-
Scientific Reports Jun 2024Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects...
Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8-10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [C]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.
Topics: Animals; Acute Kidney Injury; Liver; Glutathione; Energy Metabolism; Kidney; Male; Mice; Mice, Inbred C57BL; Ischemia; Metabolomics; Disease Models, Animal; Oxidative Stress; Glycolysis; Metabolome
PubMed: 38879688
DOI: 10.1038/s41598-024-64586-4 -
Trials Jun 2024A significant proportion of the global population has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at some point since the onset of...
BACKGROUND
A significant proportion of the global population has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at some point since the onset of the pandemic. Although most individuals who develop coronavirus disease 2019 (COVID-19) recover without complications, about 6% have persistent symptoms, referred to as post-COVID-19 condition (PCC). Intervention studies investigating treatments that potentially alleviate PCC-related symptoms and thus aim to mitigate the global public health burden and healthcare costs linked to PCC are desperately needed. The PYCNOVID trial investigates the effects of Pycnogenol®, a French maritime pine bark extract with anti-inflammatory and antioxidative properties, versus placebo on patient-reported health status in people with PCC.
METHODS
This is a single-center, placebo-controlled, quadruple blind, randomized trial. We aim to randomly assign 150 individuals with PCC (1:1 ratio) to receive either 200 mg Pycnogenol® or placebo daily for 12 weeks. Randomization is stratified for duration of PCC symptoms (≤ 6 months versus > 6 months) and presence of symptomatic chronic disease(s). The primary endpoint is perceived health status at 12 weeks (EuroQol-Visual Analogue Scale) adjusted for baseline values and stratification factors. Secondary endpoints include change in self-reported PCC symptoms, health-related quality of life, symptoms of depression and anxiety, cognitive function, functional exercise capacity, physical activity measured with accelerometry, and blood biomarkers for endothelial health, inflammation, coagulation, platelet function, and oxidative stress. Investigators, study participants, outcome assessors, and data analysts are blinded regarding the intervention assignment. Individuals with PCC were involved in the design of this study.
DISCUSSION
This is the first trial to investigate the effects of Pycnogenol® versus placebo on patient-reported health status in people with PCC. Should the trial proof clinical effectiveness, Pycnogenol® may serve as a therapeutic approach to mitigate symptoms associated with PCC.
TRIAL REGISTRATION
The study is registered at ClinicalTrials.gov. :NCT05890534, June 6, 2023.
Topics: Humans; Plant Extracts; Flavonoids; Randomized Controlled Trials as Topic; Quality of Life; COVID-19; Treatment Outcome; SARS-CoV-2; Health Status; COVID-19 Drug Treatment; Post-Acute COVID-19 Syndrome; Adult; Female; Male; Antioxidants; Anti-Inflammatory Agents
PubMed: 38879571
DOI: 10.1186/s13063-024-08187-6 -
Scientific Reports Jun 2024Hydroxyurea (HU; hydroxycarbamide) is a chemotherapy medication used to treat various types of cancer and other diseases such as sickle cell anemia. HU inhibits DNA...
Hydroxyurea (HU; hydroxycarbamide) is a chemotherapy medication used to treat various types of cancer and other diseases such as sickle cell anemia. HU inhibits DNA synthesis by targeting ribonucleotide reductase (RNR). Recent studies have suggested that HU also causes oxidative stress in living systems. In the present study, we investigated if HU could directly affect the activity and/or conformation of DNA. We measured in vitro gene expression in the presence of HU by adapting a cell-free luciferase assay. HU exhibited a bimodal effect on gene expression, where promotion or inhibition were observed at lower or higher concentrations (mM range), respectively. Using atomic force microscopy (AFM), the higher-order structure of DNA was revealed to be partially-thick with kinked-branching structures after HU was added. An elongated coil conformation was observed by AFM in the absence of HU. Single DNA molecules in bulk aqueous solution under fluctuating Brownian motion were imaged by fluorescence microscopy (FM). Both spring and damping constants, mechanical properties of DNA, increased when HU was added. These experimental investigations indicate that HU directly interacts with DNA and provide new insights into how HU acts as a chemotherapeutic agent and targets other diseases.
Topics: Hydroxyurea; DNA; Microscopy, Atomic Force; Nucleic Acid Conformation; Humans; Gene Expression
PubMed: 38879539
DOI: 10.1038/s41598-024-64538-y -
Journal of Advanced Research Jun 2024Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the...
INTRODUCTION
Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined.
OBJECTIVES
We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet.
METHODS
Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue.
RESULTS
Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-κB) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation.
CONCLUSION
Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity.
PubMed: 38879122
DOI: 10.1016/j.jare.2024.06.005 -
Nitric Oxide : Biology and Chemistry Jun 2024Obesity is commonly linked with adipose tissue (AT) dysfunction, setting off inflammation and oxidative stress, both key contributors to the cardiometabolic...
Obesity is commonly linked with adipose tissue (AT) dysfunction, setting off inflammation and oxidative stress, both key contributors to the cardiometabolic complications associated with obesity. To improve metabolic and cardiovascular health, countering these inflammatory and oxidative signaling processes is crucial. Offering potential in this context, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by nitro-fatty acids (NO-FA) promote diverse anti-inflammatory signaling and counteract oxidative stress. Additionally, we previously highlighted that nitro-oleic acid (NO-OA) preferentially accumulates in white adipose tissue (AT) and provides protection against already established high fat diet (HFD)-mediated impaired glucose tolerance. The precise mechanism accounting for these protective effects remained largely unexplored until now. Herein, we reveal that protective effects of improved glucose tolerance by NO-OA is absent when Nrf2 is specifically ablated in adipocytes (ANKO mice). NO-OA treatment did not alter body weight between ANKO and littermate controls (Nrf2) mice on both the HFD and low-fat diet (LFD). As expected, at day 76 (before NO-OA treatment) and notably at day 125 (daily treatment of 15 mg/kg NO-OA for 48 days), both HFD-fed Nrf2 and ANKO mice exhibited increased fat mass and reduced lean mass compared to LFD controls. However, throughout the NO-OA treatment, no distinction was observed between Nrf2 and ANKO in the HFD-fed mice as well as in the Nrf2 mice fed a LFD. Glucose tolerance tests revealed impaired glucose tolerance in HFD-fed Nrf2 and ANKO compared to LFD-fed Nrf2 mice. Notably, NO-OA treatment improved glucose tolerance in HFD-fed Nrf2 but did not yield the same improvement in ANKO mice at days 15, 30, and 55 of treatment. Unraveling the pathways linked to NO-OA's protective effects in obesity-mediated impairment in glucose tolerance is pivotal within the realm of precision medicine, crucially propelling future applications and refining novel drug-based strategies.
PubMed: 38879114
DOI: 10.1016/j.niox.2024.06.002 -
Progress in Neuro-psychopharmacology &... Jun 2024The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic... (Review)
Review
BACKGROUND
The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic symptomatology of bipolar disorder (BD). Among a broad range of mechanisms implicated, immune dysregulation may contribute to the increased inflammation that influences the course of BD. Inflammatory, neurotrophic and oxidative stress factors may be identified as promising peripheral biomarkers in brain functioning, perhaps serving as predictors of an effective response to treatment for BD. The present systematic review aimed to examine the evidence supporting the pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in BD.
METHODS
PubMed, PsychINFO, Scopus and Web of Science were searched from inception to May 2024 by two independent reviewers. A total of 40 studies with 3371 patients with diagnosis and intervention of BD were selected.
RESULTS
Inconsistencies in the effects of pharmacological treatments on the connection between the expected anti-inflammatory response and symptomatologic improvement were identified. Mood stabilizers (lithium), antipsychotics (quetiapine), antidepressants (ketamine) or their combination were described to increase both pro-inflammatory (TNFα, IL-6) and anti-inflammatory (IL-4, IL-8) factors. Other medications, such as memantine and dextromethorphan, autoimmune (infliximab) non-steroidal anti-inflammatory (aspirin, celecoxib) drugs, antidiabetics (pioglitazone), and even dietary supplementation (omega-3), or their combination, clearly decrease inflammatory factors (TNFα, IL-6, IL-1β, C-reactive protein) and/or increase the neurotrophic factor BDNF in BD patients.
CONCLUSION
Inflammation in BD requires further investigation to understand the underlying immunologic mechanism, to identify predictors of treatment response, and to make informed decisions about the use and development of more effective pharmacological interventions for BD.
PubMed: 38879067
DOI: 10.1016/j.pnpbp.2024.111056 -
Cellular Signalling Jun 2024The term ferroptosis, coined in 2012, has been widely applied in various disease research fields. Ferroptosis is a newly regulated form of cell death distinct from... (Review)
Review
The term ferroptosis, coined in 2012, has been widely applied in various disease research fields. Ferroptosis is a newly regulated form of cell death distinct from apoptosis, necrosis, and autophagy, the mechanisms of which have been extensively studied. Chronic kidney disease, characterized by renal dysfunction, is a common disease severely affecting human health, with its occurrence and development influenced by multiple factors and leading to dysfunction in multiple systems. It often lacks obvious clinical symptoms in the early stages, and thus, diagnosis is typically made in the later stages, complicating treatment. While research on ferroptosis and acute kidney injury has made continuous progress, studies on the association between ferroptosis and chronic kidney disease remain limited. This review aims to summarize chronic kidney disease, investigate the mechanism and regulation of ferroptosis, and attempt to elucidate the role of ferroptosis in the occurrence and development of chronic kidney disease.
PubMed: 38878804
DOI: 10.1016/j.cellsig.2024.111256 -
Biomedicine & Pharmacotherapy =... Jun 2024Myocardial reperfusion injury occurs when blood flow is restored after ischemia, an essential process to salvage ischemic tissue. However, this phenomenon is intricate,... (Review)
Review
Myocardial reperfusion injury occurs when blood flow is restored after ischemia, an essential process to salvage ischemic tissue. However, this phenomenon is intricate, characterized by various harmful effects. Tissue damage in ischemia-reperfusion injury arises from various factors, including the production of reactive oxygen species, the sequestration of proinflammatory immune cells in ischemic tissues, the induction of endoplasmic reticulum stress, and the occurrence of postischemic capillary no-reflow. Secretory phospholipase A2 (sPLA2) plays a crucial role in the eicosanoid pathway by releasing free arachidonic acid from membrane phospholipids' sn-2 position. This liberated arachidonic acid serves as a substrate for various eicosanoid biosynthetic enzymes, including cyclooxygenases, lipoxygenases, and cytochromes P450, ultimately resulting in inflammation and an elevated risk of reperfusion injury. Therefore, the activation of sPLA2 directly correlates with the heightened and accelerated damage observed in myocardial ischemia-reperfusion injury (MIRI). Presently, clinical trials are in progress for medications aimed at sPLA2, presenting promising avenues for intervention. Cardiolipin (CL) plays a crucial role in maintaining mitochondrial function, and its alteration is closely linked to mitochondrial dysfunction observed in MIRI. This paper provides a critical analysis of CL modifications concerning mitochondrial dysfunction in MIRI, along with its associated molecular mechanisms. Additionally, it delves into various pharmacological approaches to prevent or alleviate MIRI, whether by directly targeting mitochondrial CL or through indirect means.
PubMed: 38878685
DOI: 10.1016/j.biopha.2024.116936 -
Biomedicine & Pharmacotherapy =... Jun 2024Spinal cord injury (SCI) is a serious and disabling central nervous system injury. Its complex pathological mechanism can lead to sensory and motor dysfunction. It has... (Review)
Review
Spinal cord injury (SCI) is a serious and disabling central nervous system injury. Its complex pathological mechanism can lead to sensory and motor dysfunction. It has been reported that signaling pathway plays a key role in the pathological process and neuronal recovery mechanism of SCI. Such as PI3K/Akt, MAPK, NF-κB, and Wnt/β-catenin signaling pathways. According to reports, various stimuli and cytokines activate these signaling pathways related to SCI pathology, thereby participating in the regulation of pathological processes such as inflammation response, cell apoptosis, oxidative stress, and glial scar formation after injury. Activation or inhibition of relevant pathways can delay inflammatory response, reduce neuronal apoptosis, prevent glial scar formation, improve the microenvironment after SCI, and promote neural function recovery. Based on the role of signaling pathways in SCI, they may be potential targets for the treatment of SCI. Therefore, understanding the signaling pathway and its inhibitors may be beneficial to the development of SCI therapeutic targets and new drugs. This paper mainly summarizes the pathophysiological process of SCI, the signaling pathways involved in SCI pathogenesis, and the potential role of specific inhibitors/activators in its treatment. In addition, this review also discusses the deficiencies and defects of signaling pathways in SCI research. It is hoped that this study can provide reference for future research on signaling pathways in the pathogenesis of SCI and provide theoretical basis for SCI biotherapy.
PubMed: 38878684
DOI: 10.1016/j.biopha.2024.116938 -
Biomedicine & Pharmacotherapy =... Jun 2024Amauroderma rugosum (AR) is a medicinal mushroom commonly used to treat inflammation, gastric disorders, epilepsy, and cancers due to its remarkable anti-inflammatory...
Protective effects of Amauroderma rugosum on dextran sulfate sodium-induced ulcerative colitis through the regulation of macrophage polarization and suppression of oxidative stress.
BACKGROUND
Amauroderma rugosum (AR) is a medicinal mushroom commonly used to treat inflammation, gastric disorders, epilepsy, and cancers due to its remarkable anti-inflammatory and anti-oxidative properties. This study was designed to evaluate the pharmacological effects of AR and its underlying mechanism of action against ulcerative colitis (UC) in vitro and in vivo.
METHODS
A UC mouse model was established by administration of dextran sulfate sodium (DSS). AR extract was administered intragastrically to mice for 7 days. At the end of the experiment, histopathology, macrophage phenotype, oxidative stress, and inflammatory status were examined in vivo. Furthermore, RAW 264.7, THP-1, and Caco-2 cells were used to elucidate the mechanism of action of AR in vitro.
RESULTS
AR extract (0.5-2 mg/mL) significantly suppressed lipopolysaccharide (LPS) and interferon-gamma (IFN-γ)-induced M1 macrophage (pro-inflammatory) polarization in both RAW 264.7 and THP-1 cells. LPS-induced pro-inflammatory mediators (nitric oxide, TNF-α, IL-1β, MCP-1, and IL-6) were reduced by AR extract in a concentration-dependent manner. Similarly, AR extract downregulated MAPK signaling activity in LPS-stimulated RAW 264.7 cells. AR extract elicited a concentration-dependent increase in the mRNA expression of M2 (anti-inflammatory) phenotype markers (CD206, Arg-1, Fizz-1, and Ym-1) in RAW 264.7 cells. Moreover, AR extract suppressed DSS-induced ROS generation and mitochondrial dysfunction in Caco-2 cells. The in vivo experiment revealed that AR extract (200 mg/kg) increased colon length compared to the DSS-treated group. In addition, disease activity index, spleen ratio, body weight, oxidative stress, and colonic inflammation were markedly improved by AR treatment in DSS-induced UC mice. Finally, AR suppressed M1 and promoted M2 macrophage polarization in UC mice.
CONCLUSION
The AR extract protected against DSS-induced UC by regulating macrophage polarization and suppressing oxidative stress. These valuable findings suggest that adequate intake of AR can prevent and/or treat UC.
PubMed: 38878683
DOI: 10.1016/j.biopha.2024.116901