Bibliometric and visualization analysis of macrophages associated with osteoarthritis from 1991 to 2021.

Background: Macrophages significantly contributes to symptomology and structural progression of osteoarthritis (OA) and raise increasing attention in the relative research field. Recent studies have shown that tremendous progress has been made in the research of macrophages associated with osteoarthritis. However, a comprehensive bibliometric analysis is lacking in this research field. This study aimed to introduce the research status as well as hotspots and explore the field of macrophages research in OA from a bibliometric perspective. Methods: This study collected 1481 records of macrophages associated with osteoarthritis from 1991 to 2021 in the web of science core collection (WoSCC) database. CiteSpace, VOSviewer, and R package "bibliometrix" software were used to analyze regions, institutions, journals, authors, and keywords to predict the latest trends in macrophages associated with osteoarthritis research. Results: The number of publications related to macrophages associated with osteoarthritis is increasing annually. China and the USA, contributing more than 44% of publications, were the main drivers for research in this field. League of European Research Universities was the most active institution and contributed the most publications. Arthritis and Rheumatism is the most popular journal in this field with the largest publications, while Osteoarthritis and Cartilage is the most co-cited journal. Koch AE was the most prolific writer, while Bondeson J was the most commonly co-cited author. "Rheumatology", "Orthopedics", and "Immunology" were the most widely well-represented research areas of OA associated macrophages. "Rheumatoid arthritis research", "clinical symptoms", "regeneration research", "mechanism research", "pathological features", and "surgery research" are the primary keywords clusters in this field. Conclusion: This is the first bibliometric study comprehensively mapped out the knowledge structure and development trends in the research field of macrophages associated with osteoarthritis in recent 30 years. The results comprehensively summarize and identify the research frontiers which will provide a reference for scholars studying macrophages associated with osteoarthritis.

In vivo imaging of heart failure with preserved ejection fraction by simultaneous monitoring of cardiac nitric oxide and glutathione using a three-channel fluorescent probe.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains unclear, making the diagnosis and treatment challenging. Cardiac oxidative and nitrative stress are strongly implicated in the pathogenesis of HFpEF. Herein, we present a unique three-channel fluorescent probe for evaluating cardiac oxidative and nitrative stress in HFpEF by simultaneous detection of NO and GSH. The probe exhibits a native green fluorescence (probe channel), while the presence of GSH and NO can sensitively turn the native green fluorescence into red fluorescence (GSH channel) and near-infrared fluorescence (NO channel), respectively. The probe clearly reveals that both GSH and NO levels are upregulated in cardiomyocytes and heart tissue with HFpEF. Moreover, it uncovers that the enhancement in NO and GSH levels are closely associated with increased level of iNOS (inducible nitric oxide synthase) and activation of the Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 (nuclear factor erythroid 2-related factor 2)/ARE (antioxidant response element) signaling pathway in cardiomyocytes, respectively. This work proposes a promising approach for distinguishing normal heart and HFpEF heart by in vivo noninvasive imaging of both GSH and NO, and greatly contributing to the improvement of the diagnosis and treatment of HFpEF.

Engineering a "three-in-one" hirudin prodrug to reduce bleeding risk: A proof-of-concept study.

An ideal anticoagulant should have at least three properties including targeted delivery to the thrombosis site, local activation or releasing to centralize the anti-thrombosis effects and thus reduce the bleeding risks, and long persistence in circulation to avoid repeated administration. In the present study, we sought to test a "three-in-one" strategy to design new protein anticoagulants. Based on these criteria, we constructed two hirudin prodrugs, R824-HV-ABD and ABD-HV-R824. The R824 peptide can bind phosphatidylserine on the surface of the procoagulant platelets and thus guide the prodrug to the thrombosis sites; albumin-binding domain (ABDs) can bind the prodrug to albumin, and thereby increase its persistence in circulation; the hirudin (HV) core in the prodrug is flanked by factor Xa recognition sites, thus factor Xa at the thrombosis site can cleave the fusion proteins and release the activated hirudin locally. Hirudin prodrugs were able to bind with procoagulant platelets and human serum albumin in vitro with high affinity, targeted concentrated and prevented the formation of occlusive thrombi in rat carotid artery injury model. Their effective time was significantly extended compared to native hirudin, and R824-HV-ABD showed a significantly improved half-life of about 24 h in rats. The bleeding time of prodrug-treated mice was much shorter than that of hirudin-treated mice. The results from the proof-of-concept studies, for the first time, demonstrate that "three-in-one" prodrug strategy may be a good solution for protein or peptide anticoagulants to reduce their bleeding risks.

Imbalance of the reciprocally inhibitory loop between the ubiquitin-specific protease USP43 and EGFR/PI3K/AKT drives breast carcinogenesis.

Hyperactivation of EGFR/PI3K/AKT is a prominent feature of various human cancers. Thus, understanding how this molecular cascade is balanced is of great importance. We report here that the ubiquitin-specific protease USP43 is physically associated with the chromatin remodeling NuRD complex and catalyzes H2BK120 deubiquitination. Functionally this coordinates the NuRD complex to repress a cohort of genes, including EGFR, which are critically involved in cell proliferation and carcinogenesis. We show that USP43 strongly suppresses the growth and metastasis of breast cancer in vivo. Interestingly, USP43 also exists in the cytoplasm, where it is phosphorylated by AKT, enabling its binding to the 14-3-3ß/ε heterodimer and sequestration in the cytoplasm. Significantly, hyperactivation of EGFR/PI3K/AKT in breast cancer is associated with the cytoplasmic retention of USP43 and thus, the inhibition of its transcriptional regulatory function. Moreover, cancer-associated mutations of USP43 affect its subcellular localization and/or epigenetic regulatory functions. Nuclear USP43 is significantly reduced in breast carcinomas and is associated with EGFR accumulation and AKT hyperactivation. A low level of nuclear USP43 correlates with higher histologic grades and poor prognosis. Our study identifies USP43 to be an H2BK120 deubiquitinase and a potential tumor suppressor and reveals a reciprocally inhibitory loop between USP43 and EGFR/PI3K/AKT, whose imbalance drives breast carcinogenesis.

Caged circular siRNAs for photomodulation of gene expression in cells and mice.

By means of RNA interference (RNAi), small interfering RNAs (siRNAs) play important roles in gene function study and drug development. Recently, photolabile siRNAs were developed to elucidate the process of gene silencing in terms of space, time and degree through chemical modification of siRNAs. We report herein a novel type of photolabile siRNA that was synthesized through cyclizing two ends of a single stranded RNA with a photocleavable linker. These circular siRNAs became more resistant to serum degradation. Using reporter assays of firefly/Renilla luciferase and GFP/RFP, the gene silencing activities of caged circular siRNAs for both genes were evaluated in HEK293 cells. The results indicated that the target genes were successfully photomodulated using these caged circular siRNAs that were formed by caged circular antisense guide RNAs and their linear complementary sense RNAs. Using the caged circular siRNA targeting GFP, we also successfully achieved photomodulation of GFP expression in mice. Upon further optimization, this new type of caged circular siRNA is expected to be a promising tool for studying gene therapy.

RNF8 promotes epithelial-mesenchymal transition of breast cancer cells.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is a crucial step for solid tumor progression and plays an important role in cancer invasion and metastasis. RNF8 is an ubiquitin E3 ligase with RING domain, and plays essential roles in DNA damage response and cell cycle regulation. However the role of RNF8 in the pathogenesis of breast cancer is still unclear. METHODS: The expression of RNF8 was examined in different types of breast cell lines by Western Blotting. EMT associated markers were examined by Immunofluorescence and Western Blotting in MCF-7 when RNF8 was ectopically overexpressed, or in MDA-MB-231 when RNF8 was depleted. Transwell and wound healing assays were performed to assess the effect of RNF8 on cell mobility. The xenograft model was done with nude mice to investigate the role of RNF8 in tumor metastasis in vivo. Breast tissue arrays were used to examine the expression of RNF8 by immunohistochemistry. Kaplan-Meier survival analysis for the relationship between survival time and RNF8 signature in breast cancer was done with an online tool ( http://kmplot.com/analysis/ ). RESULTS: RNF8 is overexpressed in highly metastatic breast cancer cell lines. Overexpression of RNF8 in MCF-7 significantly promoted EMT phenotypes and facilitated cell migration. On the contrary, silencing of RNF8 in MDA-MB-231 induced MET phenotypes and inhibited cell migration. Furthermore, we proved that these metastatic behavior promoting effects of RNF8 in breast cancer was associated with the inactivation of GSK-3ß and activation of ß-catenin signaling. With nude mice xenograft model, we found that shRNA mediated-downregulation of RNF8 reduced tumor metastasis in vivo. In addition, we found that RNF8 expression was higher in malignant breast cancer than that of the paired normal breast tissues, and was positively correlated with lymph node metastases and poor survival time. CONCLUSIONS: RNF8 induces EMT in the breast cancer cells and promotes breast cancer metastasis, suggesting that RNF8 could be used as a potential therapeutic target for the prevention and treatment of breast cancer.

SCF(JFK) is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer.

Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-κB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-κB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-κB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention.

A novel lanreotide-encoded micelle system targets paclitaxel to the tumors with overexpression of somatostatin receptors.

Many tumor cells specifically overexpress somatostatin receptors, in particular, subtype 2 (SSTR2). Lanreotide, a somatostatin analogue with high affinity for SSTR2, can be exploited as a ligand for tumor targeted therapy. In this study, lanreotide was first conjugated to poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer, and the active targeting micelles with paclitaxel (lanreotide-PM-PTX) or fluorescent agent were constructed and characterized with various analytical methods. Lanreotide-PM-PTX micelles were spherical in shape with a hydrodynamic diameter of 43.2 ± 0.4 nm, high drug encapsulation (87.1 ± 2.8%) and slow drug release rate. Two cancer cell lines (human lung cancer H446 and human breast cancer MCF-7 cells) with different expression levels of SSTR2 were used in this study. As observed by flow cytometry, confocal microscopy and cytotoxicity studies, lanreotide-encoded PEG-b-PCL micelles demonstrated more specific cell uptake and cytotoxicity in SSTR2-positive tumor cells via a receptor-mediated mechanism over the passive targeting micelles. The active targeting micelles showed higher accumulation in tumor tissue and tumor cells in tumor-bearing mice in vivo by near-infrared fluorescence (NIRF) imaging, high-performance liquid chromatography and confocal microscopy, respectively. Furthermore, treatment with lanreotide-PM-PTX micelles resulted in stronger tumor inhibition, increased life span and enhanced tumor cell apoptosis in SSTR2-overexpressing tumor model in athymic nude mice. The in vivo efficacy test with both H446 and MCF-7 tumor models further demonstrated the involvement of receptor-mediated interaction. Finally, the active targeting micelles exhibited less body weight loss, lower hemolysis and lower myelosuppression, as compared with the control groups. In conclusion, lanreotide can serve as an effective homing peptide, and the lanreotide-modified PEG-b-PCL micelles hold considerable promise in the treatment of SSTR2-overexpressing solid tumors.

SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities.

SET8 is implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression, and development. As such, it is predicted that SET8 might be involved in the development and progression of tumour. However, whether and how SET8 might be implicated in tumourigenesis is currently unknown. Here, we report that SET8 is physically associated with TWIST, a master regulator of epithelial-mesenchymal transition (EMT). We demonstrated that SET8 and TWIST are functionally interdependent in promoting EMT and enhancing the invasive potential of breast cancer cells in vitro and in vivo. We showed that SET8 acts as a dual epigenetic modifier on the promoters of the TWIST target genes E-cadherin and N-cadherin via its H4K20 monomethylation activity. Significantly, in breast carcinoma samples, SET8 expression is positively correlated with metastasis and the expression of TWIST and N-cadherin and negatively correlated with E-cadherin. Together, our experiments revealed a novel role for SET8 in tumour invasion and metastasis and provide a molecular mechanism underlying TWIST-promoted EMT, suggesting SET8 as a potential target for intervention of the metastasis of breast cancer.

Depletion of tissue factor suppresses hepatic metastasis and tumor growth in colorectal cancer via the downregulation of MMPs and the induction of autophagy and apoptosis.

Tissue factor (TF) is a significant risk factor for hepatic metastasis in patients with colorectal cancer (CRC). However, the mechanism by which TF promotes hepatic metastasis in CRC remains elusive. In this study, we first confirmed that TF expression was significantly correlated with lymph node metastasis, hepatic metastasis and TNM staging in clinical CRC samples, and found that TF expression in colon cancer cell lines was correlated with the invasion ability. Next, by employing TF-overexpressing LOVO cell line as a model we demonstrated that lentivirus mediated knockdown of TF suppressed the migration and invasion of LOVO cells in vitro, and hepatic metastasis of colorectal cancer in nude mice orthotopic model. Mechanistically, we found that TF knockdown decreases colony formation ability and induced autophagy and apoptosis of LOVO cells, and this was at least partly mediated by the activation of unfolded protein response/PERK signaling. In conclusion, our data provide new insight into hepatic metastasis of CRC. Agents targeting TF should be developed as adjuvant therapeutics for CRC metastasis.

New coumarin glycosides from the leaves of Diospyros crassiflora (Hiern).

Two new 5-methylcoumarin glycosides named diosfeboside A (1) and B (2) and five known compounds namely kaempferol 3-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranoside (3), ursolic acid (4), betulinic acid (5), stigmasterol (6) and stigmasterol 3-O-ß-D-glucopyranoside (7) were isolated from the leaves of Diospyros crassiflora (Hiern). Their structures were established through interpretation of 1 and 2D NMR, mass spectra analysis and comparison with reported data. In vitro cytotoxic activity of the new compounds against human carcinoma cell lines (HL-60, Bel-7402, BGC-823, and KB) was evaluated and no cytotoxicity was observed for each of them.

Triterpenoid glycosides from the leaves of Ilex pernyi.

Ten triterpenoid glycosides, including five new ones (1-5), were isolated from the leaves of Ilex pernyi. The chemical structures of 1-5 were determined on the basis of the chemical and spectroscopic evidence.

[Character study of content and correlativity of elements in Radix Astragali obtained from different regions].

OBJECTIVE: To study the characters of concentration of 42 elements in Radix Astragali and make an attempt at looking for relationship between the element concentration and regions where samplers are obtained. METHOD: Determining the content of elements in 40 Radix Astragali samples from 7 different provinces by ICP-MS, AFS and ASS. Analyzing the correlation of elements in Radix Astragali using statistic software (Spss). RESULT: Firstly, similar lines of element concentration have been acquired in our research. Secondly, it is observed that the content of elements in the samples shows regional diversity. Thirdly, there are 346 correlative element pairs in correlate analysis. And some of them indicate remarkable correlativity. CONCLUSION: With the aid of obtained results, it is concluded that element content in Radix Astragali display special distributing line. Remarkable correlation is presented in some element pairs. The quality of Radix Astragali gained from Neimeng, Shanxi and Gansu are better than those from other regions.

Chemical constituents from the leaves of Ilex pernyi.

A new compound and five known compounds were isolated from the ethanolic extract of the leaves of Ilex pernyi Franch. Their structures were established on the basis of spectral analysis and identified as trans-isoeugenyl-alpha-L-arabinopynosyl (1 --> 6) -beta-D-glucopyranoside (1) , kaempferol-3-O-sambubioside (2), quercetin-3-O-sambubioside (3), isoquercitrin (4), (+) -syringaresinol-O-beta-D-glucopyranoside (5), amarantholidoside IV (6). Among them, compound 1 is a new phenolic glycoside, named as ilexperphenoside A, and compounds 2-6 were isolated from this plant for the first time.

[Studies on chemical constituents of aerial parts of Ammopiptanthus mongolicus].

OBJECTIVE: To investigate the chemical constituents of the aerial parts of Ammopiptanthus mongolicus. METHOD: The chemical constituents were isolated by various column chromatographic methods. The structures were identified by spectral data. RESULT: Ten compounds were isolated and identified as m-hydroxybenzoic acid (1), 1-(4-hydroxyphenyl) ethanone (2), beta-sitosterol (3), (-)-syringaresinol (4), (+)-lariciresinol (5), blumenol A (6), blumenol B (7), beta-daucosterol (8), coniferin (9), syringin (10). CONCLUSION: The ten compounds were obtained from the genus Ammopiptanthus for the first time.

[Studies on triterpenoid constituents in leaf of Ilex pernyi].

OBJECTIVE: To investigate the chemical constituents of Ilex pernyi. METHOD: The chemical constituents were isolated by various column chromatographic methods. The structures were identified by spectral data. RESULT: Eight triterpenoid compounds were isolated and identified as ursolic acid (1), lupeol (2), alpha-amyrin (3), uvaol (4), 3beta-hydroxyurs-11-ene-13beta-olide (5), pomolic acid (6), lup-20 (29)-ene-3beta, 24-diol (7), 3beta, 23-dihydroxy-urs-12-en-28-oic acid (8). CONCLUSION: The eight compounds were obtained from this plant for the first time.

Complete assignments of (1)H and (13)C NMR spectroscopic data for two new triterpenoid saponins from Ilex pernyi.

Ilexpernoside A and ilexpernoside B, two new pentacyclic C(4)-nortriterpenoid saponins, were isolated from the leaves of Ilex pernyi Franch. Their chemical structures were determined by MS, NMR spectroscopy and chemical analysis. Complete assignments of the (1)H and (13)C NMR spectroscopic data were achieved by 1D and 2D NMR experiments (HSQC, HMBC, (1)H-(1)H COSY and NOESY).

NO spin trapping and EPR studies on the photochemistry of aliphatic aldehydes.

Radicals, such as acyl, hydrated acyl, alkyl and ketyl radicals, from aliphatic aldehyde photochemistry were detected by NO spin trapping and EPR techniques. Deuterium effects on EPR spectra and the generation of radicals by 2-amido-2-propyl radical attack on substrate molecules in aqueous solution via hydrogen-atom abstraction were applied to identify radicals produced photochemically from aldehydes. Aliphatic aldehydes used in the present investigation were formaldehyde, acetaldehyde, acetaldehyde-d4, propionaldehyde, isobutyraldehyde, isopentanal and tert-pentanal. Possible reaction mechanisms are suggested.