Detrimental or beneficial: the role of TRPM2 in ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury is the main cause of tissue damage and dysfunction. I/R injury is characterized by Ca(2+) overload and production of reactive oxygen species (ROS), which play critical roles in the process of I/R injury to the brain, heart and kidney, but the underlying mechanisms are largely elusive. Recent evidence demonstrates that TRPM2, a Ca(2+)-permeable cationic channel and ROS sensor, is involved in I/R injury, but whether TRPM2 plays a protective or detrimental role in this process remains controversial. In this review, we discuss the recent progress in understanding the role of TRPM2 in reperfusion process after brain, heart and kidney ischemia and the potential of targeting TRPM2 for the development of therapeutic drugs to treat I/R injury.

Intravenous Administration of Multiwalled Carbon Nanotubes Aggravates High-Fat Diet-Induced Nonalcoholic Steatohepatitis in Sprague Dawley Rats.

Multiwalled carbon nanotubes (MWCNTs) have been explored in pharmaceutical applications such as tumor targeting and delivery of drugs, in which MWCNTs are given through intravenous injection. However, the biosafety of MWCNTs is of concern for such application. Therefore, in the current study, we used a fatty liver model to investigate the possible toxicity of MWCNTs to the liver, as MWCNTs were retained mainly in the liver of mice after intravenous injection. Male Sprague Dawley rats were used to generate the fatty liver model, and the effects of intravenous administration of MWCNTs on fatty liver were studied. Hematoxylin and eosin staining for hepatocellular anatomy and Masson trichrome staining for hepatic fibrosis were conducted. Histologically, MWCNTs aggravated steatohepatitis with higher nonalcoholic fatty liver disease scores. Analysis of liver injury markers indicated that MWCNTs administration resulted in chronic hepatitis, along with increased liver fat and altered liver oxidation, including the increase of P6 protein and the depletion of glutathione. In conclusion, our results suggest that MWCNTs can aggravate nonalcoholic steatohepatitis in Sprague Dawley rats, and oxidative injury may be involved in this process.

A novel fluorescent cell membrane-permeable caged cyclic ADP-ribose analogue.

Cyclic adenosine diphosphate ribose is an endogenous Ca(2+) mobilizer involved in diverse cellular processes. A cell membrane-permeable cyclic adenosine diphosphate ribose analogue, cyclic inosine diphosphoribose ether (cIDPRE), can induce Ca(2+) increase in intact human Jurkat T-lymphocytes. Here we synthesized a coumarin-caged analogue of cIDPRE (Co-i-cIDPRE), aiming to have a precisely temporal and spatial control of bioactive cIDPRE release inside the cell using UV uncaging. We showed that Co-i-cIDPRE accumulated inside Jurkat cells quickly and efficiently. Uncaging of Co-i-cIDPRE evoked Ca(2+) release from endoplasmic reticulum, with concomitant Ca(2+) influx in Jurkat cells. Ca(2+) release evoked by uncaged Co-i-cIDPRE was blocked by knockdown of ryanodine receptors (RyRs) 2 and 3 in Jurkat cells. The associated Ca(2+) influx, on the other hand, was abolished by double knockdown of Stim1 and TRPM2 in Jurkat cells. Furthermore, Ca(2+) release or influx evoked by uncaged Co-i-cIDPRE was recapitulated in HEK293 cells that overexpress RyRs or TRPM2, respectively, but not in wild-type cells lacking these channels. In summary, our results indicate that uncaging of Co-i-cIDPRE incites Ca(2+) release from endoplasmic reticulum via RyRs and triggers Ca(2+) influx via TRPM2.