Skin Commensal Bacteria Modulates the Immune Balance of Mice to Alleviate Atopic Dermatitis-Induced Damage.

Objective: Although studies indicate that Staphylococcus epidermidis (S. epidermidis) can regulate inflammation and anti-inflammatory cytokines, there is limited evidence supporting their effects on atopic dermatitis (AD). Here, we aimed to investigate the effects and potential mechanism of skin commensal bacteria on the immunity of mice with AD. Methods: Twenty-four female BALB/C mice were selected and divided randomly into 4 groups: normal group, atopic dermatitis model group (AD), atopic dermatitis/substrate group (AD/substrates), and atopic dermatitis/substrates/epidermidis group (AD/S. epidermidis). All the mice were given different ways. After 14 days, their skin conditions were scored, and the serum, ear tissue, and inguinal lymph node tissue were collected and analyzed. Furthermore, the flow cytometry was used to analyze the number of CD4°+°CD25°+°Foxp3°+°Treg in the mouse lymph node tissue. Results: Compared with the AD/substrate group, the mice ear thickness and dermatitis score were significantly reduced in the AD/S. epidermidis group; skin epidermis, acanthosis, the degree of keratinization, inflammatory cell infiltration in the dermis, and the number of mast cells were declined. The serum levels of IgE, IgG1, IgG2a, and TNF-α, IFN-γ, IL-4, and Eotaxin were significantly declined in the AD/S. epidermidis compared with the AD/substrate group. The proportion of CD4°+°CD25°+°Foxp3°+°Treg cells in the lymph node tissue was significantly increased in the AD/S. epidermidis group compared with the AD/substrate group. Conclusion: Staphylococcus epidermidis can regulate mice's immune balance to alleviate AD-induced skin damage.

Bicyclic azetidines kill the diarrheal pathogen Cryptosporidium in mice by inhibiting parasite phenylalanyl-tRNA synthetase.

Cryptosporidium is a protozoan parasite and a leading cause of diarrheal disease and mortality in young children. Currently, there are no fully effective treatments available to cure infection with this diarrheal pathogen. In this study, we report a broad drug repositioning effort that led to the identification of bicyclic azetidines as a new anticryptosporidial series. Members of this series blocked growth in in vitro culture of three Cryptosporidium parvum isolates with EC50 's in 1% serum of <0.4 to 96 nM, had comparable potencies against Cryptosporidium hominis and C. parvum, and was effective in three of four highly susceptible immunosuppressed mice with once-daily dosing administered for 4 days beginning 2 weeks after infection. Comprehensive genetic, biochemical, and chemical studies demonstrated inhibition of C. parvum phenylalanyl-tRNA synthetase (CpPheRS) as the mode of action of this new lead series. Introduction of mutations directly into the C. parvum pheRS gene by CRISPR-Cas9 genome editing resulted in parasites showing high degrees of compound resistance. In vitro, bicyclic azetidines potently inhibited the aminoacylation activity of recombinant ChPheRS. Medicinal chemistry optimization led to the identification of an optimal pharmacokinetic/pharmacodynamic profile for this series. Collectively, these data demonstrate that bicyclic azetidines are a promising series for anticryptosporidial drug development and establish a broad framework to enable target-based drug discovery for this infectious disease.

Plexin-B1 and semaphorin 4D cooperate to promote cutaneous squamous cell carcinoma cell proliferation, migration and invasion.

BACKGROUND OBJECTIVES: Semaphorin 4D (Sema4D) and its receptor, Plexin-B1, are involved in the pathogenesis of squamous cell carcinoma (SCC) by mediating angiogenesis or perineural invasion through the interaction between Sema4D expression on SCC cells and Plexin-B1 expression on endothelial cells or nerves. Plexin-B1 was also recently found to be expressed on SCC cells. Plexin-B1 expression on several types of tumor cells could mediate various, and occasionally opposing, effects, including tumor cell survival, proliferation, angiogenesis, invasion, and metastasis. However, whether Sema4D exerts paracrine or autocrine effects on SCC via Plexin-B1 remains unclear. OBJECTIVES: The aim of this study is to explore the effects of Sema4D/Plexin-B1 interaction on SCC via Plexin-B1 expressed on the tumor cells. METHODS: In the present study, we detected the expression of Plexin-B1 and Sema4D in cutaneous SCC (cSCC) tissues and in the cSCC cell line A431 and analyzed the effects of the Sema4D/Plexin-B1 interaction on cSCC cell proliferation, migration, and invasion, as well as on the signaling pathway downstream of Plexin-B1. RESULTS: We observed significantly increased Plexin-B1 and Sema4D expression in keratinocytes in cSCC lesions and in A431 cells compared with that in normal skin tissue and in non-malignant keratinocytes. Plexin-B1 silencing reduced the growth, proliferation, migration, and invasion of A431 cells and inhibited the phosphorylation of Akt and extracellular signal-regulated protein kinase (Erk). Soluble recombinant Sema4D promoted the growth, proliferation, migration, and invasion of A431 cells; Akt and Erk phosphorylation is also involved in these processes with a Plexin-B1 dependent manner. CONCLUSION: Plexin-B1 induces cSCC cell proliferation, migration, and invasion by interacting with Sema4D. Plexin-B1 might serve as a useful biomarker and/or as a novel therapeutic target for cSCC.