KOTMIN13, a Korean herbal medicine alleviates allergic inflammation in vivo and in vitro.

BACKGROUND: The ethanol extract of KOTMIN13, composed of Inula japonica Flowers, Trichosanthes kirilowii Semen, Peucedanum praeruptorum Radix, and Allium macrostemon Bulbs, was investigated for its anti-asthmatic and anti-allergic activities. METHODS: The anti-asthmatic effects of KOTMIN13 were evaluated on ovalbumin (OVA)-induced murine asthma model. Anti-allergic properties of KOTMIN13 in bone-marrow derived mast cells (BMMC) and passive cutaneous anaphylaxis (PCA) in vivo were also examined. RESULTS: In asthma model, KOTMIN13 effectively suppressed airway hyperresponsiveness induced by aerosolized methacholine when compared to the levels of OVA-induced mice. KOTMIN13 treatment reduced the total leukocytes, eosinophil percentage, and Th2 cytokines in the bronchoalveolar lavage fluids in OVA-induced mice. The increased levels of eotaxin and Th2 cytokines in the lung as well as serum IgE were decreased by KOTMIN13. The histological analysis shows that the increased inflammatory cell infiltration and mucus secretion were also reduced. In addition, the degranulation and leukotriene C4 production were inhibited in BMMC with IC50 values of 3.9 µg/ml and 1.7 µg/ml, respectively. Furthermore, KOTMIN13 treatment attenuated mast-mediated PCA reaction. CONCLUSIONS: These results demonstrate that KOTMIN13 has anti-asthmatic and anti-allergic effects in vivo and in vitro models.

Maternally Instigated Diapause in Aedes albopictus: Coordinating Experience and Internal State for Survival in Variable Environments.

The Asian tiger mosquito, Aedes albopictus, is one of the most dangerous invasive species in the world. Females bite mammalian hosts, including humans, to obtain blood for egg development. The ancestral range of Ae. albopictus likely spanned from India to Japan and this species has since invaded a substantial portion of the globe. Ae. albopictus can be broadly categorized into temperate and tropical populations. One key to their ability to invade diverse ecological spaces is the capacity of females to detect seasonal changes and produce stress-resistant eggs that survive harsh winters. Females living in temperate regions respond to cues that predict the onset of unfavorable environmental conditions by producing eggs that enter maternally instigated embryonic diapause, a developmentally arrested state, which allows species survival by protecting the embryos until favorable conditions return. To appropriately produce diapause eggs, the female must integrate environmental cues and internal physiological state (blood feeding and reproductive status) to allocate nutrients and regulate reproduction. There is variation in reproductive responses to environmental cues between interfertile tropical and temperate populations depending on whether females are actively producing diapause vs. non-diapause eggs and whether they originate from populations that are capable of diapause. Although diapause-inducing environmental cues and diapause eggs have been extensively characterized, little is known about how the female detects gradual environmental changes and coordinates her reproductive status with seasonal dynamics to lay diapause eggs in order to maximize offspring survival. Previous studies suggest that the circadian system is involved in detecting daylength as a critical cue. However, it is unknown which clock network components are important, how these connect to reproductive physiology, and how they may differ between behavioral states or across populations with variable diapause competence. In this review, we showcase Ae. albopictus as an emerging species for neurogenetics to study how the nervous system combines environmental conditions and internal state to optimize reproductive behavior. We review environmental cues for diapause induction, downstream pathways that control female metabolic changes and reproductive capacity, as well as diapause heterogeneity between populations with different evolutionary histories. We highlight genetic tools that can be implemented in Ae. albopictus to identify signaling molecules and cellular circuits that control diapause. The tools and discoveries made in this species could translate to a broader understanding of how environmental cues are interpreted to alter reproductive physiology in other species and how populations with similar genetic and circuit organizations diversify behavioral patterns. These approaches may yield new targets to interfere with mosquito reproductive capacity, which could be exploited to reduce mosquito populations and the burden of the pathogens they transmit.

Stress-Induced Neural Plasticity Mediated by Glial GPCR REMO-1 Promotes C. elegans Adaptive Behavior.

Animal nervous systems remodel following stress. Although global stress-dependent changes are well documented, contributions of individual neuron remodeling events to animal behavior modification are challenging to study. In response to environmental insults, C. elegans become stress-resistant dauers. Dauer entry induces amphid sensory organ remodeling in which bilateral AMsh glial cells expand and fuse, allowing embedded AWC chemosensory neurons to extend sensory receptive endings. We show that amphid remodeling correlates with accelerated dauer exit upon exposure to favorable conditions and identify a G protein-coupled receptor, REMO-1, driving AMsh glia fusion, AWC neuron remodeling, and dauer exit. REMO-1 is expressed in and localizes to AMsh glia tips, is dispensable for other remodeling events, and promotes stress-induced expression of the remodeling receptor tyrosine kinase VER-1. Our results demonstrate how single-neuron structural changes affect animal behavior, identify key glial roles in stress-induced nervous system plasticity, and demonstrate that remodeling primes animals to respond to favorable conditions.

Anti-inflammatory Effects of KOTMIN13: A Mixed Herbal Medicine in LPS-stimulated RAW 264.7 Cells and Mouse Edema Models.

BACKGROUND: A Korean herbal medicine, KOTMIN13, composed of Inula japonica Thunberg, Trichosanthes kirilowii Maximowicz var. japonica kitamura, Peucedanum praeruptorum Dunn, and Allium macrostemon Bge, has been used for anti-allergic and anti-asthmatic treatment in oriental clinics, but its activity has not been investigated. MATERIALS AND METHODS: To evaluate the anti-inflammatory activity of KOTMIN13 for in vitro study, LPS-stimulated RAW 264.7 cells were used to induce the production and expression of inflammatory mediators and its mechanisms. 12-O-Tetradecanoylphorobol-13 aceate (TPA)-induced ear edema and carrageenan-induced paw edema models were also used to evaluate the effect of KOTMIN13 on acute inflammation in vivo. RESULTS: KOTMIN13 reduced the release of inflammatory mediators [nitric oxide, prostaglandin E2, interleukin (IL)-1ß, and IL-6] and the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated RAW 264.7 cells. Mechanism studies showed the attenuation of LPS-induced NF-κB activation by KOTMIN13 via IκBα degradation abrogation and a subsequent decrease in nuclear p65 levels. Activation of mitogen-activated protein kinases (ERK, JNK, and p38) was also suppressed. Furthermore, KOTMIN13 ameliorated the development of TPA-induced ear edema and carrageenan-induced paw edema in acute inflammatory edema mouse models. CONCLUSION: Our study demonstrates that KOTMIN13 inhibits inflammatory mediators through the inhibitions of NF-κB and MAPK activities in LPS-induced RAW 264.7 cells, as well as acute inflammation in edema models, indicating that KOTMIN13 is an effective suppressor for anti-inflammatory activities. SUMMARY: KOTMIN13 decrease the production of No, PGE2, and proinflammatory cytokine (TNF-∝, IL-1ß,IL-6).KOTMIN13 Suppressed the degradation of NF-kß and IKßα and the phosorylation of MAP Kinases.Topical application of KOTMIN13 reduced mouse ear edema.Oral administration of KOTMIN13 decreased carrageenan-induced paw edema. Abbreviations used: NO: nitric oxide; PGE2: prostaglandin E2; iNOS: inducible NO synthase; COX-2: cyclooxygenase-2; TNF-α: tumor necrosis factor-α; IL: interleukin; NF-κB: nuclear factor kappaB; MAPK: mitogen-activated protein kinases; ERK: extracellular signal regulated kinase; JNK: c-jun N terminal kinase; TPA: 12-O-tetradecanoylphorbol-13-acetate.

Redundancy in Kiss1 expression safeguards reproduction in the mouse.

Kisspeptin (Kiss1) signaling to GnRH neurons is widely acknowledged to be a prerequisite for puberty and reproduction. Animals lacking functional genes for either kisspeptin or its receptor exhibit low gonadotropin secretion and infertility. Paradoxically, a recent study reported that genetic ablation of nearly all Kiss1-expressing neurons (Kiss1 neurons) does not impair reproduction, arguing that neither Kiss1 neurons nor their products are essential for sexual maturation. We posited that only minute quantities of kisspeptin are sufficient to support reproduction. If this were the case, animals having dramatically reduced Kiss1 expression might retain fertility, testifying to the redundancy of Kiss1 neurons and their products. To test this hypothesis and to determine whether males and females differ in the required amount of kisspeptin needed for reproduction, we used a mouse (Kiss1-CreGFP) that has a severe reduction in Kiss1 expression. Mice that are heterozygous and homozygous for this allele (Kiss1(Cre/+) and Kiss1(Cre/Cre)) have ∼50% and 95% reductions in Kiss1 transcript, respectively. We found that although male Kiss1(Cre/Cre) mice sire normal-sized litters, female Kiss1(Cre/Cre) mice exhibit significantly impaired fertility and ovulation. These observations suggest that males require only 5% of normal Kiss1 expression to be reproductively competent, whereas females require higher levels for reproductive success.