Preventive and therapeutic role of traditional Chinese herbal medicine in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. The clinical management of HCC remains a substantial challenge. Although surgical resection of tumor tissues seems promising, a high recurrence and/or metastasis rate accounting for disease-related death has led to an urgent need for improved postsurgical preventive/therapeutic clinical intervention. Developing advanced target-therapy agents such as sorafenib appears to be the only effective clinical intervention for patients with HCC to date, but only limited trials have been conducted in this regard. Because of their enhanced preventive/therapeutic effects, traditional Chinese herbal medicine (CHM)-derived compounds are considered suitable agents for HCC treatment. The CHM-derived compounds also possess multilevel, multitarget, and coordinated intervention effects, making them ideal candidates for inhibition of tumor progression and HCC metastasis. This article reviews the anticancer activity of various CHMs with the hope of providing a better understanding of how to best use CHM for HCC treatment.

3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout.

Hyperuricemia, excess of uric acid in the blood, is a clinical problem that causes gout and is also considered a risk factor for cardiovascular disease. The enzyme xanthine oxidase (XO) produces uric acid during the purine metabolism; therefore, discovering novel XO inhibitors is an important strategy to develop an effective therapy for hyperuricemia and gout. We found that 3,4-dihydroxy-5-nitrobenzaldehyde (DHNB), a derivative of the natural substance protocatechuic aldehyde, potently inhibited XO activity with an IC50 value of 3 µM. DHNB inhibited XO activity in a time-dependent manner, which was similar to that of allopurinol, a clinical XO inhibitory drug. DHNB displayed potent mixed-type inhibition of the activity of XO, and showed an additive effect with allopurinol at the low concentration. Structure-activity relationship studies of DHNB indicated that the aldehyde moiety, the catechol moiety, and nitration at C-5 were required for XO inhibition. DHNB interacted with the molybdenum center of XO and was slowly converted to its carboxylic acid at a rate of 10⁻¹° mol/L/s. In addition, DHNB directly scavenged free radical DPPH and ROS, including ONOO⁻ and HOCl. DHNB effectively reduced serum uric acid levels in allantoxanamide-induced hyperuricemic mice. Furthermore, mice orally given a large dose (500 mg/kg) of DHNB did not show any side effects, while 42% of allopurinol (500 mg/kg)-treated mice died and their offspring lost their fur. Thus, DHNB could be an outstanding candidate for a novel XO inhibitory drug that has potent activity and low toxicity, as well as antioxidant activity and a distinct chemical structure from allopurinol.

Reduced selenium-binding protein 1 in breast cancer correlates with poor survival and resistance to the anti-proliferative effects of selenium.

Supplemental dietary selenium is associated with reduced incidence of many cancers. The antitumor function of selenium is thought to be mediated through selenium-binding protein 1 (SELENBP1). However, the significance of SELENBP1 expression in breast cancer is still largely unknown. A total of 95 normal and tumor tissues assay and 12 breast cancer cell lines were used in this study. We found that SELENBP1 expression in breast cancer tissues is reduced compared to normal control. Low SELENBP1 expression in ER(+) breast cancer patients was significantly associated with poor survival (p<0.01), and SELENBP1 levels progressively decreased with advancing clinical stages of breast cancer. 17-ß estradiol (E2) treatment of high SELENBP1-expressing ER(+) cell lines led to a down-regulation of SELENBP1, a result that did not occur in ER(-) cell lines. However, after ectopic expression of ER in an originally ER(-) cell line, down-regulation of SELENBP1 upon E2 treatment was observed. In addition, selenium treatment resulted in reduced cell proliferation in endogenous SELENBP1 high cells; however, after knocking-down SELENBP1, we observed no significant reduction in cell proliferation. Similarly, selenium has no effect on inhibition of cell proliferation in low endogenous SELENBP1 cells, but the inhibitory effect is regained following ectopic SELENBP1 expression. Furthermore, E2 treatment of an ER silenced high endogenous SELENBP1 expressing cell line showed no abolishment of cell proliferation inhibition upon selenium treatment. These data indicate that SELENBP1 expression is regulated via estrogen and that the cell proliferation inhibition effect of selenium treatment is dependent on the high level of SELENBP1 expression. Therefore, the expression level of SELENBP1 could be an important marker for predicting survival and effectiveness of selenium supplementation in breast cancer. This is the first study to reveal the importance of monitoring SELENBP1 expression as a potential biomarker in contributing to breast cancer prevention and treatment.

Molecular mechanisms and clinical applications of nordihydroguaiaretic acid (NDGA) and its derivatives: an update.

Creosote bush, Larrea tridentata, is known as chaparral or greasewood in the United States and as gobernadora or hediondilla in Mexico. Nordihydroguaiaretic acid (NDGA), the main metabolite of the creosote bush, has been shown to have promising applications in the treatment of multiple diseases, including cardiovascular diseases, neurological disorders and cancers. Creosote bush is a promising agent of North American herbal medicine, and it has extensive pharmacological effects and specific mechanisms of actions. This review provides an update of recent in vitro and in vivo research about NDGA and describes experimental studies using NDGA as antioxidant. Also, potential medical uses based on the effects of NDGA on the cardiovascular, immune and neurological systems; cancer; tissue engineering; as well as pharmacokinetics and toxicity are discussed.

The soybean isoflavonoid equol blocks ritonavir-induced endothelial dysfunction in porcine pulmonary arteries and human pulmonary artery endothelial cells.

HIV protease inhibitor (PI) ritonavir (RTV) may cause vascular injury through oxidative stress. Our purpose in this study was to determine whether equol, a soy isoflavone, could prevent RTV-induced endothelial dysfunction in porcine pulmonary arteries and in human pulmonary artery endothelial cells (HPAEC). Fresh porcine pulmonary artery rings were treated with 15 micromol/L of RTV and/or equol in concentrations of 0.1, 1, and 10 micromol/L for 24 h. A control was set with no amount of equol or RTV administered. Based on myograph tension analysis, RTV significantly reduced endothelium-dependent relaxation in response to bradykinin in the artery rings compared with untreated vessels, whereas the antioxidant equol effectively reversed the RTV effect in a concentration-dependent manner. RTV also reduced the contraction of artery rings in response to thromboxane A(2) analogue U46619 and this reduction was blocked by equol. In addition, RTV treatment significantly reduced endothelial nitric oxide synthase (eNOS) expression in both porcine pulmonary arteries and HPAEC, whereas equol effectively blocked RTV-induced eNOS downregulation. Furthermore, RTV significantly increased superoxide anion production, whereas equol reversed this effect of RTV in porcine pulmonary arteries. Thus, the antioxidant equol effectively protects vascular function from the detrimental effects of HIV PI RTV in both porcine pulmonary arteries and HPAEC via a reduction in the vasomotor dysfunction, eNOS downregulation, and oxidative stress induced by RTV. These novel data suggest that equol may have a clinical application in preventing HIV-associated cardiovascular complications.

Ginseng compounds: an update on their molecular mechanisms and medical applications.

Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications. Ginsenosides, the major pharmacologically active ingredients of ginseng, appear to be responsible for most of the activities of ginseng including vasorelaxation, antioxidation, anti-inflammation and anti-cancer. Approximately 40 ginsenoside compounds have been identified. Researchers now focus on using purified individual ginsenoside to reveal the specific mechanism of functions of ginseng instead of using whole ginseng root extracts. Individual ginsenosides may have different effects in pharmacology and mechanisms due to their different chemical structures. Among them the most commonly studied ginsenosides are Rb1, Rg1, Rg3, Re, Rd and Rh1. The molecular mechanisms and medical applications of ginsenosides have attracted much attention and hundreds of papers have been published in the last few years. The general purpose of this update is to provide information of recently described effects of ginsenosides on antioxidation, vascular system, signal transduction pathways and interaction with receptors. Their therapeutic applications in animal models and humans as well as the pharmacokinetics and toxicity of ginsenosides are also discussed in this review. This review concludes with some thoughts for future directions in the further development of ginseng compounds as effective therapeutic agents.

Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells.

BACKGROUND: Kaempferol is one of the most important constituents in ginkgo flavonoids. Recent studies indicate kaempferol may have antitumor activities. The objective of this study was to determine the effect and mechanisms of kaempferol on pancreatic cancer cell proliferation and apoptosis. MATERIALS AND METHODS: Pancreatic cancer cell lines MIA PaCa-2 and Panc-1 were treated with kaempferol, and the inhibitory effects of kaempferol on pancreatic cancer cell proliferation were examined by direct cell counting, 3H-thymidine incorporation, and MTS assay. Lactate dehydrogenase release from cells was determined as an index of cytotoxicity. Apoptosis was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. RESULTS: Upon the treatment with 70 microm kaempferol for 4 days, MIA PaCa-2 cell proliferation was significantly inhibited by 79% and 45.7% as determined by direct cell counting and MTS assay, respectively, compared with control cells (P < 0.05). Similarly, the treatment with kaempferol significantly inhibited Panc-1 cell proliferation. Kaempferol treatment also significantly reduced 3H-thymidine incorporation in both MIA PaCa-2 and Panc-1 cells. Combination treatment of low concentrations of kaempferol and 5-fluorouracil showed an additive effect on the inhibition of MIA PaCa-2 cell proliferation. Furthermore, kaempferol had significantly less cytotoxicity than 5-fluorouracil in normal human pancreatic ductal epithelial cells (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, apoptotic cell population was increased when treated with kaempferol in a concentration-dependent manner. CONCLUSIONS: Ginkgo biloba extract kaempferol effectively inhibits pancreatic cancer cell proliferation and induces cancer cell apoptosis, which may sensitize pancreatic tumor cells to chemotherapy. Kaempferol may have clinical applications as adjuvant therapy in the treatment of pancreatic cancer.

Rheolytic pharmacomechanical thrombectomy in experimental chronic deep vein thrombosis: effect of L-arginine on thrombogenicity and endothelial vasomotor function.

PURPOSE: Endovascular removal of intravascular thrombus using the AngioJet rheolytic thrombectomy (RT) system has been shown to be clinically effective. This system also permits the concomitant infusion of thrombolytic agent followed by thrombectomy, thus creating a novel strategy known as pharmacomechanical thrombectomy (PMT). Although these interventions have gained wide clinical application, little is known regarding the vessel wall response following thrombectomy therapy. The aims of this study were to assess the effect of thrombectomy interventions on endothelial function in a porcine model of deep venous thrombosis (DVT) and to evaluate the effect of nitric oxide (NO) precursor L-arginine on endothelial function following thrombectomy therapy. METHODS: Deep vein thrombosis was created in bilateral iliac veins by deploying a self-expanding stent-graft incorporating an intraluminal stenosis from a groin approach. Five pigs underwent sham operation. Following 14 days of DVT, animals were randomized to three groups: the first group received RT treatment (RT group, n = 5); the second group received pharmacomechanical thrombectomy (PMT) with tissue plasminogen activator (alteplase 10 mg; PMT group, n = 5); and the third group received PMT with tPA plus intravenous L-arginine (20 mmol/l) (arginine group, n = 5). Iliac vein patency was evaluated by venography and intravascular ultrasound at 1 week. Nitric oxide level was determined by a chemiluminescent assay of the nitrite/nitrate metabolites (NO(x)). Thrombogenicity was evaluated by radiolabeled platelet and fibrin deposition. Veins were harvested and evaluated with light microscopy and scanning electron microscopy (SEM). Endothelial function was evaluated using organ chamber analysis. RESULTS: The luminal areas in the sham, RT, PMT, and arginine groups were 34 +/- 10 mm(2), 21 +/- 13 mm(2), 35 +/- 18 mm(2), and 37 +/- 16 mm(2), respectively. All iliac veins remained patent at 2 weeks. No difference in endothelial cell structure was observed between the three treatment groups by means of light microscopic or SEM examination. A decrease in platelet deposition occurred in the arginine group compared to the RT and PMT groups (P < 0.05). The arginine group also showed a greater endothelium-dependent relaxation compared to the RT or PMT groups in response to A23187, bradykinin, and ADP (P < 0.05). Local NO(x) level was higher in the arginine group than in the RT or PMT group (2.6 +/- 0.6 micromol/l versus 0.3 +/- 0.1 micromol/l and 0.3 +/- 0.2 micromol/l; P < 0.01). CONCLUSIONS: AngioJet RT and PMT interventions resulted in similar attenuated endothelium-dependent vasoreactivity and morphologic effect. L-Arginine supplementation preserves endothelial vasoreactivity and reduces platelet deposition following PMT in iliac DVT. Additionally, L-arginine enhances NO production at sites of venous thrombosis. The NO precursor L-arginine may have a therapeutic potential in preserving endothelial function following mechanical thrombectomy.

Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries.

BACKGROUND: Homocysteine is an independent risk factor for atherosclerosis. The objective of this study was to investigate whether ginkgolide A (GA), a major constituent of Ginkgo biloba, could block homocysteine-induced endothelial dysfunction in porcine coronary arteries. METHODS: Porcine coronary artery rings were assigned to six treatment groups: control; homocysteine (50 micromol/L); low-dose (50 micromol/L) or high-dose (100 micromol/L) GA; and homocysteine plus low-dose or high-dose GA. After 24 hours' incubation, the rings were analyzed for vasomotor function in response to a thromboxane A2 analogue (U46619), bradykinin, and sodium nitroprusside. Endothelial nitric oxide synthase (eNOS) was studied by using real-time polymerase chain reaction and immunohistochemistry analysis. Superoxide anion production was assessed by chemoluminescence analysis. RESULTS: Endothelium-dependent relaxation (bradykinin) was significantly reduced in ring segments treated with homocysteine as compared with the control (P < .05). When homocysteine was combined with either low-dose or high-dose GA, endothelium-dependent relaxation was markedly recovered. There was no significant difference in maximal contraction (U46619) or endothelium-independent relaxation (sodium nitroprusside) among all groups. In addition, superoxide anion production was increased by 113% in the homocysteine-treated group, whereas there was no statistically significant difference between the control and GA/homocysteine groups. Furthermore, eNOS messenger RNA and protein levels were substantially reduced in the homocysteine-treated group (P < .05), but not in the GA/homocysteine combined groups. CONCLUSIONS: Homocysteine significantly impairs endothelium-dependent vasorelaxation through oxidative stress and downregulation of eNOS in porcine coronary arteries. GA effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores the potential clinical benefits and applications of GA in controlling homocysteine-associated vascular injury and cardiovascular disease. CLINICAL RELEVANCE: Homocysteine is an independent risk factor for atherosclerosis. This study showed that ginkgolide A, a major constituent of Ginkgo biloba, effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores potential clinical benefits and applications of ginkgolide A in controlling homocysteine-associated vascular injury and cardiovascular disease.

Clinical use and molecular mechanisms of action of extract of Ginkgo biloba leaves in cardiovascular diseases.

Ginkgo biloba is one of the oldest living tree species that has been referred to as a living fossil. Extract from Ginkgo biloba leaves (GBE) is among the most commonly used herbal drugs and is popularized for its alleged tonic effect and possible curative and restorative properties. There is an increasing evidence of the potential role of GBE in treating cardiovascular diseases. We examined the history of GBE usage and reviewed the literature on its effects on the cardiovascular system. In the extensive studies involving cell cultures and animal models, GBE has been shown to exert its action through diverse mechanisms. GBE has been reported to have antioxidatant properties, to modify vasomotor function, to reduce adhesion of blood cells to endothelium, to inhibit activation of platelets and smooth muscle cells, to affect ion channels, and to alter signal transduction. In addition, relevant clinical trials with CBE are being carried out, particularly in the treatment of arterial and venous insufficiency and in the prevention of thrombosis. Finally, the controversial clinical findings and the possible adverse interactions between GBE and other drugs are discussed. This review underscores the potential benefits of Ginkgo biloba in cardiovascular diseases, highlights the gaps in our current research, and suggests the necessity for more rigorous systematic investigation of cardiovascular properties of CBE.

Molecular mechanisms and clinical applications of ginseng root for cardiovascular disease.

Ginseng root is used extensively in traditional Chinese medicine for its alleged tonic effect and possible curative and restorative properties. There are increasing evidences in the literature on the potential role of ginseng in treating cardiovascular diseases. We herein examine the history of ginseng usage and review the current literature on a myriad pharmacological function of ginseng on the cardiovascular system. From the published studies involving cell cultures and animal models, ginseng is shown to have potential benefits on the cardiovascular system through diverse mechanisms, including antioxidant, modifying vasomotor function, reducing platelet adhesion, influencing ion channels, altering autonomic neurotransmitters release, improving lipid profiles, and involving in glucose metabolism and glycemic control. In addition, the relevant clinical trials regarding the effects of ginseng on the cardiovascular disease are summarized, particularly in managing hypertension and improving cardiovascular function. Finally, the controversies in the literature and the possible adverse interactions between ginseng and other drugs are discussed. This review underscores the potential benefit effects of ginseng on cardiovascular diseases, highlights the gaps in our current research, and emphasizes the necessity for more rigorous systemic investigation.

L-arginine improves endothelial vasoreactivity and reduces thrombogenicity after thrombolysis in experimental deep venous thrombosis.

PURPOSE: Nitric oxide (NO) is important in regulation of platelet aggregation, endothelial function, and intravascular thrombosis. The purposes of this study were to assess the effect of thrombolysis on endothelial function in a porcine model of deep venous thrombosis (DVT) and to evaluate the effect of NO precursor l-arginine on endothelial function after thrombolytic therapy. METHODS: DVT was created in bilateral iliac veins by deploying a self-expanding stent-graft that incorporated an intraluminal stenosis, from a groin approach. Five pigs underwent sham operation. After 7 days of DVT, animals were randomized to three groups: saline pulse-spray (saline group, n = 5), thrombolytic pulse-spray with tissue plasminogen activator (alteplase, 8 mg; t-PA group, n = 5), and thrombolytic pulse-spray plus intravenous l-arginine (20 mmol/L; arginine group, n = 5). At 2 weeks iliac vein patency was evaluated at venography and intravascular ultrasound scanning. NO level was determined with a chemiluminescent assay of the nitrite and nitrate metabolites (NO(x)). Thrombogenicity was evaluated with radiolabeled platelet and fibrin deposition. Veins were harvested and evaluated with light microscopy and scanning electron microscopy. Endothelial function was evaluated with organ chamber analysis. RESULTS: All iliac veins remained patent at 2 weeks. The luminal areas in the sham, saline, t-PA, and arginine groups were 53 +/- 23 mm(2), 14 +/- 11 mm(2), 34 +/- 19 mm(2), and 42 +/- 21 mm(2), respectively. No difference in endothelial cell structure was observed between the three treatment groups at light microscopy or scanning electron microscopy. Although no difference in fibrin deposition was noted among the three treatment groups, decreased platelet deposition occurred in the arginine group compared with the saline or t-PA groups (P <.05). The arginine group showed greater endothelial-dependent relaxation compared with the t-PA or saline groups (73% +/- 23% vs 49% +/- 18% and 32% +/- 21%; P <.05). Local NO(x) level in the arginine group was correspondingly higher compared with the saline or t-PA groups (1.8 +/- 0.3 micromol/L vs 0.3 +/- 0.05 micromol/L and 0.2 +/- 0.04 micromol/L; P <.05). CONCLUSIONS: NO precursor l-arginine supplementation enhances NO production at sites of venous thrombosis. Moreover, l-arginine preserves endothelial vasoreactivity and reduces platelet deposition after thrombolysis in iliac DVT. These data suggest that l-arginine may preserve endothelial function after thrombolysis and may reduce the likelihood of postthrombotic syndrome.