The YAP/SERCA2a signaling pathway protects cardiomyocytes against reperfusion-induced apoptosis.

Mitochondria and the endoplasmic reticulum (ER) are known to promote cardiac ischemia/reperfusion (I/R) injury. Overexpression of yes-associated protein (YAP) and/or sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) has been shown to protect cardiomyocytes against I/R-induced injury. Here, we show that activation of the YAP/SERCA2a pathway attenuated mitochondrial damage and ER stress (ERS) to maintain cardiomyocyte viability in the setting of I/R injury. Our results demonstrate that I/R treatment reduced the transcription and expression of YAP and SERCA2a, along with a decline in cardiomyocyte viability. The overexpression of YAP promoted SERCA2a transcription, whereas SERCA2a upregulation did not affect the YAP transcription, suggesting that YAP functions upstream of SERCA2a. Activation of the YAP/SERCA2a pathway suppressed mitochondrial damage by sustaining the mitochondrial redox balance and restoring mitochondrial bioenergetics. Additionally, its activation repressed ERS, reduced calcium overload, and eventually blocked caspase activation. The knockdown of SERCA2a suppressed the protective effects of YAP overexpression on mitochondrial damage and ERS. Overall, our findings reveal that the YAP/SERCA2a pathway attenuates the mitochondrial damage and ERS in response to cardiac I/R injury by regulating the mitochondria-ER communication.

Macrocyclic Diterpenoids from Euphorbia helioscopia and Their Potential Anti-inflammatory Activity.

Guided by 1H NMR spectroscopic experiments using the aromatic protons as probes, 11 macrocyclic diterpenes (1-11) were isolated from the aerial parts of Euphorbia helioscopia. Their full three-dimensional structures, including absolute configurations, were established unambiguously by spectroscopic analysis and single-crystal X-ray crystallographic experiments. Among the isolated compounds, compound 1 is the third member thus far of a rare class of Euphorbia diterpenes featuring an unusual 5/10 fused ring system, and 2-4 are new jatrophane diterpenes. Based on the NMR data of the jatrophane diterpenes obtained in this study as well as those with crystallographic structures reported in the literature, the correlations of the chemical shifts of the relevant carbons and the configurations of C-2, C-13, and C-14 of their flexible macrocyclic ring were considered. Moreover, the anti-inflammatory activities of 1-11 were investigated by monitoring their inhibitory effects on nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells. Compound 1 showed an IC50 of 7.4 ± 0.6 µM, which might be related to the regulation of the NF-κB signaling pathway by suppressing the translocation of the p65 subunit and the consequent reduction of IL-6 and TNF-α secretions.

Tanshinone IIA attenuates cardiac microvascular ischemia-reperfusion injury via regulating the SIRT1-PGC1α-mitochondrial apoptosis pathway.

Cardiac microvascular ischemia-reperfusion (IR) injury has been a neglected topic in recent decades. In the current study, we investigated the mechanism underlying microvascular IR injury, with a focus on mitochondrial homeostasis. We also explored the protective role of tanshinone IIA (Tan IIA) in microvascular protection in the context of IR injury. Through animal studies and cell experiments, we demonstrated that IR injury mediated microvascular wall destruction, lumen stenosis, perfusion defects, and cardiac microvascular endothelial cell (CMEC) apoptosis via inducing mitochondrial damage. In contrast, Tan IIA administration had the ability to sustain CMEC viability and microvascular homeostasis, finally attenuating microvascular IR injury. Function studies have confirmed that the SIRT1/PGC1α pathway is responsible for the microvascular protection from the Tan IIA treatment. SIRT1 activation by Tan IIA sustained the mitochondrial potential, alleviated the mitochondrial pro-apoptotic factor leakage, reduced the mPTP opening, and blocked mitochondrial apoptosis, providing a survival advantage for CMECs and preserving microvascular structure and function. By comparison, inhibiting SIRT1 abrogated the beneficial effects of Tan IIA on mitochondrial function, CMEC survival, and microvascular homeostasis. Collectively, this study indicated that Tan IIA should be considered a microvascular-protective drug that alleviates acute cardiac microcirculation IR injury via activating the SIRT1/PGC1α pathway and thereby blocking mitochondrial damage.

Inhibitory effect of melatonin on Mst1 ameliorates myocarditis through attenuating ER stress and mitochondrial dysfunction.

Viral myocarditis has been found to be one of the leading causes of sudden death in young adults. However, no effective drugs have been developed to intervene the progression of myocarditis. Accordingly, the present study is carried out to explore the protective role played by melatonin in the setting of viral myocarditis with a focus on Mst1-Hippo pathway, mitochondrial dysfunction and ER stress. Cardiac function was determined via echocardiographic examination. Mitochondrial function and ER stress were detected via ELISA, western blots, and immunofluorescence. Our data demonstrated that virus injection induced cardiac dysfunction as evidenced by reduced contractile function in myocardium. Besides, LDH release assay and western blotting analysis demonstrated that cardiomyocyte death was activated by virus injection. Interestingly, melatonin treatment improved cardiac function and repressed virus-mediated cardiomyocyte apoptosis. At the molecular levels, mitochondrial dysfunction was induced by virus infection, as indicated by mitochondrial membrane potential reduction, mPTP opening rate elevation and caspase-9-related apoptosis activation. Besides, ER stress parameters were also elevated in virus-treated cardiomyocytes. Interestingly, melatonin treatment maintained mitochondrial dysfunction and repressed ER stress. To the end, we found that Mst1 was upregulated by virus infection; this effect was attenuated through supplementation with melatonin. However, Mst1 overexpression reduced the beneficial impact exerted by melatonin on cardiomyocyte viability, mitochondrial function and ER homeostasis. Our study illustrated that melatonin treatment attenuated viral myocarditis via sustaining cardiomyocyte viability, repressing mitochondrial dysfunction and inhibiting ER stress in a manner dependent on Mst1 inhibition.

Stilbene Glycoside Oligomers from the Roots of Polygonum multiflorum.

Five new trans-2,3,5,4'-tetrahydroxystilbene 2-O-ß-d-glucopyranoside (TSG)-based stilbene glycoside oligomers (1-5) were isolated from the roots of Polygonum multiflorum. Their structures were elucidated by comprehensive spectroscopic analyses and chemical evidences. The absolute configurations of 1, 2, 4, and 5 were established by quantum-chemical electronic circular dichroism (ECD) calculations. Putative biosynthetic pathways of 1-5 were proposed using TSG as the key precursor. In addition, compounds 1 (multiflorumiside H) and 3 (multiflorumiside J) exhibited moderate inhibitory activities against NO production in LPS-stimulated RAW264.7 cells.

Antiviral activity of ethanol extract of Lophatherum gracile against respiratory syncytial virus infection.

ETHNOPHARMACOLOGICAL RELEVANCE: Lophatherum gracile, an important medicinal plant, is used traditionally in the treatment of cough associated with lung heat and inflammation. In this study, an ethanol extract of L. gracile (DZY) was shown to inhibit respiratory syncytial virus (RSV) infection and RSV-induced inflammation in vitro and in vivo. These findings provide a strong and powerful support for the traditional use of L. gracile in the treatment of RSV-related diseases. AIM OF THE STUDY: To determine the anti-RSV activities of DZY and its ingredients, and explore the relationship between RSV infection and inflammation. MATERIALS AND METHODS: DZY was extracted from L. gracile and its major ingredients were determined by high-performance liquid chromatography (HPLC). RSV-infected HEp-2 and RAW264.7 cell models were established to assess the inhibitory effect of DZY on RSV replication and nitric oxide (NO) production in vitro. Three-week-old BALB/c mice challenged intranasally with RSV were used to establish RSV-infected animal mode. The mice were respectively administered DZY at high-, middle-, and low-dose in different groups. The anti-RSV activity of DZY was evaluated by detecting viral load, lung lesion, CD4+ and CD8+ T cell population, and interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ expression in the lung tissue. RESULTS: In HEp-2 cell line, DZY effectively inhibited RSV infection in a dose-dependent manner with IC50 values of 20 µg/mL against RSV (Long strain) and IC50 values of 25 µg/mL against RSV (A2 strain). The anti-RSV activity of DZY was mainly determined by isoorientin, swertiajaponin, 3, 5-di-caffeoylquinic acid, and 3, 4-di-caffeoylquinic acid. Moreover, DZY suppressed NO production induced by RSV in vitro. In vivo, oral administration of DZY significantly reduced the viral load and ameliorated lesions in the lung tissue. A probable antiviral mechanism was mediated by slightly improving the ratio of CD4+/CD8+ T cells and inhibiting the mRNA and protein expression of IL-1ß, TNF-α, and IFN-γ. CONCLUSIONS: (1) DZY exhibits anti-RSV activities both in vitro and in vivo. (2) RSV infection can trigger a series of inflammatory reactions; thus, ameliorating inflammation is helpful to control the course of disease caused by RSV. These findings provide the rationale and scientific evidence behind the extensive use of L. gracile in traditional medicine for the treatment of diseases potentially caused by RSV.

Antiviral Triketone-Phloroglucinol-Monoterpene Adducts from Callistemon rigidus.

Callistrilones F - K (1 - 6), six new triketone-phloroglucinol-monoterpene hybrids were isolated from the twigs and leaves of Callistemon rigidus. Their structures with absolute configurations were established by a combination analysis of NMR spectra, X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 3 and 4 exhibited moderate inhibitory activities against herpes simplex virus (HSV-1) with IC50 values of 10.00 ± 2.50 and 12.50 ± 1.30 µm, respectively.

New Acetophenone Derivatives from Acronychia oligophlebia and Their Anti-inflammatory and Antioxidant Activities.

Seven new acetophenone derivatives (acroliones A - G, 1 - 7) and three known ones (8 - 10) were isolated from the leaves of Acronychia oligophlebia. Their structures were elucidated based on extensive spectroscopic analyses (IR, UV, HR-ESI-MS, 1D- and 2D-NMR), X-ray diffraction and comparison with literature data. The anti-inflammatory and antioxidant activities of all isolates were evaluated.

Cajanusflavanols A-C, Three Pairs of Flavonostilbene Enantiomers from Cajanus cajan.

Three pairs of new flavonostilbene enantiomers, cajanusflavanols A-C (1-3), along with their putative biogenetic precursors 4-6, were isolated from Cajanus cajan. Compound 1 possesses an unprecedented carbon skeleton featuring a unique highly functionalized cyclopenta[1,2,3-de]isobenzopyran-1-one tricyclic core. Compounds 2 and 3 are the first examples of methylene-unit-linked flavonostilbenes. Their structures with absolute configurations were elucidated by spectroscopic analyses, X-ray diffraction, and computational calculations. Compounds 1 and 2 exhibited significant in vitro anti-inflammatory activities.