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.

Association of polymorphisms of the acetyl-coA acetyltransferase 1 gene and the melatonin receptor 1B gene with the susceptibility to nonalcoholic fatty liver disease / 临床肝胆病杂志

ObjectiveTo investigate the association of the polymorphisms of the acetyl-CoA acetyltransferase 1 （ACAT1） gene and the melatonin receptor 1B （MTNR1B） gene with the susceptibility to nonalcoholic fatty liver disease （NAFLD）. MethodsA total of 164 healthy controls and 228 NAFLD patients were enrolled in this study. PCR and sequencing methods were used to determine the genotypes of the polymorphisms of the ACAT1 gene at the rs1044925 and rs1157651 loci and the MTNR1B gene at the rs10830963 locus， and fasting venous blood samples were collected for biochemical analysis. The t-test was used for comparison of normally distributed continuous data between groups， and the non-parametric Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups； the chi-square test was used for comparison of categorical data between groups. ResultsThere were no significant differences between the NAFLD group and the healthy control group in the genotype distribution of the ACAT1 gene at the rs1044925 and rs1157651 loci and the MTNR1B gene at the rs10830963 locus （all P>0.05）. The carriers of AA genotype at the rs1044925 locus of the ACAT1 gene had a significantly higher level of low-density lipoprotein than the carriers of C allele （Z=-2.08， P=0.04）， and the carriers of G allele at the rs10830963 locus of the MTNR1B gene had a significantly higher level of fasting blood glucose than the carriers of CC genotype （Z=-3.01， P<0.01）. ConclusionThe polymorphisms of the ACAT1 gene at the rs1044925 and rs1157651 loci and the MTNR1B gene at the rs10830963 locus were not associated with the susceptibility to NAFLD. The rs1044925 locus of the ACAT1 gene and the rs10830963 locus of the MTNR1B gene are associated with the levels of low-density lipoprotein and fasting blood glucose， respectively.

Efeito Anti-Hipertensivo de Novos Agonistas do Receptor de Adenosina em Ratos Espontaneamente Hipertensos / Antihypertensive Effect of New Agonist of Adenosine Receptor in Spontaneously Hypertensive Rats

Resumo Fundamento A hipertensão arterial sistêmica é um fator de risco para disfunções cardíacas, renais e metabólicas. A busca por novas estratégias para prevenir e tratar doenças cardiovasculares levou à síntese de novas N-acilidrazonas para produzir efeito anti-hipertensivo. Os receptores de adenosina são um alvo alternativo para reduzir a pressão arterial devido à sua ação vasodilatadora e propriedades antioxidantes, que podem reduzir o estresse oxidativo característico da hipertensão arterial sistêmica. Objetivo Avaliar o perfil anti-hipertensivo de novos compostos contendo selênio desenvolvidos para melhorar sua interação com os receptores de adenosina. Métodos Foi avaliada a reatividade vascular, registrando-se a tensão isométrica da aorta torácica pré-contraída de ratos Wistar machos após exposição a concentrações crescentes de cada derivado (0,1 a 100 μM). Para investigar o efeito anti-hipertensivo em ratos espontaneamente hipertensos, foram determinadas a pressão arterial sistólica, pressão arterial diastólica, pressão arterial média e a frequência cardíaca após administração intravenosa de 10 e 30 μmol/kg do composto selecionado LASSBio-2062. Resultados Os compostos denominados LASSBio-2062, LASSBio-2063, LASSBio-2075, LASSBio-2076, LASSBio-2084, LASSBio-430, LASSBio-2092 e LASSBio-2093 promoveram vasodilatação com concentrações efetivas médias de 15,5 ± 6,5; 14,6 ± 2,9; 18,7 ± 9,6; 6,7 ± 4,1; > 100; 6,0 ± 3,6; 37,8 ± 11,8; e 15,9 ± 5,7 μM, respectivamente. O LASSBio-2062 (30 μmol/kg) reduziu a pressão arterial média em ratos espontaneamente hipertensos de 124,6 ± 8,6 para 72,0 ± 12,3 mmHg (p < 0,05). A ativação do receptor de adenosina subtipo A3 e dos canais de potássio parece estar envolvida no efeito anti-hipertensivo do LASSBio-2062. Conclusões O novo agonista do receptor de adenosina e ativador dos canais de potássio é um potencial agente terapêutico para o tratamento da hipertensão arterial sistêmica.

Abstract Background Systemic arterial hypertension is a risk factor for cardiac, renal, and metabolic dysfunction. The search for new strategies to prevent and treat cardiovascular diseases led to the synthesis of new N-acylhydrazones to produce antihypertensive effect. Adenosine receptors are an alternative target to reduce blood pressure because of their vasodilatory action and antioxidant properties, which may reduce oxidative stress characteristic of systemic arterial hypertension. Objective To evaluate the antihypertensive profile of novel selenium-containing compounds designed to improve their interaction with adenosine receptors. Methods Vascular reactivity was evaluated by recording the isometric tension of pre-contracted thoracic aorta of male Wistar rats after exposure to increasing concentrations of each derivative (0.1 to 100 μM). To investigate the antihypertensive effect in spontaneously hypertensive rats, systolic, diastolic, and mean arterial pressure and heart rate were determined after intravenous administration of 10 and 30 μmol/kg of the selected compound LASSBio-2062. Results Compounds named LASSBio-2062, LASSBio-2063, LASSBio-2075, LASSBio-2076, LASSBio-2084, LASSBio-430, LASSBio-2092, and LASSBio-2093 promoted vasodilation with mean effective concentrations of 15.5 ± 6.5; 14.6 ± 2.9; 18.7 ± 9.6; 6.7 ± 4.1; > 100; 6.0 ± 3.6; 37.8 ± 11.8; and 15.9 ± 5.7 μM, respectively. LASSBio-2062 (30 μmol/kg) reduced mean arterial pressure in spontaneously hypertensive rats from 124.6 ± 8.6 to 72.0 ± 12.3 mmHg (p < 0.05). Activation of adenosine receptor subtype A3 and potassium channels seem to be involved in the antihypertensive effect of LASSBio-2062. Conclusions The new agonist of adenosine receptor and activator of potassium channels is a potential therapeutic agent to treat systemic arterial hypertension.

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.

Aparente respuesta rápida a la combinación de zolpidem, memantina y aripiprazol en un caso de catatonía esquizofrénica / Apparent rapid response to the combination of zolpidem, memantine and aripiprazole in a case of schizophrenic catatonia

RESUMEN El tratamiento de la catatonía considera habitualmente el uso de benzodiacepinas y, de fallar estas, se procede a la terapia electroconvulsiva. Sin embargo, las hipotéticas vías neurobiológicas implicadas en la catatonía postulan un efecto benéfico de fármacos gabaérgicos y bloqueadores de glutamato. Se presenta el caso clínico de una paciente mujer de 45 años de edad, con diagnóstico de esquizofrenia paranoide, que desarrolló un cuadro de estupor catatónico (sin respuesta a las benzodiacepinas) y varias complicaciones médicas; sin embargo, el cuadro mejoró rápidamente con la combinación de zolpidem, memantina y aripiprazol. De este modo, se registró un desenlace no logrado con la terapia estándar de benzodiacepinas. Se concluye que la combinación de medicamentos gabaérgicos y bloqueadores de glutamato puede ser utilizada beneficiosamente en casos de estupor catatónico que no logran responder al manejo usual con benzodiacepinas.

ABSTRACT Objective: The treatment of catatonia usually involves the use of benzodiazepines and, if these fail, electroconvulsive therapy is applied. Nevertheless, hypothetical neurobiological pathways involved in catatonia postulate beneficial effects of GABAergic drugs and glutamate blockers. Clinical case: A 45-year-old female patient, diagnosed with paranoid schizophrenia who developed a catatonic stupor (with no response to benzodiazepines) and various medical complications; however, the condition improved rapidly with the combination of zolpidem, memantine and aripiprazole. Result: A favorable outcome was obtained in this case, not achieved with the previous use of standard benzodiazepine therapy. Conclusions: The combination of GABAergic drugs and glutamate blockers can be beneficially implemented in cases of catatonic stupor that fail to respond to the usual management with benzodiazepines.

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.

Research on expression of Toll-like receptors and IFN-α in HCV infected patients with different clinical outcomes / 中国热带医学

@#Abstract: Objective To investigate the changes in expression of Toll-like receptor 3 (TLR3) and interferon-α (IFN-α) in patients with different clinical outcomes of hepatitis C virus (HCV) infection treated with direct-acting antiviral agents (DAAs), and to explore the relationship between the expression of TLR3 and IFN-α with the clinical outcomes of HCV infection. Methods A total of 149 HCV infected patients who received initial treatment were selected from Hainan General Hospital between September 2020 and August 2022. The patients were divided into two groups: chronic hepatitis C (CHC) group (n=129) and liver cirrhosis (LC) group (n=20). Additionally, 28 volunteers were selected as the control group during the same period. All patients with HCV infection were first treated with Sofosbuvir/Vipatavir tablets for 12 weeks. Blood samples were collected at 0, 4, 12, 24 and 48 weeks after treatment. Liver function indicators were detected by enzyme-linked immunosorbent assay (ELISA), while TLR3 mRNA were detected by real-time fluorescence quantitative polymerase chain reaction (qRCR), IFN-α was detected by Luminex multiplex cytokine assays. Measurement data subject to normal distribution were represented by x±s, and t test was used between groups. Compare differences between groups. Results TLR3 mRNA in CHC group was higher than that in LC group and control group at baseline (P<0.05). After 4 weeks of DAAs treatment, TLR3 mRNA in CHC and LC groups was significantly up-regulated (P<0.05). TLR3 mRNA in the CHC group was gradually down-regulated to the level of the control group at 12, 24, and 48 weeks. In addition, IFN-α expression gradually increased with prolonged treatment, while it decreased in the LC group. The liver inflammation indicators in both the CHC and LC groups partially recovered after treatment with DAAs. Conclusions TLR3 is involved in viral clearance and chronic inflammatory response. The expression difference of TLR3 in patients with different clinical outcomes of HCV infection after DAAs treatment may be related to the severity of the disease.

S1P/S1P Receptor Pathway: A New Target for Treatment of Inflammatory Bowel Disease / 胃肠病学

The development of targeted oral drugs that can stably treat inflammatory bowel disease (IBD) is still a clinical problem to be solved. In recent years, studies have confirmed that sphingosine⁃1⁃phosphate (S1P)/S1P receptor pathway can regulate lymphocyte homing and immune regulation, inhibit intestinal inflammation, protect intestinal endothelial barrier, and affect intestinal microbial metabolism, which may play a key role in the treatment of IBD. This article reviewed the effect of S1P/S1P receptor pathway on IBD and its potential mechanism.

Nerve repair effect of olanzapine-mediated cyclic AMP response element binding protein/brain-derived neurotrophic factor/receptor tyrosine kinase receptors B pathway on schizophrenic rats / 解剖学报

Objective To stud)' the nerve repair effect of olanzapine on schizophrenia model rats through its effect on cyclic AMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/receptor tyrosine kinase receptors B (TrkB) pathway. Methods Total 60 rats were divided into control group, model group, olanzapine low, middle and high dose group. The rats in the model group, olanzapine low, middle and high dose groups were injected intraperitoneally with MK-801[0. 2 mg/(kg-d) ], while the control injected with the same amount of normal saline. The low, middle and high dose olanzapine groups were perfused with olanzapine solution of 0. 5 mg/(kg-d),1. 0 mg/(kg-d) and 1. 5 mg/(kg-d) respectively. The behavior of rats was scored according to ataxia and stereotyped behavior standards, cognitive function and learning ability were evaluated by Moms water maze test, serum tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) levels were detected by ELISA method, hippocampal histopathology was observed under microscope, and apoptosis and expression of CREB/BDNF/TrkB pathway related proteins in hippocampus were detected. Results Compared with the control group, the ataxia, the score of stereotyped behavior, the expression of TNF-a, IL-6 and the rate of apoptosis in the model group increased significantly (P < 0 . 01). Compared with the control group, the number of crossing the platform, the time of staying in the target quadrant and the relative expression of CREB, p-CREB, p-TrkB, TrkB and BDNF protein in the model group decreased significantly (P<0. 01), and those in the low and middle dose olanzapine groups decreased significantly (P < 0 . 05). Compared with the model group, the times of crossing the platform and the stay time in the target quadrant increased significantly in the low and middle dose olanzapine groups (P< 0. 05). In the model group and the low dose olanzapine group, the hippocampal cells were swollen obviously, the nucleus was broken and divided, pyknosis, and the tissue aiTangement was disorderly, while the phenomenon of fragmentation and nuclear pyknosis was rarely seen in the middle and high dose olanzapine groups. Conclusion The nerve repair mechanism of olanzapine on schizophrenic model rats is related to improving cognitive impainnent, protecting hippocampal neurons and activating the expression of CREB/BDNF/TrkB signal pathway in rats.

Effect of NMDA receptor blocker in relieving HIV-1/gp120 induced learning and memory disorder in rats and its mechanism / 中国药理学通报

Aim: To investigate the alleviating effect of NMDA receptor blocking on learning and memory impairment induced by gp120 in rats and its mechanism. Methods: (1 ) Thirty-two SD rats were randomly divided into control group, sham operation group, gpl20 group, and gp120 + Memantine group. Except for the control group, the other groups underwent a bilateral hippocampal injection to establish the model of learning and memory impairment in rats. Memantine (10 mg • kg

Research progress on potential therapeutic targets of chronic cough / 中国药理学通报

Chronic cough is caused by low levels of heat, mechanical or chemical exposure, which is characterized by the disorders of channels and receptors in neuroregulation such as the peripheral and central nerves. Potential regulatory targets of peripheral nerves include P2X3 receptors and transient receptor potential channels, while potential regulatory targets of central nerves include voltage-gated sodium channels, neurokinin-1 receptors, α-7acetylcholine receptors and gamma aminobutyric acid receptors. This paper focuses on the principle and clinical research evidence of several ongoing targeted therapy strategies, in order to provide new ideas for the development of drugs for the treatment of chronic cough.

Protective effects of ginseng total saponins on reward-directed operant conditioning in hindlimb suspension rats / 数字中医药（英文）

Objective@#To explore the therapeutic effects of ginseng total saponins (GTSs) on cognitive impairments in astronauts caused by prolonged exposure to microgravity environment.@*Methods@#Fifty specific pathogen-free (SPF) male Wistar rats were randomized into control, hindlimb suspension (HLS), Huperzine A (HLS-Hup A 0.1 mg/kg), low-dose GTSs (HLS-GTSs 100 mg/kg), and high-dose GTSs (HLS-GTSs 200 mg/kg) groups, based on the completion time of reward-directed conditioning tasks. Except for rats in the control group, the others were subjected to HLS and treated with drugs (day 20 – 58), received reflex test under the condition of rewarding, and underwent Nissl body staining and Western blot detection on hippocampal.@*Results@#After modeling, rats in HLS group exhibited a reduction in the number of lever presses and an increase in the completion time of the reward-directed operant conditioning task Ⅰ (P < 0.05) when compared with the control group, which were not substantially altered in the HLS-GTSs 100 and 200 mg/kg groups (P > 0.05). In the reward-directed operant conditioning task Ⅱ, the HLS group rats demonstrated a marked decrease in the number of lever presses (P < 0.05) and nose pokes (P < 0.01) when compared with the control group rats; the HLS-GTSs 100 mg/kg showed a significant increase in the number of lever presses and nose pokes (P < 0.05), while the HLS-GTSs 200 mg/kg demonstrated a significant reduction in completion time and an elevation in the number of lever presses (P < 0.05) when compared with the HLS group rats. In visual signal discrimination task, compared with the control group rats, the HLS group rats showed decrease in the indexes of the visual signal discrimination(P < 0.01), while HLS-GTSs 100 and 200 mg/kg groups exhibited manifest increase in it (P < 0.01). In reward extinction experiment, the number of lever presses in HLS rats significantly increased when compared with the control group (P < 0.01); compared with the HLS group, HLS-GTSs 100 and 200 mg/kg groups demonstrated a marked descrease (P < 0.05). The expressions of N-methyl-D-aspartic acid receptor 1 (NR1) and phosophorylated N-methyl-Daspartic acid receptor 2B (p-NR2B) proteins were markedly decreased in rats in the HLS group (P < 0.05 and P < 0.01, respectively), while that of NR2B protein maintained the same (P > 0.05). GTSs increased the expression levels of p-NR2B (P < 0.01).@*Conclusion@#GTSs improved the learning and memory ability of complex operations by regulating the NR1/NR2B phosphorylation pathways in rats.

Microbial sensing in the intestine

The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune-microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system. In this review, we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes. We further highlight the essential roles of pattern recognition receptors (PRRs), the G protein-coupled receptors (GPCRs), aryl hydrocarbon receptor (AHR) and the nuclear receptors expressed in the intestinal epithelial cells (IECs) and the intestine-resident immune cells. We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease (IBD).

Blockade of the Dopamine D3 Receptor Attenuates Opioids-Induced Addictive Behaviours Associated with Inhibiting the Mesolimbic Dopamine System / 神经科学通报·英文版

Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.