Loss of airway epithelial integrity contributes significantly to asthma pathogenesis. Thymic stromal lymphopoietin (TSLP) may have dual immunoregulatory roles. In inflammatory disorders of the bowel, the long isoform of TSLP (lfTSLP) promotes inflammation while the short isoform (sfTSLP) inhibits inflammation. We hypothesize that lfTSLP contributes to house dust mite (HDM)-induced airway epithelial barrier dysfunction and that synthetic sfTSLP can prevent these effects. In vitro, airway epithelial barrier function was assessed by monitoring transepithelial electrical resistance, fluorescent-dextran permeability, and distribution of E-cadherin and β-catenin. In vivo, BALB/c mice were exposed to HDM by nasal inhalation for 5 consecutive days per week to establish an asthma model. sfTSLP and 1α,25-Dihydroxyvitamin D3 (1,25D3) were administered 1 h before HDM exposure. After 8 weeks, animal lung function tests and pathological staining were performed to evaluate asthma progression. We found that HDM and lfTSLP impaired barrier function. Treatment with sfTSLP and 1,25D3 prevented HDM-induced airway epithelial barrier disruption. Moreover, sfTSLP and 1,25D3 treatment ameliorated HDM-induced asthma in mice. Our data emphasize the importance of the different expression patterns and biological properties of sfTSLP and lfTSLP. Moreover, our results indicate that sfTSLP and 1,25D3 may serve as novel therapeutic agents for individualized treatment of asthma.

α-synuclein abnormal accumulation and mitochondria dysfunction are involved in the pathogenesis of Parkinson’s disease. Selective autophagy of mitochondria (mitophagy) is a crucial component of the network controlling the mitochondrial homeostasis. However, the underlying mechanism that mutant α-synuclein induces mitochondrial abnormality through mitophagy impairment is not fully understood. Here, we showed that mutant A53T α-synuclein accumulation impaired mitochondrial function and Parkin-mediated mitophgy in α-synucleinA53T model. α-synucleinA53T overexpression caused p38 MAPK activation, then p38 MAPK directly phosphorylated Parkin at serine 131 to disrupt the Parkin’s protective function. The p38 MAPK inhibition significantly reduced cellular apoptosis, restored mitochondrial membrane potential as well as increased synaptic density both in SN4741 cells and primary midbrain neurons. These findings show that the p38 MAPK-Parkin signaling pathway regulates mitochondrial homeostasis and neuronal degeneration, which may be a potential therapeutic strategy of PD via enhancing mitochondrial turn-over and maintenance.

Poly (ADP‐ribose) polymerase 1 (PARP1) is a master regulator of diverse biological processes such as DNA repair, oxidative stress, and apoptosis. PARP1 can be activated by aggregated α‐synuclein, and this process in turn exacerbates toxicity of α‐synuclein. This circle is closely linked to the evolution of Parkinson's disease (PD) that characterized by progressive neurodegeneration and motor deficits. Here, we reported the PARP1, as a novel upstream molecular of transcription factor EB (TFEB), participates in regulation of autophagy in α‐synuclein aggregated cells and mice. PARP1 inhibition not only enhances the nuclear transcription of TFEB via SIRT1 mediated down‐regulation of mTOR signaling but also reduces nuclear export of TFEB by attenuating the TFEB‐CRM1 interaction. Our results revealed that PARP1 inhibition lessened the accumulation of α‐synuclein in PD models. Also, oral administration of PARP1 inhibitor Veliparib prevented neurodegeneration and improved motor ability in α‐synucleinA53T transgenic mice. These findings identify that PARP1 signaling pathway regulates TFEB‐mediated autophagy, pointing to potential therapeutic strategy of PD via enhancing protein degradation systems.

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