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1.
J Ethnopharmacol ; 302(Pt A): 115873, 2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36309114

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Houpo Mahuang Decoction (HPMHD is one of the classic traditional Chinese prescriptions that has been used in the treatment of asthma. The therapeutic effects and mechanism of HPMHD in aggravated asthma remain to be explored, especially from the perspective of metabolomics and Transient Receptor Potential Vanilloid-1 (TRPV1)/Ca2+/Tight junction (TJ) regulation. AIM OF THE STUDY: To investigate the therapeutic and metabolic regulatory effects and the underlying mechanism of HPMHD in asthmatic rats. MATERIALS AND METHODS: The asthmatic rats were administered with the corresponding HPMHD (at dosages of 5.54, 11.07, 22.14 mg/kg). Then inflammatory cells in peripheral blood and bronchoalveolar lavage fluid (BALF) were counted, the levels of interleukin (IL)-4 and IL-13 in BALF were measured, and the changes in enhanced pause (Penh) and pathological damage of lung tissues were also detected to evaluate the protective effects of HPMHD. The serum metabolic profile of HPMHD in asthmatic rats was explored using Ultra-High-Performance Liquid Chromatography-mass spectrometer (UHPLC-MS), and the regulatory effects on TRPV1 and TJs of HPMHD in asthmatic rats were detected by Western blotting analysis. In vitro, 16HBE cells were stimulated with IL-4 plus SO2 derivatives and then administered HPMHD. The intracellular Ca2+ regulated by TRPV1, and the expression levels of TRPV1 and TJ proteins (TJs) were then detected by calcium imaging and Western blotting. The effects were verified by inhibition of TRPV1 and in short hairpin RNA (shRNA)-mediated TRPV1 silencing cells. RESULTS: HPMHD significantly attenuated the airway inflammation of asthmatic rats, and reduced the levels of inflammatory cells in peripheral blood and BALF as well as the levels of IL-4 plus IL-13 in BALF. In addition, the airway hyperresponsiveness and lung pathological damage were alleviated. Serum metabolomic analysis showed that 31 metabolites were differentially expressed among the normal saline-, model-, and HPMHD-treated rats. Pathway enrichment analysis showed that the metabolites were involved in 45 pathways, among which, TJs regulation-relevant pathway was associated with the Ca2+ concentration change mediated by the TRP Vanilloid channel. In vivo and in vitro experiments indicated that HPMHD reduced the concentration of intracellular Ca2+ via suppressing the expression and activation of TRPV1, increased the expression of ZO-1, Occludin, and Claudin-3, and protected the integrity of TJs. CONCLUSION: The current study indicates that HPMHD alleviates rat asthma and participates in the regulation of serum metabolism. The anti-asthma effects of HPMHD might be related to the protection of TJs by inhibiting the intracellular Ca2+ concentration via TRPV1.


Assuntos
Asma , Interleucina-13 , Ratos , Animais , Camundongos , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Asma/patologia , Pulmão , Modelos Animais de Doenças , Ovalbumina/farmacologia , Líquido da Lavagem Broncoalveolar , Camundongos Endogâmicos BALB C , Canais de Cátion TRPV/metabolismo
2.
J Tradit Chin Med ; 42(6): 932-939, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36378051

RESUMO

OBJECTIVE: To investigate the effects of shikonin (SKN) on M1 and M2 polarization of macrophages both and . METHODS: Collagen-induced arthritis (CIA) in male DBA/1 mice were treated with a dose of 4 mg/kg/day of SKN for 23 d ( = 6/group). The histopathology of inflamed joints in CIA mice was evaluated to test the anti-arthritic effect of SKN. M1/M2 polarization of macrophages induced by lipopolysaccharide (LPS) and interferon (IFN)-γ or interleukin (IL)-4 and IL-13, were used to assess the effect of SKN (0.05, 0.1, and 0.2 µM). The effect of SKN on the protein expression of nitric oxide synthase, arginase, CD68, and CD206 was evaluated using western blot analysis. RESULTS: The results of this study revealed that SKN delayed the arthritis feet symptom score, reduced the incidence rate of arthritis, and relieved the inflammation of joints in CIA mice. SKN inhibited M1 macrophage polarization but did not affect M2 macrophage polarization in the joints of CIA mice. Moreover, SKN inhibited M1 polarization induced by LPS and IFN-γ, but did not affect M2 polarization induced by IL-4 and IL-13. CONCLUSION: These findings suggest that SKN alleviated CIA through inhibiting M1 macrophage polarization and has great potential as a new drug for RA treatment.


Assuntos
Artrite Experimental , Camundongos , Masculino , Animais , Artrite Experimental/metabolismo , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Interleucina-13/uso terapêutico , Lipopolissacarídeos/efeitos adversos , Camundongos Endogâmicos DBA , Macrófagos
3.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430676

RESUMO

Research of the last decade has remarkably increased our understanding of innate lymphoid cells (ILCs). ILCs, in analogy to T helper (Th) cells and their cytokine and transcription factor profile, are categorized into three distinct populations: ILC1s express the transcription factor T-bet and secrete IFNγ, ILC2s depend on the expression of GATA-3 and release IL-5 and IL-13, and ILC3s express RORγt and secrete IL-17 and IL-22. Noteworthy, ILCs maintain a level of plasticity, depending on exposed cytokines and environmental stimuli. Furthermore, ILCs are tissue resident cells primarily localized at common entry points for pathogens such as the gut-associated lymphoid tissue (GALT). They have the unique capacity to initiate rapid responses against pathogens, provoked by changes of the cytokine profile of the respective tissue. Moreover, they regulate tissue inflammation and homeostasis. In case of intracellular pathogens entering the mucosal tissue, ILC1s respond by secreting cytokines (e.g., IFNγ) to limit the pathogen spread. Upon infection with helminths, intestinal epithelial cells produce alarmins (e.g., IL-25) and activate ILC2s to secrete IL-13, which induces differentiation of intestinal stem cells into tuft and goblet cells, important for parasite expulsion. Additionally, during bacterial infection ILC3-derived IL-22 is required for bacterial clearance by regulating antimicrobial gene expression in epithelial cells. Thus, ILCs can limit infectious diseases via secretion of inflammatory mediators and interaction with other cell types. In this review, we will address the role of ILCs during enteric infectious diseases.


Assuntos
Doenças Transmissíveis , Imunidade Inata , Humanos , Imunidade Inata/fisiologia , Linfócitos/metabolismo , Interleucina-13/metabolismo , Citocinas/metabolismo , Doenças Transmissíveis/metabolismo
4.
Int J Mol Sci ; 23(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36362303

RESUMO

Indole-3-lactic acid (I3LA) is a well-known metabolite involved in tryptophan metabolism. Indole derivatives are involved in the differentiation of immune cells and the synthesis of cytokines via the aryl hydrocarbon receptors for modulating immunity, and the indole derivatives may be involved in allergic responses. I3LA was selected as a candidate substance for the treatment of atopic dermatitis (AD), and its inhibitory effect on AD progression was investigated. Full-thickness human skin equivalents (HSEs) consisting of human-derived cells were generated on microfluidic chips and stimulated with major AD-inducing factors. The induced AD-HSEs were treated with I3LA for 7 days, and this affected the AD-associated genetic biomarkers and increased the expression of the major constituent proteins of the skin barrier. After the treatment for 14 days, the surface became rough and sloughed off, and there was no significant difference between the increased AD-related mRNA expression and the skin barrier protein expression. Therefore, the short-term use of I3LA for approximately one week is considered to be effective in suppressing AD.


Assuntos
Dermatite Atópica , Humanos , Interleucina-13/metabolismo , Triptofano/farmacologia , Triptofano/metabolismo , Interleucina-4/metabolismo , Células Th2 , Pele/metabolismo , Indóis/farmacologia , Indóis/metabolismo , Citocinas/metabolismo
5.
Allergol. immunopatol ; 50(6): 22-31, 01 nov. 2022. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-211505

RESUMO

Chronic inflammation in the airway passage leads to the clinical syndrome of pediatric asthma. Allergic reactions caused by bacterial, viral, and fungal infection lead to the immune dis-balance which primes T helper cells (Th2), a specific cluster of differentiation 4 (CD4) T cell differentiation. This favors the Th2-specific response by activating the inter-leukin 4/interleukin 13 (IL-4/IL-13) cytokine signaling and further activates the secretion of immunoglobulin E (IgE). IL-13 develops bronchial asthma by elevating bronchial hyperresponsiveness and enables production of immunoglobulin M (IgM) and IgE. The present study aims to target IL-13 signaling using molecular docking and understanding molecular dynamic simulation (MDS) to propose a compelling candidate to treat asthma. We developed a library of available allergic drugs (n=20) and checked the binding affinity against IL-13 protein (3BPN.pdb) through molecular docking and confirmed the best pose binding energy of –3.84 and –3.71 for epinephrine and guaifenesin, respectively. Studying the interaction of hydrogen bonds and Van der Walls, it is estimated that electrostatic energy is sufficient to interact with the active site of the IL-13 and has shown to inhibit inflammatory signaling. These computational results confirm epinephrine and guaifenesin as potential ligands showing potential inhibitory activity for IL-13 signaling. This study also suggests the designing of a new ligand and screening of a large cohort of drugs, in the future, to predict the exact mechanism to control the critical feature of asthma (AU)


Assuntos
Animais , Camundongos , Asma , Epinefrina/uso terapêutico , Receptores Adrenérgicos/uso terapêutico , Guaifenesina/uso terapêutico , Hipersensibilidade Imediata , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E , Interleucina-13/metabolismo , Camundongos Endogâmicos BALB C
6.
Allergol Immunopathol (Madr) ; 50(6): 22-31, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36335442

RESUMO

Chronic inflammation in the airway passage leads to the clinical syndrome of pediatric asthma. Allergic reactions caused by bacterial, viral, and fungal infection lead to the immune dis-balance which primes T helper cells (Th2), a specific cluster of differentiation 4 (CD4) T cell differentiation. This favors the Th2-specific response by activating the inter-leukin 4/interleukin 13 (IL-4/IL-13) cytokine signaling and further activates the secretion of immunoglobulin E (IgE). IL-13 develops bronchial asthma by elevating bronchial hyperresponsiveness and enables production of immunoglobulin M (IgM) and IgE. The present study aims to target IL-13 signaling using molecular docking and understanding molecular dynamic simulation (MDS) to propose a compelling candidate to treat asthma. We developed a library of available allergic drugs (n=20) and checked the binding affinity against IL-13 protein (3BPN.pdb) through molecular docking and confirmed the best pose binding energy of -3.84 and -3.71 for epinephrine and guaifenesin, respectively. Studying the interaction of hydrogen bonds and Van der Walls, it is estimated that electrostatic energy is sufficient to interact with the active site of the IL-13 and has shown to inhibit inflammatory signaling. These computational results confirm epinephrine and guaifenesin as potential ligands showing potential inhibitory activity for IL-13 signaling. This study also suggests the designing of a new ligand and screening of a large cohort of drugs, in the future, to predict the exact mechanism to control the critical feature of asthma.


Assuntos
Asma , Guaifenesina , Hipersensibilidade , Humanos , Criança , Animais , Camundongos , Interleucina-13/metabolismo , Células Th2 , Simulação de Acoplamento Molecular , Guaifenesina/metabolismo , Guaifenesina/uso terapêutico , Imunoglobulina E , Epinefrina/uso terapêutico , Citocinas/metabolismo , Camundongos Endogâmicos BALB C , Ovalbumina , Modelos Animais de Doenças
7.
J Immunol Res ; 2022: 1800401, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36213326

RESUMO

Respiratory syncytial virus (RSV) infection can deteriorate asthma by inducing persistent airway inflammation. Increasing evidence elucidated that pyroptosis plays a pivotal role in asthma. Conciliatory anti-allergic decoction (CAD) exhibits an anti-inflammatory effect in ovalbumin (OVA)-induced asthma; however, the effects and mechanisms of CAD in RSV-infected asthmatic mice have not yet been elucidated. The RSV-infected asthmatic mice model and lipopolysaccharide (LPS)-induced 16HBE cell pyroptosis model were established, respectively. Pulmonary function, ELISA, and histopathologic analysis were performed to assess the airway inflammation and remodeling in mice with CAD treatment. Furthermore, ultra-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry (UPLC-Q-TOF/MS) was conducted to identify the chemical compounds of high-dose CAD (30 g/kg). Cell viability and apoptosis of 16HBE cells were assessed by CCK-8 and flow cytometry assays, respectively. Finally, the expression levels of apoptosis-, pyroptosis-, and TLR3/NLRP3/NF-κB/IRF3 signaling-related genes were measured with qRT-PCR or western blotting, respectively. Pulmonary function tests showed that CAD significantly ameliorated respiratory dysfunction, airway hyperresponsiveness, inflammation cell recruitment in BALF, pulmonary inflammation, collagen deposition, and cell death in lung tissues. CAD significantly decreased the content of TNF-α, IL-13, IL-4, IL-1ß and IL-5 in the bronchoalveolar lavage fluid (BALF), IL-17, IL-6, and OVA-specific IgE in serum and increased serum IFN-γ in asthma mice. The results of UPLC-Q-TOF/MS showed that high-dose CAD had 88 kinds of chemical components. In vitro, CAD-contained serum significantly suppressed LPS-induced 16HBE cell apoptosis. Additionally, CAD and CAD-contained serum attenuated the up-regulated expressions of Bax, Cleaved caspase-3, NLRP3, ASC, Cleaved caspase-1, GSDMD-N, IL-18, IL-1ß, TLR3, p-P65, p-IκBα, and IRF3 but increased Bcl-1 and GSDMD levels in the asthma mice and LPS-induced 16HBE cells, respectively. These results illustrated that CAD may have a potential role in improving airway inflammation and pyroptosis through inhibition of the TLR3/NLRP3/NF-κB/IRF3 signaling pathway.


Assuntos
Antialérgicos , Asma , Animais , Antialérgicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/química , Caspase 3/metabolismo , Imunoglobulina E , Inflamação/metabolismo , Fator Regulador 3 de Interferon , Interleucina-13/metabolismo , Interleucina-17/metabolismo , Interleucina-18/metabolismo , Interleucina-4/metabolismo , Interleucina-5 , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ovalbumina/efeitos adversos , Piroptose , Transdução de Sinais , Sincalida/metabolismo , Sincalida/farmacologia , Sincalida/uso terapêutico , Receptor 3 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
8.
PLoS One ; 17(10): e0275064, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36201508

RESUMO

BACKGROUND: Lower urinary tract symptoms (LUTS) are a costly and pervasive medical problem for millions of aging men. Recent studies have showed that peri-urethral tissue fibrosis is an untreated pathobiology contributing to LUTS. Fibrosis results from excessive extracellular matrix deposition which increases transition zone and peri-urethral tissue stiffness and compromises prostatic urethral flexibility and compliance, producing urinary obstructive symptoms. Inflammatory cells, including neutrophils, macrophages, and T-lymphocytes, secrete a medley of pro-fibrotic proteins into the prostatic microenvironment, including IFNγ, TNFα, CXC-type chemokines, and interleukins, all of which have been implicated in inflammation-mediated fibrosis. Among these, IL-4 and IL-13 are of particular interest because they share a common signaling axis that, as shown here for the first time, promotes the expression and maintenance of IL-4, IL-13, their cognate receptors, and ECM components by prostate fibroblasts, even in the absence of immune cells. Based on studies presented here, we hypothesize that the IL-4/IL-13 axis promotes prostate fibroblast activation to ECM-secreting cells. METHODS: N1 or SFT1 immortalized prostate stromal fibroblasts were cultured and treated, short- or long-term, with pro-fibrotic proteins including IL-4, IL-13, TGF-ß, TNF-α, IFNγ, with or without prior pre-treatment with antagonists or inhibitors. Protein expression was assessed by immunohistochemistry, immunofluorescence, ELISA, immunoblot, or Sircoll assays. Transcript expression levels were determined by qRT-PCR. Intact cells were counted using WST assays. RESULTS: IL-4Rα, IL-13Rα1, and collagen are concurrently up-regulated in human peri-urethral prostate tissues from men with LUTS. IL-4 and IL-13 induce their own expression as well as that of their cognate receptors, IL-4Rα and IL-13Rα1. Low concentrations of IL-4 or IL-13 act as cytokines to promote prostate fibroblast proliferation, but higher (>40ng/ml) concentrations repress cellular proliferation. Both IL-4 and IL-13 robustly and specifically promote collagen transcript and protein expression by prostate stromal fibroblasts in a JAK/STAT-dependent manner. Moreover, IL-4 and IL-13-mediated JAK/STAT signaling is coupled to activation of the IL-4Rα receptor. CONCLUSIONS: Taken together, these studies show that IL-4 and IL-13 signal through the IL-4Rα receptor to activate JAK/STAT signaling, thereby promoting their own expression, that of their cognate receptors, and collagens. These finding suggest that the IL-4/IL-13 signaling axis is a powerful, but therapeutically targetable, pro-fibrotic mechanism in the lower urinary tract.


Assuntos
Sintomas do Trato Urinário Inferior , Próstata , Quimiocinas CXC/metabolismo , Colágeno/metabolismo , Fibrose , Humanos , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucinas/metabolismo , Sintomas do Trato Urinário Inferior/patologia , Masculino , Próstata/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Mol Sci ; 23(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36232814

RESUMO

Betacellulin (BTC) is a peptide ligand that belongs to the epidermal growth factor family, the members of which have been implicated in skin morphogenesis, homeostasis, repair, and angiogenesis; however, the role of BTC in the regulation of the skin barrier remains unknown. To examine the role of BTC in skin barrier function, we analyzed atopic dermatitis (AD) transcriptomic data from Gene Expression Omnibus (GEO) datasets, performed BTC immunohistochemistry using human skin tissues, and evaluated the effects of BTC on primary human keratinocytes by real-time PCR, Western blotting, and assay of the transepidermal electrical resistance (TER), a functional parameter to monitor the tight junction barrier. We found that the gene expression of BTC was downregulated in skin lesions from patients with AD, and this downregulated expression recovered following biological treatments. Consistently, the BTC protein levels were downregulated in the lesional skin of AD patients compared with the normal skin of healthy participants, suggesting that the BTC levels in skin might be a biomarker for the diagnosis and therapy of AD. Furthermore, in human keratinocytes, BTC knockdown reduced the levels of skin-derived antimicrobial peptides and skin barrier-related genes, whereas BTC addition enhanced their levels. Importantly, in human skin equivalents, BTC restored the increased tight junction permeability induced by Th2 cytokine IL-4/IL-13 treatment. In addition, specific inhibitors of epidermal growth factor receptor (EGFR) and protein kinase C (PKC) abolished the BTC-mediated improvement in skin barrier-related proteins in keratinocyte monolayers. Collectively, our findings suggest that treatment with BTC might improve the Th2-type cytokine-mediated impairment of skin barrier function through the EGFR/PKC axis and that BTC might be a novel potential biomarker and therapeutic target for the treatment of skin conditions characterized by the overproduction of Th2 cytokines and dysfunctional skin barriers, such as AD.


Assuntos
Citocinas , Dermatite Atópica , Betacelulina/metabolismo , Citocinas/metabolismo , Dermatite Atópica/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Interleucina-4/metabolismo , Queratinócitos/metabolismo , Ligantes , Proteína Quinase C/metabolismo , Pele/metabolismo
10.
Immun Inflamm Dis ; 10(11): e692, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36301023

RESUMO

INTRODUCTION: Allergic rhinitis (AR) is frequently known as a chronic respiratory disease with a global high prevalence. The pivotal roles of histone deacetylase 4 (HDAC4) in multiple human diseases have been underlined by numerous studies. Nevertheless, whether HDAC4 is implicated in AR remains to be elaborated. The objective of the current study is to clarify the impacts of HDAC4 on AR. METHODS: First, human nasal epithelial cells (hNECs) were pretreated by interleukin-13 (IL-13). HDAC4 expression in hNECs with the presence or absence of IL-13 treatment was tested by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) and western blot. Following, after HDAC4 was depleted, levels of histamine, Immunoglobulin E (IgE) and inflammatory factors were analyzed by ELISA assay. Then, Mucin-5AC (MUC5AC) expression was examined through RT-qPCR, western blot, and IF assay. Western blot was to analyze the expression of sirtuin 1 (SIRT1)/nuclear factor-kappaB (NF-κB) signaling-related proteins. After IL-13-induced hNECs were cotransfected with HDAC4 interference plasmids and SIRT1 inhibitor EX527, the functional experiments above were conducted again. RESULTS: The experimental data in this study presented that HDAC4 expression was increased in IL-13-induced hNECs. Silencing of HDAC4 cut down the levels of histamine, IgE and inflammatory factors and the expression of MUC5AC. Additionally, knockdown of HDAC4 led to the activation of SIRT1/NF-κB signaling. Further, the downregulated levels of histamine, IgE and inflammatory factors and the expression of MUC5AC imposed by HDAC4 interference were all reversed by EX527. CONCLUSIONS: In short, HDAC4 inhibition activated SIRT1/NF-κB signaling to mitigate inflammatory response and mucus production in IL-13-treated nasal epithelial cells in AR.


Assuntos
NF-kappa B , Rinite Alérgica , Humanos , NF-kappa B/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Interleucina-13/metabolismo , Histamina/farmacologia , Mucosa Nasal/metabolismo , Células Epiteliais/metabolismo , Imunoglobulina E/metabolismo , Muco/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Proteínas Repressoras/metabolismo
11.
Front Endocrinol (Lausanne) ; 13: 973962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187125

RESUMO

Purpose: This study compared the changes in tear inflammatory cytokine levels after intense pulsed light (IPL) combined with meibomian gland expression (MGX) (IPL group) and instant warm compresses combined with MGX (physiotherapy group) as treatments for meibomian gland dysfunction (MGD)-related dry eye disease (DED) to explore their similarities and differences in therapeutic mechanisms. Methods: This study was a post-hoc analysis of a randomized controlled trial. Thirteen patients with MGD-related DED were enrolled in each group and received three treatments correspondingly with 3-week intervals. The levels of 20 tear cytokines, namely, TNF-α, IL-6, MMP-9, CXCL8/IL-8, CXCL10/IP-10, IL-10, EGF, IL-6R, IL-1ß, IFN-γ, lactoferrin, Fas ligand, IL-17A, LT-α, S100A9, LCN2/NGAL, IL-13, IL-12/IL-23p40, Fas, and CCL11/Eotaxin, were measured at baseline, before the second and third treatments, and 3 weeks after the third treatment. The primary outcome was the difference in cytokine levels between baseline and the last measurement, and the trends were analyzed at each measurement point. Results: At the last measurement, a significant decrease was observed in all tear cytokines for both IPL and physiotherapy groups compared with baseline. The IPL group showed greater reductions in IL-6, IL-6R, IL-1ß, IL-13, and CCL11/Eotaxin than the physiotherapy group. TNF-α, CXCL8/IL-8, CXCL10/IP-10, IL-10, EGF, IL-1ß, IFN-γ, and Lipocalin-2/NGAL levels continued to decrease with treatment time. Important interactions were found in the changes of IL-6 and IL-13 levels, where the levels first decreased and then slightly increased in the physiotherapy group after treatment, while they continued to decrease in the IPL group. Conclusions: The mechanisms of IPL and physiotherapy in treating MGD-related DED were both associated with reducing inflammation, and the superiority of IPL could be attributed to its better inhibitory effect on inflammatory cytokines like IL-6. In addition, several cytokines were on a downward trend during treatment, suggesting that the vicious cycle of DED was suppressed.


Assuntos
Síndromes do Olho Seco , Disfunção da Glândula Tarsal , Quimiocina CXCL10/metabolismo , Citocinas/metabolismo , Síndromes do Olho Seco/metabolismo , Síndromes do Olho Seco/terapia , Fator de Crescimento Epidérmico/metabolismo , Proteína Ligante Fas/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-13/metabolismo , Interleucina-17 , Interleucina-6 , Interleucina-8/metabolismo , Lactoferrina/metabolismo , Lipocalina-2/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Disfunção da Glândula Tarsal/terapia , Glândulas Tarsais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Cells ; 11(19)2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36230993

RESUMO

The incidence of allergic disease has grown tremendously in the past three generations. While current treatments are effective for some, there is considerable unmet need. Mast cells are critical effectors of allergic inflammation. Their secreted mediators and the receptors for these mediators have long been the target of allergy therapy. Recent drugs have moved a step earlier in mast cell activation, blocking IgE, IL-4, and IL-13 interactions with their receptors. In this review, we summarize the latest therapies targeting mast cells as well as new drugs in clinical trials. In addition, we offer support for repurposing FDA-approved drugs to target mast cells in new ways. With a multitude of highly selective drugs available for cancer, autoimmunity, and metabolic disorders, drug repurposing offers optimism for the future of allergy therapy.


Assuntos
Hipersensibilidade , Mastócitos , Reposicionamento de Medicamentos , Humanos , Imunoglobulina E/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Mastócitos/metabolismo
13.
Int J Oncol ; 61(6)2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36263619

RESUMO

Tumor­associated macrophages/M2­type (TAM/M2) play a key role in the metastasis and angiogenesis of cancer, and are considered to be critical targets for cancer treatment. However, it remains unclear whether α­programmed death­ligand 1 (αPD­L1; PD­L1 inhibitor) inhibits tumor progression via targeting TAMs. In the present study, it was demonstrated that αPD­L1 significantly inhibited IL­13­induced TAM/M2 polarization in vitro. Moreover, αPD­L1 inhibited the epithelial­mesenchymal transition (EMT) process and the stemness of triple­negative breast cancer (TNBC) cells, which were mediated via the reversal of TAM/M2 polarization. This therefore inhibited the migration and angiogenesis of TNBC cells. Furthermore, αPD­L1 prevented STAT3 phosphorylation and nuclear translocation, which resulted in the arrest of TAM/M2 polarization. In vivo experiments further demonstrated that αPD­L1 reduced the number of lung metastases without affecting tumor growth. Moreover, αPD­L1 reduced the expression levels of TAM/M2, EMT, stemness and vascular markers in tumor tissues. In summary, these data suggest that αPD­L1 plays a vital role in the anti­metastasis and anti­angiogenesis of TNBC in vitro and in vivo via the inhibition of TAM/M2 polarization. These findings may thus provide a novel therapeutic strategy for clinically refractory TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Antígeno B7-H1/metabolismo , Interleucina-13/metabolismo , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico , Macrófagos/patologia , Tamoxifeno , Microambiente Tumoral
14.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232895

RESUMO

The mechanisms of mast cell (MC) degranulation and MC-driven skin symptoms are well-described. In contrast, data about the role of mitochondrial respiration for immune functions of human skin MCs are lacking. Oxygen consumption rate (OCR) in primary human skin MCs during IgE-mediated activation in the absence of glucose was examined using a metabolic flux analyzer. Effects of the inhibition of mitochondrial complex I (by rotenone A) and III (by myxothiazol) on degranulation and cytokine secretion (IL-4, IL-5, IL-6, IL-13, TNF-α, and GM-CSF) were explored by the ß-hexosaminidase release assay and multiplex ELISA. IgE-mediated activation rapidly increased the mitochondrial OCR and extracellular acidification; the contribution of non-mitochondrial oxygen consumption remained unchanged at lower levels. Both myxothiazol and rotenone A reduced OCR, the mitochondrial parameters, and extracellular acidification; however, myxothiazol did not affect degranulation and cytokine secretion. In contrast, degranulation and the secretion of IL-6, IL-13, TNF-α, and GM-CSF were reduced by rotenone A, whereas the secretion of IL-4 and IL-5 was not significantly affected. The inhibitors did not affect cell viability. Our results highlight the important role played by mitochondrial respiration in primary human skin MCs and allow for a conclusion on a hierarchy of their effector functions. Drugs targeting specific pathways in mitochondria may provide future options to control MC-driven skin symptoms.


Assuntos
Degranulação Celular , Mastócitos , Transporte de Elétrons , Complexo I de Transporte de Elétrons/metabolismo , Glucose/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Imunoglobulina E , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Mastócitos/metabolismo , Metacrilatos , Rotenona/metabolismo , Rotenona/farmacologia , Tiazóis , Fator de Necrose Tumoral alfa/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismo
15.
Drug Des Devel Ther ; 16: 3677-3689, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36277599

RESUMO

Background: Tumor microenvironment has attracted more and more attention in oncology. Alisol B23 acetate (AB23A) inhibits the proliferation of tumor cells including non-small cell lung cancer (NSCLC) cells. However, whether AB23A plays a role in the tumor microenvironment of NSCLC still remains obscure. Methods: After THP-1 cells were polarized to M0 type by PMA, M0 macrophages were differentiated into M1 by LPS and IFNγ, and were differentiated into M2 by IL-4 and IL-13. The differentiation of THP-1 cells was detected by flow cytometry. After AB23A was given to macrophage RT-qPCR and ELISA detected the expressions of IL-6, IL-1ß, IL-10 and TGF-ß. Western blot and RT-qPCR detected the expressions of CD11b and CD18 at both mRNA and protein levels. Lung cancer cell A549 cells were induced by above related macrophage culture medium. Cell proliferation was detected by CCK-8. Tunel, wound healing and Transwell detected the apoptotic, migration and invasion capabilities. Next, M0 and M1-type macrophages were cultured in the cell culture medium of conventional A549 cells, to which AB23A was added. Subsequently, cell differentiation and inflammatory response were measured. Finally, the expression of CD18 in A549 cells was knocked down to construct NSCLC tumor-bearing mice and AB23A was applied for intragastric administration. Immunohistochemistry detected the polarization of macrophages in tumor tissues. Western blot detected the expressions of CD11b, CD18, invasion-, migration- and apoptosis-related proteins. Results: AB23A promoted the polarization of macrophages towards M1, thus promoting the apoptosis and inhibiting the invasion and migration of A549 cells. The tumor cell culture medium induced M0 macrophages to M2, while AB23A reversed this effect. AB23A targeted CD11b/CD18 and improved the polarization of macrophages, thereby affecting tumor invasion, migration and apoptosis. Conclusion: AB23A affected the polarization of tumor-associated macrophages through the targeted regulation of CD11b/CD18, thus inhibiting the development of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Colestenonas , Neoplasias Pulmonares , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/patologia , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Colestenonas/farmacologia
16.
Front Immunol ; 13: 1005981, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36300113

RESUMO

Heart failure (HF) is one of the leading causes of death worldwide. HF results not only in cardiovascular dysfunction, but also numerous pathologies in the oral cavity and salivary glands. The present study is the first to evaluate whether salivary inflammatory and anti-inflammatory factors may be related with the occurrence of hyposalivation in HF patients. We also evaluated the potential of salivary biomarkers in the diagnostics of HF. The study included 30 women with HF and 30 sex- and age-matched healthy controls. We demonstrated significantly higher levels of pro-inflammatory cytokines, anti-inflammatory cytokines, Th1, Th2, Th17, chemokines and growth factors in unstimulated saliva of HF patients compared to controls. However, the results do not indicate dominance of either branch of the immune response. The concentration of selected biomarkers is significantly higher in patients with HF and salivary gland dysfunction compared to patients with normal saliva secretion and healthy subjects (IL-1ß, TNF-α, IL-7, IL-13, INF-γ, IL-12, IL-15, IL-5, IL-6, IL-9, IL-17, MCP-1/CCL-2, EOTAXIN/CCL11, RANTES/CCL5, GM-CSF, VEGF, FGF basic, PDFG-BB). Multivariate regression analysis showed that the content of salivary cytokines, chemokines and growth factors is highly dependent on salivary gland function, i.e. salivary flow rate, total protein content and amylase activity. Using receiver operating characteristic (ROC) analysis, we showed that salivary TNF-α, INF-γ, IL-12 and EOTAXIN/CCL11 differentiated patients with HF and hyposalivation with the highest sensitivity and specificity compared to patients with normal salivary secretion and controls. Interestingly, the content of some pro- and anti-inflammatory mediators in saliva significantly exceeds their concentration in plasma. In addition, salivary biomarker levels do not reflect their plasma content, which may suggest a different nature/severity of inflammatory changes at the central (blood) and local (salivary) levels. Although our study was purely observational, the significantly higher concentration of inflammatory parameters in saliva compared to plasma, as well as the lack of saliva-blood correlation, may suggest increased production/secretion of these compounds in salivary cells of HF patients. ROC analysis did not confirm the diagnostic utility of salivary cytokines and chemokines in the differential diagnosis of HF patients.


Assuntos
Insuficiência Cardíaca , Xerostomia , Humanos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-13/metabolismo , Interleucina-15/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Interleucina-5/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Interleucina-7/metabolismo , Interleucina-9/metabolismo , Glândulas Salivares/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Xerostomia/metabolismo , Xerostomia/patologia , Insuficiência Cardíaca/metabolismo , Interleucina-12/metabolismo , Amilases
17.
Parasit Vectors ; 15(1): 386, 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36271450

RESUMO

BACKGROUND: Clonorchiasis caused by Clonorchis sinensis is a zoonotic parasitic disease characterized by cholangitis, biliary proliferation, biliary fibrosis, and even cholangiocarcinoma. Our previous study showed that the expression of interleukin (IL)-33 is increased in both humans and mice infected by C. sinensis, suggesting that IL-33 is potentially involved in the pathogenesis of clonorchiasis. However, the roles and potential mechanism of IL-33 underlying remain unknown. METHODS: Wild-type (WT) and IL-33 knockout (KO) mice (BALB/c female mice) were orally infected with 45 metacercariae of C. sinensis for 8 weeks. Biliary injuries and fibrosis were extensively evaluated. Hepatic type II cytokines (IL-4, IL-13, and IL-10) were detected by ELISA. RESULTS: For wild-type mice, we found that the mice infected with C. sinensis showed severe biliary injuries and fibrosis compared with the normal mice that were free from worm infection. In addition, the levels of type II cytokines such as IL-4, IL-13, and IL-10 in infected wild-type mice were significantly higher than in the control mice without infection (P < 0.05). However, IL-33 deficiency (IL-33 KO) prevents the augmentation of biliary injuries and fibrosis caused by C. sinensis infection. Furthermore, the increased levels of these type II cytokines induced by worm infection were also reversed in IL-33 KO mice. CONCLUSION: Our present study demonstrates that IL-33 contributes to the pathogenesis of C. sinensis-induced biliary injuries and repair, which can potentially orchestrate type 2 responses. These findings highlight the pathophysiological role of IL-33 in the progression of clonorchiasis.


Assuntos
Clonorquíase , Clonorchis sinensis , Interleucina-13 , Animais , Feminino , Humanos , Camundongos , Clonorquíase/imunologia , Clonorchis sinensis/fisiologia , Citocinas/metabolismo , Fibrose , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Interleucina-4/genética , Camundongos Endogâmicos BALB C
18.
Front Immunol ; 13: 1020902, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275703

RESUMO

Background: Previous studies implicated matrix metalloproteinases (MMPs), such as MMP-7, in inflammatory bowel diseases (IBD) by showing increased activity during inflammation of the gut. However, the pathophysiological roles of MMP-7 have not been clearly elucidated. Methods: The expression of MMP-7 was assessed in colonic biopsies of patients with ulcerative colitis (UC), in rodents with experimental colitis, and in cell-based assays with cytokines. Wild-type and MMP-7-null mice treated with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid were used for determining the pro-inflammatory function(s) of MMP-7 in vivo. Results: MMP-7 was highly expressed in patients with UC and in rodents with experimental colitis. IL-1ß, IL-4, IL-13, TNFα, or lipopolysaccharide enhanced MMP-7 expression in human colonic epithelial cells, rat colonic smooth muscle cells, and THP-1-derived macrophages. Active MMP-7 degraded tight junction protein Claudin-7 in epithelial cells, cleaved recombinant Claudin-7 in cell-free system, and increased Caco-2 monolayer permeability. Immunostaining of colon biopsies revealed up-regulation of MMP-7 and reduction of Claudin-7 in UC patients. Compared to wild-type mice, Mmp7 -/- mice had significantly less inflammation in the colon upon DSS insult. DSS-induced alterations in junction proteins were mitigated in Mmp7 -/- mice, suggesting that MMP-7 disrupts the intestinal barrier. MMP-7 antibody significantly ameliorated colonic inflammation and Claudin-7 reduction in 2 different rodent models of colitis. Summary: MMP-7 impairs intestinal epithelial barrier by cleavage of Claudin-7, and thus aggravating inflammation. These studies uncovered Claudin-7 as a novel substrate of MMP-7 in the intestinal epithelium and reinforced MMP-7 as a potential therapeutic target for IBD.


Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Ratos , Animais , Proteínas de Junções Íntimas/metabolismo , Sulfato de Dextrana/toxicidade , Metaloproteinase 7 da Matriz/genética , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-13/metabolismo , Junções Íntimas/metabolismo , Células CACO-2 , Lipopolissacarídeos/efeitos adversos , Interleucina-4/metabolismo , Colite/patologia , Doenças Inflamatórias Intestinais/metabolismo , Colite Ulcerativa/patologia , Inflamação/metabolismo , Camundongos Knockout , Citocinas/metabolismo , Claudinas/genética , Claudinas/metabolismo , Trinitrobenzenos/metabolismo , Trinitrobenzenos/uso terapêutico , Ácidos Sulfônicos/efeitos adversos , Ácidos Sulfônicos/metabolismo
19.
Front Endocrinol (Lausanne) ; 13: 869053, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120440

RESUMO

Background: Endometriosis is defined by implantation and invasive growth of endometrial tissue in extra-uterine locations causing heterogeneous symptoms, and a unique clinical picture for each patient. Understanding the complex biological mechanisms underlying these symptoms and the protein networks involved may be useful for early diagnosis and identification of pharmacological targets. Methods: In the present study, we combined three approaches (i) a text-mining analysis to perform a systematic search of proteins over existing literature, (ii) a functional enrichment analysis to identify the biological pathways in which proteins are most involved, and (iii) a protein-protein interaction (PPI) network to identify which proteins modulate the most strongly the symptomatology of endometriosis. Results: Two hundred seventy-eight proteins associated with endometriosis symptomatology in the scientific literature were extracted. Thirty-five proteins were selected according to degree and betweenness scores criteria. The most enriched biological pathways associated with these symptoms were (i) Interleukin-4 and Interleukin-13 signaling (p = 1.11 x 10-16), (ii) Signaling by Interleukins (p = 1.11 x 10-16), (iii) Cytokine signaling in Immune system (p = 1.11 x 10-16), and (iv) Interleukin-10 signaling (p = 5.66 x 10-15). Conclusion: Our study identified some key proteins with the ability to modulate endometriosis symptomatology. Our findings indicate that both pro- and anti-inflammatory biological pathways may play important roles in the symptomatology of endometriosis. This approach represents a genuine systemic method that may complement traditional experimental studies. The current data can be used to identify promising biomarkers for early diagnosis and potential therapeutic targets.


Assuntos
Endometriose , Endometriose/metabolismo , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Mapas de Interação de Proteínas
20.
Int J Mol Sci ; 23(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36142703

RESUMO

Bisphenol S (BPS) is increasingly being used as an alternative for bisphenol A; however, its health effects remain unclear. We investigated the effects of oral exposure to low-dose BPS on allergic asthma. C3H/HeJ male mice were intratracheally administered with allergen (ovalbumin (OVA), 1 µg/animal) every 2 weeks from 6 to 11 weeks old. BPS was ingested by drinking water at doses equivalent to 0.04, 0.4, and 4 µg/kg/day. We then examined pulmonary inflammation, airway hyperresponsiveness, serum OVA-specific immunoglobulin (Ig) levels, Th2 cytokine/chemokine production, and mediastinal lymph node (MLN) cell activities. Compared with OVA alone, moderate-dose BPS (BPS-M) with OVA significantly enhanced pulmonary inflammation, airway hyperresponsiveness, and OVA-specific IgE and IgG1. Furthermore, interleukin (IL)-5, IL-13, IL-33, and CCL11/Eotaxin protein levels in the lungs increased. Conversely, these allergic responses were reduced in the high-dose BPS+OVA group. In MLN cells, BPS-M with OVA increased the total cell count and activated antigen-presenting cells including conventional dendritic cell subset (cDC2). After OVA restimulation, cell proliferation and Th2 cytokine production (IL-4, IL-5, and IL-13) in the culture supernatant also increased. Therefore, oral exposure to low-dose BPS may exacerbate allergic asthmatic responses by enhancing Th2-polarized responses and activating the MLN cells.


Assuntos
Asma , Água Potável , Pneumonia , Hipersensibilidade Respiratória , Alérgenos/metabolismo , Animais , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E , Imunoglobulina G/metabolismo , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Interleucina-4/metabolismo , Interleucina-5 , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Ovalbumina/metabolismo , Fenóis , Pneumonia/metabolismo , Hipersensibilidade Respiratória/metabolismo , Sulfonas , Células Th2
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