Lysine-specific demethylase 1 in primary sensory neurons participates in chronic compression of dorsal root ganglion-induced neuropathic pain.

Low back and radicular pain syndromes, usually caused by local inflammation and irritation to the nerve root and dorsal root ganglion (DRG), are common throughout medical practice, but sufficient pain relief is scarce. In this study, we employed a chronic compression of DRG (CCD)-induced radicular pain model in rats to explore whether lysine-specific demethylase 1 (LSD1), a histone demethylase and transcriptional co-repressor, is involved in the pathological process of radicular pain. We found that LSD1 was expressed in various-sized DRG neurons by immunohistochemistry. CCD induced the upregulation of LSD1 in compressed L4-L5 DRGs. Moreover, either LSD1 small interfering RNAs or LSD1 inhibitor attenuated CCD-induced pain hypersensitivities. LSD1 was also upregulated in the injured lumbar 4 (L4) DRG in a spinal nerve ligation (SNL)-induced neuropathic pain mouse model. Nevertheless, LSD1 was not altered in L3-L5 DRGs in complete Freund's adjuvant-induced inflammatory pain mouse model, paclitaxel- or streptozotocin-induced neuropathic pain models. Furthermore, knockdown of LSD1 in the injured L4 DRG reversed SNL-induced pain hypersensitivities in mice. Therefore, we speculate that nerve injury induced the upregulation of LSD1 in the injured DRGs, which contributes to neuropathic pain hypersensitivities; thus, LSD1 may serve as a potential target for the treatment of radicular pain and neuropathic pain.

Pharmacological screening of Acalypha indica L.: Possible role in the treatment of asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Acalypha indica Linn (Euphorbiaceae), a popular traditional medicine, is an erect herb found throughout various parts of India. In Ayurveda, Acalypha indica was commonly used in asthma and allergy. However, no attempts were made in past to validate the antiasthmatic potential of Acalypha indica. AIM OF THE STUDY: The present study was aimed to assess the anti-asthmatic potential of ethanolic extracts of Acalypha indica leaves (EAIL) using various experimental animal models. MATERIALS AND METHODS: EAIL was analyzed using different screening methods such as acetylcholine and histamine-induced contraction of goat tracheal chain, clonidine-induced catalepsy in mice, milk-induced leucocytosis and eosinophilia in mice, clonidine-induced mast cell degranulation in rats, passive paw anaphylaxis in rats, histamine-induced bronchoconstriction in guinea pigs, and ovalbumin (OVA)-induced histopathological alterations in mice. RESULTS: Data received in the present study showed that EAIL drastically antagonized acetylcholine and histamine-induced contraction of goat tracheal chain, suggesting its anticholinergic and antihistaminic activity respectively. The duration of immobility, produced by clonidine, was found to be decreased in mice which showed its H1 receptor blocking activity. In milk-induced leucocytosis and eosinophilia in mice, EAIL significantly reduced the number of leucocytes and eosinophils suggesting its adaptogenic and anti-allergic potential. Inhibition of clonidine-induced mast cell degranulation in rats displayed its mast cell stabilizing potential. Reduction of paw edema in passive paw anaphylaxis exhibited antianaphylactic activity of EAIL. Guinea pigs were protected from histamine-induced bronchoconstriction by EAIL which revealed its bronchodilator potential. Furthermore, the histopathological architecture of lung tissue was near to normal. CONCLUSION: Our results contribute towards validation of the traditional use of Acalypha indica in the treatment of asthma due to the presence of a wide range of phytoconstituents. Hence our investigation revealed that EAIL possessed strong antiasthmatic property by virtue of various mechanisms.

Alteration of lung tissues proteins in birch pollen induced asthma mice before and after SCIT.

Subcutaneous immunotherapy (SCIT) is a classic form of allergen-specific immunotherapy that is used to treat birch pollen induced allergic asthma. To investigate the underlying molecular mechanisms of SCIT, we aimed to profile lung samples to explore changes in the differential proteome before and after SCIT in mice with allergic asthma. Fresh lungs were collected from three groups of female BALB/c mice: 1) control mice, 2) birch pollen-induced allergic mice, and 3) birch pollen-induced allergic mice with SCIT. Tandem mass tag (TMT) labelling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the lung proteome in the mice. Ingenuity pathway analysis (IPA) and Gene Ontology (GO) classification analysis were applied to identify differentially expressed proteins (DEPs) and crucial pathways. The screened DEPs were validated by immunohistochemistry analysis. A total of 317 proteins were upregulated and 184 proteins were downregulated in the asthma group compared to those of the control group. In contrast, 639 DEPs (163 upregulated and 456 downregulated proteins) were identified after SCIT in comparison with those of the asthma group. Among the 639 DEPs, 277 proteins returned to similar levels as those of the relative non-asthma condition. Bioinformatic analysis revealed that the 277 proteins played a significant role in the leukocyte extravasation signaling pathway. The leukocyte extravasation signaling pathway and related DEPs were of crucial importance in birch pollen SCIT.

Intense Pulsed Light Attenuates UV-Induced Hyperimmune Response and Pigmentation in Human Skin Cells.

The skin of an organism is affected by various environmental factors and fights against aging stress via mechanical and biochemical responses. Photoaging induced by ultraviolet B (UVB) irradiation is common and is the most vital factor in the senescence phenotype of skin, and so, suppression of UVB stress-induced damage is critical. To lessen the UVB-induced hyperimmune response and hyperpigmentation, we investigated the ameliorative effects of intense pulsed light (IPL) treatment on the photoaged phenotype of skin cells. Normal human epidermal keratinocytes and human epidermal melanocytes were exposed to 20 mJ/cm2 of UVB. After UVB irradiation, the cells were treated with green (525-530 nm) and yellow (585-592 nm) IPL at various time points prior to the harvest step. Subsequently, various signs of excessive immune response, including expression of proinflammatory and melanogenic genes and proteins, cellular oxidative stress level, and antioxidative enzyme activity, were examined. We found that IPL treatment reduced excessive cutaneous immune reactions by suppressing UVB-induced proinflammatory cytokine expression. IPL treatment prevented hyperpigmentation, and combined treatment with green and yellow IPL synergistically attenuated both processes. IPL treatment may exert protective effects against UVB injury in skin cells by attenuating inflammatory cytokine and melanogenic gene overexpression, possibly by reducing intracellular oxidative stress. IPL treatment also preserves antioxidative enzyme activity under UVB irradiation. This study suggests that IPL treatment is a useful strategy against photoaging, and provides evidence supporting clinical approaches with non-invasive light therapy.

Brainstem local microglia induce whisker map plasticity in the thalamus after peripheral nerve injury.

Whisker deafferentation in mice disrupts topographic connectivity from the brainstem to the thalamic ventral posteromedial nucleus (VPM), which represents whisker map, by recruiting "ectopic" axons carrying non-whisker information in VPM. However, mechanisms inducing this plasticity remain largely unknown. Here, we show the role of region-specific microglia in the brainstem principal trigeminal nucleus (Pr5), a whisker sensory-recipient region, in VPM whisker map plasticity. Systemic or local manipulation of microglial activity reveals that microglia in Pr5, but not in VPM, are necessary and sufficient for recruiting ectopic axons in VPM. Deafferentation causes membrane hyperexcitability of Pr5 neurons dependent on microglia. Inactivation of Pr5 neurons abolishes this somatotopic reorganization in VPM. Additionally, microglial depletion prevents deafferentation-induced ectopic mechanical hypersensitivity. Our results indicate that local microglia in the brainstem induce peripheral nerve injury-induced plasticity of map organization in the thalamus and suggest that microglia are potential therapeutic targets for peripheral nerve injury-induced mechanical hypersensitivity.

Green synthesis of silver nanoparticles from Eriobotrya japonica extract: a promising approach against cancer cells proliferation, inflammation, allergic disorders and phagocytosis induction.

Nanoparticles (NPs) have biological activities like antibacterial, antifungal, drug delivery, immunomodulation and antitumor activities. The aim of the current study was to investigate some of biomedical applications of silver NP synthesis using extracts from leaves of Eriobotrya japonica. Colour changes, UV-visible spectroscopy, SEM, zeta potential, dynamic light scattering, FTIR and XRD were used to confirm AgNPs formation. The UV-vis spectrum absorption band was observed at almost 430 nm. The SEM image shows quasi-spherical shape of AgNPs. The zeta potential demonstrated the negative surface charge of NPs. FTIR results showed the functional groups of AgNPs. Crystalline nature of AgNPs was confirmed by XRD pattern. MTT assay was used to study the anti-proliferative activity against MCF-7 and HeLa cells. Apoptosis was tested using a DNA-fragmentation test, and expression of P53. AgNPs inhibited the proliferation of MCF-7 and HeLa cells, and reduced inflammation. Treatment with AgNPs significantly decreased allergic disorder. AgNPs stimulated the phagocytosis process in BMDMs. The results suggested that AgNPs could be a promising therapy for future and preventing inflammation, reduce allergic disorders and prevent bacterial infection through the up-regulation of phagocytosis. Hence, future work such as developed and improved NPs as adjuvants, immune-modulating substances and nano-drug delivery system is needed.

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.

Potential of phytochemicals as immune-regulatory compounds in atopic diseases: A review.

Atopic diseases (atopic dermatitis, asthma and allergic rhinitis) affects a huge number of people around the world and their incidence rate is on rise. Atopic dermatitis (AD) is more prevalent in paediatric population which sensitizes an individual to develop allergic rhinitis and asthma later in life. The complex pathogenesis of these allergic diseases though involves numerous cellular signalling pathways but redox imbalance has been reported to be critical for induction/perpetuation of inflammatory process under such conditions. The realm of complementary and alternative medicine has gained greater attention because of the reported anti-oxidant/anti-inflammatory properties. Several case studies of treating atopic diseases with homeopathic remedies have provided positive results. Likewise, pre-clinical studies suggest that various natural compounds suppress allergic response via exhibiting their anti-oxidant potential. Despite the reported beneficial effects of phytochemicals in experimental model system, the clinical success has not been documented so far. It appears that poor absorption and bioavailability of natural compounds may be one of the reasons for realizing their full potential. The current paper throws light on impact of phytochemicals in the redox linked cellular and signalling pathways that may be critical in manifestation of atopic diseases. Further, an effort has been made to identify the gaps in the area so that future strategies could be evolved to exploit the medicinal value of various phytochemicals for an improved efficiency.

Cryptotanshinone attenuates allergic airway inflammation through negative regulation of NF-κB and p38 MAPK.

This study is to determine the role and mechanism of cryptotanshinone (CTS) in allergic airway inflammation. Asthma induced by OVA was established in BALB/c mice. We found increased airway hyperresponsiveness (AHR), increased inflammatory cell infiltration, elevated levels of TNF-α, interleukin-1ß (IL-1ß), IL-4, IL-5, IL-6 and IL-13, decreased interferon gamma (IFN-γ) in lung tissue, increased content of total immunoglobulin E (IgE), OVA specific IgE, Eotaxin, ICAM-1, VCAM-1, nuclear factor-kappaB (NF-κB) and phosphorylation of p38 MAPK in lung tissue. However, the administration of CTS significantly decreased AHR in asthmatic mice, reduced inflammation around the bronchioles and inflammatory cells around airway, regulated cytokine production, reduced the total IgE and OVA-specific IgE levels, and inhibited NF-κB activation and p38 MAPK phosphorylation. In vitro experiments in 16 HBE cells revealed that CTS attenuated CAM-1 and IL-6 expression. These results indicate that CTS alleviates allergic airway inflammation by modulating p38 MAPK phosphorylation and NF-κB activation.

Grifola frondosa extract and ergosterol reduce allergic reactions in an allergy mouse model by suppressing the degranulation of mast cells.

The increasing number of patients suffering from allergic diseases is a global health problem. Grifola frondosa is an edible mushroom consumed as a health food in Asia, and has recently been reported to have anti-allergic effects. We previously reported that G. frondosa extract (GFE) and its active components, ergosterol and its derivatives, inhibited the antigen-induced activation of RBL-2H3 cells. Here, we demonstrated that GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow-derived mast cells (BMMCs) and alleviated anaphylactic cutaneous responses in mice. Using an air pouch-type allergic inflammation mouse model, we confirmed that oral administration of GFE and ergosterol suppressed the degranulation of mast cells in vivo. Our findings suggest that G. frondosa, including ergosterol as its active component, reduces type I allergic reactions by suppressing mast cell degranulation in mice, and might be a novel functional food that prevents allergic diseases.

IL33: Roles in Allergic Inflammation and Therapeutic Perspectives.

Interleukin (IL)-33 belongs to IL-1 cytokine family which is constitutively produced from the structural and lining cells including fibroblasts, endothelial cells, and epithelial cells of skin, gastrointestinal tract, and lungs that are exposed to the environment. Different from most cytokines that are actively secreted from cells, nuclear cytokine IL-33 is passively released during cell necrosis or when tissues are damaged, suggesting that it may function as an alarmin that alerts the immune system after endothelial or epithelial cell damage during infection, physical stress, or trauma. IL-33 plays important roles in type-2 innate immunity via activation of allergic inflammation-related eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) through its receptor ST2. In this review, we focus on the recent advances of the underlying intercellular and intracellular mechanisms by which IL-33 can regulate the allergic inflammation in various allergic diseases including allergic asthma and atopic dermatitis. The future pharmacological strategy and application of traditional Chinese medicines targeting the IL-33/ST2 axis for anti-inflammatory therapy of allergic diseases were also discussed.

High Expression of IL-1RI and EP2 Receptors in the IL-1ß/COX-2 Pathway, and a New Alternative to Non-Steroidal Drugs-Osthole in Inhibition COX-2.

BACKGROUND: Osthole (7-methoxy-8-isopentenylcoumarin) is natural coumarin isolated from the fruit of Cnidium monnieri (L.) Cusson, which is commonly used in medical practice of traditional Chinese medicine (TCM) in various diseases including allergies and asthma disorders. PURPOSE: Osthole was tested for the anti-histamine, anti-allergic, and inhibitory effects of COX-2 (cyclooxygenase-2) in children with diagnosed allergies. Additionally, we hypothesize that stated alterations in children with diagnosed allergies including increased expression of interleukin 1-ß receptor type 1 (IL-1 type I) and E-prostanoid (EP) 2 receptors, as well as raised expression, production, and activity of COX-2 and IL-1ß in incubated medium are approximately connected. Furthermore, we establish the mechanisms included in the changed regulation of the COX-2 pathway and determine whether osthole may be COX-2 inhibitor in peripheral blood mononuclear cells (PBMCs). METHOD: PBMCs were obtained from peripheral blood of healthy children (control, n = 28) and patients with diagnosed allergies (allergy, n = 30). Expression of the autocrine loop components regulating PGE2 production and signaling namely IL-1 type I receptor (IL-1RI), cyclooksygenaze-2 (COX-2), E-prostanoid (EP) 2, and also histamine receptor-1 (HRH-1) was assessed at baseline and after stimulation with histamine, osthole, and a mixture of histamine/osthole 1:2 (v/v). This comprised the expression of histamine receptor 1 (HRH-1), IL-1RI, COX-2, EP2 receptor, and the secretion of IL-1ß and COX-2 in cultured media and sera. RESULTS: Compared with control group, basal mRNA expression levels of HRH-1, IL-1RI, COX-2, and EP2 were higher in the allergy group. Histamine-induced EP2 and COX-2 expression mRNA levels were also increased. CONCLUSIONS: Osthole successively inhibits PGE2 and COX-2 mRNA expression. Furthermore, osthole reduces the secretion of COX-2 protein in signaling cellular mechanisms. Changed EP2 expression in children with allergies provides higher IL-1RI induction, increasing IL-1ß capacity to increase COX-2 expression. This effects in higher PGE2 production, which in turn increases its capability to induce IL-1RI.

The micromorphological investigation of pollen grains of some important allergenic plants in Kermanshah (West of Iran).

Allergenic pollens are found in gardens, fields and green spaces around cities. In Kermanshah, located in the west of Iran, seven allergen pollen samples were collected directly from nature and studied according to the Erdtman acetolysis method by using Light Microscope (LM) and Scanning Electron Microscope (SEM). In this study, atmospheric pollens were also examined by the Durham method. The results showed that the pollen grains were small, medium, and large in terms of size, and Triporate, Pantoporate, Colpate and Tricolporate in terms of aperture. In addition, they were Striate, Perforate, Macroechinate, Microechinate, and Psilate with regard to exine ornamentation; however, the echinate type was more common. In general, Prolate to a spherical shape, medium-sized, perforate, and echinate pollen characteristics are popular in the important allergenic plants. Therefore, due to the human's manipulations in nature and also the extensive size of gardens and fields, there are many types of weeds in Kermanshah Province which are significant in terms of being allergenic.

Ameliorating effects of Nigella sativa oil on aggravation of inflammation, oxidative stress and cytotoxicity induced by smokeless tobacco extract in an allergic asthma model in Wistar rats.

BACKGROUND: The comparison of smokeless tobacco (ST) exposure versus Ovalbumin (Ova) sensitized rats or asthmatic patients has hardly been studied in the literature. Thus, the present study aims to investigate the aggravation of inflammation, exacerbation of asthma, oxidative stress and cytotoxicity induced by ST. METHODS: ST was given at the dose of 40mg/kg in an allergic asthma model in Wistar rats. Furthermore, the effects of oral administration of Nigella sativa oil (NSO), at a dose of 4mL/kg/day, were investigated. RESULTS: The obtained results showed that ST clearly enhanced lung inflammation through interleukin-4 (IL-4) and Nitric oxide (NO) increased production. Actually, ST was found to intensify the oxidative stress state induced by Ova-challenge in rats, which was proven not only by augmenting lipid peroxidation and protein oxidation, but also by altering the non-enzymatic and enzymatic antioxidant status. Furthermore, the aggravation of inflammation and oxidative stress was obviously demonstrated by the histopathological changes observed in lung. In contrast, NSO administration has shown anti-inflammatory effects by reducing IL-4 and NO production, restoring the antioxidant status, reducing lipid peroxidation and improving the histopathological alterations by both protein oxidation and NSO treatment. CONCLUSIONS: Our data have proven that severe concurrent exposure to allergen and ST increases airway inflammation and oxidative stress in previously sensitized rats. They also suggest that the oral NSO treatment could be a promising treatment for asthma.

A Cyfip2-Dependent Excitatory Interneuron Pathway Establishes the Innate Startle Threshold.

Sensory experiences dynamically modify whether animals respond to a given stimulus, but it is unclear how innate behavioral thresholds are established. Here, we identify molecular and circuit-level mechanisms underlying the innate threshold of the zebrafish startle response. From a forward genetic screen, we isolated five mutant lines with reduced innate startle thresholds. Using whole-genome sequencing, we identify the causative mutation for one line to be in the fragile X mental retardation protein (FMRP)-interacting protein cyfip2. We show that cyfip2 acts independently of FMRP and that reactivation of cyfip2 restores the baseline threshold after phenotype onset. Finally, we show that cyfip2 regulates the innate startle threshold by reducing neural activity in a small group of excitatory hindbrain interneurons. Thus, we identify a selective set of genes critical to establishing an innate behavioral threshold and uncover a circuit-level role for cyfip2 in this process.

Conjugation of wildtype and hypoallergenic mugwort allergen Art v 1 to flagellin induces IL-10-DC and suppresses allergen-specific TH2-responses in vivo.

Allergies to weed pollen including members of the Compositae family, such as mugwort, ragweed, and feverfew are spreading worldwide. To efficiently treat these newly arising allergies, allergen specific immunotherapy needs to be improved. Therefore, we generated novel vaccine candidates consisting of the TLR5-ligand Flagellin A from Listeria and the major mugwort allergen Art v 1 including either the wild type Art v 1 sequence (rFlaA:Artv1) or a hypoallergenic variant (rFlaA:Artv1hyp) with reduced IgE-binding capacity. Immune modulating capacity of these constructs and respective controls was evaluated in vitro and in vivo. Incorporation of hypoallergenic Art v 1 derivative did not interfere with the resulting fusion proteins' immune stimulatory capacity. Both rFlaA:Artv1 and rFlaA:Artv1hyp induced a prominent, mTOR-dependent, IL-10 secretion from murine dendritic cells, and suppressed allergen-specific TH2-cytokine secretion in vitro and in vivo. Both conjugates retained the capacity to induce rFlaA-specific antibody responses while efficiently inducing production of Art v 1-specific IgG1 and IgG2a antibodies in mice. Interestingly, only the suppression of TH2-cytokine secretion by rFlaA:Artv1 (but not rFlaA:Artv1hyp) was paralleled by a strong secretion of IFN-γ. In summary, we provided evidence that incorporating hypoallergens into flagellin:allergen fusion proteins is a suitable strategy to further improve these promising vaccine candidates.

Pollen-induced oxidative DNA damage response regulates miRNAs controlling allergic inflammation.

A mucosal oxidative burst is a hallmark response to pollen exposure that promotes allergic inflammatory responses. Reactive species constituents of oxidative stress signal via the modification of cellular molecules including nucleic acids. One of the most abundant forms of oxidative genomic base damage is 8-oxo-7,8-dihydroguanine (8-oxoG), which is removed from DNA by 8-oxoguanine DNA glycosylase 1 (OGG1). OGG1 in complex with 8-oxoG acts as a GDP-GTP exchange factor and induces acute inflammation; however, the mechanism(s) by which OGG1 signaling regulates allergic airway inflammation is not known. Here, we postulate that the OGG1 signaling pathway differentially altered the levels of small regulatory RNAs and increased the expression of T helper 2 (Th2) cytokines in ragweed pollen extract (RWPE)-challenged lungs. To determine this, the lungs of sensitized mice expressing or lacking OGG1 were challenged with RWPE and/or with OGG1's excision product 8-oxoG. The responses in lungs were assessed by next-generation sequencing, as well as various molecular and histological approaches. The results showed that RWPE challenge induced oxidative burst and damage to DNA and activated OGG1 signaling, resulting in the differential expression of 84 micro-RNAs (miRNAs), which then exacerbated antigen-driven allergic inflammation and histological changes in the lungs. The exogenous administration of the downregulated let-7b-p3 mimetic or inhibitors of upregulated miR-23a or miR-27a decreased eosinophil recruitment and mucus and collagen production via controlling the expression of IL-4, IL-5, and IL-13. Together, these data demonstrate the roles of OGG1 signaling in the regulation of antigen-driven allergic immune responses via differential expression of miRNAs upstream of Th2 cytokines and eosinophils.

Carica papaya ameliorates allergic asthma via down regulation of IL-4, IL-5, eotaxin, TNF-α, NF-ĸB, and iNOS levels.

BACKGROUND: Natural products have a prime importance as an essential source for new drug discovery. Carica papaya leaves (CPL) have been used to treat inflammation in traditional system of medicine. AIM/HYPOTHESIS: Current study evaluates the anti-inflammatory and immunomodulatory effects of CPL extract using mouse model of ovalbumin- (OVA) induced allergic asthma. METHODS: All the mice were intraperitoneally sensitized and subsequently given intranasal challenge with OVA except the control group. Group-III and -IV were treated for seven consecutive days with CPL extract and methylprednisolone (MP), respectively. At the end of study, histopathological examination of the lungs was performed and inflammatory cell counts were done in blood as well as bronchoalveolar lavage fluid (BALF). The mRNA expression levels of IL-4, IL-5, eotaxin, TNF-α, NF-ĸB, and iNOS were measured using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Results showed significant attenuation of lung infiltration of inflammatory cells, alveolar thickening, and goblet cell hyperplasia after treatment with CPL extract. We also found significant suppression of total and differential leukocyte counts in both blood and BALF samples of CPL extract treated group. CPL extract also alleviated the expression levels of IL-4, IL-5, eotaxin, TNF-α, NF-ĸB, and iNOS. Similarly, treatment with MP, used as a reference drug, also significantly ameliorated all the pro-inflammatory markers. CONCLUSION: Current study shows that CPL extract possesses anti-inflammatory effect in mouse model of allergic airway inflammation by down-regulating IL-4, IL-5, eotaxin, TNF-α, NF-ĸB, and iNOS expression levels.