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Article: Natural Citrus flavanone 5-demethylnobiletin stimulates melanogenesis through the activation of cAMP/CREB pathway in B16F10 cells

Wang, Hui Miao / Qu, Li Qun / Ng, Jerome P.L. / Zeng, Wu / Yu, Lu / Song, Lin Lin / Wong, Vincent Kam Wai / Xia, Cheng Lai / Law, Betty Yuen Kwan

Phytomedicine. 2022 Apr., v. 98

2022

Abstract: 5-demethylnobiletin is a natural polymethoxyflavone which is isolated from the extract of citrus fruits peels. It exhibits a broad spectrum of biological activities such as anti-cancer, anti-inflammatory, cardiovascular protective and neuroprotective ... ...

Abstract	5-demethylnobiletin is a natural polymethoxyflavone which is isolated from the extract of citrus fruits peels. It exhibits a broad spectrum of biological activities such as anti-cancer, anti-inflammatory, cardiovascular protective and neuroprotective effects, however, its effect in melanogenesis remains uninvestigated. Melanin synthesis is a very important biological process in curing disease such as vitiligo with depigmentation on the skin. In the current work, we aim to confirm the bioactivity and mechanism of 5-demethylnobiletin in stimulating melanogenesis. To confirm the mechanistic role of 5-demethylnobiletin in enhancing melanogenesis, its effect on the activity of tyrosinase, together with the level of microphthalmia-associated transcription factor (MITF), Trp-1, Trp-2, melanocyte-specific marker protein PMEL17, Rab27a, Melanophilin and Myosin VA were studied in B16F10 melanoma cells. Multiple biological assays on melanogenesis-associated proteins such as melanin content detection, tyrosinase activity colorimetric assay, qPCR, western blot analysis, dual-luciferase reporter assay, cAMP activity assay and Fontana-Masson ammoniacal silver staining were used to confirm the role of 5-demethylnobiletin in stimulating melanin synthesis and the transportation of melanosomes. As confirmed by multiple biological assays, 5-demethylnobiletin is found to stimulate dendrite structure formation in cells, melanin synthesis and the transportation of melanosomes, via inducing the phosphorylation of cAMP response element-binding protein (CREB) and increasing the intracellular levels of cAMP in vitro through the PKA-dependent pathway. The findings suggested that 5-demethylnobiletin may be considered as a potential natural product candidate for patients with pigment disorder.
Keywords	Citrus ; Western blotting ; bioluminescence assay ; colorimetry ; flavanones ; melanin ; melanogenesis ; melanoma ; myosin ; phosphorylation ; polymethoxyflavones ; silver ; transcription factors ; transportation
Language	English
Dates of publication	2022-04
Publishing place	Elsevier GmbH
Document type	Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2022.153941
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Raddeanin A isolated from Anemone raddeana Regel improves pathological and cognitive deficits of the mice model of Alzheimer's disease by targeting β-amyloidosis.

Liu, Meng Han / Tang, Yong / Qu, Li Qun / Song, Lin Lin / Lo, Hang Hong / Zhang, Rui Long / Yun, Xiao Yun / Wang, Hui Miao / Chan, Joyce Tsz Wai / Wu, Jian Hui / Wang, Cai Ren / Wong, Vincent Kam Wai / Wu, An Guo / Law, Betty Yuen-Kwan

Phytomedicine : international journal of phytotherapy and phytopharmacology

2023 Volume 122, Page(s) 155121

Abstract: Background: Raddeanin A is a triterpenoid isolated from Anemone raddeana Regel. It exhibits a broad spectrum of biological activities such as anti-tumor and anti-inflammatory, however, its neuroprotective effect in targeting Alzheimer's disease (AD) ... ...

Abstract	Background: Raddeanin A is a triterpenoid isolated from Anemone raddeana Regel. It exhibits a broad spectrum of biological activities such as anti-tumor and anti-inflammatory, however, its neuroprotective effect in targeting Alzheimer's disease (AD) remains uninvestigated. Purpose: To provide scientific base for the development of novel AD drug by clarifying the neuroprotective effect and molecular mechanisms of raddeanin A in both in vitro and in vivo AD model. Study design: To confirm the neuroprotective role of raddeanin A in the treatment of AD, its mechanisms and effects on β-amyloidosis and Aβ fibrillation was studied in U87 cells. Besides, the improvement on cognitive deficit, pathological defects, reactive astrocyte clusters, inhibition on neuronal inflammation and apoptosis were further studied in 3 x Tg-AD mice model of AD. Methods: Real-time PCR, western blot, dot blot, biolayer interferometry and bioinformatics analysis were used to confirm the in vitro effect and targets of raddeanin A on β-amyloidosis and its associated protein network. A series of experiments including Morris water maze, H&E staining, nissl staining and immunofluorescence analysis were conducted to confirm the protective behavioral effect of raddeanin A in the in vivo AD mice model. Results: Raddeanin A was identified to reduce β-amyloidosis in U87 cells and 3 x Tg-AD mice model of AD by decreasing level of BACE1, APP, APP-β and Aβ. Raddeanin A improved behavioral, spatial memory and learning ability in the AD mice. In the cortex and hippocampus, raddeanin A improved the morphology and arrangement of neurons, lower the level of reactive astrocyte marker GFAP and apoptotic marker proteins Bax/Bcl2 ratio. Moreover, raddeanin A upregulated the mRNA and protein level of Prkcα in the hippocampus of AD mice whose neuroprotective effect was exerted possibly via the activation of protein kinase C. Conclusion: As a novel natural agent targeting β-amyloidosis, our results provide the first evidence of the multiple in vitro and in vivo neuroprotective effect of raddeanin A, suggesting its potential therapeutic application in preventing or alleviating the symptoms of AD.
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/metabolism ; Anemone/metabolism ; Amyloid Precursor Protein Secretases ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Aspartic Acid Endopeptidases ; Amyloidosis ; Cognition ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics
Chemical Substances	raddeanin A ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Neuroprotective Agents ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor
Language	English
Publishing date	2023-10-01
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2023.155121
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Article: Extracellular Vesicle Delivery of Neferine for the Attenuation of Neurodegenerative Disease Proteins and Motor Deficit in an Alzheimer's Disease Mouse Model.

Tang, Bin / Zeng, Wu / Song, Lin Lin / Wang, Hui Miao / Qu, Li Qun / Lo, Hang Hong / Yu, Lu / Wu, An Guo / Wong, Vincent Kam Wai / Law, Betty Yuen Kwan

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 1

Abstract: Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood-brain barrier in order to target the ... ...

Abstract	Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood-brain barrier in order to target the central nervous system (CNS). In this study, high-purity exosomes isolated by the ultra-high-speed separation method were applied as the natural compound carrier, with the loading efficiency confirmed by UHPLC-MS analysis. Through the optimization of various cargo loading methods using exosomes, this study compared the efficiency of different ways for the separation of exosomes and the exosome encapsulation of natural compounds with increasing molecular weights via extensive in vitro and in vivo efficacy studies. In a pharmacokinetic study, our data suggested that the efficiency of compound's loading into exosomes is positively correlated to its molecular weight. However, with a molecular weight of greater than 1109 Da, the exosome-encapsulated natural compounds were not able to pass through the blood-brain barrier (BBB). In vitro cellular models confirmed that three of the selected exosome-encapsulated natural compounds-baicalin, hederagenin and neferine-could reduce the level of neurodegenerative disease mutant proteins-including huntingtin 74 (HTT74), P301L tau and A53T α-synuclein (A53T α-syn)-more effectively than the compounds alone. With the traditional pharmacological role of the herbal plant
Language	English
Publishing date	2022-01-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15010083
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Natural Citrus flavanone 5-demethylnobiletin stimulates melanogenesis through the activation of cAMP/CREB pathway in B16F10 cells.

Wang, Hui Miao / Qu, Li Qun / Ng, Jerome P L / Zeng, Wu / Yu, Lu / Song, Lin Lin / Wong, Vincent Kam Wai / Xia, Cheng Lai / Law, Betty Yuen Kwan

Phytomedicine : international journal of phytotherapy and phytopharmacology

2022 Volume 98, Page(s) 153941

Abstract: Background: 5-demethylnobiletin is a natural polymethoxyflavone which is isolated from the extract of citrus fruits peels. It exhibits a broad spectrum of biological activities such as anti-cancer, anti-inflammatory, cardiovascular protective and ... ...

Abstract	Background: 5-demethylnobiletin is a natural polymethoxyflavone which is isolated from the extract of citrus fruits peels. It exhibits a broad spectrum of biological activities such as anti-cancer, anti-inflammatory, cardiovascular protective and neuroprotective effects, however, its effect in melanogenesis remains uninvestigated. Purpose: Melanin synthesis is a very important biological process in curing disease such as vitiligo with depigmentation on the skin. In the current work, we aim to confirm the bioactivity and mechanism of 5-demethylnobiletin in stimulating melanogenesis. Study design: To confirm the mechanistic role of 5-demethylnobiletin in enhancing melanogenesis, its effect on the activity of tyrosinase, together with the level of microphthalmia-associated transcription factor (MITF), Trp-1, Trp-2, melanocyte-specific marker protein PMEL17, Rab27a, Melanophilin and Myosin VA were studied in B16F10 melanoma cells. Methods: Multiple biological assays on melanogenesis-associated proteins such as melanin content detection, tyrosinase activity colorimetric assay, qPCR, western blot analysis, dual-luciferase reporter assay, cAMP activity assay and Fontana-Masson ammoniacal silver staining were used to confirm the role of 5-demethylnobiletin in stimulating melanin synthesis and the transportation of melanosomes. Results: As confirmed by multiple biological assays, 5-demethylnobiletin is found to stimulate dendrite structure formation in cells, melanin synthesis and the transportation of melanosomes, via inducing the phosphorylation of cAMP response element-binding protein (CREB) and increasing the intracellular levels of cAMP in vitro through the PKA-dependent pathway. Conclusion: The findings suggested that 5-demethylnobiletin may be considered as a potential natural product candidate for patients with pigment disorder.
Language	English
Publishing date	2022-01-19
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1205240-1
ISSN	1618-095X ; 0944-7113
ISSN (online)	1618-095X
ISSN	0944-7113
DOI	10.1016/j.phymed.2022.153941
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Hyperoside alleviates toxicity of β-amyloid via endoplasmic reticulum-mitochondrial calcium signal transduction cascade in APP/PS1 double transgenic Alzheimer's disease mice.

Song, Lin Lin / Qu, Yuan Qing / Tang, Yong Pei / Chen, Xi / Lo, Hang Hong / Qu, Li Qun / Yun, Yun Xiao / Wong, Vincent Kam Wai / Zhang, Rui Long / Wang, Hui Miao / Liu, Meng Han / Zhang, Wei / Zhang, Hui Xia / Chan, Joyce Tsz Wai / Wang, Cai Ren / Wu, Jian Hui / Law, Betty Yuen Kwan

Redox biology

2023 Volume 61, Page(s) 102637

Abstract: Alzheimer's disease is a neurodegenerative disorder characterized by a decline in cognitive function. The β-amyloid (Aβ) hypothesis suggests that Aβ peptides can spontaneously aggregate into β-fragment-containing oligomers and protofibrils, and this ... ...

Abstract	Alzheimer's disease is a neurodegenerative disorder characterized by a decline in cognitive function. The β-amyloid (Aβ) hypothesis suggests that Aβ peptides can spontaneously aggregate into β-fragment-containing oligomers and protofibrils, and this activation of the amyloid pathway alters Ca
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Calcium/metabolism ; Signal Transduction ; Endoplasmic Reticulum/metabolism ; Disease Models, Animal
Chemical Substances	Amyloid beta-Peptides ; Calcium (SY7Q814VUP) ; hyperoside (8O1CR18L82)
Language	English
Publishing date	2023-02-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2023.102637
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis.

Luo, Wei-Dan / Wang, Yu-Ping / Lv, Jun / Liu, Yong / Qu, Yuan-Qing / Xu, Xiong-Fei / Yang, Li-Jun / Lin, Zi-Cong / Wang, Lin-Na / Chen, Rui-Hong / Yang, Jiu-Jie / Zeng, Ya-Ling / Zhang, Rui-Long / Huang, Bai-Xiong / Yun, Xiao-Yun / Wang, Xuan-Ying / Song, Lin-Lin / Wu, Jian-Hui / Wang, Xing-Xia /

Chen, Xi / Zhang, Wei / Wang, Hui-Miao / Qu, Li-Qun / Liu, Meng-Han / Liu, Liang / Law, Betty Yuen Kwan / Wong, Vincent Kam Wai

Nature communications

2023 Volume 14, Issue 1, Page(s) 4394

Abstract: The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that ... ...

Abstract	The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant-induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.
MeSH term(s)	Humans ; Rats ; Animals ; Arthritis, Rheumatoid ; Proto-Oncogene Proteins c-fos/genetics ; Inflammation ; Transcription Factor AP-1/metabolism ; Arthritis, Experimental
Chemical Substances	Proto-Oncogene Proteins c-fos ; Transcription Factor AP-1
Language	English
Publishing date	2023-07-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40113-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The New Application of UHPLC-DAD-TOF/MS in Identification of Inhibitors on β-Amyloid Fibrillation From

Yu, Lu / Wu, An-Guo / Wong, Vincent Kam-Wai / Qu, Li-Qun / Zhang, Ni / Qin, Da-Lian / Zeng, Wu / Tang, Bin / Wang, Hui-Miao / Wang, Qiong / Law, Betty Yuen-Kwan

Frontiers in pharmacology

2019 Volume 10, Page(s) 194

Abstract: Literary evidence depicts that aggregated β-amyloid (Aβ) leads to the pathogenesis of Alzheimer's disease (AD). Although many traditional Chinese medicines (TCMs) are effective in treating neurodegenerative diseases, there is no effective way for ... ...

Abstract	Literary evidence depicts that aggregated β-amyloid (Aβ) leads to the pathogenesis of Alzheimer's disease (AD). Although many traditional Chinese medicines (TCMs) are effective in treating neurodegenerative diseases, there is no effective way for identifying active compounds from their complicated chemical compositions. Instead of using a traditional herbal separation method with low efficiency, we herein apply UHPLC-DAD-TOF/MS for the accurate identification of the active compounds that inhibit the fibrillation of Aβ (1-42), via an evaluation of the peak area of individual chemical components in chromatogram, after incubation with an Aβ peptide. Using the neuroprotective herbal plant
Language	English
Publishing date	2019-03-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2019.00194
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Saponins isolated from Radix polygalae extent lifespan by modulating complement C3 and gut microbiota.

Pharmacological research

2021 Volume 170, Page(s) 105697

Abstract: With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. ... ...

Abstract	With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. Progressive neuroinflammation contributes to aging, cognitive malfunction, and neurodegenerative diseases. However, precise mechanisms or drugs targeting age-related neuroinflammation and cognitive impairment remain un-elucidated. Traditional herbal plants have been prescribed in many Asian countries for anti-aging and the modulation of aging-related symptoms. In general, herbal plants' efficacy is attributed to their safety and polypharmacological potency via the systemic manipulation of the body system. Radix polygalae (RP) is a herbal plant prescribed for anti-aging and the relief of age-related symptoms; however, its active components and biological functions remained un-elucidated. In this study, an active methanol fraction of RP containing 17 RP saponins (RPS), was identified. RPS attenuates the elevated C3 complement protein in aged mice to a level comparable to the young control mice. The active RPS also restates the aging gut microbiota by enhancing beneficial bacteria and suppressing harmful bacteria. In addition, RPS treatment improve spatial reference memory in aged mice, with the attenuation of multiple molecular markers related to neuroinflammation and aging. Finally, the RPS improves the behavior and extends the lifespan of C. elegans, confirming the herbal plant's anti-aging ability. In conclusion, through the mouse and C. elegas models, we have identified the beneficial RPS that can modulate the aging process, gut microbiota diversity and rectify several aging-related phenotypes.
MeSH term(s)	Age Factors ; Aging/drug effects ; Aging/genetics ; Aging/immunology ; Aging/metabolism ; Animals ; Behavior, Animal/drug effects ; Caenorhabditis elegans/drug effects ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/growth & development ; Caenorhabditis elegans/metabolism ; Cell Line, Tumor ; Complement C3/metabolism ; Down-Regulation ; Gastrointestinal Microbiome/drug effects ; Longevity/drug effects ; Male ; Maze Learning/drug effects ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/genetics ; Neuroinflammatory Diseases/immunology ; Neuroinflammatory Diseases/metabolism ; Neuroinflammatory Diseases/prevention & control ; Neuroprotective Agents/isolation & purification ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Plant Extracts/isolation & purification ; Plant Extracts/pharmacology ; Plant Roots ; Polygala/chemistry ; Saponins/isolation & purification ; Saponins/pharmacology ; Spatial Memory/drug effects ; Transcriptome ; Mice
Chemical Substances	C3 protein, mouse ; Complement C3 ; Neuroprotective Agents ; Plant Extracts ; Saponins
Language	English
Publishing date	2021-05-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2021.105697
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Article ; Online: Sirtuin 5 deficiency increases disease severity in rats with adjuvant-induced arthritis.

Zhang, Ni / Zhang, Hui / Law, Betty Yuen Kwan / Dias, Ivo Ricardo De Seabra Rodrigues / Qiu, Cong Ling / Zeng, Wu / Dan Pan, Hu / Chen, Jin Yun / Bai, Yan Fu / Lv, Jing / Qu, Li Qun / Chen, Xi / Huang, Qi / Zhang, Wei / Yang, Li Jun / Yu, Lu / Han, Yu / Huang, Guo Xin / Wang, Hui Miao /

Sun, Xiao Lei / Zhang, Yun / He, Hu Qiang / Dan Luo, Wei / Xiao, Yao / Zhou, Jian / Xu, Ting / Huang, Qing Chun / Wu, Min / Huang, Zhi Sheng / Liu, Wei / Wong, Vincent Kam Wai / Liu, Liang

Cellular & molecular immunology

2020 Volume 17, Issue 11, Page(s) 1190–1192

MeSH term(s)	Animals ; Anti-Inflammatory Agents/metabolism ; Arthritis, Experimental/diagnostic imaging ; Arthritis, Experimental/metabolism ; Arthritis, Experimental/pathology ; Arthritis, Rheumatoid/diagnostic imaging ; Arthritis, Rheumatoid/metabolism ; Arthritis, Rheumatoid/pathology ; Energy Metabolism ; Humans ; Rats ; Severity of Illness Index ; Sirtuins/deficiency ; Sirtuins/metabolism ; X-Ray Microtomography
Chemical Substances	Anti-Inflammatory Agents ; SIRT5 protein, rat (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-)
Language	English
Publishing date	2020-02-25
Publishing country	China
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2435097-7
ISSN	2042-0226 ; 1672-7681
ISSN (online)	2042-0226
ISSN	1672-7681
DOI	10.1038/s41423-020-0380-4
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