GRK2 Orchestrates VSMC Phenotypic Modulation via DNMT1-Mediated DNA Methylation Reprogramming.

Background: Vascular smooth muscle cell (VSMC) phenotypic modulation is responsible for the pathogenesis of hyper-muscularized arterial diseases. Recent studies have highlighted the critical role of epigenetic regulation in VSMC fate. However, the mechanisms underlying the precise regulation of the epigenetic machinery in VSMC remain unclear.

Light-triggered toll-like receptor activation in a nanoscale metal-organic framework for synergistic PDT and cancer immunotherapy.

Although innate immune modulators (IIMs) have shown promise as cancer immunotherapeutics, their clinical application is hindered by the challenge of achieving tumour-specific activation while minimizing systemic immune-related toxicity. Nanoscale metal-organic frameworks (MOFs) have emerged as effective carriers for photosensitizers to enable photodynamic therapy (PDT), which induces immunogenic cell death reactive oxygen species (ROS) generation. We hypothesized that covalent conjugation of IMMs to nanoscale MOFs through ROS-cleavable linkers could localize immune activation to the tumour microenvironment while synergizing with PDT to enhance antitumour immunity.

FAP Promotes Pulmonary Artery Hypertension via Activation of the PTEN/PI3K/Akt Pathway.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by significant pulmonary vascular remodeling and right ventricular dysfunction. Activated fibroblasts can induce collagen deposition around blood vessels, thereby promoting vascular hardening and PAH development. Fibroblast activation protein (FAP) is a proline-specific serine protease expressed in active fibroblasts that is closely associated with tissue remodeling, inflammation, fibrosis, tumor growth, and cellular proliferation.

The GRK2/AP-1 Signaling Axis Mediates Vascular Endothelial Dysfunction and Atherosclerosis Induced by Oscillatory Low Shear Stress.

Disturbed blood flow and the resulting oscillatory low shear stress (OSS) are key contributors to vascular endothelial dysfunction and the initiation of atherosclerosis. However, the molecular mediators that translate abnormal hemodynamic signals into pathological vascular endothelial responses remain unclear. G protein-coupled receptors (GPCRs) are classical mechanosensors in the vascular endothelium.

Transforming malignant tumors into vulnerable phenotypes via nanoscale coordination polymer mediated cell senescence and photodynamic therapy.

Induction of senescence in cancer cells can thwart the proliferation of malignant tumors. Herein we report the design of AZT-P/pyro nanoscale coordination polymer particles consisting of 3-azido-2,3-dideoxythymidine monophosphate (AZT-P) in the core and photosensitizing pyro-lipid (pyro) in the shell for potent antitumor treatment. Gradual release of AZT-P in response to an acidic tumor microenvironment transforms cancer cells with unlimited proliferation capacity into senescent cells that are vulnerable to reactive oxygen species (ROS).

Prenatal exposure to temperature variability, gestational duration and preterm birth: A nationwide birth cohort with 3 million singleton births in China.

Background: Little is known about how temperature variability (TV) affects the risk of preterm birth (PTB).

Objective: This cohort study aims to evaluate the associations of prenatal TV exposure with gestational age and PTB risk.

Methods: This study included 3,012,744 live singleton births from 336 Chinese cities delivered between January 2013 and December 2015.

Nanoparticle-Mediated Toll-Like Receptor Activation and Dual Immune Checkpoint Downregulation for Potent Cancer Immunotherapy.

Dual blockade of CD47 and PD-L1 immune checkpoints has shown potential in cancer treatment, but its clinical application is hindered by the on-target off-tumor immunotoxicities of monoclonal antibodies. Herein, we report a core-shell nanoparticle, PPA/HG, comprising polyinosinic: polycytidylic acid (PPA) in the core and a cholesterol-conjugated prodrug of 3-(hydroxyolinoyl)glycine (HG) on the shell, for potent cancer immunotherapy. PPA/HG shows a long half-life in the bloodstream to efficiently accumulate in tumors, where PPA/HG rapidly releases HG and PPA.

Metal-organic layer delivers 3-bromopyruvate to mitochondria for metabolic regulation and cancer radio-immunotherapy.

Abnormal cancer metabolism causes hypoxia and immunosuppression, limiting the anti-tumor efficacy of radiotherapy. Herein, we report a positively charged, mitochondria-targeted nanoscale metal-organic layer conjugated with 3-bromopyruvate (BP), BP/Hf-Ir, for metabolic reprogramming and radiosensitization. BP/Hf-Ir disrupts oxidative phosphorylation and glycolysis, reducing energy production and alleviating hypoxia to enhance radiotherapy and anti-tumor immunity.

Innate Immune Activation with Multifunctional Nanoparticles for Cancer Immunotherapy.

Immune checkpoint blockade (ICB) has revolutionized the treatment of many cancers by leveraging the immune system to combat malignancies. However, its efficacy is limited by the immunosuppressive tumor microenvironment and other regulatory mechanisms of the immune system. Innate immune modulators (IIMs) provide potent immune activation to complement adaptive immune responses and help overcome resistance to ICB.

Nitric Oxide-Releasing Nanoscale Metal-Organic Layer Overcomes Hypoxia and Reactive Oxygen Species Diffusion Barriers to Enhance Cancer Radiotherapy.

Hafnium (Hf)-based nanoscale metal-organic layers (MOLs) enhance radiotherapeutic effects of tissue-penetrating X-rays via a unique radiotherapy-radiodynamic therapy (RT-RDT) process through efficient generation of hydroxy radical (RT) and singlet oxygen (RDT). However, their radiotherapeutic efficacy is limited by hypoxia in deep-seated tumors and short half-lives of reactive oxygen species (ROS). Herein the conjugation of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), to the Hf secondary building units (SBUs) of Hf-5,5'-di-p-benzoatoporphyrin MOL is reported to afford SNAP/MOL for enhanced cancer radiotherapy.

Nanoscale Mixed-Ligand Metal-Organic Framework for X-ray Stimulated Cancer Therapy.

Concurrent localized radiotherapy and systemic chemotherapy are standards of care for many cancers, but these treatment regimens cause severe adverse effects in many patients. Herein, we report the design of a mixed-ligand nanoscale metal-organic framework (nMOF) with the ability to simultaneously enhance radiotherapeutic effects and trigger the release of a potent chemotherapeutic under X-ray irradiation. We synthesized a new functional quaterphenyl dicarboxylate ligand conjugated with SN38 (HQP-SN) via a hydroxyl radical-responsive covalent linkage.

Cationic Metal-Organic Layer Delivers siRNAs to Overcome Radioresistance and Potentiate Cancer Radiotherapy.

Radiotherapy plays an important role in modern oncology, but its treatment efficacy is limited by the radioresistance of tumor cells. As a member of the inhibitor of apoptosis protein family, survivin plays a key role in developing radioresistance by mediating apoptosis evasion, promoting epithelial-mesenchymal transition, and modulating cell cycle dynamics. Efficient downregulation of survivin expression presents a promising strategy to enhance the antitumor effects of radiotherapy.

Associations of artificial sweetener intake with cardiometabolic disorders and mortality: a population-based study.

Artificial sweeteners are generally used and recommended to alternate added sugar for health promotion. However, the health effects of artificial sweeteners remain unclear. In this study, we included 6371 participants from the National Health and Nutrition Examination Survey with artificial sweetener intake records.

STING activation disrupts tumor vasculature to overcome the EPR limitation and increase drug deposition.

The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics.

Nanoscale Metal-Organic Layer Reprograms Cellular Metabolism to Enhance Photodynamic Therapy and Antitumor Immunity.

Abnormal cancer metabolism causes hypoxic and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal-organic layer (MOL) with anchored 3-bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production.

Vitamin D supplementation for cardiometabolic risk markers in pregnant women based on the gestational diabetes mellitus or obesity status : a randomized clinical trial.

Purpose: Women with gestational diabetes mellitus (GDM) or obesity are vulnerable to impaired gestational cardiovascular health (CVH) and cardiovascular disease (CVD) in the future. It is unclear if prenatal vitamin D supplementation improves gestational CVH, especially in women at high risk for developing CVD. Our goal was to find out if vitamin D supplementation could protect against gestational CVH, including the women with GDM or obesity.

Alpha-Hederin induces incomplete autophagic injury in non-small cell lung cancer by interfering with the lysosomal acidification.

Lung cancer is the most common oncological disease worldwide, with non-small cell lung cancer accounting for approximately 85% of lung cancer cases. α-Hederin is a monodesmosidic triterpenoid saponin isolated from the leaves of Hedera helix L. or Nigella sativa and has been extensively studied for its antitumor activity against a variety of tumor cells.

Insulinemic and Inflammatory Dietary Patterns Show Enhanced Predictive Potential for Gestational Diabetes Mellitus Risk.

Context: The putative association between pro-inflammatory and hyperinsulinemic dietary patterns and susceptibility to gestational diabetes mellitus (GDM) remains unclear.

Objective: We aimed to compare the risk associated with the Mediterranean diet, as well as insulinemic and pro-inflammatory dietary patterns, in relation to the occurrence of GDM, and evaluate their predictive value.

Methods: We prospectively followed 8495 women from the Maternal and Infant Health cohort in Hefei, China (2015-2021).

Phosphate Coordination to Metal-Organic Layer Secondary Building Units Prolongs Drug Retention for Synergistic Chemoradiotherapy.

Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy.

USP36-mediated PARP1 deubiquitination in doxorubicin-induced cardiomyopathy.

Doxorubicin (Dox) is a potent antineoplastic agent, but its use is curtailed by severe cardiotoxicity, known as Dox-induced cardiomyopathy (DIC). The molecular mechanism underlying this cardiotoxicity remains unclear. Our current study investigates the role of Ubiquitin-Specific Protease 36 (USP36), a nucleolar deubiquitinating enzyme (DUB), in the progression of DIC and its mechanism.