Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naïve T cells into cytokine-producing mature T cells

T cells have been classified as belonging to the Th1 or Th2 subsets according to the production of defining cytokines such as IFN-γ and IL-4. The discovery of the Th17 lineage and regulatory T cells shifted the simple concept of the Th1/Th2 balance into a 4-way mechanistic pathway of local and systemic immunological activity. Clinically, the blockage of cytokine signals or non-specific suppression of cytokine predominance by immunosuppressants is the first-line treatment for inflammatory T cell-mediated disorders. Cyclosporine A (CsA) and Tacrolimus (Tac) are commonly used immunosuppressants for the treatment of autoimmune disease, psoriasis, and atopic disorders. Many studies have shown that these compounds suppress the activation of the calcium-dependent phosphatase calcineurin, thereby inhibiting T-cell activation. Although CsA and Tac are frequently utilized, their pharmacological mechanisms have not yet been fully elucidated.In the present study, we focused on the effects of CsA and Tac on cytokine secretion from purified human memory CD4(+)T cells and the differentiation of na?ve T cells into cytokine-producing memory T cells. CsA or Tac significantly inhibited IFN-γ, IL-4, and IL-17 production from memory T cells. These compounds also inhibited T cell differentiation into the Th1, Th2, and Th17 subsets, even when used at a low concentration. This study provided critical information regarding the clinical efficacies of CsA and Tac as immunosuppressants.     

Mycorrhizal diversity and specificity in Lecanorchis (Orchidaceae)

Lecanorchis is a nonphotosynthetic plant genus in Vanilloideae, Orchidaceae. Because of the distribution of many Lecanorchis taxa in various climate conditions, we hypothesized that mycorrhizal diversity and specificity are different among the different taxa of Lecanorchis. In the present study, identities of mycorrhizal fungi were examined for 90 individuals of 10 Lecanorchis taxa at 26 sites from Niigata to Okinawa Prefectures in Japan. Phylogenetic analyses of Lecanorchis taxa based on the internal transcribed spacer (ITS) region of the nuclear ribosomal RNA gene (rDNA) divided the examined Lecanorchis taxa into three groups, groups A, B, and C. ITS rDNA sequences suggested that fungi associating with Lecanorchis were ectomycorrhiza-forming fungi in Lactarius, Russula, Atheliaceae, and Sebacina, with Lactarius and Russula dominant. Our results suggested some degree of mycorrhizal specialization among Lecanorchis taxa. Interestingly, the Lecanorchis group C had some specific relationships with Lactarius, whereas less specificity was found in the relationships with Russula. However, observed specificity results may be biased by geographic opportunity, and we suggest further research to assess whether Lecanorchis species are limited to the associations we observed.     

Discovery of S-444823, a potent CB1/CB2 dual agonist as an antipruritic agent

The optimization of a series of 3-carbamoyl 2-pyridone derivatives as CB agonists is reported. These efforts resulted in the discovery of 3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoic acid (21), a potent dual CB1/CB2 agonist without CNS side effects induced by CB1 receptor activation. It exhibited strong inhibition of scratching as a 1.0% acetone solution in the pruritic model.     

Size-mediated dominance and aggressive behavior of male Japanese fluvial sculpin Cottus pollux (Pisces: Cottidae) reduce nest-site abundance and mating success of conspecific rivals

Despite growing evidence for plasticity in the mating patterns of nest-holding animals in relation to the changes in nest abundance, the effects of aggressive interaction by dominant males on nest availability for conspecific rivals remains unclear. To quantify the effects of male–male competition on nest-site choice and mating success of the male Japanese fluvial sculpin Cottus pollux, we conducted experiments on 5 males from different 5 size classes under both sufficient and shortage nest-abundance conditions. Nest-choice experiments showed that both male size class and nest-abundance condition had significant effects on the nesting rates of males. Following the nest-choice experiments, 10 gravid females were added in the experimental tanks. Mating experiments revealed that male size, nesting rate before addition of females, and the number of courtship attempts on females were valid variables of male mating success, regardless of nest-abundance conditions. After achieving initial mating success, the largest nesting male exhibited more frequent aggressive interaction with other conspecific males than he did before obtaining eggs in his nest. Our results suggest that size-mediated dominance and aggressive behavior of males may disrupt nest acquisition of other conspecific males, and may consequently result in extreme variation in mating success among males even under sufficient nest-abundance conditions.     

Transformation of the edible mushroom Pleurotus ostreatus by particle bombardment

Uracil auxotroph of Pleurotus ostreatus was transformed to prototrophy by means of particle bombardment. Five transformants were obtained under three conditions differing in the two parameters of target distance and helium pressure. The transformation frequency was one transformant per microg of DNA. In the transformants, plasmid DNAs were integrated into the genomic DNA and stably maintained. This is the first report on transformation of P. ostreatus by particle bombardment.     

Ustekinumab Improves Psoriasis without Altering T Cell Cytokine Production,Differentiation, and T Cell Receptor Repertoire Diversity

Ustekinumab is a fully human IgG1κ monoclonal antibody targeting interleukin (IL)-12/23 p40 subunit. The role of IL-12/23-mediated pathway in the mechanism of various inflammatory disorders especially psoriasis has been well recognized. Recently the long-term efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis has been evaluated in phase 2/3 clinical trials, and the results showed no significant risk for serious adverse effects, infections, or malignancies. Ustekinumab inhibits the function of the IL-12/23 p40 subunit, and therefore it is believed that inhibition of IL-12 p40 pathway decreases IFN-γ production. The major concern for the use of ustekinumab is the possibility of increased immunosuppression due to low IFN-γ production. However, the effects of ustekinumab on CD4⁺ T cell function have not been fully investigated so far. In this study, we explored changes in cytokine production by memory CD4⁺ T cells as well as in the differentiation of naïve T cells to helper T cell (Th) 1, Th2, or Th17 cells in psoriasis patients treated with ustekinumab. The effect of the treatment on T cell receptor repertoire diversity was also evaluated. The results showed that ustekinumab improves clinical manifestation in patients with psoriasis without affecting cytokine production in memory T cells, T cell maturation, or T cell receptor repertoire diversity. Although the number of patients is limited, the present study suggests that T cell immune response remains unaffected in psoriasis patients treated with ustekinumab.     

Chloroplastic NADPH-dependent alkenal/one oxidoreductase contributes to the detoxification of reactive carbonyls produced under oxidative stress

Lipid peroxide-derived reactive carbonyls (RCs) can cause serious damage to plant functions. A chloroplastic NADPH-dependent alkenal/one oxidoreductase (AOR) detoxifies RCs, but its physiological significance remains unknown. In this study, we investigated the biological impacts of AOR using an AOR-knock out Arabidopsis line (aor). Methyl viologen treatment, mainly to enhance photosystem (PS) I-originated reactive oxygen species (ROS) production, caused more severe damage to aor than wild type (Col-0). In contrast, the high light treatment used to enhance PSII-originated ROS production resulted in no difference in PSII damage between Col-0 and aor. In conclusion, AOR can contribute to detoxify stromal RCs produced under oxidative stress.