Bibliometric Analyses of the Research Trends of Female Pelvic Organ Prolapse.

INTRODUCTION AND HYPOTHESIS: The study was aimed at systematically analyzing the research status and trends of pelvic organ prolapse (POP) using bibliometrics. METHODS: We retrieved documents published between 1975 and 2022 from the Web of Science Core Collection (WoSCC) database, and manually selected them for bibliometric analyses of country, institution, journal, highly locally cited documents and research trends based on co-citation clustering and keywords using the R Bibliometricx package and CiteSpace software. RESULTS: A total of 5,703 publications were included. Although the number of annual publications on POP increased, the trend of annual publication reached an obvious plateau in the first half of the 2010s. The USA, China, the UK, the University of Michigan, the University of Pittsburgh, and the University of Sydney were the top three countries and institutions with the most publications respectively. International Urogynecology Journal, American Journal of Obstetrics and Gynecology, and Obstetrics and Gynecology were the journals with the most extensive academic influence on the field of POP research. The international cooperation was lacking and the highly cited documents focused on high-level, evidence-based studies. Epidemiological studies and surgical treatment have achieved a plateau or decline. Recent studies have focused on conservative treatment, physical therapy, and minimally invasive surgery. In addition to evidence-based medicine studies, tissue engineering is the future direction of POP. CONCLUSIONS: This study used bibliometric analyses to provide insights into the status and potential research directions of POP. More high-quality, evidence-based medicine studies and in-depth tissue engineering research should be propelled forward.

Pan-cancer analyses reveal genomics and clinical outcome association of the fatty acid oxidation regulators in cancer.

Background: Fatty acid oxidation (FAO) is considered to play a vital part in tumor metabolic reprogramming. But the comprehensive description of FAO dysregulation in tumors has not been unknown. Methods: We obtained FAO genes, RNA-seq data and clinical information from the Msigdb, TCGA and GTEx databases. We assessed their prognosis value using univariate cox analysis, survival analysis and Kaplan-Meier curve. We determined the function of FAO genes using gene set variation analysis. The correlation analysis was calculated by corrplot R package. Immunotherapy response was assessed through TIDE scores. The protein expression levels of FAO genes were validated using immunohistochemistry (IHC). Results: The FAO scores were highest in COAD but lowest in PCPG. FAO scores were significantly associated with the prognosis of some cancers in OS, DSS, DFI and PFI. Besides, gene set variation analysis identified that FAO scores were related to immune-related pathways, and immune infiltration analysis showed FAO scores were positively related to cancer-associated fibroblasts and various immune-related genes. TIDE scores were significantly decreased in ACC, CHOL, ESCA, GBM, LAML, SARC, SKCM and THCA compared with normal samples, while it was significantly increased in BLCA, LUAD, LUSC, PCPG, PRAD and STAD. Besides, most FAO genes were downregulated in pan-cancer compared with normal samples. Moreover, we found copy number variation (CNV) of FAO genes played a positive role in their mRNA expression, while methylation was negative. We determined FAO genes were closely related to some drugs in pan-cancer. Conclusions: FAO score is a novel and promising factor for predicting outcomes.

Development and validation of a risk-prediction model for immune-related adverse events in patients with non-small-cell lung cancer receiving PD-1/PD-L1 inhibitors.

Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.

Metabolic-suppressed cancer-associated fibroblasts limit the immune environment and survival in colorectal cancer with liver metastasis.

Background: Colorectal cancer liver metastasis is a major risk factor of poor outcomes, necessitating proactive interventions and treatments. Cancer-associated fibroblasts (CAFs) play essential roles in metastasis, with a focus on metabolic reprogramming. However, knowledge about associations between Cancer-associated fibroblasts metabolic phenotypes and immune cell is limited. This study uses single-cell and bulk transcriptomics data to decode roles of metabolism-related subtype of Cancer-associated fibroblasts and immune cells in liver metastasis, developing a CAF-related prognostic model for colorectal cancer liver metastases. Methods: In this study, Cancer-associated fibroblasts metabolism-related phenotypes were screened using comprehensive datasets from The Cancer Genome Atlas and gene expression omnibus (GEO). Cox regression and Lasso regression were applied to identify prognostic genes related to Cancer-associated fibroblasts, and a model was constructed based on the Cancer-associated fibroblasts subtype gene score. Subsequently, functional, immunological, and clinical analyses were performed. Results: The study demonstrated the metabotropic heterogeneity of Cancer-associated fibroblasts cells. Cancer-associated fibroblasts cells with varying metabolic states were found to exhibit significant differences in communications with different immune cells. Prognostic features based on Cancer-associated fibroblasts signature scores were found to be useful in determining the prognostic status of colorectal cancer patients with liver metastases. High immune activity and an enrichment of tumor-related pathways were observed in samples with high Cancer-associated fibroblasts signature scores. Furthermore, Cancer-associated fibroblasts signature score could be practical in guiding the selection of chemotherapeutic agents with higher sensitivity. Conclusion: Our study identified a prognostic signature linked to metabotropic subtype of Cancer-associated fibroblasts. This signature has promising clinical implications in precision therapy for colorectal cancer liver metastases.

TRIM28 recruits E2F1 to regulate CBX8-mediated cell proliferation and tumor metastasis of ovarian cancer.

Chromobox protein homolog 8 (CBX8) is a transcriptional suppressor participated in various cancers. However, the function and mechanism of CBX8 in the progression of ovarian cancer (OC) are unclear. In this study, we found that CBX8 was upregulated in OC tissues originating from GEPIA and TNM databases, OC patients' samples from hospital, and OC cell lines. Furthermore, CBX8 knockdown by short hairpin RNA (shRNA) technology markedly inhibited proliferation and invasion, induced migration, cell cycle arrest, and apoptosis in vitro. Mechanistically, CBX8 activated PI3K/AKT/mTOR signaling pathway to take effect. In addition, TRIM28 and E2F1 were enriched in OC tissues from the TNM database and OC patients' samples similar to the results of CBX8. Correlation analysis indicated positive correlations among TRIM28, E2F1, and CBX8. E2F1 was proved to bind to the promoter regions of CBX8 and TRIM28, while TRIM28 recruited E2F1 to increase the expression of CBX8 to further increase cell viability, proliferation, and invasion, and decrease migration, apoptosis, and cell cycle progression. Finally, CBX8 or TRIM28 knockdown repressed tumor growth and metastasis of OC in vivo. Therefore, our study showed that the promoting effect of CBX8 on tumor growth and metastasis of OC was participated in the PI3K/AKT/mTOR signaling, TRIM28 and E2F1. Our findings suggested that CBX8 could serve as a potential marker and therapeutic target for OC patients.

Liver metastases across cancer types sharing tumor environment immunotolerance can impede immune response therapy and immune monitoring.

BACKGROUND: Hepatic immune tolerance might contribute to the development of therapeutic resistance to immunotherapy. However, addressing this issue is challenging since the efficacy of immunotherapy in the context of liver metastasis (LM) remains poorly studied. Here, we aimed to establish an LM common immune feature (LMCIF) score to quantify the characteristics of LM immunotolerance across cancer types for assisting clinical disease management. METHODS: Large-scale clinical data were collected to identify the prognosis of LM. Multi-omics datasets of metastatic cancers with LM special immune-related pathways (LMSIPs) from the Molecular Signatures Database (MSigDB)were used to obtain an LMCIF cluster. Based on differential expression genes (DEGs), a novel LMCIF score for the LMCIF cluster was constructed. In addition, multi-omics, and immunohistochemistry (IHC) data from the public and in-house cohorts were used to explore the features of LM, and LMCIF score. RESULTS: Patients with LM had a worse prognosis and significantly lower infiltration of immune cells than patients with metastasis to other organs when analyzed with combined clinical and RNA sequencing data. After extracting the LMCIF cluster from 373 samples by utilizing 29 LMSIPs and validating them in a microarray cohort, an LMCIF score was established to confirm the role of the immunosuppressive environment as a contributor to the poor prognosis of LM across cancer types. Moreover, this LMCIF score could be used to predict the immune response of cancer patients undergoing immunotherapy. Finally, we identified that the majority of the 31 LMCIF genes exhibited a negative correlation with TME cells in LM patients, one of them, KRT19, which possessed the strongest positive correlation with LMCIF score, was confirmed to have an immunosuppressive effect through IHC analysis. CONCLUSIONS: Our results suggest that LM across cancer types share similar immunological profiles that induce immunotolerance and escape from immune monitoring. The novel LMCIF score represents a common liver metastasis immune cluster for predicting immunotherapy response, the results of which might benefit clinical disease management.

Hepatitis C Virus Down-Regulates the Expression of Ribonucleotide Reductases to Promote Its Replication.

Ribonucleotide reductases (RRs or RNRs) catalyze the reduction of the OH group on the 2nd carbon of ribose, reducing four ribonucleotides (NTPs) to the corresponding deoxyribonucleotides (dNTPs) to promote DNA synthesis. Large DNA viruses, such as herpesviruses and poxviruses, could benefit their replication through increasing dNTPs via expression of viral RRs. Little is known regarding the relationship between cellular RRs and RNA viruses. Mammalian RRs contain two subunits of ribonucleotide reductase M1 polypeptide (RRM1) and two subunits of ribonucleotide reductase M2 polypeptide (RRM2). In this study, expression of cellular RRMs, including RRM1 and RRM2, is found to be down-regulated in hepatitis C virus (HCV)-infected Huh7.5 cells and Huh7 cells with HCV subgenomic RNAs (HCVr). As expected, the NTP/dNTP ratio is elevated in HCVr cells. Compared with that of the control Huh7 cells with sh-scramble, the NTP/dNTP ratio of the RRM-knockdown cells is elevated. Knockdown of RRM1 or RRM2 increases HCV replication in HCV replicon cells. Moreover, inhibitors to RRMs, including Didox, Trimidox and hydroxyurea, enhance HCV replication. Among various HCV viral proteins, the NS5A and/or NS3/4A proteins suppress the expression of RRMs. When these are taken together, the results suggest that HCV down-regulates the expression of RRMs in cultured cells to promote its replication.

Acceleration of burn wound healing by micronized amniotic membrane seeded with umbilical cord-derived mesenchymal stem cells.

Umbilical cord-derived mesenchymal stem cells (UC-MSC) are promising candidates for wound healing. However, the low amplification efficiency of MSC in vitro and their low survival rates after transplantation have limited their medical application. In this study, we fabricated a micronized amniotic membrane (mAM) as a microcarrier to amplify MSC in vitro and used mAM and MSC (mAM-MSC) complexes to repair burn wounds. Results showed that MSC could live and proliferate on mAM in a 3D culture system, exhibiting higher cell activity than in 2D culture. Transcriptome sequencing of MSC showed that the expression of growth factor-related, angiogenesis-related, and wound healing-related genes was significantly upregulated in mAM-MSC compared to traditional 2D-cultured MSC, which was verified via RT-qPCR. Gene ontology (GO) analysis of differentially expressed genes (DEGs) showed significant enrichment of terms related to cell proliferation, angiogenesis, cytokine activity, and wound healing in mAM-MSC. In a burn wound model of C57BL/6J mice, topical application of mAM-MSC significantly accelerated wound healing compared to MSC injection alone and was accompanied by longer survival of MSC and greater neovascularization in the wound.

Recent Progress in Nanomaterial-Based Biosensors and Theranostic Nanomedicine for Bladder Cancer.

Bladder cancer (BCa) is one of the most expensive and common malignancies in the urinary system due to its high progression and recurrence rate. Although there are various methods, including cystoscopy, biopsy, and cytology, that have become the standard diagnosis methods for BCa, their intrinsic invasive and inaccurate properties need to be overcome. The novel urine cancer biomarkers are assisted by nanomaterials-based biosensors, such as field-effect transistors (FETs) with high sensitivity and specificity, which may provide solutions to these problems. In addition, nanomaterials can be applied for the advancement of next-generation optical imaging techniques and the contrast agents of conventional techniques; for example, magnetic resonance imaging (MRI) for the diagnosis of BCa. Regarding BCa therapy, nanocarriers, including mucoadhesive nanoparticles and other polymeric nanoparticles, successfully overcome the disadvantages of conventional intravesical instillation and improve the efficacy and safety of intravesical chemotherapy for BCa. Aside from chemotherapy, nanomedicine-based novel therapies, including photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), and combination therapy, have afforded us new ways to provide BC therapy and hope, which can be translated into the clinic. In addition, nanomotors and the nanomaterials-based solid tumor disassociation strategy provide new ideas for future research. Here, the advances in BCa diagnosis and therapy mentioned above are reviewed in this paper.

TEM1 up-regulates MMP-2 and promotes ECM remodeling for facilitating invasion and migration of uterine sarcoma.

OBJECTIVES: To explore the correlation between tumor endothelial marker 1 (TEM1) and matrix metalloproteinase 2 (MMP-2) in uterine sarcoma and their roles in the progression of uterine sarcoma. METHODS: Uterine leiomyosarcoma (uLMS, n = 25) and uterine leiomyoma (n = 25) specimens were collected from a total of 50 patients. Immunohistochemistry assay was conducted to determine the expression of TEM1, MMP-2 and MMP-9. TEM1 over expression (hTEM1) and low expression (shRNA-TEM1) MES-SA cell lines were established as in vitro uterine sarcoma models. MMP-2 mRNA, protein expression and enzymatic activity were verified using qPCR, Western blot and gelatin zymography respectively. MMP-2 expression was downregulated using MMP-2 siRNA in hTEM1 MES-SA cells to better study the role of MMP-2. The invasive and migratory capacities of hTEM1, shRNA-TEM1, and hTEM1 treated with MMP-2 siRNA MES-SA cells were determined using transwell assays. Extracellular matrix (ECM) remodeling mediated by TEM1 was examined using cell-ECM adhesion and fluorescent gelatin-ECM degradation assays. The immunofluorescence of F-actin was examined to analyze the formation of invadopodia. Subcutaneous and intraperitoneal xenografts were established to validate the role of TEM1 in promoting uterine sarcoma metastasis. RESULTS: TEM1 and MMP-2 were expressed in 92% (n = 23) and 88% (n = 22) of uterine leiomyosarcoma specimens, respectively. Both TEM1 and MMP-2 were highly expressed in 100% (n = 17) of high stage (III-IV) uterine leiomyosarcoma specimens. In addition, TEM1 expression was positively correlated with MMP-2 expression in uterine leiomyosarcoma. The successful establishment of in vitro uterine sarcoma models was confirmed with qPCR and Western blotting tests. TEM1 promoted the invasion and metastasis of uterine sarcoma in vivo and in vitro. MMP-2 expression and activity were up-regulated in hTEM1 cells but down-regulated in shRNA-TEM1 cells. Importantly, MMP-2 knockdown impaired the invasive and migratory capacity of hTEM1 cells. TEM1 promoted ECM remodeling by increasing cell-ECM adhesion and ECM degradation. TEM1 overexpression also induced the formation of invadopodia. CONCLUSION: TEM1 was co-expressed and positively correlated with MMP-2 in uterine leiomyosarcoma specimens. In addition, both TEM1 and MMP-2 were associated with tumor development. TEM1 promoted uterine sarcoma progression by regulating MMP-2 activity and ECM remodeling.

A Biomimetic Metal-Organic Framework Nanosystem Modulates Immunosuppressive Tumor Microenvironment Metabolism to Amplify Immunotherapy.

In the immunosuppressive tumor microenvironment (iTME), lactate secretion by cancer cells facilitates cell escape via M1 to M2 macrophage polarization, and T cell exhaustion. Therefore, lactate is a promising tumor immunotherapy target. In this study, we constructed a biomimetic nanosystem to modulate iTME metabolism to amplify immunogenic cell death (ICD)-induced immunotherapy. Metal-organic frameworks were coated with platelet membranes (PM) for tumor site-specific delivery and rationally designed to carry lactate oxidase (Lox) which catalytically consumed lactate, while oxaliplatin (Oxa) induced ICD. Due to PM-mediated targeting, the biomimetic nanosystem selectively accumulated in tumors and inhibited tumor growth. Encouragingly, due to effective iTME modulation, enhanced cytotoxic T cell infiltration in tumors was observed. Also, tumor-associated macrophage (TAM) phenotypes were polarized from M2 to M1 types, and regulatory T cell (Treg) levels decreased in vivo. Increased CD8+ T to CD4+ T cell ratios in peripheral blood and spleen were also observed. Thus, our biomimetic nanosystem effectively modulated the iTME and inhibited tumor growth by consuming lactate and amplifying ICD-induced immunotherapy. We provide new avenues into cancer immunotherapy, with a specific emphasis on iTME modulation, which lays the foundation for translational biomimetic nanosystems in clinical settings.

Six-year follow-up outcomes of the P(LLA-CL)/Fg bio-patch for anterior vaginal wall prolapse treatment.

INTRODUCTION AND HYPOTHESIS: There were few data about the long-term outcomes of bio-compatible patches for pelvic organ prolapse (POP). The efficacy of poly (L-lactide-co-caprolactone) blended with fibrinogen [P(LLA-CL)/Fg] bio-patches were investigated for anterior vaginal wall prolapse treatment in a 6-year follow-up. METHODS: The P(LLA-CL)/Fg bio-patch was fabricated through electrospinning. Nineteen patients with symptomatic anterior prolapse (Pelvic Organ Prolapse Quantification [POP-Q] stage ≥ 2) were treated with anterior pelvic reconstruction surgery using a P(LLA-CL)/Fg bio-patch and were followed up at 1, 2, 3, 6 months, and 6 years. The primary outcome was objective anatomical cure (anterior POP-Q stage ≤ 1). Secondary outcomes included complications, MRI evaluation, and scores of the Pelvic Floor Impact Questionnaire-7 (PFIQ-7) and the Pelvic Floor Distress Inventory-20 (PFDI-20). RESULTS: The micro-morphology of the bio-patch resembled the extracellular matrix, which was suitable for the growth of fibroblasts. Sixteen (84.2%) patients were finally assessed, with a mean follow-up of 6.08 ± 0.18 years. The cure rate without anterior prolapse recurrence was 93.8% at 6 years. Compared with baseline, the POP-Q measurements of Aa, Ba, and C points and scores of PFIQ-7 and PFDI-20 manifested significant differences at all times (all p < 0.05). One (5.26%) case of bio-patch-related infection, 1 (5.26%) case of urinary retention, and no exposures and erosion occurred. MRI evaluation showed that the bio-patch gradually degraded to fragments at 1 month and was completely absorbed at 3 months. CONCLUSIONS: Among long-term follow-ups, anterior pelvic reconstruction surgery with a P(LLA-CL)/Fg bio-patch demonstrated significant improvements in anatomical correction of anterior pelvic prolapse and pelvic function without severe morbidity.

Bioinformatically deciphering immune cell infiltration and signature genes in pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The study is aimed at bioinformatically deciphering immune cell infiltration, signature genes, and their correlations in POP. METHODS: Three microarray datasets were included. Matrixes representing the uterosacral ligament were merged as a test matrix and the others representing vaginal tissues were merged as a validation matrix. The single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm was performed to evaluate immune cell infiltration. Correlations among differential immune cells were revealed by Spearman's rank correlation. Differentially expressed genes (DEGs) were screened by both "Batch correction" and "RobustRankAggreg" methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes were conducted for functional analysis. Hub genes were identified through cytoHubba of Cytoscape, and further validated by a validation matrix and clinical samples as signature genes. Correlations of differential immune cells with signature genes were analyzed by Spearman's rank correlation. RESULTS: Five differential immune cells (macrophages, monocytes, regulatory T cell [Treg], type 1 T cell [Th1], and natural killer T cells [NKT]) were identified and eight pairs of immune cells had significant correlations. Screened 230 DEGs were extracellular matrix (ECM) and immune related. Eleven hub genes were initially identified and five of them (LOX, IL-6, SDC1, ICAM1, and CD38) were validated as signature genes. Significant correlations of differential immune cells with signature genes were shown in twelve pairs, especially Th1-IL6, NKT-IL6, Th1-ICAM1, macrophage-IL6, and macrophage-LOX pairs. CONCLUSIONS: Pelvic organ prolapse could be considered immune related. Significantly infiltrated immune cells may contribute to the development of POP through close involvement with ECM- and immune-related signature genes.

Numerical Simulation of the Combustion Characteristics in a Flue Gas Internal Recirculation Burner.

The combustion characteristics and NOx emissions of a newly designed flue gas internal recirculation low-NOx burner (FIR) were studied. In the study, experimental and numerical simulations of the FIR low-NOx burner were conducted under natural inlet air conditions at three different powers. Results show that the fuel inlet strongly influences the jet effect, thus influencing the flue gas recirculation rate, flame stability, and NOx emissions. With a medium power of 20 kW, the NOx emission of a FIR low-NOx burner is lower than 30 mg/N m3. Higher or lower power will increase the NOx emissions or induce combustion instability. The swirling flow and bluff body structure can effectively improve the combustion stability. Three dominant frequencies of 54, 264, and 448 Hz can be observed from the power spectral densities of axial velocity, corresponding to the shedding vortex in the shear layer, the swirl frequency of processing vortex core (PVC), and the vortex induced by the PVC structure, respectively. The influences of vortex shedding and PVC structure are weak and inadequate to affect the overall flame stability.

Tannic acid-loaded hydrogel coating endues polypropylene mesh with hemostatic and anti-inflammatory capacity for facilitating pelvic floor repair.

The application of polypropylene mesh (PPM) in pelvic organ prolapse (POP) treatment was severely limited by the complications associated with PPM, such as mesh exposure, chronic inflammatory reactions and postoperative hematoma. This study applied a method of fabricating a hydrogel-mesh complex (PPM + TA@GelMA) to cross-link tannic acid (TA) directly with Methacrylate Gelatin (GelMA) hydrogel and thus to form a coating for PPM. This one-step coating modification improved the hydrophilicity and cyto-compatibility of PPM. The hemostatic effect of PPM+TA@GelMA was confirmed through tail amputation test. Through the defect tissue repair experiments in vivo, it was proved that PPM+TA@GelMA had effects of anti-inflammation and promoting tissue repair and regulated the M2 subtype macrophages polarization for tissue repair. The TA-loaded hydrogel coating endued PPM with multiple functions. It is believed that the novel hydrogel-mesh complex and its fabrication method will have great significance in basic research and clinical application.

Microneedle Patch Delivery of Methotrexate-Loaded Albumin Nanoparticles to Immune Cells Achieves a Potent Antipsoriatic Effect.

Introduction: Transdermal drug delivery provides a desirable alternative method of penetrating the skin for psoriasis treatment, by virtue of its ability to dampen the overactivation of immune cells and inflammation, while attenuating the detrimental effects of systemic administration. Lymph nodes (LNs), as a critical organ of the lymphatic and the acquired immune system, are suitable sites for drug homing to suppress the immune cells. Methods: In this context, we developed a microneedle (MN) patch that delivers nanodrugs locally to LNs for improving the antipsoriatic treatment. In this study, human serum albumin nanoparticles carrying methotrexate (HM) were synthesized and loaded into hyaluronic acid (HA)-based microneedles (HM/MN). Results: The patch showed an excellent ability to pierce the skin, which enhanced drug delivery. In a mouse model of psoriasis, the HM/MN patch significantly prevented the erythema with decreased skin thickness, thus inhibiting the progression of psoriasis. Further analysis for immune cells in LNs, the percent of dendritic cells (DC) and T cells reduced after the local treatment with HM/MN. Notably, the feasibility of targeted delivery of methotrexate to LNs using nanoparticles was verified by detecting increased accumulation of methotrexate in LNs. In addition, the HM/MN patch pronouncedly decreased the levels of tumor necrosis factor α and interleukin 6 in the skin. Conclusion: The results suggested the high efficacy of using the HM/MN patch to treat psoriasis, and provided new insight into the mechanism of the transdermal drug delivery system.

Intestinal Epithelial Cell Exosome Launches IL-1ß-Mediated Neuron Injury in Sepsis-Associated Encephalopathy.

BACKGROUND: Gut-microbiota-brain axis links the relationship between intestinal microbiota and sepsis-associated encephalopathy (SAE). However, the key mediators between them remain unclear. METHODS: Memory test was determined by Water maze. Intestinal flora was measured by 16S RNA sequencing. Neurotransmitter was detected by high-performance liquid chromatography (HPLC). Histopathology was determined by H&E, immunofluorescence (IF), and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining. Flow cytometry was employed to determine the proportion of macrophages. RESULTS: Fecal microbiota transplantation (FMT) relieved hippocampus impairment of SAE rats by inhibiting inflammation cytokine secretion, the expression of IBA-1 and neurotransmitter disturbance, and cell apoptosis and autophagy, accompanied by the reduced M1 polarization and M1 pro-inflammation factors produced by macrophages in mesenteric lymph nodes (MLNs). Actually, M1 polarization in SAE rats depended on intestinal epithelial cell (IEC)-derived exosome. GW4869-initiated inhibition of exosome secretion notably abolished M1 polarization and the secretion of IL-1ß. However, GW4869-mediated improvement of hippocampus impairment was counteracted by the delivery of recombinant interleukin (IL)-1ß to hippocampus. Mechanistically, IEC-derived exosome induced the excessive circulating IL-1ß produced by CP-R048 macrophages, which subsequently induced damage and apoptosis of hippocampal neurons H19-7 in an autophagy-dependent manner. And reactivation of autophagy facilitates intestinal IL-1ß-mediated hippocampal neuron injury. CONCLUSION: Collectively, intestinal flora disturbance induced the exosome release of IECs, which subsequently caused M1 polarization in MLNs and the accumulation of circulating IL-1ß. Circulating IL-1ß promoted the damage and apoptosis of neurons in an autophagy-dependent manner. Possibly, targeting intestinal flora or IEC-derived exosome contributes to the treatment of SAE.

MicroRNA-Independent Modulation of DICER1 Expression by hAgo2.

Many proteins, including DICER1 and hAgo2, are involved in the biogenesis of microRNAs (miRNAs). Whether hAgo2 regulates DICER1 expression is unknown. Exogenously overexpressed hAgo2 suppressed DICER1 expression at the levels of both protein and mRNA, and the reduction in hAgo2 expression enhanced DICER1 expression. Precursor miRNA processing mediated by DICER1 was also modulated by hAgo2. However, hAgo2 protein did not suppress DICER1 promoter activity. Therefore, hAgo2 protein probably regulates DICER1 expression at the posttranscriptional level. Indeed, hAgo2 protein inhibited the reporter assay of the DICER1 mRNA 3' untranslated region (3'-UTR). Previous reports have demonstrated that miRNAs (e.g., let-7 and miR-103/107) inhibited DICER1 expression posttranscriptionally. However, hAgo2 still suppressed DICER1 expression in the cells depleted of these miRNAs. Moreover, the reporter activities of the DICER1 mRNA 3'-UTR without these miRNA binding sites were still suppressed by hAgo2. Therefore, in addition to an miRNA-dependent pathway, hAgo2 can also modulate DICER1 expression through an miRNA-independent mechanism. Downregulation of DICER1 expression was further proven to be dependent on both hAgo2 and AUF1 proteins. Interactions of hAgo2 and AUF1 proteins were demonstrated by the coimmunoprecipitation assay. As expected, hAgo2 could not suppress the DICER1 mRNA 3'-UTR reporter with a mutation in the potential AUF1-binding site. Thus, downregulation of DICER1 expression through the 3'-UTR requires both hAgo2 and AUF1.

Deletion of MicroRNA-144/451 Cluster Aggravated Brain Injury in Intracerebral Hemorrhage Mice by Targeting 14-3-3ζ.

This study aims at evaluating the importance and its underlying mechanism of the cluster of microRNA-144/451 (miR-144/451) in the models with intracerebral hemorrhage (ICH). A model of collagenase-induced mice with ICH and a model of mice with simple miR-144/451 gene knockout (KO) were used in this study. Neurodeficits and the water content of the brain of the mice in each group were detected 3 days after collagenase injection. The secretion of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß), as well as certain biomarkers of oxidative stress, was determined in this study. The results revealed that the expression of miR-451 significantly decreased in the mice with ICH, whereas miR-144 showed no significant changes. KO of the cluster of miR-144/451 exacerbated the neurological deficits and brain edema in the mice with ICH. Further analyses demonstrated that the KO of the cluster of miR-144/451 significantly promoted the secretion of TNF-α and IL-1ß and the oxidative stress in the perihematomal region of the mice with ICH. In addition, the miR-144/451's depletion inhibited the regulatory axis' activities of miR-451-14-3-3ζ-FoxO3 in the mice with ICH. In conclusion, these data demonstrated that miR-144/451 might protect the mice with ICH against neuroinflammation and oxidative stress by targeting the pathway of miR-451-14-3-3ζ-FoxO3.

Synthesis and Structural Evolution of Nickel-Cobalt Nanoparticles Under H2 and CO2.

Bimetallic nanoparticle (NP) catalysts are interesting for the development of selective catalysts in reactions such as the reduction of CO2 by H2 to form hydrocarbons. Here the synthesis of Ni-Co NPs is studied, and the morphological and structural changes resulting from their activation (via oxidation/reduction cycles), and from their operation under reaction conditions, are presented. Using ambient-pressure X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and transmission electron microscopy, it is found that the initial core-shell structure evolves to form a surface alloy due to nickel migration from the core. Interestingly, the core consists of a Ni-rich single crystal and a void with sharp interfaces. Residual phosphorous species, coming from the ligands used for synthesis, are found initially concentrated in the NP core, which later diffuse to the surface.