, we found that treatment of MCF-7 human breast cancer cells with DBeQ, a VCP inhibitor, or VCP knockdown in MCF-7 cells arrested cells at G1 phase, accompanied with the blockage of both p21 and p27 degradation.
View Article and Find Full Text PDFAutophagy, an evolutional conserved lysosomal degradation process, has been implicated to play an important role in cellular defense against a variety of microbial infection. Interestingly, numerous studies found that some pathogens, especially positive-single-strand RNA viruses, actually hijacked autophagy machinery to promote virus infection within host cells, facilitating different stages of viral life cycle, from replication, assembly to egress. Enterovirus, a genus of positive-strand RNA virus, can cause various human diseases and is one of main public health threat globally, yet no effective clinical intervention is available for enterovirus infection.
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