Sunesenwhittaker8546

Rationale MCL-1 is up-regulated in cancer and a target for cancer treatment. How MCL-1 is up-regulated and whether MCL-1 up-regulation plays a role in tumorigenic process is not well-known. Arsenic and benzo(a)pyrene (BaP) are well-recognized lung carcinogens and we recently reported that arsenic and BaP co-exposure acts synergistically in inducing cancer stem cell (CSC)-like property and lung tumorigenesis. This study was performed to further investigate the underlying mechanism focusing on the role of MCL-1. Methods The spheroid formation assay and nude mouse tumorigenesis assay were used to determine the CSC-like property and tumorigenicity of arsenic plus BaP co-exposure-transformed human bronchial epithelial BEAS-2B cells, respectively. Biochemical, pharmacological and genetic approaches were used to manipulate gene expressions, dissect signaling pathways and determine protein-protein interactions. Both loss-of-function and gain-of-function approaches were used to validate the role of MCL-1 in arsenic plus BaP co-exposure-enhanced CSC-like property and tumorigenicity. Results Arsenic plus BaP co-exposure-transformed cells express significantly higher protein levels of MCL-1 than the passage-matched control, arsenic or BaP exposure alone-transformed cells. Knocking down MCL-1 levels in arsenic plus BaP co-exposure-transformed cells significantly reduced their apoptosis resistance, CSC-like property and tumorigenicity in mice. Mechanistic studies revealed that arsenic plus BaP co-exposure up-regulates MCL-1 protein levels by synergistically activating the PI3K/Akt/mTOR pathway to increase the level of a deubiquitinase USP7, which in turn reduces the level of MCL-1 protein ubiquitination and prevents its subsequent proteasome degradation. Conclusions The deubiquitinase USP7-mediated MCL-1 up-regulation enhances arsenic and BaP co-exposure-induced CSC-like property and tumorigenesis, providing the first evidence demonstrating that USP7 stabilizes MCL-1 protein during the tumorigenic process.Rationale Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that can cause a variety of clinical syndromes including mucocutaneous disease and HSV-1 encephalitis (HSE). Here, we characterize the molecular mechanisms underlying the susceptibility to HSV-1 under stressful conditions. Methods Restraint stress and corticosterone (CORT, a primary stress hormone) were respectively used to establish HSV-1 susceptible model in vivo and in vitro. Viral titers were determined by plaque assay. Western blotting, immunofluorescence, transmission electron microscopy (TEM), qRT-PCR, H&E staining, IHC staining and flow cytometry were employed to evaluate virus-related protein expressions and detect the activation of autophagy. Loss- and gain-function assays, co-immunoprecipitation (co-IP) technique and autophagy agonist/antagonist treatments were applied in mechanistic experiments. Results Restraint stress increased the susceptibility of mouse brain to HSV-1. Similarly, CORT treatment enhanced the susceptibility of rotein LC3. Additionally, CORT failed to increase gB protein level when PML was silenced, providing direct evidence linking autophagic degradation of PML and CORT-induced virus susceptibility. Conclusion Our results revealed that restraint stress/CORT increased HSV-1 susceptibility by delivering PML into autolysosomes for degradation. The results obtained from in vitro and in vivo models not only demonstrated the adverse effects of stress on HSV-1 infection, but also systematically investigated the underlying molecular mechanisms. These discoveries broaden our understanding of the interplay between host and viruses, and a comprehensive understanding of the role of autophagy in viral infection will provide information for future development of innovative drugs against viral infection.Silver nanoparticles (AgNPs) have been one of the most attractive nanomaterials in biomedicine due to their unique physicochemical properties. In this paper, we review the state-of-the-art advances of AgNPs in the synthesis methods, medical applications and biosafety of AgNPs. The synthesis methods of AgNPs include physical, chemical and biological routes. AgNPs are mainly used for antimicrobial and anticancer therapy, and also applied in the promotion of wound repair and bone healing, or as the vaccine adjuvant, anti-diabetic agent and biosensors. This review also summarizes the biological action mechanisms of AgNPs, which mainly involve the release of silver ions (Ag+), generation of reactive oxygen species (ROS), destruction of membrane structure. Despite these therapeutic benefits, their biological safety problems such as potential toxicity on cells, tissue, and organs should be paid enough attention. Besides, we briefly introduce a new type of Ag particles smaller than AgNPs, silver Ångstrom (Å, 1 Å = 0.1 nm) particles (AgÅPs), which exhibit better biological activity and lower toxicity compared with AgNPs. Finally, we conclude the current challenges and point out the future development direction of AgNPs.Rationale Peripheral nerves are unique in their remarkable elasticity. Schwann cells (SCs), important components of the peripheral nervous system (PNS), are constantly subjected to physiological and mechanical stresses from dynamic stretching and compression forces during movement. So far, it is not clear if SCs sense and respond to mechanical signals. It is also unknown whether mechanical stimuli can interfere with the intercellular communications between neurons and SCs, and what role extracellular vesicles (EVs) play in this process. The present study aimed to examine the effect of mechanical stimuli on the EV-mediated intercellular communication between neurons and SCs, explore their effect on axonal regeneration, and investigate the underlying mechanism. Methods Purified SCs were stimulated using a magnetic force-based mechanical stimulation (MS) system and EVs were purified from mechanically stimulated SCs (MS-SCs-EVs) and non-stimulated SCs (SCs-EVs). learn more The effect of MS-SCs-EVs on axonal elongation was emore, we identified neuropilin 1 (Nrp1) in neurons as the target gene of miR-23b-3p in MS-SCs-EVs. This observation was supported by the evidence that miR-23b-3p could decrease Nrp1-3'-UTR-WT luciferase activity in vitro and down-regulate Nrp1 expression in neurons. Conclusion Our findings suggested that mechanical stimuli are capable of modulating the intercellular communication between neurons and SCs by altering miRNA composition in MS-SCs-EVs. Transfer of miR-23b-3p by MS-SCs-EVs from mechanically stimulated SCs to neurons decreased neuronal Nrp1 expression, which was responsible, at least in part, for the beneficial effect of MS-SCs-EVs on axonal regeneration. Our results highlighted the potential therapeutic value of MS-SCs-EVs and miR-23b-3p-enriched EVs in peripheral nerve injury repair.