Treatment of calcific arterial disease via enhancement of autophagy using GSK343.

Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp-/-) and small (Abcc6-/-) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.

Oral Administration of Glutathione Trisulfide Increases Reactive Sulfur Levels in Dorsal Root Ganglion and Ameliorates Paclitaxel-Induced Peripheral Neuropathy in Mice.

Peripheral neuropathy is a dose-limiting side effect of chemotherapy with paclitaxel. Paclitaxel-induced peripheral neuropathy (PIPN) is typically characterized by a predominantly sensory neuropathy presenting with allodynia, hyperalgesia and spontaneous pain. Oxidative mitochondrial damage in peripheral sensory neurons is implicated in the pathogenesis of PIPN. Reactive sulfur species, including persulfides (RSSH) and polysulfides (RSnH), are strong nucleophilic and electrophilic compounds that exert antioxidant effects and protect mitochondria. Here, we examined the potential neuroprotective effects of glutathione trisulfide (GSSSG) in a mouse model of PIPN. Intraperitoneal administration of paclitaxel at 4 mg/kg/day for 4 days induced mechanical allodynia and thermal hyperalgesia in mice. Oral administration of GSSSG at 50 mg/kg/day for 28 days ameliorated mechanical allodynia, but not thermal hyperalgesia. Two hours after oral administration, 34S-labeled GSSSG was detected in lumber dorsal root ganglia (DRG) and in the lumber spinal cord. In mice treated with paclitaxel, GSSSG upregulated expression of genes encoding antioxidant proteins in lumber DRG, prevented loss of unmyelinated axons and inhibited degeneration of mitochondria in the sciatic nerve. In cultured primary neurons from cortex and DRG, GSSSG mitigated paclitaxel-induced superoxide production, loss of axonal mitochondria, and axonal degeneration. These results indicate that oral administration of GSSSG mitigates PIPN by preventing axonal degeneration and mitochondria damage in peripheral sensory nerves. The findings suggest that administration of GSSSG may be an approach to the treatment or prevention of PIPN and other peripheral neuropathies.

Electronic cigarette vaping with aged coils causes acute lung injury in mice.

Electronic cigarettes (e-cigarettes) have been used widely as an alternative to conventional cigarettes and have become particularly popular among young adults. A growing body of evidence has shown that e-cigarettes are associated with acute lung injury and adverse effects in multiple other organs. Previous studies showed that high emissions of aldehydes (formaldehyde and acetaldehyde) in aerosols were associated with increased usage of the same e-cigarette coils. However, the impact on lung function of using aged coils has not been reported. We investigated the relationship between coil age and acute lung injury in mice exposed to experimental vaping for 1 h (2 puffs/min, 100 ml/puff). The e-liquid contains propylene glycol and vegetable glycerin (50:50, vol) only. The concentrations of formaldehyde and acetaldehyde in the vaping aerosols increased with age of the nichrome coils starting at 1200 puffs. Mice exposed to e-cigarette aerosols produced from 1800, but not 0 or 900, puff-aged coils caused acute lung injury, increased lung wet/dry weight ratio, and induced lung inflammation (IL-6, TNF-α, IL-1ß, MIP-2). Exposure to vaping aerosols from 1800 puff-aged coils decreased heart rate, respiratory rate, and oxygen saturation in mice compared to mice exposed to air or aerosols from new coils. In conclusion, we observed that the concentration of aldehydes (formaldehyde and acetaldehyde) increased with repeated and prolonged usage of e-cigarette coils. Exposure to high levels of aldehyde in vaping aerosol was associated with acute lung injury in mice. These findings show significant risk of lung injury associated with prolonged use of e-cigarette devices.

Late-Stage Chemoenzymatic Installation of Hydroxy-Bearing Allyl Moiety on the Indole Ring of Tryptophan-Containing Peptides.

The late-stage functionalization of indole- and tryptophan-containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. Here, the synthesis of two hydroxy-bearing allyl pyrophosphates is described. A chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy-bearing allyl moiety directly on the indole ring of tryptophan-containing peptides. This is the first report of late-stage indole modifications with this reactive group.

Physiological roles of mammalian transmembrane adenylyl cyclase isoforms.

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors (GPCRs). The transmembrane ACs display varying expression patterns across tissues, giving the potential for them to have a wide array of physiological roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gαs, so it was long assumed that all ACs are activated by Gαs-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form prearranged signaling complexes with specific GPCRs that contribute to cAMP signaling compartments. This compartmentation allows for a diversity of cellular and physiological responses by enabling unique signaling events to be triggered by different pools of cAMP. Isoform-specific pharmacological activators or inhibitors are lacking for most ACs, making knockdown and overexpression the primary tools for examining the physiological roles of a given isoform. Much progress has been made in understanding the physiological effects mediated through individual transmembrane ACs. GPCR-AC-cAMP signaling pathways play significant roles in regulating functions of every cell and tissue, so understanding each AC isoform's role holds potential for uncovering new approaches for treating a vast array of pathophysiological conditions.