Malvidin attenuates trauma-induced heterotopic ossification of tendon in rats by targeting Rheb for degradation via the ubiquitin-proteasome pathway.

The pathogenesis of trauma-induced heterotopic ossification (HO) in the tendon remains unclear, posing a challenging hurdle in treatment. Recognizing inflammation as the root cause of HO, anti-inflammatory agents hold promise for its management. Malvidin (MA), possessing anti-inflammatory properties, emerges as a potential agent to impede HO progression. This study aimed to investigate the effect of MA in treating trauma-induced HO and unravel its underlying mechanisms. Herein, the effectiveness of MA in preventing HO formation was assessed through local injection in a rat model. The potential mechanism underlying MA's treatment was investigated in the tendon-resident progenitor cells of tendon-derived stem cells (TDSCs), exploring its pathway in HO formation. The findings demonstrated that MA effectively hindered the osteogenic differentiation of TDSCs by inhibiting the mTORC1 signalling pathway, consequently impeding the progression of trauma-induced HO of Achilles tendon in rats. Specifically, MA facilitated the degradation of Rheb through the K48-linked ubiquitination-proteasome pathway by modulating USP4 and intercepted the interaction between Rheb and the mTORC1 complex, thus inhibiting the mTORC1 signalling pathway. Hence, MA presents itself as a promising candidate for treating trauma-induced HO in the Achilles tendon, acting by targeting Rheb for degradation through the ubiquitin-proteasome pathway.

Efficacy of reinforcing sutures for prevention of anastomotic leakage after low anterior resection for rectal cancer: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Anastomotic leakage is a serious complication following surgery for cancer of the rectum. It is not clear whether reinforcing sutures could prevent anastomotic leakage. Therefore, this study aims at evaluating the efficacy of reinforcing sutures on anastomotic leakage. METHODS: We searched PubMed, Embase, and the Cochrane Library databases from inception to January 31, 2023. We included studies comparing anastomosis with reinforcing sutures to anastomosis without reinforcing sutures after low anterior resection. Risk of bias was assessed by the Cochrane tool for RCTs and the Risk of Bias in Non-Randomized Studies (ROBINS)-I tool for observational studies. The overall quality of evidence for primary outcome was assessed using Grading of Recommendations Assessment, Development, and Evaluations methodology. RESULTS: Two RCTs (345 patients) and four observational studies (783 patients) were included. Anastomotic leakage occurred in 4.4% (24 of 548) of patients with reinforcing sutures and 11.9% (69 of 580) of patients without reinforcing sutures. Meta-analysis showed a lower incidence of anastomotic leakage (RR, 0.41; 95% CI 0.25 to 0.66, low certainty) in patients with reinforcing sutures. Operative time (WMD, -3.66; 95% CI -18.58 to 11.25) and reoperation for anastomotic leakage (RR, 0.69; 95% CI 0.23 to 2.08) were similar between patients with reinforcing sutures and those without reinforcing sutures. CONCLUSIONS: While observational data suggest that, there is a clear benefit in terms of reducing the risk of anastomotic leakage with the use of reinforcing sutures, RCT data are less clear. Further large, prospective studies are warranted to determine whether a true clinically important benefit exists with this technique.

3D Bioprinting tissue analogs: Current development and translational implications.

Three-dimensional (3D) bioprinting is a promising and rapidly evolving technology in the field of additive manufacturing. It enables the fabrication of living cellular constructs with complex architectures that are suitable for various biomedical applications, such as tissue engineering, disease modeling, drug screening, and precision regenerative medicine. The ultimate goal of bioprinting is to produce stable, anatomically-shaped, human-scale functional organs or tissue substitutes that can be implanted. Although various bioprinting techniques have emerged to develop customized tissue-engineering substitutes over the past decade, several challenges remain in fabricating volumetric tissue constructs with complex shapes and sizes and translating the printed products into clinical practice. Thus, it is crucial to develop a successful strategy for translating research outputs into clinical practice to address the current organ and tissue crises and improve patients' quality of life. This review article discusses the challenges of the existing bioprinting processes in preparing clinically relevant tissue substitutes. It further reviews various strategies and technical feasibility to overcome the challenges that limit the fabrication of volumetric biological constructs and their translational implications. Additionally, the article highlights exciting technological advances in the 3D bioprinting of anatomically shaped tissue substitutes and suggests future research and development directions. This review aims to provide readers with insight into the state-of-the-art 3D bioprinting techniques as powerful tools in engineering functional tissues and organs.

Identification of significant genes associated with prognosis of gastric cancer by bioinformatics analysis.

BACKGROUND: Gastric cancer (GC) ranks second in mortality among all malignant diseases worldwide. However, the cause and molecular mechanism underlying gastric cancer are not clear. Here, we used integrated bioinformatics to identify possible key genes and reveal the pathogenesis and prognosis of gastric cancer. METHODS: The gene expression profiles of GSE118916, GSE79973, and GSE29272 were available from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between GC and normal gastric tissues were screened by R software and Venn diagram software. GO and KEGG pathway enrichment of DEGs was performed using the DAVID database. A protein-protein interaction (PPI) network was established by STRING and visualized using Cytoscape software. Then the influence of hub genes on expression and survival was assessed using TCGA database. RESULTS: A total of 83 DEGs were found in the three datasets, including 41 up-regulated genes and 42 down-regulated genes. These DEGs were mainly enriched in extracellular matrix organization and cell adhesion. The enriched pathways obtained in the KEGG pathway analysis were extracellular matrix (ECM)-receptor interaction and focal adhesion. A PPI network of DEGs was analyzed using the Molecular Complex Detection (MCODE) app of Cytoscape. Four genes were considered hub genes, including COL5A1, FBN1, SPARC, and LUM. Among them, LUM was found to have a significantly worse prognosis based on TCGA database. CONCLUSIONS: We screened DEGs associated with GC by integrated bioinformatics analysis and found one potential biomarker that may be involved in the progress of GC. This hub gene may serve as a guide for further molecular biological experiments.

3D Printing GelMA/PVA Interpenetrating Polymer Networks Scaffolds Mediated with CuO Nanoparticles for Angiogenesis.

Biocompatible hydrogels have been considered one of the most well-known and promising in various materials used in the fabrication of tissue-engineering scaffolds. Although considerable progress has been made in recent decades, many limitations remain, such as poor mechanical and degradation properties of biomaterials. In addition, vascularization of tissue-engineering scaffold is an enduring challenge, which limited the fabrication and application of scaffold with clinically relevant dimension. To cover these challenges, in this work, a novel nanocomposite interpenetrating polymer networks (IPN) hydrogel scaffold consists of methacrylated gelatin (GelMA), poly(vinyl alcohol) (PVA), and copper oxide nanoparticles (CuONPs) is fabricated by extrusion-based 3D printing. A series of physiochemical and biological characterizations of the nanocomposite GelMA/PVA scaffolds are performed. Results showed that the mechanical and degradation properties of the nanocomposite GelMA/PVA scaffolds are obviously improved compared to GelMA scaffolds with single network. In vitro cell experiments and chick embryo angiogenesis (CEA) assay confirmed good cytocompatibility of the fabricated scaffold and its potential to promote cell migration and angiogenesis. In conclusion, altogether the results demonstrated that GelMA/PVA IPN scaffolds modified with CuONPs have great potential for fabrication of volumetric scaffolds and promote angiogenesis during tissue growth and repair.

Alginate/Gelatin-Based Hydrogel with Soy Protein/Peptide Powder for 3D Printing Tissue-Engineering Scaffolds to Promote Angiogenesis.

In recent years, 3D bioprinting has attracted broad research interest in biomedical engineering and clinical applications. However, there are two issues need to be solved urgently at present, the development of ink is the first pressing thing for 3D printing tissue engineering scaffold, other thing is the promotion of angiogenesis in the scaffold. Therefore, a gelatin/sodium alginate-based hydrogel with protein-rich is developed here, which is prepared by gelatin, sodium alginate, and soy protein/soy peptide powder. The prepared inks exhibit excellent shear-thinning behavior, which contribute to extrusion-based printing; also shown good crosslinking ability by calcium chloride. The macroporous composite scaffolds are printed by 3D printing using the developed ink and the physicochemical properties of the scaffolds are evaluated. Moreover, the cytocompatibility of printed scaffold is characterized by using human umbilical vein epidermal cells, results show that the scaffolds with soy protein and soy peptide powder can promote cell attach, spread, migration, and proliferation. The further research of chicken embryo allantoic membrane assay and animal experiment are carried, and results present that the scaffold can promote the growth of neo-vessels in the scaffold, which means the developed ink with soy protein and soy peptide powder has great potential for angiogenesis.

Development and external validation of a nomogram predicting overall survival after curative resection of colon cancer.

OBJECTIVE: To develop and externally validate a prognostic nomogram to predict overall survival (OS) in patients with resectable colon cancer. METHODS: Data for 50,996 patients diagnosed with non-metastatic colon cancer were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were assigned randomly to the training set (n = 34,168) or validation set (n = 16,828). Independent prognostic factors were identified by multivariate Cox proportional hazards regression analysis and used to construct the nomogram. Harrell's C-index and calibration plots were calculated using the SEER validation set. Additional external validation was performed using a Chinese dataset (n = 342). RESULTS: Harrell's C-index of the nomogram for OS in the SEER validation set was 0.71, which was superior to that using the 7th edition of the American Joint Committee on Cancer TNM staging (0.59). Calibration plots showed consistency between actual observations and predicted 1-, 3-, and 5-year survival. Harrell's C-index (0.72) and calibration plot showed excellent predictive accuracy in the external validation set. CONCLUSIONS: We developed a nomogram to predict OS after curative resection for colon cancer. Validation using the SEER and external datasets revealed good discrimination and calibration. This nomogram may help predict individual survival in patients with colon cancer.

MicroRNA-143 Increases Oxidative Stress and Myocardial Cell Apoptosis in a Mouse Model of Doxorubicin-Induced Cardiac Toxicity.

BACKGROUND Oxidative stress and myocardial apoptosis are features of doxorubicin-induced cardiac toxicity that can result in cardiac dysfunction. Previous studies showed that microRNA-143 (miR-143) was expressed in the myocardium and had a role in cardiac function. This study aimed to investigate the effects and possible molecular mechanisms of miR-143 on oxidative stress and myocardial cell apoptosis in a mouse model of doxorubicin-induced cardiac toxicity. MATERIAL AND METHODS Mice underwent intraperitoneal injection of doxorubicin (15 mg/kg) daily for eight days to develop the mouse model of doxorubicin-induced cardiac toxicity. Four days before doxorubicin administration, a group of mice was pretreated daily with a miR-143 antagonist (25 mg/kg/day) for four consecutive days by tail vein injection. The study included the use of a miR-143 antagomir, or anti-microRNA, an oligonucleotide that silenced endogenous microRNA (miR), and an agomir to miR-143, and also the AKT inhibitor, MK2206. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblot analysis were used to measure mRNA and protein expression, respectively. RESULTS Doxorubicin treatment increased the expression of miR-143, which was reduced by the miR-143 antagomir. Overexpression of miR-143 increased doxorubicin-induced myocardial apoptosis and oxidative stress. The use of the miR-143 antagomir significantly activated protein kinase B (PKB) and AKT, which were reduced in the presence of the AKT inhibitor, MK2206. However, the use of the miR-143 antagomir further down-regulated AKT phosphorylation following doxorubicin treatment and increased AKT activation. CONCLUSIONS In a mouse model of doxorubicin-induced cardiac toxicity, miR-143 increased oxidative stress and myocardial cell apoptosis following doxorubicin treatment by inhibiting AKT.

Reduced PDZRN4 promotes breast cancer progression and predicts poor prognosis.

Breast cancer (BC) is one of the most lethal types of cancer throughout the world due its proliferation and invasion. PDZ domain containing ring finger 4 (PDZRN4) belongs to the LNX family, which has E3 ubiquitin ligase activity and is involved in the progression of cancer. However, the role of PDZRN4 in the progression of BC remains unknown. In the present study, the public database Oncomine was used to detect PDZRN4 expression for primary screening. BC tissues and matched normal tissues were collected for detection of expression and cohort analysis. BC cells were used for invasion and proliferation function tests in vitro and in vivo. The results revealed that both the mRNA and protein levels of PDZRN4 in the BC tissues were markedly reduced compared to normal tissues. The expression of PDZRN4 was significantly correlated with LNM, histological grade and perineural invasion. Prognostic analysis confirmed that PDZRN4 expression is an independent risk factor for overall survival and disease-free survival of patients with BC. The functional experiments demonstrated that knockdown of PDZRN4 significantly improved the invasive and proliferative abilities of BT-20 cells in vitro and in vivo. Furthermore, overexpression of PDZRN4 markedly inhibited the malignant aspects of MDA-MB-231 cells. Therefore, reduced PDZRN4 correlates with the progression of BC and may act as a novel prognostic marker for patients with BC.