IL-1β and IL-17 in cutaneous lupus erythematous skin biopsies: could immunohistochemicals indicate a tendency towards systemic involvement?

Abstract Background: Only a fraction of patients with cutaneous lupus erythematosus (CLE) will eventually progress toward systemic disease (SLE). Objective: To find inflammatory biomarkers which could predict the progression of cutaneous lupus erythematosus (CLE) into systemic lupus erythematosus (SLE) using immunohistochemical (IHC) assays. Methods: Immunohistochemical markers for cytotoxic, inflammatory, and anti-inflammatory responses and morphometric methods were applied to routine paraffin sections of skin biopsies, taken from lesions of 59 patients with discoid lupus, subacute lupus, and lupus tumidus. For the diagnosis of SLE, patients were classified by both the American College of Rheumatology (ACR-82) and the Systemic Lupus International Collaborating Clinics (SLICC-12) systems. Results: Skin samples from CLE/SLE +patients presented higher expression of IL-1β (ARC-82: p = 0.024; SLICC-12: p = 0.0143) and a significantly higher number of cells marked with granzyme B and perforin (ARC: p = 0.0097; SLICC-12: p = 0.0148). Biopsies from CLE/SLE- individuals had higher expression of IL-17 (ARC-82: p = 0.0003; SLICC-12: p = 0.0351) and presented a positive correlation between the density of granzyme A+and FoxP3+ cells (ARC-82: p = 0.0257; SLICC-12: p = 0.0285) and CD8+ cells (ARC-82: p = 0.0075; SLICC-12: p = 0.0102), as well as between granulysin-positive and CD8+ cells (ARC-82: p = 0.0024; SLICC-12: p = 0.0116). Study limitations: Patients were evaluated at a specific point in their evolution and according to the presence or not of systemic disease. The authors cannot predict how many more, from each group, would have evolved towards SLE in the following years. Conclusions: In this cohort, immunohistochemical findings suggested that patients with a tendency to systemic disease will show strong reactivity for IL-1β, while those with purely cutaneous involvement will tend to express IL-17 more intensely.

Use of probiotics and similar in pediatric patients with Type 1 Diabetes Mellitus: a systematic review / Uso de probióticos e similares em pacientes pediátricos com Diabetes Mellitus tipo 1: uma revisão sistemática

ABSTRACT Objective: To perform a systematic review of randomized controlled trials, evaluating the effect of probiotics, prebiotics or symbiotics supplementation on glycemic and inflammatory control in children with Type 1 Diabetes Mellitus (T1DM). Data source: The Medical Literature Analysis and Retrieval System Online (MEDLINE/PubMed), Clinical Trials, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and Scientific Electronic Library Online (SciELO) databases were searched. Randomized clinical trials of pediatric patients with DM1 using probiotics, prebiotics or symbiotics were included, regardless of year or language of publication. Studies that did not evaluate glycated hemoglobin (HbA1c) were excluded. Metabolic results (HbA1c, total insulin dose and C-peptide) and inflammatory control [interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ)] during probiotic supplementation or similar, related to modification of the intestinal microbiota, were analyzed. PROSPERO ID: CRD42022384485. Data synthesis: Five studies were selected for a systematic review. Regarding metabolic markers, only one of the articles that analyzed HbA1c showed a significant decrease (p=0.03) in the intervention group. One study identified a reduction in the total dose of insulin and increased C-peptide levels. Regarding the evaluation of inflammatory parameters (IL-10, TNF-α, INF-γ), there were no statistical relevant modifications. Conclusions: Current data from the literature were not conclusive in identifying an improvement in glycemic control and did not observe changes in inflammatory parameters with the use of probiotics, prebiotics or symbiotics in pediatric patients with T1DM.

RESUMO Objetivo: Realizar uma revisão sistemática de ensaios clínicos randomizados controlados avaliando o efeito da suplementação de probióticos, prebióticos ou simbióticos no controle glicêmico e inflamatório em crianças com diabetes mellitus tipo 1 (DM1). Fontes de dados: As bases Medical Literature Analysis and Retrieval System Online (MEDLINE/PubMed), Clinical Trials, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) e Scientific Electronic Library Online (SciELO) foram pesquisadas. Foram incluídos ensaios clínicos randomizados de pacientes pediátricos com DM1 em uso de probióticos, prebióticos ou simbióticos, independentemente de ano ou idioma de publicação. Foram excluídos os trabalhos que não avaliaram hemoglobina glicada (HbA1c). Os resultados metabólicos (HbA1c, dose de insulina total e peptídeo C) e o controle inflamatório [interleucina-10 — IL-10), fator de necrose tumoral-alfa (TNF-α) e interferon-gama (IFN-γ)] durante a suplementação de probióticos ou similares, relacionados à modificação da microbiota intestinal, foram analisados. ID PROSPERO: CRD42022384485. Síntese dos dados: Cinco estudos foram selecionados para revisão sistemática. Com relação aos marcadores metabólicos, apenas um dos artigos que analisaram a HbA1c apresentou diminuição significativa (p=0,03) no grupo intervenção. Um estudo identificou redução da dose total de insulina e aumento dos níveis de peptídeo C. Quanto à avaliação dos parâmetros inflamatórios (IL-10, TNF-α, INF-γ), não houve modificações de relevância estatística. Conclusões: Os dados atuais da literatura não foram conclusivos em identificar melhora no controle glicêmico e não observaram mudanças nos parâmetros inflamatórios com o uso de probióticos, prebióticos ou simbióticos em pacientes pediátricos com DM1.

Higher IL-6 and IL-4 plasma levels in depressed elderly women are influenced by diabetes mellitus

Abstract Objective This study aimed at investigating a set of peripheral cytokines in elderly female patients with MDD, comparing them to controls, and assessing the potential influence of clinical comorbidities on inflammatory markers. Methods Twenty-five elderly female patients diagnosed with MDD and 19 age-matched female controls were enrolled on this study. Plasma levels of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were evaluated with commercially-available assays. Results Elderly female patients with MDD exhibited higher plasma IL-6 and IL-4 levels when compared to controls. In a logistic regression model taking cytokine levels, comorbidities, and age into account, only type 2 diabetes mellitus (DM2) remained associated with MDD. Conclusion Diabetes influences the association between MDD and higher levels of cytokines in elderly female patients. Future studies should take this evidence into account in order to mitigate confounding factors.

Serum TNF-α level and probing depth as a combined indicator for peri-implant disease

Peri-implant disease (PID) is a general term for inflammatory diseases of soft and hard tissues that occur around implants, including peri-implant mucositis and peri-implantitis. Cytokines are a class of small molecule proteins, which have various functions such as regulating innate immunity, adaptive immunity, and repairing damaged tissues. In order to explore the characteristics and clinical significance of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and tumor growth factor (TGF)-β1 expression levels in serum of patients with peri-implant disease, 31 patients with PID and 31 patients without PID were enrolled. The modified plaque index (mPLI), modified sulcus bleeding index (mSBI), and peri-implant probing depth (PD) were recorded. The levels of serum TNF-α, IL-6, IL-10, and TGF-β1 were detected by ELISA. TNF-α, mPLI, mSBI, and PD levels were significantly higher in the PID group. TGF-β1 levels were significantly higher in the control group. There was a significant positive correlation between TNF-α and mPLI, mSBI, and PD. TGF-β1 was negatively associated with TNF-α, mPLI, mSBI, and PD. Multiple logistic regression analysis showed that TNF-α and PD were risk factors for the severity of PID. The receiver operating curve analysis showed that high TNF-α levels (cut-off value of 140 pg/mL) and greater PD values (cut-off value of 4 mm) were good predictors of PID severity with an area under the curve of 0.922. These results indicated that TNF-α and PD can be used as a biological indicator for diagnosing the occurrence and progression of PID.

Evaluation of cardiac autonomic function and low-grade inflammation in children with obesity living in the Northeast Brazilian region

Abstract Objective Evaluate autonomic function and low-grade inflammation and characterize the correlation between these variables in schoolchildren with obesity living in the Brazilian northeast region. Methods 84 children with obesity and 41 with normal weight were included in this cross-sectional study. Anthropometry, body composition, blood pressure (BP), inflammatory biomarkers, and heart rate variability (HRV) indexes were analyzed in children aged 7 to 11 years. Results children with obesity had increased systolic (p= 0.0017) and diastolic (p= 0.0131) BP and heart rate (p= 0.0022). The children with obesity displayed significantly lower SDNN, RMSSD, NN50, HF (ms), HF (nu), SD1, SD2, and higher LF (ms), LF (nu), LF/HF, SD1/SD2, DFA-α1, and DFA-α2, compared to normal weight. A lower and higher capacity for producing IL-10 (p= 0.039) and IL-2 (p= 0.009), respectively, were found in children with obesity compared to children with normal weight. Although IL-2, IL-4 and IL17A did not correlate with HRV parameters, IL-6 was positively correlated with SDNN, LF (ms) and SD2, TNF-α was positively correlated with LF/HF and SD1/SD2 ratio, and IFN-γ was positively correlated with SDNN, RMMSSD, NN50, LF (ms), HF (ms), SD1, and SD2. Conclusions The findings suggest that children with obesity have impaired autonomic function and systemic low-grade inflammation compared to children within the normal weight range, the inflammatory biomarkers were correlated with HRV parameters in schoolchildren living in the northeastern region of Brazil.

Clinical Efficacy of Modified Banxia Xiexintang Combined with Vedolizumab in Treatment of Crohn's Disease with Syndrome of Cold and Heat in Complexity / 中国实验方剂学杂志

ObjectiveTo evaluate the clinical efficacy of modified Banxia Xiexintang combined with vedolizumab （VDZ） in the treatment of active moderate to severe Crohn's disease （CD） with the syndrome of cold and heat in complexity and the effect of the therapy on intestinal flora. MethodEighty patients were randomized based on the random number table method into a control group （40 cases） and an observation group （40 cases）. The control group was treated with VDZ， and the observation group was treated with modified Banxia Xiexintang （1 bag per day） combined with VDZ. The treatment in both groups lasted for 14 weeks and the follow-up lasted until the 52th weeks. The CD activity index （CDAI）， CD simplified endoscopic score （SES-CD）， inflammatory bowel disease questionnaire （IBDQ） score， and syndrome score of cold and heat in complexity were assessed before treatment， after treatment， and at the end of follow-up. The levels of hemoglobin （HGB）， hematocrit （HCT）， albumin （ALB）， C-reactive protein （CRP）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， interleukin-17 （IL-17）， and fecal calprotectin （FC） were measured before and after treatment. Intestinal flora was examined before and after treatment. The safety of the therapy was evaluated. ResultCompared with those before treatment， the scores of CDAI， SES-CD， and the syndrome of cold and heat in complexity decreased （P<0.05） and the IBDQ score increased after treatment （P<0.05）. Compared with those before treatment， the scores of CDAI， SES-CD， and the syndrome of cold and heat in complexity increased （P<0.05） and the IBDQ score decreased （P<0.05） at the end of follow-up. After treatment and at the end of follow-up， the observation group had lower scores of CDAI， SES-CD， and syndrome of cold and heat （P<0.05） and higher IBDQ score （P<0.05） than the control group. Moreover， the observation group had higher clinical remission rate（χ2=4.381，3.962） and response rate（χ2=5.541，4.306） and lower non-response rate（χ2=6.646，4.306） than the control group at the two time points （P<0.05）. The endoscopic remission rate（χ2=4.072，3.985） and response rate（χ2=4.528，5.161） in the observation group were higher than those in the control group （P<0.05）. After treatment， the HGB， HCT， and ALB levels in both groups elevated， and the observation group had higher levels than the control group （P<0.05）. The treatment in both groups lowered the levels of CRP， IL-6， TNF-α， IL-17， and FC （P<0.05）， and the observation group had lower levels of CRP， IL-6， TNF-α， IL-17， and FC than the control group after treatment （P<0.05）. The relative abundance of Bifidobacterium， Lactobacillus， and Prevotella increased （P<0.05）， while that of Proteus， Klebsiella， and Enterococcus decreased （P<0.05） in the two groups after treatment. Moreover， the changes in the relative abundance of these bacteria in the observation group were more obvious than those in the control group （P<0.05）. No adverse reactions related to the modified Modified Banxia Xiexintang were observed during the study period. ConclusionModified Banxia Xiexintang combined with VDZ can play a synergistic role and has good short-term and long-term efficacy. This therapy can improve the nutritional status， regulate intestinal flora， and reduce inflammatory injury in the treatment of moderate to severe active CD patients with the syndrome of cold and heat in complexity without causing severe adverse reactions.

Comparison on Ameliorating Effect of Arisaematis Rhizoma and Arisaematis Rhizoma Preparatum on Allergic Asthma in Rats / 中国实验方剂学杂志

ObjectiveTo investigate the therapeutic effects and difference in the effects of Arisaematis Rhizoma （AR） before and after processing （i.e.， Arisaematis Rhizoma Preparatum， ARP） with Zingiberis Rhizoma Recens-Alumen on allergic asthma in rats and to provide a basis for the theory of processing improving the efficacy. MethodA rat model of allergic asthma was established in 70 SD rats by intraperitoneal injection of ovalbumin （OVA）-aluminum hydroxide. The rats were administrated with the aqueous extracts of AR （1.2， 0.3 g∙kg-1） and ARP （1.2， 0.3 g∙kg-1） aqueous extracts by gavage， and montelukast sodium （0.001 g∙kg-1） was used as the positive drug. The T helper cell type 1/type 2 （Th1/Th2） ratio in the serum and bronchoalveolar lavage fluid （BALF） and percentages of inflammatory cells in BALF were determined. Polymerase chain reaction （PCR） was employed to determine the mRNA level of mucin 5AC （MUC5AC） in the lung tissue. The pathological changes in the lung tissue were observed by hematoxylin-eosin （HE） staining and PAS staining. Immunohistochemical assay was employed to measure the expression of c-Jun amino-terminal kinase （JNK）， extracellular signal regulated protein kinase （ERK）， and p38 mitogen-activated protein kinase （p38 MAPK） in rat lung tissue. Western blot was employed to determine the protein levels of ERK， p-ERK， JNK， p-JNK， p38， p-p38 in the lung tissue. The effects of AR and ARP were compared based on overall desirability. ResultCompared with the blank group， the levels of interleukin-12 （IL-12） and γ interferon （IFN-γ） in serum and BALF of rats in the model group were significantly lower （P<0.05， P<0.01）， and the levels of interleukin-4 （IL-4）， interleukin-5 （IL-5） and interleukin-13 （IL-13） were significantly higher （P<0.05， P<0.01）. Compared with the model group， the serum and BALF contents of IL-12 and IFN-γ in rats in the montelukast sodium group， high-dose AR group and high-dose ARP group were significantly higher （P<0.05， P<0.01）， and the contents of IL-4， IL-5 and IL-13 were significantly lower （P<0.05， P<0.01）， and the serum contents of IFN-γ in rats in the low-dose AR group and low-dose ARP group were in BALF was significantly higher （P<0.05） and IL-4 and IL-13 were significantly lower （P<0.05， P<0.01）， the percentages of macrophages， lymphocytes， neutrophils， and eosinophils were reduced in BALF， and the expression of JNK/ERK/p38 MAPK signaling pathway and MUC5AC protein was inhibited in lung tissues. Overall assessment of the normalized analysis revealed that the ARP group was slightly more potent than the AR group after administration of the same dose. ConclusionAR and ARP can effectively treat allergic asthma by inhibiting JNK/ERK/p38 MAPK signaling pathway， and the effect is better after concoction， which can provide data support for its "concoction efficiency".

Strength and endurance training in cytokine and body composition of people with hiv/aids / Entrenamiento de fuerza y resistencia en citoquinas y composición corporal de personas con vih/sida / Treinamento de força e resistência em citocinas e composição corporal de pessoas com hiv/aids

ABSTRACT Introduction: HIV/AIDS is considered one of the great cases of public health, but it is seen that patients who use antiretroviral therapy (ART) and practice strength training promote a promotion of their health. Objectives: Assess the impact of strength and resistance training on cytokines and body composition in people living with HIV/AIDS. Methods: Randomized clinical trial, the sample consisted of 12 patients, 7 from the Strength Group (GF) and 5 from Group 2, Muscular Resistance (MGR). We compared the levels of IL-2, IL-4, IL-6, IL-10 and TNF-α cytokines and body composition in the first and last sessions. The patients completed 36 strength and resistance training sessions over 12 weeks. Results: After 36 sessions of GRM resistance training, there was a significant increase from 4,734 pg/mL to 5,050 pg/mL of IL-10 (p=0.002). Regarding the GFR, no significant results were found. For body composition, there were significant differences in GFR due to the increase in lean mass of the arms from 6,441g to 7,014g (p=0.04), legs from 16,379g to 17,281g (p=0.02) and whole body of 45,640g to 47,343g (p=0.01). In G2 there was a significant decrease in the percentage of fat in the arms from 23,160% to 20,750% (p = 0.04). To assess quality of life, the WHOQOL-HIV-Bref questionnaire was used, where significant improvement was found in all domains, except for the level of independence domain. Conclusion: We conclude that muscular resistance training is effective in increasing IL-10 and decreasing the percentage of fat in the arms, whereas strength training increases lean mass in arms, legs, and the whole body. Level of Evidence I; Randomized Clinical Trial.

RESUMEN Introducción: El VIH/SIDA es considerado uno de los grandes casos de salud pública, sin embargo, está comprobado que pacientes que hacen uso de la terapia antirretroviral (TARV) y practican entrenamiento de fuerza provoca una promoción de su salud. Objetivos: Evaluar el impacto del entrenamiento de fuerza en la resistencia a las citoquinas y en la composición corporal de las personas que viven con VIH/SIDA. Métodos: Ensayo clínico aleatorizado, la muestra estuvo compuesta por 12 pacientes, siete del Grupo de Fuerza (TFG) y cinco del Grupo de Resistencia Muscular (GRM). Se compararon los niveles de las citocinas IL-2, IL-4, IL-6, IL-10 y TNF-α y la composición corporal en la primera y la última sesión. Los pacientes completaron 36 sesiones de entrenamiento de fuerza y resistencia durante 12 semanas. Resultados: Tras 36 sesiones de entrenamiento de resistencia GRM, se produjo un aumento significativo de 4.734 pg/mL a 5.050 pg/mL de IL-10 (p=0,002). En cuanto a la TFG, no se encontraron resultados significativos. En cuanto a la composición corporal, hubo diferencias significativas en la TFG debido al aumento de la masa magra en brazos de 6.441g a 7.014g (p=0,04), piernas de 16.379g a 17.281g (p=0,02) y cuerpo entero de 45.640g a 47.343g (p=0,01). En el GRM hubo una disminución significativa del porcentaje de grasa en los brazos de 23.160% a 20.750% (p = 0,04). Para la evaluación de la calidad de vida se utilizó el cuestionario WHOQOL-HIV-Bref, donde se encontró una mejoría significativa en todos los dominios, excepto en el dominio nivel de independencia. Conclusión: Concluimos que el entrenamiento de resistencia muscular es eficaz para aumentar la IL-10 y disminuir el porcentaje de grasa en los brazos, mientras que el entrenamiento de fuerza aumenta la masa magra total. Nivel de Evidencia I; Ensayo clínico aleatorizado.

RESUMO Introdução: O HIV/AIDS é considerado um dos grandes casos de saúde pública, porém verifica-se que pacientes que fazem uso de terapia antirretroviral (TARV) e praticam treinamento de força provocam uma promoção de sua saúde. Objetivos: Avaliar o impacto do treinamento de força sobre a resistência nas citocinas e a composição corporal de pessoas vivendo com HIV/AIDS. Métodos: Ensaio clínico randomizado, a amostra foi composta por 12 pacientes, sendo sete do Grupo Força (TFG) e cinco do Grupo Resistência Muscular (GRM). Comparou-se os níveis das citocinas IL-2, IL-4, IL-6, IL-10 e TNF-α e a composição corporal na primeira e na última sessão. Os pacientes completaram 36 sessões de treinamento de força e resistência ao longo de 12 semanas. Resultados: Após 36 sessões de treinamento resistido GRM, houve um aumento significativo de 4.734 pg/mL para 5.050 pg/mL de IL-10 (p=0,002). Em relação à TFG, não foram encontrados resultados significativos. Para composição corporal, houve diferenças significativas na TFG devido ao aumento da massa magra dos braços de 6.441g para 7.014g (p=0,04), pernas de 16.379g para 17.281g (p=0,02) e corpo inteiro de 45.640g para 47.343g (p=0,01). No GRM houve diminuição significativa do percentual de gordura nos braços de 23.160% para 20.750% (p = 0,04). Para avaliação da qualidade de vida foi utilizado o questionário WHOQOL-HIV-Bref, onde foi encontrada uma melhora significativa em todos os domínios, exceto no domínio nível de independência. Conclusão: Conclui-se que o treinamento de resistência muscular é eficaz em aumentar a IL-10 e diminuir o percentual de gordura nos braços, enquanto o treinamento de força aumenta a massa magra geral. Nível de Evidência I; Ensaio Clínico Randomizado.

Systemic Inflammatory Patterns in Ovarian Cancer Patients: Analysis of Cytokines, Chemokines, and Microparticles / Padrões inflamatórios sistêmicos em pacientes com câncer de ovário: Análise de citocinas, quimiocinas e micropartículas

Abstract Objective To compare the patterns of systemic inflammatory response in women with epithelial ovarian cancer (EOC) or no evidence of malignant disease, as well as to evaluate the profile of systemic inflammatory responses in type-1 and type-2 tumors. This is a non-invasive and indirect way to assess both tumor activity and the role of the inflammatory pattern during pro- and antitumor responses. Materials and Methods We performed a prospective evaluation of 56 patients: 30 women without evidence of malignant disease and 26 women with EOC. The plasma quantification of cytokines, chemokines, and microparticles (MPs) was performed using flow cytometry. Results Plasma levels of proinflammatory cytokines interleukin-12 (IL12), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) interleukin-1 beta (IL-1β), and interleukin-10 (IL-10), and C-X-C motif chemokine ligand 9 (CXCL-9) and C-X-C motif chemokine ligand 10 (CXCL-10) were significantly higher in patients with EOC than in those in the control group. Plasma levels of cytokine interleukin-17A (IL-17A) and MPs derived from endothelial cells were lower in patients with EOC than in the control group. The frequency of leukocytes and MPs derived from endothelial cells was higher in type-2 tumors than in those without malignancy. We observed an expressive number of inflammatory/regulatory cytokines and chemokines in the cases of EOC, as well as negative and positive correlations involving them, which leads to a higher complexity of these networks. Conclusion The present study showed that, through the development of networks consisting of cytokines, chemokines, and MPs, there is a greater systemic inflammatory response in patients with EOC and a more complex correlation of these biomarkers in type-2 tumors.

Resumo Objetivo Comparar os padrões de resposta inflamatória sistêmica em mulheres com câncer epitelial de ovário (CEO) ou sem evidência de doença maligna, bem como avaliar o perfil de respostas inflamatórias sistêmicas em tumores dos tipos 1 e 2. Esta é uma forma não invasiva e indireta de avaliar tanto a atividade tumoral quanto o papel do padrão inflamatório durante as respostas pró- e antitumorais. Métodos Ao todo, 56 pacientes foram avaliados prospectivamente: 30 mulheres sem evidência de doença maligna e 26 mulheres com CEO. A quantificação plasmática de citocinas, quimiocinas e micropartículas (MPs) foi realizada por citometria de fluxo. Resultados Os níveis plasmáticos das citocinas pró-inflamatórias interleucina-12 (IL12), interleucina-6 (IL-6), fator de necrose tumoral alfa (tumor necrosis factor alpha, TNF-α, em inglês), interleucina-1 beta (IL-1β), e interleucina-10 (IL-10), e da quimiocina de motivo C-X-C 9 (CXCL-9) e da quimiocina de motivo C-X-C 10 (CXCL-10) foram significativamente maiores em pacientes com EOC do que nos controles. Os níveis plasmáticos da citocina interleucina-17A (IL17A) e MPs derivados de células endoteliais foram menores em pacientes com CEO do que no grupo de controle. A frequência de leucócitos e de MPs derivadas de células endoteliais foi maior nos tumores de tipo 2 do que naqueles sem malignidade. Observou-se um número expressivo de citocinas e quimiocinas inflamatórias/regulatórias nos casos de CEO, além de correlações negativas e positivas entre elas, o que leva a uma maior complexidade dessas redes. Conclusão Este estudo mostrou que, por meio da construção de redes compostas por citocinas, quimiocinas e MPs, há maior resposta inflamatória sistêmica em pacientes com CEO e correlação mais complexa desses biomarcadores em tumores de tipo 2.

Antitumor and immunomodulatory activity of fucoidan from the brown alga Lessonia trabeculata (Lessoniaceae) on breast cancer spheroids / Actividad antitumoral e inmunomoduladora de fucoidan del alga parda Lessonia trabeculata (Lessoniaceae) en esferoides de cáncer de mama

Abstract Introduction: The therapeutic benefits of the brown algae fucoidan in the treatment of breast cancer have attracted considerable interest in recent years. However, research using spheroids which provide relevant results in trials for antitumor and immunomodulatory products because they adequately simulate the tumor microenvironment, is limited. Objective: To evaluate the antitumor and immunomodulatory activity of Lessonia trabeculata fucoidan (LtF), native to the Peruvian Sea, on two types of multicellular tumor spheroids. Methods: The study was conducted from January to December 2021. Two types of spheroides were elaborated: from 4T1 tumor cells (MTS), and from 4T1 tumor cells+mouse splenocytes (MTSs). The antitumor activity of LtF was evaluated in MTS by quantifying cell viability with MTT. Immunomodulatory activity was determined in MTSs using the IC50 for two types of treatment: simple, fucoidan alone (LtF) and combined, fucoidan+doxorubicin (LtF+Dox). Pro-inflammatory (TNF-α, IL-6) and anti-inflammatory (IL-10, TGF-β) cytokine production was quantified by sandwich ELISA 72 h after treatment. Dox was used as positive control in all assays. Results: LtF exerted antitumor activity as evidenced by increased necrotic zone and cell debris formation compared to the untreated control. Antitumor activity was concentration dependent between 100 and 6 000 μg/ml. In MTSs, simple treatment increased IL-6 and decreased IL-10 and TGF-β production. The combined treatment significantly reduced TGF-β production. In both treatments and Dox, there was an increase in IL-6 compared to the untreated control. The highest production of IL-10 and TGF-β was observed in the untreated control, compatible with a highly immunosuppressive tumor microenvironment. Conclusions: LtF is a good candidate for the treatment of breast cancer and can immunomodulate the tumor microenvironment alone or in combination with Dox.

Resumen Introduccción: Los beneficios terapéuticos del fucoidan de algas pardas en el tratamiento del cáncer de mama han despertado gran interés en los últimos años. Sin embargo, las investigaciones con esferoides son limitadas, éstos proporcionan resultados relevantes en ensayos de productos antitumorales e inmunomoduladores porque simulan adecuadamente el microambiente tumoral. Objetivo: Evaluar la actividad antitumoral e inmunomoduladora del fucoidan de Lessonia trabeculata (LtF), nativa del Mar Peruano, en dos tipos de esferoides tumorales multicelulares. Métodos: El estudio se realizó de enero a diciembre de 2021. Se elaboraron dos tipos de esferoides: con células tumorales 4T1 (MTS) y con células tumorales 4T1+esplenocitos de ratón (MTSs). La actividad antitumoral de LtF se evaluó en MTS cuantificando la viabilidad celular con MTT. La inmunomodulación se determinó en MTSs utilizando la IC50 para dos tipos de tratamiento: simple, fucoidan solo (LtF) y combinado, fucoidan+doxorubicina (LtF+Dox). La producción de citoquinas proinflamatorias (TNF-α, IL-6) y antiinflamatorias (IL-10, TGF-β) se cuantificó mediante ELISA sándwich 72 h post-tratamiento. En todos los ensayos se utilizó Dox como control positivo. Resultados: En los MTS, el LtF ejerció actividad antitumoral evidenciada por aumento de la zona necrótica y formación de restos celulares respecto al control no tratado. La actividad antitumoral fue concentración-dependiente entre 100 y 6 000 μg/ml. En los MTSs, con el tratamiento simple se incrementó IL-6 y disminuyeron IL-10 y TGF-β. El tratamiento combinado redujo significativamente la producción de TGF-β. Los dos tratamientos y Dox incrementaron IL-6 respecto al control no tratado. La mayor producción de IL-10 y TGF-β se observó en los no tratados, compatible con un microambiente tumoral altamente inmunosupresor. Conclusiones: El LtF es un buen candidato para tratar el cáncer de mama y puede inmunomodular el microambiente tumoral solo o en combinación con Dox.

Regulación de la respuesta inflamatoria dependiente de citocinas / Regulation of the inflammatory response dependent on cytokines i: en

Las citocinas son hormonas proteicas que permiten la comunicación intercelular, estimulan la activación de receptores de membrana específicos, poseen funciones de diferenciación celular y proliferación, participan en la quimiotaxis, así como en el crecimiento y la modulación de la secreción de inmunoglobulinas; no obstante, su acción principal está dada por la regulación del mecanismo de la inflamación. Las principales citocinas encargadas de esto son las interleucinas 1, 8, 12 y 16; además del factor de necrosis tumoral alfa e interferones, todas ellas proinflamatorias. Las interleucinas 6 y 12 también actúan en la inmunidad específica.

Cytokines are protein hormones that allow the intercellular communication, stimulate the activation of specific membrane receptors, have cell differentiation functions and proliferation, participate in the chemotaxis, as well as in the growth and modulation of immunoglobulin secretion; nevertheless, their main action is given by the regulation of the inflammation mechanism. The main cytokines in charge of this are interleukins 1, 8, 12 and 16, besides the tumor necrosis factor alpha and interferons, all of them proinflammatory. Interleukins 6 and 12 also act in the specific immunity.

Coronavirus disease 19 (COVID-19) and viral keratouveitis – unraveling the mystery

To demonstrate viral proteins/inflammatory cytokines in a patient with unilateral keratouveitis. Retrospective case report. A 70-year-old Asian-Indian male presented with acute onset of blurring of vision in the left eye (OS) of 2 days duration. He had was coronavirus disease 2019 (COVID-19)-positive 3 months earlier. He had undergone cataract surgery/retinal laser photocoagulation in both the eyes. The corrected distance visual acuity (CDVA) (Snellen) in the right eye (RE) (OD) and left eye (LE) (OS) was 20/20 and 20/80, respectively. OS showed decreased corneal sensation, Descemet’s folds, mild stromal edema, and fine and pigmented keratic precipitates with anterior chamber 1+ flare and 1+ cells. Fundus evaluation showed scattered laser marks in the OD and temporal sectoral laser marks in OS. He was diagnosed with viral keratouveitis in OS. Tear samples were collected on Schirmer’s strips and tear wash for mass spectrometry and cytokines, which had 368 and 451 viral proteins in the RE and LE, respectively, using nano liquid chromatography–mass spectrometry, which were more than controls. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and varicella zoster virus proteins were detected. Cytokine analysis using flow cytometer analysis showed higher inflammation in OS as compared to OD. The patient was treated with oral acyclovir and topical steroids and resulted in resolution of his keratouveitis. SARS-CoV-2 proteins were present in the tear sample 3 months after COVID-19. The presence of viral proteins does not indicate causality

Cytokines in Oral Submucous Fibrosis: A Bird’s Eye View

Introduction: Oral Submucous Fibrosis (OSF) is a chronic fibrosis condition of oral cavity. It is a multifactorial condition, are- canut chewing being the prime etiologic factors. Objectives: Arecanut alkaloids stimulate the oral tissue initiating the inflammatory response. As an inflammatory response, cells release cytokines activating the cascade of different fibrinogenic pathways leading to fibrosis. Conclusion: This review briefs about the various cytokines studied in Oral Submucous Fibrosis.

Inflammation in Cardiovascular Disease: Current Status and Future Perspectives

Abstract Atherosclerosis has been defined as an inflammatory disease. Three decades of research have pointed to a pivotal role of interleukin 6 for many aspects of cardiovascular disease, not the least of which is atherosclerosis. In this review, experimental and clinical studies are reported on a timeline, exploring mechanisms and possible explanations that form the basis of current knowledge. Some successful clinical trials were proof of concept studies, showing that not only inflammatory biomarkers are related to cardiovascular outcomes, but also that decreasing inflammation can reduce cardiovascular events. Great advances have been made in the management of residual cardiovascular risk due to cholesterol, thrombosis, and metabolic diseases, but the next frontier now seems to be targeting inflammation. In the upcoming years, the importance of inflammation will be evaluated in high-risk patients with chronic kidney disease, after acute coronary heart disease or heart failure with preserved ejection fraction. Inflammation seems to precede the development of cardiovascular risk factors. Moreover, counseling for a heathy lifestyle and, when necessary, the use of cardiometabolic therapies capable of decreasing inflammation, might be important.

Mecanismos y dianas terapéuticas del inflamasoma NLRP3 en la miocardiopatía diabética / NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy

Resumen La cardiomiopatía diabética es una complicación grave de la diabetes causada por estrés oxidativo, inflamación, resistencia a la insulina, fibrosis miocárdica y lipotoxicidad. Se trata de un padecimiento insidioso, complejo y difícil de tratar. El inflamasoma NLRP3 desencadena la maduración y liberación de citoquinas proinflamatorias, participa en procesos fisiopatológicos como la resistencia a la insulina y la fibrosis miocárdica, además de estar estrechamente relacionado con la aparición y progresión de la cardiomiopatía diabética. El desarrollo de inhibidores dirigidos a aspectos específicos de la inflamación sugiere que el inflamasoma NLRP3 puede utilizarse para tratar la cardiomiopatía diabética. Este artículo pretende resumir el mecanismo y las dianas terapéuticas del inflamasoma NLRP3 en la cardiomiopatía diabética, así como aportar nuevas sugerencias para el tratamiento de esta enfermedad.

Abstract Diabetic cardiomyopathy (DCM) is a serious complication of diabetes caused by oxidative stress, inflammation, insulin resistance, myocardial fibrosis, and lipotoxicity; its nature is insidious, complex and difficult to treat. NLRP3 inflammasome triggers the maturation and release of pro-inflammatory cytokines, participates in pathophysiological processes such as insulin resistance and myocardial fibrosis, in addition to being closely related to the development and progression of diabetic cardiomyopathy. The development of inhibitors targeting specific aspects of inflammation suggests that NLRP3 inflammasome can be used to treat diabetic cardiomyopathy. This paper aims to summarize NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy, and to provide new suggestions for the treatment of this disease.

The role of pro-inflammatory cytokines – tumor necrosis factor-alpha and interleukin 6 – in the evolution of diabetic nephropathy: A comparative study

Background: Diabetes is highly prevalent and it is responsible for the increased financial burden on healthcare. Type II diabetes is a more prevalent form of diabetes. Uncontrolled and unsupervised type II diabetes may lead to various microvascular and macrovascular complications which are responsible for high morbidity and mortality. Diabetic nephropathy (DN) is a common complication characterized by the expansion of mesangial cells with thickening of the basement and nodular glomerulosis. TNF-alpha and IL-6 play an important role in causing detrimental changes leading to nephropathy. The study of the role of these inflammatory cytokines in patients with DN may help in the early diagnosis and management. Aims and Objectives: The objectives of this study were to compare the levels of proinflammatory cytokines, TNF-?, and IL-6 in the evolution of DN patients. Materials and Methods: The present study was conducted in the Department of Biochemistry, in collaboration with the Department of Medicine (Nephrology unit); Pt. B.D. Sharma, Post Graduate Institute of Medical Sciences, Rohtak after ethical clearance. Forty patients with DN (Stages 3, 4, and 5) and forty patients with diabetes mellitus without nephropathy were taken up for study after taking informed consent. Results: The mean serum TNF-? levels in cases was 33.05 ± 29.22 pg/mL and in controls was 17.67 ± 12.33 pg/mL. On the basis of unpaired t-test, the difference between the groups was statistically highly significant (P < 0.05). The mean serum interleukin-6 levels in cases was 24.92 ± 30.16 pg/mL (2.95–155.55 pg/mL) and in controls was 6.76 ± 5.82 pg/mL (2.22–35.42 pg/mL). On the basis of the t-test, the difference between the groups was statistically highly significant (P < 0.05). Conclusion: TNF-? and IL-6 may serve as potential biomarkers for patients with DN and also in the development of newer therapeutic modalities for the prevention and treatment of DN.

Effect of maqui-berry extract in dry eye disease – A clinical and molecular analysis

Purpose: This study aims to investigate the effects of maqui?berry extract (MBE) in improving signs and symptoms of dry eye disease (DED) along with ocular surface inflammation in patients with DED. Methods: Twenty patients were randomly assigned to a MBE or a placebo group (PLC). DED parameters including Schirmer’s test 1 (ST1), tear film break?up time (TBUT), ocular surface disease index (OSDI), and corneal staining were assessed before treatment and 2 months post?treatment. Tear fluid samples before and after treatment from a subset of these patients were collected from the study subjects using sterile Schirmer’s strips, and the levels of interleukin (IL)?1?, IL?10, IL?6, IL?17A, tumor necrosis factor?? (TNF?), matrix metalloproteinase?9 (MMP9), soluble intercellular adhesion molecule?1 (sICAM1), and vascular endothelial growth factor?A (VEGF?A) were measured using a microfluidic cartridge?based multiplex ELISA. Results: The MBE group demonstrated a significant (p < 0.05) decrease in OSDI scores along with a significant increase in Schirmer’s test 1 compared to the PLC group. No significant change in TBUT and corneal staining was observed between the study groups. Levels of proinflammatory factors such as IL?1?, IL?6, IL?17A, TNF?, and MMP9 were observed to be significantly reduced, along with a significant increase in IL?10 levels following treatment in the MBE group compared with the PLC group. Conclusion: Consumption of MBE resulted in the resolution of DED signs and symptoms, along with a reduction in ocular surface inflammation.

Serum Amyloid A Levels and Severity of COVID-19 in Children

Objective: The aim of this study was to determine the availability of serum amyloid A (SAA) in the diagnosis of coronavirus disease 2019 (COVID-19), to asses disease severity and to predict hospitalization status. Methods: Between March, 2020 and March, 2021, a total of 80 children (40 cases with COVID-19 and 40 cases in healthy group) were included in this study. Patients were divided into two groups (mild and moderate/severe) to evaluate SAA levels in terms of clinical severity and also hospitalization status. Results: Comparisons between the two groups revealed that median SAA values were significantly higher in children with COVID-19 than in their healthy peers (21.45vs3.05 mg/L, P=0.002). There was no significant difference in the median serum SAA levels between mild and moderate/severe clinical disease (P=0.837). The SAA difference between the two groups with regards to hospitalization was not statistically significant (P=0.098). Conclusions: Although SAA level was found to be higher in children with COVID 19 compared to healthy controls, the sensitivity of SAA for the disease was found to be low. In addition, there was no difference between the groups in terms of clinical severity.

Effect of dexamethasone implant on intraocular cytokines in diabetic macular edema

Purpose: Our primary aim was to evaluate intraocular cytokines (IC) before and after dexamethasone in diabetic macular edema (DME). Our secondary aim was to study the early and late effects of single dexamethasone implant in DME. Methods: This before and after comparative study was conducted at the Department of Ophthalmology and Centre for Nanosciences at a quaternary referral center in Kerala, India, from September 2016 to September 2018. Patients underwent complete ophthalmological examination and cytokine analysis before and after dexamethasone implant. Levels of cytokines at baseline and repeat sample were studied. Results: Twenty?seven eyes (21 patients) were divided into two groups depending on time from baseline to second injection. Group 1 included patients with <3 months between the two samples – 12 (44.4%). Group 2 included patients with >3 months between the two samples –15 (55.6%). Best corrected visual acuity (BCVA) and central macular thickness (CMT) improved significantly post?dexamethasone in group 1, but not in group 2. Interleukin (IL)?4, IL?6, IL?10, vascular endothelial growth factor (VEGF), IL?1?, interferon?gamma inducible protein?10 (IP?10), monocyte chemoattractant protein?1 (MCP?1), and IL?2 decreased post?injection in group 1. But cytokines increased post?dexamethasone in group 2, except IL?10. When compared to baseline, IL?6 reduced to half in group 1 (P?value 0.814) and it tripled in group 2 ( P?value 0.009). The level of VEGF in the first and second samples was not different in either group. Conclusion: Our study suggests that dexamethasone acts more on IC than VEGF in DME. This is significant in the first 3 months with a rebound effect on IL?6 after 3 months. Our study also suggests that repeat injection of DEX in DME should be done at 3 months to prevent deterioration of visual acuity (VA) and worsening of CMT.

Reduced Angiopoietin Factor 2 Levels Are Correlated with Better Cardiac Function and Prognosis in Valvular Heart Disease

ABSTRACT Introduction: There are few circulating biomarkers for valvular heart disease. Angiopoietin (Ang) 1, Ang2, and vascular endothelial growth factor are important inflammation-associated cytokines. The aim of this study was to investigate the clinical significance and association of Ang1, Ang2, and vascular endothelial growth factor in valvular heart disease. Methods: This is a retrospective study; a total of 62 individuals (valvular heart disease patients [n=42] and healthy controls [n=20]) were included. Plasma levels of Ang1, Ang2, and vascular endothelial growth factor were detected by enzyme-linked immunosorbent assays. We retrospectively collected the baseline characteristics and short-term outcomes; logistic regression was performed to identify predictor for short-term mortality. Results: Ang2 was significantly decreased in the valvular heart disease group compared with the healthy control group (P=0.023), while no significant difference was observed in the Ang1 and vascular endothelial growth factor levels. The Ang2 level of New York Heart Association (NYHA) I/II patients — but not NYHA III/IV patients — was significantly decreased compared with that of healthy control individuals (NYHA I/II: P=0.017; NYHA III/IV: P=0.485). Univariable logistic regression analysis indicated that Ang2 was a significant independent predictor for short-term mortality (odds ratio 18.75, P=0.033, 95% confidence interval 8.08-102.33). Ang1 was negatively correlated with Ang2 (P=0.032, Pearson's correlation coefficient =-0.317) and was positively correlated with vascular endothelial growth factor (P=0.019, Pearson's correlation coefficient = 0.359). Conclusion: Ang2 might serve as a therapeutic and prognostic target for valvular heart disease.