Metabolic comorbidities modulate kidney cholesterol crystal embolism

Die Cholesterinkristallembolie (CCE) ist eine häufige Komplikation der fortgeschrittenen Atherosklerose bei Patienten mit multiplen Begleiterkrankungen. Die CCE kann unter Umständen zu einer thrombotischen (Mikro-)Angiopathie führen und letztlich einen akuten Nierenschaden (AKI) mit ischämischer Nekrose verursachen. Das Ziel dieser Arbeit war es, die Pathomechanismen des CCE-induzierten AKI genauer zu untersuchen und inwiefern metabolische Begleiterkrankungen, wie Diabetes (Hyperglykämie) oder Hyperurikämie, den Nierenschaden, die Entzündung, Infiltration von Immunzellen, sowie den Verschluss von Arterien und Infarkt beeinflussen. Um dies zu untersuchen, haben wir ein Tiermodell zur CCE etabliert. Hierbei wurden Cholesterinkristalle (CC) in die Nierenarterie von Mäusen injiziert und die CC-induzierte Niereninfarktgröße, Nierenfunktion, entzündliche Biomarker und Leukozyteninfiltration zu verschiedenen Zeitpunkten analysiert und quantifiziert. Diese Parameter wurden mit denen von Mäusen mit und ohne Hyperglykämie (Serumglukosespiegel ≈500 mg/dl) oder Hyperurikämie (Serumharnsäurespiegel ≈9 mg/dl) verglichen. Tubuläre Epithelzellen, Endothelzellen und gewaschene Thrombozyten wurden für mechanistische in vitro Studien unter erhöhten Glukose- oder Harnsäurebedingungen stimuliert. Unsere Daten zeigten, dass die Hyperglykämie die Nierenfunktion nach CC Injektion sehr stark bei den Mäusen beeinträchtigt und vermehrt Niereninfarkte und -verschlüsse sowie Entzündung auftreten, was sich letztlich in erhöhten Entzündungsbiomarkern, vermehrte Leukozyteninfiltration, und beschleunigten Zelltod von Tubulusepithelzellen und Endothelzellen widerspiegelte. In in vitro Studien konnten wir zeigen, dass eine hohe Glukosekonzentration die Thrombozytenaggregation und -aktivierung im Vergleich zu normalen Bedingungen signifikant erhöht. Im Gegensatz dazu stehen die gefäßverengenden und antioxidativen Effekte der Hyperurikämie, welche zur Verbesserung der Nierenfunktion beitragen und die Niere vor ischämischen Infarkt und Gewebeschaden im Vergleich zu Tieren ohne Hyperurikämie nach CC-induzierten AKI schützt. Dies deutet auf einen kompensatorischen und autoregulatorischen physiologischen Mechanismus der Hyperurikämie zum Schutz der Niere hin. Zusammenfassend lässt sich sagen, dass sowohl eine Hyperglykämie als auch eine Hyperurikämie einen AKI verschlimmern können, obwohl sie entgegengesetzte Auswirkungen auf den Niereninfarkt haben. Während die Hyperglykämie die Outcomes insbesondere bei Gewebsinfarkten in Mäusen nach CCE verschlechtert, vermindert die Hyperurikämie die Infarktgröße möglicherweise durch eine antioxidative Wirkung der löslichen Harnsäure und zeigt vasoaktive Effekte auf die Nierenfunktion in der kontralateralen Niere. Daher spiegelt der Grad der akuten Nierenfunktionsstörung möglicherweise nicht vollständig den Grad der Nierenschädigung bei der Hyperurikämie wieder. Insgesamt tragen die weit verbreiteten Komorbiditäten unabhängig voneinander zum Schweregrad der AKI und zum Ausmaß des Niereninfarkts bei CCE bei

How does the COVID-19 pandemic reshape the lending behavior of financial institutions?

In this study, I explore the impact of COVID-19 on the lending behavior of traditional and FinTech banks. I use difference-in-difference and triple-diff-in-diff approach with 2019-2020 HMDA loan application data and the Covid Community Vulnerability Index (CVI) to study 1) borrower profiles and loan application demand, 2) lender scrutiny stringency i.e. application approval rates, 3) loan interest rates, and 4) securitization of loans in counties with different level of epidemic vulnerability before and after the epidemic. I find that borrowers in regions with high vulnerability are able to embrace FinTech more quickly. At the same time, FinTech has expanded its previous target demographic to older, non-white, and ethnic minority borrowers. However, the supply side has not softened its application review criteria in response to the surge in demand. Lenders have been more cautious, and while minorities are more willing to apply for FinTech loans, it is worth noting that traditional banks have taken on a social responsibility at this time to increase their lending approval rates for such community. FinTech banks, on the other hand, have expanded the sale of loans, shifting the uncertainty risk to the broad investors

Extracellular DNA-A Danger Signal Triggering Immunothrombosis

Clotting and inflammation are effective danger response patterns positively selected by evolution to limit fatal bleeding and pathogen invasion upon traumatic injuries. As a trade-off, thrombotic, and thromboembolic events complicate severe forms of infectious and non-infectious states of acute and chronic inflammation, i.e., immunothrombosis. Factors linked to thrombosis and inflammation include mediators released by platelet granules, complement, and lipid mediators and certain integrins. Extracellular deoxyribonucleic acid (DNA) was a previously unrecognized cellular component in the blood, which elicits profound proinflammatory and prothrombotic effects. Pathogens trigger the release of extracellular DNA together with other pathogen-associated molecular patterns. Dying cells in the inflamed or infected tissue release extracellular DNA together with other danger associated molecular pattern (DAMPs). Neutrophils release DNA by forming neutrophil extracellular traps (NETs) during infection, trauma or other forms of vascular injury. Fluorescence tissue imaging localized extracellular DNA to sites of injury and to intravascular thrombi. Functional studies using deoxyribonuclease (DNase)-deficient mouse strains or recombinant DNase show that extracellular DNA contributes to the process of immunothrombosis. Here, we review rodent models of immunothrombosis and the evolving evidence for extracellular DNA as a driver of immunothrombosis and discuss challenges and prospects for extracellular DNA as a potential therapeutic target

Stomatal Conductance and Morphology of Arbuscular Mycorrhizal Wheat Plants Response to Elevated CO2 and NaCl Stress

Stomata play a critical role in the regulation of gas exchange between the interior of the leaf and the exterior environment and are affected by environmental and endogenous stimuli. This study aimed to evaluate the effect of the arbuscular mycorrhizal (AM) fungus, Rhizophagus irregularis, on the stomatal behavior of wheat (Triticum aestivum L.) plants under combination with elevated CO2 and NaCl stress. Wheat seedlings were exposed to ambient (400 ppm) or elevated (700 ppm) CO2 concentrations and 0, 1, and 2 g kg−1 dry soil NaCl treatments for 10 weeks. AM symbiosis increased the leaf area and stomatal density (SD) of the abaxial surface. Stomatal size and the aperture of adaxial and abaxial leaf surfaces were higher in the AM than non-AM plants under elevated CO2 and salinity stress. AM plants showed higher stomatal conductance (gs) and maximum rate of gs to water vapor (gsmax) compared with non-AM plants. Moreover, leaf water potential (Ψ) was increased and carbon isotope discrimination (Δ13C) was decreased by AM colonization, and both were significantly associated with stomatal conductance. The results suggest that AM symbiosis alters stomatal morphology by changing SD and the size of the guard cells and stomatal pores, thereby improving the stomatal conductance and water relations of wheat leaves under combined elevated CO2 and salinity stress

Recruitment and metabolomics between Canna indica and rhizosphere bacteria under Cr stress

It is of positive significance to explore the mechanism of antioxidant and metabolic response of Canna indica under Cr stress mediated by rhizosphere niche. However, the mechanisms of recruitment and interaction of rhizosphere microorganisms in plants still need to be fully understood. This study combined physiology, microbiology, and metabolomics, revealing the interaction between C. indica and rhizosphere microorganisms under Cr stress. The results showed that Cr stress increased the content of malondialdehyde (MDA) and oxygen-free radicals (ROS) in plants. At the same time, the activities of antioxidant enzymes (SOD, POD, and APX) and the contents of glutathione (GSH) and soluble sugar were increased. In addition, Cr stress decreased the α diversity index of C. indica rhizosphere bacterial community and changed its community structure. The dominant bacteria, namely, Actinobacteriota, Proteobacteria, and Chloroflexi accounted for 75.16% of the total sequence. At the same time, with the extension of stress time, the colonization amount of rhizosphere-dominant bacteria increased significantly, and the metabolites secreted by roots were associated with the formation characteristics of Proteobacteria, Actinobacteria, Bacteroidetes, and other specific bacteria. Five critical metabolic pathways were identified by metabolome analysis, involving 79 differentially expressed metabolites, which were divided into 15 categories, mainly including lipids, terpenoids, and flavonoids. In conclusion, this study revealed the recruitment and interaction response mechanism between C. indica and rhizosphere bacteria under Cr stress through multi-omics methods, providing the theoretical basis for the remediation of Cr-contaminated soil

Photo-functionalized TiO2 nanotubes decorated with multifunctional Ag nanoparticles for enhanced vascular biocompatibility

Titanium dioxide (TiO2) has a long history of application in blood contact materials, but it often suffers from insufficient anticoagulant properties. Recently, we have revealed the photocatalytic effect of TiO2 also induces anticoagulant properties. However, for long-term vascular implant devices such as vascular stents, besides anticoagulation, also anti-inflammatory, anti-hyperplastic properties, and the ability to support endothelial repair, are desired. To meet these requirements, here, we immobilized silver nanoparticles (AgNPs) on the surface of TiO2 nanotubes (TiO2-NTs) to obtain a composite material with enhanced photo-induced anticoagulant property and improvement of the other requested properties. The photo-functionalized TiO2-NTs showed protein-fouling resistance, causing the anticoagulant property and the ability to suppress cell adhesion. The immobilized AgNPs increased the photocatalytic activity of TiO2-NTs to enhances its photo-induced anticoagulant property. The AgNP density was optimized to endow the TiO2-NTs with anti-inflammatory property, a strong inhibitory effect on smooth muscle cells (SMCs), and low toxicity to endothelial cells (ECs). The in vivo test indicated that the photofunctionalized composite material achieved outstanding biocompatibility in vasculature via the synergy of photo-functionalized TiO2-NTs and the multifunctional AgNPs, and therefore has enormous potential in the field of cardiovascular implant devices. Our research could be a useful reference for further designing of multifunctional TiO2 materials with high vascular biocompatibility

Natural compounds protect against the pathogenesis of osteoarthritis by mediating the NRF2/ARE signaling

Osteoarthritis (OA), a chronic joint cartilage disease, is characterized by the imbalanced homeostasis between anabolism and catabolism. Oxidative stress contributes to inflammatory responses, extracellular matrix (ECM) degradation, and chondrocyte apoptosis and promotes the pathogenesis of OA. Nuclear factor erythroid 2-related factor 2 (NRF2) is a central regulator of intracellular redox homeostasis. Activation of the NRF2/ARE signaling may effectively suppress oxidative stress, attenuate ECM degradation, and inhibit chondrocyte apoptosis. Increasing evidence suggests that the NRF2/ARE signaling has become a potential target for the therapeutic management of OA. Natural compounds, such as polyphenols and terpenoids, have been explored to protect against OA cartilage degeneration by activating the NRF2/ARE pathway. Specifically, flavonoids may function as NRF2 activators and exhibit chondroprotective activity. In conclusion, natural compounds provide rich resources to explore the therapeutic management of OA by activating NRF2/ARE signaling

The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer

Matrix metalloproteinases (MMPs) are an important class of enzymes in the body that function through the extracellular matrix (ECM). They are involved in diverse pathophysiological processes, such as tumor invasion and metastasis, cardiovascular diseases, arthritis, periodontal disease, osteogenesis imperfecta, and diseases of the central nervous system. MMPs participate in the occurrence and development of numerous cancers and are closely related to immunity. In the present study, we review the immunomodulatory role of MMPs in colitis-associated cancer (CAC) and discuss relevant clinical applications. We analyze more than 300 pharmacological studies retrieved from PubMed and the Web of Science, related to MMPs, cancer, colitis, CAC, and immunomodulation. Key MMPs that interfere with pathological processes in CAC such as MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13, as well as their corresponding mechanisms are elaborated. MMPs are involved in cell proliferation, cell differentiation, angiogenesis, ECM remodeling, and the inflammatory response in CAC. They also affect the immune system by modulating differentiation and immune activity of immune cells, recruitment of macrophages, and recruitment of neutrophils. Herein we describe the immunomodulatory role of MMPs in CAC to facilitate treatment of this special type of colon cancer, which is preceded by detectable inflammatory bowel disease in clinical populations

Fe-assisted epitaxial growth of 4-inch single-crystal transition-metal dichalcogenides on c-plane sapphire without miscut angle

Epitaxial growth and controllable doping of wafer-scale single-crystal transition-metal dichalcogenides (TMDCs) are two central tasks for extending Moore's law beyond silicon. However, despite considerable efforts, addressing such crucial issues simultaneously under two-dimensional (2D) confinement is yet to be realized. Here we design an ingenious epitaxial strategy to synthesize record-breaking 4-inch single-crystal Fe-doped TMDCs monolayers on industry-compatible c-plane sapphire without miscut angle. In-depth characterizations and theoretical calculations reveal that the introduction of Fe significantly decreases the formation energy of parallel steps on sapphire surfaces and contributes to the edge-nucleation of unidirectional TMDCs domains (>99%). The ultrahigh electron mobility (~86 cm2 V -1 s-1) and remarkable on/off current ratio (~108) are discovered on 4-inch single-crystal Fe-MoS2 monolayers due to the ultralow contact resistance and perfect Ohmic contact with metal electrodes. This work represents a substantial leap in terms of bridging the synthesis and doping of wafer-scale single-crystal 2D semiconductors without the need for substrate miscut, which should promote the further device downscaling and extension of Moore's law.Comment: 17 pages, 5 figure