Natural products in atherosclerosis therapy by targeting PPARs: a review focusing on lipid metabolism and inflammation.

Inflammation and dyslipidemia are critical inducing factors of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and control the expression of multiple genes that are involved in lipid metabolism and inflammatory responses. However, synthesized PPAR agonists exhibit contrary therapeutic effects and various side effects in atherosclerosis therapy. Natural products are structural diversity and have a good safety. Recent studies find that natural herbs and compounds exhibit attractive therapeutic effects on atherosclerosis by alleviating hyperlipidemia and inflammation through modulation of PPARs. Importantly, the preparation of natural products generally causes significantly lower environmental pollution compared to that of synthesized chemical compounds. Therefore, it is interesting to discover novel PPAR modulator and develop alternative strategies for atherosclerosis therapy based on natural herbs and compounds. This article reviews recent findings, mainly from the year of 2020 to present, about the roles of natural herbs and compounds in regulation of PPARs and their therapeutic effects on atherosclerosis. This article provides alternative strategies and theoretical basis for atherosclerosis therapy using natural herbs and compounds by targeting PPARs, and offers valuable information for researchers that are interested in developing novel PPAR modulators.

Laminaria japonica Aresch-Derived Fucoidan Ameliorates Hyperlipidemia by Upregulating LXRs and Suppressing SREBPs.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, and hyperlipidemia is one major inducing factor of CVD. It is worthy to note that fucoidans are reported to have hypolipidemic activity with species specificity; however, the underlying mechanisms of action are far from clarification. This study is aimed at investigating the plasma lipid-lowering mechanisms of the fucoidan from L. japonica Aresch by detecting the levels of hepatic genes that are involved in lipid metabolism. Our results demonstrated that the fucoidan F3 significantly lowered total cholesterol and triglyceride in C57BL/6J mice fed a high-fat diet. In the mouse liver, fucoidan F3 intervention significantly increased the gene expression of peroxisome proliferator-activated receptor (PPAR) α, liver X receptor (LXR) α and ß, and ATP-binding cassette transporter (ABC) G1 and G8 and decreased the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, cholesterol 7 alpha-hydroxylase A1, and sterol regulatory element-binding protein (SREBP) 1c and SREBP-2. These results demonstrated that the antihyperlipidemic effects of fucoidan F3 are related to its activation of PPARα and LXR/ABC signaling pathways and inactivation of SREBPs. In conclusion, fucoidan F3 may be explored as a potential compound for prevention or treatment of lipid disorders.

Phenotypic and functional differences of dendritic cells in tumor.

Dendritic cells (DCs) are a unique class of immune cells vital to the immune system, functioning as antigen-presenting cells that play a key role in launching both cellular and humoral immune responses. They are crucial in preventing infectious diseases and regulating tumor growth. DCs can be categorized based on various criteria such as phenotype, function, and tissue location, resulting in several subgroups. Generally, DCs are divided into two primary groups: plasmacytoid DCs (pDCs) and conventional DCs (cDCs), which are further classified into Type I classical DCs (cDC1) and Type II classical DCs (cDC2). cDC1 cells are distinguishable by specific gene programs and associated markers, while cDC2 cells display more diversity. Moreover, there is an ongoing debate surrounding a recently identified subgroup called DC3, and whether it can be considered a distinct cell type in the maturation process of DCs remains uncertain. Most of these DC subgroups rely on the growth factor Fms-like tyrosine kinase 3 ligand (FLT3L) for differentiation from a common DC precursor (CDP), guided by various cytokines. Although the general classification of DC subgroups is similar in both humans and mice, numerous phenotypic and functional variations exist within each subgroup. Therefore, comprehending these differences between DC subgroups in humans and mice holds the potential to significantly advance relevant research.

Soluble DPP4 can act as a diagnostic biomarker in Hashimoto's thyroiditis with thyroid papillary carcinoma.

Background: Hashimoto's thyroiditis (HT) is an independent risk factor for papillary thyroid carcinoma (PTC), but the underlying mechanism remains unknown. The incidence of PTC in patients with HT is significantly elevated, and the presence of both HT and PTC contributes to a higher rate of misdiagnosis. Materials and Methods: Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the thyroid nodule gene chip dataset from GEO Datasets. Serum and clinical data from 191 patients with thyroid nodules at the affiliated hospital were collected for analysis. Experimental techniques, including real-time quantitative PCR, ELISA, immunohistochemistry (IHC), and enzyme activity detection, were used to measure the level of dipeptidyl peptidase 4 (DPP4) in thyroid nodule tissues and serum. Results: Thyroid nodules in patients with HT and PTC exhibit high levels of DPP4, along with elevated concentrations of soluble DPP4 in the serum. These findings demonstrate the potential predictive value of soluble DPP4 for PTC diagnosis. Conclusions: The concentration and enzymatic activity of soluble DPP4 in serum can serve as diagnostic biomarkers for patients with HT-associated PTC.

Ste20-Like Kinase TAOK1 Positively Regulates Antiviral Responses by Controlling the TBK1-IRF3 Signaling Axis.

The cytosolic viral nucleic acid-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor interferon (IFN)-regulatory factor 3 (IRF3) to induce type I IFN production and antiviral immune responses. However, the mechanism that triggers the binding of TBK1 and IRF3 after virus infection remains not fully understood. Here, we identified that thousand and one kinase 1 (TAOK1), a Ste20-like kinase, positively regulated virus-induced antiviral immune responses by controlling the TBK1-IRF3 signaling axis. Virus invasion downregulated the expression of TAOK1. TAOK1 deficiency resulted in decreased nucleic acid-mediated type I IFN production and increased susceptibility to virus infection. TAOK1 was constitutively associated with TBK1 independently of the mitochondrial antiviral signaling protein MAVS. TAOK1 promoted IRF3 activation by enhancing TBK1-IRF3 complex formation. TAOK1 enhanced virus-induced type I IFN production in a kinase activity-dependent manner. Viral infection induced TAOK1 to bind with dynein instead of microtubule-associated protein 4 (MAP4), leading to the trafficking of TBK1 to the perinuclear region to bind IRF3. Thus, the depolymerization of microtubule impaired virus-mediated IRF3 activation. Our results revealed that TAOK1 functioned as a new interaction partner and regulated antiviral signaling via trafficking TBK1 along microtubules to bind IRF3. These findings provided novel insights into the function of TAOK1 in the antiviral innate immune response and its related clinical significance.

Analysis of antitumor immunity in mouse glioma microenvironment through intercellular communication.

Objective: This study aimed to map the antitumor immunity in the glioma microenvironment by analyzing intercellular communication. Materials and Methods: The single-cell RNA-sequencing (scRNA-Seq) data were obtained from fresh mouse gliomas. Tumor cells were inferred by estimating genomic copy number profiles. CellMarker database was used to identify cell types. Intercellular communication was inferred using CellChat. Flow cytometry was used to detect the effect of microglia or stroma-educated monocytes on CD4+ T cell proliferation. Results: Mouse glioma contained at least eight cell populations, and T cells were the only infiltrating immunocytes. Whether in signal outgoing or signal incoming, intercellular communication could be divided into four patterns by which cell populations in the tumor microenvironment (TME) cooperate with each other. By analyzing the complex communication between brain cell populations and infiltrating T cells in TME, we found that the brain cell populations used 25 signaling pathways to connect to T cells, and T cells used 21 signaling pathways to connect to brain cell populations. We also found that microglia from normal mice and brain stroma-educated monocytes exhibited immunosuppressive activity against CD4+ T cell proliferation. Conclusions: We described the previously underestimated complex communication between infiltrating T cells and brain cell populations. Our data suggest that the tolerogenic property of glioma TME is related to the immune privilege of CNS.

Acute stress induces an inflammation dominated by innate immunity represented by neutrophils in mice.

It is well known that psychological stress could affect the immune system and then regulate the disease process. Previous studies mostly focused on the effects of chronic stress on diseases and immune cells. How acute stress affects the immune system remains poorly understood. In this study, after 6 hours of restraint stress or no stress, RNA was extracted from mouse peripheral blood followed by sequencing. Through bioinformatics analysis, we found that when compared with the control group, differentially expressed genes in the stress group mainly displayed up-regulated expression. Gene set enrichment analysis results showed that the enriched gene terms were mainly related to inflammatory response, defense response, wounding response, wound healing, complement activation and pro-inflammatory cytokine production. In terms of cell activation, differentiation and chemotaxis, the enriched gene terms were related to a variety of immune cells, among which neutrophils seemed more active in stress response. The results of gene set variation analysis showed that under acute stress, the inflammatory reaction dominated by innate immunity was forming. Additionally, the concentration of serum IL-1ß and IL-6 increased significantly after acute stress, indicating that the body was in an inflammatory state. Importantly, we found that acute stress led to a significant increase in the number of neutrophils in peripheral blood, while the number of T cells and B cells decreased significantly through flow cytometric analysis. Through protein-protein interaction network analysis, we screened 10 hub genes, which mainly related to inflammation and neutrophils. We also found acute stress led to an up-regulation of Ccr1, Ccr2, Xcr1 and Cxcr2 genes, which were involved in cell migration and chemotaxis. Our data suggested that immune cells were ready to infiltrate into tissues in emergency through blood vessels under acute stress. This hypothesis was supported in LPS-induced acute inflammatory models. After 48 hours of LPS treatment, flow cytometric analysis showed that the lungs of mice with acute stress were characterized by increased neutrophil infiltration, decreased T cell and B cell infiltration. Immunohistochemical analysis also showed that acute stress led to more severe lung inflammation. If mice received repeat acute stress and LPS stimulation, the survival rate was significantly lower than that of mice only stimulated by LPS. Altogether, acute stress led to rapid mobilization of the immune system, and the body presented an inflammatory state dominated by innate immune response represented by neutrophils.

Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut-brain communications.

Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn's disease (CD), is an autoimmune gastrointestinal disease characterized by chronic inflammation and frequent recurrence. Accumulating evidence has confirmed that chronic psychological stress is considered to trigger IBD deterioration and relapse. Moreover, studies have demonstrated that patients with IBD have a higher risk of developing symptoms of anxiety and depression than healthy individuals. However, the underlying mechanism of the link between psychological stress and IBD remains poorly understood. This review used a psychoneuroimmunology perspective to assess possible neuro-visceral integration, immune modulation, and crucial intestinal microbiome changes in IBD. Furthermore, the bidirectionality of the brain-gut axis was emphasized in the context, indicating that IBD pathophysiology increases the inflammatory response in the central nervous system and further contributes to anxiety- and depression-like behavioral comorbidities. This information will help accurately characterize the link between psychological stress and IBD disease activity. Additionally, the clinical application of functional brain imaging, microbiota-targeted treatment, psychotherapy and antidepressants should be considered during the treatment and diagnosis of IBD with behavioral comorbidities. This review elucidates the significance of more high-quality research combined with large clinical sample sizes and multiple diagnostic methods and psychotherapy, which may help to achieve personalized therapeutic strategies for IBD patients based on stress relief.

Characteristics of human oral microbiome and its non-invasive diagnostic value in chronic kidney disease.

BACKGROUND: Morbidity of chronic kidney disease (CKD) is increased, with many complications and high mortality rates. The characteristics of oral microbiome in CKD patients have not been reported. This study aims to analyze the oral microbiome, and to demonstrate the potential of microbiome as noninvasive biomarkers for CKD patients. METHODS: The study collected 253 oral samples from different regions of China (Central China and East China) prospectively and finally 235 samples completed Miseq sequencing, including 103 samples from CKD patients and 132 healthy controls (HCs). RESULTS: Compared with HCs (n=88), the oral microbial diversity in CKD patients (n=44) was increased. Fourteen genera including Streptococcus, Actinomyces and Leptotrichia were enriched, while six genera including Prevotella and Haemophilus were decreased in CKD patients. Moreover, 49 predicted microbial gene functions including arginine metabolism and tryptophan metabolism increased, while 55 functions including Ribosome and DNA repair recombination proteins decreased. Furthermore, correlation analysis demonstrated that 38 operational taxonomic units (OTUs) were closely related to 5 clinical indicators of CKD. Notably, 7 optimal biomarkers were identified using random forest model, and the classifier model respectively reached an area under the curve (AUC) of 0.9917 and 0.8026 in the discovery and validation phase, achieving a cross-region validation. CONCLUSIONS: We first illustrated the characteristics of the oral microbiome of patients with CKD, identified the potential of oral microbial makers as noninvasive tools for the diagnosis of CKD and achieved cross-region validation.

MEF2C promotes M1 macrophage polarization and Th1 responses.

The polarization of macrophages to the M1 or M2 phenotype has a pivotal role in inflammation and host defense; however, the underlying molecular mechanism remains unclear. Here, we show that myocyte enhancer factor 2 C (MEF2C) is essential for regulating M1 macrophage polarization in response to infection and inflammation. Global gene expression analysis demonstrated that MEF2C deficiency in macrophages downregulated the expression of M1 phenotypic markers and upregulated the expression of M2 phenotypic markers. MEF2C significantly promoted the expression of interleukin-12 p35 subunit (Il12a) and interleukin-12 p40 subunit (Il12b). Myeloid-specific Mef2c-knockout mice showed reduced IL-12 production and impaired Th1 responses, which led to susceptibility to Listeria monocytogenes infection and protected against DSS-induced IBD in vivo. Mechanistically, we showed that MEF2C directly activated the transcription of Il12a and Il12b. These findings reveal a new function of MEF2C in macrophage polarization and Th1 responses and identify MEF2C as a potential target for therapeutic intervention in inflammatory and autoimmune diseases.

Microbial hydrogen economy alleviates colitis by reprogramming colonocyte metabolism and reinforcing intestinal barrier.

With the rapid development and high therapeutic efficiency and biosafety of gas-involving theranostics, hydrogen medicine has been particularly outstanding because hydrogen gas (H2), a microbial-derived gas, has potent anti-oxidative, anti-apoptotic, and anti-inflammatory activities in many disease models. Studies have suggested that H2-enriched saline/water alleviates colitis in murine models; however, the underlying mechanism remains poorly understood. Despite evidence demonstrating the importance of the microbial hydrogen economy, which reflects the balance between H2-producing (hydrogenogenic) and H2-utilizing (hydrogenotrophic) microbes in maintaining colonic mucosal ecosystems, minimal efforts have been exerted to manipulate relevant H2-microbe interactions for colonic health. Consistent with previous studies, we found that administration of hydrogen-rich saline (HS) ameliorated dextran sulfate sodium-induced acute colitis in a mouse model. Furthermore, we demonstrated that HS administration can increase the abundance of intestinal-specific short-chain fatty acid (SCFA)-producing bacteria and SCFA production, thereby activating the intracellular butyrate sensor peroxisome proliferator-activated receptor γ signaling and decreasing the epithelial expression of Nos2, consequently promoting the recovery of the colonic anaerobic environment. Our results also indicated that HS administration ameliorated disrupted intestinal barrier functions by modulating specific mucosa-associated mucolytic bacteria, leading to substantial inhibition of opportunistic pathogenic Escherichia coli expansion as well as a significant increase in the expression of interepithelial tight junction proteins and a decrease in intestinal barrier permeability in mice with colitis. Exogenous H2 reprograms colonocyte metabolism by regulating the H2-gut microbiota-SCFAs axis and strengthens the intestinal barrier by modulating specific mucosa-associated mucolytic bacteria, wherein improved microbial hydrogen economy alleviates colitis.

miR-139-5p Loss-Mediated WTAP Activation Contributes to Hepatocellular Carcinoma Progression by Promoting the Epithelial to Mesenchymal Transition.

Background: Hepatocellular carcinoma (HCC) is a primary aggressive gastrointestinal neoplasm that affects patients worldwide. It has been shown that Wilms' tumor 1-associating protein (WTAP) is frequently upregulated in various cancers. However, the potential role of WTAP in HCC remains largely unknown. Methods: The expression levels of WTAP in human HCC tissues were determined by the western blotting and immunohistochemical (IHC) staining. A correlation between the WTAP expression, clinicopathological features, and the HCC prognosis was analyzed. The WTAP expression was silenced by short hairpin RNA (shRNA), and effects of the knockdown of WTAP on the proliferation and invasion of HCC cells were assessed. The microRNAs (miRNAs) involved in the regulation of the WTAP expression were identified by a bioinformatics analysis and further confirmed by in vitro assays. Results: The expression levels of WTAP in liver cancer tissues were significantly elevated and compared with those in the adjacent normal tissues and significantly correlated with the clinical stage and prognosis in patients with HCC. Further investigation revealed that the knockdown of WTAP drastically suppressed HCC cell proliferation and invasion abilities. Luciferase reporter assay and validation experiments confirmed that WTAP was a direct target of miR-139-5p. Moreover, the overexpression of WTAP could partly abolish the inhibitory effects of miR-139-5p on the HCC cell growth and invasion. Mechanistically, we revealed that the miR-139-5p/WTAP axis regulated the HCC progression by controlling the epithelial to mesenchymal transition (EMT). Conclusions: In summary, the results indicate that WTAP is a potential oncogene in HCC and miR-139-5p negatively regulates the WTAP expression. MiR-139-5p/WTAP can be utilized as a potential therapeutic target for HCC.

The landscape and prognostic value of immune characteristics in uterine corpus endometrial cancer.

In the present study, we explored the clinical and immunological characteristics of 575 uterine corpus endometrial carcinoma (UCEC) samples obtained from The Cancer Genome Atlas (TCGA) using the ESTIMATE and CIBERSORT algorithms. First, Kaplan-Meier and univariate Cox regression analyses indicated that the immune cell score was a prognostic factor for overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox regression analysis further revealed that the immune cell score was an independent prognostic factor for UCEC patients. Second, we investigated the correlation between the infiltration levels of 22 types of immune cells and the immune score. Survival analysis based on the 22 immune cell types showed that higher levels of regulatory T cell, activated NK cell, and follicular helper T-cell infiltration were associated with longer OS, while higher levels of CD8+ T cell and naive B-cell infiltration were associated with longer RFS. Next, we performed differential expression and prognosis analyses on 1534 immune-related genes and selected five from 14 candidate genes to construct a prognostic prediction model. The area under the receiver-operating characteristic (ROC) curve (AUC) for 3- and 5-year survival were 0.711 and 0.728, respectively. Further validation using a stage I-II subgroup showed similar results, presenting AUC values for 3- and five-year survival of 0.677 and 0.692, respectively. Taken together, the present study provides not only a deeper understanding of the relationship between UCEC and the immune landscape but also guidance for the future development of UCEC immunotherapy.

Strontium ranelate incorporated 3D porous sulfonated PEEK simulating MC3T3-E1 cell differentiation.

Polyetheretherketone (PEEK) has been used as an implant material because it has similar mechanical properties to natural bone. However, inferior osseointegration and bioinertness hamper the clinical application of PEEK. In this study, the surfaces of sulfonated three-dimensional (3D) PEEK porous structures were loaded with different concentrations of strontium ranelate, a compound commonly used in the treatment or prevention of osteoporosis by promoting bone formation and inhibiting bone resorption. Field-emission scanning electron microscopy was used to characterize the topography of the structures, elemental carbon, oxygen and strontium contents were measured by X-ray photoelectron spectroscopy, and surface zeta potentials and water-contact angle were also measured. The results indicated that strontium ranelate was successfully loaded onto the 3D porous structures. In vitro cellular results showed that strontium ranelate-treated sulfonated PEEK (SP-SR) strengthened the adhesion of MC3T3-E1 cells. The activity of alkaline phosphatase, collagen secretion and extracellular matrix mineralization deposition of MC3T3-E1 cells were also improved on the surface of SP-SR. These results indicate that SP-SR could serve a new implant candidate for surgical treatment.

Medical Morphology Training Using the Xuexi Tong Platform During the COVID-19 Pandemic: Development and Validation of a Web-Based Teaching Approach.

BACKGROUND: Histology and Embryology and Pathology are two important basic medical morphology courses for studying human histological structures under healthy and pathological conditions, respectively. There is a natural succession between the two courses. At the beginning of 2020, the COVID-19 pandemic suddenly swept the world. During this unusual period, to ensure that medical students would understand and master basic medical knowledge and to lay a solid foundation for future medical bridge courses and professional courses, a web-based medical morphology teaching team, mainly including teachers of courses in Histology and Embryology and Pathology, was established. OBJECTIVE: This study aimed to explore a new teaching mode of Histology and Embryology and Pathology courses during the COVID-19 pandemic and to illustrate its feasibility and acceptability. METHODS: From March to July 2020, our team selected clinical medicine undergraduate students who started their studies in 2018 and 2019 as recipients of web-based teaching. Meanwhile, nursing undergraduate students who started their studies in 2019 and 2020 were selected for traditional offline teaching as the control group. For the web-based teaching, our team used the Xuexi Tong platform as the major platform to realize a new "seven-in-one" teaching method (ie, videos, materials, chapter tests, interactions, homework, live broadcasts, and case analysis/discussion). This new teaching mode involved diverse web-based teaching methods and contents, including flipped classroom, screen-to-screen experimental teaching, a drawing competition, and a writing activity on the theme of "What I Know About COVID-19." When the teaching was about to end, a questionnaire was administered to obtain feedback regarding the teaching performance. In the meantime, the final written pathology examination results of the web-based teaching and traditional offline teaching groups were compared to examine the mastery of knowledge of the students. RESULTS: Using the Xuexi Tong platform as the major platform to conduct "seven-in-one" teaching is feasible and acceptable. With regard to the teaching performance of this new web-based teaching mode, students demonstrated a high degree of satisfaction, and the questionnaire showed that 71.3% or more of the students in different groups reported a greater degree of satisfaction or being very satisfied. In fact, more students achieved high scores (90-100) in the web-based learning group than in the offline learning control group (P=.02). Especially, the number of students with objective scores >60 in the web-based learning group was greater than that in the offline learning control group (P=.045). CONCLUSIONS: This study showed that the web-based teaching mode was not inferior to the traditional offline teaching mode for medical morphology courses, proving the feasibility and acceptability of web-based teaching during the COVID-19 pandemic. Our findings lay a solid theoretical foundation for follow-up studies of medical students.

Glycogen Phosphorylase B Is Regulated by miR101-3p and Promotes Hepatocellular Carcinoma Tumorigenesis.

Glycogen metabolism plays a key role in tumorigenesis. High expression levels of glycogen phosphorylase B (PYGB) were reported in several cancers and might be served as a prognostic biomarker for cancer from precancerous lesions. Previous studies indicated the high expression of PYGB in hepatocellular carcinoma (HCC) tissues. However, the detailed roles of PYGB in HCC, as well as the regulatory mechanisms, are still unclear. In this study, we confirmed that PYGB was overexpressed in HCC tissues. PYGB overexpression was significantly associated with an aggressive tumor phenotype and poor prognosis of HCC patients. Functionally, PYGB knockdown suppressed HCC cell proliferation, migration and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Bioinformatics analysis indicated that PYGB overexpression might enhance epithelial to mesenchymal transition (EMT) in HCC. Moreover, miR-101-3p was identified to post-transcriptionally inhibit the expression of PYGB via binding to 3'-UTR of PYGB. Overexpression of PYGB antagonized the regulatory effect of miR-101-3p on cell proliferation, migration and invasion in HCC cells. In summary, our results suggest that miR-101-3p/PYGB axis has an important role in HCC and PYGB could be served as a novel prognostic biomarker and therapeutic target for improving the prognosis of HCC patients.

Polygonatum sibiricum polysaccharide potentially attenuates diabetic retinal injury in a diabetic rat model.

AIMS/INTRODUCTION: To investigate the protective effect of Polygonatum sibiricum polysaccharide (PSP) on the retina in diabetic rats. MATERIALS AND METHODS: A total of 120 Sprague-Dawley rats were randomly divided into blank control, control model (meaning diabetes mellitus), and diabetes mellitus with PSP intervention of high, medium and low doses groups. The difference of retinal vascularization between groups was evaluated by fluorescein isothiocyanate-dextran perfusion. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to assess apoptosis in the retinal ganglion cells; reverse transcriptase polymerase chain reaction and western blotting were utilized to evaluate the expression of Bcl2-associated X protein, B-cell lymphoma-2 factor, epidermal growth factor, p38 mitogen-activated protein kinases, transforming growth factor-ß and vascular endothelial growth factor at the messenger ribonucleic acid and protein level. RESULTS: Fluorescein isothiocyanate-dextran perfusion showed retinal vascular anomaly in diabetes mellitus rats, but vascular tortuosity and leakage were relatively alleviated after PSP intervention. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining showed numerous terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive retinal cells in the diabetes mellitus group, which then were reduced by PSP treatment. Reverse transcriptase polymerase chain reaction showed that PSP intervention decreased Bcl2-associated X protein, epidermal growth factor, p38 mitogen-activated protein kinases, vascular endothelial growth factor and transforming growth factor-ß messenger ribonucleic acid expression, but increased B-cell lymphoma-2 factor messenger ribonucleic acid expression. Western blot showed that PSP intervention upregulated the expression of B-cell lymphoma-2 factor, and downregulated the expression of Bcl2-associated X protein, epidermal growth factor, p38 mitogen-activated protein kinases, vascular endothelial growth factor and transforming growth factor-ß proteins. CONCLUSIONS: Polygonatum sibiricum polysaccharide shows a protective effect against diabetes-induced retinal injury in a dose-dependent manner. The mechanism of action deserves further study and exploration.

Eosinophil recruitment is dynamically regulated by interplay among lung dendritic cell subsets after allergen challenge.

Eosinophil infiltration, a hallmark of allergic asthma, is essential for type 2 immune responses. How the initial eosinophil recruitment is regulated by lung dendritic cell (DC) subsets during the memory stage after allergen challenge is unclear. Here, we show that the initial eosinophil infiltration is dependent on lung cDC1s, which require nitric oxide (NO) produced by inducible NO synthase from lung CD24-CD11b+ DC2s for inducing CCL17 and CCL22 to attract eosinophils. During late phase responses after allergen challenge, lung CD24+ cDC2s inhibit eosinophil recruitment through secretion of TGF-ß1, which impairs the expression of CCL17 and CCL22. Our data suggest that different lung antigen-presenting cells modulate lung cDC1-mediated eosinophil recruitment dynamically, through secreting distinct soluble factors during the memory stage of chronic asthma after allergen challenge in the mouse.

Deleting MyD88 signaling in myeloid cells promotes development of adenocarcinomas of the colon.

Intestinal myeloid cells are not only essential for keeping local homeostasis, but also play an important role in regulating the occurrence of colitis and colitis-associated cancer (CAC). In these diseases, the manner in which the myeloid cells work and which molecular pathways influence them are still not fully understood. In our study, we discovered that MyD88 signaling in colonic myeloid cells participates in the development of CAC. Myeloid MyD88-deficient mice showed greater susceptibility to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC, as evidenced by the increase in the number and sizes of tumors. Myeloid MyD88 deletion markedly increased production of pro-inflammatory and pro-tumor cytokines; recruitment of more IL-1ß producing-neutrophils in colon from bone marrow; increased in epithelial cell apoptosis and decreased in epithelial cell proliferation; enhancement of colon mucosal expression of COX-2, p-STAT3, ß-catenin, and cyclinD1; induction of further DNA damage and ß-catenin mutation. To sum up, these results suggest that myeloid MyD88 signaling protects the intestine from tumorigenesis during the development of CAC.