c-Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment.

Inflammatory microenvironment is an important factor for promoting cancer invasion and metastasis, but the underlying molecular mechanisms remain unclear. Here, we mimicked an inflammatory microenvironment both in vitro and in vivo and investigated its effects on the invasion and metastasis of colon cancer. Moreover, colon cancer patient samples were also analyzed statistically. Conditioned medium from the differentiated macrophages induced invasion and migration of colon cancer cells in vitro, which could be reversed by the treatment of a neutralizing anti-growth differentiation factor 15 (GDF15) antibody, indicating GDF15 involvement in inflammation-induced invasiveness. Also, we observed similar effects of human recombinant GDF15 on colon cancer cells. Mechanistically, GDF15 activated c-Fos by separating it from Lamin A/C, increasing transcriptional activity of c-Fos and regulating EMT gene expressions. However, c-Fos knockdown using lentivirus shRNA plasmid inhibited GDF15-triggered invasion and migration in vitro. In vivo, inflammation caused by lipopolysaccharides obviously increased GDF15 secretion, and c-Fos knockdown reduced the lung metastasis of colon cancer cells in mice model. In addition, c-Fos expressions in patient samples were found to be associated with colon cancer metastasis and TNM stages. Taken together, GDF15 in inflammatory microenvironment induces colon cancer invasion and metastasis by regulating EMT genes by activating c-Fos, which might be a potential therapeutic target for metastatic colon cancer.

Oroxylin A increases the sensitivity of temozolomide on glioma cells by hypoxia-inducible factor 1α/hedgehog pathway under hypoxia.

Microenvironmental hypoxia-mediated drug resistance is responsible for the failure of cancer therapy. To date, the role of the hedgehog pathway in resistance to temozolomide (TMZ) under hypoxia has not been investigated. In this study, we discovered that the increasing hypoxia-inducible factor 1α (HIF-1α) activated the hedgehog pathway in hypoxic microenvironment by promoting autocrine secretion of sonic hedgehog protein (Shh), and then upregulating transfer of Gli1 to the nucleus, finally contributed to TMZ resistance in glioma cells. Oroxylin A (C16H12O5), a bioactive flavonoid, could induce HIF-1α degradation via prolyl-hydroxylases-VHL signaling pathway, resulting in the inactivation of the hedgehog. Besides, oroxylin A increased the expression of Sufu, which is a negative regulator of Gli1. By this mechanism, oroxylin A sensitized TMZ on glioma cells. U251 intracranial transplantation model and GL261 xenograft model were used to confirm the reversal effects of oroxylin A in vivo. In conclusion, our results demonstrated that HIF-1α/hedgehog pathway conferred TMZ resistance under hypoxia, and oroxylin A was capable of increasing the sensitivity of TMZ on glioma cells in vitro and in vivo by inhibiting HIF-1α/hedgehog pathway and depressing the activation of Gli1 directly.

The STING-mediated antiviral effect of fucoidan from Durvillaea antarctica.

Fucoidans have attracted increasing attention due to their minimal toxicity and various biological activities, such as antioxidant, anti-inflammatory, anti-tumor and immunomodulatory effects. In this study, the antiviral effect and mechanism of fucoidan (FU) derived from Durvillaea antarctica were explored in vitro. The results demonstrated that FU effectively inhibited the infection of both RNA virus (VSV) and DNA virus (HSV-1). The potential antiviral mechanism of FU is to trigger the production of type I IFN (IFN-I) and IFN-stimulated genes dependent on the cytoplasmic DNA adaptor STING (stimulator of interferon genes), and to enhance innate immune response via activating the STING-TBK1-IRF3 pathway. FU possesses the potential to be an antiviral and immunomodulatory agent in the future.

Knowledge, Attitude, and Practice Towards Mpox and Associated Factors Among HIV-Infected Individuals - Beijing Municipality, China, 2023.

What is already known about this topic?: Approximately 50% of patients with mpox are human immunodeficiency virus (HIV)-infected globally. Studies have shown that individuals with advanced HIV infection tend to have more severe clinical manifestations and higher mortality rates after mpox infection. What is added by this report?: The study revealed that individuals living with HIV have a low level of Knowledge, Attitude, and Practice (KAP) towards mpox. Several factors, including age, registered residence, sexual orientation, education level, viral load, and co-occurrence of other sexually transmitted diseases, were found to influence the KAP towards mpox. What are the implications for public health practice?: This study is the first to investigate the KAP of mpox among individuals living with HIV. The findings suggest that mpox health education should prioritize individuals with co-existing sexually transmitted diseases (STDs) and a high viral load.

Cautions should be taken when using cell models for gastric cancer research.

Gastric cancer (GC)-derived cell lines were generally used in basic cancer research and drug screening. However, it is always concerned about the difference between cultured cells and primary tumor by oncologists. To address this question, we compared differentially expressed genes (DEGs) in primary cancers, healthy tissues, and cell lines both in vitro and in silico. Seven reported genes with decreased expression in GCs by DNA methylation were analyzed in our cohort studies and experimentally validation. Selected datasets from TCGA (The Cancer Genome Atlas), CCLE (The Broad Institute Cancer Cell Line Encyclopedia), and GTEx (The Genotype-Tissue Expression project) were used to represent GCs, GC-derived cell lines, and healthy tissues respectively in the in silico analysis. Thirty gastric tissues together with six cell lines were used for validations. Unexpectedly, we experimentally found that reported cancer-related downregulated genes were only found in cancer cell lines but not in biopsies. The unchanged gene expressions in primary GCs were generally consistent with our cohort study, using information from cancerous (TCGA) and healthy tissues (GETx). Substantial differences were also found between DEGs of cancer tissues (TGCA)/ healthy tissues (GTEx) pair and cell lines (CCLE)/ healthy tissues (GTEx) pair, which confirmed the significant differences between primary cancer and cancer cell lines. Moreover, elevated expression of YWHAQ (14-3-3 δ) and THBS1 were observed in the GC biopsies, which might be potential biomarkers for GC diagnosis, considering the increased YWHAQ and THBS1 associated with poor survival rates in gastric cancer patients. In sum, it is suggested that cautions should be taken when using GC cell lines to study genes that show great differences between cell lines and tissues.

When STING Meets Viruses: Sensing, Trafficking and Response.

To effectively defend against microbial pathogens, the host cells mount antiviral innate immune responses by producing interferons (IFNs), and hundreds of IFN-stimulated genes (ISGs). Upon recognition of cytoplasmic viral or bacterial DNAs and abnormal endogenous DNAs, the DNA sensor cGAS synthesizes 2',3'-cGAMP that induces STING (stimulator of interferon genes) undergoing conformational changes, cellular trafficking, and the activation of downstream factors. Therefore, STING plays a pivotal role in preventing microbial pathogen infection by sensing DNAs during pathogen invasion. This review is dedicated to the recent advances in the dynamic regulations of STING activation, intracellular trafficking, and post-translational modifications (PTMs) by the host and microbial proteins.

Oroxylin A reversed Fibronectin-induced glioma insensitivity to Temozolomide by suppressing IP3R1/AKT/ß-catenin pathway.

AIMS: Cell adhesion mediated-drug resistance (CAM-DR) is one of main reasons for. the limitation to chemotherapy, but the underlying mechanism remains unclear in glioma. In this study, we investigated the mechanism of CAM-DR induced by Fibronectin (Fn). Besides, we studied the reversal effect of Oroxylin A, a natural flavonoid extracted from Scutellaria radix, on Temozolomide (TMZ) insensitivity of glioma cells. MAIN METHODS: Human Fn protein was used to mimic cell adhesion model and investigate its effect on the insensitivity of glioma cells to TMZ. Moreover, Oroxylin A was studied regarding its reversal effect on TMZ insensitivity of glioma via multiple molecular biological methods such as MTT, cell apoptosis assay, siRNA transfection, western blot, immunofluorescence assay. KEY FINDINGS: Fn could decrease the apoptosis-inducing effect of TMZ and led to the CAM-DR in glioma cells. Further studies showed that up-regulations of IP3R1 and intracellular Ca2+ level induced the activation of AKT kinase which increased the phosphorylation of GSK-3ß and subsequently caused the entry of ß-catenin into the nucleus. Knocking down IP3R1 significantly improved the sensitivity of glioma cells to TMZ. Meanwhile, after treatment with low-toxic concentration of Oroxylin A, the apoptosis induced by TMZ under Fn condition increased dramatically. Furthermore, our results revealed that Oroxylin A markedly inhibited the expression of IP3R1 and the activation of AKT/ß-catenin pathway. SIGNIFICANCE: Oroxylin A could reverse the insensitivity of TMZ via suppressing IP3R1/AKT/ß-catenin pathway and it might be helpful for enhancing the anti-cancer effect of TMZ in glioma.

Roles of integrin in tumor development and the target inhibitors.

Integrin is a large family of cell adhesion molecules (CAMs) which involves in the interaction of cells/cells and cells/ extracellular matrix (ECM) to mediate cell proliferation, differentiation, adhesion, migration, etc. In recent years, aberrant expression of integrin has been clearly found in many tumor studies, indicating that integrin is closely related to tumor formation and development. Meanwhile, it has effects on tumor cell differentiation, cell migration, proliferation and tumor neovascularization. The study of drugs targeting integrins is of great significance for the clinical treatment of tumors. Because of its important role in tumorigenesis and development, integrin has become a promising target for the treatment of cancer. This review summarizes the role of integrin in tumor development and the current state of integrin inhibitors to provide a valuable reference for subsequent research.

Effect of physical exercise on medical rehabilitation treatment of depression / Efeito de exercícios físicos no tratamento médico para reabilitação da depressão / Efectos de ejercicios físicos en el tratamiento médico para rehabilitación de la depresión

ABSTRACT Introduction: Depression is a common disease worldwide. The main treatment methods currently include medication, psychotherapy, and physical therapy. However, due to limitations in treatment methods, treatment compliance is poor. Participating in various sports is very effective in treating depression. Objective: To verify the influence of sports on the condition of depression and on the effect of its clinical treatment. Methods: The article selected a total of 60 hospitalized patients with depression who were randomly divided into two groups: an experimental group and a control group. The control group took antidepressant drugs for eight weeks, and the experimental group took the drugs with the supplementary practice of sports. The two groups of patients were tested for serum β-endorphin (β-EP) levels before and after treatment, and HAMD scores were performed. Results: The scores and serum β-endorphin (β-EP) levels of the two groups of patients were different, showing that effect of the treatment was better in the experimental group. Conclusion: Physical exercise therapy can mobilize the enthusiasm of patients with depression. This treatment plan increases treatment efficiency and is suitable for long-term clinical promotion and application. Level of evidence II; Therapeutic studies - investigation of treatment results.

RESUMO Introdução: A depressão é uma doença comum em todo o mundo. Os principais métodos de tratamento atuais incluem medicação, psicoterapia e fisioterapia. Contudo, graças às limitações dos métodos de tratamento, a aderência a eles é pequena. Participar de vários esportes é uma maneira eficiente de se tratar a depressão. Objetivo: Verificar a influência de esportes na condição depressiva e seu efeito no tratamento clínico da doença. Método: Selecionou-se 60 pacientes hospitalizados, que foram aleatoriamente divididos em dois grupos: um grupo experimental e um grupo controle. O grupo controle tomou antidepressivos por oito semanas, e o grupo experimental usou os medicamentos somados à prática de esportes. Testou-se os níveis de beta-endorfina (β-EP) dos dois grupos antes e depois do tratamento, e a pontuação na escala HAMD foi avaliada. Resultados: Houve diferença na pontuação e nos níveis de β-EP entre os grupos, indicando que o efeito do tratamento foi melhor no grupo experimental. Conclusão: A terapia com exercício físico é capaz de mobilizar o entusiasmo dos pacientes com depressão. Esse plano de tratamento aumenta a eficiência da terapia e é adequado para promoção e aplicação a longo prazo. Nível de evidência II; Estudos terapêuticos - investigação de resultados de tratamento.

RESUMEN Introducción: La depresión es una enfermedad común en todo el mundo. Los principales métodos de tratamiento actuales incluyen medicación, psicoterapia y fisioterapia. Sin embargo, gracias a las limitaciones de los métodos de tratamiento, la adherencia a los mismos es baja. Practicar varios deportes es una forma eficaz de tratar la depresión. Objetivo: Verificar la influencia de los deportes en la condición depresiva y su efecto en el tratamiento clínico de la enfermedad. Método: Se seleccionaron 60 pacientes hospitalizados, que fueron aleatoriamente divididos en dos grupos: un grupo experimental y un grupo control. El grupo control tomó antidepresivos por ocho semanas, y el grupo experimental usó los medicamentos sumados a la práctica de deportes. Se analizaron los niveles de beta-endorfina (β-EP) de ambos grupos antes y después del tratamiento, y se evaluó la puntuación de la escala HAMD. Resultados: Hubo diferencia en la puntuación y en los niveles de β-EP entre los grupos, indicando que el efecto del tratamiento fue mejor en el grupo experimental. Conclusión: La terapia con ejercicio físico es capaz de movilizar el entusiasmo de los pacientes con depresión. Este plan de tratamiento aumenta la eficacia de la terapia y es adecuado para la promoción y aplicación a largo plazo. Nivel de evidencia II; Estudios terapéuticos - investigación de resultados de tratamiento.

Functional characterization of protein 4.1 homolog in amphioxus: defining a cryptic spectrin-actin-binding site.

Vertebrate 4.1 proteins have a spectrin-actin-binding (SAB) domain, which is lacking in all the invertebrate 4.1 proteins indentified so far, and it was therefore proposed that the SAB domain emerged with the advent of vertebrates during evolution. Here we demonstrated for the first time that amphioxus (an invertebrate chordate) protein 4.1, though lacking a recognizable SAB, was able to bind both spectrin and actin, with a binding capacity comparable to that of human protein 4.1. Detailed structure-activity analyses revealed that the unique domain U2/3 was a newly identified SAB-like domain capable of interacting with spectrin and actin, suggesting the presence of a "cryptic" SAB domain in amphioxus 4.1 protein. We also showed that amphioxus 4.1 protein gene was the common ancestor of vertebrate 4.1 protein genes, from which 4.1R, 4.1N, 4.1G, and 4.1B genes originated. This work will encourage further study on the structure-activity of invertebrate 4.1 protein and its interacting proteins.

Identification and bioactivity analysis of transthyretin-like protein in amphioxus: a case demonstrating divergent evolution from an enzyme to a hormone distributor.

Transthyretin-like proteins are a family of proteins that share remarkable structural similarities to transthyretin, that have been identified in a variety of taxa such as bacteria, fungi, plants, invertebrates and vertebrates. Despite the enormous progress in the study of transthyretin-like protein, little is known about it in amphioxus, a model organism for insights into the origin and evolution of vertebrates. Here we identified a transthyretin-like protein gene in Branchiostoma japonicum, named Bjtlp, which possessed a TLP-HIUase (an enzyme hydrolyzing 5-hydroxyisourate) domain and a consensus C-terminal tetrapeptide Tyr-Arg-Gly-Ser that are both characteristics of all known transthyretin-like proteins. Phylogenetic and intron-exon structure analyses support that TTR likely arose from a vertebrate specific duplication after vertebrates diverged from invertebrate chordates. Quantitative real-time PCR analysis revealed that Bjtlp was expressed in a tissue-specific fashion, with the transcript levels being most abundant in the hepatic caecum and hind gut. Enzymatic activity assays demonstrated that recombinant BjTLP had the capacity to hydrolyze 5-hydroxyisourate. Site-directed mutagenesis showed that both Y156 and R93 residues were critical for 5-hydroxyisourate hydrolase activity of recombinant BjTLP. Moreover, the single mutation, Y156T, at the active site of BjTLP caused approximately 97% loss of its enzymatic activity, and meanwhile gained the thyroxine binding activity. All these data together suggest that the single mutation Y156T is critical for converting BjTLP to a new transport protein capable of distributing thyroxine.

Advances and challenges in screening traditional Chinese anti-aging materia medica.

To provide a better service for senior health care, we summarized screening studies of traditional Chinese anti-aging materia medica (TCAM). We collected and analyzed literature of TCAM screening studies using the lifespan test and animal models of aging from 1984 to 2012. We found 26 screening methods for TCAM, and 153 single herbs or active ingredients of TCAM that have been screened out during the past 28 years. The cell lifespan test, the fruit fly lifespan test, and D-galactose aging model were the most widely used and intensively studied screening methods. However, the method for establishing the D-galactose aging model needs to be standardized, and the D-galactose aging model cannot completely be a substitute for the normal aging mouse model. Great success has been achieved in screening studies in TCAM. To further improve screening studies in TCAM, we suggest that the D-galactose aging model be incorporated into the lifespan test in the New Drugs of Traditional Chinese Medicine Research Guide.

A novel short peptidoglycan recognition protein in amphioxus: identification, expression and bioactivity.

Peptidoglycan recognition proteins (PGRPs) are widely distributed in invertebrates and vertebrates, and structure-activity relationship of insect and mammalian PGRPs has been well characterized, but functional and structural insights into PGRPs in other species are rather limited. Here we identified a novel short PGRP gene from the amphioxus Branchiostoma japonicum, named pgrp-s, which possesses a domain combination of ChtBD1 domain-PGRP domain, which is unique to all known PGRPs. Amphioxus pgrp-s was predominantly expressed in the hepatic caecum, hind-gut and muscle in a tissue-specific manner. Recombinant PGRP-S, rPGRP-S, and truncated protein with ChtBD1 domain deleted, rP86/250, both showed affinity to Dap-type PGN, Lys-type PGN and chitin. Consistently, they were also able to bind to Escherichia coli, Staphylococcus aureus and Pichia pastoris. Moreover, both rPGRP-S and rP86/250 had amidase enzymatic activity, capable of hydrolyzing Dap-type and Lys-type PGNs. Like vertebrate PGRPs, rPGRP-S was directly microbicidal, capable of killing E. coli, S. aureus and P. pastoris, whereas rP86/250 only inhibited the growth of E. coli and S. aureus, and its anti-P. pastoris activity was significantly reduced. It is clear that neither the binding of amphioxus PGRP-S nor its amidase enzymatic activity depend on the N-terminal ChtBD1 domain, but its antifungal activity does. Collectively, these data suggested that amphioxus PGRP-S may function as a multivalent pattern recognition receptor, capable of recognizing PGN and chitin, a microbicidal agent, capable of killing bacteria such as E. coli and S. aureus and fungus like P. pastoris, and probably a PGN scavenger, capable of hydrolyzing PGN.