Chromane Derivatives from Underground Parts of Iris tenuifolia and Their In Vitro Antimicrobial, Cytotoxicity and Antiproliferative Evaluation.

Phytochemical investigation of the ethanol extract of underground parts of Iris tenuifolia Pall. afforded five new compounds; an unusual macrolide termed moniristenulide (1), 5-methoxy-6,7-methylenedioxy-4-O-2'-cycloflavan (2), 5,7,2',3'-tetrahydroxyflavanone (3), 5-hydroxy-6,7-dimethoxyisoflavone-2'-O-ß-d-glucopyranoside (9), 5,2',3'-dihydroxy-6,7-dimethoxyisoflavone (10), along with seven known compounds (4-8, 11-12). The structures of all purified compounds were established by analysis of 1D and 2D NMR spectroscopy and HR-ESI-MS. The antimicrobial activity of the compounds 1-3, 5, 9, and 10 was investigated using the agar diffusion method against fungi, Gram-positive and Gram-negative bacteria. In consequence, new compound 3 was found to possess the highest antibacterial activity against Enterococcus faecalis VRE and Mycobacterium vaccae. Cell proliferation and cytotoxicity tests were also applied on all isolated compounds and plant crude extract in vitro with the result of potent inhibitory effect against leukemia cells. In particular, the newly discovered isoflavone 10 was active against both of the leukemia cells K-562 and THP-1 while 4-6 of the flavanone type compounds were active against only THP-1.

Antioxidant and anticoagulant effects of phenylpropanoid glycosides isolated from broomrapes (Orobanche caryophyllacea, Phelipanche arenaria, and P. ramosa).

Holoparasitic plants of the Orobanchaceae, including Cistanche, Orobanche, and Phelipanche spp, are known for their richness of phenylpropanoid glycosides (PPGs). Many PPG compounds have been found to possess a wide spectrum of activities, such as antimicrobial, anti-inflammatory, antioxidant, and memory-enhancing. To better explore the bioactivity potential of European broomrapes (O. caryophyllacea - OC, P. arenaria - PA, P. ramosa - PR) and ten single isolated phenylpropanoid constituents, we investigated their antiradical action, protective effect against oxidation in plasma in vitro system, and influence on coagulation parameters. The tested extracts showed a scavenging activity of 50-70% of Trolox's power. The OC extract, rich in acteoside, had over 20% better antiradical potential than PR extract which was the only one containing PPGs lacking a B-ring catechol moiety in the acyl unit. Moreover, it was found that only eight tested PPGs demonstrated antioxidant potential in human plasma treated with H2O2/Fe; however, the three tested PPGs possessed anticoagulant potential in addition to antioxidant properties. It appears that the structure of PPGs, especially the presence of acyl and catechol moieties, is mainly related to their antioxidant properties. The anticoagulant potential of these compounds is also related to their chemical structure. Selected PPGs exhibit the potential for treating cardiovascular diseases associated with oxidative stress.

γ-Tocotrienol-Loaded Liposomes for Radioprotection from Hematopoietic Side Effects Caused by Radiotherapeutic Drugs.

With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. Methods: GT3 was loaded into liposomes using passive loading. 64Cu-GT3-Nano and 3H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. The radioprotection efficacy of GT3-Nano was assessed after acute 137Cs whole-body irradiation at a sublethal (4 Gy), a lethal (9 Gy), or a single high-dose administration of 153Sm-ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) (EDTMP). Flow cytometry and fluorescence microscopy were used to analyze hematopoietic cell population dynamics and the cellular site of GT3-Nano localization in the spleen and bone marrow, respectively. Results: Bone marrow uptake and retention (percentage injected dose per gram of tissue) at 24 h was 6.98 ± 2.34 for 64Cu-GT3-Nano and 7.44 ± 2.52 for 3H-GT3-Nano. GT3-Nano administered 24 h before or after 4 Gy of total-body irradiation (TBI) promoted rapid and complete hematopoietic recovery, whereas recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9-Gy TBI. Flow cytometry of the bone marrow indicated that progenitor bone marrow cells MPP2 and CMP were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. Conclusion: GT3-Nano is highly effective in mitigating the marrow-suppressive effects of sublethal and lethal TBI in mice. GT3-Nano can facilitate rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent 153Sm-EDTMP.

In vitro study on the effect of peucedanol on the activity of cytochrome P450 enzymes.

CONTEXT: Peucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy. OBJECTIVE: The interaction between peucedanol and CYP450s was investigated. MATERIALS AND METHODS: Peucedanol (0, 2.5, 5, 10, 25, 50, and 100 µM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro. RESULTS: Peucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC50 values of 6.03, 13.57, and 7.58 µM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a Ki value of 4.07 µM and a competitive inhibitor of CYP1A2 and 2D6 with a Ki values of 3.39 and 6.77 µM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the Ki/Kinact value of 5.44/0.046 min/µM. DISCUSSION AND CONCLUSIONS: In vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation.

New In Vitro Model of Oxidative Stress: Human Prostate Cells Injured with 2,2-diphenyl-1-picrylhydrazyl (DPPH) for the Screening of Antioxidants.

The antioxidant activity of natural compounds consists in their ability to modulate gene and protein expression, thus inducing an integrated cell protective response and repair processes against oxidative stress. New screening tools and methodologies are crucial for the actual requirement of new products with antioxidant activity to boost endogenous oxidative stress responsive pathways, Reactive Oxygen Species (ROS) metabolism and immune system activity, preserving human health and wellness. In this study, we performed and tested an integrated oxidative stress analysis, using DPPH assay and PNT2 cells injured with DPPH. We firstly investigated the mechanism of action of the oxidising agent (DPPH) on PNT2 cells, studying the variation in cell viability, oxidative stress genes, inflammatory mediator and ROS levels. The results reveal that DPPH activated ROS production and release of Prostaglandin E2 in PNT2 at low and intermediate doses, while cells switched from survival to cell death signals at high doses of the oxidising agent. This new in vitro oxidative stress model was validated by using Trolox, ß-carotene and total extract of the green microalga Testraselmis suecica. Only the T. suecica extract can completely counteract DPPH-induced injury, since its chemical complexity demonstrated a multilevel protecting and neutralising effect against oxidative stress in PNT2.

Role of peripheral 5-HT5A receptors in 5-HT-induced cardiac sympatho-inhibition in type 1 diabetic rats.

5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.

Daurichromenic Acid from the Chinese Traditional Medicinal Plant Rhododendron dauricum Inhibits Sphingomyelin Synthase and Aß Aggregation.

Species of the genus Rhododendron have been used in traditional Chinese medicine, with the medicinal herb "Manshanfong" used as an expectorant and for the treatment of acute bronchitis. Daurichromenic acid (DCA), a constituent of Rhododendron dauricum, is a meroterpenoid with antibacterial, anti-HIV, and anti-inflammatory activities. However, the mechanisms underlying these pharmacologic activities are poorly understood. To develop new drugs based on DCA, more information is required regarding its interactions with biomolecules. The present study showed that DCA inhibits the activity of the enzyme sphingomyelin synthase, with an IC50 of 4 µM. The structure-activity relationships between DCA and sphingomyelin synthase were evaluated using derivatives and cyclized hongoquercin A. In addition, DCA was found to inhibit amyloid ß aggregation. These results may help in the design of effective drugs based on DCA.

Efficiency comparison of apigenin-7-O-glucoside and trolox in antioxidative stress and anti-inflammatory properties.

OBJECTIVES: Chamomile has long been used as a medicinal plant due to its antioxidative and anti-inflammatory activity. Apigenin-7-O-glucoside (AG) is one of the major ethanol extract components from chamomile; however, the underlying mechanism remains unclear. METHODS: In this study, the antioxidant potential and the anti-inflammatory activities of AG were analysed and compared with those of trolox. We demonstrate the protective effects of AG on free radical-induced oxidative damage of DNA, proteins and erythrocytes. Flow cytometry assay was used to detect ROS production. Additionally, the expression of anti-oxidation-related and inflammation-related factors was detected by ELISA and Western blotting, respectively. KEY FINDINGS: AG and trolox showed different efficiency as antioxidant in different experimental systems. AG had similar effect as trolox to inhibit H2 O2 -induced ROS production in RAW264.7 cells, while exerted stronger inhibition against free radical-induced oxidative damage on erythrocytes than trolox. Interestingly, compared with trolox, AG also had stronger inhibitory effect on LPS-induced NF-κB/NLRP3/caspase-1 signalling in RAW246.7 cells. CONCLUSIONS: These results suggest the potential of AG as a pharmaceutical drug for anti-oxidation and anti-inflammation, and the combined usage of AG and trolox might promote its efficacy. Our findings will provide new insights into the development of new drugs with antioxidative and anti-inflammatory functions.

Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a metabolic liver disease that progresses from simple steatosis to the disease state of inflammation and fibrosis. Previous studies suggest that apoptosis and necroptosis may contribute to the pathogenesis of NASH, based on several murine models. However, the mechanisms underlying the transition of simple steatosis to steatohepatitis remain unclear, because it is difficult to identify when and where such cell deaths begin to occur in the pathophysiological process of NASH. In the present study, our aim is to investigate which type of cell death plays a role as the trigger for initiating inflammation in fatty liver. By establishing a simple method of discriminating between apoptosis and necrosis in the liver, we found that necrosis occurred prior to apoptosis at the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model. To further investigate what type of necrosis is involved in the initial necrotic cell death, we examined the effect of necroptosis and ferroptosis inhibition by administering inhibitors to wild-type mice in the CDE diet model. In addition, necroptosis was evaluated using mixed lineage kinase domain-like protein (MLKL) knockout mice, which is lacking in a terminal executor of necroptosis. Consequently, necroptosis inhibition failed to block the onset of necrotic cell death, while ferroptosis inhibition protected hepatocytes from necrotic death almost completely, and suppressed the subsequent infiltration of immune cells and inflammatory reaction. Furthermore, the amount of oxidized phosphatidylethanolamine, which is involved in ferroptosis pathway, was increased in the liver sample of the CDE diet-fed mice. These findings suggest that hepatic ferroptosis plays an important role as the trigger for initiating inflammation in steatohepatitis and may be a therapeutic target for preventing the onset of steatohepatitis.

Seven chromanoid norbisabolane derivatives from the marine-alga-endophytic fungus Trichoderma asperellum A-YMD-9-2.

An examination of the endophytic fungus Trichoderma asperellum A-YMD-9-2 obtained from the marine red alga Gracilaria verrucosa led to the isolation of seven new chromanoid norbisabolane derivatives, trichobisabolins I-L (1-4) and trichaspsides C-E (5-7). Their structures and relative configurations were established on the basis of spectroscopic techniques, mainly including 1D/2D NMR and MS, and the absolute configuration of 1 was assigned by X-ray crystallographic analysis using Cu Kα radiation. All of these isolates feature a 1,9-epoxy ring system, and 5-7 represent the second occurrence of norbisabolane aminoglycosides. Compounds 1-7 exhibited potent inhibition of several marine phytoplankton species.

N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress.

During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure-activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure-activity relationships. A representative compound N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-10H-phenothiazine-10-carboxamide (DT-PTZ-C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30- to 100-fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug-like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress.

Gamma-Tocotrienol Induces Apoptosis in Prostate Cancer Cells by Targeting the Ang-1/Tie-2 Signalling Pathway.

Emerging evidence suggests that gamma-tocotrienol (γ-T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. γ-T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. Recently, γ-T3 was found to target cancer stem cells (CSCs), leading to suppression of tumour formation and chemosensitisation. Despite its promising anti-cancer potential, the exact mechanisms responsible for the effects of γ-T3 are still largely unknown. Here, we report the identification of Ang-1 (Angiopoietin-1)/Tie-2 as a novel γ-T3 downstream target. In prostate cancer cells, γ-T3 treatment leads to the suppression of Ang-1 at both the mRNA transcript and protein levels. Supplementing the cells with Ang-1 was found to protect them against the anti-CSC effect of γ-T3. Intriguingly, inactivation of Tie-2, a member receptor that mediates the effect of Ang-1, was found to significantly enhance the cytotoxic effect of γ-T3 through activation of AMP-activated protein kinase (AMPK) and subsequent interruption of autophagy. Our results highlighted the therapeutic potential of using γ-T3 in combination with a Tie-2 inhibitor to treat advanced prostate cancer.

Proteomic profiling of senescent human diploid fibroblasts treated with gamma-tocotrienol.

BACKGROUND: Replicative senescence of human diploid fibroblasts (HDFs) has been used as a model to study mechanisms of cellular aging. Gamma-tocotrienol (γT3) is one of the members of vitamin E family which has been shown to increase proliferation of senescent HDFs. However, the modulation of protein expressions by γT3 in senescent HDFs remains to be elucidated. Therefore, this study aimed to determine the differentially expressed proteins (DEPs) in young and senescent HDFs; and in vehicle- and γT3-treated senescent HDFs using label-free quantitative proteomics. METHODS: Whole proteins were extracted and digested in-gel with trypsin. Peptides were detected by Orbitrap liquid chromatography mass spectrometry. Mass spectra were identified and quantitated by MaxQuant software. The data were further filtered and analyzed statistically using Perseus software to identify DEPs. Functional annotations of DEPs were performed using Panther Classification System. RESULTS: A total of 1217 proteins were identified in young and senescent cells, while 1218 proteins in vehicle- and γT3-treated senescent cells. 11 DEPs were found in young and senescent cells which included downregulation of platelet-derived growth factor (PDGF) receptor beta and upregulation of tubulin beta-2A chain protein expressions in senescent cells. 51 DEPs were identified in vehicle- and γT3-treated senescent cells which included upregulation of 70 kDa heat shock protein, triosephosphate isomerase and malate dehydrogenase protein expressions in γT3-treated senescent cells. CONCLUSIONS: PDGF signaling and cytoskeletal structure may be dysregulated in senescent HDFs. The pro-proliferative effect of γT3 on senescent HDFs may be mediated through the stimulation of cellular response to stress and carbohydrate metabolism. The expressions and roles of these proteins in relation to cellular senescence are worth further investigations. Data are available via ProteomeXchange with identifier PXD009933.

Oxidative Imbalance, Nitrative Stress, and Inflammation in C6 Glial Cells Exposed to Hexacosanoic Acid: Protective Effect of N-acetyl-L-cysteine, Trolox, and Rosuvastatin.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo ß-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-L-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1ß) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.

Effect of rice variety and modification on antioxidant and anti-inflammatory activities.

The effects of variety and modification of rice on its antioxidant and anti-inflammatory activities were investigated. White rice varieties; Jasmine (JM) and Saohai (SH), and pigmented rice varieties; Doisket (DS) and Homnil (HN) were used. The modified rice samples were obtained from chemical modification using etherification reaction. The activities of the modified rice samples were compared with the ethanol extracts of the raw rice at the same rice concentration. Antioxidant activity was measured by the free radical scavenging activity tests and ferric reducing power assay. Results indicated that the ethanol extracts of raw rice had higher antioxidant activity than the modified rice. Among the raw rice tested, the pigmented rice showed higher antioxidant activity than white rice. Trolox equivalent antioxidant capacity values from free radical scavenging activity test were revealed that 50% ethanol extracts of HN and DS possessed the highest antioxidant activity. Ferric reducing power assay showed that 50% ethanol extracts of DS had the highest antioxidant activity. The anti-inflammatory activity was evaluated in vitro using a lipopolysaccharide-stimulated RAW264.7 macrophage cell model with enzyme-linked immunosorbent assay. Absolute ethanol extracts of HN reduced interleukin-6 secretion whereas that of DS suppressed interleukin-6 and tumor necrosis factor -α secretion. These results indicate that variety of rice, chemical modification, and extracting solvent were the factors that play an important role on antioxidant and anti-inflammatory activity. This study supports the potential use of the pigmented rice, especially DS, as a promising choice of a natural source because of its antioxidant and anti-inflammatory activities.

Isolation and Identification of Benzochroman and Acylglycerols from Massa Medicata Fermentata and Their Inhibitory Effects on LPS-Stimulated Cytokine Production in Bone Marrow-Derived Dendritic Cells.

Massa Medicata Fermentata (MMF), known as Shenqu, is an important traditional Chinese medicine widely used to treat indigestion, vomiting, and diarrhea. In this study, a new benzochroman, 3(S)-3,4-dihydro-5,10-di-ß-d-glucopyranoside-2,2-dimethyl-2H-naphtho(2,3-b)pyran-3-ol (1), and five known galactosyl acylglycerols (2⁻6) were isolated from a methanol extract from MMF. In addition, their chemical structures were determined by chemical and spectroscopic methods, which were compared with the previously reported data. Furthermore, the effects of isolated compounds on lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells were investigated. Compounds 1⁻3 exhibited significant inhibitory effects on the LPS-induced production of IL-6 and IL-12 p40, with IC50 values ranging from 1.6 to 10.2 µM. Compounds 2 and 3 also exhibited strong inhibitory effects on the LPS-stimulated production of TNF-α with IC50 values of 12.0 and 11.2 µM, respectively. The results might provide a scientific basis for the development of the active components in MMF, as well as for novel anti-inflammatory agents.

Gamma-Tocotrienol Attenuates the Hepatic Inflammation and Fibrosis by Suppressing Endoplasmic Reticulum Stress in Mice.

SCOPE: Gamma-tocotrienol (γT3), an unsaturated isoform of vitamin E, is implicated in the hepatoprotective effects. The aim is to determine the effectiveness of γT3 on nonalcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: C57BL/6 male mice are fed a diet containing high fat (45%) and cholesterol (0.2%) along with sucrose drink (HFCS) or HFCS diet supplemented with 0.1% γT3 (HFCS + Î³T3). The inclusion of γT3 robustly decreases the HFCS diet-induced de novo lipogenesis (DNL), ER stress, and inflammation leading to reduced hepatic steatosis and fibrosis. Next, mice are fed a methionine- and choline-deficient (MCD) diet or MCD diet with γT3 (MCD + Î³T3). The γT3 supplementation significantly reduces the MCD diet-induced hepatic ER stress and fibrosis despite the minimal impact on steatosis. To further investigate the role of ER stress, the mice with genetic ablation of CHOP are fed an MCD or MCD + Î³T3 diet. CHOP deletion abolishes the γT3-mediated suppression of hepatic fibrosis, suggesting that modulation of ER stress is a prerequisite to inhibit hepatic inflammation and fibrosis. CONCLUSION: γT3 supplementation is effective in attenuating NAFLD and fibrosis through a synergistic mechanism of decreased DNL and hepatic ER stress. This work strongly supports the translational potential of γT3 supplementation against NAFLD.

(3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one ameliorates retinal degeneration in Pde6brd10 mice.

As a severe photoreceptor-degenerative disease, retinitis pigmentosa (RP) is currently incurable and eventually leads to partial or complete blindness. (3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIM) is a novel antioxidant isolated from the plant of Alpinia katsumadai Hayata, with protective effects on photoreceptor cells against lipoteichoic acid-induced damage through inhibiting oxidative stress. The present study was to further demonstrate whether TIM could ameliorate retinal degeneration of Pde6brd10 (rd10) mice, a mouse model of RP. rd10 mice were treated with TIM by intraperitoneal injection daily from postnatal Day 10 (P10) to P26. Retinal function was tested by electroretinography. Histology was evaluated by toluidine blue staining and TUNEL assay. Oxidative stress markers were measured by ELISA. Immunohistochemistry, real-time PCR, and western blotting were applied to explore the protective mechanism. Results showed TIM significantly improved the retinal function and decreased photoreceptor cell apoptosis in rd10 mice through reducing oxidative stress. For the first time, this study demonstrated the protective effects of TIM against retinal degeneration in rd10 mice, providing scientific rationale to use TIM treating the RP.

Contradictory effects of mitochondria- and non-mitochondria-targeted antioxidants on hepatocarcinogenesis by altering DNA repair in mice.

Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients. Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma, antioxidants may still play a role in cancer prevention. Both tumor and antioxidants types influence the actual efficacy. However, little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma (HCC), including non-mitochondrial- and mitochondrial-targeted antioxidants. Utilizing mouse models of chemical hepatocarcinogenesis, we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine (NAC) and the soluble vitamin E analog, Trolox, prevented tumorigenesis, whereas administration of mitochondria-targeted antioxidants SS-31 (the mitochondria-targeted peptide) and Mito-Q (a derivative of ubiquinone) facilitated tumorigenesis. RNA sequencing revealed that NAC and SS-31 caused very different changes in the oxidation-reduction state and DNA damage response. In diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ataxia-telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) for DNA repair whereas SS-31 and Mito-Q aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial reactive oxygen species (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was altered after NAC and SS-31 treatment. Furthermore, blockage of phospho-ATR (p-ATR) led to the recurrence of NAC-ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted DEN HCC. Conclusion: These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis, and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer. (Hepatology 2018;67:623-635).

Natural Forms of Vitamin E as Effective Agents for Cancer Prevention and Therapy.

Initial research on vitamin E and cancer has focused on α-tocopherol (αT), but recent clinical studies on cancer-preventive effects of αT supplementation have shown disappointing results, which has led to doubts about the role of vitamin E, including different vitamin E forms, in cancer prevention. However, accumulating mechanistic and preclinical animal studies show that other forms of vitamin E, such as γ-tocopherol (γT), δ-tocopherol (δT), γ-tocotrienol (γTE), and δ-tocotrienol (δTE), have far superior cancer-preventive activities than does αT. These vitamin E forms are much stronger than αT in inhibiting multiple cancer-promoting pathways, including cyclo-oxygenase (COX)- and 5-lipoxygenase (5-LOX)-catalyzed eicosanoids, and transcription factors such as nuclear transcription factor κB (NF-κB) and signal transducer and activator of transcription factor 3 (STAT3). These vitamin E forms, but not αT, cause pro-death or antiproliferation effects in cancer cells via modulating various signaling pathways, including sphingolipid metabolism. Unlike αT, these vitamin E forms are quickly metabolized to various carboxychromanols including 13'-carboxychromanols, which have even stronger anti-inflammatory and anticancer effects than some vitamin precursors. Consistent with mechanistic findings, γT, δT, γTE, and δTE, but not αT, have been shown to be effective for preventing the progression of various types of cancer in preclinical animal models. This review focuses on cancer-preventive effects and mechanisms of γT, δT, γTE, and δTE in cells and preclinical models and discusses current progress in clinical trials. The existing evidence strongly indicates that these lesser-known vitamin E forms are effective agents for cancer prevention or as adjuvants for improving prevention, therapy, and control of cancer.