Correction: The Effects of 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone on the Pressure Overload-Induced Progression of Cardiac Hypertrophy to Cardiac Failure.

[This corrects the article DOI: 10.1371/journal.pone.0091834.].

Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR-mutant non-small cell lung cancer.

BACKGROUND: The resistance mechanism of the third generation of epidermal growth factor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is complex. Epithelial mesenchymal transition (EMT) is a common mechanism of EGFR-TKI acquired resistance. Snail is an important transcription factor related to EMT. Whether targeting Snail can reverse the resistance of osimertinib by downregulating Snail is unknown. METHODS: The presence of EMT in H1975/OR (osimertinib resistance) cells was confirmed by transwell assay. To explore the EMT role in resistance, the expression levels of EMT markers were detected in both parental cells H1975 and resistant cells H1975OR. We used RNA interference technology to knockdown the key regulator Snail in resistant cells. After the interference efficiency was confirmed, changes in EMT-related molecules of Snail were explicitly downregulated, and changes in sensitivity and migration and invasion ability were also examined. We used CDK4/6 inhibitor to test the ability of reversing drug resistance by downregulating Snail. RESULTS: Compared with the H1975 cell line, the H1975/OR resistant cell line showed increased invasiveness, upregulated expression of vimentin and downregulation of E-cadherin. EMT occurred in the H1975/OR resistant cell line. The expression of Snail was upregulated in the osimertinib-resistant cell line H1975/OR. Knockdown of Snail increased the sensitivity of H1975/OR cells to osimertinib. CDK4/6 inhibitor palbociclib could downregulate the expression of Snail. CDK 4/6 inhibitor palbociclib combined with osimertinib could reverse the resistance of osimertinib in H1975/OR. CONCLUSIONS: Snail plays an important role in the third generation of EGFR-TKI osimertinib resistance, which may be reversed by downregulating Snail.

Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer.

The third-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), represented by osimertinib, has achieved remarkable clinical outcomes in the treatment of non-small-cell lung cancer (NSCLC) with EGFR mutation. However, resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood. In this study, we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations. We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells, evidenced by increased levels of γH2AX and higher intensity of the comet tail after withdrawal from cisplatin. Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK, a key kinase in DNA damage response (DDR), sensitized the resistant cells to osimertinib. Combination of osimertinib with the DNA-PK inhibitor, PI-103, or NU7441, synergistically suppressed the proliferation of the resistant cells. Mechanistically, we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest. These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair, and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.

CDK4/6 inhibitor palbociclib overcomes acquired resistance to third-generation EGFR inhibitor osimertinib in non-small cell lung cancer (NSCLC).

BACKGROUND: The third-generation EGFR-TKI, represented by osimertinib, has been widely used in clinical practice; however, resistance eventually emerges. At present, it remains unclear whether an abnormal cell cycle is involved in acquired resistance, and whether the combination of palbociclib (CDK4/6 inhibitor) and osimertinib can overcome the third-generation TKI resistance. METHODS: We established osimertinib-resistant cells (H1975 OR) derived from EGFR-mutant NSCLC cells H1975. Drug effects on cells were assessed with Cell Counting Kit-8 (CCK8). Protein alterations were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA. Cell cycle distribution of H1975 S and H1975 OR cells was compared using flow cytometry. RESULTS: Compared with H1975, the sensitivity of H1975OR to the CDK4/6 inhibitor was increased and the proportion of cells in G1 phase was decreased. The mRNA level of CDK4, CDK 6 and the protein level of CDK4, pRB were increased in H1975OR. In the H1975OR cells, palbociclib significantly increased the proportion of G1 phase cells. The combination of osimertinib and palbociclib synergistically decreased the survival of H1975OR by cell cycle arrest. Combined treatment was found to inhibit the initial phosphorylation of RB by inhibiting the function of CDK4/6, significantly reducing the level of p-RB, and blocking cell proliferation. CONCLUSIONS: An osimertinib acquired resistance cell line (H1975 OR) was successfully established. The expression of cell cycle related genes was altered in H1975OR. The expression of CDK4 and the phosphorylation of Rb, the downstream molecule of CDK4/6, was increased in H1975OR cells. The combination of CDK4/6 inhibitor palbociclib and osimertinib could overcome the acquired resistance of osimertinib.

Effect of an aqueous extract of Averrhoa carambola L. on endothelial function in rats with ventricular remodelling.

Ventricular remodelling leads to cardiomyocyte hypertrophy, myocardial fibrosis, endothelial vasoactive substance changes and endothelial dysfunction. Our purpose was to research the effect of an aqueous extract of Averrhoa carambola L. (AEA) on endothelial function in rats with ventricular remodelling induced by isoprenaline. Rats were subjected to injection of isoprenaline and administration of various drugs. Vasoactive substances were measured, and the ventricular remodelling index was detected by the weighing method. Immunohistochemical analysis, pathological examination, Western blot and Masson's trichrome staining were performed. After AEA administration, the levels of transforming growth factor-ß (TGF-ß), angiotensin II (AngII), inducible NO synthase (iNOS), endothelin-converting enzyme (ECE), and endothelin 1 (ET-1); the ventricular remodelling index; and the collagen volume fraction were decreased, while the levels of total NO synthase (tNOS) and endothelial NO synthase (eNOS) were increased. The pathological examination results showed that apoptosis, fibrosis, necrosis and inflammatory infiltration of myocardial tissue were attenuated by AEA treatment. AEA might alleviate ventricular remodelling in rats by maintaining the balance of vasoactive substances and the function of the vascular endothelium.

Glutamine-ß-cyclodextrin for targeted doxorubicin delivery to triple-negative breast cancer tumors via the transporter ASCT2.

Chemotherapy is the primary therapy for triple-negative breast cancer (TNBC) and the tumor-targeted delivery of chemotherapeutic drugs is necessary to minimize their side effects on normal tissues. TNBC cells display addictions to glutamine in culture, and the levels of the glutamine transporter, alanine-serine-cysteine transporter 2 (ASCT2), are elevated in many types of cancer. However, glutamine- or ASCT2-based carriers have not been used in tumor-targeted drug delivery. In this study, a novel derivative of ß-cyclodextrin (ß-CD), glutamine-ß-cyclodextrin (GLN-CD), was developed by conjugating glutamine with the 6-hydroxy of ß-CD, and GLN-CD was then used to prepare doxorubicin (DOX) inclusion complexes (DOX@GLN-CD) for TNBC treatment. GLN-CD and glutamine have similar ASCT2-binding sites, and GLN-CD has the potential to enter cells through ASCT2-dependent facilitated diffusion. An increase in the degree of substitution did not promote binding between GLN-CD and ASCT2. GLN-CD and DOX formed inclusion complexes at a molar ratio of 1 : 1. DOX@GLN-CD specifically accumulated in TNBC cells, including MDA-MB-231 and BT549 cells, where it subsequently induced G2/M blockade and apoptosis, but hardly affected nontumorigenic MCF10A cells. l-γ-Glutamyl-p-nitroanilide (GPNA), which is a specific inhibitor of ASCT2, antagonistically decreased the cellular uptake of DOX@GLN-CD by TNBC cells, which further confirmed the role of ASCT2 in DOX@GLN-CD transport. In vivo, DOX@GLN-CD accumulated specifically in tumors, achieved improved outcomes and minimized the toxic effects on main organs at the same dose as DOX. As a novel derivative of ß-CD, GLN-CD is an effective carrier that can specifically deliver DOX to TNBC cells via targeting ASCT2 and minimize its uptake by normal cells.

High kinesin family member 18A expression correlates with poor prognosis in primary lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent pathological subtype of lung cancer. Kinesin family member 18A (KIF18A) plays an important role in tumorigenesis. Its roles in breast cancer, colorectal cancer, and other tumors have been demonstrated; however, studies of KIF18A in LUAD are limited. This study aimed to determine the role of KIF18A in LUAD progression and prognostic prediction. METHODS: KIF18A expression was examined in LUAD cells and tissues by immunohistochemistry and Western blotting. Cell proliferation assay was performed to study the role of KIF18A in LUAD cells. Correlations between KIF18A expression and clinicopathological features were analyzed. The role of KIF18A in LUAD prognosis was evaluated using data from The Cancer Genome Atlas (TCGA). RESULTS: KIF18A expression was increased in tumor cells and tissues. Downregulation of KIF18A expression resulted in the suppression of cancer cell proliferation in in vitro assays, and was particularly related to poor tumor differentiation, big tumor size, lymph node metastasis, and more advanced tumor stage. In the TCGA dataset, high KIF18A messenger RNA expression was associated with poor disease-free and overall survival in patients with LUAD. In addition, multivariate analysis indicated that KIF18A is an independent prognostic factor of disease-free and overall survival in LUAD. CONCLUSIONS: Collectively, our results demonstrate that KIFl8A is highly expressed in LUAD. KIFl8A plays an important role in LUAD cell proliferation, but is a poor prognostic factor.

The Multiple Applications and Possible Mechanisms of the Hyperbaric Oxygenation Therapy.

Hyperbaric Oxygenation Therapy (HBOT) is used as an adjunctive method for multiple diseases. The method meets the routine treating and is non-invasive, as well as provides 100% pure oxygen (O2), which is at above-normal atmospheric pressure in a specialized chamber. It is well known that in the condition of O2 deficiency, it will induce a series of adverse events. In order to prevent the injury induced by anoxia, the capability of offering pressurized O2 by HBOT seems involuntary and significant. In recent years, HBOT displays particular therapeutic efficacy in some degree, and it is thought to be beneficial to the conditions of angiogenesis, tissue ischemia and hypoxia, nerve system disease, diabetic complications, malignancies, Carbon monoxide (CO) poisoning and chronic radiation-induced injury. Single and combination HBOT are both applied in previous studies, and the manuscript is to review the current applications and possible mechanisms of HBOT. The applicability and validity of HBOT for clinical treatment remain controversial, even though it is regarded as an adjunct to conventional medical treatment with many other clinical benefits. There also exists a negative side effect of accepting pressurized O2, such as oxidative stress injury, DNA damage, cellular metabolic, activating of coagulation, endothelial dysfunction, acute neurotoxicity and pulmonary toxicity. Then it is imperative to comprehensively consider the advantages and disadvantages of HBOT in order to obtain a satisfying therapeutic outcome.

Effect of Yulangsan Polysaccharide on the Reinstatement of Morphine-Induced Conditioned Place Preference in Sprague-Dawley Rats.

We previously reported that Yulangsan polysaccharide (YLSP), which was isolated from the root of Millettia pulchra Kurz, attenuates withdrawal symptoms of morphine dependence by regulating the nitric oxide pathway and modulating monoaminergic neurotransmitters. In this study, we investigated the effects and mechanism of YLSP on the reinstatement of morphine-induced conditioned place preference (CPP) in rats. A CPP procedure was employed to assess the behavior of rats, and indicators of serum and four brain regions (nucleus accumbens, ventral tegmental area, hippocampus and prefrontal cortex) were determined to explore its underlying mechanism. YLSP inhibited priming morphine-induced reinstatement of CPP in a dose-dependent manner. YLSP markedly reduced nitric oxide and nitric oxide synthase levels in the brain. Moreover, YLSP significantly decreased the dopamine and norepinephrine levels in the serum and brain. Furthermore, YLSP significantly decreased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) concentrations, inhibited the expression of dopamine D1 receptors and cAMP response element binding protein mRNA, and improved the expression of dopamine D2 receptor mRNA in the four brain regions. Our findings indicated that YLSP could inhibit the reinstatement of morphine-induced CPP possibly by modulating the NO-cGMP and D1R-cAMP signaling pathways.

Development and evaluation of a speech-generating AAC mobile app for minimally verbal children with autism spectrum disorder in Mainland China.

BACKGROUND: Mobile touchscreen devices are currently being used as speech-generating devices (SGDs) and have been shown to promote the communication skills, particularly the requesting skills of children with autism spectrum disorders (ASD) who have limited spoken language. However, no augmentative and alternative communication (AAC) mobile app has been developed and evaluated in the Chinese language in Mainland China. METHODS: We developed an AAC mobile app, which is the first in Mainland China, to our knowledge, named Yuudee (Chinese name (xiaoyudi)). Yuudee was developed using the Objective-C and Java programming languages. A five-phase training protocol for making requests using Yuudee was developed based on the Picture Exchange Communication System. We trained ten minimally verbal children with ASD to make requests using Yuudee and evaluated the effectiveness of the training. RESULTS: Yuudee has a built-in library of over 400 pictures with corresponding spoken phrases that are divided into 39 categories ranging from making simple requests to expressing emotions. An additional important feature of Yuudee is its customization functions that allow a parent or trainer to easily select pictures and phrases to display, create new pictures and phrases, and change the layouts and orders of the pictures to fit the personal needs of each child. Yuudee is freely available in an iOS version from the iTunes App Store (https://itunes.apple.com/cn/app/xiao-yu-di/id794832934?mt=8) and in an Android version from Google Play (https://play.google.com/store/apps/details?id=com.supersuperstar.yuudee.vue) and domestic Chinese Android App stores. Three consecutive unprompted successful responses, which were defined as an initial training success, were achieved in at least three of the five phases for all ten of the evaluated children. The accuracy rate of a given phase was calculated for each child who achieved three consecutive unprompted successful responses in the phase. Seven children achieved at least 50% accuracy in at least two of the five phases. The other three children achieved at least 50% accuracy in only one phase. Two children achieved at least 50% accuracy in all of the phases in which they were trained. CONCLUSIONS: Our data suggest that Yuudee is a useful tool for helping minimally verbal children with ASD make requests.

Hepatoprotective effects of Yulangsan flavone against carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats.

BACKGROUND: Yulangsan flavone (YLSF) was extracted from the root of Millettia pulchra Kurz var-laxior (Dunn) Z. Wei, which has been widely used for liver disease treatment in the Guangxi province of China. HYPOTHESIS/PURPOSE: The study was conducted to demonstrate the hepatoprotective effects of YLSF against CCl4-induced hepatic fibrosis in rats, meanwhile revealing the potential mechanism. STUDY DESIGN: Sprague-Dawley (SD) rats of both sexes were randomly divided into two groups: hepatic fibrosis group and normal control (NC) group. The rats in the hepatic fibrosis group were given 1 ml/kg 50% CCl4 (1:1 mixed with peanut oil), while those in the NC group were given 1 ml/kg normal saline (NS), both via intragastric administration. The established experimental rat model from the hepatic fibrosis group was confirmed by pathological inspection and randomly divided into five groups: three YLSF groups (20 mg/kg, 40 mg/kg and 80 mg/kg), a colchicine group (0.20 mg/kg) and a model group (10 ml/kg NS). All rats were treated with corresponding drugs or NS once a day for four consecutive weeks. Twenty-four hours after the last administration, blood serum and hepatic tissue were collected. METHODS: The activities of ALT and AST in the serum and the levels of SOD, MDA, GSH and GSH-Px in hepatic tissue were analysed, the indexes of liver, spleen and thymus were counted, the degree of hepatic injury was examined using HE and Masson staining, and the mRNA expression of Col-1, TIMP-1 and TGF-ß1 in hepatic tissues was detected. RESULTS: Compared with the model group, experimental results showed that YLSF and colchicine could reduce the levels of AST, ALT and MDA, increase the levels of SOD, GSH and GSH-Px, enhance rat survivability, decrease the liver, spleen and thymus index, significantly lessen collagen deposition and tissue damage and down-regulate the mRNA expression of Col-1, TIMP-1 and TGF-ß1. CONCLUSIONS: Our findings confirm that YLSF has a certain curative effect on rats with liver fibrosis induced by CCl4, and its mechanism may include attenuating free radicals, inhibiting lipid peroxidation and accelerating extracellular matrix degradation by down-regulating expression of related genes.

Rictor regulates the vasculogenic mimicry of melanoma via the AKT-MMP-2/9 pathway.

Vasculogenic mimicry (VM)-positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin-insensitive complex of mTOR (mTORC2), is up-regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan-Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma. In vitro, Rictor knockdown by short hairpin RNA (shRNA) significantly inhibited the ability of A375 and MUM-2B melanoma cells to form VM structures, as evidenced by most tubes remaining open. Cell cycle analysis revealed that Rictor knockdown blocked cell growth and resulted in the accumulation of cells in G2/M phase, and cell migration and invasion were greatly affected after Rictor down-regulation. Western blotting assays indicated that down-regulating Rictor significantly inhibited the phosphorylation of AKT at Ser473 and Thr308 , which subsequently inhibited the expression and activity of downstream MMP-2/9, as confirmed by real-time PCR and gelatin Zymography. MK-2206, a small-molecule inhibitor of AKT, similarly inhibited the activity of AKT and secretion of MMP-2/9, further supporting that Rictor down-regulation inhibits the phosphorylation of AKT and activity of downstream MMP-2/9 to affect VM formation. In conclusion, Rictor plays an important role in melanoma VM via the Rictor-AKT-MMP-2/9 signalling pathway.

Effect of the Total Extract of Averrhoacarambola (Oxalidaceae) Root on the Expression Levels of TLR4 and NF-κB in Streptozotocin-Induced Diabetic Mice.

BACKGROUND: Averrhoacarambola L., which is a folk medicine used in diabetes mellitus (DM) in ancient China, has been reported to have anti-diabetic efficacy. AIMS: The aim of this study was to evaluate the hypoglycemic effect of the extract of Averrhoacarambola L. root (EACR) on the regulation of the Toll-like receptor 4 (TLR4)-Nuclear-factor kappa B (NF-κB) pathway in B) pathway in streptozotocin (STZ)-induced diabetic mice. METHODS: the mice were injected with STZ (120 mg/kg body weight) via a tail vein. After 72 h, the mice with FBG ≥ 11.1 mmol/L were confirmed as having diabetes. Subsequently, the mice were treated intragastrically with EACR (300, 600, 1200 mg/kg body weight/d) and metformin (320 mg/kg body weight/d) for 14 days. RESULTS: As a result the serum fasting blood glucose (FBG), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were decreased following EACR administration. Immunohistochemical analysis revealed that the pancreatic tissue expression levels of TLR4 and NF-κB were downregulated after EACR administration. EACR suppressed pancreatic mRNA expression level of TLR4 and blocked the downstream NF-κB pathway in the pancreas. According to Western blot analysis EACR suppressed pancreatic TLR4 and NF-κB protein expression levels. Histopathological examination of the pancreas showed that STZ-induced pancreas lesions were alleviated by the EACR treatment. CONCLUSION: These findings suggest that the modulation of the IL-6 and TNF-α inflammatory cytokines and the suppression of the TLR4-NF-κB pathway are most likely involved in the anti-hyperglycemic effect of EACR in STZ-induced diabetic mice.

The Effects of 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone on Pressure Overload-Induced Cardiac Remodeling in Rats and the Endothelial Mechanisms Based on PGI2.

AIM: The primary objective of this study was to study the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) on pressure overload-induced cardiac remodeling in rats, as well as the endothelial mechanisms based on PGI2. METHODS: Six weeks following surgery, rats were divided randomly into the following groups: a sham group, a model group, an MHBFC 12 mg/kg/day group (MHBFC 12), an indomethacin 2 mg/kg/day group (Indo 2), and an Indo 2+ MHBFC 12 group. The MS 4000 organism signal system was used to record the rats' hemodynamic indices. Additionally, the heart weight was determined, and the cardiac remodeling index was calculated. HE and Masson's stains were utilized to perform histological analyses; the immunofluorescence was used to observe the microvessel density of myocardial tissue; the colorimetric method was used to determine the hydroxyproline content of cardiac tissue; the ELISA method was used to measure the plasma PGI2 content; and transmission electron microscopy was used to observe the ultrastructure of the myocardium. RESULTS: A hyperdynamic circulation state, cardiac remodeling, decreased microvessel density and decreased plasma PGI2 content were each observed in the model group compared with the sham group, in which any changes in the above parameters were effectively reversed by MHBFC. Single-use Indo administration resulted in the progression of these pathophysiological changes; however, MHBFC prevented the worsening of these parameters. CONCLUSION: MHBFC significantly reverses pressure overload-induced cardiac remodeling, and its mechanism may partially contribute to the amelioration of endothelial cell function and the augmentation of PGI2 synthesis and secretion.

Mechanism of the protective effect of Yulangsan flavonoid on myocardial ischemia/reperfusion injury in rats.

AIMS: Effect and mechanism of Yulangsan flavonoid (YLSF) on rat myocardial ischemia/reperfusion injury (MI/RI) has been investigated. METHODS: Sprague-Dawley (SD) rats were randomly divided into seven groups (sham group, model group and NS group: 2 mL of normal saline/kg body weight was administered; diltiazem group: 5 mg of diltiazem hydrochloride/kg body weight was administered; YLSFL, YLSFM and YLSFH groups: 20, 40 and 80 mg of YLSF/kg body weight was administered) and the MI/RI model was established. Myocardial infarct area, levels of myocardial enzymes and nitric oxide synthase (NOS) were measured. Caspase-3 and adenine nucleotide translocator-1 (ANT1) mRNA expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Pathological structure and cardiocyte ultrastructure were also analysed. RESULTS: Compared with the MI/RI group, pretreatment with YLSF or diltiazem hydrochloride decreased the infarct area, levels of inducible nitric oxide synthase (iNOS), caspase-3 as well as the leakage of myocardial enzyme and increased activities of total nitric oxide synthase (tNOS) as well as constitutive nitric oxide synthase (cNOS). Cellular edema and the infiltration of inflammatory cells were alleviated. CONCLUSIONS: The experiment showed that YLSF protected the heart against MI/RI, possibly by reducing lipid peroxidation damage, regulating NOS activity and modulating the apoptosis genes expression.

The effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone on the pressure overload-induced progression of cardiac hypertrophy to cardiac failure.

We investigated the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC), which was isolated from the roots of Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z.Wei (Papilionaceae) (MKL), on the progression of cardiac hypertrophy to failure in a rat model of abdominal aortic banding (AAB)-induced pressure overloading. Endothelial dysfunction is central to pressure overload-induced cardiac hypertrophy and failure. It would be useful to clarify whether MHBFC could prevent this dysfunction. The effects of pressure overload were assessed in male Sprague-Dawley rats 6 weeks after AAB using the progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats exhibited a greater progression to heart failure and had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, and evidence of left ventricular hypertrophy (LVH). LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These symptoms could be prevented by treatment with MHBFC at daily oral doses of 6 and 12 mg/kg for 6 weeks. The progression to cardiac failure, which was demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial natriuretic peptide (ANP) mRNA, could also be prevented. Furthermore, MHBFC partialy rescued the downregulated nitric oxide signaling system, whereas inhibited the upregulated endothelin signaling system, normalizing the balance between these two systems. MHBFC protected the endothelium and prevented the pressure overload-induced progression of cardiac hypertrophy to cardiac failure.

The effect of 17-methoxyl-7-hydroxy-benzene-furanchalcone on NF-κB and the inflammatory response during myocardial ischemia reperfusion injury in rats.

The aim of this study was to investigate the effect of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) on nuclear factor-kappa-binding (NF-κB) and the inflammatory response in rats with myocardial ischemia reperfusion injury (MI/RI). Sprague-Dawley rats were randomly divided into 7 groups, and the rat MI/RI model was established by the ligation of the left anterior descending for 30 minutes followed by ligation release for 1 hour. Areas of myocardial infarction were measured using Evans blue-2,3,5-Triphenyltetrazolium chloride (TTC) staining. Levels of malondialdehyde, glutathione peroxidase, and total superoxide dismutase were assessed. Release of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-10 (IL-10) was measured by means of an enzyme-linked immunosorbent assay. NF-κBp65 and intercellular adhesion molecule-1 protein expression and caspase-3 and adenine nucleotide translocator-1 messenger RNA expression were evaluated by immunohistochemistry and reverse transcription polymerase chain reaction, respectively. Pretreatment with MHBFC decreased the infarction areas, the malondialdehyde, IL-1ß and IL-6 levels, the expression of caspase-3, NF-κBp65, and intercellular adhesion molecule-1. Further, MHBFC increased total superoxide dismutase and glutathione peroxidase activities, the release of IL-10, and the expression of adenine nucleotide translocator-1 messenger RNA compared with the results of the model group. The experiment showed that MHBFC protected the heart against MI/RI possibly by reducing lipid peroxidation damage while inhibiting the activity of NF-κBp65 and the inflammatory response.