The recent advance and prospect of natural source compounds for the treatment of heart failure.

Heart failure is a continuously developing syndrome of cardiac insufficiency caused by diseases, which becomes a major disease endangering human health as well as one of the main causes of death in patients with cardiovascular diseases. The occurrence of heart failure is related to hemodynamic abnormalities, neuroendocrine hormones, myocardial damage, myocardial remodeling etc, lead to the clinical manifestations including dyspnea, fatigue and fluid retention with complex pathophysiological mechanisms. Currently available drugs such as cardiac glycoside, diuretic, angiotensin-converting enzyme inhibitor, vasodilator and ß receptor blocker etc are widely used for the treatment of heart failure. In particular, natural products and related active ingredients have the characteristics of mild efficacy, low toxicity, multi-target comprehensive efficacy, and have obvious advantages in restoring cardiac function, reducing energy disorder and improving quality of life. In this review, we mainly focus on the recent advance including mechanisms and active ingredients of natural products for the treatment of heart failure, which will provide the inspiration for the development of more potent clinical drugs against heart failure.

Natural products as the calcium channel blockers for the treatment of arrhythmia: Advance and prospect.

Arrhythmia is one of the commonly heart diseases with observed abnormal heart-beat rhythm that caused by the obstacles of cardiac activity and conduction. The arrhythmic pathogenesis is complex and capricious and related with other cardiovascular diseases that may lead to heart failure and sudden death. In particular, calcium overload is recognized as the main reason causing arrhythmia through inducing apoptosis in cardiomyocytes. Moreover, calcium channel blockers have been widely used as the routine drugs for the treatment of arrhythmia, but the different arrhythmic complications and adverse effects limit their further applications and demand new drug discovery. Natural products have always been the rich minerals for the development of new drugs that could be employed as the versatile player for the discovery of safe and effective anti-arrhythmia drugs with new mechanisms. In this review, we summarized natural products with the activity against calcium signaling and the relevant mechanism of actions. We are expected to provide an inspiration for the pharmaceutical chemists to develop more potent calcium channel blockers for the treatment of arrhythmia.

Phosphoinositide kinases play key roles in norepinephrine- and angiotensin II-induced increase in phosphatidylinositol 4,5-bisphosphate and modulation of cardiac function.

The seemly paradoxical Gq agonist-stimulated phosphoinositide production has long been known, but the underlying mechanism and its physiological significance are not known. In this study, we studied cardiac phosphoinositide levels in both cells and whole animals under the stimulation of norepinephrine (NE), angiotensin II (Ang II), and other physiologically relevant interventions. The results demonstrated that activation of membrane receptors related to NE or Ang II caused an initial increase and a later fall in phosphatidylinositol 4,5-bisphosphate (PIP2) levels in the primary cultured cardiomyocytes from adult rats. The possible mechanism underlying this increase in PIP2 was found to be through an enhanced activity of phosphatidylinositol 4-kinase IIIß, which was mediated by an up-regulated interaction between phosphatidylinositol 4-kinase IIIß and PKC; the increased activity of phosphatidylinositol 4-phosphate 5-kinase γ was also involved for NE-induced increase of PIP2. When the systolic functions of the NE/Ang II-treated cells were measured, a maintained or failed contractility was found to be correlated with a rise or fall in corresponding PIP2 levels. In two animal models of cardiac hypertrophy, PIP2 levels were significantly reduced in hypertrophic hearts induced by isoprenaline but not in those induced by swimming exercise. This study describes a novel mechanism for phosphoinositide metabolism and modulation of cardiac function.

[Zero-valent iron-enhanced azoreduction by the Shewanella decolorationis S12].

Characteristics and optimal reaction conditions of anaerobic azoreduction by the Shewanella decolorationis S12 in the presence of zero-valent iron (ZVI) were evaluated in this study. The results showed that the presence of ZVI significantly enhanced the decolorization rate of azo dye. In the presence of 20 mmol x L(-1) ZVI, the decolorization rate of 1 mmol x L(-1) amaranth reached up to 100% by the Shewanella decolorationis S12 after 30 h incubation, which was significantly higher than 23.16% and 94.66% in the pure strain S12 and pure ZVI treatment systems, respectively. When 20 mmol x L(-1) of sodium formate was added in the medium, ZVI still improved the decolorization rate of amaranth by 20.54%. In addition, the presence of ZVI significantly increased the azo dye treatment amount in the ZVI plus S12 system. In the system with ZVI, 1 mmol x L(-1) amaranth was completely reduced 11 times in fed-batch process within 276 h, while the dye could only be completely reduced 3 times in the system without ZVI. The optimal pH and the Fe(0) dose for the ZVI plus S12 system was 9.0 and 60 mmol c L(-1), respectively. The microscale ZVI was more suitable for the decolorization than those with larger size and the nanoscale ZVI. This study may provide some useful information for improving the biodegradation of azo dye in the treatment system with ZVI.

Agonist-dependent potentiation of vanilloid receptor transient receptor potential vanilloid type 1 function by stilbene derivatives.

Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel activated by capsaicin, low pH, and noxious heat and plays a key role in nociception. Understanding mechanisms for functional modulation of TRPV1 has important implications. One characteristic of TRPV1 is that channel activity induced by either capsaicin or other activators can be sensitized or modulated by factors involving different cell signaling mechanisms. In this study, we describe a novel mechanism for the modulation of TRPV1 function: TRPV1 function is modulated by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and its analogs. We found that, in rat dorsal root ganglion neurons, although DIDS did not induce the activation of TRPV1 per se but drastically increased the TRPV1 currents induced by either capsaicin or low pH. DIDS also blocked the tachyphylaxis of the low pH-induced TRPV1 currents. 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), a DIDS analog, failed to enhance the capsaicin-evoked TRPV1 current but increased the low pH-evoked TRPV1 currents, with an effect comparable with that of DIDS. SITS also blocked the low pH-induced tachyphylaxis. DIDS also potentiated the currents of TRPV1 channels expressed in human embryonic kidney 293 cells, with an effect of left-shifting the concentration-response curve of the capsaicin-induced TRPV1 currents. This study demonstrates that DIDS and SITS, traditionally used chloride channel blockers, can modify TRPV1 channel function in an agonist-dependent manner. The results provide new input for understanding TRPV1 modulation and developing new modulators of TRPV1 function.

[Effects of iron on azoreduction by Shewanella decolorationis S12].

The effects of soluble and insoluble Fe(III) on anaerobic azoreduction by Shewanella decolorationis S12 were examined in a series of experiments. Results showed that the effects of iron on anaerobic azoreduction depended on the solubility and concentration of the compounds. Azoreduction was inhibited by insoluble Fe(III) and 0.05-2 mmol/L Fe2 O3 all decelerated the azoreduction activity of 0.2 mmol/L amaranth, but the increase in the concentrations of Fe2O3 did not cause an increasing inhibition. Soluble Fe(III) of which concentration less than 0.4 mmol/L enhanced azoreduction activity of 0.2 mmol/L amaranth but there was no linear relationship between the concentration of soluble Fe(III) and azoreduction activity. Soluble Fe(III) of which concentration more than 1 mmol/L inhibited azoreduction activity of 0.2 mmol/L amaranth and an increasing concentration resulted in an increased inhibition. The inhibition was strengthened under the conditions of limited electron donor. On the other hand, soluble Fe(III) and Fe(II) could relieve the inhibition of azoreduction by dicumarol which blocked quinone cycle. It suggests that in addition to quinone cycle, there is a Fe(III) <--> Fe(II) cycle shuttling electrons in cytoplasmic and periplasmic environment. That is the reason why low concentration of soluble Fe(III) or Fe (II) can enhance azoreduction of S. decolorationis S12. It also indicates that insoluble Fe(III) and high concentration of soluble Fe(III) do compete with azo dye for electrons once it acts as electron acceptor. Thus, when iron and azo dye coexisted, iron could serve as an electron transfer agent or electron competitive inhibitor for anaerobic azoreduction under different conditions. High efficiency of azoreduction can be achieved through controlling the solubility and concentration of irons.

Specificity of Gbetagamma signaling depends on Galpha subunit coupling with G-protein-sensitive K(+) channels.

Many neurotransmitters activate G-protein-gated inwardly rectifying K(+) (Kir3) channels by stimulating G-protein-coupled receptors. However, in native systems, only receptors coupled to pertussis-toxin (PTX)-sensitive G proteins (Gi/Go) have been shown to be able to activate Kir3 channels through the betagamma subunits of G proteins (Gbetagamma), whereas activation of receptors coupled to PTX-insensitive G proteins such as Gq or Gs do not activate Kir3 channels. The question remains as to how signaling specificity is achieved and what are its key determinants. In this study, we have used the Xenopus oocyte expression system to investigate specific activation of Kir3 channels by heterotrimeric G proteins. We have demonstrated the activation of Kir3.4 channels by agonist stimulation of non-PTX-sensitive G proteins under conditions of Galpha subunit overexpression. We present evidence to suggest a key role for the coupling efficiency of Galpha subunits in determining the specificity of Gbetagamma signaling to the channel.

[Anaerobic humus respiration by Shewanella cinica D14T].

Experimental results suggested Shewanella cinica D14T is capable of humus respiration utilizing various organic acids and some important environmental pollutants (e.g., toluene. etc) as electron donors and AQS or AQDS as a sole terminal electron acceptor under anaerobic condition. The dissimilatory reduction of 1mmol/L AQDS can couple to the production of enough ATP to support cell growth about 60 generations; The oxidization of electron donors was coupled to the reduction of humus, as reduced humus increased corresponding with increasing of electron donor; The typical inhibitors such as Cu2+ which inhibited Fe-S center, Stigmatellin which was methyl-naphthoquinone model, Dicumarol which inhibited oxidized methyl-naphthoquinone transform to reduced one, Metyrapone which was specific inhibitor for P450 enzyme blocked the humus respiration seriously. These were powerful evidences for humus-respiration by D14.