ABSTRACT
BACKGROUND: Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. METHODS: Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. RESULTS: We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1+ metabolism subtype (Metab-subtype), TOP2A+ proliferation phenotype (Prol-phenotype), and S100A6+ pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-ß signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-ß-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis. CONCLUSION: By establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6+ tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Single-Cell Analysis , Tumor Microenvironment , Liver Neoplasms/pathology , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Humans , Gene Expression Regulation, Neoplastic , Epithelial-Mesenchymal Transition/genetics , Animals , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Fibroblasts/metabolism , Fibroblasts/pathology , Genetic Heterogeneity , Mice , Cell Line, Tumor , Prognosis , Gene Expression Profiling , Transcriptome , Computational Biology/methods , Neoplasm MetastasisABSTRACT
Efficient and multiple CO2 utilization into high-value-added chemicals holds significant importance in carbon neutrality and industry production. However, most catalysis systems generally exhibit only one type of CO2 transformation with the efficiency to be improved. The restricted abundance of active catalytic sites or an inefficient utilization rate of these sites results in the constraint. Consequently, we designed and constructed two metal hydrogen-bonded organic frameworks (M-HOFs) {[M3(L3-)2(H2O)10]·2H2O}n (M = Co (1), Ni (2); L = 1-(4-carboxyphenyl)-1H-pyrazole-3,5-dicarboxylic acid) in this research. 1 and 2 are well-characterized, and both show excellent stability. The networks connected by multiple hydrogen bonds enhance the structural flexibility and create accessible Lewis acidic sites, promoting interactions between the substrates and catalytic centers. This enhancement facilitates efficient catalysis for two types of CO2 transformations, encompassing both cycloaddition reactions with epoxides and aziridines to afford cyclic carbonates and oxazolidinones. The catalytic activities (TON/TOF) are superior compared with those of most other catalysts. These heterogeneous catalysts still exhibited high performance after being reused several times. Mechanistic studies indicated intense interactions between the metal sites and substrates, demonstrating the reason for efficient catalysis. This marks the first instance on M-HOFs efficiently catalyzing two types of CO2 conversions, finding important significance for catalyst design and CO2 utilization.
ABSTRACT
Effective CO2 transformations hold essential significance for carbon neutrality and sustainable energy development. Carboxylative cyclization of propargylic amines with CO2 serves as an atom-economic reaction to afford oxazolidinones, showing broad applications in organic synthesis and pharmaceutical fields. However, most catalysts involved noble metals, exhibited low efficiency, or required large amounts of base. Hence, it is imperative to explore alternative noble-metal-free catalysts in order to achieve efficient conversion while minimizing the use of additives. Herein, a novel nanopore-based Cu(II)-organic framework (1) based on a new imidazole carboxylic ligand was successfully constructed and exhibited excellent stability. Catalytic investigations revealed that the combination of 1 with 1,4-diaza[2.2.2]bicyclooctane (DABCO) efficiently catalyzed the carboxylative cyclization of propargylic amines with CO2, achieving turnover numbers of 142 based on the catalyst and 7.1 based on DABCO. 1 as a heterogeneous catalyst maintained high catalytic performance even after being reused at least 5 cycles, with its structure remaining stable. The strong activation of Cu(II) cluster nodes of catalyst 1 toward -NH- groups within organic substrates, as demonstrated by mechanism experiments, along with excellent CO2 adsorption performance and the presence of regular 1D channels, synergistically facilitates the reaction rate. This research presents the first instance of a Cu(II)-organic framework achieving this cyclization reaction, offering wide prospects for novel catalyst design and CO2 utilization.
ABSTRACT
AIMS: In this study, the control effects of synthetic microbial communities composed of peanut seed bacteria against seed aflatoxin contamination caused by Aspergillus flavus and root rot by Fusarium oxysporum were evaluated. METHODS AND RESULTS: Potentially conserved microbial synthetic communities (C), growth-promoting synthetic communities (S), and combined synthetic communities (CS) of peanut seeds were constructed after 16S rRNA Illumina sequencing, strain isolation, and measurement of plant growth promotion indicators. Three synthetic communities showed resistance to root rot and CS had the best effect after inoculating into peanut seedlings. This was achieved by increased defense enzyme activity and activated salicylic acid (SA)-related, systematically induced resistance in peanuts. In addition, CS also inhibited the reproduction of A. flavus on peanut seeds and the production of aflatoxin. These effects are related to bacterial degradation of toxins and destruction of mycelia. CONCLUSIONS: Inoculation with a synthetic community composed of seed bacteria can help host peanuts resist the invasion of seeds by A. flavus and seedlings by F. oxysporum and promote the growth of peanut seedlings.
Subject(s)
Aflatoxins , Seeds , RNA, Ribosomal, 16S/genetics , Seeds/microbiology , Fungi/genetics , Seedlings/microbiology , Bacteria/genetics , Arachis/microbiologyABSTRACT
Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1-10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.
Subject(s)
Antineoplastic Agents , Frizzled Receptors , Neoplasms , Wnt Signaling Pathway , Humans , Frizzled Receptors/metabolism , Frizzled Receptors/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Wnt Signaling Pathway/drug effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Animals , Molecular Targeted Therapy/methodsABSTRACT
The evaluation of germplasm resources is the prerequisite for the development, utilization, and conservation of Chinese medicinal resources. The selection of excellent germplasm is the key to the breeding and orderly production of Pinellia ternata. In this study, 21 germplasm materials of P. ternata from major production areas in China were collected and analyzed for population diversity after phenotypic preliminary screening. The results have revealed that the P. ternata population has abundant phenotypic variation, and the phenotypic changes could be divided into five phenotypes in terms of organ trait variation. Further analysis of variation in 20 quantitative traits of the population revealed that the coefficient of variation for adenosine content(339.05%) was the largest, while the coefficient of variation for the underground plant height(16.35%) was the smallest. Correlation analysis showed that there was a strong correlation among various traits, with 52 pairs of traits showing highly significant correlation(P<0.01) and 19 pairs of traits showing a significant correlation(P<0.05). The 21 germplasms in the test could be classified into three major clusters by cluster analysis, with Cluster â ¡ having the highest number and content of nucleosides, making it suitable for the selection and breeding of P. ternata varieties with high content of nucleosides. The yield in Cluster â ¢ was higher than that in other groups, making it suitable for the selection and breeding of P. ternata varieties with a high yield. All trait indicators could be simplified into five principal component factors through principal component analysis, and the cumulative contribution rate was up to 86.04%. Further, comprehensive analysis using membership function and stepwise regression analysis identified nine traits, such as plant height, main leaf length, and underground plant height as characteristic indicators for the comprehensive evaluation of germplasm resources of P. ternata. BX007, BX008, and BX005 were identified as germplasms with both high yield and high uridine content, with BX007 having the highest uridine content of 479.51 µg·g~(-1). It belonged to the germplasm of P. ternata with double bulbils and could be cultivated as a potential good variety. Based on the phenotypic classification of P. ternata, systematic resource evaluation was carried out in this study, which could lay a foundation for the excavation of genetic resources and the breeding of new varieties of P. ternata.
Subject(s)
Pinellia , Plants, Medicinal , Pinellia/genetics , Plant Breeding , Phenotype , UridineABSTRACT
Liver metastasis is a leading indicator of poor prognosis in patients with colorectal cancer (CRC). Exosomal intercellular communication has been reported to play an important role in cancer invasion and metastasis. Here, we characterized exosomal miRNAs underlying liver metastasis in CRC patients (Cohort 1, n = 30) using miRNA arrays. Exosomal miR-150 was found to be downregulated in CRC patients with liver metastases compared to those without (P = 0.025, fold change [FC] = 2.01). These results were then validated using another independent cohort of CRC patients (Cohort 2, n = 64). Patients with low expression of exosomal miR-150 had significantly shorter overall survival (OS) time (33.3 months versus 43.3 months, P = 0.002). In addition, the low expression of exosomal miR-150 was significantly correlated with advanced tumor node metastasis staging (P = 0.013), higher CA199 level (P = 0.018), and the presence of liver metastasis (P = 0.048). Multivariate analysis showed that low expression of exosomal miR-150 (P = 0.035) and liver metastasis (P < 0.001) were independent prognostic factors for overall survival. In vivo and in vitro studies showed that the viability and invasion of CRC cells were both significantly suppressed by ExomiR-150. Target-prediction assessment and dual-luciferase reporter assay indicated that FTO (the fat mass and obesity-associated gene) was a direct target for miR-150. This study first demonstrated that exosomal miR-150 may be a potential prognostic factor and treatment target for CRC.
Subject(s)
Colorectal Neoplasms , Exosomes , Liver Neoplasms , MicroRNAs , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/surgery , Colorectal Neoplasms/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/surgery , Liver Neoplasms/metabolism , Prognosis , Exosomes/metabolism , Gene Expression Regulation, Neoplastic , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/geneticsABSTRACT
Metastasis is an important cause of cancer-related death. Previous studies in our laboratory found that pregnane alkaloids from Pachysandra terminalis had antimetastatic activity against breast cancer cells. In the current study, we demonstrated that treatment with one of the alkaloid derivatives, (Z)-3ß-ethylamino-pregn-17(20)-en (1), led to the downregulation of the HIF-1α/VEGF/VEGFR2 pathway, suppressed the phosphorylation of downstream molecules Akt, mTOR, FAK, and inhibited breast cancer metastasis and angiogenesis both in vitro and in vivo. Furthermore, the antimetastasis and antiangiogenesis effects of 1 treatment (40 mg/kg) were more effective than that of Sorafenib (50 mg/kg). Surface plasmon resonance (SPR) analysis was performed and the result suggested that HSP90α was a direct target of 1. Taken together, our results suggested that compound 1 might represent a candidate antitumor agent for metastatic breast cancer.
Subject(s)
Alkaloids , Antineoplastic Agents , Triple Negative Breast Neoplasms , Humans , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Vascular Endothelial Growth Factor A/metabolism , Triple Negative Breast Neoplasms/drug therapy , Sorafenib/therapeutic use , Cell Line, Tumor , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Antineoplastic Agents/pharmacology , TOR Serine-Threonine Kinases/metabolism , Alkaloids/pharmacology , Alkaloids/therapeutic use , Pregnanes/pharmacology , Hypoxia-Inducible Factor 1, alpha SubunitABSTRACT
PURPOSE: Magnesium-based alloy scaffold is a promising biodegradable stent due to its intrinsic mechanical performance and biocompatibility. Based on our preliminary experiments, we designed a novel sirolimus-eluting magnesium-based alloy scaffold. This work aimed to assess its safety and degradation performance in vivo. METHODS: The scaffolds were implanted in the lower limb arteries of Bama mini-pigs. Safety was defined as no immediate thrombosis or >30% residual stenosis, which was assessed with optical coherence tomography and digital subtraction angiography. Blood biochemical analyses were performed to evaluate hepatorenal toxicity. The degradation process of the scaffolds, the endothelialization, and lumen loss of the stented-vessels were detected with scanning electron microscopy, immunohistochemical, hematoxylin-eosin staining and optical coherence tomography. RESULTS: Twenty-four scaffolds were successfully implanted in six pigs with no signs of immediate thrombosis or >30% residual stenosis. The scaffolds were covered by endothelium at one month and absolutely resorbed at six months post implantation. Blood analysis showed that the hepatorenal function except for alanine aminotransferase and γ-glutamyl transpeptidase was normal. Obvious intimal hyperplasia and lumen loss were found in the stented vessels at three months, while the diameters and inner lumen areas of stented segments had increased significantly at six months (p.
Subject(s)
Magnesium , Sirolimus , Absorbable Implants , Alloys , Animals , Arteries , Coronary Angiography , Coronary Vessels , Swine , Swine, MiniatureABSTRACT
This paper describes the identification of chlorhexidine, an agent commonly used in clinical as a novel potential allosteric inhibitor of PAK1. In cellular assays, chlorhexidine showed a good inhibitory profile, and its inhibitory profile was even better than IPA-3, a well-known allosteric inhibitor. In pharmacology experiments, chlorhexidine successfully inhibited the relief of PAK1 dimer and inhibited the activation of PAK1. Our findings offer an insight for the new drug development of PAK1 inhibitor. We also provide a possible explanation for the phenomenon that the application of the chlorhexidine in peritoneal lavage inhibited the development of tumor.
Subject(s)
Chlorhexidine/administration & dosage , Chlorhexidine/chemistry , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , p21-Activated Kinases/chemistry , p21-Activated Kinases/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Binding Sites , Cell Line, Tumor , Humans , Molecular Docking Simulation , Molecular Targeted Therapy/methods , Neoplasms, Experimental/pathology , Protein Binding , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistryABSTRACT
BACKGROUND: Lung cancer ranks as the leading cause of cancer-related deaths worldwide and we performed this meta-analysis to investigate eligible studies and determine the prognostic effect of Ki-67. METHODS: In total, 108 studies in 95 articles with 14,732 patients were found to be eligible, of which 96 studies reported on overall survival (OS) and 19 studies reported on disease-free survival (DFS) with relation to Ki-67 expression in lung cancer patients. RESULTS: The pooled hazard ratio (HR) indicated that a high Ki-67 level could be a valuable prognostic factor for lung cancer (HR = 1.122 for OS, P < 0.001 and HR = 1.894 for DFS, P < 0.001). Subsequently, the results revealed that a high Ki-67 level was significantly associated with clinical parameters of lung cancer including age (odd ratio, OR = 1.246 for older patients, P = 0.018), gender (OR = 1.874 for males, P < 0.001) and smoking status (OR = 3.087 for smokers, P < 0.001). Additionally, significant positive correlations were found between Ki-67 overexpression and poorer differentiation (OR = 1.993, P = 0.003), larger tumor size (OR = 1.436, P = 0.003), and higher pathologic stages (OR = 1.867 for III-IV, P < 0.001). Furthermore, high expression of Ki-67 was found to be a valuable predictive factor for lymph node metastasis positive (OR = 1.653, P < 0.001) and advanced TNM stages (OR = 1.497 for stage III-IV, P = 0.024). Finally, no publication bias was detected in any of the analyses. CONCLUSIONS: This study highlights that the high expression of Ki-67 is clinically relevant in terms of the prognostic and clinicopathological characteristics for lung cancer. Nevertheless, more prospective well-designed studies are warranted to validate these findings.
Subject(s)
Biomarkers, Tumor/biosynthesis , Gene Expression Regulation, Neoplastic , Ki-67 Antigen/biosynthesis , Lung Neoplasms/diagnosis , Lung Neoplasms/metabolism , Biomarkers, Tumor/genetics , Humans , Ki-67 Antigen/genetics , Prognosis , Prospective StudiesABSTRACT
OBJECTIVE: Circular RNAs (circRNAs) are a newfound class of non-coding RNA in animals and plants. Recent studies have revealed that circRNAs play important roles in cell proliferation, differentiation, autophagy and apoptosis during development. However, there are few reports about muscle development-related circRNAs in livestock. METHODS: RNA sequencing analysis was employed to identify and annotate circRNAs from longissimus dorsi of sheep. Reverse transcription followed by real-time quantitative (q) polymerase chain reaction (PCR) analysis verified the presence of these circRNAs. Targetscan7.0 and miRanda were used to analyse the interaction of circRNA-microRNA (miRNA). To investigate the function of circRNAs, an experiment was conducted to perform enrichment analysis hosting genes of circRNAs using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways. RESULTS: About 75.5 million sequences were obtained from RNA libraries of sheep skeletal muscle. These sequences were mapped to 729 genes in the sheep reference genome. We identified 886 circRNAs, including numerous circular intronic RNAs and exonic circRNAs. Reverse transcription PCR (RT-PCR) and DNA sequencing analysis confirmed the presence of several circRNAs. Real-Time RT-PCR analysis exhibited resistance of sheep circRNAs to RNase R digestion. We found that many circRNAs interacted with muscle-specific miRNAs involved in growth and development of muscle, especially circ776. The GO and KEGG enrichment analysis showed that hosting genes of circRNAs was involved in muscle cell development and signaling pathway. CONCLUSION: The study provides comprehensive expression profiles of circRNAs in sheep skeletal muscle. Our study offers a large number of circRNAs to facilitate a better understanding of their roles in muscle growth. Meanwhile, we suggested that circ776 could be analyzed in future study.
ABSTRACT
Direct functionalization of the benzylic C-H bond of diarylmethanes is an important strategy for the synthesis of diarylmethine-containing compounds. However, the methods developed to date for this purpose require a stoichiometric amount (usually more) of either a strong base or an oxidant. Reported here is the first catalytic benzylic C-H bond addition of diarylmethanes to styrenes and conjugated dienes. A potassium zincate complex, generated from potassium benzyl and zinc amide, acts as a catalyst and displays good activity and chemoselectivity. Considering the atom economy of the reaction and the ready availability of the catalyst, this reaction constitutes a practical, efficient method for diarylalkane synthesis.
ABSTRACT
The benzylic functionalization of alkylpyridines is an important pathway for pyridine derivatives synthesis. The reaction partners, however, were mostly limited to highly reactive polar electrophiles. Herein, we report a potassium amide-catalyzed selective benzylic C-H bond addition of alkylpyridines to styrenes. Potassium bis(trimethylsilyl)amide (KHMDS), a readily available Brønsted base, showed excellent catalytic activity and chemoselectivity. A series of alkylpyridine derivatives, including benzylic quaternary carbon substituted pyridines, were obtained in good to high yield. Preliminary mechanistic studies revealed that the deprotonation equilibrium is probably responsible for the excellent selectivity.
ABSTRACT
Three new (1-3) and one known (4) bioactive terpenoids were isolated from the seeds of Silybum marianum based on the investigation to get new NO inhibitors. Their structures were determined by extensive NMR (1D and 2D NMR) and MS spectroscopic data, and the absolute configurations were identified by experimental and calculated ECD spectra. The NO inhibitory activities in murine microglial BV-2 cells and interactions with iNOS protein by molecular docking were evaluated for all compounds. The results showed that these compounds had potent NO inhibitory effects.
Subject(s)
Nitric Oxide Synthase Type II/metabolism , Nitric Oxide/metabolism , Silybum marianum/chemistry , Terpenes/chemistry , Animals , Binding Sites , Cell Line , Circular Dichroism , Lipopolysaccharides/toxicity , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Silybum marianum/metabolism , Molecular Conformation , Molecular Docking Simulation , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Nitric Oxide Synthase Type II/antagonists & inhibitors , Plant Extracts/chemistry , Protein Structure, Tertiary , Seeds/chemistry , Seeds/metabolism , Terpenes/isolation & purification , Terpenes/pharmacologyABSTRACT
PURPOSE: To clearly delineate the anatomy of the musculus longus capitis, determine its clinical applications for reconstruction surgery, and provide a safer surgical method of developing the longus capitis muscle flap. METHODS: Anatomical investigations were performed in seven adult cadavers (five cadavers for gross anatomy and two for transparent specimen preparation) with respect to the location, morphology, arterial supply, and innervation of the musculus longus capitis, as well as its spatial relationship with the cervical sympathetic trunk, superior cervical ganglion, carotid sheath, and other surrounding structures. RESULTS: The musculus longus capitis is located anterior to the C1-6 vertebrae, segmentally supplied by branches of the ascending cervical artery, innervated by the C1-5 nerve, and spatially close to the cervical sympathetic trunk, superior cervical ganglion, and carotid sheath. These anatomic findings indicate that the development of a cranial or caudal pedicled longus capitis muscle flap is feasible. CONCLUSION: The musculus longus capitis can be developed into a cranial or caudal pedicled flap for repair of head and neck defects with negligible morbidity of the donor site.
Subject(s)
Cervical Plexus/anatomy & histology , Neck Muscles/anatomy & histology , Plastic Surgery Procedures/methods , Superior Cervical Ganglion/anatomy & histology , Surgical Flaps/surgery , Cadaver , Feasibility Studies , Female , Head/surgery , Humans , Male , Middle Aged , Neck/surgery , Neck Muscles/blood supply , Neck Muscles/innervationABSTRACT
Five new icetexane diterpenoids, namely, perovskatones B-D (1, 3, 4), 1α-hydroxybrussonol (2), and 1α-hydroxypisiferanol (5), were isolated from Perovskia atriplicifolia, together with a new natural product (6) and two known compounds, przewalskin E (7) and brussonol (8). The structures of the new compounds were elucidated by detailed analyses of their MS, IR, 1D, and 2D NMR data. Compounds 1-8 were assayed for their inhibitory hepatitis B virus activities in the HepG 2.2.15 cell line. The results suggested that compounds 1 and 2 possessed noticeable anti-hepatitis B virus activity in vitro, suppressing the replication of hepatitis B virus DNA with selectivity index values of 154.3 and 137.7, respectively.
Subject(s)
Antiviral Agents/pharmacology , Diterpenes/pharmacology , Hepatitis B virus/drug effects , Lamiaceae/chemistry , Plant Extracts/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/therapeutic use , Diterpenes/chemistry , Diterpenes/isolation & purification , Diterpenes/therapeutic use , Hep G2 Cells , Hepatitis B/drug therapy , Hepatitis B/virology , Humans , Molecular Structure , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/therapeutic useABSTRACT
Procyanidin B2 has demonstrated several health benefits and medical properties. However, its protective effects against CCl4-induced hepatotoxicity have not been clarified. The present study aimed to investigate the hepatoprotective effects of procyanidin B2 in CCl4-treated mice. Our data showed that procyanidin B2 significantly decreased the CCl4-induced elevation of serum alanine aminotransferase activities, as well as improved hepatic histopathological abnormalities. Procyanidin B2 also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD, CAT and GSH-Px. Further research demonstrated that procyanidin B2 decreased the expression of TNF-α, IL-1ß, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inhibited the translocation of nuclear factor-kappa B (NF-κB) p65 from the cytosol to the nuclear fraction in mouse liver. Moreover, CCl4-induced apoptosis in mouse liver was measured by (terminal-deoxynucleotidyl transferase mediated nick end labeling) TUNEL assay and the cleaved caspase-3. Meanwhile, the expression of apoptosis-related proteins Bax and Bcl-xL was analyzed by Western blot. Results showed that procyanidin B2 significantly inhibited CCl4-induced hepatocyte apoptosis, markedly suppressed the upregulation of Bax expression and restored the downregulation of Bcl-xL expression. Overall, the findings indicated that procyanidin B2 exhibited a protective effect on CCl4-induced hepatic injury by elevating the antioxidative defense potential and consequently suppressing the inflammatory response and apoptosis of liver tissues.
Subject(s)
Biflavonoids/pharmacology , Carbon Tetrachloride Poisoning/prevention & control , Catechin/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Proanthocyanidins/pharmacology , Animals , Apoptosis/drug effects , Carbon Tetrachloride Poisoning/metabolism , Chemical and Drug Induced Liver Injury/metabolism , Male , Mice , Mice, Inbred ICR , Oxidative Stress/drug effectsABSTRACT
OBJECTIVE: To evaluate the effect of crosslinks on the stability of the spine and pedicle screws. METHODS: Compression fracture of the L1 vertebra was produced in 30 fresh thoracic and lumbar vertebrae samples obtained from adult sheep, which were divided into 3 groups (n=10)with lot-drawing method. Four screws were fixed onto the superior and inferior pedicles of vertebral arch close to the fractured vertebrae, with different number of crosslinks (0 in Group A,1 in Group B, and 2 in Group C) on the rods. After fixation, the samples were subject to 10 000 times of fatigue test with 1.5 Hz load on the HY-3080 computer-control electronic universal test machine and HY-1000NM computer-control torsion test machine. The axial compressive stiffness, maximum pullout strength,and range of motion (ROM) of 6 directions, i.e., flexion, extension, left and right lateral bending, and left and right axial rotation of the 3 groups were measured and compared. RESULTS: There were no statistically significant differences in axial compressive stiffness as well as the ROM of flexion, extension, and left and right lateral bending (all P>0.05). The maximum pullout strength was significantly smaller in Group A and Group B than in Group C [(129.56±29.63)N vs.(294.67±23.25) N,P=0.000;(254.02±36.29)vs.(294.67±23.25)N, P=0.006]. The ROM of left axial rotation was the highest in Group A(13.35°±1.06°), followed by Group B(12.23°±1.06°)and Group C (11.04°±0.74°)(F=13.44, P=0.000; Group B vs. Group A, P=0.000; Group B vs. Group C, P=0.001; Group C vs. Group A,P=0.000). The ROM of right axial rotation was also the highest in Group A(13.56°±1.15°), lower in Group B (12.39°±1.01°) and the lowest in Group C (10.81°±0.51°) (F=21.91, P=0.000; Group B vs. Group A,P=0.002; Group B vs. Group C, P=0.001; Group C vs. Group A, P=0.000). CONCLUSION: Crosslinks may reinforce the pullout strength of the screws and improve the axial stability of the spine.
Subject(s)
Pedicle Screws , Spinal Fractures , Animals , Lumbar Vertebrae , SheepABSTRACT
Compressive mechanical stress-induced cartilage thinning has been characterized as a key step in the progression of temporomandibular joint diseases, such as osteoarthritis. However, the regulatory mechanisms underlying this loss have not been thoroughly studied. Here, we used an established animal model for loading compressive mechanical stress to induce cartilage thinning in vivo. The mechanically stressed mandibular chondrocytes were then isolated to screen potential candidates using a proteomics approach. A total of 28 proteins were identified that were directly or indirectly associated with endoplasmic reticulum stress, including protein disulfide-isomerase, calreticulin, translationally controlled tumor protein, and peptidyl-prolyl cis/trans-isomerase protein. The altered expression of these candidates was validated at both the mRNA and protein levels. The induction of endoplasmic reticulum stress by mechanical stress loading was confirmed by the activation of endoplasmic reticulum stress markers, the elevation of the cytoplasmic Ca(2+) level, and the expansion of endoplasmic reticulum membranes. More importantly, the use of a selective inhibitor to block endoplasmic reticulum stress in vivo reduced the apoptosis observed at the early stages of mechanical stress loading and inhibited the proliferation observed at the later stages of mechanical stress loading. Accordingly, the use of the inhibitor significantly restored cartilage thinning. Taken together, these results demonstrated that endoplasmic reticulum stress is significantly activated in mechanical stress-induced mandibular cartilage thinning and, more importantly, that endoplasmic reticulum stress inhibition alleviates this loss, suggesting a novel pharmaceutical strategy for the treatment of mechanical stress-induced temporomandibular joint diseases.