Capsaicin reduces blood glucose and prevents prostate growth by regulating androgen, RAGE/IGF-1/Akt, TGF-ß/Smad signalling pathway and reversing epithelial-mesenchymal transition in streptozotocin-induced diabetic mice.

Type 2 diabetes mellitus (T2DM) is a metabolic disease. Diabetes increases the risk of benign prostatic hyperplasia (BPH). Capsaicin is extracted from chili peppers and possesses many pharmacological properties, including anti-diabetic, pain-relieving, and anti-cancer properties. This study aimed to investigate the effects of capsaicin on glucose metabolism and prostate growth in T2DM mice and uncover the related mechanisms. Mice model of diabetes was established by administering a high-fat diet and streptozotocin. Oral administration of capsaicin for 2 weeks inhibited prostate growth in testosterone propionate (TP)-treated mice. Furthermore, oral administration of capsaicin (5 mg/kg) for 2 weeks decreased fasting blood glucose, prostate weight, and prostate index in diabetic and TP-DM mice. Histopathological alterations were measured using hematoxylin & eosin (H&E) staining. The protein expression of 5α-reductase type II, androgen receptor (AR), and prostate-specific antigen (PSA) were upregulated in diabetic and TP-DM mice, but capsaicin reversed these effects. Capsaicin decreased the protein expression of p-AKT, insulin-like growth factor-1 (IGF-1), IGF-1R, and the receptor for advanced glycation end products (RAGE) in diabetic and TP-DM mice. Capsaicin also regulated epithelial-mesenchymal transition (EMT) and modulated the expression of fibrosis-related proteins, including E-cadherin, N-cadherin, vimentin, fibronectin, α-SMA, TGFBR2, TGF-ß1, and p-Smad in TP-DM mice. In this study, capsaicin alleviated diabetic prostate growth by attenuating EMT. Mechanistically, capsaicin affected EMT by regulating RAGE/IGF-1/AKT, AR, and TGF-ß/Smad signalling pathways. These results provide with new therapeutic approach for treating T2DM or T2DM-induced prostate growth.

Neferine attenuates development of testosterone-induced benign prostatic hyperplasia in mice by regulating androgen and TGF-ß/Smad signaling pathways.

Benign prostatic hyperplasia (BPH) is a common urinary disease among the elderly, characterized by abnormal prostatic cell proliferation. Neferine is a dibenzyl isoquinoline alkaloid extracted from Nelumbo nucifera and has antioxidant, anti-inflammatory and anti-prostate cancer effects. The beneficial therapeutic effects and mechanism of action of neferine in BPH remain unclear. A mouse model of BPH was generated by subcutaneous injection of 7.5 mg/kg testosterone propionate (TP) and 2 or 5 mg/kg neferine was given orally for 14 or 28 days. Pathological and morphological characteristics were evaluated. Prostate weight, prostate index (prostate/body weight ratio), expression of type Ⅱ 5α-reductase, androgen receptor (AR) and prostate specific antigen were all decreased in prostate tissue of BPH mice after administration of neferine. Neferine also downregulated the expression of pro-caspase-3, uncleaved PARP, TGF-ß1, TGF-ß receptor Ⅱ (TGFBR2), p-Smad2/3, N-cadherin and vimentin. Expression of E-cadherin, cleaved PARP and cleaved caspase-3 was increased by neferine treatment. 1-100 µM neferine with 1 µM testosterone or 10 nM TGF-ß1 were added to the culture medium of the normal human prostate stroma cell line, WPMY-1, for 24 h or 48 h. Neferine inhibited cell growth and production of reactive oxygen species (ROS) in testosterone-treated WPMY-1 cells and regulated the expression of androgen signaling pathway proteins and those related to epithelial-mesenchymal transition (EMT). Moreover, TGF-ß1, TGFBR2 and p-Smad2/3, N-cadherin and vimentin expression were increased but E-cadherin was decreased after 24 h TGF-ß1 treatment in WPMY-1 cells. Neferine reversed the effects of TGF-ß1 treatment in WPMY-1 cells. Neferine appeared to suppress prostate growth by regulating the EMT, AR and TGF-ß/Smad signaling pathways in the prostate and is suggested as a potential agent for BPH treatment.

Sinularin Exerts Anti-cancer Effects by Inducing Oxidative Stress-mediated Ferroptosis, Apoptosis, and Autophagy in Prostate Cancer Cells.

INTRODUCTION: Prostate cancer is the second-leading cause of cancer death in men. Sinularin is a soft coralsderived natural compound that has anticancer activity in many cancer cells. However, the pharmacological action of sinularin in prostate cancer is unclear. AIM: The aim of the study is to examine the anticancer effects of sinularin in prostate cancer cells. METHODS: We explored the anticancer effects of sinularin on the prostate cancer cell lines, PC3, DU145, and LNCaP, by MTT, Transwell assay, wound healing, flow cytometry, and western blotting. RESULTS: Sinularin inhibited the cell viability and colony formation of these cancer cells. Furthermore, sinularin inhibited testosterone-induced cell growth in LNCaP cells by downregulating the protein expression levels of androgen receptor (AR), type Ⅱ 5α-reductase, and prostate-specific antigen (PSA). Sinularin significantly attenuated the invasion and migration ability of PC3 and DU145 cells, with or without TGF-ß1 treatment. Sinularin inhibited epithelialmesenchymal transition (EMT) in DU145 cells after 48 h of treatment by regulating the protein expression levels of Ecadherin, N-cadherin, and vimentin. Sinularin induced apoptosis, autophagy, and ferroptosis by regulating the protein expression levels of Beclin-1, LC3B, NRF2, GPX4, PARP, caspase-3, caspase-7, caspase-9, cleaved-PARP, Bcl-2, and Bax. Moreover, intracellular reactive oxygen species (ROS) were increased but glutathione was decreased after sinularin treatment in PC3, DU145 and LNCaP cells. CONCLUSION: Sinularin regulated the androgen receptor signaling pathway and triggered apoptosis, autophagy, and ferroptosis in prostate cancer cells. In conclusion, the results indicated that sinularin may be a candidate agent for human prostate cancer and need further study for being applied to human.

6-Gingerol suppresses cell viability, migration and invasion via inhibiting EMT, and inducing autophagy and ferroptosis in LPS-stimulated and LPS-unstimulated prostate cancer cells.

6-Gingerol is a bioactive compound isolated from Zingiber officinale. 6-Gingerol has been shown to have anticancer effects in numerous types of cancer cell. The mechanisms underlying the anticancer effect of 6-Gingerol in prostate cancer requires investigation. In the present study, the effect on cell viability of 6-Gingerol on LNCaP, PC3 and DU145 prostate cancer cells were determined using the MTT and colony formation assays. 6-Gingerol significantly inhibited cell migration, adhesion and invasion in LPS-stimulated and LPS-unstimulated prostate cancer cells. Furthermore, these changes were accompanied by alterations in the protein expression levels of epithelial-mesenchymal transition biomarkers, including E-cadherin, N-cadherin, Vimentin and zonula occludens-1. 6-Gingerol also induced autophagy by significantly increasing LC3B-II and Beclin-1 protein expression levels in prostate cancer cells. Combining 6-Gingerol with LY294002, an autophagy inhibitor, significantly increased cell survival in DU145 cells. Furthermore, 6-Gingerol significantly decreased the protein expression levels of glutathione (GSH) peroxidase 4 and nuclear factor erythroid 2-related factor 2 in prostate cancer cells. Reactive oxygen species (ROS) levels were significantly increased but GSH levels were decreased following 6-Gingerol treatment in prostate cancer cells. Co-treatment with the ferroptosis inhibitor, ferrostatin-1, significantly increased cell viability and significantly decreased ROS levels in 6-Gingerol-treated cells. These results suggested that 6-Gingerol may have inhibited prostate cell cancer viability via the regulation of autophagy and ferroptosis. In addition, 6-Gingerol inhibited cell migration, adhesion and invasion via the regulation of EMT-related protein expression levels in LPS-stimulated and LPS-unstimulated prostate cancer cells. In conclusion, 6-Gingerol may induce protective autophagy, autophagic cell death and ferroptosis-mediated cell death in prostate cancer cells. These findings may provide a strategy for the treatment and prevention of prostate cancer.

The antiandrogenic effect of neferine, liensinine, and isoliensinine by inhibiting 5-α-reductase and androgen receptor expression via PI3K/AKT signaling pathway in prostate cancer.

Neferine, liensinine, and isoliensinine are bisbenzylisoquinoline alkaloids extracted from seed-embryos of Nelumbo nucifera Gaertn. In this study, we evaluated the anticancer activities and mechanism of action of these natural products in prostate cancer cells by MTT, wound healing, ELISA and Western blotting. Neferine, liensinine, and isoliensinine showed growth inhibition and displayed a significant anti-migration activity in prostate cancer cells. They induced apoptosis and autophagy by activating cleaved caspase-9, cleaved PAPR, Bax, LC3B-II, but decreased Bcl-2 and PARP protein expression in LNCaP cells 24 h after treatments. The apoptotic and cytotoxic effects of neferine, liensinine, and isoliensinine were significantly attenuated in the presence of the caspase inhibitor, Z-VAD-FMK. However, the effects were enhanced in the presence of Akt inhibitor (MK2206) and PI3K inhibitor (LY294002). Moreover, neferine, liensinine, and isoliensinine also downregulated the protein expression of androgen receptor, prostate-specific antigen, and type II 5-α-reductase. These results demonstrated that these bisbenzylisoquinoline alkaloids have the potential as promising therapeutics agents. They induced apoptosis via inactivation with the PI3K/AKT signal pathway.

Involvement of Aquaporins in the Intense Pulsed Light-Enhanced Wound Healing in Diabetic Rats.

BACKGROUND AND OBJECTIVES: We previously demonstrated that intense pulsed light (IPL) irradiation prior to wounding improved the wound healing in rats with diabetes mellitus (DM). Also, we found that IPL upregulated the expression of aquaporin 3 (AQP3), a protein that is crucial for wound healing, in normal rats. This present study aimed to examine the involvement of AQPs in the IPL-enhanced wound healing in diabetic rats. STUDY DESIGN/MATERIALS AND METHODS: Streptozotocin was used to induce diabetes in Sprague-Dawley rats. Animals were divided into four groups: normal group, DM only group, DM rats with IPL treatment 2 weeks before wounding (DM + IPL-Pre group), and DM rats with concurrent IPL irradiation and wounding (DM + IPL-Con group). Wounds were created on the dorsal skin of rats. The expressions of AQP1, 3, 4, 7, and 9 in the pre-injured skin, periwound, and wound were determined. RESULTS: Among all the AQPs analyzed, only the expressions of AQP3 and AQP7 were significantly altered. Unirradiated diabetic rats showed much higher expression level of AQP3 in the regenerating skin compared with normal rats. IPL pretreatment, but not concurrent treatment, attenuated the expression toward the level detected in the normal wounds. In contrast, a lower expression level of AQP7 was noted in the regenerating skin of DM only rats and IPL pretreatment upregulated the expression to a level similar to that in the normal rats. CONCLUSION: The beneficial effect of IPL pretreatment on the wound healing in diabetic rats might involve a mechanism by which the expression of AQPs is regulated. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Magnetic Graphene-Based Sheets for Bacteria Capture and Destruction Using a High-Frequency Magnetic Field.

Magnetic reduced graphene oxide (MRGO) sheets were prepared by embedding Fe3O4 nanoparticles on polyvinylpyrrolidone (PVP) and poly(diallyldimethylammonium chloride) (PDDA)-modified graphene oxide (GO) sheets for bacteria capture and destruction under a high-frequency magnetic field (HFMF). The characteristics of MRGO sheets were evaluated systematically by transmission electron microscopy (TEM), scanning electron microscopy (SEM), zeta potential measurement, X-ray diffraction (XRD), vibrating sample magnetometry (VSM), and X-ray photoelectron spectroscopy (XPS). TEM observation revealed that magnetic nanoparticles (8-10 nm) were dispersed on MRGO sheets. VSM measurements confirmed the superparamagnetic characteristics of the MRGO sheets. Under HFMF exposure, the temperature of MRGO sheets increased from 25 to 42 °C. Furthermore, we investigated the capability of MRGO sheets to capture and destroy bacteria (Staphylococcus aureus). The results show that MRGO sheets could capture bacteria and kill them through an HFMF, showing a great potential in magnetic separation and antibacterial application.

Docosahexaenoic acid inhibits lipopolysaccharide-induced metastatic activities by decreasing inflammation on prostate cancer cell.

Docosahexaenoic acid (DHA) is rich in fish oil with many pharmacological impacts such as anti-inflammation and anti-cancer activities. In the present study, we aimed to investigate the inhibitory effects of DHA on the invasion and inflammation in prostate cancer cells. The cytotoxicity of DHA with or without lipopolysaccharides (LPS) treatment was evaluated by MTT assay. The invasion and wound healing assays were used to determine the roles of DHA in cell migration and invasion after LPS treatment. The expression levels of IL-6 and IL-8 were detected using ELISA assay. The protein expression was investigated by Western blotting. DHA exhibited significant cytotoxicity at the concentration of 100 µM in PC3 cells. Exposure to DHA (6, 12 and 25 µM) dose-dependently inhibited invasion and wound closure potential in PC3 cells after LPS treatment. DHA dose-dependently downregulated LPS-induced expression levels of IL-6 and IL-8. In addition, the LPS-induced protein levels of p-AKT and COX-2 were suppressed by DHA treatment. Our results indicate that low doses of DHA effectively inhibit metastasis by decreasing IL-6, IL-8, p-AKT and COX-2 expression levels after LPS treatment.

The Cancer Prevention, Anti-Inflammatory and Anti-Oxidation of Bioactive Phytochemicals Targeting the TLR4 Signaling Pathway.

Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors that play an important role in a host immune system. TLR triggering leads to the induction of pro-inflammatory cytokines and chemokines, driving the activation of both innate and adaptive immunity. Recently, an increasing number studies have shown the link between TLRs and cancer. Among them, the toll-like receptor 4 (TLR4) signaling pathway is associated with inflammatory response and cancer progression. Dietary phytochemicals are potential modulators of immunological status with various pharmacological properties including anti-cancer, anti-oxidant and anti-inflammatory. Curcumin, 6-gingerol, 6-shogaol, 1-dehydro-10-gingerdione, epigallocatechin gallate (EGCG), luteolin, quercetin, resveratrol, caffeic acid phenethyl ester, xanthohumol, genistein, berberine, and sulforaphane can inhibit TLR4 activation. The aim of the present review is to describe the role of the TLR4 signaling pathway between inflammatory response and cancer progression. We further introduce bioactive phytochemicals with potential anti-inflammation and chemoprevention by inhibiting TLR activation.

Resveratrol prevents nanoparticles-induced inflammation and oxidative stress via downregulation of PKC-α and NADPH oxidase in lung epithelial A549 cells.

BACKGROUND: Exposure to carbon black nanoparticles (CBNPs), a well-known industrial production, promotes pulmonary toxicity through inflammation and oxidative stress. Recent studies show that some polyphenols exert their antioxidant properties through regulation of protein kinase C-α (PKC-α) and NADPH oxidase (Nox) signaling. Resveratrol, a dietary polyphenol in fruits, possesses various health beneficial effects including anti-inflammatory and antioxidative properties. In this study, we aimed to elucidate the involvement of PKC-α and Nox in CBNPs-induced inflammation and oxidative stress, and to investigate the protective effects of resveratrol on CBNP-induced inflammation and oxidative stress in human lung epithelial A549 cells. METHODS: The production of reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm) were measured by flow cytometry. Nitric oxide (NO) was measured using the Griess reagent, and prostaglandin E2 (PGE2) production was detected by ELISA, while protein expressions were measured by Western blotting analysis. RESULTS: In lung epithelial A549 cells, CBNPs significantly enhanced oxidative stress by upregulation of Nox2 and membrane expression of p67phox accompanied with increase of ROS production. CBNPs also increased inflammatory factors, including iNOS, COX-2, NO and PGE2. However, resveratrol attenuated the above effects induced by CBNPs in A549 cells; additionally, CBNPs-induced activation of PKC-α was observed. We found that PKC-α inhibitor (Gö6976) could attenuate CBNPs-induced inflammation by down-regulation of ROS, NO and PGE2 production in A549 cells, suggesting PKC-α might be involved in CBNPs-induced oxidative stress and inflammation. Our results also found resveratrol was able to inhibit protein expression of PKC-α induced by CBNPs. Moreover, ROS scavenger (NAC) and Nox inhibitor (DPI) attenuated CBNPs-induced expressions of iNOS and COX-2. DPI could also attenuate CBNPs-induced ROS, NO and PGE2 production. CONCLUSIONS: Resveratrol attenuated CBNPs-induced oxidative and inflammatory factors in lung epithelial A549 cells, at least in part via inhibiting PKC-α- and Nox-related signaling.

Ginger Phytochemicals Inhibit Cell Growth and Modulate Drug Resistance Factors in Docetaxel Resistant Prostate Cancer Cell.

Ginger has many bioactive compounds with pharmacological activities. However, few studies are known about these bioactive compounds activity in chemoresistant cells. The aim of the present study was to investigate the anticancer properties of ginger phytochemicals in docetaxel-resistant human prostate cancer cells in vitro. In this study, we isolated 6-gingerol, 10-gingerol, 4-shogaol, 6-shogaol, 10-shogaol, and 6-dehydrogingerdione from ginger. Further, the antiproliferation activity of these compounds was examined in docetaxel-resistant (PC3R) and sensitive (PC3) human prostate cancer cell lines. 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol at the concentration of 100 µM significantly inhibited the proliferation in PC3R but 6-gingerol, 6-shogaol, and 10-shogaol displayed similar activity in PC3. The protein expression of multidrug resistance associated protein 1 (MRP1) and glutathione-S-transferase (GSTπ) is higher in PC3R than in PC3. In summary, we isolated the bioactive compounds from ginger. Our results showed that 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol inhibit the proliferation of PC3R cells through the downregulation of MRP1 and GSTπ protein expression.

Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na(+) and Ca(2+) -activated K(+) currents in GH3 pituitary tumour cells.

BACKGROUND AND PURPOSE: 7-[2-[4-(2-Chlorophenyl)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) is a xanthine-based derivative. It has soluble GC activation and K(+) -channel opening activity. Effects of this compound on ion currents in pituitary GH3 cells were investigated in this study. EXPERIMENTAL APPROACH: The aim of this study was to evaluate effects of KMUP-1 on the amplitude and gating of voltage-gated Na(+) current (INa ) in pituitary GH3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca(2+) -activated K(+) current and the activity of large-conductance Ca(2+) -activated K(+) (BKCa ) channels were also studied. KEY RESULTS: KMUP-1 depressed the transient and late components of INa with different potencies. The IC50 values required for its inhibitory effect on transient and late INa were 22.5 and 1.8 µM respectively. KMUP-1 (3 µM) shifted the steady-state inactivation of INa to a hyperpolarized potential by -10 mV, despite inability to alter the recovery of INa from inactivation. In cell-attached configuration, KMUP-1 applied to bath increased BKCa -channel activity; however, in inside-out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP-1 decreased the peak INa with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A. CONCLUSIONS AND IMPLICATIONS: Apart from activating BKCa channels, KMUP-1 preferentially suppresses late INa . The effects of KUMP-1 on ion currents presented here constitute an underlying ionic mechanism of its actions.

Biofunctional Constituents from Michelia compressa var. lanyuensis with Anti-Melanogenic Properties.

Seven compounds were extracted and purified from the roots of Michelia compressa var. lanyuensis. These compounds are liriodenine, (-)-N-acetylanonaine, pressalanine A, p-dihydroxybenzaldehyde, 3,4-dihydroxybenzoic acid, (-)-bornesitol and ß-sitostenone. These compounds were screened for anti-proliferation and anti-tyrosinase activities in B16F10 cells. Liriodenine, pressalanine A, (-)-bornesitol and ß-sitostenone displayed cytotoxicity at high concentration (100 µM), but liriodenine (5 µM), (-)-N-acetylanonaine (10 µM), and ß-sitostenone (5 µM) inhibit tyrosinase activity and reduce the melanin content in B16F10 cells without cytotoxicity, suggesting that liriodenine and ß-sitostenone could be safe and potentially used in cosmetic skin whitening.

Antioxidant and anticancer aporphine alkaloids from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena.

Fifteen compounds were extracted and purified from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena. These compounds include liriodenine (1), lysicamine (2), (-)-anonaine (3), (-)-asimilobine (4), (-)-caaverine (5), (-)-N-methylasimilobine (6), (-)-nuciferine (7), (-)-nornuciferine (8), (-)-roemerine (9), 7-hydroxydehydronuciferine (10) cepharadione B (11), ß-sitostenone (12), stigmasta-4,22-dien-3-one (13) and two chlorophylls: pheophytin-a (14) and aristophyll-C (15). The anti-oxidation activity of the compounds was examined by antiradical scavenging, metal chelating and ferric reducing power assays. The results have shown that these compounds have antioxidative activity. The study has also examined the antiproliferation activity of the isolated compounds against human melanoma, prostate and gastric cancer cells. The results shown that 7-hydroxydehydronuciferine (10) significantly inhibited the proliferation of melanoma, prostate and gastric cancer cells. Together, these findings suggest that leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena are a good resource for obtaining the biologically active substances with antioxidant properties.

Deguelin inhibits the migration and invasion of U-2 OS human osteosarcoma cells via the inhibition of matrix metalloproteinase-2/-9 in vitro.

Osteosarcoma is the most common malignant primary bone tumor in children and young adults and lung metastasis is the main cause of death in those patients. Deguelin, a naturally occurring rotenoid, is known to be an Akt inhibitor and to exhibit cytotoxic effects, including antiproliferative and anticarcinogenic activities, in several cancers. In the present study, we determined if deguelin would inhibit migration and invasion in U-2 OS human osteosarcoma cells. Deguelin significantly inhibited migration and invasion of U-2 OS human osteosarcoma cells which was associated with a reduction of activities of matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinases-9 (MMP-9). Furthermore, results from western blotting indicated that deguelin decreased the cell proliferation and cell growth-associated protein levels, such as SOS1, PKC, Ras, PI3K, p-AKT(Ser473), IRE-1α, MEKK3, iNOS, COX2, p-ERK1/2, p-JNK1/2, p-p38; the cell motility and focal adhesion-associated protein levels, such as Rho A, FAK, ROCK-1; the invasion-associated protein levels, such as TIMP1, uPA, MMP-2. MMP-9, MMP-13, MMP-1 and VEGF in U-2 OS cells. Confocal microscopy revealed that deguelin reduced NF-κB p65, Rho A and ROCK-1 protein levels in cytosol. MMP-7, MMP-9 and Rho A mRNA levels were suppressed by deguelin. These in vitro results provide evidence that deguelin may have potential as a novel anti-cancer agent for the treatment of osteosarcoma and provides the rationale for in vivo studies in animal models.

Urotensin II inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating ATF expression and via the ERK and Akt pathway.

BACKGROUND AND PURPOSE: Regulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Urotensin II (U-II), a potent vasoactive peptide, participates in vascular and myocardial remodeling after injury. We investigated the protective effect of U-II on doxorubicin (DOX)-induced apoptosis in cultured human umbilical vein endothelial cells (HUVECs) and the potential mechanisms involved in this process. EXPERIMENTAL APPROACH: Cultured HUVECs were treated with vehicle, DOX (1 µM), U-II, or U-II plus DOX. Apoptosis was evaluated by DNA strand break level with TdT-mediated dUTP nick-end labeling (TUNEL) staining. Western blot analysis was employed to determine the related protein expression and flow cytometry assay was used to determine the TUNEL positive cells. KEY RESULTS: U-II reduced the quantity of cleaved caspase-3 and cytosol cytochrome c and increased Bcl-2 expression, which results in protecting HUVECs from DOX-induced apoptosis. U-II induced Activating transcription factor 3 (ATF3) at both mRNA and protein levels in U-II-treated cells. Knockdown of ATF3 with ATF3 siRNA significantly reduced ATF3 protein levels and U-II protective effect under DOX-treated condition. U-II downregulated p53 expression in DOX-induced HUVECs apoptosis, and it rapidly activated extracellular signal-regulated protein kinase (ERK) and Akt. The DOX induced change of p53 was not affected by U-II antagonist (urantide) under ATF-3 knockdown. The inhibitory effect of U-II on DOX-increased apoptosis was attenuated by inhibitors of ERK (U0126) and PI3K/Akt (LY294002). CONCLUSION AND IMPLICATIONS: Our observations provide evidence that U-II protects HUVECs from DOX-induced apoptosis. ERK-Akt phosphorylation, ATF3 activation, and p53 downregulation may play a signal-transduction role in this process.

Antioxidant and anticancer constituents from the leaves of Liriodendron tulipifera.

Sixteen compounds were extracted and purified from the leaves of Liriodendron tulipifera. These compounds include aporphines, oxoaporphine, coumarin, sesquiterpene lactone, benzenoids, cyclitol and steroids. (+)-Norstephalagine (2) (an aporphine) and scopoletin (8) (a coumarin) were isolated from Liriodendron tulipifera leaves from the first time. The identified compounds were screened for their antiradical scavenging, metal chelating and ferric reducing power activities. The results have showed that these compounds have antioxidative activity. The study has also examined the chemopreventive property of the isolated compounds against human melanoma cells A375. The results shown that (-)-anonaine (1), (-)-liridinine (3), (+)-lirinidine (6), lysicamine (7) and epitulipinolide diepoxide (9) significantly inhibited the proliferation of melanoma cells. These results revealed that these compounds have antioxidative activity and chemopreventive activity in skin melanoma cells.

The correlation between cholecystectomy and seasonal impact in Taiwan.

Many diseases and illnesses are known to be induced by changes in season and have seasonal fluctuations, and are affected by meteorological factors. Cholecystectomy is a very common surgical procedure used to treat gallstone disease and related complications. This study aimed to examine possible impacts of the seasons on the incidence of cholecystectomy with respect to gender and age as well as whether meteorological variables showed an association with incidences of cholecystectomy. The study was retrospectively conducted using the nationwide population-based datasets of National Health Insurance System in Taiwan. Patients who had undergone cholecystectomy were identified according to the International Classification of Diseases version 9 codes and categorized in terms of age and gender. Autoregression integrated moving average (ARIMA) multivariate models were applied to investigate the association of cholecystectomy incidence rates, time and meteorological variables. A total of 192,833 patients who underwent cholecystectomy between 1996 and 2008 were identified for the analysis. A trend indicating an overall increase was observed for the incidence rate of cholecystectomy over the study period. There were more females who underwent cholecystectomy than males. The highest incidence was found to occur during the summer and the lowest during the winter correlating with the cyclic pattern of temperature in Taiwan. Overall, the cholecystectomy incidence rate increased steadily over the 13-year study period for all age groups. In conclusion, the incidence of cholecystectomy was found to be correlated with the seasons. Temperature is the most notable variable among the relevant meteorological factors. Culture may also play a role in these correlations.

Cyclic guanosine monophosphate-enhancing reduces androgenic extracellular regulated protein kinases-phosphorylation/Rho kinase II-activation in benign prostate hyperplasia.

OBJECTIVES: To investigate whether 7-[2-[4-(2-chlorophenyl) piperazinyl] ethyl]-1,3-di-methylxanthine (KMUP-1) inhibits the effects of testosterone on the development of benign prostatic hyperplasia and sensitizes prostate contraction. METHODS: A benign prostatic hyperplasia animal model was established by subcutaneous injections of testosterone (3 mg/kg/day, s.c.) for 4 weeks in adult male Sprague-Dawley rats. Animals were divided into six groups: control, testosterone, testosterone with KMUP-1 (2.5, 5 mg/kg/day), sildenafil (5 mg/kg/day) or doxazosin (5 mg/kg/day). After 4 weeks, the animals were killed, and prostate tissues were prepared for isometric tension measurement and western blotting analysis. KMUP-1, Y27632, zaprinast, doxazosin or tamsulosin were used at various concentrations to determine the contractility sensitized by phenylephrine (10 µmol/L). RESULTS: KMUP-1 inhibited testosterone-induced phosphorylation of extracellular signal-regulated phosphorylated protein kinase and mitogen-activated protein kinase kinase and Rho kinase-II activation. Sildenafil and doxazosin significantly decreased benign prostatic hyperplasia-induced mitogen-activated protein kinase kinase and Rho kinase-II activation. The decreased expressions of soluble guanylate cyclase α1 was reversed by KMUP-1, doxazosin and sildenafil. Soluble guanylate cyclase ß1 and protein kinase G were increased by KMUP-1, doxazosin, and sildenafil in the testosterone-treated benign prostatic hyperplasia group. Phosphodiesterase-5A was increased by testosterone and inhibited by KMUP-1 (5 mg/kg/day) or sildenafil (5 mg/kg/day). KMUP-1 inhibited phenylephrine-sensitized prostate contraction of rats treated with testosterone. CONCLUSIONS: Mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase, soluble guanylate cyclase/cyclic guanosine monophosphate, protein kinase/protein kinase G and Rho kinase-II are related to prostate smooth muscle tone and proliferation induced by testosterone. KMUP-1 inhibits testosterone-induced prostate hyper-contractility and mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase-phosphorylation, and it inactivates Rho kinase-II by cyclic guanosine monophosphate, protein kinase and α1A-adenergic blockade. Thus, KMUP-1 might be a beneficial pharmacotherapy for benign prostatic hyperplasia.

The pharmacological activities of (-)-anonaine.

Several species of Magnoliaceae and Annonaceae are used in Traditional Chinese Medicine. (-)-Anonaine, isolated from several species of Magnoliaceae and Annonaceae, presents antiplasmodial, antibacterial, antifungal, antioxidation, anticancer, antidepression, and vasorelaxant activity. This article provides an overview of the pharmacological functions of (-)-anonaine.