Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction.

As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for "energy information transfer," can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.

High-Strength Injectable Hydrogel into Perivascular Interstitial Space Enhances Arterial Adventitial Stress.

Injectable hydrogels with strong mechanical properties have significant potential for biomedical applications, including the development of electronic skin, intelligent medical robots, as well as tissue engineering. In this study, we report on an injectable hydrogel with notable tensile strength and adhesion properties, achieved through cross-linking thiol-terminated four-arm poly (ethylene glycol) using silver-doped nano-hydroxyapatite, modified with dopamine. Subsequently, the hydrogel was injected in vivo through the perivascular interstitial space of rats. The hydrogel wrapped around the damaged abdominal aortic adventitia, which greatly increases the stress strength of the arterial adventitia. We found that the hydrogel was characterized by excellent biocompatibility, and it induced little immune response over a span of 21 days post-implantation. This simple and minimally invasive vascular protection strategy appears promising for the treatment of vascular diseases, such as abdominal aortic aneurysm (AAA).

Adhesion Anisotropy Substrate with Janus Micropillar Arrays Guides Cell Polarized Migration and Division Cycle.

Cell migration is a ubiquitous and important cell behaviour. Construction of an interface that can guide and induce cell migration is of significance for studying cell behaviour and carrying out the transplantation of biological materials. Herein, we prepare a micropillar array by precise modification of two different functional groups on each micropillar unit to obtain a "Janus" structure with anisotropic cell-adhesion properties. This anisotropic structure was capable of influencing the focal adhesion pathway of melanoma cells as shown by transcriptome sequencing and bioinformatics analysis. This the anisotropic substrate can considerably affect the migration ability of highly invasive melanoma cells. The anisotropic structure with Janus micropillar arrays could also affect the cell division cycle. The experiments showed that the anisotropic microstructures regulate cell migration and are thus of use in the research of cell migration without drug stimulation.

Novel strategy of combined interstitial macrophage depletion with intravenous targeted therapy to ameliorate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease with poor prognosis and high mortality rate. In the process of IPF, inflammatory dysregulation of macrophages and massive fibroblast aggregation and proliferation destroy alveoli, which cause pulmonary dysfunction, and ultimately lead to death due to respiratory failure. In the treatment of IPF, crossing biological barriers and delivering drugs to lung interstitium are the major challenges. In order to avoid the side effect of macrophages proliferation, we proposed, designed, and evaluated the strategy which combined macrophage depletion by intervaginal space injection and intravenous targeted therapy on bleomycin mouse model. We found that it inhibited pulmonary macrophages, reduced macrophage depletion in non-target organs, improved pulmonary drug targeting, impeded the progression of pulmonary fibrosis, and accelerated the recovery of pulmonary function. This combination therapeutic strategy shows good biosafety and efficacy, induces a targeted response, and is promising as a practical new clinical approach towards the treatment of pulmonary fibrosis.

Rapamycin nanoparticles improves drug bioavailability in PLAM treatment by interstitial injection.

BACKGROUND: Pulmonary lymphangiomyomatosis (PLAM) is a rare interstitial lung disease characterized by diffuse cystic changes caused by the destructive proliferation of smooth muscle-like cells or LAM cells. PLAM is more common in young women than other people, and a consensus is lacking regarding PLAM treatment. The clinical treatment of PLAM is currently dominated by rapamycin. By inhibiting the mTOR signaling pathway, rapamycin can inhibit and delay PLAM's occurrence and development. However, the application of rapamycin also has shortcomings, including the drug's low oral bioavailability and a high binding rate to hemoglobin, thus significantly decreasing the amount of drug distributed to the lungs. METHODS AND RESULTS: Here, we developed a new mode of rapamycin administration in which the drug was injected into the intrathecal space after being nanosized; the directional flow characteristics of the liquid in the intrathecal space were exploited to increase the drug content in the interstitial fluid to the greatest extent possible. We studied the rapamycin content in the interstitial fluid and blood after intervaginal space injection (ISI). Compared with oral administration, ISI significantly increased the drug concentration in the lung interstitial fluid. CONCLUSIONS: These results provided new ideas for treating PLAM and optimizing the dosing regimens of drugs with similar characteristics to rapamycin.

Phloridzin Reveals New Treatment Strategies for Liver Fibrosis.

Liver fibrosis is an urgent public health problem which is difficult to resolve. However, various drugs for the treatment of liver fibrosis in clinical practice have their own problems during use. In this study, we used phloridzin to treat hepatic fibrosis in the CCl4-induced C57/BL6N mouse model, which was extracted from lychee core, a traditional Chinese medicine. The therapeutic effect was evaluated by biochemical index detections and ultrasound detection. Furthermore, in order to determine the mechanism of phloridzin in the treatment of liver fibrosis, we performed high-throughput sequencing of mRNA and lncRNA in different groups of liver tissues. The results showed that compared with the model group, the phloridzin-treated groups revealed a significant decrease in collagen deposition and decreased levels of serum alanine aminotransferase, aspartate aminotransferase, laminin, and hyaluronic acid. GO and KEGG pathway enrichment analysis of the differential mRNAs was performed and revealed that phloridzin mainly affects cell ferroptosis. Gene co-expression analysis showed that the target genes of lncRNA were obvious in cell components such as focal adhesions, intercellular adhesion, and cell-substrate junctions and in metabolic pathways such as carbon metabolism. These results showed that phloridizin can effectively treat liver fibrosis, and the mechanism may involve ferroptosis, carbon metabolism, and related changes in biomechanics.

Amiodarone inhibits arrhythmias in hypertensive rats by improving myocardial biomechanical properties.

The prevalence of arrhythmia in patients with hypertension has gradually attracted widespread attention. However, the relationship between hypertension and arrhythmia still lacks more attention. Herein, we explore the biomechanical mechanism of arrhythmia in hypertensive rats and the effect of amiodarone on biomechanical properties. We applied micro-mechanics and amiodarone to stimulate single ventricular myocytes to compare changes of mechanical parameters and the mechanism was investigated in biomechanics. Then we verified the expression changes of genes and long non-coding RNAs (lncRNAs) related to myocardial mechanics to explore the effect of amiodarone on biomechanical properties. The results found that the stiffness of ventricular myocytes and calcium ion levels in hypertensive rats were significantly increased and amiodarone could alleviate the intracellular calcium response and biomechanical stimulation. In addition, experiments showed spontaneously hypertensive rats were more likely to induce arrhythmia and preoperative amiodarone intervention significantly reduced the occurrence of arrhythmias. Meanwhile, high-throughput sequencing showed the genes and lncRNAs related to myocardial mechanics changed significantly in the spontaneously hypertensive rats that amiodarone was injected. These results strengthen the evidence that hypertension rats are prone to arrhythmia with abnormal myocardial biomechanical properties. Amiodarone effectively inhibit arrhythmia by improving the myocardial biomechanical properties and weakening the sensitivity of mechanical stretch stimulation.

Nitrogen doped carbon dots for turn-off fluorescent detection of alkaline phosphatase activity based on inner filter effect.

The abnormal expression level of alkaline phosphatase (ALP) will lead to serious diseases. Therefore, a sensitive and rapid assay for ALP activity monitoring is of vital importance. In this work, a fluorescence turn-off approach for the detection of ALP is designed on the basis of nitrogen doped carbon dots (N-CDs), which were synthesized by one-step hydrothermal method and applied as signal readout. p-Nitrophenylphosphate (PNPP) can be hydrolyzed into p-nitrophenol (PNP) by ALP and their absorption peaks are different under alkaline conditions, so it was chosen as the ALP substrate. The absorption spectrum of PNP has good overlap with the excitation and emission spectra of N-CDs, thus the fluorescence of N-CDs can be effectively quenched by PNP via the inner filter effect (IFE). Consequently, quantitative detection of ALP is realized because the relative fluorescence intensity is linearly with the ALP activity in a wide range from 0.05 to 40 U L-1. The detection limit is 0.02 U L-1 (S/N = 3), which is much lower than the normal level of serum ALP in adults (about 40-190 U L-1). Moreover, the assay was successfully applied to evaluate ALP inhibitor efficiency and screen ALP inhibitors in drug discovery. It is also demonstrated that N-CDs possesses low cytotoxicity, excellent biocompatibility and photostability, and can be successfully applied in vivo fluorescence imaging, showing great potential in clinical applications.