Activated Protein C Ameliorates Tubular Mitochondrial Reactive Oxygen Species and Inflammation in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is an emerging pandemic, paralleling the worldwide increase in obesity and diabetes mellitus. DKD is now the most frequent cause of end-stage renal disease and is associated with an excessive risk of cardiovascular morbidity and mortality. DKD is a consequence of systemic endothelial dysfunction. The endothelial-dependent cytoprotective coagulation protease activated protein C (aPC) ameliorates glomerular damage in DKD, in part by reducing mitochondrial ROS generation in glomerular cells. Whether aPC reduces mitochondrial ROS generation in the tubular compartment remains unknown. Here, we conducted expression profiling of kidneys in diabetic mice (wild-type and mice with increased plasma levels of aPC, APChigh mice). The top induced pathways were related to metabolism and in particular to oxidoreductase activity. In tubular cells, aPC maintained the expression of genes related to the electron transport chain, PGC1-α expression, and mitochondrial mass. These effects were associated with reduced mitochondrial ROS generation. Likewise, NLRP3 inflammasome activation and sterile inflammation, which are known to be linked to excess ROS generation in DKD, were reduced in diabetic APChigh mice. Thus, aPC reduces mitochondrial ROS generation in tubular cells and dampens the associated renal sterile inflammation. These studies support approaches harnessing the cytoprotective effects of aPC in DKD

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis

BACKGROUND: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. METHODS: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. RESULTS: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region. INTERPRETATION: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis.

BackgroundNeurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome.MethodsWe conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models.ResultsWe included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region.InterpretationNeurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission

Utilization of Buildings’ Foundations for a Seasonal Thermal Energy Storage Medium to Meet Space and Water Heat Demands

Seasonal thermal energy storage (STES) can be utilized to cover a portion or meet the whole space and water heat demands in residential and commercial buildings. With the scarcity of fuel resources, scientists have become aware of the importance of the utilization of thermal energy. An STES system can be charged using solar collectors to heat a storage medium when solar radiation is available. Solar irradiance is seasonal so this type of system can compensate for the shortage of energy in the winter by storing surplus solar energy in the summer. This study offers an innovative design of an STES system that takes advantage of the backfill space in a building’s underground foundation to install the thermal storage medium on the excavated surface among the support pillars’ base. To study the feasibility and the feasibility of such STES system, the design was simulated using the TRNSYS® tool where the STES medium was charged by a solar thermal system. The chosen building type was a four-story hotel located in three cities each with its unique climate: Potsdam (Germany), Zarqa (Jordan), and Doha (Qatar). The results showed the coverage rate of the building’s annual heat demand was 56%, 82%, and 84%, and the payback periods were 3.4, 4.4, and 29 years for Potsdam, Zarqa, and Doha, respectively. Zarqa is the most efficient and feasible for STES compared to the other two cities

Daphne mucronata enhances cell proliferation and protects human adipose stem cells against monosodium iodoacetate induced oxidative stress in vitro

Mesenchymal stem cells (MSCs) are being used to treat many diseases as they exhibit great regenerative potential. However, MSC’s transplantation sometimes does not yield the maximum regenerative outcome as they are unable to survive in inflammatory conditions. Several approaches including preconditioning are used to improve the survival rate of mesenchymal stem cells. One such recently reported approach is preconditioning MSCs with plant extracts. The present study was designed to evaluate the effect of Daphne mucronata extract on stressed human adipose-derived mesenchymal stem cells (hADMSCs). Isolated hADMSCs were preconditioned with different concentrations of Daphne muconata extract and the protective, proliferative, antioxidant and anti-inflammatory effect was assessed through various assays and expression analysis of inflammatory markers regulated through NF-κB pathway. Results suggest that preconditioning hADMSCs with Daphne mucronata increased the cell viability, proliferative and protective potential of hADMSCs with a concomitant reduction in LDH, ROS and elevation in SOD activity. Moreover, both the ELISA and gene expression analysis demonstrated down regulations of inflammatory markers (IL1-β, TNF-α, p65, p50, MMP13) in Daphne mucronata preconditioned hADMSCs as compared to stress. This is the first study to report the use of MIA induced oxidative stress against hADMSC’s and effect of Daphne mucronata on stressed hADMSCs. Results of these studies provided evidence that Daphne mucronata protects the hADMSCs during stress conditions by down regulating the inflammatory markers and hence increase the viability and proliferative potential of hADMSCs that is crucial for transplantation purposes

Hypercoagulability Impairs Plaque Stability in Diabetes-Induced Atherosclerosis

Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic mice expressing dysfunctional TM (TMPro/Pro mice), which have a pro-coagulant phenotype due to impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TMPro/Pro ApoE-/- mice compared to diabetic ApoE-/- mice. While lipid accumulation in lesions of diabetic TMPro/Pro ApoE-/- mice was lower than that in diabetic ApoE-/- mice, morphometric analyses revealed more prominent signs of instable plaques, such as a larger necrotic core area and decreased fibrous cap thickness in diabetic TMPro/Pro ApoE-/- mice. Congruently, more macrophages and fewer smooth muscle cells were observed within lesions of diabetic TMPro/Pro ApoE-/- mice. Thus, impaired TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis

ER-Stress and Senescence Coordinately Promote Endothelial Barrier Dysfunction in Diabetes-Induced Atherosclerosis

Diabetes mellitus is hallmarked by accelerated atherosclerosis, a major cause of mortality among patients with diabetes. Efficient therapies for diabetes-associated atherosclerosis are absent. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we directly compared the effects of high glucose and oxidized LDL, revealing that high glucose induced more pronounced responses in regard to maladaptive unfolded protein response (UPR), senescence, and vascular endothelial cell barrier disruption. Ex vivo, diabetic ApoE−/− mice displayed increased levels of senescence and UPR markers within atherosclerotic lesions compared with nondiabetic ApoE−/− mice. Activated protein C pretreatment maintained barrier permeability and prevented glucose-induced expression of senescence and UPR markers in vitro. These data suggest that high glucose-induced maladaptive UPR and associated senescence promote vascular endothelial cell dysfunction, which—however—can be reversed by aPC. Taken together, current data suggest that reversal of glucose-induced vascular endothelial cell dysfunction is feasible

Novel Nongenetic Murine Model of Hyperglycemia and Hyperlipidemia-Associated Aggravated Atherosclerosis

Objective: Atherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s). Methods and Results: Wild-typemice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less a-SMA-positive area) and had more inflammation (increased plasma IL-1b level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemicmice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks. Conclusion: We established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice

Effective citric acid and EDTA treatments in cadmium stress tolerance in pepper (Capsicum annuum L.) seedlings by regulating specific gene expression

Soil contamination with toxic environmental pollutants [such as cadmium (Cd)] is becoming a serious global problem due to rapid development of social economy. To improve the growth and yield of a plant, various chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and citric acid (CA), can be applied to the soil; such application not only increases plant uptake of metals from the soil but also promotes plant absorption of micronutrient fertilizers from the medium. For this purpose, we have conducted a pot experiment using the exogenous application of CA (2.5 mM) and EDTA (2.5 mM) in pepper (Capsicum annuum L.) seedlings grown under the varying levels of Cd (0, 50 and 100 µM) in the soil. M]. Our results depicted that Cd addition to the soil significantly (P \u3c 0.05) decreased plant growth and biomass, gas exchange attributes, and mineral uptake by C. annuum when compared to the plants grown without the addition of Cd. However, Cd toxicity boosted the production of reactive oxygen species (ROS) by increasing the content of malondialdehyde (MDA), which is the indication of oxidative stress in C. annuum, and was also manifested by hydrogen peroxide (H2O2) content and electrolyte leakage to the membrane-bound organelles. The results showed that the activities of various antioxidative enzymes, such as superoxidase dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX), and their specific gene expression and also the content of non-enzymatic antioxidants, such as phenolic, flavonoid, ascorbic acid, and anthocyanin, initially increased with an increase in the Cd concentration in the soil. The results also revealed that the levels of soluble sugar, reducing sugar, and non-reducing sugar were decreased in plants grown under elevating Cd levels, but the accumulation of the metal in the roots and shoots of C. annuum, was found to be increased. The negative impacts of Cd injury were reduced by the application of EDTA and CA, which increased plant growth and biomass, improved photosynthetic apparatus, antioxidant enzymes and their gene expression, and mineral uptake, as well as diminished the exudation of organic acids and oxidative stress indicators in C. annuum by decreasing Cd toxicity. Here, we conclude that the application of EDTA and CA under the exposure to Cd stress significantly improved plant growth and biomass, photosynthetic pigments, and gas exchange characteristics; regulated antioxidant defense system and essential nutrient uptake; and balanced organic acid exudation pattern in C. annuum

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis.

BACKGROUND: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. METHODS: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. RESULTS: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region. INTERPRETATION: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission