A novel glycopeptide from mountain-cultivated ginseng residue protects type 2 diabetic symptoms-induced heart failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Mountain-cultivated Panax ginseng C.A.Mey. (MCG) with high market price and various properties was valuable special local product in Northeast of Asia. MCG has been historically used to mitigate heart failure (HF) for thousand years, HF is a clinical manifestation of deficiency of "heart-qi" in traditional Chinese medicine. However, there was little report focus on the activities of extracted residue of MCG. AIM OF THE STUDY: A novel glycopeptide (APMCG-1) was isolated from step ethanol precipitations of alkaline protease-assisted extract from MCG residue. MATERIALS AND METHODS: The molecular weight and subunit structure of APMCG-1 were determined by FT-IR, HPLC and GPC technologies, as well as the H9c2 cells, Tg (kdrl:EGFP) zebrafish were performed to evaluated the protective effect of APMCG-1. RESULTS: APMCG-1 was identified as a glycopeptide containing seven monosaccharides and seven amino acids via O-lined bonds. Further, in vitro, APMCG-1 significantly decreased reactive oxygen species production and lactate dehydrogenase contents in palmitic acid (PA)-induced H9c2 cells. APMCG-1 also attenuated endoplasmic reticulum stress and mitochondria-mediated apoptosis in H9c2 cells via the PI3K/AKT signaling pathway. More importantly, APMCG-1 reduced the blood glucose, lipid contents, the levels of heart injury, oxidative stress and inflammation of 5 days post fertilization Tg (kdrl:EGFP) zebrafish with type 2 diabetic symptoms in vivo. CONCLUSIONS: APMCG-1 protects PA-induced H9c2 cells while reducing cardiac dysfunction in zebrafish with type 2 diabetic symptoms. The present study provides a new insight into the development of natural glycopeptides as heart-related drug therapies.

A class of geranylquinol-derived polycyclic meroterpenoids from Arnebia euchroma against heart failure by reducing excessive autophagy and apoptosis in cardiomyocytes.

Ten new B-ring aromatized 6/6/6-tricyclic dearomatized benzocogeijerene-based meroterpenoids with unusual methyl 1,2-shift or demethylation (2-9b), and two new geranylquinol derivatives (1 and 10), together with two known compounds (11 and 12), were isolated from the roots of Arnebia euchroma. Their structures were elucidated by extensive spectroscopic methods, X-ray diffraction crystallography, and ECD calculations. The plausible biosynthetic pathways including the unusual methyl 1,2-shfit and demethylation for B-ring aromatized 6/6/6-tricyclic meroterpenoids were discussed. Compounds 1, 2, 5, 6, 11, and 12 showed significant cardioprotective activities comparable to diltiazem against isoprenaline (ISO)-induced H9C2 cell damage in vitro. Compound 11 probably exerted heart-protective effect on ISO-induced H9C2 cells by modulating the PI3K-AKT-mTOR pathway, reducing excessive autophagy, and decreasing myocardial apoptosis.

Chemical components with biological activities in the roots of Ilex pubescens.

Two new triterpenoids, ilexsaponin U (1) and ilexsaponin V (2), and three new phenylpropanoids, pubescenoside S (3), pubescenoside T (38), and pubescenoside U (39), along with thirty-four existing compounds were isolated from the roots of Ilex pubescens. The elucidation of their structures involved comprehensive spectroscopic techniques, including IR, UV, HR-ESI-MS, and NMR experiments. The anti-inflammatory effects of almost all the compounds were evaluated in LPS-induced RAW264.7 cells. Among these, compounds 1, 4, 8, 11, 12, 26, 27, 29 and 33 exhibited varying degrees of inhibition of inflammatory factors. Notably, compounds 1, 4 and 8 significantly inhibited the mRNA levels of iNOS, IL-6, IL-1ß and TNFα, comparable to or exceeding the effect of the positive control (dexamethasone, DEX). We also evaluated the cardioprotective effects of these compounds in OGD/R-induced H9c2 cells. The results revealed that compounds 2, 3, 7, 8, 26, 35, 36 and 37 at 20 µM significantly increased cell viability by 24.9 ± 3.4%, 28.0 ± 0.3%, 37.6 ± 0.2%, 44.86 ± 0.5%, 9.47 ± 2.1%, 23.9 ± 0.4%, 39.5 ± 3.1% and 28.2 ± 0.1%, respectively. Some of them exhibited effects equal to or greater than that of the positive control (diazoxide, DZ) at 100 µM, showing a 21.9 ± 3.0% increase.

Atranones and dolabellanes with cardiomyocyte protective activity against cold ischemic injury from a coral-associated fungus Stachybotrys chartarum.

Five undescribed atranones, namely atranones V-Z (1-5), three undescribed dolabellane-type diterpenoids, namely stachatranones D-F (7-9), together with four known congeners (6 and 10-12), were obtained from a coral-associated strain of the toxigenic fungus Stachybotrys chartarum. Their structures were elucidated via extensive spectroscopic analyses, mainly including the HRESIMS and NMR data, single-crystal X-ray diffraction analysis, electronic circular dichroism calculation, and [Mo2(OAc)4] induced circular dichroism spectrum. The cardiomyocyte protective activity assay revealed that compound 9 significantly ameliorated cold ischemic injury at 24 h post cold ischemia (CI) in a dose-dependent manner. Moreover, compound 9 prevented CI induced dephosphorylation of phosphatidylinositol-3-kinase and RAC-α serine/threonine-protein kinase at 12 h post CI in a dose-dependent manner. In this work, the undescribed compound 9 could significantly protect cardiomyocytes against cold ischemic injury, highlighting the promising potential to be designed and developed as a novel cardioprotectant in heart transplant medicine.

Cardioprotective effects of the aqueous extract of Echinops cephalotes on myocardial ischemia-reperfusion in rats by modulation of MMP-2, MMP-9, TIMP, and oxidative stress.

Echinops plants have received great attention for the treatment of many diseases due to pharmacological properties such as their antidiabetic, antioxidant, and anti-inflammatory characteristics. The major purpose of the present study was to investigate the cardioprotective benefits of Echinops cephalotes (Ech) against myocardial ischemia-reperfusion (MI/R) injury. Male Wistar rats were randomly allocated to three groups: sham, MI, and MI + Ech. The left coronary artery (LAD) was blocked for 30 minutes to induce MI. In the treatment group, rats were given 150 mg/kg/day of Ech extract for 28 days. Aqueous extracts were made from Echinops plants. To study heart function, fibrosis, cardiac damage indicators, and oxidative stress factors, echocardiography, Masson's trichrome staining, and biochemical tests were used. The expression of matrix metalloproteinase 2 and 9 (MMP2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP) was determined using Western blotting. Tissue damage was assessed using hematoxylin and eosin staining. MI group exhibited significantly reduced ejection fraction (EF) and fractional shortening (FS), enhanced levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), cardiac Troponin I (cTnI), and malondialdehyde (MDA), as well as a decrease in the Glutathione (GSH) tissue content, reduced activity of superoxide dismutase (SOD), increasing fibrosis, upregulations of MMP-2 and MMP-9, and reduction of TIMP compared to the sham group. The findings suggest that Ech in particular, could be a promising therapeutic agent to reduce the damage in MI by targeting oxidative stress and modulating the activities of matrix metalloproteinases and their tissue inhibitors.

Exploring the effective components of honey-processed licorice (Glycyrrhiza uralensis Fisch.) in attenuating Doxorubicin-induced myocardial cytotoxicity by combining network pharmacology and in vitro experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is widely used clinically as one of the most famous traditional Chinese herbs. Its herb roasted with honey is called honey-processed licorice (HPL). Modern studies have shown that HPL has a stronger cardioprotective ability compared to raw licorice (RL), however the material basis and mechanism of action of the potential cardioprotection have not been fully elucidated. AIM OF THE STUDY: To screen and validate the material basis of cardioprotection exerted by HPL and to preliminarily predict the potential mechanism of action. MATERIALS AND METHODS: UPLC-QTOF-MS/MS was used to analyze HPL samples with different processing levels, and differential compounds were screened out through principal component analysis. Network pharmacology and molecular docking were applied to explore the association between differential compounds and doxorubicin cardiomyopathy and their mechanisms of action were predicted. An in vitro model was established to verify the cardioprotective effects of differential compounds. RESULTS: Six differential compounds were screened as key components of HPL for potential cardioprotection. Based on network pharmacology, 113 potential important targets for the treatment of Dox-induced cardiotoxicity were screened. KEGG enrichment analysis predicted that the PI3K-Akt pathway was closely related to the mechanism of action of active ingredients. Molecular docking results showed that the six differential compounds all had good binding activity with Nrf2 protein. In addition, in vitro experiments had shown that five of the active ingredients (liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, and licochalcone A) can significantly increase Dox-induced H9c2 cell viability, SOD activity, and mitochondrial membrane potential, significantly reduces MDA levels and inhibits ROS generation. CONCLUSION: Liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin and licochalcone A are key components of HPL with potential cardioprotective capabilities. Five active ingredients can alleviate Dox-induced cardiotoxicity by inhibiting oxidative stress and mitochondrial damage.

Ethanol extracts of Rhaponticum uniflorum (L.) DC flowers attenuate doxorubicin-induced cardiotoxicity via alleviating apoptosis and regulating mitochondrial dynamics in H9c2 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Loulu flowers (LLF) is the inflorescence of Rhaponticum uniflorum (L.) DC. (R. uniflorum), a member of the Compositae family. This plant possesses heat-clearing properties, detoxification effects, and is therefore frequently used for the treatment of cardiovascular diseases. AIM OF THIS STUDY: This study aimed to investigate the cardioprotective effects of ethanol extracts of LLF against doxorubicin (DOX)-induced cardiotoxicity and explore the associated mechanisms. MATERIAL AND METHODS: Ethanol extracts of LLF were prepared and analyzed by LC-ESI-MS/MS. DOX-treated H9c2 cells and DOX-treated zebrafish models were used to explore the cardioprotective effect of ethanol extracts on myocardial function. The effects of LLF on DOX-induced cytotoxicity in H9c2 cells were investigated by MTT assay. Reactive Oxygen Species (ROS) levels, mitochondrial membrane potential (MMP), and nuclear translocation of NF-κB p65 were examined using fluorescent probes. The expression level of Bax, Bcl-2, PARP, caspase-3, cleaved-caspase3, caspase9, IκBα, p-IκBα, IKK, p-IKK, p65, p-p65, OPA1, Mfn1, MFF and Fis 1 and GAPDH was determined by western blotting. RESULTS: Twenty-five compounds were detected in ethanol extracts of LLF, include Nicotinamide, Coumarin, Parthenolide, and Ligustilide. Pre-treatment with LLF attenuated the DOX-induced decrease in viability and ROS production in H9c2 cells. Moreover, LLF treatment maintained the mitochondrial membrane integrity and suppressed apoptosis by upregulating expression level of Bcl-2 and downregulating the expression level of Bax, cleaved-caspase-3, cleaved-caspase-9 and cleaved-PARP. In addition, LLF significantly inhibited the DOX-induced activation of NF-κB signaling. Cells treated with DOX showed aberrant expression of mitochondrial dynamics related proteins, and these effects were alleviated by LLF pre-treatment. In conclusion, these results show that LLF can alleviate DOX-induced cardiotoxicity by blocking NF-κB signaling and re-balancing mitochondrial dynamics. CONCLUSION: Ethanol extracts of LLF is a potential treatment option to against DOX-induced cardiotoxicity.

Genotoxicity, nitric oxide level modulation and cardio-protective potential of Kalanchoe Integra Var. Crenata (Andr.) Cuf Leaves in murine models.

ETHNOPHARMACOLOGICAL RELEVANCE: Advancement in cancer therapy has improved survival among patients. However, use of anticancer drugs like anthracyclines (e.g., doxorubicin) is not without adverse effects. Notable among adverse effects of doxorubicin (DOX) is cardiotoxicity, which ranges from mild transient blood pressure changes to potentially serious heart failure. Anecdotal reports suggest that Kalanchoe integra (KI) may have cardio-protective potential. AIMS OF THE STUDY: This study sought to determine the cardio-protective potential of KI against doxorubicin-induced cardiotoxicity and also examined any possible genotoxic potential of KI in selected organs. Additionally, the nitric oxide modulatory potential of KI was assessed. MATERIALS AND METHODS: The leaves of KI were collected, air-dried, pulverised and extracted using 70% ethanol. High-performance liquid chromatography (HPLC) fingerprinting was done for KI. Also, the single-cell gel electrophoresis assay (Comet assay) was employed to ascertain the genotoxic potential of KI. In assessment of cardio-protective potential of KI against doxorubicin-induced cardiotoxicity, a total of 42 female Sprague-Dawley rats were put into 7 groups (n = 6). Group I: vehicle control, received normal saline (1 mL/kg p.o) for 30 days. Group II: toxic control, received DOX (20 mg/kg i.p.) once on the 29th day. Group III: KI control, received KI (300 mg/kg p.o) for 30 days. Group IV: vitamin E control, received vitamin E (100 mg/kg p.o) for 30 days. Group V: KI treated-1, received KI (300 mg/kg p.o) for 30 days and DOX (20 mg/kg i.p) on the 29th day. Group VI: KI treated-2, received KI (600 mg/kg p.o) for 30 days and DOX (20 mg/kg i.p) on the 29th day. Group VII: vitamin E treated, received vitamin E (100 mg/kg p.o) for 30 days and DOX (20 mg/kg i.p) on the 29th day. Thirty-six (36) hours after last administration, rats were sacrificed. Blood samples were taken via cardiac puncture to determine levels of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), creatine kinase (CK), lactate dehydrogenase (LDH), enzymatic antioxidants such as glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Nitric oxide level was also determined. Hearts of rats in each group were excised and taken through histopathological examination. RESULTS: In the HPLC fingerprint analysis, 13 peaks were identified, and peak with retention time of 24.0 min had the highest peak area (3.223 x104 mAU). Comet assay showed that the KI extract was non-genotoxic. Pretreatment with KI protected rats against doxorubicin-induced cardiotoxicity as evidenced by the low levels of AST, ALT, ALP, CK and LDH compared with the controls (p < 0.05). SOD, CAT and GPX levels were also high for rats administered KI extracts, further showing that KI protected rats against doxorubicin-induced cardiotoxicity. KI also inhibited nitric oxide levels at 300 mg/kg and 600 mg/kg effective doses. Histological examination revealed that rats pretreated with KI showed no signs of abnormal myocardial fibres (shape, size and configuration). CONCLUSION: Ethanolic (70%) leaf extract of KI showed no genotoxic potential and possessed cardioprotective effects against doxorubicin-induced cardiotoxicity in Sprague-Dawley rats. KI also inhibited nitric oxide production, thus, a potential nitric oxide scavenger.

Aqueous extract of Solanum nigrum attenuates Angiotensin-II induced cardiac hypertrophy and improves cardiac function by repressing protein kinase C-ζ to restore HSF2 deSUMOlyation and Mel-18-IGF-IIR signaling suppression.

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum nigrum, commonly known as Makoi or black shade has been traditionally used in Asian countries and other regions of world to treat liver disorders, diarrhoea, inflammatory conditions, chronic skin ailments (psoriasis and ringworm), fever, hydrophobia, painful periods, eye diseases, etc. It has been observed that S. nigrum contains substances, like steroidal saponins, total alkaloid, steroid alkaloid, and glycoprotein, which show anti-tumor activity. However; there is no scientific evidence of the efficacy of S. nigrum in the treatment of cardiac hypertrophy. AIM: To investigate the ability of S. nigrum to attenuate Angiotensin II - induced cardiac hypertrophy and improve cardiac function through the suppression of protein kinase PKC-ζ and Mel-18-IGF-IIR signaling leading to the restoration of HSF2 desumolyation. MATERIALS AND METHODS: Cardiomyoblast cells (H9c2) were challenged with 100 nM Angiotensin-II (AngII) for 24 h and were then treated with different concentration of S.nigrum or Calphostin C for 24 h. The hypertrophic effect in cardiomyoblast cells were determined by immunofluorescence staining and the modulations in hypertrophic protein marker along with Protein Kinase C-ζ, MEL18, HSF2, and Insulin like growth factor II (IGFIIR), markers were analyzed by western blotting. In vivo experiments were performed using 12 week old male Wistar Kyoto rats (WKY) and Spontaneously hypertensive rats (SHR) separated into five groups. [1]Control WKY, [2] WKY -100 mg/kg of S.nigrum treatment, [3] SHR, [4] SHR-100 mg/kg of S.nigrum treatment, [5] SHR-300 mg/kg of S.nigrum treatment. S. nigrum was administered intraperitoneally for 8 week time interval. RESULTS: Western blotting results indicate that S. nigrum significantly attenuates AngII induced cardiac hypertrophy. Furthermore, actin staining confirmed the ability of S. nigrum to ameliorate AngII induced cardiac hypertrophy. Moreover, S. nigrum administration suppressed the hypertrophic signaling mediators like Protein Kinase C-ζ, Mel-18, and IGFIIR in a dose-dependent manner and HSF2 activation (restore deSUMOlyation) that leads to downregulation of IGF-IIR expression. Additionally in vivo experiments demonstrate the reduced heart sizes of S. nigrum treated SHRs rats when compared to control WKY rats. CONCLUSION: Collectively, the data reveals the cardioprotective effect of S. nigrum inhibiting PKC-ζ with alleviated IGF IIR level in the heart that profoundly remits cardiac hypertrophy for hypertension-induced heart failure.

Optimized separation of anhydrosafflor yellow B from safflower by high-speed counter-current chromatography and evaluation of its cardio-protective effect.

Anhydrosafflor yellow B (AHSYB) is a major active water-soluble pigment in Safflower, but it has not received enough attention yet. In this study, high-speed counter-current chromatography (HSCCC) was used to prepare AHSYB from safflower. The parameters of the separation process were optimized by response surface methodology for the first time. The entropy weight method (EWM) was applied to calculate the information entropy and the weight of five indexes, and then figure out a comprehensive index of the HSCCC separation effect. Under the optimized separation conditions, a HSCCC apparatus speed of 850 rpm, a flow rate of 2 mL min-1 for the mobile phase and a separation temperature of 40 °C for AHSYB were achieved with a purity of 98%. Furthermore, AHSYB was found to have cardio-protective effects by inhibiting apoptosis via the mitochondrial-mediated pathway in oxygen-glucose deprivation/reoxygenation-induced H9c2 cells. This research provides good method guides for the rapid and efficient separation of active compounds from food-grade Chinese herb medicines.

Cardioprotective, hypotensive and toxicological studies of Populus ciliata (Wall. ex Royle).

Populus ciliata Wall ex. Royle has folkloric repute to treat various cardiovascular ailments and related disorders. The current study was designed to evaluate the toxic profile, cardioprotective and hypotensive effects of Populus ciliata (Wall. ex Royle). Populus ciliata crude ethanolic extract (Pc. Cr) and its aqueous (Pc. Aq) & organic (Pc. Dcm) fractions were tested on isolated aorta of rat and rabbit having intact and non-intact endothelium respectively. Pc. Cr & Pc. Aq relaxed the contractions induced by PE (1 µM)-induced and K+ (80 mM)-induced on aorta, possibly by mediating endothelium derived relaxing factor (EDRF) in intact endothelium and voltage dependent L-type calcium channels blocking (CCB) mechanism in non-intact endothelium. Pc. Cr showed anti-hypertensive & cardioprotective activity by decreasing force of contraction & heart rate on isolated rabbit paired atria and reduced blood pressure in anesthetized rat. Cardioprotective effect of Pc. Cr was assessed in isoproterenol induced acute myocardial infarction (AMI) and left ventricular hypertrophy (LVH) in Sprague Dawley rats. In LVH, Pc. Cr exerted positive effects by decreasing angiotensin II & renin and increasing cGMP & nitric oxide (NO) with reduced cardiac fibrosis, necrosis and cardiac cell size. In AMI, Pc. Cr responded effectively by decreasing cardiac markers creatinine kinase (CK), creatinine kinase myocardial band (CK-MB) and lactate dehydrogenase (LD) in blood associated with less edema and necrosis. Presence of catechin, vinallic acid, P-coumeric acid and quercitin identified through HPLC support the effectiveness of Pc. Cr in hypertension, AMI and LVH. Pc. Cr showed no significant adverse effects in Sprague Dawley albino rats after acute & sub-acute treatment in histopathological investigation. Extract of Populus ciliata showed vasorelaxant, hypotensive and cardioprotective effect in Sprague Dawley albino rats and white albino rabbit by mediating EDRF and voltage dependent L-type CCB mechanism respectively.

Alkaloids of Delphinium grandiflorum and their implication to H2O2-induced cardiomyocytes injury.

Three new diterpenoid alkaloids (1-3), and eight known alkaloids (4-11) were isolated from the aerial parts of Delphinium grandiflorum. Grandifline A (1) represents an unprecedented diterpenoid alkaloid ring system featuring a C-7NC17 hemiaminal moiety and a lactone fragment through the linkage of C-17OC19 unit. And we named this newly-discovered class of rearranged C19-diterpenoid alkaloid scaffold as grandiflodines (B-12). Grandifline B (2) is the first naturally-occurring 7,17-secolycoctonine diterpenoid alkaloid with a C-7OC17 unit forming a hemiacetal. Their structures were elucidated via spectroscopic data and single-crystal X-ray diffraction analysis. The protective effects of compounds 1-11 on H2O2-induced cardiomyocytes injury were assayed. And compounds 6 and 10 showed significant protective effects, with IC50 values of 1.881 ± 0.680 µM and 1.904 ± 0.750 µM, respectively. Further, compound 6 could reduce oxidative damage by inhibiting cell death via the AMPK/AKT/mTOR signaling pathway in H2O2-induced H9C2 cells.

Structurally diverse alkaloids from Buxus sempervirens with cardioprotective activity.

Extensive phytochemical study of the methanol extract of twigs and leaves of Buxus sempervirens resulted in the identification of 17 Buxus alkaloids, including 12 new ones, namely buxusemines A-L (1-12). Their structures were delineated by detailed analysis of the HRESIMS and NMR data, as well as quantum chemical NMR calculations. Buxusemine A (1) represents the second Buxus alkaloid with a unique spiro[4.6]undecatriene moiety, buxusemines B-C (2-3) are a rarely occurring class of Buxus alkaloids featured with an additional five-membered ring through the ether or lactone linkage between C-10 and C-23, and buxusemines D-F (4-6) are another rare type of Buxus alkaloids with an epoxy motif. In the assessment of their bioactivities, buxusemine F (6) and buxanoldine (17) displayed more potent protective effects than the positive control cyclovirobuxinum D in the doxorubicin-induced cardiac injury model.

Ginsenoside Rg2 alleviates myocardial fibrosis by regulating TGF-ß1/Smad signalling pathway.

CONTEXT: Panax ginseng C.A. Meyer (Araliaceae) has cardioprotective effects. Ginsenosides are responsible for most of the pharmacological activities of ginseng. OBJECTIVE: This study investigates the effect of ginsenoside Rg2 on myocardial fibrosis in myocardial ischaemia rats. MATERIALS AND METHODS: Male Wistar rats were divided into control, isoproterenol, ginsenoside Rg2 (5, 20 mg/kg) groups (n = 8). The rats were subcutaneously injected with isoproterenol (5 mg/kg) or normal saline (control group) once daily for 7 days. The animals were intragastrically treated with ginsenoside Rg2 or 0.5% CMC-Na (control and isoproterenol groups) daily for 28 days. At day 28, cardiac function, myocardial fibrosis, and TGF-ß1/Smad signalling pathway were evaluated. RESULTS: Compared with myocardial ischaemic rats, ginsenoside Rg2 at doses of 5, 20 mg/kg abated partially the augment of LVEDP (8.9 ± 1.3 vs. 7.5 ± 0.7, 7.2 ± 1.0 mmHg) and the decreases of the LVSP (96.75 ± 13.2 vs. 118.3 ± 19.4, 124.3 ± 21.3 mmHg), the + dp/dt (2142.8 ± 309.3 vs. 2598.6 ± 404.0, 2661.5 ± 445.2 mmHg/s), and the -dp/dt (1996.3 ± 306.3 vs. 2476.6 ± 289.7, 2509.6 ± 353.1 mmHg/s). Ginsenoside Rg2 (9.2 ± 0.9%, 8.5 ± 0.8%) alleviated myocardial fibrosis when compared with the isoproterenol group (10.1 ± 1.0%), which was accompanied by suppressed TGF-ß1/Smad signalling in heart tissues. CONCLUSIONS: Ginsenosides from ginseng possess the property of alleviating myocardial fibrosis, improving cardiac function after myocardial ischaemia. Ginsenosides may be promising agents for improving the outcomes of patients with myocardial ischaemia.

Cardioprotective effects and concentration-response relationship of aminoalcohol-diterpenoid alkaloids from Aconitum carmichaelii.

Fuzi, a well-known traditional Chinese medicine developed from the lateral roots of Aconitum carmichaelii Debx., has been widely used for the treatment of heart failure. In order to search for active compounds from Fuzi, a phytochemical study was performed, which resulted in the isolation of 14 aminoalcohol-diterpenoid alkaloids, including one new compound (1). Their cardioprotective effects against doxorubicin-induced toxicity in H9c2 cells were evaluated. All of the alkaloids showed cardioprotective effects in a nonmonotonic concentration-response manner, with the maximum protection rates ranging from 17.96 ± 2.93% to 98.31 ± 0.35%. Compound 5 exhibited the most potent cardioprotective activity. Taking the maximum protection rate as an indicator, the preliminary structure-activity relationship analysis indicated that the substitutions of C-1, C-13, C-15, C-16, and N and the configurations of OMe-6 and OH-15 are important structural features for the cardioprotective activities of the aminoalcohol-diterpenoid alkaloids.

Protective effects of medicinal plant against diabetes induced cardiac disorder: A review.

ETHNOPHARMACOLOGY RELEVANCE: Nowadays, there is an increase in global tendency to use medicinal plants as preventive and therapeutic agents to manage diabetes and its long-term complications such as cardiovascular disorders owing to their availability and valuable traditional background. AIM OF STUDY: This review aims to introduce common medicinal plants, which have been demonstrated to have cardioprotective effects on diabetes and their mechanisms of action. MATERIALS AND METHODS: Online literature databases, including Web of Sciences, PubMed, Science Direct, Scopus and Google Scholar were searched without date limitation by May 2020. The following keywords (natural products or medicinal plants or herbal medicine or herb or extract) and (diabetes or antidiabetic or hyperglycemic) and (cardiomyopathy or heart or cardioprotective or cardiac or cardio) were used, and after excluding non-relevant articles, 81 original English articles were selected. RESULTS: The surveyed medicinal plants induced cardioprotective effects mostly through increasing antioxidant effects leading to attenuating ROS production as well as by inhibiting inflammatory signaling pathways and related cytokines. Moreover, they ameliorated the Na+/K + ATPase pump, the L-type Ca2+ channel current, and the intracellular ATP. They also reduced cardiac remodeling and myocardial cell apoptosis through degradation of caspase-3, Bax, P53 protein, enhancement of Bcl-2 protein expression as well as downregulation of TGFß1 and TNFα expression. In addition, the extracts improved cardiac function through increasing EF% and FS% as well as restoring hemodynamic parameters. CONCLUSIONS: The reviewed medicinal plants demonstrated cardioprotective manifestations in diabetes through intervention with mechanisms involved in the diabetic heart to restore cardiovascular complications.

Leech extract: A candidate cardioprotective against hypertension-induced cardiac hypertrophy and fibrosis.

ETHNOPHARMACOLOGICAL RELEVANCE: The prevalence of cardiovascular diseases (CVDs) has been increasing worldwide. Despite significant improvements in therapeutics and on-going developments of novel targeted-treatment regimens, cardiac diseases lack effective preventive and curative therapies with minimal side effects. Therefore, there is an urgent need to identify and propagate alternative and complementary therapies against cardiovascular diseases. Some traditional Chinese medicines can contribute to the prevention and treatment of CVDs and other chronic diseases, with few side effects. Hirudo, a medicinal leech, has been acclaimed for improving blood circulation and overcoming blood stagnation; however, the precise molecular mechanisms of leech extract treatment against pathological cardiac remodeling remain elusive. In this study, we aimed to delineate the molecular mechanisms of medicinal leech extract in the treatment of cardiac hypertrophy and fibrosis, using both in vitro and in vivo assessments. MATERIALS AND METHODS: We conducted in vitro and in vivo animal experiments, including cell-viability assays, fluorescence microscopy, immunoblotting, immunohistochemistry, and Masson's trichrome staining. RESULTS: Pre-treatment with leech extract conferred a survival benefit to spontaneously-hypertensive rats (SHRs) and significantly reduced angiotensin II (ANG II)-induced cardiac hypertrophy and fibrosis. ANG II-stimulated cardiac hypertrophy markers were attenuated by leech extract treatment, versus controls. Translational expression of stress-associated mitogen-activated protein kinases (MAPKs) was also repressed. In vivo, leech extract treatment significantly ameliorated the cardiac hypertrophy phenotype in SHRs and diminished interstitial fibrosis, accompanied with reduced fibrosis markers. CONCLUSION: Leech extract treatment under a hypertensive condition exerted significant cardio-protective benefits by reducing the expression of cardiac hypertrophy-related transcription factors, stress-associated MAPKs, and fibrosis mediators. Our findings imply that medicinal leach extract may be effective against hypertension-induced cardiac hypertrophy and fibrosis.

Withania somnifera (L.) Dunal - Modern perspectives of an ancient Rasayana from Ayurveda.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal, commonly known as Ashwagandha, is an important medicinal plant that has been used in Ayurvedic and indigenous medicine for more than 3000 years. According to Charaka Samhita, Susruta Samhita and other ancient texts, Ashwagandha is known as Balya (increases strength), Brusya (sexual performance enhancer), vajikari (spermatogenic), Kamarupini (libido-enhancing), Pustida (nourishing). AIM OF THE REVIEW: This review article documented and critically assessed W. somnifera regarding its ethnopharmacology, traditional use, botanical description, phytochemicals present, pharmacological activities, clinical trials, and marketed formulations. MATERIALS AND METHODS: The sources of information used in the study are traditional Ayurvedic books like Charaka Samhita, Susruta Samhita, Astanga Hridaya etc, government reports, dissertations, books, research articles and databases like Science-Direct, SciFinder, Web of Science, PubMed, Wiley Online Library, and ACS Publications on Ashwagandha and Withania somnifera (L.) Dunal. RESULTS: Traditional uses of Ashwagandha in Ayurveda are very prominent in several texts where formulations with various dosage forms have been mentioned in Charaka Samhita, Susruta Samhita, Astanga Hridaya, different nighantus etc. The drugs were identified based on their composition containing Ashwagandha as one of the major ingredients and their medicinal uses. Phytochemical studies on W. somnifera revealed the presence of important chemical constituents such as flavonoids, phenolic acids, alkaloids, saponins, tannins, and withanolides. The phytochemicals showed various pharmacological activities like anti-cancer, immunomodulatory, cardioprotective, neuroprotective, anti-aging, anti-stress/adaptogenic and anti-diabetic. Various clinical trials show that the plant extract and its bioactive compounds are used in the prevention and treatment of many diseases, such as arthritis, impotence, amnesia, anxiety, cancer, neurodegenerative and cardiovascular diseases, and others. CONCLUSIONS: Pharmacological data reviewed here revealed that W. somnifera is a potential source for the treatment of a wide range of diseases especially anxiety and other CNS disorders. From its ancient use to its modern application it has been proven to be non-toxic and effective clinically for human health and wellness. W. somnifera based herbal formulation has been marketed in the form of supplement, extract, capsule, powder etc. This review will be helpful to correlate the mechanism of action with the phytochemical profile of this well-known plant from Ayurveda.

Ginger (Zingiber Officinale Roscoe) Extract Protects the Heart Against Inflammation and Fibrosis in Diabetic Rats.

BACKGROUND: Fibrosis and inflammation in the heart of patients with diabetes mellitus alongside increased production of free radicals and collagen are together known as diabetic cardiomyopathy. Ginger rhizome has antidiabetic, antioxidant and anti-inflammatory effects. Thus, we investigated the effect of ginger extract on diabetes-induced cardiomyopathy in streptozotocin-induced diabetic rats. METHODS: Animals were divided into 7 groups: control; diabetic; diabetic treated with different doses of ginger extract of 100, 200 and 400 mg/kg; metformin (200 mg/kg); and metformin-valsartan (200 and 30 mg/kg, respectively). Serum levels of glucose, aspartate aminotransferase, lactate dehydrogenase and creatine kinase-muscle/brain were measured. Fibrosis and inflammation were determined by histologic assessment. Gene expression of transforming growth factor (TGF)-ß1, TGF-ß3 and angiotensin II type 1 receptor was evaluated by real-time polymerase chain reaction in heart tissue. RESULTS: Serum glucose level in all treated groups, except for the ginger extract 100-mg/kg group, was significantly lower than in the diabetic group. Serum levels of aspartate aminotransferase, lactate dehydrogenase and creatine kinase-muscle/brain were significantly reduced in all treated groups compared with the diabetic group. In the study of fibrosis, collagen amount in the heart tissue of all treated groups, except the ginger extract 100-mg/kg group, was significantly lower than in the diabetic group. Inflammatory cell infiltrates were decreased, and disarrangement was improved in cardiac tissues of all treated groups compared with the diabetic group. Expression of angiotensin II type 1 receptor and TGF-ß1 and TGF-ß3 genes in all treated groups downregulated compared with the diabetic group. CONCLUSIONS: Treatment by ginger extract reduced myocardial fibrosis and inflammation in the course of diabetic cardiomyopathy, possibly through regulation of the expression of genes involved in the SMAD/TGF-ß pathway.

Triterpenoid saponins from Ilex cornuta protect H9c2 cardiomyocytes against H2O2-induced apoptosis by modulating Ezh2 phosphorylation.

ETHNOPHARMACOLOGICAL RELEVANCE: Ilex cornuta Lindl. et Paxt. (Aquifoliaceae family) belongs to the Ilex genus. The leaves of this plant are used for the popular herbal tea "Ku-Ding-Cha" in China due to their health benefits for sore throat, obesity and hypertension. Our previous studies have shown that the extract of Ilex cornuta root exerts cardioprotective effects in rat models of myocardial ischaemic injury, and several new kinds of triterpenoid saponins from Ilex cornuta (TSIC) have protective effects against hydrogen peroxide (H2O2)-induced cardiomyocyte injury. AIM OF THE STUDY: The aim of this study was to clarify the underlying mechanisms by which TSIC protect against H2O2-induced cardiomyocyte injury. MATERIALS AND METHODS: An H2O2-treated H9c2 cardiomyocyte line was used as an in vitro model of oxidation-damaged cardiomyocytes to evaluate the effects of TSIC. Apoptosis was detected with CCK-8 and annexin V assays and via analysis of the levels of apoptosis-associated proteins or genes. The underlying mechanisms related to Akt signalling, Ezh2 expression and activity, and ROS were clarified by Western blotting, quantitative PCR, flow cytometry and rescue experiments. RESULTS: TSIC protected H9c2 cells from H2O2-induced apoptosis. This effect of TSIC was attributable to inhibition of Ezh2 activity, as exhibited by attenuation of H2O2-induced Akt signalling-dependent phosphorylation of Ezh2 at serine 21 (pEzh2S21) upon TSIC pretreatment. In addition, feedback pathway between Akt-dependent Ezh2 phosphorylation and ROS was involved in TSIC-mediated protection of H9c2 cells from apoptosis. CONCLUSIONS: Our findings indicate a pivotal role of the pEzh2S21 network in TSIC-mediated protection against cardiomyocyte apoptosis, potentially providing evidence of the mechanism of TSIC in the treatment and prevention of cardiovascular diseases.