Novel insights into stress-induced susceptibility to influenza: corticosterone impacts interferon-ß responses by Mfn2-mediated ubiquitin degradation of MAVS.

Although stress has been known to increase the susceptibility of pathogen infection, the underlying mechanism remains elusive. In this study, we reported that restraint stress dramatically enhanced the morbidity and mortality of mice infected with the influenza virus (H1N1) and obviously aggravated lung inflammation. Corticosterone (CORT), a main type of glucocorticoids in rodents, was secreted in the plasma of stressed mice. We further found that this stress hormone significantly boosted virus replication by restricting mitochondrial antiviral signaling (MAVS) protein-transduced IFN-ß production without affecting its mRNA level, while the deficiency of MAVS abrogated stress/CORT-induced viral susceptibility in mice. Mechanistically, the effect of CORT was mediated by proteasome-dependent degradation of MAVS, thereby resulting in the impediment of MAVS-transduced IFN-ß generation in vivo and in vitro. Furthermore, RNA-seq assay results indicated the involvement of Mitofusin 2 (Mfn2) in this process. Gain- and loss-of-function experiments indicated that Mfn2 interacted with MAVS and recruited E3 ligase SYVN1 to promote the polyubiquitination of MAVS. Co-immunoprecipitation experiments clarified an interaction between any two regions of Mfn2 (HR1), MAVS (C-terminal/TM) and SYVN1 (TM). Collectively, our findings define the Mfn2-SYVN1 axis as a new signaling cascade for proteasome-dependent degradation of MAVS and a 'fine tuning' of antiviral innate immunity in response to influenza infection under stress.

Tianma Gouteng granules decreases the susceptibility of Parkinson's disease by inhibiting ALOX15-mediated lipid peroxidation.

ETHNOPHARMACOLOGICAL RELEVANCE: Tianma Gouteng granules (TG), a clinical prescription of traditional Chinese medicine, has been clinically applied to treat Parkinson's disease (PD) in combination with Madopar, as included in the Chinese Pharmacopoeia (2015). TG has the potential to decrease the susceptibility of PD pharmacologically, however the mechanisms need detailed demonstration. AIM OF THE STUDY: To evaluate the pharmacological activities, as well as the possible mechanism of TG in diverse models of PD. MATERIALS AND METHODS: 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice, were utilized as PD animal models. Rotarod, locomotor activity, inclined plane and traction tests were used for behavioral assessment. Immunohistochemistry was used for tyrosine hydrolase determination. Western blot were conducted for detection of 4-HNE and 15-lipoxygenase-1 (ALOX15). The interactions of ALOX15 with the components in TG were predicted by molecular docking approach. RESULTS: Lipid peroxidation was involved in dopaminergic neuron damage in 6-OHDA-induced rat models. In MPTP-treated mice, the inhibition of lipid peroxidation improved behavioral and pathological symptoms of PD. The lipid peroxidation-related protein, ALOX15 was found to be the key factor in PD process in diverse PD models including 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice. TG treatment significantly relieved behavioral and pathological symptoms of MPTP-induced PD mouse models with a potential mechanism of alleviating ALOX15-induced lipid peroxidation. Moreover, the results of molecular docking analysis show that compounds in TG might have interactions with ALOX15. CONCLUSIONS: TG effectively improved the behavioral and dopaminergic neuron damage in diverse PD models. The mechanism of this action may be related to the direct inhibition of ALOX15 and the relief of lipid peroxidation.

Clinical Prescription-Protein-Small Molecule-Disease Strategy (CPSD), A New Strategy for Chinese Medicine Development: A Case Study in Cardiovascular Diseases.

Chinese medicine is a national treasure that has been passed down for thousands of years in China. According to the statistics of the World Health Organization, there are currently four billion people in the world who use Chinese medicine to treat diseases, accounting for 80% of the world's total population. However, the obscurity of its theory, its unmanageable quality, its complex compositions, and the unknown effective substances and mechanisms are great obstacles to the internationalization of Chinese medicine. Here, we propose a new strategy for the development of Chinese medicine: the clinical prescription (C)-protein (P)-small-molecule (S)-disease (D) strategy, namely the CPSD strategy. The strategy uses clinical prescriptions as the source of medicine and uses computer simulation technology to find small-molecule drugs targeting therapeutic proteins for treating specific diseases so as to deepen awareness of the value of Chinese medicine. At the same time, this article takes cardiovascular drug development as an example to introduce the application of CPSD, which will be instrumental in the further development, modernization, and internationalization of Chinese medicine.