Causal effects from inflammatory bowel disease on liver function and disease: a two-sample Mendelian randomization study

BackgroundAccumulating evidence has shown that patients with inflammatory bowel disease (IBD) have liver function abnormalities and are susceptible to liver diseases. However, the existence of a causal relationship between IBD and liver function or disease remains unclear.MethodsA two-sample Mendelian randomization (MR) analysis was performed using genetic associations from publicly available genome-wide association studies (GWAS). These associations encompass ulcerative colitis (UC), Crohn’s disease (CD), liver function traits, and liver disease phenotypes. The liver function traits comprised hepatic biochemistries, percent liver fat, and liver iron content from the UK Biobank. Furthermore, the liver disease phenotypes included cholelithiasis, non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC) in cohorts of European ancestry. The primary estimation used the inverse-variance weighted method, with GWAS of C-reactive protein (CRP) in the UK Biobank serving as a positive control outcome.ResultsGenetically predicted UC is causally associated with decreased levels of albumin (ALB) and liver iron content, while genetically predicted CD is causally associated with increased levels of alkaline phosphatase (ALP). Moreover, genetically predicted UC or CD increases the risk of PSC, and CD increases the risk of PBC. Neither UC nor CD causally increases the risk of cholelithiasis and NAFLD.ConclusionUC affects the levels of ALB and liver iron content, while CD affects the levels of ALP. Both UC and CD increase the risk of PSC, and CD increases the risk of PBC

Bioinspired One Cell Culture Isolates Highly Tumorigenic and Metastatic Cancer Stem Cells Capable of Multilineage Differentiation

Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Cancer stem cells (CSCs) are rare cancer cells that are postulated to be responsible for cancer relapse and metastasis. However, CSCs are difficult to isolate and poorly understood. Here, a bioinspired approach for label-free isolation and culture of CSCs, by microencapsulating one cancer cell in the nanoliter-scale hydrogel core of each prehatching embryo-like core–shell microcapsule, is reported. Only a small percentage of the individually microencapsulated cancer cells can proliferate into a cell colony. Gene and protein expression analyses indicate high stemness of the cells in the colonies. Importantly, the colony cells are capable of cross-tissue multilineage (e.g., endothelial, cardiac, neural, and osteogenic) differentiation, which is not observed for “CSCs” isolated using other contemporary approaches. Further studies demonstrate the colony cells are highly tumorigenic, metastatic, and drug resistant. These data show the colony cells obtained with the bioinspired one-cell-culture approach are truly CSCs. Significantly, multiple pathways are identified to upregulate in the CSCs and enrichment of genes related to the pathways is correlated with significantly decreased survival of breast cancer patients. Collectively, this study may provide a valuable method for isolating and culturing CSCs, to facilitate the understanding of cancer biology and etiology and the development of effective CSC-targeted cancer therapies.https://doi.org/10.1002/advs.20200025

The role and mechanisms of ambient fine particulate matter exposure in cardiac dysfunction in mice

[EMBARGOED UNTIL 8/1/2023] Ambient fine particulate matter (PM) exposure associates with an increased risk of cardiovascular diseases (CVDs). Oxidative stress and inflammation are considered important mechanisms for the development and progression of CVDs. Cytokines including tumor necrosis factor- [alpha] (TNF-[alpha]) play an important role in reactive oxygen species (ROS) production, oxidative stress, and inflammation. Caspase recruitment domain-containing protein 9 (CARD9) signaling is critically involved in the regulation of cytokines production, and thus oxidative stress. Major sex differences exist in epidemiology, pathophysiology, and outcome of CVDs with females being protected against premature CVDs with largely undefined mechanisms. The present project was designed to test the hypothesis that PM exposure impairs cardiac function in male mice due to increased ROS production through CARD9-mediated TNF-[alpha] production. The aims were: 1) to determine if PM exposure leads to cardiac dysfunction in mice; 2) to define the role of oxidative stress in PM exposure-induced cardiac dysfunction in mice; 3) to examine if PM exposure-induced cardiac dysfunction is through TNF-[alpha]-mediated oxidative stress in mice; 4) to determine if CARD9-mediated TNF-[alpha] production is critical for PM exposure-induced ROS production and cardiac dysfunction in mice; and 5) to demonstrate if a significant sex difference in PM exposure-induced cardiac dysfunction is present, and the role of oxidative stress. Age-matched (8-12 weeks) male and female wild-type (WT) C57BL/6 mice, TNF-[alpha] knockout (KO) mice, CARD9 KO mice, and transgenic (TG) mice with concomitant overexpression of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase-1 (GPX-1) were exposed to PM for 6 weeks. Echocardiography and cardiac MRI were used to detect cardiac structure and function. DHE staining, Masson's trichrome staining, and Western blotting were used to determine ROS production, collagen level, and expression of antioxidant enzymes in cardiac tissues, respectively. ELISA was used to measure the levels of plasma cytokines, including interleukin (IL)-6, IL-[alpha], and TNF-[alpha]. Experiments were repeated in WT male mice when ROS or TNF-[alpha] signaling was blocked using antioxidants N-acetylcysteine (NAC), Tempol, or anti- TNF-[alpha] antibody to determine the role of ROS and TNF-[alpha] in PM-induced cardiac dysfunction. To define the role of estrogen in PM-induced cardiac dysfunction, experiments were conducted with female mice with and without ovariectomy. The data from the present study demonstrated that PM exposure significantly decreased both systolic and diastolic cardiac function with increased cardiac fibrosis and increased ROS production in cardiac tissues selectively in male mice, not in females, in association with decreased expressions of SOD1 and GPX-1. Treatment of WT male mice with NAC or Tempol or concomitant overexpression of SOD1 and GPX-1 effectively prevented PM exposure-induced ROS production, cardiac fibrosis, and cardiac dysfunction. Plasma TNF-[alpha] level was significantly increased in male mice, not in females, with PM exposure. Treatment of WT male mice with TNF-[alpha] produced similar level of cardiac ROS production and decreased expressions of SOD1 and GPX-1 as male mice with PM exposure. TNF-[alpha] deficiency using TNF-[alpha] KO mice or treatment with anti-TNF-[alpha] antibody also effectively attenuated PM exposure-induced ROS production, cardiac fibrosis, and cardiac dysfunction in male mice. PM exposure significantly increased the protein expression of CARD9 in macrophages in male mice with increased levels of plasma TNF-[alpha] and cardiac ROS. CARD9 deficiency completely prevented PM exposure-induced increases in plasma TNF-[alpha] and cardiac ROS, as well as cardiac fibrosis, and preserved cardiac function in male mice. No changes in cardiac ROS production and cardiac function were observed in female mice with or without ovariectomy after PM exposure. It is concluded that PM exposure induces cardiac fibrosis and cardiac dysfunction selectively in male mice due to increased ROS formation through CARD9-mediated TNF-[alpha] production. Cardiac structure and function were preserved in female mice with PM exposure independent of estrogen.Includes bibliographical references

Tempol Preserves Endothelial Progenitor Cells in Male Mice with Ambient Fine Particulate Matter Exposure

Ambient fine particulate matter (PM) exposure associates with an increased risk of cardiovascular diseases (CVDs). Major sex differences between males and females exist in epidemiology, pathophysiology, and outcome of CVDs. Endothelial progenitor cells (EPCs) play a vital role in the development and progression of CVDs. PM exposure-induced reduction of EPCs is observed in male, not female, mice with increased reactive oxygen species (ROS) production and oxidative stress. The lung is considered an important source of ROS in mice with PM exposure. The aim of the present study was to investigate the sex differences in pulmonary superoxide dismutase (SOD) expression and ROS production, and to test the effect of SOD mimic Tempol on the populations of EPCs in mice with PM exposure. Both male and female C57BL/6 mice (8–10 weeks) were exposed to intranasal PM or vehicle for 6 weeks. Flow cytometry analysis demonstrated that PM exposure significantly decreased the levels of EPCs (CD34+/CD133+) in both blood and bone marrow with increased ROS production in males, but not in females. ELISA analysis showed higher levels of serum IL-6 and IL-1βin males than in females. Pulmonary expression of the antioxidant enzyme SOD1 was significantly decreased in males after PM exposure, but not in females. Administration of the SOD mimic Tempol in male mice with PM exposure attenuated the production of ROS and inflammatory cytokines, and preserved EPC levels. These data indicated that PM exposure-induced reduction of EPC population in male mice may be due to decreased expression of pulmonary SOD1 in male mice

An Integrative Human Pan-Cancer Analysis of Cyclin-Dependent Kinase 1 (CDK1)

Cyclin-dependent kinase 1 (CDK1) is essential for cell division by regulating the G2/M phase and mitosis. CDK1 overexpression can also promote the development and progression of a variety of cancers. However, the significance of CDK1 in the formation, progression, and prognosis of human pan-cancer remains unclear. In the present study, we used The Cancer Genome Atlas database, Clinical Proteomic Tumor Analysis Consortium, Human Protein Atlas, Genotype-Tissue Expression, and other well-established databases to comprehensively examine CDK1 genetic alterations and gene/protein expression in various cancers and their relationships with the prognosis, immune reactivities, and clinical outcomes for 33 tumor types. Gene set enrichment analysis was also conducted to examine the potential mechanisms of CDK1 in tumorigenesis. The data showed that CDK1 mutation was frequently present in multiple tumors. CDK1 expression was significantly increased in various types of tumors as compared with normal tissues and was associated with poor overall and disease-free survival. In addition, CDK1 expression was significantly correlated with oncogenic genes, proteins, cellular components, myeloid-derived suppressor cell infiltration, ESTMATEScore, and signaling pathways associated with tumor development and progression and tumor microenvironments. These data indicate that CDK1 could serve as a promising biomarker for predicting tumor prognosis and a potential target for cancer treatment

An Integrative Pan-Cancer Analysis of Kinesin Family Member C1 (KIFC1) in Human Tumors

Kinesin family member C1 (KIFC1) is a minus-end-directed motor protein that is critically involved in microtubule crosslinking and spindle formation. KIFC1 is essential for supernumerary centrosomes, and it is associated with the initiation and progression of cancers. In the present study, we initially reviewed the The Cancer Genome Atlas database and observed that KIFC1 is abundantly expressed in most types of tumors. We then analyzed the gene alteration profiles, protein expressions, prognoses, and immune reactivities of KIFC1 in more than 10,000 samples from several well-established databases. In addition, we conducted a gene set enrichment analysis to investigate the potential mechanisms for the roles of KIFC1 in carcinogenesis. The pan-cancer analysis of KIFC1 demonstrates significant statistical correlations of the KIFC1 expression with the clinical prognoses, the oncogenic signature gene sets, the myeloid-derived suppressor cell infiltration, the ImmunoScore, the immune checkpoints, the microsatellite instabilities, and the tumor mutational burdens across multiple tumors. These data may provide important information on the understanding of the role and mechanisms of KIFC1 in carcinogenesis and immunotherapy, as well as on the clinical progression of a variety of cancers

Tempol Preserves Endothelial Progenitor Cells in Male Mice with Ambient Fine Particulate Matter Exposure

Ambient fine particulate matter (PM) exposure associates with an increased risk of cardiovascular diseases (CVDs). Major sex differences between males and females exist in epidemiology, pathophysiology, and outcome of CVDs. Endothelial progenitor cells (EPCs) play a vital role in the development and progression of CVDs. PM exposure-induced reduction of EPCs is observed in male, not female, mice with increased reactive oxygen species (ROS) production and oxidative stress. The lung is considered an important source of ROS in mice with PM exposure. The aim of the present study was to investigate the sex differences in pulmonary superoxide dismutase (SOD) expression and ROS production, and to test the effect of SOD mimic Tempol on the populations of EPCs in mice with PM exposure. Both male and female C57BL/6 mice (8–10 weeks) were exposed to intranasal PM or vehicle for 6 weeks. Flow cytometry analysis demonstrated that PM exposure significantly decreased the levels of EPCs (CD34+/CD133+) in both blood and bone marrow with increased ROS production in males, but not in females. ELISA analysis showed higher levels of serum IL-6 and IL-1βin males than in females. Pulmonary expression of the antioxidant enzyme SOD1 was significantly decreased in males after PM exposure, but not in females. Administration of the SOD mimic Tempol in male mice with PM exposure attenuated the production of ROS and inflammatory cytokines, and preserved EPC levels. These data indicated that PM exposure-induced reduction of EPC population in male mice may be due to decreased expression of pulmonary SOD1 in male mice

Recovery of Ischemic Limb and Femoral Artery Endothelial Function Are Preserved in Mice with Dextran Sodium Sulfate-Induced Chronic Colitis

Inflammatory bowel disease (IBD) produces significant systemic inflammation and increases the risk of endothelial dysfunction and peripheral artery disease. Our recent study demonstrated that abdominal aortic endothelial cell function was impaired selectively in female mice with chronic colitis. This study aimed to test the hypothesis that experimental colitis leads to femoral artery endothelial cell dysfunction and impairs limb ischemia recovery in female mice. An experimental chronic colitis model was created in female C57BL/6 mice with dextran sodium sulfate (DSS) treatment. Unilateral hind limb ischemia was produced by femoral artery ligation. Limb blood perfusion, vascular density, tissue ROS levels, and plasma levels of proinflammatory cytokines were assessed. Femoral artery endothelium-dependent and -independent vasodilation of the contralateral limb were evaluated ex vivo using acetylcholine and nitroglycerin, respectively. As expected, the plasma levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-17, were significantly increased in the DSS-induced colitis model. However, ROS levels in the ischemic muscle tissues were not significantly increased in colitis model as compared to the controls. There were no significant changes in endothelium-dependent or -independent vasodilation of the femoral artery between colitis model and the control. Recovery of function and blood flow in the ischemic limb and capillary density in the ischemic gastrocnemius muscle were preserved in the colitis model as compared with the control. The data demonstrated that DSS-induced chronic colitis had no significant impact on femoral artery endothelial function or ischemic limb recovery in female mice

Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance

Multidrug resistance is a major challenge in cancer therapy. Here, the authors develop a mitochondria-targeting nanoparticle system that inhibits adenosine triphosphate transporter activity via reactive oxygen species generation and can thus be used to target multidrug-resistant cancer