Biomechanical characteristics of ligament injuries in the knee joint during impact in the upright position: a finite element analysis.

BACKGROUND: Our study aims to examine stress-strain data of the four major knee ligaments-the anterior cruciate ligament (ACL), the posterior cruciate ligament (PCL), the medial collateral ligament (MCL), and the lateral collateral ligament (LCL)-under transient impacts in various knee joint regions and directions within the static standing position of the human body. Subsequently, we will analyze the varying biomechanical properties of knee ligaments under distinct loading conditions. METHODS: A 3D simulation model of the human knee joint including bone, meniscus, articular cartilage, ligaments, and other tissues, was reconstructed from MRI images. A vertical load of 300 N was applied to the femur model's top surface to mimic the static standing position, and a 134 N load was applied to the impacted area of the knee joint. Nine scenarios were created to examine the effects of anterior, posterior, and lateral external forces on the upper, middle, and lower regions of the knee joint. RESULTS: The PCL exhibited the highest stress levels among the four ligaments when anterior loads were applied to the upper, middle, and lower parts of the knee, with maximum stresses at the PCL-fibula junction measuring 59.895 MPa, 27.481 MPa, and 28.607 MPa, respectively. Highest stresses on the PCL were observed under posterior loads on the upper, middle, and lower knee areas, with peak stresses of 57.421 MPa, 38.147 MPa, and 26.904 MPa, focusing notably on the PCL-tibia junction. When a lateral load was placed on the upper knee joint, the ACL showed the highest stress 32.102 MPa. Likewise, in a lateral impact on the middle knee joint, the ACL also had the highest stress of 29.544 MPa, with peak force at the ACL-tibia junction each time. In a lateral impact on the lower knee area, the LCL had the highest stress of 22.279 MPa, with the highest force at the LCL-fibula junction. Furthermore, the maximum stress data table indicates that stresses in the ligaments are typically higher when the upper portion of the knee is affected compared to when the middle and lower parts are impacted. CONCLUSIONS: This study recommends people avoid impacting the upper knee and use the middle and lower parts of the knee effectively against external forces to minimize ligament damage and safeguard the knee.

A quinoline-2-thione derivative as a novel chemotherapy drug candidate displays anti-tumor activity in vitro and in vivo.

Ovarian cancer is the fifth most prevalent cancer in women. Chemotherapy is a major treatment option for patients with advanced ovarian cancer (OC). Quinoline-2-thione and its derivatives are potential candidates for tumor therapy. In this study, we investigated the anticancer activity of the quinoline-2-thione derivative KA3D against ovarian cancer. The effect of KA3D on the viability of ovarian cancer cells was evaluated using MTT assay, and its effects on apoptosis and the cell cycle were detected using flow cytometry. Western blotting was performed to identify apoptosis-and cell cycle-related proteins altered by KA3D treatment. A xenograft model was used to verify the inhibitory effect of KA3D in vivo. H&E staining, biochemical indicator detection, and blood cell counts were used to observe the toxicity and side effects of KA3D. KA3D treatment impeded cell viability, induced apoptosis, and impeded the G2 phase of the cell cycle in ovarian cancer cells. Mechanistically, we found that KA3D enhanced the expression of proapoptotic molecules such as BAX and Caspase 3, while antiapoptotic proteins such as BCL2 were inhibited. The G0/G1 phase-related protein cyclin D1 was reduced and the G2 phase-related protein cyclin B1 was upregulated. In vivo, KA3D displayed potent anticancer activity, with no apparent toxicity in BABLC/c nude mice bearing SKOV3 cells. KA3D demonstrated remarkable chemotherapeutic drug efficacy in terms of significant cancer suppression in vitro and in vivo with low toxicity.

[Mechanism of salidroside in inhibiting proliferation, migration and promoting phenotypic switching of arterial smooth muscle cells].

This study aims to examine the effect of salidroside(SAL) on the phenotypic switching of human aortic smooth muscle cells(HASMC) induced by the platelet-derived growth factor-BB(PDGF-BB) and investigate the pharmacological mechanism. Firstly, the safe concentration of SAL was screened by the lactate dehydrogenase release assay. HASMC were divided into control, model, and SAL groups, and the cells in other groups except the control group were treated with PDGF-BB for the modeling of phenotypic switching. Cell proliferation and migration were detected by the cell-counting kit(CCK-8) assay and Transwell assay, respectively. The cytoskeletal structure was observed by F-actin staining with fluorescently labeled phalloidine. The protein levels of proliferating cell nuclear antigen(PCNA), migration-related protein matrix metalloprotein 9(MMP-9), fibronectin, α-smooth muscle actin(α-SMA), and osteopontin(OPN) were determined by Western blot. To further investigate the pharmacological mechanism of SAL, this study determined the expression of protein kinase B(Akt) and mammalian target of rapamycin(mTOR), as well as the upstream proteins phosphatase and tensin homologue(PTEN) and platelet-derived growth factor receptor ß(PDGFR-ß) and the downstream protein hypoxia-inducible factor-1α(HIF-1α) of the Akt/mTOR signaling pathway. The results showed that the HASMCs in the model group presented significantly increased proliferation and migration, the switching from a contractile phenotype to a secretory phenotype, and cytoskeletal disarrangement. Compared with the model group, SAL weakened the proliferation and migration of HASMC, promoted the expression of α-SMA(a contractile phenotype marker), inhibited the expression of OPN(a secretory phenotype marker), and repaired the cytoskeletal disarrangement. Furthermore, compared with the control group, the modeling up-regulated the levels of phosphorylated Akt and mTOR and the relative expression of PTEN, HIF-1α, and PDGFR-ß. Compared with the model group, SAL down-regulated the protein levels of phosphorylated Akt and mTOR, PTEN, PDGFR-ß, and HIF-1α. In conclusion, SAL exerts a protective effect on the HASMCs exposed to PDGF-BB by regulating the PDGFR-ß/Akt/mTOR/HIF-1α signaling pathway.

Tumor microenvironment-responsive size-changeable and biodegradable HA-CuS/MnO2 nanosheets for MR imaging and synergistic chemodynamic therapy/phototherapy.

Tumor microenvironment (TME)-responsive size-changeable and biodegradable nanoplatforms for multimodal therapy possess huge advantages in anti-tumor therapy. Hence, we developed a hyaluronic acid (HA) modified CuS/MnO2 nanosheets (HCMNs) as a multifunctional nanoplatform for synergistic chemodynamic therapy (CDT)/photothermal therapy (PTT)/photodynamic therapy (PDT). The prepared HCMNs exhibited significant NIR light absorption and photothermal conversion efficiency because of the densely deposited ultra-small sized CuS nanoparticles on the surface of MnO2 nanosheet. They could precisely target the tumor cells and rapidly decomposed into small sized nanostructures in the TME, and then efficiently promote intracellular ROS generation through a series of cascade reactions. Moreover, the local temperature elevation induced by photothermal effect also promote the PDT based on CuS nanoparticles and the Fenton-like reaction of Mn2+, thereby enhancing the therapeutic efficiency. Furthermore, the T1-weighted magnetic resonance (MR) imaging was significantly enhanced by the abundant Mn2+ ions from the decomposition process of HCMNs. In addition, the CDT/PTT/PDT synergistic therapy using a single NIR light source exhibited considerable anti-tumor effect via in vitro cell test. Therefore, the developed HCMNs will provide great potential for MR imaging and multimodal synergistic cancer therapy.

Salidroside Regulates Mitochondrial Homeostasis After Polarization of RAW264.7 Macrophages.

ABSTRACT: Salidroside has anti-inflammatory and antiatherosclerotic effects, and mitochondrial homeostasis imbalance is closely related to cardiovascular disease. The aim of this study was to investigate the effect of salidroside on mitochondrial homeostasis after macrophage polarization and elucidate its possible mechanism against atherosclerosis. RAW264.7 cells were stimulated with 1 µg·mL -1 Lipopolysaccharide and 50 ng·mL -1 IFN-γ establish M1 polarization and were also pretreated with 400 µM salidroside. The relative expression of proinflammatory genes was detected by RT-PCR whereas that of mitochondrial homeostasis-related proteins and nuclear factor kappa-B (NF-κB) was detected by WB. Levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential, and mass were measured by chemifluorescence whereas that of NF-κB nuclear translocation was detected by immunofluorescence. Compared with the Mφ group, the M1 group demonstrated increased mRNA expression of interleukin-1ß , inductible nitric oxide synthase (iNOS), and tumor necrosis factor-α ; increased protein expression of iNOS, NOD-like receptor protein 3, putative kinase 1 , and NF-κB p65 but decreased protein expression of MFN2, Tom20, and PGC-1α; decreased mitochondrial membrane potential and mass; and increased ROS levels and NF-κB p65 nuclear translocation. Salidroside intervention decreased mRNA expression of interleukin-1ß and tumor necrosis factor-α compared with the M1 group but did not affect that of iNOS. Furthermore, salidroside intervention prevented the changes in protein expression, mitochondrial membrane potential and mass, ROS levels, and NF-κB p65 nuclear translocation observed in the M1 group. In summary, salidroside ultimately inhibits M1 macrophage polarization and maintains mitochondrial homeostasis after macrophage polarization by increasing mitochondrial membrane potential, decreasing ROS levels, inhibiting NF-κB activation, and in turn regulating the expression of proinflammatory factors and mitochondrial homeostasis-associated proteins.

Proteomics-based evaluation of the mechanism underlying vascular injury via DNA interstrand crosslinks, glutathione perturbation, mitogen-activated protein kinase, and Wnt and ErbB signaling pathways induced by crotonaldehyde.

Crotonaldehyde (CRA)-one of the major environmental pollutants from tobacco smoke and industrial pollution-is associated with vascular injury (VI). We used proteomics to systematically characterize the presently unclear molecular mechanism of VI and to identify new related targets or signaling pathways after exposure to CRA. Cell survival assays were used to assess DNA damage, whereas oxidative stress was determined using colorimetric assays and by quantitative fluorescence study; additionally, cyclooxygenase-2, mitogen-activated protein kinase pathways, Wnt3a, ß-catenin, phospho-ErbB2, and phospho-ErbB4 were assessed using ELISA. Proteins were quantitated via tandem mass tag-based liquid chromatography-mass spectrometry and bioinformatics analyses, and 34 differentially expressed proteins were confirmed using parallel reaction monitoring, which were defined as new indicators related to the mechanism underlying DNA damage; glutathione perturbation; mitogen-activated protein kinase; and the Wnt and ErbB signaling pathways in VI based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses. Parallel reaction monitoring confirmed significant (p < 0.05) upregulation (> 1.5-fold change) of 23 proteins and downregulation (< 0.667-fold change) of 11. The mechanisms of DNA interstrand crosslinks; glutathione perturbation; mitogen-activated protein kinase; cyclooxygenase-2; and the Wnt and ErbB signaling pathways may contribute to VI through their roles in DNA damage, oxidative stress, inflammation, vascular dysfunction, endothelial dysfunction, vascular remodeling, coagulation cascade, and the newly determined signaling pathways. Moreover, the Wnt and ErbB signaling pathways were identified as new disease pathways involved in VI. Taken together, the elucidated underlying mechanisms may help broaden existing understanding of the molecular mechanisms of VI induced by CRA.

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications.

Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review, we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.

Glyoxal damages human aortic endothelial cells by perturbing the glutathione, mitochondrial membrane potential, and mitogen-activated protein kinase pathways.

BACKGROUND: Exposure to glyoxal, the smallest dialdehyde, is associated with several diseases; humans are routinely exposed to glyoxal because of its ubiquitous presence in foods and the environment. The aim of this study was to examine the damage caused by glyoxal in human aortic endothelial cells. METHODS: Cell survival assays and quantitative fluorescence assays were performed to measure DNA damage; oxidative stress was detected by colorimetric assays and quantitative fluorescence, and the mitogen-activated protein kinase pathways were assessed using western blotting. RESULTS: Exposure to glyoxal was found to be linked to abnormal glutathione activity, the collapse of mitochondrial membrane potential, and the activation of mitogen-activated protein kinase pathways. However, DNA damage and thioredoxin oxidation were not induced by dialdehydes. CONCLUSIONS: Intracellular glutathione, members of the mitogen-activated protein kinase pathways, and the mitochondrial membrane potential are all critical targets of glyoxal. These findings provide novel insights into the molecular mechanisms perturbed by glyoxal, and may facilitate the development of new therapeutics and diagnostic markers for cardiovascular diseases.

Upregulated Tripartite Motif 47 Could Facilitate Glioma Cell Proliferation and Metastasis as a Tumorigenesis Promoter.

INTRODUCTION: Tripartite motif 47 (TRIM47) belongs to a category of the TRIM family. It takes part in cancer tumorigenesis, thus demonstrating important functions across numerous carcinomas. Unfortunately, it is still elusive towards TRIM47 expression, characteristic, and biological function in brain gliomas. METHODS: Public database analysis was applied to analyze TRIM47 expression, and quantitative real-time PCR (qRT-PCR) was applied to detect the expression of TRIM47 in 9 paired tissues of glioma. The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were applied to evaluate the overall survival (OS). Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied to analyze differentially expressed gene (DEG) functions. In vitro experiments were performed to validate TRIM47-mediated effects on glioma cell proliferation, migration, and invasion. RESULTS: Compared to that in normal tissues, TRIM47 expression was greatly higher in glioma tissues, and its expression level was associated with different grades of glioma. Our data indicated that highly expressed TRIM47 displayed an association with the poor prognosis of glioma patients. Ablating TRIM47 obviously impeded glioma cell invasion and migration. CONCLUSION: TRIM47 could modulate glioma cell proliferation, invasion, and migration. Highly expressed TRIM47 exhibited a correlation with poor prognosis. All data imply that TRIM47 is a probable biomarker for glioma and has the potentiality to become a newly generated target for glioma treatment.

Antioxidant Effects of Salidroside in the Cardiovascular System.

Cardiovascular disease is one of the main human health risks, and the incidence is increasing. Salidroside is an important bioactive component of Rhodiola rosea L., which is used to treat Alzheimer's disease, tumor, depression, and other diseases. Recent studies have shown that salidroside has therapeutic effects, to some degree, in cardiovascular diseases via an antioxidative mechanism. However, evidence-based clinical data supporting the effectiveness of salidroside in the treatment of cardiovascular diseases are limited. In this review, we discuss the effects of salidroside on cardiovascular risk factors and cardiovascular diseases and highlight potential antioxidant therapeutic strategies.

Fasting Plasma Glucose and Coronary Heart Disease in a Rural Population of North Henan, China.

Even in individuals without diabetes, the incidence of coronary heart disease (CHD) increases with the rise in fasting plasma glucose (FPG); however, the threshold of FPG for CHD in rural areas of China is unclear. We retrospectively examined 2,987 people. Coronary angiography records were used to determine the presence of CHD as well as its severity. Risk factors for CHD and the relationship between different levels of FPG and CHD were analyzed. After adjusting for age, hypertension, dyslipidemia, smoking, drinking, chronic kidney disease, and previous ischemic stroke, the incidence of CHD in nondiabetic women began to increase when FPG exceeded 5.2 mmol/L (odds ratio (OR) = 1.438, 95% confidence interval (CI) = 1.099-1.880, p=0.008), and the degree of coronary artery lesions also became more severe (OR = 1.406, 95% CI = 1.107-1.788, p=0.005). However, no such correlations were found in nondiabetic men. In conclusion, among the nondiabetic women in rural areas of northern Henan, both the incidence of CHD and the severity of lesions increased when FPG levels were greater than 5.2 mmol/L, while no significant correlation between FPG and CHD was observed in diabetes-free men.

Laparoscopic and Robotic-Assisted Partial Nephrectomy: An Overview of Hot Issues.

Laparoscopic partial nephrectomy and robot-assisted partial nephrectomy are attracting increased attention from urologists. They can achieve the same effect of oncology control as radical nephrectomy; moreover, they can offer better preservation of renal function, thus obtaining long-term living benefits. The indications are also expanding, making it possible for larger and more difficult tumors. Laparoscopic partial nephrectomy and robot-assisted partial nephrectomy can be performed by transperitoneal and retroperitoneal approaches, with their individual advantages and limitations. In addition, the renal tumor scoring systems have been widely used and studied in laparoscopic partial nephrectomy and robot-assisted partial nephrectomy. In -order to better preserve renal function, the zero-ischemia technique is widely used. The application of intraoperative imaging technology provides convenience and greater benefits. Besides, whether minimal invasive partial nephrectomy can be performed without stop antiplatelet treatment is still disputed. Clinicians perform substantial exploration and practice to achieve the "trifecta" of surgery: complete resection of the tumor, maximum protection of renal function, and no complications.

Physcion 8-O-ß-Glucopyranoside Alleviates Oxidized Low-Density Lipoprotein-Induced Human Umbilical Vein Endothelial Cell Injury by Inducing Autophagy Through AMPK/SIRT1 Signaling.

AIM: Vascular endothelial cell dysfunction plays a crucial role in the initiation and development of atherosclerosis. Physcion 8-O-ß-glucopyranoside (PG), an anthraquinone extracted from Polygonum cuspidatum, has a number of pharmacological functions. The aim of this study was to elucidate the protective effects of PG against oxidized low-density lipoprotein (ox-LDL) in VECs. METHODS AND MATERIALS: Human umbilical vein endothelial cells (HUVECs) were used as the in vitro model. Cell viability and apoptosis were, respectively, assessed by CCK-8 assay and Annexin-V/PI staining. Formation of autophagosomes was visualized by acridine orange staining, and the autophagy flux was tracked after infecting the cells with the mRFP-GFP-LC3 adenovirus. The expression levels of various apoptosis and autophagy-associated marker proteins were detected by Western blotting. RESULTS: Pretreatment with PG protected the HUVECs from ox-LDL-induced apoptosis. In addition, PG promoted autophagy in HUVECs, which was responsible for its antiapoptotic effects. Finally, activation of AMPK/SIRT1 signaling was upstream of PG-induced autophagy. CONCLUSIONS: PG has potential pharmacological effects against oxidative damage-induced HUVEC injury through inducing AMPK/SIRT1-mediated autophagy.

Long non-coding RNAs in renal cell carcinoma: A systematic review and clinical implications.

Renal cell carcinoma is one of the most common malignancy in adults, its prognosis is poor in an advanced stage and early detection is difficult due to the lack of molecular biomarkers. The identification of novel biomarkers for RCC is an urgent and meaningful project. Long non-coding RNA (lncRNA) is transcribed from genomic regions with a minimum length of 200 bases and limited protein-coding potential. Recently, lncRNAs have been greatly studied in a variety of cancer types. They participate in a wide variety of biological processes including cancer biology. In this review, we provide a new insight of the profiling of lncRNAs in RCC and their roles in renal carcinogenesis, with an emphasize on their potential in diagnosis, prognosis and potential roles in RCC therapy.