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Ferroptosis is a new cell death process characterized by massive iron accumulation and lipid peroxidation. Emerging evidence demonstrates that ferroptosis plays a crucial role in the development and progression of tumorigenesis. Targeting it is a potentially effective cancer prevention and treatment strategy in the clinic. A comprehensive review of molecular mechanisms of targeting ferroptosis in cancer by natural products needs to be re-summarized and updated due to the advances in research. We searched and reviewed relevant literature through the database Web of Science, mainly focusing on the regulatory effects of natural products and their active compounds in treating or preventing cancer by regulating ferroptosis. A total of 62 kinds of natural products and their active compounds were reported to exert antitumor effects via causing ferroptosis of cancer cells by regulating the System Xc−-GPX4 axis and lipid, mitochondrial, and iron metabolism. Natural products have advantages in improving chemotherapy’s therapeutic effects by causing cancer cell ferroptosis through their polypharmacological actions. These molecular mechanisms of ferroptosis regulation by natural products will pave the way for developing natural antitumor drugs based on regulating ferroptosis.

Migraine is one of the most prevalent and disabling neurological disease. The current treatments are limited. Acupuncture is a promising complementary and replacement therapy, but further clinical evidence is needed. Besides, the influence of acupuncture on migraine is not an immediate effect, the mechanism of this effect is not clear yet. This study is to provide further clinical evidence for the anti-migraine effects of acupuncture and explore the mechanism. Herein, a randomized controlled trial (48 participants in total; 10 normal controls and 38 migraineurs) was performed. The 38 migraine patients were divided into blank control, sham acupuncture, and acupuncture. The baseline characteristics were assessed for 2 weeks before the study. After that, patients were subjected to two courses of treatment, each of which lasted 5 days, with an interval of 1 day between the two courses (11 days in total). Outcome data collection, fMRI measurement, and blood sample collection were performed before and at the end of the treatment period. Effectiveness of treatment was evaluated using pain questionnaire. The fMRI data was analysed. Blood plasma was collected for metabolomics and proteomics studies. Results showed that acupuncture effectively relieves migraine symptoms, and not merely via the placebo effect. The anti-migraine mechanism involves a complex network which is related to regulating the blood oxygen levels, reversing brain energy imbalance and regulating inflammation. Brain regions of migraineurs affected by acupuncture include the limbic system and default mode network, and regions involved in cognitive and emotional processing of pain, sleep, and attention.

Modified Bu-Fei decoction (MBFD), a formula of traditional Chinese medicine, is used for treating lung cancer in clinic. The actions and mechanisms of MBFD on modulating lung microenvironment is not clear.Lung microenvironment is rich in vascular endothelial cells (ECs). This study is aimed to examine the actions of MBFD on tumor biology, and to uncover the underlying mechanisms by focusing on pulmonary ECs.The Lewis lung carcinoma (LLC) xenograft model and the metastatic cancer model were used to determine the efficacy of MBFD on inhibiting tumor growth and metastasis. Flow cytometry and trans-well analysis were used to determine the role of ECs in anti-metastatic actions of MBFD. The in silico analysis and function assays were used to identify the mechanisms of MBFD in retarding lung metastasis. Plasma from lung cancer patients were used to verify the effects of MBFD on angiogenin-like protein 4 (ANGPTL4) in clinical conditions.MBFD significantly suppressed spontaneous lung metastasis of LLC tumors, but not tumor growth, at clinically relevant concentrations. The anti-metastatic effects of MBFD were verified in metastatic cancer models created by intravenous injection of LLC or 4T1 cells. MBFD inhibited lung infiltration of circulating tumor cells, without reducing tumor cell proliferations in lung. In vitro, MBFD dose-dependently inhibited trans-endothelial migrations of tumor cells. RNA-seq assay and verification experiments confirmed that MBFD potently depressed endothelial ANGPTL4 which is able to broke endothelial barrier and protect tumor cells from anoikis. Database analysis revealed that high ANGPTL4 levels is negatively correlated with overall survival of cancer patients. Importantly, MBFD therapy reduced plasma levels of ANGPTL4 in lung cancer patients. Finally, MBFD was revealed to inhibit ANGPTL4 expressions in a hypoxia inducible factor-1α (HIF-1α)-dependent manner, based on results from specific signaling inhibitors and network pharmacology analysis.MBFD, at clinically relevant concentrations, inhibits cancer lung metastasis via suppressing endothelial ANGPTL4. These results revealed novel effects and mechanisms of MBFD in treating cancer, and have a significant clinical implication of MBFD therapy in combating metastasis.

A water supply system is a critical infrastructure to support industrial and agricultural production and human life. It often operates abnormally in an emergent risk situation, resulting in shortage or suspension of water supply, even health risk and economic losses. In order to reduce negative impacts posed by these potential threats, identifying and evaluating possible risks in a water supply system has been becoming more necessary. For this reason, we establish two risk assessment models in accordance with two different situations based on uncertainty theory in the presence of insufficient historical data. In the proposed models, we first discuss emergency in three respects: the possibility of emergency occurrence, the consequence caused by emergency and system vulnerability. Then the risk to a water supply system is defined by the uncertain measure of loss-positive by incorporating a risk tolerance index and loss function contributed by the above analysis. Moreover, several theorems for calculating the risk index of series and parallel water supply systems are presented. Finally, we illustrate the feasibility and validity of the proposed models by implementing a series of numerical examples and further present some noteworthy observations.

Neointimal formation and atherogenesis are major vascular complications following percutaneous coronary intervention, and there is lack of pharmacological therapy. This study was aimed to examine the effect of forskolin (FSK), a cyclic adenosine monophosphate (cAMP)‐elevating agent, on vascular response to angioplasty wire injury and on atherogenesis in mice. Forskolin treatment reduced neointima formation at 7 and 28 days after wire injury. Early morphometrics of the injured vessels revealed that FSK treatment enhanced endothelial repair and reduced inflammatory cell infiltration. In vitro treatment of primary aortic cells with FSK, at 3‐100 μmol/L, increased endothelial cell proliferation, whereas FSK, at 30‐100 μmol/L, inhibited smooth muscle cell proliferation. FSK inhibited lipopolysaccharide‐induced leucocyte‐endothelial interaction in vitro and in vivo. In a mouse model of atherosclerosis driven by dyslipidaemia and hypertension, FSK administration increased endothelial repair and reduced atherosclerotic plaque formation, without affecting blood pressure, plasma lipids or aortic aneurysms formation. In summary, FSK, at doses relevant to human therapeutic use, protects against neointimal hyperplasia and atherogenesis, and this is attributable to its activities on pro‐endothelial repair and anti‐inflammation. This study raises a potential of clinical use of FSK as an adjunct therapy to prevent restenosis and atherosclerosis after percutaneous coronary intervention.

Poststroke thalamic pain (PSTP) is one of the most common sequelae following stroke. Analgesics, antidepressants, anticonvulsants, and surgical treatment are conventional treatment methods of PSTP, but these methods have limited efficacy, cost more, and cause a likelihood of adverse reactions. Clinical studies have shown that acupuncture has a significant analgesic effect on PSTP without obvious side effects. But, there is a lack of high-quality evidence concerning its effectiveness and safety to support its use. Therefore, this study aimed to evaluate the clinical efficacy and safety of acupuncture versus Western medicine for the treatment of PSTP to provide evidence to support clinical PSTP treatment. Searches were conducted to identify randomized controlled trials investigating the use of acupuncture for PSTP across six databases, including PubMed, the Cochrane Library, EMBASE, the China National Knowledge Infrastructure, Wan Fang Database, and the Chinese Scientific Journal Database VIP. RevMan 5.3 software was used for the meta-analysis. The results showed that compared with Western medicine, acupuncture had a higher total effective rate for the treatment of PSTP, reduced visual analog scale scores, increased beta-endorphin content, and decreased incidence of adverse reactions. However, the sample sizes of the included studies were insufficient, and the quality of the articles was relatively poor. In future studies, the clinical study design should be standardized and the sample size should be expanded to validate these results.卒中后丘脑疼痛(Poststroke thalamic pain, PSTP)是卒中后最常见的后遗症之一。止痛药、抗抑郁药、抗惊厥药和手术治疗是目前PSTP的常规治疗方法，但这些方法疗效有限、费用高且可能出现不良反应。临床研究表明，针刺治疗PSTP镇痛作用疗效显著，且无明显副作用，但缺乏关于其有效性和安全性的高质量证据支持其使用。本研究旨在系统评价针刺治疗PSTP的有效性和安全性，以期为临床PSTP治疗提供依据。通过检索6个数据库PubMed、Cochrane Library、EMBASE、中国期刊全文数据库(CNKI)、万方数据库(WanFang Data)及维普数据库(VIP)以获取针刺治疗PSTP的随机对照试验(Randomized controlled trials, RCTs)文献。采用RevMan5.3软件对结果进行Meta分析。研究结果表明与西药相比，针刺治疗PSTP总有效率较高，且可改善患者视觉模拟评分(VAS)、提高患者β-内啡肽(β-EP)含量、降低不良反应的发生率。然而，目前相关研究的样本量不足和数据质量不高，还需进一步规范临床研究设计和扩大样本量对结果进行验证。.

Objective— Deletion of mPGES-1 (microsomal prostaglandin E synthase-1)—an anti-inflammatory target alternative to COX (cyclooxygenase)-2—attenuates injury-induced neointima formation in mice. This is attributable to the augmented levels of PGI 2 (prostacyclin)—a known restraint of the vascular response to injury, acting via IP (I prostanoid receptor). To examine the role of mPGES-1–derived PGE 2 (prostaglandin E 2 ) in vascular remodeling without the IP. Approach and Results— Mice deficient in both IP and mPGES-1 (DKO [double knockout] and littermate controls [IP KO (knockout)]) were subjected to angioplasty wire injury. Compared with the deletion of IP alone, coincident deletion of IP and mPGES-1 increased neointima formation, without affecting media area. Early pathological changes include impaired reendothelialization and increased leukocyte invasion in neointima. Endothelial cells (ECs), but not vascular smooth muscle cells, isolated from DKOs exhibited impaired cell proliferation. Activation of EP (E prostanoid receptor) 4 (and EP2, to a lesser extent), but not of EP1 or EP3, promoted EC proliferation. EP4 antagonism inhibited proliferation of mPGES-1–competent ECs, but not of mPGES-1–deficient ECs, which showed suppressed PGE 2 production. EP4 activation inhibited leukocyte adhesion to ECs in vitro, promoted reendothelialization, and limited neointima formation post-injury in the mouse. Endothelium-restricted deletion of EP4 in mice suppressed reendothelialization, increased neointimal leukocytes, and exacerbated neointimal formation. Conclusions— Removal of the IP receptors unmasks a protective role of mPGES-1–derived PGE 2 in limiting injury-induced vascular hyperplasia. EP4, in the endothelial compartment, is essential to promote reendothelialization and restrain neointimal formation after injury. Activating EP4 bears therapeutic potential to prevent restenosis after percutaneous coronary intervention.

Thrombosis, the localized clotting of blood that affects arterial or venous circulation, is one of the leading causes of death worldwide.1 Currently used antithrombotic drugs have increased bleeding risk.2,3 Exploring new antithrombotic strategies that preserve physiological hemostasis is under intensive investigation. Classical triad of causative factors leading to thrombosis includes alterations in blood content, alterations in blood flow, and alterations in the vessel wall. Endothelium, the inner most single layer of cells lining the blood vessels, provides a surface for thrombosis formation and critically regulates blood fluidity and homeostasis. As barrier, endothelium separates blood clotting factors from exposure to subendothelial prothrombotic extracellular matrix components. Endothelium also secretes or expresses vasoactive factors that modulate platelet reactivity, coagulation, fibrinolysis, and vascular contractility, all of which contribute to thrombotic formation. Such factors include nitric oxide, prostacyclin, Von Willebrand factor (VWF), thrombomodulin, endothelin, etc. Accumulating evidences show that endothelial cells (ECs) play a pivotal role in modulating thrombosis, highlighting ECs as a potential target for thrombosis control. In this Recent Highlights, we reviewed recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology and other leading journals that are focused on the mechanisms of endothelial regulation of thrombosis and discussed their merits in therapeutic discovery. Arterial thrombosis is commonly initiated by vascular endothelial erosions and ruptures of an atherosclerotic plaque3,4 while venous thrombosis mainly stems from blood stasis.5 Despite these differences, platelet adhesion/activation, and fibrin deposition as the result of coagulation constitute the fundamental processes of thrombus formation.6,7 Platelet activation occurs when they interact with activated ECs (with increased VWF release and selectin expression) via glycoprotein Ib-V-IX complex binding to VWF, or when they expose to subendothelial extracellular matrix components, such as collagen (via glycoprotein VI receptor), in the cases of endothelial injury or plaques …

Objective: Myocardial (M) ischemia/reperfusion (I/R) injury limits the efficacy of reperfusion therapy in patients with myocardial infarction (MI) and contributes to the development of heart failure. Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit both cyclooxygenase (COX)-1 and COX-2, or those selective for COX-2 inhibition, are associated with an increased risk of heart failure. Although suppression of COX-2-derived prostaglandin (PG) I 2 predisposes cardiovascular risks, it remains unknown whether microsomal (m) PGE synthase (S)-1, a therapeutic target alternative to COX-2, might participate in MI/R injury. Approach and Results: Mice deficient in COX-1 or -2, mPGES-1, or endothelial PGE receptor-4 (EP4), together with pharmacological interventions, were utilized in a mouse model of MI/R. Microvascular perfusion was assessed in vivo using laser Doppler flow technique. COX-1 deficiency reduced biosynthesis of PGE 2 and increased infarct size in the heart after MI/R. Deletion of mPGES-1 also depressed PGE 2 while exacerbated MI/R injury. Cardiac perfusion was impaired by mPGES-1 deletion following reperfusion, without change in baseline flow. Consistently, mPGES-1 deletion abolished arteriolar dilation in I/R, and mPGES-1-derived PGE 2 acting on EP4 receptor restrains myeloid cell adhesion to endothelial cells in vitro and limits leukocyte adhesion to vasculature in I/R in vivo. Endothelium-restricted deletion of EP4 receptor impaired microcirculatory perfusion and exacerbated cardiac injury in MI/R. By contrast, treatment with misoprostol, a clinically available PGE 2 analogue, improved cardiac microcirculation post MI and protected against I/R injury. Conclusions: mPGES-1-derived PGE 2 and endothelial EP4 receptor protect against MI/R injury via preserving cardiac microcirculation. mPGES-1 inhibitors may harm microcirculation in patients with acute MI undergoing revascularization. Inhibition of COX-1-derived PGE 2 may contribute to the cardiovascular side effects of NSAIDs in the setting of I/R. Key Words: myocardial infarction, ischemia reperfusion, cyclooxygenase, prostaglandin E synthase-1, PGE 2 , EP4, microcirculation, endothelium

OBJECTIVE: Deletion of microsomal (m) prostaglandin (PG) E synthase (S)-1, an anti-inflammatory target alternative to cyclooxygenase-2, attenuates injury-induced neointima formation in mice. This is attributable to the augmented levels of PGI(2), a known restraint of the vascular response to injury, acting via I prostanoid receptor (IP). To examine the role of mPGES-1 derived PGE(2) in vascular remodeling without the IP. APPROACH AND RESULTS: Mice deficient in both IP and mPGES-1 (double knockout, DKO) and littermate controls (IP KO) were subjected to angioplasty-wire injury. Compared with the deletion of IP alone, coincident deletion of IP and mPGES-1 increased neointima formation, without affecting media area. Early pathological changes include impaired reendothelialization and increased leukocyte invasion in neointima. Endothelial cells (ECs), but not vascular smooth muscle cells, isolated from DKOs exhibited impaired cell proliferation. Activation of PGE(2) receptor (EP)4 (and EP2, to a lesser extent), but not of EP1 or EP3, promoted EC proliferation. EP4 antagonism inhibited proliferation of mPGES-1-competent ECs, but not of mPGES-1-deficient ECs, which showed suppressed PGE(2) production. EP4 activation inhibited leukocyte adhesion to ECs in vitro, promoted reendothelialization and limited neointima formation post injury in the mouse. Endothelium-restricted deletion of EP4 in mice suppressed reendothelialization, increased neointimal leukocytes, and exacerbated neointimal formation. CONCLUSIONS: Removal of the IP receptors unmasks a protective role of mPGES-1 derived PGE(2) in limiting injury-induced vascular hyperplasia. EP4, in the endothelial compartment, is essential to promote reendothelialization and restrain neointimal formation after injury. Activating EP4 bears therapeutic potential to prevent restenosis after percutaneous coronary intervention.

Prostanoids, which are synthesized from the cyclooxygenase cascade and inhibited by nonsteroidal anti-inflammatory drugs, participate in vascular remodeling. Deletion of microsomal prostaglandin (PG) E synthase-1 increases prostacyclin and attenuates injury-induced neointimal formation in mice. The role of E prostanoid receptor 4 (EP4) in vascular response to injury is unknown. Using an inducible Cre-LoxP-based approach, we generated the endothelial-restricted EP4 knockout mice (cKO) and their littermate controls (Ctl). After tamoxifen treatment, one side femoral arteries of the mice were subjected to wire-injury. Twenty-eight days later, the femoral arteries were harvested and the neointima formation were evaluated. Deletion of endothelial EP4 strikingly exacerbated intima area and the ratio of intima to media area, without affecting media area. Treatment of wild type mice with AE1-329, a selective EP4 agonist, significantly reduced neointimal hyperplasia after wire-injury. Mechanistically, activation of endothelial EP4 signaling with AE1-329 promoted endothelial cell proliferation. Notably, the adhesion of leukocytes to endothelial cells was significantly inhibited by AE1-329 treatment. Collectively, endothelial EP4 may protect against vascular remodeling via enhancing endothelial repair and reducing leukocytes adhesion to the endothelium.

The morbidity of lower extremity atherosclerotic disease(LEAD) has increased year by year. Chronic stress attenuates the ability of angiogenesis and deteriorates the prognosis of LEAD. Chronic stress increases plasma and tissue DPP-4 activities in mice. DPP-4 plays an important role in angiogenesis

CXCR7 is a non-classical chemokine receptor for CXCL12, whose gene represents a genome-wide association locus for coronary artery disease. Global deletion of CXCR7 increased experimentally induced neointimal formation and atherosclerosis in hyperlipidemic mice, with evidence that CXCR7 modified cholesterol uptake to adipose tissue. We found that CXCR7 was expressed in endothelial cells of mouse neointima and human aortic lesions. To examine a role of endothelial CXCR7 in vascular remodeling, endothelial CXCR7 inducible knockout mice were studied for their vascular response to wire injury in femoral arteries. Tamoxifen treatment of mice harboring floxed CXCR7 and Cdh5 -promoter driven CreERT2 , essentially abolished endothelial CXCR7 expression in vitro and in vivo. Postnatal deletion of endothelial CXCR7 exacerbated neointimal formation on normalipidemic background, four weeks after injury. Mechanistically, this was attributable to attenuated endothelial repair following endothelial injury. Collectively, endothelial CXCR7 is a key regulator of vascular remodeling, independent of lipid traits.