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Showing papers by "Mark E. Cooper published in 2020"


Journal ArticleDOI
TL;DR: A large number of patients with or at risk of diabetes and metabolic complications of preexisting diabetes, including diabetic ketoacidosis and h...
Abstract: Diabetes and Covid-19 Diabetes is associated with an increased risk of severe Covid-19. New-onset diabetes and metabolic complications of preexisting diabetes, including diabetic ketoacidosis and h...

578 citations


Journal ArticleDOI
TL;DR: Metal complexes were evaluated against dangerous ESKAPE pathogens and found to have a higher hit-rate than organic molecules.
Abstract: There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.

228 citations


Posted ContentDOI
01 Jun 2020-medRxiv
TL;DR: First estimates of potential excess mortality among people with cancer and multimorbidity due to the COVID-19 emergency are provided and there is an urgent need for weekly data on cause-specific excess mortality, cancer diagnosis and treatment provision and better intelligence on the use of effective treatments for comorbidities.
Abstract: Background Cancer and multiple non-cancer conditions are considered by the Centers for Disease Control and Prevention (CDC) as high risk conditions in the COVID-19 emergency. Professional societies have recommended changes in cancer service provision to minimize COVID-19 risks to cancer patients and health care workers. However, we do not know the extent to which cancer patients, in whom multi-morbidity is common, may be at higher overall risk of mortality as a net result of multiple factors including COVID-19 infection, changes in health services, and socioeconomic factors. Methods We report multi-center, weekly cancer diagnostic referrals and chemotherapy treatments until April 2020 in England and Northern Ireland. We analyzed population-based health records from 3,862,012 adults in England to estimate 1-year mortality in 24 cancer sites and 15 non-cancer comorbidity clusters (40 conditions) recognized by CDC as high-risk. We estimated overall (direct and indirect) effects of COVID-19 emergency on mortality under different Relative Impact of the Emergency (RIE) and different Proportions of the population Affected by the Emergency (PAE). We applied the same model to the US, using Surveillance, Epidemiology, and End Results (SEER) program data. Results Weekly data until April 2020 demonstrate significant falls in admissions for chemotherapy (45-66% reduction) and urgent referrals for early cancer diagnosis (70-89% reduction), compared to pre-emergency levels. Under conservative assumptions of the emergency affecting only people with newly diagnosed cancer (incident cases) at COVID-19 PAE of 40%, and an RIE of 1.5, the model estimated 6,270 excess deaths at 1 year in England and 33,890 excess deaths in the US. In England, the proportion of patients with incident cancer with ≥1 comorbidity was 65.2%. The number of comorbidities was strongly associated with cancer mortality risk. Across a range of model assumptions, and across incident and prevalent cancer cases, 78% of excess deaths occur in cancer patients with Harry ≥1 comorbidity. Conclusion We provide the first estimates of potential excess mortality among people with cancer and multimorbidity due to the COVID-19 emergency and demonstrate dramatic changes in cancer services. To better inform prioritization of cancer care and guide policy change, there is an urgent need for weekly data on cause-specific excess mortality, cancer diagnosis and treatment provision and better intelligence on the use of effective treatments for comorbidities.

136 citations


Journal ArticleDOI
TL;DR: An advanced multiscale crop modelling framework will enable a gene-to-farm design of resilient and sustainable crop production systems under a changing climate at regional- to-global scales.
Abstract: Predicting the consequences of manipulating genotype (G) and agronomic management (M) on agricultural ecosystem performances under future environmental (E) conditions remains a challenge. Crop modelling has the potential to enable society to assess the efficacy of G × M technologies to mitigate and adapt crop production systems to climate change. Despite recent achievements, dedicated research to develop and improve modelling capabilities from gene to global scales is needed to provide guidance on designing G × M adaptation strategies with full consideration of their impacts on both crop productivity and ecosystem sustainability under varying climatic conditions. Opportunities to advance the multiscale crop modelling framework include representing crop genetic traits, interfacing crop models with large-scale models, improving the representation of physiological responses to climate change and management practices, closing data gaps and harnessing multisource data to improve model predictability and enable identification of emergent relationships. A fundamental challenge in multiscale prediction is the balance between process details required to assess the intervention and predictability of the system at the scales feasible to measure the impact. An advanced multiscale crop modelling framework will enable a gene-to-farm design of resilient and sustainable crop production systems under a changing climate at regional-to-global scales.

134 citations


Journal ArticleDOI
01 Feb 2020-Glia
TL;DR: It is demonstrated using Nlrp3‐GFP gene knock‐in mice that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NL RP3 inflammasome, andNLRP3 inhibition may be a potential therapeutic approach to arrest microglian neuroinflammation and ALS disease progression.
Abstract: Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β-amyloid and α-synuclein trigger microglial NLRP3 activation, leading to caspase-1 activation and IL-1β secretion. Both caspase-1 and IL-1β contribute to disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1G93A mice microglia do not express NLRP3, and SOD1G93A protein generated IL-1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3-GFP gene knock-in mice that microglia express NLRP3 in SOD1G93A mice. We show that both aggregated and soluble SOD1G93A activates inflammasome in primary mouse microglia leading caspase-1 and IL-1β cleavage, ASC speck formation, and the secretion of IL-1β in a dose- and time-dependent manner. Importantly, SOD1G93A was unable to induce IL-1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1-induced microglial IL-1β secretion. Microglial NLRP3 upregulation was also observed in the TDP-43Q331K ALS mouse model, and TDP-43 wild-type and mutant proteins could also activate microglial inflammasomes in a NLRP3-dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1G93A -mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.

108 citations


Journal ArticleDOI
TL;DR: Evidence from this review highlights that the duration and timing of exposure to racial discrimination matters, and the need to gain evidence for the mechanisms linking early racism exposure to adverse health outcomes in later life is emphasised.

104 citations


Journal ArticleDOI
TL;DR: It is shown that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice, and this metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL- 1β production.

102 citations


Journal ArticleDOI
TL;DR: An optimized peptide antibiotic with broad-spectrum in vitro activities, in vivo efficacy in multiple disease models against multidrug-resistant Gram-negative infections, and reduced toxicity is presented.
Abstract: Peptide antibiotics are an abundant and synthetically tractable source of molecular diversity, but they are often cationic and can be cytotoxic, nephrotoxic and/or ototoxic, which has limited their clinical development. Here we report structure-guided optimization of an amphipathic peptide, arenicin-3, originally isolated from the marine lugworm Arenicola marina. The peptide induces bacterial membrane permeability and ATP release, with serial passaging resulting in a mutation in mlaC, a phospholipid transport gene. Structure-based design led to AA139, an antibiotic with broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant bacteria, including ESBL, carbapenem- and colistin-resistant clinical isolates. The antibiotic induces a 3-4 log reduction in bacterial burden in mouse models of peritonitis, pneumonia and urinary tract infection. Cytotoxicity and haemolysis of the progenitor peptide is ameliorated with AA139, and the 'no observable adverse effect level' (NOAEL) dose in mice is ~10-fold greater than the dose generally required for efficacy in the infection models.

93 citations


Journal ArticleDOI
TL;DR: It is shown in patient cells and in mice that oncogenic K-Ras activatesNLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade, which paves the way for a therapeutic approach based on immune modulation via NL RP3 blockade in KRAS-mutant myeloid malignancies.
Abstract: Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic KrasG12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active KrasG12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in KrasG12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, KrasG12D-RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies. Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.

83 citations


Journal ArticleDOI
TL;DR: The identification and delivery of novel pathways to improved crop productivity can be accelerated through use of the proposed framework to design crop improvement strategies that integrate genetic gains from breeding and crop management strategies that reduce yield gaps.
Abstract: A Crop Growth Model (CGM) is used to demonstrate a biophysical framework for predicting grain yield outcomes for Genotype by Environment by Management (G×E×M) scenarios. This required development of a CGM to encode contributions of genetic and environmental determinants of biophysical processes that influence key resource (radiation, water, nutrients) use and yield‐productivity within the context of the target agricultural system. Prediction of water‐driven yield‐productivity of maize for a wide range of G×E×M scenarios in the U.S. corn‐belt is used as a case study to demonstrate applications of the framework. Three experimental evaluations are conducted to test predictions of G×E×M yield expectations derived from the framework: (1) A maize hybrid genetic gain study, (2) A maize yield potential study, and (3) A maize drought study. Examples of convergence between key G×E×M predictions from the CGM and the results of the empirical studies are demonstrated. Potential applications of the prediction framework for design of integrated crop improvement strategies are discussed. The prediction framework opens new opportunities for rapid design and testing of novel crop improvement strategies based on an integrated understanding of G×E×M interactions. Importantly the CGM ensures that the yield predictions for the G×E×M scenarios are grounded in the biophysical properties and limits of predictability for the crop system. The identification and delivery of novel pathways to improved crop productivity can be accelerated through use of the proposed framework to design crop improvement strategies that integrate genetic gains from breeding and crop management strategies that reduce yield gaps.

67 citations


Journal ArticleDOI
TL;DR: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease and may suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus.
Abstract: RATIONALE: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear OBJECTIVE: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis METHODS AND RESULTS: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9 Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis CONCLUSIONS: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus Graphic Abstract: A graphic abstract is available for this article

Journal ArticleDOI
TL;DR: This review focuses on the antibacterial activity of natural and synthetic tyrosinase inhibitors reported in the past ten years and explores the possibilities for synergism of anti-tyrosinases with anti-bacterials.

Journal ArticleDOI
TL;DR: The findings suggest that the NLRP3–caspase‐1 inflammasome directly activates MMP‐9 and that preventing matrix metallopeptidase 9 expression and activation in macrophages is an important mechanism underlying MCC950's protective effect.
Abstract: Background Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3)-caspase-1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation. Methods and Results In a model of sporadic aortic aneurysm and dissection induced by challenging wild-type mice with a high-fat, high-cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge-induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3-caspase-1 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP-9) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase-1 directly activated MMP-9 by cleaving its N-terminal inhibitory domain. Moreover, the genetic knockdown of Nlrp3 or Casp-1 in mice or treatment of mice with MCC950 diminished the challenge-induced N-terminal cleavage of MMP-9, MMP-9 activation, and aortic destruction. Conclusions Our findings suggest that the NLRP3-caspase-1 inflammasome directly activates MMP-9. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.

Journal ArticleDOI
01 Jan 2020-Diabetes
TL;DR: Evidence is provided for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.
Abstract: The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.

Journal ArticleDOI
TL;DR: It is determined that diabetic spontaneously hypertensive rats had exacerbated retinal vascular permeability and expression of angiogenic and inflammatory factors, compared with normotensive diabetic Wistar Kyoto rats, and GKT136901, a specific dual inhibitor of Nox1 and Nox4, prevented these events.
Abstract: Hypertension is a risk factor for the vascular permeability and neovascularization that threatens vision in diabetic retinopathy. Excess reactive oxygen species derived from the Nox (NADPH oxidase)...

Journal ArticleDOI
TL;DR: The exposition of the details of the interactions between 6c and the catalytic pocket of tyrosinase provides a basis for rational design of additional potent inhibitors of tyosinase, built on the cinnamic acid scaffold.

Journal ArticleDOI
TL;DR: Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events, and AEs were balanced among groups overall and across eGFR categories.
Abstract: OBJECTIVE Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to RESEARCH DESIGN AND METHODS Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia. RESULTS A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories. CONCLUSIONS Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c and no difference in AEs were observed.

Journal ArticleDOI
TL;DR: It is concluded that maize conserves water by restricting transpiration upon increasing VPD and under higher soil moisture than sorghum and millet, giving maize significantly higher TE, whereas sorghums and pearl millet rely mostly on reduced leaf area and somewhat on transpiration restriction.

Journal ArticleDOI
TL;DR: This article critically evaluates both preclinical studies with cell culture experiments and animal models of diabetic kidney disease as well as covering the current findings from clinical studies addressing targeted interventions towards these pathways.
Abstract: There is an unmet need for new strategies to prevent or postpone the development of diabetic kidney disease. The pathophysiology of this condition includes as a central mechanism an imbalance between the excessive production of reactive oxygen species (ROS) and inadequate anti-oxidant defense. Reduction of ROS is therefore an interesting therapeutic target that warrants further investigation. Herein, we review the drivers of oxidative stress in diabetic kidney disease including NADPH oxidases, mitochondrial ROS production, xanthine oxidase, cytochrome P450, uncoupled eNOS and lipoxygenase. Secondly, the role of anti-oxidative mechanisms in diabetic kidney disease is discussed including the role of the kelch-like ECH-associated protein 1- nuclear factor erythroid 2-related factor 2, lipoxin, oral anti-oxidants and glutathione peroxidase-1. We will also review data supporting the concept that the beneficial renal effects of anti-diabetic drugs that target the glucagon-like peptide 1 receptor and the sodium glucose transporter 2 are, at least in part, due to their impact on oxidative stress in diabetic kidney disease. In the present article we critically evaluate both preclinical studies with cell culture experiments and animal models of diabetic kidney disease as well as covering the current findings from clinical studies addressing targeted interventions towards these pathways.

Journal ArticleDOI
TL;DR: A novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD is identified and should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists.
Abstract: The major clinical associations with the progression of diabetic kidney disease (DKD) are glycemic control and systemic hypertension. Recent studies have continued to emphasize vasoactive hormone pathways including aldosterone and endothelin which suggest a key role for vasoconstrictor pathways in promoting renal damage in diabetes. The role of glucose per se remains difficult to define in DKD but appears to involve key intermediates including reactive oxygen species (ROS) and dicarbonyls such as methylglyoxal which activate intracellular pathways to promote fibrosis and inflammation in the kidney. Recent studies have identified a novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD. This should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists.

Journal ArticleDOI
TL;DR: It is indicated that cyclophilin D has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.
Abstract: Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif-/-) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif-/- mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif-/- as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.

Journal ArticleDOI
TL;DR: It is reported that MCC950 attenuates metabolic and hepatic dysfunction in aged mice and mediates the protective effects by mTOR inhibiton activating autophagy and PPARα in vivo and in vitro.
Abstract: The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-related metabolic syndrome.

Journal ArticleDOI
01 Jan 2020-Lithos
TL;DR: In this article, the authors describe the transformation from harzburgite protolith to listvenite (quartz + magnesite/± dolomite + relict Cr-spinel) in the late Cretaceous mantle peridotite of the Birjand ophiolite of Iran.

Journal ArticleDOI
TL;DR: It is demonstrated that sequence-controlled copolymers with shorter amine blocks increase the antimicrobial efficacy of the resulting material towards Gram-negative bacteria while shorter hydrophobic blocks improve the efficacy towards Gram -positive bacteria.


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TL;DR: Results reveal non-canonical caspase-1 signaling in vivo, and loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-α.

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TL;DR: Although the severity of DR predicted diabetic ESRD in patients with T2DM and DN, the severities of DR and DN were not always consistent, especially in Patients with mild retinopathy or microalbuminuria.

Journal ArticleDOI
TL;DR: Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al., Chem.
Abstract: Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al., Chem. Sci., 2020, 11, 2627–2639.


Journal ArticleDOI
TL;DR: A light‐activated rhenium complex with activity against drug‐resistant S. aureus and E. coli suggests two distinct modes of action.
Abstract: New antibiotics and innovative approaches to kill drug-resistant bacteria are urgently needed. Metal-complexes offer access to potential alternative modes of action and have only sparingly been investigated in antibacterial drug discovery. We have developed a light-activated rhenium complex with activity against drug resistant bacteria. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.