Engineered MgO nanoparticles for cartilage-bone synergistic therapy.

The emerging therapeutic strategies for osteoarthritis (OA) are shifting toward comprehensive approaches that target periarticular tissues, involving both cartilage and subchondral bone. This shift drives the development of single-component therapeutics capable of acting on multiple tissues and cells. Magnesium, an element essential for maintaining skeletal health, shows promise in treating OA. However, the precise effects of magnesium on cartilage and subchondral bone are not yet clear. Here, we investigated the therapeutic effect of Mg2+ on OA, unveiling its protective effects on both cartilage and bone at the cellular and animal levels. The beneficial effect on the cartilage-bone interaction is primarily mediated by the PI3K/AKT pathway. In addition, we developed poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with nano-magnesium oxide modified with stearic acid (SA), MgO&SA@PLGA, for intra-articular injection. These microspheres demonstrated remarkable efficacy in alleviating OA in rat models, highlighting their translational potential in clinical applications.

PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.

Integrated machine learning and bioinformatic analyses used to construct a copper-induced cell death-related classifier for prognosis and immunotherapeutic response of hepatocellular carcinoma patients.

Background: Copper as phytonutrient has powerful activity against health diseases. A newly discovered mechanism of cell death that affects energy metabolism by copper ("cuproptosis") can induce multiple cuproptosis-related genes. Hepatocellular carcinoma (HCC) is a poorly prognosed widespread cancer having danger of advanced metastasis. Therefore, earlier diagnosis followed by the specific targeted therapy are required for improved prognosis. The work herein constructed scoring system built on ten cuproptosis-related genes (CRGs) to predict progression of tumor and metastasis more accurately and test patient reaction toward immunotherapy. Methods: A comprehensive assessment of cuproptosis patterns in HCC samples from two databases and a real-world cohort was performed on ten CRGs, that were linked to immune cell infiltration signatures of TME (tumor microenvironment). Risk signatures were created for quantifying effect of cuproptosis on HCC, and the effects of related genes on cellular function of HCC were investigated, in addition to the effects of immunotherapy and targeted therapy drugs. Results: Two distinct cuproptosis-associated mutational patterns were identified, with distinct immune cell infiltration characteristics and survival likelihood. Studies have shown that assessment of cuproptosis-induced tumor mutational patterns can help predict tumor stage, phenotype, stromal activity, genetic diversity, and patient prognosis. High risk scores are characterized by lower survival and worse treatment with anti-PD-L1/CTAL4 immunotherapy and first-line targeted drugs. Cytological functional assays show that CDKN2A and GLS promote proliferation, migration and inhibit copper-dependent death of HCC cells. Conclusion: HCC patients with high-risk scores exhibit significant treatment disadvantage and survival rates. Cuproptosis plays a non-negligible role in the development of HCC. Quantifying cuproptosis-related designs of tumors will aid in phenotypic categorization, leading to efficient personalized and targeted therapeutics and precise prediction of prognosis and metastasis.

GATA6 coordinates cross-talk between BMP10 and oxidative stress axis in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and often death. Here we report that deficiency of transcription factor GATA6 is a shared pathological feature of PA endothelial (PAEC) and smooth muscle cells (PASMC) in human PAH and experimental PH, which is responsible for maintenance of hyper-proliferative cellular phenotypes, pulmonary vascular remodeling and pulmonary hypertension. We further show that GATA6 acts as a transcription factor and direct positive regulator of anti-oxidant enzymes, and its deficiency in PAH/PH pulmonary vascular cells induces oxidative stress and mitochondrial dysfunction. We demonstrate that GATA6 is regulated by the BMP10/BMP receptors axis and its loss in PAECs and PASMC in PAH supports BMPR deficiency. In addition, we have established that GATA6-deficient PAEC, acting in a paracrine manner, increase proliferation and induce other pathological changes in PASMC, supporting the importance of GATA6 in pulmonary vascular cell communication. Treatment with dimethyl fumarate resolved oxidative stress and BMPR deficiency, reversed hemodynamic changes caused by endothelial Gata6 loss in mice, and inhibited proliferation and induced apoptosis in human PAH PASMC, strongly suggesting that targeting GATA6 deficiency may provide a therapeutic advance for patients with PAH.

Nesfatin-1 suppresses autophagy of chondrocytes in osteoarthritis via remodeling of cytoskeleton and inhibiting RhoA/ROCK signal pathway.

Autophagy and cytoskeleton integrity of chondrocytes are a considered as major factors in the progression of osteoarthritis (OA) involving excessive chondrocyte apoptosis and senescence. Nesfatin-1, an adipokine, has been reported to be closely related to cell autophagy and cytoskeleton malfunction. Our previous study found that nesfatin-1 was highly correlated with OA progress in OA patient, and the expression of nesfatin-1 rises in knee articular tissue, serum and chondrocytes. In current study, we aimed to explore the therapeutic effect of nesfatin-1 on OA and its molecular mechanism related to chondrocyte autophagy and cytoskeleton malfunction. We firstly demonstrated that nesfatin-1 effectively suppressed excessive autophagy of OA chondrocytes at both gene and protein levels. Meanwhile, we also found that nesfatin-1 significantly improved cytoskeleton integrity by showing higher F-actin/G-actin ratio, as well as more organized actin fiber structure. Mechanistically, utility of RhoA activator and inhibitor revealed that regulation of autophagy and cytoskeleton integrity via nesfatin-1 was realized via RhoA/ROCK pathway. We also confirmed that nesfatin-1 significantly ameliorated IL-1ß induced cartilage degeneration via destabilization of the medial meniscus (DMM) model. Overall, our study indicates that nesfatin-1 might be a promising therapeutic molecule for OA intervention.

Enhancing the Management of Metastatic Tumors by Robust Co-Delivery of 5-Fluorouracil/MicroRNA-10b Inhibitor Using EGFR-Targeted Nanovehicles.

Invasion and metastasis are the leading causes of death of patients with CRC. 5-Fluorouracil is widely used in clinic practice as the basic chemotherapy drug for CRC. However, it is inefficient in inhibiting tumor metastasis. MicroRNA-10b is uninvolved in regulating the growth of primary tumors; however, it could induce early tumor metastases and is a key regulator of chemotherapeutic resistance to 5-FU. A multifunctional nanovehicle that can carry small molecule drugs not only through the hydrophobic pockets of conjugated ß-cyclodextrin but also through electrostatic interaction between the conjugated peptides and siRNA to target functional genes is previously developed. In this study, a nanovehicle, named GCD, with epithelium growth factor receptor (EGFR)-targeted characteristics to simultaneously deliver chemotherapeutic and nucleotide drugs to distinct targets in CRC, is employed. These data show that co-delivery of 5-FU and anti-miR-10b can be effectively applied to targeted therapy of EGFR-overexpressed CRC, particularly inhibiting the metastasis of CRC. Furthermore, the therapeutic effect of this combination on tumor xenograft models derived from patients with CRC is evaluated. Taken together, this study may provide insights into the inhibition of tumor growth and metastasis simultaneously.

Cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation and pulmonary hypertension.

Increased proliferation and survival of cells in small pulmonary arteries (PAs) drive pulmonary arterial hypertension (PAH). Because cell growth mediated by the mTOR-containing mTORC1 complex is inhibited by tuberous sclerosis complex 2 (TSC2), we investigated the role of this GTPase-activating protein in PAH pathology. TSC2 abundance was decreased in remodeled small PAs and PA vascular smooth muscle cells (PAVSMCs) from patients with PAH or from rodent pulmonary hypertension (PH) models, as well as PAVSMCs maintained on substrates that reproduced pathology-induced stiffness. Accordingly, mice with smooth muscle-specific reduction in TSC2 developed PH. At the molecular level, decreased TSC2 abundance led to stiffness-induced PAVSMC proliferation, increased abundance of the mechanosensitive transcriptional coactivators YAP/TAZ, and enhanced mTOR kinase activity. Moreover, extracellular matrix (ECM) produced by TSC2-deficient PAVSMCs stimulated the proliferation of nondiseased PA adventitial fibroblasts and PAVSMCs through fibronectin and its receptor, the α5ß1 integrin. Reconstituting TSC2 in PAVSMCs from patients with PAH through overexpression or treatment with the SIRT1 activator SRT2104 decreased YAP/TAZ abundance, mTOR activity, and ECM production, as well as inhibited proliferation and induced apoptosis. In two rodent models of PH, SRT2104 treatment restored TSC2 abundance, attenuated pulmonary vascular remodeling, and ameliorated PH. Thus, TSC2 in PAVSMCs integrates ECM composition and stiffness with pro-proliferative and survival signaling, and restoring TSC2 abundance could be an attractive therapeutic option to treat PH.

HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway.

Esophageal cancer (EC) is an extremely aggressive malignant tumor. Homeobox A10 (HOXA10) is highly expressed and plays an important role in a variety of tumors. However, the function of HOXA10 in EC remains unclear. In this study, HOXA10 was observed to highly express in EC tissues and cells. Interestingly, the CCK-8 assay, flow cytometry, and colony formation assay confirmed that overexpression of HOXA10 promoted proliferation and suppressed cell apoptosis in EC cells. More importantly, the western blot assay indicated that the phosphorylation levels of ERK and p38 were elevated in EC cells overexpressed HOXA10, indicating that overexpression of HOXA10 activated p38/ERK signaling pathway in EC cells. These findings concluded that HOXA10 aggravated EC progression via activating p38/ERK signaling pathway, providing a potential therapeutic target for EC.

Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension.

Hyper-proliferation of pulmonary arterial vascular smooth muscle cells (PAVSMC) is an important pathological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Lipogenesis is linked to numerous proliferative diseases, but its role in PAVSMC proliferation in PAH remains to be elucidated. We found that early-passage human PAH PAVSMC had significant up-regulation of key fatty acids synthesis enzymes ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN), and increased unstimulated proliferation compared to control human PAVSMC. Treatment with an allosteric ACC inhibitor 5-tetradecyloxy-2-furoic acid (TOFA) significantly decreased proliferation and induced apoptosis of human PAH PAVSMC. Intracellular lipid content and proliferation of PAH PAVSMC were not reduced by incubation in lipid-depleted media but suppressed by a non-metabolizable analog of glucose 2-Deoxy-D-glucose (2-DG) and partially restored by addition of pyruvate. Protein kinase Akt was upregulated in human PAH PAVSMC in a sirtuin 7 (SIRT7)- and c-Jun N-terminal kinase (JNK)-dependent manner. Pharmacological inhibition of Akt down-regulated ACLY and ACC, significantly reduced intracellular lipid content, inhibited proliferation and induced apoptosis of human PAH PAVSMC. Taken together, these data demonstrate that human PAH PAVSMC have up-regulated lipogenesis, which is supported in an Akt- and glycolysis-dependent manner and is required for increased proliferation and survival. Our data suggest that there is a mechanistic link between glycolysis, lipogenesis, and the proliferation of human PAH PAVSMC and call for further studies to determine the potential attractiveness of a SIRT7/JNK-Akt-lipogenesis axis as a target pathway to inhibit PAVSMC hyper-proliferation in PAH.

Long Noncoding RNA SNHG16 Regulates the Growth of Human Lung Cancer Cells by Modulating the Expression of Aldehyde Dehydrogenase 2 (ALDH2).

The involvement of long noncoding RNA (lncRNA) SNHG16 has been reported in several human cancers. Notwithstanding, the role of lncRNA SNHG16 is yet largely unknown in human lung cancer. Consequently, this study was undertaken to investigate the role and therapeutic potential of SNHG16 in human lung cancer. The results showed a significant (P < 0.05) transcriptional upregulation of SNHG16 in lung cancer tissues and cell lines. However, downregulation of SNHG16 resulted in significant (P < 0.05) inhibition of lung cancer A549 and SK-LU-1 cell proliferation. DAPI and annexin V/PI assays revealed apoptosis to be responsible for inhibition of cell proliferation and colony formation observed upon SNHG16 knockdown. This was accompanied by enhancement of Bax and suppression of Bcl-2 expression in A549 and SK-LU-1 cells. Transwell assays revealed that silencing of SNHG16 also significantly (P < 0.05) inhibited migration and invasion of A549 and SK-LU-1 cells. Bioinformatic analysis revealed that SNHG16 interacted with ALDH2 to exert its effects in human lung cancer cells. The expression of ALDH2 was found to be significantly (P < 0.05) suppressed in human lung cancer tissues and cell lines. Overexpression of ALDH2 inhibited the proliferation and colony formation of the A549 and SK-LU-1 cells. However, silencing of ALDH2 could avoid the tumor-suppressive effects of SNHG16 knockdown. Finally, SNHG16 silencing was also found to inhibit in vivo tumor growth. Collectively, the study unveils the molecular role of SNHG16 in regulating the development of lung cancer by interacting with ALDH2.

Modified Peroral Endoscopic Myotomy Technique for Type II Achalasia: A Multicenter Retrospective Study.

Aim: This retrospective study is aimed at evaluating the outcomes of a modified peroral endoscopic myotomy (POEM) technique in patients with type II achalasia. Methods: We performed a modified POEM procedure, which involved a shorter (total myotomy length = 4 cm), full-thickness myotomy, on 31 patients with type II achalasia. Clinical success rates, technical success rates, pre- and postoperative esophageal manometry results, complications, and reflux-related adverse events were evaluated. Results: The clinical success (Eckardt score ≤ 3) rates were 100% and 88.9% within 2 years and beyond 2 years postoperatively, respectively. The median lower esophageal sphincter pressures (LESP) decreased from 31.6 (26.7-49.7) mmHg preoperatively to 13.4 (10.5-21.6) and 11.8 (7.4-16.7) mmHg (P < 0.001) at 6 and 12 months postoperatively, respectively. The median integrated relaxation pressure (IRP) decreased from 27.8 (20.6-37.5) mmHg preoperatively to 12.9 (11.3-23.4) and 11.6 (9.6-16.8) mmHg (P < 0.001) at 6 and 12 months after POEM, respectively. Only one case (3.2%) of mucosal injury, four (12.9%) cases of reflux esophagitis, and two (6.5%) cases of gastroesophageal reflux symptoms were reported. Conclusions: The modified POEM technique showed excellent outcomes in patients with type II achalasia.

The effect of mitochondrial fusion on chondrogenic differentiation of cartilage progenitor/stem cells via Notch2 signal pathway.

BACKGROUND: Osteoarthritis (OA) is a debilitating disease that inflicts intractable pain, a major problem that humanity faces, especially in aging populations. Stem cells have been used in the treatment of many chronic diseases, including OA. Cartilage progenitor/stem cells (CPSCs) are a type of stem cells with the ability to self- renew and differentiate. They hold a promising future for the understanding of the progression of OA and for its treatment. Previous studies have reported the relationship between mitochondrial dynamics and mesenchymal stem cell (MSC) proliferation, differentiation and aging. Mitochondrial dynamic and morphology change during stem cell differentiation. METHODS: This study was performed to access the relationship between mitochondrial dynamics and chondrogenic differentiation of CPSCs. Mitochondrial fusion and fission levels were measured during the chondrogenic differentiation process of CPSCs. After that, we used mitochondrial fusion promoter to induce fusion in CPSCs and then the chondrogenic markers were measured. Transmission electron microscopy (TEM) and confocal microscopy were used to capture the mass and fusion status of mitochondria. Lentiviruses were used to detect the role of mitofusin 2 (Mfn2) in CPSC chondrogenic differentiation. In vivo, Mfn2 was over-expressed in sheets of rat CPSCs, which were then injected intra-articularly into the knees of rats. RESULTS: Mitochondrial fusion markers were upregulated during the chondrogenic induction process of CPSCs. The mass of mitochondria was higher in differentiated CPSC, and the fusion status was obvious relative to un-differentiated CPSC. Chondrogenesis of CPSCs was upregulated with the induction by mitochondrial fusion promoter. Mfn2 over-expression significantly increased chondrocyte-specific gene expression and reversed OA through NOTCH2 signal pathway. CONCLUSIONS: Our study demonstrated that the mitochondrial fusion promotes chondrogenesis differentiation of CPSCs. Mfn2 accelerates the chondrogenesis differentiation of CPSCs through Notch2. In vivo, Mfn2-OE in sheets of rCPSCs ameliorated OA in the rat model.

Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.

RATIONALE: The MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown. OBJECTIVE: To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. METHODS AND RESULTS: Using early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension. CONCLUSIONS: Together, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.

Identification of a Gene Signature Closely Related to Immunosuppressive Tumour Microenvironment Predicting Prognosis of Patients in EGFR Mutant Lung Adenocarcinoma.

Lung adenocarcinomas (LUADs) harbouring epidermal growth factor receptor (EGFR) mutations are generally unable to benefit from immune checkpoint inhibitors (ICIs) due to an immunosuppressive tumour microenvironment (TME) and a lower tumour mutation burden. Currently, no gene signature can comprehensively evaluate the TME and predict the prognosis of patients with EGFR-mutant LUAD. Using the Cancer Genome Atlas database of EGFR-mutant LUAD based on the immune score derived from the ESTIMATE algorithm, we divided 80 patients with EGFR-mutant LUAD samples into high and low immune score groups with different immune microenvironments. Subsequently, we screened 396 differentially expressed immune-related genes with prognostic value. The top Gene Ontology terms were significantly enriched in biological functions related to T cell differentiation, immune response, cell cycle, and cell proliferation, which are closely related to the immune microenvironment of tumours. In addition, the KEGG pathway enrichment analysis mainly focused on cell cycle, cell adhesion molecules, and cytokine-cytokine receptor interaction, which also had a relationship with the immune response. Subsequently, we identified a three-gene signature including BTLA, BUB1B, and CENPE using the LASSO Cox regression model. The three-gene signature could accurately identify patients at risk of EGFR-mutant LUAD in the training and validation sets and high-risk patients from both the sets exhibited significantly shorter overall survival (p=0.0053 and p=0.035, respectively). CIBERSORT was used to evaluate the abundance of immune cell infiltration in the EGFR-mutant LUAD microenvironment. The immune activity of B cells and macrophages was higher in the low-risk group, while the immune activity of natural killer cells and T cells was higher in the high-risk group. Thus, the three-gene signature closely related to immunosuppressive TME could predict the risk and prognosis in patients with EGFR-mutant LUAD.

miR-7/EGFR/MEGF9 axis regulates cartilage degradation in osteoarthritis via PI3K/AKT/mTOR signaling pathway.

Osteoarthritis (OA) is a common degenerative disease in middle-aged and elderly people. Our previous study has proved that microRNA-7 (miR-7) exacerbated the OA process. This study was aimed to explore the downstream genes and mechanism regulated by miR-7 to affect OA. Multiple EGF-like-domains 9 (MEGF9) was the predicted target of miR-7 by databases. Luciferase report experiment results confirmed that MEGF9 could bind to miR-7. Among the 10 collected pairs of OA and healthy samples, the expression levels of miR-7 and MEGF9 were both up-regulated when compared with healthy subjects by qRT-PCR and immunohistochemistry (IHC). The increased MEGF9 levels were due to the interaction with epidermal growth factor receptor (EGFR) by co-immunoprecipitation. Evaluations found that upregulation of miR-7 or MEGF9 can increase the expression of EGFR, matrix metalloproteinase-13 (MMP-13) and a disintegrin like and metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS-5), so as to aggravate cartilage degradation. In addition, this effect induced by miR-7/EGFR/MEGF9 axis was by activation of PI3K/AKT signaling. The IHC and western blot assay results on OA model mice also demonstrated that miR-7/EGFR/MEGF9 axis regulated cartilage degradation in vivo. In summary, miR-7/EGFR/MEGF9 axis may perform a crucial function in the regulation of OA, providing potential for OA treatment.

The elevated expression of IL-38 serves as an anti-inflammatory factor in osteoarthritis and its protective effect in osteoarthritic chondrocytes.

The objective of this study is to investigate the role of IL-38 in osteoarthritis (OA). IL-38 levels in serum and synovial fluid (SF) of patients with OA were examined to identify the correlation between IL-38 expression and OA activity and to determine its anti-inflammatory effects in IL-1ß-induced chondrocytes. A total of 75 patients with OA who underwent joint replacement surgery and 25 age- and sex-matched healthy volunteers were recruited. The levels of IL-38 in serum and SF are shown to be significant elevated in OA patients compared with that of healthy controls. Serum and SF IL-38 levels of OA patients are positively correlated with Kellgren-Lawrence (K-L) grades 2 to 3, as well as with pro-inflammatory cytokines IL-6, IL-23, and TNF-α, but are negatively correlated with the anti-inflammatory cytokine IL-10 in K-L grades 3 to 4. Furthermore, overexpression of IL-38 in vitro is shown to attenuate the expression of pro-inflammatory cytokines such as COX-2, IL-6, IL-8, IL-36Ra, IL-36α/ß/γ, iNOS, and TNF-α, as well as matrix degrading enzymes such as MMP3, MMP13, and ADAMTS5, and apoptosis-related indicators Bax/Bcl-2, cleaved caspase 3/pro-caspase 3, and cleaved caspase 9/pro-caspase 9. IL-38 overexpression also reduces expression of the signaling proteins p-p38, p-p65, p-JNK, and RhoA significantly. Taken together, our results show that expression of IL-38 is increased in OA tissues and OA rat chondrocytes, and is positively correlated with early disease activity. This increased IL-38 expression lead to the inactivation of MAPK, NF-κB, JNK, and RhoA signaling pathways, which might have impletion on OA chondrocytes apoptosis, degradation and inflammatory effect. Thus, IL-38 probably serves as a novel therapeutic target for the treatment of OA.

Upregulation of LINC01426 promotes the progression and stemness in lung adenocarcinoma by enhancing the level of SHH protein to activate the hedgehog pathway.

Long noncoding RNAs (lncRNAs) play crucial roles in regulating a variety of biological processes in lung adenocarcinoma (LUAD). In our study, we mainly explored the functional roles of a novel lncRNA long intergenic non-protein coding RNA 1426 (LINC01426) in LUAD. We applied bioinformatics analysis to find the expression of LINC01426 was upregulated in LUAD tissue. Functionally, silencing of LINC01426 obviously suppressed the proliferation, migration, epithelial-mesenchymal transition (EMT), and stemness of LUAD cells. Then, we observed that LINC01426 functioned through the hedgehog pathway in LUAD. The effect of LINC01426 knockdown could be fully reversed by adding hedgehog pathway activator SAG. In addition, we proved that LINC01426 could not affect SHH transcription and its mRNA level. Pull-down sliver staining and RIP assay revealed that LINC01426 could interact with USP22. Ubiquitination assays manifested that LINC01426 and USP22 modulated SHH ubiquitination levels. Rescue assays verified that SHH overexpression rescued the cell growth, migration, and stemness suppressed by LINC01426 silencing. In conclusion, LINC01426 promotes LUAD progression by recruiting USP22 to stabilize SHH protein and thus activate the hedgehog pathway.

DUSP5 suppresses interleukin-1ß-induced chondrocyte inflammation and ameliorates osteoarthritis in rats.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by deterioration of articular cartilage. Dual specificity phosphatase 5 (DUSP5), a member of the DUSP subfamily, is known to regulate cellular inflammation. Here, we studied the relationship between DUSP5 and OA by knockdown and overexpression DUSP5, respectively. Results from in vitro experiments demonstrated that the knockdown of DUSP5 increased interleukin-1ß (IL-1ß)-induced expression of inflammatory genes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), and matrix metalloproteinases (MMPs) in chondrocytes, whereas it decreased the expression of anti-inflammatory genes, such as tissue inhibitor of metalloproteinase 3 (TIMP3) and IL-10. Conversely, the overexpression of DUSP5 suppressed the IL-1ß-induced expression of iNOS, COX-2, and MMPs, and upregulated the expression of TIMP3 and IL-10. Moreover, knockdown of DUSP5 enhanced the IL-1ß-induced activation of NF-κB and ERK pathways, whereas its overexpression inhibited these pathways. DUSP5 overexpression prevented cartilage degeneration in a rat OA model, while its knockdown reversed that effect. Our findings reveal that DUSP5 suppresses IL-1ß-induced chondrocyte inflammation by inhibiting the NF-κB and ERK signaling pathways and ameliorates OA.