Cereblon contributes to cardiac dysfunction by degrading Cav1.2α.

AIMS: Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. METHODS AND RESULTS: Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN-/-) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. CONCLUSION: Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics.

Development of Thin-Film Composite Membranes from Aromatic Cardo-Type Co-Polyimide for Mixed and Sour Gas Separations from Natural Gas.

The consumption of natural gas (NG) is rapidly increasing worldwide as it is becoming the second largest fuel source after coal. However, many of the world gas reserves contain high levels of subquality NG including the presence of carbon dioxide (CO2), hydrogen sulfide (H2S), nitrogen (N2), benzene/toluene/xylene (BTX) etc., in varying amounts (up to 50% v/v in some reserves), which constitute several problems. Membrane-based NG sweetening/upgrading processes emerge as among the fastest growing technologies, due to their lower capital cost, higher energy savings, greater economic viability, etc. as compared to conventional technologies. Thus, a defective-free, multilayer thin-film composite membrane is developed from 6FDA-Durene/6FDA-CARDO block co-polyimide for the separation of sour gas from NG. The membrane shows good performance as it exhibit CO2/CH4 and H2S/CH4 selectivities ranges from 8 to 10 and 15 to 19, respectively, and CO2 and H2S permeance are 122 and 220 GPU, respectively.

Protective effect of Carthamus tinctorius L. seed on oxidative stress and cognitive impairment induced by chronic alcohol consumption in mice.

Chronic alcohol consumption induces damage to the brain that can cause various forms of dementia. An abundance of acetaldehyde is produced by excessive alcohol consumption and accumulates in the body to induce oxidative stress, apoptosis, and inflammation in neuronal cells, which results in learning and cognitive decline. In the present study, C57BL/N mice were orally administered alcohol (16%) and Carthamus tinctorius L. seed (CTS) (100 and 200 mg/kg/day). Behavioral experiments showed that memory and cognitive abilities were significantly higher in the CTS groups than the alcohol-treated control group in the T-maze test, novel object recognition test, and Morris water maze test. In addition, CTS inhibited alcohol-induced lipid peroxidation and nitric oxide production in the brain, kidney, and liver. Moreover, alcohol increased acetylcholinesterase activity in the brain, but this was significantly decreased by the administration of CTS. Therefore, CTS may play role in the prevention of alcohol-related dementia.