The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes.

BACKGROUND: Heat shock protein family A member 5 (HSPA5), a recently identified suppressor of ferroptosis, was reported to potentially regulating osteoarthritis. However, the exact role of HSPA5 and how its expression was regulated in osteoarthritis are largely unclear. METHODS: Rat primary chondrocytes were treated with 10 ng/mL IL-1ß for 24 h and incubated with ferrostatin-1 (a ferroptosis inhibitor). Cell viability, production of TNF-α, ROS and MDA, expression levels of collagen II, MMP13, GPX4, and SND1, and Fe2+ concentration were detected. Gain- and loss-of-function manipulations were performed to investigate the effect of HSPA5 on chondrocyte functions, and SND1 shRNA (sh-SND1) was transfected into IL-1ß-treated primary chondrocytes alone or together with sh-HSPA5. Furthermore, the interaction between HSPA5 and GPX4 and the regulation of HSPA5 on GPX4 were explored. Finally, SND1 was knocked down in the rats with osteoarthritis, and the histopathology, expression of HSPA5-GPX4 axis, and levels of oxidative stress markers were evaluated. RESULTS: IL-1ß treatment could enhance extracellular matrix (ECM) degradation (collagen II reduced and MMP13 increased), promote ferroptosis, manifested by decreased cell viability, increased levels of TNF-α, ROS, MDA, and Fe2+ concentrations, and decreased level of GPX4 protein, and increase SND1 expression in chondrocytes, which could be reversed by ferrostatin-1. Knockdown of SND1 enhanced ECM degradation and suppressed ferroptosis IL-1ß-treated chondrocytes, which could be eliminated by knockdown of HSPA5. SND1 bound with HSPA5 at the 3'UTR and destabilized the HSPA5 mRNA. HSPA5 protein directly bound with GPX4 protein and positively regulate its expression. HSPA5 overexpression suppressed IL-1ß-induced chondrocyte ferroptosis, while this effect was counteracted by GPX4 silencing. Knockdown of SND1 upregulated HSPA5 and GPX4 in rat cartilage, inhibited inflammatory damage and ferroptosis, and alleviated OA progression. CONCLUSION: The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes.

Formononetin attenuates osteoclast differentiation and calcium loss by mediating transcription factor AP-1 in type I diabetic mice.

Formononetin (FMN) has been reported as a prospective antiosteoporotic medication. However, the antiosteoporotic properties of FMN are still unclear in a mouse model with diabetes-induced osteoporosis. An osteoporotic or osteopenic mouse model with type I diabetes mellitus (T1DM) was established using streptozotocin (40 mg/kg) injection for 5 consecutive days. After 12 weeks with FMN intragastric administration (0.5, 5, 20 mg/kg), the antiosteoporotic activity of FMN was evaluated in T1DM mice. FMN supplementation effectively improves Ca excretion and trabecular bone degeneration and impedes osteoclast differentiation and function to attenuate hyperglycemia-induced bone deterioration. In addition, FMN inhibited activating protein 1 (AP-1) and osteoclast-specific gene expression, Nfatc1, Ctsk, and TRAP. The administration of FMN has a beneficial effect to attenuate hyperglycemia-induced bone deteriorations, including osteoclastogenesis, trabecular bone, and Ca loss. Our study provided a prospective medication for the treatment of T1DM-related osteopenia or osteoporosis with FMN.

C1q/tumor necrosis factor-related protein 9 protects cultured chondrocytes from IL-1ß-induced inflammatory injury by inhibiting NLRP3 inflammasome activation via the AdipoR1/AMPK axis.

C1q/tumor necrosis factor-related protein 9 (CTRP9) has been identified as a novel anti-inflammatory factor that participates in numerous pathological conditions. However, whether CTRP9 participates in the regulation of osteoarthritis has not been studied. This work sought to determine the possible role of CTRP9 in osteoarthritis using an in vitro model, namely interleukin-1ß (IL-1ß)-stimulated chondrocytes. There was a decreased level of CTRP9 in chondrocytes after IL-1ß stimulation. CTRP9 upregulation dramatically repressed IL-1ß-evoked apoptosis and inflammatory response in cultured chondrocytes. The mechanistic investigation revealed that CTRP9 overexpression restrained the activation of the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome in IL-1ß-stimulated chondrocytes via the adiponectin receptor 1 (AdipoR1)/adenosine monophosphate-activated protein kinase (AMPK) axis. Notably, inhibition of AdipoR1 or AMPK abolished the regulatory effects of CTRP9 overexpression on IL-1ß-evoked apoptosis and inflammasome activation. Overall, the results of this work delineate that CTRP9 protects cultured chondrocytes from IL-1ß-induced inflammatory injury by inhibiting NLRP3 inflammasome activation via the AdipoR1/AMPK axis. This work underscores a potential role of CTRP9 in the progression of osteoarthritis.

LIGHT aggravates sepsis-associated acute kidney injury via TLR4-MyD88-NF-κB pathway.

Sepsis-associated acute kidney injury (SA-AKI) is a common clinical critical care syndrome. It has received increasing attention due to its high morbidity and mortality; however, its pathophysiological mechanisms remain elusive. LIGHT, the 14th member of the tumour necrosis factor (TNF) superfamily and a bidirectional immunoregulatory molecule that regulates inflammation, plays a pivotal role in disease pathogenesis. In this study, mice with an intraperitoneal injection of LPS and HK-2 cells challenged with LPS were employed as a model of SA-AKI in vivo and in vitro, respectively. LIGHT deficiency notably attenuated kidney injury in pathological damage and renal function and markedly mitigated the inflammatory reaction by decreasing inflammatory mediator production and inflammatory cell infiltration in vivo. The TLR4-Myd88-NF-κB signalling pathway in the kidney of LIGHT knockout mice was dramatically down-regulated compared to the controls. Recombinant human LIGHT aggravated LPS-treated HK-2 cell injury by up-regulating the expression of the TLR4-Myd88-NF-κB signalling pathway and inflammation levels. TAK 242 (a selective TLR4 inhibitor) reduced this trend to some extent. In addition, blocking LIGHT with soluble receptor fusion proteins HVEM-Fc or LTßR-Fc in mice attenuated renal dysfunction and pathological damage in SA-AKI. Our findings indicate that LIGHT aggravates inflammation and promotes kidney damage in LPS-induced SA-AKI via the TLR4-Myd88-NF-κB signalling pathway, which provide potential strategies for the treatment of SA-AKI.

ABIN-1 protects chondrocytes from lipopolysaccharide-induced inflammatory injury through the inactivation of NF-κB signalling.

The A20-binding inhibitor of nuclear factor (NF)-κB-1 (ABIN-1) protein has recently been implicated as a key regulator of inflammation with involvement in multiple inflammatory diseases. However, the function of ABIN-1 in osteoarthritis (OA) remains unclear. In the current study, we explored the role of ABIN-1 in the regulation of lipopolysaccharide (LPS)-induced inflammatory injury of chondrocytes, which served as an in vitro model of OA. Results revealed that ABIN-1 expression was induced by chondrocyte exposure to LPS. ABN-1 silencing exacerbated LPS-induced apoptosis and the inflammatory response, while ABIN-1 overexpression alleviated the inflammatory response and LPS-induced apoptosis in chondrocytes. Moreover, ABIN-1 overexpression resulted in significantly decreased LPS-induced NF-κB activation. Notably, activation of NF-κB signalling significantly reversed ABIN-1-mediated inhibitory effects on LPS-induced inflammatory injury in chondrocytes. Taken together, these results demonstrate that ABIN-1 protects chondrocytes against LPS-induced inflammatory injury through the suppression of NF-κB signalling. Our study suggests a potential role for ABIN-1 in OA. Further, we show that ABIN-1 may serve as a potential target for controlling joint inflammation.

LncRNA PART-1 targets TGFBR2/Smad3 to regulate cell viability and apoptosis of chondrocytes via acting as miR-590-3p sponge in osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease that commonly occurs in the elderly. This study focused on apoptosis and explored the modulating effects of long non-coding (lncRNAs) prostate androgen-regulated transcript-1 (PART-1) on chondrocytes apoptosis. In the present study, the PART-1 expression level was down-regulated in the OA cartilages. Silence of PART-1 decreased the cell viability and promoted chondrocytes apoptosis. Overexpression of PART-1 could reverse the effects induced by interleukin 1ß (IL-1ß) stimulation, thus slowing down the apoptosis rate. MiR-590-3p was found to be the potential target, and RNA immunoprecipitation and luciferase activity assay confirmed the binding between PART-1 and miR-590-3p. Moreover, miR-590-3p was down-regulated by PART-1 and was negatively associated with PART-1. Transforming growth factor-beta receptor type 2 (TGFBR2) was positively associated with PART-1. Down-regulation of PART-1 decreased cell viability and induced cell apoptosis, which was partially reversed by miR-590-3p silence or TGFBR2 overexpression; while overexpression of PART-1 increased the cell viability and decreased the caspase 3 activity and apoptotic rates, and the effects were partially attenuated by miR-590-3p overexpression or silence of TGFBR2 in IL-1ß-stimulated chondrocytes. Knock-down of PART-1 down-regulated both Smad3 and p-Smad3 protein levels, which was reversed by miR-590-3p inhibition or TGFBR2 overexpression. Smad3 expression level was lower in the OA group than that in the normal group and was positively associated with the PART-1 expression level. Collectively, the study revealed that lncRNA PART-1 regulates the apoptosis of chondrocytes in OA by acting as a sponge for miR-590-3p, which subsequently regulates TGFBR2/Smad3 signalling.

RRAS2 knockdown suppresses osteosarcoma progression by inactivating the MEK/ERK signaling pathway.

Aberrant function of RRAS2 drives malignant transformation in a various of cancers. However, little information exists on the function of RRAS2 in tumorigenesis of osteosarcoma. In this study, we investigated the effect of RRAS2 on osteosarcoma progression and its underlying mechanism. The gene expression level and prognostic power of RRAS2 in osteosarcoma were first investigated using the data from the Gene Expression Omnibus database. Then RNA interference was performed to silence the expression of RRAS2 in osteosarcoma cells. Quantitative real-time-PCR and western blot were used to examine the gene and protein expressions of RRAS2 in osteosarcoma cells. In-vitro cancer proliferation and migration were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide solution and wound-healing assays, respectively. We found that RRAS2 was significantly upregulated in osteosarcoma cells and high expression of RRAS2 was associated with a poor prognosis for patients with osteosarcoma. RNA interference decreased the gene and protein expression of RRAS2, reduced in-vitro the proliferation and migration of osteosarcoma cells, and suppressed the activation of the MEK/ERK signaling pathway. RRAS2 as an adverse prognostic factor promoted cell proliferation and migration by activating the MEK/ERK signaling pathway, and may provide new therapeutic value for osteosarcoma.

The polymorphism of SMAD3 rs1065080 is associated with increased risk for knee osteoarthritis.

The mechanism of knee osteoarthritis (OA) is still not clearly elucidated. SMAD3 gene polymorphisms are considered to play a vital role in OA pathogenesis. We thus investigated the relationship of SMAD3 rs1065080 gene polymorphism and susceptibility to knee osteoarthritis in a Chinese Han population. A total of 237 patients and 142 healthy control participants were enrolled in a case-control study. DNA was extracted from peripheral blood samples and genotyped by using the Mass-ARRAY method. Our results revealed that there was a significant difference between patients and healthy controls in the genotype of A and G (p = 0.019); those with a GG genotype had a significant increase in OA risk (OR 2.881, 95% CI 1.993-7.353, p = 0.025). In addition, logistic regression analysis showed that the recessive genetic model decreased OA morbidity (OR 0.648, 95% CI 0.416-0.911, p = 0.046). In conclusion, the GG genotype of rs1065080 was associated with a higher risk of OA and the recessive genetic model decreased the risk of OA.

Integrated evaluation of biomechanical and biological properties of the biomimetic structural bone scaffold: Biomechanics, simulation analysis, and osteogenesis.

A porous structure is essential for bone implants because it increases the bone ingrowth space and improves mechanical and biological properties. The biomimetically designed porous Voronoi scaffold can reconstruct the structure and function of cancellous bone; however, its comprehensive properties need to be investigated further. In this study, algorithms based on scaling factors were used to design the Voronoi scaffolds. Classic approaches, such as computer-aided design and the implicit surface method, have been used to design Diamond, Gyroid, and I-WP scaffolds as controls. All scaffolds were prepared by selective laser melting of titanium alloys and three-dimensional printing. Mechanical tests, finite element analysis, and in vitro and in vivo experiments were performed to investigate the biomechanical, cytologic, and osteogenic performance of the scaffolds, while computational fluid dynamics simulations were used to explore the underlying mechanisms. Diamond scaffolds have a better loading capacity, and the mechanical behaviors and fluid flow of Voronoi scaffolds are similar to those of the human trabecular bone. Cells showed more proliferation and distribution on the Diamond and Voronoi scaffolds and exhibited evident differentiation on Gyroid and Voronoi scaffolds. Bone formation was apparent on the inner part of the Gyroid, the outer part of the I-WP, and the entire Diamond and Voronoi scaffolds. The hydrodynamic properties and stimulus response of cells influenced by the porous structure account for the varied biological performance of the scaffolds. The Voronoi scaffolds with bionic mechanical behavior and an appropriate hydrodynamic response exhibit evident cell growth and osteogenesis, making them preferable for porous structural bone implants.

EGFL6 activates the ERK signaling to improve angiogenesis and osteogenesis of BMSCs in patients with steroid-induced osteonecrosis of the femoral head.

Recently, epidermal growth factor-like domain protein 6 (EGFL6) was proposed as a candidate gene for coupling angiogenesis to osteogenesis during bone repair; however, the exact role and underlying mechanism are largely unknown. Here, using immunohistochemical and Western blotting analyses, we found that EGFL6 was downregulated in the femoral head tissue of patients with steroid-induced osteonecrosis of the femoral head (SONFH) compared to patients with traumatic femoral neck fracture (FNF), accompanied by significantly downregulation of osteogenic and angiogenic marker genes. Then, bone marrow mesenchymal stem cells (BMSCs) were isolated from the FNF and the SONFH patients, respectively, and after identification by immunofluorescence staining surface markers, the effect of EGFL6 on their abilities of osteogenic differentiation and angiogenesis was evaluated. Our results of alizarin red staining and tubular formation experiment revealed that BMSCs from the SONFH patients (SONFH-BMSCs) displayed an obviously weaker ability of osteogenesis than FNF-BMSCs, and EGFL6 overexpression improved the abilities of osteogenic differentiation and angiogenesis of SONFH-BMSCs. Moreover, EGFL6 overexpression activated extracellular signal-regulated kinases 1/2 (ERK1/2). ERK1/2 inhibitor U0126 reversed the promoting effect of EGFL6 overexpression on the expression of osteogenesis and angiogenesis-related genes in the SONFH femoral head. In conclusion, EGFL6 plays a protective role in SONFH, it promotes osteogenesis and angiogenesis of BMSCs, and its effect is likely to be related to ERK1/2 activation.

Rhombic dodecahedron nanoframes of PtIrCu with high-index faceted hyperbranched nanodendrites for efficient electrochemical ammonia oxidation via preferred NHx dimerization pathways.

Ammonia has been emerging as a sustainable and environmentally friendly fuel. However, direct electrochemical ammonia oxidation reaction (AOR) in low-temperature fuel cells seriously suffers from high overpotential and deficient durability. Herein, rhombic dodecahedron nanoframe of platinum iridium copper (PtIrCu) with high-index faceted hyperbranched nanodendrites (RDNF-HNDs) was developed using a one-step self-etching solvothermal method. The framework structure with the high-index facets enables the PtIrCu nanocrystals to expose more effective active sites. They exhibit an ultra-low onset potential of 0.33 V vs. RHE and high mass activity of 26.1 A gPtIr-1 at 0.50 V, which is 140 mV lower and 7.5 times higher than that of commercial Pt/C in the AOR. In situ attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy verifies that AOR on PtIrCu RDNF-HNDs prefers to the NHx dimerization pathways, effectively alleviating the poison of Nads and NOx. The theoretical calculation also shows that both introducing Cu atoms into PtIr alloy and increasing the content of Ir in PtIrCu alloy can reduce the reaction energy barrier of electrochemical dehydrogenation from *NH2 to *NH. The specific structure of PtIrCu RDNF-NDs provides a new inspiration to solve the critical issue of electrocatalysts for AOR with low activity and durability.

TRIM38 protects chondrocytes from IL-1ß-induced apoptosis and degeneration via negatively modulating nuclear factor (NF)-κB signaling.

Tripartite motif protein 38 (TRIM38) has been documented as a vital modulator of inflammation. However, the relevance of TRIM38 in osteoarthritis is not yet known. In this work, we aimed to explore any possible effects of TRIM38 on interleukin-1ß (IL-1ß)-stimulated chondrocytes, an in vitro cellular model of osteoarthritis. Analyzing our data showed significant decreases in the levels of TRIM38 in chondrocytes following IL-1ß stimulation. Gain-of-function studies revealed that overexpression of TRIM38 markedly increased the viability of IL-1ß-stimulated chondrocytes while decreasing their rate of apoptosis and degeneration. Conversely, depletion of TRIM38 enhanced the sensitivity of chondrocytes to IL-1ß-induced injury. Further research demonstrated that TRIM38 was capable of inhibiting IL-1ß-induced activation of nuclear factor (NF)-κB signaling. Reactivation of NF-κB markedly reversed TRIM38-overexpression-mediated effects, while inhibition of NF-κB significantly abolished TRIM38-depletion-induced effects in IL-1ß-stimulated chondrocytes. In summary, the findings of this work suggest that TRIM38 is capable of ameliorating IL-1ß-induced apoptosis and degeneration of chondrocytes via suppression of NF-κB signaling. Our work indicates a potential role of TRIM38 in osteoarthritis and proposes it as a new therapeutic target for osteoarthritis.

Two kinds of DNA enzyme-powered bidirectional one-dimensional DNA walking nanomachine for payload release and biosensing.

Herein, we present a target-triggered bidirectional one-dimensional (1D) DNA walking nanomachine, built from a well-designed track, which could simultaneously move two different DNA walkers to the opposite direction along the track and release payload. This track is composed of a DNA walker station (chain S3) in the middle of track for storing two kinds of DNA walker (W1 and W2), and corresponding two kinds of payload conjugated DNA stators (chain S1, S2 and S4, S5) for the moving of walker on the two flanks of chain S3 respectively. Moreover, the chain S3 also serves as a target-assisted amplification platform based on a catalytic hairpin assembly (CHA)-like strategy. In the presence of target (nucleic acid), the dynamic assembly between hairpin (HP) and S3 is triggered for multiple recycling of target and releasing of W1 and W2. Since the W1 and W2 respectively correspond to 8-17 DNAzyme and 10-23 DNAzyme, they could cleave the RNA substrates with sequence specificity to move towards two opposite directions along the track at the same time, accompanying the release of payloads. Such a 1D DNA walking nanomachine is not only could propel the walker to move in two directions respectively but also improve the locomotion efficiency compared to the traditional single-directional 1D DNA walking nanomachine with the same amounts of stators. This concept of inducing the locomotion manner change on a 1D DNA device may provide a thought to facilitate the development of DNA dynamic nanomachines and intelligent nanosensors.

Identification of Key Genes and Pathways for Enchondromas by Bioinformatics Analysis.

BACKGROUND: The risk of malignant transformation of enchondromas (EC) toward central chondrosarcoma is increased up to 35%, while the exact etiology of EC is unknown. The purpose of this research was to authenticate gene signatures during EC and reveal their potential mechanisms in occurrence and development of EC. METHODS: The gene expression profiles was acquired from Gene Expression Omnibus database (no. GSE22855). The gene ontology (GO), protein-protein interaction (PPI) network and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were utilized to identify differentially expressed genes (DEGs). RESULTS: Finally, 242 DEGs were appraisal, containing 200 overregulated genes and 42 downregulated genes. The outcomes of GO analysis indicated that upregulated DEGs were mainly enriched in several biological processes containing response to hypoxia, calcium ion, and negative regulation extrinsic apoptotic signaling pathway. Furthermore, the upregulated DEGs were enriched in extracellular matrix (ECM)-receptor interaction, protein processing in endoplasmic reticulum and ribosome, which was analyzed by KEGG pathway. From the PPI network, the top 10 hub genes were identified, which were related to significant pathways containing ribosome, protein processing in endoplasmic reticulum, and ECM-receptor interaction. CONCLUSION: In conclusion, the present study may be helpful for understanding the diagnostic biomarkers of EC.

Eupatilin alleviates airway remodeling via regulating phenotype plasticity of airway smooth muscle cells.

Childhood asthma is a common chronic airway disease, and its severe form remains a challenge. Eupatilin is a bioactive natural flavone that has been found to possess potential anti-asthma activity. However, the roles of eupatilin in asthma remain to be elucidated. In the present study, airway smooth muscle cells (ASMCs) were applied for the in vitro investigation since their phenotype plasticity make great contribution to airway remodeling during asthma pathogenesis. Our results showed that eupatilin suppressed the transforming growth factor ß1 (TGF-ß1)-induced proliferation and migration of ASMCs. Exposure of ASMCs to eupatilin increased the expressions of contractile markers smooth muscle α-actin (α-SMA) and myocardin, whereas expressions of extracellular matrix (ECM) proteins type I collagen (Coll I) and fibronectin were reduced. Furthermore, eupatilin treatment reversed the activation of nuclear factor-κ B (NF-κB), signal transducer and activator of transcription 3 (STAT3) and AKT pathways caused by TGF-ß1 in ASMCs. These findings suggested that eupatilin might attenuate airway remodeling via regulating phenotype plasticity of ASMCs.

A well-directional three-dimensional DNA walking nanomachine that runs in an orderly manner.

Herein, we report a three-dimensional (3D) DNA walking nanomachine innovatively constructed from a functionalized 3D DNA track, which runs in an orderly manner with favorable directionality to allow for programming certain pathways of information transduction for some target tasks. The nanomachine was constructed using a departure station of walker (UB + W) and a functionalized 3D track, which was made up of a rolling circle amplification (RCA)-generated backbone chain and numerous triangular rung units with stators (UA + S) assembled into a repeating array along the backbone. A specific domain (SD) was designed at the 5'-end of the backbone to capture the UB + W, and stators with specific RNA substrates were immobilized at the three UA corners for the DNA walker to travel on. Powered by 10-23 DNAzyme, the DNA walker started moving from the SD end to the other end of the track by the autonomous cleavage of RNA substrates. Significantly, the homogeneous distribution of stators in the longitudinal and horizontal extensions paved a specific path for each walker to move along the 3D track. This resulted in random and inactive self-avoiding walking; thus, the nanomachine exhibited good executive ability. These properties allowed the DNA walking nanomachine to program the certain pathways of information transduction for the stepwise and programmed execution of some target tasks, such as the synthesis of specific polyorganics and cargo delivery. We believe that such a 3D DNA walking nanomachine could enrich the concept in the field of dynamic DNA nanotechnology, and may improve the development of novel DNA nanomachines in cargo delivery and composite product synthesis.

LIGHT deficiency aggravates cisplatin-induced acute kidney injury by upregulating mitochondrial apoptosis.

Cisplatin is widely used as a chemotherapeutic agent for treating patients with solid tumors. The most common side effect of cisplatin treatment is nephrotoxicity. Recent studies have shown that mitochondrial apoptotic pathways are involved in cisplatin-induced acute kidney injury (Cis-AKI). LIGHT, the 14th member of the tumor necrosis factor superfamily (TNFSF14), was found to induce apoptosis of certain types of tumor cells. So far, a link between LIGHT and Cis-AKI has not been reported. In this study, we observed that expression of LIGHT and its receptors HVEM and LTßR was increased in kidney tissues of mice after cisplatin treatment. LIGHT deficiency aggravated kidney injury, as evidenced by more severe tubular injury; remarkably increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and both kidney injury molecule-1 (KIM-1) and inflammatory cytokine mRNAs in renal tissues. Moreover, in the renal tissues of LIGHT KO mice, cisplatin-induced mitochondrion injury and the levels of the pro-apoptotic molecules Bax, Cytochrome C (Cyt C), cleaved caspase-3, and cleaved caspase-9 were dramatically increased; in contrast, the expression of anti-apoptotic molecule Bcl-2 was markedly reduced, compared to those in WT mice, suggesting that LIGHT deficiency accelerated cisplatin-induced mitochondrial apoptosis of renal tubular cells in these mice. Accordingly, treatment with recombinant human LIGHT (rLIGHT) was shown to alleviate cisplatin-induced kidney injury in vivo. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to rLIGHT stimulation, evidenced by the reduction in the mitochondrion dysfunction (as confirmed by the significant reduced oxidative stress and membrane potential changes) and in the percentage of cells apoptosis. While blocking LIGHT with the soluble fusion protein LTßR-Ig or HVEM-Ig accelerated the HK-2 cells apoptosis. In conclusion, LIGHT deficiency aggravates Cis-AKI by promoting mitochondrial apoptosis pathways.

Scoparone prevents IL-1ß-induced inflammatory response in human osteoarthritis chondrocytes through the PI3K/Akt/NF-κB pathway.

Osteoarthritis (OA) is a degenerative joint disease that is commonly accompanied by inflammation. Scoparone is a biologically active constituent isolated from Artemisia capillaris and possesses anti-inflammatory activity. However, the effect of scoparone on inflammatory response in OA has not been authenticated. The aim of this study was to evaluate the role of scoparone in OA in vitro. Our results showed that IL-1ß treatment significantly inhibited the cell viability of chondrocytes, whereas the inhibition effect was attenuated by scoparone in a dose-dependent manner. IL-1ß also efficiently induced the production of nitric oxide (NO), prostaglandin E2 (PGE2), MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in chondrocytes. However, scoparone dose-dependently suppressed the induction. In addition, scoparone repressed IL-1ß-induced the expression of iNOS and COX-2 in chondrocytes. Furthermore, the activation of the PI3K/Akt/NF-κB pathway induced by IL-1ß was diminished by scoparone treatment. Taken together, these findings indicated that scoparone inhibited the expression of inflammatory mediators in IL-1ß-induced chondrocytes via regulating the PI3K/Akt/NF-κB pathway. Thus, scoparone may be used as a new therapeutic agent for the treatment of OA.

miR-18a-5p promotes cell invasion and migration of osteosarcoma by directly targeting IRF2.

An increasing number of studies have suggested that microRNAs (miRNAs) are involved in the progress of many human cancers including osteosarcoma (OS). Especially, microRNA-18a-5p (miR-18a-5p) has been reported to associate with the occurrence, development and clinical outcomes of human cancers. Therefore, we investigated the functions of miR-18a-5p in OS. Reverse transcription-quantitative PCR (RT-qPCR) showed that miR-18a-5p was significantly upregulated in OS tissues and cell lines (MG-63 and Saos-2). The overexpression of miR-18a-5p was found to significantly promote cell migration and invasion in MG-63 cells via Transwell assay. Moreover, luciferase reporter assays indicated that interferon regulatory factor (IRF)2 was a direct target of miR-18a-5p. IRF2 was downregulated in MG-63 and Saos-2 cell lines. Furthermore, Transwell analysis showed that the knockout of IRF2 promoted cell migration and invasion in MG-63 cells. Carcinogenesis of miR-18a-5p was reversed by the overexpression of IRF2 in OS. In conclusion, miR-18a-5p promoted the invasion and migration of OS cells through inhibiting IRF2 expression. Thus, miR-18a-5p might act as a potential target for the diagnosis and treatment of OS in the future.

The relationship of PADI4_94 polymorphisms with the morbidity of rheumatoid arthritis in Caucasian and Asian populations: a meta-analysis and system review.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is characterized by chronic, destructive, and debilitating arthritis. Peptidyl arginine deiminase type 4 (PADI4) polymorphisms (PADI4_94) have been reported to play a vital role in the disease. Nevertheless, the results were inconclusive. An electronic search of Embase, PubMed, CNKI, and WANFANG Date was performed to the identification of relevant studies published from 2003 to 2017. A total of 20 studies were enrolled as being eligible for analysis. In overall analysis, we had found a significant correlation between the PADI4_94 polymorphisms and RA under T vs. C (OR = 1.05, 95% CI 1.01-1.08, P = 0.01). Nevertheless, there were no significant associations under other four genetic models. In the subgroup analysis, we had observed the similar results in Asian population (T vs. C: OR = 1.11, 95% CI 1.05-1.17, P = 0.001), whereas no significant difference were observed in Caucasian population under any genetic model (P > 0.05). In conclusion, our meta-analysis demonstrated that the PADI4_94 polymorphisms might contribute to RA susceptibility especially in Asian populations but not in Caucasian populations. More well-designed studies with larger sample size are still required to further elucidate the relationship.