Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study,...Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study, we present proof that hydrogen peroxide - like nitric oxide - acts as a true first (intercellular) messenger for a multitude of pro-inflammatory ligands. RAW 264.7 macrophages were activated with three different ligands, lipopolysaccharide, interferon-gamma or advanced glycation end products in the presence of increasing concentrations of (hydrogen peroxide scavenging) catalase. As inflammatory readouts, nitric oxide and tumor necrosis factor were determined. We hypothesize that hydrogen peroxide travels between cells propagating the signal, then a certain percentage of the readout should be inhibited by catalase in a concentration- dependent manner. The experiment showed concentration-dependent inhib让ion of nitric oxide and tumor necrosis factor-a production in response to all three ligands/ligand combinations (interferon-gamma, lipopolysaccharide, and chicken egg albumin-derived advanced glycation end product) in the presence of increasing concentration of catalase. For example, catalase inhibited 100% of nitric oxide and 40% of tumor necrosis factor-a production at its highest concentration. Our results suggest that hydrogen peroxide travels through cell membranes into the extracellular space and enters and activates ad;acent cells. Like rdtric oxide, we suggest that it is a ubiquitous first messenger, able to transmit cell-to-cell pro-inflammatory signals such as nitric oxide and tumor necrosis factor-a. In a therapeutic setting, our data suggest that compounds acting as hydrogen peroxide scavengers might not even need to enter the cell to act as anti-inflammatory drugs.展开更多
The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be in...The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.展开更多
Molecular hydrogen is an effective antioxidant.Numerous studies have demonstrated the therapeutic effects of hydrogen in the treatment of various human diseases.The possibility of using hydrogen in the treatment of ca...Molecular hydrogen is an effective antioxidant.Numerous studies have demonstrated the therapeutic effects of hydrogen in the treatment of various human diseases.The possibility of using hydrogen in the treatment of cancer was first discovered in 1975,and in recent studies,researchers have reported numerous positive effects of hydrogen in cancer therapy,including:1)the alleviation of complications caused by chemotherapy;2)a reduction of complications caused by radiotherapy;3)delays in the progression of cancer;and 4)enhanced efficacy of conventional therapy when used in combination with hydrogen.This article reviews the research progress in the use of hydrogen in the treatment of cancer,and proposes future directions for research in this field.展开更多
Hydrogen sul fi de(H_2S) is recognized as one of three gasotransmitters together with nitric oxide(NO) and carbon monoxide(CO). As a signaling molecule, H_2S plays an important role in physiology and shows great poten...Hydrogen sul fi de(H_2S) is recognized as one of three gasotransmitters together with nitric oxide(NO) and carbon monoxide(CO). As a signaling molecule, H_2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H_2S prodrugs for various reasons. In this review, we summarize different H_2S prodrugs, their chemical properties, and some of their potential therapeutic applications.展开更多
To explore the possibility of hydrogen sulfide (H 2S) as a messenger molecule in cardiovascular system, the authors discovered that H 2S (5×10 -5 -5×10 -4 mol·L -1 )exerted an effect on inhibiting endot...To explore the possibility of hydrogen sulfide (H 2S) as a messenger molecule in cardiovascular system, the authors discovered that H 2S (5×10 -5 -5×10 -4 mol·L -1 )exerted an effect on inhibiting endothelin 1 induced proliferation of cultured vascular smooth muscle cells (VSMCs) of rats in vitro . The 3H TdR incorporation decreased by 16.8%～37.4% in H 2S treated VSMCs as compared with the controls ( P <0.01). The inhibitory effect was found to be associated with reduced activity of MAPK. The authors also observed that endogenous H 2S levels markedly increased in vessels of rats with either endotoxic shock or septic shock [H 2S level (pmol·min -1 ·mg -1 ):tail artery (16.18±2.06) vs (8.12±0.55);mesenteric artery (10.17±1.11) vs (6.19 ±0.55);pulmonary artery(11.38±1.24) vs (5.27±0.51); aorta(6.21±0.48) vs (4.10± 0.28), P < 0.01 ]. The above findings suggested that H 2S might play an important role in the regulation of cardiovascular pathophysiologic events.展开更多
Hydrogen sulfide (H 2S) is recently found to be a new gaseous messenger playing an important role in many physiological and pathophysiological processes. The aim of this study was to explore the changes in endogenous ...Hydrogen sulfide (H 2S) is recently found to be a new gaseous messenger playing an important role in many physiological and pathophysiological processes. The aim of this study was to explore the changes in endogenous H 2S pathway and examine the effects of H 2S on the development of spontaneous hypertensive rats (SHR). A controlled study on SHR and WKY rats at the age of 4 weeks showed that after 5 weeks of experiment, the blood pressure of SHR was markedly increased as compared with WKY rats (183.57±11.80 mm Hg vs 107.5± 22.68 mm Hg, P <0.05)and the ratio of left heart weight to whole heart weight of SHR was also increased as compared with WKY rats (0.85±0.02 vs 0.83±0.02, P <0.05). While, the aortic H 2S producing rate and H 2S plasma level were decreased in SHR compared with WKY rats (15.63±2.89 nmol·min -1 ·g -1 vs 25.31± 5.99 nmol·min -1 ·g -1 , 20.35±9.20 μmol·L -1 vs 48.40±13.36 μmol·L -1 , P <0.05). NaHS, however, attenuated the high blood pressure and the ratio of left heart weight to whole heart weight of SHR (158.13± 12.52 mm Hg vs 183.57±11.80 mm Hg and 0.83±0.03 vs 0.85±0.02), respectively. The above findings suggested that the reduced production of endogenous H 2S was important in the development of spontaneous hypertension. The authors also observed that 5 weeks after the experiment the relaxing rate of aortic rings in response to acetylcholine in SHR was higher than that of WKY rats and NaHS enhanced the relaxingresponse of aortic rings to acetylcholine in SHR significantly( P <0.05). The aortic relaxing activities in both SHR and WKY rats displayed a dose dependent response to different doses of NaHS. In conclusion, the reduced production of endogenous H 2S in aorta is involved in the pathogenesis of spontaneous hypertension and is of great biological importance in modulating vasorelaxation.展开更多
基金Australian Postgraduate Award(APA)Ph.D. fellowship by Western Sydney University to DG
文摘Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study, we present proof that hydrogen peroxide - like nitric oxide - acts as a true first (intercellular) messenger for a multitude of pro-inflammatory ligands. RAW 264.7 macrophages were activated with three different ligands, lipopolysaccharide, interferon-gamma or advanced glycation end products in the presence of increasing concentrations of (hydrogen peroxide scavenging) catalase. As inflammatory readouts, nitric oxide and tumor necrosis factor were determined. We hypothesize that hydrogen peroxide travels between cells propagating the signal, then a certain percentage of the readout should be inhibited by catalase in a concentration- dependent manner. The experiment showed concentration-dependent inhib让ion of nitric oxide and tumor necrosis factor-a production in response to all three ligands/ligand combinations (interferon-gamma, lipopolysaccharide, and chicken egg albumin-derived advanced glycation end product) in the presence of increasing concentration of catalase. For example, catalase inhibited 100% of nitric oxide and 40% of tumor necrosis factor-a production at its highest concentration. Our results suggest that hydrogen peroxide travels through cell membranes into the extracellular space and enters and activates ad;acent cells. Like rdtric oxide, we suggest that it is a ubiquitous first messenger, able to transmit cell-to-cell pro-inflammatory signals such as nitric oxide and tumor necrosis factor-a. In a therapeutic setting, our data suggest that compounds acting as hydrogen peroxide scavengers might not even need to enter the cell to act as anti-inflammatory drugs.
基金Financial support from the University of Copenhagen and the Phospholipid Research Center(Heidelberg,Germany)is kindly acknowledged
文摘The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.
基金supported by the Major State Basic Research Development Program(2015CB856302,2015CB553602)the National Natural Science Foundation of China(31870848,81741110,81802787)the Natural Science Foundation of Shaanxi(2018JZ3005).
文摘Molecular hydrogen is an effective antioxidant.Numerous studies have demonstrated the therapeutic effects of hydrogen in the treatment of various human diseases.The possibility of using hydrogen in the treatment of cancer was first discovered in 1975,and in recent studies,researchers have reported numerous positive effects of hydrogen in cancer therapy,including:1)the alleviation of complications caused by chemotherapy;2)a reduction of complications caused by radiotherapy;3)delays in the progression of cancer;and 4)enhanced efficacy of conventional therapy when used in combination with hydrogen.This article reviews the research progress in the use of hydrogen in the treatment of cancer,and proposes future directions for research in this field.
文摘Hydrogen sul fi de(H_2S) is recognized as one of three gasotransmitters together with nitric oxide(NO) and carbon monoxide(CO). As a signaling molecule, H_2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H_2S prodrugs for various reasons. In this review, we summarize different H_2S prodrugs, their chemical properties, and some of their potential therapeutic applications.
文摘To explore the possibility of hydrogen sulfide (H 2S) as a messenger molecule in cardiovascular system, the authors discovered that H 2S (5×10 -5 -5×10 -4 mol·L -1 )exerted an effect on inhibiting endothelin 1 induced proliferation of cultured vascular smooth muscle cells (VSMCs) of rats in vitro . The 3H TdR incorporation decreased by 16.8%～37.4% in H 2S treated VSMCs as compared with the controls ( P <0.01). The inhibitory effect was found to be associated with reduced activity of MAPK. The authors also observed that endogenous H 2S levels markedly increased in vessels of rats with either endotoxic shock or septic shock [H 2S level (pmol·min -1 ·mg -1 ):tail artery (16.18±2.06) vs (8.12±0.55);mesenteric artery (10.17±1.11) vs (6.19 ±0.55);pulmonary artery(11.38±1.24) vs (5.27±0.51); aorta(6.21±0.48) vs (4.10± 0.28), P < 0.01 ]. The above findings suggested that H 2S might play an important role in the regulation of cardiovascular pathophysiologic events.
文摘Hydrogen sulfide (H 2S) is recently found to be a new gaseous messenger playing an important role in many physiological and pathophysiological processes. The aim of this study was to explore the changes in endogenous H 2S pathway and examine the effects of H 2S on the development of spontaneous hypertensive rats (SHR). A controlled study on SHR and WKY rats at the age of 4 weeks showed that after 5 weeks of experiment, the blood pressure of SHR was markedly increased as compared with WKY rats (183.57±11.80 mm Hg vs 107.5± 22.68 mm Hg, P <0.05)and the ratio of left heart weight to whole heart weight of SHR was also increased as compared with WKY rats (0.85±0.02 vs 0.83±0.02, P <0.05). While, the aortic H 2S producing rate and H 2S plasma level were decreased in SHR compared with WKY rats (15.63±2.89 nmol·min -1 ·g -1 vs 25.31± 5.99 nmol·min -1 ·g -1 , 20.35±9.20 μmol·L -1 vs 48.40±13.36 μmol·L -1 , P <0.05). NaHS, however, attenuated the high blood pressure and the ratio of left heart weight to whole heart weight of SHR (158.13± 12.52 mm Hg vs 183.57±11.80 mm Hg and 0.83±0.03 vs 0.85±0.02), respectively. The above findings suggested that the reduced production of endogenous H 2S was important in the development of spontaneous hypertension. The authors also observed that 5 weeks after the experiment the relaxing rate of aortic rings in response to acetylcholine in SHR was higher than that of WKY rats and NaHS enhanced the relaxingresponse of aortic rings to acetylcholine in SHR significantly( P <0.05). The aortic relaxing activities in both SHR and WKY rats displayed a dose dependent response to different doses of NaHS. In conclusion, the reduced production of endogenous H 2S in aorta is involved in the pathogenesis of spontaneous hypertension and is of great biological importance in modulating vasorelaxation.
