BACKGROUND:Arterial endothelial dysfunction is a critical early pathological change in cardiovascular diseases. Exercise-induced wall shear stress (WSS) exerts protective effects on impaired arterial endothelial function, while the underlying mechanism remains unclear. YAP/TAZ are core mechanotransduction molecules. This study aims to investigate whether YAP/TAZ mediate the ameliorative effect of moderate intensity exercise (MIE)-induced WSS on endothelial dysfunction via AMPK regulation. METHODS:Lipopolysaccharide (LPS)-injured HUVECs were exposed to MIE-induced WSS using a multicomponent parallel-plate flow chamber system. SiRNA-mediated knockdown of AMPK and YAP was performed to verify the regulatory signaling pathway. In vivo, high-fat diet ApoE-/- mice received MIE intervention to assess the impacts of MIE on endothelial function and YAP expression. RESULTS:LPS induced YAP/TAZ activation and endothelial dysfunction, whereas MIE-induced WSS inhibited YAP/TAZ activation and reversed endothelial dysfunction in LPS-treated cells. YAP knockdown strengthened the ameliorative effect of MIE-induced WSS on endothelial dysfunction. Furthermore, AMPK knockdown promoted YAP activation and attenuated the beneficial impact of MIE-induced WSS on endothelial dysfunction. Consistently, MIE intervention reversed high-fat diet-induced impairment of common carotid arterial endothelial function, concurrent with YAP downregulation in vivo. These results indicate that MIE-induced WSS ameliorates endothelial dysfunction via activating AMPK, which in turn inhibits YAP/TAZ. CONCLUSIONS:This study provides novel insights into the molecular mechanism by which MIE-induced WSS alleviates endothelial dysfunction, and provides a theoretical foundation for the clinical application of MIE as a rehabilitation strategy to improve impaired arterial endothelial function.

The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.

Atherosclerosis constitutes the primary pathological basis for cardiovascular diseases. It most commonly develops at the branching and curved regions of blood vessels. The disturbed blood flow in these regions can generate oscillatory shear stress (OSS). Endothelial cells exposed to OSS progressively undergo a transformation into mesenchymal cells, a process known as endothelial-to-mesenchymal transition (EndMT). EndMT is a critical event in the development of atherosclerosis. OSS promotes the occurrence of EndMT through multiple pathways. This paper provides a comprehensive analysis of the phenomena and mechanisms of OSS-induced EndMT, offering theoretical insights into the pathogenic mechanisms of atherosclerosis and corresponding therapeutic strategies.

Mitochondria, serving as central organelles for energy metabolism, play a critical regulatory role in stem cell self-renewal and differentiation—a function increasingly supported by accumulating evidence and closely linked to various aging-related diseases. Central to their function in stem cell pluripotency are several key mechanisms, such as the control of reactive oxygen species, mitophagy, and mitochondrial-endoplasmic reticulum communication. Mitochondrial transfer, as an emerging intercellular communication mechanism, can enhance stem cell pluripotency and function by replacing damaged mitochondria or activating mitophagy in recipient cells. However, different transfer mechanisms can induce distinct effects on recipient cells. The development of artificial mitochondrial transfer technology, compared to traditional cell transplantation, reduces immune rejection and offers new strategies for stem cell therapy. This review examines the interplay between mitochondrial function and stem cell fate determination, discusses the therapeutic potential of mitochondrial transfer in stem cell-based regenerative strategies, and establishes a theoretical framework for understanding and treating mitochondrial dysfunctions and aging-associated pathologies. Mitochondria provide energy to stem cells and influence their fate and aging processes. Moderate levels of reactive oxygen species (ROS) promote stem cell proliferation and differentiation, whereas excessive ROS accumulation impairs their function. Mitophagy maintains stem cell mitochondrial homeostasis through two distinct pathways. Mitochondria interact with the endoplasmic reticulum to regulate various characteristics of stem cells. Mitochondria undergo intercellular transfer to regulate the function of stem cells.

Toll-like receptors (TLRs) belong to the family of pattern recognition receptors (PRRs), playing critical roles in linking innate with adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). TLRs and TLR signaling pathways serve as not only the first line of pulmonary defense against pathogens infection but crucial factors in maintaining pulmonary immune homeostasis. However, aberrant activation of TLR signaling leads to inflammation and immune dysregulations, contributing to various pulmonary diseases, including inflammation, infection, fibrosis, and malignancy. This review summarizes the updated roles of TLRs and TLR signaling in lung development and the establishment and regulation of pulmonary region-specific immunity. We further elucidate the involvement of TLRs and TLR signaling in the onset and progression of lung diseases, such as infections, fibrosis, malignancies, and immune disorders. It would provide updated insights into the exploration of novel diagnostic and therapeutic strategies targeting TLRs and TLR signaling in pulmonary diseases.

Tissue-resident macrophage (TRM) is a specialized subset of macrophage that resides within specific tissues and organs. TRMs play crucial roles in resisting pathogen invasion, maintaining the homeostasis of the immune microenvironment, and promoting tissue repair and regeneration. The development and function of TRMs exhibit significant heterogeneity across different tissues. Kidney TRMs (KTRMs) originate from both embryonic yolk sac erythro-myeloid progenitors and the fetal liver, demonstrating the capacity for self-renewal independent of bone marrow hematopoiesis. KTRMs are not only essential for the maintenance of renal homeostasis and the monitoring of microvascular environment, but contribute to renal injury due to inflammation, fibrosis and immune dysfunction in kidneys. In this review, we summarize currently available studies on the regulatory role of KTRMs in processes of renal injury and repair. The altering effects and underlying mechanisms of KTRMs in regulating local tissue cells and immune cells in different renal diseases are reviewed, primarily including lupus nephritis, diabetic nephropathy, renal fibrosis, and renal carcinoma. Understanding the plasticity and immune regulatory functions of KTRMs may offer new insights into the pathogenesis and the exploration of therapeutic strategies of kidney diseases.

The abnormally active tumor vasculature provides a good blood supply for the rapid proliferation of tumors. The tumor microenvironment of tumor cells is associated with the secretion of a lot of angiogenic factors to promote the formation of blood vessels. However, the blood vessels are often irregular and immature. Additionally, the tumor tissue, in the process of its rapid proliferation, oppresses tumor blood vessels, causing hypoperfusion and leading to high interstitial pressure and hypoxia, which also results in changes to the fluid mechanics in the tumor microenvironment. Different fluid mechanics affect circulating tumor cell behavior and control various functions. A good mechanical microenvironment may be one of the important targets for inhibiting tumor proliferation and migration. Therefore, regulating tumor blood vessels to maintain a steady fluid mechanical microenvironment has the potential to be one of the key targets for tumor treatment. Numerous studies have demonstrated that certain natural medicines exhibit significant potential for inhibiting tumor growth and metastasis by selectively targeting tumor blood vessels, regulating the production of angiogenic cytokines, facilitating vascular normalization, etc. Furthermore, natural medicines enhance the anti-tumor effects of chemoradiotherapy and act as adjuvant agents to alleviate its associated side effects. This review summarizes the angiogenesis of the tumor microenvironment, changes induced by mechanical conditions, and the response of tumor cells and vasculature to different fluid shear stress to promote vascular normalization treatment strategies.

beta1-adrenergic receptor (β1-AR) belongs to G protein-coupled receptors, regulating cardiac physiological and pathological process through complex signaling pathways. Physiologically, the activation of β1-AR produces positive chronotropic, positive inotropic and positive dromotropic effects in the heart. However, excessive or sustained activation of β1-AR can cause myocardial injury, arrhythmias, and heart failure. The β1-AR in the heart exhibits tissue-specific distribution patterns and subcellular localization features adapted to its function within cardiomyocytes. Upon ligand binding, the β1-AR undergoes conformational changes and transmits signaling through G protein-dependent pathways (β1-AR/Gs and β1-AR/Gi) as well as a G protein-independent pathway (β1-AR/β-arrestin) to regulate cardiac activity. Subsequently, the β1-AR can either dissociate from G protein to undergo desensitization and terminate signal transduction, or it can be endocytosed into the cell, transported to the lysosome to be degraded, or returned to the plasma membrane to continue its function. Additionally, it has been found that β1-AR can cause or exacerbate heart disease when abnormal changes occur in its distribution density, localization, and mediated downstream signaling pathways. Therefore, β1-AR represents an important pharmacotherapeutic target for the treatment of cardiac diseases. Among the relevant therapeutic agents, β1-AR blockers designed specifically against β1-AR have evolved to the third generation. This review comprehensively analyzes β1-AR from perspectives including its research history, expression, and distribution in the heart, protein structure, signaling pathways, and associations with cardiac diseases.

Mitochondria‑derived peptides (MDPs) are a unique class of peptides encoded by short open reading frames in mitochondrial DNA, including the mitochondrial open reading frame of the 12S ribosomal RNA type‑c (MOTS‑c). Recent studies suggest that MDPs offer therapeutic benefits in various diseases, including neurodegenerative disorders and types of cancer, due to their ability to increase cellular resilience. Mitochondrial dysfunction is a key factor in the onset and progression of cardiovascular diseases (CVDs), such as atherosclerosis and heart failure, as it disrupts energy metabolism, increases oxidative stress and promotes inflammation. MDPs such as humanin and MOTS‑c have emerged as important regulators of mitochondrial health, as they show protective effects against these processes. Recent studies have shown that MDPs can restore mitochondrial function, reduce oxidative damage and alleviate inflammation, thus counteracting the pathological mechanisms that drive CVDs. Therefore, MDPs hold promise as therapeutic agents that are capable of slowing, stopping, or even reversing CVD progression and their use presents a promising strategy for future treatments. However, the clinical application of MDPs remains challenging due to their low bioavailability, poor stability and high synthesis costs. Thus, it is necessary to improve drug delivery systems to enhance the bioavailability of MDPs. Moreover, integrating basic research with clinical trials is essential to bridge the gap between experimental findings and clinical applications.

The vascular microenvironment comprises of anatomical structures, extracellular matrix components, and various cell populations, which play a crucial role in regulating vascular homeostasis and influencing vascular structure and function. Under physiological conditions, intrinsic regulation of the vascular microenvironment is required to sustain vascular homeostasis. In contrast, under pathological conditions, alterations to this microenvironment lead to vascular injury and pathological remodeling. According to the anatomy, the vascular microenvironment can be subdivided into three sections from the inside out. The vascular endothelial microenvironment, centered on vascular endothelial cells (VECs), includes the extracellular matrix and various vascular physicochemical factors. The VECs interact with vascular physicochemical factors to regulate the function of various parenchymal cells, including hepatocytes, neurons and tumor cells. The vascular wall microenvironment, comprising the vasa vasorum and their unique stem/progenitor cell niches, plays a pivotal role in vascular inflammation and pathological remodeling. Additionally, the perivascular microenvironment, which includes perivascular adipose tissue, consists of adipocytes and stem cells, which contribute to the pathological processes of atherosclerosis. It is anticipated that targeted regulation of the vascular microenvironment will emerge as a novel approach for the treatment of various diseases. Accordingly, this review will examine the structure of the vascular microenvironment, the regulation of vascular function by vascular cells and stem/progenitor cells, and the role of the vascular microenvironment in regulating cardiovascular diseases.

Oscillatory shear stress (OSS) can induce senescence in endothelial cells (ECs), driving atherosclerosis (AS), while the role of endoplasmic reticulum stress (ERS) remains unclear. OSS induced senescence in ECs by increasing SA-β-gal staining levels and upregulating p53, p21, and p16 levels, as well as the senescence-associated secretory phenotype (SASP). The SASP factors IL-1β, MIP-1α, and TNFα indicated the activation of the p53/p21 pathway. Transcriptomic analysis (GSE276195) showed that OSS activated ERS, enriched signaling pathways, and upregulated the expression levels of core ERS markers such as ATF4, IRE1α, and BIP. By using 4-PBA markedly inhibit ERS, the OSS-induced senescence. The integrated WGCNA and PPI analyses identified HMOX1 as a central hub gene, which was proven by in vivo and in vitro experiments. It displayed increased expression following OSS treatment and co-expression with ERS-genes. By inhibiting HMOX1 expression using Znpp, we found that HMOX1 suppression decreased the upregulation of ERS markers (BIP and IRE1α) and senescence markers (p53 and p21) induced by OSS; however, co-treatment with tunicamycin and HMOX1 silencing restored these upregulated levels, further demonstrating the importance of HMOX1-dependent mediation of ERS-induced senescence. This study elucidated the OSS-HMOX1-ERS axis governing senescence in ECs and suggested that HMOX1-mediated ERS plays a pivotal role in AS.

Piezo1 is a mechanosensitive cation channel protein that responds to mechanical stimuli such as fluid shear stress, stretch force, and extracellular matrix stiffness. It converts mechanical signals into biochemical signals, thereby regulating cellular biological behaviours including inflammation, oxidative stress, mitochondrial homeostasis, and angiogenesis. Growing evidence indicates that multiple cellular biological behaviours modulated by Piezo1 play a critical role in the physiological and pathological processes of cardiovascular diseases (CVDs). This review focuses on the regulatory factors and mechanisms of Piezo1 in CVDs, including atherosclerosis, hypertension, myocardial fibrosis, cardiac hypertrophy, and heart failure. Furthermore, based on the regulatory factors of Piezo1, potential therapeutic strategies and pharmacological agents targeting Piezo1 are discussed. In conclusion, Piezo1 holds promise as a novel therapeutic target for the prevention and treatment of CVDs, providing new strategies for drug development and clinical intervention.

Ferroptosis is a kind of programmed cell death characterized by the iron-dependent lipid peroxides accumulation, playing a pivotal role in the pathogenesis of various diseases, including neurodegenerative disorders, cardiovascular diseases, and osteoporosis. Mesenchymal stem cells (MSCs) and MSCs-derived exosomes (MSC-exos) are actively implicated in key biological processes, such as inflammatory and immune responses, tissue regeneration and repair, and aging. Emerging studies highlight the potential of MSCs and MSC-exos as effective regulators of ferroptosis, offering novel strategies for targeted therapeutic intervention in ferroptosis-related pathologies. This review comprehensively explores the precise regulatory mechanisms by which MSCs and MSC-exos modulate ferroptosis. We also evaluate the impact of ferroptosis on MSC biological functions and MSC-exos release. Furthermore, the therapeutic potentials and advantages of engineered MSCs and MSC-exos in the treatment of various diseases have also been explored, emphasizing their mechanistic roles in ferroptosis modulation across different organs and systems. This review provides insights and future directions for the development of novel MSC- or MSC-exos-based therapeutic strategies targeting ferroptosis. MSCs/Exo regulate ferroptosis via xCT/GPX4 and ACSL4 inhibition to protect cells. Bidirectional relationship: Ferroptosis influences MSC function and Exo release. Engineered MSCs/Exo target ferroptosis, immunomodulation, and regeneration.

BackgroundOvarian cancer (OC) is one of the most prevalent gynecologic malignancies and exhibites the highest fatality rate among all gynecologic malignancies. The absence of an early diagnostic biomarker and therapeutic target contributes to an overall 5-year survival rate ranging from 30 to 50%. Plectin (PLEC), a 500 kDa scaffolding protein, has gained prominence in recent years due to its pivotal role in various cellular biological functions such as cell morphology, migration and adhesion, while the accurate role of PLEC in OC remains elusive.ResultsIn this study, our findings demonstrate that PLEC exerts a positive influence on the progression of OC, encompassing cellular proliferation, migration, invasion, and adhesion both in vitro and in vivo.ConclusionsThe results providing new insights for the diagnosis and treatment in OC.

The mechanical microenvironment plays a crucial regulatory role in the growth and development of cells. Mechanical stimuli, including shear, tensile, compression, and extracellular matrix forces, significantly influence cell adhesion, migration, proliferation, differentiation, and various other cellular functions. Extracellular vesicles (EVs) are involved in numerous physiological and pathological processes, with their occurrence and secretion being strictly regulated by the mechanical microenvironment. Recent studies have confirmed that alterations in the mechanical microenvironment are present in cardiovascular diseases, and the components of EVs can respond to changes in mechanical signals, thereby impacting the progression of these diseases. Additionally, engineered EVs, created by leveraging mechanical microenvironments, can serve as natural drug-delivery vehicles for treating and managing specific diseases. This article systematically reviews the regulatory mechanisms through which the mechanical microenvironment influences EVs and summarizes the role and advancements of EVs derived from this environment in the context of cardiovascular diseases.

The treatment of ovarian cancer remains a medical challenge and its malignant progression is connected with obvious changes in both tissue and cell stiffness. However, the accurate mechanical-responsive molecules and mechanism remains unclear in ovarian cancer. Based on our previous results combined with the crucial regulatory role of STAT3 in the malignant progression of various cancer types, we want to investigate the relationship between STAT3 and matrix stiffness in ovarian cancer and further explore the potential mechanisms. Collagen-coated polyacrylamide gels (1, 6, and 60 kPa) were prepared to mimic soft or hard matrix stiffness. Western blotting, qRT-PCR, flow cytometry, IHC, EdU assays, and TEM were used to evaluate the effect of STAT3 in vitro under different matrix stiffnesses. Furthermore, a BALB/c nude mouse model was established to assess the relationship in vivo. Our results confirmed the differential expression of STAT3/p-STAT3 not only in normal and malignant ovarian tissues but also under different matrix stiffnesses. Furthermore, we verified that STAT3 was a mechanically responsive gene both in vitro and in vivo, and the mechanical response was carried out by altering the migration-related molecules (TNFAIP1) and adhesion-related molecules (LPXN, CNN3). The novel findings suggest that STAT3, a potential therapeutic target for clinical diagnosis and treatment, is a mechanically responsive gene that responds to matrix stiffness, particularly regulation in migration and adhesion in the progression of ovarian cancer.

Chitinase‑3 like‑protein‑1 (CHI3L1), a glycoprotein belonging to the glycoside hydrolase family 18, binds to chitin; however, this protein lacks chitinase activity. Although CHI3L1 is not an enzyme capable of degrading chitin, it plays significant roles in abnormal glucose and lipid metabolism, indicating its involvement in metabolic disorders. In addition, CHI3L1 is considered a key player in inflammatory diseases, with clinical data suggesting its potential as a predictor of cardiovascular disease. CHI3L1 regulates the inflammatory response of various cell types, including macrophages, vascular smooth muscle cells and fibroblasts. In addition, CHI3L1 participates in vascular remodeling and fibrosis, contributing to the pathogenesis of cardiovascular disease. At present, research is focused on elucidating the role of CHI3L1 in cardiovascular disease. The present systematic review was conducted to comprehensively evaluate the effects of CHI3L1 on cardiovascular cells, and determine the potential implications in the occurrence and progression of cardiovascular disease. The present study may further the understanding of the involvement of CHI3L1 in cardiovascular pathology, demonstrating its potential as a therapeutic target or biomarker in the management of cardiovascular disease.

Atherosclerosis (AS) is the leading cause of cardiovascular disease, causing a major burden on patients as well as families and society. Exosomes generally refer to various lipid bilayer microvesicles originating from different cells that deliver various bioactive molecules to the recipient cells, exerting biological effects in cellular communication and thereby changing the internal environment of the body. The mechanisms of correlation between exosomes and the disease process of atherosclerosis have been recently clarified. Exosomes are rich in nucleic acid molecules and proteins. For example, the exosome miRNAs reportedly play important roles in the progression of atherosclerotic diseases. In this review, we focus on the composition of exosomes, the mechanism of their biogenesis and release, and the commonly used methods for exosome extraction. By summarizing the latest research progress on exosomes and atherosclerosis, we can explore the advances in the roles of exosomes in atherosclerosis to provide new ideas and targets for atherosclerosis prevention, diagnosis, and treatment.

Cardiovascular Disease (CVD) is the leading cause of morbidity and death worldwide and has become a global public health problem. Traditional Chinese medicine (TCM) has been used in China to treat CVD and achieved promising results. Therefore, TCM has aroused significant interest among pharmacologists and medical practitioners. Previous research showed that TCM can regulate the occurrence and development of atherosclerosis (AS), ischemic heart disease, heart failure, myocardial injury, and myocardial fibrosis by inhibiting vascular endothelial injury, inflammation, oxidant stress, ischemia-reperfusion injury, and myocardial remodeling. It is well-known that TCM has the characteristics of multi-component, multi-pathway, and multitarget. Here, we systematically review the bioactive components, pharmacological effects, and clinical application of TCM in preventing and treating CVD.

The endothelial-mesenchymal transition (EndMT) of endothelial progenitor cells (EPCs) plays a notable role in pathological vascular remodeling. Emerging evidence indicated that long non-coding RNA-regulator of reprogramming (linc-ROR) can promote epithelial-mesenchymal transition (EMT) in a variety of cancer cells. Nevertheless, the function of linc-ROR in EPC EndMT has not been well elucidated. The present study investigated the effect and possible mechanisms of function of linc-ROR on the EndMT of EPCs. A linc-ROR overexpression lentiviral vector (LV linc-ROR) or a linc-ROR short hairpin RNA lentiviral vector (LV-shlinc-ROR) was used to up or downregulate linc-ROR expression in EPCs isolated from human umbilical cord blood. Functional experiments demonstrated that LV-linc-ROR promoted the proliferation and migration of EPCs, but inhibited EPC angiogenesis in vitro. In the meantime, reverse transcription-quantitative PCR and western blotting results showed that the expression of the endothelial cell markers vascular endothelial-cadherin and CD31 was decreased, while the expression of the mesenchymal cell markers ?-smooth muscle actin and SM22? was increased at both mRNA and protein levels in LV-linc-ROR-treated EPCs, indicating that linc-ROR induced EPC EndMT. Mechanistically, the dual-luciferase reporter assay demonstrated that microRNA (miR/miRNA)-145 was a direct target of linc-ROR, and miR-145 binds to the 3'-untranslated region of Smad3. Moreover, LV-shlinc-ROR increased the expression of miR-145, but decreased the expression of Smad3. In conclusion, linc-ROR promotes EPC EndMT, which may be associated with the miR-145/Smad3 signaling pathway. Keywords: Endothelial progenitor cells, Endothelial to mesenchymal transition, Linc-ROR, MiR-145, Atherosclerosis.