N6-Methyladenosine Regulator-Mediated Methylation Modification Patterns with Distinct Prognosis, Oxidative Stress, and Tumor Microenvironment in Renal Cell Carcinoma.

OBJECTIVE: Emerging evidence suggests the biological implications of N6-methyladenosine (m6A) in carcinogenesis. Herein, we systematically analyzed the role of m6A modification in renal cell carcinoma (RCC) progression. METHODS: Based on 23 m6A regulators, unsupervised clustering analyses were conducted to determine m6A modification subtypes across 893 RCC specimens in the Cancer Genome Atlas (TCGA) cohort. By performing principal component analysis (PCA) analysis, m6A scoring system was developed for evaluating m6A modification patterns of individual RCC patients. The activity of signaling pathways was assessed by gene-set variation analysis (GSVA) algorithm. The single-sample gene set enrichment analysis (ssGSEA) algorithm was applied for quantifying the infiltration levels of immune cells and the activity of cancer immunity cycle. Drug responses were estimated by genomics of drug sensitivity in cancer (GDSC), the Cancer Therapeutics Response Portal (CTRP) and Preservice Research Institute for Science and Mathematics (PRISM) database. RESULTS: Five m6A modification subtypes were characterized by different survival outcomes, oxidative stress, cancer stemness, infiltrations of immune cells, activity of cancer immunity cycle, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression and microsatellite instability (MSI) levels. According to m6A score, RCC patients were categorized into high and low m6A score groups. Patients with high m6A score displayed a prominent survival advantage, and the prognostic value of m6A score was confirmed in two anti-PD-1/PD-L1 immunotherapy cohorts. m6A score was significantly linked to oxidative stress-related genes, and high m6A score indicated the higher sensitivity to axitinib, pazopanib and sorafenib and the lower sensitivity to sunitinib. CONCLUSION: This study analyzed the extensive regulatory mechanisms of m6A modification on oxidative stress, the tumor microenvironment, and immunity. Quantifying m6A scores may enhance immunotherapeutic effects and assist in developing more effective agents.

Oleoylethanolamide ameliorates motor dysfunction through PPARα-mediates oligodendrocyte differentiation and white matter integrity after ischemic stroke.

BACKGROUND AND AIM: Our previous study has revealed that OEA promotes motor function recovery in the chronic stage of ischemic stroke. However, the neuroprotective mechanism of OEA on motor function recovery after stroke still is unexplored. Therefore, the aim of this study was to explore the effects of OEA treatment on angiogenesis, neurogenesis, and white matter repair in the peri-infarct region after cerebral ischemia. EXPERIMENTAL PROCEDURE: The adult male rats were subjected to 2 h of middle cerebral artery occlusion. The rats were treated with 10 and 30 mg/kg OEA or vehicle daily starting from day 2 after ischemia induction until they were sacrificed. KEY RESULTS AND CONCLUSIONS: The results revealed that OEA increased cortical angiogenesis, neural progenitor cells (NPCs) proliferation, migration, and differentiation. OEA treatment enhanced the survival of newborn neurons and oligodendrogenesis, which eventually repaired the cortical neuronal injury and improved motor function after ischemic stroke. Meanwhile, OEA treatment promoted the differentiation of oligodendrocyte progenitor cells (OPCs) and oligodendrogenesis by activating the PPARα signaling pathway. Our results showed that OEA restores motor function by facilitating cortical angiogenesis, neurogenesis, and white matter repair in rats after ischemic stroke. Therefore, we demonstrate that OEA facilitates functional recovery after ischemic stroke and propose the hypothesis that the long-term application of OEA mitigates the disability after stroke.

Multi-omics analysis uncovers clinical, immunological, and pharmacogenomic implications of cuproptosis in clear cell renal cell carcinoma.

OBJECTIVE: The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective. METHODS: This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation. RESULTS: Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients' survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group. CONCLUSION: Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.

Integrated bioinformatics analysis uncovers characteristic genes and molecular subtyping system for endometriosis.

Objective: Endometriosis is a chronic inflammatory estrogen-dependent disease with the growth of endometrial tissues outside the uterine cavity. Nevertheless, the etiology of endometriosis is still unclear. Integrated bioinformatics analysis was implemented to reveal the molecular mechanisms underlying this disease. Methods: A total of four gene expression datasets (GSE7305, GSE11691, GSE23339, and GSE25628) were retrieved from the GEO, which were merged into a meta-dataset, followed by the removal of batch effects via the sva package. Weighted gene co-expression network analysis (WGCNA) was implemented, and endometriosis-related genes were screened under normal and endometriosis conditions. Thereafter, characteristic genes were determined via Lasso analysis. The diagnostic performance was estimated via receiver operating characteristic curves, and epigenetic and post-transcriptional modifications were analyzed. Small molecular compounds were predicted. Unsupervised clustering analysis was conducted via non-negative matrix factorization algorithm. The enriched pathways were analyzed via gene set enrichment analysis or GSVA. Immune features were evaluated according to immune-checkpoints, HLA, receptors, chemokines, and immune cells. Results: In total, four characteristic genes (BGN, AQP1, ELMO1, and DDR2) were determined for endometriosis, all of which exhibited the favorable efficacy in diagnosing endometriosis. Their aberrant levels were modulated by epigenetic and post-transcriptional modifications. In total, 51 potential drugs were predicted against endometriosis. The characteristic genes exhibited remarkable associations with immunological function. Three subtypes were classified across endometriosis, with different mechanisms and immune features. Conclusion: Our study reveals the characteristic genes and novel molecular subtyping of endometriosis, contributing to the early diagnosis and intervention in endometriosis.

Safety and biodistribution of exosomes derived from human induced pluripotent stem cells.

As a new cell-free therapy, exosomes have provided new ideas for the treatment of various diseases. Human induced pluripotent stem cells (hiPSCs) cannot be used in clinical trials because of tumorigenicity, but the exosomes derived from hiPSCs may combine the advantages of iPSC pluripotency and the nanoscale size of exosomes while avoiding tumorigenicity. Currently, the safety and biodistribution of hiPSC-exosomes in vivo are unclear. Here, we investigated the effects of hiPSC-exosomes on hemolysis, DNA damage, and cytotoxicity through cell experiments. We also explored the safety of vein injection of hiPSC-exosomes in rabbits and rats. Differences in organ distribution after nasal administration were compared in normal and Parkinson's disease model mice. This study may provide support for clinical therapy and research of intravenous and nasal administration of hiPSC-exosomes.

Aging-based molecular classification and score system in ccRCC uncovers distinct prognosis, tumor immunogenicity, and treatment sensitivity.

Objective: Aging is a complex biological process and a major risk factor for cancer development. This study was conducted to develop a novel aging-based molecular classification and score system in clear cell renal cell carcinoma (ccRCC). Methods: Integrative analysis of aging-associated genes was performed among ccRCC patients in the TCGA and E-MTAB-1980 cohorts. In accordance with the transcriptional expression matrix of 173 prognostic aging-associated genes, aging phenotypes were clustered with the consensus clustering approach. The agingScore was generated to quantify aging phenotypes with principal component analysis. Tumor-infiltrating immune cells and the cancer immunity cycle were quantified with the ssGSEA approach. Immunotherapy response was estimated through the TIDE algorithm, and a series of tumor immunogenicity indicators were computed. Drug sensitivity analysis was separately conducted based on the GDSC, CTRP, and PRISM analyses. Results: Three aging phenotypes were established for ccRCC, with diverse prognosis, clinical features, immune cell infiltration, tumor immunogenicity, immunotherapeutic response, and sensitivity to targeted drugs. The agingScore was developed, which enabled to reliably and independently predict ccRCC prognosis. Low agingScore patients presented more undesirable survival outcomes. Several small molecular compounds and three therapeutic targets, namely, CYP11A1, SAA1, and GRIK4, were determined for the low agingScore patients. Additionally, the high agingScore patients were more likely to respond to immunotherapy. Conclusion: Overall, our findings introduced an aging-based molecular classification and agingScore system into the risk stratification and treatment decision-making in ccRCC.

Alternative splicing and alternative polyadenylation define tumor immune microenvironment and pharmacogenomic landscape in clear cell renal carcinoma.

Two major posttranscriptional mechanisms-alternative splicing (AS) and alternative polyadenylation (APA)-have attracted much attention in cancer research. Nevertheless, their roles in clear cell renal carcinoma (ccRCC) are still ill defined. Herein, this study was conducted to uncover the implications of AS and APA events in ccRCC progression. Through consensus molecular clustering analysis, two AS or APA RNA processing phenotypes were separately constructed with distinct prognosis, tumor-infiltrating immune cells, responses to immunotherapy, and chemotherapy. The AS or APA score was constructed to quantify AS or APA RNA processing patterns of individual ccRCCs with principal-component analysis. Both high AS and APA scores were characterized by undesirable survival outcomes, relatively high response to immunotherapy, and low sensitivity to targeted drugs, such as sorafenib and pazopanib. Moreover, several small molecular compounds were predicted for patients with a high AS or APA score. There was a positive correlation between AS and APA scores. Their interplay contributed to poor prognosis and reshaped the tumor immune microenvironment. Collectively, this study is the first to comprehensively analyze two major posttranscriptional events in ccRCC. Our findings uncovered the potential functions of AS and APA events and identified their therapeutic potential in immunotherapy and targeted therapy.

Discovery and Validation of an Epithelial-Mesenchymal Transition-Based Signature in Gastric Cancer by Genomics and Prognosis Analysis.

OBJECTIVE: Epithelial-mesenchymal transition (EMT) exerts a key function in cancer initiation and progression. Herein, we aimed to develop an EMT-based prognostic signature in gastric cancer. METHODS: The gene expression profiles of gastric cancer were obtained from TCGA dataset as a training set and GSE66229 and GSE84437 datasets as validation sets. By LASSO regression and Cox regression analyses, key prognostic EMT-related genes were screened for developing a risk score (RS) model. Potential small molecular compounds were predicted by the CMap database based on the RS model. GSEA was employed to explore signaling pathways associated with the RS. ESTIMATE and seven algorithms (TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, MCPCOUNTER, XCELL, and EPIC) were applied to assess the RS and immune microenvironment. RESULTS: This study developed an EMT-related gene signature comprised of SERPINE1, PCOLCE2, MATN3, and DKK1. High-RS patients displayed poorer survival outcomes than those with low RS. ROC curves demonstrated the robustness of the model in predicting the prognosis. After external validation, the RS model was an independent risk factor for gastric cancer. Several compounds were predicted for gastric cancer treatment based on the RS model. ECM receptor interaction, focal adhesion, pathway in cancer, TGF-beta, and WNT pathways were distinctly activated in high-RS samples. Also, high RS was significantly associated with increased stromal and immune scores and increased infiltration of CD4+ T cell, CD8+ T cell, cancer-associated fibroblast, and macrophage in gastric cancer tissues. CONCLUSION: Our findings suggested that the EMT-related gene model may robustly predict gastric cancer prognosis, which could improve the efficacy of personalized therapy.

Development and Application of Patient-Derived Cancer Organoidsin Clinical Management of Gastrointestinal Cancer: A State-of-the-Art Review.

Human gastrointestinal cancer (e.g., gastric cancer and colorectal cancer) has been a leading cause of cancer-related deaths worldwide and has imposed a great threat to the public health. Although early-stage gastrointestinal cancer can be effectively treated by surgery, followed by postoperative chemotherapy, patients with advanced gastrointestinal cancer often exhibit poor prognosis and cancer relapse due to the absence of effective personalized treatment strategies. Patient-derived cancer organoid technology has been rapidly developed in recent years, and its emergence has opened up an unprecedented approach to model human cancers in vitro. Patient-derived cancer organoids involve the ex vivo culture of fragments of freshly resected human tumors that retain the histological features of original tumors. This review thoroughly discussed the evolutionary process of human gastrointestinal organoids cultured since 2009, and highlighted the potentials of patient-derived cancer organoids in clinical management of gastrointestinal cancer in terms of advances achieved in cancer modelling compared with conventional modelling methods, high-throughput drug screening, and development of personalized treatment selection. Additionally, the current limitations of patient-derived cancer organoids and the potential solutions to overcome these problems were summarized.

USP52 inhibits cell proliferation by stabilizing PTEN protein in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer. Ubiquitination is closely related to the development of lung cancer. However, the biological importance of newly discovered ubiquitin-specific peptidase (USP) 52 (USP52) in NSCLC remained unclear. Here, our findings identify USP52 as a novel tumor suppressor of NSCLC, the low expression of USP52 predicts a poor prognosis for NSCLC patients. The present study demonstrates that USP52 inhibits cancer cell proliferation through down-regulation of cyclin D1 (CCND1) as well as AKT/mTOR signaling pathway inhibition. Meanwhile, USP25 also suppresses NSCLC progression via enhancing phosphatase and tensin homolog (PTEN) stability in cancer cells, which further indicates the significance/importance of USP52 in NSCLC suppression.

miR-128-3p serves as an oncogenic microRNA in osteosarcoma cells by downregulating ZC3H12D.

Osteosarcoma is the second leading cause of cancer-associated mortality worldwide in children and adolescents. ZC3H12D has been shown to negatively regulate Toll-like receptor signaling and serves as a possible tumor suppressor gene. MicroRNAs (miRNAs/miRs) are known to play an important role in the proliferation of human osteosarcoma cells. However, whether miRNAs can affect tumor development by regulating the expression of ZC3H12D has not yet been investigated. The aim of the present study was to investigate the role of miR128-3p in regulating ZC3H12D expression, as well as its function in tumor cell proliferation, apoptosis, and metastasis. Reverse transcription-quantitative PCR, western blotting and dual luciferase reporter assays were performed to analyze the regulation of ZC3H12D expression by miR-128-3p. MTT, colony formation and flow cytometry assays were also used to analyze the effect of miR-128-3p on cell proliferation and apoptosis. A wound healing assay was performed to investigate the cell migration ability. The results demonstrated that miR-128-3p directly targeted ZC3H12D and downregulated its expression, thereby promoting cell proliferation and migration. miR-128-3p overexpression also improved resistance to cisplatin in MG-63 and 143B cell lines, supporting the hypothesis that miR-128-3p may function as an oncogene in osteosarcoma cells. The potential clinical significance of miR-128-3p as a biomarker and therapeutic target provides rationale for further investigation into the miR-128-3p-mediated molecular pathway and how it is associated with osteosarcoma development.

A Novel RNA-Binding Protein-Based Nomogram for Predicting Survival of Patients with Gastric Cancer.

BACKGROUND We attempted to develop a prognostic model and characterize molecular subtypes for gastric cancer on the basis of ribonucleic acid (RNA)-binding proteins (RBPs). MATERIAL AND METHODS RNA sequence data of gastric cancer were obtained from The Cancer Genome Atlas. Univariate Cox regression analysis was used to screen survival-related RBPs, followed by least absolute shrinkage and selection operator Cox modeling. Overall and stratified survival analysis was carried out between high and low risk score groups, followed by receiver operator characteristic curve construction. Univariate and multivariate survival analysis was applied to assess its independent prognostic potential. A nomogram was constructed by combining age and the risk score, which was verified by calibration curves and decision curve analyses for 1-, 3-, and 5-year survival. Molecular subtypes were identified using nonnegative matrix factorization method. Clinical features of the identified subtypes were characterized on prognosis, drug sensitivity, and immune infiltration. An external Gene Expression Omnibus dataset was used to verify the above findings. RESULTS On the basis of 44 survival-related RBPs, a robust prognostic 15-RBP signature was constructed. Patients with high risk score had a poorer prognosis than those with low risk score. The risk score had good performance in predicting clinical outcomes for 1-, 3-, and 5-year survival. The signature was effectively independent of other clinical features. The nomogram model combining age and the 15-RBP prognostic model exhibited better practicality and reliability for prognosis. RBP expression data were utilized to define 2 distinct molecular subtypes obviously related to survival outcomes, chemotherapeutic drug sensitivity, and immune infiltration. CONCLUSIONS Our study provides a nomogram model that consists of age and a 15-RBP signature and identifies 2 molecular subtypes for gastric cancer that possess potential value for preclinical, clinical, and translational research on gastric cancer.

Development and Validation of Nine-RNA Binding Protein Signature Predicting Overall Survival for Kidney Renal Clear Cell Carcinoma.

Cumulative studies have shown that RNA binding proteins (RBPs) play an important role in numerous malignant tumors and are related to the occurrence and progression of tumors. However, the role of RBPs in kidney renal clear cell carcinoma (KIRC) is not fully understood. In this study, we first downloaded gene expression data and corresponding clinical information of KIRC from the Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) database, respectively. A total of 137 differentially expressed RBPs (DERBPs) were then identified between normal and tumor tissue, including 38 downregulated and 99 upregulated RBPs. Nine RBPs (EIF4A1, RPL36A, EXOSC5, RPL28, RPL13, RPS19, RPS2, EEF1A2, and OASL) were served as prognostic genes and exploited to construct a prognostic model through survival analysis. Kaplan-Meier curves analysis showed that the low-risk group had a better survival outcome when compared with the high-risk group. The area under the curve (AUC) value of the prognostic model was 0.713 in the TCGA data set (training data set), 0.706 in the ICGC data set, and 0.687 in the GSE29609 data set, respectively, confirming a good prognostic model. The prognostic model was also identified as an independent prognostic factor for KIRC survival by performing cox regression analysis. In addition, we also built a nomogram relying on age and the prognostic model and internal validation in the TCGA data set. The clinical benefit of the prognostic model was revealed by decision curve analysis (DCA). Gene set enrichment analysis revealed several crucial pathways (ERBB signaling pathway, pathways in cancer, MTOR signaling pathway, WNT signaling pathway, and TGF BETA signaling pathway) that may explain the underlying mechanisms of KIRC. Furthermore, potential drugs for KIRC treatment were predicted by the Connectivity Map (Cmap) database based on DERBPs, including several important drugs, such as depudecin and vorinostat, that could reverse KIRC gene expression, which may provide reference for the treatment of KIRC. In summary, we developed and validated a robust nine-RBP signature for KIRC prognosis prediction. A nomogram with risk score and age can be applied to promote the individualized prediction of overall survival in patients with KIRC. Moreover, the two drugs depudecin and vorinostat may contribute to KIRC treatment.

USP16 Regulates the Stability and Function of LDL receptor by Deubiquitination.

Low-density lipoprotein (LDL) particles are known to be atherogenic agents in coronary artery diseases. They adjust to other electronegative forms and can be the subject for the enhancement of inflammatory events in vessel subendothelial spaces. The LDL uptake is related to the membrane scavenger receptors, including LDL receptor (LDLR). The LDLR expression is closely associated with LDL uptake and occurrence of diseases, such as atherosclerotic cardiovascular diseases. Our findings identified USP16 as a novel regulator of LDLR due to its ability to prevent ubiquitylation-dependent LDLR degradation, further promoting the uptake of LDL. The enhancement of USP16-mediated deubiquitination andthe suppressive degradation of the LDLR cause the presentation of a potential strategy to increase LDL cholesterol clearance.

miR-142-5p promotes renal cell tumorigenesis by targeting TFAP2B.

The transcription factor AP-2 ß (TFAP2B) serves an important role in kidney development. MicroRNAs (miRNAs) regulate carcinogenic pathways and have gained increasing attention owing to their association with human clear cell renal cell carcinoma (ccRCC) tumorigenesis. However, whether miRNAs could affect renal cell tumorigenesis by regulating TFAP2B expression has not been identified. The aim of this study was to investigate the effects of miRNA on TFAP2B and its potential role in cell growth, invasion and migration. PCR, western blot and dual luciferase reporter assays were performed to analyze the effects of miR-142-5p on TFAP2B. Furthermore, MTT, flow cytometry, wound healing and Transwell migration assays were used to analyze the effect of miR-142-5p on cell proliferation and migration. The results demonstrated that miR-142-5p targeted TFAP2B and downregulated the expression of TFAP2B at the mRNA and protein levels, promoting cell proliferation and migration in two ccRCC cell lines, 786-O and A-498. This phenomenon supported the theory that miR-142-5p may function as an oncogene in ccRCC. The potential clinical significance of miR-142-5p as a biomarker and a therapeutic target provides rationale for further investigation into miR-142-5p-mediated molecular pathways and how these may be associated with ccRCC development.

USP22 promotes proliferation in renal cell carcinoma by stabilizing survivin.

Renal cell carcinoma (RCC) is one of the commonest urological tumors. The incidence of RCC ranks third among urological tumors, after prostate cancer and bladder tumors. However, the etiology of RCC remains unclear. Ubiquitin-specific protease 22 (USP22), a potential marker of cancer stem cells, is associated with the occurrence and progression of numerous tumors. However, the roles of USP22 in RCC have not yet been investigated. Survivin is a member of the inhibitor of apoptotic protein family involved in RCC progression. The present study first detected the expression of USP22 and survivin in RCC tissues using immunohistochemistry and western blotting. It was revealed that the protein levels of USP22 and survivin in RCC tissues were higher than those in adjacent normal renal tissue. Subsequently, it was demonstrated that USP22 knockdown inhibited the growth of an RCC cell line ACHN and downregulated the protein level of survivin, accompanied by an increased level of cleaved-caspase-3. By contrast, overexpression of USP22 promoted the growth of ACHN cells, upregulated the expression of survivin and decreased the level of cleaved-caspase-3. Notably, the changes in USP22 expression did not affect the SURVIVIN mRNA level. Finally, it was confirmed that USP22 interacted with survivin and stabilized it by downregulating its ubiquitination. The present results indicate that USP22 may regulate survivin via deubiquitination, thereby promoting the proliferation of RCC cells. The results of the current study suggest that USP22 may represent a novel therapeutic target for patients with RCC.

Identification of 12 immune-related lncRNAs and molecular subtypes for the clear cell renal cell carcinoma based on RNA sequencing data.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma (RCC). Despite the existing extensive research, the molecular and pathogenic mechanisms of ccRCC are elusive. We aimed to identify the immune-related lncRNA signature and molecular subtypes associated with ccRCC. By integrating 4 microarray datasets from Gene Expression Omnibus database, we identified 49 immune-related genes. The corresponding immune-related lncRNAs were further identified in the TCGA dataset. 12-lncRNAs prognostic and independent signature was identified through survival analysis and survival difference between risk groups was further identified based on the risk score. Besides, we identified 3 molecular subtypes and survival analysis result showed that cluster 2 has a better survival outcome. Further, ssGSEA enrichment analysis for the immune-associated gene sets revealed that cluster 1 corresponded to a high immune infiltration level. While cluster 2 and cluster 3 corresponded to low and medium immune infiltration level, respectively. In addition, we validated the 12-lncRNA prognostic signature and molecular subtypes in an external validation dataset from the ICGC database. In summary, we identified a 12-lncRNA prognostic signature which may provide new insights into the molecular mechanisms of ccRCC and the molecular subtypes provided a theoretical basis for personalized treatment by clinicians.

Propane-2-sulfonic acid octadec-9-enyl-amide alleviates scopolamine-induced spatial learning and memory deficits in mice.

Our previous reports demonstrated that the novel peroxisome proliferator-activated receptors α and γ (PPARα/γ) dual agonist propane-2-sulfonic acid octadec-9-enyl-amide (N15) alleviates cognitive ability in the chronic phase of ischemic stroke. However, the potential effects of N15 on Alzheimer's disease (AD) animal models have not been elucidated. In the present study, we investigated the effects of N15 on scopolamine-induced cognitive dysfunction and cholinergic system ability. N15 (50, 100 or 200 mg/kg) was administered to mice via oral gavage for 21 days, and spatial cognitive dysfunction was induced via an intraperitoneal injection of scopolamine (4 mg/kg) for 6 days. We found that N15 pretreatment markedly ameliorated scopolamine-induced spatial cognitive impairment and enhanced cholinergic system reactivity in the hippocampus. N15 pretreatment also significantly increased the expression levels of growth-associated protein-43, synaptophysin, brain-derived neurotrophic factor and neurotrophin-3 in the hippocampus. Our data demonstrate that N15 has an anti-amnesic effect, which may be mediated by enhancing cholinergic activity and synaptic plasticity. These findings support N15 as a potent neuropharmacological drug against AD.

Thalidomide with blockade of co-stimulatory molecules prolongs the survival of alloantigen-primed mice with cardiac allografts.

BACKGROUND: Miscellaneous memory cell populations that exist before organ transplantation are crucial barriers to transplantation. In the present study, we used a skin-primed heart transplantation model in mouse to evaluate the abilities of Thalidomide (TD), alone or in combination with co-stimulatory blockade, using monoclonal antibodies (mAbs) against memory T cells and alloantibodies to prolong the second cardiac survival. RESULTS: In the skin-primed heart transplantation model, TD combined with mAbs significantly prolonged the second cardiac survival, accompanied by inhibition of memory CD8+ T cells. This combined treatment enhanced the CD4+Foxp3+ regulatory T cells ratio in the spleen, restrained the infiltration of lymphocytes into the allograft, and suppressed the allo-response of spleen T cells in the recipient. The levels of allo-antibodies also decreased in the recipient serum. In addition, we detected low levels of the constitutions of the lytic machinery of cytotoxic cells, which cause allograft damage. CONCLUSIONS: Our study indicated a potential synergistic action of TD in combination with with mAbs to suppress the function of memory T cells and increase the survival of second allografts in alloantigen-primed mice.