The Use and Impact of Antibiotics in Plant Agriculture: A Review.

Growers have depended on the specificity and efficacy of streptomycin and oxytetracycline as a part of their plant disease arsenal since the middle of the 20th century. With climate change intensifying plant bacterial epidemics, the established success of these antibiotics remains threatened. Our strong reliance on certain antibiotics for devastating diseases eventually gave way to resistance development. Although antibiotics in plant agriculture equal to less than 0.5% of overall antibiotic use in the United States, it is still imperative for humans to continue to monitor usage, environmental residues, and resistance in bacterial populations. This review provides an overview of the history and use, resistance and mitigation, regulation, environmental impact, and economics of antibiotics in plant agriculture. Bacterial issues, such as the ongoing Huanglongbing (citrus greening) epidemic in Florida citrus production, may need antibiotics for adequate control. Therefore, preserving the efficacy of our current antibiotics by utilizing more targeted application methods, such as trunk injection, should be a major focus. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Risk of partial school closure for COVID-19 by socio-economic level in the period 2020-22.

BACKGROUND: The objective was to analyse the risk of partial school closure by economic level in Barcelona city. METHODS: In this ecological study, the risk of partial school closure for the academic years 2020-21 and 2021-22 was estimated by dividing the total number of days that each child was in quarantine or isolation by the total number of days that each child was at risk to be in quarantine or isolation in the academic year. The association between partial school closure risk and mean income by district was estimated with the Spearman rho. RESULTS: The lower the mean income, the higher the risk of partial closure (Spearman rho = 0.83; P-value = 0.003) during the academic year 2020-21. Specifically, the children from the district with the lowest income had a six times greater risk of partial school closure compared with those from the highest-income district. This risk did not show a significant socioeconomic gradient in the academic year 2021-22. CONCLUSIONS: The risk of partial school closure presented an inverse socioeconomic gradient in the city of Barcelona according to average income by district in the academic year 2020-21. This distribution was not observed in the academic year 2021-22.

Specialized Pro-Resolving Lipid Mediators: New Therapeutic Approaches for Vascular Remodeling.

Vascular remodeling is a typical feature of vascular diseases, such as atherosclerosis, aneurysms or restenosis. Excessive inflammation is a key mechanism underlying vascular remodeling via the modulation of vascular fibrosis, phenotype and function. Recent evidence suggests that not only augmented inflammation but unresolved inflammation might also contribute to different aspects of vascular diseases. Resolution of inflammation is mediated by a family of specialized pro-resolving mediators (SPMs) that limit immune cell infiltration and initiate tissue repair mechanisms. SPMs (lipoxins, resolvins, protectins, maresins) are generated from essential polyunsaturated fatty acids. Synthases and receptors for SPMs were initially described in immune cells, but they are also present in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), where they regulate processes important for vascular physiology, such as EC activation and VSMC phenotype. Evidence from genetic models targeting SPM pathways and pharmacological supplementation with SPMs have demonstrated that these mediators may play a protective role against the development of vascular remodeling in atherosclerosis, aneurysms and restenosis. This review focuses on the latest advances in understanding the role of SPMs in vascular cells and their therapeutic effects in the vascular remodeling associated with different cardiovascular diseases.

A Blunted Sympathetic Function and an Enhanced Nitrergic Activity Contribute to Reduce Mesenteric Resistance in Hyperthyroidism.

We aimed to determine whether an experimental model of hyperthyroidism could alter the function of sympathetic and nitrergic components of mesenteric innervation. For this purpose, male Wistar rats were divided into (1) control rats (CT) and (2) rats infused with L-Thyroxine (HT). Body weight gain and adipose tissue accumulation were lower in HT rats, while systolic blood pressure and citrate synthase activity in the soleus muscle were increased by HT. In segments from the superior mesenteric artery, the application of an electrical field stimulation (EFS) induced a vasoconstrictor response, which was lower in arteries from HT animals. The alpha-adrenoceptor antagonist phentolamine diminished EFS-induced vasoconstriction to a lower extent in HT arteries, while the purinergic receptor antagonist suramin reduced contractile response to EFS only in segments from CT. In line with this, noradrenaline release, tyrosine hydroxylase expression and activation and dopamine ß hydroxylase expression were diminished in HT. The unspecific nitric oxide synthase (NOS) inhibitor L-NAME increased EFS-induced vasoconstriction more markedly in segments from HT rats. NO release was enhanced in HT, probably due to an enhancement in neuronal NOS activity, in which a hyperactivation of both PKC and PI3K-AKT signaling pathways might play a relevant role. In conclusion, perivascular mesenteric innervation might contribute to reduce the vascular resistance observed in hyperthyroidism.

Interleukin-17A induces vascular remodeling of small arteries and blood pressure elevation.

An important link exists between hypertension and inflammation. Hypertensive patients present elevated circulating levels of proinflammatory cytokines, including interleukin-17A (IL-17A). This cytokine participates in host defense, autoimmune and chronic inflammatory pathologies, and cardiovascular diseases, mainly through the regulation of proinflammatory factors. Emerging evidence also suggests that IL-17A could play a role in regulating blood pressure and end-organ damage. Here, our preclinical studies in a murine model of systemic IL-17A administration showed that increased levels of circulating IL-17A raised blood pressure induced inward remodeling of small mesenteric arteries (SMAs) and arterial stiffness. In IL-17A-infused mice, treatment with hydralazine and hydrochlorothiazide diminished blood pressure elevation, without modifying mechanical and structural properties of SMA, suggesting a direct vascular effect of IL-17A. The mechanisms of IL-17A seem to involve an induction of vascular smooth muscle cell (VSMC) hypertrophy and phenotype changes, in the absence of extracellular matrix (ECM) proteins accumulation. Accordingly, treatment with an IL-17A neutralizing antibody diminished SMA remodeling in a model of angiotensin II (Ang II) infusion. Moreover, in vitro studies in VSMCs reported here, provide further evidence of the direct effects of IL-17A on cell growth responses. Our experimental data suggest that IL-17A is a key mediator of vascular remodeling of the small arteries, which might contribute, at least in part, to blood pressure elevation.

The nuclear receptor NOR-1 modulates redox homeostasis in human vascular smooth muscle cells.

The nuclear receptor NOR-1 (Neuron-derived Orphan Receptor-1) has recently been involved in vascular remodeling and coronary artery disease, however, to date, only a few NOR-1 target genes have been described. We aimed to identify genes regulated by NOR-1 in human vascular smooth muscle cells (VSMC). Lentiviral overexpression of NOR-1 increases reactive oxygen species (ROS) in human VSMC. In accordance, NOR-1 strongly increased NADPH oxidase NOX1 mRNA and protein levels, while NOR-1 silencing significantly reduced NOX1 expression. Luciferase reporter, site-directed mutagenesis and EMSA studies identified two nerve growth factor-induced clone B (NGFI-B)-response elements (NBREs) in NOX1 promoter as essential elements for NOR-1 responsiveness. NOR-1 and NOX1 were co-expressed by VSMC in human atherosclerotic lesions, and NOX1 knockdown counteracted the increased ROS production and cell migration induced by NOR-1 overexpression. NOR-1 also modulated the expression of other enzymes involved in cellular redox status, in particular, upregulated superoxide dismutase-1 (SOD1) and SOD3 while downregulated SOD2 and NOX4. NOR-1 induced SOD1 and SOD3 transcriptional activity and participated in the modulation of SOD3 by inflammatory stimuli. By contrast, NOR-1 impaired SOD2 transcription antagonizing NFκB signaling. These results indicate that NOR-1 induces NOX1 in human VSMC and participates in the complex gene networks regulating oxidative stress and redox homeostasis in the vasculature.

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea.

Transcriptional regulatory networks are essential during the formation and differentiation of organs. The transcription factor N-myc is required for proper morphogenesis of the cochlea and to control correct patterning of the organ of Corti. We show here that the Otx2 gene, a mammalian ortholog of the Drosophila orthodenticle homeobox gene, is a crucial target of N-myc during inner ear development. Otx2 expression is lost in N-myc mouse mutants, and N-myc misexpression in the chick inner ear leads to ectopic expression of Otx2. Furthermore, Otx2 enhancer activity is increased by N-myc misexpression, indicating that N-myc may directly regulate Otx2. Inactivation of Otx2 in the mouse inner ear leads to ectopic expression of prosensory markers in non-sensory regions of the cochlear duct. Upon further differentiation, these domains give rise to an ectopic organ of Corti, together with the re-specification of non-sensory areas into sensory epithelia, and the loss of Reissner's membrane. Therefore, the Otx2-positive domain of the cochlear duct shows a striking competence to develop into a mirror-image copy of the organ of Corti. Taken together, these data show that Otx2 acts downstream of N-myc and is essential for patterning and spatial restriction of the sensory domain of the mammalian cochlea.

Regulator of calcineurin 1 modulates vascular contractility and stiffness through the upregulation of COX-2-derived prostanoids.

Cyclooxygenase-2 (COX-2) derived-prostanoids participate in the altered vascular function and mechanical properties in cardiovascular diseases. We investigated whether regulator of calcineurin 1 (Rcan1) participates in vascular contractility and stiffness through the regulation of COX-2. For this, wild type (Rcan1+/+) and Rcan1-deficient (Rcan1-/-) mice untreated or treated with the COX-2 inhibitor rofecoxib were used. Vascular function and structure were analysed by myography. COX-2 and phospo-p65 expression were studied by western blotting and immunohistochemistry and TXA2 production by ELISA. We found that Rcan1 deficiency increases COX-2 and IL-6 expression and NF-κB activation in arteries and vascular smooth muscle cells (VSMC). Adenoviral-mediated re-expression of Rcan1.4 in Rcan1-/- VSMC normalized COX-2 expression. Phenylephrine-induced vasoconstrictor responses were greater in aorta from Rcan1-/- compared to Rcan1+/+ mice. This increased response were diminished by etoricoxib, furegrelate, SQ 29548, cyclosporine A and parthenolide, inhibitors of COX-2, TXA2 synthase, TP receptors, calcineurin and NF-κB, respectively. Endothelial removal and NOS inhibition increased phenylephrine responses only in Rcan1+/+ mice. TXA2 levels were greater in Rcan1-/- mice. In small mesenteric arteries, vascular function and structure were similar in both groups of mice; however, vessels from Rcan1-/- mice displayed an increase in vascular stiffness that was diminished by rofecoxib. In conclusion, our results suggest that Rcan1 might act as endogenous negative modulator of COX-2 expression and activity by inhibiting calcineurin and NF-kB pathways to maintain normal contractility and vascular stiffness in aorta and small mesenteric arteries, respectively. Our results uncover a new role for Rcan1 in vascular contractility and mechanical properties.

Deficiency of MMP17/MT4-MMP proteolytic activity predisposes to aortic aneurysm in mice.

RATIONALE: Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries. These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome. OBJECTIVE: To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology. METHODS AND RESULTS: Screening of patients with inherited thoracic aortic aneurysms and dissections identified a missense mutation (R373H) in the MMP17 gene that prevented the expression of the protease in human transfected cells. Using a loss-of-function genetic mouse model, we demonstrated that the lack of Mmp17 resulted in the presence of dysfunctional vascular smooth muscle cells and altered extracellular matrix in the vessel wall; and it led to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. We also showed that Mmp17-mediated osteopontin cleavage regulated vascular smooth muscle cell maturation via c-Jun N-terminal kinase signaling during aorta wall development. Some features of the arterial phenotype were prevented by re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment in Mmp17-null neonates. CONCLUSIONS: Mmp17 proteolytic activity regulates vascular smooth muscle cell phenotype in the arterial vessel wall, and its absence predisposes to thoracic aortic aneurysm in mice. The rescue of part of the vessel-wall phenotype by a lentiviral strategy opens avenues for therapeutic intervention in these life-threatening disorders.

NADPH oxidases and vascular remodeling in cardiovascular diseases.

Reactive oxygen species (ROS) are key signaling molecules that regulate vascular function and structure in physiological conditions. A misbalance between the production and detoxification of ROS increases oxidative stress that is involved in the vascular remodeling associated with cardiovascular diseases such as hypertension by affecting inflammation, hypertrophy, migration, growth/apoptosis and extracellular matrix protein turnover. The major and more specific source of ROS in the cardiovascular system is the NADPH oxidase (NOX) family of enzymes composed of seven members (NOX1-5, DUOX 1/2). Vascular cells express several NOXs being NOX-1 and NOX-4 the most abundant NOXs present in vascular smooth muscle cells. This review focuses on specific aspects of NOX-1 and NOX-4 isoforms including information on regulation, function and their role in vascular remodeling. In order to obtain a more integrated view about the role of the different NOX isoforms in different types of vascular remodeling, we discuss the available literature not only on hypertension but also in atherosclerosis, restenosis and aortic dilation.

Phosphatidylethanol (PEth) in blood samples from "driving under the influence" cases as indicator for prolonged excessive alcohol consumption.

Phosphatidylethanol (PEth) is considered as specific biomarker of alcohol consumption. Due to accumulation after repeated drinking, PEth is suitable to monitor long-term drinking behavior. To examine the applicability of PEth in "driving under the influence of alcohol" cases, 142 blood samples with blood alcohol concentrations (BAC) ranging from 0.0-3.12‰ were analyzed for the presence of PEth homologues 16:0/18:1 (889 ± 878 ng/mL; range

Carnitine palmitoyltransferase-1 up-regulation by PPAR-ß/δ prevents lipid-induced endothelial dysfunction.

Fatty acids cause endothelial dysfunction involving increased ROS (reactive oxygen species) and reduced NO (nitric oxide) bioavailability. We show that in MAECs (mouse aortic endothelial cells), the PPARß/δ (peroxisome- proliferator-activated receptor ß/δ) agonist GW0742 prevented the decreased A23187-stimulated NO production, phosphorylation of eNOS (endothelial nitric oxide synthase) at Ser1177 and increased intracellular ROS levels caused by exposure to palmitate in vitro. The impaired endothelium-dependent relaxation to acetylcholine in mouse aorta induced by palmitate was restored by GW0742. In vivo, GW0742 treatment prevented the reduced aortic relaxation, phosphorylation of eNOS at Ser1177, and increased ROS production and NADPH oxidase in mice fed on a high-fat diet. The PPARß/δ antagonist GSK0660 abolished all of these protective effects induced by GW0742. This agonist enhanced the expression of CPT (carnitine palmitoyltransferase)-1. The effects of GW0742 on acetylcholine- induced relaxation in aorta and on NO and ROS production in MAECs exposed to palmitate were abolished by the CPT-1 inhibitor etomoxir or by siRNA targeting CPT-1. GW0742 also inhibited the increase in DAG (diacylglycerol), PKCα/ßII (protein kinase Cα/ßII) activation, and phosphorylation of eNOS at Thr495 induced by palmitate in MAECs, which were abolished by etomoxir. In conclusion, PPARß/δ activation restored the lipid-induced endothelial dysfunction by up-regulation of CPT-1, thus reducing DAG accumulation and the subsequent PKC-mediated ROS production and eNOS inhibition.

Integrin-linked kinase plays a key role in the regulation of angiotensin II-induced renal inflammation.

ILK (integrin-linked kinase) is an intracellular serine/threonine kinase involved in cell-matrix interactions. ILK dysregulation has been described in chronic renal disease and modulates podocyte function and fibrosis, whereas data about its role in inflammation are scarce. AngII (angiotensin II) is a pro-inflammatory cytokine that promotes renal inflammation. AngII blockers are renoprotective and down-regulate ILK in experimental kidney disease, but the involvement of ILK in the actions of AngII in the kidney has not been addressed. Therefore we have investigated whether ILK signalling modulates the kidney response to systemic AngII infusion in wild-type and ILK-conditional knockout mice. In wild-type mice, AngII induced an inflammatory response, characterized by infiltration of monocytes/macrophages and lymphocytes, and up-regulation of pro-inflammatory factors (chemokines, adhesion molecules and cytokines). AngII activated several intracellular signalling mechanisms, such as the NF-κB (nuclear factor κB) transcription factor, Akt and production of ROS (reactive oxygen species). All these responses were prevented in AngII-infused ILK-deficient mice. In vitro studies characterized further the mechanisms regulating the inflammatory response modulated by ILK. In cultured tubular epithelial cells ILK blockade, by siRNA, inhibited AngII-induced NF-κB subunit p65 phosphorylation and its nuclear translocation. Moreover, ILK gene silencing prevented NF-κB-related pro-inflammatory gene up-regulation. The results of the present study demonstrate that ILK plays a key role in the regulation of renal inflammation by modulating the canonical NF-κB pathway, and suggest a potential therapeutic target for inflammatory renal diseases.

Our 7-year experience supporting the Ross autograft with the novel technique of Personalized External Aortic Root Support.

Objective: The Ross operation is a widely accepted option for aortic valve replacement in children, and evidence shows its excellent results in terms of hemodynamics and durability. However, indications are still limited due to the fact that it is a technically demanding procedure, only performed by specialized surgeons. On top of that, and despite numerous techniques being applied, autograft dilatation remains a key disadvantage, which can lead to graft failure. In recent years, the ExoVasc Personalized External Aortic Root Support (PEARS) has proven to be a safe and effective option to prevent aortic root dilatation in various aortopathies and is a technique that lends itself to support the pulmonary autograft in the Ross operation. Methods: During the past 7 years, we have used the ExoVasc PEARS graft, manufactured from the patients' pulmonary artery measurements from computed tomography scan data, to support the pulmonary autograft in the Ross operation. This graft (manufactured by Exstent Ltd, UK) is implanted at the same time as the autograft. We have reviewed all the patients who underwent this surgery, including demographic data, aorta measurements, operative data, and follow-up assessment consisting of periodic echocardiograms and magnetic resonance imaging scans. Results: Fifty patients were included in the study. Mean age at the time of the operation was 29.84 years, the youngest patient was 9 years-old. Nineteen patients (38%) had previous sternotomies; 11 of them having had a previous aortic valve replacement. Seventy-two percent of patients had initially a bicuspid aortic valve. Mean diameter of the ascending aorta was 3.83 cm. Forty-four percent of patients required a concomitant reduction aortoplasty due to mismatch sizes between the ascending aorta and the autograft. Mean bypass and crossclamp times were 200.66 and 151.14 minutes, respectively. Median length of stay was 6 days. Mean follow-up was 16.88 months. Two patients required subsequent aortic valve replacement (1 had rheumatic valve disease and the other had iatrogenic damage in his autograft valve leaflet). Ascending aorta dimensions remain stable when compared with immediate postoperative studies. There were no deaths. Conclusions: The ExoVasc PEARS graft has proven to be an excellent support in the Ross operation to prevent the autograft failure related to autograft dilatation that can offer several advantages compared with other existing techniques. With this type of support, we believe the Ross indications can be expanded to multiple clinical scenarios, given the good long-term results this operation offers in terms of durability, life expectancy, and hemodynamics.

Lysyl Oxidase in Ectopic Cardiovascular Calcification: Role of Oxidative Stress.

Lysyl oxidase (LOX)-mediated extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease; however, this enzyme also induces oxidative stress. We addressed the contribution of LOX-dependent oxidative stress to cardiovascular calcification. LOX is upregulated in human-calcified atherosclerotic lesions and atheromas from atherosclerosis-challenged LOX transgenic mice (TgLOXVSMC) and colocalized with a marker of oxidative stress (8-oxo-deoxyguanosine) in vascular smooth muscle cells (VSMCs). Similarly, in calcific aortic valves, high LOX expression was detected in valvular interstitial cells (VICs) positive for 8-oxo-deoxyguanosine, while LOX and LOXL2 expression correlated with osteogenic markers (SPP1 and RUNX2) and NOX2. In human VICs, mito-TEMPO and TEMPOL attenuated the increase in superoxide anion levels and the mineralization induced by osteogenic media (OM). Likewise, in OM-exposed VICs, ß-aminopropionitrile (a LOX inhibitor) ameliorated both oxidative stress and calcification. Gain- and loss-of-function approaches in VICs demonstrated that while LOX silencing negatively modulates oxidative stress and calcification induced by OM, lentiviral LOX overexpression exacerbated oxidative stress and VIC calcification, effects that were prevented by mito-TEMPO, TEMPOL, and ß-aminopropionitrile. Our data indicate that LOX-induced oxidative stress participates in the procalcifying effects of LOX activity in ectopic cardiovascular calcification, and highlight the multifaceted role played by LOX isoenzymes in cardiovascular diseases.

Chymase-independent vascular Ang-(1-12)/Ang II pathway and TXA2 generation are involved in endothelial dysfunction in the murine model of heart failure.

The angiotensin (Ang)-(1-12)/Ang II pathway contributes to cardiac pathology. However, its involvement in the development of peripheral endothelial dysfunction associated with heart failure (HF) remains unknown. Therefore, this study aimed to characterise the effect of exogenous Ang-(1-12) and its conversion to Ang II on endothelial function using the murine model of HF (Tgαq*44 mice), focusing on the role of chymase and vascular-derived thromboxane A2 (TXA2). Ex vivo myographic assessments of isolated aorta showed impaired endothelium-dependent vasodilation in late-stage HF in 12-month-old Tgαq*44 mice. However, endothelium-dependent vasodilation was fully preserved in the early stage of HF in 4-month-old Tgαq*44 mice and 4- and 12-month-old FVB control mice. Ang-(1-12) impaired endothelium-dependent vasodilation in 4- and 12-month-old Tgαq*44 mice, that was associated with increased Ang II production. The chymase inhibitor chymostatin did not inhibit this response. Interestingly, TXA2 production reflected by TXB2 measurement was upregulated in response to Ang-(1-12) and Ang II in aortic rings isolated from 12-month-old Tgαq*44 mice but not from 4-month-old Tgαq*44 mice or age-matched FVB mice. Furthermore, in vivo magnetic resonance imaging showed that Ang-(1-12) impaired endothelium-dependent vasodilation in the aorta of Tgαq*44 mice and FVB mice. However, this response was inhibited by angiotensin I converting enzyme (ACE) inhibitor; perindopril, angiotensin II receptor type 1 (AT1) antagonist; losartan and TXA2 receptor (TP) antagonist-picotamide in 12-month-old-Tgαq*44 mice only. In conclusion, the chymase-independent vascular Ang-(1-12)/Ang II pathway and subsequent TXA2 overactivity contribute to systemic endothelial dysfunction in the late stage of HF in Tgαq*44 mice. Therefore, the vascular TXA2 receptor represents a pharmacotherapeutic target to improve peripheral endothelial dysfunction in chronic HF.

Resolvin D2 prevents vascular remodeling, hypercontractility and endothelial dysfunction in obese hypertensive mice through modulation of vascular and proinflammatory factors.

During resolution of inflammation, specialized proresolving mediators (SPMs), including resolvins, are produced to restore tissue homeostasis. We hypothesized that there might be a dysregulation of SPMs pathways in pathological vascular remodeling and that resolvin D2 (RvD2) might prevent vascular remodeling and contractile and endothelial dysfunction in a model of obesity and hypertension. In aortic samples of patients with or without abdominal aortic aneurysms (AAA), we evaluated gene expression of enzymes involved in SPMs synthesis (ALOXs), SPMs receptors and pro-inflammatory genes. In an experimental model of aortic dilation induced by high fat diet (HFD, 60%, eighteen weeks) and angiotensin II (AngII) infusion (four weeks), we studied the effect of RvD2 administration in aorta and small mesenteric arteries structure and function and markers of inflammation. In human macrophages we evaluated the effects of AngII and RvD2 in macrophages function and SPMs profile. In patients, we found positive correlations between AAA and obesity, and between AAA and expression of ALOX15, RvD2 receptor GPR18, and pro-inflammatory genes. There was an inverse correlation between the expression of aortic ALOX15 and AAA growth rate. In the mice model, RvD2 partially prevented the HFD plus AngII-induced obesity and adipose tissue inflammation, hypertension, aortic and mesenteric arteries remodeling, hypercontratility and endothelial dysfunction, and the expression of vascular proinflammatory markers and cell apoptosis. In human macrophages, RvD2 prevented AngII-induced impaired efferocytosis and switched SPMs profile. RvD2 might represent a novel protective strategy in preventing vascular damage associated to hypertension and obesity likely through effects in vascular and immune cells.

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

BACKGROUND: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. METHODS: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. RESULTS: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. CONCLUSIONS: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin.

BACKGROUND: Obesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1-encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown. METHODS: A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models. RESULTS: MiR-137/325 repressed human KISS1 3'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats. CONCLUSIONS: Our data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity. SIGNIFICANCE STATEMENT: Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity.

Dose-response association of physical activity with acute myocardial infarction: do amount and intensity matter?

OBJECTIVE: The aims of this study were to analyze the dose-response association between leisure time physical activity (PA) practice and myocardial infarction (MI), considering not only the total amount but also the amount of PA at different levels of intensity, and to determine whether these associations were modified by age. METHOD: In a population-based age- and sex-matched case-control study, all first acute MI patients aged 25 to 74 years were prospectively registered in four Spanish hospitals between 2002 and 2004. Controls were randomly selected from population-based samples recruited during the same period of time. The Minnesota PA questionnaire was administered to assess total energy expenditure in PA and in light-, moderate-, and high-intensity PA. RESULTS: Finally, 1339 cases and 1339 controls were included. The association between PA and MI likelihood was non-linear, with significantly lower MI odds at low practice levels (≥ 500 MET·min/week), lowest odds around 1500 MET·min/week, and a plateau thereafter. Light- (in subjects older than 64 years), moderate-, and high-intensity PA produced similar benefits. CONCLUSION: Most of the population could reduce their likelihood of MI by engaging in PA at a moderate level of intensity or, in individuals older than 64 years, at a light level of intensity.