Pathological Changes In Heart Research Articles

Da-Chuan-Xiong Decoction Ameliorates Sodium Sensitivity and Plasma Norepinephrine via Attenuation of Brain Oxidative Stress in the DOCA-Salt Hypertensive Rats.

Da-Chuan-Xiong Decoction (DCXD) is an aqueous extract from a classic Chinese herbal formula composed of dried rhizomes of Ligusticum chuanxiong Hort and Gastrodia elata Bl. in the mass ratio of 4 : 1. It has been long used to treat chronic cardiovascular disease caused by blood stasis and wind pathogen in the clinic. This experimental study aimed to investigate the blood pressure (BP)-lowering effect of DCXD treatment on hypertension and underlying mechanisms. Male Sprague-Dawley rats were used in the experiment, and the hypertensive models were created by administering deoxycorticosterone acetate (DOCA) in conjunction with a high salt intake in uninephrectomized rats. DCXD was administered to hypertensive rats by oral gavage daily at a dose of 5 g/kg or 2.5 g/kg bodyweight for 28 days. The brain sodium sensitivity, ENaC function, superoxide anion level, NADPH oxidase activity, and expression of ENaC, p67phox, p47phox, and Rac1 in the paraventricular nucleus were assessed by using the appropriate methods. The 28 days of DCXD (5 g/kg) treatment significantly reduced the increased BP effectively, inhibited the enhanced heart index, kidney index, and 24 h urinary protein, and improved the progressive pathological changes of heart and kidney, which was comparable to that of the positive control amlodipine. DCXD treatment also caused a marked reduction in plasma norepinephrine and induced a significant improvement in brain sodium sensitivity and ENaC function in DOCA-salt hypertensive rats. Rats in DCXD-treated groups also exhibited decreased superoxide anion levels and NADPH oxidase activity in the paraventricular nucleus. The level of ENaC, p67phox, and Rac1 protein expression in the paraventricular nucleus was significantly downregulated by DCXD treatment in DOCA-salt hypertensive rats. These findings indicate that the depressor action and sympathetic inhibition of DCXD on salt-sensitive hypertension may be by ameliorating brain sodium sensitivity, modulating ENaC function, and inhibiting the expression of ENaC and NADPH oxidase in the hypothalamic paraventricular nucleus.

Whole-transcriptome sequencing analysis reveal mechanisms of Yiqi Huoxue Yangyin (YHY) decoction in ameliorating D-gal-induced cardiac aging.

Aging is a major factor for cardiovascular disease, and cardiac aging is closely related to the incidence of cardiovascular disease. Clarifying the mechanism of cardiac aging and finding reliable intervention is critical for preventing cardiovascular diseases and achieving healthy longevity. Traditional Chinese medicine Yiqi Huoxue Yangyin (YHY) decoction has unique advantage in the treatment of cardiovascular disease and aging. However, the associated molecular mechanisms remain unknown. The present study aimed to verify the efficacy of YHY decoction against cardiac aging in D-gal-induced mouse model, and explore the potential mechanism of YHY decoction treatment through whole-transcriptome sequencing technique, providing novel insights into the molecular basis of YHY decoction in treating cardiac aging. The component of YHY decoction was identified by High Performance Liquid Chromatography (HPLC). D-gal-induced aging mouse model was established for this study. HE and Masson staining were applied to determine pathological changes of heart; telomere length, telomerase activity, AGEs and p53 were used to evaluate the degree of heart aging. Transcriptome sequencing, GO, KEGG, GSEA and ceRNA network were applied to analyze the potential mechanism of YHY decoction treatment of cardiac aging. In this study, we found that YHY decoction not only improved the pathological structure of aging heart, but also regulated the expression of aging-related markers, telomere length, telomerase activity, AGEs and p53, the myocardial tissue, suggesting that it has a specific effect in delaying cardiac aging. Whole-transcriptome sequencing showed that the total of 433 mRNAs, 284 lncRNAs, 62 miRNAs, and 39 circRNAs were significantly differentially expressed after YHY decoction treatment. According to the analysis results of KEGG and GSEA, the differentially expressed mRNAs were found significantly involved in immune system, cytokine-cytokine receptor interaction and cell adhesion molecules. The ceRNA network showed that miR-770, miR-324, and miR-365 are localized in center, mainly affecting the immune system, PI3K-Akt signaling pathway, and MAPK signaling pathway. In conclusion, our results evaluated the ceRNA network of YHY decoction in treating cardiac aging for the first time, which could provide better understanding of the potential mechanism of YHY decoction treatment of cardiac aging.

Histone deacetylase inhibitor panobinostat in combination with rapamycin confers enhanced efficacy against triple-negative breast cancer

Triple-negative breast cancer (TNBC) accounts for about 15% of diagnosed breast cancer patients, which has a poor survival outcome owing to a lack of effective therapies. This study aimed to explore the in vitro and in vivo efficiency of histone deacetylase (HDAC) inhibitor panobinostat (PANO) in combination with mTOR inhibitor rapamycin (RAPA) against TNBC. TNBC cells were treated with PANO, RAPA alone or the combination of drugs, then cell growth and apoptosis were evaluated by CCK-8, colony formation and flow cytometry. Cell migration and invasion were detected by wound healing assay and transwell assay, respectively. ROS production was detected by DCFH-DA staining. Western blotting was performed to detect protein levels. In vivo tumor growth was assessed in nude mice. The expression of cleaved caspase-3 and Ki-67 in tumor tissues was detected by immunofluorescence staining. H&E staining was conducted to observe the pathological changes in heart, liver, and kidney tissues. The combination of PANO and RAPA exerted a stronger role in repressing growth, migration, invasion, and inducing apoptosis of TNBC cells compared with monotherapy. Furthermore, this combination presented a more effective anti-cancer efficacy than a single treatment in the xenograft model without apparent toxic side effects. Importantly, mechanistic studies indicated that PANO and RAPA combination led to ROS overproduction, which subsequently activated endoplasmic reticulum stress. Conclusion: PANO in combination with RAPA exhibits enhanced efficacy against TNBC, which may be considered a promising therapeutic candidate.

EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation

BackgroundThe role of Diphenyldifluoroketone (EF24), a synthetic analogue of curcumin with noteworthy antitumor potential, remains unclear in non-small cell lung cancer (NSCLC). Herein, the inhibitory effect of EF24 on NSCLC and its mechanism were studied.MethodsCytotoxicity was measured by MTT assay, colony formation assay and xenograft model. Cell apoptosis and reactive oxygen species (ROS) level were quantified by flow cytometer. Protein level was detected by western blot assay. Mitochondria and autophagosomes were observed using transmission electron microscope and confocal microscopy.ResultsIn-vitro, EF24 significantly induced proliferation inhibition, apoptosis, mitochondrial fission and autophagy of NSCLC cell lines. These cytotoxic effects were significantly attenuated by two reactive oxygen species (ROS) scavengers, indicating its anti-cancer effects largely depend on ROS accumulation. In-vivo, EF24 inhibited tumor growth in a dose-dependent manner. Moreover, no pathological changes of heart, lung, spleen, kidney and liver of mice were observed. Collectively, EF24 induced ROS accumulation, in turn activates cell apoptosis, and then exerts its cytotoxicity on NSCLC cells.ConclusionsThe results showed that EF24 exerted cytotoxicity against NSCLC via ROS accumulation. Thus, EF24 might serve as a potential anti-cancer agent for the treatment of NSCLC.

Anthocyanins from purple sweet potato alleviate doxorubicin‐induced cardiotoxicity in vitro and in vivo

In this study, anthocyanins were extracted and purified from purple sweet potato anthocyanins (PSPA) and the alleviative effect of PSPA on doxorubicin (DOX)-induced cardiotoxicity was investigated. High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) results showed that 10 kinds of substances were identified in PSPA and the PSPA was mainly composed of cyanidin (62.9%) and peonidin (21.46%). In in vitro experiments, PSPA reduced the excessive release of inflammatory factors (NO and TNF-α) induced by DOX and decreased the secretion of trimethylamine oxide (TMAO), lactic dehydrogenase (LDH), and creatine kinase (CK) caused by myocardial injury. In in vivo experiments, PSPA inhibited the release of NO and MDA levels in heart tissue. Meanwhile, mice treated with PSPA decreased the levels of LDH, CK, TNF-α, and TMAO in serum and heart tissue when compared with the DOX group. In addition, the histopathological results of the heart tissue also showed a protective effect of PSPA on the pathological changes in heart. These results provide a reference for the application of PSPA as a functional food to intervene in DOX-induced cardiotoxicity. PRACTICAL APPLICATIONS: The effects of anthocyanins from purple sweet potato anthocyanins (PSPA) on doxorubicin (DOX)-induced cardiotoxicity were investigated in vitro and in vivo. The results indicated that PSPA could significantly ameliorate DOX-induced heart failure. The obtained results could provide the potential application of PSPA as an alternative therapy for cardiotoxicity caused by DOX in the functional food industry.

Biocompatibility Assessment Of DNR-Peg-PLL-PLGA Nanoparticles In Vitro and In Vivo

The present study was designed to evaluate the biocompatibility of DNR-PEG-PLL-PLGA as nanoparticles which provide the evidence before clinical application. We applied some tests to assess the safety of DNR-PEG-PLL-PLGA nanoparticles. There was low cytotoxicity of the PEG-PLL-PLGA nanoparticles in vitro when detected by the MTT assay. Cell apoptosis and intracellular accumulation of PEG-PLL-PLGA were determined by FCM assay. The apoptosis induced by nanoparticles and the fluorescence intensity of intracellular DNR demonstrated that DNR-PEG-PLL-PLGA could be taken up by L929 cells, in which DNR was persistently released. Hemolysis test and micronucleus (MN) assay were carried out to estimate the nanoparticles that they were no blood toxicity and no genotoxicity. DNR-PEG-PLL-PLGA nanoparticles were injected into mice through tail vein to calculate the median lethal dose (LD50), the results showed that they had a wide safe scale. The pathologic changes of heart, liver, spleen, lung and kidney were observed in nanoparticles treated mice. The influence of DNR-PEG-PLL-PLGA to mice hepatic and renal functions were measured by extracting the blood by retro orbital injection, they were no significant difference compared with the control group. These results clearly illustrated that DNR-PEG-PLL-PLGA appear to be highly biocompatible and safe nanoparticles that are suitable for further application in the treatment of tumor. Disclosures:No relevant conflicts of interest to declare.

Constructing Brain Aβ-Targeting Nanoparticles Loaded with EGCG for Treating Alzheimer's Disease in Mice

To construct a nanodelivery system surface-modified with RD2 peptide (polypeptide sequence PTLHTHNRRRRR) for brain tissue penetration and β-amyloid (Aβ) binding. Epigallocatechin-3-gallate (EGCG) was selected for encapsulation in the targeted delivery system and its therapeutic potential for Alzheimer's disease (AD) was investigated. EGCG-load nanoparticles (NP/EGCG), NP/EGCG with RD2 peptide surface modification (RD2-NP/EGCG), as well as RD2 peptide-modified blank nanoparticles (RD2-NP) were prepared and characterized. Thioflavin T assay was done to assess the ability of RD2-NP to bind with Aβ and ex vivo imaging was conducted to evaluate the distribution of RD2-NP in brain lesion sites. The AD mice model was established by injecting oligomeric Aβ 42 in the bilateral hippocampi of ICR mice. Then AD mice were administered intravenously through the tail vein with normal saline, EGCG solution, NP/EGCG or RD2-NP/EGCG for 28 d, respectively, and the Morris water maze tests were performed to assess the spatial memory of mice. Subsequently, RT-PCR method was used to determine the mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampus of the mice, and the morphological changes of hippocampal neurons were observed with Nissl staining. Additionally, the pathological changes of heart, liver, spleen, lung, and kidney were characterized by hematoxylin-eosin (HE) staining. The particle diameter of the prepared RD2-NP/EGCG was (204.83±2.80) nm and the zeta potential was -23.88 mV. The encapsulation efficiency and drug loading capacity were 94.39% and 5.90%, respectively. The RD2 peptide modification has no significant effect on the physiochemical properties of the nanoparticles. RD2-NP had good Aβ binding ability, and it could be concentrated in hippocampus and cerebral cortex, the most common Aβ deposition sites. The four-week RD2-NP/EGCG treatment significantly decreased the expression of the pro-inflammatory cytokine TNF-α and IL-1β, restored neuronal losses and hippocampal damage, and ameliorated spatial memory impairment in AD model mice. Moreover, treatment with the RD2-NP/EGCG did not present organ toxicity. Surface modified RD2 peptide nanodelivery system can efficiently deliver drugs to AD lesions and improve the therapeutic effect of EGCG on AD.

Scutellarin protects against diabetic cardiomyopathy via inhibiting oxidative stress and inflammatory response in mice.

Scutellarin (Scu) shows both anti-inflammatory and antioxidant activities. The study investigates cardioprotective effects of Scu in mice with type 1 diabetes and the underlying molecular mechanism. Streptozotocin (STZ) was used to induce diabetic cardiomyopathy (DCM) in C57BL/6 mice by intraperitoneal injection (i.p.). Normal and diabetic mice were divided into 6 groups: control, diabetic model group (DM), DM + Scu (5 mg/kg), DM + Scu (10 mg/kg), DM + Scu (20 mg/kg), DM + pioglitazone (Pio) (10 mg/kg). Scu was administered to the mice intraperitoneally and Pio was administrated by oral. Mice in control and DM groups were simply treated normal saline. Four weeks later, myocardial function, myocardial fibrosis, the levels inflammatory factors and oxidative stress were detected. Scu improved cardiac function and reduced heart injury in diabetic mice, which was indicated by increasing Left ventricular (LV) end-diastolic volume (LVVd), fractional shortening (FS), and ejection fraction (EF) levels and decreased pathological changes of heart. Scu inhibited the level of myocardial fibrosis by reducing the release of inflammatory cytokines and increasing activities of antioxidant enzymes. Further study showed that Scu inhibited the activation of nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) and nuclear factor-kappa B (NF-κB) and activated phospho-protein kinase B (p-AKT), nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase (HO-1). Scu protects against DCM in STZ-induced diabetic mice by inhibiting oxidative stress and inflammatory responses and might be a potential therapeutic agent to treat DCM.

Acute toxicity of C60–Cis-Pt nanocomplex in vivo

Acute toxicity of noncovalent nanocomplex of C60 fullerene with Cisplatin (Cis-Pt) (the ratio of compounds C60:Cis-Pt by weight 1:1) in a dose progression (7.5 + 7.5, 15.0 + 15.0, 22.5 + 22.5, 30.0 + 30.0, 37.5 + 37.5, and 45.0 + 45.0 mg/kg) was investigated in mice of BALB/c line. Mice were injected with C60–Cis-Pt nanocomplex or free Cis-Pt at the same doses single intraperitoneally and observed for 14 days. A comparative study of the toxicity of free Cis-Pt and Cis-Pt at noncovalent complexation with C60 fullerene (C60–Cis-Pt nanocomplex) demonstrated halving the toxicity of C60–Cis-Pt nanocomplex in comparison with free Cis-Pt: LD50 (Cis-Pt) 15.6 ± 1.3 mg/kg vs LD50 (C60–Cis-Pt) 36.1 ± 2.8 mg/kg. The toxic effects of C60–Cis-Pt nanocomplex and free Cis-Pt were detected at doses 22.5 + 22.5 mg/kg and 15.0 mg/kg, respectively, and were accompanied by impaired mice behavior, decreased body weight and animal survival, hematotoxicity, and pathological changes in heart, liver, spleen, and kidneys. It was shown that C60 fullerene complexed with Cis-Pt prevented drug-induced decrease in animal survival, anemia, thrombocytosis, and leukopenia development, as well as inflammatory processes in spleen, heart, kidney, and liver. The obtained results indicate the prospects for using noncovalent nanocomplex C60–Cis-Pt in antitumor therapy at low therapeutic doses of Cis-Pt.

Sargassum fusiforme fucoidan modifies gut microbiota and intestinal metabolites during alleviation of hyperglycemia in type 2 diabetic mice.

Type 2 diabetic mellitus (T2DM) is a complicated metabolic disorder that is now considered as a major global public health problem. Fucoidan exhibits diverse biological activities, especially prevention of metabolic diseases. In this regard, we herein aimed to reveal the beneficial effect of Sargassum fusiforme fucoidan (SFF) on high-fat diet (HFD) and streptozotocin (STZ) induced T2DM mice. We noted that on the one hand, SFF significantly decreased fasting blood glucose, diet and water intake, and hyperlipidemia, while on the other hand, it improved glucose tolerance. Furthermore, SFF reduced epididymal fat deposition, attenuated the pathological changes in heart and liver tissues, and decreased oxidative stress in diabetic mice. To explore the underlying mechanisms of these ameliorative effects, the gut microbiota was analyzed. Notably, SFF highly enriched benign microbes including Bacteroides, Faecalibacterium and Blautia, as well as increased levels of (R)-carnitine and choline in the colon of diabetic mice. This may be a potential mechanism for alleviating T2DM, thus implying the benefits of SFF as an adjuvant agent for T2DM treatment. Taken together, this study demonstrated a promising application of fucoidan as one of the adjuvant agents for the management of T2DM in the future.

Safety research on treatment of cough reflex disorder after cerebral hemorrhage with crossing nape electroacupuncture in guinea pig

To observe the effect of crossing nape electroacupuncture(EA) on cough count (CCnt), cough incubation period and blood routine, liver function, renal function, myocardial enzymology, and heart, liver and kidney pathological structure in guinea pig with cough reflex disorder after cerebral hemorrhage, so as to evaluate the efficacy and safety of crossing nape EA in the treatment of cough reflex disorder after cerebral hemorrhage. A total of 160 male pure white guinea pigs were randomly divided into normal group, model group, acupuncture group, crossing nape EA group and nape EA group (n=32 in each group). These 5 groups were further divided into 1, 3, 7 and 14 d subgroups(n=8 in each subgroup). The model of cough reflex disorder after cerebral hemorrhage was established by injection of the guinea pigs' autoblood (50 μL) into the basal ganglia region confirmed by Longa's neurologic examination grading system(0-4 points). Acupuncture was applied to bilateral "Fengchi" (GB20) and "Yifeng" (SJ17) in the acupuncture group. In the crossing nape EA group, the positive pole of the needle is connected to SJ17, while the negative pole is connected to the opposite side of GB20(2 Hz, 0.5 mA). In the nape EA group, the positive pole of the needle is connected to SJ17, while the negative pole is connected to the same side of GB20(2 Hz, 0.5 mA). All treatments were applied 20 min each time, once a day. The changes of CCnt and cough incubation period were recorded by Buxco device. The changes of blood routine, liver function, kidney function, myocardial enzyme and other laboratory indexes were monitored by automatic analyzer instrument. The pathological changes of heart, liver and kidney of guinea pigs were observed by transmission electron microscopy. Compared with the normal group, the guinea pigs' neurological deficit scores in the model group were significantly increased at each time point (P<0.01). Compared with the model group, the neurological deficit scores of the acupuncture group, crossing nape EA group and nape EA group at 3 d, 7 d and 14 d all decreased (P<0.01, P<0.05). Following modeling, the CCnt at each time point in the model group was significantly reduced (P<0.01), and the cough latency was significantly prolonged (P<0.01). After interventions, the CCnts were increased and the incubation periods of cough were shortened (P<0.05, P<0.01) at 7 d and 14 d in the 3 intervention groups, and were superior in the crossing nape EA group than those of acupuncture group and nape EA group (P<0.05, P<0.01). The improvement degrees of these 2 indexes in the nape EA group at 14 d were better than those of the acupuncture group (P<0.05). There were no significant differences among the 3 groups in red blood cells counting, hemoglobin, myocardial enzymes, liver and kidney function (P>0.05). Compared with the normal group, the WBC counts in all the time points (except 1 d after operation) were significantly increased(P<0.01) in the model group. In comparison with the model group, the WBC counts at 3 d in crossing nape EA group, and at 7 d and 14 d in the 3 intervention groups decreased (P<0.01, P<0.05). Meanwhile, the WBC counts were lower in the crossing nape EA group at 7 d and 14 d than those of acupuncture group and nape EA group (P<0.05). The results of transmission electron microscopy showed that the histopathological structure of heart, liver and kidney of guinea pigs in each group had no significant changes. Crossing nape EA is safe and effective in the treatment of cough reflex disorder after cerebral hemorrhage in guinea pigs. In addition, guinea pigs will have an inflammatory response after cerebral hemorrhage, and crossing nape EA may have a certain anti-inflammatory effect.

A study of post mortem examination of heart in acute myocardial infraction

The prevalence of the ischemic heart diseases is increasing globally which is also associated with high prevalence as well mortality. Associated comorbidities like diabetes and hypertension increases the associated mortality and morbidity. Atherosclerosis of the coronaries and resultant narrowing of the lumen is the associated underlying cause. The aim of the present study was to study gross pathological changes in heart in case of acute MI as well as the sex preponderance of the disease and other related factors. In this prospective study, conducted at the tertiary care government hospital, 35 cases of sudden death subsequent to acute myocardial infraction were enrolled. This study was conducted during the period from April 2017 to July 2018. All the cases were studied for myocardial infraction and its underlying pathological changes in the myocardium as well as the blockade of coronary arteries.A total of 35 subjects (20 M, 15 F), the mean age of the subjects was 55.02 years whereas the maximum numbers of subjects were of 50-59 years of age. Majority of the subjects were found to follow sedentary lifestyle. 28 subjects showed grade 2 and 6 cases showed grade 3 blockade in the right coronary artery. In the left anterior descending artery: Out of 35 cases, 1 case showed grade 1 block, 25 cases showed grade 2 blockages and 9 cases showed grade 3 blocks. The examination of aorta showed in 2 cases grade 1 block, in 20 cases grade 2 block and in 13 cases grade 3 block. 8 cases showed hemorrhagic myocardium. It was concluded in the present study that the maximum incidence of MI was associated in the age group of 50-59 years and it is associated with sedentary lifestyle. Males were more commonly affected than females. Coronary atherosclerosis is one of the most common underlying cause, the right coronary being the commonest artery involved.

Specifics of the diagnosis and treatment of diabetic cardiomyopathy

A complex of pathological changes in heart that are caused by metabolic, vascular and electrolyte disorders during diabetes mellitus is called diabetic cardiomyopathy. The clinical pictures of this condition can be diverse — from an asymptomatic course to severe heart failure with shortness of breath, edema, cardialgia, acrocyanosis.

Defeat technical electric current (retrospective analysis of mortal cases)

Introduction. Daily in the world people perish as a result of action of electric current. Research of dyings as a result of elektrotravmi behaves to jurisdiction of medico-legal experts. It is known that the specific diagnostic signs of elektrotravmi is a presence on the body of man of electro-mark, which has proper morphological makro- and microscopic descriptions. Gistopatologichni changes in a skin at the action of electric current have a decision value at diagnostics of elektrotravmi, when external damages do not have specific. The purpose of work was a leadthrough of retrospective analysis of cases of mortal defeat by an electric current in a period from 2015 to 2018 Material and research methods. Material for research was the archived material of KZ «DOBSME»DOR», namely, acts of medico-legal researches of dyings as a result of defeat technical elektrostrumom in a period from 2015 to 2018 Age, floor, circumstances of event, presence and localization of electro-marks, information of microscopic research, studied at an analysis. Сonclusion. A defeat as reason of death an electric current meets mainly by chance among other reasons of violent death. But, without regard to rareness of elektrotravmi, there are cases, when absence of markers of defeat (electro-mark) at external research of dead body needs research of changes of internalss with the purpose of exposure of characteristic signs. An analysis of pathological changes of heart, as literary sources testify, can be an additional marker at a defeat an electric current.

Suppression of angiotensin II-induced pathological changes in heart and kidney by the caveolin-1 scaffolding domain peptide.

Dysregulation of the renin-angiotensin system leads to systemic hypertension and maladaptive fibrosis in various organs. We showed recently that myocardial fibrosis and the loss of cardiac function in mice with transverse aortic constriction (TAC) could be averted by treatment with the caveolin-1 scaffolding domain (CSD) peptide. Here, we used angiotensin II (AngII) infusion (2.1 mg/kg/day for 2 wk) in mice as a second model to confirm and extend our observations on the beneficial effects of CSD on heart and kidney disease. AngII caused cardiac hypertrophy (increased heart weight to body weight ratio (HW/BW) and cardiomyocyte cross-sectional area); fibrosis in heart and kidney (increased levels of collagen I and heat shock protein-47 (HSP47)); and vascular leakage (increased levels of IgG in heart and kidney). Echocardiograms of AngII-infused mice showed increased left ventricular posterior wall thickness (pWTh) and isovolumic relaxation time (IVRT), and decreased ejection fraction (EF), stroke volume (SV), and cardiac output (CO). CSD treatment (i.p. injections, 50 μg/mouse/day) of AngII-infused mice significantly suppressed all of these pathological changes in fibrosis, hypertrophy, vascular leakage, and ventricular function. AngII infusion increased β1 and β3 integrin levels and activated Pyk2 in both heart and kidney. These changes were also suppressed by CSD. Finally, bone marrow cell (BMC) isolated from AngII-infused mice showed hyper-migration toward SDF1. When AngII-infused mice were treated with CSD, BMC migration was reduced to the basal level observed in cells from control mice. Importantly, CSD did not affect the AngII-induced increase in blood pressure (BP), indicating that the beneficial effects of CSD were not mediated via normalization of BP. These results strongly indicate that CSD suppresses AngII-induced pathological changes in mice, suggesting that CSD can be developed as a treatment for patients with hypertension and pressure overload-induced heart failure.

Effect of long-term crotonaldehyde exposure on heart damage in male rats

Objective: To observe the effect of long term crotonaldehyde exposure on heart damage in male rats, and to explore the possible mechanism of toxic action. Methods: 24 specific pathogen free healthy male wistar rats were randomly divided into 4 groups with 6 rats in each group. Rats were treated with with 8.5, 4.5, 2.5 and 0.0 mg/kg body weight crotonaldehyde by gavage, once a day for consecutive 150 days. After the last treatment, they were anesthetized and collected blood samples by cardiac puncture. The heart was rapidly separated after cervical dislocation. The cardiac organ coefficient was calculated and the histopathology changes in heart were observed by HE staining. At the same time, the activities of creatine kinase (CK) , lactate dehydrogenase-L (LDH-L) in serum were determined by automatic biochemical analyzer. Moreover, the levels of cardiac troponin (cTnT) , Angiotensin Ⅱ (Ang Ⅱ) , Brain natriuretic peptide (BNP) , Aldosterone (ALD) and interleukin (IL) -6, 8, 1β, interferon (IFN) -γ and tumor necrosis factor (TNF) -α in heart were determined by enzyme linked immunosorbent assay. Results: At the 90d, 120 d, and 150 d exposure, compared with the control group, the body weight gain in 4.5 and 8.5 mg/kg groups were decreased. Moreover, the heart weight in 4.5 and 8.5 mg/kg groups, and heart coefficient in 8.5 mg/kg group were decreased (P<0.05) . With the increasing dosage of crotonaldehyde, the degree of pathological changes in the heart of exposed rats were aggravated. The major pathological changes of heart in 4.5 and 8.5 mg/kg groups could be summarized as lymphocyte infiltration, abnormal cardiac muscle fiber arrangements, necrosis and fibrous connective tissue hyperplasia. Compared with the control group, the serum CK activity in 4.5 mg/kg group, CK and LDH-L activitivies in 8.5 mg/kg group were increased (P<0.05) ; Compared with the control group, the levels of ALD and ANGII in the heart of 4.5 and 8.5 mg/kg groups were increased, BNP level were decreased, and cTNT level in 8.5 mg/kg group were increased (P<0.05) . Compared with the control group, the levels of IL-1β、IL-6、IL-8 in 4.5 mg/kg group and IL-1β、IL-6、IL-8、TNF-α、IFN-γ in 8.5 mg/kg group were increased (P<0.05) . Conclusion: Crotonaldehyde could up-regulate cardiac inflammatory cytokines and alter the balance ofangiotensin-aldosterone-brain natriuretic peptide causing heart damage.

Psoralen induced cell cycle arrest by modulating Wnt/\u03b2-catenin pathway in breast cancer cells

Psoralen could inhibit the proliferation of human breast cancer cells, however, the molecular mechanism was unclear. We evaluated the anti-proliferative effects of psoralen by MTT, plate colony formation assay and cell cycle analysis in MCF-7 and MDA-MB-231 cells. The effects of psoralen on activation of Wnt/β-catenin and the related target genes were examined by quantitative real-time PCR, western blotting and cell immunofluorescence. The tumor growth was conducted in BALB/c nude mice and the pathological changes of heart, liver and kidney were also observed. Our results demonstrate that psoralen significantly inhibited cell proliferation by inducing G0/G1 phase arrest in MCF-7 cells and G2/M phase arrest in MDA-MB-231 cells. The expression of Fra-1 was reduced and Axin2 was promoted both in MCF-7 and MDA-MB-231 cells after psoralen treatment. The cytoplasmic accumulation and nuclear translocation of β-catenin were significantly reduced by psoralen. Psoralen increased the levels of phospho-(Y142) β-catenin, while decreased the expression of total β-catenin and its downstream target Fra-1 in vitro and vivo. Moreover, psoralen didn’t cause any significant toxicity at the effective concentration. Overall, our results might provide theoretical basis for clinical application of psoralen in breast cancer.

Effects of Xin-Ji-Er-Kang on heart failure induced by myocardial infarction: Role of inflammation, oxidative stress and endothelial dysfunction

BackgroundXin-Ji-Er-Kang (XJEK) is a Chinese herbal formula, which has been reported to exert effective protection on cardiovascular diseases like hypertension and myocarditis. PurposeTo elucidate the protective effects of XJEK on heart failure (HF) induced by myocardial infarction (MI) through the amelioration of inflammation, oxidative stress (OS) and endothelial dysfunction(ED). Materials and methodsFifty-seven male KM mice were randomized into the following six groups (n = 9–10 for each): control group, model group, MI+XJEK low dose group(XJEKL) group, MI+XJEK middle dose group(XJEKM), MI+XJEK high dose group(XJEKH), and MI+fosinopril group (positive control group). After treatment for four weeks, electrocardiography (ECG) and haemodynamics were recorded. Serum and tissues were collected for further analysis. Endothelium-dependent relaxation induced by acetylcholine was assessed in isolated thoracic aorta ring experiment. Hematoxylin and eosin (HE) and Van Gieson (VG) staining were used to detect the pathological changes of heart and thoracic aorta. Colorimetric analysis was employed to determine serum nitric oxide level (NO), malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity. ELISA was used to detect serum B-type natriuretic peptide (BNP) and serum inflammatory cytokines, as well as endothelial NO synthetase (eNOS), angiotensinII (Ang II) and endothelin-1(ET-1) concentration in both serum and cardiac tissues. Immunohistochemistry and Western blotting (WB) were employed to detect eNOS and inflammatory cytokine expressions in cardiac tissues. ResultsXJEK administration markedly ameliorated cardiac dysfunction and abnormal ECG manifested by decreased weight/body weight (HW/BW) ratio, BNP and remedied hypertrophy of cardiomyocytes and deposition of collagen, which might be in part attributed to the increased SOD and decreased MDA in serum. Furthermore, XJEK administration improved ED with boosted eNOS activities in serum and cardiac tissues, as well as up-regulated NO levels in serum, down-regulated Ang II and ET-1 content in serum and cardiac tissues. Lastly, protein expression of pro-inflammation cytokines significantly decreased, and anti-inflammatory cytokine was significantly enhanced in serum and cardiac tissues compared to model group. ConclusionXJEK may exert beneficial effects on HF induced by MI in mice, and the underlying mechanism may be attributable to the amelioration of ED, anti-OS and anti-inflammation effects.

Antihyperlipidemic activity of Hridayarnava Rasa (an Ayurvedic herbo-metalo-mineral formulation) in Charles Foster albino rats

Background: Hyperlipidemia is modifiable risk factor for cardiovascular diseases, and its prevalence is alarmingly increased in India. Although many treatment modalities are effectively used in the conventional system, they have certain limitations and adverse effects. Ayurvedic metallic and herbo-mineral formulations are safely practiced in Indian subcontinent without any noticeable side effects. Hridayarnava Rasa is one such Ayurvedic herbo-metalo-mineral formulation containing Tamra Bhasma (incinerated copper) as an integral component that is being successfully prescribed in the management of lipid disorders. Materials and Methods: Tamra Bhasma is prepared with different Amritikarana methods which are said to eliminate all the blemishes from the end product and increases its therapeutic efficacy. The antihyperlipidemic activity of Hridayarnava Rasa prepared from Tamra Bhasma processed in Panchamrita (HRTBP) was carried out in Charles Foster albino rats having hyperlipidemia induced by high-fat diet. The parameters including body weight, organ weight, serum lipid profile, and histopathology of liver, heart, kidney, and aorta were studied. Results and Coclusion: Results revealed that HRTBP attenuated increased lipid profile and pathological changes in heart, liver, and kidney induced by administration of hyperlipidemic diet. Hridayarnava Rasa has shown mild antihyperlipidemic activity in experimental animals.Background: Hyperlipidemia is modifiable risk factor for cardiovascular diseases, and its prevalence is alarmingly increased in India. Although many treatment modalities are effectively used in the conventional system, they have certain limitations and adverse effects. Ayurvedic metallic and herbo-mineral formulations are safely practiced in Indian subcontinent without any noticeable side effects. Hridayarnava Rasa is one such Ayurvedic herbo-metalo-mineral formulation containing Tamra Bhasma (incinerated copper) as an integral component that is being successfully prescribed in the management of lipid disorders. Materials and Methods: Tamra Bhasma is prepared with different Amritikarana methods which are said to eliminate all the blemishes from the end product and increases its therapeutic efficacy. The antihyperlipidemic activity of Hridayarnava Rasa prepared from Tamra Bhasma processed in Panchamrita (HRTBP) was carried out in Charles Foster albino rats having hyperlipidemia induced by high-fat diet. The parameters including body weight, organ weight, serum lipid profile, and histopathology of liver, heart, kidney, and aorta were studied. Results and Coclusion: Results revealed that HRTBP attenuated increased lipid profile and pathological changes in heart, liver, and kidney induced by administration of hyperlipidemic diet. Hridayarnava Rasa has shown mild antihyperlipidemic activity in experimental animals.

Abstract P125: RNA Sequencing of Left-ventricular Tissue Highlights Novel Pathways Impacted by the Loss of miR-146b-5p in a Rat Model of Chronic Kidney Disease

Chronic kidney disease (CKD) mediates pathological changes in heart and vascular tissues, yet many molecular mechanisms by which renal injury directly affects cardiovascular pathology (CVD) are unknown. miRNAs are proposed to be powerful regulators of pathophysiological signaling networks; having the potential to radically change the landscape of mRNA transcript expression and protein abundance in the context of health and disease. We have profiled the expression of miRNAs in a rat model of CKD – the 5/6 nephrectomy (5/6Nx) – with the objective to identify miRNAs with strong effects on CKD-mediated CVD. One such miRNA, miR-146b-5p (miR-146b), is highly upregulated in 5/6Nx rats compared to sham-operated controls at 7-weeks post-5/6Nx in both the kidney (5.4 fold increase; p&lt;0.05) and the heart (1.6 fold increase, p&lt;0.05), a time-point at which we see maximal renal and cardiac pathology. To examine the effects of miR-146b upregulation in our model of CKD, we performed RNA sequencing on cardiac tissue at 7 weeks post-5/6Nx in both wild-type (WT) Sprague-Dawley (SD) rats and a unique CRISPR-Cas9-mediated miR-146b knockout strain (miR-146b -/- ) created on the SD background. Of 3,018 genes differentially regulated by more than 1.5-fold (absolute value) in miR-146b -/- vs. WT rats after 5/6Nx, 135 had significantly altered expression (adjusted p-value &lt;0.05). We filtered all differentially expressed genes through Ingenuity Pathway Analysis to identify affected signaling networks in miR-146b -/- vs. WT rats that correlate with observed pathological phenotypes. The expression pattern of differentially regulated genes in these networks indicates predicted activation of pathways that contribute to tissue fibrosis and mineralization, reactive oxygen species signaling, and the inflammatory and immune responses. These pathways are enriched with predicted miR-146b target genes and correlate closely with observed phenotypes in miR-146b -/- 5/6Nx rats; including increased renal fibrosis and mineralization of cardiovascular tissue, and the well-known role of miR-146b in negative feedback regulation of NFκB signaling. These preliminary analyses uncover unique networks of genes regulated by miR-146b that may contribute to CKD-mediated CVD.