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Atherosclerosis treatments are generally aimed at altering systemic lipid metabolism such that atherogenesis, the formation of plaque, is curtailed. The plaques themselves offer some potential therapeutic targets. For example, selective depletion of macrophages, which play a key role in atherogenesis, inhibits plaque formation. However, it has not been possible to take advantage of these targets because the drugs that have been tested have not been sufficiently selective. We have developed a peptide, LyP-1, which specifically targets atherosclerotic plaques, penetrates into plaque interior, and accumulates in plaque macrophages. In tumors, LyP-1 can cause apoptosis in cells that take up the peptide. Here we show, using three different atherosclerosis models in ApoE null mice that prolonged systemic treatment with LyP-1 triggers apoptosis of plaque macrophages and reduces plaque in advanced hypoxic plaques, and that it does so without increasing necrotic core of plaques or causing detectable side effects. We also show that LyP-1 recognizes human plaque. These findings suggest that LyP-1 could serve as a lead compound for the development of a new class of anti-atherosclerosis drugs. [ABSTRACT FROM AUTHOR]

With its unique structure of two compartments, Janusparticles can be used for many applications for which monomorphicparticles are inadequate, including to be used as a drug deliverysystem to deliver multiple payloads with widely different solubility.Here we report on a fluidic nanoprecipitation system (FNPS), capableof fabricating biocompatible Janus polymeric nanoparticles comprisedof the FDA-approved polymer poly(lactic-co-glycolicacid) (PLGA). The FNPS contains dual inlets, one for each half ofthe particle, that insert into the precipitation stream. The systemprovides a one-step approach for production of Janus polymeric particleswith submicrometer diameters and is likely amenable to substantialscale-up. To the best of our knowledge, this is the first demonstrationof biocompatible Janus nanoparticles that encapsulate a hydrophobicdrug (paclitaxel) on one side and a hydrophilic drug (doxorubicinhydrochloride) on the other. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying neointima formation remain unclear. Interferon regulatory factors (IRFs), which are key innate immune regulators, play important roles in cardiometabolic diseases. However, the function of IRF4 in arterial restenosis is unknown.Methods: IRF4 expression was first detected in human and mouse restenotic arteries. Then, the effects of IRF4 on neointima formation were evaluated with universal IRF4-deficient mouse and rat carotid artery injury models. We performed immunostaining to identify IRF4-expressing cells in the lesions. Smooth muscle cell (SMC)-specific IRF4-knockout (KO) and -transgenic (TG) mice were generated to evaluate the effects of SMC-IRF4 on neointima formation. We used microarray, bioinformatics analysis, and chromatin immunoprecipitation assay to identify the downstream signals of IRF4 and to verify the targets in vitro. We compared SMC-IRF4-KO/Krüppel-like factor 4 (KLF4)-TG mice with SMC-IRF4-KO mice and SMC-specific IRF4-TG/KLF4-KO mice with SMC-specific IRF4-TG mice to investigate whether the effect of IRF4 on neointima formation is KLF4-dependent. The effect of IRF4 on SMC phenotype switching was also evaluated.Results: IRF4 expression in both the human and mouse restenotic arteries is eventually downregulated. Universal IRF4 ablation potentiates neointima formation in both mice and rats. Immunostaining indicated that IRF4 was expressed primarily in SMCs in restenotic arteries. After injury, SMC-IRF4-KO mice developed a thicker neointima than control mice. This change was accompanied by increased SMC proliferation and migration. However, SMC-specific IRF4-TG mice exhibited the opposite phenotype, demonstrating that IRF4 exerts protective effects against neointima formation. The mechanistic study indicated that IRF4 promotes KLF4 expression by directly binding to its promoter. Genetic overexpression of KLF4 in SMCs largely reversed the neointima-promoting effect of IRF4 ablation, whereas ablation of KLF4 abolished the protective function of IRF4, indicating that the protective effects of IRF4 against neointima formation are KLF4-dependent. In addition, IRF4 promoted SMC dedifferentiation.Conclusions: IRF4 protects arteries against neointima formation by promoting the expression of KLF4 by directly binding to its promoter. Our findings suggest that this previously undiscovered IRF4-KLF4 axis plays a key role in vasculoproliferative pathology and may be a promising therapeutic target for the treatment of arterial restenosis. [ABSTRACT FROM AUTHOR]

The distribution of lipoprotein(a) [Lp(a)] has not been well-studied in a large population in China. The relationship between Lp(a) and carotid atherosclerosis remains undefined. In this study, we aimed to investigate the distribution of Lp(a) levels and to assess their association with carotid arteriopathy in China. In this cross-sectional study, 411,634 adults with Lp(a) measurements from 22 health check-up centers were used to investigate Lp(a) distribution in China. Among participants with Lp(a) data, carotid ultrasound was performed routinely at seven health check-up centers covering 75,305 subjects. Carotid intima-media thickness (cIMT) and carotid plaque were used as surrogate biomarkers of carotid arteriopathy. The multivariate logistic regression model was applied to evaluate the association of increased Lp(a) levels with carotid arteriopathy. The distribution of Lp(a) concentrations was right-skewed, with a median concentration of 10.60 mg/dL. The proportions of Lp(a) levels ≥30 mg/dL and ≥50 mg/dL were 16.75% and 7.10%, respectively. The median Lp(a) level was higher in females individuals in northern China, and increased with age. Spearman's analysis revealed weak correlations between the Lp(a) concentration as a continuous variable and other lipid profiles. The multiple logistic regression analysis showed that participants with Lp(a) levels ≥50 mg/dL had an increased risk of cIMT ≥1.0 mm (OR = 1.138, 95% CI, 1.071–1.208) and carotid plaque (OR = 1.296, 95% CI, 1.219–1.377) compared with those with Lp(a) levels <50 mg/dL. This is the first study of the Lp(a) distribution in a large population in China. Our findings revealed a positive association between elevated Lp(a) levels (≥50 mg/dL) and increased prevalence of carotid atherosclerosis, which implies an increased risk of cardiovascular disease in the future. [Display omitted] • Lp(a) distribution is evaluated for the first time in large-scale Chinese adults. • Lp(a) ≥ 50 mg/dL is associated with carotid arteriopathy in a health check-up population. • The association between Lp(a) and arteriopathy is independent of LDL-C. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common type of treated heart arrhythmia contributing to adverse cardiovascular events. The association between short-term air pollution exposure and AF episodes has been recognized. But the evidence of the association between long-term air pollution exposure and AF was limited, especially in developing countries. We performed a nationwide cross-sectional study among 1,374,423 individuals aged ≥35 years from 13 health check-up centers. Using logistic regression models, we assessed the association between long-term exposure to single air pollution and AF prevalence, including particulate matter (PM 2.5 and PM 10), ozone (O 3) and PM 2.5 compositions, which were estimated by high-resolution and high-quality spatiotemporal datasets of ground-level air pollutants for China. The quantile g-computation model was used to explore the joint effect of all exposures to air pollution and the contribution of an individual component to the mixture. In single-pollutant models, an increase of 10 μg/m3 in PM 2.5 (OR 1.031[95%CI 1.010,1.053]) and PM 10 (OR = 1.021 [95%CI 1.009,1.033]) was positively associated with AF prevalence. The stratified analyses revealed that these associations were significantly stronger in females, people <65 years old, and those with hypertension and diabetes. In the further exploration of the joint effect of PM 2.5 compositions (OR 1.060 [95%CI 1.022,1.101]) per quintile increase in all five PM 2.5 components), we found that PM 2.5 sulfate contributed the most. These findings provide important evidence for the positive relationship between long-term exposure to air pollution and AF prevalence in China and identify sulfate particles of PM 2.5 as having the highest contribution to the overall mixture effects among all PM2.5 chemical constituents. • Long-term exposure to PM 2.5 and PM 10 was associated with an increased risk for AF prevalence. • The risk of AF prevalence was higher with PM5 exposure than with PM10. • The associations were stronger in females, people <65 years old, and those with hypertension and diabetes. • PM2.5 sulfate contributed the most to the overall mixture effects among PM2.5 constituents. [ABSTRACT FROM AUTHOR]

Carnosol is a phytopolyphenol (diterpene) found and extracted from plants of Mediterranean diet, which has anti-tumor, anti-inflammatory and antioxidant effects. However, its role in ischemic stroke has not been elucidated. Primary neurons subjected to oxygen-glucose deprivation (OGD) was used to investigate the effect of carnosol in vitro. A mouse MCAO model was used to evaluate the effect of carnosol on ischemic stroke in vivo. The mRNA level of inflammatory and apoptosis-related genes was determined by RT-PCR. The protein level of total and phosphorylated AMPK was determined by WB. H&E and Immunofluorescent assay was used to investigate the necrosis, inflammation and apoptosis in brain tissue. Carnosol protected the activity of primary neurons subjected to oxygen-glucose deprivation (OGD) in vitro, as well as inhibited inflammation and apoptosis. Furthermore, carnosol could significantly reduce the infarct and edema volume and protect against neurological deficit in vivo, and had a significant inhibitory effect on brain neuroinflammation and apoptosis. Mechanically, carnosol could activate AMPK, and the effect of carnosol on cerebral ischemia-reperfusion injury cell model could be abolished by AMPK phosphorylation inhibitor. Carnosol has a protective effect on ischemic stroke, and this effect is achieved through AMPK activation. Our study demonstrates the protective effect of carnosol on cerebral ischemia-reperfusion injury and provides a new perspective for the clinical treatment of ischemic stroke. • A new function of carnosol in regulating cerebral ischemia reperfusion injury was found. • It was found that carnosol could inhibit OGD/R induced neurons injury, inflammatory response and apoptosis. • It was found that carnosol can promote phosphorylation of AMPK in cerebral ischemia reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms. Methods: A drug repositioning strategy was used to screen an FDA-approved drug library with approximately 3000 compounds in an in vitro hepatocyte model of lipid accumulation, with honokiol identified as an effective anti-NAFLD candidate. We systematically examined the therapeutic effect of honokiol in NAFLD and metabolic syndrome in multiple in vitro and in vivo models. Transcriptomic examination and biotin-streptavidin binding assays were used to explore the underlying molecular mechanisms, confirmed by rescue experiments. Results: Honokiol significantly inhibited metabolic syndrome and NAFLD progression as evidenced by improved hepatic steatosis, liver fibrosis, adipose inflammation, and insulin resistance. Mechanistically, the beneficial effects of honokiol were largely through AMPK activation. Rather than acting on the classical upstream regulators of AMPK, honokiol directly bound to the AMPKγ1 subunit to robustly activate AMPK signaling. Mutation of honokiol-binding sites of AMPKγ1 largely abolished the protective capacity of honokiol against NAFLD. Conclusion: These findings clearly demonstrate the beneficial effects of honokiol in multiple models and reveal a previously unappreciated signaling mechanism of honokiol in NAFLD and metabolic syndrome. This study also provides new insights into metabolic disease treatment by targeting AMPKγ1 subunit-mediated signaling activation. [ABSTRACT FROM AUTHOR]

Alterations of multiple metabolites characterize distinct features of metabolic reprograming in hepatocellular carcinoma (HCC). However, the role of most metabolites, including propionyl-CoA (Pro-CoA), in metabolic reprogramming and hepatocarcinogenesis remains elusive. In this study, we aimed to dissect how Pro-CoA metabolism affects these processes. TCGA data and HCC samples were used to analyze ALDH6A1-mediated Pro-CoA metabolism and its correlation with HCC. Multiple metabolites were assayed by targeted mass spectrometry. The role of ALDH6A1-generated Pro-CoA in HCC was evaluated in HCC cell lines as well as xenograft nude mouse models and primary liver cancer mouse models. Non-targeted metabolomic and targeted energy metabolomic analyses, as well as multiple biochemical assays, were performed. Decreases in Pro-CoA and its derivative propionyl-L-carnitine due to ALDH6A1 downregulation were tightly associated with HCC. Functionally, ALDH6A1-mediated Pro-CoA metabolism suppressed HCC proliferation in vitro and impaired hepatocarcinogenesis in mice. The aldehyde dehydrogenase activity was indispensable for this function of ALDH6A1, while Pro-CoA carboxylases antagonized ALDH6A1 function by eliminating Pro-CoA. Mechanistically, ALDH6A1 caused a signature enrichment of central carbon metabolism in cancer and impaired energy metabolism: ALDH6A1-generated Pro-CoA suppressed citrate synthase activity, which subsequently reduced tricarboxylic acid cycle flux, impaired mitochondrial respiration and membrane potential, and decreased ATP production. Moreover, Pro-CoA metabolism generated 2-methylcitric acid, which mimicked the inhibitory effect of Pro-CoA on citrate synthase and dampened mitochondrial respiration and HCC proliferation. The decline of ALDH6A1-mediated Pro-CoA metabolism contributes to metabolic remodeling and facilitates hepatocarcinogenesis. Pro-CoA, propionyl-L-carnitine and 2-methylcitric acid may serve as novel metabolic biomarkers for the diagnosis and treatment of HCC. Pro-CoA metabolism may provide potential targets for development of novel strategies against HCC. Our study presents new insights on the role of propionyl-CoA metabolism in metabolic reprogramming and hepatocarcinogenesis. This work has uncovered potential diagnostic and predictive biomarkers, which could be used by physicians to improve clinical practice and may also serve as targets for the development of therapeutic strategies against HCC. [Display omitted] • ALDH6A1 downregulation mediates the decline in propionyl-CoA metabolism that facilitates hepatocarcinogenesis. • Propionyl-CoA and 2-methylcitric acid suppress citrate synthase activity contributing to metabolic reprogramming in HCC. • Propionyl-CoA, propionyl-L-carnitine and 2-methylcitric acid may serve as novel metabolic biomarkers in HCC. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common disease worldwide in an era of rapid economic growth. NAFLD is a multifactorial disease, involving multiple genetic, metabolic, and environmental factors, and is closely associated with metabolic syndrome, obesity, and cardiovascular disease. NAFLD can be classified into nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH), which can both progress to cirrhosis and even hepatocellular carcinoma (HCC). Due to the enormous burden of NAFLD and its complications, no FDA-approved drugs for the treatment of NAFLD are on the market, and therapeutic targets and drug therapies are being actively investigated. In view of the various pathological mechanisms of NAFLD, numbers of preclinical studies and clinical trials have made rapid progress. This review mainly summarizes the most recently characterized mechanisms and therapeutic targets in each mechanism of NAFLD, focusing on the mechanism and application potential. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Increasing evidence suggests that, in addition to traditional metabolic risk factors such as obesity, hypercholesterolemia, hypertension, diabetes mellitus, and insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD) is an emerging driver of ASCVD via multiple mechanisms, mainly by disrupting lipid metabolism. The lack of pharmaceutical treatment has spurred substantial investment in the research and development of NAFLD drugs. However, many reagents with promising therapeutic potential for NAFLD also have considerable impacts on the circulating lipid profile. In this review, we first summarize the mechanisms linking lipid dysregulation in NAFLD to the progression of ASCVD. Importantly, we highlight the potential risks of/benefits to ASCVD conferred by NAFLD pharmaceutical treatments and discuss potential strategies and next-generation drugs for treating NAFLD without the unwanted side effects. [Display omitted] • Nonalcoholic fatty liver disease has emerged as a driver of atherosclerotic cardiovascular disease. • Acetyl-coenzyme A carboxylase inhibitors and farnesoid X receptor agonists disrupt the circulating lipid profile, which may increase the risk of atherosclerotic cardiovascular disease. • A novel molecule, IMA-1, moderately represses acetyl-coenzyme A carboxylase 1 activity and has promising potential in treating nonalcoholic steatohepatitis without causing a significant decrease in polyunsaturated fatty acid levels or hyperlipidemia. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether interferon regulatory factor 9 (IRF9) is involved in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury and to explore the underlying molecular mechanisms of this process. Cell death plays a major role in myocardial I/R injury. We recently determined the importance of IRF9 in coordinating molecular events in response to hypertrophic stress in cardiomyocytes. However, the roles of IRF9 in lethal myocardial injury remain to be elucidated. The involvement of IRF9 was assessed via functional assays in a mouse myocardial I/R injury model by genetic knockout and cardiomyocyte-specific transgenic overexpression of IRF9, and its effects on cardiomyocyte apoptosis and inflammation were further studied in vivo and in vitro. IRF9 was upregulated in human ischemic heart tissue and mouse hearts after I/R injury. Ablation of IRF9 protected the heart against I/R-induced cardiomyocyte death, development of inflammation, and loss of heart function. In contrast, cardiomyocyte-specific transgenic overexpression of IRF9 aggravated myocardial reperfusion injury and inflammation. IRF9 negatively regulated the Sirt1-p53 axis under I/R conditions in vivo and in vitro. Downregulation of Sirt1 expression and its downstream apoptosis-related signaling cascade, which results from I/R, was ameliorated by loss of IRF9 and exacerbated by overexpression of IRF9. Cardiomyocyte-specific deletion of Sirt1 abolished the protective effect of IRF9 knockout against I/R injury, which further indicated that IRF9 mediated myocardial reperfusion injury by modulating the Sirt1-p53 axis. Thus, IRF9 may be a novel therapeutic target for the prevention of I/R injury resulting from revascularization therapy after acute myocardial infarction (MI). [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is a prevalent cardiovascular disease. Understanding current and future disease burden of PAD and its attributable risk factors is critical for developing prevention measures targeting PAD and associated complications. We analyzed the death burden of PAD and the trends of six risk factors from 1990 to 2019 using the updated 2019 Global Burden of Disease study database, and projected the next decade death burden using a Bayesian age-period-cohort (BAPC) model. The global age-standardized mortality rate (ASMR) of PAD has a modest downward trend from 1990 to 2019. Regionally, ASMRs in higher-sociodemographic index (SDI) areas remained more remarkable than in lower-SDI areas by 2019, while the rate of increase in death burden in the lower-SDI regions increased rapidly over time. ASMR in males was greater than in females. In the population aged older than 40 years, the sex difference in PAD-associated mortality decreased with age. High fasting plasma glucose (FPG) became the primary risk factor for PAD-related death. The contributions of risk factors to PAD-related death varied by age group. Kidney dysfunction was the primary contributor to PAD-related death in people aged 40–59 years, particularly in women. The global death burden of PAD has not substantially decreased over the three decades. There are large variations in the trend of PAD mortality and its attributable risk factors by SDI regions, sex, and age group. Targeted and effective strategies are needed for the management of PAD-related mortality in specific subgroups. [Display omitted] • The global death burden of peripheral artery disease (PAD) has been neglected atherosclerotic disease. • The growth rate of the death burden of PAD in lower-sociodemographic index (SDI) regions exceeded that in higher-SDI regions. • The mortality rate of PAD in males was greater than that in females in all SDI regions and all age groups. • High FPG has become the primary risk factor for PAD-related death in the overall population. • Kidney dysfunction was the primary contributor to PAD-related death in the 40–59 age group, especially in women. [ABSTRACT FROM AUTHOR]

Background: Global distributions and trends of the risk-attributable burdens of chronic obstructive pulmonary disease (COPD) have rarely been systematically explored. To guide the formulation of targeted and accurate strategies for the management of COPD, we analyzed COPD burdens attributable to known risk factors.Methods: Using detailed COPD data from the Global Burden of Disease study 2019, we analyzed disability-adjusted life years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), and deaths attributable to each risk factor from 1990 to 2019. Additionally, we calculated estimated annual percentage changes (EAPCs) during the study period. The population attributable fraction (PAF) and summary exposure value (SEV) of each risk factor are also presented.Results: From 1990 to 2019, the age-standardized DALY and death rates of COPD attributable to smoking and household air pollution, occupational particles, secondhand smoke, and low temperature presented consistently declining trends in almost all socio-demographic index (SDI) regions. However, the decline in YLD was not as dramatic as that of the death rate. In contrast, the COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure showed undesirable increasing trends in the low- and low-middle-SDI regions. In addition, the age-standardized DALY and death rates attributable to each risk factor except household air pollution and low temperature were the highest in the low-middle-SDI region. In 2019, the COPD burden attributable to smoking ambient particulate matter, ozone, occupational particles, low and high temperature was obviously greater in males than in females. Meanwhile, the most important risk factors for female varied across regions (low- and low-middle-SDI regions: household air pollution; middle-SDI region: ambient particles; high-middle- and high-SDI region: smoking).Conclusions: Increasing trends of COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure in the low-middle- and low-SDI regions call for an urgent need to implement specific and effective measures. Moreover, considering the gender differences in COPD burdens attributable to some risk factors such as ambient particulate matter and ozone with similar SEV, further research on biological differences between sexes in COPD and relevant policy-making of disease prevention are required. [ABSTRACT FROM AUTHOR]

Vascular disease is the prime determinant to cardiovascular morbidities and mortalities, which comprises the early vascular damage and subsequent cardiovascular events. Non-alcohol Fatty Liver Disease (NAFLD) is a systemic metabolic disorder that drives the progression of vascular disease through complex interactions. Although a causal relationship between NAFLD and cardiovascular disease (CVD) has not been established, a growing number of epidemiological studies have demonstrated an independent association between NAFLD and early vascular disease and subsequent cardiovascular events. In addition, mechanistic studies suggest that NAFLD initiates and accelerates vascular injury by increasing systemic inflammation and oxidative stress, impairing insulin sensitivity and lipid metabolism, and modulating epigenetics, the intestinal flora and hepatic autonomic nervous system; thus, NAFLD is a putative driving force for CVD progression. In this review, we summarize the clinical evidence supporting the association of NAFLD with subclinical vascular disease and cardiovascular events and discuss the potential mechanisms by which NAFLD promotes the progression of vascular disease. [ABSTRACT FROM AUTHOR]

Abstract: The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors. [Copyright &y& Elsevier]

Abstract: Endothelial inflammation plays a critical role in the development and progression of cardiovascular disease, albeit the mechanisms need to be fully elucidated. We here report that treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor (TNF) α substantially increased the expression of MCP-induced protein 1 (MCPIP1). Overexpression of MCPIP1 protected ECs against TNFα-induced endothelial activation, as characterized by the attenuation in the expression of the adhesion molecule VCAM-1 and monocyte adherence to ECs. Conversely, small interfering RNA-mediated knock down of MCPIP1 increased the expression of VCAM-1 and monocytic adherence to ECs. These studies identified MCPIP1 as a feedback control of cytokines-induced endothelial inflammation. [Copyright &y& Elsevier]

Two new metabolites, named no. 2106 A (1) and cyclo-(N-MeVal-N-MeAla) (2), have been produced by the endophytic fungus no. 2106 isolated from the seeds of the mangrove Avicennia marina in Hong Kong. The structures were elucidated by 2D NMR, HR-MS, and X-ray diffraction analyses. [ABSTRACT FROM AUTHOR]

The metatrophic fungus Paecilomyces sp. (Tree1-7) was isolated from an estuarine mangrove from the Taiwan Strait. The methanol extract of the fungal mycelium exhibited cytotoxicity against hepG2. Paeciloxanthone (1), a new xanthone, and the known compounds emodin (2) and chrysophanol (3), were isolated from the extract. Their structures were elucidated by spectroscopic experiments. Paeciloxanthone (1) exhibited in vitro cytotoxicity against hepG2 (IC50 = 1.08 μg/mL), acetylcholineesterase (AChE) inhibitory (IC50 = 2.25 μg/mL) and antimicrobial activities. [ABSTRACT FROM AUTHOR]

Abstract: Twelve allenic aromatic ethers, some of them are natural products isolated from the mangrove fungus Xylaria sp. 2508 in the South China Sea, were synthesized. Their antitumor activities against KB and KBv200 cells were determined. All these compounds demonstrated cytotoxic potential, ranging from weak to strong activity. The analysis of structure–activity relationships suggested that the introduction of allenic moiety could generate or enhance cytotoxicity of these phenol compounds. [Copyright &y& Elsevier]

Macrophages play important and diverse roles during cancer progression. However, cancer therapies based on macrophage modulation are lacking in tools that can recognize and deliver therapeutic payloads to macrophages in a tumor-specific manner. As a result, treatments tend to interfere with normal macrophage functions in healthy organs. We previously identified a macrophage-binding peptide, termed CRV. Here, we show that upon systemic administration into tumor-bearing mice, CRV selectively homes to tumors, extravasates, and preferentially binds to macrophages within. CRV exhibits a higher affinity for tumor macrophages than for other cells in tumors or for other macrophage types elsewhere in the body. We further identified and validated retinoid X receptor beta (RXRB) as the CRV receptor. Intriguingly, although it is known as a nuclear receptor, RXRB shows a prominent cell surface localization that is largely restricted to tumor macrophages. Systemic administration of anti-RXRB antibodies also results in tumor-selective binding to macrophages similar to CRV. Lastly, we demonstrate the ability of CRV to improve the delivery of nano-carriers into solid tumors and macrophages within. In summary, we describe here a novel cell surface marker and targeting tools for tumor macrophages that may aid in future development of macrophage-modulatory cancer therapies. Unlabelled Image • A peptide selectively homes to tumors and recognizes macrophages within. • Retinoid X receptor beta (RXRB) is the target of the peptide on the macrophage surface. • First report of RXRB on the cell surface and as a novel marker for tumor macrophages. • Targeting RXRB can distinguish tumor macrophages from those in other tissues. • Enables improved cargo delivery to tumor macrophages. [ABSTRACT FROM AUTHOR]

Skin aging is a complex process involving intricate genetic and environmental factors. In this study, we performed a comprehensive analysis of the transcriptional regulatory landscape of skin aging in canines. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify aging-related gene modules. We subsequently validated the expression changes of these module genes in single-cell RNA sequencing (scRNA-seq) data of human aging skin. Notably, basal cell (BC), spinous cell (SC), mitotic cell (MC), and fibroblast (FB) were identified as the cell types with the most significant gene expression changes during aging. By integrating GENIE3 and RcisTarget, we constructed gene regulation networks (GRNs) for aging-related modules and identified core transcription factors (TFs) by intersecting significantly enriched TFs within the GRNs with hub TFs from WGCNA analysis, revealing key regulators of skin aging. Furthermore, we demonstrated the conserved role of CTCF and RAD21 in skin aging using an H 2 O 2 -stimulated cell aging model in HaCaT cells. Our findings provide new insights into the transcriptional regulatory landscape of skin aging and unveil potential targets for future intervention strategies against age-related skin disorders in both canines and humans. • Aging is accompanied by systemic changes in blood indices, skin histology, and skin transcriptome. • Dysregulation of aging-related genes is cell type-specific. • Intercellular communication plays a critical role in skin aging. • Network-based analysis identifies key regulators of skin aging. • Downregulation of CTCF or RAD21 accelerates HaCaT aging. [ABSTRACT FROM AUTHOR]

The article discusses a study on the isolation of secondary metabolites from the Fungus Aspergillus species (sp.) (TA01-14) derived from Gorgonian Carijoa sp. (GX-WZ-2010001) to examine the EtOAc extract's antibacterial activity against pathogenic bacterias. The study uses semipreparative HPLC in isolating 1-6 compounds through separation and purification, where diorcinol compound showed wide antibacterial activity against bacterias including Bacillus subtilis and Bacillus cereus.

The rapid development of fluorescence imaging technologies requires concurrent improvements in the performance of fluorescent probes. Quantum dots have been extensively used as an imaging probe in various research areas because of their inherent advantages based on unique optical and electronic properties. However, their clinical translation has been limited by the potential toxicity especially from cadmium. Here, a versatile bioimaging probe is developed by using highly luminescent cadmium-free CuInSe2/ZnS core/shell quantum dots conjugated with CGKRK (Cys-Gly-Lys-Arg-Lys) tumor-targeting peptides. This probe exhibits excellent photostability, reasonably long circulation time, minimal toxicity, and strong tumor-specific homing property. The most important feature of this probe is that it shows distinctive versatility in tumor-targeted multimodal imaging including near-infrared, time-gated, and two-photon imaging in different tumor models. In a glioblastoma mouse model, the targeted probe clearly denotes tumor boundaries and positively labels a population of diffusely infiltrating tumor cells, suggesting its utility in precise tumor detection during surgery. This work lays a foundation for potential clinical translation of the probe. [ABSTRACT FROM AUTHOR]

Five pairs of new dihydroisocoumarin enantiomers, (±)-eurotiumides A–E, and two related racemates, (±)-eurotiumides F and G, were isolated from a gorgonian-derived fungus, Eurotium sp. XS-200900E6. The enantiomeric separations for (±)-eurotiumides A–E were achieved by chiral-HPLC, and their absolute configurations were determined by ECD spectra. All of the isolated compounds are rare dihydroisocoumarin derivatives with a methoxy at C-4. (+)- And (−)-eurotiumides B and D with cis configurations of H-3/H-4 exhibited potent antifouling activities against the larval settlement of the barnacle Balanus amphitrite with the EC 50 values ranging from 0.7 to 2.3 μg/mL, and displayed high therapeutic ratios (LC 50 /EC 50 >15). The tested compounds also showed extensive antibacterial activities. It was the first report of antifouling activities for dihydroisocoumarin derivatives. [ABSTRACT FROM AUTHOR]

One new anthraquinone derivative, named 8-O-methylnidurufin ( 1), together with five known analogues ( 2- 6), have been isolated from a gorgonian-derived fungus, Aspergillus sp. The structures were elucidated by combined spectroscopic methods including 1D and 2D NMR spectral data. All isolated metabolites were evaluated for their cytotoxic and antibacterial activities in vitro. Compound 2 showed significant cytotoxic activity against K562 and HL-60 cell lines with IC values of 0.87 and 1.46 μM, respectively. [ABSTRACT FROM AUTHOR]

There is considerable interest in using nanoparticles as labels or to deliver drugs and other bioactive compounds to cells in vitro and in vivo. Fluorescent imaging, commonly used to study internalization and subcellular localization of nanoparticles, does not allow unequivocal distinction between cell surface-bound and internalized particles, as there is no methodology to turn particles 'off'. We have developed a simple technique to rapidly remove silver nanoparticles outside living cells, leaving only the internalized pool for imaging or quantification. The silver nanoparticle (AgNP) etching is based on the sensitivity of Ag to a hexacyanoferrate-thiosulphate redox-based destain solution. In demonstration of the technique we present a class of multicoloured plasmonic nanoprobes comprising dye-labelled AgNPs that are exceptionally bright and photostable, carry peptides as model targeting ligands, can be etched rapidly and with minimal toxicity in mice, and that show tumour uptake in vivo. [ABSTRACT FROM AUTHOR]

Two polyketides were isolated from the mangrove endophytic fungus, Penicillium sp. sk14JW2P, and one derivative with a modified structure. The structures were elucidated by spectroscopic analyses, the structure of the compound 1 was further confirmed by single-crystal X-ray diffraction, and its absolute configuration was determined. Compound 1 and 2 showed acetylcholinesterase (AchE) inhibitory activities with IC50 values of 12±0.3 and 79±2 n M, respectively. [ABSTRACT FROM AUTHOR]

Nkx2.5 plays protective roles in cardiac homeostasis and survival in the postnatal hearts. However, the underlying molecular mechanisms that mediate the protective functions of Nkx2.5 remain unknown. Here, we showed that Nkx2.5 was downregulated in response to various stresses and was required for protection against the stress-induced apoptosis of cardiomyocytes. SIRT1, a member of the sirtuin family of proteins, was found to be a direct transcriptional target of Nkx2.5 and was required for the Nkx2.5-mediated protection of cardiomyocytes from doxorubicin (DOX)-induced apoptosis. Moreover, using chromatin immunoprecipitation assays, we found that Nkx2.5 was able to bind to the SIRT1 promoter and that this binding was significantly decreased in DOX-treated mouse hearts. Furthermore, the cardiac-specific overexpression of SIRT1 decreased the DOX-induced apoptosis of cardiomyocytes in SIRT1 transgenic mouse hearts compared with the hearts of their wild-type littermates. These findings demonstrate that SIRT1 acts as a direct transcriptional target of Nkx2.5 that maintains cardiomyocyte homeostasis and survival. [ABSTRACT FROM AUTHOR]

The novel natural product xyloallenoide A, isolated from the marine mangrove endophytic fungus from the South China Sea, and its diastereoisomer xyloallenoide A1, which contain N-methyl-substituted amino acids, were synthesized. The absolute configurations of the amino acid units of xyloallenoide A were finally confirmed to be L-Lys, Me- D-Val, and Me- L-Ala. This report represents a practical and attractive alternative for the synthesis of N-methyl-substituted cyclotripeptides. In the preliminary bioassay, synthetic xyloallenoide A showed marginal activities against KB ( IC50=9.6 μ M) and KBv200 cells ( IC50=10.3 μ M), and xyloallenoide A1 was inactive against KB and KBv200 cells. [ABSTRACT FROM AUTHOR]

Abstract: Three new phenolic bisabolane sesquiterpenoid dimers, disydonols A–C (1–3), and one known compound (S)-(+)-sydonol (4) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Their structures were elucidated on the basis of comprehensive spectral analysis including 1D and 2D NMR spectra and HR-ESI-MS. These compounds were evaluated for cytotoxic activity against HepG-2 and Caski human tumour cell lines. Among them, compounds 1 and 3 exhibited cytotoxicity against the two cell lines. [Copyright &y& Elsevier]

It is unclear how stress granule (SG) formation and cellular apoptosis are coordinately regulated. MCPIP1 (monocyte chemotactic protein-induced protein 1), also known as Zc3h12a, is a critical regulator of the inflammatory response and immune homeostasis. However, the role of MCPIP1 in stress response remains unknown. Here, we report that overexpression of MCPIP1 inhibited the assembly of SGs in response to various stresses. Conversely, MCPIP1-deficient splenocytes developed more SGs even without stress. On the other hand, overexpression of MCPIP1 sensitized RAW 264.7 cells to apoptosis under stress, whereas MCPIP1-deficient cells were resistant to stress-induced apoptosis. Mutagenesis study showed that the ability of MCPIP1 to repress SG formation is dependent on its deubiquitinating activity. Consistently, MCPIP1 negatively regulated stress-induced phosphorylation of eIF2α and thus released stress-induced inhibition of protein translation. However, MCPIP1 also inhibited 15-deoxy-Δ12,14-prostaglandin J2-induced SG formation, which was reported to be independent of eIF2α phosphorylation. Taken together, these results suggest that MCPIP1 coordinates SG formation and apoptosis during cellular stress and may play a critical role in immune homeostasis and resolution of macrophage inflammation. [ABSTRACT FROM AUTHOR]

Two new meroterpenes, 'acetoxydehydroaustin B' ( 1) and '1,2-dihydro-acetoxydehydroaustin B' ( 2) were isolated in the form of a mixed crystal from the mangrove endophytic fungus Aspergillus sp. 085241B. Their structures and absolute configurations were determined by extensive analysis of their spectra and X-ray diffraction data. In a preliminary bioassay, the mixed crystal did not exhibit activities against cancer cell lines of MDA-MB-435, SKBR3, HepG2, HEP3B, PC-3, and A549, as well as against α-glucosidase and tyrosinase. [ABSTRACT FROM AUTHOR]

Four new dimeric naphtho- γ-pyrones, named rubasperone D ( 1), rubasperone E ( 2), rubasperone F ( 3), and its atropisomer rubasperone G ( 4), together with four known monomeric naphtho- γ-pyrones, TMC 256 A1 ( 5), rubrofusarin B ( 6), fonsecin ( 7), and flavasperone ( 8), were isolated from the mangrove endophytic fungus Aspergillus tubingensis (GX1-5E) cultivated in solid rice medium. Their structures were elucidated by spectroscopic methods, including IR, 1D- and 2D-NMR, and MS. In the in vitro cytotoxicity assays, 5 displayed inhibitory activities against tumor cell lines of MCF-7, MDA-MB-435, Hep3B, Huh7, SNB19, and U87 MG with IC50 values between 19.92 and 47.98 μ M. Compounds 1, 6, and 8 also showed mild cytotoxic activity. [ABSTRACT FROM AUTHOR]

Abstract: Eleven transition metal complexes of three asymmetrical tridentate thioether ligands, 8-((pyridin-2-yl)methylthio) quinoline (TQMP2), 8-((pyridin-3-yl)methylthio) quinoline (TQMP3), 8-((pyridin-4-yl)methylthio) quinoline (TQMP4) and one symmetrical pentadentate ligand 2,6-bis (8-quinolinylthiomethyl) pyridine (DTQMP) were prepared. The structures of all these complexes were identified by means of elemental analysis (EA), infrared spectra (IR) and single-crystal diffraction, providing three different kinds of basic conformations, (1) discrete mononuclear structures, (2) dinuclear rings and (3) 1D polymer chains. The antibacterial, antifungal and pesticide activities of the four ligands and 11 complexes were also studied. [Copyright &y& Elsevier]

The type of hapten linkage to a carrier protein can play an important role in determining the nature of the resulting antibody response. Generic haptens using three types of linkers were synthesized (a monocarboxylic acid, an unsaturated hydrocarbon and a carboxamido spacer). These haptens were conjugated to bovine serum albumin (BSA) and used as immunogens to produce broad-specificity monoclonal antibodies (MAbs) to organophosphorus pesticides (OPs). Three-dimensional (3D) structures of hapten-lysine conjugates were optimized using molecular modeling (MM) to mimic conformations of hapten-BSA conjugates. The results from MM studies revealed a change of the 3D conformation and electrostatic potential of hapten 1 when the monocarboxylic acid linker was coupled to lysine. This result was consistent with the observed high-cross-reactivity of the corresponding MAb–H1 for the OPs. The competitive indirect enzyme-linked immunosorbent assay based on MAb–H1 is ideally suited to be used as a screening method for OP contaminants. [ABSTRACT FROM AUTHOR]

Abstract: Two novel benzylazaphilone derivatives with an unprecedented carbon skeleton, aspergilone A (1), and its symmetrical dimer with a unique methylene bridge, aspergilone B (2), have been isolated from the culture broth of a marine-derived fungus Aspergillus sp. from a gorgonian Dichotella gemmacea. Their structures and relative stereochemistries of 1 and 2 were elucidated using a combination of NMR spectroscopy and X-ray crystallography. Compound 1 not only exhibited in vitro selective cytotoxicity but also showed potent antifouling activity. [ABSTRACT FROM AUTHOR]

A new diimide derivative, named ( - )-byssochlamic acid bisdiimide (1), was isolated from the mixed broth of two mangrove fungi (strain no. K38 and E33) from the South China sea coast. The structure of 1 was determined by comprehensive spectroscopic methods, including 1D and 2D NMR (COSY, HMQC, and HMBC) and semi-synthesis. Primary bioassays showed that 1 had weak cytotoxic activity against Hep-2 and HepG2 cells. [ABSTRACT FROM AUTHOR]

Abstract: The semirigid tridentate 8-(2-pyridinylmethylthio)quinoline ligand (Q1) is shown to form the structurally characterized transition metal complexes [Cu(Q1)Cl2] (1), [Co(Q1)(NO3)2] (2), [Cd(Q1)(NO3)2] (3), [Cd(Q1)I2] (4). [Cu(Q1)2](BF4)2·(H2O)2 (5), [Cu(Q1)2](ClO4)2·(CH3COCH3)2 (6), [Zn(Q1)2](ClO4)2(H2O)2 (7), [Cd2(Q1)2Br4] (8), [Ag2(Q1)2(ClO4)2] (9), and [Ag2(Q1)2(NO3)2] (10). Four types of structures have been observed: ML-type in complexes 1–4, in which the anions Cl−, NO3 − or I− also participate in the coordination; ML 2 − type in complexes 5–7 without direct coordination of the anions BF4 − or ClO4 − and with more (Cu2+) or less (Zn2+) distorted bis-fac coordinated Q1; M 2 L 2 -type in complex 8, in which two Br− ions act as bridges between two metal ions; and M 2 (μ-L) 2-type in complexes 9 and 10, in which the ligand bridges two anion binding and Ag–Ag bonded ions. Depending on electron configuration and size, different coordination patterns are observed with the bonds from the metal ions to Npyridyl longer or shorter than those to Nquinoline. Typically Q1 acts as a facially coordinating tridentate chelate ligand except for the compounds 9 and 10 with low-coordinate silver(I). Except for 6 and 8, the complexes exhibit distinct constraining effects against both G(+) and G(-) bacteria. Complexes 1, 3, 4, 5, 7 have considerable antifungal activities and complexes 1, 5, 7, and 10 show selective effects to restrain certain botanic bacteria. Electrochemical studies show quasi-reversible reduction behavior for the copper(II) complexes 1, 5 and 6. [Copyright &y& Elsevier]

A new hTopo I isomerase inhibitor, (+)-3,3',7,7',8,8'-hexahydroxy-5,5'-dimethylbianthraquinone (2240A), was isolated from the mangrove endophytic fungus no. 2240 collected from an estuarine mangrove at the South China Sea coast. Its structure was elucidated by spectral analyses including two-dimensional NMR, HR-EI-MS, IR, and UV. The hTopo I isomerase inhibition experiment showed that 2240A (1) possessed strong inhibiting activity. When its inhibition concentration was 4.65 μmol/l, its percent inhibition rate was 59.1%, while the lowest inhibition concentration of the positive control camptothecin was 1.00 × 103 μmol/l. [ABSTRACT FROM AUTHOR]

A novel nitro-phenyl glucoside (1) was isolated from mangrove endophytic fungus (fungus B60), collected from the Shenzhen mangrove Acanthus ilicifolius linn. Four related nitro-phenyl compounds (2-5) were also obtained, which were isolated for the first time as natural products. Their structures were established on the basis of NMR spectroscopic, mass spectrometric data and some chemical transformations. In the preliminary bioassay, compound 1 had a slight inhibitory effect on α-glucosidase with an IC50 of 160.3 μM. [ABSTRACT FROM AUTHOR]

Abstract: Two new metabolites named 6-oxo-de-O-methyllasiodiplodin (1) and (E)-9-etheno-lasiodiplodin (2), with three known compounds lasiodiplodin (3), de-O-methyllasiodiplodin (4), and 5-hydroxy-de-O-methyllasiodiplodin (5), were isolated from the mycelium extracts of a brown alga endophytic fungus (No. ZZF36) obtained from the South China Sea. Their structures were elucidated using spectroscopic methods, mainly 1D and 2D NMR. Additionally, the structure of compound 1 was confirmed by single crystal X-ray diffraction analysis. The antimicrobial activities of lasiodiplodins, and the 13-acetyl and 12,14-dibromo derivatives of lasiodiplodin were tested for the first time and the results were compared to each other. [Copyright &y& Elsevier]

Abstract: Two new metabolites, 3R,5R-Sonnerlactone (1) and 3R,5S-Sonnerlactone (2), were isolated from the mangrove endophytic fungus Zh6-B1 obtained from the South China Sea. Their structures were elucidated by MS and NMR. The absolute configuration of compound 1 was determined by single-crystal X-ray analysis using Cu Kα radiation. The absolute configuration of compound 2 was determined by NOESY analysis and comparing circular dichroism spectroscopy with compound 1. The antiproliferative activity of compound 1 and 2 against the multi-drug resistant human oral floor carcinoma cells (KV) was evaluated. [Copyright &y& Elsevier]

Abstract: A new pyrrolyl 4-quinolinone alkaloid with an unprecedented ring system, named penicinoline (1) was isolated from a mangrove endophytic fungus. The structure of 1 was elucidated by spectroscopic methods and comparison with its derivative, penicinotam (1a), an unexpected lactam that was obtained from 1 by intramolecular dehydration. The structure of 1a was unambiguously confirmed by single-crystal X-ray analysis. Penicinoline (1) showed potent in vitro cytotoxicity toward 95-D and HepG2 cell lines with IC50 values of 0.57 and 6.5μg/mL, respectively. [Copyright &y& Elsevier]

Six steroid derivatives including the novel, highly conjugated one (I), and five known butyrolactone derivatives are isolated and their structures are elucidated based on NMR and MS data. [ABSTRACT FROM AUTHOR]

Three new diphenyl ether derivatives, talaromycins A-C, are isolated together with six known analogues and evaluated for their cytotoxic and antifouling activities. [ABSTRACT FROM AUTHOR]

Palitantin (II) and the new analogue, 13-hydroxypalitantin (I), exhibit acetylcholinesterase (AchE) inhibitory activities. [ABSTRACT FROM AUTHOR]

Title compound (Ia) and its diastereomer xyloallenoide A1 (Ib) are prepared. [ABSTRACT FROM AUTHOR]