PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.

Circadian dysfunction is prevalent in neurodevelopmental disorders, particularly in autism spectrum disorder (ASD). A plethora of empirical studies demonstrate a strong correlation between ASD and circadian disruption, suggesting that modulation of circadian rhythms and the clocks could yield satisfactory advancements. Research indicates that circadian dysfunction associated with abnormal neurodevelopmental phenotypes in ASD individuals, potentially contribute to synapse plasticity disruption. Therefore, targeting circadian rhythms may emerge as a key therapeutic approach. In this study, we did a brief review of the mammalian circadian clock, and the correlation between the circadian mechanism and the pathology of ASD at multiple levels. In addition, we highlight that circadian is the target or modulator to participate in the therapeutic approaches in the management of ASD, such as phototherapy, melatonin, modulating circadian components, natural compounds, and chronotherapies. A deep understanding of the circadian clock's regulatory role in the neurodevelopmental phenotypes in ASD may inspire novel strategies for improving ASD treatment.

The co-occurrence of Alzheimer's disease (AD) and cardiovascular diseases (CVDs) in older adults highlights the necessity for the exploration of potential shared risk factors. A total of 566 adults were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 111 individuals with AD, 383 with mild cognitive impairment (MCI), and 410 with CVD. The multivariable linear mixed model (LMM) was used to investigate the associations of AD and CVD with longitudinal changes in 146 plasma proteomic biomarkers (measured at baseline and the 12-month follow-up). The LMM showed that 48 biomarkers were linked to AD and 46 to CVD (p < 0.05). Both AD and CVD were associated with longitudinal changes in 14 biomarkers (α1Micro, ApoH, β2M, BNP, complement C3, cystatin C, KIM1, NGAL, PPP, TIM1, THP, TFF3, TM, and VEGF), and both MCI and CVD were associated with 12 biomarkers (ApoD, AXL, BNP, Calcitonin, CD40, C-peptide, pM, PPP, THP, TNFR2, TTR, and VEGF), suggesting intricate connections between cognitive decline and cardiovascular health. Among these, the Tamm Horsfall Protein (THP) was associated with AD, MCI, CVD, and APOE-ε4. This study provides valuable insights into shared and distinct biological markers and mechanisms underlying AD and CVD.

Melatonin, N-acetyl-5-methoxytryptamine, is a neuroendocrine hormone secreted by the pineal gland. This pleiotropic indoleamine possesses amphiphilic properties, allowing it to penetrate most biological barriers and exert its effects at the subcellular level. Importantly, melatonin also plays a crucial role in regulating the body's response to circadian rhythms, adapting to internal and external environmental cues. Melatonin functions as a powerful antioxidant and free radical scavenger, protecting cells from oxidative damage. Its diverse physiological roles include maintaining the functional integrity of endothelial cells, thereby preventing atherosclerosis, a major contributor to cardiovascular disease. Additionally, melatonin exhibits antioxidant and free radical scavenging properties, potentially improving metabolic disorders. These combined effects suggest a unique adjunctive therapeutic potential for melatonin in treating cardiovascular diseases. This review aims to explore the mechanisms by which melatonin interacts with the cardiovascular system and investigates its potential use as an adjunctive therapeutic agent in managing cardiovascular disease.

Rosuvastatin (RVS) is an excellent drug with anti-inflammatory and lipid-lowering properties in the academic and medical fields. However, this drug faces a series of challenges when used to treat atherosclerosis caused by hyperhomocysteinemia (HHcy), including high oral dosage, poor targeting, and long-term toxic side effects. In this study, we applied nanotechnology to construct a biomimetic nano-delivery system, macrophage membrane (Møm)-coated RVS-loaded Prussian blue (PB) nanoparticles (MPR NPs), for improving the bioavailability and targeting capacity of RVS, specifically to the plaque lesions associated with HHcy-induced atherosclerosis. In vitro assays demonstrated that MPR NPs effectively inhibited the Toll-like receptor 4 (TLR4)/hypoxia-inducible factor-1α (HIF-1α)/nucleotide-binding and oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) signaling pathways, reducing pyroptosis and inflammatory response in macrophages. Additionally, MPR NPs reversed the abnormal distribution of adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1)/ATP binding cassette transporter G1 (ABCA1)/ATP binding cassette transporter G1 (ABCG1) caused by HIF-1α, promoting cholesterol efflux and reducing lipid deposition. In vivo studies using apolipoprotein E knockout (ApoE -/-) mice confirmed the strong efficacy of MPR NPs in treating atherosclerosis with favorable biosecurity, and the mechanism behind this efficacy is believed to involve the regulation of serum metabolism and the remodeling of gut microbes. These findings suggest that the synthesis of MPR NPs provides a promising nanosystem for the targeted therapy of HHcy-induced atherosclerosis.

Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator-activated receptor delta (PPARδ) has been shown to modulate vascular smooth muscle cell (SMC) phenotypic switching, and, hence, atherosclerotic plaque stability. Melatonin reportedly plays a beneficial role in cardiovascular diseases; however, the mechanisms underlying improvements in atherosclerotic plaque vulnerability remain unknown. In this study, we assessed the role of melatonin in regulating SMC phenotypic switching and its consequential contribution to the amelioration of atherosclerotic plaque vulnerability and explored the mechanisms underlying this process. We analyzed features of atherosclerotic plaque vulnerability and markers of SMC phenotypic transition in high-cholesterol diet (HCD)-fed apolipoprotein E knockout (ApoE-/-) mice and human aortic SMCs (HASMCs). Melatonin reduced atherosclerotic plaque size and necrotic core area while enhancing collagen content, fibrous cap thickness, and smooth muscle alpha-actin positive cell coverage on the plaque cap, which are all known phenotypic characteristics of vulnerable plaques. In atherosclerotic lesions, melatonin significantly decreased the synthetic SMC phenotype and KLF4 expression and increased the expression of PPARδ, but not PPARα and PPARγ, in HCD-fed ApoE-/- mice. These results were subsequently confirmed in the melatonin-treated HASMCs. Further analysis using PPARδ silencing and immunoprecipitation assays revealed that PPARδ plays a role in the melatonin-induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPARδ-mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis.

Atherosclerosis, an immunoinflammatory disease of medium and large arteries, is associated with life-threatening clinical events, such as acute coronary syndromes and stroke. Chronic inflammation and impaired lipoprotein metabolism are considered to be among the leading causes of atherosclerosis, while numerous risk factors, including arterial hypertension, diabetes mellitus, obesity, and aging, can contribute to the development of the disease. In recent years, emerging evidence has underlined the key role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Mitochondrial dysfunction is believed to result in an increase in reactive oxygen species, leading to oxidative stress, chronic inflammation, and intracellular lipid deposition, all of which can contribute to the pathogenesis of atherosclerosis. Critical cells, including endothelial cells, vascular smooth muscle cells, and macrophages, play an important role in atherosclerosis. Mitochondrial function is also involved in maintaining the normal function of these cells. To better understand the relationship between mitochondrial dysfunction and atherosclerosis, this review summarizes the findings of recent studies and discusses the role of mitochondrial dysfunction in the risk factors and critical cells of atherosclerosis. FACTS: OPEN QUESTIONS.

Resin monomer-induced dental pulp injury presents a pathology related to mitochondrial dysfunction. Melatonin has been regarded as a strong mitochondrial protective bioactive compound from the pineal gland. However, it remains unknown whether melatonin can prevent dental pulp from resin monomer-induced injury. The aim of this study is to investigate the effects of melatonin on apoptosis of mouse preodontoblast cells (mDPC6T) induced by triethylene glycol dimethacrylate (TEGDMA), a major component in dental resin, and to determine whether the JNK/MAPK signaling pathway mediates the protective effect of melatonin. A well-established TEGDMA-induced mDPC6T apoptosis model is adopted to investigate the preventive function of melatonin by detecting cell viability, apoptosis rate, expressions of apoptosis-related proteins, mitochondrial ROS (mtROS) production, mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) level. Inhibitors of MAPKs are used to explore which pathway is involved in TEGDMA-induced apoptosis. Finally, the role of the JNK/MAPK pathway is verified using JNK agonists and antagonists. Our results show that melatonin attenuates TEGDMA-induced mDPC6T apoptosis by reducing mtROS production and rescuing MMP and ATP levels. Furthermore, mitochondrial dysfunction and apoptosis are alleviated only by the JNK/MAPK inhibitor SP600125 but not by other MAPK inhibitors. Additionally, melatonin downregulates the expression of phosphorylated JNK and counteractes the activating effects of anisomycin on the JNK/MAPK pathway, mimicking the effects of SP600125. Our findings demonstrate that melatonin protects mDPC6T cells against TEGDMA-induced apoptosis partly through JNK/MAPK and the maintenance of mitochondrial function, offering a novel therapeutic strategy for the prevention of resin monomer-induced dental pulp injury.

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. It is essential to develop novel interventions to prevent/delay CVDs by targeting their fundamental cellular and molecular processes. Melatonin is a small indole molecule acting both as a hormone of the pineal gland and as a local regulator molecule in various tissues. It has multiple features that may contribute to its cardiovascular protection. Moreover, melatonin enters all cells and subcellular compartments and crosses morphophysiological barriers. Additionally, this indoleamine also serves as a safe exogenous therapeutic agent. Increasing evidence has demonstrated the beneficial effects of melatonin in preventing and improving cardiovascular risk factors. Exogenous administration of melatonin, as a result of its antioxidant and anti-inflammatory properties, has been reported to decrease blood pressure, protect against atherosclerosis, attenuate molecular and cellular damage resulting from cardiac ischemia/reperfusion, and improve the prognosis of myocardial infarction and heart failure. This review aims to summarize the beneficial effects of melatonin against these conditions, the possible protective mechanisms of melatonin, and its potential clinical applicability in CVDs.

Chimeric antigen receptor CAR-T cell therapies have ushered in a new era of treatment for specific blood cancers, offering unparalleled efficacy in cases of treatment resistance or relapse. However, the emergence of cytokine release syndrome (CRS) as a side effect poses a challenge to the widespread application of CAR-T cell therapies. Melatonin, a natural hormone produced by the pineal gland known for its antioxidant and anti-inflammatory properties, has been explored for its potential immunomodulatory effects. Despite this, its specific role in mitigating CAR-T cell-induced CRS remains poorly understood.

In this study, our aim was to investigate the potential of melatonin as an immunomodulatory agent in the context of CD19-targeting CAR-T cell therapy and its impact on associated side effects. Using a mouse model, we evaluated the effects of melatonin on CAR-T cell-induced CRS and overall survival. Additionally, we assessed whether melatonin administration had any detrimental effects on the antitumor efficacy and persistence of CD19 CAR-T cells.

Our findings demonstrate that melatonin effectively mitigated the severity of CAR-T cell-induced CRS in the mouse model, leading to improved overall survival outcomes. Remarkably, melatonin administration did not compromise the antitumor effectiveness or persistence of CD19 CAR-T cells, indicating its compatibility with therapeutic goals. These results suggest melatonin's potential as an immunomodulatory compound to alleviate CRS without compromising the therapeutic benefits of CAR-T cell therapy.

The study's outcomes shed light on melatonin's promise as a valuable addition to the existing treatment protocols for CAR-T cell therapies. By attenuating CAR-T cell-induced CRS while preserving the therapeutic impact of CAR-T cells, melatonin offers a potential strategy for optimizing and refining the safety and efficacy profile of CAR-T cell therapy. This research contributes to the evolving understanding of how to harness immunomodulatory agents to enhance the clinical application of innovative cancer treatments.

Atherosclerosis (AS)-associated cardiovascular diseases are predominant causes of morbidity and mortality worldwide. Melatonin, a circadian hormone with anti-inflammatory activity, may be a novel therapeutic intervention for AS. However, the exact mechanism is unclear. This research intended to investigate the mechanism of melatonin in treating AS. Melatonin (20 mg/kg/d) was intraperitoneally administered in a high-fat diet (HFD)-induced AS model using apolipoprotein E-deficient (ApoE-/-) mice for 12 weeks. Immunohistochemical and immunofluorescence analyses, data-independent acquisition (DIA)-based protein profiling, ingenuity pathway analysis (IPA), and western blotting were employed to investigate the therapeutic effects of melatonin in treating HFD-induced AS. An adeno-associated virus (AAV) vector was further used to confirm the antiatherosclerotic mechanism of melatonin. Melatonin treatment markedly attenuated atherosclerotic lesions, induced stable phenotypic sclerotic plaques, inhibited macrophage infiltration, and suppressed the production of proinflammatory cytokines in ApoE-/- mice with HFD-induced AS. Notably, DIA-based quantitative proteomics together with IPA identified S100a9 as a pivotal mediator in the protective effects of melatonin. Moreover, melatonin significantly suppressed HFD-induced S100a9 expression at both the mRNA and protein levels. The overexpression of S100a9 significantly activated the NF-κB signaling pathway and markedly abolished the antagonistic effect of melatonin on HFD-induced vascular inflammation during atherogenesis. Melatonin exerts a significant antiatherogenic effect by inhibiting S100a9/NF-κB signaling pathway-mediated vascular inflammation. Our findings reveal a novel antiatherosclerotic mechanism of melatonin and underlie its potential clinical use in modulating AS with good availability and affordability.

The Chinese herbal compound Xinmaikang (XMK) is effective in treating atherosclerosis (AS), although the associated mechanisms of action remain unclear. We hypothesize that XMK increases mitophagy via the PINK1/Parkin signaling pathway and decreases reactive oxygen species (ROS), thus treating AS.

To explore the above-mentioned mechanisms of action of XMK in AS.

Ultra-performance liquid chromatography assay was performed to clarify the composition of XMK. A 16-week high-fat diet was fed to APOE-/- mice to form an AS model. Next, mice were given XMK(0.95 g/kg/d, 1.99 g/kg/d, 3.98 g/kg/d, i.g.) or Atorvastatin(3 mg/kg/d, i.g.) or Rapamycin(4 mg/kg/d, i.p.) or XMK with Mdivi-1(40 mg/kg/d, i.p.) or an equivalent amount of normal saline for 4 weeks. Then mice were examined for AS plaque area, lesion area, collagen fiber, pro-inflammatory cytokines, lipid level, ROS level and mitophagy level. We assessed AS using Oil Red O, hematoxylin and eosin, and Sirius red staining, as well as ROS measurements. Mitophagy was evaluated by transmission electron microscopy, real-time quantitative polymerase chain reaction (RT-qPCR), Western blot, single-cell Western blot, and immunofluorescence staining. In vitro, by oxidizing low-density lipoprotein, formation of RAW264.7 macrophage-derived foam cells induced. we induced foam cell formation in RAW264.7 macrophages. Then cells were incubated with XMK-medicated serum with or without Mdivi-1. We examined foam cell formation, ROS level, mitophagy level in cells. Finally, we knocked down the PINK1, and examined foam cell formation and PINK1/Parkin level in RAW264.7 macrophages.

UPLC analysis revealed 102 main ingredients in XMK. In vivo, XMK at medium-dose or high-dose significantly reduced AS plaques, lipids, pro-inflammatory cytokines, and ROS and increased mitophagy. In further study, Single-cell western blot showed that mitophagy level in macrophages sorted from AS mice was lower than the control mice. While XMK improved mitophagy level. In vitro, XMK reduced foam cell formation and ROS and increased mitophagy. When PINK1 was knocked down, XMK's effects on foam cell formation and PINK1/Parkin pathway activation were reduced.

The study shows that XMK is effective against AS by mediating macrophage mitophagy via the PINK1/Parkin signaling pathway. For the treatment of AS and drug discovery, it provides an experimental basis and target.

Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been administered to patients, including the elderly and children, in clinical trials. In this review, we critically review the corresponding literature, including the hypotheses that melatonin acts as a scavenger molecule, in particular in mitochondria, by trying not only to contextualize these interests but also by attempting to separate the wheat from the chaff (or the wishful thinking from the facts). We conclude that most claims remain hypotheses and that the experimental evidence used to promote them is limited and sometimes flawed. Our review will hopefully encourage clinical researchers to reflect on what melatonin can and cannot do and help move the field forward on a solid basis.

Mammalian infertile-20-like kinase 4 (MST4) plays major roles in the progression of malignant tumor types, but its function in gastric cancer (GC) remains poorly understood.

To investigate the regulatory mechanism of MST4 in GC.

Immunohistochemistry was used to detect MST4 protein in GC tissue. Additionally, the correlation between MST4 expression and the clinicopathological characteristics and prognosis of GC was evaluated. The MST4 expression level in GC cells was measured by western blotting and quantitative real-time polymerase chain reaction. Moreover, the regulatory mechanism of MST4 was investigated in vitro and in vivo.

Overexpression of MST4 was found in GC tissue and cell lines, which correlated to the tumor size, histological type, invasion depth, ulcer, lymph node metastasis, lymphovascular invasion, perineural invasion and TNM stage (all P < 0.01). In terms of MST4 functions in vitro, its upregulation facilitated the proliferation, migration, and invasion of GC cells. Furthermore, MST4 promoted these processes by facilitating autophagy, whereas downregulation of MST4 significantly attenuated these processes. Downregulation of MST4 also attenuated tumor growth in vivo.

High expression of MST4 indicates a poor prognosis and promotes GC cell proliferation, invasion, and metastasis by enhancing autophagy.

Mitophagy is a type of autophagy that can selectively eliminate damaged and depolarized mitochondria to maintain mitochondrial activity and cellular homeostasis. Several pathways have been found to participate in different steps of mitophagy. Mitophagy plays a significant role in the homeostasis and physiological function of vascular endothelial cells, vascular smooth muscle cells, and macrophages, and is involved in the development of atherosclerosis (AS). At present, many medications and natural chemicals have been shown to alter mitophagy and slow the progression of AS. This review serves as an introduction to the field of mitophagy for researchers interested in targeting this pathway as part of a potential AS management strategy.

Aging triggers a wide range of cellular and molecular aberrations in the body, giving rise to inflammation and associated diseases. In particular, aging is associated with persistent low-grade inflammation even in absence of inflammatory stimuli, a phenomenon commonly referred to as 'inflammaging'. Accumulating evidence has revealed that inflammaging in vascular and cardiac tissues is associated with the emergence of pathological states such as atherosclerosis and hypertension. In this review we survey molecular and pathological mechanisms of inflammaging in vascular and cardiac aging to identify potential targets, natural therapeutic compounds, and other strategies to suppress inflammaging in the heart and vasculature, as well as in associated diseases such as atherosclerosis and hypertension.

The endoplasmic reticulum (ER) governs the proper folding of polypeptides and proteins through various chaperones and enzymes residing within the ER organelle. Perturbation in the ER folding process ensues when overwhelmed protein folding exceeds the ER handling capacity, leading to the accumulation of misfolded/unfolded proteins in the ER lumen-a state being referred to as ER stress. In turn, ER stress induces a gamut of signaling cascades, termed as the "unfolded protein response" (UPR) that reinstates the ER homeostasis through a panel of gene expression modulation. This type of UPR is usually deemed "adaptive UPR." However, persistent or unresolved ER stress hyperactivates UPR response, which ultimately, triggers cell death and inflammatory pathways, termed as "maladaptive/terminal UPR." A plethora of evidence indicates that crosstalks between ER stress (maladaptive UPR) and inflammation precipitate obesity pathogenesis. In this regard, the acquisition of the mechanisms linking ER stress to inflammation in obesity might unveil potential remedies to tackle this pathological condition. Herein, we aim to elucidate key mechanisms of ER stress-induced inflammation in the context of obesity and summarize potential therapeutic strategies in the management of obesity through maneuvering ER stress and ER stress-associated inflammation.

Cardiovascular disease (CVD) is a group of systemic disorders threatening human health with complex pathogenesis, among which mitochondrial energy metabolism reprogramming has a critical role. Mitochondria are cell organelles that fuel the energy essential for biochemical reactions and maintain normal physiological functions of the body. Mitochondrial metabolic disorders are extensively involved in the progression of CVD, especially for energy-demanding organs such as the heart. Therefore, elucidating the role of mitochondrial metabolism in the progression of CVD is of great significance to further understand the pathogenesis of CVD and explore preventive and therapeutic methods. In this review, we discuss the major factors of mitochondrial metabolism and their potential roles in the prevention and treatment of CVD. The current application of mitochondria-targeted therapeutic agents in the treatment of CVD and advances in mitochondria-targeted gene therapy technologies are also overviewed.

With the growing prevalence of cardiovascular disease (CVD), there is an urgent need to explore non-conventional therapeutic measures to alleviate the burden of CVD on global healthcare. Mitochondrial injury plays a cardinal role in the pathogenesis of CVD. Mitochondrial dynamics and mitophagy are essential machineries that govern mitochondrial health in cardiomyocytes in physiological and pathophysiological settings. However, with the onset and progression of CVD, homeostasis of mitophagy is disturbed through largely unknown pathological mechanisms, causing mitochondrial damage and ultimately cardiomyocyte death. In this review we decipher the dual regulatory role of mitophagy in CVD pathogenesis, summarize controversies in mitophagy, and highlight recently identified compounds capable of modulating mitophagy. We share our perspectives on future mitophagy research directions in the context of CVD.