Effects of Oral Carotenoids on Oxidative Stress: A Systematic Review and Meta-Analysis of Studies in the Recent 20 Years.

Carotenoids protect organs, tissues, and cells from the damaging action of singlet oxygen, oxygen radicals, and lipid peroxides. This systematic review was sought to evaluate the influence of oral carotenoids on antioxidant/oxidative markers, blood carotenoids levels, and lipid/lipoprotein parameters in human subjects. A comprehensive review of relevant literature was conducted in PubMed, Web of Sciences, and the Cochrane library, from 2000 to December 2020. Randomized controlled trials, case-controlled trials, or controlled trials were identified. A total of eighteen trials were included, with the target populations being healthy subjects in 16 studies, athletes in 1 study, and pregnant women in 1 study. The meta-analysis results showed that carotenoids complex supplementation significantly increased the levels of antioxidative parameters ferric-reducing ability of plasma (FRAP) and oxygen radical absorbance capacity (ORAC) [standardized mean difference (SMD) = 0.468; 95% CI: 0.159-0.776, p = 0.003; SMD = 0.568; 95% CI: 0.190-0.947, p = 0.003] and decreased the blood triglyceride (TG) level (SMD = -0.410, 95% CI: -0.698 to -0.122, p = 0.005). Oral carotenoids supplement significantly increased the blood levels of ß-carotene (SMD = 0.490, 95% CI: 0.123-0.858, p = 0.009), α-tocopherol (SMD = 0.752, 95%CI: 0.020-1.485, p = 0.044), and the intaking durations were 8 weeks. The levels of antioxidative enzymes and other lipid/lipoprotein parameters were not different between subjects receiving carotenoids and controls (p > 0.05). In conclusion, our systematic review showed that the carotenoids complex is beneficial for alleviating potential oxidative stress via interacting with free radicals or decreasing blood TG levels. The intaking duration of carotenoids should be 8 weeks to reach enough concentration for function.

Phytochemistry and pharmacological activities of Arundina graminifolia (D.Don) Hochr. And other common Orchidaceae medicinal plants.

ETHNOPHARMACOLOGICAL RELEVANCE: Arundina graminifolia (Orchidaceae) has been widely used for heat clearance and detoxification, anti-inflammatory diuretic, and anti-microbes for two thousand years in national minorities, especially among the Dai people. It was known as "Zhuyelan" (Chinese: ), "Wenshanghai" (Chinese: ) and "Baiyangjie" (Chinese: ) in the Dai nationality, and mainly used as antidote, which is characterized by "relieving the poison before getting sick and treating illness". Therefore, it has been typically applied in the treatment of food poisoning, snake bites, rheumatism, stomachache and traumatic injuries. It is also used to treat bronchitis, tuberculosis and pneumonia in the Bulang and the Wa ethnic people. AIM OF THIS REVIEW: This review aims to provide up-to-date information about the botanical characterization, traditional uses, phytochemistry, and pharmacology of A. graminifolia, and the related importantly medicinal plants (e.g. Bletilla striata, Cremastra appendiculata, and Dendrobium officinale) of the same Orchidaceae family. Our work aims to further promote scientific cognition, basic research and in-depth discovery of potential drug candidates for Minority Medicine of our nation. MATERIALS AND METHODS: Relevant information was obtained via piles of resources including classic books about Chinese herbal medicine, and worldwide accepted scientific databases including Web of Science, Pubmed, Google Scholar, SciFinder, Elsevier, Springer, NCBI, ACS Publications, CNKI and Wanfang data. RESULTS: Phytochemical investigations have been intensively performed for these two decades, over 134 compounds, mainly include stilbenoids, phenanthrenes, quinones, ketones, phenolic acids, and glycosides, have been isolated and identified from A. graminifolia. The literature surveys exhibited that the ethnomedicinal uses of A. graminifolia, such as detoxification, anti-inflammation and the ability to cure trauma and pain associated with infections, are correlated with its modern pharmacological activities, including antibacterial, anti-oxidation, anti-lipid peroxidation. Stilbenoids and phenanthrenes have been regarded as the main active substances, among which stilbenoids with open ring style have superior antitumor activity. Furthermore, phytochemical investigations, biological activities, as well as the main molecular mechanism involved the coexisted stilbenoids and phenanthrenes from other most common used medicinal plants of the same Orchidaceae family were presented, compared and discussed together. CONCLUSIONS: This review presents the current research findings of A. graminifolia and three other related medicinal plants of the same family. Some of the traditional uses of A. graminifolia have been assessed by pharmacological studies. Despite A. graminifolia is used as an antidote and anti-aging dote, a few unsolved problems including the molecular mechanism underlying biological activities, pharmacokinetics, and in vivo detoxification tests still need to be settled extensively. Therefore, it is necessary to conduct a comprehensive survey and collect investigation information on A. graminifolia.

Gypenosides Altered Hepatic Bile Acids Homeostasis in Mice Treated with High Fat Diet.

Gypenosides extracted from Gynostemma pentaphyllum (Thunb.) Makino have significant role in reducing serum lipid level and treating fatty liver diseases, however, without clear mechanism. As gypenosides share the similar core structures with bile acids (the endogenous ligands of nuclear receptor FXR), we hypothesize that gypenosides may improve hypercholesterolemia via FXR-mediated bile acids signaling. The present study was designed to validate the role of gypenosides in reducing levels of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), as well as in regulating bile acids homeostasis and related gene expression levels. The C57BL/6 male mice were divided into four groups. Mice in groups ND and HFD were fed with normal diet and high fat diet for 38 weeks, respectively. In groups HFD+GP and HFD+ST, mice were fed with high fat diet for 38 weeks and treated with gypenosides and simvastatin (positive control) from weeks 16 to 38, respectively. Serum TC and LDL-C levels were assayed by commercially available kits. Expression levels of genes were tested by the quantitative real-time PCR. The LC-MS/MS was applied to quantify major bile acids in mice livers. Our results showed that gypenosides significantly decreased serum TC and LDL-C levels. The gene expression level of Shp was downregulated while the levels of Cyp7a1, Cyp8b1, Fxr, Lrh1, Jnk1/2, and Erk1/2 were upregulated by gypenosides. Indicated by LC-MS/MS technology, gypenosides increased the hepatic levels of several free bile acids and most taurine-conjugated bile acids while decreasing glycine-conjugated bile acids levels. In addition, gypenosides decreased the CA/CDCA ratio. Gypenosides may improve the abnormal lipid profile of HFD-fed mice via two pathways: (1) enhancing the bile acids biosynthesis from cholesterol; (2) decreasing the CA/CDCA ratio which is positively related to cholesterol absorption.

18ß-Glycyrrhetinic acid potently inhibits Kv1.3 potassium channels and T cell activation in human Jurkat T cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice has been extensively used in traditional medicines for treatment of many diseases, including inflammations and immunological disorders. Recent studies have shown that the anti-inflammatory and immunomodulation activities of licorice have been attributed to its active component, glycyrretinic acid (GA). GA consists of two isoforms, 18α- and 18ß-. However, its mechanism remains poorly understood. AIM OF THE STUDY: We compared the effects of two isoforms on Kv1.3 channels in Jurkat T cells and further characterized the inhibition of Kv1.3 channels by 18ß-GA in CHO cells. In addition, we examined the effects of 18ß-GA on Kv1.3 gene expression, Ca(2+) influx, proliferation, as well as IL-2 production in Jurkat T cells. MATERIALS AND METHODS: Whole-cell patch-clamp technique was applied to record Kv1.3 currents in Jurkat T or CHO cells. Real-time PCR and Western blotting were used to detect gene expression. Fluo-4, CCK-8 kit and ELISA kit were used to measure Ca(2+) influx, proliferation, and IL-2 secretion in Jurkat T cells, respectively. RESULTS: Superfusion of 18ß-GA (10-100 µM) blocked Kv1.3 currents in Jurkat T cells, while 18α-GA at the same concentration had no effect. The 18ß-GA induced inhibition had a voltage- and concentration-dependent manner with an IC50 of 23.9±1.5 µM at +40 mV in CHO cells. Furthermore, 18ß-GA significantly inhibited Kv1.3 gene expression. In addition, paralleling Kv1.3 inhibition, 18ß-GA also inhibited Ca(2+) influx, proliferation as well as IL-2 production in Jurkat T cells. CONCLUSION: 18ß-GA blocks Kv1.3 channels, which probably involves its anti-inflammatory and immunomodulation effects.

Aconitine blocks HERG and Kv1.5 potassium channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum has been widely used to treat various diseases in China for a long time. However, improper use of this drug results in severe intoxication. Aconitine (ACO), a diterpenoid alkaloid from aconitum, mainly contributes to cardio-toxic effects of aconitum and has also been commonly known to induce arrhythmias in animal models. However, its pro-arrhythmic mechanisms are not clear. AIM OF THE STUDY: The effects of ACO on HERG and Kv1.5 channels were investigated. MATERIALS AND METHODS: HERG and Kv1.5 channels were expressed in Xenopus laevis oocytes, and the resulting currents were recorded using a two-microelectrode voltage clamp technique. RESULTS: In HERG channels, ACO exhibited a blockade in a voltage- and time-dependent manner. The blockade was enhanced by further activation of currents, which were consistent with an open-channel blockade. In Kv1.5 channels, ACO produced a voltage-, time-, and frequency-dependent inhibition. The blockade was enhanced by higher rates of stimulation, consistent with preferential binding of the drug to the open state. In addition, ACO blocked Kv1.5 and HERG channels in a concentration-dependent manner with an IC(50) of 0.796+/-0.123 and 1.801+/-0.332 microM, respectively. CONCLUSIONS: ACO blocks HERG and Kv1.5 potassium channels in the open state. Blockade of potassium channels, particular the HERG channel, may be one of the important mechanisms of how ACO induces arrhythmias.

Effect of matrine on human ether à go-go related gene (HERG) channels expressed in Chinese hamster ovary cells.

OBJECTIVE: To observe the effect of matrine on human ether à go-go related gene (HERG) potassium channels expressed in Chinese hamster ovary (CHO) cells and investigate whether HERG channel is a new target of the pharmacological effect of matrine on arrhythmia and tumor METHODS: HERG channel potassium current in CHO cell was recorded using whole-cell patch-clamp technique, and the influence of matrine on the current was explored. RESULTS: Matrine inhibited HERG potassium current in a dose-dependent manner, and the 50% inhibitory concentration (IC IC(50)) was 411±23 µmol/L. Matrine had no significant effect on the activation kinetics, and mainly blocked HERG channels in their closed state. CONCLUSIONS: The blocking effect of matrine on HERG channels might be one of the mechanisms against arrythmias and tumors. Unlike most other blockers exerting blocking effect at the intracellular sites by entering the cell with the opening of HERG channel, matrine blocked HERG channels at the extracellular sites.

Glycyrretinic acid blocks cardiac sodium channels expressed in Xenopus oocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice has been used to treat many ailments including cardiovascular disorders in China for long time. Recent studies have shown that the cardiac actions of licorice have been attributed to its active component, glycyrretinic acid (GA). However, its mechanism remains poorly understood. AIM OF THE STUDY: The effects of GA on the cardiac sodium currents (I(Na)), L-type calcium currents (I(Ca,L)) and hyperpolarization-activated inward currents (I(f)) were investigated. MATERIALS AND METHODS: Human isoforms of wild-type and DeltaKPQ-mutant type sodium channels were expressed in Xenopus oocytes, and the resulting currents (peak and late I(Na)) were recorded using a two-microelectrode voltage-clamp technique. A perforated patch clamp technique was employed to record I(Ca,L) and I(f) from isolated rabbit sinoatrial node pacemaker cells. RESULTS: GA inhibited peak I(Na) (33% at 90 microM) and late I(Na) (72% at 90 microM), but caused no significant effects on I(Ca,L) and I(f). CONCLUSION: GA blocked cardiac sodium currents, particularly late I(Na.) Our findings might help to understand the traditional use of licorice in the treatment of cardiovascular disorders, because reduction of sodium currents (particularly late I(Na)) would be expected to provide protection from Na(+)-induced Ca(2+) overload and cell damage.

Blockade of the human ether-a-go-go-related gene potassium channel by ketanserin.

In the present study, we investigated the inhibitory action of ketanserin on wild-type (WT) and Y652 mutant human ether-a-go-go-related gene (HERG) potassium channels expressed in Xenopus oocytes and the effects of changing the channel molecular determinants characteristics on the blockade with and without ketanserin intervention using standard two-microelectrode voltage-clamp techniques. Point mutations were introduced into HERG gene (Y652A and Y652R) and subcloned into the pSP64 plasmid expression vector. Complementary RNAs for injection into oocytes were prepared with SP6 Cap-Scribe after linearization of the expression construct with EcoR I. Clampfit 9.2 software was employed for data collection and analysis. Origin 6.0 software was used to fit the data, calculate time constants and plot histograms. The results showed that ketanserin blocked WT HERG currents in voltage- and concentration-dependent manner and showed minimal tonic blockade of HERG current evaluated by the envelope of tails test. The IC50 value was (0.38+/-0.04) micromol/L for WT HERG potassium channel. The peaks of the I-V relationship for HERG channel suggested a negative shift in the voltage-dependence of activation after using ketanserin, whose midpoint of activation values (V1/2) were (-16.59+/-1.01) mV (control) vs (-20.59+/-0.87) mV (ketanserin) at 0.1 micromol/L, (-22.39+/-0.94) mV at 1 micromol/L, (-23.51+/-0.91) mV at 10 micromol/L, respectively (P<0.05, n=6). Characteristics of blockade were consistent with an open-state channel blockade, because the extent and rate of onset of blockade was voltage-dependent, increasing at more potentials even in the condition of leftward shift of activation curve. Meanwhile, in the different depolarization duration, the fractional blockade of end-pulse step current and peak tail current at 100 ms duration was significantly lower than that at 400 ms and 700 ms, which indicated that following the channel activation fractional blockade was enhanced by the activated channels. Ketanserin could also modulate the inactivation of HERG channel, which shifted the voltage-dependence of WT HERG channel inactivation curve from (-51.71+/-2.15) mV to (-80.76+/-14.98) mV (P<0.05, n=4). The S6 mutation, Y652A and Y652R, significantly attenuated the blockade by ketanserin. The IC50 value were (27.13+/-9.40) micromol/L and (20.20+/-2.80) micromol/L, respectively, increased by approximately 72-fold for Y652A and 53-fold for Y652R compared to that of WT HERG channel blockade [(0.38+/-0.04) micromol/L]. However, between the inhibitory effects of Y652A and Y652R, there was no significant difference. In conclusion, ketanserin blocks WT HERG currents in voltage- and concentration-dependent manner and preferentially blocks open-state HERG channels. Tyr-652 is one of the critical residues in the ketanserin-binding sites.