Effects of Interleukin-19 overexpression in the medial prefrontal cortex on anxiety-related behaviors, BDNF expression and p38/JNK/ERK pathways.

Anxiety is a prevalent mental illness known for its high incidence, comorbidity, and tendency to recur, posing significant societal and individual burdens. Studies have highlighted Interleukin-19 (IL-19) as having potential relevance in neuropsychiatric disorders. Our previous research revealed that IL-19 overexpression in colonies exacerbated anxiety-related behaviors induced by dextran sodium sulfate/stress. However, the precise role and molecular mechanisms of IL-19 in anxiety regulation remain uncertain. In this study, we initiated an acute restraint stress (ARS)-induced anxious mouse model and identified heightened expression of IL-19 and IL-20Rα in the medial prefrontal cortex (mPFC) of ARS mice. Notably, IL-19 and IL-20Rα were predominantly present in the excitatory pyramidal neurons of the mPFC under both basal and ARS conditions. Utilizing the adeno-associated virus (AAV) strategy, we demonstrated that IL-19 overexpression in the mPFC induced anxiety-related behaviors and elevated stress susceptibility. Additionally, we observed decreased protein levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the mPFC of IL-19 overexpression mice, accompanied by reduced phosphorylation of in the p38, JNK, and Erk signaling pathways. These findings emphasize the role of IL-19 in modulating anxiety-related behaviors within the mPFC and suggest its potential as a pathological gene and therapeutic target for anxiety.

Traditional herbal pair Portulacae Herba and Granati Pericarpium alleviates DSS-induced colitis in mice through IL-6/STAT3/SOCS3 pathway.

BACKGROUND: Portulacae Herba and Granati Pericarpium pair (PGP) is a traditional Chinese herbal medicine treatment for colitis, clinically demonstrating a relatively favorable effect on relieving diarrhea and abnormal stools. However, the underlying mechanism remain uncertain. PURPOSE: The present study intends to evaluate the efficacy of PGP in treating colitis in mice and investigate its underlying mechanism. METHODS: The protective effect of PGP against colitis was determined by monitoring body weight, colon length, colon weight, and survival rate in mice. Colonic inflammation was assessed by serum cytokine levels, colonic H&E staining, and local neutrophil infiltration. The reversal of intestinal epithelial barrier damage by PGP was subsequently analyzed with Western blot and histological staining. Furthermore, RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by PGP. Following the hints of the transcriptomic results, the role of PGP through the IL-6/STAT3/SOCS3 pathway in DSS-induced colitis mice was verified by Western blot. RESULTS: DSS-induced colitis in mice was significantly curbed by PGP treatment. PGP treatment significantly mitigated DSS-induced colitis in mice, as evidenced by improvements in body weight, DAI severity, survival rate, and inflammatory cytokines levels in serum and colon. Moreover, PGP treatment up-regulated the level of Slc26a3, thereby increasing the expressions of the tight junction/adherens junction proteins ZO-1, occludin and E-cadherin in the colon. RNA-seq analysis revealed that PGP inhibits the IL-6/STAT3/SOCS3 pathway at the transcriptional level. Molecular docking indicated that the major components of PGP could bind tightly to the proteins of IL-6 and SOCS3. Meanwhile, the result of Western blot revealed that the IL-6/STAT3/SOCS3 pathway was inhibited at the protein level after PGP administration. CONCLUSION: PGP could alleviate colonic inflammation and reverse damage to the intestinal epithelial barrier in DSS-induced colitis mice. The underlying mechanism involves the inhibition of the IL-6/STAT3/SOCS3 pathway.

Echinacoside: A promising active natural products and pharmacological agents.

Echinacoside, a natural phenylethanoid glycoside, was discovered and isolated from the garden plant Echinacea angustifolia DC., belonging to the Compositae family, approximately sixty years ago. Extensive investigations have revealed that it possesses a wide array of pharmacologically beneficial activities for human health, particularly notable for its neuroprotective and anticancer activity. Several crucial concerns surfaced, encompassing the recognition of active metabolites that exhibited inadequate bioavailability in their prototype form, the establishment of precise molecular signal pathways or targets associated with the aforementioned effects of echinacoside, and the scarcity of dependable clinical trials. Hence, the question remains unanswered as to whether scientific research can effectively utilize this natural compound. To support future studies on this natural product, it is imperative to provide a systematic overview and insights into potential future prospects. The current review provides a comprehensive analysis of the existing knowledge on echinacoside, encompassing its wide distribution, structural diversity and metabolism, diverse therapeutic applications, and improvement of echinacoside bioavailability for its potential utilization.

Case report: A rare case of sintilimab-induced gastric stenosis and literature review.

Sintilimab is a fully human IgG4 monoclonal antibody against programmed death-1 (PD-1) used to treat classical Hodgkin's lymphoma and various solid tumors. With increasing use of sintilimab, some rare adverse reactions have been reported. Here, we report a case of a 50-year-old woman with squamous non-small cell lung cancer (NSCLC) (metastasis to pericardium and pleura) who received two cycles of 200 mg sintilimab immunotherapy combined with albumin-bound paclitaxel and carboplatin chemotherapy and one cycle of sintilimab monotherapy. She was diagnosed with Sjogren's syndrome (with symptoms of fever, dry mouth, dysphagia, and eating difficulty) after three cycles' treatment and received standard steroidal therapy. Prior to admission, the patient experienced severe stomach discomfort with vomiting and was hospitalized. Upper gastrointestinal iodine angiography showed significant gastric stenosis as well as lower esophageal stenosis. Subsequent ultrafine gastroscopy revealed ulceration at the stenotic site and an absence of normal peristalsis of the gastric wall. Pathological examination of the lesions showed reactive changes, including ulceration, fibrosis, and inflammatory cell infiltration. After multidisciplinary consultation, it was considered that the patient's gastric stenosis with inflammatory fibrosis changes was due to a sintilimab-induced immune hyperinflammatory reaction. The patient had been treated with standard steroidal therapy since suffering from Sjogren's syndrome, but the gastric stenotic changes were not relieved. The patient then received regular bouginage of esophago-cardiac stenosis under gastroscopy to physically reexpand the fibrous hyperplasia and stenotic site, enabling normal eating function. To our knowledge, this is the first case of gastric stenosis in a patient with squamous NSCLC after using sintilimab and may help clinicians better understand potential immune-related adverse events due to sintilimab and improve assessment and management.

A systematic study on body control in golf players / Estudo sistemático sobre o controle corporal em jogadores de golfe / Estudio sistemático sobre el control corporal en jugadores de golf

ABSTRACT Introduction: Golf is a high-precision sport that requires excellent manual skills and motor coordination. These requirements are essential to determine a player's swing level and, consequently, their sports performance. Objective: Investigate the impact of athletes' body control on golf performance. Methods: To study the three-dimensional motion of golf players in China, the relevant theories and techniques of sports biomechanics were used on 12 golfing volunteers. Real-time sampling correction and analysis were performed using APAS dynamic analysis technology. This paper uses the DLT method to analyze the spatial location of each point three-dimensionally. SPSS15.0 software was used for statistical processing and screening of the results of the tests. Statistics are presented as mean and standard values. Results: The correlation between the golfers' center of gravity in hitting and the rate of motion in the swing was evidenced. The velocity obtained by the racket when hitting the ball is related to the golfer's hip inversion angle. Conclusion: A lower body center of gravity is beneficial to improve golf swing efficiency. Keeping the body in balance is the key to mastering the stroke and acceleration of the racquet. When the athlete performs the reverse pull, the energy they receive also increases, highlighting the need for specific training to promote the athlete's body balance. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O golfe é um esporte de alta precisão que requer excelentes habilidades manuais e coordenação motora. Estes requisitos são essenciais para determinar o nível de balanço de um jogador e, consequentemente, o seu desempenho esportivo. Objetivo: Investigar o impacto do controle corporal dos atletas no desempenho do golfe. Métodos: Para estudar o movimento tridimensional dos jogadores de golfe na China, foram utilizadas as teorias e técnicas relevantes da biomecânica do esporte sobre 12 voluntários praticantes de golfe. A correção e a análise em tempo real da amostragem foram realizadas utilizando a tecnologia de análise dinâmica da APAS. Este artigo usa o método DLT para analisar a localização espacial de cada ponto tridimensionalmente. O programa SPSS15.0 foi usado para processamento estatístico e triagem dos resultados nos testes. As estatísticas são apresentadas como valores médios e padrão. Resultados: A correlação entre o centro de gravidade dos golfistas no acerto e na taxa de movimento no balanço foi evidenciada. A velocidade obtida pela raquete no momento da tacada da bola está relacionada ao ângulo de inversão do quadril do golfista. Conclusão: Um centro de gravidade inferior do corpo é benéfico para melhorar a eficiência da tacada de golfe. Manter o corpo em equilíbrio é a chave para dominar a batida e a aceleração da raquete. Quando o atleta realiza a tração reversa, a energia que ele recebe também aumenta, evidenciando a necessidade de um treinamento específico para promover o equilíbrio corporal do esportista. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El golf es un deporte de alta precisión que requiere excelentes habilidades manuales y coordinación motora. Estos requisitos son esenciales para determinar el nivel de balanceo de un jugador y, en consecuencia, su rendimiento deportivo. Objetivo: Investigar el impacto del control corporal de los atletas en el rendimiento del golf. Métodos: Para estudiar el movimiento tridimensional de los jugadores de golf en China, se utilizaron las teorías y técnicas pertinentes de la biomecánica deportiva en 12 voluntarios golfistas. La corrección y el análisis del muestreo en tiempo real se realizaron mediante la tecnología de análisis dinámico APAS. Este trabajo utiliza el método DLT para analizar la ubicación espacial de cada punto en tres dimensiones. Se utilizó el programa informático SPSS15.0 para el tratamiento estadístico y el cribado de los resultados en las pruebas. Las estadísticas se presentan como media y valores estándar. Resultados: Se evidenció la correlación entre el centro de gravedad de los golfistas en el golpeo y la velocidad de movimiento en el balanceo. La velocidad obtenida por la raqueta en el momento de golpear la pelota está relacionada con el ángulo de inversión de la cadera del golfista. Conclusión: Un centro de gravedad corporal más bajo es beneficioso para mejorar la eficiencia del balanceo de golf. Mantener el cuerpo en equilibrio es clave para dominar el golpe y la aceleración de la raqueta. Cuando el atleta realiza el tirón inverso, la energía que recibe también aumenta, lo que pone de manifiesto la necesidad de un entrenamiento específico para favorecer el equilibrio corporal del atleta. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Cetuximab and Dabrafenib Plus Trametinib for Untreated Colonic Metastasis of BRAFV600E Mutant Primary Lung Adenocarcinoma with Signet Ring Cell Features: An Interesting and Rare Case Report.

Colonic metastases of lung adenocarcinoma are extremely rare. Signet ring cell adenocarcinoma (SRCA) has not been described in patients with gastrointestinal metastasis of lung adenocarcinoma. SRCA is a unique subtype of adenocarcinoma with strong invasion and a poor prognosis, and most SRCA found in the lung are due to gastrointestinal metastases. This report describes a rare case of colonic metastasis from primary lung SRCA. A 64-year-old female was admitted to Sun Yat-sen University Cancer Center for feeling of nausea and malaise. Following a positron emission tomography CT (PET-CT) scan, widespread metastases of tumor cells were found in the bilateral lung, liver, bone, and multiple lymph nodes, but there was no evidence of metastasis to the colon. Two months later, the patient received a liver biopsy at Tongji Hospital in Wuhan. Pathology revealed a poorly differentiated adenocarcinoma with SRCA conformation, but immunohistochemical staining did not identify the original source of tumor cells. Considering that SRCA mainly derives from the gastrointestinal tract and that serum gastrointestinal tumor markers were elevated, we performed gastrointestinal endoscopy on the patient. The results showed an isolated polyp in the colon, and the pathology results indicated a poorly differentiated adenocarcinoma that was considered to originate from the lung based on immunohistochemical staining. Meanwhile, genetic tests identified a BRAF V600E mutation. The final diagnosis was colonic metastasis of BRAFV 600E mutated lung SRCA. Considering the positive expression of EGFR in this case, cetuximab was innovatively added to the first-line treatment regime (dabrafenib and trametinib). To date, the patient has received thirty-two weeks of treatment. Interestingly, lung and liver tumors shrank and tumor markers in the blood normalized. Our findings offer valuable diagnostic and therapeutic information for colonic metastasis of BRAFV600E mutant primary lung adenocarcinoma with signet ring cell features.

Comparison between outcomes of IgA nephropathy with nephrotic-range proteinuria and nephrotic syndrome: do podocytes play a role?

BACKGROUND: Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. METHODS: We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. RESULTS: Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan-Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835-76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078-0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047-0.689; p = 0.012) was further reduced. CONCLUSIONS: NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi.

Anti-pseudo-allergic components in licorice extract inhibit mast cell degranulation and calcium influx.

Pseudo-allergic reactions (PARs) widely occur upon application of drugs or functional foods. Anti-pseudo-allergic ingredients from natural products have attracted much attention. This study aimed to investigate anti-pseudo-allergic compounds in licorice. The anti-pseudo-allergic effect of licorice extract was evaluated in rat basophilic leukemia 2H3 (RBL-2H3) cells. Anti-pseudo-allergic compounds were screened by using RBL-2H3 cell extraction and the effects of target components were verified further in RBL-2H3 cells, mouse peritoneal mast cells (MPMCs) and mice. Molecular docking and human MRGPRX2-expressing HEK293T cells (MRGPRX2-HEK293T cells) extraction were performed to determine the potential ligands of MAS-related G protein-coupled receptor-X2 (MRGPRX2), a pivotal target for PARs. Glycyrrhizic acid (GA) and licorice chalcone A (LA) were screened and shown to inhibit Compound48/80-induced degranulation and calcium influx in RBL-2H3 cells. GA and LA also inhibited degranulation in MPMCs and increase of histamine and TNF-α in mice. LA could bind to MRGPRX2, as determined by molecular docking and MRGPRX2-HEK293T cell extraction. Our study provides a strong rationale for using GA and LA as novel treatment options for PARs. LA is a potential ligand of MRGPRX2.

Celastrol: An Update on Its Hepatoprotective Properties and the Linked Molecular Mechanisms.

The liver plays an important role in glucose and lipid homeostasis, drug metabolism, and bile synthesis. Metabolic disorder and inflammation synergistically contribute to the pathogenesis of numerous liver diseases, such as metabolic-associated fatty liver disease (MAFLD), liver injury, and liver cancer. Celastrol, a triterpene derived from Tripterygium wilfordii Hook.f., has been extensively studied in metabolic and inflammatory diseases during the last several decades. Here we comprehensively review the pharmacological activities and the underlying mechanisms of celastrol in the prevention and treatment of liver diseases including MAFLD, liver injury, and liver cancer. In addition, we also discuss the importance of novel methodologies and perspectives for the drug development of celastrol. Although celastrol has been claimed as a promising agent against several metabolic diseases, both preclinical and clinical studies are highly required to accelerate the clinical transformation of celastrol in treating different liver illness. It is foreseeable that celastrol-derived therapeutics is evolving in the field of liver ailments.

Effect of PPM1F in dorsal raphe 5-HT neurons in regulating methamphetamine-induced conditioned place preference performance in mice.

Methamphetamine (METH), a synthetically produced central nervous system stimulant, is one of the most illicit and addictive drugs worldwide. Protein phosphatase Mg2 + /Mn2 + -dependent 1F F (PPM1F) has been reported to exert multiple biological and cellular functions. Nevertheless, the effects of PPM1F and its neuronal substrates on METH addiction remain unclear. Herein, we first established a METH-induced conditioned place preference (CPP) mouse model. We showed that PPM1F is widely distributed in 5-HT neurons of the dorsal raphe nucleus (DRN), and METH treatment decreased the expression of PPM1F in DRN, which was negatively correlated with METH-induced CPP behaviors. Knockout of PPM1F mediated by adeno-associated virus (AAV) in DRN produced enhanced susceptibility to METH-induced CPP, whereas the overexpression of PPM1F in DRN attenuated METH-induced CPP phenotypes. The expression levels of Tryptophan hydroxylase2 (TPH2) and serotonin transporter (SERT) were down-regulated with a concurrent reduction in 5-hydroxytryptamine (5-HT), tryptophan hydroxylase2 (TPH2)-immunoreactivity neurons and 5-HT levels in DRN of PPM1F knockout mice. In the end, decreased expression levels of PPM1F were found in the blood of METH abusers and METH-taking mice. These results suggest that PPM1F in DRN 5-HT neurons regulates METH-induced CPP behaviors by modulating the key components of the 5-HT neurotransmitter system, which might be an important pathological gene and diagnostic marker for METH-induced addiction.

Identification of Key lncRNA-mRNA Pairs and Functional lncRNAs in Breast Cancer by Integrative Analysis of TCGA Data.

Long non-coding RNAs (lncRNAs) play an important role in many diseases and are involved in the post-transcriptional regulatory network of tumors. The purpose of this study is to mine new lncRNA-mRNA regulatory pairs and analyze the new mechanism of lncRNA involvement in breast cancer progression. Using breast cancer miRNA and mRNA expression profiling from The Cancer Genome Atlas (TCGA), we identified 59 differentially expressed lncRNAs, 88 differentially expressed miRNAs, and 1,465 differentially expressed mRNAs between breast cancer tissue and adjacent normal breast cancer. Whereafter, four candidate lncRNAs (FGF14-AS2, LINC01235, AC055854.1, and AC124798.1) were identified by the Kaplan-Meier (K-M) plotter. Furthermore, we screened the hub lncRNA (LINC01235) through univariate Cox analysis, multivariate Cox analysis, and qPCR validation, which was significantly correlated with breast cancer stage, ER status, and pathological N. Subsequently, 107 LINC01235-related mRNAs were obtained by combining differentially expressed miRNAs, differentially expressed mRNAs, and LINC01235 targeting miRNAs and mRNAs. The protein-protein interaction (PPI) network was established by Cytoscape software, and 53 key genes were screened. Function and pathway enrichment showed that LINC01235-related key genes might be involved in the process of cell differentiation, cell proliferation, and p53 signal pathway. In addition, LINC01235 has been confirmed to regulate the proliferation, migration, and invasion of MCF-7 cells in in vitro experiments. Furthermore, we screened three mRNAs (ESR1, ADRA2A, and DTL) associated with breast cancer drug resistance from key genes. Through RNA interference experiments in vitro and correlation analysis, we found that there was a negative feedback mechanism between LINC01235 and ESR1/ADRA2A. In conclusion, our results suggest that LINC01235-ESR1 and LINC01235-ADRA2A could serve as important co-expression pairs in the progression of breast cancer, and LINC01235 plays a key role as an independent prognostic factor in patients with breast cancer. The findings of this work greatly increase our understanding of the molecular regulatory mechanisms of lncRNA in breast cancer.

PPM1F in Dentate Gyrus Modulates Anxiety-Related Behaviors by Regulating BDNF Expression via AKT/JNK/p-H3S10 Pathway.

Anxiety is a serious psychiatric disorder, with a higher incidence rate in women than in men. Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on anxiety remain largely unclear. In this study, we showed that chronic restraint stress (CRS) induced anxiety-related behaviors only in female mice, while acute restraint stress (ARS) produced anxiety-related behaviors in both male and female mice in light-dark and elevated plus maze tests and induced upregulation of PPM1F and downregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Adeno-associated virus-mediated overexpression of PPM1F or conditional knockout of BDNF in dentate gyrus (DG) led to a more pronounced anxiety-related behavior in female than in male mice as indicated by the behavioral evaluations. Meanwhile, overexpression of PPM1F in the DG decreased total Bdnf exon-specific messenger RNA expression in the hippocampus with the decreased binding activity of phosphorylated H3S10 to its individual promoters in female mice. Furthermore, we identified that overexpression of PPM1F decreased the phosphorylation levels of AKT and JNK in the hippocampus of female mice. These results may suggest that PPM1F regulates anxiety-related behaviors by modulating BDNF expression and H3S10 phosphorylation-mediated epigenetic modification, which may be served as potentially pathological genes associated with anxiety or other mental diseases.

PPM1F in hippocampal dentate gyrus regulates the depression-related behaviors by modulating neuronal excitability.

Major depressive disorder (MDD) is a common, serious, debilitating mental illness. Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F), a serine/threonine phosphatase, has been reported to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on depressive behaviors remain largely unknown. Here, we showed that PPM1F is widely distributed in the hippocampus, and chronic unpredictable stress (CUS) can induce increased expression of PPM1F in the hippocampus, which was correlated with depression-associated behaviors. Overexpression of PPM1F mediated by adeno-associated virus (AAV) in the dentate gyrus (DG) produced depression-related behaviors and enhanced susceptibility to subthreshold CUS (SCUS) in both male and female mice, while, knockout of PPM1F in DG produced antidepressant phonotypes under stress conditions. Whole-cell patch-clamp recordings demonstrated that overexpression of PPM1F increased the neuronal excitability of the granule cells in the DG. Consistent with neuronal hyperexcitability, overexpression of PPM1F regulated the expression of certain ion channel genes and induced decreased phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CAMKII) and Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in hippocampus. These results suggest that PPM1F in the DG regulates depression-related behaviors by modulating neuronal excitability, which might be an important pathological gene for depression or other mental diseases.

The Association Between Obesity and Risk of Acute Kidney Injury After Cardiac Surgery.

Objective: To determine the relationship between obesity and the risk of AKI after cardiac surgery (CS-AKI) in a cohort study. Methods: A total of 1,601 patients undergoing cardiac surgery were collected and their incidence of CS-AKI was recorded. They were divided into underweight, normal weight, overweight, and obese groups. Logistic regression was used to estimate the association between BMI (body mass index) and CS-AKI risk. Then, a meta-analysis of published cohort studies was conducted to confirm this result using PubMed and Embase databases. Results: A significant association was observed in this independent cohort after adjusting age, gender, hypertension and New York Heart Association classification (NYHA) class. Compared with normal BMI group (18.5 ≤ BMI < 24.0), the individuals with aberrant BMI level had an increased AKI risk (OR: 1.68, 95% CI: 1.01-2.78) for BMI < 18.5 group and (OR: 1.43, 95% CI: 0.96-2.15) for BMI ≥ 28.0. Interestingly, the U-shape curve showed the CS-AKI risk reduced with the increasing of BMI when BMI ≤ 24.0. As BMI increases with BMI > 24.0, the risk of developing CS-AKI increased significantly. In the confirmed meta-analysis, compared with normal weight, overweight group with cardiac surgery had higher AKI risk (OR: 1.28, 95% CI: 1.16-1.41, Pheterogeneity = 0.49). The similar association was found in obesity subgroup (OR: 1.79, 95% CI: 1.57-2.03, Pheterogeneity = 0.42). Conclusion: In conclusion, the results suggested that abnormal BMI was a risk factor for CS-AKI independently.

Bufalin attenuates triple-negative breast cancer cell stemness by inhibiting the expression of SOX2/OCT4.

Triple-negative breast cancer (TNBC) has the poorest prognosis among all types of breast cancer and there is yet no effective therapy. Chemotherapy is the traditional standard of care for patients with TNBC; however, treatment of TNBC with chemotherapy may lead to the enrichment of cancer stem cells (CSCs), which exhibitan enhanced capacity for self-renewal, tumor initiation and metastasis. The present study demonstrated that bufalin, a small molecular compound used in traditional Chinese medicine, exerted anticancer effects on a wide range of cancer cell lines, inhibited cell proliferation through inducing G2/M cell cycle arrest, and triggered apoptosis in the TNBC cell lines MDA-MB-231 and HCC-1937. Consistently, bufalin markedly suppressed TNBC growth in a cell line-derived xenograft model. More importantly, unlike common chemotherapeutic drugs, bufalin reduced the stemness of TNBC stem cells. A mechanistic study suggested that bufalin may suppress the proliferation of TNBC stem cells by inhibiting the expression of octamer-binding transcription factor 4 (OCT4) and sex determining region Y-box 2 (SOX2) in MDA-MB-231 and HCC-1937 cells. These results indicated that bufalin may hold promise as a therapeutic agent in TNBC, and its effects may be mediated through the SOX2/OCT4 axis.

MEX3A promotes triple negative breast cancer proliferation and migration via the PI3K/AKT signaling pathway.

Triple-negative breast cancer (TNBC) has the characteristics of fast growth, easy invasion, metastasis, poor prognosis, low tumor-free survival rate and overall survival rate. In this study, the RNA-binding protein MEX3A was selected by using the methods of TCGA database analysis, mRNA microarrays, and tissue chip immunohistochemistry experiments. The high expression of MEX3A is associated with malignancy and poor prognosis of TNBC. In addition, MEX3A knockdown can inhibit the growth and migration of TNBC cells while MEX3A overexpression shows the opposite effect. In vivo experiments, we also demonstrated that downregulating MEX3A can inhibit the tumorigenicity of TNBC cells. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MEX3A, and verified the relationship between PI3K/AKT signaling pathway and MEX3A. Additionally, we have simultaneously up-regulated MEX3A and treated with pathway inhibitors in vitro experiments and found that it can slow down the growth of TNBC cells. In short, we identified MEX3A as a tumor promoter, potential prognostic indicator and therapeutic target for TNBC, may function through the regulation of the PI3K/AKT signaling pathway.

Pro-inflammatory cytokines in the paraventricular nucleus mediate the adipose afferent reflex in rats.

Our previous study showed that the adipose afferent reflex (AAR) induced by chemical stimulation of white adipose tissue (WAT) increased sympathetic outflow and blood pressure. We also found that pro-inflammatory cytokines (PICs) in the hypothalamic paraventricular nucleus (PVN) potentiate the cardiac sympathetic afferent reflex in rats. However, the role of PICs in the PVN in regulating the AAR is still not clear. This study determined whether PICs in the PVN mediate the AAR in rats. The AAR was evaluated based on renal sympathetic nerve activity and mean arterial blood pressure in response to capsaicin injection into inguinal WAT (iWAT). PIC levels were measured by ELISA. PVN microinjection with the PICs tumor necrosis factor (TNF)-α or interleukin (IL)-1ß enhanced the AAR in a dose-dependent manner. Furthermore, pretreatment via the bilateral microinjection of the TNF-α-blocker etanercept or IL-1ß blocker IL-1ra into the PVN attenuated the AAR. In rats pretreated with TNF-α or IL-1ß, a sub-response dose of angiotensin II (Ang II) significantly enhanced the AAR. Moreover, delivery of the angiotensin II type 1(AT1) receptor antagonist losartan into the PVN attenuated the effects of TNF-α or IL-1ß on the AAR. In addition, stimulating either iWAT or retroperitoneal WAT with capsaicin increased TNF-α or IL-1ß levels in the PVN, but the injection of capsaicin into the jugular vein, skeletal muscle, and skin had no effects on TNF-α or IL-1ß levels in the PVN. These results suggest that TNF-α or IL-1ß and Ang II in the PVN synergistically enhance the AAR in rats.

Inhibitory effects of berberine on proinflammatory M1 macrophage polarization through interfering with the interaction between TLR4 and MyD88.

BACKGROUNDS: Inflammation is recognized as the key pathological mechanism of type 2 diabetes. The hypoglyceamic effects of berberine (BBR) are related to the inhibition of the inflammatory response, but the mechanism is not completely clear. METHODS: The inflammatory polarization of Raw264.7 cells and primary peritoneal macrophages were induced by LPS, and then effects and underlying mechanisms of BBR were explored. An inflammatory model was established by LPS treatment at different concentrations for different treatment time. An ELISA assay was used to detect the secretions of TNF-α. RT-PCR was applied to detect M1 inflammatory factors. The F4/80+ ratio and CD11c+ ratio of primary peritoneal macrophages were determined by flow cytometry. The expressions of p-AMPK and TLR4 were detected by Western blot. The cytoplasmic and nuclear distributions of NFκB p65 were observed by confocal microscopy. The binding of TLR4 to MyD88 was tested by CoIP, and the affinity of BBR for TLR4 was assessed by molecular docking. RESULTS: Upon exposure to LPS, the secretion of TNF-α and transcription of inflammatory factors in macrophages increased, cell morphology changed and protrusions appeared gradually, the proportion of F4/80+CD11c+ M1 macrophages increased, and the nuclear distribution of NFκB p65 increased. BBR pretreatment partially inhibited the changes mentioned above. However, the expression of TLR4 and p-AMPK did not change significantly after LPS intervention for 3 h. Meanwhile, CoIP showed that the interaction between TLR4 and MyD88 increased, and BBR inhibited the binding. Molecular docking suggested that BBR might interact with TLR4. CONCLUSIONS: Inflammatory changes were induced in macrophages after LPS stimulation for 3 h, and BBR pretreatment inhibited inflammatory polarization. BBR might interact with TLR4 and disturb TLR4/MyD88/NFκB signalling pathway, and it might be the mechanism by which BBR attenuated inflammation in the early phase.

Inhibition of PPARγ, adipogenesis and insulin sensitivity by MAGED1.

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE family member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and loss of MAGED1 promoted preadipocyte proliferation and differentiation in vitro. MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to WT littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors and hyperplasia of white adipose tissues (WATs). Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity, normal levels of serum lipids and enhanced secretion of adipokines such as leptin and adiponectin. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

Sorption of three synthetic musks by microplastics.

Microplastics and synthetic musks (SMs) are two typical organic pollutants in the marine environment. In this study, the sorption of three SMs to microplastics in a simulated seawater environment was examined. Tonalide (AHTN), musk xylene (MX), and musk ketone (MK) were the musks investigated, while polypropylene (PP) was used as the microplastic. It was found that the equilibrium sorption time was about 10h and the adsorption kinetics model conformed to a Lagergren adsorption model. The adsorption capacity increased with decreasing particle size. Adsorption reached a peak at 25°C, and the adsorption capacity was not sensitive to the concentration of sodium chloride. There is a need for more research and monitoring of microplastics in the marine environment due to their strong ability to absorb organic pollutants.