Sargachromenol Attenuates Inflammatory Responses by Regulating NF-κB and Nrf2 Pathways in RAW 264.7 Cells and LPS-treated Mice.

This study aims to explore the anti-inflammatory mechanisms of sargachromenol in both RAW 264.7 cells and lipopolysaccharide (LPS)-treated mice, as previous reports have suggested that sargachromenol possesses anti-aging, anti-inflammatory, antioxidant, and neuroprotective properties. Although the precise mechanism behind its anti-inflammatory activity remains unclear, pretreatment with sargachromenol effectively reduced the production of nitric oxide, prostaglandin E2, and interleukin (IL)-1ß in LPS-stimulated RAW 264.7 cells by inhibiting cyclooxygenase-2. Moreover, sargachromenol inhibited the activation of nuclear factor-κB (NF-κB) by preventing the degradation of the inhibitor of κB-α (IκB-α) and inhibiting protein kinase B (Akt) phosphorylation in LPS-stimulated cells. We also found that sargachromenol induced the production of heme oxygenase-1 (HO-1) by activating the nuclear transcription factor erythroid-2-related factor 2 (Nrf2). In LPS-treated mice, oral administration of sargachromenol effectively reduced the levels of IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in the serum, suggesting its ability to suppress the production of inflammatory mediators by inhibiting the Akt/NF-κB pathway and upregulating the Nrf2/HO-1 pathway.

Meroterpenoid-Rich Ethanoic Extract of Sargassum macrocarpum Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice.

Colitis is a colon mucosal disorder characterized by intestinal damage and inflammation. This current study aimed to evaluate the effect of meroterpenoid-rich ethanoic extract of a brown algae, Sargassum macrocarpum (MES) on dextran sulfate sodium (DSS)-induced colitis in mice and explore the possible mechanisms. Mice were given 4% DSS in drinking water for 7 days to induce colitis, followed by 3 days of regular water. MES (12 mg/kg body weight) or celecoxib (10 mg/kg body weight) was administrated orally to mice on a daily basis during these 10 days. Both MES and celecoxib supplementations significantly attenuated DSS-induced weight loss, shortening of colon length, elevated myeloperoxidase activity as well as histomorphological changes of colon. MES and celecoxib reduced the inflammation level of colon tissue, as indicated by its suppression on a panel of pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-17, tumor necrosis factor α, and interferon γ, and a group of inflammatory proteins, including intracellular adhesion molecule 1, vascular adhesion molecule 1, matrix metalloproteinase (MMP)-2, MMP-9, MMP-13, and inducible nitric oxidase. In addition, their administration down-regulated pro-inflammatory cytokines in serum. Moreover, the supplementation of MES suppressed the DSS-induced hyperactivation of Akt, JNK, and NF-κB signaling pathways. Taken together, our results demonstrate that MES ameliorates DSS-induced colitis in mice, suggesting that MES may have therapeutic implications for the treatment of colitis.

Sargahydroquinoic Acid Suppresses Hyperpigmentation by cAMP and ERK1/2-Mediated Downregulation of MITF in α-MSH-Stimulated B16F10 Cells.

Hyperpigmentation diseases of the skin require topical treatment with depigmenting agents. We investigated the hypopigmented mechanisms of sargahydroquinoic acid (SHQA) in alpha-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 cells. SHQA reduced cellular tyrosinase (TYR) activity and melanin content in a concentration-dependent manner and attenuated the expression of TYR and tyrosinase-related protein 1 (TRP1), along with their transcriptional regulator, microphthalmia-associated transcription factor (MITF). SHQA also suppressed α-MSH-induced cellular production of cyclic adenosine monophosphate (cAMP), which inhibited protein kinase A (PKA)-dependent cAMP-responsive element-binding protein (CREB) activation. Docking simulation data showed a potential binding affinity of SHQA to the regulatory subunit RIIß of PKA, which may also adversely affect PKA and CREB activation. Moreover, SHQA activated ERK1/2 signaling in B16F10 cells, stimulating the proteasomal degradation of MITF. These data suggest that SHQA ameliorated hyperpigmentation in α-MSH-stimulated B16F10 cells by downregulating MITF via PKA inactivation and ERK1/2 phosphorylation, indicating that SHQA is a potent therapeutic agent against skin hyperpigmentation disorders.

Hypothalamic administration of sargahydroquinoic acid elevates peripheral thermogenic signaling and ameliorates high fat diet-induced obesity through the sympathetic nervous system.

Sargassum serratifolium (C. Agardh) C.Agardh, a marine brown alga, has been consumed as a food and traditional medicine in Asia. A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of S. serratifolium (MES) induced adipose tissue browning and suppressed diet-induced obesity and metabolic syndrome when orally supplemented. Sargahydroquinoic acid (SHQA) is a major component of MES. However, it is unclear whether SHQA regulates energy homeostasis through the central nervous system. To examine this, SHQA was administrated through the third ventricle in the hypothalamus in high-fat diet-fed C57BL/6 mice and investigated its effects on energy homeostasis. Chronic administration of SHQA into the brain reduced body weight without a change in food intake and improved metabolic syndrome-related phenotypes. Cold experiments and biochemical analyses indicated that SHQA elevated thermogenic signaling pathways, as evidenced by an increase in body temperature and UCP1 signaling in white and brown adipose tissues. Peripheral denervation experiments using 6-OHDA indicated that the SHQA-induced anti-obesity effect is mediated by the activation of the sympathetic nervous system, possibly by regulating genes associated with sympathetic outflow and GABA signaling pathways. In conclusion, hypothalamic injection of SHQA elevates peripheral thermogenic signaling and ameliorates diet-induced obesity.

The multi-functional roles of forkhead box protein O in skin aging and diseases.

Forkhead box, class O (FoxO) family members are multifunctional transcription factors that are involved in several metabolic processes, including energy metabolism, apoptosis, DNA repair, and oxidative stress. However, their roles in skin health have not been well-documented. Recent studies have indicated that FoxOs are important factors to control skin homeostasis and health. The activation or deactivation of some FoxO family members is closely related to melanogenesis, wound healing, acne, and melanoma. In this review, we have discussed the recent findings that demonstrate the relationship between FoxOs and skin health as well as the underlying mechanisms associated with their functions.

Sargahydroquinoic Acid, a Cyclooxygenase-2 Inhibitor, Attenuates Inflammatory Responses by Regulating NF-κB Inactivation and Nrf2 Activation in Lipopolysaccharide-Stimulated Cells.

Sargahydroquinoic acid (SHQA) is a major plastoquinone in Sargassum macrocarpum and has shown the capacity to prevent inflammation and oxidative stress. However, the protective mechanisms were unclear. The molecular mechanisms of SHQA on ameliorating inflammation and oxidative stress have been investigated, using lipopolysaccharide (LPS)-stimulated macrophages. SHQA was isolated and purified from S. macrocarpum and the anti-inflammatory mechanisms were explored using LPS-stimulated murine macrophage RAW 264.7 cells. SHQA did not change the expression of cyclooxygenase-2 (COX-2) but inhibited the activity of COX-2. As a result, SHQA significantly diminished the secretions of nitric oxide (NO), prostaglandin E2 (PGE2), and multiple pro-inflammatory cytokines. LPS-induced activation of nuclear factor-κB (NF-κB) was inhibited by SHQA by preventing the degradation of inhibitor κB-α (IκBα). NF-κB activation was also downregulated by the inhibition of Akt phosphorylation in LPS-stimulated cells. Furthermore, SHQA induced the expression of heme oxygenase 1 via Nrf2 activation. These results indicated that SHQA inhibited LPS-induced expressions of inflammatory mediators via suppressing the Akt-mediated NF-κB pathway as well as upregulating the Nrf2/HO-1 pathway. Our findings suggest that SHQA might be a potential therapeutic agent in various inflammatory diseases.

Sargahydroquinoic acid (SHQA) suppresses cellular senescence through Akt/mTOR signaling pathway.

AIM: The effects of sargahydroquinoic acid (SHQA) on cellular senescence and the underlying mechanisms were investigated using human umbilical vascular endothelial cells (HUVECs). METHODS: SHQA or DMSO was supplemented into the medium. Low dose of H2O2 was used to induce premature senescence. Replicative senescence was achieved by continuously culturing cells until they reached a plateau phase. Senescence biomarkers, including p53, p21, and p16 proteins, and SA-ß-Gal activity were measured. RESULTS: Pretreatment of SHQA significantly suppressed the oxidative stress-induced protein expression of p53, p21, and p16, as well as the activity of SA-ß-Gal. Additionally, SHQA also delayed the replicative senescence as indicated by an increased population doubling number, reduced protein expression of p53, p21, and p16, as well as a decreased SA-ß-Gal activity. SHQA inhibited the phosphorylation of Akt, mTOR, and downstream targets of mTOR, such as p-S6K, which was elevated by premature senescence and replicative senescence. In the absence of senescence stimuli, SHQA also inhibited the Akt/mTOR signaling pathway and promoted autophagy. CONCLUSIONS: SHQA suppressed senescence induced by oxidative stress and replication through inhibiting the Akt/mTOR pathway. With the potential of acting as an Akt/mTOR inhibitor, SHQA might be useful for developing anti-ageing therapy.

Dieckol Ameliorates Aß Production via PI3K/Akt/GSK-3ß Regulated APP Processing in SweAPP N2a Cell.

The proteolytic processing of amyloid precursor protein (APP) by ß-secretase (BACE1) and γ-secretase releases amyloid-ß peptide (Aß), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer's disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aß accumulation. In addition, dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), ß-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPß, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3ß at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3ß. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3ß activation and Aß expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on Aß production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3ß, resulting in the reduction in Aß levels.

Tunable porosity of covalently crosslinked alginate-based hydrogels and its significance in drug release behavior.

Task-specific drug release is essential in the development of hydrogels as drug delivery systems. The aim of the study is to report the effect of porosity on alginate hydrogels, which may be controlled by the design of crosslinkers, on drug release behavior. Two alginate-based hydrogels were prepared: alginate-norbornene (Alg-Nb) crosslinked by disulfide-tetrazine (S-Tz; hydrogel A) and alginate-furfuryl amine (Alg-FA) crosslinked by disulfide-maleimide (S-Ma; hydrogel B). Results showed the porosity of hydrogel A was controllable by adjusting the amount of S-Tz. Gel formation was facilitated by a "click" reaction between Alg-Nb and S-Tz, producing nitrogen gas, which, in turn, acted as an in-situ pore generator. Hydrogel B showed a non-porous morphology, as gelation was processed via addition reaction between Alg-FA and S-Ma, which produced no by-product. The study showed that crosslinker proportion and porosity were significant factors influencing drug release behavior of the alginate hydrogels. The presence of a porous structure increased the drug release while non-porous hydrogels led to a very slow release. In addition, the porous alginate hydrogels could sustainably release doxorubicin for 35 days.

Potential Anti-Aging Substances Derived from Seaweeds.

Aging is a major risk factor for many chronic diseases, such as cancer, cardiovascular disease, and diabetes. The exact mechanisms underlying the aging process are not fully elucidated. However, a growing body of evidence suggests that several pathways, such as sirtuin, AMP-activated protein kinase, insulin-like growth factor, autophagy, and nuclear factor erythroid 2-related factor 2 play critical roles in regulating aging. Furthermore, genetic or dietary interventions of these pathways can extend lifespan by delaying the aging process. Seaweeds are a food source rich in many nutrients, including fibers, polyunsaturated fatty acids, vitamins, minerals, and other bioactive compounds. The health benefits of seaweeds include, but are not limited to, antioxidant, anti-inflammatory, and anti-obese activities. Interestingly, a body of studies shows that some seaweed-derived extracts or isolated compounds, can modulate these aging-regulating pathways or even extend lifespans of various animal models. However, few such studies have been conducted on higher animals or even humans. In this review, we focused on potential anti-aging bioactive substances in seaweeds that have been studied in cells and animals mainly based on their anti-aging cellular and molecular mechanisms.

Diselenide Core Cross-Linked Micelles of Poly(Ethylene Oxide)-b-Poly(Glycidyl Methacrylate) Prepared through Alkyne-Azide Click Chemistry as a Near-Infrared Controlled Drug Delivery System.

In this article, a drug delivery system with a near-infrared (NIR) light-responsive feature was successfully prepared using a block copolymer poly(ethylene oxide)-b-poly(glycidyl methacrylate)-azide (PEO-b-PGMA-N3) and a cross-linker containing a Se-Se bond through "click" chemistry. Doxorubicin (DOX) was loaded into the core-cross-linked (CCL) micelles of the block copolymer along with indocyanine green (ICG) as a generator of reactive oxygen species (ROS). During NIR light exposure, ROS were generated by ICG and attacked the Se-Se bond of the cross-linker, leading to de-crosslinking of the CCL micelles. After NIR irradiation, the CCL micelles were continuously disrupted, which can be a good indication for effective drug release. Photothermal analysis showed that the temperature elevation during NIR exposure was negligible, thus safe for normal cells. In vitro drug release tests demonstrated that the drug release from diselenide CCL micelles could be controlled by NIR irradiation and affected by the acidity of the environment.

Meroterpenoid-Rich Fraction of the Ethanol Extract of Sargassum Serratifolium Suppresses Collagen-Induced Rheumatoid Arthritis in DBA/1J Mice Via Inhibition of Nuclear Factor κB Activation.

SCOPE: Rheumatoid arthritis (RA) is an autoimmune disorder related to the inflammation of cartilage due to the infiltration of inflammatory cells. Sargassum serratifolium, a brown alga, possesses strong anti-inflammatory activities. METHODS AND RESULTS: The effect of meroterpenoid-rich fraction from the ethanol extract of S. serratifolium (MES) on RA and its underlying mechanisms on the inhibition of RA using a collagen-induced arthritis (CIA) mouse model are examined. The results show that MES ameliorates paw swelling and reduces the arthritis score. MES considerably decreases the secretion of pro-inflammatory cytokines in the serum and joint tissue of mice. Histopathological analysis demonstrates that MES strongly inhibited bone damage and inflammatory cell intrusion in the joint tissue. The expression of inflammatory enzymes and adhesion molecules is significantly inhibited in the serum and joint tissue of MES-fed mice. In addition, MES downregulates the nuclear factor κB (NF-κB) signaling pathway by suppressing the phosphorylation of protein kinase B, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases. CONCLUSIONS: MES supplementation remarkably reduces inflammatory response in CIA mouse model. These results indicate that MES can be used as a pharmaceutical agent against RA.

Effects of Sargaquinoic Acid in Sargassum Serratifolium on Inducing Brown Adipocyte-like Phenotype in Mouse Adipocytes In Vitro.

A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of Sargassum serratifolium (MES) stimulated adipose tissue browning and inhibited diet-induced obesity and metabolic syndrome. Sargaquinoic acid (SQA) is a major component in MES. We investigated the effects of SQA on the differentiation of preadipocytes to the beige adipocytes. SQA was treated in 3T3-L1 adipocytes differentiated under a special condition that has been reported to induce the browning of adipocytes. SQA at 10 µM reduced lipid accumulation by approximately 23%. SQA at 2.5 - 10 µM induced the differentiation of white adipocytes to beige adipocytes partially by increasing the mitochondrial density and the expression of beige/brown adipocyte markers. In addition, SQA activated lipid catabolic pathways, evidenced by the increased expression levels of perilipin, carnitine palmitoyltransferase 1, and acyl-CoA synthetase long-chain family member 1. As a partial mechanism, biochemical and in silico analyses indicate that SQA activated AMP-activated protein kinase signaling in adipocytes.

Phlorotannins with Potential Anti-tyrosinase and Antioxidant Activity Isolated from the Marine Seaweed Ecklonia stolonifera.

Compounds were isolated from Ecklonia stolonifera Okamura, a marine brown alga widely consumed as food. Among the isolated compounds, 974-A was demonstrated for the first time to be a potent competitive inhibitor of mushroom tyrosinase activity towards l-tyrosine and l-DOPA (IC50 values = 1.57 ± 0.08 and 3.56 ± 0.22 µM, respectively). Molecular docking simulations clarified that the hydroxyl residues of the isolated compounds formed hydrogen bonds with residues at the catalytic and allosteric sites of tyrosinase, while other residues participated in hydrophobic interactions. Moreover, 974-A, phlorofucofuroeckol-A and eckol reduced the cellular melanin content and tyrosinase activity, and downregulated the expression of melanogenesis enzymes including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 in B16F10 melanoma cells. These compounds also effectively scavenged radicals at the cellular level. Thus, our results revealed that compounds isolated from E. stolonifera are potent tyrosinase inhibitors with potential applications in the cosmetic industry for treatment of hyperpigmentation and for the anti-browning effect in the agricultural field.

Evaluation of antioxidant activities of various solvent extract from Sargassum serratifolium and its major antioxidant components.

Sargassum serratifolium has been known to contain a high level of meroterpenoids as antioxidant components. We investigated antioxidant activities and active components in various solvent extracts from S. serratifolium. Ethyl acetate, ethanol, and methanol extracts showed relatively strong DPPH, ABTs, and superoxide radical scavenging activities. Hexane and ethyl acetate extract showed the strongest hydroxyl radical and reactive oxygen species (ROS), respectively, scavenging activities. Sargahydroquinoic acid (SHQA), sargachromanol (SCM) and sargaquinoic acid (SQA) were main antioxidant components in S. serratifolium. Ethanol extract showed the highest levels of SHQA, SCM, and SQA which comprised to be 227 ±â€¯6.31 mg/g. SHQA and SCM exhibited stronger antioxidant capacities than SQA based on lower IC50 values in ROS, DPPH, ABTs, and superoxide radical scavenging assays. The result showed that ethanol is the most efficient extracting solvent for the active components from S. serratifolium and the plant has the potential as a natural antioxidant.

Meroterpenoid-Rich Fraction of the Ethanolic Extract from Sargassum serratifolium Suppressed Oxidative Stress Induced by Tert-Butyl Hydroperoxide in HepG2 Cells.

Sargassum species have been reported to be a source of phytochemicals, with a wide range of biological activities. In this study, we evaluated the hepatoprotective effect of a meroterpenoid-rich fraction of the ethanolic extract from Sargassum serratifolium (MES) against tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells. Treatment with MES recovered the cell viability from the t-BHP-induced oxidative damage in a dose-dependent manner. It suppressed the reactive oxygen species production, lipid peroxidation, and glutathione depletion in the t-BHP-treated HepG2 cells. The activity of the antioxidants induced by t-BHP, including superoxide dismutase (SOD) and catalase, was reduced by the MES treatment. Moreover, it increased the nuclear translocation of nuclear factor erythroid 2-related factor 2, leading to the enhanced activity of glutathione S transferase, and the increased production of heme oxygenase-1 and NAD(P)H:quinine oxidoreductase 1 in t-BHP-treated HepG2 cells. These results demonstrate that the antioxidant activity of MES substituted the activity of the SOD and catalase, and induced the production of detoxifying enzymes, indicating that MES might be used as a hepatoprotectant against t-BHP-induced oxidative stress.

Sargaquinoic acid ameliorates hyperpigmentation through cAMP and ERK-mediated downregulation of MITF in α-MSH-stimulated B16F10 cells.

Hyperpigmentation disorders of the skin adversely influence the quality of life. We previously demonstrated the hypopigmenting properties of the ethanolic extract from Sargassum serratifolium and identified sargaquinoic acid (SQA) as an active component. The current study aims to investigate the hypopigmenting action of SQA in α-melanocyte stimulating hormone (α-MSH)-stimulated B16F10 cells. SQA attenuated cellular melanin synthesis by inhibiting the expression of the melanogenic enzymes, including tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and TRP2. SQA also inhibited cellular TYR activity in a dose-dependent manner. Reduced intracellular cAMP accumulation by SQA treatment resulted in the suppressed phosphorylation of cAMP-responsive element-binding protein (CREB), leading to the downregulation of microphthalmia-associated transcription factor (MITF) in α-MSH-stimulated B16F10 cells. SQA increased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and MITF (Ser73), inducing proteasomal degradation of MITF. SQA showed high binding affinity to the cAMP binding domain of PKA; the direct binding of SQA to PKA may exert an additional inhibitory effect on the PKA-dependent CREB activation. Our data demonstrated that SQA suppressed melanin production through the cAMP/CREB- and ERK1/2-mediated downregulation of MITF in α-MSH-stimulated B16F10 cells and SQA has a potential therapeutic agent for the treatment of skin hyperpigmentation disorders.

α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitory Activity of Plastoquinones from Marine Brown Alga Sargassum serratifolium.

Sargassum serratifolium C. Agardh (Phaeophyceae, Fucales) is a marine brown alga that belongs to the family Sargassaceae. It is widely distributed throughout coastal areas of Korea and Japan. S. serratifolium has been found to contain high concentrations of plastoquinones, which have strong anti-cancer, anti-inflammatory, antioxidant, and neuroprotective activity. This study aims to investigate the anti-diabetic activity of S. serratifolium and its major constituents through inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO--mediated albumin nitration. S. serratifolium ethanolic extract and fractions exhibited broad PTP1B and α-glucosidase inhibitory activity (IC50, 1.83~7.04 and 3.16~24.16 µg/mL for PTP1B and α-glucosidase, respectively). In an attempt to identify bioactive compounds, three plastoquinones (sargahydroquinoic acid, sargachromenol and sargaquinoic acid) were isolated from the active n-hexane fraction of S. serratifolium. All three plastoquinones exhibited dose-dependent inhibitory activity against PTP1B in the IC50 range of 5.14-14.15 µM, while sargachromenol and sargaquinoic acid showed dose-dependent inhibitory activity against α-glucosidase (IC50 42.41 ± 3.09 and 96.17 ± 3.48 µM, respectively). In the kinetic study of PTP1B enzyme inhibition, sargahydroquinoic acid and sargaquinoic acid led to mixed-type inhibition, whereas sargachromenol displayed noncompetitive-type inhibition. Moreover, plastoquinones dose-dependently inhibited ONOO--mediated albumin nitration. Docking simulations of these plastoquinones demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B and α-glucosidase, indicating that these plastoquinones have high affinity and tight binding capacity towards the active site of the enzymes. These results demonstrate that S. serratifolium and its major plastoquinones may have the potential as functional food ingredients for the prevention and treatment of type 2 diabetes.

Hypopigmenting Effects of Brown Algae-Derived Phytochemicals: A Review on Molecular Mechanisms.

There is a rapid increase in the demand for natural hypopigmenting agents from marine sources for cosmeceutical and pharmaceutical applications. Currently, marine macroalgae are considered as a safe and effective source of diverse bioactive compounds. Many research groups are exploring marine macroalgae to discover and characterize novel compounds for cosmeceutical, nutraceutical, and pharmaceutical applications. Many types of bioactive secondary metabolites from marine algae, including phlorotannins, sulfated polysaccharides, carotenoids, and meroterpenoids, have already been documented for their potential applications in the pharmaceutical industry. Among these metabolites, phlorotannins from brown algae have been widely screened for their pharmaceutical and hypopigmenting effects. Unfortunately, the majority of these articles did not have detailed investigations on molecular targets, which is critical to fulfilling the criteria for their cosmeceutical and pharmaceutical use. Very recently, a few meroterpenoids have been discovered from Sargassum sp., with the examination of their anti-melanogenic properties and mechanisms. Despite the scarcity of in vivo and clinical investigations of molecular mechanistic events of marine algae-derived hypopigmenting agents, identifying the therapeutic targets and their validation in humans has been a major challenge for future studies. In this review, we focused on available data representing molecular mechanisms underlying hypopigmenting properties of potential marine brown alga-derived compounds.

Protective effects of flavonoids isolated from Korean milk thistle Cirsium japonicum var. maackii (Maxim.) Matsum on tert-butyl hydroperoxide-induced hepatotoxicity in HepG2 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Milk thistle leaves and flowers have been traditionally used as herbal remedy to alleviate liver diseases for decades. Korean milk thistle, Cirsium japonicum var. maackii (Maxim.) Matsum has been employed in traditional folk medicine as diuretic, antiphlogistic, hemostatic, and detoxifying agents. AIM OF THE STUDY: The aim of current investigation was to evaluate hepatoprotective properties of the MeOH extract of the roots, stems, leaves and flowers of Korean milk thistle as well as four isolated flavonoids, luteolin, luteolin 5-O-glucoside, apigenin and apigenin 7-O-glucuronide during t-BHP-induced oxidative stress in HepG2 cells. MATERIALS AND METHODS: Hepatoprotective potential of the MeOH extracts and flavonoids derived from Korean milk thistle against t-BHP-induced oxidative stress in HepG2 cells were evaluated following MTT method. Incubating HepG2 cells with t-BHP markedly decreased the cell viability and increased the intracellular ROS generation accompanied by depleted GSH levels. Protein expression of heme oxygenase (HO-1) and nuclear factor-E2-related factor 2 (Nrf-2) was determined by Western blot. RESULTS: Our findings revealed that pretreating HepG2 cells with MeOH extracts and bioactive flavonoids significantly attenuated the t-BHP-induced oxidative damage, followed by increased cell viability in a dose-dependent manner. The results illustrate that excess ROS generation was reduced and GSH levels increased dose-dependently when HepG2 cells were pretreated with four flavonoids. Moreover, Western blotting analysis demonstrated that protein expressions of Nrf-2 and HO-1 were also up-regulated by flavonoids treatment. CONCLUSIONS: These results clearly demonstrate that the MeOH extracts and flavonoids from Korean milk thistle protected HepG2 cells against oxidative damage triggered by t-BHP principally by modulating ROS generation and restoring depleted GSH levels in addition to the increased Nrf-2/HO-1 signaling cascade. These flavonoids are potential natural antioxidative biomarkers against oxidative stress-induced hepatotoxicity.