The Influence of Fatty Acid Oxygenases PpoA and PpoC on Caspofungin Susceptibility.

can cause invasive pulmonary aspergillosis (IPA). Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. Treatment of with CAS or micafungin induces the production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA.

An oxylipin signal confers protection against antifungal echinocandins in pathogenic aspergilli.

Aspergillus fumigatus is the leading causative agent of life-threatening invasive aspergillosis in immunocompromised individuals. One antifungal class used to treat Aspergillus infections is the fungistatic echinocandins, semisynthetic drugs derived from naturally occurring fungal lipopeptides. By inhibiting beta-1,3-glucan synthesis, echinocandins cause both fungistatic stunting of hyphal growth and repeated fungicidal lysis of apical tip compartments.

Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis.

Background: is a well-known opportunistic pathogen that causes a range of diseases including the often-fatal disease, invasive pulmonary aspergillosis (IPA), in immunocompromised populations. The severity of IPA is dependent on both host- and pathogen-derived signaling molecules that mediate host immunity and fungal growth. Oxylipins are bioactive oxygenated fatty acids known to influence host immune response and developmental programs.

Aspergillus fumigatus transcription factor ZfpA regulates hyphal development and alters susceptibility to antifungals and neutrophil killing during infection.

Hyphal growth is essential for host colonization during Aspergillus infection. The transcription factor ZfpA regulates A. fumigatus hyphal development including branching, septation, and cell wall composition.

Autonomic Nervous System Adaptation and Circadian Rhythm Disturbances of the Cardiovascular System in a Ground-Based Murine Model of Spaceflight.

Whether in real or simulated microgravity, Humans or animals, the kinetics of cardiovascular adaptation and its regulation by the autonomic nervous system (ANS) remain controversial. In this study, we used hindlimb unloading (HU) in 10 conscious mice. Blood pressure (BP), heart rate (HR), temperature, and locomotor activity were continuously monitored with radio-telemetry, during 3 days of control, 5 days of HU, and 2 days of recovery.

transcription factor ZfpA regulates hyphal development and alters susceptibility to antifungals and neutrophil killing during infection.

Unlabelled: Hyphal growth is essential for host colonization during infection. The transcription factor ZfpA regulates hyphal development including branching, septation, and cell wall composition. However, how ZfpA affects fungal growth and susceptibility to host immunity during infection has not been investigated.

Cardiac macrophage subsets differentially regulate lymphatic network remodeling during pressure overload.

The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking. We observed a remodeling of the cardiac lymphatic vessels and a reduced lymphatic efficiency during heart hypertrophy and failure induced by transverse aortic constriction. The lymphatic endothelial cell number of the failing hearts was positively correlated with cardiac function and with a subset of cardiac macrophages.

Cardiac sensory afferents modulate susceptibility to anxio-depressive behaviour in a mouse model of chronic heart failure.

Aim: Impairments in cerebral structure and cognitive performance in chronic heart failure (CHF) are critical components of its comorbidity spectrum. Autonomic afferents that arise from cardiac sensory fibres show enhanced activity with CHF. Desensitization of these fibres by local application of resiniferatoxin (RTX) during myocardial infarction (MI) is known to prevent cardiac hypertrophy, sympathetic hyperactivity and CHF.

Multimodal gadolinium oxysulfide nanoparticles for bioimaging: A comprehensive biodistribution, elimination and toxicological study.

For some years now, gadolinium oxysulfide nanoparticles (NPs) appear as strong candidates for very efficient multimodal in vivo imaging by: 1) Magnetic Resonance (MRI), 2) X-ray Computed Tomography (CT) and 3) photoluminescence imaging. In this paper, we present a selection of results centered on the evaluation of physico-chemical stability, toxicity, bio-distribution and excretion mechanisms of GdOS:Ln nanoparticles intravenously injected in rats. Two formulations are here tested with a common matrix and different dopants: GdOS:Eu and GdOS:Yb/Tm.

Macrophage-derived HMGB1 is dispensable for tissue fibrogenesis.

Alarmins and damage-associated molecular patterns (DAMPs) are powerful inflammatory mediators, capable of initiating and maintaining sterile inflammation during acute or chronic tissue injury. Recent evidence suggests that alarmins/DAMPs may also trigger tissue regeneration and repair, suggesting a potential contribution to tissue fibrogenesis. High mobility group B1 (HMGB1), a bona fide alarmin/DAMP, may be released passively by necrotic cells or actively secreted by innate immune cells.

Evaluation of upconverting nanoparticles towards heart theranostics.

Restricted and controlled drug delivery to the heart remains a challenge giving frequent off-target effects as well as limited retention of drugs in the heart. There is a need to develop and optimize tools to allow for improved design of drug candidates for treatment of heart diseases. Over the last decade, novel drug platforms and nanomaterials were designed to confine bioactive materials to the heart.

Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings.

Maytansinoids, the potent cytotoxic derivatives of the alkaloid maytansine are used as payloads in antibody maytansinoid conjugates. This article reviews clinical and preclinical hepatotoxicity observed with antibody maytansinoid conjugates used to treat cancer. Specific aspects of drug distribution, metabolism and excretion that may impact hepatotoxicity are reviewed vis-à-vis the kind of maytansinoid in the conjugate, cleavable or non-cleavable linkers, linker-payload combinations, drug to antibody ratio, metabolite formation, hepatic enzyme induction in relation to drug-drug interactions and species, age and gender differences.

Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart.

Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function.

Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction.

Aims: Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood.

Methods And Results: We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice.

Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction.

Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility.

Lens Capsule Perforation Without Inflammation in 4 Rabbits From Intravitreal Injection Studies.

Historically, it was thought that lens protein was sequestered, and injury to the lens capsule causing release of lens material into the eye would always result in ocular inflammation. Currently, it is believed that lens antigens are recognized as self, subject to normal T-cell tolerance. Three different single-dose intravitreal injection/implantation studies of 4 different test materials, ranging from 4 to 6 weeks in length, were performed in New Zealand White rabbits.

Systems biology combining human- and animal-data miRNA and mRNA data identifies new targets in ureteropelvic junction obstruction.

Background: Although renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined. In an attempt towards improved understanding of obstructive nephropathy and improved translatability of the results to clinical practice we have developed a systems biology approach combining omics data of both human and mouse obstructive nephropathy.

Results: We have studied in parallel the urinary miRNome of infants with ureteropelvic junction obstruction and the kidney tissue miRNome and transcriptome of the corresponding neonatal partial unilateral ureteral obstruction (UUO) mouse model.

Apelin-13 administration protects against ischaemia/reperfusion-mediated apoptosis through the FoxO1 pathway in high-fat diet-induced obesity.

Background And Purpose: Apelin-13, an endogenous ligand for the apelin (APJ) receptor, behaves as a potent modulator of metabolic and cardiovascular disorders. Here, we examined the effects of apelin-13 on myocardial injury in a mouse model combining ischaemia/reperfusion (I/R) and obesity and explored their underlying mechanisms.

Experimental Approach: Adult male C57BL/6J mice were fed a normal diet (ND) or high-fat diet (HFD) for 6 months and then subjected to cardiac I/R.

Apelin regulates FoxO3 translocation to mediate cardioprotective responses to myocardial injury and obesity.

The increasing incidence of obesity accentuates the importance of identifying mechanisms and optimal therapeutic strategies for patients with heart failure (HF) in relation to obesity status. Here, we investigated the association between plasma level of apelin, an adipocyte-derived factor, and clinicopathological features of obese and non-obese patients with HF. We further explored potential regulatory mechanisms of cardiac cell fate responses in conditions combining myocardial injury and obesity.

Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody.

Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV.

Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive.

Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin-angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed.

Targeting PI3Kγ activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response.

Interventional strategies to treat atherosclerosis, such as transluminal angioplasty and stent implantation, often cause vascular injury. This leads to intimal hyperplasia (IH) formation that induces inflammatory and fibroproliferative processes and ultimately restenosis. We show that phosphoinositide 3-kinase γ (PI3Kγ) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment.

Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin.

Background/objectives: Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin has a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state.

CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload.

Background: The mechanisms by which the heart adapts to chronic pressure overload, producing compensated hypertrophy and eventually heart failure (HF), are still not well defined. We aimed to investigate the involvement of T cells in the progression to HF using a transverse aortic constriction (TAC) model.

Methods And Results: Chronic HF was associated with accumulation of T lymphocytes and activated/effector CD4(+) T cells within cardiac tissue.