Bradykinin inhibits oxidative stress-induced senescence of endothelial progenitor cells through the B2R/AKT/RB and B2R/EGFR/RB signal pathways

Histone modifications function in both cellular and viral gene expression. However, the roles of acetyltransferases and histone acetylation in parvoviral infection remain poorly understood. In the current study, we found the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), promoted the replication and transcription of parvovirus minute virus of canines (MVC). Notably, the expression of host acetyltransferases KAT5, GTF3C4, and KAT2A was increased in MVC infection, as well as H4 acetylation (H4K12ac). KAT5 is not only responsible for H4K12ac but also crucial for viral replication and transcription. The viral nonstructural protein NS1 interacted with KAT5 and enhanced its expression. Further study showed that Y44 in KAT5, which may be tyrosine-phosphorylated, is indispensable for NS1-mediated enhancement of KAT5 and efficient MVC replication. The data demonstrated that NS1 interacted with KAT5, which resulted in an enhanced H4K12ac level to promote viral replication and transcription, implying the epigenetic addition of H4K12ac in viral chromatin-like structure by KAT5 is vital for MVC replication. IMPORTANCE: Parvoviral genomes are chromatinized with host histones. Therefore, histone acetylation and related acetyltransferases are required for the virus to modify histones and open densely packed chromatin structures. This study illustrated that histone acetylation status is important for MVC replication and transcription and revealed a novel mechanism that the viral nonstructural protein NS1 hijacks the host acetyltransferase KAT5 to enhance histone acetylation of H4K12ac, which relies on a potential tyrosine phosphorylation site, Y44 in KAT5. Other parvoviruses share a similar genome organization and coding potential and may adapt a similar strategy for efficient viral replication and transcription.

The Minute Virus of Canines (MVC), belonging to the genus Bocaparvovirus within the family Parvoviridae, is associated with enteritis and embryonic infection in neonatal canines. Viral attachment to host cells is a critical step in infection, and viral protein 2 (VP2) as an important structural protein of MVC influences host selection and infection severity. Nevertheless, little is known about the interaction between VP2 protein and host cells. In this study, we identified that VP2 directly interacts with the kinase domain of RhoA-associated protein kinase 1 (ROCK1) by using mass spectrometry and immunoprecipitation approach and demonstrated that the RhoA/ROCK1/myosin light chain 2 (MLC2) signaling pathway was activated during the early stage of MVC infection in Walter Reed canine cell/3873D (WRD) cells. Further studies indicated that RhoA/ROCK1-mediated phosphorylation of MLC2 triggers the contraction of the actomyosin ring, disrupts tight junctions, and exposes the tight junction protein Occludin, which facilitates the interaction between VP2 and Occludin. Specific inhibitors of RhoA and ROCK1 restored the MVC-induced intracellular translocation of Occludin and the increase in cell membrane permeability. Moreover, the two inhibitors significantly reduced viral protein expression and genomic copy number. Collectively, our study provides the first evidence that there is a direct interaction between the structural protein VP2 of MVC and ROCK1, and that the tight junction protein Occludin can serve as a potential co-receptor for MVC infection, which may offer new targets for anti-MVC strategies.

The pathogenesis underlying diabetic peripheral neuropathy (DPN) remains largely elusive. Due to current unsatisfactory therapeutic approaches, new strategies for the control of DPN are needed. The present study was designed to assess whether inulin could serve as a potential neuroprotection against DPN in diverse stages of diabetes. Leptin receptor-mutant db/db mice were used as a model for DPN to dynamically assess the effects of inulin on DPN in diverse diabetic groups. According to blood glucose, the mice were randomly divided into prediabetes group (PDM group), inulin treated prediabetes group (INU/PDM group), diabetes group (DM group) and inulin treated diabetes group (INU/DM group). After 6 weeks of treatment, we found that inulin supplementation attenuated the neuropathic phenotypes in PDM and DM, including mechanical allodynia, thermal hyperalgesia and nerve conduction. Furthermore, inulin administration remarkably suppressed the levels of pro-inflammatory IL-6, TNF-α, and IL-17A in diverse diabetic groups with DPN, but increased an anti-inflammatory IL-10 in INU/PDM group, suggesting that dietary inulin intervention may suppress the DPN inflammation in different diabetic stages. Moreover, inulin supplementation markedly reduced the circulating LPS translocation. Metabolomics analysis revealed that inulin treatment significantly modulated the levels of 8 stage-specific metabolites; notably, it increased anti-inflammatory, anti-diabetic and neuroprotective metabolites taurine and dodecanoic acid in prediabetic mice, while decreasing pro-inflammatory mediators including oleamide and adrenic acid. In diabetic mice, inulin elevated metabolites including methylation (S-Adenosylmethionine), glucose homeostasis (glucose 6-phosphate), N-acetyl-L-phenylalanine and quinate. These metabolites are implicated in pathways such as bile acid metabolism, fatty acid oxidation, and neurotransmitter regulation, suggesting that inulin may exert neuroprotective effects by restoring metabolic homeostasis in a stage-dependent manner. Furthermore, rectification of gut dysbiosis by dietary inulin administration, with a major impact on increasing intestinal beneficial bacteria |( Bacteroides and Cyanobacteria ) and decreasing pro-inflammatory bacteria ( Ruminiclostridium_6 , Mucispirillum, Deferribacteres and Tenericutes ), exerted a close and complex interactions with metabolites, inflammatory factors, and peripheral neuropathic indicators. Collectively, dietary inulin intervention ameliorated DPN via reshaping gut microbial metabolism and suppressing inflammation, which may potentially provide an effective and safe therapeutics for the control of the disease.