Fluorescent probes capable of in vivo lipids labeling are highly desirable for studying lipid‐accumulation‐related metabolic diseases, such as nonalcoholic fatty liver disease, type‐2 diabetes, and ...atherosclerosis. However, most of the current lipid‐specific fluorophores cannot be used for in vivo labeling due to their strong hydrophobicity. Herein, organic dots from bright luminogens with aggregation‐induced emission (AIEgen) are developed for in vivo labeling and three‐photon fluorescence imaging of lipid‐rich tissues, such as fatty liver, atherosclerotic plaques in brain vasculatures, and carotid arteries. The organic dots show excellent stability in an aqueous medium with high targeting specificity to lipids and strong three‐photon fluorescence in the far‐red/near‐infrared (NIR) region under NIR‐II laser excitation, which enables efficient in vivo labeling and imaging of lipids in deep tissues. The study will inspire the development of lipid‐targeting fluorophores for in vivo applications.
Stable aggregation‐induced‐emission (AIE) dots in an aqueous medium are synthesized for in vivo labeling of lipids. The ultrabright fluorescence in the far‐red/near‐infrared (NIR) region (quantum yield of 26%) enables intravital three‐photon fluorescence imaging of lipids in fatty liver and atherosclerotic plaques in brain vasculatures and carotid arteries under NIR‐II laser excitation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ischemic heart disease (IHD) is the leading cause of disability and mortality worldwide. Reactive oxygen species (ROS) have been shown to play key roles in the progression of diabetes, hypertension, ...and hypercholesterolemia, which are independent risk factors that lead to atherosclerosis and the development of IHD. Engineered biomaterial‐based nanomedicines are under extensive investigation and exploration, serving as smart and multifunctional nanocarriers for synergistic therapeutic effect. Capitalizing on cell/molecule‐targeting drug delivery, nanomedicines present enhanced specificity and safety with favorable pharmacokinetics and pharmacodynamics. Herein, the roles of ROS in both IHD and its risk factors are discussed, highlighting cardiovascular medications that have antioxidant properties, and summarizing the advantages, properties, and recent achievements of nanomedicines that have ROS scavenging capacity for the treatment of diabetes, hypertension, hypercholesterolemia, atherosclerosis, ischemia/reperfusion, and myocardial infarction. Finally, the current challenges of nanomedicines for ROS‐scavenging treatment of IHD and possible future directions are discussed from a clinical perspective.
The current developments, achievements, challenges, and future directions of reactive oxygen species (ROS)‐scavenging nanomedicine for the treatment of ischemic heart disease (IHD), as well as their risk factors, are reviewed. The properties, generation, and physiological roles of ROS in the process of IHD development and progression are discussed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The COVID‐19 pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has caused great impact on the global economy and people's daily life. In the clinic, most patients ...with COVID‐19 show none or mild symptoms, while approximately 20% of them develop severe pneumonia, multiple organ failure, or septic shock due to infection‐induced cytokine release syndrome (the so‐called “cytokine storm”). Neutralizing antibodies targeting inflammatory cytokines may potentially curb immunopathology caused by COVID‐19; however, the complexity of cytokine interactions and the multiplicity of cytokine targets make attenuating the cytokine storm challenging. Nonspecific in vivo biodistribution and dose‐limiting side effects further limit the broad application of those free antibodies. Recent advances in biomaterials and nanotechnology have offered many promising opportunities for infectious and inflammatory diseases. Here, potential mechanisms of COVID‐19 cytokine storm are first discussed, and relevant therapeutic strategies and ongoing clinical trials are then reviewed. Furthermore, recent research involving emerging biomaterials for improving antibody‐based and broad‐spectrum cytokine neutralization is summarized. It is anticipated that this work will provide insights on the development of novel therapeutics toward efficacious management of COVID‐19 cytokine storm and other inflammatory diseases.
Enabled by recent advances in materials science and nanotechnology, emerging biomaterials hold great potential to provide better solutions for COVID‐19 cytokine storm and other inflammatory diseases. By reviewing the state‐of‐the‐art cytokine neutralization systems and highlighting the promising technology development, this work intends to spark further research and development activity in this critical research area.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients. We recently developed an effective protocol for the isolation of ...extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune-active proteins and modulated the gut immunity and microbiota in healthy mice. Here, we aimed to explore the therapeutic effects of mEVs on inflammatory bowel disease.
MicroRNAs and protein content in mEVs were analyzed by RNA sequencing and proteomics, respectively, followed by functional annotation. Ulcerative colitis (UC) was induced by feeding mice with dextran sulfate sodium. Intestinal immune cell populations were phenotyped by flow cytometry, and the gut microbiota was analyzed
16S rRNA sequencing.
We showed that abundant proteins and microRNAs in mEVs were involved in the regulation of immune and inflammatory pathways and that oral administration of mEVs prevented colon shortening, reduced intestinal epithelium disruption, inhibited infiltration of inflammatory cells and tissue fibrosis in a mouse UC model. Mechanistically, mEVs attenuated inflammatory response
inhibiting TLR4-NF-κB signaling pathway and NLRP3 inflammasome activation. Furthermore, mEVs were able to correct cytokine production disorder and restore the balance between T helper type 17 (Th17) cells and interleukin-10
Foxp3
regulatory T (Treg) cells in the inflamed colon. The disturbed gut microbiota in UC was also partially recovered upon treatment with mEVs. The correlation between the gut microbiota and cytokines suggests that mEVs may modulate intestinal immunity
influencing the gut microbiota.
These findings reveal that mEVs alleviate colitis by regulating intestinal immune homeostasis
inhibiting TLR4-NF-κB and NLRP3 signaling pathways, restoring Treg/Th17 cell balance, and reshaping the gut microbiota.
Cardiovascular diseases (CVD) represent the leading cause of morbidity and mortality globally. The emerging role of extracellular vesicles (EVs) in intercellular communication has stimulated renewed ...interest in exploring the potential application of EVs as tools for diagnosis, prognosis, and therapy in CVD. The ubiquitous nature of EVs in biological fluids presents a technological advantage compared to current diagnostic tools by virtue of their notable stability. EV contents, such as proteins and microRNAs, represent specific signatures of cellular activation or injury. This feature positions EVs as an alternative source of biomarkers. Furthermore, their intrinsic activity and immunomodulatory properties offer EVs unique opportunities to act as therapeutic agents per se or to serve as drug delivery carriers by acting as miniaturized vehicles incorporating bioactive molecules. In this article, we aim to review the recent advances and applications of EV-based biomarkers and therapeutics. In addition, the potential of EVs as a drug delivery and theranostic platform for CVD will also be discussed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cell Derived Nanovesicles (CDNs) have been developed from the rapidly expanding field of exosomes, representing a class of bioinspired Drug Delivery Systems (DDS). However, translation to clinical ...applications is limited by the low yield and multi-step approach in isolating naturally secreted exosomes. Here, we show the first demonstration of a simple and rapid production method of CDNs using spin cups via a cell shearing approach, which offers clear advantages in terms of yield and cost-effectiveness over both traditional exosomes isolation, and also existing CDNs fabrication techniques. The CDNs obtained were of a higher protein yield and showed similarities in terms of physical characterization, protein and lipid analysis to both exosomes and CDNs previously reported in the literature. In addition, we investigated the mechanisms of cellular uptake of CDNs in vitro and their biodistribution in an in vivo mouse tumour model. Colocalization of the CDNs at the tumour site in a cancer mouse model was demonstrated, highlighting the potential for CDNs as anti-cancer strategy. Taken together, the results suggest that CDNs could provide a cost-effective alternative to exosomes as an ideal drug nanocarrier.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
SerpinF2, SerpinG1, CystatinC and CD14 are involved in inflammatory processes and plasma extracellular vesicle (EV) -levels of these proteins have been reported to be associated with systemic ...vascular events. Evidence is accumulating that inflammatory processes may play a pivotal role both in systemic vascular events and in heart failure. Therefore, we studied the association between plasma extracellular vesicle SerpinF2-, SerpinG1-, CystatinC and CD14-levels and the occurrence of acute heart failure in patients.
Extracellular vesicle protein levels of SerpinG1, SerpinF2, CystatinC and CD14 were measured in an observational study of 404 subjects presenting with dysponea at the emergency department (4B-cohort). Plasma extracellular vesicles were precipitated in a total extracellular vesicles (TEX)-fraction and in separate LDL- and HDL-subfractions. Extracellular vesicle protein levels were measured with a quantitative immune assay in all 3 precipitates. Out of 404 subjects, 141 (35%) were diagnosed with acutely decompensated heart failure. After correction for confounders (including comorbidities and medications), levels of CD14 in the HDL-fraction (OR 1.53, p = 0.01), SerpinF2 in the TEX-and LDL-fraction (ORs respectively 0.71 and 0.65, p<0.05) and SerpinG1 in the TEX-fraction (OR 1.55, p = 0.004) were statistically significantly related to heart failure. Furthermore, extracellular vesicle CD14- and SerpinF2-levels were significantly higher in heart failure patients with preserved ejection fraction than in those with reduced ejection fraction.
Extracellular vesicle levels of CD14, SerpinG1 and SerpinF2 are associated with the occurrence of heart failure in subjects suspected for acute heart failure, suggesting common underlying pathophysiological mechanisms for heart failure and vascular events.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
Patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) are at increased risk of incident cardiovascular disease. However, the clinical characteristics and prognostic ...importance of MASLD in patients presenting with acute myocardial infarction (AMI) have yet to be examined.
Methods
This study compared the characteristics and outcomes of patients with and without MASLD presenting with AMI at a tertiary centre in Singapore. MASLD was defined as hepatic steatosis, with at least one of five metabolic criteria. Hepatic steatosis was determined using the Hepatic Steatosis Index. Propensity score matching was performed to adjust for age and sex. The Kaplan‐Meier curve was constructed for long‐term all‐cause mortality. Cox regression analysis was used to investigate independent predictors of long‐term all‐cause mortality.
Results
In this study of 4446 patients with AMI, 2223 patients with MASLD were matched with patients without MASLD using propensity scores. The mean follow‐up duration was 3.4 ± 2.4 years. The MASLD group had higher rates of obesity, diabetes and chronic kidney disease than their counterparts. Patients with MASLD had early excess all‐cause mortality (6.8% vs. 3.6%, p < .001) at 30 days, with unfavourable mortality rates sustained in the long‐term (18.3% vs. 14.5%, p = .001) compared with those without MASLD. After adjustment, MASLD remained independently associated with higher long‐term all‐cause mortality (hazard ratio 1.330, 95% confidence interval 1.106‐1.598, p = .002).
Conclusion
MASLD embodies a higher burden of metabolic dysfunction and is an independent predictor of long‐term mortality in the AMI population. Its early identification may be beneficial for risk stratification and provide therapeutic targets for secondary preventive strategies in AMI.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. ...Among them, familial DCM is the major form of DCM, with pathogenic variants in
LMNA
being the second most common form of autosomal dominant DCM.
LMNA
DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate
LMNA
DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy.
Methods
We evaluated 14 potential candidates including
Lmna
gene products (Lamin A and Lamin C), key signaling pathways (Tgfβ/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific
Lmna
DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating
Lmna
DCM were dissected by comparing marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment.
Results
Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in
Lmna
DCM. Lamin C or
Sun1
shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation.
Conclusions
In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of
Sun1
significantly suppressed
Lmna
DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of
LMNA
DCM.
Graphical Abstract
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BACKGROUND:L-type CaV1.2 channels play crucial roles in the regulation of blood pressure. Galectin-1 (Gal-1) has been reported to bind to the I-II loop of CaV1.2 channels to reduce their current ...density. However, the mechanistic understanding for the downregulation of CaV1.2 channels by Gal-1 and whether Gal-1 plays a direct role in blood pressure regulation remain unclear.
METHODS:In vitro experiments involving coimmunoprecipitation, Western blot, patch-clamp recordings, immunohistochemistry, and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 downregulates CaV1.2 channel in transfected, human embryonic kidney 293 cells, smooth muscle cells, arteries from Lgasl1 mice, rat, and human patients. In vivo experiments involving the delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting CaV1.2-Gal-1 interaction on blood pressure monitored by tail-cuff or telemetry methods.
RESULTS:Our study reveals that Gal-1 is a key regulator for proteasomal degradation of CaV1.2 channels. Gal-1 competed allosterically with the CaVβ subunit for binding to the I-II loop of the CaV1.2 channel. This competitive disruption of CaVβ binding led to CaV1.2 degradation by exposing the channels to polyubiquitination. It is notable that we demonstrated that the inverse relationship of reduced Gal-1 and increased CaV1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice because of the upregulated CaV1.2 protein level in arteries. To directly regulate blood pressure by targeting the CaV1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1 by a miniosmotic pump, and this specific disruption of CaV1.2-Gal-1 coupling increased smooth muscle CaV1.2 currents, induced larger arterial contraction, and caused hypertension in rats. In contrasting experiments, overexpression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats.
CONCLUSIONS:We have defined molecularly that Gal-1 promotes CaV1.2 degradation by replacing CaVβ and thereby exposing specific lysines for polyubiquitination and by masking I-II loop endoplasmic reticulum export signals. This mechanistic understanding provided the basis for targeting CaV1.2-Gal-1 interaction to demonstrate clearly the modulatory role that Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.
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