Baicalin attenuates acute skin damage induced by ultraviolet B via inhibiting pyroptosis.

As the outermost layer of the human body, the skin suffers from various external factors especially light damage, among which ultraviolet B (UVB) irradiation is common and possesses a relatively high biological damage capacity. Pyroptosis is a newly discovered type of programmed cell death, which can induce cell rupture and induce local inflammatory response. However, the molecular mechanisms of pyroptosis in photodamaged skin is poorly understood. Baicalin, a flavonoid extracted from the desiccated root of Scutellaria baicalensis Georgi (Huang Qin). Despite its antioxidant abilities, whether baicalin protects skin by attenuating UVB-induced pyroptosis remains unclear, which was the aim of this study. The UVB-induced acute skin damage model was established by using human immortalized keratinocytes (HaCaT cells) and Kunming (KM) strain mice. The protective dose selection for baicalin is 50 µM in vitro and 100 mg/kg in vivo. In in vitro study, UVB irradiation significantly decreased cell viability, increased cell death and oxidative stress in HaCaT cells, while pretreatment with baicalin improved these phenomena. Furthermore, the baicalin pretreatment notably suppressed nuclear factor kappa B (NF-κB) translocation, the NLRP3 inflammasome activation and gasdermin D (GSDMD) maturation, thus effectively attenuating UVB-induced pyroptosis. In in vivo study, the baicalin pretreatment mitigated epidermal hyperplasia, collagen fiber fragmentation, oxidative stress and pyroptosis in UVB-irradiated mouse skin. In a nutshell, this study suggests that baicalin could be a potential protective agent to attenuate acute skin damage induced by UVB irradiation through decreasing oxidative stress and suppressing NF-κB/NLRP3/GSDMD-involved pyroptosis.

Therapeutic effect of mitochondrial transplantation on burn injury.

As mitochondrial damage or dysfunction is commonly observed following burn injuries, we investigated whether mitochondrial transplantation (MT) can result in therapeutic benefits in the treatment of burns. Human immortalized epidermal cells (HaCaT) and Kunming mice were used to establish a heat-injured cell model and a deep partial-thickness skin burn animal model, respectively. The cell model was established by exposing HaCaT cells to 45 or 50 °C for 10 min, after which cell proliferation was assayed using fluorescent double-staining and colony formation assays, cell migration was assessed using colloidal gold migration and scratch assays, and cell cycle progression and apoptosis were measured by flow cytometry. Histopathological staining, immunohistochemistry, nick-end labeling analysis, and enzyme-linked immunosorbent assays were used to evaluate the effects of MT on inflammation, tissue recovery, apoptosis, and scar growth in a mouse model. The therapeutic effects were observed in the heat-injured HaCaT cell model. MT promoted cell viability, colony formation, proliferation, and migration; decreased G1 phase; promoted cell division; and decreased apoptosis. Wound-healing promotion, anti-inflammation (decreased mast cell aggregation, down-regulated of TNF-α, IL-1ß, IL-6, and up-regulated IL-10), acceleration of proliferation recovery (up-regulated CD34 and VEGF), apoptosis reduction, and scar formation reduction (decreased collagen I/III ratio and TGF-ß1) were observed in the MT mouse model. The MT mode of action was, however, not investigated in this study. In conclusion, our data indicate that MT exerts a therapeutic effect on burn injuries both in vitro and in vivo.

Lycium barbarum polysaccharide inhibits blue-light-induced skin oxidative damage with the involvement of mitophagy.

Although blue light can damage the skin to a certain extent, the pathogenesis of its damage remains still unclear. The available evidence suggests that oxidative stress may be the main cause of its damage. Lycium barbarum polysaccharide (LBP) has antioxidative effects in a variety of cells. In this paper, we investigated the protective role of LBP and its mechanism of action related to mitophagy in blue-light-damaged skin cells. The findings indicated that in HaCaT cells and mouse skin, LBP pretreatment was effective in reducing blue-light-induced apoptosis and ameliorating the elevated level of cellular autophagy/mitophagy caused by excessive blue light exposure. The markers reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were used to assess oxidative stress. LBP could effectively inhibit blue-light-induced oxidative stress. It was also found that blue light exposure caused mitochondrial dysfunction in HaCaT cells, including increased intracellular calcium ion levels and decreased mitochondrial membrane potential. LBP pretreatment significantly relieved mitochondrial dysfunction in HaCaT cells. These findings imply that LBP pretreatment protects skin cells from damage induced by blue light irradiation and that mitophagy may be a significant factor in skin photodamage.

Pyroptosis as a double-edged sword: The pathogenic and therapeutic roles in inflammatory diseases and cancers.

Pyroptosis is a programmed cell death mode discovered in recent years. It is caused by inflammasomes and the perforation of Gasdermin family proteins, and results in the release of inflammatory factors and triggering of an inflammatory cascade response. The pathways of pyroptosis include the caspase-1-dependent canonical pathway, the caspase-4/5/11-dependent non-canonical pathway, other caspase-dependent pathways and caspase-independent pathways. Its morphological features are different from other programmed cell death modes (apoptosis, autophagy, etc.). Pyroptosis can be observed microscopically that abundant pores are formed in the cell membrane, resulting in cell swelling and rupture, and eventually leading to the outflow of cellular contents. In addition to causing tissue damage and dysfunction through inflammation, pyroptosis can also become a potential cancer treatment strategy by reducing drug resistance in cancer cells. However, many details are still unclear on the molecular mechanisms of its role in pathogenicity and therapeutics, and therefore lots of work needs to be done. This article reviews the morphological characteristics, pathogenic and therapeutic mechanisms of pyroptosis and its related research progress in inflammatory diseases and cancers. It helps to further understand the mechanism of pyroptosis and provide new ideas for the research and prevention of inflammatory diseases and cancers.

Carbonation Resistance and Pore Structure of Mixed-Fiber-Reinforced Concrete Containing Fine Aggregates of Iron Ore Tailings.

The disposal of industrial by-product tailings has become an important issue in solving environmental pollution. In this study, 15%, 30%, 50%, and 70% iron tailings were used to replace the natural sand in concrete, and 1.5% steel fiber and 0-0.75% PVA fibers were added to the iron tailings concrete. The effects of the iron tailings replacement rate and the fiber content on the mechanical properties, carbonization depth, and concrete porosity were studied in a carbonization environment. The results demonstrated that the compressive and splitting tensile strengths of concrete first increased and subsequently decreased with an increase in the iron tailings replacement rate, while the carbonation depth and porosity initially decreased and subsequently increased. When the replacement rate of iron tailings was 30%, the compressive strength and split tensile strength were increased by 7.6% and 17.7%, respectively, and the porosity was reduced by 8.9%. The compressive strength, carbonation depth and porosity of single-doped steel-fiber concrete were superior to those of ordinary iron tailings concrete. However, compared with single-doped steel fiber, the performance of steel-PVA fiber was further improved. Based on the mechanical properties, the carbonation depth test results of the three aforementioned types of concrete, the mathematical expression of the uniaxial compression stress-strain curve of iron tailings concrete, and the prediction equation of the carbonation depth of mixed-fiber iron tailings concrete were proposed. This study provides a reference for the application and popularization of fiber-reinforced iron tailings concrete in carbonization environments.

Structural integrity is essential for the protective effect of mitochondrial transplantation against UV-induced cell death.

Mitochondrial transplantation (MT) is a new technology developed in recent years, which injects healthy mitochondria directly into damaged tissues or blood vessels to play a therapeutic role. This technology has been studied in many animal models of various diseases including myocardial ischemia, cerebral stroke, liver and lung injury, and even has been successfully used in the treatment of childhood heart disease. MT can quickly improve tissue function within a few minutes after injection. The speed with which MT improves tissue function is frequently questioned, for it is hard to understand how the whole mitochondrion transports to the damaged sites, enters cells and functions within such a short period of time. Are there small molecules of mitochondrial component responsible for the function of MT? To test this hypothesis, we established an ultra-violet (UV)-irradiated HeLa cell model. The results of colony formation, sulforhodamine B (SRB), and Hoechst 33342/PI double staining assay strongly indicated that MT exhibited a significant protective effect against UV irradiation damage. The UV irradiation-induced cell cycle arresting at S phase, apoptosis, mitochondrial membrane potential (MMP) decreasing, and the related apoptosis signaling factors p-IKKα, p-p65, I-κB and the activation of caspase3 were all reversed by MT treatments to some extent. The mechanisms of MT were evaluated through comparing the effect of thermal inactivation, ultrasonic crushing, and repeated freezing and thawing treatments on MT function. These results denied the above hypothesis that mitochondrial component may be responsible for MT, excluded the function of ATP, mtDNA and other small molecules, and indicated that the mitochondria structural integrity is essential. We also evaluated the effect of Ca2+ concentrations (1 and 1.8 mM) on MT, and the results showed no effect was found in this UV-irradiated HeLa cell model. Our data support a potent anti-UV irradiation effect of MT, and that structural integrity of the mitochondria is critical for its function.

Hydrogen sulfide protects retina from blue light-induced photodamage and degeneration via inhibiting ROS-mediated ER stress-CHOP apoptosis signal.

Background: Hydrogen sulfide (H2S) is a small reducing gas molecule with various biological functions such as anti-oxidative, anti-apoptotic and anti-inflammatory activities. In this study, we investigated the therapeutic effects of exogenous H2S in the experimental models of retinal photodamage in vivo and in vitro.Methods: Rats with open eyelids were pretreated with H2S (80~120 µmol/kg) for 10 days and then continuously exposed to blue light (435~445nm, 11.2W/m2) for 8 h to establish in vivo experimental model. ARPE-19 cells were pretreated with H2S and then exposed to blue light to establish in vitro experimental model.Results: In vivo experiments, H2S significantly ameliorated blue light-induced retinal oxidative stress, apoptosis and degeneration. Moreover, H2S inhibited the activation of blue light-induced endoplasmic reticulum (ER) stress CHOP apoptotic signaling. In vitro experiments, H2S improved blue light-induced oxidative stress and oxidative damage. H2S inhibited ROS-mediated activation of ER stress CHOP apoptotic signaling. H2S alleviated blue light-induced apoptosis and increases cell viability. The ER stress inhibitor 4-PBA alleviated blue light-induced apoptosis and increases cell viability.Conclusion: Taken together, these results indicate that H2S can inhibit ROS-mediated ER stress-CHOP apoptosis signal, thereby alleviating blue light-triggered retinal apoptosis and degeneration.

Blue light induces skin apoptosis and degeneration through activation of the endoplasmic reticulum stress-autophagy apoptosis axis: Protective role of hydrogen sulfide.

Research on the phototoxicity of blue light (BL) to the skin is increasing. Although blue light can induce oxidative stress, inflammation, and inhibition of proliferation in skin cells, the mechanism by which blue light damages the skin is not yet clear. Endoplasmic reticulum (ER) stress and autophagy are two mechanisms by which cells resist external interference factors and maintain cell homeostasis and normal function, and both can affect cell apoptosis. Interestingly, we have found that blue light (435 nm ~ 445 nm, 8000 lx, 6-24 h)-induced oxidative stress triggers the ER stress-CHOP (C/EBP homologous protein) signal and affects the protein levels of B-cell lymphoma-2 (Bcl-2) and Bcl2-associated X (Bax), thereby promoting apoptosis. In addition, blue light activates autophagy in skin cells, which intensifies cell death. When ER stress is inhibited, autophagy is subsequently inhibited, suggesting that blue light-induced autophagy is influenced by ER stress. These evidences suggest that blue light induces activation of reactive oxygen species (ROS)-ER stress-autophagy-apoptosis axis signaling, which further induces skin injury and apoptosis. This is the first report on the relationships among oxidative stress, ER stress, autophagy, and apoptosis in blue light-induced skin injury. Furthermore, we have studied the effect of hydrogen sulfide (H2S) on blue light-induced skin damage, and found that exogenous H2S can protect skin from blue light-induced damage by regulating the ROS-ER stress-autophagy-apoptosis axis. Our data shows that when we are exposed to blue light, such as sunbathing and jaundice treatment, H2S may be developed as a protective agent.

Lycium Barbarum polysaccharide protects HaCaT cells from PM2.5-induced apoptosis via inhibiting oxidative stress, ER stress and autophagy.

Objectives: Lycium barbarum polysaccharide (LBP) is a natural polysaccharide extracted from Lycium barbarum that has anti-inflammatory, anti-apoptotic and anti-aging effects, and plays a role in the prevention and treatment of various diseases. In this study, we investigated the therapeutic effect of LBP on particulate matter 2.5 (PM2.5)-induced skin damage.Methods: Cell viability was analyzed by MTT and LDH assays. Apoptosis was analyzed by Annexin V-FITC/PI staining. Oxidative stress/damage were assessed by intracellular ROS levels, MDA content and SOD activity. The intracellular protein expression was analyzed by Western blot. Mitochondrial damage was assayed by mitochondrial membrane potential with JC-1 probe. LC3-GFP adenovirus was transfected into HaCaT cells to analyze intracellular autophagosome levels.Results: In PM2.5-treated HaCaT cells, LBP pretreatment reduced PM2.5-induced cytotoxicity, ameliorated cell morphology and reduced cell apoptosis. LBP also inhibited the expression levels of GRP78 and CHOP, reduced the conversion of LC3I to LC3II, inhibited Bax protein and activated Bcl-2 protein. Furthermore, LBP inhibited PM2.5-induced mitochondrial autophagy (mitophagy) and mitochondrial damage. PM2.5-induced autophagy was regulated by endoplasmic reticulum (ER) stress.Conclusion: LBP protects skin cells from PM2.5-induced cytotoxicity by regulating the oxidative stress-ER stress-autophagy-apoptosis signaling axis, revealing that LBP has a great potential for the skin protection.

Hydrogen Sulfide Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Apoptosis and Affects Autophagy.

Age-related macular degeneration (AMD) is a major cause of visual impairment and blindness among the elderly. AMD is characterized by retinal pigment epithelial (RPE) cell dysfunction. However, the pathogenesis of AMD is still unclear, and there is currently no effective treatment. Accumulated evidence indicates that oxidative stress and autophagy play a crucial role in the development of AMD. H2S is an antioxidant that can directly remove intracellular superoxide anions and hydrogen peroxide. The purpose of this study is to investigate the antioxidative effect of H2S in RPE cells and its role in autophagy. The results show that exogenous H2S (NaHS) pretreatment effectively reduces H2O2-induced oxidative stress, oxidative damage, apoptosis, and inflammation in ARPE-19 cells. NaHS pretreatment also decreased autophagy levels raised by H2O2, increased cell viability, and ameliorated cell morphological damage. Interestingly, the suppression of autophagy by its inhibitor 3-MA showed an increase of cell viability, amelioration of morphology, and a decrease of apoptosis. In summary, oxidative stress causes ARPE-19 cell injury by inducing cell autophagy. However exogenous H2S is shown to attenuate ARPE-19 cell injury, decrease apoptosis, and reduce the occurrence of autophagy-mediated by oxidative stress. These findings suggest that autophagy might play a crucial role in the development of AMD, and exogenous H2S has a potential value in the treatment of AMD.

An acute lytic cell death induced by xanthohumol obstructed ROS detecting in HL-60 cells.

Serum is an important component in cell culture medium. It also possesses potent antioxidant properties. Therefore, the conventional protocols for detecting reactive oxygen species (ROS) in cultured cells with fluorescent probes include washing and suspending cells with serum-free buffers, such as PBS. This transient serum deprivation is essential for the ROS detecting. Unfortunately, it may also cause unexpected results, which push us to choose more optimal experiment conditions. In the present study, we found an acute lytic cell death induced by xanthohumol (XN), which obstructed ROS detecting in human leukemia cell line HL-60 cells. XN induced ROS burst, caused cell swelling, membrane permeability increase, LDH release, and ultimately an acute lytic cell death and cell rupture. These effects could be alleviated by the antioxidant N-Acetyl-L-cysteine (NAC). Apoptosis, pyroptosis or necroptosis were not observed in this process. Results also indicated that 2% serum addition had already completely scavenged ROS induced by 10 µM XN. Taken together, it is strongly suggested to detecting ROS in a serum-free medium when studying where and how ROS generated in cells. The concentration at the ROS maximum point (10 µM XN in this study) can be selected as the optimal concentration.

Isolation, Structure Elucidition, and Immunosuppressive Activity of Diterpenoids from Ligularia fischeri.

Six new (1-3 and 6-8) and seven known diterpenoids were isolated from the whole plant of Ligularia fischeri. Compound 1 is a new 15,16-dinorerythroxylane-type diterpenoid possessing a C18 skeleton, and 2 is the first example of a 6/6/6/6/5/5-fused hexacyclic ent-kaurane diterpenoid with 19,20-olide and 11,16-epoxy moieties. The structures of the new compounds were elucidated by spectroscopic analysis and chemical methods. The absolute configurations of 1 and 7 were determined by single-crystal X-ray diffraction. Compounds 1-13 were evaluated for their immunosuppressive activity, and 4, 7, and 13 showed moderate inhibitory activities against human B lymphoblast HMy2.CIR cells with IC50 values of 56.3 ± 2.2, 13.3 ± 0.8, and 31.4 ± 0.9 µM, respectively.

Diterpenoids from Salvia miltiorrhiza and Their Immune-Modulating Activity.

Danshen, the dried root of Salvia miltiorrhiza (Lamiaceae), is one of the most popular traditional herbal medicines commonly used in China. Recently, danshen has been used as a health-promoting functional tea to prevent diseases by strengthening the human immunity in China. To search for secondary metabolites with immune-modulating activity, a phytochemical investigation was carried out on the roots of S. miltiorrhiza, which led to the isolation of 6 new diterpenoids (1-4, 16, and 20) along with 20 known diterpenoids. The structures and absolute configurations of these new compounds were elucidated on the basis of spectroscopic analysis, X-ray diffraction analysis, calculated optical rotation, and calculated electronic circular dichroism spectra. Among these isolates, compounds 3, 17, 19, and 23 promoted the proliferation of HMy2.CIR, exhibiting a protective effect on lymphocytes at the concentration from 2.50 to 40 µM, whereas compounds 2, 7, 8, 10, 14, 18, 22, and 25 inhibited the cell proliferation in a concentration-dependent manner.

Determination of Hydroxylated Polybrominated Diphenyl Ethers in Chinese Aquatic Products by LC-MS/MS.

In this reported work, a sensitive and reliable method for detecting 11 hydroxylated polybrominated diphenyl ethers (OH-PBDEs) was established by a combination of pressurized liquid extraction (PLE) and liquid chromatography tandem mass spectrometry (LC/MS/MS). The aquatic products (mainly crayfish and grass carp) from 12 cities in China's HuBei province were examined for the presence of the target OH-PBDEs. The analytical process involved first extracting the OH-PBDEs from the crayfish and grass carp using a PLE, followed by purification using gel permeation chromatography. To eliminate the interference from matrix, isotopic dilution was used in the quantitative analysis. Compared with the existing methods, OH-PBDEs were determined without a need for derivatizing, and it was more efficient and quicker. The condition of extraction and cleanup were also optimized. Experimental results showed that the proposed method exhibited a low detection limit of 0.04-0.2 µg/kg, with a wide linearity range 1-400 ng/L and a good linear correlation coefficient (r2 > 0.990) using this method. These results indicated the steadiness of the established method has the advantages of high sensitivity and facile sample preparation without matrix interference.

MicroRNAs in tumor angiogenesis.

As it is necessary for tumor growth, angiogenesis has been an attractive target for drug therapy. Accumulating evidences indicate that microRNAs (miRNAs), which are short non-coding RNAs, delicately regulate the angiogenic signals through targeting angiogenic factors and protein kinases. They can modulate pro-angiogenic signals induced by vascular endothelial growth factor (VEGF) and anti-angiogenic signals induced by thrombospondin-1 (TSP-1), and therefore promote or inhibit tumor angiogenesis. Receptor tyrosine kinases (RTKs) and hypoxia inducible factor (HIF) are also targeted by miRNAs. Moreover, miRNAs crosstalk with reactive oxygen species (ROS) influencing tumor angiogenesis. It is critical to understand the role of miRNAs in tumor angiogenesis due to their therapeutic potential to improve outcome for cancer patients. The following review discusses the current state of knowledge related to tumor angiogenesis-regulatory miRNAs and their targets.

Simultaneous Determination of Methoxylated Polybrominated Diphenyl Ethers and Polybrominated Diphenyl Ethers in Water, Soil and Sediment from China by GC-MS.

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants, which are increasingly reported in the environment. Methoxylated polybrominated diphenyl ethers (MeO-PBDEs) are structural analogs to PBDEs and reported as natural products and novel pollutants present in the environment. First, a new isotopic dilution GC-MS method was developed in this study to simultaneously determine 13 PBDEs and 8 MeO-PBDEs in water, soil and sediment. Liquid/liquid extraction, pressurized liquid extraction and multi-layer silica gel column chromatography cleanup were used, and some important steps and crucial parameters were modified and intensified compared with the other literatures. Besides, the conditions of GC and MS were also optimized. The limits of quantitation values of 0.005-0.1 and 0.02-0.1 µg L(-1) in water were calculated for PBDEs and MeO-PBDEs, respectively; so did 0.25-5 and 1-5 µg kg(-1) dry weight in soil and sediment. In addition, good repeatability and accuracy of the whole method were achieved. Moreover, 60 water and 30 sediment samples for aquaculture crayfish and freshwater fish collected from aquatic products production base, 40 soil samples collected from agricultural products production base and also 20 Yangtze River water samples and 20 Hanjiang River water samples collected from different sampling situations near Wuhan, Hubei province along the Yangtze River and the Hanjiang River were analyzed to determine whether they are contaminated by PBDEs and MeO-PBDEs. Using the established methods, it was found that PBDEs or MeO-PBDEs emerged in 4 of 60 water samples for aquatic products, 3 of 40 soils, and 2 of 30 sediments and in low µg kg(-1) dry weight for soil and sediments and low µg L(-1) for water.

Simulated microgravity increases heavy ion radiation-induced apoptosis in human B lymphoblasts.

AIMS: Microgravity and radiation, common in space, are the main factors influencing astronauts' health in space flight, but their combined effects on immune cells are extremely limited. Therefore, the effect of simulated microgravity on heavy ion radiation-induced apoptosis, and reactive oxygen species (ROS)-sensitive apoptosis signaling were investigated in human B lymphoblast HMy2.CIR cells. MAIN METHODS: Simulated microgravity was achieved using a Rotating Wall Vessel Bioreactor at 37°C for 30 min. Heavy carbon-ion irradiation was carried out at 300 MeV/u, with a linear energy transfer (LET) value of 30 keV/µm and a dose rate of 1Gy/min. Cell survival was evaluated using the Trypan blue exclusion assay. Apoptosis was indicated by Annexin V/propidium iodide staining. ROS production was assessed by cytometry with a fluorescent probe dichlorofluorescein. Malondialdehyde was detected using a kit. Extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase phosphatase-1 (MKP-1) and caspase-3 activation were measured by immunoblotting. KEY FINDINGS: Simulated microgravity decreased heavy ion radiation-induced cell survival and increased apoptosis in HMy2.CIR cells. It also amplified heavy ion radiation-elicited intracellular ROS generation, which induced ROS-sensitive ERK/MKP-1/caspase-3 activation in HMy2.CIR cells. The above phenomena could be reversed by the antioxidants N-acetyl cysteine (NAC) and quercetin. SIGNIFICANCE: These results illustrated that simulated microgravity increased heavy ion radiation-induced cell apoptosis, mediated by a ROS-sensitive signal pathway in human B lymphoblasts. Further, the antioxidants NAC and quercetin, especially NAC, might be good candidate drugs for protecting astronauts' and space travelers' health and safety.

NADPH oxidase is involved in H2O2-induced differentiation of human promyelocytic leukaemia HL-60 cells.

The expression and activity of NADPH oxidase increase when HL-60 cells are induced into terminally differentiated cells. However, the function of NADPH oxidase in differentiation is not well elucidated. With 150-500 µM H2O2 inducing differentiation of HL-60 cells, we measured phagocytosis of latex beads and investigated cell electrophoresis. Two inhibitors of NADPH oxidase, DPI (diphenyleneiodonium) and APO (apocynin), blocked the differentiation potential of cells induced by 200 µM H2O2. However, H2O2 stimulated the generation of intracellular superoxide (O2•-), which decreased in the presence of the two inhibitors. DPI also inhibited H2O2-induced ERK (extracellular-signal-regulated kinase) activation, as detected by Western blotting. Furthermore, PD98059, the inhibitor of the ERK pathway, inhibited the differentiation of HL-60 cells induced by H2O2. This shows that H2O2 can activate NADPH oxidase, leading to O2•- production, followed by ERK activation and ultimately resulting in the differentiation of HL-60 cells. The data indicate that NADPH oxidase is an important cell signal regulating cell differentiation.

Dual effects of curcumin on neuronal oxidative stress in the presence of Cu(II).

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Elevated copper (Cu) ions are thought to link AD pathology. Curcumin is suggested to treat AD because of its high anti-oxidative activity and coordination to transitional metal ions. In this study, the protective effect of curcumin against the Cu(II)-induced oxidative damage was investigated in primary rat cortical neurons. The neuronal damage was assessed by morphological observation, cell viability, and oxidative stress level. The results showed that curcumin at low dosage protected primary cultured neurons from the 20 µM Cu(II)-induced damage. Low dosage of curcumin depressed oxidative stress levels exacerbated by Cu(II). However, high dosage of curcumin failed to decrease the Cu(II)-induced oxidative stress. When Cu(II) was presented in primary neurons, curcumin at high dosage resulted in chromosomal aberration and cell damage. These results suggest that curcumin, in a concentration-dependent manner, plays both anti-oxidative and pro-oxidative roles in primary neurons treated with Cu(II).

Studies on chemical modification and biology of a natural product, gambogic acid (III): determination of the essential pharmacophore for biological activity.

Caged 4-oxa-tricyclo[4.3.1.0(3,7)]dec-2-one structural motifs are found in Garcinia natural products that demonstrate anti-tumor activity. Gambogic acid (GA, 1), the most abundant caged Garcinia xanthones, has been reported to be a promising anti-cancer agent. To identify the essential pharmacophore for its anti-tumor activity, a series of GA analogues that address potential key structural features for biological activity were synthesized, among which compound 11a displayed comparable in vitro anti-tumor activity as GA. Mechanistic studies on 11a determined that the compound induces apoptosis as well as arrests the G2/M phase of the cell cycle in HepG2 cells. The determination of the essential part of the scaffold found in GA to maintain anti-tumor effects, and the SAR based on the caged pharmacophore are reported and will provide key information for future anti-cancer drug development studies.