Tissue Accumulation Research Articles

From insects to mammals! Tissue accumulation and transgenerational transfer of micro/nano-plastics through the food chain

Despite extensive global attention on microplastic pollution, our understanding of the pathways underlying microplastic translocation, accumulation, and their potential impacts on ecosystems and human health through the food chain remains incomplete. To investigate the translocation and accumulation of microplastics from insects to mammals, we developed a novel oral exposure model that Tenebrio molitor larvae (yellow mealworms, invertebrate terrestrial insects) were firstly orally exposed to both micro and nanometer-sized plastics (M/NPs), and subsequently fed as a food source to mice (mammals). Our results provide clear evidence that micro/nanoplastics (M/NPs) do indeed translocate through the food chain, from lower to higher trophic levels. Fluorescence microscopy and tissue quantification revealed the accumulation of M/NPs in the digestive, somatic, and circulatory systems of the larvae. Specifically, the food chain transferred M/NPs were later detected in the digestive, respiratory, and urinary systems of mice, showcasing strong fluorescent signals in vital organs such as the lungs, liver, intestines, brain, and kidneys, as well as in embryos. These findings highlight the intricate dynamics of M/NPs contamination, emphasizing their ability to traverse biological barriers, accumulate in organisms, and potentially impact embryonic development via food chain transfer. Environmental ImplicationMicro/nano plastics (M/NPs) have emerged as a critical environmental hazard, with their ability to infiltrate food chains and accumulate in organisms posing serious risks. Despite rising awareness, the M/NPs translocation, bioaccumulation, and impacts on ecosystems and human health within food chains, remains poorly understood. In this study, we developed a novel model in which insects exposed to M/NPs are subsequently fed to mammals, revealing the transfer of M/NPs between species through the food chain. Our results demonstrate that the M/NPs penetrate biological barriers, accumulate in vital organs, and even reach embryos, raising serious concerns for environmental and human health.

Unveiling the potential of intranasal delivery of renin-angiotensin system drugs: Insights on the pharmacokinetics of irbesartan

The therapeutic interest of renin-angiotensin system (RAS) drugs for the treatment of neuroinflammation has been recently acknowledged. Nevertheless, most RAS drugs display limited passage across the blood–brain barrier (BBB). Therefore, this study investigated the potential of intranasal (IN) delivery of six RAS drugs to circumvent the BBB and attain the brain, envisioning its future use in central nervous system (CNS) neuroinflammatory diseases, such as Alzheimer’s disease (AD).Captopril, enalaprilat, irbesartan, lisinopril, losartan and valsartan were firstly screened based on their impact on the viability of nasal, lung, and neuronal cell lines and their apparent permeability (Papp) across porcine olfactory mucosa. Irbesartan, identified as the one with the best safety and permeability balance, was selected for pharmacokinetic characterization following single and multidose IN administration to CD-1 mice. The results were compared to those obtained by intravenous (IV) injection to assess direct nose-to-brain drug delivery. Olfactory toxicity and anxiety were also evaluated after multidose IN treatment.Irbesartan IN administration significantly enhanced brain targeting, with a 3-fold increase in the maximum concentration (Cmax) and a 2.5-fold increase in the area under the curve (AUCt) in the brain compared to IV route. The drug exhibited a tmax of 15 min post-IN administration and achieved a brain targeting efficiency of 239.56%, with a significant direct transport percentage of 58.26%. Multidose administration indicated no systemic or tissue accumulation, with accumulation ratio (Rac) values below 1.0, and no significant olfactory toxicity.Overall, the study highlights the potential of IN delivery of irbesartan as a promising strategy to improve brain targeting and therapeutic outcomes in CNS diseases such as AD, providing an effective approach to bypass BBB limitations.

Hypoxia-inducible factor-2α enhances neutrophil survival to promote cardiac injury following myocardial infarction.

Heart failure is a major cause of mortality following myocardial infarction. Neutrophils are among the first immune cells to accumulate in the infarcted region. Although beneficial functions of neutrophils in heart injury are now appreciated, neutrophils are also well known for their ability to exacerbate inflammation and promote tissue damage. Myocardial infarction induces hypoxia, where hypoxia-inducible factors (HIFs) are activated and play critical roles in cellular functions. In this context, the role of Hif2α in neutrophils during myocardial infarction is unknown. Here, we demonstrate that neutrophil Hif2α deletion markedly attenuates myocardial infarct size, improves cardiac function, reduces neutrophil survival and tissue accumulation, and correlates with increased macrophage engulfment rates. Mechanistic studies revealed that Hif2α promotes neutrophil survival through binding to hypoxia response element (HRE) in the promoter region of Birc2 to regulate expression of the prosurvival factor, cellular inhibitor of apoptosis protein-1 (cIAP1). Inhibition of cIAP1 in neutrophils using the pharmacological agent, Birinapant resulted in increased cell death, establishing a critical role of cIAP1 downstream of Hif2α in neutrophil survival. Taken together, our data demonstrate a protective effect of Hif2α deletion in neutrophils on cardiac injury outcomes through modulation of neutrophil cell survival.NEW & NOTEWORTHY Hif2α in neutrophils increases infarct size, cardiac dysfunction, and ventricular scar after myocardial infarction. Hif2α in neutrophils supports neutrophil survival via cIAP-1 signaling and delays macrophage engulfment.

Lack of adipocyte FAM20C improves whole body glucose homeostasis.

FAM20C, a member of the family with sequence similarity 20, is involved in many physiological functions. Obesity, characterized by excessive accumulation of adipose tissue, has attracted more and more attention as a worldwide health problem. Here we generated adipocyte-specific FAM20C knockout mice to investigate the role of FAM20C in adipose tissue expansion and obesity. Our results demonstrate that knockout mice are protected against high fat diet-induced obesity, adiposity, and fatty liver disease. Additionally, knockout mice exhibited improved metabolic phenotypes, including enhanced glucose tolerance and insulin sensitivity compared with control mice. Furthermore, we observed reduced inflammatory infiltration and collagen deposition in the adipose tissues of knockout mice. Taken together, our results indicate that targeting FAM20C in adipocytes may be a promising strategy for the treatment of obesity and associated metabolic disorders.

Radish red protects against early diabetic kidney disease through inhibiting inflammation, pyroptosis and insulin resistance via IRAK1 signaling suppression

Diabetic kidney disease (DKD) is a major diabetic complication and a leading cause of end-stage renal disease (ESRD), but the therapeutic strategies for DKD are still limited. Red radishes (Raphanus sativus L.) are a rich source of natural anthocyanins that have antioxidant, anti-apoptotic and anti-inflammatory activities. In this study, we attempted to explore the effects of natural pigment anthocyanin called radish red (RR) extracted from red radishes on DKD progression and the underlying molecular mechanisms. RR dose-dependently reduced the tubular cell injury, indicated by the decreased expression of kidney injury molecule 1 (KIM1). Furthermore, releases of pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) stimulated by HF were strongly relieved by RR. Inflammatory response and pyroptosis were also identified to be induced by HF stimulation but were mitigated by RR in HK2 cells through repressing nuclear factor-κB (NF-κB) activation and NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. IR and lipogenesis due to HF exposure were also significantly ameliorated by RR in HK2 cells. Mechanistically, RNA-Seq analysis showed that RR strongly depressed interleukin-1 receptor-associated kinase-1 (IRAK1)-mediated NLRP3 inflammasome, pyroptosis, IR and lipid deposition. Importantly, IRAK1 overexpression almost diminished the beneficial effects of RR, while being rescued upon NLRP3 knockdown in HF-treated HK2 cells, revealing that RR performed its nephroprotective functions in diabetic kidney via inactivating the IRAK1-NLRP3 signaling pathway. Similarly, animal studies confirmed that RR supplementation efficiently ameliorated HFF-caused metabolic disturbance, IR, renal dysfunctions in mice and improved structural kidney damage. Consistently, RR consumption dramatically reduced lipid accumulation, inflammatory response and pyroptosis in kidney tissues of HFF-challenged mice mainly through repressing IRAK1-NLRP3 axis. Our results demonstrated that dietary supplementation with RR may serve as an IRAK1-NLRP3 inhibitor for preventing and treating diabetic nephropathy.

Pulmonary Delivery of Dual-Targeted Nanoparticles Improves Tumor Accumulation and Cancer Cell Targeting by Restricting Macrophage Interception in Orthotopic Lung Tumors

Despite the recognized potential of inhaled nanomedicines to enhance and sustain local drug concentrations for lung cancer treatment, the influence of macrophage uptake on targeted nanoparticle delivery to and within tumors remains unclear. Here, we developed three ligand-coated nanoparticles for pulmonary delivery in lung cancer therapy: phenylboronic acid-modified nanoparticles (PBA-NPs), PBA combined with folic acid (FA-PBA-NPs), and PBA with mannose (MAN-PBA-NPs). In vitro, MAN-PBA-NPs were preferentially internalized by macrophages, whereas FA-PBA-NPs exhibited superior uptake by cancer cells compared to macrophages. Following intratracheal instillation into mice with orthotopic Lewis lung carcinoma tumors, all three nanoparticles showed similar lung retention. However, MAN-PBA-NPs were more prone to interception by lung macrophages, which limited their accumulation in tumor tissues. In contrast, both PBA-NPs and FA-PBA-NPs achieved comparable high tumor accumulation (∼11.3% of the dose). Furthermore, FA-PBA-NPs were internalized by ∼30% of cancer cells, significantly more than the 10-18% seen with PBA-NPs or MAN-PBA-NPs. Additionally, FA-PBA-NPs loaded with icaritin effectively inhibited the Wnt/β-catenin pathway, resulting in superior anti-tumor efficacy through targeted cancer cell delivery. Overall, FA-PBA-NPs demonstrated advantageous competitive uptake kinetics by cancer cells compared to macrophages, enhancing tumor targeting and therapeutic outcomes.

Detrimental Effect of Chloride on Suppressing Cadmium Accumulation in Rice Grains: A Field-Based Investigations

Cadmium (Cd) contamination in rice ecosystems poses significant threats to global food security and ecological sustainability. This study addresses the urgent need to understand how chloride (Cl-) addition impacts on Cd dynamics in the soil-rice system, given the widespread use of Cl-containing materials in agriculture practices. Our findings indicated that Cl- addition significantly lowered soil pH, increased redox potential (Eh), and facilitated the formation of Cl-Cd complexes, enhancing Cd solubility, mobility, and bioavailability. Cl- also decreased DTPA-extractable iron (Fe) and manganese (Mn), indirectly increasing Cd uptake by rice roots (by 17.4% to 65.0%) through upregulation of OsNramp1 and OsNramp5 transport genes, while diminishing iron plaque formation on roots by 23.1% to 27.2%. Furthermore, Cl- facilitated Cd translocation from roots to shoots via upregulation of OsHMA2 gene, leading to elevating Cd accumulation in rice tissues and increasing Cd levels in brown rice by 41.3% to 76.1%. Field trials corroborated that Cl- application in slightly acidic, Cd-contaminated soils exacerbated Cd accumulation in rice grains, posing heightened risks to food safety. These results underscore the critical need to limit Cl-containing materials in agriculture to safeguard crop safety and protect ecological health.

Cardiovascular profile drugs and the state of periodontal tissues

People with CVD, mostly over 50 years of age, regularly take medications such as beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), statins and acetylsalicylic acid (ASA). Periodontal tissue disease (PTD) occurs in the age group 35–44 years in 60% of cases, in the group of people 65–74 years – about 70%, that is, in that period of life when cardiovascular disease (CVD) begins to develop and progress. Some cardioprotective drugs, such as antihypertensives, cause xerostomia. Medication-induced xerostomia is one of the common causes of oral health problems in older adults who are on long-term drug therapy. Xerostomia is a common debilitating condition that causes problems such as dysphagia, loss of taste, and oral pain, as well as increasing the risk of tooth decay and oral infections. Drug-induced gingival overgrowth is an abnormal hypertrophy of the gingiva that can be caused by a number of medications, including calcium channel blockers. Drug-induced gingival overgrowth is characterized by the accumulation of connective tissue that primarily affects the anterior regions of the upper and lower jaw, and also causes problems with oral hygiene, which leads to susceptibility to infections and periodontal disease and can lead to tooth loss. Anticoagulants used in CVD due to the risk of bleeding require special approaches in the prevention and therapy of periodontal tissue disease. The possibilities of using statins in PTD due to their pleiotropic properties, independent of hypolipidemic action. The review article is devoted to the influence of drugs of cardiovascular profile on the state of periodontal tissues and mechanisms of development of side effects, as well as the possibilities of using statins taking into account their pleiotropic effects.

Interactions between glucagon like peptide 1 (GLP-1) and estrogens regulates lipid metabolism

Obesity, characterized by excessive fat accumulation in white adipose tissue (WAT), is linked to numerous health issues, including insulin resistance (IR), and type 2 diabetes mellitus (DM2). The distribution of adipose tissue differs by sex, with men typically exhibiting android adiposity and pre-menopausal women displaying gynecoid adiposity. After menopause, women have an increased risk of developing android-type obesity, IR, and DM2. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are important in treating obesity and DM2 by regulating insulin secretion, impacting glucose and lipid metabolism. GLP-1Rs are found in various tissues including the pancreas, brain, and adipose tissue. Studies suggest GLP-1RAs and estrogen replacement therapies have similar effects on tissues like the liver, central nervous system, and WAT, probably by converging pathways involving protein kinasesTo investigate these interactions, female rats underwent ovariectomy (OVR) to promote a state of estrogen deficiency. After 20 days, the rats were euthanized and the tissues were incubated with 10 μM of liraglutide, a GLP-1RA. Results showed significant changes in metabolic parameters: OVR increased lipid catabolism in perirenal WAT and basal lipolysis in subcutaneous WAT, while liraglutide treatment enhanced stimulated lipolysis in subcutaneous WAT. Liver responses included increased stimulated lipolysis with liraglutide. Transcriptome analysis revealed distinct gene expression patterns in WAT of OVR rats and those treated with GLP-1RA, highlighting pathways related to lipid and glucose metabolism. Functional enrichment analysis showed estrogen’s pivotal role in these pathways, influencing genes involved in lipid metabolism regulation.Overall, the study underscores GLP-1RA acting directly on adipose tissues and highlights the complex interactions between GLP-1 and estrogen in regulating metabolism, suggesting potential synergistic therapeutic effects in treating metabolic disorders like obesity and DM2.

Mesenchymal stem/stromal cells alleviate early-stage pulmonary fibrosis in a uPAR-dependent manner.

Pulmonary fibrosis, a debilitating lung disorder characterised by excessive fibrous tissue accumulation in lung parenchyma, compromises respiratory function leading to a life-threatening respiratory failure. While its origins are multifaceted and poorly understood, the urokinase system, including urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plays a significant role in regulating fibrotic response, extracellular matrix remodelling, and tissue repair. Mesenchymal stem/stromal cells (MSCs) hold promise in regenerative medicine for treating pulmonary fibrosis. Our study aimed to investigate the potential of MSCs to inhibit pulmonary fibrosis as well as the contribution of uPAR expression to this effect. We found that intravenous MSC administration significantly reduced lung fibrosis in the bleomycin-induced pulmonary fibrosis model in mice as revealed by MRI and histological evaluations. Notably, administering the MSCs isolated from adipose tissue of uPAR knockout mice (Plaur-/- MSCs) attenuated lung fibrosis to a lesser extent as compared to WT MSCs. Collagen deposition, a hallmark of fibrosis, was markedly reduced in lungs treated with WT MSCs versus Plaur-/- MSCs. Along with that, endogenous uPA levels were affected differently; after Plaur-/- MSCs were administered, the uPA content was specifically decreased within the blood vessels. Our findings support the potential of MSC treatment in attenuating pulmonary fibrosis. We provide evidence that the observed anti-fibrotic effect depends on uPAR expression in MSCs, suggesting that uPAR might counteract the uPA accumulation in lungs.

Human peripancreatic adipose tissue paracrine signaling impacts insulin secretion, blood flow, and gene transcription.

Adipose tissue accumulation around non-adipose tissues is associated with obesity and metabolic disease. One relatively unstudied depot is peripancreatic adipose tissue (PAT) that accumulates in obesity and insulin resistance and may impact beta cell function. Pancreatic lipid accumulation and PAT content are negatively related to metabolic outcomes in humans, but these studies are limited by the inability to pursue mechanisms. We obtained PAT from human donors through the Human Pancreas Analysis Program to evaluate differences in paracrine signaling compared to subcutaneous adipose tissue (SAT), as well as effects of the PAT secretome on aortic vasodilation, human islet insulin secretion, and gene transcription using RNAseq. PAT had greater secretion of IFN-γ and most inflammatory eicosanoids compared to SAT. Secretion of adipokines negatively related to metabolic health were also increased in PAT compared to SAT. We found no overall effects of PAT compared to SAT on human islet insulin secretion, however, insulin secretion was suppressed after PAT exposure from men compared to women. Vasodilation was significantly dampened by PAT conditioned media, an effect explained almost completely by PAT from men and not women. Islets treated with PAT showed selective changes in lipid metabolism pathways while SAT altered cellular signaling and growth. RNAseq analysis showed changes in islet gene transcription impacted by PAT compared to SAT, with the biggest changes found between PAT based on sex. The PAT secretome is metabolically negative compared to SAT, and impacts islet insulin secretion, blood flow, and gene transcription in a sex dependent manner.

Mutation of the K+ transporter SlHAK5 of tomato alters pistil morphology, ionome, metabolome and transcriptome in flowers.

K+ accumulation in plant tissues is a crucial factor for plant growth and development. The tomato high-affinity K+ transporter SlHAK5 is essential for root K+ acquisition from low external concentrations. It is also involved in K+ accumulation in pollen and plant fertility as slhak5 KO plants show a low rate of pollen germination, impaired pollen tube growth and parthenocarpic fruits. Here, we present a thorough analysis of slhak5 flowers, which showed relevant defects at the anatomic, ionomic, metabolomic and transcriptomic levels. First, slhak5 flowers exhibited shorter styles and enlarged ovaries that, together with a low number of seeds in fruits from slhak5 X WT crosses, indicated an effect of the slhak5 mutation on female fertility. Second, a lower accumulation of Ca2+, as well as of several metabolites such as amino acids, citric acid and sugars, was observed in mutant flowers, whereas indole-3-acetic acid content was increased when compared to the wild-type. Third, RNAseq conducted on pistils and stamens of wild-type and slhak5 plants revealed that transport and signalling pathways are significantly enriched in the gene expression analyses of stamens. Thus, it can be concluded that a functional SlHAK5 transporter is required to maintain appropriate Ca2+, metabolite and gene expression levels in flowers, and its absence leads to important reductions in both male and female fertility.

Non-invasive system delivering microwaves energy for localized adiposity reduction, skin laxity, and cellulite: Clinical evidence

Localized adiposities are the accumulation of subcutaneous adipose tissue resulting in an alteration of the body silhouette. This study evaluates the efficacy and safety of a non-invasive microwaves (MWs) device for the treatment of localized adiposities of the thighs and abdomen. Sixteen women enrolled underwent four sessions with the study device at intervals of 30 days. Clinical evaluation, anthropometric evaluation, ultrasound evaluations, and 3D photographs were performed. Cellulite and skin laxity were evaluated. Patients filled 4-points Global Aesthetic Improvement Scale (GAIS) and 10-points Visual Analog Scale. The mean abdominal circumference significantly (P <0.05) decreased 4 weeks after the last treatment, and the mean culotte/thighs circumference significantly (P < 0.05) decreased 4 weeks after the last treatment. Both cellulite and skin laxity were improved. The GAIS scores showed satisfactory results. No adverse effects were observed. This MWs system has been found to be safe and effective in the reduction of body circumferences.

Ror2 signaling regulated by differential Wnt proteins determines pathological fate of muscle mesenchymal progenitors

Skeletal muscle mesenchymal progenitors (MPs) play a critical role in supporting muscle regeneration. However, under pathological conditions, they contribute to intramuscular adipose tissue accumulation, involved in muscle diseases, including muscular dystrophy and sarcopenia, age-related muscular atrophy. How MP fate is determined in these different contexts remains unelucidated. Here, we report that Ror2, a non-canonical Wnt signaling receptor, is selectively expressed in MPs and regulates their pathological features in a differential ligand-dependent manner. We identified Wnt11 and Wnt5b as ligands of Ror2. In vitro, Wnt11 inhibited MP senescence, which is required for normal muscle regeneration, and Wnt5b promoted MP proliferation. We further found that both Wnts are abundant in degenerating muscle and synergistically stimulate Ror2, leading to unwanted MP proliferation and eventually intramuscular adipose tissue accumulation. These findings provide evidence that Ror2-mediated signaling elicited by differential Wnts plays a critical role in determining the pathological fate of MPs.

Myocardial DNA damage is responsible for the relationship between genotype and treatment response in patients with dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) is one of the leading causes of heart transplantation. Our group and others have previously reported that DNA damage accumulation in myocardial tissue and certain genetic variants such as those in LMNA are associated with treatment response and prognosis (ref 1-5). However, the potential association between myocardial DNA damage and genotype, and their contribution when combined to predicting treatment response, remains unclear. Methods We identified the deleterious variants in cardiomyopathy-related genes by analyzing the whole exome sequencing data from 89 patients with DCM who were recruited from two participating facilities. Immunostaining of γ-H2A.X, a DNA damage marker, was performed on endomyocardial biopsy specimens from the same patients, from which the percentage of nuclei positive for γ-H2A.X signals (%γ-H2A.X) was calculated. Left ventricular reverse remodeling (LVRR) was assessed by transthoracic echocardiography at 1 year after biopsy. We examined the associations among genotype, myocardial DNA damage, and the achievement of LVRR. Results Among the 89 patients with DCM, 11 (12.4%) carried pathogenic or likely pathogenic (P/LP) variants in sarcomere genes such as TTN, and 21 (23.6%) carried P/LP variants in non-sarcomere genes such as LMNA, while the rest had no P/LP variants in cardiomyopathy-related genes (Figure A). Patients with P/LP variants in sarcomere genes had a lower %γ-H2A.X [21.2 (10.7–29.0)% vs. 7.0 (4.3–12.4)%, P = 0.002] (Figure B), and a higher probability to achieve LVRR at 1-year (81.8% vs. 23.8%, P = 0.003) (Figure C) when compared to those with P/LP variants in non-sarcomere genes. The odds ratio for carriers of P/LP variants in sarcomere genes to achieve LVRR was 14.40 (95%CI 2.31–89.94) compared to that for carriers of P/LP variants in non-sarcomere genes. However, this effect was markedly attenuated after adjusting for the proportion of γ-H2A.X-positive nuclei [adjusted odds ratio 6.05 (95%CI 0.86–42.53)] (Table). Conclusions Among patients with DCM, carriers of P/LP variants in sarcomere genes showed less DNA damage and a favorable treatment response, when compared with carriers of P/LP variants in non-sarcomere genes. Our results suggest that myocardial DNA damage was partially responsible for the relationship between genotype and treatment response in patients with DCM.Figure, panels A-C

Dapagliflozin reduces epicardial adipose tissue in patients with heart failure with reduced ejection fraction and type 2 diabetes

Abstract Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse outcome in heart failure with preserved ejection fraction, however its role in HF with reduced ejection fraction (HFrEF) is less clear. The relationship between EAT thickness and their impact on patients who have diabetes and heart failure remains unclear. SGLT2 inhibitors such as dapagliflozin improve outcomes in heart failure and diabetes, however their mechanism of benefit is not well understood. The aim of our study was to assess whether dapagliflozin reduced EAT in patients with type 2 diabetes and HFrEF. Methods We performed an analysis of individuals with type 2 diabetes and HFrEF who were randomised to receive either dapagliflozin or a placebo for 12 months as part of the REFORM trial. Participants had cardiac magnetic resonance (CMR) scans at baseline and at 12 months. Epicardial fat was measured utilizing 4-chamber cine images to quantify adipose tissue between the myocardium and the visceral layer of the pericardium. This assessment was carried out using the single end-diastolic image, with measurements conducted by evaluators blinded to the randomisation status of participants. Results 47 participants completed the stud. At baseline, not only EAT thickness and BMI level (placebo: 33, dapagliflozin 32, p=0.49) but also heart rate (74.39 bpm vs. 77.61 bpm, p=0.35), systolic blood pressure (132.75 mmHg vs. 135.00 mmHg, p=0.63), diastolic blood pressure (71.39 mmHg vs. 74.04 mmHg, p=0.33) and age (67 vs. 66, p=0.79) were comparable between the two groups. 23 randomised to placebo and 24 to dapagliflozin. Baseline EAT was similar in both groups (placebo: 11.54 cm², dapagliflozin 11.74 cm², p=0.414). After 12 months of treatment dapagliflozin caused a significant reduction in EAT compared to placebo (1.21 cm² vs. 0.09 cm², p=0.007). Conclusion Dapagliflozin significantly reduced epicardial adipose tissue compared to placebo in patients with type 2 diabetes and HFrEF. The reduction in EAT may play a role in the beneficial effects of dapagliflozin in heart failure patients.4 Ch CMRBox plot

The dynamic increment of epicardial adipose tissue is associated with reverse remodeling after guideline-directed medical treatment in dilated cardiomyopathy patients

Abstract Background/Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse prognosis in patients with HFpEF and a better prognosis in HFrEF patients. Whether EAT is playing a protective role in dilated cardiomyopathy (DCM) patients have been described sparingly. Purpose Aim to explore whether the epicardial fat would change along with the dynamic changes in cardiac function and volumes after receiving guideline-directed medical therapy (GDMT) in patients with DCM. Methods We prospectively enrolled 232 DCM patients who underwent complete baseline and follow-up Cardiac magnetic resonance (CMR) examinations. The measurement of the epicardial fat composition includes epicardial fat thickness, paracardial fat thickness, and paracardial fat volume, while the measurement of body fat composition includes subcutaneous and visceral abdominal fat, while We used univariable and multivariable logistic regression to evaluate the association between different body and cardiac fat depots with the changes in bi-ventricular structure (delta indexed EDV) and function (delta EF). Results The study included 232 patients (mean age 46.1±14.1 years, 157 (67.7%) males). After GDMT, we found that the visceral fat thickness and EAT (thickness and volume) tend to significantly increase. The increase in the (left ventricular reverse remodeling) LVRR group was significantly higher compared with the non-LVRR group. Independently with the changes of BMI and body fat depots, the increment of EAT was associated with the improvement in bi-ventricular function and volumes (significantly positively correlated with the improvement of LVEF (r = 0.499, p < 0.001), and RVEF (r = 0.482, p < 0.001), negatively correlated with delta LVEDVi (r = -0.407, p < 0.001), delta RVEDVi (r = -0.305, p < 0.001)). Conclusions After GDMT, the increment of EAT was positively correlated with the improvement of bi-ventricular structure and function, independent of the changes in BMI and body fat depots.Graphic Abstract

Secretomes from human epicardial adipocytes modulate atrial lymphatics and atrial fibrosis

Abstract Background Cardiac lymphatics maintains myocardial fluid and immune cell homeostasis. Downregulation of cardiac lymphatics leads to cardiac dysfunction through impairment of inflammation and edema. On the other hand, it is well known that adipose tissue accumulation causes lymphatic dysfunction and impairs lymphedema. Purpose We evaluated the expression of atrial lymphatics in human left atrial appendage (LAA) histologically and biologically. Subsequently, we examined secretomes from epicardial adipose tissue (EAT)-derived adipocytes and validated if they change atrial lymphatics expression using ex vivo Organo-culture system. Methods Human LAA samples were collected from forty-two patients during cardiovascular surgery. They were categorized into the sinus rhythm (SR) group (n=16, 73.1±10.4 years), the paroxysmal AF (PAF) group (n=13, 69.8±12.6 years) and the persistent AF (PeAF) group (n=13, 71.2±6.5 years). Human EAT were also excised from patients with and without AF (SR; n=5, AF; n=11) during cardiovascular surgery. Preadipocytes were extracted from EAT by homogenization and collagenase treatment, and cultured to confluence. After differentiation and maturation to adipocytes, cell culture supernatant (CCS) was collected, and was dropped onto the epicardial side of left atrial tissues excised from 8 weeks old male rats for 7 days using an ex vivo organo-culture system. Results In human LAA samples, mRNA expression of lymphangiogenesis-related genes (LYVE1, PROX1, VEGFC, and VEGFR3) was significantly lower in the PeAF group compared to the SR group (p=0.0370, <0.0001, 0.0157, and 0.0009). The number of LYVE1-positive atrial lymphatic endothelial cells (LECs) was also significantly lower in the PeAF group compared to the SR group and the PAF group (p=0.0186 and 0.038). There was a negative correlation between the number of LYVE1-positive atrial LECs and the area percentage of atrial myocardial fibrosis (r=-0.5350, p<0.001). In the experiment using organo-culture system, lymphangiogenesis-related genes expression (Lyve1, Prox1, Vegfc, and Vegfr3) of rat atria treated with CCS of adipocytes from AF patients was significantly lower than those from SR patients (p=0.0391, 0.0100, 0.0034, and 0.0338). Furthermore, the CCS of adipocytes from AF patients contained higher protein levels of leptin, which is known to suppress lymphangiogenesis (p=0.0357). Leptin treatment (100ng/ml) on rat atria also decreased lymphangiogenesis-related genes expression such as Lyve1, Prox1, Vegfc, and Vegfr3 (p=0.0413, < 0.0001, <0.0001, and 0.0190). Conclusions Our study with human LAA demonstrated that atrial lymphatics interact with atrial myocardial fibrosis/progression of AF. Furthermore, our findings indicate that secretomes from EAT-derived adipocytes regulate atrial lymphatics expression, and leptin plays an important role in modulating atrial lymphangiogenesis.

A cross‐sectional study on quality of life in adult indolent systemic mastocytosis and its association with cutaneous involvement

AbstractBackgroundSystemic mastocytosis (SM) is characterized by abnormal mast cell accumulation in various tissues, including the skin, and encompasses several clinical variants, ranging from less aggressive to more severe forms. ISM, the most common variant, often presents with cutaneous manifestations, causing significant impairment in QoL due to mediator‐release symptoms and stigma associated with typical cutaneous lesions.ObjectivesThe study aimed to assess QoL impairment in ISM patients and its correlation with demographic and clinical data.MethodsA cohort of 52 adult ISM patients was evaluated using the Dermatology Life Quality Index (DLQI) and the mastocytosis QoL questionnaire (MC‐QoL). Questionnaire scores were then analyzed in relation to the clinical and demographic characteristics of the patients.ResultsOver half of the patients experienced mild or higher levels of impairment in QoL, with female patients showing greater impairment than males. Patients with recent symptom onset reported higher MC‐QoL scores, possibly due to psychological factors and lack of disease knowledge. Cutaneous symptoms significantly impacted QoL, and the visibility of lesions affected DLQI scores more than MC‐QoL scores. A moderately strong correlation was observed between DLQI and MC‐QoL scores, particularly in the Skin and Social Life domains. The study highlights gender differences in QoL impairment, suggesting the need for further investigation into potential social or cultural factors.ConclusionsWhile the study provides valuable insights into QoL impairment in ISM patients, its monocentric nature and small sample size are notable limitations. Further research is warranted to better understand the impact of SM on patients' well‐being and to identify effective strategies for managing symptoms and improving overall QoL in this population.

Oxidative Stress Associated With Increased Reactive Nitrogen Species Generation in the Liver and Kidney Caused by a Major Metabolite Accumulating in Tyrosinemia Type 1.

Tyrosinemia type 1 (TT1) is caused by fumarylacetoacetate hydrolase activity deficiency, resulting in tissue accumulation of upstream metabolites, including succinylacetone (SA), the pathognomonic compound of this disease. Since the pathogenesis of liver and kidney damage observed in the TT1-affected patients is practically unknown, this study assessed the effects of SA on important biomarkers of redox homeostasis in the liver and kidney of adolescent rats, as well as in hepatic (HepG2) and renal (HEK-293) cultured cells. SA significantly increased nitrate and nitrite levels and decreased the concentrations of reduced glutathione (GSH) in the liver and kidney, indicating induction of reactive nitrogen species (RNS) generation and disruption of antioxidant defenses. Additionally, SA decreased the GSH levels and the activities of glutathione peroxidase, glutathione S-transferase, glutathione reductase, and superoxide dismutase in hepatic and renal cells. Noteworthy, melatonin prevented the SA-induced increase of nitrate and nitrite levels in the liver. Therefore, SA-induced increase of RNS generation and impairment of enzymatic and nonenzymatic antioxidant defenses may contribute to hepatopathy and renal disease in TT1.