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Cardiovascular diseases have been closely linked to abnormal epigenetic regulation. In the context of epigenetic regulation, BRG1, a pivotal SWI/SNF chromatin remodeling enzyme, emerges as a key epigenetic regulator with significant impact on the development and progression of cardiovascular disorders. From the perspective of epigenetic regulation of cardiovascular diseases, BRG1 emerges as a pivotal SWI/SNF chromatin remodeling enzyme, functioning as a key epigenetic regulator. It exerts substantial influence on the development and progression of cardiovascular disorders by exerting precise control over gene expression and protein levels. Therefore, a comprehensive understanding of BRG1's epigenetic regulatory role in cardiovascular disease is essential for unraveling its underlying pathophysiological mechanisms. This paper summarizes and discusses the function of BRG1 in the epigenetic regulation of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

M1 polarization of macrophages in the intestine is an important maintenance factor of the inflammatory response in Crohn's disease (CD). Eriocalyxin B (EriB) is a natural medicine that antagonizes inflammation. Our study aimed to determine the effects of EriB on CD-like colitis in mice, as well as the possible mechanism. 2,4,6-trinitrobenzene sulfonic acid (TNBS) mice and Il-10 −/− mice were used as CD animal models, and the therapeutic effect of EriB on CD-like colitis in mice was addressed by the disease activity index (DAI) score, weight change, histological analysis and flow cytometry assay. To assess the direct role of EriB in regulating macrophage polarization, bone marrow-derived macrophages (BMDMs) were induced to M1 or M2 polarization separately. Molecular docking simulations and blocking experiments were performed to explore the potential mechanisms by which EriB regulates the macrophage polarization. EriB treatment reduced body weight loss, DAI score and histological score, demonstrating the improvement of colitis symptoms in mice. In vivo and in vitro experiments both showed that EriB decreased the M1 polarization of macrophages, and suppressed the release of proinflammatory cytokines (IL-1β, TNF-α and IL-6) in mouse colons and BMDMs. The activation of Janus kinase 2/signal transducer and activator of transcription 1 (JAK2/STAT1) signals could be inhibited by EriB, which may be related to the regulation of EriB on M1 polarization. EriB inhibits the M1 polarization of macrophages by attenuating the JAK2/STAT1 pathway, which partially explains the potential mechanism by which EriB ameliorates colitis in mice, and provides a new regimen for the clinical treatment of CD. [ABSTRACT FROM AUTHOR]

Interleukin 33 (IL33) has been found to be cardioprotective on various cardiovascular pathologies. However, it is not clear whether IL33 may inhibit myocardial infarction-related ventricular remodeling through inducing macrophage polarization. The objective of present study is to assess whether IL33 can improve ventricular remodeling after myocardial infarction by inducing macrophage polarization. In this study, the direct influence of IL33 on the polarization of macrophages and its mechanism in vitro were investigated. The potential protective effects of IL33 on acute and chronic myocardial infarction (MI) in vivo as well as its underlying mechanism through macrophage polarization were also determined. We found that IL33 significantly enhanced M2 macrophage and decreased the proportion of M1 macrophage. Importantly, IL33 induced M2 macrophage polarization by activating the JAK/STAT signaling pathway. In vivo , IL33 weaken the inflammatory level and myocardial apoptosis after MI and improved the systolic and diastolic function of the heart. Furthermore, IL33 significantly reduced infarct area and prevented the progression of fibrosis by inducing M2 macrophage polarization. The protective effects of IL33 were suppressed by JAK/STAT signaling pathway inhibitor. Our findings highlighted that IL33 not only reduced the early inflammatory response and inhibited myocardial apoptosis, but also increased the number of M2 macrophage in the infarcted area, significantly reduced infarct area and prevented the progression of fibrosis by activating JAK/STAT pathway. Therefore, IL33 may be a novel cardiac protective cytokine for myocardial infarction. [ABSTRACT FROM AUTHOR]

Fasudil is a potent Rho-kinase (ROCK) inhibitor and can relax smooth muscle or cardiac muscle contraction through decreasing the phosphorylation level of myosin regulatory light chain (p-MLC 20 or p-MLC2v), while p-MLC2v can function as a transcription factor to promote the NADPH oxidase 2 (NOX2) expression in rat hearts subjected to ischemia/reperfusion (I/R). This study aims to explore whether fasudil can protect the rat hearts against I/R oxidative injury through suppressing NOX2 expression via reduction of p-MLC2v level. The SD rat hearts were subjected to 1 h-ischemia plus 3 h-reperfusion, which showed myocardial injuries (myocardial fiber loss and disarray, increase of creatine kinase release and myocardial infarction/apoptosis), increase in ROCK activity and nuclear p-MLC 2v level concomitant with up-regulation of NOX2 and H 2 O 2 production; these phenomena were attenuated by fasudil in a dose-dependent manner. Next, we verified the cardioprotective effect of fasudil and the underlying mechanisms in hypoxia-reoxygenation (H/R) -treated H9c2 cells. Consistent with the results in vivo, the H/R-treated H9c2 cells showed cellular injury (increase in apoptotic ratio), elevation in ROCK activity and nuclear p-MLC 2v level, accompanied by up-regulation of NOX2 and H 2 O 2 production; these effects were blocked in the presence of fasudil in a dose-dependent way. Based on these observations, we conclude that beneficial effect of fasudil against myocardial I/R or H/R oxidative injury is related to the suppression of NOX2 expression through decrease of the p-MLC2v level. Our findings also highlight that intervention of MLC2v phosphorylation by drugs may provide a novel strategy to protect heart from I/R oxidative injury. [ABSTRACT FROM AUTHOR]

Abstract: Four novel 4-hydroxycoumarin derivatives (4-MBH, 3-MBH, 4-MDT and 3-MDT) were successfully synthesized and their structures were verified by single-crystal X-ray crystallography. All target compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ 75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300 (Los Angeles County clone, LAC). The minimum inhibitory concentration and time–kill curves were obtained for the test compounds and antibiotics. Among the tested compounds, 3-MBH showed the most potent antibacterial activities. [Copyright &y& Elsevier]

Abstract: Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury. [Copyright &y& Elsevier]

Abstract: The present study was aimed to evaluate the behavioral and biochemical effects of macranthol, a triphenyl lignan isolated from Illicium dunnianum. To this aim, mice were treated with macranthol (10, 20 and 40mg/kg) and then subjected to the forced swimming test, tail suspension test and chronic unpredictable mild stress. It was observed that macranthol significantly reduced the immobility time in the forced swimming test and tail suspension test after acute (1-day) treatment, and reversed the reduction of sucrose preference induced by chronic unpredictable mild stress after chronic (5-week) treatment. In addition, macranthol completely ameliorated the corticosterone hypersecretion by acute swim stress or chronic unpredictable mild stress. Chronic macranthol treatment attenuated the reduction of serotonergic neurotransmission in brain regions of frontal cortex and hippocampus. Taken together, our findings suggested that macranthol produced an antidepressant-like effect, which may be mediated by serotonergic and neuroendocrine system. Moreover, the finding that only chronic but not acute treatment enhanced brain-derived neurotrophic factor (BDNF) expression suggested that macranthol did not produce a rapid antidepressant-like response and long-term treatment was required in its clinical application. [Copyright &y& Elsevier]

Abstract: During the course of liver fibrogenesis, hepatic stellate cell (HSC) proliferation as well as subsequent synthesis of excessive extracellular matrix components is known to be the central events. Thus, factors that could limit HSC proliferation are potential anti-fibrotic agents. The aim of this study was to investigate the effects of indole-3-carbinol (I3C), a nutritional component derived from Brassica family vegetables, on the proliferation of cultured HSC and to clarify the underline molecular mechanism. HSC-T6, an activated rat HSC line, was treated with I3C (50, 100 and 200μM) for 24h. The results indicated that I3C can significantly inhibit HSC proliferation in a concentration-dependent manner with or without platelet-derived growth factor-BB (PDGF-BB) stimulation (P <0.01). I3C could also block HSC in the G0/G1 phase from entering the S phase. The expressions of α-smooth muscle actin in HSC treated with I3C, were significantly decreased at levels of protein and mRNA (P <0.01). In addition, the type I collagen level, cyclin D1 and cyclin-dependent kinase 4 mRNA expressions, intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species generation were significantly decreased by I3C (P <0.05). We also observed that the phosphorylated p38 MAPK in HSC-T6 was inhibited by I3C in a concentration-dependent manner; however, the phosphorylated ERK1/2 was unaltered. In conclusion, I3C could inhibit the proliferation of HSC by blocking the NADPH oxidase/reactive oxygen species/p38 MAPK signal pathway. These findings suggest that dietary I3C might play a novel role in prevention and treatment of chronic liver diseases. [ABSTRACT FROM AUTHOR]

Abstract: Berberine can improve insulin resistance, lower blood glucose, and regulate lipid metabolism disorders which cause endothelial dysfunction, leading to vascular complications of type 2 diabetes mellitus. The aim of the present study was to investigate the effects of berberine on endothelial dysfunction of aortas in type 2 diabetes mellitus rats and its mechanism. Wistar rats were randomly divided into four groups: diabetic rats, control rats, diabetic rats treated with berberine (100 mg/kg), and control rats treated with berberine. The serum fasting blood glucose, insulin, total cholesterol, triglyceride and nitric oxide (NO) levels were tested. Acetylcholine-induced endothelium-dependent relaxation and sodium nitroprusside induced endothelium-independent relaxation were measured in aortas for estimating endothelial function. The expression of endothelial nitric oxide synthase (eNOS) mRNA was measured by RT-PCR, and the protein expressions of eNOS and NADPH oxidase (NOX4) were analyzed by western blot. The results showed that berberine significantly decreased fasting blood glucose, and triglyceride levels in diabetic rats. Berberine also improved endothelium-dependent vasorelaxation impaired in aorta. The expressions of eNOS mRNA and protein were significantly increased, while NOX4 protein expression was decreased in aortas from diabetic rats with berberine treatment. Moreover, serum NO levels were elevated after berberine treatment. In conclusion, berberine restores diabetic endothelial dysfunction through enhanced NO bioavailability by up-regulating eNOS expression and down-regulating expression of NADPH oxidase. [Copyright &y& Elsevier]

Abstract: Ligustrazine has a renoprotective effect against nephritis. In this study, we further characterized the renoprotective properties of ligustrazine in an experimental model using accelerated anti-glomerular basement membrane antibody (AGBM-Ab). Ligustrazine was given i.p. once daily at 50, 100 mg/kg for 15 days after singly giving i.v. of rabbit anti-rat glomerular basement membrane serum, and showed dose-dependent inhibition the elevation of urinary protein, serum creatinine and blood urea nitrogen as well as the development of glomerular histological changes. Ligustrazine (50 mg/kg) had no affect on glutathione (GSH) content, glutathione peroxidase and catalase activities, but decreased the malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity in nephritis induced by AGBM-Ab. Ligustrazine (100 mg/kg) significantly decreased MDA content while significantly increased GSH content and SOD, glutathione peroxidase, catalase activities of kidney tissues in the rats treated with AGBM-Ab alone. In conclusion, our results show that ligustrazine has protective activity against accelerated AGBM-Ab nephritis, and its renoprotective effect may be due to its antioxidant properties and inhibition reactive oxygen species (ROS). [Copyright &y& Elsevier]

Abstract: Renal cyclooxygenase (COX)-2 expression and arachidonic acid-stimulated prostaglandin release are increased in streptozotocin-diabetic rats and are reduced by tempol treatment, indicating a role for superoxide. Generation of nitric oxide (NO) and its product with superoxide, peroxynitrite, is also increased in diabetes and can induce COX-2. To investigate a role of NO, rats were treated with l-nitroarginine methyl ester (l-NAME; 100 mg/kg/day) to inhibit NO synthase (NOS) for 14–18 days. In isolated perfused kidneys from diabetic rats, prostaglandin release and vasoconstrictor responses to arachidonic acid were increased and renal cortical expression of COX-2 was 2-fold that of control rats. Treatment of diabetic rats with l-NAME reduced arachidonic acid-stimulated release of prostaglandins and the expression of COX-2. l-NAME increased vasoconstrictor responses to AA in diabetic and non-diabetic rats but abolished the differences between the two. These results, coupled with those using tempol, suggest that NO or its product with superoxide may contribute to the induction of renal COX-2 in the diabetic rat. [Copyright &y& Elsevier]

RIPK1/RIPK3/MLKL (Receptor-interacting protein kinase 1/Receptor-interacting protein kinase 3/Mixed lineage kinase domain-like protein) pathway-mediated necroptosis contributes to myocardial ischemia/reperfusion (I/R) injury, and Arctiin can prevent myocardial fibrosis and hypertrophy. This study aims to explore the effect of Arctiin on myocardial I/R injury and the underlying mechanisms. SD rat hearts or cardiomyocytes were subjected to I/R or hypoxia/reoxygenation (H/R) to establish the I/R or H/R injury model. The methods of biochemistry, PI/DAPI (propidium iodide/4′,6-Diamidino-2-Phenylindole) and H&E (Hematoxylin & eosin) staining were used to evaluate the I/R or H/R injury. The effects of Arctiin on necroptosis in I/R-treated hearts or H/R-treated cardiomyocytes were assessed. The results showed that Arctiin reduced myocardial I/R injury (decreases in myocardial infarction and creatine kinase release), concomitant with a decrease in levels of necroptosis-associated proteins (RIPK1/p-RIPK1, RIPK3/p-RIPK3 and MLKL/p-MLKL) in I/R-treated rat hearts. Consistently, the necrosis and LDH release in H/R-treated cardiomyocytes were attenuated in the presence of Arctiin, accompanied by suppression of necroptosis-relevant proteins. Furthermore, H/R-induced reactive oxygen species (ROS) generation and mitochondrial dysfunctions (increase in mitochondrial membrane potential and decrease in ATP production) were impaired by Arctiin. Using the program of the Molecular Operating Environment (MOE), we predict that RIPK1 and MLKL (but not RIPK3) might be the potential targets of Arctiin. Based on these observations, we conclude that Arctiin can protect the rat heart from I/R injury, and its beneficial effect is related to reduction of necroptosis via scavenging reactive oxygen species and restoring mitochondrial functions or targeting RIPK1 and/or MLKL. Image 1 • Arctiin protects rat heart from myocardial I/R injury. • Arctiin suppresses necroptosis in I/R-treated rat hearts. • Arctiin scavenge ROS and restore mitochondrial functions in cardiomyocyte. [ABSTRACT FROM AUTHOR]

Pathological cardiac hypertrophy is an independent risk factor of cardiovascular diseases. Although the function of p53 and p21 in pathological cardiac hypertrophy have been studied, the relationship between them in cardiomyocytes is still unclear. By using specific adenoviruses and siRNAs to modulate p53 or p21 expression in neonatal rat ventricular myocytes (NRVMs), we found that both upregulated p53 and p21 expression induced hypertrophic responses, and they promote each other's expression. Overexpression of p53 aggravated the hypertrophic response of cardiomyocytes in vitro and in vivo , while knockdown of p21 diminished the hypertrophic responses induced by angiotensin Ⅱ and the increase of p53 expression. Additionally, Angiotensin Ⅱ treatment promoted the nuclear translocation of p21 in NRVMs. Notably, increased p53 expression alone did not promote p21 translocation to the nucleus. Together, these data suggest a self-limiting bidirectional positive feedback interaction between p53 and p21 during cardiac hypertrophy. [Display omitted] • Both P53 and P21 promote each other's expression in cardiomyocytes. • They both induce and facilitate hypertrophy of cardiomyocytes. • P53 expression alternate the subcellular localization of p21. • These is a self-limited bidirectional feedback loop between p53 and p21. [ABSTRACT FROM AUTHOR]

Mammalian tachykinins are a family of neuropeptides which are potent modulators of smooth muscle function with a significant contractile effect on human smooth muscle preparations. Tachykinins act via three distinct G protein-coupled neurokinin (NK) receptors, NK 1 , NK 2 and NK 3 , coded by the genes TACR1, TACR2 and TACR3 respectively. The purpose of this paper was to measure the mRNA and protein expression of these receptors and their isoforms in the clasp and sling fibers of the human lower esophageal sphincter complex and circular muscle from the adjacent distal esophagus and proximal stomach. We found differences in expression between the different receptors within these muscle types, but the rank order of the receptor expression did not differ between the different muscle types. The rank order of the mRNA expression was TACR2 (α isoform)>TACR2 (β isoform)>TACR1 (short isoform)>TACR1 (long isoform)>TACR3. The rank order of the protein expression was NK 2 >NK 1 >NK 3 . This is the first report of the measurement of the transcript and protein expression of the tachykinin receptors and their isoforms in the muscles of the human lower esophageal sphincter complex. The results provide evidence that the tachykinin receptors could contribute to the regulation of the human lower esophageal sphincter, particularly the TACR2 α isoform which encodes the functional isoform of the tachykinin NK 2 receptor was the most highly expressed of the tachykinin receptors in the muscles associated with the lower esophageal sphincter. [ABSTRACT FROM AUTHOR]

Macranthol is a lignans natural product isolated from Illicium dunnianum Tutch. Our previous study has demonstrated that macranthol exerted an antidepressant-like effect in mice, at least in part, by increasing expression of hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the relationship between macranthol and BDNF downstream signaling pathway in the hippocampus remains unknown. The aim of this present study was to explore the mechanism of macranthol-modulated BDNF signaling pathway in a depression-like model of chronic unpredictable mild stress. Our results found that pharmacological inhibition of tropomyosin related kinase B (TrkB) with K252a abolished the improvement of macranthol on sucrose preference and immobility time, and attenuated the stimulatory effect of macranthol on hippocampal BDNF and phospho-Akt. Furthermore, K252a also reversed the improvement of macranthol on hippocampal Bcl-2, caspase-3 expression and hippocampal neuronal cell proliferation. Therefore, our findings verify that macranthol-mediated antidepressant-like action is associated with BDNF–TrkB and downstream activation of PI3K/Akt–Bcl-2/caspase-3 signaling pathway. [ABSTRACT FROM AUTHOR]

Osteoporosis is an osteolytic disease with a disrupted balance between the resorption and formation of bone as well as bone microstructure degeneration, leading to bone loss and increased fracture risk, which greatly affects patients' quality of life. Currently, inhibition of osteoclast bone resorption remains the mainstream treatment for osteoporosis. Onc201, a new compound, induces the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and has an efficient anticancer effect in clinical trials. However, its effects on osteolytic disease and the mechanism of action are unclear. We examined the effect of Onc201 on nuclear factor κB ligand-receptor activator (RANKL)-induced osteoclasts via Cell Counting Kit-8, bone resorption assay, luciferase reporter assay, immunofluorescence staining, calcium ion intensity assay and employed an ovariectomy model to investigate the effect of Onc201 on osteoporosis in the mice. Results showed that Onc201 inhibited the function and formation of osteoclasts induced by RANKL in a manner that was dependent on time and concentration, and did not cause cytotoxicity. Mechanistically, Onc201 inhibited osteoclast-relevant genes and NFATc1 expression, the main transcriptional regulatory factor of the formation of osteoclasts induced by RANKL; meanwhile, downregulating the expressions of the osteoclast cytoskeleton key signal molecules integrin αvβ3, focal adhesion kinase (FAK), c-Src, and spleen-associated tyrosine kinase (SYK). In addition, Onc201 had a protective effect on the mouse model of bone loss caused by ovariectomy-induced estrogen deficiency, which is consistent with the in vitro results. Our findings suggest that the new small-molecular compound Onc201 has the potential to prevent osteoclast-related osteolytic diseases. • Onc201, a new compound, can inhibit the function and formation of osteoclasts induced by RANKL. • Onc201 downregulates the expressions of the osteoclast cytoskeleton key signal molecules integrin αvβ3. • Onc201 has a protective effect on the mouse model of bone loss caused by ovariectomy-induced estrogen deficiency. [ABSTRACT FROM AUTHOR]

Abstract: Modulation of Na+, K+-ATPase activity by acute and chronic opiates has been established for many years. However, the effects of digoxin, a putative inhibitor of Na+, K+-ATPase, on naloxone-precipitated morphine withdrawal syndrome are unknown. In the present study, a digoxin dose-response curve was conducted to observe the effects on naloxone-precipitated withdrawal and locomotor activity in mice. Higher doses of digoxin (1.0 and 2.5mg/kg) inhibited locomotor activity and naloxone-precipitated withdrawal jumping and weight loss, while lower doses of digoxin (0.1 and 0.25mg/kg) inhibited withdrawal weight loss precipitated by naloxone without affecting locomotor activity and naloxone-precipitated withdrawal jumping. To explore the possible mechanisms underlying this behavior, another Na+, K+-ATPase inhibitor ouabain, which does not cross the blood brain barrier, and another cardiotonic drug milrinone, a non-inhibitor of Na+, K+-ATPase, were also included in the present study. Both milrinone and ouabain inhibited, in a dose-dependent manner, naloxone-precipitated weight loss while neither affected naloxone-precipitated withdrawal jumping nor locomotor activity in mice. These results indicate that both the cardiotonic effects and central inhibition of Na+, K+-ATPase contribute to the inhibitory effects of digoxin on morphine withdrawal syndrome in mice. [Copyright &y& Elsevier]

Abstract: Cardiac fibroblasts play an important role in myocardial remodeling by proliferating, differentiating, and secreting extracellular matrix proteins. Estrogen has been reported to have a number of cardioprotective properties. However, it is unclear whether estrogen affects cardiac fibroblast differentiation. The purpose of the present study was to investigate the effect of estrogen on angiotensin II-induced cardiac fibroblast proliferation and differentiation. Cardiac fibroblasts were stimulated with angiotensin II (1 μM) in the presence or absence of 17β-estradiol (100 nM). Pretreatment of cardiac fibroblasts with 17β-estradiol significantly inhibited angiotensin II-induced cardiac fibroblast proliferation and differentiation (indicated by a reduction in alpha-smooth muscle actin (α-SMA) expression) by 25% and 20%. Pretreatment of 17β-estradiol significantly reduced angiotensin II-increased levels of phospho-p38 mitogen-activated protein kinase (MAPK) by 40% and nuclear factor-κB (NF-κB) binding activity in cardiac fibroblasts by 55%. Our data suggests estrogen could have an anti-fibrotic effect through limiting cardiac fibroblast proliferation and differentiation, which are the critical steps in the pathogenesis of cardiac fibrosis. [Copyright &y& Elsevier]

Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Dysfunction of epithelial barrier is crucial for the development of acute lung injury (ALI). This study was aimed to evaluate the role of glucose transporter 1 (GLUT1) in dysregulation of epithelial tight junction in ALI. GLUT1 was inhibited with specific antagonists WZB117 or BAY876 to see the effects on epithelial tight junction in a well-established LPS-induced mouse ALI model as well as in vitro cultured epithelial cells. Pharmacological inhibition of GLUT1 with WZB117 at either a low or high dose had no effects on lung injury and inflammation 24 h after LPS challenge, but significantly decreased the pulmonary inflammatory responses induced by LPS at 72 h with a high dose, which was verified by treatment with BAY876. WZB117 or BAY876 also recovered the expression of epithelial tight junction proteins ZO-1 and occludin. In cultured BEAS-2B and A549 cells, LPS induced increased GLUT1 expression, accompanied by decreased expression of tight junction protein ZO-1 and occludin. Blockade of GLUT1 restored LPS-induced disruption of ZO-1 and occludin in BEAS-2B rather than A549. Taken together, our results showed that GLUT1 is responsible for dysfunction of epithelial tight junctions in the late phase of LPS-induced ALI. • GLUT1 was activated in the late phase of LPS-induced acute lung injury. • Inhibition of GLUT1 attenuated LPS-induced lung injury and inflammation in the late phase. • GLUT1 participates in the disruption of airway epithelial tight junction. [ABSTRACT FROM AUTHOR]

Escin is an active ingredient used in the treatment of phlebitis. However, the pharmacological mechanism of escin remains largely unclear. Here, we aimed to determine the molecular basis for the therapeutic effect of escin. Human umbilical vein endothelial cells (HUVECs) were subjected to shear-stress assays with or without escin. Intracellular Ca2+ levels, inflammatory factors and the activity of NF-κB were measured in endothelial cells (ECs) after mechanical-stretch or Yoda1 activation. Isometric tensions in aortic rings were identified. In addition, murine liver endothelial cells (MLECs) isolated from Piezo1 endothelial specific knockout mice (Piezo1 △ EC ) were used to explore the role of Piezo1. Our results showed that escin inhibited inflammatory factors, intracellular Ca2+ levels and Yoda1-evoked relaxation of thoracic aorta rings. Cell alignment induced by shear stress was inhibited by escin in HUVECs, and Piezo1 siRNA was used to show that this effect was dependent on Piezo1 channels. Moreover, escin reduced the inflammation and inhibited the activity of NF-κB in ECs with mechanical-stretch, which were insensitive to Piezo1 deletion. SN50, an NF-κB antagonist, significantly inhibited the mechanical stretch-induced inflammatory response. In addition, escin reduced inflammation in ECs subjected to mechanical-stretch, which was insensitive after using NF-κB antagonist. Collectively, our results demonstrate that escin inhibits the mechanical stretch-induced inflammatory response via a Piezo1-mediated NF-κB pathway. This study improves our understanding of a molecular target of escin that mediates its effect on chronic vascular inflammation. [ABSTRACT FROM AUTHOR]

Impaired endothelium-dependent vasodilation in atherosclerosis is a high-risk factor for myocardial infarction and ischemic stroke, and inflammation, necroptosis and apoptosis contribute to endothelial dysfunction in atherosclerosis. Although DL-3-n-butylphthalide (NBP) has been widely used in treating ischemic stroke, its effect on endothelium-dependent vasodilation remains unknown. This study aims to explore whether NBP is able to improve endothelium-dependent vasodilation in atherosclerosis and the underlying mechanisms. Male ApoE−/− mice were fed with a high-fat diet (HFD) for 9–16 weeks to establish a model of atherosclerosis. NBP were given to the mice after eating HFD for 6 weeks and atorvastatin served as a positive control. The endothelium-dependent vasodilation, the blood flow velocity, the atherosclerotic lesion area, the serum levels of lipids, inflammatory cytokines and necroptosis-relevant proteins (RIPK1, RIPK3 and MLKL), and the endothelial necroptosis and apoptosis within the aorta were measured. Human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL) for 48 h to mimic endothelial injury in atherosclerosis, lactate dehydrogenase release, the ratio of necroptosis and apoptosis and the expression of necroptosis-relevant proteins were examined. Similar to atorvastatin, NBP improves endothelium-dependent vasodilation, decreases aortic flow velocity and reduces atherosclerotic lesion area in HFD-fed ApoE−/− mice, concomitant with a reduction in serum lipids, inflammatory cytokines and necroptosis-relevant proteins, and endothelial necroptosis and apoptosis. Consistently, NBP inhibited necroptosis and apoptosis in ox-LDL-treated HUVECs. Based on these observations, we conclude that NBP exerts beneficial effects on improving the endothelium-dependent vasodilation in atherosclerosis via suppressing inflammation, endothelial necroptosis and apoptosis. [ABSTRACT FROM AUTHOR]

The tyrosine kinase inhibitor (TKI) gefitinib exerts good therapeutic effect on NSCLC patients with sensitive EGFR-activating mutations. However, most patients ultimately relapse due to the development of drug resistance after 6–12 months of treatment. Here, we showed that a HIF-1α inhibitor, YC-1, potentiated the antitumor efficacy of gefitinib by promoting EGFR degradation in a panel of human NSCLC cells with wild-type or mutant EGFRs. YC-1 alone had little effect on NSCLC cell survival but significantly enhanced the antigrowth and proapoptotic effects of gefitinib. In insensitive NSCLC cell lines, gefitinib efficiently inhibited the phosphorylation of EGFR but not the downstream signaling of ERK, AKT and STAT3; however, when combined with YC-1 treatment, these signaling pathways were strongly impaired. Gefitinib treatment induced EGFR arrest in the early endosome, and YC-1 treatment promoted delayed EGFR transport into the late endosome as well as receptor degradation. Moreover, the YC-1-induced reduction of HIF-1α protein was associated with the enhancement of EGFR degradation. HIF-1α knockdown promoted EGFR degradation, showing synergistic antigrowth and proapoptotic effects similar to those of the gefitinib and YC-1 combination treatment in NSCLC cells. Our findings provide a novel combination treatment strategy with gefitinib and YC-1 to extend the usage of gefitinib and overcome gefitinib resistance in NSCLC patients. [ABSTRACT FROM AUTHOR]

The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction. [Display omitted] • Upregulation of MALT1 occurs in rat hearts suffered ischemia/reperfusion. • Inhibition of MALT1 reduces I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. • Micafungin mitigate myocardial I/R injury via inhibition of MALT1. [ABSTRACT FROM AUTHOR]

Factor Xa (FXa) is a serine protease that plays key roles in linking the intrinsic and extrinsic coagulation pathways to the final common pathway. DJT06001 is an oral, highly specific and direct FXa inhibitor for the prevention and treatment of thromboembolic diseases. We characterized the compound in vitro and studied its in vivo activity in rat thrombosis models, as well as bleeding risk and Pharmacokinetics and Pharmacodynamics (PK/PD) relationship. DJT06001 inhibited free FXa with an inhibitory constant (Ki) of 0.99 nM, and exhibited >10000-fold selectivity for FXa than for other related serine proteases. DJT06001 concentration-dependently inhibited FXa activity in the prothrombinase complex with an IC 50 of 2.53 nM. The concentrations for DJT06001 to double the prothrombin time (PT) and activated partial thromboplastin time (APTT) were 0.74 and 0.57 μM, respectively. Importantly, DJT06001 did not impair platelet aggregation induced by ADP, platelet activating factor (PAF) and collagen. Furthermore, DJT06001 inhibited thrombus formation in rat thrombosis models in a dose dependent manner. And in rat tail bleeding risk test, it caused less bleeding than rivaroxaban at doses that achieve the same antithrombotic effect. PK/PD studies further demonstrated that there was a good correlation between the plasma concentrations of DJT06001and its inhibition of plasma FXa activity and prolongation of PT. In conclusion, DJT06001 was shown to be a potent and specific FXa inhibitor with excellent PK/PD profiles and it could be developed as a new anticoagulant for the management of thromboembolic diseases. [ABSTRACT FROM AUTHOR]

Rutin, a natural bioflavonoid, has demonstrated anti-diabetic and anti-oxidative bioactivity. Oxidative stress is a potential therapeutic target for diabetic cardiomyopathy. We investigated whether rutinadministration (60 mg/kg body weight) reduces diabetic cardiomyopathy in a diabetic ApoE knock out mouse model. Diabetes was induced in ApoEknockout mice (male, C57BL/6 background) with a high fat diet combined with injection of streptozotocin. Cardiac function was evaluated by echocardiography and cardiac catheter hemodynamic analysis. Cardiac myocardial hypertrophy, myocardial fibrosis, lipid content, myocardial capillary density, and oxidative stress were detected by a series of histopathological analyses, western blotting, and reactive oxygen species analysis. Diabetic mice showed myocardial hypertrophy, lipid accumulation, myocardial fibrosis, elevated collagen content, deteriorating oxidative stress, and left ventricular systolic and diastolic dysfunction. Rutin reversed the myocardial hypertrophy, alleviated extracellular collagen deposition, and lipid accumulation, but increased capillary density in diabetic myocardial tissues. Moreover, rutin substantially improved cardiac function while decreasing blood glucose and lipid content. Therapeutic rutin administration reduced cardiac remodeling and improved myocardial function in diabetic mice, at least in part by reducing oxidative damage and ectopic lipid deposition, inhibiting fibrosis, and promoting angiogenesis. Thus, rutin may represent a potential therapeutic agent for diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Tumor chemoresistance is often a major cause for the failure of chemotherapy. The resistance of hepatocellular carcinoma (HCC) cells to sorafenib significantly limits its therapeutic effect in HCC patients. For the first time, we found that FXYD domain-containing ion transport regulator 5 (FXYD5) is highly expressed in sorafenib-resistant HCC cells. In addition, the protein expression level of FXYD5 was markedly higher in HCC tissues than in paracancerous tissues. Remarkably, downregulation of FXYD5 expression in Huh7/sora cells reversed their resistance to sorafenib. Moreover, overexpression of FXYD5 reduced the sensitivity of HCC cells to sorafenib, while the downregulation of its expression in HCC cells had the opposite effect. We also found abnormal activation of the Akt/mTOR signaling pathway in Huh7/sora cells. Furthermore, MK2206, an Akt inhibitor, was found to significantly increase the sensitivity of HCC cells to sorafenib. More importantly, the expression level of p-Akt was positively correlated with the expression of FXYD5 in HCC tissues. Therefore, mechanistically, FXYD5 enhances the resistance of HCC cells to sorafenib by activating the Akt/mTOR signaling pathway. In conclusion, this study showed that the activation of the FXYD5/Akt/mTOR signaling axis plays key role in the resistance of HCC cells to sorafenib, and FXYD5 may represent a new potential target for HCC therapy. [ABSTRACT FROM AUTHOR]

Liver fibrosis is characterized by the abnormal deposition of the extracellular matrix with a severe inflammatory response and/or metabolic disorder. Asiatic acid (AA), a natural compound derived from Centella asiatica , exhibited potent anti-fibrosis effects. This investigation first confirmed the anti-fibrosis effects of AA in TGF- β -LX-2 cells and CCl 4 -induced liver fibrosis mice, and then sought to elucidate a novel mechanism of action by integrating network pharmacology and lipidomics. Network pharmacology was used to find potential targets of AA, while lipidomics was used to identify differential metabolites between fibrosis and recovered cohorts. AA could suppress hepatic stellate cell activation in vitro and improve liver fibrosis in vivo. Network pharmacology unveiled the genes involved in pathways in cancer, peroxisome proliferators-activated receptors signaling pathway, and arachidonic acid metabolism pathway. Furthermore, five key genes were found in the both human and mouse databases, indicating that arachidonic acid metabolism was important. Changes in lyso-phosphocholine (22:5), prostaglandin F2α, and other related lipid metabolites also suggested the involvement of arachidonic acid metabolism the anti-fibrotic effect. In summary, our integrated strategies demonstrated that AA targeted multiple targets and impeded the progression of liver fibrosis by ameliorating arachidonic acid metabolism. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain (CNP) can result from surgery or traumatic injury, but also from peripheral neuropathies caused by diseases, viral infections, or toxic treatments. Opioids, although very effective for acute pain, do not prevent the development of CNP, and are considered as insufficient treatment. Therefore, there is high need for effective and safe non-opioid options to treat, prevent and eventually reverse CNP. A more effective approach to alleviating CNP would constitute a treatment that acts concurrently on various mechanisms involved in relieving pain symptoms and preventing or reversing chronification by enhancing both neuroprotection and neuroregeneration. We have identified and characterized GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-caboxylic acid amide), a novel drug which is able to activate both voltage-gated potassium channels of the Kv7 family and the mitochondrial translocator protein 18 kDa (TSPO). The dual mode-of-action (MoA) of GRT-X was indicated in in vitro studies and in vivo in a rat model of diabetic neuropathy. In this model, mechanical hyperalgesia was dose-dependently inhibited. After severe crush lesion of cervical spinal nerves in rats, GRT-X promoted survival, speeded up regrowth of sensory and motor neurons, and accelerated recovery of behavioral and neuronal responses to heat, cold, mechanical and electrical stimuli. These properties may reduce the likelihood of chronification of acute pain, and even potentially relieve established CNP. The absence of a conditioned place preference in rats suggests lack of abuse potential. In conclusion, GRT-X offers a promising preclinical profile with a novel dual MoA. • GRT-X is a novel first-in-class drug with a dual mode-of-action on Kv7 and TSPO. • Activation of both targets by GRT-X was shown in in vitro and in vivo studies. • GRT-X inhibited hyperalgesia in rats. • It promoted survival and regrowth of rat neurons after peripheral nerve lesion. • GRT-X also accelerated recovery of behavioral and neuronal functions. [ABSTRACT FROM AUTHOR]

Biliary cholesterol may contribute to the formation of cholesterol gallstones, and regulation of these levels could be a useful therapeutic strategy for gallstones disease. Piperine (PA) is a potential cholesterol lowering agent. In this study, we assessed the effect and mechanism of PA in preventing cholesterol gallstones formation induced by feeding lithogenic diet containing high cholesterol levels to mice. C57BL/6 inbred mice were fed lithogenic or chow diets for 10 weeks, with or without PA (15, 30 and 60 mg/kg) or ursodeoxycholic acid (UDCA, 60 mg/kg) administration. Cholesterol, phospholipids and crystals in bile, the lipid in serum, pathological changes and proteins expression in liver were analyzed. The results showed that PA could decrease the cholesterol potency and crystals in bile, reduce total cholesterol (TC), triglycerides (TG) and increase high-density lipoprotein/low-density lipoprotein (HDL/LDL) levels in serum. Furthermore, PA treatment reduced liver lipid peroxidation and protected hepatobiliary cells from liver injury by decreasing malondialdehyde (MDA) and increasing superoxide dismutase (SOD). In addition, PA inhibited the expression of ATP-binding cassette transporters G5/8 (ABCG5/8) and liver X receptor (LXR) in liver, and reduced cholesterol transport from the hepatocytes to the gallbladder. It may be the mechanism of PA in preventing cholesterol gallstones formation. PA as a potential drug for prevention cholesterol gallstones merits further investigation. [ABSTRACT FROM AUTHOR]

Hepatocyte growth-promoting factor (pHGF) has a significant effect in promoting liver cell proliferation and restoring liver function. In this study, 815 short peptides of pHGF were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), of which 574 short peptides were assigned to 152 proteins related to hemoglobin subunits and some catalytic enzymes, indicating that pHGF might participate in the oxidation-reduction process by regulating reactive oxygen species (ROS) production. Proteomic analysis was used to identify the differentially expressed proteins (DEPs) in SMMC-7721 and L-02 cells after pHGF treatment, which suggested that pHGF had a significant impact on the JAK-STAT signaling pathway and the cell cycle of liver cells. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed the mechanisms through which pHGF might activate the JAK2/STAT3/c-MYC pathway to up-regulate the expression of CDK4/6, thereby accelerating the G1/S transition to promote liver cell proliferation. These findings, for the first time, indicate the potential role of pHGF against the early or middle stages of acute, sub-acute, and chronic severe hepatitis. pHGF was also found to restore the reduced SOD1 and SOD2 protein levels that result from H 2 O 2 exposure and significantly increase the HO-1 protein levels in L-02 cells, thus improving the viability of L-02 cells that have been damaged by H 2 O 2 by reducing the ROS and lipid peroxidation levels. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Cucurbitacin B is a triterpenoid compound isolated from Trichosanthes kirilowii Maximowicz, which has been used in oriental medicine for its antitumor activities. However, the mechanisms by which cucurbitacin B inhibits tumor growth are not fully understood. We here demonstrated the effect of cucurbitacin B on hypoxia-inducible factor-1 (HIF-1) activation. Cucurbitacin B showed the potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently, whereas it did not affect the expressions of HIF-1β. Further analysis revealed that cucurbitacin B inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. Rather, we found that suppression of HIF-1α accumulation by cucurbitacin B correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and extracellular signal-regulated kinase-1/2 (ERK1/2), a pathway known to regulate HIF-1α expression at the translational level. Cucurbitacin B also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumor cells. Furthermore, cucurbitacin B prevented hypoxia-induced expression of HIF-1 target genes and suppresses the invasiveness of tumor cells. In vivo studies further confirmed the inhibitory effect of cucurbitacin B on the expression of HIF-1α proteins, leading to a decrease growth of HeLa cells in a xenograft tumor model. These results show that cucurbitacin B is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity. [Copyright &y& Elsevier]

Abstract: A novel strontium salt compound strontium fructose 1, 6-diphosphate (FDP-Sr) has been proved to have highly effective for bone loss via dual effects of stimulating bone formation and suppressing bone absorption. In the present study, metabolomic approach was used to identify and study potential biomarkers associated with the effect and safety of FDP-Sr. The metabolomic profiles of bone loss induced by estrogen deficiency in a rat model was described to attain a system-level map of the shift on the metabolic response in plasma using GC/TOF-MS, after FDP-Sr was orally administered at the dose of 110mg/kg/day for the prevention and 220mg/kg/day for the treatment. Meanwhile, bone turnover biomarkers and bone mineral density were investigated to identify the specific changes of potential anti-osteoporosis effects of FDP-Sr. The differences in metabolic profiles between osteoporosis rats and FDP-Sr treated rats were well observed by the partial least squares-discriminant analysis (PLS-DA) to the MS spectra. Some metabolites including homocysteine, arachidonic acid, alanine, and hydroxyproline, which significantly changed during osteoporosis progression could be effectively reversed after FDP-Sr therapy. Of course some metabolites such as uric acid, glyceric acid, octadecadienoic acid, docosahexaenoic acid, oleic acid, and hexadecanoic acid were not found to reverse significantly after FDP-Sr administration. These results delineated the FDP-Sr effects-related metabolic alterations in the bone loss rats, suggesting that metabonomic analysis could provide helpful information on the new potential biomarkers relating to the mechanism of anti-osteoporosis action and side effects of FDP-Sr against estrogen deficiency induced bone loss. [Copyright &y& Elsevier]

Abnormal melanogenesis and melanosome transport can cause skin pigmentation disorders that are often treated using ginseng-based formulation. We previously found that phenolic acid compounds in ginseng root could inhibit melanin production and as a skin-whitening agents. However, mechanisms of action underlying effects of ginseng phenolic acid monomers on melanogenesis remain unclear. This study was conducted to investigate effects of salicylic acid, a main ginseng root phenolic acid component, on melanogenesis and melanosome functions in melanocytes of zebrafish and other species. Salicylic acid exhibited no cytotoxicity and reduced melanin levels and tyrosinase activity in B16F10 murine melanoma cells and normal human epidermal melanocytes regardless of prior cell stimulation with α-melanocyte stimulating hormone. Additionally, salicylic acid treatment reduced expression of melanogenic enzymes tyrosinase, tyrosinase-related protein 1 and tyrosinase-related protein 2, while reducing expression of their master transcriptional regulator, microphthalmia-associated transcription factor. Moreover, reduced phosphorylation of cAMP response-element binding protein was observed due to reduced cAMP levels resulting from salicylic acid inhibition of upstream signal regulators (adenylyl cyclase and protein kinase A). Furthermore, salicylic acid treatment suppressed expression of transport complex-associated proteins melanophilin and myosin Va in two UVB-treated melanocytic cell lines, suppressed phagocytosis of fluorescent microspheres by UVB-stimulated human keratinocytes (HaCaT), inhibited protease-activated receptor 2 activation by reducing both Ca2+ release and activation of phosphoinositide 3 kinase/AKT and mitogen-activated protein kinases and induced anti-melanogenic effects in zebrafish. Collectively, these results indicate that salicylic acid within ginseng root can inhibit melanocyte melanogenesis and melanin transport, while also suppressing keratinocyte phagocytic function. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: This study is designed to investigate the protection of tanshinone IIA (TSIIA) against atherosclerosis in apolipoprotein E deficient (ApoE−/−) mice and to explore the mechanisms by focusing on the expressions of scavenger receptors, scavenger receptor-A (SR-A) and CD36. The in vivo study demonstrated that TSIIA (10–90mg/kg) inhibited the atherosclerotic lesions, down-regulated the CD68 protein expression in lesion and decreased the contents of cholesterol in aortas of ApoE−/− mice. In addition, TSIIA reduced the serum levels of oxidized LDL (oxLDL) and down-regulated the mRNA expression of CD36, SR-A and peroxisome proliferator-activated receptor gamma (PPARγ) in aortas. The in vitro study showed that TSIIA (0.1–10μM) decreased cholesterol level and DiI-oxLDL uptake in mouse peritoneal macrophages treated with oxLDL (50μg/ml). In addition, TSIIA down-regulated the mRNA and protein expression of CD36 but not that of SR-A in oxLDL treated macrophages. TSIIA also down-regulated the mRNA expression of PPARγ in oxLDL treated macrophages. Furthermore, TSIIA reduced the mRNA expression of CD36 in macrophages treated with PPARγ agonist 15d-PGJ2 (2μM) or troglitazone (50μM), whereas both 15d-PGJ2 (0.5–1.5μM) and troglitazone (5–20μM) dose-dependently abolished the down-regulation of CD36 expression by TSIIA in oxLDL treated macrophages. These results suggest that TSIIA attenuates the atherosclerotic lesion in ApoE−/− mice, which might be attributed to the properties of both anti-oxidation and down-regulation of scavenger receptors. Furthermore, antagonism of PPARγ might be involved in the down-regulation of CD36 by TSIIA. [ABSTRACT FROM AUTHOR]

Abstract: Linaclotide is a first-in-class, orally administered 14-amino acid peptide that is in development for the treatment of irritable bowel syndrome with constipation and chronic constipation. We have characterized the solution structure of linaclotide, the in vitro binding and agonist activity to guanylate cyclase C receptors, the stability of linaclotide under conditions mimicking the gastric environment, oral bioavailability, and the pharmacodynamic effects in rat models of gastrointestinal transit and intestinal secretion. Nuclear magnetic resonance spectroscopy analysis determined that the molecular structure of linaclotide is stabilized by three intramolecular disulfide bridges. Linaclotide exhibited high affinity and pH-independent binding (K i: 1.23–1.64nM) to guanylate cyclase C receptors on human colon carcinoma T84 cells and concomitantly, linaclotide binding resulted in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3′, 5′-monophosphate (cGMP) (EC50:99nM). Linaclotide was stable after 3h incubation in simulated gastric fluid (pH 1) and similarly, was completely resistant to hydrolysis by pepsin. Pharmacokinetic analysis of linaclotide showed very low oral bioavailability (0.1%). Orally administered linaclotide elicited a significant, dose-dependent increase in gastrointestinal transit rates in rats at doses of ≥5μg/kg. Exposure of surgically ligated small intestinal loops to linaclotide induced a significant increase in fluid secretion, accompanied by a significant increase in intraluminal cGMP levels. These results suggest that the guanylate cyclase C agonist linaclotide elicits potent pharmacological responses locally in the gastrointestinal tract, and that orally administered guanylate cyclase C agonists may be capable of improving bowel habits in patients suffering from irritable bowel syndrome with constipation and chronic constipation. [Copyright &y& Elsevier]

Abstract: Nicotine was reported to reduce the plaque burden and could be used as a possible anti-Alzheimer''s disease agent. However, the effect of nicotine on memory and tau pathology in Alzheimer''s disease has been less studied. The present study investigated the effect of nicotine on tau phosphorylation and cognitive impairment induced by hippocampus injections of amyloid-beta (Aβ) 25–35. Rats were treated with nicotine hydrogen tartrate salt dissolved in normal saline by subcutaneous injection twice per day for 14days. The age and gender matched rats treated with same amount of normal saline were used as the control. Morris water maze was used to detect the cognitive impairment induced by Aβ25–35. Compared to the sham-operated rats, Aβ25–35 injection significantly prolonged the mean escape latency in vehicle-treated rats in the Morris water maze test and increased the number of tau(pS202) and tau(pT231) immunoreactive cells. The data show that nicotine (1mg/kg in base weight) treatment significantly exacerbates cognitive impairment and tau phosphorylation at Ser-202 and Thr-231 in the hippocampus compared with Aβ25–35 injection groups in the Aβ rat model of Alzheimer''s disease. The use of nicotine for treatment of Alzheimer''s disease should be reassessed. [Copyright &y& Elsevier]

Abstract: Plasma cell membrane glycoprotein-1, or ectonucleotide pyrophosphatase/phosphodieterase (PC-1/ENPP1) has been shown to inhibit insulin signaling in cultured cells in vitro and in transgenic mice in vivo when overexpressed. Furthermore, both genetic polymorphism and increased expression of PC-1 have been reported to be associated with type 2 diabetes in humans. Thus it was proposed that PC-1 inhibition represents a potential strategy for the treatment of type 2 diabetes. However, it has not been proven that suppression of PC-1 expression or inhibition of its function will actually improve insulin sensitivity. We show in the current study that transient overexpression of PC-1 inhibits insulin-stimulated insulin receptor tyrosine phosphorylation in HEK293 cells, while knockdown of PC-1 with siRNA significantly increases insulin-stimulated Akt phosphorylation in HuH7 human hepatoma cells. Adenoviral vector expressing a short hairpin RNA against mouse PC-1 (PC-1shRNA) was utilized to efficiently knockdown PC-1 expression in the livers of db/db mice. In comparison with db/db mice treated with a control virus, db/db mice treated with the PC-1shRNA adenovirus had ~80% lower hepatic PC-1 mRNA levels, ~30% lower ambient fed plasma glucose, ~25% lower fasting plasma glucose, and significantly improved oral glucose tolerance. Taken together, these results demonstrate that suppression of PC-1 expression improves insulin sensitivity in vitro and in an animal model of diabetes, supporting the proposition that PC-1 inhibition is a potential therapeutic approach for the treatment of type 2 diabetes. [Copyright &y& Elsevier]

Abstract: Corosolic acid, a triterpenoid compound widely existing in many traditional Chinese medicinal herbs, has been proved to have antidiabetic effects on animal experiments and clinical trials. However, the underlying mechanisms remain unknown. Here, we investigate its cellular effects and related signaling pathway. We demonstrate that it enhances glucose uptake in L6 myotubes and facilitates glucose transporter isoform 4 translocation in CHO/hIR cells. These actions are mediated by insulin pathway activation and can be blocked by phosphatidylinositol 3-kinase (PI3 Kinase) inhibitor Wortmannin. Furthermore, Corosolic acid inhibits the enzymatic activities of several diabetes-related non-receptor protein tyrosine phosphatases (PTPs) in vitro, such as PTP1B, T-cell-PTP, src homology phosphatase-1 and src homology phosphatase-2. [Copyright &y& Elsevier]

Abstract: We have previously demonstrated that American ginseng berry extract exhibited significant protection against oxidant-mediated injury in cardiomyocytes. To extend this work, we sought to investigate the antioxidant effects of Re, a protopanaxatriols-type and single chemical integrant present in American ginseng berry extract, using the same chick cardiomyocyte model of oxidant injury as well as ESR spectroscopy in a cell-free chemical system. In cells exposed to 2 h of H2O2 (0.5 mM), pretreatment with Re (0.05, 0.1, or 0.5 mg/ml for 2 h) significantly attenuated 2′,7′-dichlorofluorescein (DCF) fluorescence by 51% (from 1345±67 to 658±46 a.u., P <0.001), and remarkably reduced cell death (from 51.5±3.0% to 11.8±1.5%, P <0.001, compared to the control). Similar results were also observed in cells exposed to antimycin A (100 μM), a mitochondrial electron transport chain site III inhibitor which increases endogenous oxidative stress. In the ESR study, however, Re failed to reduce the formation of the superoxide/DMPO adduct and DPPH radicals. These results suggest that ginsenoside Re functions as an antioxidant, protecting cardiomyocytes from oxidant injury induced by both exogenous and endogenous oxidants, and that its protective effects may be mostly attributed to scavenging H2O2 and hydroxyl radicals. [Copyright &y& Elsevier]

Despite the remarkable clinical response in ovarian cancer therapy, the distinctively high metastasis rate is still a barrier to achieve satisfying prognosis. Our study aimed to decipher the role of berberine in inhibiting chemotherapy-exacerbated ovarian cancer metastasis. We found that chemotherapy exacerbated the migration and cancer stem cell (CSC)-like characteristics through transcriptional factor GLI1, which regulated the pluripotency-associated gene BMI1 and the epithelial-mesenchymal transition (EMT) markers Vimentin and Snail. Berberine could not only down-regulate CSC-like characteristics but also reverse EMT and migration through inhibiting chemotherapy-activated GLI1/BMI1 signaling pathway. Together, our study revealed the pivotal role of berberine in overcoming chemotherapy-exacerbated ovarian cancer metastasis, thereby provided a potential adjuvant therapeutic agent in combination with chemotherapeutics to prevent metastasis during ovarian cancer chemotherapy. Image 1 [ABSTRACT FROM AUTHOR]

Ergosterol peroxide has been shown to exhibit anti-tumor, antioxidant and anti-bacterial properties. However, the effects of ergosterol peroxide isolated from the herbal Baphicacanthus cusia root on influenza virus infection remain poorly understood. In the present study, ergosterol peroxide (compound 22) was obtained from the B. cusia root and subjected to investigation regarding its immunoregulatory effect on influenza A virus (IAV)-induced inflammation in A549 human alveolar epithelial cells. The structure of compound 22 isolated from B. cusia root. was elucidated by NMR analyses. Structure determination showed that the chemical structure of compound 22 closely resembles that of ergosterol peroxide. We observed that ergosterol peroxide treatment significantly suppressed IAV-induced upregulation of RIG-I expression. Additionally, ergosterol peroxide inhibited the activation of RIG-I downstream signaling pathways, including p38 MAP kinase and NF-κB, which ultimately resulted in the reduced production of an array of pro-inflammatory mediators and interferons (IFN-β and IFN-λ1). Interestingly, inhibitory effects of ergosterol peroxide on the expression of IFNs did not affect the expression of antiviral effectors or enhance viral replication. On the other hand, ergosterol peroxide effectively abolished the amplified production of pro-inflammatory mediators in cells pretreated with IFN-β (500 ng/ml) prior to IAV infection. Moreover, Annexin V and Hoechst 33258 staining revealed that increased apoptosis of IAV-infected cells was reversed by the presence of ergosterol peroxide. Our findings suggest that ergosterol peroxide from the B. cusia root suppressed IAV-associated inflammation and apoptosis via blocking RIG-I signaling, which may serve as a supplementary approach to the treatment of influenza. [ABSTRACT FROM AUTHOR]