Pan-cancer analysis of the prognostic significance of ACKR2 expression and the related genetic/epigenetic dysregulations.

OBJECTIVE: ACKR2 is a scavenger for most inflammation-related CC chemokines. This study aimed to assess the pan-cancer prognostic significance of ACKR2 and the genetic and epigenetic mechanisms underlying its dysregulation. METHODS: Pan-cancer data from The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and The Genotype-Tissue Expression (GTEx) were integrated and analyzed. RESULTS: ACKR2 is consistently associated with favorable progression-free interval (PFI) and overall survival (OS) in TCGA-uveal melanoma (UVM) and TCGA-liver hepatocellular carcinoma (LIHC). ACKR2 is negatively correlated with the expression of CCL1, CCL4, CCL5, CXCL8, CCL17, and CCL20 in TCGA-UVM and TCGA-LIHC. The group with gene copy gain had significantly higher ACKR2 expression than those with loss. The lower ACKR2 expression groups were associated with a significantly higher ratio of BAP1 mutations. In addition, ACKR2 was negatively corrected with DNMT1 expression but was positively corrected with ZC3H13, an m6A writer gene and NSUN3, an RNA m5C writer gene. CONCLUSIONS: ACKR2 expression was associated with favorable prognosis in patients with uveal melanoma and hepatocellular carcinoma. ACKR2 dysregulation might be an accumulated result of gene copy number alterations, transcriptional disruption, and RNA modifications.

Targeting progranulin alleviated silica particles-induced pulmonary inflammation and fibrosis via decreasing Il-6 and Tgf-ß1/Smad.

Long term exposure to silica particles leads to various diseases, among which silicosis is of great concern. Silicosis is an interstitial lung disease caused by inhalation of silica particles in production environments. However, the mechanisms underlying silicosis remains unclear. Our previous studies revealed that progranulin (Pgrn) promoted the expression of pro-inflammatory factors in alveolar macrophages treated with silica particles and the secretion of extracellular matrix of pulmonary fibroblasts. Nevertheless, the role of Pgrn in silica particles-induced silicosis in vivo was unknown. This study found that silica particles increased Pgrn expression in silicosis patients. Pgrn deficiency reduced lung inflammation and fibrosis in silica particles-induced silicosis mouse models. Subsequently, based on transcriptional sequencing and interleukin (Il) -6 knockout mouse models, results demonstrated that Pgrn deficiency might decrease silicosis inflammation by reducing the production of Il-6, thereby modulating pulmonary fibrosis in the early stage of silicosis mouse models. Furthermore, another mechanism through which Pgrn deficiency reduced fibrosis in silicosis mouse models was the regulation of the transforming growth factor (Tgf) -ß1/Smad signaling pathway. Conclusively, Pgrn contributed to silicosis inflammation and fibrosis induced by silica particles, indicating that Pgrn could be a promising therapeutic target.

Design and synthesis of 1H-benzo[d]imidazole selective HDAC6 inhibitors with potential therapy for multiple myeloma.

Pan-HDAC inhibitors exhibit significant inhibitory activity against multiple myeloma, however, their clinical applications have been hampered by substantial toxic side effects. In contrast, selective HDAC6 inhibitors have demonstrated effectiveness in treating multiple myeloma. Compounds belonging to the class of 1H-benzo[d]imidazole hydroxamic acids have been identified as novel HDAC6 inhibitors, with the benzimidazole group serving as a specific linker for these inhibitors. Notably, compound 30 has exhibited outstanding HDAC6 inhibitory activity (IC50 = 4.63 nM) and superior antiproliferative effects against human multiple myeloma cells, specifically RPMI-8226. Moreover, it has been shown to induce cell cycle arrest in the G2 phase and promote apoptosis through the mitochondrial pathway. In a myeloma RPMI-8226 xenograft model, compound 30 has demonstrated significant in vivo antitumor efficacy (T/C = 34.8%) when administered as a standalone drug, with no observable cytotoxicity. These findings underscore the immense potential of compound 30 as a promising therapeutic agent for the treatment of multiple myeloma.

Effects of plant-based medicinal food on postoperative recurrence and lung metastasis of gastric cancer regulated by Wnt/ß-catenin-EMT signaling pathway and VEGF-C/D-VEGFR-3 cascade in a mouse model.

BACKGROUND: The plant-based medicinal food (PBMF) is a functional compound extracted from 6 medicinal and edible plants: Coix seed, L. edodes, A. officinalis L., H. cordata, Dandelion, and G. frondosa. Our previous studies have confirmed that the PBMF possesses anti-tumor properties in a subcutaneous xenograft model of nude mice. This study aims to further investigate the effects and potential molecular mechanisms of the PBMF on the recurrence and metastasis of gastric cancer (GC). METHODS: Postoperative recurrence and metastasis model of GC was successfully established in inbred 615 mice inoculated with mouse forestomach carcinoma (MFC) cells. After tumorectomy, 63 GC mice were randomly divided into five groups and respectively subject to different treatments for 15 days as below: model control group, 5-Fu group, and three doses of PBMF (43.22, 86.44, 172.88 g/kg PBMF in diet respectively). The inhibition rate (IR) of recurrence tumor weights and organ coefficients were calculated. Meanwhile, histopathological changes were examined and the metastasis IR in lungs and lymph node tissues was computed. The mRNA expressions related to the canonical Wnt/ß-catenin signaling pathway, epithelial-mesenchymal transition (EMT) and lymphangiogenesis were detected by RT-qPCR in recurrence tumors and/or lung tissues. Protein expressions of ß-catenin, p-ß-catenin (Ser33/37/Thr41), GSK-3ß, p-GSK-3ß (Ser9), E-cadherin, and Vimentin in recurrence tumors were determined by Western Blot. LYVE-1, VEGF-C/D, and VEGFR-3 levels in recurrence tumors and/or lung tissues were determined by immunohistochemistry staining. RESULTS: The mRNA, as well as protein expression of GSK-3ß were up-regulated and the mRNA expression of ß-catenin was down-regulated after PBMF treatment. Meanwhile, the ratio of p-ß-catenin (Ser33/37/Thr41) to ß-catenin protein was increased significantly and the p-GSK-3ß (Ser9) protein level was decreased. And PMBF could effectively decrease the mRNA and protein levels of Vimentin while increasing those of E-cadherin. Furthermore, PBMF markedly reduced lymphatic vessel density (LVD) (labeled by LYVE-1) in recurrence tumor tissues, and mRNA levels of VEGF-C/D, VEGFR-2/3 of recurrence tumors were all significantly lower in the high-dose group. CONCLUSIONS: PBMF had a significant inhibitory effect on recurrence and lung metastasis of GC. The potential mechanism may involve reversing EMT by inhabiting the Wnt/ß-catenin signaling pathway. Lymphatic metastasis was also inhibited by PBMF via down-regulating the activation of the VEGF-C/D-VEGFR-2/3 signaling cascade.

Nicotinamide Mononucleotide Ameliorates Silica-Induced Lung Injury through the Nrf2-Regulated Glutathione Metabolism Pathway in Mice.

Nicotinamide mononucleotide (NMN) is a natural antioxidant approved as a nutritional supplement and food ingredient, but its protective role in silicosis characterized by oxidative damage remains unknown. In this study, we generated a silicosis model by intratracheal instillation of silica, and then performed histopathological, biochemical, and transcriptomic analysis to evaluate the role of NMN in silicosis. We found that NMN mitigated lung damage at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1, Gstm2, and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Gene interaction analysis showed that Nrf2 interacted with Gstm1 and Mgst1 through Gtsm2. Promisingly, oxidative damage mediated by these genes occurred mainly in fibroblasts. In summary, NMN alleviates silica-induced oxidative stress and lung injury by regulating the endogenous glutathione metabolism pathways. This study reveals that NMN supplementation might be a promising strategy for mitigating oxidative stress and inflammation in silicosis.

Regulation of an Antimicrobial Peptide GL13K-Modified Titanium Surface on Osteogenesis, Osteoclastogenesis, and Angiogenesis Base on Osteoimmunology.

Creating a pro-regenerative immune microenvironment around implant biomaterial surfaces is significant to osseointegration. Immune cells, especially macrophages that participate in the osseointegration, including osteogenesis, osteoclastogenesis, and angiogenesis, should be considered when testing biomaterials. In this study, we immobilized an antimicrobial peptide GL13K with immunomodulatory properties onto a titanium surface via silanization. The modified surfaces show good biocompatibility with bone mesenchymal stromal cells (BMSCs), human umbilical vein endothelial cells (HUVECs), and RAW264.7. By co-culturing BMSCs with RAW264.7, we found that the GL13K-coated titanium surfaces could promote late-stage osteogenesis as demonstrated by the upregulated expression of recombinant collagen type I alpha 1 (COL-1α1) and more extracellular matrix mineralization, while the early phase remained unchanged. The surfaces inhibited the osteoclastogenic differentiation of RAW264.7 cells by restraining nuclear factor-activated T cells, cytoplasmic 1 (NFATc1), the main factor of the receptor activator of nuclear factor-κ B, and the receptor activator of the nuclear factor-κ B ligand signaling pathway, from entering the nucleus and further reduced the expression of the activating osteoclastogenic tartrate-resistant acid phosphatase gene. Moreover, the GL13K-coated titanium surface demonstrated significant promotion of angiogenesis differentiation of HUVECs as indicated by the upregulated expression of essential angiogenesis function genes, including hypoxia-inducible factor-1α, endothelial nitric oxide synthase, kinase insert domain receptor, and vascular endothelial growth factor A (HIF-1α, eNOS, KDR, and VEGF-A). Taken together, these results demonstrated that the GL13K coating had properties of osteogenesis, angiogenesis, and anti-osteoclastogenesis via its immunomodulatory potential.

Exposure interval to ambient fine particulate matter (PM2.5) collected in Southwest China induced pulmonary damage through the Janus tyrosine protein kinase-2/signal transducer and activator of transcription-3 signaling pathway both in vivo and in vitro.

PM2.5 is a well-known air pollutant threatening public health. Studies confirmed that exposure to the particles could impair pulmonary function, cause chronic obstructive pulmonary disease, and increase the incidence of lung cancer. The characteristic of PM2.5 varies across regions. The toxic function of PM2.5 in southwest China remains to be elucidated. This study aimed to investigate lung injury and its mechanisms induced by PM2.5 collected in Chengdu. Rats were administered with PM2.5 by intratracheal instillation for 4 weeks. Biochemical, cell count, and inflammation-related parameters were measured. Lung tissues were obtained for hematoxylin and eosin and Masson's trichrome staining. The expression levels of vascular endothelial growth factor (VEGF), Janus tyrosine protein kinase-2 (JAK-2), and signal transducer and activator of transcription-3 (STAT-3) were detected by immunohistochemistry assays. Meanwhile, A549 cells were treated with the PM2.5. The cell cycle, and apoptosis were measured by flow cytometry. mRNA and protein expressions of JAK-2, STAT-3, p-STAT-3, and VEGFA were detected using qPCR and Western blot analysis respectively. Results of in vivo study showed that PM2.5 induced lung pathological injury, aggravated the accumulation of inflammatory cells, and increased the serum levels of inflammatory factors. In vitro experiments showed that PM2.5 disrupted the cell growth cycle and increased cell apoptosis through the activation of the JAK-2/STAT-3 signaling pathway. Taken together, this study provided convincing experimental evidence that PM2.5 collected in southwest China could induce pulmonary injury as manifested by inflammatory response and lung fibrosis, possibly through the modulation of the JAK-2/STAT-3 signaling pathway.

A plant-based medicinal food inhibits the growth of human gastric carcinoma by reversing epithelial-mesenchymal transition via the canonical Wnt/ß-catenin signaling pathway.

BACKGROUND: Natural products, especially those with high contents of phytochemicals, are promising alternative medicines owing to their antitumor properties and few side effects. In this study, the effects of a plant-based medicinal food (PBMF) composed of six medicinal and edible plants, namely, Coix seed, Lentinula edodes, Asparagus officinalis L., Houttuynia cordata, Dandelion, and Grifola frondosa, on gastric cancer and the underlying molecular mechanisms were investigated in vivo. METHODS: A subcutaneous xenograft model of gastric cancer was successfully established in nude mice inoculated with SGC-7901 cells. The tumor-bearing mice were separately underwent with particular diets supplemented with three doses of PBMF (43.22, 86.44, and 172.88 g/kg diet) for 30 days. Tumor volumes were recorded. Histopathological changes in and apoptosis of the xenografts were evaluated by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, respectively. Serum levels of TNF-α, MMP-2, and MMP-9 were detected by enzyme-linked immunosorbent assay. The mRNA expression levels of ß-catenin, GSK-3ß, E-cadherin, N-cadherin, MMP-2/9, Snail, Bax, Bcl-2, Caspase-3/9, and Cyclin D1 were evaluated via real-time quantitative polymerase chain reaction. The protein expression levels of GSK-3ß, E-cadherin, N-cadherin, and Ki-67 were determined by immunohistochemistry staining. RESULTS: PBMF treatment efficiently suppressed neoplastic growth, induced apoptosis, and aggravated necrosis in the xenografts of SGC-7901 cells. PBMF treatment significantly decreased the serum levels of MMP-2 and MMP-9 and significantly increased that of TNF-α. Furthermore, PBMF treatment notably upregulated the mRNA expression levels of GSK-3ß, E-cadherin, Bax, Caspase-3, and Caspase-9 but substantially downregulated those of ß-catenin, N-cadherin, MMP-2, MMP-9, Snail, and Cyclin D1 in tumor tissues. The Bax/Bcl-2 ratio was upregulated at the mRNA level. Moreover, PBMF treatment remarkably increased the protein expression levels of GSK-3ß and E-cadherin but notably reduced those of Ki-67 and N-cadherin in tumor tissues. CONCLUSIONS: The PBMF concocted herein exerts anti-gastric cancer activities via epithelial-mesenchymal transition reversal, apoptosis induction, and proliferation inhibition. The underlying molecular mechanisms likely rely on suppressing the Wnt/ß-catenin signaling pathway.

Bioinformatics analysis and quantitative weight of evidence assessment to map the potential mode of actions of bisphenol A.

Bisphenol A (BPA) is a classical chemical contaminant in food, and the mode of action (MOA) of BPA remains unclear, constraining the progress of risk assessment. This study aims to assess the potential MOAs of BPA regarding reproductive/developmental toxicity, neurological toxicity, and proliferative effects on the mammary gland and the prostate potentially related to carcinogenesis by using the Comparative Toxicogenomics Database (CTD)-based bioinformatics analysis and the quantitative weight of evidence (QWOE) approach on the basis of the principles of Toxicity Testing in the 21st Century. The CTD-based bioinformatics analysis results showed that estrogen receptor 1, estrogen receptor 2, mitogen-activated protein kinase (MAPK) 1, MAPK3, BCL2 apoptosis regulator, caspase 3, BAX, androgen receptor, and AKT serine/threonine kinase 1 could be the common target genes, and the apoptotic process, cell proliferation, testosterone biosynthetic process, and estrogen biosynthetic process might be the shared phenotypes for different target organs. In addition, the KEGG pathways of the BPA-induced action might involve the estrogen signaling pathway and pathways in cancer. After the QWOE evaluation, two potential estrogen receptor-related MOAs of BPA-induced testis dysfunction and learning-memory deficit were proposed. However, the confidence and the human relevance of the two MOAs were moderate, prompting studies to improve the MOA-based risk assessment of BPA.

Effects of Malania oleifera Chun Oil on the Improvement of Learning and Memory Function in Mice.

BACKGROUND: The fruits of Malania oleifera Chun & S. K. Lee have been highly sought after medically because its seeds have high oil content (>60%), especially the highest known proportion of nervonic acid (>55%). Objective of the Study. The objective was to explore the effects of different doses of Malania oleifera Chun oil (MOC oil) on the learning and memory of mice and to evaluate whether additional DHA algae oil and vitamin E could help MOC oil improve learning and memory and its possible mechanisms. METHODS: After 30 days of oral administration of the relevant agents to mice, behavioral tests were conducted as well as detection of oxidative stress parameters (superoxide dismutase, malondialdehyde, and glutathione peroxidase) and biochemical indicators (acetylcholine, acetyl cholinesterase, and choline acetyltransferase) in the hippocampus. RESULTS: Experimental results demonstrated that MOC oil treatment could markedly improve learning and memory of mouse models in behavioral experiments and increase the activity of GSH-PX in hippocampus and reduce the content of MDA, especially the dose of 46.27 mg/kg. The addition of DHA and VE could better assist MOC oil to improve the learning and memory, and its mechanism may be related to the inhibition of oxidative stress and restrain the activity of AChE and also increase the content of ACh. CONCLUSION: Our results demonstrated that MOC oil treatment could improve learning and memory impairments. Therefore, we suggest that MOC oil is a potentially important resource for the development of nervonic acid products.

The Effects of Titanium Surfaces Modified with an Antimicrobial Peptide GL13K by Silanization on Polarization, Anti-Inflammatory, and Proinflammatory Properties of Macrophages.

The polarization of macrophages and its anti-inflammatory and proinflammatory properties play a significant role in host response after implant placement to determine the outcome of osseointegration and long-term survival. In the previous study, we immobilized an antimicrobial peptide, GL13K, onto titanium surfaces to provide immune regulation property. In the herein presented study, we aimed at investigating whether GL13K immobilized titanium surface could improve osteogenesis and reduce the inflammatory reaction around the biomaterials by altering macrophage response. We evaluated the cell proliferation of the different phenotypes of macrophages seeded in GL13K-coated titanium surface, which indicated an inhibition of M1 macrophages and a good cytocompatibility to M2 macrophages. Then, we measured the inflammatory and anti-inflammatory activity of the M1 and M2 macrophages seeded on the GL13K-coated titanium surfaces. The results of the enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction showed that the group with the GL13K modified surface had a downregulation in the expression level of the tumor necrosis factor-α and interleukin-1ß in M1 macrophages and an upregulation of IL-10 and transforming growth factor-ß3 (TGF-ß3) levels in M2 macrophages. This study demonstrated that the GL13K modified titanium surfaces can regulate macrophages' polarization and the expression of inflammatory and anti-inflammatory effects, reducing the effects of the inflammatory process, which may promote the process of bone regeneration and osseointegration.