The relationship between IL-4 polymorphisms and asthma: a systematic review / A relação entre polimorfismos de IL-4 e asma: uma revisão sistemática

Asthma is a chronic and heterogeneous disease of the airways that begins in childhood and persists, in many cases, into adulthood. The disease is the result of environmental, epigenetic and genetic interactions. This work aims to review the polymorphisms described in the literature in the IL-4 gene associated with susceptibility or protection to the development of asthma. This is a systematic literature review, carried out in PubMed, MEDLINE and Science Direct databases in the time frame from 2000 to July 2021, revealing the following key points: IL-4, Polymorphisms and Asthma. The search resulted in 29 articles, all in English. Despite some divergent studies, the SNP rs2243250, which was the most studied in populations from different countries, was also the one that found the most correlations of susceptibility with the disease. It is concluded that although there is controversial data on IL-4 SNPs related to the disease, the association of pangenomic studies has brought a list of genes and their variations associated with the risk of developing asthma, such as the rs2243250 SNP that was well related in populations of several countries analyzed. (AU)

A asma é uma doença crônica e heterogênea das vias aéreas que tem início na infância e persiste em muitos casos até a vida adulta. A doença é resultado de interações ambientais, epigenéticas e genéticas. Este trabalho tem como objetivo revisar sobre os polimorfismos descritos na literatura no gene IL-4 associados à susceptibilidade ou proteção ao desenvolvimento da asma. Trata-se de uma revisão sistemática da literatura, feita nos bancos de dados PubMed, MEDLINE e Science Direct no corte temporal de 2000 a julho de 2021, ressaltando os seguintes pontos-chave: IL-4, Polimorfismos e Asma. A pesquisa resultou em 29 artigos, sendo em sua totalidade em língua inglesa. Apesar de alguns estudos divergentes, o SNP rs2243250, que foi o mais estudado em populações de diversos países, também foi o que mais encontrou correlações de susceptibilidade com a doença. Conclui-se que, apesar de haver dados controversos sobre os SNPs de IL-4 relacionados à doença, a associação dos estudos pangenômicos tem trazido uma lista de genes e variações deles associados com o risco de desenvolver a asma, como o SNP rs2243250 que foi bem relacionado em populações de vários países analisados (AU).

Effects of butyphthalide on microglia polarization after intracerebral hemorrhage and the underlying mechanisms / 中南大学学报(医学版)

OBJECTIVES@#Because intracerebral hemorrhage (ICH) has high morbidity, disability and mortality, it is significant to find new and effective treatments for ICH. This study aims to explore the effect of butyphthalide (NBP) on neuroinflammation secondary to ICH and microglia polarization.@*METHODS@#A total of 48 healthy male SD rats were randomly divided into 6 groups: a sham 24 h group, a sham 72 h group, an ICH 24 h group, an ICH 72 h group, an ICH+NBP 24 h group, and an ICH+NBP 72 h group (8 rats per group). After operation, the neurological deficiencies were assessed based on improved Garcia scores and corner test. The expressions of Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), aquaporin-4 (AQP4), zonula occludens-1 (ZO-1), occludin, CD68, CD86, and CD206 were observed by Western blotting. Inflammatory cytokines were detected by ELISA. The immunofluorescence was to detect the polarization of microglia.@*RESULTS@#1) Compared with the sham groups, the expression of TLR4 (24 h: P<0.05; 72 h: P<0.01), NF-κB (both P<0.01) and Nrf2 (both P<0.01) in the perihematoma of the ICH group was increased, leading to microglia activation (P<0.01). The expressions of IL-6 (24 h: P<0.05; 72 h: P<0.01) and TNF-α (both P<0.01), the pro-inflammatory cytokines were up-regulated, and the expression of anti-inflammatory cytokine IL-4 was down-regulated (both P<0.01). Besides, the expression of AQP4 was enhanced (both P<0.01). The protein level of tightly connected proteins (including ZO-1, occludin) was decreased (all P<0.01). The neurological function of the rats in the ICH group was impaired in the 2 time points (both P<0.01). 2) Compared with the sham group at 24 h and 72 h after the intervention of NBP, the expressions of TLR4 (both P<0.05) and NF-κB (both P<0.01) were significantly declined, and the expression of Nrf2 was further enhanced (both P<0.05) in the perihematoma of the ICH+NBP group. Furthermore, the expression of M1 microglia marker was inhibited (P<0.05), and the polarization of microglia to the M2 phenotype was promoted (P<0.01). 3) In terms of inflammation after ICH, the IL-4 expression in the ICH+NBP group was increased compared with the ICH group (24 h: P<0.05; 72 h: P<0.01); the expression of IL-6 was decreased significantly in the ICH+NBP 72 h group (P<0.01); the level of AQP4 was declined significantly in the ICH+NBP 24 h group (P<0.05), there was a downward trend in the 72-hour intervention group but without significant statistical difference. 4) Compared with the ICH group, the ZO-1 protein levels were increased (24 h: P<0.05; 72 h: P<0.01), and the symptoms of nerve defect were improved eventually (both P<0.05) in the ICH+NBP groups.@*CONCLUSIONS@#After ICH, the TLR4/NF-κB pathway is activated. The M1 microglia is up-regulated along with the release of detrimental cytokines, while the anti-inflammatory cytokines are down-regulated. The expression of AQP4 is increased, the tight junction proteins from the blood-brain barrier (BBB) is damaged, and the neurological function of rats is impaired. On the contrary, NBP may regulate microglia polarization to M2 phenotype and play a role in the neuroprotective effect mediated via inhibiting TLR4/NF-κB and enhancing Nrf2 pathways, which relieves the neuroinflammation, inhibits the expression of AQP4, repairs BBB, and improves neurological functional defects.

Acupoint Autohemotherapy Attenuates Atopic Dermatitis Lesions by Regulating Th1/Th2 Balance in DNCB-Induced BALB/c Mice / 中国结合医学杂志

OBJECTIVE@#To evaluate the therapeutic effects of acupoint autohemotherapy (A-AHT) on 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD) in mice focusing on regulating T helper 1/T helper 2 (Th1/Th2) immune responses.@*METHODS@#Thirty BALB/c mice were divided into 5 groups by a random number table, including normal control (NC), AD model (AD), A-AHT, sham A-AHT (sA-AHT), and acupoint injection of normal saline (A-NS) groups, 6 mice per group. Mice were challenged by DNCB for the establishment of experimental AD model. On the 8th day, except for the NC and AD groups, the mice in the other groups received management once every other day for a total of 28 days. For the A-AHT and sA-AHT groups, 0.05 mL of autologous whole blood (AWB) was injected into bilateral Zusanli (ST 36) and Quchi (LI 11) and sham-acupoints (5 mm lateral to ST 36 and LI 11), respectively. The A-NS group was administrated with 0.05 mL of normal saline by acupoint injection into ST 36 and LI 11. Dermatitis severity for dorsal skin of mice was determined using the Severity Scoring of Atopic Dermatitis (SCORAD) every week. The total immunoglobulin E (IgE), interleukin-4 (IL-4), and interferon-gamma (IFN-γ) cytokine levels in serum were examined by enzyme-linked immunosorbent assay (ELISA). Spleen Th1/Th2 expression were analyzed via flow cytometry and immunohistochemical assay was used to detect T-box expressed in T cell (T-bet) and GATA-binding protein 3 (GATA3) expressions in skin lesions of mice.@*RESULTS@#Compared with the AD group, both A-AHT and sA-AHT reduced the SCORAD index and serum IgE level (P<0.05 or P<0.01); A-AHT, sA-AHT and A-NS down-regulated serum IL-4 level and upregulated IFN-γ/IL-4 ratio (P<0.05 or P<0.01); A-AHT regulated the Th1/Th2 shift specifically and increased the related transcription factors such as T-bet expression and T-bet/GATA3 ratio (P<0.05).@*CONCLUSION@#A-AHT showed significant effectiveness on the AD model mice, through regulating Th1/Th2 immune responses.

Effect of acupuncture and moxibustion on skin barrier function in guinea pigs with eczema of skin damp-heat accumulation / 中国针灸

OBJECTIVE@#To observe the effect of acupuncture and moxibustion on the water content of stratum corneum (WCSC), expression of serum inflammatory factors and aquaporin 3 (AQP3) in skin, lung and rectum in guinea pigs with eczema of skin damp-heat accumulation, and to explore the possible mechanism of acupuncture and moxibustion for regulating skin barrier function.@*METHODS@#A total of 24 male albino guinea pigs were randomly divided into a blank group (n=6) and a modeling group (n=18). The guinea pigs in the modeling group were induced by 2,4-dinitrochlorobenzene (DNCB) to establish the eczema model of skin damp-heat accumulation. The guinea pigs with successful modeling were further randomly divided into a model group, a medication group and an acupuncture-moxibustion group, 6 guinea pigs in each group. The guinea pigs in the medication group were treated with loratadine tablets (0.8 mg/kg) by gavage, once a day for 7 days; the guinea pigs in the acupuncture-moxibustion group were treated with acupuncture at "Feishu" (BL 13), "Pishu" (BL 20), "Quchi" (LI 11), "Zusanli" (ST 36) and "Xuehai" (SP 10); at the same time, moxibustion was applied at "Feishu" (BL 13) and "Zusanli" (ST 36), moxibustion intervention for 10 min and needle retaining for 15 min at each acupoint, once a day for 7 days. The eczema area and severity index (EASI) score was evaluated before and After intervention, and WCSC and trans-epidermal water loss (TEWL) were measured by skin tester. After intervention, The HE staining was used to observe the changes of skin histomorphology in each group; ELISA was used to measure the contents of serum immunoglobulin E (IgE), interleukin (IL)-4 and IL-17; Western blot was used to measure the protein expression of AQP3 in skin, lung and rectum.@*RESULTS@#Before the intervention, compared with the blank group, the EASI scores and TEWL were increased in the remaining groups (P<0.01), and the WCSC was decreased (P<0.01). After the intervention, compared with the model group, the EASI scores and TEWL were decreased (P<0.05, P<0.01), and WCSC was increased (P<0.01) in the medication group and the acupuncture-moxibustion group. The epidermal structure in the blank group was complete and the fibers in the dermis were arranged orderly; in the model group, epidermal hyperkeratosis, proliferation of granular layer, spinous cell layer and basal layer, and disordered arrangement of dermal fibers and infiltration of inflammatory cells were observed. The morphological performance in the medication group and the acupuncture-moxibustion group was better than that in the model group. Compared with the blank group, the contents of serum IgE and IL-17 were increased (P<0.01), and the content of serum IL-4 and the protein expression of AQP3 in skin, lung and rectum were decreased in the model group (P<0.01, P<0.05). Compared with the model group, the contents of serum IgE and IL-17 were decreased and the contents of serum IL-4 were increased in the medication group and the acupuncture-moxibustion group (P<0.01), and the protein expression of AQP3 in skin, lung and rectum in the acupuncture- moxibustion group were increased (P<0.05). Compared with the medication group, the contents of serum IgE and IL-17 were increased (P<0.01), and the content of serum IL-4 was decreased (P<0.01) in the acupuncture-moxibustion group.@*CONCLUSION@#Acupuncture and moxibustion could improve the epidermal water metabolism and skin tissue morphology in guinea pigs with eczema of skin damp-heat accumulation. Its mechanism may be related to regulating inflammatory factors, up-regulating the expression of AQP3, and then repairing the skin barrier function.

Acupuncture combined with western medication for ocular myasthenia gravis: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the clinical efficacy between acupuncture combined with western medication and simple western medication for ocular myasthenia gravis (OMG), and to explore its possible mechanism.@*METHODS@#A total of 60 patients of ocular myasthenia gravis were randomized into an acupuncture combined with western medication group (30 cases, 1 case dropped off) and a western medication group (30 cases, 2 cases dropped off). Oral pyridostigmine bromide tablet and prednisone acetate tablet were given in the western medication group. On the basis of the treatment in the western medication group, Tongdu Tiaoqi acupuncture (acupuncture for unblocking the governor vessel and regulating qi ) was applied at Baihui (GV 20), Fengfu (GV 16), Hegu (LI 4), Zusanli (ST 36), etc. in the acupuncture combined with western medication group, once a day, 6 days a week. The treatment was given 8 weeks in both groups. Before and after treatment, the OMG clinical absolute score was observed, electrophysiological indexes of orbicularis oculi (value of mean jitter, percentage of jitter >55 μs and percentage of blocks) were measured by single-fiber electromyography (SFEMG), serum levels of acetylcholine receptor antibody (AChR-Ab), interferon-gamma (IFN-γ) and interleukin-4 (IL-4) were detected by ELISA method.@*RESULTS@#After treatment, the OMG clinical absolute scores, values of mean jitter, percentages of jitter >55 μs, percentages of blocks and serum levels of AChR-Ab, IFN-γ and IL-4 were decreased compared before treatment in both groups (P<0.05), and those in the acupuncture combined with western medication group were lower than the western medication group (P<0.05).@*CONCLUSION@#Acupuncture combined with western medication can effectively improve ptosis, palpebra superior fatigability, eye movement disorder and neuromuscular junction dysfunction in patients with ocular myasthenia gravis, the therapeutic effect is superior to simple western medication. Its mechanism may be related to down-regulating serum levels of AChR-Ab, IFN-γ and IL-4 and promoting the recovery of orbicularis oculi function.

Effect of Buyi Pishen acupuncture on inflammatory factor and cartilage matrix in adjuvant arthritis rats / 中国针灸

OBJECTIVE@#To observe the effect of Buyi Pishen acupuncture (acupuncture for invigorating spleen and kidney) on inflammatory factor and synovial cartilage matrix in adjuvant arthritis (AA) rats, and to explore the mechanism of acupuncture for rheumatoid arthritis (RA).@*METHODS@#A total of 60 clean male Wistar rats were randomized into a normal group, a model group, a tripterygium wilfordii polyglycoside tablet (TWP) group and an acupuncture group, 15 rats in each group. Rats in the model group, the TWP group and the acupuncture group received intradermal injection of Freund's complete adjuvant (FCA) at right hind foot pad to induce the AA model. TWP suspension of 8 mg/kg was given by gavage in the TWP group. Acupuncture was applied at "Shenshu" (BL 23), "Pishu" (BL 20) and right "Housanli" (ST 36), "Sanyinjiao" (SP 6), "Yanglingquan" (GB 34) in the acupuncture group, 15 min a time, once a day. The intervention was given 15 days in both TWP group and acupuncture group. The foot-pad swelling degree before modeling, before and after intervention and the arthritis index (AI) score before and after intervention were calculated; the serum levels of interleukin (IL)-1β, IL-4, IL-10 and tumor necrosis factor-α (TNF-α) were detected by ELISA method; the ultrastructure and histomorphological changes of synovium issue were observed by transmission electron microscope and HE staining; the positive expression of matrix metalloproteinase (MMP)-3 and MMP-9 in synovium issue was detected by immunohistochemistry method.@*RESULTS@#Before intervention, foot-pad swelling degree of the model group, the TWP group and the acupuncture group was increased compared with the normal group (P<0.01). After intervention, foot-pad swelling degree and AI score were increased compared with the normal group (P<0.01), foot-pad swelling degree and AI scores in the TWP group and the acupuncture group were lower than the model group (P<0.05), and those in the acupuncture group were decreased compared with the TWP group (P<0.05). The model group exhibited unclear nuclear membrane of synovial cells, chromatin pyknosis, massive inflammatory cell infiltration and hyperplasia in synovial tissue; the TWP group and the acupuncture group exhibited clear and smooth nuclear membrane of synovial cells, inapparent chromatin pyknosis, less inflammatory cell infiltration and hyperplasia in synovial tissue, the acupuncture group exhibited less matrix destruction as well. Compared with the normal group, serum levels of IL-1β and TNF-α and positive expression of MMP-3 and MMP-9 in synovium issue were increased (P<0.01), while serum levels of IL-4 and IL-10 were decreased (P<0.01) in the model group. Compared with the model group, serum levels of IL-1β and TNF-α and positive expression of MMP-3 and MMP-9 in synovium issue were decreased (P<0.05, P<0.01), while serum levels of IL-4 and IL-10 were increased (P<0.05) in the TWP group and the acupuncture group; compared with the TWP group, serum level of TNF-α and positive expression of MMP-3 and MMP-9 in synovium issue were decreased (P<0.05), while serum levels of IL-4 and IL-10 were increased (P<0.05) in the acupuncture group.@*CONCLUSION@#Buyi Pishen acupuncture can effectively improve the injury of articular cartilage in AA rats, its mechanism maybe related to reducing the inflammatory reaction in synovium and inhibiting the degradation of articular cartilage matrix.

Triptolide inhibits inflammatory response and migration of fibroblast like synovial cells in rheumatoid arthritis through the circRNA 0003353/JAK2/STAT3 signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of triptolide (TPL) on inflammatory response and migration of fibroblast like synovial cells (FLS) in rheumatoid arthritis (RA-FLS) and the mechanism of circular noncoding RNA (circRNA) 0003353 for mediating this effect.@*METHODS@#We collected peripheral blood mononuclear cells (PBMCs) and serum samples from 50 hospitalized RA patients and 30 healthy individuals for detecting the expression of circRNA 0003353, immune and inflammatory indexes (ESR, CRP, RF, anti-CCP, IgA, IgG, IgM, C3, and C4) and DAS28 score. Cultured RA-FLS was treated with 10 ng/mL TPL and transfected with a circRNA 0003353 overexpression plasmid, and cell counting kit-8 (CCK-8) assay and Transwell assay were used to detect the changes in the viability and migration of the cells. Enzyme-linked immunosorbent assay (ELISA) was used to examine the cytokines IL-4, IL-6, and IL-17, and real-time fluorescence quantitative PCR (RT-qPCR) was performed to detect the expression of circRNA 003353; Western blotting was used to detect the expressions of p-JAK2, pSTAT3, JAK2 and STAT3 proteins in the treated cells.@*RESULTS@#The expression of circRNA 0003353 was significantly increased in PBMCs from RA patients and showed a good performance in assisting the diagnosis of RA (AUC=90.5%, P < 0.001, 95% CI: 0.83-0.98). CircRNA 0003353 expression was positively correlated with ESR, RF and DAS28 (P < 0.05). Treatment with TPL significantly decreased the expression of circRNA 0003353, suppressed the viability and migration ability, decreased the expressions of IL-6 and IL-17, and increased the expression IL-4 in cultured RA-FLS in a time-dependent manner (P < 0.01). TNF-α stimulation of RA-FLS significantly increased the ratios of p-JAK2/JAK2 and p-STAT3/STAT3, which were obviously lowered by TPL treatment (P < 0.01). TPL-treated RA-FLS overexpressing circRNA 0003353 showed significantly increased cell viability and migration ability with decreased IL-4 expression and increased IL-6 and IL-17 expressions and ratios of p-JAK2/ JAK2 and p-STAT3/STAT3 (P < 0.01).@*CONCLUSION@#The expression of circRNA 0003353 is increased in PBMCs in RA patients and in RA-FLS. TPL treatment can regulate JAK2/STAT3 signal pathway and inhibit the inflammatory response and migration of RA-FLS through circRNA 0003353.

Advances of using antibody against B cell activating factor for treatment of autoimmune diseases / 生物工程学报

In recent decades, the treatment of autoimmune diseases has moved from the use of hormones and conventional immunosuppressive drugs to biological agents. B cell proliferation and maturation play crucial roles in the development of autoimmune diseases. The tumor necrosis factor superfamily ligand B cell activating factor (BAFF) and its receptor mediate B cell survival through regulating signaling pathways. Therefore, BAFF and its receptors are important therapeutic targets for the treatment of autoimmune diseases. This review describes the mechanism of BAFF and its receptor in the human body system and introduces the latest views on how over-activation of BAFF pathway promotes the development of autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, and rheumatoid arthritis. In connection to the treatment of the above three diseases, this review discusses the clinical trials and application status of three BAFF-targeting antibody drugs, including Belimumab, Tabalumab and Atacicept. Finally, this review proposes new strategies that targeting the BAFF pathway to provide a new treatment for autoimmune diseases.

Effect of ulinastatin on the inflammatory response after video-assisted thoracic lobectomy in patients with lung cancer: a randomized controlled study / 中华医学杂志(英文版)

BACKGROUND@#The first-line treatment for lung cancer is surgical resection, and one-lung ventilation (OLV) is the most basic anesthetic management method in lung surgery. During OLV, inflammatory cytokines are released in response to the lung tissue damage and promote local and contralateral lung damage through the systemic circulation. We designed a randomized, prospective study to evaluate the effect of the urinary trypsin inhibitor (UTI) ulinastatin on the inflammatory response after video-assisted thoracic lobectomy in patients with lung cancer.@*METHODS@#Adult patients aged 19 to 70 years, who were scheduled for video-assisted thoracic lobectomy surgery to treat lung cancer between May 2020 and August 2020, were enrolled in this randomized, prospective study. UTI (300,000 units) mixed with 100 mL of normal saline in the ulinastatin group and 100 mL of normal saline in the control group was administered over 1 h after inducing anesthesia.@*RESULTS@#The baseline (T0) interferon-γ (IFN-γ)/interleukin-4 (IL-4) ratio was not different between the groups (6941.3 ± 2778.7 vs. 6954.3 ± 2752.4 pg/mL, respectively; P  > 0.05). The IFN-γ/IL-4 ratio was significantly higher in ulinastatin group at 30 min after entering the recovery room than control group (20,148.2 ± 5054.3 vs. 6674.0 ± 2963.6, respectively; adjusted P < 0.017).@*CONCLUSION@#Administering UTI attenuated the anti-inflammatory response, in terms of INF-γ expression and the IFN-γ/IL-4 ratio, after video-assisted thoracic surgery in lung cancer patients.@*TRIAL REGISTRATION@#Clinical Research Information Service of Korea National Institute of Health (CRIS), KCT0005533.

Acupuncture for improving neuroinflammation in vascular dementia rats by regulating Th1/Th2 cells balance in peripheral blood / 中国针灸

OBJECTIVE@#To observe the effect of acupuncture on the balance of T helper (Th) 1/Th2 cells in peripheral blood, inflammatory reaction and intracerebral neuroinflammation in vascular dementia (VD) rats, and to explore the mechanism of acupuncture for improving cognitive function in VD.@*METHODS@#A total of 60 SPF Wistar rats were randomized into a normal group (n=12), a sham operation group (n=12) and an operation group (n=36). Bilateral common carotid artery occlusion was adopted to establish the VD model in rats of the operation group. The rats of successful modeling were randomized into a model group and an acupuncture group, 12 rats in each one. In the acupuncture group, Sanjiao acupuncture was applied at "Danzhong" (CV 17), "Zhongwan" (CV 12), "Qihai" (CV 6), "Xuehai" (SP 10) and "Zusanli" (ST 36), the needles were manipulated for 30 s at each acupoint, without retaining. The intervention was given once a day for 15 days, and there was 1-day rest on day 8. Morris water maze test was adopted to observe the ethology, flow cytometry was used to detect the ratio of Th1/Th2 in peripheral blood, and Luminex liquid chip technology was used to detect the levels of interleukin (IL)-4, IL-10, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in serum and hippocampus.@*RESULTS@#There were no significant differences in various indexes between the normal group and the sham operation group (P>0.05). Compared with the sham operation group, in the model group, the escape latency of hidden platform test and reversal platform test was prolonged (P<0.01), the residence time of the original platform quadrant was shortened and the number of crossing the original platform was reduced in probe test (P<0.01, P<0.05), the proportion of Th1 cells was increased, the proportion of Th2 cells was decreased and the ratio of Th1/Th2 cells was increased in peripheral blood (P<0.01), the levels of TNF-α and IFN-γ were increased, the levels of IL-4 and IL-10 were decreased in serum and hippocampus (P<0.05, P<0.01). Compared with the model group, in the acupuncture group, the escape latency of hidden platform test and reversal platform test was shortened (P<0.01), the residence time of the original platform quadrant of the probe test was prolonged (P<0.05), the proportion of Th1 cells was decreased, the proportion of Th2 cells was increased and the ratio of Th1 / Th2 cells was decreased in peripheral blood (P<0.05), the levels of TNF-α and IFN-γ were decreased, the levels of IL-4 and IL-10 were increased in serum and hippocampus (P<0.05, P<0.01).@*CONCLUSION@#Acupuncture can improve the cognitive dysfunction and reduce the intracerebral neuroinflammation in VD rats, its mechanism may relate to the regulation of Th1/Th2 cells balance and reduce the inflammatory reaction in peripheral blood.

Resposta ao dupilumabe na dermatite atópica grave sem uso prévio de imunossupressor sistêmico durante a pandemia de COVID-19 / Response to dupilumab in severe atopic dermatitis without prior use of systemic immunosuppressive agents during the COVID-19 pandemic

A dermatite atópica (DA) é uma doença inflamatória crônica da pele, caracterizada por intenso prurido e eczema recorrente. Acomete principalmente a infância, mas tem se tornado bastante prevalente em adolescentes e até em adultos. Apesar de ser geralmente não fatal, apresenta uma carga psicossocial importante para os pacientes e seus familiares. O tratamento da DA envolve a hidratação cutânea e medicações anti-inflamatórias. Em casos graves, pode haver necessidade de terapia sistêmica com imunossupressores como ciclosporina, metotrexato e azatioprina. Mais recentemente, alguns imunobiológicos estão em desenvolvimento para controle da DA. O dupilumabe é um anticorpo monoclonal com ação dupla anti-IL-4/IL-13, liberado para tratamento de crianças a partir de 6 anos com DA grave e adolescentes/adultos com DA moderada a grave. O objetivo deste artigo foi relatar uma série de casos de pacientes adolescentes e adultos com DA grave e sua resposta ao dupilumabe durante a pandemia do COVID-19. Trata-se de quatro pacientes (três do sexo feminino), com piora significativa da DA durante o ano de 2020. Todos tinham história de DA desde a infância, com exames complementares evidenciando sensibilização IgE-mediada para ácaros. Já haviam sido submetidos a diversos tratamentos tópicos e sistêmicos, inclusive a cursos de corticosteroides orais. Nenhum deles havia recebido imunossupressor sistêmico, porém estavam recusando este tipo de tratamento devido ao medo da pandemia. Todos apresentaram boa resposta ao dupilumabe, evidenciada pela redução do número de lesões cutâneas e prurido, com poucos efeitos colaterais. Dois pacientes apresentaram sintomas sugestivos de COVID-19 durante o tratamento com dupilumabe (um com confirmação por PCR), com boa evolução. Concluindo, os pacientes com DA grave possuem grande impacto na qualidade de vida e, durante a pandemia de COVID-19, muitos apresentaram piora significativa do seu quadro dermatológico. Nesse contexto, o dupilumabe se mostrou uma opção terapêutica eficaz e segura para tratamento destes pacientes.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itching and recurrent eczema. It mainly affects childhood but has become quite prevalent in adolescents and even adults. Despite being generally nonfatal, it has an important psychosocial burden for patients and their families. AD treatment involves skin hydration and antiinflammatory medications. In severe cases, systemic therapy with immunosuppressive agents such as cyclosporine, methotrexate, and azathioprine may be necessary. More recently, some biologicals are being developed to control AD. Dupilumab is a monoclonal antibody with anti-IL-4/IL-13 dual-action, approved for the treatment of children from 6 years of age with severe AD and adolescents/adults with moderate to severe AD. This article aimed to report a case series of adolescent and adult patients with severe AD and their response to dupilumab during the COVID-19 pandemic. These are four patients (three female), with a significant worsening of AD during the year 2020. All had a history of AD since childhood, with complementary exams showing IgE-mediated sensitization to mites. They had already undergone several topical and systemic treatments, including courses on oral corticosteroids. None of them had received systemic immunosuppressive agents, but they were refusing this type of treatment due to fear of the pandemic. All had a good response to dupilumab, evidenced by a reduction in the number of skin lesions and pruritus, with few side effects. Two patients had symptoms suggestive of COVID-19 during treatment with dupilumab (one confirmed by PCR) with a good outcome. In conclusion, patients with severe AD have a great impact on quality of life and, during the COVID-19 pandemic, many had a significant worsening of their dermatological condition. In this context, dupilumab proved to be an effective and safe therapeutic option for the treatment of these patients.

Evaluation of the level of serum Interleukins (IL-2, IL-4, IL-15 andIL-17) and its relationship with disease severity in patients with alopecia areata

Abstract Background: Alopecia areata (AA) is a hair disease that causes hair loss without scarring. The etiopathogenesis of AA has not been fully understood yet. Objective: To determine serum interleukin levels (IL-2, IL-4, IL-15, and IL-17) in patients diagnosed with alopecia areata and to investigate the relationship of IL levels with the duration and severity of alopecia areata and the response to tofacitinib therapy. Methods: Patients (≥16 years old) diagnosed with alopecia areata and healthy individuals as a control group was enrolled. Baseline serum interleukin levels of the patients and controls were measured. In the patient group receiving tofacitinib therapy, serum interleukin levels were measured again after 6 months. Disease severity for alopecia areata was assessed using the Severity of Alopecia Tool. Results: Sixty-one AA patients and 30 healthy individuals were included; they were comparable regarding age and sex. The mean disease duration for AA was 7 ± 6 years and the baseline mean Severity of Alopecia Tool score was 71 ± 30 (range, 20-100). Baseline IL-2, IL-4 and IL-15 levels were significantly higher in the patient group than those in the control group (p < 0.001 for each). No significant correlation was found between the baseline interleukin levels and either disease duration or disease severity (baseline Severity of Alopecia Tool score). Among the patients receiving tofacitinib (n = 22), all interleukin levels significantly decreased after treatment. However, no significant relationship between the change in interleukin levels and the change in the Severity of Alopecia Tool scores was observed after tofacitinib treatment. Study limitations: This is a monocentric study conducted in a single university hospital. Conclusion: High interleukin levels in alopecia areata patients and the significant decrease with treatment support the idea that interleukins have a role in pathogenesis. Nevertheless, no relationship could be demonstrated between IL levels and disease duration or severity.

IL-4-C-590T locus polymorphism and susceptibility to asthma in children: a meta-analysis

Abstract Objectives The study aimed to evaluate the link between the IL-4-C590T polymorphism and asthma susceptibility in children by meta-analysis. Sources The study collected all the case-control studies found in PubMed, Embase, CNKI, Wanfang, VIP, and other databases until September 2019. Stata v. 15.0 was used to conduct meta-analysis, calculate the combined OR and its 95% CI, and then conduct subgroup analysis. Summary of the findings Seven studies were included in the study, containing 860 cases and 810 controls. Relative to the C allele, the T allele at the IL-4-C590T locus was associated with susceptibility to asthma in children (OR = 1.45, 95% CI: 1.05-2.01). The results of ethnicity subgroup analysis showed that there was statistical significance, with OR = 1.61 (95% CI: 1.01-2.57) in the Asian population. In the dominant and recessive genetic models, the overall test and the Asian population subgroup analysis were statistically significant. In the homozygous model, there was statistical significance, but no statistical significance in heterozygous model. Conclusions The IL-4-C590T polymorphism was associated with asthma susceptibility, and T allele and TT genotype may increase the risk of asthma susceptibility in children, especially in the Asian population.

Study on effect of anemoside B4 in improving COPD rats by regulating IL-12/STAT4 and IL-4/STAT6 signaling pathways / 中国中药杂志

To study the effect of anemoside B4 on rats with chronic obstructive pulmonary disease (COPD).Seventy-two SD male rats were randomly divided into blank group and model group.The method of exposure to cigarette smoke and combined with lipopolysaccharide (LPS) was used to replicate the rat model of COPD.After the model was maintained for 5 weeks,the rats were randomly divided into model group,dexamethasone group (0.81 mg·kg~(-1)) and anemoside B4 low,medium and high (2,4,8 mg·kg~(-1)) dose groups,a group of 12 animals were administered,and then the administration was started.The administration was maintained until the28th day,and the pulmonary function parameters of rats were measured by an animal pulmonary function instrument.After testing the rat lung function parameters,immediately draw rat alveolar lavage fluid (BALF),and use high-throughput protein chip technology to determined the expression levels of inflammatory cytokines in rat BALF.HE staining was used to observe the general pathological changes of rat lung and tracheal tissue.Masson staining was used to observe the collagen deposition in rat lung tissue.Real-time q PCR method was used to determine the mRNA expression level of related genes in rat lung tissue.Western blot method was used to determine the expression levels of related proteins in rat lung tissues.According to the findings,compared with the model group,the dexamethasone group and the anemoside B4 drug groups had different degrees of increase in the lung function parameters of rats (P<0.01,P<0.05),improved the expression level of inflammatory cytokines in the BALF of rats to varying degrees (P<0.01,P<0.05),and improved the pathological structure of rat lung tissue to varying degrees.Relative mRNA expressions of matrix metalloproteinase 2 (MMP-2),matrix metalloproteinase 12 (MMP-12),matrix metalloproteinase inhibitor 1 (TIMP-1),interleukin-6 (IL-6),and transforming growth factor-β1 (TGF-β1) were significantly reduced (P<0.01);whereas relative mRNA expressions of matrix metalloproteinase 9(MMP-9) and matrix metalloproteinase inhibitor 2 (TIMP-2) were increased significantly (P<0.01).The mRNA and protein expression levels of T-box transcription factor (T-bet),interleukin-12 (IL-12) and signal transducer and activator of transcription 4(STAT4) reduced to varying degrees (P<0.01,P<0.05).The mRNA of transcription factor GATA3 (binding protein-3),interleukin-4 (IL-4) and signal transducer and activator of transcription 6 (STAT6) in rat lung tissues and the protein expression levels of IL-4 and STAT6 were increased to varying degrees (P<0.01,P<0.05).In conclusion,anemoside B4 has a certain protective effect on COPD rats caused by cigarette smoke exposure and combined with LPS.The mechanism of action may be related to the regulation of IL-12/STAT4 and IL-4/STAT6 signaling pathways.

Biomarcadores suPAR y citocinas en la detección temprana de cáncer gástrico / suPAR and cytokines as biomarkers in early detection of gastric cancer

El cáncer gástrico (CG) es un problema prevalente a nivel mundial, presentándose aproximadamente 18 millones de casos nuevos en el año 2018, representa el 5.7% del total de cánceres, siendo la quinta neoplasia maligna más común en el mundo. En Guatemala se sitúa entre los primeros cinco cánceres respecto a morbilidad y mor-talidad. El CG se ha asociado de manera contundente a infección por Helicobacter pylori el cual desencadena un proceso inflamatorio crónico; adicionalmente algunas cepas de H. pylori producen toxinas bacterianas capaces de inducir cambios celulares que conllevan al desarrollo del proceso neoplásico. La alta mortalidad por CG en parte, se relaciona con la etapa tardía en la que se diagnostica ya que se requiere el uso de métodos invasivos, lo que dificulta su detección temprana. El objetivo de la presente revisión, fue realizar una narrativa de los estudios y las evidencias científicas, respecto de la identificación de biomarcadores séricos en la detección temprana del cáncer gástrico. Se revisaron dos tipos de biomarcadores, la proteína soluble uPAR (suPAR) que es el receptor del activador del plasminógeno (uroquinasa) y promotora de angiogénesis y por otro lado, la detección sérica de las citocinas IL-1ß, IL-6, TNFα, IL-10, IFNγ, IL-4 e IL-17 en el CG así como su potencial utilidad en su detección temprana. Estos biomarcadores fueron seleccionados por la ventaja que tendrían de ser métodos no invasivos que podrían mejorar la detección, tratamiento y pronóstico de esta enfermedad.

Gastric cancer (GC) is a prevalent problem worldwide, presenting approximately 18 million new cases in 2018, representing 5.7% of all cancers, being the fifth most common malignancy in the world. In Guatemala it is among the first five cancers in terms of morbidity and mortality. CG has been strongly associated with Helicobacter pylori infection, which triggers a chronic inflammatory process; additionally, some strains of H. pylori produce bacterial toxins capable of inducing cellular changes that lead to the development of cancer. The high mortality due to GC in part is related to the late stage in which it is diagnosed since the use of invasive methods is required, making it difficult to detect it early. The objective of this review was to make a narrative of the studies carried out and the scientific evidence regarding the identification of serum biomarkers in the early detection of gastric cancer. Two types of biomarkers were reviewed, the soluble protein uPAR (suPAR) which is the receptor for plasminogen activator (urokinase) and promoter of angiogenesis and, on the other hand, serum detection of cytokines IL-1ß, IL-6, TNFα, IL-10, IFNγ, IL-4 and IL-17 in the CG as well as its potential usefulness in its early detection. These biomarkers were selected for the advantage they would have of being non-invasive methods that could improve the detection, treatment and prognosis of this disease.

Circulating MicroRNAs and T-Cell Cytokine Expression Are Associated With the Characteristics of Asthma Exacerbation

PURPOSE: Immunological mechanisms underlying asthma exacerbation have not been elucidated. The aim of this study was to assess the associations of various asthma exacerbation traits with selected serum microRNA (miRNA) expression and T-cell subpopulations. METHODS: Twenty-one asthmatics were studied during asthma exacerbation (exacerbation visit [EV] and the follow-up visit [FV] at 6 weeks). At both visits, spirometry was performed, fractional exhaled nitric oxide (FeNO) was measured, and nasopharyngeal and blood samples were collected. In nasopharyngeal samples, respiratory viruses were assayed by multiplex polymerase chain reaction (PCR), and bacterial cultures were performed. Serum miRNAs were assayed with real-time PCR. T-cell surface markers, eosinophil progenitors and intracellular cytokines were assessed by flow cytometry. RESULTS: Two-thirds of patients had moderate or severe exacerbation and the FV, overall improvement in asthma control was observed. The mean expression of serum miRNA-126a, miRNA-16 and miRNA-21 was significantly lower at the EV than at the FV. At EV, miRNA-29b correlated with FeNO (r = 0.44, P < 0.05), and 5 of 7 miRNA tested correlated with pulmonary function tests. The number of cluster of differentiation (CD)45+CD4+interleukin (IL)4+ cells was significantly higher at the EV than at the FV, and positive correlations of T-regulatory cells and eosinophil progenitors with asthma control was found. At the EV, serum miRNAs negatively correlated with the number of T cells expressing IL-4, IL-17, IL-22 and interferon gamma, while at the FV both positive and negative correlations with T-cell subsets were observed. No association of detected pathogen (viruses and bacteria) in nasopharyngeal fluid with clinical, functional and immunological parameters was found. CONCLUSIONS: Epigenetic dysregulation during asthma exacerbation could be related to respiratory function, airway inflammation and T-cell cytokine expression.

Burnt sugarcane harvesting is associated with rhinitis symptoms and inflammatory markers / Colheita de cana-de-açúcar queimada está associada a sintomas de rinite e marcadores inflamatórios

Abstract Introduction: Burnt sugarcane harvesting requires intense physical exertion in an environment of high temperature and exposure to particulate matter. Objective: To evaluate the effects of burnt sugarcane harvesting on rhinitis symptoms and inflammatory markers in sugarcane workers. Methods: A total of 32 male sugarcane workers were evaluated with questionnaire for rhinitis symptoms, and for inflammatory markers on peripheral blood and nasal lavage, in the non-harvesting, and 3 and 6 months into the sugarcane harvesting period. Weather data and particulate matter fine concentrations were measured in the same day. Results: The particulate matter concentrations in sugarcane harvesting were 27 (23-33 µg/m3), 112 (96-122 µg/m3), and 63 (17-263 µg/m3); 24 h temperatures were 32.6 (25.4-37.4 ºC), 32.3 (26.7-36.7 ºC) and 29.7 (24.1-34.0 ºC) and relative humidities were 45.4 (35.0-59.7%), 47.9 (39.1-63.0%), and 59.9 (34.7-63.2%) in the non-harvesting period, three and 6 months of the harvesting period. The age was 37.4 ± 10.9 years. The prevalence of rhinitis symptoms was significantly higher at 3 months of the harvesting period (53.4%), compared to non-harvesting period (26.7%; p = 0.039) and at 6 months into the harvesting period (20%; p = 0.006). Concentrations of interleukin 6 (IL-6) in nasal lavage increased after 3 months of the harvesting period compared to the non-harvesting period (p = 0.012). The presence of rhinitis symptoms, after 3 months of the harvesting period, was directly associated with blood eosinophils and inversely associated with neutrophils. Conclusions: After 3 months of work in burnt sugarcane harvesting the prevalence of rhinitis symptoms and IL-6 in nasal lavage increased. Furthermore, eosinophil counts were directly associated with the rhinitis symptoms in the period of higher concentration of particulate matter.

Resumo Introdução: A colheita de cana-de-açúcar queimada requer esforço físico intenso em um ambiente com altas temperaturas e exposição a material particulado. Objetivo: Avaliar os efeitos da colheita de cana-de-açúcar queimada nos sintomas de rinite e marcadores inflamatórios de cortadores de cana-de-açúcar. Método: Foram avaliados 32 cortadores de cana-de-açúcar do sexo masculino por meio de um questionário para sintomas de rinite, e marcadores inflamatórios em sangue periférico e lavado nasal, no período de entressafra, e em 3 e 6 meses após o início da colheita da cana-de-açúcar. Os dados climáticos e as concentrações de material particulado fino foram medidos no mesmo dia. Resultados: O material particulado fino na entressafra e em 3 e 6 meses de safra foi 27 (23-33 µg/m3), 112 (96-122 µg/m3) e 63 (17-263 µg/m3), respectivamente; a temperatura de 24 horas foi 32,6 (25,4º-37,4ºC), 32,3 (26,7º-36,7ºC) e 29,7 (24,1º-340ºC) e a umidade relativa do ar foi 45,4 (35,0%-59,7%), 47,9 (39,1%-63,0%), e 59,9 (34,7%-63,2%), na entressafra, 3 e 6 meses após o início da colheita. A idade foi de 37,4 ± 10,9 anos. A prevalência de sintomas de rinite foi significativamente maior em 3 meses da S (53,4%), comparado com a entressafra (26,7%; p = 0,039) e 6 meses da safra (20%; p = 0,006). As concentrações de interleucina 6 (IL-6) no lavado nasal aumentaram após 3 meses do início da colheita comparado com a entressafra (p = 0,012). A presença de sintomas de rinite, após 3 meses do início da colheita, foi diretamente associada com eosinófilos e inversamente associada com neutrófilos. Conclusões: Após 3 meses do início da colheita da cana-de-açúcar queimada, houve aumento na prevalência de sintomas de rinite e IL-6 em LN. Além disso, as contagens de eosinófilos foram diretamente associadas aos sintomas de rinite no período de maior concentração de material particulado.

Dupilumab in the treatment of severe atopic dermatitis refractory to systemic immunosuppression: case report / Dupilumabe no tratamento da dermatite atópica grave refratária à imunossupressão sistêmica: relato de caso

ABSTRACT Case report of a patient with severe atopic dermatitis who showed a good response to dupilumab. She had already used two immunosuppressive agents, cyclosporine A and mycophenolate mofetil, for the treatment of atopic dermatitis with no proper control of the disease. She had also been taking all measures to control severe cases of the disease: bath and environmental controls, topical potent corticosteroids and emollients. She presented constant pruritus and skin lesions, frequent skin infections e poor quality of life. She also developed depression due to her disease. Recently, dupilumab, a new biological agent, was approved for the treatment of moderate/severe atopic dermatitis in many countries, including Brazil. Dupilumab is a monoclonal antibody with a common alpha chain of interleukin (IL) 4 and IL-13 receptors, two cytokines involved in the Th2 profile immune response that promote atopic inflammation. In a pioneer way in Brazil, the patient initiated the treatment with an attack dose of 600mg subcutaneous of dupilumab and 300mg subcutaneous every other week. Up to now, she has taken four applications, presenting a great improvement of the disease and her quality of life. There were no adverse effects, nor in the injection site nor of other kind. Patient and her family are very satisfied, and the medical team evaluates that the treatment is being well succeed. The case report described here subsidizes the use of dupilumab in the treatment of severe atopic dermatitis refractory to use of immunosuppressive agents.

RESUMO Relatamos o caso de uma paciente com dermatite atópica grave, que mostrou boa resposta ao dupilumabe. Ela já tinha usado dois agentes imunossupressores, a ciclosporina A e o micofenolato de mofetila, para o tratamento da dermatite atópica, sem obter o controle adequado da doença. Ela também vinha fazendo uso de todas as medidas de controle para casos graves da doença: cuidados com o banho, controle ambiental, corticosteroides potentes tópicos e emolientes. Apresentava prurido e lesões cutâneas constantes, infeções de pele frequentes e qualidade de vida ruim. Passou a apresentar depressão devido à sua doença. Recentemente, o dupilumabe, um agente biológico novo, foi aprovado para o tratamento de dermatite atópica moderada a severa em muitos países, incluindo o Brasil. Dupilumabe é um anticorpo monoclonal cujo alvo é a cadeia alfa comum aos receptores da interleucina (IL) 4 e IL-13, duas citocinas envolvidas no perfil de resposta imune Th2, que promove inflamação atópica. De modo pioneiro no Brasil, a paciente iniciou o tratamento, com dose de ataque de 600mg por via subcutânea de dupilumabe e 300mg também por via subcutânea a cada 2 semanas. Até o momento deste relato, ela realizou quatro aplicações, apresentando grande melhora da doença e da qualidade de vida. Não houve efeitos adversos, nem no local da injeção e nem de outro tipo. A paciente e sua família estão muito satisfeitas, e os médicos que a tratam avaliam que a terapia está sendo bem-sucedida. Este relato de caso subsidia o uso de dupilumabe no tratamento da dermatite atópica grave refratária ao uso de imunossupressores.

N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL in rheumatoid arthritis

BACKGROUND/AIMS: This study aimed to determine the regulatory role of N-acetyl-l-cysteine (NAC), an antioxidant, in interleukin 17 (IL-17)-induced osteoclast differentiation in rheumatoid arthritis (RA). METHODS: After RA synovial fibroblasts were stimulated by IL-17, the expression and production of receptor activator of nuclear factor κ-B ligand (RANKL) was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Osteoclastogenesis was also determined after co-cultures of IL-17-stimulated RA synovial fibroblasts, Th17 cells and various concentrations of NAC with monocytes. After human peripheral CD4⁺ T cells were cultured with NAC under Th17 condition, IL-17, interferon γ, IL-4, Foxp3, RANKL, and IL-2 expression and production was determined by flow cytometry or ELISA. RESULTS: When RA synovial fibroblasts were stimulated by IL-17, IL-17 stimulated the production of RANKL, and NAC reduced the IL-17-induced RANKL production in a dose-dependent manner. NAC decreased IL-17-activated phosphorylation of mammalian target of rapamycin, c-Jun N-terminal kinase, and inhibitor of κB. When human peripheral blood CD14⁺ monocytes were cultured with macrophage colony-stimulating factor and IL-17 or RANKL, osteoclasts were differentiated, and NAC reduced the osteoclastogenesis. After human peripheral CD4⁺ T cells were co-cultured with IL-17-pretreated RA synovial fibroblasts or Th17 cells, NAC reduced their osteoclastogenesis. Under Th17 polarizing condition, NAC decreased Th17 cell differentiation and IL-17 and RANKL production. CONCLUSIONS: NAC inhibits the IL-17-induced RANKL production in RA synovial fibroblasts and IL-17-induced osteoclast differentiation. NAC also reduced Th17 polarization. NAC could be a supplementary therapeutic option for inflammatory and bony destructive processes in RA.