Celastrol alleviates atopic dermatitis by regulating Ezrin-mediated mitochondrial fission and fusion.

Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1ß, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.

miR-128-3p alleviates airway inflammation in asthma by targeting SIX1 to regulate mitochondrial fission and fusion.

Bronchial asthma is known for airway inflammation, hyperresponsiveness, and remodeling.MicroRNAs (MiRNAs) have been involved in the development of asthma, whereas, the mechanism of various MiRNAs in asthma remains to be elucidated. In this study, we aim to explore the mechanism of miR-128-3p in asthma-related airway inflammation by targeting sine oculis homeobox homolog 1 (SIX1) to regulate the mitochondrial function. In an ovalbumin (OVA) asthma mouse model, miR-128-3p levels were found to be significantly diminished. Administration of miR-128-3p agomir decreased peribronchial inflammatory cell infiltration and improved airway inflammation. Afterwards, we used the luciferase reporter assay to predict and confirmed that SIX1 is a target gene of miR-128-3p. Overexpression of miR-128-3p attenuated IL-13-induced cellular inflammation and ROS production in bronchial epithelial cells (BEAS-2B). In vitro, overexpression of miR-128-3p and SIX1 knockdown mitigated mitochondrial fragmentation, reduced Drp1-mediated mitochondrial division, and upregulated mitochondrial membrane potential. Moreover, led to decreased production of ROS/mitochondrial ROS, P-Drp1(616) and Fis1 expression, while enhancing P-Drp1(637), MFN1, caspase-3/9, and Bax-mediated apoptosis. Our findings demonstrated that miR-128-3p could alleviate airway inflammation by downregulating SIX1 and improving mitochondrial function, positioning the miR-128-3p/SIX1/Drp1 signaling as a potential therapeutic target for asthma.

IL-4 activates ULK1/Atg9a/Rab9 in asthma, NLRP3 inflammasomes, and Golgi fragmentation by increasing autophagy flux and mitochondrial oxidative stress.

During asthma, there is an intensification of pulmonary epithelial inflammation, mitochondrial oxidative stress, and Golgi apparatus fragmentation. However, the underlying mechanism remains largely unknown. Therefore, this study investigated the roles of ULK1, Atg9a, and Rab9 in epithelial inflammation, mitochondrial oxidative stress, and Golgi apparatus fragmentation. We found that ULK1 gene knockout reduced the infiltration of inflammatory cells, restored the imbalance of the Th1/Th2 ratio, and inhibited the formation of inflammatory bodies in the lung tissue of house dust mite-induced asthma mice. Moreover, we demonstrated that Atg9a interacted with ULK1 at S467. ULK1 phosphorylated Atg9a at S14. Treatment with ULK1 activator (LYN-1604) and ULK1 inhibitor (ULK-101) respectively promoted and inhibited inflammasome activation, indicating that the activation of inflammasome induced by house dust mite in asthma mice is dependent on ULK1. For validation of the in vivo results, we then used a lentivirus containing ULK1 wild type and ULK1-S467A genes to infect Beas-2b-ULK1-knockout cells and establish a stable cell line. The results suggest that the ULK1 S467 site is crucial for IL-4-induced inflammation and oxidative stress. Experimental verification confirmed that Atg9a was the superior signaling pathway of Rab9. Interestingly, we found for the first time that Rab9 played a very important role in inflammation-induced fragmentation of the Golgi apparatus. Inhibiting the activation of the ULK1/Atg9a/Rab9 signaling pathways can inhibit Golgi apparatus fragmentation and mitochondrial oxidative stress in asthma while reducing the production of NLRP3-mediated pulmonary epithelial inflammation.

PEGylated-liposomal astaxanthin ameliorates Aß neurotoxicity and Alzheimer-related phenotypes by scavenging formaldehyde.

Alzheimer's disease (AD), which is a prevailing type of dementia, presents a significant global health concern. The current therapies do not meet clinical expectations. Amyloid-beta (Aß) has been found to induce endogenous formaldehyde (FA) accumulation by inactivating FA dehydrogenase (FDH); in turn, excessive FA triggers Aß aggregation that eventually leads to AD onset. Hence, scavenging FA by astaxanthin (ATX, a strong exogenous antioxidant) may be pursued as a promising disease-modifying approach. Here, we report that liposomal nanoparticles coupled with PEG (PEG-ATX@NPs) could enhance water-solubility of ATX and alleviate cognitive impairments by scavenging FA and reducing Aß deposition. To enable drug delivery to the brain, liposomes were used to encapsulate ATX and then coupled with PEG, which produced liposomal nanoparticles (PEGATX@NPs) with a diameter of <100 nm. The PEG-ATX@NPs reduced Aß neurotoxicity by both degrading FA and reducing FA-induced Aß assembly in vitro. Intraperitoneal administration of PEG-ATX@NPs in APPswe/PS1dE9 mice (APP/PS1, a familial model of AD), not only decreased the levels of brain FA and malondialdehyde (MDA, a typical product of oxidative stress), but also attenuated both intracellular Aß oligomerization and extracellular Aß-related senile plaque (SP) formation. These pathological changes were accompanied by rescued ability of spatial learning and memory. Collectively, PEG-ATX@NPs improved the water-solubility, bioavailability, and effectiveness of ATX. Thus, it has the potential to be developed as a safe and effective strategy for treating AD.

Phototherapy for age-related brain diseases: Challenges, successes and future.

Brain diseases present a significant obstacle to both global health and economic progress, owing to their elusive pathogenesis and the limited effectiveness of pharmaceutical interventions. Phototherapy has emerged as a promising non-invasive therapeutic modality for addressing age-related brain disorders, including stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), among others. This review examines the recent progressions in phototherapeutic interventions. Firstly, the article elucidates the various wavelengths of visible light that possess the capability to penetrate the skin and skull, as well as the pathways of light stimulation, encompassing the eyes, skin, veins, and skull. Secondly, it deliberates on the molecular mechanisms of visible light on photosensitive proteins, within the context of brain disorders and other molecular pathways of light modulation. Lastly, the practical application of phototherapy in diverse clinical neurological disorders is indicated. Additionally, this review presents novel approaches that combine phototherapy and pharmacological interventions. Moreover, it outlines the limitations of phototherapeutics and proposes innovative strategies to improve the treatment of cerebral disorders.

DEK deficiency suppresses mitophagy to protect against house dust mite-induced asthma.

DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. PINK1-Parkin mitophagy, NLRP3 inflammasome, and apoptosis were examined after gene silencing or treatment with specific inhibitors (MitoTEMPO, MCC950, and Ac-DEVD-CHO) in house dust mite (HDM) or recombinant DEK (rmDEK)-induced WT and DEK-/- asthmatic mice and BEAS-2B cells. The regulatory role of DEK on ATAD3A was detected using ChIP-sequence and co-immunoprecipitation. rmDEK promoted eosinophil recruitment, and co-localization of TOM20 and LC3B, MFN1 and mitochondria, LC3B and VDAC, and ROS generation, reduced protein level of MnSOD in HDM induced-asthmatic mice. Moreover, rmDEK also increased DRP1 expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. These effects were partially reversed in DEK-/- mice. In BEAS-2B cells, siDEK diminished the Parkin, LC3B, and DRP1 translocation to mitochondria, mtROS, TOM20, and mtDNA. ChIP-sequence analysis showed that DEK was enriched on the ATAD3A promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models and interacted with DRP1, and siATAD3A could down-regulate DRP1 and mtDNA-mediated mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.