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1.
Inflamm Res ; 73(6): 961-978, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38587531

ABSTRACT

BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by abnormal lipid deposition in the arteries. Programmed cell death is involved in the inflammatory response of atherosclerosis, but PANoptosis, as a new form of programmed cell death, is still unclear in atherosclerosis. This study explored the key PANoptosis-related genes involved in atherosclerosis and their potential mechanisms through bioinformatics analysis. METHODS: We evaluated differentially expressed genes (DEGs) and immune infiltration landscape in atherosclerosis using microarray datasets and bioinformatics analysis. By intersecting PANoptosis-related genes from the GeneCards database with DEGs, we obtained a set of PANoptosis-related genes in atherosclerosis (PANoDEGs). Functional enrichment analysis of PANoDEGs was performed and protein-protein interaction (PPI) network of PANoDEGs was established. The machine learning algorithms were used to identify the key PANoDEGs closely linked to atherosclerosis. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic potency of key PANoDEGs. CIBERSORT was used to analyze the immune infiltration patterns in atherosclerosis, and the Spearman method was used to study the relationship between key PANoDEGs and immune infiltration abundance. The single gene enrichment analysis of key PANoDEGs was investigated by GSEA. The transcription factors and target miRNAs of key PANoDEGs were predicted by Cytoscape and online database, respectively. The expression of key PANoDEGs was validated through animal and cell experiments. RESULTS: PANoDEGs in atherosclerosis were significantly enriched in apoptotic process, pyroptosis, necroptosis, cytosolic DNA-sensing pathway, NOD-like receptor signaling pathway, lipid and atherosclerosis. Four key PANoDEGs (ZBP1, SNHG6, DNM1L, and AIM2) were found to be closely related to atherosclerosis. The ROC curve analysis demonstrated that the key PANoDEGs had a strong diagnostic potential in distinguishing atherosclerotic samples from control samples. Immune cell infiltration analysis revealed that the proportion of initial B cells, plasma cells, CD4 memory resting T cells, and M1 macrophages was significantly higher in atherosclerotic tissues compared to normal tissues. Spearman analysis showed that key PANoDEGs showed strong correlations with immune cells such as T cells, macrophages, plasma cells, and mast cells. The regulatory networks of the four key PANoDEGs were established. The expression of key PANoDEGs was verified in further cell and animal experiments. CONCLUSIONS: This study evaluated the expression changes of PANoptosis-related genes in atherosclerosis, providing a reference direction for the study of PANoptosis in atherosclerosis and offering potential new avenues for further understanding the pathogenesis and treatment strategies of atherosclerosis.


Subject(s)
Atherosclerosis , Gene Expression Profiling , Atherosclerosis/genetics , Atherosclerosis/immunology , Animals , Protein Interaction Maps/genetics , Transcriptome , Humans , Computational Biology , Male , Pyroptosis/genetics , Mice
2.
J Nanobiotechnology ; 21(1): 293, 2023 Aug 24.
Article in English | MEDLINE | ID: mdl-37620914

ABSTRACT

The regeneration of weight-bearing bone defects and critical-sized cartilage defects remains a significant challenge. A wide range of nano-biomaterials are available for the treatment of bone/cartilage defects. However, their poor compatibility and biodegradability pose challenges to the practical applications of these nano-based biomaterials. Natural biomaterials inspired by the cell units (e.g., nucleic acids and proteins), have gained increasing attention in recent decades due to their versatile functionality, compatibility, biodegradability, and great potential for modification, combination, and hybridization. In the field of bone/cartilage regeneration, natural nano-based biomaterials have presented an unparalleled role in providing optimal cues and microenvironments for cell growth and differentiation. In this review, we systematically summarize the versatile building blocks inspired by the cell unit used as natural nano-based biomaterials in bone/cartilage regeneration, including nucleic acids, proteins, carbohydrates, lipids, and membranes. In addition, the opportunities and challenges of natural nano-based biomaterials for the future use of bone/cartilage regeneration are discussed.


Subject(s)
Cartilage , Nucleic Acids , Biocompatible Materials/pharmacology , Bone Regeneration , Cell Cycle
3.
Mater Today Bio ; 22: 100741, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37576867

ABSTRACT

Treatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Traditional strategies in bone tissue engineering have focused primarily on mimicking the extracellular matrix (ECM) of bone in terms of structure and composition. However, the synergistic effects of other cues from the microenvironment during bone regeneration are often neglected. The bone microenvironment is a sophisticated system that includes physiological (e.g., neighboring cells such as macrophages), chemical (e.g., oxygen, pH), and physical factors (e.g., mechanics, acoustics) that dynamically interact with each other. Microenvironment-targeted strategies are increasingly recognized as crucial for successful bone regeneration and offer promising solutions for advancing bone tissue engineering. This review provides a comprehensive overview of current microenvironment-targeted strategies and challenges for bone regeneration and further outlines prospective directions of the approaches in construction of bone organoids.

4.
J Mater Chem B ; 11(36): 8565-8585, 2023 09 20.
Article in English | MEDLINE | ID: mdl-37415547

ABSTRACT

Bone tumors, including primary bone tumors and bone metastases, have been plagued by poor prognosis for decades. Although most tumor tissue is removed, clinicians are still confronted with the dilemma of eliminating residual cancer cells and regenerating defective bone tissue after surgery. Therefore, functional biomaterial scaffolds are considered to be the ideal candidates to bridge defective tissues and restrain cancer recurrence. Through functionalized structural modifications or coupled therapeutic agents, they provide sufficient mechanical strength and osteoinductive effects while eliminating cancer cells. Numerous novel approaches such as photodynamic, photothermal, drug-conjugated, and immune adjuvant-assisted therapies have exhibited remarkable efficacy against tumors while exhibiting low immunogenicity. This review summarizes the progress of research on biomaterial scaffolds based on different functionalization strategies in bone tumors. We also discuss the feasibility and advantages of the combined application of multiple functionalization strategies. Finally, potential obstacles to the clinical translation of anti-tumor bone bioscaffolds are highlighted. This review will provide valuable references for future advanced biomaterial scaffold design and clinical bone tumor therapy.


Subject(s)
Biocompatible Materials , Bone Neoplasms , Humans , Biocompatible Materials/pharmacology , Biocompatible Materials/therapeutic use , Biocompatible Materials/chemistry , Tissue Scaffolds/chemistry , Tissue Engineering , Bone Neoplasms/drug therapy , Bone and Bones
5.
Pharmaceutics ; 14(5)2022 May 17.
Article in English | MEDLINE | ID: mdl-35631656

ABSTRACT

Titanium and its alloys are the most widely applied orthopedic and dental implant materials due to their high biocompatibility, superior corrosion resistance, and outstanding mechanical properties. However, the lack of superior osseointegration remains the main obstacle to successful implantation. Previous traditional surface modification methods of titanium-based implants cannot fully meet the clinical needs of osseointegration. The construction of local drug delivery systems (e.g., antimicrobial drug delivery systems, anti-bone resorption drug delivery systems, etc.) on titanium-based implants has been proved to be an effective strategy to improve osseointegration. Meanwhile, these drug delivery systems can also be combined with traditional surface modification methods, such as anodic oxidation, acid etching, surface coating technology, etc., to achieve desirable and enhanced osseointegration. In this paper, we review the research progress of different local drug delivery systems using titanium-based implants and provide a theoretical basis for further research on drug delivery systems to promote bone-implant integration in the future.

6.
Front Pharmacol ; 13: 897539, 2022.
Article in English | MEDLINE | ID: mdl-35548357

ABSTRACT

Signal transducer and activator of transcription 3 (Stat3) is activated by phosphorylation and translocated to the nucleus to participate in the transcriptional regulation of DNA. Increasing evidences point that aberrant activation or deletion of the Stat3 plays a critical role in a broad range of pathological processes including immune escape, tumorigenesis, and inflammation. In the bone microenvironment, Stat3 acts as a common downstream response protein for multiple cytokines and is engaged in the modulation of cellular proliferation and intercellular interactions. Stat3 has direct impacts on disease progression by regulating mesenchymal stem cells differentiation, osteoclast activation, macrophage polarization, angiogenesis, and cartilage degradation. Here, we describe the theoretical basis and key roles of Stat3 in different bone-related diseases in combination with in vitro experiments and animal models. Then, we summarize and categorize the drugs that target Stat3, providing potential therapeutic strategies for their use in bone-related diseases. In conclusion, Stat3 could be a future target for bone-related diseases.

7.
Front Bioeng Biotechnol ; 10: 866627, 2022.
Article in English | MEDLINE | ID: mdl-35497358

ABSTRACT

With the global escalation of the aging process, the number of patients with bone diseases is increasing year by year. Currently, there are limited effective treatments for bone diseases. Exosome, as a vital medium in cell-cell communication, can mediate tissue metabolism through the paracrine transmission of various cargos (proteins, nucleic acids, lipids, etc.) carried by itself. Recently, an increasing number of researchers have proven that exosomes play essential roles in the formation, metabolism, and pathological changes of bone and cartilage. Because exosomes have the advantages of small size, rich sources, and low immunogenicity, they can be used not only as substitutes for the traditional treatment of bone diseases, but also as biomarkers for the diagnosis of bone diseases. This paper reviews the research progress of several kinds of cells derived-exosomes in bone diseases and provides a theoretical basis for further research and clinical application of exosomes in bone diseases in the future.

8.
Mol Med Rep ; 26(1)2022 07.
Article in English | MEDLINE | ID: mdl-35593299

ABSTRACT

Bone homeostasis is maintained by osteoclast-mediated bone resorption and osteoblast­mediated bone formation. Disruption of bone homeostasis due to excessive osteoclastogenesis or reduced osteogenesis results in various disorders, such as postmenopausal osteoporosis. Receptor activator of NF­κB ligand (RANKL) stimulation of the NF­κB signaling pathway is essential in osteoclastogenesis. The aim of the present study was to investigate the novel effects of carnosol, an active compound found in Rosmarinus officinalis, on RANKL­induced osteoclastogenesis both in vitro and in vivo. TRAP staining showed that carnosol significantly inhibited osteoclasts differentiation of bone marrow monocytes and RAW264.7 cells. Western blot results showed that the protein expression levels of osteoclastogenesis­associated genes, including cathepsin K, tartrate­resistant acid phosphatase and MMP­9, were markedly inhibited by carnosol, which may have suppressed osteoclast function. Furthermore, western blot and immunofluorescent staining results revealed that carnosol markedly suppressed the phosphorylation of p65 induced by RANKL and blocked its nuclear translocation, indicating the suppression of NF­κB signaling pathway. H&E staining and micro­CT results showed that in vivo treatment with carnosol significantly attenuated ovariectomy­induced bone loss in mice. In conclusion, the present study indicated that carnosol may suppress osteoclastogenesis both in vivo and in vitro by inhibiting the activation of the NF­κB signaling pathway. Carnosol may therefore be a potential novel therapeutic candidate for the clinical treatment of osteoclast­related disorders.


Subject(s)
Bone Resorption , Osteogenesis , Abietanes , Animals , Bone Resorption/metabolism , Cell Differentiation , Female , Humans , Mice , NF-kappa B/metabolism , Osteoclasts/metabolism , RANK Ligand/metabolism , RANK Ligand/pharmacology , RAW 264.7 Cells , Signal Transduction
9.
Front Bioeng Biotechnol ; 10: 866208, 2022.
Article in English | MEDLINE | ID: mdl-35433664

ABSTRACT

In-situ bone tissue regeneration, which harnesses cell external microenvironment and their regenerative potential to induce cell functions and bone reconstruction through some special properties of biomaterials, has been deeply developed. In which, hydrogel was widely applied due to its 3D network structure with high water absorption and mimicking native extracellular matrix (ECM). Additionally, exosomes can participate in a variety of physiological processes such as cell differentiation, angiogenesis and tissue repair. Therefore, a novel cell-free tissue engineering (TE) using exosome-laden hydrogels has been explored and developed for bone regeneration in recent years. However, related reviews in this field are limited. Therefore, we elaborated on the shortcomings of traditional bone tissue engineering, the challenges of exosome delivery and emphasized the advantages of exosome-laden hydrogels for in-situ bone tissue regeneration. The encapsulation strategies of hydrogel and exosomes are listed, and the research progress and prospects of bioactive hydrogel composite system for continuous delivery of exosomes for in-situ bone repair are also discussed in this review.

10.
Front Cell Dev Biol ; 10: 844050, 2022.
Article in English | MEDLINE | ID: mdl-35295856

ABSTRACT

There has been a rapid development of biomimetic platforms using cell membranes as nanocarriers to camouflage nanoparticles for enhancing bio-interfacial capabilities. Various sources of cell membranes have been explored for natural functions such as circulation and targeting effect. Biomedical applications of cell membranes-based delivery systems are expanding from cancer to multiple diseases. However, the natural properties of cell membranes are still far from achieving desired functions and effects as a nanocarrier platform for various diseases. To obtain multi-functionality and multitasking in complex biological systems, various functionalized modifications of cell membranes are being developed based on physical, chemical, and biological methods. Notably, many research opportunities have been initiated at the interface of multi-technologies and cell membranes, opening a promising frontier in therapeutic applications. Herein, the current exploration of natural cell membrane functionality, the design principles for engineered cell membrane-based delivery systems, and the disease applications are reviewed, with a special focus on the emerging strategies in engineering approaches.

11.
Biomed Res Int ; 2021: 6885897, 2021.
Article in English | MEDLINE | ID: mdl-34307667

ABSTRACT

Osteosarcoma (OS) is a type of bone malignancy with a high rate of treatment failure. To date, few evident biomarkers for the prognostic significance of OS have been established. Oncomine was used to integrate RNA and DNA-seq data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and the published literature. The correlation of the gene Trophinin (TRO) and different types of cancers was generated using the Cancer Cell Line Encyclopedia (CCLE) online tool. Prognostic values of featured Melanoma Antigen Gene (MAGE) members were further assessed by establishing the overall survival using the Kaplan-Meier plotter. Moreover, the online tool, Database for Annotation, Visualization and Integrated Discovery version (DAVID), was used to understand the biological meaning list of the genes. MAGEB10, MAGED2, TRO, MAGEH1, MAGEB18, MAGEB6, MAGEB4, MAGEB1, MAGED4B, MAGED1, MAGEB2, and MAGEB3 were significantly overexpressed in sarcoma. TRO was further demonstrated to be distinctively upregulated in osteosarcoma cell lines and associated with shorter overall survival. TRO may play an important role in the development of OS and may be a promising potential biomarker and prognostic factor.


Subject(s)
Biomarkers, Tumor/metabolism , Bone Neoplasms/metabolism , Cell Adhesion Molecules/metabolism , Data Mining , Databases, Genetic , Genome, Human , Osteosarcoma/diagnosis , Osteosarcoma/metabolism , Bone Neoplasms/diagnosis , Bone Neoplasms/genetics , Cell Line, Tumor , Gene Ontology , Humans , Kaplan-Meier Estimate , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Osteosarcoma/genetics , Prognosis
12.
Aging (Albany NY) ; 13(13): 17370-17379, 2021 07 01.
Article in English | MEDLINE | ID: mdl-34198266

ABSTRACT

In this study, we used bioinformatics and an in vitro cellular model of glucocorticoid-induced osteoporosis to investigate mechanisms underlying the beneficial effects of baicalein (BN) against osteoporosis. STITCH database analysis revealed 30 BN-targeted genes, including AKT1, CCND1, MTOR, and PTEN. Functional enrichment analysis demonstrated that BN-targeted genes were enriched in 49 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. MIRWALK2.0 database analysis identified 110 enriched KEGG pathways related to osteoporosis. A Venn diagram demonstrated that 26 KEGG pathways were common between osteoporosis and BN-targeted genes. The top 5 common KEGG pathways were prostate cancer, bladder cancer, glioma, pathways in cancer, and melanoma. BN-targeted genes in the top 5 shared KEGG pathways were involved in PI3K-AKT, MAPK, p53, ErbB, and mTOR signaling pathways. In addition, glucocorticoid-induced osteoporosis in MC3T3-E1 cells was partially reversed by BN through inhibition of AKT, which, by upregulating FOXO1, enhanced expression of bone turnover markers (ALP, OCN, Runx2, and Col 1) and extracellular matrix mineralization. These findings demonstrate that BN suppresses osteoporosis via an AKT/FOXO1 signaling pathway.


Subject(s)
Bone Density Conservation Agents/pharmacology , Flavanones/pharmacology , Forkhead Box Protein O1/genetics , Osteoporosis/drug therapy , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/drug effects , 3T3 Cells , Animals , Bone and Bones/drug effects , Bone and Bones/metabolism , Calcification, Physiologic/drug effects , Calcification, Physiologic/genetics , Cyclin D1/genetics , Databases, Factual , Extracellular Matrix/metabolism , Forkhead Box Protein O1/drug effects , Glucocorticoids , Humans , Mice , Osteoporosis/chemically induced , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins c-akt/drug effects , TOR Serine-Threonine Kinases/genetics
13.
Chemosphere ; 253: 126729, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32289610

ABSTRACT

Microorganisms with high tetracycline (TC) degradation efficiencies are required for biological processes for TC-containing wastewater treatment. With multiple enrichment cultures, a TC-degrading strain TR5 was isolated from chicken manure mixture in a large broiler farm, which was identified as Klebsiella pneumoniae by 16S rRNA gene sequencing and biochemical properties. Strain TR5 could degrade TC quickly (∼90% within 36 h) with the initial TC concentration of 200 mg/L under optimized conditions via single-factor experiment coupled with RSM. Strain TR5 could detoxify TC and generate much less toxic products as long as cultured more than one day. Three TC-degrading pathways were proposed based on 8 possible products. A transformant containing a plasmid from TR5 acquired TC-degrading ability, indicating that TC-degrading genes were located on this plasmid. Complete sequencing of pYK5 showed that isomerase-, oxidoreductase-, and transferases-encoding genes were found and were inferred to be involved in TC degradation. TR5 may not degrade TC completely and it can utilize some carbon-containing compounds derived from TC via the effect of formylglutathione hydrolase-encoding gene. Our findings showed that strain TR5 could be a promising agent for wastewater treatment, and genes involved in TC degradation are worthy of further investigations for enzyme preparations development.


Subject(s)
Anti-Bacterial Agents/analysis , Genes, Bacterial , Klebsiella/metabolism , Metabolic Networks and Pathways/drug effects , Tetracycline/analysis , Wastewater/chemistry , Animals , Biodegradation, Environmental , Chickens/metabolism , Klebsiella/genetics , Manure/analysis , Metabolic Networks and Pathways/genetics , Plasmids , RNA, Ribosomal, 16S/genetics
14.
Ecotoxicol Environ Saf ; 190: 110149, 2020 Mar 01.
Article in English | MEDLINE | ID: mdl-31901807

ABSTRACT

Diets are shown to be capable of shaping the gut microbiota of earthworm, while the effects of distinct foods on bacterial communities of different digestive tracts of earthworm are unknown. For this purpose, cow dung (CD) and domestic sludge (DS) were chosen as diets for earthworms (Eisenia fetida), and different gut contents, namely gizzard + foregut area, hindgut, and mature vermi-compost were sampled for Illumina sequencing analysis. We found that there existed significant reductions in bacterial diversity and abundance in the gizzard + foregut area, where there were stable bacteria with the ability of biodegradation of xenobiotics, such as Amycolatopsis, Methylobacterium, Ralstonia, Ochrobactrum, and Sphingomonas. The decreases could be recovered in the hindgut and mature vermi-compost to different extents, suggesting that a bottleneck effect on the bacterial community occurred in the gizzard + foregut area. Beta-Proteobacteria was the most abundant subclass regardless of the different diets, and bacteria affiliated with gamma-, delta- and epsilon-subclasses were taken as food by the earthworms. Vermi-composts based on the various diets should be used differently according to different aims.


Subject(s)
Gastrointestinal Microbiome , Oligochaeta/physiology , Waste Disposal, Fluid , Animals , Bacteria , Biodegradation, Environmental , Cattle , Composting , Data Analysis , Feces , Female , Gastrointestinal Tract , Manure/microbiology , Oligochaeta/drug effects , Oligochaeta/microbiology , Sewage , Soil/chemistry , Xenobiotics/metabolism
15.
Environ Sci Pollut Res Int ; 26(33): 34412-34420, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31637618

ABSTRACT

Vermi-composting is considered to be a feasible method for reducing tetracycline resistance genes (TRGs) in the sludge. Nevertheless, the way different gut passages of earthworm might affect the fates of TRGs and whether this process is affected by tetracycline (TC) concentrations need to be further investigated. In this study, we examined the effects of TC concentrations on changes in TRGs and bacterial communities in gut passages of earthworm were determined by using quantitative PCR and Illumina high-throughput sequencing. TRGs and intI1 were mainly reduced in the hindgut under the TC concentrations ranging from 0 to 25 mg/kg, while they were enriched under higher TC stress exposure. Consequently, we suggest the TC limitation of 25 mg/kg in the domestic sludge (DS) for vermi-composting. Although the predominant genera were TC sensitive under TC stress, many bacterial hosts harboring multiple TRGs (especially those in the hindgut) should be paid further attention to. In the foregut, five genera with abundant tetracycline-resistant bacteria (TRB) were specialized taxa. Among these genera, Unclassified_Solirubrobacterales and Pirellulaceae were probably related to the digestion processes. Other unclassified taxa related to the TRGs were probably derived from the DS. Five genera with abundant TRB were shared in the gut passages, and three specialized genera in the hindgut. These genera could spread TRGs and intI1 to the environment. These results suggest that vermi-composting is a feasible approach for TRG control in the DS containing TC concentration that does not exceed 25 mg/kg. Fates of TRGs and intI1 widely differ in the gut passages, showing inevitable connections with bacterial communities.


Subject(s)
Environmental Monitoring , Oligochaeta/microbiology , Sewage/microbiology , Tetracycline Resistance/genetics , Animals , Anti-Bacterial Agents , Bacteria/genetics , Composting , Genes, Bacterial , Oligochaeta/drug effects , Tetracycline
16.
J Gen Appl Microbiol ; 65(3): 151-160, 2019 Jul 19.
Article in English | MEDLINE | ID: mdl-30686793

ABSTRACT

We created a combined system using duckweed and bacteria to enhance the efficiency of ammonium nitrogen (NH4+-N) and total nitrogen (TN) removal from aquaculture wastewater. Heterotrophic nitrifying bacterium was isolated from a sediment sample at an intensive land-based aquaculture farm. It was identified as Acinetobacter sp. strain A6 based on 16S rRNA gene sequence (accession number MF767879). The NH4+-N removal efficiency of the strain and duckweed in culture media and sampled aquaculture wastewater at 15°C was over 99% without any accumulation of nitrite or nitrate. This was significantly higher than strain A6 or duckweed alone. Interestingly, the presence of NO3- increased NH4+-N removal rate by 35.17%. Strain A6 and duckweed had mutual growth promoting-effects despite the presence of heavy metals and antibiotics stresses. In addition, strain A6 colonized abundantly and possibly formed biofilms in the inner leaves of duckweed, and possessed indoleacetic acid (IAA)- and siderophore-producing characteristics. The mutual growth promotion between strain A6 and duckweed may be the reason for their synergistic action of N removal.


Subject(s)
Acinetobacter/physiology , Alismatales/microbiology , Ammonium Compounds/isolation & purification , Host Microbial Interactions/physiology , Waste Disposal, Fluid/methods , Water Pollutants, Chemical/isolation & purification , Water Purification/methods , Acinetobacter/classification , Alismatales/growth & development , Aquaculture , Biodegradation, Environmental , Heterotrophic Processes , Phylogeny , Sewage/microbiology , Temperature
17.
J Pept Sci ; 25(1): e3135, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30467919

ABSTRACT

Overexpression of gonadotropin-releasing hormone (GnRH) receptor in many tumors but not in normal tissues makes it possible to use GnRH analogs as targeting peptides for selective delivery of cytotoxic agents, which may help to enhance the uptake of anticancer drugs by cancer cells and reduce toxicity to normal cells. The GnRH analogs [d-Cys6 , desGly10 , Pro9 -NH2 ]-GnRH, [d-Cys6 , desGly10 , Pro9 -NHEt]-GnRH, and [d-Cys6 , α-aza-Gly10 -NH2 ]-GnRH were conjugated with doxorubicin (Dox), respectively, through N-succinimidyl-3-maleimidopropionate as a linker to afford three new GnRH-Dox conjugates. The metabolic stability of these conjugates in human serum was determined by RP-HPLC. The antiproliferative activity of the conjugates was examined in GnRH receptor-positive MCF-7 human breast cancer cell line by MTT assay. The three GnRH-Dox conjugates showed improved metabolic stability in human serum in comparison with AN-152. The antiproliferative effect of conjugate II ([d-Cys6 , desGly10 , Pro9 -NHEt]-GnRH-Dox) on MCF-7 cells was higher than that of conjugate I ([d-Cys6 , desGly10 , Pro9 -NH2 ]-GnRH-Dox) and conjugate III ([d-Cys6 , α-aza-Gly10 -NH2 ]-GnRH-Dox), and the cytotoxicity of conjugate II against GnRH receptor-negative 3T3 mouse embryo fibroblast cells was decreased in comparison with free Dox. GnRH receptor inhibition test suggested that the antiproliferative activity of conjugate II might be due to the cellular uptake mediated by the targeting binding of [d-Cys6 -des-Gly10 -Pro9 -NHEt]-GnRH to GnRH receptors. Our study indicates that targeting delivery of conjugate II mediated by [d-Cys6 -des-Gly10 -Pro9 -NHEt]-GnRH is a promising strategy for chemotherapy of tumors that overexpress GnRH receptors.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Cytotoxins/pharmacology , Doxorubicin/pharmacology , Drug Carriers , Gonadotropin-Releasing Hormone/pharmacology , Oligopeptides/pharmacology , Animals , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Cross-Linking Reagents/chemistry , Cytotoxins/chemistry , Cytotoxins/metabolism , Doxorubicin/analogs & derivatives , Doxorubicin/metabolism , Drug Stability , Gene Expression , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/chemical synthesis , Gonadotropin-Releasing Hormone/metabolism , Humans , MCF-7 Cells , Maleimides/chemistry , Mice , NIH 3T3 Cells , Oligopeptides/chemical synthesis , Oligopeptides/metabolism , Protein Binding , Receptors, LHRH/genetics , Receptors, LHRH/metabolism , Succinimides/chemistry
18.
Front Pharmacol ; 9: 647, 2018.
Article in English | MEDLINE | ID: mdl-29973878

ABSTRACT

Bone metabolism is determined by a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. The imbalance due to over-activated osteoclasts plays an important role in various diseases. Activation of NF-κB and MAPK signaling pathways by receptor activator of nuclear factor -κB ligand (RANKL) is vital for osteoclastogenesis. Here, we for the first time explored the effects of 18ß-glycyrrhetinic acid (18ß-GA), a pentacyclic triterpenoid found in the Glycyrrhiza glabra L roots, on RANKL-induced osteoclastogenesis, osteoclast functions and signaling pathways in vitro and in vivo. In bone marrow monocytes (BMMs) and RAW264.7 cells, 18ß-GA inhibited osteoclastogenesis, decreased expression of TRAP, cathepsin K, CTR and MMP-9, blocked actin ring formation and compromised osteoclasts functions in a dose-dependent manner at an early stage with minimal effects on osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). For underlying molecular mechanisms, 18ß-GA inhibited RANKL-induced phosphorylation of p65, p50, and IκB, blocked p65 nuclear translocation and decreased the DNA-binding activity of NF-κB. Besides, 18ß-GA inhibited the activation of the MAPK pathways. Co-immunoprecipitation showed that 18ß-GA treatment blocked RANK-TRAF6 association at an upstream site. In vivo, 18ß-GA treatment inhibited ovariectomy-induced osteoclastogenesis and reduced bone loss in mice. Overall, our results demonstrated that 18ß-GA inhibited RANKL-induced osteoclastogenesis by inhibiting RANK expression in preosteoclasts and blocking the binding of RANK and TRAF6 which lead to the inhibition of NF-κB and MAPK signaling pathways. 18ß-GA is a promising novel candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis.

19.
Sci Rep ; 8(1): 1489, 2018 01 24.
Article in English | MEDLINE | ID: mdl-29367695

ABSTRACT

By performing a microcosm experiment mimicking fertilization, we assessed the dynamic distribution of tetracycline-resistant bacteria (TRB) and corresponding tetracycline resistance genes (TRGs) from pig manure (PM) to the fertilized soil, by culture-dependent methods and PCR detection. Cultivable TRB were most abundant in PM, followed by fertilized soil and unfertilized soil. By restriction fragment length polymorphism (RFLP) analysis, TRB were assigned to 29, 20, and 153 operational taxonomic units (OTUs) in PM, unfertilized soil, and fertilized soil, respectively. After identification, they were further grouped into 19, 12, and 62 species, showing an enhanced diversity of cultivable TRB in the soil following PM application. The proportions of potentially pathogenic TRB in fertilized soil decreased by 69.35% and 41.92% compared with PM and unfertilized soil. Bacillus cereus was likely widely distributed TRB under various environments, and Rhodococcus erythropolis and Acinetobacter sp. probably spread from PM to the soil via fertilization. Meanwhile, tetL was the most common efflux pump gene in both unfertilized and fertilized soils relative to PM; tetB(P) and tet36 were common in PM, whereas tetO was predominant in unfertilized and fertilized soil samples. Sequencing indicated that over 65% of randomly selected TRB in fertilized soil with acquired resistance derived from PM.


Subject(s)
Bacteria/drug effects , Fertilizers/microbiology , Genes, Bacterial , Manure/microbiology , Soil Microbiology , Tetracycline Resistance/genetics , Tetracycline/pharmacology , Agriculture , Animals , Anti-Bacterial Agents/pharmacology , Bacteria/genetics , Bacteria/isolation & purification , Soil , Swine
20.
Yao Xue Xue Bao ; 46(10): 1221-4, 2011 Oct.
Article in Chinese | MEDLINE | ID: mdl-22242454

ABSTRACT

The study on the buds of Jasminum officinale L. var. grandiflorum was carried out to look for anti-HBV constituents. The isolation and purification were performed by HPLC and chromatography on silica gel, polyamide and Sephadex LH-20 column. The structures were elucidated on the basis of physicochemical properties and spectral analysis. Six iridoid glycosides were identified as jasgranoside B (1), 6-O-methy-catalpol (2), deacetyl asperulosidic acid (3), aucubin (4), 8-dehydroxy shanzhiside (5), and loganin (6). Jasgranoside B (1) is a new compound. Compounds 2-6 were isolated from Jasminum officinale L. var. grandiflorum for the first time.


Subject(s)
Glucosides/isolation & purification , Iridoid Glycosides/isolation & purification , Jasminum/chemistry , Plants, Medicinal/chemistry , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Flowers/chemistry , Glucosides/chemistry , Glucosides/pharmacology , Hep G2 Cells , Hepatitis B Surface Antigens/metabolism , Hepatitis B virus/immunology , Humans , Inhibitory Concentration 50 , Iridoid Glucosides/chemistry , Iridoid Glucosides/isolation & purification , Iridoid Glycosides/chemistry , Iridoid Glycosides/pharmacology , Iridoids/chemistry , Iridoids/isolation & purification , Molecular Structure
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