Icariin alleviates renal inflammation and tubulointerstitial fibrosis via Nrf2-mediated attenuation of mitochondrial damage.

Tubulointerstitial fibrosis is an inevitable consequence of all progressive chronic kidney disease (CKD) and contributes to a substantial health burden worldwide. Icariin, an active flavonoid glycoside obtained from Epimedium species, exerts potential antifibrotic effect. The study aimed to explore the protective effects of icariin against tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-induced CKD mice and TGF-ß1-treated HK-2 cells, and furthermore, to elucidate the underlying mechanisms. The results demonstrated that icariin significantly improved renal function, alleviated tubular injuries, and reduced fibrotic lesions in UUO mice. Furthermore, icariin suppressed renal inflammation, reduced oxidative stress as evidenced by elevated superoxide dismutase activity and decreased malondialdehyde level. Additionally, TOMM20 immunofluorescence staining and transmission electron microscope revealed that mitochondrial mass and morphology of tubular epithelial cells in UUO mice was restored by icariin. In HK-2 cells treated with TGF-ß1, icariin markedly decreased profibrotic proteins expression, inhibited inflammatory factors, and protected mitochondria along with preserving mitochondrial morphology, reducing reactive oxygen species (ROS) and mitochondrial ROS (mtROS) overproduction, and preserving membrane potential. Further investigations demonstrated that icariin could activate nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway both in vivo and in vitro, whereas inhibition of Nrf2 by ML385 counteracted the protective effects of icariin on TGF-ß1-induced HK-2 cells. In conclusion, icariin protects against renal inflammation and tubulointerstitial fibrosis at least partly through Nrf2-mediated attenuation of mitochondrial dysfunction, which suggests that icariin could be developed as a promising therapeutic candidate for the treatment of CKD.

Quartet RNA reference materials improve the quality of transcriptomic data through ratio-based profiling.

Certified RNA reference materials are indispensable for assessing the reliability of RNA sequencing to detect intrinsically small biological differences in clinical settings, such as molecular subtyping of diseases. As part of the Quartet Project for quality control and data integration of multi-omics profiling, we established four RNA reference materials derived from immortalized B-lymphoblastoid cell lines from four members of a monozygotic twin family. Additionally, we constructed ratio-based transcriptome-wide reference datasets between two samples, providing cross-platform and cross-laboratory 'ground truth'. Investigation of the intrinsically subtle biological differences among the Quartet samples enables sensitive assessment of cross-batch integration of transcriptomic measurements at the ratio level. The Quartet RNA reference materials, combined with the ratio-based reference datasets, can serve as unique resources for assessing and improving the quality of transcriptomic data in clinical and biological settings.

Multi-omics data integration using ratio-based quantitative profiling with Quartet reference materials.

Characterization and integration of the genome, epigenome, transcriptome, proteome and metabolome of different datasets is difficult owing to a lack of ground truth. Here we develop and characterize suites of publicly available multi-omics reference materials of matched DNA, RNA, protein and metabolites derived from immortalized cell lines from a family quartet of parents and monozygotic twin daughters. These references provide built-in truth defined by relationships among the family members and the information flow from DNA to RNA to protein. We demonstrate how using a ratio-based profiling approach that scales the absolute feature values of a study sample relative to those of a concurrently measured common reference sample produces reproducible and comparable data suitable for integration across batches, labs, platforms and omics types. Our study identifies reference-free 'absolute' feature quantification as the root cause of irreproducibility in multi-omics measurement and data integration and establishes the advantages of ratio-based multi-omics profiling with common reference materials.

Overexpression of CD99 is associated with tumor adaptiveness and indicates the tumor recurrence and therapeutic responses in gliomas.

Glioma undergoes adaptive changes, leading to poor prognosis and resistance to treatment. CD99 influences the migration and invasion of glioma cells and plays an oncogene role. However, whether CD99 can affect the adaptiveness of gliomas is still lacking in research, making its clinical value underestimated. Here, we enrolled our in-house and public multiomics datasets for bioinformatic analysis and conducted immunohistochemistry staining to investigate the role of CD99 in glioma adaptive response and its clinical implications. CD99 is expressed in more adaptative glioma subtypes and cell states. Under hypoxic conditions, CD99 is upregulated in glioma cells and is associated with angiogenesis and metabolic adaptations. Gliomas with over-expressed CD99 also increased the immunosuppressive tumor-associated macrophages. The relevance with tumor adaptiveness of CD99 presented clinical significance. We discovered that CD99 overexpression is associated with short-time recurrence and validated its prognostic value. Additionally, Glioma patients with high expression of CD99 were resistant to chemotherapy and radiotherapy. The CD99 expression was also related to anti-angiogenic and immune checkpoint inhibitor therapy response. Inhibitors of the PI3K-AKT pathway have therapeutic potential against CD99-overexpressing gliomas. Our study identified CD99 as a biomarker characterizing the adaptive response in glioma. Gliomas with high CD99 expression are highly tolerant to stress conditions such as hypoxia and antitumor immunity, making treatment responses dimmer and tumor progression. Therefore, for patients with CD99-overexpressing gliomas, tumor adaptiveness should be fully considered during treatment to avoid drug resistance, and closer clinical monitoring should be carried out to improve the prognosis.

GlioMarker: An integrated database for knowledge exploration of diagnostic biomarkers in gliomas.

Gliomas are the most frequent malignant and aggressive tumors in the central nervous system. Early and effective diagnosis of glioma using diagnostic biomarkers can prolong patients' lives and aid in the development of new personalized treatments. Therefore, a thorough and comprehensive understanding of the diagnostic biomarkers in gliomas is of great significance. To this end, we developed the integrated and web-based database GlioMarker (http://gliomarker.prophetdb.org/), the first comprehensive database for knowledge exploration of glioma diagnostic biomarkers. In GlioMarker, accurate information on 406 glioma diagnostic biomarkers from 1559 publications was manually extracted, including biomarker descriptions, clinical information, associated literature, experimental records, associated diseases, statistical indicators, etc. Importantly, we integrated many external resources to provide clinicians and researchers with the capability to further explore knowledge on these diagnostic biomarkers based on three aspects. (1) Obtain more ontology annotations of the biomarker. (2) Identify the relationship between any two or more components of diseases, drugs, genes, and variants to explore the knowledge related to precision medicine. (3) Explore the clinical application value of a specific diagnostic biomarker through online analysis of genomic and expression data from glioma cohort studies. GlioMarker provides a powerful, practical, and user-friendly web-based tool that may serve as a specialized platform for clinicians and researchers by providing rapid and comprehensive knowledge of glioma diagnostic biomarkers to subsequently facilitates high-quality research and applications.

Comprehensive microRNA-seq transcriptomic profiling across 11 organs, 4 ages, and 2 sexes of Fischer 344 rats.

Rat is one of the most widely-used models in chemical safety evaluation and biomedical research. However, the knowledge about its microRNA (miRNA) expression patterns across multiple organs and various developmental stages is still limited. Here, we constructed a comprehensive rat miRNA expression BodyMap using a diverse collection of 320 RNA samples from 11 organs of both sexes of juvenile, adolescent, adult and aged Fischer 344 rats with four biological replicates per group. Following the Illumina TruSeq Small RNA protocol, an average of 5.1 million 50 bp single-end reads was generated per sample, yielding a total of 1.6 billion reads. The quality of the resulting miRNA-seq data was deemed to be high from raw sequences, mapped sequences, and biological reproducibility. Importantly, aliquots of the same RNA samples have previously been used to construct the mRNA BodyMap. The currently presented miRNA-seq dataset along with the existing mRNA-seq dataset from the same RNA samples provides a unique resource for studying the expression characteristics of existing and novel miRNAs, and for integrative analysis of miRNA-mRNA interactions, thereby facilitating better utilization of rats for biomarker discovery.

Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage.

COVID-19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID-19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID-19-infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN-I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID-19-infected patients experiencing milder disease symptoms showed robust T-cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19.

PCC0208009 enhances the anti-tumor effects of temozolomide through direct inhibition and transcriptional regulation of indoleamine 2,3-dioxygenase in glioma models.

Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in human glioblastoma and involved in tumor immune escape and resistance to chemotherapy, is clinically correlated with tumor progression and poor clinical outcomes, and is a promising therapeutic target for glioblastoma. IDO inhibitors are marginally efficacious as single-agents; therefore, combination with other therapies holds promise for cancer therapy. The aim of this study was to investigate the anti-tumor effects and mechanisms of the IDO inhibitor PCC0208009 in combination with temozolomide. The effects of PCC0208009 on IDO activity inhibition, and mRNA and protein expression in HeLa cells were observed. In the mouse glioma GL261 heterotopic model, the effects of PCC0208009 on l-kynurenine/tryptophan (Kyn/Trp), tumor growth, flow cytometry for T cells within tumors, and immunohistochemistry for IDO and Ki67 were examined. In the rat glioma C6 orthotopic model, animal survival, flow cytometry for T cells within tumors, and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and IDO were examined. The results show that PCC0208009 is a highly effective IDO inhibitor, not only directly inhibiting IDO activity but also participating in the gene regulation of IDO expression at the transcription and translation levels. PCC0208009 significantly enhanced the anti-tumor effects of temozolomide in GL261 and C6 models, by increasing the percentages of CD3+, CD4+, and CD8+ T cells within tumors and suppressing tumor proliferation. These findings indicate that PCC0208009 can potentiate the anti-tumor efficacy of temozolomide and suggest that combination of IDO inhibitor-based immunotherapy with chemotherapy is a potential strategy for brain tumor treatment.

In Vitro and In Vivo Characterization of PCC0104005, a Novel Modulator of Serotonin-Dopamine Activity, as an Atypical Antipsychotic Drug.

PCC0104005 is a novel drug candidate for treating schizophrenia that displays high affinity for serotonin, dopamine, and noradrenaline receptors, including partial agonism at dopamine D2, D3, D4, serotonin 5-HT1A, and 5-HT2A receptors and antagonism at 5-HT2B, 5-HT6, and 5-HT7 receptors. PCC0104005 blocks MK-801-induced hyperactivity in rats, consistent with the reduction in dopamine D2 receptor stimulation and increased dopamine release in the medial prefrontal cortex. PCC0104005 inhibits 5-HTP-induced head twitches in rats, due to its moderate affinity for human 5-HT2A receptors (Ki = 5.1 nM). PCC0104005 significantly reduced the escape latency of rats and improved the MK-801-induced memory impairment. In the object recognition experiment, PCC0104005 significantly improved the recognition disorder induced by MK-801. PCC0104005 did not significantly increase the plasma prolactin level, which is thought to be related to the preferential affinity of PCC0104005 for dopamine D2 receptors compared with 5-HT1A receptors, as well as the relative antagonistic activity toward the D2 receptor. Due to its 5-HT1A agonism, PCC0104005 does not produce catalepsy in mice, a behaviour predictive of the occurrence of extra-pyramidal syndrome (EPS) in humans. PCC0104005 has unique affinities for dopamine receptors and serotonin receptors, which may lead to clinical advantages, as well as fewer adverse reactions.

Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919 and paclitaxel in a murine B16-F10 melanoma model.

Indoleamine 2,3-dioxygenase (IDO) is involved in tumor immune escape and resistance to chemotherapy, and is clinically correlated with tumor progression. IDO inhibitors show marginal efficacy as single agents; therefore, combinations of these inhibitors with other therapies hold promise for cancer therapy. The aim of this study was to investigate the synergistic antitumor effects of IDO inhibitor NLG919 in combination with different regimens of paclitaxel in a murine B16-F10 melanoma model. NLG919 increased the cytotoxic activity of paclitaxel toward B16-F10 cells in the presence of pretreatment with interferon (IFN)-γ in vitro. In B16-F10 tumor-bearing mice, NLG919 was uniformly distributed throughout tumors and decreased kynurenine levels and kynurenine/tryptophan ratios in tumors and plasma for 6-12 h. NLG919 suppressed tumor growth in a dose-dependent manner and exhibited maximum efficacy at 100 mg/kg. In combination with different regimens of paclitaxel, NLG919 displayed synergistic antitumor effects, and NLG919 did not increase the side effects of paclitaxel. Within the tumors, the percentage of CD3+, CD8+, and CD4+ T cells and secretion of IFN-γ and interleukin-2 were synergistically increased, whereas the percentage of CD4+CD25+ regulatory T cells was decreased. NLG919 can potentiate the antitumor efficacy of paclitaxel without increasing its side effects, suggesting that the combination of IDO inhibitor-based immunotherapy with chemotherapy could be a potential strategy for cancer treatment.