Effects of replication domains on genome-wide UV-induced DNA damage and repair.

Nucleotide excision repair is the primary repair mechanism that removes UV-induced DNA lesions in placentals. Unrepaired UV-induced lesions could result in mutations during DNA replication. Although the mutagenesis of pyrimidine dimers is reasonably well understood, the direct effects of replication fork progression on nucleotide excision repair are yet to be clarified. Here, we applied Damage-seq and XR-seq techniques and generated replication maps in synchronized UV-treated HeLa cells. The results suggest that ongoing replication stimulates local repair in both early and late replication domains. Additionally, it was revealed that lesions on lagging strand templates are repaired slower in late replication domains, which is probably due to the imbalanced sequence context. Asymmetric relative repair is in line with the strand bias of melanoma mutations, suggesting a role of exogenous damage, repair, and replication in mutational strand asymmetry.

Genome-wide analysis of 8-oxo-7,8-dihydro-2'-deoxyguanosine at single-nucleotide resolution unveils reduced occurrence of oxidative damage at G-quadruplex sites.

8-Oxo-7,8-dihydro-2'-deoxyguanosine (OG), one of the most common oxidative DNA damages, causes genome instability and is associated with cancer, neurological diseases and aging. In addition, OG and its repair intermediates can regulate gene transcription, and thus play a role in sensing cellular oxidative stress. However, the lack of methods to precisely map OG has hindered the study of its biological roles. Here, we developed a single-nucleotide resolution OG-sequencing method, named CLAPS-seq (Chemical Labeling And Polymerase Stalling Sequencing), to measure the genome-wide distribution of both exogenous and endogenous OGs with high specificity. Our data identified decreased OG occurrence at G-quadruplexes (G4s), in association with underrepresentation of OGs in promoters which have high GC content. Furthermore, we discovered that potential quadruplex sequences (PQSs) were hotspots of OGs, implying a role of non-G4-PQSs in OG-mediated oxidative stress response.

Nucleotide excision repair: a versatile and smart toolkit.

Nucleotide excision repair (NER) is a major pathway to deal with bulky adducts induced by various environmental toxins in all cellular organisms. The two sub-pathways of NER, global genome repair (GGR) and transcription-coupled repair (TCR), differ in the damage recognition modes. In this review, we describe the molecular mechanism of NER in mammalian cells, especially the details of damage recognition steps in both sub-pathways. We also introduce new sequencing methods for genome-wide mapping of NER, as well as recent advances about NER in chromatin by these methods. Finally, the roles of NER factors in repairing oxidative damages and resolving R-loops are discussed.

The effects of ginsenosides on platelet aggregation and vascular intima in the treatment of cardiovascular diseases: From molecular mechanisms to clinical applications.

Thrombosis initiated by abnormal platelet aggregation is a pivotal pathological event that precedes most cases of cardiovascular diseases (CVD). Recently, growing evidence indicates that platelet could be a potential target for CVD prevention. However, as the conventional antithrombotic management strategy, applications of current antiplatelet agents are somewhat limited by their various side effects, such as bleeding risk and drug resistance. Hence, efforts have been made to search for agents as complementary therapies. Ginsenoside, the principal active component extracted from Panax ginseng, has gained much attention for its regulations on multiple crucial events of platelet aggregation. From structural characteristics to clinical applications, this review anatomized the intrinsic structure-function relationship of antiplatelet potency of ginsenosides, and the involved signal pathways were specifically summarized. Additionally, the emphasis was placed on clinical studies that investigate the antithrombotic efficacy of ginsenosides in the treatment of CVD. Further, a broad overview of approaches for improving the bioavailability of ginsenosides was concluded. Limitations and prospects of current studies were also discussed. This study may provide some new insights into the systematic understanding of ginsenosides in CVD treatment and lay a foundation for future research.

A erythrocyte-platelet hybrid membrane coated biomimetic nanosystem based on ginsenosides and PFH combined with ultrasound for targeted delivery in thrombus therapy.

Thrombus is one of the culprits for global health problems. However, most current antithrombotic drugs are limited by restricted targeting ability and a high risk of systemic bleeding. A hybrid cell membrane-coated biomimetic nanosystem (PM/RM@PLGA@P/R) was constructed in this paper to fulfil the targeted delivery of ginsenoside (Rg1) and perfluorohexane (PFH). Poly lactic-co-glycolic acid (PLGA) is used as carriers to coat Rg1 and PFH. Thanks to the camouflage of erythrocyte membrane (RM) and platelet membrane (PM), the nanosystem in question possesses remarkable features including immune escape and self-targeting. Therefore, a compact nano-core with PLGA@P/R was formed, with a hybrid membrane covering the surface of the core, forming a "core-shell" structure. With its "core-shell" structure, this nanoparticle fancifully combines the advantages of both PFH (the low-intensity focused ultrasound (LIFU)-responsive phase-change thrombolysis) and Rg1(the antioxidant, anti-inflammatory and anticoagulant abilities). Meanwhile, PM/RM@PLGA@P/R nanoparticles exhibits superior in-vitro performance in terms of ROS scavenging, anticoagulant activity and immune escape compared with those without cell membranes (PLGA@P/R). Furthermore, in the animal experiment in which the tail vein thrombosis model was established by injecting k-carrageenan, the combined treatment of LIFU and PM/RM@PLGA@P/R showed a satisfactory antithrombotic efficiency (88.20 %) and a relatively higher biological safety level. This strategy provides new insights into the development of more effective and safer targeted biomimetic nanomedicines for antithrombotic treatments, possessing potential application in synergistic therapy field.

Platelet membrane-cloaked selenium/ginsenoside Rb1 nanosystem as biomimetic reactor for atherosclerosis therapy.

Cardiovascular disease remains the dominant contributor to human mortality, and the main etiology of which is atherosclerosis (AS). Enhancing the targeted ability of nanosystem and improving plaque stability are critical challenges for the current management of AS. Herein, we leverage the marked role of platelets in AS to construct a biomimetic nanodrug delivery system (PM@Se/Rb1 NPs), which prepared by cloaking platelet membrane (PM) around Selenium (Se) and ginsenoside Rb1 nanoparticles (Se/Rb1 NPs) core. The core endows the delivery system antioxidant, lipid metabolism and anti-inflammatory effects for AS effective treatment. Moreover, PM-coated nanoparticles reserve platelets' inherent biological elements to deliver drugs to plaques. We further explored the potential effect of PM@Se/Rb1 NPs' combination with the clinical anticoagulant drug warfarin (War) to treat AS and elucidated the possible drug interaction mechanism. As a result, the PM@Se/Rb1 NPs are not only capable of improving inflammatory behaviors such as inhibitory adhesion ability and anti-angiogenesis therapeutic effect in vitro, but also administer efficiently localizing to atherosclerotic plaque explaining by aortic samples from established ApoE-/- mice. Therefore, this study provided a theoretical basis of biomimetic nanodrug in the treatment of AS as well as an effective reference for the combined application of nanodrug and clinical drugs.

Protective Effects and Therapeutics of Ginsenosides for Improving Endothelial Dysfunction: From Therapeutic Potentials, Pharmaceutical Developments to Clinical Trials.

The endothelium covers the internal lumen of the entire circulatory system and plays an important modulatory role in vascular homeostasis. Endothelium dysfunction, characterized by a vasoconstrictive, pro-inflammatory, and pro-coagulant state, usually manifests as a significant pathological process of vascular diseases, including hypertension, atherosclerosis (AS), stroke, diabetes mellitus, coronary artery disease, and cancer. Therefore, there is an urgent necessity to seek promising therapeutic drugs or remedies to ameliorate endothelial dysfunction-induced vascular ailments and complications. Recently, much attention has been attached to ginsenosides, the most significant active components of ginseng, which have always been referred to as "all-healing" and widely used for its extensively medicinal value. Surprisingly, ginsenosides have diverse biological activity which might be related to inflammation, apoptosis, oxidative stress, and angiogenesis. In this review, a brief introduction about endothelial dysfunction and ginsenosides was demonstrated, and the emphasis was put on summarizing multi-faceted pharmacological effects and underlying molecular mechanisms of ginsenosides on the endothelium, including vasorelaxation, anti-oxidation, anti-inflammation, and angio-modulation. Beyond that, nanotechnology to improve efficacy and the existing clinical trials of ginsenosides were concluded. Hopefully, our work will give suggestions for promoting clinical application of traditional Chinese medicine, e.g., hypertension, AS, diabetes, ischemic stroke, and cancer. This review provides a comprehensive base of knowledge for ginsenosides to prevention and treatment of vascular injury- related diseases with clinical significance.

Biomimetic polyphenol-coated nanoparticles by Co-assembly of mTOR inhibitor and photosensitizer for synergistic chemo-photothermal therapy.

Rapamycin (RAPA) functions as effectively clinical immunosuppressive agent, its significant tumor growth suppression effect via various pathways in diverse cancers, especially combined with photothermal therapy, is gaining a burgeoning attention. However, its critical defects, low solubility and poor stability, have severely hampered its further application. Herein, RAPA, indocyanine green (ICG) and epigallocatechin gallate (EGCG) serving as chemotherapeutic drug, photosensitizer and biomimetic coatings, respectively, were co-assembled into carrier-free, high biocompatible ICG-RAPA-EGCG nanoparticles (IRE NPs) for synergistic cancer therapy. Particularly, the bioinspired EGCG coatings not only improved the stability of IRE NPs under physiological conditions to avert NPs disassembly and drug release, but also maintained the photostability of ICG to achieve excellent photothermal response. The results indicated that the as-prepared IRE NPs displayed good monodispersity and enhanced stability at various stored media after introducing of EGCG. Compared with monotherapy of RAPA or ICG, IRE NPs showed higher dose-dependent toxicity in MCF-7 cells, HepG2 cells and HeLa cells, especially plus near-infrared laser irradiation. Furthermore, IRE NPs exhibited quicker uptake in cells, higher accumulation in tumor region (even in 48 h) than free ICG and effectively inhibited tumor growth without side effect in H22 tumor-bearing mice. Collectively, the carrier-free IRE NPs provided a simply alternative approach to fabricate RAPA/photosensitizer co-loaded nanoparticles for combinatorial tumor therapy.

Biomimetic nanoparticles: U937 cell membranes based core-shell nanosystems for targeted atherosclerosis therapy.

Atherosclerosis (AS), with its intricate pathogenesis, is primarily responsible for the development and progression of cardiovascular diseases. Although drug development has made some achievements in AS therapy, limited targeting ability and rapid blood clearance remain great challenges for achieving superior clinical outcomes. Herein, ginsenoside (Re)- and catalase (CAT)-coloaded porous poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs) were prepared and then surface modified with U937 cell membranes (UCMs) to yield a dual targeted model and multimechanism treatment biomimetic nanosystem (Cat/Re@PLGA@UCM). The nanoparticles consisted of a core-shell spherical morphology with a favorable size of 112.7 ± 0.4 nm. Furthermore, UCM assisted the nanosystem in escaping macrophage phagocytosis and targeting atherosclerotic plaques. Meanwhile, loading with catalase might not only exhibit favorable antioxidant effects but also enable H2O2-responsive drug release ability. The Cat/Re@PLGA@UCM NPs also exhibited outstanding ROS scavenging properties, downregulating ICAM-1, TNF-α and IL-1ß, while preventing angiogenesis to attenuate the progression of AS. Moreover, the nanodrugs displayed 2.7-fold greater efficiency in reducing the atherosclerotic area in ApoE-/- mouse models compared to free Re. Our nanoformulation also displayed excellent biosafety in response to long-term administration. Overall, our study demonstrated the superiority of UCM-coated stimuli-responsive nanodrugs for effective and safe AS therapy.

Cell adhesion molecule-mediated therapeutic strategies in atherosclerosis: From a biological basis and molecular mechanism to drug delivery nanosystems.

Atherosclerosis (AS), characterized by pathological constriction of blood vessels due to chronic low-grade inflammation and lipid deposition, is a leading cause of human morbidity and mortality worldwide. Cell adhesion molecules (CAMs) have the ability to regulate the inflammatory response and endothelial function, as well as potentially driving plaque rupture, which all contribute to the progression of AS. Moreover, recent advances in the development of clinical agents in the cardiovascular field are based on CAMs, which show promising results in the fight against AS. Here, we review the current literature on mechanisms by which CAMs regulate atherosclerotic progression from the earliest induction of inflammation to plaques formation. In particular, we focused on therapeutic strategies based on CAMs inhibitors that prevent leukocyte from migrating to endothelium, including high-affinity antibodies and antagonists, nonspecific traditional medicinal formulas and lipid lowering drugs. The CAMs-based drug delivery nanosystem and the available data on the more reasonable and effective clinical application of CAMs inhibitors have been emphasized, raising hope for further progress in the field of AS therapy.