Csk restrains BCR-mediated ROS production and contributes to germinal center selection and affinity maturation.

Compared with naïve B cells, the B cell receptor (BCR) signal in germinal center (GC) B cells is attenuated; however, the significance of this signaling attenuation has not been well defined. Here, to investigate the role of attenuation of BCR signaling, we employed a Csk mutant mouse model in which Csk deficiency in GC B cells resulted in augmentation of net BCR signaling with no apparent effect on antigen presentation. We found that Csk is required for GC maintenance and efficient antibody affinity maturation. Mechanistically, ROS-induced apoptosis was exacerbated concomitantly with mitochondrial dysfunction in Csk-deficient GC B cells. Hence, our data suggest that attenuation of the BCR signal restrains hyper-ROS production, thereby protecting GC B cells from apoptosis and contributing to efficient affinity maturation.

Modeling Type-1 Iodothyronine Deiodinase with Peptide-Based Aliphatic Diselenides: Potential Role of Highly Conserved His and Cys Residues as a General Acid Catalyst.

Type-1 iodothyronine deiodinase (ID-1) catalyzes the reductive elimination of 5'-I and 5-I on the phenolic and tyrosyl rings of thyroxine (T4), respectively. Chemically verifying whether I atoms with different chemical properties undergo deiodination through a common mechanism is challenging. Herein, we report the modeling of ID-1 using aliphatic diselenide (Se-Se) and selenenylsulfide (Se-S) compounds. Mechanistic investigations of deiodination using the ID-1-like reagents suggested that the 5'-I and 5-I deiodinations proceed via the same mechanism through an unstable intermediate containing a Se⋅⋅⋅I halogen bond between a selenolate anion, reductively produced from Se-Se (or Se-S) in the compound, and an I atom in T4. Moreover, imidazolium and thiol groups, which may act as general acid catalysts, promoted the heterolytic cleavage of the C-I bond in the Se⋅⋅⋅I intermediate, which is the rate-determining step, by donating a proton to the C atom.

Flavan 3-ol delays the progression of disuse atrophy induced by hindlimb suspension in mice.

Periods of skeletal muscle disuse, for example due to a sedentary lifestyle or bed rest, are associated with aging and can lead to muscle atrophy. We previously found that the flavan 3-ol fraction derived from cocoa (FL) enhanced energy expenditure with metabolic changes in skeletal muscle. In the present study, we examined the effect of FL on disuse muscle atrophy induced by hindlimb suspension in mice. Male C57BL/6J mice were assigned to four groups as follows: unsuspended-vehicle, unsuspended-FL, suspended-vehicle, and suspended-FL. Mice in the vehicle treatment groups were administered distilled water and those in the FL treatment groups were dosed with FL (50mg/kg/day) for 2weeks. The weights of the gastrocnemius (GC), tibialis anterior (TA), and soleus (SOL), but not the extensor digitorum longus (EDL), decreased significantly in mice with hindlimb suspension (-11.8%, -16.5%, and -41.0%, respectively). This reduction in GC, TA, and SOL mass was inhibited by FL (-5.3%, +2.0%, and -16.6%, respectively). The FL increased the EDL weight >20% with or without hindlimb suspension. The protein level of the ubiquitin ligase, muscle ring finger-1, in the SOL was significantly increased by hindlimb suspension, but inhibited by treatment with FL. Protein expression of p70S6 kinase in the SOL was significantly decreased by hindlimb suspension, and FL treatment inhibited this change. These results suggested that FL delayed disuse muscle atrophy by metabolic alteration.