ABSTRACT
PURPOSE: Tumor initiating cells (TICs) or cancer stem cells (CSCs) are considered to be the main culprit of hepatocellular carcinoma (HCC) initiation and progression, nevertheless the mechanism by which tumor microenvironment maintains the HCC 'stemness' is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC. METHODS: Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC 'stemness'. Additionally, after forced expression or inhibition of FoxP3, ß-catenin expression and HCC 'stemness' were investigated. RESULTS: Tregs enhanced the 'stemness' of HCC cells by upregulating TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and inducting epithelial to mesenchymal transition (EMT), increasing TICs ratio, as well as promoting tumorigenic ability. Moreover, ß-catenin and c-Myc were upregulated in HCC cells after co-cultured with Tregs. HCC 'stemness' was inhibited after treatment with Wnt/ß-catenin pathway inhibitor. Furthermore, forced expression of FoxP3 resulted in increased GSK3ß, decreased ß-catenin and TIC ratio in HCC. In contrast, FoxP3 interference reduced GSK3ß, enhanced ß-catenin and TIC ratio of HCC. CONCLUSION: This study, for the first time, demonstrated that Tregs increased the population of TICs in HCC by inhibiting FoxP3 as well as promoting ß-catenin expression.
Subject(s)
Carcinoma, Hepatocellular , Forkhead Transcription Factors , Kruppel-Like Factor 4 , Liver Neoplasms , Neoplastic Stem Cells , T-Lymphocytes, Regulatory , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/immunology , Liver Neoplasms/metabolism , Humans , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/immunology , Forkhead Transcription Factors/metabolism , T-Lymphocytes, Regulatory/immunology , Kruppel-Like Factor 4/metabolism , Mice , Animals , Cell Line, Tumor , Tumor Microenvironment/immunology , Epithelial-Mesenchymal Transition , beta Catenin/metabolism , Mice, Nude , Wnt Signaling Pathway , Mice, Inbred BALB CABSTRACT
The secretory leukocyte protease inhibitor (SLPI) is mainly produced by immune cells and various epithelial cells, and is regulated by a variety of cytokines, such as transforming growth factor ß1, interleukin 1ß and tumor necrosis factor α. In addition to commonly known anti-protease activity, it has been found in recent years that SLPI plays essential roles in anti-apoptosis, regulating cell cycle, cell differentiation and proliferation, and inhibiting inflammatory response. SLPI can also assist the immune system to clear pathogens/damaged cells by enhancing the phagocytic function of phagocytes, so as to ameliorate tissue damage and promote repair. Moreover, recent studies have shown that the change of SLPI level in the serum of patients post cardiovascular surgery has a high diagnostic value in predicting the occurrence of acute kidney injury, suggesting that SLPI is involved in ischemia-reperfusion (IR) induced acute kidney injury. In this review, we summarized the expression, regulation, signaling pathways and associated biological events of SLPI in different organ injury models, and also discussed and evaluated the potential role of SLPI in renoprotection against IR induced acute kidney injury and its potential as a new biomarker.
Subject(s)
Acute Kidney Injury , Reperfusion Injury , Secretory Leukocyte Peptidase Inhibitor , Acute Kidney Injury/metabolism , Acute Kidney Injury/etiology , Acute Kidney Injury/physiopathology , Humans , Reperfusion Injury/metabolism , Animals , Secretory Leukocyte Peptidase Inhibitor/metabolism , Secretory Leukocyte Peptidase Inhibitor/physiology , Signal TransductionABSTRACT
The recovery of biopolymers, particularly alginate-like extracellular polymers, from municipal sludge represents a promising step toward sustainable sludge treatment practices. Originating from wastewater plants in complexly polluted environments, alginate-like extracellular polymers carry potential environmental risks concerning their reuse. This study employs ultrahigh-performance liquid chromatography-tandem mass spectrometry to investigate the distribution coefficients and occurrence of alginate-like extracellular polymers and sulfamethoxazole. Results demonstrate a negative distribution coefficient, suggesting an inhibitory effect on sulfamethoxazole dissolution. The ethanol-extracted alginate-like extracellular polymers exhibits higher sulfamethoxazole levels (approximately 52%) than those obtained via dialysis extraction. Three-dimensional excitation-emission matrix analysis and adsorption studies indicate the absence of tyrosine-like substances in the alginate-like extracellular polymers, unlike in other extracellular polymeric substances. This absence diminishes hydrophobic interactions, highlighting that electrostatic interactions play a more important role. These insights are crucial for understanding the adsorption behavior of alginate-like extracellular polymers and optimizing their large-scale extraction processes.
Subject(s)
Alginates , Sewage , Sulfamethoxazole , Alginates/chemistry , Sewage/chemistry , Adsorption , Glucuronic Acid/chemistry , Chromatography, High Pressure Liquid , Extracellular Polymeric Substance Matrix/chemistry , Extracellular Polymeric Substance Matrix/metabolism , Polymers/chemistry , Tandem Mass SpectrometryABSTRACT
This study aims to investigate the impact of Kuntai Capsules(KTC) on polycystic ovarian syndrome(PCOS) rat models and explore the underlying mechanism. Fifty female SD rats were randomly divided into five groups(10 rats in each group), including control group, model group, low-, medium-, and high-dose KTC group. Except for the control group, the other groups were injected with dehydroepiandrosterone(DHEA) combined with a high-fat diet(HFD) to induce the PCOS rat model for 28 days. 0.315, 0.63, and 1.26 g·kg~(-1)·d~(-1) KTC was dissolved in the same amount of normal saline and given to low-, medium-, and high-dose KTC groups by gavage. Both control group and model group were given the same amount of normal saline for 15 days. After administration, fasting blood glucose(FBG) was measured by a glucose meter. Fasting insulin(FINS), luteinizing hormone(LH), testosterone(T), and follicle-stimulating hormone(FSH) were detected by enzyme-linked immunosorbent assay(ELISA), and LH/FSH ratio and insulin resistance index(HOMA-IR) were calculated. The pathological morphology of ovarian tissue was observed by hematoxylin-eosin(HE) staining. The expression levels of collagen α type â ¢ 1 chain(COL3A1), apoptotic factors Bax, and Bcl-2 were detected using Western blot and immunofluorescence. The mRNA expressions of COL3A1, Bax, and Bcl-2 in ovarian tissue were performed by real-time PCR(RT-PCR). The results show that compared with the control group, the body weight, serum levels of FBG, FINS, LH, T, LH/FSH, and HOMA-IR are higher in model group(P<0.05 or P<0.01), and the level of FSH is lower(P<0.05). In model group, a large number of white blood cells are found in the vaginal exfoliated cells, mainly in the interictal phase. There are more cystic prominences on the surface of the ovary. The thickness of the granular cell layer is reduced, and oocytes are absent. COL3A1 and Bax protein expression levels are increased(P<0.01), while Bcl-2 protein expression levels are decreased(P<0.05) in the ovarian tissue COL3A1 and Bax mRNA expression levels are increased in ovarian tissue(P<0.05). Compared with the model group, the body weight, FBG, FINS, LH, T, LH/FSH, and HOMA-IR in low-, medium-, and high-dose KTC groups are decreased(P<0.05 or P<0.01), while the levels of FSH in medium-, and high-dose KTC groups are increased(P<0.05 or P<0.01). Low-, medium-, and high-dose KTC groups gradually show a stable interictal phase. The surface of the ovary is smooth. Oocytes and mature follicles can be seen in ovarian tissue, and the thickness of the granular cell layer is increased. The expression level of COL3A1 protein decreases in low-and medium-dose KTC groups(P<0.05 or P<0.01), and that of Bax protein decreases in low-dose KTC group(P<0.05 or P<0.01), and the expression level of Bcl-2 protein increases in low-dose KTC group(P<0.01). The expression levels of COL3A1 and Bax mRNA decreased in the low-dose KTC group(P<0.05), while the expression levels of Bcl-2 mRNA increased(P<0.05). In summary, KTC can inhibit ovarian granulosa cell apoptosis and reduce follicular atresia by regulating the AGE-RAGE signaling pathway. It can promote insulin secretion, reduce blood sugar and body weight, restore serum hormone levels, improve symptoms of PCOS, alleviate morphological damage of the ovary, and restore ovarian function, which is of great value in the treatment of PCOS.
Subject(s)
Polycystic Ovary Syndrome , Humans , Rats , Female , Animals , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/genetics , bcl-2-Associated X Protein , Saline Solution , Rats, Sprague-Dawley , Follicular Atresia , Signal Transduction , Body Weight , Follicle Stimulating Hormone , RNA, MessengerSubject(s)
Fractures, Bone , Muscular Diseases , Infant , Humans , Mutation , Fractures, Bone/epidemiology , Fractures, Bone/etiologyABSTRACT
Central nervous system (CNS) diseases have become one of the leading causes of death in the global population. The pathogenesis of CNS diseases is complicated, so it is important to find the patterns of the disease to improve the treatment strategy. Microglia are considered to be a double-edged sword, playing both harmful and beneficial roles in CNS diseases. Therefore, it is crucial to understand the progression of the disease and the changes in the polar phenotype of microglia to provide guidance in the treatment of CNS diseases. Microglia activation may evolve into different phenotypes: M1 and M2 types. We focused on the roles that M1 and M2 microglia play in regulating intercellular dialogues, pathological reactions and specific diseases in CNS diseases. Importantly, we summarized the strategies used to modulate the polarization phenotype of microglia, including traditional pharmacological modulation, biological therapies, and physical strategies. This review will contribute to the development of potential strategies to modulate microglia polarization phenotypes and provide new alternative therapies for CNS diseases.
Subject(s)
Central Nervous System Diseases , Microglia , Humans , Microglia/pathology , Central Nervous System Diseases/therapy , Central Nervous System Diseases/pathology , PhenotypeABSTRACT
This study was to evaluate the efficacy of an integrated mycotoxin-mitigating agent in reducing the adverse effects of co-occurring dietary aflatoxin B1 deoxynivalenol and ochratoxin A on broiler breeder hens. 360 30-week-old Hubbard Efficiency Plus broiler breeder hens were allocated into four groups and received a basal diet (BD; Control), BD added 0.15 mg/kg aflatoxin B1+1.5 mg/kg deoxynivalenol+0.12 mg/kg ochratoxin A (Toxins), BD plus Toxins with 0.1% TOXO-XL (Toxins + XL1), and BD plus Toxins with 0.2% TOXO-XL (Toxins + XL2), respectively, for 8 weeks, and then received the same BD for another 4 weeks. Compared with control, mycotoxins decreased total egg weigh, egg laying rate, settable eggs rate, hatch of total eggs rate, egg quality, but increased feed/egg ratio and mortality rate, and impaired the liver and oviduct health during weeks 1-8 and(or) 9-12. It also increased PC and MDA concentrations, TUNEL-positive cells and IL-1ß and IL-6 expression, and decreased T-AOC, GPX and CAT activities in liver and/or oviduct. Notably, most of these negative changes were mitigated by both dosages of TOXO-XL. Generally, 0.2% TOXO-XL displayed better mitigation effects than 0.1% TOXO-XL. Conclusively, these findings revealed that TOXO-XL could mitigate the combined mycotoxins-induced toxicity on the performance, liver and oviduct health, through the regulation of redox, immunity, and apoptosis in broiler breeder hens.
Subject(s)
Mycotoxins , Humans , Animals , Female , Mycotoxins/toxicity , Mycotoxins/metabolism , Chickens/metabolism , Aflatoxin B1/toxicity , Aflatoxin B1/metabolism , Diet , Liver/metabolism , Oviducts/metabolism , Animal Feed/analysisABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there is a lack of effective therapeutic drugs. There is great potential for natural products to be used in the development of anti-AD drugs. P-coumaric acid (PCA), a small molecule phenolic acid widely distributed in the plant kingdom, has pharmacological effects such as neuroprotection, but its anti-AD mechanism has not been fully elucidated. In the current study, we investigated the mechanism of PCA intervention in the Aß25-35-induced AD model using gut microbiomics and serum metabolomics combined with in vitro and in vivo pharmacological experiments. PCA was found to ameliorate cognitive dysfunction and neuronal cell damage in Aß25-35-injected mice as measured by behavioral, pathological and biochemical indicators. 16S rDNA sequencing and serum metabolomics showed that PCA reduced the abundance of pro-inflammatory-associated microbiota (morganella, holdemanella, fusicatenibacter and serratia) in the gut, which were closely associated with metabolites of the glucose metabolism, arachidonic acid metabolism, tyrosine metabolism and phospholipid metabolism pathways in serum. Next, in vivo and in vitro pharmacological investigations revealed that PCA regulated Aß25-35-induced disruption of glucose metabolism through activation of PI3K/AKT/Glut1 signaling. Additionally, PCA ameliorated Aß25-35-induced neuroinflammation by inhibiting nuclear translocation of NF-κB and by modulating upstream MAPK signaling. In conclusion, PCA ameliorated cognitive deficits in Aß25-35-induced AD mice by regulating glucose metabolism and neuroinflammation, and the mechanism is related not only to restoring homeostasis of gut microbiota and serum metabolites, but also to PI3K/AKT/Glut1 and MAPK/NF-κB signaling.
Subject(s)
Alzheimer Disease , Gastrointestinal Microbiome , Neurodegenerative Diseases , Mice , Animals , Amyloid beta-Peptides/metabolism , Glucose Transporter Type 1/metabolism , NF-kappa B/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Neuroinflammatory Diseases , Neurodegenerative Diseases/pathology , Alzheimer Disease/chemically induced , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Glucose/metabolism , BrainABSTRACT
OBJECTIVE: To analyze the immunological phenotype of chronic myeloid leukemia (CML), and explore its characteristics and significance. METHODS: The immunophenotypes of 40 CML children and 40 controls were analyzed by multicolor flow cytometry. CD45/SSC, as the basic gate, was used to delineate neutrophils. Then, the distribution of cluster differentiation (CD) molecules on the surface of granulocytes was analyzed in three ranges (≥1%, ≥5%, and ≥20%), and the expression rates of CD molecules (≥1% included in the statistical analysis) and the mean fluorescence intensity (MFI) were compared between the two groups. RESULTS: The proportion of granulocytes in the CML group was (82.1±6.4)%, which was significantly higher than (57.8±11.8)% in the control group (P <0.001). The expression rates of CD15/CD11b/CD33/CD13 in CML and control groups were high, and both distributed in the range of ≥20%. The differentiation trajectory of CD33/CD13 was normal and there were no significant differences in the expression rate and MFI between the two groups. However, both the expression rate of CD11b and CD15 MFI in the CML group were significantly lower than those in the control group (P <0.001). There were no significant differences in the expression rate and MFI of CD10 between the two groups, and the expression levels of CD10 between the two groups were consistent in different distributions. In the CML group, there was a large number of cases with abnormal high expression of CD56, 52.5% of the cases had a CD56 expression rate of ≥5%, and 42.5% had a CD56 expression rate of ≥20%, while the control group did not express CD56 (<1%). The expression distribution of CD117 was different between the two groups. In the range of expression rate ≥5%, there were 35.0% cases in the CML group, while only 2.5% in the control group. The expression rate of CD117 in the CML group was higher than that in the control group (P <0.001), though there was no significant difference in MFI. CONCLUSION: The immunophenotyping of CML is characterized by increased proportion of mature neutrophils, decreased CD15 MFI, decreased proportion of CD11b and abnormal high expression of CD56 and CD117. Flow cytometric analysis of immunophenotype can effectively distinguish normal granulocytes from chronic granulocytes, and help in the diagnosis of CML.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid , Child , Humans , Flow Cytometry , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Granulocytes , Neutrophils , ImmunophenotypingABSTRACT
Interferon-induced tetrapeptide repeat (IFIT) family proteins are an important component of the antiviral immune response. There are four known members of the human IFIT family, namely IFIT1, IFIT2, IFIT3 and IFIT5. More and more evidence shows that IFIT family members are involved in a variety of pathophysiological processes in vivo, regulate the homeostasis and differentiation of a variety of cells including immune cells, and are closely related to a variety of autoimmune diseases, which is expected to become a new therapeutic target. This review reviews the biological roles of different IFIT proteins in various autoimmune diseases, and highlights the potential use of these molecules as biomarkers and prognostic factors in autoimmune diseases, with a view to providing ideas for exploring the diagnosis and treatment of autoimmune diseases.
Subject(s)
Interferons , Tetratricopeptide Repeat , Humans , Adaptor Proteins, Signal Transducing , RNA-Binding Proteins/geneticsABSTRACT
This study was to evaluate the efficacy of TOXO-XL (XL), an integrated mycotoxin-mitigating agent, on aflatoxin B1 (AFB1)-induced damage in Leghorn male hepatoma (LMH), porcine jejunum epithelial cell line (IPEC-J2) and porcine alveolar macrophages (3D4/21) cells, and to explore its potential mechanisms. The results showed that 30% inhibition concentration (IC30) of AFB1 in LMH, IPEC-J2 and 3D4/21 cells was 0.5, 15.0, and 2.5 mg/L, respectively. Notably, cell viability, ROS, apoptosis and DNA lesion induced by AFB1 (IC30) could be ameliorated by the supplementation with XL at the dosage of 0.025, 0.025 and 0.005%, respectively. Additionally, the migration and phagocytosis abilities impaired by AFB1 were also restored by XL in 3D4/21. Further experiments revealed that XL supplementation markedly attenuated AFB1-induced inflammatory response by decreasing IL-1ß, IL-6 and IL-10 in LMH, IL-6 in IPEC-J2 and IL-1ß in 3D4/21 cells. Meanwhile, XL supplementation reversed the alterations of BAX, BCL-2 and caspase-3 induced by AFB1 in the three cells, suggesting that AFB1-induced apoptosis may be suppressed via the mitochondria-dependent pathway. Furthermore, XL may have a protective effect on the intestinal barrier through the restoration of occludin protein. Conclusively, these findings indicated that XL could alleviate AFB1-induced cytotoxicity in the three cells, potentially through the regulation of cytokines, ROS, apoptotic and DNA damage signaling.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Male , Swine , Animals , Reactive Oxygen Species/metabolism , Aflatoxin B1/toxicity , Aflatoxin B1/metabolism , Carcinoma, Hepatocellular/metabolism , Chickens/metabolism , Interleukin-6/metabolism , Epithelial Cells , Apoptosis , Liver Neoplasms/metabolismABSTRACT
A series of O-phenanthroline silver(I) complexes were synthesized and characterized by infrared (IR) spectroscopy, mass spectrometry (MS), 1H nuclear magnetic resonance (NMR) spectroscopy and single-crystal X-ray crystallography. The cytotoxicity of the silver(I) complex (P-131) was evaluated in the cancer cell lines HCT-116, HeLa, and MDA-MB-231 and the normal cell line LO2 via MTT assays. The 50% inhibition concentration (IC50) of P-131 on HCT116 cell line is 0.86 ± 0.03 µM. It is far lower than the IC50 value of cisplatin (9.08 ± 1.10 µM), the IC50 value of normal cell LO2 (76.20 ± 0.48 µM) is much higher than that of cisplatin (3.99 ± 0.74 µM), indicating that its anticancer effect is stronger than that of cisplatin, and its biological safety is greater than that of cisplatin. Furthermore, anticancer mechanistic studies showed that P-131 inhibited cell proliferation by blocking DNA synthesis and acted temporally on the nucleus in dividing HCT-116 cells. Moreover, P-131 increased intracellular reactive oxygen species (ROS) levels in a dose-dependent manner. Notably, 10 mg/kg P-131 showed better antitumor effects than oxaliplatin in an HCT116 human colorectal xenograft mouse model without inducing toxicity. Moreover, the microdilution broth method was used to evaluate the antimicrobial properties of P-131 against Pseudomonas aeruginosa and Candida albicans. A biofilm eradication study was also performed using the crystal violet method and confocal laser scanning microscopy.
Subject(s)
Adenocarcinoma , Anti-Infective Agents , Antineoplastic Agents , Colorectal Neoplasms , Coordination Complexes , Humans , Animals , Mice , Cisplatin/pharmacology , Silver/pharmacology , Silver/chemistry , Anti-Infective Agents/pharmacology , HeLa Cells , Colorectal Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Cell Proliferation , Cell Line, TumorABSTRACT
Rheumatoid arthritis (RA) is a chronic autoimmune disease of unexplained causes. Its pathological features include synovial tissue hyperplasia, inflammatory cell infiltration in joint cavity fluid, cartilage bone destruction, and joint deformation. C-C motif chemokine ligand 3 (CCL3) belongs to inflammatory cell chemokine. It is highly expressed in inflammatory immune cells. Increasingly, studies have shown that CCL3 can promote the migration of inflammatory factors to synovial tissue, the destruction of bone and joint, angiogenesis, and participate in the pathogenesis of RA. These symptoms indicate that the expression of CCL3 is highly correlated with RA disease. Therefore, this paper reviews the possible mechanism of CCL3 in the pathogenesis of RA, which may provide some new insights for the diagnosis and treatment of RA.
ABSTRACT
The essential oils of Ligusticum chuanxiong Hort. (CXEO) are considered to be important parts of the pharmacological action of Ligusticum chuanxiong Hort. CXEO have a wide range of applications in various fields. Despite the interesting properties of CXEO, the volatility and low solubility have limited the application. Liposomes are vesicles composed of concentric bilayer lipids arranged around the water environment. Therefore, this study aimed to prepare stable CXEO liposomes (CXEO-LP) to improve the properties. Then, CXEO-LP were prepared by thin film dispersion method and optimized. The results showed that CXEO-LP were well dispersed. Subsequently, in vitro release and antioxidant properties of CXEO-LP were researched. CXEO-LP had slow release effect and oxidation resistance, indicating CXEO-LP may be a potential drug for treating cerebral ischemia-reperfusion injury (CIRI). The nasal mucosa toxicity test and acute toxicity test showed that CXEO-LP had no obvious toxicity to nasal cavity, heart, liver, spleen, lung and kidney tissues. Pharmacodynamic studies found that CXEO-LP significantly improved neurological deficits and brain pathology in a mouse model of CIRI compared to CXEO after intranasal administration. In general, this study showed that CXEO-LP were easy to prepare and continuously released, and had an important development prospect in the treatment of CIRI.
Subject(s)
Drugs, Chinese Herbal , Ligusticum , Oils, Volatile , Reperfusion Injury , Mice , Animals , Oils, Volatile/pharmacology , Oils, Volatile/therapeutic use , Liposomes , Drugs, Chinese Herbal/therapeutic use , Reperfusion Injury/drug therapyABSTRACT
Acute kidney injury (AKI) is a common critical disease clinically with high morbility and mortality and some survival patients also progress to chronic kidney disease. Renal ischemia-reperfusion (IR) is one of the main causes of AKI, in which, its repair and potential fibrosis, apoptosis, inflammation and phagocytosis play important roles. During the progression of IR-induced AKI, the expression of erythropoietin homodimer receptor (EPOR)2 and EPOR and ß common receptor formed heterodimer receptor (EPOR/ßcR) is changed dynamically. Moreover, (EPOR)2 and EPOR/ßcR may synergistically participate in renoprotection at the stage of AKI and early repair, whereas at the late stage of AKI, the (EPOR)2 induces renal fibrosis and the EPOR/ßcR facilitates repair and remodelling. The underlying mechanism, signaling pathways and the different effect turning point of (EPOR)2 and EPOR/ßcR have not been well defined. It has been reported that EPO, according to its 3D structure, derived helix B surface peptide (HBSP) and cyclic HBSP (CHBP) only bind to EPOR/ßcR. Synthesized HBSP, therefore, provides an effective tool to distinguish the different roles and mechanisms of both receptors, with the (EPOR)2 promoting fibrosis or the EPOR/ßcR leading to repair/remodelling at the late stage of AKI. This review discusses the similarities and differences of (EPOR)2 and EPOR/ßcR in their impacts on apoptosis, inflammation and phagocytosis in AKI, repair and fibrosis post IR, associated mechanisms, signaling pathways and outcomes.
Subject(s)
Acute Kidney Injury , Reperfusion Injury , Humans , Receptors, Erythropoietin , Apoptosis , Inflammation , PhagocytosisABSTRACT
A macrocyclic tetra-imidazolium salt (2) based on quinoxaline was prepared and characterized. The recognition of 2 to nitro compounds was investigated by fluorescence spectroscopy, 1H NMR titrations, MS, IR spectroscopy, and UV/vis spectroscopy. The results displayed that 2 was able to effectively differentiate p-dinitrobenzene from other nitro compounds via the fluorescence method.
ABSTRACT
A series of (8-hydroxyquinoline) gallium(III) complexes (CP-1-4) was synthesized and characterized by single X-ray crystallography and density functional theory (DFT) calculation. The cytotoxicity of the four gallium complexes toward a human nonsmall cell lung cancer cell line (A549), human colon cancer cell line (HCT116), and human normal hepatocyte cell line (LO2) was evaluated using MTT assays. CP-4 exhibited excellent cytotoxicity against HCT116 cancer cells (IC50 = 1.2 ± 0.3 µM) and lower toxicity than cisplatin and oxaliplatin. We also evaluated the anticancer mechanism studies in cell uptake, reactive oxygen species analysis, cell cycle, wound-healing, and Western blotting assays. The results showed that CP-4 affected the expression of DNA-related proteins, which led to the apoptosis of cancer cells. Moreover, molecular docking tests of CP-4 were performed to predict other binding sites and to confirm its higher binding force to disulfide isomerase (PDI) proteins. The emissive properties of CP-4 suggest that this complex can be used for colon cancer diagnosis and treatment, as well as in vivo imaging. These results also provide a foundation for the development of gallium complexes as potent anticancer agents.
ABSTRACT
Background: Gallium (III) metal-organic complexes have been shown to have the ability to inhibit tumor growth, but the poor water solubility of many of the complexes precludes further application. The use of materials with high biocompatibility as drug delivery carriers for metal-organic complexes to enhance the bioavailability of the drug is a feasible approach. Methods: Here, we modified the ligands of gallium 8-hydroxyquinolinate complex with good clinical anticancer activity by replacing the 8-hydroxyquinoline ligands with 5-bromo-8-hydroxyquinoline (HBrQ), and the resulting Ga(III) + HBrQ complex had poor water solubility. Two biocompatible materials, bovine serum albumin (BSA) and graphene oxide (GO), were used to synthesize the corresponding Ga(III) + HBrQ complex nanoparticles (NPs) BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs in different ways to enhance the drug delivery of the metal complex. Results: Both of BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs can maintain stable existence in different solution states. In vitro cytotoxicity test showed that two nanomedicines had excellent anti-proliferation effect on HCT116 cells, which shown higher level of intracellular ROS and apoptosis ratio than that of cisplatin and oxaliplatin. In addition, the superior emissive properties of BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs allow their use for in vivo imaging showing highly effective therapy in HCT116 tumor-bearing mouse models. Conclusion: The use of biocompatible materials for the preparation of NPs against poorly biocompatible metal-organic complexes to construct drug delivery systems is a promising strategy that can further improve drug delivery and therapeutic efficacy.
Subject(s)
Antineoplastic Agents , Drug Carriers , Gallium , Graphite , Metal Nanoparticles , Oxyquinoline , Animals , Humans , Mice , Biocompatible Materials , Cell Line, Tumor , Drug Carriers/chemical synthesis , Gallium/chemistry , Graphite/chemistry , HCT116 Cells , Metal Nanoparticles/analysis , Nanoparticles/analysis , Oxyquinoline/chemistry , Particle Size , Serum Albumin, Bovine/pharmacology , Water , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistryABSTRACT
Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg-1·d-1) or rosiglitazone (4 mg·kg-1·d-1) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ+/- mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ+/-) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ+/- CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.
Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Synoviocytes , Rats , Mice , Humans , Animals , Synoviocytes/metabolism , Tumor Necrosis Factor-alpha/metabolism , PPAR gamma/metabolism , Rosiglitazone/pharmacology , Rosiglitazone/therapeutic use , Rosiglitazone/metabolism , Pioglitazone/pharmacology , Pioglitazone/metabolism , Tumor Suppressor Protein p53/metabolism , Cell Proliferation , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Fibroblasts/metabolism , Cells, Cultured , Synovial Membrane/metabolismABSTRACT
Background: The frequent exacerbator phenotype of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is characterized by experiencing at least two exacerbations per year, leading to a significant economic burden on healthcare systems worldwide. Although several biomarkers have been shown to be effective in assessing AECOPD severity in recent years, there is a lack of studies on markers to predict the frequent exacerbator phenotype of AECOPD. The current study aimed to develop a new predictive model for the frequent exacerbator phenotype of AECOPD based on rapid, inexpensive, and easily obtained routine markers. Methods: This was a single-center, retrospective study that enrolled a total of 2,236 AECOPD patients. The participants were divided into two groups based on the frequency of exacerbations: infrequent group (n=1,827) and frequent group (n=409). They underwent a complete blood count, as well as blood biochemistry, blood lipid and coagulation testing, and general characteristics were also recorded. Univariate analysis and binary multivariate logistic regression analyses were used to explore independent risk factors for the frequent exacerbator phenotype of AECOPD, which could be used as components of a new predictive model. The receiver operator characteristic (ROC) curve was used to assess the predictive value of the new model, which consisted of all significant risk factors predicting the primary outcome. The nomogram risk prediction model was established using R software. Results: Age, gender, length of stay (LOS), neutrophils, monocytes, eosinophils, direct bilirubin (DBil), gamma-glutamyl transferase (GGT), and the glucose-to-lymphocyte ratio (GLR) were independent risk factors for the frequent exacerbator phenotype of AECOPD. The area under the curve (AUC) of the new predictive model was 0.681 [95% confidence interval (CI): 0.653-0.708], and the sensitivity was 63.6% (95% CI: 58.9-68.2%) and the specificity was 65.0% (95% CI: 60.3-69.6%). Conclusions: A new predictive model based on demographic characteristics and blood parameters can be used to predict the frequency of acute exacerbations in the management of chronic obstructive pulmonary disease (COPD).