High fat diet- induced obesity decreases ErbB receptors expression in liver and adipose tissue in C57BL/6 mice

Neuregulins (NRGs) are a family of signaling proteins that bind to receptor tyrosine kinases of the ErbB family (ErbB2 to ErbB4), which can homo- or heterodimerize depending on their structural features and cell type. Many studies have proposed that decreased NRG levels are a common characteristic of obesity. In liver and adipose tissue, the increase in NRG expression has protective effects against obesity. However, it is still unknown whether ErbBs expression is altered in this pathology. We hypothesized that high fat diet-induced obesity downregulates ErbB receptors expression in obese mice compared to normal weight mice. Males C57BL/6 mice (n=6-7 for each group) were fed for 12 weeks and divided into: (i) control diet (CD; 10%-kcal fat, 20%-kcal protein, 70%-kcal carbohydrates), and (ii) high fat diet (HFD; 60%-kcal fat, 20%-kcal protein, 20%-kcal carbohydrates). General parameters and ErbBs expression (qPCR, immunohistochemistry and Western blot) were evaluated. We observed a significant increase in final body weight (47%), adipose tissue to body weight ratio (244%) and HOMA-IR (69%), among other parameters, in obese mice. In HFD group significantly decreased ErbB2 (48%) and ErbB3 (66%) mRNA levels in liver (no change in ErbB4), and ErbB2 (43%), ErbB3 (76%) and ErbB4 (35%) in adipose tissue, compared to CD. Furthermore, ErbB2 and ErbB3 protein levels decreased significantly in HFD group compared to the CD in liver. Therefore, our results suggest that HFD-induced obesity significantly decreases ErbBs expression in liver and adipose tissue in this murine model, that may be associated with alterations in the NRG pathway in obese mice.

Las neuregulinas (NRGs) son una familia de proteínas de señalización que se unen a receptores tirosina quinasas de la familia ErbB (ErbB2 a ErbB4), que pueden homo- o heterodimerizar dependiendo de sus características estructurales y del tipo celular. Estudios han propuesto que la disminución de los niveles de NRG es una característica común de la obesidad. En el hígado y el tejido adiposo (TA), el aumento de la expresión de NRG tiene efectos protectores contra la obesidad. Sin embargo, aún se desconoce si la expresión de ErbBs está alterada en esta patología. Nuestra hipótesis es que la obesidad inducida por una dieta alta en grasas (DAG) disminuye la expresión de los ErbB en ratones obesos. Ratones machos C57BL/6 (n=6-7 para c/grupo) fueron alimentados durante 12 semanas y divididos en: (i) dieta control (DC; 10%-kcal grasa, 20%-kcal proteína, 70%-kcal carbohidratos), y (ii) DAG (60%-kcal grasa, 20%-kcal proteína, 20%-kcal carbohidratos). Se evaluaron los parámetros generales y la expresión de ErbBs (qPCR, inmunohistoquímica y Western blot). Observamos un aumento significativo del peso corporal final (47%), de la relación tejido adiposo/peso corporal (244%) y del HOMA-IR (69%), entre otros parámetros, en ratones obesos. En este grupo disminuyó significativamente los niveles de ARNm de ErbB2 (48%) y ErbB3 (66%) en el hígado (sin cambios en ErbB4), y de ErbB2 (43%), ErbB3 (76%) y ErbB4 (35%) en el TA. Además, los niveles de proteína ErbB2 y ErbB3 disminuyeron significativamente, en comparación con el grupo DC en el hígado. Nuestros resultados sugieren que la obesidad inducida por DAG disminuye significativamente la expresión de ErbBs en el hígado y el TA, que puede estar asociado con alteraciones en la vía NRG en ratones obesos.

Methotrexate for refractory adult atopic dermatitis leads to alterations in cutaneous IL-31 and IL-31RA expression

Abstract Background: Methotrexate (MTX) is an alternative treatment for patients with moderate/severe atopic dermatitis (AD). Objective: The authors evaluated the effect of MTX on the cutaneous expression of cytokines and chemokines that are involved in the inflammatory response in adult AD patients who received treatment with methotrexate for 24 weeks. Methods: The authors conducted a prospective single-institution cohort study with 12 adults with moderate/severe AD who received oral MTX (15 mg/wk for 24 wks) and 10 non-atopic matched controls. The comparison was made of skin biopsies of lesional and non-lesional skin, pre- and post MTX treatment. The authors analyzed mean epidermal thickness and expression of IL-31, IL-31RA, OSMR, TSLP, Ki67, IL-4 mRNA, IL-6, IL-10, TNF-α, IFN-γ, TARC, and CCL-22. Results: There was a reduction in mean epidermal thickness (p = 0.021), an increase in IL-31RA expression (immunohistochemistry) in the epidermis (p = 0.016) and a decrease in IL-31 gene expression (p = 0.019) on lesional AD skin post-MTX treatment. No significant changes in the cutaneous expression of the other evaluated markers were identified. Study limitations: Small sample size and limited length of follow-up. Conclusions: Treatment with MTX in adults with moderate/severe AD reduced epidermal hyperplasia and changed the cutaneous expression of inflammatory cytokines and receptors that are mainly related to pruritus, including IL-31 and IL-31RA.

Triple-seronegative myasthenia gravis: clinical and epidemiological characteristics / Miastenia gravis triplo-soronegativa: características clínicas e epidemiológicas

Abstract Background Myasthenia gravis (MG) is an autoimmune disease usually caused by antibodies against the acetylcholine receptor (AChR-Abs), muscle-specific tyrosine kinase (MuSK-Abs), or low-density lipoprotein receptor-related protein 4 (LRP4-Abs). However, there are MG patients who do not have these antibodies and are thus said to have triple-seronegative (triple-SN) MG. Objective This study aims to describe the frequency and clinical and epidemiological characteristics of patients with triple-SN MG. Methods This was a retrospective cross-sectional study carried out through the analysis of medical records. Descriptive and analytical statistical analysis was performed comparing subgroups of myasthenic patients, classified according to serological profile. Results The sample population consisted of 93 MG patients: 85 were positive for antibodies, 80 (86%) with AChR-Abs, 5 (5.4%) with MuSK-Abs, and no MG patients with LRP4-Abs. Eight patients (8.6%) had triple-SN MG; they had a median age at disease onset of 30 years (21-45). Their most common initial symptoms were ptosis, diplopia, and generalized weakness. Most patients presented with mild symptoms at their last visit, reflecting a median MG composite scale score of 4 (0-6), and 75% of patients had an adequate response to treatment. Conclusion Our study showed a low frequency of triple-SN MG in Brazilian MG patients. Triple-SN MG was predominant in females, who presented with ptosis, diplopia, and generalized weakness, and most patients had an adequate response to immunosuppressive treatment. There was no significant difference between triple-SN MG and the other subgroups.

Resumo Antecedentes A Miastenia gravis (MG) é uma desordem autoimune geralmente causada por anticorpos antirreceptores de acetilcolina (anti-RACh), tirosina quinase músculo-específica (anti-MuSK) ou proteína 4 relacionada ao receptor de lipoproteína de baixa densidade (anti-LRP4). No entanto, em uma parcela dos pacientes, nenhum destes três anticorpos pôde ser detectado, sendo estes casos denominados "triplo-soronegativos". Objetivo Descrever a frequência, bem como as características clínicas e epidemiológicas dos pacientes com MG triplo-soronegativa. Métodos Consiste em um estudo transversal e restrospectivo, realizado através da análise de prontuários médicos. Foi realizada análise estatística descritiva e analítica entre os subgrupos de pacientes, classificados de acordo com o perfil sorológico. Resultados A população consistiu de 93 pacientes com MG: 85 pacientes apresentavam positividade para anticorpos, sendo 80 (86%) com anticorpos anti-RACh, cinco (5,4%) com anti-MuSK, e não foram encontrados pacientes com anti-LRP4. Oito (8,6%) eram pacientes triplo-soronegativos, que apresentaram idade média de início da doença de 30 anos (21-45), e com sintomas iniciais mais comuns de ptose, diplopia e fraqueza generalizada. 75% dos pacientes triplo-soronegativos apresentaram resposta adequada ao tratamento. Conclusão O estudo demonstrou uma baixa frequência da pacientes com MG triplo-soronegativa na população brasileira. A MG triplo-soronegativa foi predominante nas mulheres, que se apresentaram com ptose, diplopia ou fraqueza generalizada, e a maioria dos pacientes apresentou resposta adequada ao tratamento imunossupressor. Não houve diferença significativa entre a MG triplo-soronegativa e os demais subgrupos.

A molecular approach to triple-negative breast cancer: targeting the Notch signaling pathway

ABSTRACT Introduction Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This phenotype renders triple-negative breast cancer cells refractory to conventional therapies, resulting in poor clinical outcomes and an urgent need for novel therapeutic approaches. Recent studies have implicated dysregulation of the Notch receptor signaling pathway in the development and progression of triple-negative breast cancer. Objective This study aimed to conduct a comprehensive literature review to identify potential therapeutic targets of the Notch pathway. Our analysis focused on the upstream and downstream components of this pathway to identify potential therapeutic targets. Results Modulating the Notch signaling pathway may represent a promising therapeutic strategy to treat triple-negative breast cancer. Several potential therapeutic targets within this pathway are in the early stages of development, including upstream (such as Notch ligands) and downstream (including specific molecules involved in triple-negative breast cancer growth). These targets represent potential avenues for therapeutic intervention in triple-negative breast cancer. Comments Additional research specifically addressing issues related to toxicity and improving drug delivery methods is critical for the successful translation of these potential therapeutic targets into effective treatments for patients with triple-negative breast cancer.

Survivin expression as a prognostic marker for breast cancer

SUMMARY OBJECTIVE: Due to the speed of development observed in breast cancer, several studies aimed at discovering new biomarkers have been carried out in order to arrive at an early diagnosis. As survivin plays a fundamental role in the evasion of apoptosis in tumor cells, the aim of this study was to verify the expression profile of the survivin gene in paraffin-embedded breast tumor samples and associate it with the clinical characteristics of the patients. METHODS: This is a cross-sectional study, for which 100 tumor samples were obtained from cancer patients treated throughout the year 2019 at Instituto de Mama do Cariri (Juazeiro do Norte, in the state of Ceará). This study included women over 30 years old who had confirmed breast cancer through anatomopathological examination but excluded those with non-neoplastic breast comorbidities, other neoplasms, or chronic diseases. Survivin gene expression was assessed by quantitative polymerase chain reaction. RESULTS: The expression of survivin is associated with the lack of expression of estrogen (p=0.027) and progesterone (p>0.0005) receptors. It means that survivin expression is higher in patients in which labeling was absent for estrogen receptor and progesterone receptor. CONCLUSION: Our data reinforce that survivin expression is higher in estrogen receptor-patients, thus representing an additional prognostic tool.

OLFATO: forma más antigua de comunicación y sentido preciso que el otorrinolaringólogo debe conocer a profundidad / SMELL: oldest form of communication and precise sense that the otolaryngologist must know in depth

Introducción: el papel clave del olfato, antiguo sistema sensorial, es proporcionar información sobre las sustancias químicas en el medio ambiente. El olfato desempeña un papel en la detección de compuestos peligrosos, el mantenimiento de la nutrición, el comportamiento interpersonal, la salud neurológica y la sensación de placer, entre otras funciones. En consecuencia, la disfunción olfativa puede conducir a un riesgo de lesiones, desnutrición, aislamiento social y una mala calidad de vida. Materiales y métodos: se realizó una exploración bibliográfica y se identificaron artículos de acuerdo con los criterios de inclusión y exclusión definidos y se tomaron aquellos con calidad en la evidencia. Discusión: el sistema olfativo humano tiene diferencias anatómicas, fisiológicas y genéticas considerables con respecto al de otros mamíferos. Conclusiones: las destrezas olfativas varían con factores como la edad, el sexo, la etapa de desarrollo, ciertas enfermedades otorrinolaringológicas y enfermedades generales.

Introduction: The key role of the ancient olfactory sensory system is to provide information about chemicals in the environment. Smell plays a role in the detection of dangerous compounds, the maintenance of nutrition, interpersonal behavior, neurological health, and the sensation of pleasure, among other functions. Consequently, olfactory dysfunction can lead to a risk of injury, malnutrition, social isolation, and a poor quality of life. Materials and methods: A bibliographical exploration was carried out and articles were identified according to the inclusion and exclusion criteria defined and those with quality evidence were taken. Discussion: The human olfactory system has considerable anatomical, physiological, and genetic differences from that of other mammals. Conclusions: Olfactory skills vary with factors such as age, sex, stage of development, certain ear, nose and throat diseases and general diseases.

Comparative Analysis of TNF-alpha, TNF-R1, and TNF-R2 in Patients with Low-impact Fractures Due to Osteoporosis / Análise comparativa de TNF-alfa, TNF-R1 e TNF-R2 em pacientes com fraturas de baixo impacto decorrentes de osteoporose

Abstract Objective To analyze the serum levels of TNF-alpha and its TNF-R1 and TNF-R2 receptors in the blood of patients with low-impact fractures due to osteoporosis, comparing between genders and with healthy patients. Methods The present study was conducted with a blood sample of 62 patients, divided into patients with osteoporosis and healthy patients. The results were obtained using the ELISA method. Cytokine concentrations were determined based on the absorbance values obtained. Results Serum TNF-alpha levels were undetectable in female patients, while in males they were found only in one patient, with no significant difference. Similar results were found in the analyses of TNF-R1 and TNF-R2 levels, a significant increase in levels of TNF-alpha receptors in the groups of patients with osteoporosis compared with the control groupinbothsexes.There wasnosignificant difference between the sexes in the dosage of both receptors within the group with osteoporosis. There was also a positive and significant correlation in the levels of TNF-R1 and TNF-R2 only in women. Conclusion The significant increase in TNF-R1 and TNF-R2 levels in women with osteoporosis suggest that the release and expression of these receptors may be contributing differently to the development of osteoporosis in men and women.

Resumo Objetivo Analisar os níveis séricos de TNF-alfa e de seus receptores TNF-R1 e TNF-R2 no sangue de pacientes com fraturas de baixo impacto, decorrentes de osteoporose, comparando entre os sexos e com pacientes saudáveis. Métodos Oestudofoi realizadocom amostradesanguede 62 pacientes,divididos em pacientes com osteoporose e pacientes saudáveis. Os resultados foram obtidos através do método de ELISA. As concentrações de citocinas foram determinadas com base nos valores de absorbância obtidos. Resultados Os níveis séricos de TNF-alfa foram indetectáveis nos pacientes do sexo feminino, enquanto no masculino encontrou-se somente em um paciente, não havendo diferença significativa. Encontrou-se resultados semelhantes nas análises dos níveis de TNF-R1 e TNF-R2, aumento significativo nos níveis dos receptores de TNF-alfa nos grupos de pacientes com osteoporose em comparação com o grupo controle, em ambos os sexos. Não houve diferença significativa entre os sexos na dosagem de ambos os receptores dentro do grupo com osteoporose. Houve ainda correlação positiva e significativa nos níveis de TNF-R1 e TNF-R2 apenas nas mulheres. Conclusão O aumento significativo nos níveis de TNF-R1 e TNF-R2 em mulheres com osteoporose sugerem que a liberação e expressão destes receptores pode estar contribuindo de maneira distinta no desenvolvimento da osteoporose em homens e mulheres.

A logarithmic model for hormone receptor-positive and breast cancer patients treated with neoadjuvant chemotherapy

SUMMARY OBJECTIVE: The aim of this study was to investigate the predictive importance of the previously validated log(ER)*log(PgR)/Ki-67 predictive model in a larger patient population. METHODS: Patients with hormone receptor positive/HER-2 negative and clinical node positive before chemotherapy were included. Log(ER)*log(PgR)/Ki-67 values of the patients were determined, and the ideal cutoff value was calculated using a receiver operating characteristic curve analysis. It was analyzed with a logistic regression model along with other clinical and pathological characteristics. RESULTS: A total of 181 patients were included in the study. The ideal cutoff value for pathological response was 0.12 (area under the curve=0.585, p=0.032). In the univariate analysis, no statistical correlation was observed between luminal subtype (p=0.294), histological type (p=0.238), clinical t-stage (p=0.927), progesterone receptor level (p=0.261), Ki-67 cutoff value (p=0.425), and pathological complete response. There was a positive relationship between numerical increase in age and residual disease. As the grade of the patients increased, the probability of residual disease decreased. Patients with log(ER)*log(PgR)/Ki-67 above 0.12 had an approximately threefold increased risk of residual disease when compared to patients with 0.12 and below (odds ratio: 3.17, 95% confidence interval: 1.48-6.75, p=0.003). When age, grade, and logarithmic formula were assessed together, the logarithmic formula maintained its statistical significance (odds ratio: 2.47, 95% confidence interval: 1.07-5.69, p=0.034). CONCLUSION: In hormone receptor-positive breast cancer patients receiving neoadjuvant chemotherapy, the logarithmic model has been shown in a larger patient population to be an inexpensive, easy, and rapidly applicable predictive marker that can be used to predict response.

FcγRIIa and Fcγ RIIIa genes polymorphism in Egyptian children with primary immune thrombocytopenia

Abstract Introduction Phagocytosis of autoantibody-sensitized coated platelets through Fc gamma receptors on phagocytic cells is an important mechanism of thrombocytopenia in primary immune thrombocytopenia (ITP). Objective We aimed to investigate the contribution of the FcγRIIa and FcγRIIIa genes polymorphism to the risk of ITP and their association with disease characteristics in Egyptian children. Methods A case control study was conducted on eighty children with primary ITP and eighty age and sex healthy matched subjects as a control group. The FcγRIIa and FcγRIIIa genes polymorphism was detected using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results We found that the FcγRIIa‐131H and ‐131R allele frequencies were 51.3 % and 48.7%, respectively, in children with ITP, versus 75% and 25%, respectively, in controls (p= 0.002). The compound heterozygous HR genotype was significantly higher in ITP patients (p < 0.05). The FcγRIIIa-158F and ‐158V allele frequencies were 46.3% and 53.7%, respectively, in children with ITP, versus 70% and 30%, respectively, in controls (p= 0.002). The compound heterozygous VF genotype was significantly higher in ITP patients (p < 0.05). The combined HR/FV genotype was 47.5% in ITP patients, versus 10% in controls (p < 0.001). No significant difference was found between children with newly diagnosed ITP and those who developed chronic ITP, regarding the frequency distribution of the FcγRIIa and FcγRIIIa alleles and genotypes (p > 0.05). Conclusion There is a possible association of the FcγRIIa and FcγRIIIa genes polymorphism with the risk for, and genetic susceptibility to ITP in Egyptian children, but large-scale studies are still needed to support our findings.

Por trás da leptina: uma revisão de literatura / Behind the leptin: a literature review / Detrás de leptin: una revisión de la literatura

A obesidade é uma doença crônica, multifatorial, que afeta todas as idades e classes sociais. Esta comorbidade tem avançado em decorrência de diversos fatores e sua prevalência está ancorada em diferentes dimensões como as biológicas, sociais, históricas, comportamentais, saúde pública e política. O presente estudo tem como objetivo caracterizar o gene da leptina, seu produto e de seus receptores, assim como os mecanismos que corroboram com o desenvolvimento da obesidade e seu envolvimento com distúrbios alimentares. A leptina é uma proteína secretada principalmente nos adipócitos, ela reduz o apetite por meio da inibição da formação de neuropeptídeos relacionados ao apetite, como o neuropeptídeo Y e eleva a expressão de neuropeptídeos anorexígenos, como o hormônio liberador de corticotropina, por isso que os altos níveis de leptina reduzem a ingestão alimentar, em contraste com os níveis baixos que induzem hiperfagia. Como a leptina realiza o controle da saciedade e regulação do gasto energético, o indivíduo com disfunção neste gene não desenvolve essa função corretamente. Isso se deve aos SNPs, que de acordo com estudos aumentam a susceptibilidade à obesidade. Além do mais, a leptina pode estar envolvida com processo patológico de alguns distúrbios alimentares, predispondo o paciente às condições como anorexia nervosa e bulimia.

Obesity is a chronic, multifactorial disease that affects all ages and social classes. This comorbidity has advanced as a result of several factors and its prevalence is anchored in different dimensions such as biological, social, historical, behavioral, public health and political. The present study aims to characterize the leptin gene, its product and its receptors, as well as the mechanisms that corroborate the development of obesity and its involvement with eating disorders. Leptin is a protein secreted mainly in adipocytes, it reduces appetite by inhibiting the formation of appetite-related neuropeptides such as neuropeptide Y and elevates the expression of anorexic neuropeptides such as corticotropin-releasing hormone, so high levels of leptin reduce dietary intake, in contrast to low levels that induce hyperphagia. As leptin performs satiety control and regulation of energy expenditure, the individual with dysfunction in this gene does not develop this function properly. This is due to SNPs, which according to studies increase susceptibility to obesity. Furthermore, leptin may be involved with the pathological process of some eating disorders, predisposing the patient to conditions such as anorexia nervosa and bulimia.

La obesidad es una enfermedad crónica multifactorial que afecta a todas las edades y clases sociales. Esta comorbilidad ha avanzado como resultado de diversos factores y su prevalencia está anclada en diferentes dimensiones, como la biológica, la social, la histórica, la conductual, la salud pública y la política. El objetivo de este estudio es caracterizar el gen de la leptina, su producto y sus receptores, así como los mecanismos que corroboran el desarrollo de la obesidad y su participación en los trastornos alimentarios. La leptina es una proteína secretada principalmente en los adipocitos, reduce el apetito inhibiendo la formación de neuropéptidos relacionados con el apetito, como el neuropéptido Y y eleva la expresión de neuropéptidos anorexógenos, como la hormona que libera la corticotropina, razón por la cual los altos niveles de leptina reducen la ingesta dietética, en contraste con los bajos niveles inducir hiperagia. Como la leptina lleva a cabo el control de la saciedad y la regulación del gasto energético, el individuo con disfunción en este gen no desarrolla esta función correctamente. Esto se debe a los SNP, que según los estudios aumentan la susceptibilidad a la obesidad. Además, la leptina puede estar implicada en el proceso patológico de algunos trastornos alimentarios, predisponiéndose al paciente a condiciones tales como anorexia nerviosa y bulimia.

IL17A and IL17RA gene polymorphisms in Fanconi anemia

Abstract Fanconi anemia is a rare autosomal recessive disease. In this disease, cytokine pathways can induce the bone marrow failure that is observed in individuals with Fanconi anemia. Interleukin IL-17 exhibits a protective effect in organisms because it induces neutrophil recruitment and shows a pathological role in several models of autoimmune diseases, periodontal disease, cancer, allograft rejection, and graft versus host disease. Polymorphisms in the IL17A and IL17RA genes were evaluated from DNA in saliva, comparing individuals with or without Fanconi anemia, using models of genotypic transmission (additive, dominant, and recessive). Polymorphisms in the IL17A and IL17RA genes (rs2241044 [C allele], rs879577 [C allele], rs9606615 [T allele], and rs2241043 [C allele]) were risk factors for developing Fanconi anemia. We also performed an analysis of gene markers with clinical variables in the Fanconi group. Polymorphisms in the IL17A gene (rs3819025 [A allele] and rs2275913 [G allele], respectively) were associated with an age of less than 20 years (p = 0.026; RP 0.65) and the female sex (p = 0.043; RP 0.88). The IL17RA gene was also associated with age and the presence of leukoplakia (a potentially malignant oral disorder). An age of less than 20 years was associated with rs917864 (T allele; p = 0.036; RP 0.67). The presence of leukoplakia was associated with rs17606615 (T allele; p = 0.042; RP 0.47). To our knowledge, this is the first study that associates IL17A and IL17RA gene polymorphisms with Fanconi anemia and examines rs2241044 polymorphisms in scientific literature thus far.

Mechanism of Buyang Huanwutang in Regulating Macrophage Cell Polarization Based on TLR4/NF-κB/NLRP3 Pathway / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Buyang Huanwutang in regulating macrophage polarization based on the Toll-like receptor 4 （TLR4） / nuclear factor-κB （NF-κB） / nucleotide-binding oligomerization domain-like receptor 3 （NLRP3） pathway. MethodRAW264.7 macrophages were intervened with lipopolysaccharide （LPS） of different concentrations （0， 1.25， 2.5， 5， 10， 20， 40， and 80 mg·L-1） for 24 hours. Cell Counting Kit-8 （CCK-8） assay was used to determine the cell viability of RAW264.7 macrophages. The optimal concentration was chosen to establish an in vitro inflammation model induced by LPS. Cells were divided into a blank group （20% blank serum）， a model group （20% blank serum + 10 mg·L-1 LPS）， a model control group （20% FBS + 10 mg·L-1 LPS）， low-， medium-， and high-dose （5%， 10%， and 20%） Buyang Huanwutang-containing serum groups， a high-dose （20%） Buyang Huanwutang combined with NLRP3 inhibitor MCC950 （50 μmol·L-1） group， a high-dose （20%） Buyang Huanwutang combined with reactive oxygen species （ROS） inhibitor NAC （10 μmol·L-1） group， and a high-dose （20%） Buyang Huanwutang combined with NF-κB inhibitor PDTC （10 μmol·L-1） group. Enzyme-linked immunosorbent assay （ELISA） was used to detect the expression of interleukin-1β （IL-1β）， interleukin-18 （IL-18）， and tumor necrosis factor-α （TNF-α） in RAW264.7 macrophages. Flow cytometry was employed to measure ROS levels in macrophages. Western blot was used to determine the protein expression of M1-type macrophage-related factors inducible nitric oxide synthase （iNOS） and TNF-α， M2-type macrophage-related factors arginase-1 （Arg-1） and interleukin-10 （IL-10）， as well as the proteins in the TLR4/NF-κB/NLRP3 pathway. ResultCCK-8 results indicated that under 10 mg·L-1 LPS stimulation， RAW264.7 macrophages exhibited the highest cell viability （P<0.01）. Compared with the blank group， the model group showed significantly increased levels of IL-1β， IL-18， and TNF-α （P<0.05，P<0.01）， increased ROS expression （P<0.05，P<0.01）， increased protein expression of M1-type macrophage factors iNOS and TNF-α （P<0.01）， decreased protein expression of M2-type macrophage factors Arg-1 and IL-10 （P<0.05，P<0.01）， and upregulated expression levels of TLR4， myeloid differentiation factor 88 （MyD88）， phosphorylated inhibitor of NF-κB （p-IκB）/NF-κB inhibitor （IκB）， phosphorylated NF-κB （p-NF-κB） p65/NF-κB p65， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， and pro-Caspase-1 （P<0.05， P<0.01）. Compared with the model group， all Buyang Huanwutang-treated groups and inhibitor groups significantly reduced levels of IL-1β， IL-18， and TNF-α （P<0.01）， suppressed the expression of inflammatory factors in RAW264.7 macrophages， decreased cellular ROS expression levels （P<0.01）， downregulated M1-type macrophages iNOS and TNF-α protein expression （P<0.01）， upregulated M2-type macrophages Arg-1 and IL-10 protein expression （P<0.01）， and lowered protein expression levels of TLR4， MyD88， p-IκB/IκB， p-NF-κB p65/NF-κB p65， NLRP3， ASC， and pro-Caspase-1 （P<0.05， P<0.01）. ConclusionBuyang Huanwutang can improve macrophage inflammation， potentially by reducing macrophage ROS levels， inhibiting RAW264.7 macrophage polarization， and downregulating the protein expression levels of the TLR4/NF-κB/NLRP3 pathway.

Preliminary study on the distribution of T cell receptor β chain in patients with Takayasu arteritis / 中华风湿病学杂志

Objective:To investigate the diversity of T cell receptor repertoire in patients with Takayasu arteritis and analyze the side chain gene expression and distribution pattern of V、J gene rearrangement of T cell receptors.Methods:The peripheral blood samples of 8 patients with Takayasu arteritis and 4 healthy controls were collected. After constructing the library, high-throughput sequencing was performed with Illumina hiseq X10 sequencer. Bioinformatics analysis was conducted to obtain the sequences and compared with the reference sequences. the frequency information of V/D/J genes, and extraction of CDR region sequenceswere compared. The diversity of the TCR repertoire was also evaluated, and the comparative analysis and cluster analysis between groups and within samples were carried out. The data were analyzed by R language statistical software. Comparisons between two groups were analyzed by Mann-Whitney U test. Results:There was no significant difference in D50 index and Shannon entropy of chain CDR3 between Takayasu arteritis group and healthy control group. There was no significant difference in high-frequency cloning between the two groups. However, a total of 21 gene rearrangement fragments were different between the two groups. The expression of 14 V/J gene rearrangement fragments such as TRBV15-TRBJ2-3 [0.31 (0.27, 0.70) ], TRBV26-TRBJ2-6[0.30 (0.23, 0.57) ], TRBV28-TRBJ1-4[179 (139, 412) ], TRBV28-TRBJ1-6[362 (253, 419) ] in the patient group was significantly higher than that in the control group ( Z score were 2.65, 2.08, 2.27, 2.27, 2.27, 2.08, 2.65, 2.08, 2.27, 2.27, 2.08, 2.08, 2.46 and 2.22 respectively, P<0.05). The expression of seven V/J gene rearrangement fragments such as TRBV10-1-TRBJ1-2 [7.49 (4.9, 12.1) ],TRBV29-1-TRBJ2-2[10.5 (4.0, 12.8) ], TRBV-4-2-TRBJ2-6 [3.31 (1.8, 5.8) ] in the patients with Takayasu arteritis group was significantly lower than that in the control group ( Z score were -2.08, -2.27, -2.08, -2.08, -2.27, -2.08 and -2.29, P<0.05). Conclusion:Although there is no significant decrease in the diversity of peripheral blood TCR repertoire in patients with Takayasu arteritis, there are differences in the expression of chain V and J genes of TCR genes, and there is unique V/J rearrangement clones.

Diagnostic value of soluble interleukin 7 receptor in combination with other biomarkers for emergency sepsis / 中国医师杂志

Objective:To investigate the diagnostic value of soluble interleukin 7 receptors (sIL-7R) in combination with other biomarkers for emergency sepsis.Methods:A prospective study method was used to select 102 emergency patients from the Chuiyangliu Hospital affiliated to Tsinghua University and Baoding First Central Hospital from December 2020 to June 2022. They were divided into sepsis group (80 cases) and non-sepsis group (22 cases), and 20 healthy people in the same period were selected as the control group. The patient data were collected, the relevant biomarker examination was improved and the values were recorded. Using statistical methods, the significance of sIL-7R for the diagnosis of sepsis was assessed, and important indicators related to the presence of sepsis were also screened to construct a model for the early diagnosis of sepsis.Results:The levels of interleukin-6 (IL-6), C-reactive protein (CRP), age and sIL-7R in sepsis group were significantly higher than those in non-sepsis group and control group (all P<0.01). Further, the sIL-7R, age, CRP, and IL-6 were selected as important diagnostic indicators of sepsis by comparing the sepsis and non-sepsis groups using R-language statistical software. Receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) for diagnosing sepsis of the four indexes were calculated as 0.759, 0.622, 0.716 and 0.640, respectively. The diagnostic model based on the four indexes performed better than other indexes, and the AUC value reached 0.869. The AUC of sIL-7R in the diagnosis of sepsis was higher than that of the other three indexes, and the detection of SIL-7R in combination with other inflammatory indexes was significantly higher than that of the four indexes, which had obvious advantages for the early diagnosis of sepsis. Conclusions:sIL-7R is a good biological marker for the early diagnosis of sepsis, and its combination with age, CRP, and IL-6 can better improve the early diagnosis of sepsis.

Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signal-ing to hypothalamus and habenula / 中国药理学与毒理学杂志

Depressive disorder ranks as a major bur-den of disease worldwide,yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects.The lateral septum(LS)is thought to control of depression,however,the cellular and circuit substrates are largely unknown.Here,we identified a subpopulation of LS GABAergic adenosine A2A receptors(A2AR)-positive neurons mediating depres-sive symptoms via direct projects to the lateral habenula(LHb)and the dorsomedial hypothalamus(DMH).Activa-tion of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipula-tion of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive pheno-types.Thus,the optogenetic modulation(stimulation or inhibition)of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH,phenocopied depressive behaviors.Moreover,A2AR are upregulated in the LS in two male mouse mod-els of repeated stress-induced depression.This identifica-tion that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant poten-tial of A2AR antagonists,prompting their clinical transla-tion.

Research progress of soluble growth stimulating gene 2 protein in cardiovascular disease / 中国基层医药

Growth stimulating gene 2 (ST2) protein is a member of the interleukin-1 receptor family. It is mainly divided into a soluble secreted form sST2 and a transmembrane form ST2L. sST2 is a decoy receptor that competitively binds to interleukin-33 to block the interleukin-33/ST2L signaling pathway, worsening myocardial hypertrophy, fibrosis, and ventricular dysfunction. Measuring sST2 is of important value for diagnosis and/or prognosis evaluation of cardiovascular diseases. This paper mainly reviews the research progress in the relationship between cardiovascular diseases such as heart failure, coronary heart disease, hypertension, atrial fibrillation, myocarditis, cardiomyopathy, acute aortic dissection, and pulmonary hypertension, and sST2.

Role of serum CX3CR1 in the diagnosis of coronary artery stenosis and in the evaluation of prognosis after percutaneous coronary intervention / 中国基层医药

Objective:To investigate the role of serum CX3CR1 in the diagnosis of coronary artery stenosis and in the evaluation of prognosis after percutaneous coronary intervention.Methods:A total of 101 patients with coronary artery stenosis (≥ 50% stenosis) confirmed with coronary angiography (CAG) in Haiyang People's Hospital from January 2018 to May 2019 who were followed up till May 2021 were included in the observation group. Thirty-four healthy individuals who underwent physical examination during the same period were included in the control group. Patients in the observation group were divided into an in-stent restenosis group (ISR group, n = 28) and a non-ISR group ( n = 73). The expression of CX3CR1 was detected. The incidence of adverse cardiac events was calculated. The sensitivity, specificity, and area under the curve (AUC) plotted for the use of CX3CR1 to diagnose coronary artery stenosis and predict adverse cardiac events were evaluated. Results:The expression of CX3CR1 in the observation group was (3.95 ± 1.05) μg/L, which was significantly higher than (2.30 ± 0.65) μg/L in the control group ( t = 2.87, P < 0.05). The receiver operating characteristic curve analysis showed that the AUC, sensitivity, and specificity of the use of CX3CR1 in diagnosing coronary artery stenosis were 0.892, 75.2%, and 88.2%. The incidence of non-fatal myocardial infarction, angina pectoris, heart failure, and cardiac death in the ISR group was significantly higher compared with the non-ISR group ( χ2 = 8.06, 7.17, 8.06, 7.17, all P < 0.05). The receiver operating characteristic curve analysis results showed that the AUC value of CX3CR1 in predicting non-fatal myocardial infarction, angina pectoris, heart failure, and cardiac death were 0.786, 0.895, 0.997, and 0.887, respectively. Conclusion:CX3CR1 is highly expressed in coronary artery stenosis, which can provide a reference for the diagnosis and prognostic evaluation of coronary artery stenosis.

Value of normalized apparent diffusion coefficient in predicting HER2 expression in bladder cancer / 现代泌尿外科杂志

【Objective】 To predict the expression of human epidermal growth factor receptor 2 (HER2) in urothelial bladder carcinoma based on normalized apparent diffusion coefficient (ADC). 【Methods】 The preoperative pelvic 3.0T magnetic resonance imaging (MRI) images of 127 patients with urothelial bladder carcinoma were retrospectively studied, the ADC was measured, and the HER2 expression in postoperative tissue specimens was determined with immunohistochemistry (IHC). The differences in normalized ADC were analyzed among different HER2 expressions and among different expression divisions. Correlation between normalized ADC and HER2 expression was analyzed. The optimal diagnostic threshold for distinguishing different expression divisions were determined with receiver operating characteristic (ROC) curve. 【Results】 Normalized ADC was negatively correlated with HER2 expression (tau-b=-0.180, P=0.008). Normalized ADC of HER2 overexpression group (IHC 2+, 3+) was lower than that of HER2 negative group (IHC 0, 1+) (P=0.081). Normalized ADC of HER2 expression group (IHC 1+, 2+, 3+) was significantly lower than that of HER2 zero-expression group (IHC 0) (P=0.020). Normalized ADC of HER2 strong positive group (IHC 3+) was significantly lower than that of HER2 non-strong positive group (IHC 0, 1+, 2+) (P=0.024). The optimal diagnostic threshold of HER2 strong positive group was 0.849; the sensitivity, specificity and accuracy were 0.621, 0.909 and 0.765, respectively. The optimal diagnostic threshold of HER2 overexpression group was 0.909; the sensitivity, specificity and accuracy were 0.547, 0.667 and 0.607, respectively. 【Conclusion】 Normalized ADC is negatively correlated with HER2 expression. ADC may be a potential marker for predicting HER2 expression.

The effects and mechanisms of Toll like receptors 4/9 mediating IL-10, IL-35 and TGF-β expressions by CD25+B cells from periodontitis individuals / 西安交通大学学报(医学版)

【Objective】 To analyze the expressions of IL-10, IL-35 and TGF-β in CD25+B cells from periodontitis individuals, and then establish how the activation of TLR4/9 affects the above processes. 【Methods】 SD rats were randomly divided into healthy group, primary periodontitis groups and severe periodontitis group; experimental models were performed by ligation. Expression of IL-10, IL-35 and TGF-β mRNA in CD25+B cells from gingiva and peripheral blood, expression and activation of TLR 2/4/7/9, MyD88, TRAF6 in gingival CD25+B cells were detected. The effect of TLRs/MyD88 on IL-10, IL-35 and TGF-β expressions and production were evaluated by cell culture experiments. 【Results】 CD25+B cells from gingiva of primary periodontitis individuals showed improved expression of IL-10 and TGF-β mRNA compared with the healthy ones (P<0.05); cells from peripheral blood did not present the same tendency. CD25+B cells from gingiva of severe periodontitis individuals showed improved expression of IL-10, IL-35 and TGF-β mRNA compared with the healthy ones (P<0.05), cells from peripheral blood showed higher IL-10 mRNA level than the healthy ones (P<0.05). Compared with healthy individuals, the expression and phosphorylation of TLR4/9 and MyD88 in CD25+B cells from gingiva of severe periodontitis individuals were increased (P<0.01). In cell culture experiments, TLR4 agonist promoted IL-10, IL-35 and TGF-β mRNA expression and IL-10 secretion (P<0.05); TLR9 agonist improved IL-10 and TGF-β mRNA expression and IL-10 secretion (P<0.05). The combined use of TLR4/9 agonist could increase the expression and secretion of all the detected indexes (P<0.05); MyD88 antagonism decrease the above effects (P<0.05). 【Conclusion】 The expressions of IL-10, IL-35 and TGF-β in gingiva CD25+B cells increase during periodontitis, which may be regulated by TLR4 /9-MyD88 pathway.