Collagen type X expression and chondrocyte hypertrophic differentiation during OA and OS development.

Chondrocyte hypertrophy and the expression of its specific marker, the collagen type X gene (COL10A1), constitute key terminal differentiation stages during endochondral ossification in long bone development. Mutations in the COL10A1 gene are known to cause schmid type metaphyseal chondrodysplasia (SMCD) and spondyloepiphyseal dyschondrodysplasia (SMD). Moreover, abnormal COL10A1 expression and aberrant chondrocyte hypertrophy are strongly correlated with skeletal diseases, notably osteoarthritis (OA) and osteosarcoma (OS). Throughout the progression of OA, articular chondrocytes undergo substantial changes in gene expression and phenotype, including a transition to a hypertrophic-like state characterized by the expression of collagen type X, matrix metalloproteinase-13, and alkaline phosphatase. This state is similar to the process of endochondral ossification during cartilage development. OS, the most common pediatric bone cancer, exhibits characteristics of abnormal bone formation alongside the presence of tumor tissue containing cartilaginous components. This observation suggests a potential role for chondrogenesis in the development of OS. A deeper understanding of the shifts in collagen X expression and chondrocyte hypertrophy phenotypes in OA or OS may offer novel insights into their pathogenesis, thereby paving the way for potential therapeutic interventions. This review systematically summarizes the findings from multiple OA models (e.g., transgenic, surgically-induced, mechanically-loaded, and chemically-induced OA models), with a particular focus on their chondrogenic and/or hypertrophic phenotypes and possible signaling pathways. The OS phenotypes and pathogenesis in relation to chondrogenesis, collagen X expression, chondrocyte (hypertrophic) differentiation, and their regulatory mechanisms were also discussed. Together, this review provides novel insights into OA and OS therapeutics, possibly by intervening the process of abnormal endochondral-like pathway with altered collagen type X expression.

Construction of 3D and 2D contrast-enhanced CT radiomics for prediction of CGB3 expression level and clinical prognosis in bladder cancer.

Objective: The purpose of this study was to construct a 3D and 2D contrast-enhanced computed tomography (CECT) radiomics model to predict CGB3 levels and assess its prognostic abilities in bladder cancer (Bca) patients. Methods: Transcriptome data and CECT images of Bca patients were downloaded from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) database. Clinical data of 43 cases from TCGA and TCIA were used for radiomics model evaluation. The Volume of interest (VOI) (3D) and region of interest (ROI) (2D) radiomics features were extracted. For the construction of predicting radiomics models, least absolute shrinkage and selection operator regression were used, and the filtered radiomics features were fitted using the logistic regression algorithm (LR). The model's effectiveness was measured using 10-fold cross-validation and the area under the receiver operating characteristic curve (AUC of ROC). Result: CGB3 was a differential expressed prognosis-related gene and involved in the immune response process of plasma cells and T cell gamma delta. The high levels of CGB3 are a risk element for overall survival (OS). The AUCs of VOI and ROI radiomics models in the training set were 0.841 and 0.776, while in the validation set were 0.815 and 0.754, respectively. The Delong test revealed that the AUCs of the two models were not statistically different, and both models had good predictive performance. Conclusion: The CGB3 expression level is an important prognosis factor for Bca patients. Both 3D and 2D CECT radiomics are effective in predicting CGB3 expression levels.

Berberine improves DSS-induced colitis in mice by modulating the fecal-bacteria-related bile acid metabolism.

Ulcerative colitis (UC) has been confirmed as a disease with a high incidence and low cure rate worldwide. In severe cases, UC can develop into colon cancer. Modern research has confirmed that berberine (BBR) can treat UC by inhibiting the expressions of inflammatory factors. However, the contribution of gut microbiota and flora metabolites in treating UC with BBR remains unclear. In this study, the ameliorative effects of BBR on gut microbiota dysbiosis and flora metabolites were investigated in a dextran sodium sulfate (DSS)-induced UC rodent model. We found that BBR significantly improved the pathological phenotype, attenuated intestinal barrier disruption, and mitigated colonic inflammation in DSS mice. By 16 S rDNA sequencing, BBR alleviated gut microbiota dysbiosis in UC mice. Moreover, the gut microbiota depletion experiment confirmed that the therapeutic effect of BBR was inextricably correlated with the gut microbiota. Besides, the flora metabolites (e.g., short-chain fatty acids, bile acids, and 5-hydroxytryptamine) were studied using HPLC-MS. The results suggested that BBR ameliorated the bile acid imbalance induced by DSS in the liver and gut. Furthermore, BBR treatment repaired gut barrier damage. The above results revealed that BBR alleviated DSS-induced UC in mice by restoring the disturbed gut microbiota, elevating unconjugated and secondary bile acids in the gastrointestinal tract, and activating the FXR and TGR5 signal pathway. This study provides novel insights into the mechanism of BBR in treating UC.

YuPingFengSan ameliorates LPS-induced acute lung injury and gut barrier dysfunction in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Yupingfengsan (YPFS) is a traditional Chinese medicine decoction. YPFS comprises Astragalus mongholicus Bunge (Huangqi), Atractylodes rubra Dekker (Baizhu), and Saposhnikovia divaricata (Turcz.ex Ledeb.) Schischk (Fangfeng). YPFS is commonly used to treat chronic obstructive pulmonary disease, asthma, respiratory infections, and pneumonia, but the mechanism of action remains unclear. AIM OF THE STUDY: Acute lung injury (ALI) and its severe form of acute respiratory distress syndrome (ARDS) cause morbidity and mortality in critical patients. YPFS is a commonly used herbal soup to treat respiratory and immune system diseases. Nevertheless, the effect of YPFS on ALI remains unclear. This study aimed to investigate the effect of YPFS on lipopolysaccharide (LPS)-induced ALI in mice and elucidate its potential molecular mechanisms. MATERIALS AND METHODS: The major components of YPFS were detected by High-performance liquid chromatography (HPLC). C57BL/6J mice were given YPFS for seven days and then treated with LPS. IL-1ß, IL-6, TNF-α, IL-8, iNOS, NLRP3, PPARγ, HO-1, ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCß, EnaCγ mRNA in lung and ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCß, and EnaCγ mRNA in colon tissues were measured by Real-Time Quantitative PCR (RT-qPCR). The expressions of TLR4, MyD88, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), ASC, MAPK signaling pathway, Nrf2, and HO-1 in the lung were detected by Western blot. Plasma inflammatory factors Interleukin (IL)-1ß, IL-6, and Tumor Necrosis Factor-α (TNF-α) were determined by Enzyme-linked Immunosorbent Assay (ELISA). Lung tissues were processed for H & E staining, and colon tissues for HE, WGA-FITC, and Alcian Blue staining. RESULTS: The results showed that YPFS administration alleviated lung injury and suppressed the production of inflammatory factors, including IL-1ß, IL-6, and TNF-α. Additionally, YPFS reduced pulmonary edema by promoting the expressions of aquaporin and sodium channel-related genes (AQP3, AQP4, AQP5, ENaCα, ENaCß, and EnaCγ). Further, YPFS intervention exhibited a therapeutic effect on ALI by inhibiting the activation of the NLRP3 inflammasome and MAPK signaling pathways. Finally, YPFS improved gut barrier integrity and suppressed intestinal inflammation in LPS-challenged mice. CONCLUSIONS: YPFS protected mice against LPS-induced ALI by attenuating lung and intestinal tissue damage. This study sheds light on the potential application of YPFS to treat ALI/ARDS.

SOMOphilic Alkynylation of Unreactive Alkenes Enabled by Iron-Catalyzed Hydrogen Atom Transfer.

We report an efficient and practical iron-catalyzed hydrogen atom transfer protocol for assembling acetylenic motifs into functional alkenes. Diversities of internal alkynes could be obtained from readily available alkenes and acetylenic sulfones with excellent Markovnikov selectivity. An iron hydride hydrogen atom transfer catalytic cycle was described to clarify the mechanism of this reaction.

Cell Signaling Pathway in 12-O-Tetradecanoylphorbol-13-acetate-Induced LCN2 Gene Transcription in Esophageal Squamous Cell Carcinoma.

LCN2 is involved in various cellular functions, including transport of small hydrophobic molecules, protection of MMP9 from proteolytic degradation, and regulating innate immunity. LCN2 is elevated in multiple human cancers, frequently being associated with tumor size, stage, and invasiveness. Our previous studies have shown that LCN2 expression could be induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in esophageal squamous cell carcinoma (ESCC) by the binding of five nucleoproteins (MISP, KLF10, KLF15, PPP1R18, and RXRß) at a novel TPA-responsive element (TRE), at -152~-60 bp of the 5' flanking region of the LCN2 promoter. However, much is unknown about whether these proteins can respond to TPA stimulation to regulate LCN2 transactivation and which cell signaling pathways mediate this process. In this study, expression plasmids encoding these five nucleoproteins were stably transfected into EC109 cells. Then, stable transfectant was characterized by a Dual-Luciferase Reporter Assay System. RT-PCR, real-time PCR, western blotting, specific kinase inhibitor treatment, and bioinformatics analyses were applied in this study. We found that MISP, KLF10, KLF15, PPP1R18, and RXRß proteins could strongly respond to TPA stimulation and activate LCN2 transcriptional expression. MEK, ERK, JNK, and P38 kinases were involved in the LCN2 transactivation. Furthermore, the MEK-ERK signal pathway plays a major role in this biological process but does not involve PKCα signaling.

Preventing graft restenosis after coronary artery bypass grafting with tissue-type plasminogen activator.

OBJECTIVE: To explore the feasibility and safety of using tissue-type plasminogen activator (t-PA) to prevent graft restenosis after coronary artery bypass grafting (CABG). METHODS: In this prospective observational study, 37 patients underwent CABG between June 2009 and May 2013. These patients were grouped according to the anti-coagulation strategy after surgery: t-PA (n = 12) and conventional treatments (n = 25). In the t-PA group, the patients received acetylsalicylic acid (ASA) and clopidogrel plus intravenous infusion of t-PA (0.25 mg/kg/day) starting at 24 h after surgery and that lasted for 3 days. In the conventional group, the patients received only ASA and clopidogrel. 64-row spiral computed tomographic coronary angiography was performed at 1 week, 1, and 3 months after surgery to evaluate the patency of the graft vessel. RESULTS: The mean stenosis severity of the saphenous vein grafts was lower in the t-PA group compared with the conventional group at 3 months after surgery (p < 0.05), but there was no significant difference at 1 week and 1 month (p > 0.05). The patency rate of the grafts was not significantly different between the two groups at 1 week, 1, and 3 months after surgery (p > 0.05). CONCLUSION: Early application of t-PA after CABG was feasible and safe, and might help prevent early restenosis of SV grafts. Additional clinical randomized trials are necessary to address this issue.

Establishment of an animal model of vascular restenosis with bilateral carotid artery grafting.

BACKGROUND: Vascular restenosis occurring after CABG is a major clinical problem that needs to be addressed. Vein grafts are associated with a higher degree of stenosis than artery grafts. However, the mechanism responsible for this effect has not been elucidated. We aimed to establish a rabbit model of vascular restenosis after bilateral carotid artery grafting, and to investigate the associated spatiotemporal changes of intimal hyperplasia in carotid artery and jugular vein grafts after surgery. MATERIAL AND METHODS: Twenty adult New Zealand white rabbits (10 males; 10 females), weighing 2.0-2.5 kg, were obtained from the Experimental Animal Center of Southern Medical University, Guangzhou, China (License No.: scxk-Guangdong-2006-0015). We quantitatively analyzed intimal thickness, area, and degree of stenosis in carotid artery and jugular vein bridges. RESULTS: After 8 weeks of a high-fat diet, rabbit carotid arteries showed early atherosclerotic lesions. With increasing time after surgery, carotid artery and jugular vein grafts showed histopathological and morphological changes, including smooth muscle cell migration, lipid deposition, intimal hyperplasia, and vascular stenosis. The degree of vascular stenosis was significantly higher in vein grafts than in artery grafts at all time points - 35.1±6.7% vs. 16.1±2.6% at Week 12, 56.2±8.5% vs. 23.4±3.4% at Week 16, and 71.2±1.3% vs. 25.2±5.3% at Week 20. CONCLUSIONS: Rabbit bilateral carotid arteries were grafted with carotid artery and jugular vein bridges to simulate pathophysiological processes that occur in people after CABG surgery.

[Comparative study on the quality of life in patients with prevertebral or retrosternal reconstruction after cervical tubular gastroesophagostomy].

OBJECTIVE: To compare the quality of life in patients with prevertebral or retrosternal reconstruction after cervical tubular gastroesophagostomy. METHODS: A total of 167 patients enrolled in this prospective study from July 2008 to June 2012 in Shantou Central Hospital, and divided into prevertebral route group(85 cases) and retrosternal route group(82 cases) according to the random number table method. Quality of life questionnaire was investigated 1, 3, 6, 9, and 12 months after operation respectively. RESULTS: The incidence of anastomotic stenosis was lower in the prevertebral route group (P<0.05). However, the differences in perioperative general conditions between the two groups were not statistically significant(all P>0.05). One hundred and forty-nine patients completed the postoperative quality of life questionnaire. Dysphagia and swallowing retching symptom were better, while acid reflux and heartburn symptom were more serious in prevertebral route group as compared to retrosternal route group(all P<0.05). Overall quality of life score difference between the two groups was not statistically significant(P>0.05). CONCLUSIONS: For digestive tract reconstruction after resection of esophageal cancer, tubular gastroesophagostomy by prevertebral or retrosternal route both can obtain better quality of life after surgery. Swallowing function after surgery of the former is superior to the latter, but the reflux symptoms is more serious. Therefore the two mehods have their own advantages and disadvantages, and the choice of route should be depended on clinical experience and patient condition.

ECM-related gene expression profile in vascular smooth muscle cells from human saphenous vein and internal thoracic artery.

UNLABELLED: Currently, Saphenous vein (SV) and internal thoracic artery (ITA) are still the most common graft materials in Coronary Artery Bypass Grafting (CABG) whereas SV graft have a lower long-term patency than ITA. Vascular smooth muscle cells (VSMCs) phenotype conversion, proliferation and migration may play a key role in mechanism of vein graft restenosis. To explore differential gene expression profile in VSMCs from SV and ITA will help to further elucidate the mechanism of VSMCs in vein graft restenosis after CABG and to provide new thread of gene therapy. METHODS: VSMCs from paired SV and ITA were cultured for experiments of Affymetrix microarrays and verification using FQ RT-PCR, while the database for annotation, visualization and integrated discovery bioinformatics resources (DAVID 2.0) was utilized for bioinformatics analysis of differential gene expression profile between SV VSMCs and ITA VSMCs. RNA of tunica media from SV and ITA segments were extracted for FQ RT-PCR to display differential expression of PLAT RESULTS: 54,613 probe sets were examined by gene microarray experiments. In SV VSMCs, 1,075 genes were up-regulated and 406 of them were higher than two-fold; 1,399 genes were down-regulated and 424 of them were lower than two-fold as compare with ITA VSMCs.14 ECM-related genes differentially expressed were verificated and listed as following: COL4A4, COL11A1, FN1, TNC, THBS, FBLN, MMP3, MMP9, TIMP3, WNT5A, SGCD were higher whereas COL14A1, ELN, PLAT lower in SV VSMCs than ITA VSMCs. In addition, PLAT was lower in tunica media from SV segments than ITA. CONCLUSION: VSMCs from SV and ITA have distinct phenotypes characteristics. Both promoting and inhibiting migration ECM-related genes were higher in VSMCs from SV as compared with ITA, suggesting that VSMCs from SV have more potential migrating capability whereas less PLAT both in SV VSMCs and vascular tissue,implying that SV may prone to be restenosis after CABG.