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Article ; Online: Galgravin Isolated from

Ou, Shih-Ming / Hsu, Yin-Chieh / Fu, Shu-Ling / Lin, Lie-Chwen / Lin, Chao-Hsiung

International journal of molecular sciences

2023 Volume 24, Issue 23

Abstract: Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated ... ...

Abstract	Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from
MeSH term(s)	Mice ; Animals ; Lipopolysaccharides/toxicity ; NF-kappa B/metabolism ; Kadsura/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Endotoxemia/chemically induced ; Endotoxemia/drug therapy ; Anti-Inflammatory Agents/adverse effects ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; Piper ; Inflammation/metabolism ; Lignans/therapeutic use
Chemical Substances	Lipopolysaccharides ; galgravin (528-63-2) ; NF-kappa B ; Tumor Necrosis Factor-alpha ; Anti-Inflammatory Agents ; Interleukin-6 ; Cyclooxygenase 2 (EC 1.14.99.1) ; Lignans
Language	English
Publishing date	2023-11-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242316572
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Article ; Online: Plasma metabolomic profiles associated with hypertension and blood pressure in response to thiazide diuretics.

Huang, Chin-Chou / Huang, Yi-Long / Lin, Chao-Hsiung / Chen, Jaw-Wen

Hypertension research : official journal of the Japanese Society of Hypertension

2021 Volume 45, Issue 3, Page(s) 464–473

Abstract: This study aimed to identify the metabolomic alterations associated with hypertension (HTN) and the response of blood pressure (BP) to thiazide diuretics. A total of 50 participants previously untreated for HTN were prospectively recruited. After a 2- ... ...

Abstract	This study aimed to identify the metabolomic alterations associated with hypertension (HTN) and the response of blood pressure (BP) to thiazide diuretics. A total of 50 participants previously untreated for HTN were prospectively recruited. After a 2-week lifestyle adjustment, 30 participants with systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg were classified into the HTN group and prescribed hydrochlorothiazide (HCTZ) at 50 mg per day for 2 weeks. The remaining 20 participants, who had relatively normal BP, were assigned to the normotension group. Metabolomic profiles related to the response of BP to thiazide diuretics were analyzed. A total of 73 differential metabolites were found to be associated with HTN, and 27 metabolites were significantly changed upon HCTZ treatment (HCTZ-sensitive metabolites). Among the identified metabolites, 7 (aspartate, histidine, C5-DC, C5-M-DC, C14:1, phosphatidylcholine ae C34:1, and phosphatidylcholine ae C34:3) were positively associated with HTN and decreased in abundance upon HCTZ treatment (HCTZ-reduced/HTN-associated metabolites). Moreover, multivariate analysis of 20 metabolites whose baseline levels were associated with the response of BP revealed that aspartate, glutamate, lysophosphatidylcholine C16:0, lysophosphatidylcholine C20:3, and sphingomyelin C24:1 were independently related to systolic BP reduction, and lysophosphatidylcholine C20:3 was independently associated with diastolic BP reduction. In conclusion, we identified 5 metabolites independently related to BP changes with HCTZ treatment. An advanced biomarker profile of thiazide-induced metabolomic changes may provide a clue with which to further explore the complex and mixed effects of thiazide treatment in a clinical setting.
MeSH term(s)	Antihypertensive Agents/pharmacology ; Antihypertensive Agents/therapeutic use ; Blood Pressure ; Diuretics/therapeutic use ; Drug Therapy, Combination ; Humans ; Hydrochlorothiazide/therapeutic use ; Hypertension ; Sodium Chloride Symporter Inhibitors/pharmacology ; Treatment Outcome
Chemical Substances	Antihypertensive Agents ; Diuretics ; Sodium Chloride Symporter Inhibitors ; Hydrochlorothiazide (0J48LPH2TH)
Language	English
Publishing date	2021-12-24
Publishing country	England
Document type	Journal Article
ZDB-ID	1175297-x
ISSN	1348-4214 ; 0916-9636
ISSN (online)	1348-4214
ISSN	0916-9636
DOI	10.1038/s41440-021-00825-9
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Article ; Online: Sebacic Acid as a Potential Age-Related Biomarker of Liver Aging: Evidence Linking Mice and Human.

Huang, Chen-Hua / Lee, Wei-Ju / Huang, Yi-Long / Tsai, Ting-Fen / Chen, Liang-Kung / Lin, Chao-Hsiung

The journals of gerontology. Series A, Biological sciences and medical sciences

2023 Volume 78, Issue 10, Page(s) 1799–1808

Abstract: The aging process is complicated and involves diverse organ dysfunction; furthermore, the biomarkers that are able to reflect biological aging are eagerly sought after to monitor the system-wide decline associated with the aging process. To address this, ...

Abstract	The aging process is complicated and involves diverse organ dysfunction; furthermore, the biomarkers that are able to reflect biological aging are eagerly sought after to monitor the system-wide decline associated with the aging process. To address this, we performed a metabolomics analysis using a longitudinal cohort study from Taiwan (N = 710) and established plasma metabolomic age using a machine learning algorithm. The resulting estimation of age acceleration among the older adults was found to be correlated with HOMA-insulin resistance. In addition, a sliding window analysis was used to investigate the undulating decrease in hexanoic and heptanoic acids that occurs among the older adults at different ages. A comparison of the metabolomic alterations associated with aging between humans and mice implied that ω-oxidation of medium-chain fatty acids was commonly dysregulated in older subjects. Among these fatty acids, sebacic acid, an ω-oxidation product produced by the liver, was significantly decreased in the plasma of both older humans and aged mice. Notably, an increase in the production and consumption of sebacic acid within the liver tissue of aged mice was observed, along with an elevation of pyruvate-to-lactate conversion. Taken together, our study reveals that sebacic acid and metabolites of ω-oxidation are the common aging biomarkers in both humans and mice. The further analysis suggests that sebacic acid may play an energetic role in supporting the production of acetyl-CoA during liver aging, and thus its alteration in plasma concentration potentially reflects the aging process.
MeSH term(s)	Humans ; Mice ; Animals ; Aged ; Longitudinal Studies ; Fatty Acids/metabolism ; Liver/metabolism ; Aging ; Biomarkers
Chemical Substances	sebacic acid (97AN39ICTC) ; Fatty Acids ; Biomarkers
Language	English
Publishing date	2023-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glad121
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Article: Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice.

Huang, Chen-Hua / Huang, Yi-Long / Shen, Zhao-Qing / Lin, Chao-Hsiung / Tsai, Ting-Fen

Biomedicines

2021 Volume 9, Issue 9

Abstract: Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which ...

Abstract	Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.
Language	English
Publishing date	2021-09-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines9091229
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Article ; Online: Cisd2 slows down liver aging and attenuates age-related metabolic dysfunction in male mice.

Huang, Yi-Long / Shen, Zhao-Qing / Huang, Chen-Hua / Lin, Chao-Hsiung / Tsai, Ting-Fen

Aging cell

2021 Volume 20, Issue 12, Page(s) e13523

Abstract: The liver plays a pivotal role in mammalian aging. However, the mechanisms underlying liver aging remain unclear. Cisd2 is a pro-longevity gene in mice. Cisd2 mediates lifespan and healthspan via regulation of calcium homeostasis and mitochondrial ... ...

Abstract	The liver plays a pivotal role in mammalian aging. However, the mechanisms underlying liver aging remain unclear. Cisd2 is a pro-longevity gene in mice. Cisd2 mediates lifespan and healthspan via regulation of calcium homeostasis and mitochondrial functioning. Intriguingly, the protein level of Cisd2 is significantly decreased by about 50% in the livers of old male mice. This down-regulation of Cisd2 may result in the aging liver exhibiting non-alcoholic fatty liver disease (NAFLD) phenotype. Here, we use Cisd2 transgenic mice to investigate whether maintaining Cisd2 protein at a persistently high level is able to slow down liver aging. Our study identifies four major discoveries. Firstly, that Cisd2 expression attenuates age-related dysregulation of lipid metabolism and other pathological abnormalities. Secondly, revealed by RNA sequencing analysis, the livers of old male mice undergo extensive transcriptomic alterations, and these are associated with steatosis, hepatitis, fibrosis, and xenobiotic detoxification. Intriguingly, a youthful transcriptomic profile, like that of young 3-month-old mice, was found in old Cisd2 transgenic male mice at 26 months old. Thirdly, Cisd2 suppresses the age-associated dysregulation of various transcription regulators (Nrf2, IL-6, and Hnf4a), which keeps the transcriptional network in a normal pattern. Finally, a high level of Cisd2 protein protects the liver from oxidative stress, and this is associated with a reduction in mitochondrial DNA deletions. These findings demonstrate that Cisd2 is a promising target for the development of therapeutic agents that, by bringing about an effective enhancement of Cisd2 expression, will slow down liver aging.
MeSH term(s)	Aging ; Animals ; Autophagy-Related Proteins/metabolism ; Liver/pathology ; Male ; Metabolic Diseases/genetics ; Mice ; Nerve Tissue Proteins/metabolism
Chemical Substances	Autophagy-Related Proteins ; Nerve Tissue Proteins ; Noxp70 protein, mouse
Language	English
Publishing date	2021-11-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2113083-8
ISSN	1474-9726 ; 1474-9718
ISSN (online)	1474-9726
ISSN	1474-9718
DOI	10.1111/acel.13523
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Article ; Online: Arginine Methylation of hnRNPK Inhibits the DDX3-hnRNPK Interaction to Play an Anti-Apoptosis Role in Osteosarcoma Cells.

Chen, Chiao-Che / Yang, Jen-Hao / Fu, Shu-Ling / Lin, Wey-Jinq / Lin, Chao-Hsiung

International journal of molecular sciences

2021 Volume 22, Issue 18

Abstract: Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA binding protein involved in diverse cell processes; it is also a p53 coregulator that initiates apoptosis under DNA damage conditions. However, the upregulation of hnRNPK is correlated with ...

Abstract	Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA binding protein involved in diverse cell processes; it is also a p53 coregulator that initiates apoptosis under DNA damage conditions. However, the upregulation of hnRNPK is correlated with cancer transformation, progression, and migration, whereas the regulatory role of hnRNPK in cancer malignancy remains unclear. We previously showed that arginine methylation of hnRNPK attenuated the apoptosis of U2OS osteosarcoma cells under DNA damage conditions, whereas the replacement of endogenous hnRNPK with a methylation-defective mutant inversely enhanced apoptosis. The present study further revealed that an RNA helicase, DDX3, whose C-terminus preferentially binds to the unmethylated hnRNPK and could promote such apoptotic enhancement. Moreover, C-terminus-truncated DDX3 induced significantly less apoptosis than full-length DDX3. Notably, we also identified a small molecule that docks at the ATP-binding site of DDX3, promotes the DDX3-hnRNPK interaction, and induces further apoptosis. Overall, we have shown that the arginine methylation of hnRNPK suppresses the apoptosis of U2OS cells via interfering with DDX3-hnRNPK interaction. On the other hand, DDX3-hnRNPK interaction with a proapoptotic role may serve as a target for promoting apoptosis in osteosarcoma cells.
MeSH term(s)	Amino Acid Motifs ; Apoptosis/genetics ; Arginine/metabolism ; Cell Line, Tumor ; DEAD-box RNA Helicases/chemistry ; DEAD-box RNA Helicases/metabolism ; DNA Damage ; DNA-Binding Proteins/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein K/genetics ; Heterogeneous-Nuclear Ribonucleoprotein K/metabolism ; Humans ; Methylation ; Models, Molecular ; Mutation ; Osteosarcoma/metabolism ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs
Chemical Substances	DNA-Binding Proteins ; Heterogeneous-Nuclear Ribonucleoprotein K ; HNRNPK protein, human (146410-60-8) ; Arginine (94ZLA3W45F) ; DDX3X protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2021-09-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22189764
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Article ; Online: Cisd2 Protects the Liver from Oxidative Stress and Ameliorates Western Diet-Induced Nonalcoholic Fatty Liver Disease

Huang, Yi-Long / Shen, Zhao-Qing / Huang, Zhenhua / Teng, Yuan-Chi / Lin, Chao-Hsiung / Tsai, Ting-Fen

Antioxidants. 2021 Apr. 03, v. 10, no. 4

2021

Abstract: Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide ... ...

Abstract	Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide evidence that Cisd2 is a molecular target for the development of treatments targeting NAFLD and NASH. Several discoveries are pinpointed. The first is that Cisd2 dosage modulates the severity of Western diet-induced (WD-induced) NAFLD. Specifically, Cisd2 haploinsufficiency accelerates NAFLD development and exacerbates progression toward NASH. Conversely, an enhanced Cisd2 copy number attenuates liver pathogenesis. Secondly, when a WD is fed to mice, transcriptomic analysis reveals that the major alterations affecting biological processes are related to inflammation, lipid metabolism, and DNA replication/repair. Thirdly, among these differentially expressed genes, the most significant changes involve Nrf2-mediated oxidative stress, cholesterol biosynthesis, and fatty acid metabolism. Finally, increased Cisd2 expression protects the liver from oxidative stress and reduces the occurrence of mitochondrial DNA deletions. Taken together, our mouse model reveals that Cisd2 plays a crucial role in protecting the liver from WD-induced damages. The development of therapeutic agents that effectively enhance Cisd2 expression is one potential approach to the treatment of WD-induced fatty liver diseases.
Keywords	DNA replication ; biosynthesis ; cholesterol ; fatty acid metabolism ; fatty liver ; gene expression regulation ; haploinsufficiency ; inflammation ; liver ; mice ; mitochondrial DNA ; oxidative stress ; pathogenesis ; therapeutics ; transcriptomics
Language	English
Dates of publication	2021-0403
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
Note	NAL-AP-2-clean
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10040559
Database	NAL-Catalogue (AGRICOLA)

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Article: Hypericum sampsonii

Hsu, Yin-Chieh / Ou, Shih-Ming / Zhuang, Kai-Ru / Kuo, Ai-Ling / Li, Wan-Jhen / Huang, Chun-Yi / Lin, Chao-Hsiung / Chen, Jih-Jung / Fu, Shu-Ling

Journal of traditional and complementary medicine

2023 Volume 13, Issue 4, Page(s) 379–388

Abstract: Background and aim: Sepsis causes an uncontrolled systemic response characterized by excessive inflammation and immune suppression, leading to multiple organ failure and death. An effective therapeutic strategy for sepsis-related syndromes is urgently ... ...

Abstract	Background and aim: Sepsis causes an uncontrolled systemic response characterized by excessive inflammation and immune suppression, leading to multiple organ failure and death. An effective therapeutic strategy for sepsis-related syndromes is urgently needed. Experimental procedure: Models of bacterial lipopolysaccharide (LPS)-induced activated macrophages and endotoxemia mice were used, in which the TLR4/NF-κB signaling pathway is upregulated to trigger inflammatory responses. The HS extract (HSE) was delivered into LPS-induced endotoxemia mice via oral administration. Three compounds were purified using column chromatography and preparative thin layer chromatography and were validated by physical and spectroscopic data. Results: HSE suppressed NF-κB activation and proinflammatory molecules (TNF-α, IL-6, iNOS) in LPS-activated RAW 264.7 macrophages. Furthermore, oral administration of HSE (200 mg/kg) to LPS-treated mice improved the survival rate, restored body temperature, decreased TNF-α and IL-6 in serum, and reduced IL-6 expression in bronchoalveolar lavage fluid (BALF). In lung tissues, HSE reduced LPS-induced leukocyte infiltration and the expression of proinflammatory molecules (TNF-α, IL-6, iNOS, CCL4 and CCL5). Three pure compounds isolated from HSE, including 2,4,6-trihydroxybenzophenone-4-O-geranyl ether, 1-hydroxy-7 methoxyxanthone and euxanthone, were demonstrated to exhibit anti-inflammatory activities in LPS-stimulated RAW 264.7 macrophages. Conclusion: The present study demonstrated the anti-inflammatory effects of HS
Language	English
Publishing date	2023-03-02
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2709698-1
ISSN	2225-4110
ISSN	2225-4110
DOI	10.1016/j.jtcme.2023.03.002
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Article ; Online: Design, synthesis, and anti-cancer evaluation of C-14 arylcarbamate derivatives of andrographolide.

Yang, Tzu-Ching / Chiang, Yun-Jou / Chiang, Po-Yu / Chen, Han-Yu / Zhuang, Kai-Ru / Wang, Yu-Chia / Lin, Chao-Hsiung / Lo, Lee-Chiang / Fu, Shu-Ling

Bioorganic & medicinal chemistry

2023 Volume 98, Page(s) 117582

Abstract: In this study, we explored a concise and mild synthetic route to produce novel C-14 arylcarbamate derivatives of andrographolide, a known anti-inflammatory and anticancer natural product. Upon assessing their anti-cancer efficacy against pancreatic ... ...

Abstract	In this study, we explored a concise and mild synthetic route to produce novel C-14 arylcarbamate derivatives of andrographolide, a known anti-inflammatory and anticancer natural product. Upon assessing their anti-cancer efficacy against pancreatic ductal adenocarcinoma (PDAC) cells, some derivatives showed stronger cytotoxicity against PANC-1 cells than andrographolide. In addition, we demonstrated one derivative, compound 3m, effectively reduced the expression of oncogenic p53 mutant proteins (p53
MeSH term(s)	Humans ; Tumor Suppressor Protein p53/metabolism ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/pathology ; Diterpenes/pharmacology ; Cell Line, Tumor
Chemical Substances	andrographolide (410105JHGR) ; Tumor Suppressor Protein p53 ; Diterpenes
Language	English
Publishing date	2023-12-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2023.117582
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Article: Cisd2 Protects the Liver from Oxidative Stress and Ameliorates Western Diet-Induced Nonalcoholic Fatty Liver Disease.

Huang, Yi-Long / Shen, Zhao-Qing / Huang, Chen-Hua / Teng, Yuan-Chi / Lin, Chao-Hsiung / Tsai, Ting-Fen

Antioxidants (Basel, Switzerland)

2021 Volume 10, Issue 4

Abstract	Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide evidence that Cisd2 is a molecular target for the development of treatments targeting NAFLD and NASH. Several discoveries are pinpointed. The first is that Cisd2 dosage modulates the severity of Western diet-induced (WD-induced) NAFLD. Specifically, Cisd2 haploinsufficiency accelerates NAFLD development and exacerbates progression toward NASH. Conversely, an enhanced Cisd2 copy number attenuates liver pathogenesis. Secondly, when a WD is fed to mice, transcriptomic analysis reveals that the major alterations affecting biological processes are related to inflammation, lipid metabolism, and DNA replication/repair. Thirdly, among these differentially expressed genes, the most significant changes involve Nrf2-mediated oxidative stress, cholesterol biosynthesis, and fatty acid metabolism. Finally, increased Cisd2 expression protects the liver from oxidative stress and reduces the occurrence of mitochondrial DNA deletions. Taken together, our mouse model reveals that Cisd2 plays a crucial role in protecting the liver from WD-induced damages. The development of therapeutic agents that effectively enhance Cisd2 expression is one potential approach to the treatment of WD-induced fatty liver diseases.
Language	English
Publishing date	2021-04-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10040559
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