RESUMEN
DNA demethylase (DML) is involved in plant development and responses to biotic and abiotic stresses; however, its role in plant-herbivore interaction remains elusive. Here, we found that herbivory by the potato tuber moth, Phthorimaea operculella, rapidly induced the genome-wide DNA methylation and accumulation of DML gene transcripts in potato plants. Herbivory induction of DML transcripts was suppressed in jasmonate-deficient plants, whereas exogenous application of methyl jasmonate (MeJA) improved DML transcripts, indicating that the induction of DML transcripts by herbivory is associated with jasmonate signaling. Moreover, P. operculella larvae grew heavier on DML gene (StDML2) knockdown plants than on wild-type plants, and the decreased biosynthesis of jasmonates in the former may be responsible for this difference, since the larvae feeding on these two genotypes supplemented with MeJA showed similar growth. In addition, P. operculella adult moths preferred to oviposit on StDML2 knockdown plants than on wild-type plants, which was associated with the reduced emission of ß-caryophyllene in the former. In addition, supplementing ß-caryophyllene to these two genotypes further disrupted moths' oviposit choice preference for them. Interestingly, in StDML2 knockdown plants, hypermethylation was found at the promoter regions for the key genes StAOS and StAOC in the jasmonate biosynthetic pathway, as well as for the key gene StTPS12 in ß-caryophyllene production. Our findings suggest that knocking down StDML2 can affect herbivore defense via jasmonate signaling and defense compound production in potato plants.
Asunto(s)
Mariposas Nocturnas , Solanum tuberosum , Animales , Herbivoria , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Insectos , Ciclopentanos/metabolismo , Oxilipinas/metabolismo , Mariposas Nocturnas/genética , Mariposas Nocturnas/metabolismo , Larva , ADNRESUMEN
Idiopathic pulmonary fibrosis (IPF), as the most common idiopathic interstitial pneumonia, is caused by a complex interaction of pathological mechanisms. Interestingly, IPF frequently occurs in the middle-aged and elderly populations but rarely affects young people. Salvianolic acid B (SAB) exerts antioxidant, antiinflammatory, and antifibrotic bioactivities and is considered a promising drug for pulmonary disease treatment. However, the pharmacological effects and mechanisms of SAB on cellular senescence of lung cells and IPF development remain unclear. We used bleomycin (BLM)-induced pulmonary fibrosis mice and different lung cells to investigate the antisenescence impact of SAB and explain its underlying mechanism by network pharmacology and the Human Protein Atlas database. Here, we found that SAB significantly prevented pulmonary fibrosis and cellular senescence in mice, and reversed the senescence trend and typical senescence-associated secretory phenotype (SASP) factors released from lung macrophages and alveolar type II (AT2) epithelial cells, which further reduced lung fibroblasts activation. Additionally, SAB alleviated the epithelial-mesenchymal transition process of AT2 cells induced by transforming growth factor beta. By predicting potential targets of SAB that were then confirmed by chromatin immunoprecipitation-qPCR technology, we determined that SAB directly hampered the binding of transcription factor stimulating protein 1 to the promoters of SASPs (P21 and P16), thus halting lung cell senescence. We demonstrated that SAB reduced BLM-induced AT2 and macrophage senescence, and the subsequent release of SASP factors that activated lung fibroblasts, thereby dual-relieving IPF. This study provides a new scientific foundation and perspective for pulmonary fibrosis therapy.
Asunto(s)
Benzofuranos , Depsidos , Fibrosis Pulmonar Idiopática , Pulmón , Persona de Mediana Edad , Anciano , Humanos , Ratones , Animales , Adolescente , Pulmón/patología , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Senescencia Celular/fisiología , Macrófagos Alveolares , Bleomicina/efectos adversosRESUMEN
Semiconducting polymer has a high extinction coefficient and a long band absorption and can be used as a photoacoustic imaging contrast agent. However, nonbiodegradable semiconducting polymers may cause biosafety issues due to being retained in the body. Therefore, developing degradable semiconducting polymers is necessary for in vivo imaging. Herein, we developed three degradable semiconducting polymers with unique optical properties. We adjusted the optical properties of semiconducting polymers by designing the molecular structure of semiconducting polymers. Polymers with a donor-π-acceptor structure could easily improve the optical properties through adjusting the donor or acceptor units. Through adjusting the electron-donor and -acceptor units, three diketopyrrolopyrrole derivative polymers (DPPTz, DPPQu, and DPPWu) were synthesized and converted into nanosize particles. By introducing the degradable chemical groups in the main chain structure of semiconducting polymers, diketopyrrolopyrrole polymers could be degraded by ClO-. Among these nanosize particles, DPPTz NPs and DPPQu NPs were used to achieve the in vivo photoacoustic imaging of λ-carrageenan-induced arthritis mouse model. This work provides a novel design idea for the designing of red-shifted semiconducting polymer with degradable properties.
Asunto(s)
Artritis , Nanopartículas , Técnicas Fotoacústicas , Animales , Carragenina , Medios de Contraste , Modelos Animales de Enfermedad , Cetonas , Ratones , Nanopartículas/química , Técnicas Fotoacústicas/métodos , Polímeros/química , Pirroles , Espectroscopía Infrarroja Corta/métodosRESUMEN
Nerve gas mimic binding with Rhodamine B ethylenediamine (1) was studied in organic media. Binding of the nerve gas mimic, diethyl chlorophosphate (DCP), with the probe generated a non-fluorescent intermediate and a fluorescent product. Fluorescent and non-fluorescent products generated were identified using mass spectrometry and X-ray crystallography. Time-dependent density functional theory calculations were also used to investigate the electronic structure of the fluorescent probe in the ground and lowest lying π â π* singlet excited state. Though good agreement between theory and experiment can be obtained for the intense peak in the experimental spectrum using non-hybrid functionals, care must be taken when modelling these complexes due to the appearance of an n â π* transition that is too low in energy and appears to fall in the shoulders of the π â π* transitions.
Asunto(s)
Agentes Nerviosos , Etilenodiaminas , Colorantes Fluorescentes/química , Agentes Nerviosos/química , Rodaminas/químicaRESUMEN
Liver fibrosis is the common consequence of almost all liver diseases and has become an urgent clinical problem without efficient therapies. Recent evidence has shown that hepatocytes-derived extracellular vesicles (EVs) play important roles in liver pathophysiology, but little is known about the role of damaged hepatocytes-derived EVs in hepatic stellate cell (HSC) activation and following fibrosis. Tetramethylpyrazine (TMP) from Ligusticum wallichii Franchat exhibits a broad spectrum of biological activities including liver protection. In this study, we investigated whether TMP exerted liver-protective action through regulating EV-dependent intercellular communication between hepatocytes and HSCs. Chronic liver injury was induced in mice by CCl4 (1.6 mg/kg, i.g.) twice a week for 8 weeks. In the last 4 weeks of CCl4 administration, mice were given TMP (40, 80, 160 mg·kg-1·d-1, i.g.). Acute liver injury was induced in mice by injection of a single dose of CCl4 (0.8 mg/kg, i.p.). After injection, mice were treated with TMP (80 mg/kg) every 24 h. We showed that TMP treatment dramatically ameliorated CCl4-induced oxidative stress and hepatic inflammation as well as acute or chronic liver fibrosis. In cultured mouse primary hepatocytes (MPHs), treatment with CCl4 or acetaminophen resulted in mitochondrial dysfunction, release of mitochondrial DNA (mtDNA) from injured hepatocytes to adjacent hepatocytes and HSCs through EVs, mediating hepatocyte damage and fibrogenic responses in activated HSCs; pretreatment of MPHs with TMP (25 µM) prevented all these pathological effects. Transplanted serum EVs from TMP-treated mice prevented both initiation and progression of liver fibrosis caused by CCl4. Taken together, this study unravels the complex mechanisms underlying the protective effects of TMP against mtDNA-containing EV-mediated hepatocyte injury and HSC activation during liver injury, and provides critical evidence inspiring the development of TMP-based innovative therapeutic agents for the treatment of liver fibrosis.
Asunto(s)
Vesículas Extracelulares , Hepatopatías , Animales , Tetracloruro de Carbono/efectos adversos , Tetracloruro de Carbono/metabolismo , ADN Mitocondrial/metabolismo , ADN Mitocondrial/farmacología , ADN Mitocondrial/uso terapéutico , Fibrosis , Células Estrelladas Hepáticas , Hepatocitos , Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Hepatopatías/metabolismo , Ratones , Mitocondrias/patología , PirazinasRESUMEN
Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 fl/fl Lyz2-Cre ert2 mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-κB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC.
Asunto(s)
ADN Mitocondrial , Células Dendríticas , Interleucina-12 , Mucosa Intestinal , Proteínas de la Membrana , Ratones Noqueados , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Interleucina-12/metabolismo , Interleucina-12/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/inmunología , Ratones Endogámicos C57BL , Colitis/patología , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/genética , Transducción de Señal , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inmunología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/metabolismo , Neoplasias Asociadas a Colitis/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Modelos Animales de Enfermedad , Sulfato de DextranRESUMEN
Cholangiopathies lack effective medicines and can progress into end-stage liver diseases. Mining natural product transcriptome databases for bioactive ingredients, which can reverse disease-associated transcriptomic phenotypes, holds promise as an effective approach for drug discovery. To identify disease-associated transcriptomic changes, we performed RNA-sequencing on bile duct ligation (BDL)-induced cholestatic liver fibrosis mice, as well as PBC and PSC patients, and found that PANoptosis and activation of type-I interferon (IFN) signaling were observed in BDL mice and patients with PBC and PSC. We then established a transcriptotype-driven screening system based on HERB and ITCM databases. Among 283 natural ingredients screened, apigenin (Api), which is widely distributed in varieties of food and medicinal plants, was screened out by our screen system since it reversed the expression pattern of key genes associated with PANoptosis and type-I IFN responses. In BDL, Abcb4-/-, and DDC-fed mice, Api effectively ameliorated liver injuries, inflammation, and fibrosis. It also protected cholangiocytes from bile acid-stimulated PANoptosis, thus alleviating damage-associated molecular pattern-mediated activation of TBK1-NF-κB in macrophages. Additionally, Api directly inhibited type-I IFN-induced downstream inflammatory responses. Our study demonstrated the pathogenic roles of PANoptosis and type-I IFN signaling in cholestatic liver fibrosis and verified the feasibility of transcriptotype-based drug screening. Furthermore, this study revealed a novel anti-inflammatory mechanism of Api and identified it as a promising candidate for the treatment of cholestatic liver fibrosis.
RESUMEN
OBJECTIVES: To evaluate the effectiveness and safety of Qishen Yiqi Dripping Pill (QSYQ) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: This multicentre prospective cohort study was conducted at 40 centers in China. Patients with ACS after PCI entered either the QSYQ or Western medicine (WM) groups naturally based on whether they had received QSYQ before enrollment. QSYQ group received QSYQ (0.52 g, 3 times a day for 12 months) in addition to WM. The primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization. The secondary endpoint included rehospitalization due to ACS, heart failure, stroke, and other thrombotic events. Quality of life was assessed by the Seattle Angina Questionnaire (SAQ). RESULTS: A total of 936 patients completed follow-up of the primary endpoint from February 2012 to December 2018. Overall, 487 patients received QSYQ and WM. During a median follow-up of 566 days (inter quartile range, IQR, 517-602), the primary endpoint occurred in 46 (9.45%) and 65 (14.48%) patients in QSYQ and WM groups respectively [adjusted hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.41-0.90; P=0.013]. The secondary endpoint occurred in 61 (12.53%) and 74 (16.48%) patients in QSYQ and WM groups, respectively (adjusted HR 0.76, 95% CI 0.53-1.09; P=0.136). In sensitivity analysis, the results still demonstrated that WM combined with QSYQ reduced the risk of the primary endpoint (HR 0.67, 95% CI 0.46-0.98; P=0.039). Moreover, QSYQ improved the disease perception domain of the SAQ (P<0.05). CONCLUSION: In patients with ACS after PCI, QSYQ combined with WM reduced the incidence of the primary endpoint. These findings provide a promising option for managing ACS after PCI and suggest the potential treatment for reducing the risk of primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization through intermittent administration of QSYQ (Registration No. ChiCTR-OOC-14005552).
RESUMEN
Diabetic kidney disease (DKD) is a prevalent complication of diabetes, often leading to end-stage renal disease. Animal models have been widely used to study the pathogenesis of DKD and evaluate potential therapies. However, current animal models often fail to fully capture the pathological characteristics of renal injury observed in clinical patients with DKD. Additionally, modeling DKD is often a time-consuming, costly, and labor-intensive process. The current review aims to summarize modeling strategies in the establishment of DKD animal models by utilizing meta-analysis related methods and to aid in the optimization of these models for future research. A total of 1215 articles were retrieved with the keywords of "diabetic kidney disease" and "animal experiment" in the past 10 years. Following screening, 84 articles were selected for inclusion in the meta-analysis. Review manager 5.4.1 was employed to analyze the changes in blood glucose, glycosylated hemoglobin, total cholesterol, triglyceride, serum creatinine, blood urea nitrogen, and urinary albumin excretion rate in each model. Renal lesions shown in different models that were not suitable to be included in the meta-analysis were also extensively discussed. The above analysis suggested that combining various stimuli or introducing additional renal injuries to current models would be a promising avenue to overcome existing challenges and limitations. In conclusion, our review article provides an in-depth analysis of the limitations in current DKD animal models and proposes strategies for improving the accuracy and reliability of these models that will inspire future research efforts in the DKD research field.
Asunto(s)
Diabetes Mellitus , Nefropatías Diabéticas , Fallo Renal Crónico , Humanos , Animales , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Reproducibilidad de los Resultados , Riñón , Pruebas de Función Renal , Fallo Renal Crónico/complicacionesRESUMEN
Type I interferon (IFN) is considered as a bridge between innate and adaptive immunity. Proper activation or inhibition of type I IFN signaling is essential for host defense against pathogen invasion, tumor cell proliferation, and overactive immune responses. Due to intricate and diverse chemical structures, natural products and their derivatives have become an invaluable source inspiring innovative drug discovery. In addition, some natural products have been applied in clinical practice for infection, cancer, and autoimmunity over thousands of years and their promising curative effects and safety have been well-accepted. However, whether these natural products are primarily targeting type I IFN signaling and specific molecular targets involved are not fully elucidated. In the current review, we thoroughly summarize recent advances in the pharmacology researches of natural products for their type I IFN activity, including both agonism/activation and antagonism/inhibition, and their potential application as therapies. Furthermore, the source and chemical nature of natural products with type I IFN activity are highlighted and their specific molecular targets in the type I IFN pathway and mode of action are classified. In conclusion, natural products possessing type I IFN activity represent promising therapeutic strategies and have a bright prospect in the treatment of infection, cancer, and autoimmune diseases.
Asunto(s)
Productos Biológicos , Interferón Tipo I , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Inmunidad Innata , Transducción de Señal , Interferón Tipo I/metabolismoRESUMEN
Background: The downregulation of monoamines, especially dopamine in substantia nigra (SN) and norepinephrine in locus coeruleus (LC), may be responsible for freezing of gait (FOG) pathological basis in Parkinson's disease (PD). Methods: Thirty-two Parkinson's disease patients with freezing of gait (PD-FOG), 32 Parkinson's disease patients without freezing of gait (PD-NFOG) and 32 healthy controls (HC) underwent neuromelanin magnetic resonance imaging (NM-MRI). The volume, surface area and contrast to noise ratio (CNR) of SN and LC were measured and compared. The correlation analyses were conducted between the measurements of SN and LC with clinical symptoms. We plotted the receiver operating characteristic (ROC) curve and determined the sensitivity and specificity of the CNR of SN and LC for discriminating the PD-FOG from the PD-NFOG. Results: Both PD-FOG and PD-NFOG showed decreased volume, surface area and CNR of SN compared with HC. The PD-FOG exhibited decreased volume and surface area of LC compared with both PD-NFOG and HC groups, and decreased CNR of LC compared with HC group. The volume, surface area and CNR of SN were negatively correlated with the Unified Parkinson's Disease Rating Scale part III scores. The illness durations in PD patients were negatively correlated with the volume, surface area of SN, while not the CNR. And the volume and surface area of LC were negatively correlated with new freezing of gait questionnaire scores. ROC analyses indicated that the area under the curve (AUC) was 0.865 and 0.713 in the CNR of SN and LC, respectively, in PD versus HC, whereas it was 0.494 and 0.637 respectively, in PD-FOG versus PD-NFOG. Among these, for discriminating the PD from the HC, the sensitivity and specificity in the CNR of the SN was 90.6 and 71.9%, respectively, when the cut-off value was set at 2.101; the sensitivity and specificity in the CNR of the LC was 90.6 and 50.0%, respectively, when the cut-off value for CNR was set at 1.411. Conclusion: The dopaminergic changes in the SN were found across both PD-FOG and PD-NFOG, whilst LC noradrenergic neuron reduction was more evident in PD-FOG.
RESUMEN
Lipid-lowering therapy is an important tool for the treatment of lipid metabolic diseases, which are increasing in prevalence. However, the failure of conventional lipid-lowering drugs to achieve the desired efficacy in some patients, and the side-effects of these drug regimens, highlight the urgent need for novel lipid-lowering drugs. The liver and intestine are important in the production and removal of endogenous and exogenous lipids, respectively, and have an important impact on circulating lipid levels. Elevated circulating lipids predisposes an individual to lipid deposition in the vascular wall, affecting vascular function. Berberine (BBR) modulates liver lipid production and clearance by regulating cellular targets such as cluster of differentiation 36 (CD36), acetyl-CoA carboxylase (ACC), microsomal triglyceride transfer protein (MTTP), scavenger receptor class B type 1 (SR-BI), low-density lipoprotein receptor (LDLR), and ATP-binding cassette transporter A1 (ABCA1). It influences intestinal lipid synthesis and metabolism by modulating gut microbiota composition and metabolism. Finally, BBR maintains vascular function by targeting proteins such as endothelial nitric oxide synthase (eNOS) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). This paper elucidates and summarizes the pharmacological mechanisms of berberine in lipid metabolic diseases from a multi-organ (liver, intestine, and vascular system) and multi-target perspective.
RESUMEN
Idiopathic pulmonary fibrosis (IPF), characterized by aggravated alveolar destruction and fibrotic matrix deposition, tendentiously experiences the stage called acute exacerbation IPF (AE-IPF) and progresses to multiple organ damage, especially liver injury. Recent studies have found a variety of immune microenvironment disorders associated with elevated IPF risk and secondary organ injury, whereas current animal models induced with bleomycin (BLM) could not completely reflect the pathological manifestations of AE-IPF patients in clinic, and the exact underlying mechanisms are not yet fully explored. In the current study, we established an AE-IPF model by tracheal administration of a single dose of BLM and then repeated administrations of lipopolysaccharide in mice. This mouse model successfully recapitulated the clinical features of AE-IPF, including excessive intrapulmonary inflammation and fibrosis and extrapulmonary manifestations, as indicated by significant upregulation of Il6, Tnfa, Il1b, Tgfb, fibronectin, and Col1a1 in both lungs and liver and elevated serum aspartate transaminase and alanine transaminase levels. These effects might be attributed to the regulation of Th17 cells. By sharing this novel murine model, we expect to provide an appropriate experimental platform to investigate the pathogenesis of AE-IPF coupled with liver injury and contribute to the discovery and development of targeted interventions.
Asunto(s)
Fibrosis Pulmonar Idiopática , Ratones , Animales , Modelos Animales de Enfermedad , Fibrosis Pulmonar Idiopática/etiología , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Inflamación/complicaciones , Inflamación/patología , Fibrosis , Bleomicina/toxicidad , Hígado/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is widely believed to be a leading risk factor of colorectal cancer. Gut microbiota is a known vital player in the progression of UC. Si-Ni-San (SNS) has been considered to effectively treat colitis in clinical practice during thousands of years, yet whether SNS ameliorated acute colitis mouse model by modulating intestinal flora has not been distinctly elucidated. AIM OF THE STUDY: Our study aimed to elucidate the effect of SNS against acute murine colitis and focused on the underlying mechanisms of SNS targeting gut microbiota. MATERIALS AND METHODS: 16S RNA sequencing, molecular biological analysis, and fecal microbiota transplants (FMT) were conducted to reveal the mechanisms of SNS in regulating gut microbiota. RESULTS: In our study, SNS dramatically inhibited DSS-induced acute inflammatory responses by improving gut microbiota dysbiosis, as evidenced by decreased abundance proinflammatory species, upregulated abundance of anti-inflammatory species and potentially altered microbiota metabolite metabolism. Additionally, intestinal flora knockout and FMT experiments confirmed that the therapeutic effect of SNS on colitis was dependent on gut microbiota, and specifically on favoring the growth of potential probiotics, Akkermansia genus. Furthermore, we found that SNS alone and SNS combined with Akkermansia muciniphila (A. muciniphila) increased Mucin 2 (MUC2) production, thus enhancing the competitive edge of A. muciniphila among pathogenic gut microbiota. CONCLUSION: Our study shed lights on the underlying mechanism of SNS in attenuating acute murine colitis from the perspective of intestinal flora and provides novel insights into the discovery of adjacent therapeutic strategy against colitis based on SNS and probiotics. CLASSIFICATION: Gastro-intestinal system.
Asunto(s)
Colitis Ulcerosa , Colitis , Medicamentos Herbarios Chinos , Ratones , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Medicamentos Herbarios Chinos/uso terapéutico , Inflamación/patología , Sulfato de Dextran/toxicidad , Ratones Endogámicos C57BL , Colon/patología , Modelos Animales de EnfermedadRESUMEN
Immunotherapy has been regarded as a breakthrough in cancer treatment and achieved great success. However, the poor response rate is still a formidable challenge of current immunotherapies, especially in solid tumors without sufficient infiltration of immune cells, also known as "cold tumor." SAR405 is a highly specific VPS34 inhibitor and has been suggested as a potential approach converting "cold tumor" into "hot tumor" by inhibiting autophagy. In this study, a tri-functional doxorubicin (DOX) plus SAR405 liposome system is established and further modified with a novel anti-PD-L1 peptide JY4 for targeted delivery (DOX-SAR-JY4LIPO ). The data here demonstrate that in a lung cancer xenograft mouse model, by facilitating the tumoral enrichment of both SAR405 and DOX, DOX-SAR-JY4LIPO effectively increases the infiltration of cytotoxic lymphocytes in the tumor by synergizing DOX-induced immunogenic cell death (ICD) and SAR405-mediated upregulation of chemokines including CCL5 and CXCL10. As results, DOX-SAR-JY4LIPO significantly inhibits tumor growth, metastasis, and resurrection by re-educating immunosuppressive tumor microenvironment. In conclusion, this study not only proves the concept of inhibiting autophagy for better immune infiltration in the tumor but also presents a novel tri-functional liposomal system that overcomes the deficiencies of current therapies and holds great promise in cancer immunotherapy.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Animales , Ratones , Liposomas , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Doxorrubicina/uso terapéutico , Inmunoterapia/métodos , Autofagia , Línea Celular Tumoral , Microambiente Tumoral , Antígeno B7-H1/uso terapéuticoRESUMEN
BACKGROUND: Selenium is a trace element that has been reported to be effective in regulating glucose and lipid metabolism. However, there is conflicting evidence from different clinical trials of selenium supplementation in treating cardiometabolic diseases (CMDs). OBJECTIVE: This meta-analysis aimed to identify the effects of selenium supplementation on insulin resistance, glucose homeostasis, and lipid profiles in patients with CMDs. METHODS: Randomized controlled trials (RCTs) of selenium supplementation for treating CMDs were screened in five electronic databases. Insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), and glycosylated hemoglobin A1C (HbA1c) were defined as the primary outcome markers, and lipid profiles were considered the secondary outcome markers. RESULTS: Ten studies involving 526 participants were included in the meta-analysis. The results suggested that selenium supplementation significantly reduced serum insulin levels (standardized men difference [SMD]: -0.53; 95% confidence interval [CI] [-0.84, -0.21], p = 0.001, I2 = 68%) and HOMA-IR (SMD: -0.50, 95% CI [-0.86, -0.14], p = 0.006, I2 = 75%) and increased high-density lipoprotein cholesterol (HDL-C) levels (SMD: 0.97; 95% CI [0.26, 1.68], p = 0.007, I2 = 92%), but had no significant effect on FPG, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C). CONCLUSION: Current evidence supports the beneficial effects of selenium supplementation on reducing insulin levels, HOMA-IR, and increasing HDL-C levels. Selenium supplementation may be an effective strategy for reducing insulin resistance in patients with CMDs. However, more high-quality clinical studies are needed to improve the certainty of our estimates.
Asunto(s)
Enfermedades Cardiovasculares , Resistencia a la Insulina , Insulinas , Selenio , Masculino , Humanos , VLDL-Colesterol , Glucosa , LDL-Colesterol , Enfermedades Cardiovasculares/prevención & control , Suplementos DietéticosRESUMEN
Constipation has become an epidemic enteric medical problem, accompanied with increasing long-term sequelae. Gut microbiota and serotonin (5-HT) have been believed as predominant player in the treatment of constipation. In clinical practices, Shouhui Tongbian Capsule (SHTB) was found to effectively improve constipation symptoms and promote gastrointestinal motility. However, the specific mechanism of SHTB is not clearly elucidated. Our current study aims to explore the therapeutic effects of SHTB against the development of constipation and the underlying mechanisms related to gut bacterial and 5-HT. We established loperamide hydrochloride (LH)-induced experimental constipation mouse model to evaluate the effect of SHTB. 16S RNA sequencing, fecal microbiota transplants (FMT), high performance liquid chromatograph, and molecular biological analysis were performed to investigate the potential mechanisms of SHTB. Our data demonstrated that SHTB significantly ameliorated LH-induced experimental constipation and accelerated enteric motility via promoting 5-HT biosynthesis in enterochromaffin cells and enteric neuron growth of the enteric nervous system (ENS) in both the small intestine and colon. Additionally, SHTB significantly modulated gut microbiota dysbiosis and potentially altered microbiota metabolites to enhance intestinal 5-HT production. Finally, FMT study confirmed that the effects of SHTB on 5-HT production and constipation are dependent on modulating intestinal microbiota dysbiosis. In conclusion, our current study deciphered therapeutic mechanism of SHTB in the treatment of experimental constipation from perspectives of gut microbiota-5-HT-intetinal motility axis and provides novel insights into the appropriate and safe application of SHTB in the clinic.
Asunto(s)
Microbioma Gastrointestinal , Animales , Estreñimiento/inducido químicamente , Estreñimiento/tratamiento farmacológico , Disbiosis , Motilidad Gastrointestinal/fisiología , Loperamida/uso terapéutico , Ratones , Serotonina/metabolismoRESUMEN
Si-Wu-Tang (SWT), a traditional Chinese medicine formula firstly recorded from the Tang dynasty, has been reported to alleviate gynecological and liver diseases. We preliminarily demonstrated that SWT could improve liver fibrosis via modulating intestinal microbiota, but little was known about the mechanisms linking its therapeutic effects to the reshaped immune microenvironment within fibrotic livers. Thus, we established a bile duct ligation (BDL)-induced liver fibrosis murine model to evaluate the hepatoprotective effects and potential mechanisms of SWT. The high-performance liquid chromatography, RNA sequencing and other molecular biological techniques were also performed in our study. Our data demonstrated that SWT significantly improved BDL-induced liver fibrosis and inflammatory responses by inhibiting the expression of genes associated with extracellular matrix synthesis and degradation. Combined with the analysis of immune cell infiltration and gene set enrichment analysis (GSEA), we found that SWT remarkably repaired the unbalanced immune microenvironment by modulating the biological functions of different immune cells, especially for macrophages, neutrophils and CD8+ T cells. In addition, SWT significantly inhibited the activation of M2-like macrophages to reduce the release of profibrotic-cytokines and prevented the activation of neutrophils to suppress neutrophil extracellular trap formation. SWT also efficiently promoted the apoptosis of activated hepatic stellate cells via Fas/FasL signaling pathway, which might be mediated by CD8+ tissue-resident memory T cells. In conclusion, our research not only unraveled the intricate mechanisms underlying the hepatoprotective activities of SWT against liver fibrosis but also provided a novel therapeutic strategy for the treatment of liver fibrosis and its relative complications.
Asunto(s)
Linfocitos T CD8-positivos , Cirrosis Hepática , Ratones , Animales , Fibrosis , Cirrosis Hepática/tratamiento farmacológico , Ligadura , Citocinas , Conductos Biliares , HígadoRESUMEN
[This corrects the article DOI: 10.3389/fphys.2020.618983.].
RESUMEN
The construction of organelle-targeting nanomaterials is an effective way to improve tumor imaging and treatment. Here, a new type of composite nanomaterial named as PTTPB is developed. PTTPB is composed of organelle-targeting aggregation-induced emission photosensitizer TTPB and polydopamine nanomaterials. With the functional modification of TTPB, PTTPB can recognize sialic acid on the cell membrane and present mitochondrial targeted capabilities. The intake of PTTPB in cancerous cells can be increased by the recognition process of cell membrane. PTTPB can generate singlet oxygen for photodynamic therapy (PDT), and present good photothermal conversion ability with irradiation. The PTTPB with organelle-targeting imaging-guided can realize the tumor ablation with the synergistic effect of PDT and photothermal therapy.