Bioinformatics and system biology approach to identify the influences among COVID-19, influenza, and HIV on the regulation of gene expression.

Background: Coronavirus disease (COVID-19), caused by SARS-CoV-2, has emerged as a infectious disease, coexisting with widespread seasonal and sporadic influenza epidemics globally. Individuals living with HIV, characterized by compromised immune systems, face an elevated risk of severe outcomes and increased mortality when affected by COVID-19. Despite this connection, the molecular intricacies linking COVID-19, influenza, and HIV remain unclear. Our research endeavors to elucidate the shared pathways and molecular markers in individuals with HIV concurrently infected with COVID-19 and influenza. Furthermore, we aim to identify potential medications that may prove beneficial in managing these three interconnected illnesses. Methods: Sequencing data for COVID-19 (GSE157103), influenza (GSE185576), and HIV (GSE195434) were retrieved from the GEO database. Commonly expressed differentially expressed genes (DEGs) were identified across the three datasets, followed by immune infiltration analysis and diagnostic ROC analysis on the DEGs. Functional enrichment analysis was performed using GO/KEGG and Gene Set Enrichment Analysis (GSEA). Hub genes were screened through a Protein-Protein Interaction networks (PPIs) analysis among DEGs. Analysis of miRNAs, transcription factors, drug chemicals, diseases, and RNA-binding proteins was conducted based on the identified hub genes. Finally, quantitative PCR (qPCR) expression verification was undertaken for selected hub genes. Results: The analysis of the three datasets revealed a total of 22 shared DEGs, with the majority exhibiting an area under the curve value exceeding 0.7. Functional enrichment analysis with GO/KEGG and GSEA primarily highlighted signaling pathways associated with ribosomes and tumors. The ten identified hub genes included IFI44L, IFI44, RSAD2, ISG15, IFIT3, OAS1, EIF2AK2, IFI27, OASL, and EPSTI1. Additionally, five crucial miRNAs (hsa-miR-8060, hsa-miR-6890-5p, hsa-miR-5003-3p, hsa-miR-6893-3p, and hsa-miR-6069), five essential transcription factors (CREB1, CEBPB, EGR1, EP300, and IRF1), and the top ten significant drug chemicals (estradiol, progesterone, tretinoin, calcitriol, fluorouracil, methotrexate, lipopolysaccharide, valproic acid, silicon dioxide, cyclosporine) were identified. Conclusion: This research provides valuable insights into shared molecular targets, signaling pathways, drug chemicals, and potential biomarkers for individuals facing the complex intersection of COVID-19, influenza, and HIV. These findings hold promise for enhancing the precision of diagnosis and treatment for individuals with HIV co-infected with COVID-19 and influenza.

Salmonella-mediated methionine deprivation drives immune activation and enhances immune checkpoint blockade therapy in melanoma.

BACKGROUND: Although immune checkpoint inhibitor (ICI)-based therapy is advantageous for patients with advanced melanoma, resistance and relapse are frequent. Thus, it is crucial to identify effective drug combinations and develop new therapies for the treatment of melanoma. SGN1, a genetically modified Salmonella typhimurium species that causes the targeted deprivation of methionine in tumor tissues, is currently under investigation in clinical trials. However, the inhibitory effect of SGN1 on melanoma and the benefits of SGN1 in combination with ICIs remain largely unexplored. Therefore, this study aims to investigate the antitumor potential of SGN1, and its ability to enhance the efficacy of antibody-based programmed cell death-ligand 1 (PD-L1) inhibitors in the treatment of murine melanoma. METHODS: The antitumor activity of SGN1 and the effect of SGN1 on the efficacy of PD-L1 inhibitors was studied through murine melanoma models. Further, The Cancer Genome Atlas-melanoma cohort was clustered using ConsensusClusterPlus based on the methionine deprivation-related genes, and immune characterization was performed using xCell, Microenvironment Cell Populations-counter, Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data, and immunophenoscore (IPS) analyses. The messenger RNA data on programmed death-1 (PD-1) immunotherapy response were obtained from the Gene Expression Omnibus database. Gene Set Enrichment Analysis of methionine deprivation-up gene set was performed to determine the differences between pretreatment responders and non-responders. RESULTS: This study showed that both, the intratumoral and the intravenous administration of SGN1 in subcutaneous B16-F10 melanomas, suppress tumor growth, which was associated with an activated CD8+T-cell response in the tumor microenvironment. Combination therapy of SGN1 with systemic anti-PD-L1 therapy resulted in better antitumor activity than the individual monotherapies, respectively, and the high therapeutic efficacy of the combination was associated with an increase in the systemic level of tumor-specific CD8+ T cells. Two clusters consisting of methionine deprivation-related genes were identified. Patients in cluster 2 had higher expression of methionine_deprivation_up genes, better clinical outcomes, and higher immune infiltration levels compared with patients in cluster 1. Western blot, IPS analysis, and immunotherapy cohort study revealed that methionine deficiency may show a better response to ICI therapy CONCLUSIONS：: This study reports Salmonella-based SGN1 as a potent anticancer agent against melanoma, and lays the groundwork for the potential synergistic effect of ICIs and SGN1 brought about by improving the immune microenvironment in melanomas.

Novel inhibitory effect of black chokeberry (Aronia melanocarpa) from selected eight berries extracts on advanced glycation end-products formation and corresponding mechanism study.

Numerous health hazards have been connected to advanced glycation end products (AGEs). In this investigation, using reaction models including BSA-fructose, BSA- methylglyoxal (MGO), and BSA-glyoxal (GO), we examined the anti-glycation potential of eight different berry species on AGEs formation. Our results indicate that black chokeberry (Aronia melanocarpa) exhibited the highest inhibitory effects, with IC50 values of 0.35 ± 0.02, 0.45 ± 0.03, and 0.48 ± 0.11 mg/mL, respectively. Furthermore, our findings suggest that black chokeberry inhibits AGE formation by binding to BSA, which alleviates the conformation alteration, prevents protein cross-linking, and traps reactive α-dicarbonyls to form adducts. Notably, three major polyphenols, including cyanidin-3-O-galactoside, cyanidin-3-O-arabinoside, and procyanidin B2 from black chokeberry, showed remarkably inhibitory effect on MGO/GO capture, and new adducts formation was verified through LC-MS/MS analysis. In summary, our research provides a theoretical basis for the use of berries, particularly black chokeberry, as natural functional food components with potential anti-glycation effects.

Resveratrol protects against high glucose-induced steroidogenesis and apoptosis in murine granulosa cells.

Resveratrol (Res) is a polyphenolic compound that exhibits a diverse array of biological effects. Herein, we detected the ability of Res on murine granulosa cells (GCs) against impaired steroidogenesis and apoptotic death in response to high glucose levels. Ovarian GCs were harvested from C57BL/6 mice and cultured in steroidogenic media supplemented with follicle-stimulating hormone (FSH, 30 ng/mL), Res (50 µmol/L), and low or high glucose concentrations (5 mM or 30 mM). After culture for 24 h, cell supernatants were harvested and the levels of progesterone and estradiol therein were measured. Also, caspase-3 activity and the expression of genes associated with apoptosis and steroidogenesis were assessed. High-glucose treatment suppressed steroidogenesis in this assay system, resulting in the impaired expression of steroidogenesis-related genes including Cyp11a1, Cyp19a1, 3ßHSD, and StAR and a concomitant decrease in progesterone and estradiol production. Cells exposed to high glucose also exhibited apoptotic phenotypes characterized by Bax upregulation, Bcl-2 downregulation, and increased caspase-3 activity levels. However, Res treatment was sufficient to reverse this high glucose level-induced apoptotic and steroidogenic phenotypes with improving progesterone and estradiol production, and these maybe related the effects of Res on Cyp11a1, Cyp19a1, 3ßHSD, and StAR expressions. These data suggested that Res is well suited to overcoming the negative effects of hyperglycemia of GC functionality.

Endogenous production of ω-3 polyunsaturated fatty acids mitigates cisplatin-induced myelosuppression by regulating NRF2-MDM2-p53 signaling pathway.

Cisplatin is a chemotherapy medication used to treat a wide range of cancers. A common side effect of cisplatin is myelosuppression. Research suggests that oxidative damages are strongly and consistently related to myelosuppression during cisplatin treatment. ω-3 polyunsaturated fatty acids (PUFAs) can enhance the antioxidant capacity of cells. Herein, we investigated the protective benefit of endogenous ω-3 PUFAs on cisplatin-induced myelosuppression and the underlying signaling pathways using a transgenic mfat-1 mouse model. The expression of mfat-1 gene can increase endogenous levels of ω-3 PUFAs by enzymatically converting ω-6 PUFAs. Cisplatin treatment reduced peripheral blood cells and bone marrow nucleated cells, induced DNA damage, increased the production of reactive oxygen species, and activated p53-mediated apoptosis in bone marrow (BM) cells of wild-type mice. In the transgenics, the elevated tissue ω-3 PUFAs rendered a robust preventative effect on these cisplatin-induced damages. Importantly, we identified that the activation of NRF2 by ω-3 PUFAs could trigger an antioxidant response and inhibit p53-mediated apoptosis by increasing the expression of MDM2 in BM cells. Thus, endogenous ω-3 PUFAs enrichment can strongly prevent cisplatin-induced myelosuppression by inhibiting oxidative damage and regulating the NRF2-MDM2-p53 signaling pathway. Elevation of tissue ω-3 PUFAs may represent a promising treatment strategy to prevent the side effects of cisplatin.

Targeting TNF-α-producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling.

Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely owing to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance, and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Our analysis reveals significant macrophage heterogeneity, with bone marrow-derived monocytes serving as the primary source for immunosuppressive TAMs. These cells also serve as a primary source of TNF-α, which suppresses expression of the alarmin IL-33 in carcinoma cells. Deletion of Ccr2 in genetically engineered mice decreased monocyte recruitment, resulting in profoundly decreased TNF-α and increased IL-33 expression, decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) rendered PDA susceptible to checkpoint blockade, resulting in reduced metastatic burden and increased survival. Our data indicate that this shift in antitumor immunity is influenced by increased levels of IL-33, which increases dendritic cell and cytotoxic T cell activity. These data demonstrate that interventions to disrupt infiltration of immunosuppressive macrophages, or their signaling, have the potential to overcome barriers to effective immunotherapeutics for PDA.

Brown adipose tissue activation with ginsenoside compound K ameliorates polycystic ovary syndrome.

BACKGROUND AND PURPOSE: Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disease affecting women of reproductive age. Due to its complex aetiology, there is no currently effective cure for PCOS. Brown adipose tissue (BAT) activity is significantly decreased in PCOS patients, and BAT activation has beneficial effects in animal models of PCOS. Here, we investigated the effect of ginsenoside compound K (CK) in an animal model of PCOS and its mechanism of BAT activation. EXPERIMENTAL APPROACH: Primary brown adipocytes, Db/Db mice and dehydroepiandrosterone (DHEA)-induced PCOS rats were used. The core body temperature, oxygen consumption, energy metabolism related gene and protein expression were assessed to identify the effect of CK on overall energy metabolism. Oestrous cycle, serum sex hormone, ovarian steroidogenic enzyme gene expression and ovarian morphology were also evaluated following CK treatment. KEY RESULTS: Our results indicated that CK treatment could significantly protect against body weight gain in Db/Db mice via BAT activation. Furthermore, we found that CK treatment could normalize hyperandrogenism, oestrous cyclicity, normalize steroidogenic enzyme expression and decrease the number of cystic follicles in PCOS rats. Interestingly, as a potential endocrine intermediate, C-X-C motif chemokine ligand-14 protein (CXCL14) was significantly up-regulated following CK administration. In addition, exogenous CXC14 supplementation was found to reverse DHEA-induced PCOS in a phenotypically similar manner to CK treatment. CONCLUSION AND IMPLICATIONS: In summary, CK treatment significantly activates BAT, increases CXCL14 expression and ameliorates PCOS. These findings suggest that CK might be a potential drug candidate for PCOS treatment.

Dietary Aronia melanocarpa Pomace Supplementation Enhances the Expression of ZO-1 and Occludin and Promotes Intestinal Development in Pigs.

A fruit juice production byproduct, Aronia melanocarpa pomace (AMP) is rich in natural polyphenol antioxidant components. The objectives of this study were to study the effects of dietary AMP supplementation on the feeding outcome and intestinal barrier function of pigs. In total, 27 growing pigs (Duroc × Landrace × Yorkshire, ~60 days, average weight of 27.77 ± 2.87 kg, males and females included at random) were randomly allotted to 3 treatment groups, with 3 repetitions per group and 3 pigs per repetition. At the experiment completion, 2 pigs (close to the average body weight of all experimental pigs) per replicate were slaughtered. The control group (CON group) was fed a basic diet, and the experimental groups were fed 4% (4% AMP group) and 8% (8% AMP group) AMP in the basic diet. These pigs were prefed for 3 days, and the formal experiments were performed for 7 weeks. The results showed that compared with the CON diet, the 4% AMP supplementation significantly increased the average daily gain of pigs (P < 0.05). Regarding intestinal development, 4% AMP significantly increased the jejunal villus height/crypt depth ratio (P < 0.05), and different AMP levels had no significant effect on the pig cecum morphology. Different AMP levels significantly decreased the relative abundance of Proteobacteria (P < 0.05). Regarding other microbial genera, 4% AMP supplementation significantly increased the levels of Lachnospira, Solobacterium, Romboutsia and other beneficial microorganisms (P < 0.05). Different AMP levels significantly decreased the relative abundances of the opportunistic pathogens Escherichia-Shigella and Pseudoscardovia (P < 0.05) and increased the contents of acetic acid and butyric acid in the pig cecal contents (P < 0.05). Compared with the CON treatment, 4% AMP supplementation significantly downregulated the jejunal gene expression of porcine proinflammatory factors (IL-1ß, IL-6, IL-8 and TNF-α) and significantly upregulated the jejunal gene expression of ZO-1, Occludin and Claudin-1 (P < 0.05). In conclusion, 4% AMP supplementation in feed is beneficial to overall pig health and growth.

Protective Effects of Taraxasterol against Deoxynivalenol-Induced Damage to Bovine Mammary Epithelial Cells.

Deoxynivalenol (DON), a mycotoxin produced by Fusarium graminearum, is one of the most prevalent contaminants in livestock feed and causes very large losses to animal husbandry every year. Taraxasterol, isolated from Taraxacum officinale, has anti-inflammatory, antioxidative stress, and antitumor effects. In the present study, bovine mammary epithelial cells (MAC-T) were used as a model, and different concentrations of taraxasterol (0, 1, 5, 10, and 20 µg/mL) were used to protect against DON-induced cell damage. The results showed that taraxasterol at a concentration of 10 µg/mL significantly increased cell viability. Analysis of lactate dehydrogenase (LDH) levels indicated that taraxasterol substantially decreased LDH release caused by DON. Taraxasterol effectively alleviated the depletion of glutathione (GSH), the increase in the lipid peroxidation of malondialdehyde (MDA), the reduction in total superoxide dismutase (T-SOD) activity, and the decrease in total antioxidant capacity (T-AOC) induced by DON. The results further showed that taraxasterol reduced the accumulation of reactive oxygen species (ROS). Taraxasterol was found to relieve endoplasmic reticulum (ER) stress by suppressing the expression of glucose-regulated protein 78 kDa (GRP78), activating transcription factor 6 (ATF6), activating transcription factor 4 (ATF4) and the transcription factor C/EBP homologous protein (CHOP), and reducing cell apoptosis by suppressing the expression of caspase-3 and Bcl2-associated X (BAX) and upregulating the expression of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2). Our research results indicate that taraxasterol could alleviate DON-induced damage to MAC-T cells.

CHST4 might promote the malignancy of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is reported as an aggressive cancer which leads to high mortality and no effective therapeutic target has yet been discovered. Surgical resection is the main method to treat patients with CCA. However, only one-third of CCA patients have the opportunity to accept the operation, leading to poor prognosis for CCA patients. Therefore, it is necessary to search for new therapeutic targets of CCA or core genes involved in the happening and growth of CCA. AIM: In this study, we utilized bioinformatics technology and accessed to several medical databases trying to find the core genes of CCA for the purpose of intervening CCA through figuring out an effective curative target. METHODS: Firstly, three differentially expressed genes (DEGs) were discovered from GEPIA, and by further observing the distribution and gene expression, CHST4 was obtained as the core gene. Afterwards, correlated genes of CHST4 in CCA were identified using UALCAN to construct a gene expression profile. We obtained PPI network by Search Tool for the Retrieval of Interacting Networks Genes (STRING) and screened core genes using cytoscape software. Functional enrichment analyses were carried out and the expression of CHST in human tissues and tumors was observed. Finally, a CCA model was established for qPCR and staining validation. RESULTS: Three differentially expressed genes (DEGs), CHST4, MBOAT4 and RP11-525K10.3, were obtained. All were more over-expressed in CCA samples than the normal, among which the change multiple and the gene expression difference of CHST4 was the most obvious. Therefore, CHST4 was selected as the core gene. We can see in our established protein-protein interaction (PPI) network that CHST4 had the highest degree of connectivity, demonstrating its close association with CCA. We found that genes were mainly enriched in CCs in the PPI networks genes which shows functional enrichment analysis results, including golgi lumen, extracellular space and extracellular region. CHST4 was found very specifically expressed in the bile duct and was significantly different from that in normal tissues. The overexpression of CHST4 was further verified in the established animal model of TAA-induced CCA in rats. Quantitative PCR (qPCR) demonstrated that CHST4 was significantly overexpressed in tumor tissues, verifying the role of CHST4 as the core gene of CCA. CONCLUSION: CHST4 was increasingly expressed in CCA and CHST4 is worth being studied much further in the intervention of CCA.

Purification and properties of a novel trypsin inhibitor from ginkgo fruits and its antiproliferative effect in triple-negative breast cancer cells.

A novel low molecular mass ginkgo biloba trypsin inhibitor (GBTI) was isolated from ginkgo fruits (GF) by trypsin inhibitory activity-guided fractionation by using ammonium sulphate precipitation, followed by ultra-filtration, affinity chromatography and RP-HPLC. The molecular mass and amino acid sequence of GBTI was determined using ESI-MS and ESI-MS/MS, respectively. The structure of GBTI was identified as MKNLTVIPPICLKFPN, with a molecular mass of 1826 Da. GBTI was stable in the pH range of 4-8 and in the temperature range of 0-80 °C for 30 min. However, the inhibitory activity of the GBTI reduced when incubated with various metalions (K+, Na+, Fe2+, Mg2+ and Ca2+) . Finally, GBTI exhibited significant antiproliferative effect in human MDA-MB-231 and mouse 4 T-1 triple-negative breast cancer cells and without toxicity to MCF-10A normal breast cells. Our results suggest that GBTI could be exploited as a natural and hyperstable anticancer agent for triple-negative breast cancer patients.

Prevalence and Clinical and Endoscopic Characteristics of Cervical Inlet Patch (Heterotopic Gastric Mucosa): A Systematic Review and Meta-Analysis.

BACKGROUND: Cervical inlet patch (CIP), also called gastric inlet patch, is a heterotopic columnar mucosal island located in the cervical esophagus, which has been under-recognized by clinicians. AIM: We conducted a systemic review and meta-analysis to explore the prevalence and clinical and endoscopic characteristics of CIP. MATERIALS AND METHODS: Studies were searched through the PubMed, EMBASE, and Cochrane Library databases. The prevalence of CIP with 95% confidence interval (CI) was pooled by using a random-effect model. The association of CIP with demographics, clinical presentations, and endoscopic features was evaluated by odds ratios (ORs). RESULTS: Fifty-three studies including 932,777 patients were eligible. The pooled prevalence of CIP was 3.32% (95% CI=2.86%-3.82%). According to the endoscopic mode, the pooled prevalence of CIP was higher in studies using narrow-band imaging than in those using white light and esophageal capsule endoscopy (9.34% vs. 2.88% and 0.65%). The pooled prevalence of CIP was higher in studies where the endoscopists paid specific attention to the detection of this lesion (5.30% vs. 0.75%). CIP was significantly associated with male (OR=1.24, 95% CI=1.09-1.42, P=0.001), gastroesophageal reflux disease (OR=1.32, 95% CI=1.04-1.68, P=0.03), reflux symptoms (OR=1.44, 95% CI=1.14-1.83, P=0.002), dysphagia (OR=1.88, 95% CI=1.28-2.77, P=0.001), throat discomfort (OR=4.58, 95% CI=1.00-21.02, P=0.05), globus (OR=2.95, 95% CI=1.52-5.73, P=0.001), hoarseness (OR=4.32, 95% CI=1.91-9.78, P=0.0004), cough (OR=3.48, 95% CI=1.13-10.72, P=0.03), Barrett's esophagus (OR=2.01, 95% CI=1.37-2.94, P=0.0003), and esophagitis (OR=1.62, 95% CI=1.27-2.07, P=0.0001). CONCLUSION: CIP appears to be common by using narrow-band imaging, especially if the endoscopists would like to pay attention to the detection of this lesion. CIP is clearly associated with acid-related symptoms and Barrett's esophagus.

Brown Adipose Tissue Activation by Cold Treatment Ameliorates Polycystic Ovary Syndrome in Rat.

Polycystic ovary syndrome (PCOS) is a common endocrine disease accompanied by energetic metabolic imbalance. Because the etiology of PCOS is complex and remains unclear, there is no effective and specific treatment for PCOS. It is often accompanied by various metabolic disorders such as obesity, insulin resistances, and others. Activated brown adipose tissue (BAT) consumes excess energy via thermogenesis, which has positive effects on energy metabolism. Our previous research and that of others indicates that BAT activity is decreased in PCOS patients, and exogenous BAT transplantation can improve PCOS rodents. Notably however, it is difficult to apply this therapeutic strategy in clinical practice. Therapeutic strategies of enhancing endogenous BAT activity and restoring whole-body endocrine homeostasis may be more meaningful for PCOS treatment. In the current study, the dehydroepiandrosterone-induced PCOS rat was exposed to low temperature for 20 days. The results show that cold treatment could reverse acyclicity of the estrous cycle and reduce circulating testosterone and luteinizing hormone in PCOS rats by activating endogenous BAT. It also significantly reduced the expression of steroidogenic enzymes as well as inflammatory factors in the ovaries of PCOS rats. Histological investigations revealed that cold treatment could significantly reduce ovary cystic follicles and increase corpus luteum, indicating that ovulation was recovered to a normal level. Concordant with these results, cold treatment also improved fertility in PCOS rats. Collectively, these findings suggest that cold treatment could be a novel therapeutic strategy for PCOS.

Informal caregivers' quality of life and management strategies following the transformation of their cancer caregiving role: A qualitative systematic review.

OBJECTIVES: Globally, informal caregivers caring for cancer patients meet challenges within their caregiving role, which significantly influence their quality of life. This qualitative systematic review aimed to analyze how cancer caregiving influence the quality of life of informal caregivers and the management strategies of informal caregivers for their role as cancer caregivers. METHODS: Following the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) statement, Wanfang database, the China National Knowledge Infrastructure (CNKI), CINAHL, MEDLINE, PubMed, Cochrane Library, PsycARTICLES and PsycINFO, and grey literature in English and Chinese from 1 May 2009 to 31 December 2019 were searched. Quality of included studies was assessed by the Critical Appraisal Skills Programme (2018) Qualitative Checklist and thematic synthesis was conducted. RESULTS: Of the 8,945 studies identified, 6 studies met the inclusion criteria. One analytical theme relating to the QoL of informal caregivers following cancer caregiving was identified: "challenges of caregiving". In terms of the management strategies to the role of cancer caregivers, two analytical themes were identified: "self-adjustment" and "seeking for formal and informal support". CONCLUSIONS: Cancer caregiving influences informal caregivers' QoL significantly and informal caregivers develop diverse coping strategies to deal with the difficulties occurred while balancing the relationship between their own lives and caregiving. However, professional and policy support remain inadequate for informal caregivers that require the need for improvement in terms of health care professionals and policymakers.

Anti-migration and anti-invasion effects of 2-hydroxy-6-tridecylbenzoic acid is associated with the enhancement of CYP1B1 expression through activating the AMPK signaling pathway in triple-negative breast cancer cells.

2-hydroxy-6-tridecylbenzoic acid is alkylsalicylic acid monomer compound, abundantly existed in the ginkgo biloba extracts, however, the underlying mechanism of its anti-migration and anti-invasion effects in triple-negative breast cancer (TNBC) is not clear. Here, 2-hydroxy-6 -tridecylbenzoic acid inhibited MDA-MB-231 and 4 T-1 cells growth without toxicity to MCF-10A normal breast cells. Meanwhile, 2-hydroxy-6-tridecylbenzoic acid inhibited cells migration and invasion as well as EMT with the increase of E-cadherin expression accompanied by the decrease of N-cadherin, Vimentin, Snail, MMP-2 and MMP-9 expression. The inhibition was further demonstrated by the enhancement of cytochrome P450 (CYP) 1B1 expression through the activation of AMP activated protein kinase (AMPK) in MDA-MB-231 and 4 T-1 cells. Silencing of CYP1B1 and AMPK with siRNA blocked the inhibitory effects of migration and invasion, and reversed the EMT related genes. These findings may provide a novel mechanism of the 2-hydroxy-6-tridecylbenzoic acid as a molecular-targeted therapeutic drug for TNBC patients.

Expression pattern analysis and drug differential sensitivity of cancer-associated fibroblasts in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has the characteristics of a complex molecular landscape, aggressive or high proliferation leading to poor prognosis, and behavioral heterogeneity. The purpose of the present study was to determine the spatiotemporal expression of α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs) at histological level in 4T1 tumors and to predict the sensitivity to 138 drugs in patients with TNBC according to α-SMA expression. The quantitative results of fibrosis showed that the volume of 4T1 tumors correlated positively with the area of tumor fibrosis. Furthermore, we divided 4T1 tumors according to the degree of fibrosis and characterized the molecular characteristics of the four regions. Finally, the difference in the signaling pathways and sensitivity to 138 drugs was analyzed in patients with TNBC according to α-SMA expression combined with The Cancer Genome Atlas (TCGA) database. The myogenesis, TGF-ß, and Notch signaling pathways were upregulated and the patients with TNBC were significantly differentially sensitive to 25 drugs. The results of in vivo experiments showed that the inhibitory effect of embelin on 4T1 tumors with high α-SMA expression was greater than that on 4TO7 tumors with low α-SMA expression. At the same time, embelin significantly decreased α-SMA and PDGFRA expression in 4T1 tumors compared with the control group. Our findings add to understanding of CAF distribution in the 4T1 tumor microenvironment and its possible role in treating cancer.

CD205+ polymorphonuclear myeloid-derived suppressor cells suppress antitumor immunity by overexpressing GLUT3.

Myeloid-derived suppressor cells (MDSCs) are responsible for antitumor immunodeficiency in tumor-bearing hosts. Primarily, MDSCs are classified into 2 groups: monocytic (M)-MDSCs and polymorphonuclear (PMN)-MDSCs. In most cancers, PMN-MDSCs (CD11b+ Ly6Clow Ly6G+ cells) represent the most abundant MDSC subpopulation. However, the functional and phenotypic heterogeneities of PMN-MDSC remain elusive, which delays clinical therapeutic targeting decisions. In the 4T1 murine tumor model, CD11b+ Ly6Glow PMN-MDSCs were sensitive to surgical and pharmacological interventions. By comprehensively analyzing 64 myeloid cell-related surface molecule expression profiles, cell density, nuclear morphology, and immunosuppressive activity, the PMN-MDSC population was further classified as CD11b+ Ly6Glow CD205+ and CD11b+ Ly6Ghigh TLR2+ subpopulations. The dichotomy of PMN-MDSCs based on CD205 and TLR2 is observed in 4T07 murine tumor models (but not in EMT6). Furthermore, CD11b+ Ly6Glow CD205+ cells massively accumulated at the spleen and liver of tumor-bearing mice, and their abundance correlated with in situ tumor burdens (with or without intervention). Moreover, we demonstrated that CD11b+ Ly6Glow CD205+ cells were sensitive to glucose deficiency and 2-deoxy-d-glucose (2DG) treatment. Glucose transporter 3 (GLUT3) knockdown by siRNA significantly triggered apoptosis and reduced glucose uptake in CD11b+ Ly6Glow CD205+ cells, demonstrating the dependence of CD205+ PMN-MDSCs survival on both glucose uptake and GLUT3 overexpression. As GLUT3 has been recognized as a target for the rescue of host antitumor immunity, our results further directed the PMN-MDSC subsets into the CD205+ GLUT3+ subpopulation as future targeting therapy.

Development of myocardial infarction and ischemic stroke after acute upper gastrointestinal bleeding.

Cardiovascular disease, mainly including coronary artery disease and stroke, is the leading cause of mortality and morbidity worldwide. The traditional risk factors of cardiovascular disease include smoking, alcohol abuse, hypertension, diabetes mellitus, hyperlipidemia, and psychosocial stress. Herein, we reported one patient who developed myocardial infarction and ischemic stroke after acute upper gastrointestinal bleeding and discussed the potential association between cardiovascular disease and acuter upper gastrointestinal bleeding.

Peptidomic analysis of pilose antler and its inhibitory effect on triple-negative breast cancer at multiple sites.

Pilose antler (PA) is a traditional Chinese functional food that has been reported to inhibit breast cancer; however, the specific substances that exert this effect and the underlying mechanisms remain unknown. This study aims to identify the specific proteins in PA water-soluble polypeptides (PAWPs) that are involved in cancer inhibition and determine the effects of PAWPs on triple-negative breast cancer in mice. In this study, peptidomic analysis of 105 varieties of polypeptides from PAWPs was carried out using LC-MS, 22 of which had functions that could potentially suppress tumors, including endopeptidase inhibitors, metal ion-binding proteins, angiogenesis inhibitors, intercellular adhesion proteins, and extracellular matrix repair proteins. Furthermore, we showed that intragastric administration of PAWPs into mice inhibited the growth and metastasis of triple-negative 4T1 breast tumors. PAWPs activated the expression of cleaved-caspase3 and increased tumor apoptosis, resulting in the reduction of platelet-endothelial cell adhesion molecule (PECAM-1/CD31) expression and the number of blood vessels, as well as the inhibition of matrix metalloproteinase (MMP) 2 and 9, increasing the ratio of Cadherin-1 (CDH1)/Cadherin-2 (CDH2) and inhibiting epithelial-mesenchymal transition (EMT) in these tumors. Therefore, PAWPs inhibit the progression and metastasis of triple-negative 4T1 breast cancer at multiple key sites in mice and contain various tumor suppressor proteins that are potentially involved in these processes.

No Association between Ischemic Stroke and Portal Vein Thrombosis in Liver Cirrhosis.

BACKGROUND AND AIMS: There seems to be a higher risk of ischemic stroke and portal vein thrombosis in liver cirrhosis. Both of them may be associated with hypercoagulability. We aim to explore the association between ischemic stroke and portal vein thrombosis in liver cirrhosis. Study Design and Methods. We selected patients from our prospectively established database of liver cirrhosis from December 2014 to July 2019. The difference between patients with and without stroke was compared. A 1 : 1 propensity score matching (PSM) analysis was performed to adjust the effect of age, sex, Child-Pugh score, and MELD score on our statistical results. RESULTS: There were 349 cirrhotic patients in the cross-sectional study. The prevalence of stroke, ischemic stroke, hemorrhagic stroke, and portal vein thrombosis was 8.88% (31/349), 8.31% (29/349), 1.15% (4/349), and 28.65% (100/349) in liver cirrhosis, respectively. Patients with ischemic stroke were significantly older and had significantly higher proportions of alcohol abuse, smoking, and arterial hypertension and higher levels of white blood cell and low-density lipoprotein. However, statistical analyses with and without PSM did not find any significant association between ischemic stroke and portal vein thrombosis in patients with liver cirrhosis. CONCLUSION: Ischemic stroke might not be associated with portal vein thrombosis in liver cirrhosis.