Steering CO2 Electroreduction to C2+ Products via Enhancing Localized *CO Coverage and Local Pressure in Conical Cavity.

The electrochemical carbon dioxide (CO2) reduction reaction (CO2RR) involves a multistep proton-coupled electron transfer (PCET) process that generates a variety of intermediates, making it challenging to transform them into target products with high activity and selectivity. Here, a catalyst featuring a nanosheet-stacked sphere structure with numerous open and deep conical cavities (OD-CCs) is reported. Under the guidance of the finite-element method (FEM) simulations and theoretical analysis, it is shown that exerting control over the confinement space results in diffusion limitation of the carbon intermediates, thereby increasing local pressure and subsequently enhancing localized *CO coverage for dimerization. The nanocavities exhibit a structure-driven shift in selectivity of multicarbon (C2+) product from 41.8% to 81.7% during the CO2RR process.

Identification of ONECUT3 as a stemness-related transcription factor regulating NK cell-mediated immune evasion in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal response to the current T cell-based immunotherapies, which is attributed to intratumoral heterogeneity caused by PDAC stem cells and lack of major histocompatibility complex class I required for neoantigen presentation. Although this scenario makes natural killer (NK) cells attractive candidates for immunotherapeutic agents targeting MHC-I-deficient cancer stem cells in heterogeneous PDACs, little is known about PDAC stem cell immunology. In our study, PDAC-specific datasets from public databases were collected for in-depth bioinformatic analysis. We found that the abundance of PDAC stemness negatively influenced the infiltration of NK cells and identified the transcription factor ONECUT3 enriched in PDACs with high stemness index scores and Pan-cancer Stemness Signature levels. A series of NK cell-targeted inhibitory immune checkpoints were highly expressed in ONECUT3high PDACs. The patient group with high levels of ONECUT3 expression had a high risk of poor overall survival, even if accompanied by high infiltration of NK cells. Furthermore, the prostanoid metabolic process was enriched in ONECUT3high PDACs with high levels of NK cell-targeted inhibitory immune checkpoints. ONECUT3 enriched in high-stemness PDACs possessed the potential to transcriptionally regulate the prostanoid metabolism-related genes. Our study reveals ONECUT3 as a candidate stemness-related transcription factor regulating NK cell-targeted inhibitory immune checkpoints in PDAC. ONECUT3-mediated prostanoid metabolism may regulate cancer stemness and immune evasion in PDAC. Synergistic inhibition of prostanoid metabolism may improve the efficacy of NK cell-based immunotherapies targeting intratumoral heterogeneity caused by PDAC stem cells.

Evaluation of 18F-FAPI-04 Imaging in Assessing the Therapeutic Response of Rheumatoid Arthritis.

PURPOSE: Fibroblast activating protein (FAP) is highly expressed in the synovial tissues of rheumatoid arthritis (RA) patients. The aim of this study was to determine the feasibility of PET imaging with an Al[18F] F-NOTA-labeled FAP inhibitor 04(18F-FAPI-04) for the evaluation of arthritic progression and therapeutic response in experimental arthritis. METHODS: Fibroblast-like synoviocytes (FLSs) were obtained from patients with RA or osteoarthritis (OA), and the relationship between 18F-FAPI-04 uptake and the inflammatory activity of RA FLSs was investigated. Collagen-induce arthritis (CIA) mice models were established and treated with methotrexate (MTX) or etanercept (ETC). Then, PET imaging was performed 24 h following 18F-FAPI-04 injection. The imaging results were compared by assessing macroscopic arthritis scores and histological staining. RESULTS: 18F-FAPI-04 uptake was obvious in RA FLSs that characterizing FAP activation. The higher the uptake of 18F-FAPI-04, the more severity of the inflammatory phenotype in RA FLS. Furthermore, the uptake of 18F-FAPI-04 in inflamed joints could be found even before the deformity of the parental joints could be observed by histological examination. Both MTX and ETC were effective in inhibiting the progression of arthritis in CIA mice was confirmed by macroscopic, histological, and radiographic pathology scores. Importantly, 18F-FAPI-04 uptake declined accordingly in CIA models following MTX and ETC treatment. CONCLUSIONS: These findings suggest that PET imaging of 18F-FAPI-04 can be used to monitor treatment response in RA, and is more sensitive in disease speculation than macroscopic arthritis scoring.

Genetic causality and site-specific relationship between sarcopenia and osteoarthritis: a bidirectional Mendelian randomization study.

Background: Previous studies demonstrated a controversial relationship between sarcopenia (SP) and osteoarthritis (OA) and their genetic causality is unclear. Thus, we conducted a Mendelian randomization (MR) analysis to evaluate the possible causal association between sarcopenia-related traits (appendicular lean mass (ALM), grip strength, usual walking pace) and OA. Method: We used pooled genetic data from the UK Biobank for ALM(n = 450,243), left-hand grip strength (n = 461,026), right-hand grip strength (n = 461,089) and usual walking pace (n = 459,915). Moreover, summary statistics for OA were obtained from the latest study conducted by the Genetics of Osteoarthritis Consortium, including all OA (n = 826,690), hand OA (n = 303,7782), hip OA (n = 353,388) and knee OA (n = 396,054). The primary method for estimating causal effects was the inverse-variance weighted (IVW) method, with the utilizing of false discovery rate adjusted p values (P FDR). Additional MR methods such as MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median were employed as supplementary analyses. Results: We discovered ALM (odds ratio (OR) = 1.103, 95% confidence interval (CI) = 1.052-1.156, P FDR = 2.87E-04), hand grip strength (left, IVW OR = 0.823, 95% CI = 0.712 to 0.952, P FDR = 0.020; right, OR = 0.826, 95% CI = 0.718 to 0.950, P FDR = 0.020), and usual walking pace (OR = 0.339, 95% CI = 0.204 to 0.564, P FDR = 2.38E-04) were causally associated with OA risk. In the reverse MR analysis, we identified a causal effect of OA on ALM (ß = -0.258, 95% CI = -0.369 to 0.146, P FDR = 0.6.07E-06), grip strength (left, ß = -0.064, 95% CI = -0.104 to 0.024, P FDR = 0.002; right, ß = -0.055, 95% CI = -0.095 to 0.014, P FDR = 0.008), and usual walking pace (ß = -0.104, 95% CI = -0.147 to 0.061, P FDR = 1.61E-05). Conclusion: This present study suggests an obvious causality of SP on OA, with condition exhibiting site-specific effects, while evidence was also provided for the causal effect of OA on SP.

Identification of CEACAM5 as a stemness-related inhibitory immune checkpoint in pancreatic cancer.

BACKGROUND: Immunotherapy has emerged as a new cancer treatment modality. However, tumour heterogeneity can diminish checkpoint blockade response and shorten patient survival. As a source of tumour heterogeneity, cancer stem cells act as an indispensable reservoir for local recurrence and distant metastasis. Thus, precision immunotherapy targeting tumour heterogeneity requires a comprehensive understanding of cancer stem cell immunology. Our study aimed to identify stemness-related inhibitory immune checkpoints and relevant regulatory pathways in pancreatic cancer. METHODS: Pancreatic cancer-specific datasets in The Cancer Genome Atlas and the Cancer Therapeutics Response Portal were collected for in-depth bioinformatic analysis. Differentially expressed genes between pancreatic cancers with high and low stemness index (mRNAsi) scores were compared to screen out inhibitory immune checkpoints. Survival analysis was used to predict the prognostic value of immune checkpoint plus immune infiltrate in patients with pancreatic cancer. The expression of stemness-related immune checkpoint across immune subtypes of pancreatic cancer was detected and gene set enrichment analysis was performed to figure out the relevant regulatory signallings. RESULTS: The abundance of cancer stemness predicted a low immunotherapy response to pancreatic cancer. The inhibitory immune checkpoint CEACAM5 that was enriched in pancreatic cancers with high mRNAsi scores also exhibited a strong correlation with invasive cell-enriched signature and Msi+ tumour-initiating cell-enriched signature. Levels of CEACAM5 expression were higher in the interferon-γ dominant immune subtype of pancreatic cancers that are characterized by high M1 macrophage infiltration. The patient group with high levels of CEACAM5 expression had a high risk of poor overall survival, even if accompanied by high infiltration of M1 macrophages. Furthermore, prostanoid and long-chain unsaturated fatty acid metabolic processes showed a significant association with cancer stemness and CEACAM5 expression. CONCLUSIONS: Our findings suggest that CEACAM5 is a candidate stemness-related innate immune checkpoint in pancreatic cancer, and is potentially regulated by prostanoid and long-chain unsaturated fatty acid metabolic processes. Immune checkpoint blockade of CEACAM5, which synergizes with inhibition of those regulatory pathways, may improve the efficacy of precision immunotherapy targeting tumour heterogeneity caused by cancer stem cells.

ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance.

Objective: The contribution of activating transcription factor 6α (ATF6α) in rheumatoid arthritis (RA) pathogenesis, especially on fibroblast-like synoviocytes (FLSs), has been suggested by its sensitivity to inflammatory stimulus. However, the exact role and therapeutic potential of ATF6α in RA remains to be fully elucidated. Methods: ATF6α expression was determined in joint tissues and FLS, and gain-of-function and loss-of-function analyses were applied to evaluate the biological roles of ATF6α in RA FLSs. A murine collagen-induced arthritis (CIA) model, combining both gene deletion of ATF6α and treatment with the ATF6α inhibitor Ceapin-A7, was employed. Joint inflammation, tissue destruction, circulating levels of inflammatory cytokines were assessed in CIA mice. Transcriptome sequencing analysis (RNASeq), molecular biology, and biochemical approaches were performed to identify target genes of ATF6α. Results: ATF6α expression was significantly increased in synovium of RA patients and in synovium of mice subjected to CIA. ATF6α silencing or inhibition repressed RA FLSs viability and cytokine production but induced the apoptosis. CIA-model mice with ATF6α deficiency displayed decreased arthritic progression, leading to profound reductions in clinical and proinflammatory markers in the joints. Pharmacological treatment of mice with Ceapin-A7 reduced arthritis severity in CIA models. RNA-sequencing of wild-type and knockdown of ATF6α in RA FLSs revealed a transcriptional program that promotes inflammation and suppresses apoptosis, and subsequent experiments identified Baculoviral IAP Repeat Containing 3 (BIRC3) as the direct target for ATF6α. Conclusion: This study highlights the pathogenic role of ATF6α-BIRC3 axis in RA and identifies a novel pathway for new therapies against RA.

Preclinical evaluation and pilot clinical study of [18F]AlF-NOTA-FAPI-04 for PET imaging of rheumatoid arthritis.

PURPOSE: Fibroblast-like synoviocytes (FLSs) are key effector cells in the inflamed joints of patients with rheumatoid arthritis (RA). Previous studies have suggested that fibroblast activation protein (FAP) is highly expressed in RA-derived FLSs and is a specific marker of activated RA FLSs. In this study, we developed aluminum-[18F]-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid-conjugated FAP inhibitor 04 ([18F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients. METHODS: RA FLSs and NIH3T3 cells transfected with FAP were used to perform in vitro-binding studies. Biodistribution was conducted in normal DBA1 mice. Collagen-induced arthritis (CIA) models with different arthritis scores were subjected to [18F]AlF-NOTA-FAPI-04 and 18F-FDG PET imaging. Histological examinations were performed to evaluate FAP expression and Cy3 dye-labeled FAPI-04(Cy3-FAPI-04) uptake. Blocking studies with excess unlabeled FAPI-04 in CIA mice and NIH3T3 xenografts in immunocompromised mice were used to evaluate the binding specificity of [18F]AlF-NOTA-FAPI-04. Additionally, [18F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients. RESULTS: The binding of [18F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/105 cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/105 cells). Compared to 18F-FDG imaging, [18F]AlF-NOTA-FAPI-04 showed high uptake in inflamed joints in the early stage of arthritis, which was positively correlated with the arthritic scores (Pearson r=0.834, P<0.001). In addition, the binding of [18F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [18F]AlF-NOTA-FAPI-04 in arthritic joints both could be blocked by excessive unlabeled FAPI-04. Fluorescent staining showed that the intensity of Cy3-FAPI-04 binding to FAP increased accordingly as the expression of FAP protein increased in cells and tissue sections. Furthermore, the uptake of [18F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [18F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints. CONCLUSION: [18F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.

Nogo-A Is a Potential Prognostic Marker for Spinal Cord Injury.

Objective: Spinal cord injury (SCI) has become prevalent worldwide in recent years, and its prognosis is poor and the pathological mechanism has not been fully elucidated. Nogo-A is one of the isoforms of the neurite outgrowth inhibitory protein reticulon 4. The purpose of this study was to determine whether Nogo-A could be used as a marker for predicting the prognosis of SCI. Methods: We screened eligible SCI patients and controls based on inclusion and exclusion criteria. We also collected baseline clinical information and peripheral venous blood of the enrolled population. Participants' baseline serum Nogo-A levels were measured by enzyme-linked immunosorbent assay (ELISA). The American Spinal Injury Association (ASIA) scale was used to evaluate the prognosis of SCI patients after 3 months. Results: Baseline clinical information (age; gender; smoking; drinking; SBP, systolic blood pressure; DBP, diastolic blood pressure; fasting blood glucose; WBC, white blood cells; CRP, C-reactive protein) of SCI patients and controls were not statistically significant academic differences (p > 0.05). The baseline serum Nogo-A levels of SCI patients and controls were 192.7 ± 13.9 ng/ml and 263.1 ± 22.4 ng/ml, respectively, and there was a statistically significant difference between the two groups (p < 0.05). We divided SCI patients into 4 groups according to their baseline serum Nogo-A quartile levels and analyzed their relationship with ASIA scores. The trend test results showed that with the increase of Nogo-A level, the ASIA sensation score and ASIA motor score were significantly decreased (p < 0.001). Multivariate regression analysis showed that serum Nogo-A levels remained a potential cause affecting the prognosis of SCI after adjusting for confounding factors in multiple models. Conclusions: Serum Nogo-A levels were significantly elevated in SCI patients. Moreover, elevated Nogo-A levels often indicate poor prognosis and can be used as a marker to predict the prognosis of SCI.

miRNA-34c-5p targets Fra-1 to inhibit pulmonary fibrosis induced by silica through p53 and PTEN/PI3K/Akt signaling pathway.

Silica dust particles are representative of air pollution and long-term inhalation of silicon-containing dust through the respiratory tract can cause pulmonary fibrosis. Epithelial-mesenchymal transformation (EMT) plays an important role in the development of fibrosis. This process can relax cell-cell adhesion complexes and enhance cell migration and invasion properties of these cells. Dysregulation of microRNA-34c (miR-34c) is highly correlated with organ fibrosis including pulmonary fibrosis. In this study, we found that miR-34c-5p could alleviate the occurrence and development of silica-mediated EMT. Fos-related antigen 1 was identified as a functional target of miR-34c-5p by bioinformatics analysis and the dual luciferase gene reporting assay. Importantly, chemically induced up-regulation of hsa-miR-34c-5p correlated inversely with the expression of Fra-1 and further exploration found that the miR-34c-5p/Fra-1 axis inhibits the activation of the phosphatase and tensin homolog deleted on chromosome 10/phosphatidylinositol-4,5-bisphosphate3-kinase/protein kinase B (PTEN/PI3K/AKT) signaling pathway. In addition, through interaction with PTEN/p53 it inhibits the proliferation and migration of human bronchial epithelial cells stimulated by silica, and promotes cell apoptosis, thereby preventing EMT. This finding provides a promising biomarker for the diagnosis and prognosis of pulmonary fibrosis. Furthermore, overexpression of miR-34c-5p represents a potential therapeutic approach.

Euphorbia factor L3 ameliorates rheumatoid arthritis by suppressing the inflammatory response by targeting Rac family small GTPase 1.

Euphorbia factor L3 (EFL3) is extracted from Euphorbia lathyris and is known for its anti-inflammatory properties. This study focused on the potential anti-inflammatory and therapeutic effects of EFL3 on rheumatoid arthritis (RA) using fibroblast-like synoviocytes (FLSs) and arthritis animal models. Functional analysis showed that EFL3 could ameliorate the inflammatory phenotype of FLSs derived from RA patients, as evidenced by the decreases in cell viability, migration, invasion and cytokine production. Luciferase activity, Western blotting and immunofluorescence assays demonstrated that EFL3 inhibited the nuclear translocation of the p65 subunit and the subsequent activation of the nuclear factor kappa-Β (NF-κB) pathway. Furthermore, the therapeutic effects of EFL3 against arthritic progression were evidenced by decreases in joint swelling, arthritis scores, inflammatory factor production, synovial hyperplasia, and bone destruction in collagen-induced arthritis (CIA) and tumor necrosis factor-α (TNF-α) transgenic (TNF-tg) mouse models. Molecular analysis identified Rac family small GTPase 1 (Rac1) as the potential target that was required for EFL3-mediated suppression of the inflammatory RA FLS phenotype. In summary, this study uncovered the therapeutic potential of EFL3 in RA, which suggests its future clinical use.

Revealing the magic of acupuncture based on biological mechanisms: A literature review.

Acupuncture has been used to treat various disease for more than 3,000 years in China and other Asian countries. As a complementary and alternative therapy, it has gained increasing popularity and acceptance among public and healthcare professionals in the West. Over the past few decades, basic and clinical research on acupuncture has made considerable progress. Internationally recognized evidence from clinical studies has been published, a preliminary system to clinically evaluate acupuncture has been created, and some clinical guidelines have been formulated. Moreover, scientists have strived to explore the physiological and biological mechanisms of acupuncture. Some basic studies have indicated that acupuncture has various actions, such as analgesic, muscle relaxing, anti-inflammatory, mild anxiolytic, and antidepressant actions, with possible biological mechanisms such as central sensitization, neurotransmitters, the intestinal flora, immune regulation, oxidative stress, and neuroinflammation. The current review describes the common indications for acupuncture recommended by the WHO and the use of acupuncture in China, the United States, Australia, and several other countries. This review then summarized the mechanisms by which acupuncture treats common conditions including lower back pain (LBP), ischemic stroke, depression, and irritable bowel syndrome (IBS) and it also cited specific acupuncture points for treating these conditions. The hope is that this review will provide useful information for both acupuncturists and researchers to better understand the mechanisms of acupuncture and reasons for its usage.

Azithromycin alleviates the severity of rheumatoid arthritis by targeting the unfolded protein response component of glucose-regulated protein 78 (GRP78).

BACKGROUND AND PURPOSE: Azithromycin is a macrolide antibiotic with anti-inflammatory properties. We aim to substantiate the treatment potential of azithromycin in rheumatoid arthritis. EXPERIMENTAL APPROACH: Gene expression profiles were collected by RNA sequencing and the effects of azithromycin were assessed by in vitro and in vivo assays on the effects of azithromycin-mediated blockade of glucose-regulated protein 78 (GRP78). Anti-inflammatory activity of azithromycin was measured in fibroblast-like synoviocytes from rheumatoid arthritis patients and in collagen-induced arthritis in DBA/1 mice. Characterization of the binding of azithromycin to GRP78 was performed using drug affinity responsive target stability, proteomics and cellular thermal shift assays. Azithromycin-mediated inhibition of GRP78 and its relationship to its anti-arthritic activity was assessed. KEY RESULTS: Azithromycin reduced proinflammatory factor production, cell migration, invasion and chemoattraction and enhanced apoptosis, reducing the deleterious inflammatory response of rheumatoid arthritis fibroblast-like synoviocytes in vitro. Azithromycin ameliorated the severity of collagen-induced arthritis lesions as efficiently as the TNFα inhibitor etanercept. Transcriptional analyses suggested that azithromycin treatment impairs signalling cascades associated with cholesterol and lipid biosynthesis. GRP78 was identified as a novel target of azithromycin. Azithromycin-mediated activation of the unfolded protein response via the inhibition of GRP78 activity is required not only for inducing the expression of C/EBP-homologous protein (ChOP) but also for the activating sterol-regulatory element binding protein (SREBP) and its targeted genes involved in cholesterol and lipid biosynthetic processes. Furthermore, deletion of GRP78 abolished the anti-arthritic activity of azithromycin. CONCLUSION AND IMPLICATIONS: These findings indicate that azithromycin can used to treat rheumatoid arthritis.

Isopsoralen ameliorates rheumatoid arthritis by targeting MIF.

BACKGROUND: Isopsoralen (IPRN), one of the active ingredients of Psoralea corylifolia Linn, has anti-inflammatory properties. We attempted to investigate the inhibitory effects of IPRN on rheumatoid arthritis (RA) and characterize its potential mechanism. METHODS: RA fibroblast-like synoviocytes (FLSs) and mice with collagen-induced arthritis (CIA) were used as in vitro and in vivo models to analyze the antiarthritic effect of IPRN. Histological analysis of the inflamed joints from mice with CIA was performed using microcomputed tomography (micro-CT) and hematoxylin-eosin (HE) staining. RNA sequencing (RNA-Seq), network pharmacology analysis, molecular docking, drug affinity responsive target stability (DARTS) assay, and cellular thermal shift assay (CETSA) were performed to evaluate the targets of IPRN. RESULTS: IPRN ameliorated the inflammatory phenotype of RA FLSs by inhibiting their cytokine production, migration, invasion, and proangiogenic ability. IPRN also significantly reduced the severity of CIA in mice by decreasing paw thickness, arthritis score, bone damage, and serum inflammatory cytokine levels. A mechanistic study demonstrated that macrophage migration inhibitory factor (MIF), a key protein in the inflammatory process, was the specific target by which IPRN exerted its anti-inflammatory effects in RA FLSs. CONCLUSION: Our study demonstrates the antiarthritic effect of IPRN, which suggests the therapeutic potential of IPRN in RA.

Identification of inhibitory immune checkpoints and relevant regulatory pathways in breast cancer stem cells.

Immune checkpoint blockade (ICB) has become one of the most promising approaches to activating antitumor immunity. However, only a small subset of patients with breast cancer benefit from ICB treatment. To improve the therapeutic effect in the clinic, precision immunotherapy is proposed to accurately eliminate cancer stem cells that contribute to local recurrence or metastasis, but currently little is known about their immunological properties. In this study, breast cancer-specific datasets in The Cancer Genome Atlas were collected and analyzed by using multiple open-access web servers. We found that the immunophenotype of breast cancer was characterized by a hypoactive immune microenvironment and a low response to immune checkpoint blockade. The innate immune checkpoint CD200 and the adaptive immune checkpoint CD276, respectively, exhibited a strong correlation with basal/stem gene signature and invasiveness gene signature, both of which represent breast cancer stem cells. Wnt, TGF-ß, and Hedgehog signaling, which are recognized as stemness-related pathways, showed a significant association with the expression of CD200 and CD276, suggesting cancer stem cell-specific immune checkpoints could be downregulated by inhibiting these pathways. Of note, levels of CD200 and CD276 expression were higher in TGF-ß dominant breast cancer than in other immune types of breast cancer. We also identified gene signatures that represent Wnt, TGF-ß, and Hedgehog signaling-related CD200 and CD276 expression in breast cancer stem cells. For the luminal A subtype, the patient group with a high level of these gene signatures plus a low infiltration of CD8+ T cells, or dendritic cells, or M1 macrophages had poor overall survival. Our study suggested that CD200 and CD276 are candidate inhibitory immune checkpoints in breast cancer stem cells, which are potentially regulated by Wnt, TGF-ß, and Hedgehog signaling. Synergistic inhibition of these stemness-related pathways may improve the efficacy of ICB treatment targeting breast cancer stem cells in precision immunotherapy.

Cyclic Mechanical Stretch Ameliorates the Degeneration of Nucleus Pulposus Cells through Promoting the ITGA2/PI3K/AKT Signaling Pathway.

BACKGROUND: Intervertebral disc degeneration (IVDD) is one of the major causes of low back pain and motor deficiency. Nucleus pulposus (NP) degeneration plays a key role in the process of IVDD. The mechanical and biological interactions involved in NP degeneration have not been elucidated. The present study is aimed at investigating the effect and mechanism of cyclic mechanical stretch in regulating the function and degeneration of NP cells. METHODS: NP cells were subjected to cyclic tensile stress (10% deformation) of 0.1 Hz for 8640 cycles. Cell proliferation was conducted through the MTT assay. The cell cycle and apoptosis were detected by flow cytometry. A gene expression profile chip was used to analyze the differentially expressed genes between the tensile stress group and the control group. Enrichment analysis of Gene Ontology (GO) annotation and signaling pathways were analyzed. Western blot and RNA interference were carried out to investigate the role of the ITGA2/PI3K/AKT pathway in the effect of cyclic mechanical stretch on NP cells. RESULTS: NP cells exhibited a greater (P < 0.05) growth rate in the tensile stress group compared to the control group. Cyclic mechanical stress significantly promoted the cell cycle transition of NP cells from the S phase to the G2/M phase. A fewer proportion of apoptotic cells were found in the tensile stress group (P < 0.05), indicating that cyclic mechanical stretch inhibits NP cell apoptosis. Microarray analysis revealed 689 significant differentially expressed genes between the two groups (P < 0.05), of which 333 genes were upregulated and another 356 genes were downregulated. Cyclic mechanical stretch altered the expression of 31 genes involved in the ITGA2/PI3K/AKT pathway and remarkably promoted this pathway in NP cells. Downregulation of ITGA2 and AKT further demonstrated that the PI3K/AKT pathway was responsible for the proliferation and COL2A1 expression of NP cells upon cyclic mechanical stretch. CONCLUSIONS: Cyclic mechanical stretch promoted the proliferation and cell cycle and reversely inhibited the apoptosis of NP cells. Cyclic mechanical stretch promoted COL2A1 expression and ameliorated the degeneration of NP cells via regulation of the ITGA2/PI3K/AKT signaling pathway. Our results may provide a potential target and a possibility of IVDD disease treatment by ameliorating the degenerative changes.

Serum IL-37 Level Is Associated with Rheumatoid Arthritis and Disease Activity: A Meta-Analysis.

Interleukin-37 (IL-37) inhibits the pathogenesis of rheumatoid arthritis (RA) via downregulating proinflammatory cytokines. Accordingly, we performed an analysis to accurately assess the relationship between serum IL-37 cytokine levels and disease activity of RA. Subgroup analysis and sensitivity analysis were applied to explore the sources of heterogeneity. Correlation coefficient (r) was utilized to evaluate the relationship between IL-37 and disease activity of RA patients. Ten studies were included into the research. Functional analysis revealed elevated serum IL-37 concentrations in RA patients (SMD = 1.61, P < 0.00001). The relationship between serum IL-37 levels and disease activity was statistically significant (C-reactive protein: r = 1.47, P = 0.0002; erythrocyte sedimentation rate: r = 1.55, P < 0.00001; rheumatoid factor: r = 1.40, P = 0.004; tumor necrosis factor⁃α: r = 1.64, P = 0.0003; Disease Activity Score for 28 joints: r = 1.63, P < 0.00001; tender joint count: r = 1.48, P < 0.00001; and swollen joint count: r = 1.52, P = 0.0003), but anti-CCP was not significant (anti-CCP: r = 0.98, P = 0.72). In summary, these data are suggesting that the elevated serum level of IL-37 in RA is positively correlated with the disease activity of RA, suggesting a role for IL-37in the pathogenesis of RA.

Corrigendum: Altered Gray Matter Volume in Patients With Type 1 Diabetes Mellitus.

[This corrects the article DOI: 10.3389/fendo.2020.00045.].

Altered Gray Matter Volume in Patients With Type 1 Diabetes Mellitus.

Background and Purpose: Many imaging studies have reported structure alterations in patients with type 1 diabetes mellitus (T1DM) by using voxel-based morphometry (VBM). Nevertheless, the results reported were inconsistent and had not been reviewed quantitatively. Accordingly, the quantitative meta-analysis which including VBM studies of patients with T1DM was conducted. Materials and Methods: The gray matter volume alterations in patients with T1DM was estimated by using the software seed-based d mapping. Meantime, the meta-regression was applied to detect the effects of some demographics and clinical characteristics. Results: Six studies were finally included, which with 6 datasets comprising 414 T1DM patients and 216 healthy controls. The pooled meta-analyses detected that patients with T1DM showed robustly increased gray matter volume in the left dorsolateral superior frontal gyrus and middle frontal gyrus and a decreased gray matter volume in the right lingual gyrus, cerebellum, precuneus, the left inferior temporal gyrus, and middle temporal gyrus. The meta-regression showed that the mean age, the female patient's ratio, duration of illness and HbAlc% for T1DM patients were not linearly related with gray matter alterations. Conclusion: This meta-analysis demonstrates that gray matter volume decreases in T1DM patients were mainly locates in the cortical regions and cerebellum.

Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling.

Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies.