Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Endoplasmic Reticulum-Targeting Self-Assembly Nanosheets Promote Autophagy and Regulate Immunosuppressive Tumor Microenvironment for Efficient Photodynamic Immunotherapy.

The poor efficiency and low immunogenicity of photodynamic therapy (PDT), and the immunosuppressive tumor microenvironment (ITM) lead to tumor recurrence and metastasis. In this work, TCPP-TER -Zn@RSV nanosheets (TZR NSs) that co-assembled from the endoplasmic reticulum (ER)-targeting photosensitizer TCPP-TER -Zn nanosheets (TZ NSs for short) and the autophagy promoting and indoleamine-(2, 3)-dioxygenase (IDO) inhibitor-like resveratrol (RSV) are fabricated to enhance antitumor PDT. TZR NSs exhibit improved therapeutic efficiency and amplified immunogenic cancer cell death (ICD) by ER targeting PDT and ER autophagy promotion. TZR NSs reversed the ITM with an increase of CD8+ T cells and reduce of immunosuppressive Foxp3 regulatory T cells, which effectively burst antitumor immunity thus clearing residual tumor cells. The ER-targeting TZR NSs developed in this paper presents a simple but valuable reference for high-efficiency tumor photodynamic immunotherapy.

Nanodrugs mediate TAMs-related arginine metabolism interference to boost photodynamic immunotherapy.

As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L-arginine (L-Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L-norvaline (L-Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L-Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L-Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8+ T cells, finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition. This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC.

Overexpression of UHRF1 promoted the proliferation of vascular smooth cells via the regulation of Geminin protein levels.

Geminin is an inhibitor of DNA replication licensing and cell cycle. Our previous study demonstrates that Geminin plays an important role in regulating phenotypic diversity and growth of vascular smooth cells (VSMCs). Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is an epigenetic coordinator, whose RING domain confers intrinsic E3 ligase activity, mediating the ubiquitination of several proteins and the protein-protein interaction. Aberrant expression of UHRF1 was related to aggressiveness of multiple human malignancies, where knockdown of UHRF1 led to decreased proliferation of cancer cells. However, it is unclear whether proper UHRF1 function is involved in aberrant proliferation and phenotypic switching of VSMCs via altering Geminin protein levels. In present study, in UHRF1-overexpressing A10 cells, 3H-thymidine and 5-ethynyl-20-deoxyuridine (EdU) and CCK8 were used to examine the proliferation of VSMCs. RT-PCR and Western blot analyses were performed to investigate whether UHRF1-mediated effects were achieved by altering Geminin expression in VSMCs. RNA-seq analysis was performed to dissect related mechanisms or signaling pathways of these effects. The results of in vitro experiments suggested that UHRF1 prompted proliferation and cell cycle of VSMCs via the down-regulation of Geminin protein levels with no change in Geminin mRNA expression. Besides, PI3K-Akt signaling pathway was increased upon UHRF1 up-regulation. Our study demonstrated that overexpressing UHRF1 was involved in VSMCs proliferation through reducing inhibitory Geminin protein levels to promote cell cycle as well as activating PI3K-Akt signaling. This may provide key knowledge for the development of better strategies to prevent diseases related to VSMCs abnormal proliferation.

Cold exposure promotes obesity and impairs glucose homeostasis in mice subjected to a high­fat diet.

Cold exposure is considered to be a form of stress and has various adverse effects on the body. The present study aimed to investigate the effects of chronic daily cold exposure on food intake, body weight, serum glucose levels and the central energy balance regulatory pathway in mice fed with a high­fat diet (HFD). C57BL/6 mice were divided into two groups, which were fed with a standard chow or with a HFD. Half of the mice in each group were exposed to ice­cold water for 1 h/day for 7 weeks, while the controls were exposed to room temperature. Chronic daily cold exposure significantly increased energy intake, body weight and serum glucose levels in HFD­fed mice compared with the control group. In addition, 1 h after the final cold exposure, c­fos immunoreactivity was significantly increased in the central amygdala of HFD­fed mice compared with HFD­fed mice without cold exposure, indicating neuronal activation in this brain region. Notably, 61% of these c­fos neurons co­expressed the neuropeptide Y (NPY), and the orexigenic peptide levels were significantly increased in the central amygdala of cold­exposed mice compared with control mice. Notably, cold exposure significantly decreased the anorexigenic brain­derived neurotropic factor (BDNF) messenger RNA (mRNA) levels in the ventromedial hypothalamic nucleus and increased growth hormone releasing hormone (GHRH) mRNA in the paraventricular nucleus. NPY­ergic neurons in the central amygdala were activated by chronic cold exposure in mice on HFD via neuronal pathways to decrease BDNF and increase GHRH mRNA expression, possibly contributing to the development of obesity and impairment of glucose homeostasis.

Different effects of neuropeptide Y on proliferation of vascular smooth muscle cells via regulation of Geminin.

The proliferation-promoting effect of neuropeptide Y (NPY) always functions in low-serum-cultured vascular smooth muscle cells (VSMCs), and the phenotypic switch of VSMCs is regulated by concentrations of serum. Whether the property of the NPY proliferative effect in VSMCs relies on phenotype of VSMCs is unclear. We aimed to explore the role of NPY on proliferation of different VSMC phenotypes in the pathogenesis of atherosclerosis. By stimulating A10 cells with 200 nM NPY in 0.5 or 10% serum, 3H-thymidine and 5-ethynyl-2'-deoxyuridine (EdU) and CCK8 measurements were used to detect VSMC proliferation. RT-PCR and Flow cytometry were performed to detect the factors involved in different properties of the NPY proliferative effect in VSMCs. Instead of facilitating proliferation, NPY had no significant effect on the growth of VSMCs when cultured in 10% serum (VSMCs stayed at synthetic states). The underlying mechanism may be involved in down-regulation of Y1 receptor (P < 0.05 vs. Vehicle) and up-regulation of Geminin (P < 0.05 vs. Vehicle) in 10% serum-cultured VSMCs co-incubated with 200 nM NPY. Besides, modulation of Geminin was effectively blocked by the Y1 receptor antagonist. The stimulation of NPY on proliferation of VSMCs could be a double-edged sword in the development of atherosclerosis and thus provides new knowledge for therapy of atherosclerosis.

Current views on neuropeptide Y and diabetes-related atherosclerosis.

Diabetes-induced atherosclerotic cardiovascular disease is the leading cause of death of diabetic patients. Neuronal regulation plays a critical role in glucose metabolism and cardiovascular function under physiological and pathological conditions, among which, neurotransmitter neuropeptide Y has been shown to be closely involved in these two processes. Elevated central neuropeptide Y level promotes food intake and reduces energy expenditure, thereby increasing adiposity. Neuropeptide Y is co-localized with noradrenaline in central and sympathetic nervous systems. As a major peripheral vascular contractive neurotransmitter, through interactions with its receptors, neuropeptide Y has been implicated in the pathology and progression of diabetes, by promoting the proliferation of endothelial cells and vascular fibrosis, which may contribute to diabetes-induced cardiovascular disease. Neuropeptide Y also participates in the pathogenesis of atherosclerosis, the major form of cardiovascular disease, via aggravating endothelial dysfunction, growth of vascular smooth muscle cells, formation of foam cells and platelets aggregation. This review highlights the causal role of neuropeptide Y and its receptor system in the development of diabetes mellitus and one of its complications: atherosclerotic cardiovascular disease. The information from this review provides both critical insights onto the mechanisms underlying the pathogenesis of atherosclerosis and evidence for the development of therapeutic strategies.