We present a mathematical model for vascular tumor growth. We use phase fields to model cellular growth and reaction-diffusion equations for the dynamics of angiogenic factors and nutrients. The model naturally predicts the shift from avascular to vascular growth at realistic scales. Our computations indicate that the negative regulation of the Delta-like ligand 4 signaling pathway slows down tumor growth by producing a larger density of non-functional capillaries. Our results show good quantitative agreement with experiments.

BackgroundNeuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation.MethodsIn our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis.ResultsThe results showed that NBP exerts a neuroprotective effect on experimental PD models. In vivo, NBP ameliorated behavioral impairments and reduced dopaminergic neuron loss in MPTP-induced mice. In vitro, treatment of SH-SY5Y cells with 6-OHDA (100uM,24 h) significantly decreased cell viability, increased intracellular ROS production, and induced apoptosis, while pretreatment with 5uM NBP could alleviated 6-OHDA-induced cytotoxicity, ROS production and cell apoptosis to some extent. Importantly, both in vivo and in vitro, NBP suppressed the activation of the NLRP3 inflammasome and the aggregation of α-Syn, thus inhibited neuroinflammation ameliorated mitochondrial impairments.ConclusionsIn summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.

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Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWltch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly upregulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished TGF-β1-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs cells or normal kidneys increased p16INK4a, p19ARF and p21 expression and senescence-associated β-galactosidase activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by siRNA-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT- 263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.

Sepsis is a life-threatening syndrome accompanied by an overwhelming inflammatory response and organ dysfunction. Selective targeting of phosphodiesterase 4 (PDE4) is currently being investigated as an effective therapeutic approach for inflammation-associated diseases. Roflumilast is a selective PDE4 inhibitor, used for the treatment of severe chronic obstructive pulmonary disease in clinic. However, its role in the treatment of sepsis-induced liver damage remains unclear. In the present study, we evaluated the effects of roflumilast in mice with cecal ligation and puncture-induced sepsis, and investigated the underlying mechanism. We found that roflumilast treatment improved survival in septic mice by reducing bacterial load locally and systemically, inhibiting the expression of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor alpha, and alleviating liver injury. These effects were associated with the inhibition of nuclear translocation of nuclear factor-kappa B (NF-κB), as well as degradation of NF-κB inhibitory protein alpha. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also markedly inhibited by roflumilast. Moreover, roflumilast significantly suppressed the activation of signal transducer and activator of transcription 3 (STAT3) and its upstream Janus kinase 1 and Janus kinase 2. Taken together, these results indicate that roflumilast prevents polymicrobial sepsis likely by suppressing NF-κB, p38 MAPK, and STAT3 pathways.