Tanshinone II-A (TSN) is the most abundant diterpene quinone isolated from Danshen (Salvia miltiorrhiza), which has been used in treating cardiovascular diseases for more than 2000 years in China. ...Interest in its versatile protective effects in cardiovascular, metabolic, neurodegenerative diseases, and cancers has been growing over the last decade. TSN is a multi-target drug, whose molecular targets include transcription factors, scavenger receptors, ion channels, kinases, pro- and anti-apoptotic proteins, growth factors, inflammatory mediators, microRNA, and others. More recently, enhanced or synergistic effects can be observed when TSN is used in combination therapy with cardioprotective and anti-cancer drugs. These combination therapy regimens may open new therapeutic avenues for the treatment of various kinds of human diseases.
This paper investigates the impact of varying the part geometric complexity and 3D printing process setup on the resulting structural load bearing capacity of fiber composites. Three levels of ...geometric complexity are developed through 2.5D topology optimization, 3D topology optimization, and 3D topology optimization with directional material removal. The 3D topology optimization is performed with the SIMP method and accelerated by high-performance computing. The directional material removal is realized by incorporating the advection-diffusion partial differential equation-based filter to prevent interior void or undercut in certain directions. A set of 3D printing and mechanical performance tests are performed. It is interestingly found that, the printing direction affects significantly on the result performance and if subject to the uni direction, the load-bearing capacity increases from the 2.5D samples to the 3D samples with the increased complexity, but the load-bearing capacity further increases for the 3D simplified samples due to directional material removal. Hence, it is concluded that a restricted structural complexity is suitable for topology optimization of 3D-printed fiber composites, since large area cross-sections give more degrees of design freedom to the fiber path layout and also makes the inter-layer bond of the filaments firmer.
Tanshinone IIA (TS), a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge (Danshen), has been clinically used in Asian countries for the ...prevention and treatment of coronary heart disease. Recently, the pharmacological properties of TS in the cardiovascular system have attracted great interest. Emerging experimental studies and clinical trials have demonstrated that TS prevents atherogenesis as well as cardiac injury and hypertrophy. In atherosclerosis, TS acts by inhibiting LDL oxidation, monocyte adhesion to endothelium, smooth muscle cell migration and proliferation, macrophage cholesterol accumulation, proinflammatory cytokine expression and platelet aggregation. TS has some activity and potential to stabilize atherosclerotic plaques. The cardioprotective effects of TS are mainly related to its anti-oxidant and anti-inflammatory actions. In this review, we focus on the protective effects and the mechanism of action of TS in the cardiovascular system, and provide a novel perspective on clinical use of TS.
Chemotherapy is still one of the principal treatments for gastric cancer, but the clinical application of 5-FU is limited by drug resistance. Here, we demonstrate that ferroptosis triggered by STAT3 ...inhibition may provide a novel opportunity to explore a new effective therapeutic strategy for gastric cancer and chemotherapy resistance. We find that ferroptosis negative regulation (FNR) signatures are closely correlated with the progression and chemoresistance of gastric cancer. FNR associated genes (GPX4, SLC7A11, and FTH1) and STAT3 are upregulated in 5-FU resistant cells and xenografts. Further evidence demonstrates that STAT3 binds to consensus DNA response elements in the promoters of the FNR associated genes (GPX4, SLC7A11, and FTH1) and regulates their expression, thereby establishing a negative STAT3-ferroptosis regulatory axis in gastric cancer. Genetic inhibition of STAT3 activity triggers ferroptosis through lipid peroxidation and Fe2+ accumulation in gastric cancer cells. We further develop a potent and selective STAT3 inhibitor, W1131, which demonstrates significant anti-tumor effects in gastric cancer cell xenograft model, organoids model, and patient-derived xenografts (PDX) model partly by inducing ferroptosis, thus providing a new candidate compound for advanced gastric cancer. Moreover, targeting the STAT3-ferroptosis circuit promotes ferroptosis and restores sensitivity to chemotherapy. Our finding reveals that STAT3 acts as a key negative regulator of ferroptosis in gastric cancer through a multi-pronged mechanism and provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance.
Targeting the STAT3-ferroptosis circuit provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance. Genetic inhibition of STAT3 triggers iron-dependent oxidative damage of ferroptosis through down-regulation of SLC7A11, GPX4, and FTH1. Novel STAT3 inhibitor W1131 suppresses gastric cancer progression and alleviates chemoresistance partly by induction of ferroptosis. Display omitted
•Genetic and pharmacological inhibition of STAT3 triggers ferroptosis by transcriptionlly regulation of GPX4, SLC7A11, and FTH1 in gastric cancer.•A potent and selective STAT3 inhibitor W1131, with strong anti-tumor effects, is developed.•Ferroptosis plays a key role in the progression and chemoresistance of gastric cancer.•Targeting the STAT3-ferroptosis circuit provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance.
Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial ...dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.
Electronic cigarettes (e-cigarettes) have attracted much attention as a new substitute for conventional cigarettes. E-cigarettes are first exposed to the respiratory system after inhalation, and ...studies on the toxicity mechanisms of e-cigarettes have been reported. Current research shows that e-cigarette exposure may have potentially harmful effects on cells, animals, and humans, while the safety evaluation of the long-term effects of e-cigarette use is still unknown. Similar but not identical to conventional cigarettes, the toxicity mechanisms of e-cigarettes are mainly manifested in oxidative stress, inflammatory responses, and DNA damage. This review will summarize the toxicity mechanisms and signal pathways of conventional cigarettes and e-cigarettes concerning the respiratory system, which could give researchers a better understanding and direction on the effects of e-cigarettes on our health.
Human Atg4 homologs are cysteine proteases, which play key roles in the macroautophagy/autophagy process by cleaving Atg8 homologs for conjugation to lipid membranes and for deconjugation of Atg8 ...homologs from membranes. Expression of ATG4B is significantly increased in colorectal cancer cells compared to normal cells, suggesting that ATG4B may be important for cancer biology. Inhibition of ATG4B may reduce the autophagy activity, thereby sensitizing cancer cells to therapeutic agents. Thus, developing specific and potent ATG4B inhibitors for research as well as for potential therapeutic uses is highly needed. In this study, we integrated in silico screening and in vitro assays to discover a potent ATG4B inhibitor, named S130, from a noncommercial library. This chemical binds to ATG4B with strong affinity and specifically suppresses the activity of ATG4B but not other proteases. S130 did not cause the impairment of autophagosome fusion, nor did it result in the dysfunction of lysosomes. Instead, S130 might attenuate the delipidation of LC3-II on the autolysosomes to suppress the recycling of LC3-I, which normally occurs after LC3-II cleavage by ATG4B. Intriguingly, S130 induced cell death, which was accompanied with autophagy stress and could be further exacerbated by nutrient deprivation. Such cytotoxicity could be partially reversed by enhancing ATG4B activity. Finally, we found that S130 was distributed in tumor tissues in vivo and was also effective in arresting the growth of colorectal cancer cells. Thus, this study indicates that ATG4B is a potential anticancer target and S130 might be a novel small-molecule candidate for future cancer therapy.
Abstract Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H2 ...S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H2 S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H2 S also decreases plasma homocysteine levels in experimental animal models. In the human body, H2 S production is predominantly catalyzed by cystathionine-β-synthase (CBS) and cystathionine γ-lyase (CSE). CSE is the primary H2 S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H2 S deficiency and that H2 S supplementation by exogenous H2 S donors (such as NaHS and GYY4137) attenuates, and H2 S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523–2534) demonstrates that decreased endogenous H2 S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE−/− mice, pinpointing that endogenously produced H2 S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H2 S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases.
Early blight (EB), caused by the pathogen
, is a major threat to global potato and tomato production. Early and accurate diagnosis of this disease is therefore important. In this study, we conducted ...a loop-mediated isothermal amplification (LAMP) assay, as well as conventional polymerase chain reaction (PCR), nested PCR, and quantitative real-time PCR (RT-qPCR) assays to determine which of these techniques was less time consuming, more sensitive, and more accurate. We based our assays on sequence-characterized amplified regions of the
gene with an accession number (FJ424058). The LAMP assay provided more rapid and accurate results, amplifying the target pathogen in less than 60 min at 63°C, with 10-fold greater sensitivity than conventional PCR. Nested PCR was 100-fold more sensitive than the LAMP assay and 1000-fold more sensitive than conventional PCR. qPCR was the most sensitive among the assays evaluated, being 10-fold more sensitive than nested PCR for the least detectable genomic DNA concentration (100 fg). The LAMP assay was more sensitive than conventional PCR, but less sensitive than nested PCR and qPCR; however, it was simpler and faster than the other assays evaluated. Despite of the sensitivity, LAMP assay provided higher specificity than qPCR. The LAMP assay amplified
artificially, allowing us to detect naturally infect young potato leaves, which produced early symptoms of EB. The LAMP assay also achieved positive amplification using diluted pure
culture instead of genomic DNA. Hence, this technique has greater potential for developing quick and sensitive visual detection methods than do other conventional PCR strategies for detecting
in infected plants and culture, permitting early prediction of disease and reducing the risk of epidemics.
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