Hyaluronic Acid Oligosaccharide Derivatives Alleviate Lipopolysaccharide-Induced Inflammation in ATDC5 Cells by Multiple Mechanisms.

High molecular weight hyaluronic acids (HMW-HAs) have been used for the palliative treatment of osteoarthritis (OA) for decades, but the pharmacological activity of HA fragments has not been fully explored due to the limited availability of structurally defined HA fragments. In this study, we synthesized a series glycosides of oligosaccharides of HA (o-HAs), hereinafter collectively referred to as o-HA derivatives. Their effects on OA progression were examined in a chondrocyte inflammatory model established by the lipopolysaccharide (LPS)-challenged ATDC5 cells. Cell Counting Kit-8 (CCK-8) assays and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showed that o-HA derivatives (≤100 µg/mL) exhibited no cytotoxicity and pro-inflammatory effects. We found that the o-HA and o-HA derivatives alleviated LPS-induced inflammation, apoptosis, autophagy and proliferation-inhibition of ATDC5 cells, similar to the activities of HMW-HAs. Moreover, Western blot analysis showed that different HA derivatives selectively reversed the effects of LPS on the expression of extracellular matrix (ECM)-related proteins (MMP13, COL2A1 and Aggrecan) in ATDC5 cells. Our study suggested that o-HA derivatives may alleviate LPS-induced chondrocyte injury by reducing the inflammatory response, maintaining cell proliferation, inhibiting apoptosis and autophagy, and decreasing ECM degradation, supporting a potential oligosaccharides-mediated therapy for OA.

Molecular and cellular insights into Zika virus-related neuropathies.

Zika virus (ZIKV), a relatively elusive Aedes mosquito-transmitted flavivirus, had been brought into spotlight until recent widespread outbreaks accompanied by unexpectedly severe clinical neuropathies, including fetal microcephaly and Guillain-Barré syndrome (GBS) in the adult. In this review, we focus on the underlying cellular and molecular mechanisms by which vertically transmitted microorganisms reach the fetus and trigger neuropathies.

Using three statistical methods to analyze the association between aldehyde exposure and markers of inflammation and oxidative stress.

BACKGROUND: Exposure to aldehydes has been linked to adverse health outcomes such as inflammation and oxidative stress, but research on the effects of these compounds is limited. This study is aimed at assessing the association between aldehyde exposure and markers of inflammation and oxidative stress. METHODS: The study used data from the NHANES 2013-2014 survey (n = 766) and employed multivariate linear models to investigate the relationship between aldehyde compounds and various markers of inflammation (alkaline phosphatase (ALP) level, absolute neutrophil count (ANC), and lymphocyte count) and oxidative stress (bilirubin, albumin, and iron levels) while controlling for other relevant factors. In addition to generalized linear regression, weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) analyses were applied to examine the single or overall effect of aldehyde compounds on the outcomes. RESULTS: In the multivariate linear regression model, each 1 standard deviation (SD) change in propanaldehyde and butyraldehyde was significantly associated with increases in serum iron levels (beta and 95% confidence interval, 3.25 (0.24, 6.27) and 8.40 (0.97, 15.83), respectively) and the lymphocyte count (0.10 (0.04, 0.16) and 0.18 (0.03, 0.34), respectively). In the WQS regression model, a significant association was discovered between the WQS index and both the albumin and iron levels. Furthermore, the results of the BKMR analysis showed that the overall impact of aldehyde compounds was significantly and positively correlated with the lymphocyte count, as well as the levels of albumin and iron, suggesting that these compounds may contribute to increased oxidative stress. CONCLUSIONS: This study reveals the close association between single or overall aldehyde compounds and markers of chronic inflammation and oxidative stress, which has essential guiding value for exploring the impact of environmental pollutants on population health.

LncRNAs as a new regulator of chronic musculoskeletal disorder.

OBJECTIVES: In recent years, long non-coding RNAs (lncRNAs) have been found to play a role in the occurrence, progression and prognosis of chronic musculoskeletal disorders. DESIGN AND METHODS: Literature exploring on PubMed was conducted using the combination of keywords 'LncRNA' and each of the following: 'osteoarthritis', 'rheumatoid arthritis', 'osteoporosis', 'osteogenesis', 'osteoclastogenesis', 'gout arthritis', 'Kashin-Beck disease', 'ankylosing spondylitis', 'cervical spondylotic myelopathy', 'intervertebral disc degeneration', 'human muscle disease' and 'muscle hypertrophy and atrophy'. For each disorder, we focused on the publications in the last five years (5/1/2016-2021/5/1, except for Kashin-Beck disease). Finally, we excluded publications that had been reported in reviews of various musculoskeletal disorders during the last three years. Here, we summarized the progress of research on the role of lncRNA in multiple pathological processes during musculoskeletal disorders. RESULTS: LncRNAs play a crucial role in regulating downstream gene expression and maintaining function and homeostasis of cells, especially in chondrocytes, synovial cells, osteoblasts, osteoclasts and skeletal muscle cells. CONCLUSIONS: Understanding the mechanisms of lncRNAs in musculoskeletal disorders may provide promising strategies for clinical practice.

Targeted cell therapy for partial-thickness cartilage defects using membrane modified mesenchymal stem cells by transglutaminase 2.

Unlike full-thickness cartilage defects (FCD), partial-thickness cartilage defects (PCD) may still have residual healthy cartilage tissue, and therefore, the conventional clinical treatments such as microfracture and autologous chondrocyte implantation (ACI) are so traumatic that they may not be the suitable therapies for PCD. Although intra-articular injection of mesenchymal stem cells (MSCs) is a minimally invasive treatment, its therapeutic efficacy is markedly limited due to anoikis caused by failure of cell colonization in the injured area. By modifying a functional polypeptide on the MSC plasma membrane and exploiting the high expression of transglutaminase 2 (TGase2) in the regions of injured cartilage, we achieved targeted recognition and capture of modified MSCs by injured articular chondrocytes (ACs). In the in vitro co-culture model, MSCs improved the function of injured ACs and enhanced the chondrogenic differentiation potential of MSCs. Results of in vitro study also revealed that the activation of the AKT/mTOR signaling pathway may play an important role in the treatment of injured ACs by MSCs. Further, membrane-modified MSCs exhibited a better therapeutic effect than wide-type MSCs in a rabbit model of PCD. Thus, this unique cell membrane modification strategy provides a new cell-based therapeutic approach for the early treatment of articular cartilage defects and other joint diseases.

Comparison of Chondrocytes in Knee Osteoarthritis and Regulation by Scaffold Pore Size and Stiffness.

In knee osteoarthritis (OA), there is more pronounced cartilage damage in the medial compartment ("lesion zone") than the lateral compartment ("remote zone"). This study fills a gap in the literature by conducting a systematic comparison of cartilage and chondrocyte characteristics from these two zones. It also investigates whether chondrocytes from the different zones respond distinctly to changes in the physical and mechanical microenvironment using three-dimensional porous scaffolds by changing stiffness and pore size. Cartilage was harvested from patients with end-stage varus knee OA. Cartilage from the lesion and remote zones were compared through histological and biomechanical assessments, and through proteomic and gene transcription analyses of chondrocytes. Gelatin scaffolds with varied pore sizes and stiffness were used to investigate in vitro microenvironmental regulation of chondrocytes from the two zones. Cartilage from the lesion and remote zones differed significantly (p < 0.05) in histological and biomechanical characteristics, as well as phenotype, protein, and gene expression of chondrocytes. Chondrocytes from both zones were sensitive to changes in the structural and mechanical properties of gelatin scaffolds. Of interest, although all chondrocytes better retained chondrocyte phenotype in stiffer scaffolds, those from the lesion and remote zones, respectively, preferred scaffolds with larger and smaller pores. Distinct variations exist in cartilage and chondrocyte characteristics in the lesion and remote zones of knee OA. Cells in these two zones respond differently to variations in the physical and mechanical microenvironment. Understanding and manipulating these differences will facilitate the development of more efficient and precise diagnostic and therapeutic approaches for knee OA.

The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES.

Copper is an essential element in human beings, alterations in serum copper levels could potentially have effect on human health. To date, no data are available regarding how serum copper affects cardiovascular disease (CVD) risk factors in children and adolescents. We examined the association between serum copper levels and CVD risk factors in children and adolescents. We analyzed data consisting of 1427 subjects from a nationally representative sample of the US population in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The CVD risk factors included total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, glycohemoglobin, fasting insulin, and blood pressure. Multivariate and generalized linear regressions were performed to investigate associations adjusted for age, gender, ethnicity, poverty:income ratio (PIR), BMI, energy intake, and physical activity. We found significant associations between serum copper and total cholesterol (coefficient = 0.132; 95% CI 0.081, 0.182; P for trend < 0.001), glycohemoglobin (coefficient = 0.044; 95% CI 0.020, 0.069; P < 0.001), and fasting insulin (coefficient = 0.730; 95% CI 0.410, 1.050; P < 0.001) among the included participants. Moreover, in the generalized linear models, subjects with the highest copper levels demonstrated a 0.83% (95% CI 0.44%, 1.24%) greater increase in serum total cholesterol (p for trend < 0.001) when compared to participants with the lowest copper concentrations. Our results provide the first epidemiological evidence that serum copper concentrations are associated with total cholesterol concentrations in children and adolescents. However, the underlying mechanisms still need further exploration.

Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases.

Neurodevelopmental biology, coupled with the application of advanced histological, imaging, molecular, cellular, biochemical, and genetic approaches, has provided new insights into these intricate genetic, cellular, and molecular events. During telencephalic development, specific neural progenitor cells (NPCs) proliferate, differentiate into numerous cell types, migrate to their apposite positions, and form an integrated circuitry. Critical disturbance to this dynamic process via genetic and environmental risk can cause neurological disorders and disability. The phosphatidylinositol-3-OH kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling cascade contributes to mediate various cellular processes, including cell proliferation and growth, and nutrient uptake. In light of its critical function, dysregulation of this node has been regarded as a root cause of several neurodevelopmental diseases, such as megalencephaly ("big brain"), microcephaly ("small brain"), autism spectrum disorders, intellectual disability, schizophrenia, and epilepsy. In this review, particular emphasis will be given to the PI3K-Akt-mTOR signaling pathway and their paramount importance in neurodevelopment of the cerebral neocortex, because of its critical roles in complex cognition, emotional regulation, language, and behaviors.

Current advances of long non-coding RNA highly upregulated in liver cancer in human tumors.

Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs (ncRNAs) >200 nucleotides in length that govern diverse biological processes. Recent evidence suggests that lncRNAs are involved in cancer cell proliferation, apoptosis, invasion, migration, and metastasis. Dysregulation of lncRNAs has been observed in various tumors, and lncRNAs act as oncogenes or tumor suppressors in these malignancies. It has been revealed that lncRNA highly upregulated in liver cancer (HULC) is tightly correlated with a number of cancers such as hepatocellular carcinoma, gastric cancer, colorectal cancer, osteosarcoma, and diffuse large B-cell lymphoma. Depletion of HULC suppressed cancer cell proliferation, migration, and invasion and induced apoptosis. Additionally, HULC may function as a diagnostic biomarker and prognostic indicator for some tumors. In this review, we summarize the current knowledge of the role of HULC in cancer progression and the clinical management of human cancers.

Long non-coding RNA SNHG15 inhibits P15 and KLF2 expression to promote pancreatic cancer proliferation through EZH2-mediated H3K27me3.

Long non-coding RNA (lncRNA) is emerging as an critical regulator in multiple cancers, including pancreatic cancer (PC). Recently, lncRNA SNHG15 was found to be up-regulated in gastric cancer and hepatocellular carcinoma, exerting oncogenic effects. Nevertheless, the biological function and regulatory mechanism of SNHG15 remain unclear in pancreatic cancer (PC). In this study, we reported that SNHG15 expression was also upregulated in PC tissues, and its overexpression was remarkably associated with tumor size, tumor node metastasis (TNM) stage and lymph node metastasis in patients with PC. SNHG15 knockdown inhibited proliferative capacities and suppressed apoptotic rate of PC cells in vitro, and impaired in-vivo tumorigenicity. Additionally, RNA immunoprecipitation (RIP) assays showed that SNHG15 epigenetically repressed the P15 and Kruppel-like factor 2 (KLF2) expression via binding to enhancer of zeste homolog 2 (EZH2), and chromatin immunoprecipitation assays (CHIP) assays demonstrated that EZH2 was capable of binding to promoter regions of P15 and KLF2 to induce histone H3 lysine 27 trimethylation (H3K27me3). Furthermore, rescue experiments indicated that SNHG15 oncogenic function partially involved P15 and KLF2 repression. Consistently, an inverse correlation between the expression of SNHG15 and traget genes were found in PC tissues. Our results reported that SNHG15 could act as an oncogene in PC, revealing its potential value as a biomarker for early detection and individualized therapy.