The roles of Th cells in myocardial infarction.

Myocardial infarction, commonly known as a heart attack, is a serious condition caused by the abrupt stoppage of blood flow to a part of the heart, leading to tissue damage. A significant aspect of this condition is reperfusion injury, which occurs when blood flow is restored but exacerbates the damage. This review first addresses the role of the innate immune system, including neutrophils and macrophages, in the cascade of events leading to myocardial infarction and reperfusion injury. It then shifts focus to the critical involvement of CD4+ T helper cells in these processes. These cells, pivotal in regulating the immune response and tissue recovery, include various subpopulations such as Th1, Th2, Th9, Th17, and Th22, each playing a unique role in the pathophysiology of myocardial infarction and reperfusion injury. These subpopulations contribute to the injury process through diverse mechanisms, with cytokines such as IFN-γ and IL-4 influencing the balance between tissue repair and injury exacerbation. Understanding the interplay between the innate immune system and CD4+ T helper cells, along with their cytokines, is crucial for developing targeted therapies to mitigate myocardial infarction and reperfusion injury, ultimately improving outcomes for cardiac patients.

Recent Advances in Biomedical Nanotechnology Related to Natural Products.

Natural product processing via nanotechnology has opened the door to innovative and significant applications in medical fields. On one hand, plants-derived bioactive ingredients such as phenols, pentacyclic triterpenes and flavonoids exhibit significant pharmacological activities, on another hand, most of them are hydrophobic in nature, posing challenges to their use. To overcome this issue, nanoencapsulation technology is employed to encapsulate these lipophilic compounds and enhance their bioavailability. In this regard, various nano-sized vehicles, including degradable functional polymer organic compounds, mesoporous silicon or carbon materials, offer superior stability and retention for bioactive ingredients against decomposition and loss during delivery as well as sustained release. On the other hand, some naturally occurring polymers, lipids and even microorganisms, which constitute a significant portion of Earth's biomass, show promising potential for biomedical applications as well. Through nano-processing, these natural products can be developed into nano-delivery systems with desirable characteristics for encapsulation a wide range of bioactive components and therapeutic agents, facilitating in vivo drug transport. Beyond the presentation of the most recent nanoencapsulation and nano-processing advancements with formulations mainly based on natural products, this review emphasizes the importance of their physicochemical properties at the nanoscale and their potential in disease therapy.

Surface-Engineered Monocyte Immunotherapy Combined Graphene Quantum Dots Effective Against Solid Tumor Targets.

Introduction: The immunosuppressive tumor microenvironment (TME) of solid tumors inhibits most drug delivery system-based nanomaterials from achieving deep penetration in tumor tissue and interferes with T cell activity in terms of differentiation and exhaustion, which is becoming a critical therapy hurdle for solid tumors. Therefore, developing a therapeutic strategy with abilities of rapid establishment of tumor-targeted cells, elimination of immune obstacles, and enhanced active immunization is very important, while is still a big challenge. Methods: A new strategy was explored to enhance immune therapy via the conjugation of microRNA155 (miR) to the surface of therapeutic monocyte with graphene quantum dots (GQDs). Results: TME was reversed using surface-engineered monocyte immunotherapy via reprogramming pro-tumoral M2 TAMs into antitumor M1, and thus tumor elimination was dramatically enhanced. Conclusion: Such a surface-engineered monocyte immunotherapy has been demonstrated to be well tolerated to intravenous administration and bio-compatible, showing the potential to be extended for the solid tumor treatment.

PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy.

Thyroid associated ophthalmopathy (TAO), characterized by T cell infiltration and orbital fibroblast activation, is an organ-specific autoimmune disease which is still short of effective and safety therapeutic drugs. The PD-1/PD-L1 pathway has been reported hindering the progression of Graves' disease to some extent by inhibiting T cell activity, and tumor therapy with a PD-1 inhibitor caused some adverse effects similar to the symptoms of TAO. These findings suggest that the PD-1/PD-L1 pathway may be associated with the pathogenesis of TAO. However, it remains unknown whether the PD-1/PD-L1 pathway is involved in orbital fibroblast activation. Here, we show that orbital fibroblasts from patients with TAO do not express PD-L1. Based on in vitro OF-T cell co-culture system, exogenous PD-L1 weakens T cell-induced orbital fibroblast activation by inhibiting T cell activity, resulting in reduced production of sICAM-1, IL-6, IL-8, and hyaluronan. Additionally, exogenous PD-L1 treatment also inhibits the expression of CD40 and the phosphorylation levels of MAPK and NF-κB pathways in orbital fibroblasts of the OF-T cell co-culture system. Knocking down CD40 with CD40 siRNA or down-regulating the phosphorylation levels of MAPK and NF-κB pathways with SB203580, PD98059, SP600125, and PDTC can both reduce the expression of these cytokines and hyaluronan. Our study demonstrates that the orbital immune tolerance deficiency caused by the lack of PD-L1 in orbital fibroblasts may be one of the causes for the active orbital inflammation in TAO patients, and the utilization of exogenous PD-L1 to reconstruct the orbital immune tolerance microenvironment may be a potential treatment strategy for TAO.

Biomimetic oral targeted delivery of bindarit for immunotherapy of atherosclerosis.

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the development of atherosclerosis. However, the application of bindarit (a specific synthetic inhibitor of MCP-1) in atherosclerosis has not been confirmed due to the non-specific distribution profile in vivo. Herein, based on the recruitment of monocytes into atherosclerotic plaques, we successfully delivered bindarit into the interior of atherosclerotic plaques through a yeast-derived microcapsule (YC) mediated biomimetic approach. In this biomimetic approach, bindarit was firstly assembled with polyethyleneimine to form the positively charged nanoparticles (BIN/PEI NPs) via multiple intermolecular forces, and then the obtained BIN/PEI NPs were packed into YCs by electrostatic force-mediated spontaneous deposition. Through an oral adsorption routine similar to yeasts, bindarit loaded YCs (BIN/YCs) were distributed into peripheral blood monocytes after oral administration, and then their targeted delivery to atherosclerotic plaques was successfully performed through monocyte transportation. Correspondingly, oral delivery of bindarit loaded YCs afforded notably potentiated efficacies for inhibiting the MCP-1 and further reducing the recruitment of monocytes into atherosclerotic plaques, and thus presented a good efficacy in preventing the formation of atherosclerotic plaques. These results demonstrated that a 'Trojan horse'-like YC mediated nanomedicine delivery strategy is expected to realize the application of certain potential anti-inflammatory drugs in the treatment of atherosclerosis and is of great significance for the development of novel strategies for atherosclerosis treatment.

Surface-Engineered Monocyte Inhibits Atherosclerotic Plaque Destabilization via Graphene Quantum Dot-Mediated MicroRNA Delivery.

Rupture-prone atherosclerotic plaque is the cause of the high mortality and morbidity rates that accompany atherosclerosis-associated diseases. MicroRNAs can regulate the expression of a variety of atherosclerotic inflammation-related genes in macrophages. There are currently no definitive methods for delivering microRNAs into the interior of plaque. Monocytes typically possess a pathological feature that allows them to be recruited to atherosclerotic plaque resulting in rupture-prone; however, whether monocytes can be modified to be gene carriers remains unclear. In this study, a novel monocyte surface-engineered gene-delivery system based on graphene quantum dots (GQDs) is developed. Briefly, GQDs-microRNA223 linked by disulfide bonds are grafted onto the monocyte membrane via a carefully designed C18-peptide (C18P) containing a hydrophobic end to afford the designed monocyte-C18P-GQDs-miR223 architecture. The system can reach and enter the interior of the plaque and release the GQDs-miRNA via C18P digestion. The released GQDs-miRNA are taken up by the macrophages in atherosclerotic plaques, and the disulfide linkages between the GQDs and the miRNA are cleaved through γ-interferon-inducible lysosomal thiol reductase (GILT) in the lysosome. Under the protection of GQDs, miRNA cargos are transfected into the cytosol and subsequently undergo nuclear translocation, allowing a significantly reduced plaque burden by regulating inflammatory response in vivo.

Engineered-Macrophage Induced Endothelialization and Neutralization via Graphene Quantum Dot-Mediated MicroRNA Delivery to Construct Small-Diameter Tissue-Engineered Vascular Grafts.

Rapid endothelialization of tissue-engineered blood vessels (TEBVs) is an essential strategy to inhibit thrombosis, chronic inflammation and intimal hyperplasia after transplantation into the body. Monocytes will be recruited to the transplantation site and converted to macrophages after TEBV implantation. Macrophages play an important role in angiogenesis; however, whether engineered macrophages can be utilized to promote rapid endothelialization of TEBVs remains unclear. Thus, a cell bioreactor that can engineer macrophages via graphene quantum dot (GQD)-mediated microRNA (miR) delivery was built in the TEBV. Briefly, GQD-miR-150 linked by disulfide bonds was adopted to functionalize both the inner and outer TEBVs. The GQD-miR-150 conjugation as an intracellular gene delivery system was taken up by macrophages. Under the protection of GQDs, miR-150 was transfected into the cytosol, allowing continuous secretion of vascular endothelial growth factor (VEGF) via upregulation of HIF-1α protein expression, and promoted the migration of endothelial cells (ECs) in vitro. An in vivo study showed a rapid endothelialization of the inner TEBVs after transplantation for 7 days, especially a holonomic endothelial layer after 30 days. For the outer TEBVs, neovascularization (vasa vasorum) accompanied by nerve growth was observed around the adventitia on day 90. In conclusion, the designed cell bioreactor consisting of GQD-miR-engineered macrophages can effectively promote endothelialization and neuralization in vivo for TEBVs.

Physalin D regulates macrophage M1/M2 polarization via the STAT1/6 pathway.

The in vitro and in vivo effects of physalin D on macrophage M1/M2 polarization were investigated. In silico analysis was first performed for biological function prediction of different physalins. The results suggest physalins have similar predicted biological functions due to their similarities in chemical structures. The cytotoxicity of physalins was then analyzed based on cell apoptosis rate and cell viability evaluation. Physalin D was chosen for further study due to its minimal cytotoxicity. Bone marrow macrophages were isolated and induced with lipopolysaccharide/interferon (IFN)-γ for M1 polarization and interleukin (IL)-4/IL-13 for M2 polarization. The results showed that physalin D can repolarize M1 phenotype cells toward M2 phenotype. In addition, physalin D is protective in M2 macrophages to maintain the M2 phenotype in the presence of IFN-γ. On the molecular level, we found that physalin D suppressed the signal transducers and activators of transcription (STAT)1 activation and blocked STAT1 nuclear translocation. Conversely, physalin D can also activate STAT6 and enhance STAT6 nuclear translocation for M2 polarization. Taken together, these results suggested that physalin D regulates macrophage M1/M2 polarization via the STAT1/6 pathway.

Antishear Stress Bionic Carbon Nanotube Mesh Coating with Intracellular Controlled Drug Delivery Constructing Small-Diameter Tissue-Engineered Vascular Grafts.

Small-diameter (<6 mm) tissue-engineered blood vessels (TEBVs) have a low patency rate due to chronic inflammation mediated intimal hyperplasia. Functional coating with drug release is a promising solution, but preventing the released drug from being rushed away by blood flow remains a great challenge. A single-walled carboxylic acid functionalized carbon nanotube (C-SWCNT) is used to build an irregular mesh for TEBV coating. However, an interaction between the released drug and the cells is still insufficient due to the blood flow. Thus, an intracellular drug delivery system mediated by macrophage cellular uptake is designed. Resveratrol (RSV) modified CNT is used for macrophage uptake. M1 macrophage uptakes CNT-RSV and then converts to the M2 phenotype upon intracellular RSV release. Prohealing M2 macrophage inhibits the chronic inflammation thus maintains the contractile phenotype of the vascular smooth muscle cell (VSMC), which reduces intimal hyperplasia. Additionally, RSV released from the mesh coating also directly protects the contractile VSMCs from being converted to a secretory phenotype. Through antishear stress coating and macrophage-based intracellular drug delivery, CNT-RSV TEBVs exhibit a long-term anti-intimal hyperplasia function. Animal transplantation studies show that the patency rate remains high until day 90 after grafting in rat carotid arteries.

Netrin-1 Promotes Inflammation Resolution to Achieve Endothelialization of Small-Diameter Tissue Engineering Blood Vessels by Improving Endothelial Progenitor Cells Function In Situ.

The transplant of small-diameter tissue engineering blood vessels (small-diameter TEBVs) (<6 mm) in vascular replacement therapy often fails because of early onset thrombosis and long-standing chronic inflammation. The specific inflammation state involved in small-diameter TEBVs transplants remains unclear, and whether promoting inflammation resolution would be useful for small-diameter TEBVs therapy need study. The neural protuberant orientation factor 1 (Netrin-1) is found present in endothelial cells of natural blood vessels and has anti-inflammatory effects. This work generates netrin-1-modified small-diameter TEBVs by using layer-by-layer self-assembly to resolve the inflammation. The results show that netrin-1 reprograms macrophages (MΦ) to assume an anti-inflammatory phenotype and promotes the infiltration and subsequent efflux of MΦ from inflamed sites over time, which improves the local microenvironment and the function of early homing endothelial progenitor cells (EPCs). Small-diameter TEBVs modified by netrin-1 achieve endothelialization after 30 d and retain patency at 14 months. These findings suggest that promoting the resolution of inflammation in time is necessary to induce endothelialization of small-diameter TEBVs and prevent early thrombosis and problems associated with chronic inflammation. Furthermore, this work finds that the MΦ-derived exosomes can target and regulate EPCs, which may serve as a useful treatment for other inflammatory diseases.

Hydrogenation of Pt/TiO2{101} nanobelts: a driving force for the improvement of methanol catalysis.

Single-crystalline anatase TiO2 nanobelts with a dominant surface of the {101} facet were hydrogenated and used as substrates of platinum for methanol oxidation reaction (MOR). The hydrogenated TiO2 anatase{101} supporting Pt exhibits a 228% increase of current density for methanol oxidation compared with the same system without hydrogenation under dark conditions. The synergetic interactions of hydrogenated anatase{101} with the Pt cluster were investigated through first principles calculations, and found that the hydrogenation shifts the conduction band minimum to the Fermi level of pristine TiO2, and reduces the activation barrier for methanol dissociation considerably. Thus, this work provides an experimental and theoretical basis for developing non-carbon substrates with high electro-catalytic activity toward MOR.