Diet-Derived Advanced Glycation End Products (dAGEs) Induce Proinflammatory Cytokine Expression in Cardiac and Renal Tissues of Experimental Mice: Protective Effect of Curcumin.

The beneficial effect of curcumin (CU) on dietary AGEs (dAGEs) involves blocking the overexpression of proinflammatory cytokine genes in the heart and kidney tissues of experimental mice. The animals were divided into six groups (n = 6/group) and were fed a heat-exposed diet (dAGEs) with or without CU for 6 months. Their blood pressure (BP) was monitored by a computerized tail-cuff BP-monitoring system. The mRNA and protein expression levels of proinflammatory genes were analyzed by RT-PCR and western blot, respectively. A marked increase in BP (108 ± 12 mmHg vs 149 ± 15 mmHg) accompanied by a marked increase in the heart and kidney weight ratio was noted in the dAGE-fed mice. Furthermore, the plasma levels of proinflammatory molecules (C5a, ICAM-1, IL-6, MCP-1, IL-1ß and TNF-α) were found to be elevated (3-fold) in dAGE-fed mice. mRNA expression analysis revealed a significant increase in the expression levels of inflammatory markers (Cox-2, iNOS, and NF-κB) (3-fold) in cardiac and renal tissues of dAGE-fed mice. Moreover, increased expression of RAGE and downregulation of AGER-1 (p < 0.001) were noticed in the heart and kidney tissues of dAGE-fed mice. Interestingly, the dAGE-induced proinflammatory genes and inflammatory responses were neutralized upon cotreatment with CU. The present study demonstrates that dietary supplementation with CU has the ability to neutralize dAGE-induced adverse effects and alleviate proinflammatory gene expression in the heart and kidney tissues of experimental mice.

Analysis of L-arginine:glycine amidinotransferase-, creatine- and homoarginine-dependent gene regulation in the murine heart.

L-arginine:glycine amidinotransferase (AGAT) and its metabolites creatine and homoarginine (HA) have been linked to cardiovascular pathologies in both human and murine studies, but the underlying molecular mechanisms are poorly understood. Here, we report the first analysis of heart transcriptome variation using microarrays in an AGAT-deficient (AGAT-/-) mouse model to evaluate AGAT-, creatine- and HA-dependent gene regulation. Our data revealed significant differences of gene expression between AGAT-/- and wild-type (WT) mice, affecting cardiac energy metabolism (Fbp2, Ucp2), cardiac hypertrophy and fibrosis (Nppa, Ctgf), immune response (Fgl2), and the conduction system of the heart (Dsc2, Ehd4, Hcn2, Hcn4, Scn4a, Scn4b). All of these genes being expressed on WT level in creatine-supplemented mice. Using in silico analysis based on the GEO database we found that most of these candidate genes (Ctgf, Dsc2, Fbp2, Fgl2, Hcn2, Nppa)  revealed significant alterations in a WT mouse model of myocardial infarction underlining a pathophysiological relationship between AGAT metabolism and cardiovascular disease.

Electroacupuncture preconditioning attenuates acute myocardial ischemia injury through inhibiting NLRP3 inflammasome activation in mice.

AIMS: Electro-acupuncture pretreatment (EAP) plays a protective role in myocardial ischemia (MI) injury. However, the underlying mechanism remains unclear. A growing body of evidence suggests postinfarction inflammatory response directly affects the remodeling of ventricular function. The purpose of this study was to investigate whether EAP alleviates MI through NLRP3 inflammasome inhibition. MATERIALS AND METHODS: We constructed an AMI model by ligating the left anterior descending (LAD) coronary artery after 3 days of EAP with C57BL/6 mice. Echocardiography and TTC staining were employed to evaluate cardiac function and infarct size after 24 h of ischemia. HE staining and immunohistochemistry were employed to determine inflammatory level. Then, inflammasome activation was detected by western blotting, and macrophage polarization and neutrophil infiltration were observed by flow cytometry. KEY FINDINGS: Our preliminary findings showed that EAP reduced the infarct area and increased fractional shortening (FS) and ejection fraction (EF) and decreased the degree of inflammation after AMI injury. Meanwhile, EAP inhibited the expression of NLRP3, cleaved caspase-1 and IL-1ß in ischemia myocardial tissue, companied by inhibiting the expression of F4/80+, CD11b+, CD206low macrophages and activated M2 macrophage, and decreasing Ly-6G+CD11b+ neutrophils in ischemia myocardial and spleen tissue. SIGNIFICANCE: EAP inhibits the activation of NLRP3 inflammasome, promotes M2 polarization of macrophages and reduces the recruitment of neutrophils in damaged myocardium, thereby decreases the infarct size and improves the cardiac function.

HPLC-DAD-ESI-QTOF-MS/MS profiling of Zygophyllum album roots extract and assessment of its cardioprotective effect against deltamethrin-induced myocardial injuries in rat, by suppression of oxidative stress-related inflammation and apoptosis via NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zygophyllum album is widely used to treat many cardiovascular diseases (CVDs) and as anti-inflammatory plant. AIM OF THE STUDY: This study aimed to investigate the mechanism of the potential protective effects of Zygophyllum album roots extract (ZARE) against myocardial damage and fibrosis induced by a chronic exposure to deltamethrin (DLM) in rats. MATERIALS AND METHODS: Bioactive compounds present in ZARE were analyzed by HPLC-DAD-ESI-QTOF-MS/MS. In vivo, DLM (4 mg/kg body weight), ZARE (400 mg/kg body weight) and DLM with ZARE were administered to rats orally for 60 days. Biochemical markers (LDH, ALT, CK, CK-MB and cTn-I) were assessed in the plasma by an auto-analyzer. Pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) were evaluated by a sandwich ELISA. NF-κB was quantified at mRNA levels by real time PCR. Heart tissue was used to determine cardiac oxidative stress markers (MDA, PC, SOD, CAT, and GPx). Masson's Trichrome (MT) and Sirius Red (SR) stainings were used for explored fibrosis statues. RESULTS: Phytochemical analysis using HPLC-DAD-ESI-QTOF-MS/MS revealed the presence of twenty six molecules including phenolic compounds and saponins. ZARE significantly improved the heart injury markers (LDH, ALT, CK, CK-MB and cTn-I), lipid peroxidation (MDA), protein oxidation (PC), antioxidant capacity (SOD, CAT, and GPx), and DNA structure, which were altered by DLM exposure. Moreover, ZARE cotreatment reduced the expressions of NF-κB, decreased plasmatic pro-inflammatory cytokines concentration (TNF-α, IL-1ß and IL-6), and suppressed the myocardial collagen deposition, as observed by Sirius Red and Masson's Trichrome staining. CONCLUSION: ZARE ameliorated the severity of DLM-induced myocardial injuries through improving the oxidative status and reducing profibrotic cytokines production. The ZARE actions could be mediated by downregulation of NF-κB mRNA.

Untargeted metabolomics reveals alterations in metabolites of lipid metabolism and immune pathways in the serum of rats after long-term oral administration of Amalaki rasayana.

Amalaki rasayana, a traditional preparation, is widely used by Ayurvedic physicians for the treatment of inflammatory conditions, cardiovascular diseases, and cancer. Metabolic alterations induced by Amalaki rasayana intervention are unknown. We investigated the modulations in serum metabolomic profiles in Wistar rats following long-term oral administration of Amalaki rasayana. Global metabolic profiling was performed of the serum of rats administered with either Amalaki rasayana (AR) or ghee + honey (GH) for 18 months and control animals which were left untreated. Amalaki rasayana components were confirmed from AR extract using HR-LCMS analysis. Significant reductions in prostaglandin J2, 11-dehydrothromboxane B2, and higher levels of reduced glutathione and glycitein metabolites were observed in the serum of AR administered rats compared to the control groups. Eleven different metabolites classified as phospholipids, glycerophospholipids, glucoside derivatives, organic acids, and glycosphingolipid were exclusively observed in the AR administered rats. Pathway analysis suggests that altered metabolites in AR administered rats are those associated with different biochemical pathways of arachidonic acid metabolism, fatty acid metabolism, leukotriene metabolism, G-protein mediated events, phospholipid metabolism, and the immune system. Targeted metabolomics confirmed the presence of gallic acid, ellagic acid, and arachidonic acid components in the AR extract. The known activities of these components can be correlated with the altered metabolic profile following long-term AR administration. AR also activates IGF1R-Akt-Foxo3 signaling axis in heart tissues of rats administered with AR. Our study identifies AR components that induce alterations in lipid metabolism and immune pathways in animals which consume AR for an extended period.

Network pharmacology based investigation of the effects of herbal ingredients on the immune dysfunction in heart disease.

Dysregulated immune system has been implicated in the pathogenesis of various cardiovascular diseases. Therefore, development of pharmacological interventions targeting the immune system is promising. However, therapy with most common anti-inflammatory and immunomodulatory agents has proved challenging in the clinical translation. It has been proved that many herbal ingredients display definite therapeutic effects on preventing excessive inflammatory and immune responses. Here, we aim to systemically explore the immunomodulatory ability of herbal ingredients on the human heart tissue-specific immune dysfunction through a network pharmacology based approach. The approach matches gene expression data between herbal ingredients and human heart phenotype based on their immunological similarities. Firstly, 608 immunological signatures were produced from 304 transcriptional profiles of immunological cell state changes. Then, the immunological features of 28 human heart phenotypes and 102 herbal ingredients were constructed by calculating the enrichments of each immune signature in the transcriptional profiles of heart phenotypes and herbal ingredients, respectively. Finally, the likelihood that an herbal drug affects the immune system in a heart phenotype was qualified by calculating the immunological similarity between the herbal drug and the heart phenotype. This strategy integrating different types of OMICs data is expected to help create new opportunities for development of drugs targeting the immune dysfunction in heart disease.

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

BACKGROUND: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated. METHODS: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI. RESULTS: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate. CONCLUSIONS: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.

Maoberry (Antidesma bunius) ameliorates oxidative stress and inflammation in cardiac tissues of rats fed a high-fat diet.

BACKGOUND: Chronic fat-rich diets consumption is increased risk associated with cardiovascular diseases (CVD). Prevention or reduction the progression of cardiac tissue deterioration could benefit in CVD. This study aimed to examine the effects of maoberry (Antidesma bunius), a antioxidant-rich tropical fruit, supplementation on oxidative stress and inflammation in cardiac tissues of rats fed a high-fat diet (HFD). METHODS: The male rats orally received HFD with maoberry extract doses of 0.38, 0.76 or 1.52 g/kg or simvastatin (10 mg/kg) for 12 weeks. At the end of the experimental period, the rats were fasted, euthanized and harvested for the hearts. RESULTS: Significantly reduced oxidative stress (malondialdehyde levels) and enhanced antioxidant capacity (ferric-reducing activities) in cardiac tissues of the rats were found. Maoberry extract remarkably ameliorated the expressions of genes involved with pro-inflammatory such as the tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and endothelial nitric oxide synthase (eNOS). CONCLUSIONS: Our findings suggest that maoberry extract has remarkable effects on preventing progression of cardiac tissue deterioration at least through lowering oxidative stress and inflammation.

Sodium tanshinone IIA sulfonate attenuates cardiac dysfunction and improves survival of rats with cecal ligation and puncture-induced sepsis.

Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg-1), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.

Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium.

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg-1·wk-1), and the second group was injected with 7.5 mg·kg-1·wk-1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD2, PGE2, and 6-keto-PG2α) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169+ metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169+ cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.

Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis.

Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.

Induction of Regulatory CD4+ Cells and Prolongation of Fully Major Histocompatibility Complex Mismatched Murine Cardiac Allograft by Shigyakusan.

Shigyakusan (also known as Tsumura Japan [TJ]-35) is composed of peony, bitter orange, licorice, and Bupleuri radix is used for cholecystitis and gastritis as an anti-inflammatory agent. We investigated the effect of TJ-35 on alloimmune response in a murine heart transplantation model. CBA mice that underwent transplantation of a C57BL/6 (B6) heart were assigned to four groups: no treatment, TJ-35-exposed, each component-exposed, or each component missing-exposed. The four groups above each received oral administration of TJ-35, each component, or TJ-35 with each component missing from the day of transplantation until 7 days, respectively. Untreated CBA recipients rejected B6 cardiac grafts acutely (median survival time [MST], 7 days). TJ-35-exposed CBA recipients had significantly prolonged B6 allograft survival (MST, 20.5 days). However, MSTs of CBA recipients that had been administered each component and TJ-35 with each component missing did not reach that of TJ-35-exposed recipients. Adoptive transfer of CD4+ splenocytes from TJ-35-exposed primary allograft recipients resulted in significant prolonged allograft survival in naïve secondary recipients (MST, 63 days). Flow cytometry studies showed that the percentage of CD4+CD25+Foxp3+ cell population was increased in TJ-35-exposed CBA recipients. In conclusion, TJ-35-induced prolongation of fully allogeneic cardiac allografts and may generate regulatory CD4+CD25+Foxp3+ cells in our model. The effect seemed to require all components of TJ-35.

The Falconoid Luteolin Mitigates the Myocardial Inflammatory Response Induced by High-Carbohydrate/High-Fat Diet in Wistar Rats.

Luteolin is a major component of many medicinal plants and traditional medicines. The current study aims at testing its protective effect against high-carbohydrate/high-fat (HCHF) diet-induced cardiac dysfunction in rats. Male Wistar rats were divided into six groups as follows: control group that received standard rat chow, group received HCHF diet (~ 30% carbohydrate and 42% fat) daily for 16 weeks, and four groups received HCHF diet concurrently with luteolin (10, 25, 50 or 100 mg/kg; 10% w/v suspension in 0.9% NaCl) daily from the first week by oral gavage. Body weight was measured weekly. At the end of the study, histopathological examinations of stained heart sections were carried out. Lipid profile, oxidative stress, and cardiac function biomarkers were measured. Furthermore, neurohumoral mediators and inflammatory cytokines (TNF-α, IL-18) were assigned. Results showed a significant improvement in cardiac function, tissue integrity, and a decrease in the compensatory neurohumoral mediators by luteolin 50 and 100 mg/kg. In addition, a significant (P < 0.05) decrease in collagen deposition, fibrosis percentage, lipid peroxidation, and inflammatory cells (macrophages and lymphocytes) infiltration was observed. Tested doses of luteolin decreased lipid peroxidation and elevated the endogenous antioxidant biomarkers (reduced glutathione and superoxide dismutase) significantly (P < 0.05). Finally, luteolin decreased TNF-α and IL-18 (P < 0.001) in a dose-dependent manner. It can be concluded that luteolin has a cardioprotective effect against HCHF diet-induced myocardial inflammation through antioxidant anti-inflammatory mechanisms.

Hypolipidemic and cardioprotective effects of Ulva lactuca ethanolic extract in hypercholesterolemic mice.

CONTEXT: Hypercholesterolemia has significant cardiac consequences, since it is among the major risk factors of ischemic heart diseases. OBJECTIVE: The aim was searching the cardioprotective effect of chemical constituents from the sea lettuce Ulva lactuca upon hypercholesterolemic regime in mice. MATERIAL AND METHODS: Mice were randomly divided into three groups: untreated group, hypercholesterolemic group, and mice receiving 1% cholesterol associated with U. lactuca ethanolic extract. RESULTS: In vitro study demonstrated that algal extract has antioxidant efficacy attributable to the presence of phenolic compounds. Additionally, the alga alleviated cardiotoxicity, as shown by the improvement of haematological parameters, white cell viability, heart oxidative stress, plasma biochemical parameters and index of atherogenesis. Gene expression of the proinflammatory cytokines TNF-α, IL-1ß and IL-6 significantly decreased in the heart of U. lactuca supplemented hypercholesterolemic animals. CONCLUSION: It was established that the green alga, thanks to its bioactive compounds, effectively counteracts cardiotoxic effects of hypercholesterolemic regime.

Phosphorus protects cardiac tissue by modifying the immune response in rats infected by Trypanosoma cruzi.

AIM: This study evaluates and correlates the number of myocarditis focuses and production of cytokines in Rattus norvegicus (Wistar lineage), experimentally infected with T. Cruzi and treated with Phosphorus. METHODS: In two blind, controlled and randomized trials, 53 45-day-old, male animals were allocated into groups Control (n=24): Control group infected and treated with 7% hydroalcoholic solution, the preparation vehicle of the test medication; and Phosphorus (n=24 on days 0, 5, 10 and 24 after infection): group infected and treated with Phosphorus 13cH, diluted 10-26 and dynamized (test medication). The animals were inoculated intraperitoneally with 5×106 blood trypomastigotes of T. cruzi-Y strain. The medication was administered overnight (16 consecutive hours), diluted in water (1mL/100mL) in amber water bottles. The animals were treated 2days before and 2, 4, and 6days after infection. Enumeration of inflammatory foci in cardiac tissue (Hematoxylin-Eosin) and dosage of cytokines TNF-α and IFN-γ in the serum were performed on days 0, 5, 10 and 24 after infection, using three animals/group. Mann-Whitney, Friedman ANOVA, Spearman correlation (p<0.05), and Statistica Single User Software version 13.2 were used for data analysis. RESULTS: The animals treated with Phosphorus 13cH had high concentration of INF-É£ on the 5th day of infection with significant decrease on the 10th and 24th days (p<0.05), and high concentration of TNF-α on the 5th and 10th days of infection with decrease on the 24th day (p<0.05). The treatment with Phosphorus caused a significant increase of INF-É£ and TNF-α on the 5th day of infection compared with the Control (p<0.05), with reestablishment on the 24th day, as well as in the Control group. The group treated with Phosphorus had 52.5% less number of myocarditis focuses in heart than Control group (p<0.05) on the 10th day of infection. The significant increase in cytokines on the5th day of infection in the Phosphorus group is related to a significant decrease in the number of inflammatory foci in cardiac tissue on the 10th day of infection in this group. DISCUSSION AND CONCLUSION: Treatment with Phosphorus 13cH promotes beneficial effects in T. cruzi infection in Wistar rats by modulating the secretion of IFN-γ and TNF-α with decreased inflammation in cardiac tissue. These results reinforce the importance of considering the use of homeopathy for establishing new therapeutic approaches in the management of patients with Chagas disease.

Curcumin as a potential protective compound against cardiac diseases.

Curcumin, which was first used 3000 years ago as an anti-inflammatory agent, is a well-known bioactive compound derived from the active ingredient of turmeric (Curcuma longa). Previous research has demonstrated that curcumin has immense therapeutic potential in a variety of diseases via anti-oxidative, anti-apoptotic, and anti-inflammatory pathways. Cardiac diseases are the leading cause of mortality worldwide and cause considerable harm to human beings. Numerous studies have suggested that curcumin exerts a protective role in the human body whereas its actions in cardiac diseases remain elusive and poorly understood. On the basis of the current evidence, we first give a brief introduction of cardiac diseases and curcumin, especially regarding the effects of curcumin in embryonic heart development. Secondly, we analyze the basic roles of curcumin in pathways that are dysregulated in cardiac diseases, including oxidative stress, apoptosis, and inflammation. Thirdly, actions of curcumin in different cardiac diseases will be discussed, as will relevant clinical trials. Eventually, we would like to discuss the existing controversial opinions and provide a detailed analysis followed by the remaining obstacles, advancement, and further prospects of the clinical application of curcumin. The information compiled here may serve as a comprehensive reference of the protective effects of curcumin in the heart, which is significant to the further research and design of curcumin analogs as therapeutic options for cardiac diseases.

Inflammatory Cell Findings in the Female Rabbit Heart and Stress-associated Exacerbation with Handling and Procedures Used in Nonclinical Studies.

Despite the use of rabbits in biomedical research, including regulatory toxicology and cardiovascular studies, little data exist on heart findings in this species. This study was designed to document myocardial findings in female rabbits and the impact of study-related procedures typical for vaccine toxicology studies. One hundred and forty 6- to 8-month-old female New Zealand White rabbits were divided equally into 2 groups, high and low study procedure groups (group 1 and group 2, respectively). All animals received intramuscular (IM) injections of sterile saline every 2 weeks for 5 times and were necropsied 2 days after the final IM injection. Clinical chemistry, hematology, and urinalysis were evaluated. Blood for stress biomarkers (norepinephrine, epinephrine, cortisol, and corticosterone), C-reactive protein, cardiac troponin I, and creatine kinase were collected at time 0 (just before dose administration) and then at 4, 24, and 48 hr after dose administration in group 1 only. Hearts were assessed histologically. Focal to multifocal minimal inflammatory cell infiltrates were common (∼80%), particularly in the left ventricle and interventricular septum, and were similar to the types of infiltrates identified in other laboratory animal species. Additionally, study-related procedures elevated serum stress biomarkers and exacerbated the frequency and severity of myocardial inflammatory cell infiltrates.

New Knowledge About Old Drugs: The Anti-Inflammatory Properties of Cardiac Glycosides.

In the 19th century, cardio-active steroid glycosides, shortly cardiac glycosides, were scientifically established as drugs against heart failure. Their in vivo, cellular, and molecular actions as well as their predominant target, Na+-K+-ATPase, have been comprehensively investigated in the 20th century and the discovery of endogenous cardiac glycosides has fostered this research field. In the last years, however, results from clinical trials and meta-analyses have questioned their therapeutic value due to efficacy and safety issues. This has led to a considerable decline of their usage. Beyond the cardiovascular system, cardiac glycosides have been increasingly recognized as antitumor compounds and Na+-K+-ATPase has evolved into a promising drug target in oncology. A wealth of review articles exists that intensively discuss these topics. Surprisingly, the anti-inflammatory actions of cardiac glycosides, which were discovered in the 1960s, have so far hardly been perceived and have not yet been summarized. This review provides an overview of the in vivo and in vitro actions of cardiac glycosides on inflammatory processes and of the signaling mechanisms responsible for these effects: cardiac glycosides have been found to decrease inflammatory symptoms in different animal models of acute and chronic inflammation. Regarding the underlying mechanisms most research has focused on leukocytes. In these cells, cardiac glycosides primarily inhibit cell proliferation and the secretion of proinflammatory cytokines.

Triptolide attenuates pressure overload-induced myocardial remodeling in mice via the inhibition of NLRP3 inflammasome expression.

Triptolide is the predominant active component of the Chinese herb Tripterygium wilfordii Hook F (TwHF) that has been widely used to treat several chronic inflammatory diseases due to its immunosuppressive, anti-inflammatory, and anti-proliferative properties. In the present study, we elucidated the cardioprotective effects of triptolide against cardiac dysfunction and myocardial remodeling in chronic pressure-overloaded hearts. Furthermore, the potential mechanisms of triptolide were investigated. For this purpose, C57/BL6 mice were anesthetized and subjected to transverse aortic constriction (TAC) or sham operation. Six weeks after the operation, all mice were randomly divided into 4 groups: sham-operated with vehicle group, TAC with vehicle group, and TAC with triptolide (20 or 100 µg/kg/day intraperitoneal injection) groups. Our data showed that the levels of NLRP3 inflammasome were significantly increased in the TAC group and were associated with increased inflammatory mediators and profibrotic factor production, resulting in myocardial fibrosis, cardiomyocyte hypertrophy, and impaired cardiac function. Triptolide treatment attenuated TAC-induced myocardial remodeling, improved cardiac diastolic and systolic function, inhibited the NLRP3 inflammasome and downstream inflammatory mediators (IL-1ß, IL-18, MCP-1, VCAM-1), activated the profibrotic TGF-ß1 pathway, and suppressed macrophage infiltration in a dose-dependent manner. Our study demonstrated that the protective effect of triptolide against pressure overload in the heart may act by inhibiting the NLRP3 inflammasome-induced inflammatory response and activating the profibrotic pathway.

Caffeoylquinic Acid Derivatives Extract of Erigeron multiradiatus Alleviated Acute Myocardial Ischemia Reperfusion Injury in Rats through Inhibiting NF-KappaB and JNK Activations.

Erigeron multiradiatus (Lindl.) Benth. has been used in Tibet folk medicine to treat various inflammatory diseases. The aim of this study was to investigate antimyocardial ischemia and reperfusion (I/R) injury effect of caffeoylquinic acids derivatives of E. multiradiatus (AE) in vivo and to explain underling mechanism. AE was prepared using the whole plant of E. multiradiatus and contents of 6 caffeoylquinic acids determined through HPLC analysis. Myocardial I/R was induced by left anterior descending coronary artery occlusion for 30 minutes followed by 24 hours of reperfusion in rats. AE administration (10, 20, and 40 mg/kg) inhibited I/R-induced injury as indicated by decreasing myocardial infarct size, reducing of CK and LDH activities, and preventing ST-segment depression in dose-dependent manner. AE decreased cardiac tissue levels of proinflammatory factors TNF-α and IL-6 and attenuated leukocytes infiltration. AE was further demonstrated to significantly inhibit I-κB degradation, nuclear translocation of p-65 and phosphorylation of JNK. Our results suggested that cardioprotective effect of AE could be due to suppressing myocardial inflammatory response and blocking NF-κB and JNK activation pathway. Thus, caffeoylquinic acids might be the active compounds in E. multiradiatus on myocardial ischemia and be a potential natural drug for treating myocardial I/R injury.