Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.

Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.

Cutaneous TRPV1+ Neurons Trigger Protective Innate Type 17 Anticipatory Immunity.

Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.

Candidiasis: From cutaneous to systemic, new perspectives of potential targets and therapeutic strategies.

Candidiasis is an infection caused by fungi from a Candida species, most commonly Candida albicans. C. albicans is an opportunistic fungal pathogen typically residing on human skin and mucous membranes of the mouth, intestines or vagina. It can cause a wide variety of mucocutaneous barrier and systemic infections; and becomes a severe health problem in HIV/AIDS patients and in individuals who are immunocompromised following chemotherapy, treatment with immunosuppressive agents or after antibiotic-induced dysbiosis. However, the immune mechanism of host resistance to C. albicans infection is not fully understood, there are a limited number of therapeutic antifungal drugs for candidiasis, and these have disadvantages that limit their clinical application. Therefore, it is urgent to uncover the immune mechanisms of the host protecting against candidiasis and to develop new antifungal strategies. This review synthesizes current knowledge of host immune defense mechanisms from cutaneous candidiasis to invasive C. albicans infection and documents promising insights for treating candidiasis through inhibitors of potential antifungal target proteins.

Neuron‒Mast Cell Cross-Talk in the Skin.

Skin-resident mast cells (MCs) and cutaneous sensory neurons both play crucial roles in microbial‒host defense and inflammatory diseases. MCs can be directly activated by pathogens or their products, resulting in the release of numerous mediators that promote innate immune responses and also activate sensory neurons. Cutaneous sensory neurons can also directly detect the presence of pathogens, resulting in the release of neuropeptides that modulate MC function. In this review, we will focus on the reciprocal interactions between cutaneous sensory neurons and MCs and the importance of this cross-talk in skin diseases.

Factors influencing emotional and behavioral problems in preschool children with cancer based on self-regulation shift theory.

OBJECTIVE: The objective is to investigate the factors influencing emotional and behavioral problems in preschool children with cancer and to provide a scientific basis for developing predictive intervention strategies. METHODS: We recruited 375 preschool children with cancer, from March 2019 to February 2020, via convenience sampling. The self-regulation shift theory was implemented as a theoretical framework and a structural equation model was applied to construct and validate this framework and to analyze the relationships among various influencing factors. RESULTS: Children's effortful control, parent-child attachment, the family environment, family upbringing, parents' marital quality, parents' education level, and social support significantly affected children's emotions and behaviors. Additionally, children's effortful control and parent-child attachment mediated the effect of the family environment, family upbringing, and parents' marital quality on children's emotions and behaviors." CONCLUSION: This study identified several factors that influence children's emotions and behaviors, which should be considered while developing predictive intervention strategies to promote children's rehabilitation and improve parents' education, thus offering improved support for children with cancer.

Plasma Dermatology: Skin Therapy Using Cold Atmospheric Plasma.

Cold atmospheric plasma-based plasma medicine has been expanding the diversity of its specialties. As an emerging branch, plasma dermatology takes advantage of the beneficial complexity of plasma constituents (e.g., reactive oxygen and nitrogen species, UV photons, and electromagnetic emission), technical versatility (e.g., direct irradiation and indirect aqueous treatment), and practical feasibility (e.g., hand-held compact device and clinician-friendly operation). The objective of this comprehensive review is to summarize recent advances in the CAP-dominated skin therapy by broadly covering three aspects. We start with plasma optimisation of intact skin, detailing the effect of CAP on skin lipids, cells, histology, and blood circulation. We then conduct a clinically oriented and thorough dissection of CAP treatment of various skin diseases, focusing on the wound healing, inflammatory disorders, infectious conditions, parasitic infestations, cutaneous malignancies, and alopecia. Finally, we conclude with a brief analysis on the safety aspect of CAP treatment and a proposal on how to mitigate the potential risks. This comprehensive review endeavors to serve as a mini textbook for clinical dermatologists and a practical manual for plasma biotechnologists. Our collective goal is to consolidate plasma dermatology's lead in modern personalized medicine.

The non-Geldanamycin Hsp90 inhibitors enhanced the antifungal activity of fluconazole.

The molecular chaperone heat shock protein 90 (Hsp90) is highly conserved in eukaryotes and facilitates the correct folding, productive assembly and maturation of a diverse cellular proteins. In fungi, especially the most prevalent human fungal pathogen Candida albicans, Hsp90 influences development and modulates drug resistance. Here, we mainly explore the effect of non-Geldanamycin Hsp90 inhibitor HSP990 on the activity of fluconazole (FLC) against Candida albicans and investigate the underlying mechanism. We demonstrate that HSP990 has potent synergistic antifungal activity with FLC against FLC-resistant C. albicans through the checkerboard microdilution assay,agar diffusion tests and time-kill curves, and shows low cytotoxicity to human umbilical vein endothelial cells. Further study shows that the activity of FLC against C. albicans biofilm formation in vitro is significantly enhanced when used in combination with HSP990. In a murine model of disseminated candidiasis, the therapeutic efficacy of FLC is also enhanced by the pharmacological inhibition of C. albicans Hsp90 function with HSP990. Thus, the combined use of small molecule compound and existing antifungal drugs may provide a potential therapeutic strategy for fungal infectious disease.

Mutation of G234 amino acid residue in candida albicans drug-resistance-related protein Rta2p is associated with fluconazole resistance and dihydrosphingosine transport.

Widespread and repeated use of azoles has led to the rapid development of drug resistance in Candida albicans. Our previous study found Rta2p, a membrane protein with 7 transmembrane domains, was involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans. Conserved amino acids in the transmembrane domain of Rta2p were subjected to site-directed mutagenesis. The sensitivity of C. albicans to fluconazole in vitro was examined by minimum inhibitory concentration and killing assay, and the therapeutic efficacy of fluconazole in vivo was performed by systemic mice candidiasis model. Furthermore, dihydrosphingosine transport activity was detected by NBD labeled D-erythro-dihydrosphingosine uptake and release assay, and the sensitivity to sphingolipid biosynthesis inhibitors. We successfully constructed 14 mutant strains of Rta2p, screened them by minimum inhibitory concentration and found Ca(2+) did not completely induce fluconazole resistance with G158E and G234S mutations. Furthermore, we confirmed that G234S mutant enhanced the therapeutic efficacy of fluconazole against systemic candidiasis and significantly increased the accumulation of dihydrosphingosine by decreasing its release. However, G158E mutant didn't affect drug therapeutic efficacy in vivo and dihydrosphingosine transport in C. albicans. G234 of Rta2p in C. albicans is crucial in calcineurin-mediated fluconazole resistance and dihydrosphingosine transport.