Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease.

Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM) is a rare and most severe form of cutaneous mastocytosis, which typically occurs in childhood. There have been reports of a familial DCM with specific gene mutations, indicating both sporadic and hereditary factors involved in its pathogenesis. DCM is associated with severe MC mediator-related symptoms and an increased risk of anaphylaxis. The diagnosis is based on the appearance of skin lesions, which typically show generalized thickening, erythroderma, blistering dermographism, and a positive Darier's sign. Recognition, particularly in infants, is challenging due to DCMs resemblance to other bullous skin disorders. Therefore, in unclear cases, a skin biopsy is crucial. Treatment focuses on symptom management, mainly including antihistamines and mast cell stabilizers. In extremely severe cases, systemic steroids, tyrosine kinase inhibitors, phototherapy, or omalizumab may be considered. Patients should be equipped with an adrenaline autoinjector. Herein, we conducted a comprehensive review of literature data on DCM since 1962, which could help to better understand both the management and prognosis of DCM, which depends on the severity of skin lesions, intensity of mediator-related symptoms, presence of anaphylaxis, and treatment response.

When Mast Cells Run Amok: A Comprehensive Review and Case Study on Severe Neonatal Diffuse Cutaneous Mastocytosis.

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is in the KIT gene. We report a rare case of a boy, born at term, already presenting at birth with generalized subcutaneous nodules on the face, scalp, trunk, back, hands, and feet. The spleen, liver, and inflammatory markers were normal at birth. Tryptase was significantly elevated. A bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin-fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical and inguinal adenopathy, while the skin nodules persisted, especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation; however, compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive, and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement.

Mast cell-derived exosomal miR-181a-5p modulated trophoblast cell viability, migration, and invasion via YY1/MMP-9 axis.

BACKGROUND: Mast cells regulate the process of preeclampsia (PE). Since we previously identified mast cells specifically expressing miR-181a-5p in the placenta of PE patients, it is plausible to examine the effect and mechanism of mast cell-derived exosomal miR-181a-5p on trophoblast cells. METHODS: The miR-181a-5p and YY1 levels were determined by quantitative real-time reverse transcription-polymerase chain reaction. Exosomes were identified by transmission electron microscopy, Western blot, and PKH-26 labeling. Mast cells or trophoblast cell malignant phenotype were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, wound healing, and Transwell assays. Quantification of YY1 and metastasis-related proteins was performed using Western blot. TargetScan, JASPAR, dual-luciferase reporter genes, and chromatin immunoprecipitation were exploited to verify the relationship between miR-181a-5p, YY1, and MMP-9. RESULTS: MiR-181a-5p was overexpressed in mast cells of PE patients. Overexpressed miR-181a-5p restrained mast cell viability. Mast cell exosomes were successfully isolated, containing high expressions of CD63 and HSP70 and low expression of Calnexin and could be transported to the cytoplasm of trophoblast cells. Mast cell exosomes attenuated the viability, migration, and invasion of HTR-8/SVneo cells, inhibited YY1, N-cadherin, Vimentin, and MMP-9 protein expressions, and promoted E-cadherin protein expression. The effect of exosomes was enhanced by miR-181a-5p mimic but was reversed by miR-181a-5p inhibitor. MiR-181a-5p targeted YY1 which bound to the MMP-9 promoter. Overexpressed YY1 in HTR-8/SVneo cells accelerated the malignant phenotype of the cells and reversed the regulatory effects of exosomal miR-181a-5p. CONCLUSION: Mast cell-derived exosomal miR-181a-5p modulates HTR-8/SVneo cell viability, migration, and invasion via YY1/MMP-9.

Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling.

Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-ß signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.

Updated Concepts in Oncologic Surgery: Apocrine Gland Anal Sac Adenocarcinoma and Mast Cell Tumors.

Advancements within the field of veterinary surgical oncology are constantly presenting themselves, especially with continued development of comprehensive cancer programs. With the use of more advanced imaging techniques within veterinary medicine, tumor staging is improving and techniques novel to veterinary medicine are being evaluated for potential clinical application. Recommended tumor staging and treatment approach for apocrine gland anal sac adenocarcinoma in dogs has evolved, with the anticipation of good long-term patient outcomes. Preoperative staging for mast cell tumors and recommendations for surgical margins to obtain for wide surgical excision is being reassessed by surgeons.

Lantana canescens (Kunth) inhibits inflammatory and hyperalgesic responses in murine models.

ETHNOPHARMACOLOGICAL RELEVANCE: Lantana canescens is popularly known in Brazil as "cidreirinha" or "chumbinho-branco". It is found in Pantanal biome and its flowers and leaves are used in traditional medicine to treat pain and inflammation. Information about this species is limited to the activity of isolated essential oils. Studies with different extracts, composition, and biological properties are still scarce. AIM OF THIS STUDY: The objective of this study was to evaluate the anti-inflammatory and anti-hyperalgesic activity of the hydroethanolic extract of L. canescens aerial parts. MATERIALS AND METHODS: The hydroethanolic extract L. canescens aerial parts (HELc) was analyzed using HPLC-DAD-EM. Male and female Swiss mice weighing 18-25 g were used in the in vivo assays. Acute toxicity was assessed (2000 mg/kg); anti-inflammatory activity through paw edema, mast cell degranulation and peritonitis, and anti-hyperalgesic activity through abdominal writhing assays induced by acetic acid and formalin sensitization, were evaluated using the doses of 3, 30 and 300 mg/kg. RESULTS: The phytochemical characterization of HELc confirmed the presence of glycosylated iridoids (theveside, theviridoside), verbascosides and flavonoids. The HELc did not present toxicity in the evaluated dose. HELc reduced formation of paw edema, degranulation of peritoneal mast cells and infiltration of polymorphonuclear cells into the animals peritoneal cavity. In addition, HELc decreased the number of abdominal writhing induced by acetic acid and the time of paw licking in the evaluation of formalin sensitization. CONCLUSIONS: These results confirm the anti-inflammatory and anti-hyperalgesic effects of hydroethanolic extract of L. canescens, validating the use of this plant in folk medicine.

Pediatric Mastocytosis: Recognition and Management.

Mastocytosis is a heterogeneous group of disorders characterized by the accumulation of clonal mast cells in organs such as the skin and bone marrow. In contrast to adults, most affected children have only cutaneous involvement. This article reviews the molecular pathogenesis, skin findings, mast cell mediator-related symptoms, evaluation, and management of childhood-onset mastocytosis, noting differences from adult-onset disease. Current classification of cutaneous mastocytosis and the natural histories of different variants in pediatric patients are highlighted, with a focus on clinical manifestations with prognostic implications. A practical algorithm is provided to guide clinical assessment, laboratory and other investigations, and longitudinal monitoring, including recognition of hepatosplenomegaly as a marker of systemic disease and utilization of allele-specific quantitative PCR (ASqPCR) to detect KIT mutations in the peripheral blood. Updated information and consensus-based recommendations regarding possible triggers of mast-cell degranulation (e.g., physical, medications) are discussed, with an emphasis on patient-specific factors and avoiding excessive parental concern. Lastly, an individualized, stepwise approach to treatment of symptoms, skin-directed therapy, and potential use of kinase inhibitors for severe systemic disease is outlined.

Wheat Bran Extract Regulates Mast Cell-Mediated Allergic Responses In Vitro and In Vivo.

In the present study the effects and molecular mechanisms of wheat bran (WB), the hard outer layer of the wheat kernel used in food ingredients, on mast cell-mediated allergic responses in vitro and in vivo were investigated. The water extract of WB inhibited degranulation and expression of allergic and inflammatory mediators such as tumor necrosis factor-α, cyclooxygenase-2 and inducible nitric oxide synthase in antigen-stimulated RBL-2H3 cells. These anti-allergic activities of WB were mediated by the inactivation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which play important roles in degranulation and expression of various allergic and inflammatory molecules. In agreement with its in vitro effects, WB inhibited immunoglobulin E (IgE)/antigen-induced and compound 48/80-induced anaphylactic reactions in vivo. Taken together, these findings suggest the pharmacological potential of WB in the regulation of allergic diseases, including allergic rhinitis, atopic dermatitis, asthma and anaphylaxis.

Streptococcal H2O2 inhibits IgE-triggered degranulation of RBL-2H3 mast cell/basophil cell line by inducing cell death.

Mast cells and basophils are central players in allergic reactions triggered by immunoglobulin E (IgE). They have intracellular granules containing allergic mediators (e.g., histamine, serotonin, inflammatory cytokines, proteases and ß-hexosaminidase), and stimulation by IgE-allergen complex leads to the release of such allergic mediators from the granules, that is, degranulation. Mast cells are residents of mucosal surfaces, including those of nasal and oral cavities, and play an important role in the innate defense system. Members of the mitis group streptococci such as Streptococcus oralis, are primary colonizers of the human oral cavity. They produce hydrogen peroxide (H2O2) as a by-product of sugar metabolism. In this study, we investigated the effects of streptococcal infection on RBL-2H3 mast cell/basophil cell line. Infection by oral streptococci did not induce degranulation of the cells. Stimulation of the RBL-2H3 cells with anti-dinitrophenol (DNP) IgE and DNP-conjugated human serum albumin triggers degranulation with the release of ß-hexosaminidase. We found that S. oralis and other mitis group streptococci inhibited the IgE-triggered degranulation of RBL-2H3 cells. Since mitis group streptococci produce H2O2, we examined the effect of S. oralis mutant strain deficient in producing H2O2, and found that they lost the ability to suppress the degranulation. Moreover, H2O2 alone inhibited the IgE-induced degranulation. Subsequent analysis suggested that the inhibition of degranulation was related to the cytotoxicity of streptococcal H2O2. Activated RBL-2H3 cells produce interleukin-4 (IL-4); however, IL-4 production was not induced by streptococcal H2O2. Furthermore, an in vivo study using the murine pollen-induced allergic rhinitis model suggested that the streptococcal H2O2 reduces nasal allergic reaction. These findings reveal that H2O2 produced by oral mitis group streptococci inhibits IgE-stimulated degranulation by inducing cell death. Consequently, streptococcal H2O2 can be considered to modulate the allergic reaction in mucosal surfaces.

Comparison of exercise training and estrogen supplementation on mast cell-mediated doxorubicin-induced cardiotoxicity.

Cardiac inflammation has been proposed as one of the primary mechanisms of anthracycline-induced acute cardiotoxicity. A reduction in cardiac inflammation might also reduce cardiotoxicity. This study aimed to evaluate the potential of estrogen therapy and regular exercise on attenuating cardiac inflammation in the context of doxorubicin-induced cardiomyopathy. Ovariectomized rats were randomly allocated into estrogen supplementation, exercise training, and mast cell stabilizer treatment groups. Eight weeks after ovariectomy, rats received six cumulative doses of doxorubicin for two weeks. Echocardiography demonstrated a progressive decrease in ejection fraction in doxorubicin-treated rats without hypertrophic effect. This systolic defect was completely prevented by either estrogen supplementation or mast cell stabilizer treatment but not by regular exercise. As a heart disease indicator, increased ß-myosin heavy chain expression induced by doxorubicin could only be prevented by estrogen supplementation. Decrease in shortening and intracellular Ca2+ transients of cardiomyocytes were due to absence of female sex hormones without further effects of doxorubicin. Again, estrogen supplementation and mast cell stabilizer treatment prevented these changes but exercise training did not. Histological analysis indicated that the hyperactivation of cardiac mast cells in ovariectomized rats was augmented by doxorubicin. Estrogen supplementation and mast cell stabilizer treatment completely prevented both increases in mast cell density and degranulation, whereas exercise training partially attenuated the hyperactivation. Our results, therefore, suggest that estrogen supplementation acts similarly to mast cell stabilizers in attenuating the effects of doxorubicin. Ineffectiveness of regular exercise in preventing the acute cardiotoxicity of doxorubicin might be due to a lesser effect on preventing cardiac inflammation.

Xanthone suppresses allergic contact dermatitis in vitro and in vivo.

Xanthone is a phenolic compound found in a few higher plant families; it has a variety of biological activities, including antioxidant, anti-inflammatory, and anticancer properties. However, the molecular and cellular mechanisms underlying the activity of xanthone in allergic contact dermatitis (ACD) remain to be explored. Therefore, this study aimed to investigate the regulatory effects of xanthone in ACD in human keratinocytes (HaCaT cell), and human mast cell line (HMC-1 cell) in vitro and in an experimental murine model. The results demonstrated that treatment with xanthone reduced the production of pro-inflammatory cytokines and chemokines including interleukin (IL)-1ß, IL-6, IL-8, and expression of chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated HaCaT cells. Xanthone also suppressed the production of pro-inflammatory cytokines, chemokines, and allergic mediators in phorbol myristate acetate/A23187 calcium ionophore (PMACI)-stimulated HMC-1 cells. Xanthone significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) and activation of caspase-1 signaling pathway in vitro model. Additionally, xanthone administration alleviated 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis like-skin lesion by reducing the serum levels of immunoglobulin E (IgE), histamine, and pro-inflammatory cytokines and suppressing MAPKs phosphorylation. Xanthone administration also inhibited mortality due to compound 48/80-induced anaphylactic shock and suppressed the passive cutaneous anaphylaxis (PCA) reaction mediated by IgE. Collectively, these results suggest that xanthone has a potential for use in the treatment of allergic inflammatory diseases.

Rhubarb-Evoke Mucus Secretion through Aggregation and Degranulation of Mast Cell in the Colon of Rat: In vivo and ex vivo studies.

Rhubarb is commonly used to treat constipation in China for its function of promoting intestinal movement and optimum water content in feces. However, its mechanism of mucus secretion is vague. The aim of the study is to investigate the role of mast cells and enteric neurons in rhubarb extract (RE)-induced mucus secretion in the rat colon. Immunofluorescence was used to detect histamine receptors. Western blotting and 3,3'-diaminobenzidine (DAB) were applied to explore the content changes of mast cells activation. The changes in colonic goblet cells (GCs) were determined by means of PAS/AB staining. An intestinal perfusion system with a Bradford protein assay kit was directly to estimate in vitro secretion. And the cytokines were investigated with ELISA. The longitudinal aspect of this study indicate that the number and water content of faecal pellets were enhanced after the administration of different doses of RE accompanied by mast cells accumulated and increased the content of interferon (IFN) -γ or decreased the levels of interleukin (IL) -10 at doses of 3 and 6 g/kg. Pretreatment with ketotifen, mast cell stabilizer, had partially inhibited on RE-induced mucus secretion. Furthermore, RE induced the release of acetylcholine and mucin-2 in the colonic tissue and the histamine levels from the faeces. The results suggest that RE induced colonic mucus secretion involves mast cell activation and some cytokine.

Hispidulin Inhibits Mast Cell-Mediated Allergic Inflammation through Down-Regulation of Histamine Release and Inflammatory Cytokines.

Hispidulin (4',5,7-trihydroxy-6-methoxyflavone) is a natural compound derived from traditional Chinese medicinal herbs, and it is known to have an anti-inflammatory effect. Here, we investigated the effect of hispidulin on the immunoglobulin E (IgE)-mediated allergic responses in rat basophilic leukemia (RBL)-2H3 mast cells. When RBL-2H3 cells were sensitized with anti-dinitrophenyl (anti-DNP) IgE and subsequently stimulated with DNP-human serum albumin (HSA), histamine and ß-hexosaminidase were released from the cells by degranulation of activated mast cells. However, pretreatment with hispidulin before the stimulation of DNP-HSA markedly attenuated release of both in anti-DNP IgE-sensitized cells. Furthermore, we investigated whether hispidulin inhibits anti-DNP IgE and DNP-HSA-induced passive cutaneous anaphylaxis (PCA), as an animal model for Type I allergies. Hispidulin markedly decreased the PCA reaction and allergic edema of ears in mice. In addition, activated RBL-2H3 cells induced the expression of inflammatory cytokines (tumor necrosis factor-α and interleukin-4), which are critical for the pathogenesis of allergic disease, through the activation of c-Jun N-terminal kinase (JNK). Inhibition of JNK activation by hispidulin treatment reduced the induction of cytokine expression in the activated mast cells. Our results indicate that hispidulin might be a possible therapeutic candidate for allergic inflammatory diseases through the suppression of degranulation and inflammatory cytokines expression.

Sex differences in the effects of early life stress exposure on mast cells in the developing rat brain.

Early life stress leads to long lasting effects on behavior. Neuroimmune cells have been implicated as key mediators of experience-induced changes in brain and behavioral development, in that they are highly responsive to stress. Mast cells are one such type of neuroimmune cell, but little is known about their role in brain development or following early life stress. Here, we assessed the impact of three different early life stress exposure paradigms on mast cell dynamics in the developing brain of male and female rats, focusing on the hippocampus and hypothalamus, where most mast cells reside. We found that exposure to two weeks of chronic variable stress during gestation led to increased mast cell number and activation in the female offspring hypothalamus on the day of birth. Acute exposure to maternal separation stress on postnatal day (PN) 2 led to significant decreases in mast cells within the hypothalamus and hippocampus of females, but not males. In contrast, one week of exposure to brief daily maternal separation stress (e.g., handling), increased mast cell numbers in the female, but not male, hippocampus. We found significant sex differences in mast cell number and activation, including males having more mast cells than females in the hippocampus on the day of birth and males having significantly more degranulated mast cells on PN11. Thus, mast cells may be an unappreciated mediator of sex-specific brain development in response to early life perturbations.

Yin-Yang of IL-33 in Human Skin Mast Cells: Reduced Degranulation, but Augmented Histamine Synthesis through p38 Activation.

Mast cells (MCs) are the principal effector cells of IgE-mediated allergy. IL-33 is released by resident skin cells as alarmin upon tissue damage or allergen contact. Owing to their pronounced receptor expression, MCs are important targets of IL-33 action, but consequences for skin MCs are ill-defined, especially upon chronic exposure to IL-33. Mimicking the inflammatory milieu of skin disorders, we found that persistent exposure to IL-33 (over a 5-week period) strengthened skin MC numbers through accelerated cell-cycle progression and restriction of apoptosis. Conversely, IL-33 attenuated degranulation and FcεRI expression, potentially as a feedback to chronic "alarmin" exposure. Interestingly, the negative impact on histamine release was counterbalanced by amplified histamine production. Considering the clinical significance of histamine and scarce information on its regulation, we explored the molecular underpinnings. IL-33 induced swift phosphorylation of p38 and JNK (but not of ERK1/2 or AKT), and stimulated histidine decarboxylase expression. Combining pharmacological inhibition and kinase elimination by Accell-facilitated RNA interference in skin MCs revealed a p38-dependent, but JNK-independent mechanism. Collectively, IL-33 exerts multifaceted effects on cutaneous MCs at a post-maturation stage. The IL-33-skin MC axis may contribute to and balance inflammation in chronic skin disorders.

Mechanisms of Probiotic VSL#3 in a Rat Model of Visceral Hypersensitivity Involves the Mast Cell-PAR2-TRPV1 Pathway.

BACKGROUND: Mast cells (MCs), PAR2 and TRPV1, play a key role in the regulation of visceral pain. Several studies have found that probiotics regulate visceral sensitivity. AIMS: The purpose of the current study was to explore the role of MC-PAR2-TRPV1 in VH and the mechanism of VSL#3 in a rat model of VH. METHODS: A total of 64 rats were randomly divided into eight groups: Control VH, VH + ketotifen, VH + FSLLRY-NH2, VH + SB366791, VH + VSL#3, VH + VSL#3 + capsaicin, and VH + VSL#3 + SLIGRL-NH2. The rat model of VH was induced by acetic acid enema and the partial limb restraint method. VH was assessed by the abdominal withdrawal reflex score. MCs in colonic tissue were detected by the toluidine blue staining assay. The expression of PAR2 and TRPV1 in DRGs (L6-S1) was measured by immunohistochemistry and Western blotting. RESULTS: The established VH was abolished by treatment with ketotifen, a mast cell stabilizer FSLLRY-NH2, a PAR2 antagonist SB366791 a TRPV1 antagonist, and probiotic VSL#3 in rats. The administration of ketotifen or probiotic VSL#3 caused a decrease in mast cell number in the colon and decreased PAR2 and TRPV1 expression in DRGs. Intrathecal injection of FSLLRY-NH2 or SB366791 caused decreased expression of PAR2 and/or TRPV1 in DRGs in VH rats. SLIGRL-NH2, a PAR2 agonist, and capsaicin, a TRPV1 agonist, blocked the effects of probiotic VSL#3. CONCLUSIONS: The probiotic VSL#3 decreases VH in rat model of VH. The mechanism may be related with the mast cell-PAR2-TRPV1 signaling pathway.

Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study.

Spleen tyrosine kinase (Syk) is a critical target protein for treating immunoreceptor signalling-mediated allergies. In this study, a virtual screening of an in-house Chinese medicine database followed by biological assays was carried out to identify novel Syk inhibitors. A molecular docking method was employed to screen for compounds with potential Syk inhibitory activity. Then, an in vitro kinase inhibition assay was performed to verify the Syk inhibitory activity of the virtual screening hits. Subsequently, a ß-hexosaminidase release assay was conducted to evaluate the anti-mast cell degranulation activity of the active compounds. Finally, tanshinone I was confirmed as a Syk inhibitor (IC50 = 1.64 µM) and exhibited anti-mast cell degranulation activity in vitro (IC50 = 2.76 µM). Docking studies showed that Pro455, Gln462, Leu377, and Lys458 were key amino acid residues for Syk inhibitory activity. This study demonstrated that tanshinone I is a Syk inhibitor with mast cell degranulation inhibitory activity. Tanshinone I may be a potential lead compound for developing effective and safe Syk-inhibiting drugs.

Effect of Neoadjuvant and Adjuvant Therapy of Experimental Breast Cancer on the Structure of Mesenteric Lymph Nodes.

The morphometric analysis of mesenteric lymph nodes was carried out in female Wistar rats with chemically induced breast cancer. In control rats with untreated breast cancer, the volume of the system of sinuses increased in parallel with the appearance of morphological signs of suppression of cell-mediated immunity, inhibition of humoral immunity, and macrophage reaction. Against the background of chemotherapy, we observed a decrease in the volume of paracortex and lymphoid nodules, suppression of proliferative activity of lymphoid cells in paracortical and B-cell zone, and a decrease in macrophage content. After resection of breast cancer followed by chemotherapy course, lymph transport activation, widening of the paracortex, enhanced proliferative activity of cells in the paracortex and B-cell zone, and reduced volumes of lymphoid nodules with and without germinal centers and medullary substance were revealed in comparison with rats subjected neoadjuvant chemotherapy.

Oral administration of Cervus nippon mantchuricus extract suppresses 2,4-dinitrochlorobenzene-induced atopic dermatitis in BALB/c mice and inflammatory effects in mast cells.

Cervus nippon mantchuricus extract, known as nok­gol (NGE) in Korean, is useful for the treatment of various inflammatory diseases, including bone resorption and neutropenia. However, NGE has not been widely investigated, and its efficacy and safety remain to be fully elucidated. In the present study, histological analysis, blood analysis, reverse transcription­semi-quantitative polymerase chain reaction analysis and enzyme­linked immunosorbent assays were performed to verify the inhibitory effect of NGE on atopic dermatitis (AD) in BALB/c mice and on inflammatory effects in HMC­1 human mast cells. NGE suppressed the development of AD in mice, and decreased the infiltration of inflammatory cells, mast cells and CD4+ T cells into AD skin lesions. NGE also decreased leukocyte levels induced by 2,4­dinitrochlorobenzene (DNCB). NGE alleviated AD­like inflammatory symptoms in mice by suppressing the production of CD4+ T cells. NGE downregulated the mRNA expression of inflammatory cytokines induced by DNCB. It also decreased the serum immunoglobulin E concentration and inflammatory cytokine levels in DNCB­treated BALB/c mice. The in vitro experiments demonstrated that NGE reduced the phorbol 12­myristate 13­acetate + ionomycin­induced expression of pro­inflammatory cytokines interleukin (IL)­4, IL­13, tumor necrosis factor­α, and IL­6 in HMC­1 cells. Taken together, the results of the present study indicated that NGE suppressed the progression of DNCB­induced AD in BALB/c mice and reduced inflammatory effects in HMC­1 cells. This suggests that NGE may be a useful drug for the treatment of AD.

Therapeutic effects of bee venom on experimental atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin inflammatory disease characterized by recurrent eczema and itching. It is caused by a poorly controlled immune response and damage to the skin barrier. Purified bee venom (BV) is a natural toxin produced by honeybees (Apis mellifera L.), and is well known for its anti­inflammatory, analgesic and anti­cancer effects against various types of disease. However, treatment strategies based on anti­inflammatory properties have not been adequately studied in AD. Thus, the present study examined the progression of AD­like skin lesions induced by ovalbumin (OVA) and the mechanism of action of BV. BV, administered by intraperitoneal inoculation, was observed to reduce the symptoms of AD, in addition to the serum immunoglobulin E levels, according to dorsal skin thickness and histopathologic analysis. The treatment also inhibited the infiltration of eosinophils and mast cells. These results suggested that it is possible to develop novel AD alternative therapy using BV by effectively suppressing allergic skin inflammation in AD.