Anti-oxidative and anti-adipogenic effects of caffeine in an &lt;i&gt;in vitro&lt;/i&gt; model of Graves’ orbitopathy

Ko, Jeong-Sik; Kim, Ji Young; Kim, Jae Woo; Yoon, Jin Sook

doi:10.1507/endocrj.ej19-0521

Cited by 21 publications

(10 citation statements)

References 32 publications

(49 reference statements)

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“…Moreover, oxidative stress can disrupt the protein-folding mechanism and enhance the production of misfolded proteins, causing further ER stress (Chong et al 2017). As the state of oxidative stress has been described in GO, and inflammation and oxidative stress are central to GO pathogenesis (Ko et al 2020), the anti-oxidative effects of BiP silencing in study indicate that modulating ER stress with BiP can block the vicious cycle of oxidative stress in GO.…”

Section: Discussionmentioning

confidence: 98%

Role of binding immunoglobulin protein (BiP) in Graves’ orbitopathy pathogenesis

Kim

Lee

et al. 2021

Journal of Molecular Endocrinology

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Inflammation and adipogenesis represent the main pathogenic mechanisms of Graves’ orbitopathy (GO), and oxidative stress is a well-known inducer of GO pathology. Endoplasmic reticulum (ER) stress has been suggested as a major contributor to inflammation and reactive oxygen species (ROS) generation. In this study, we investigated the role of the ER-stress chaperone protein, binding immunoglobulin protein (BiP), in GO pathogenesis. Using primary cultures of orbital fibroblasts from patients with GO, we examined the role of BiP in GO pathogenesis by silencing its expression with small-interfering RNA (siRNA). Inflammatory cytokine expression was analysed by western blotting and enzyme-linked immunosorbent assay. Intracellular ROS levels induced by hydrogen peroxide or cigarette smoke extract were measured by 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. After adipogenic differentiation in BiP siRNA-transfected cells, the cells were stained with Oil Red O, and the levels of adipogenic transcription factors were determined by western blot analysis. BiP mRNA expression levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. Silencing BiP attenuated the expression of pro-inflammatory cytokines (interleukin-6, intercellular adhesion molecule-1, and monocyte chemotactic protein-1) in primary cultured GO orbital fibroblasts. Silencing BiP also reduced ROS generation, hyaluronan production, and adipocyte differentiation. These findings suggest that ER stress is involved in the aetiology of GO and that modulation of ER stress has therapeutic potential for GO.

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Section: Discussionmentioning

confidence: 98%

Role of binding immunoglobulin protein (BiP) in Graves’ orbitopathy pathogenesis

Kim

Lee

et al. 2021

Journal of Molecular Endocrinology

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“…Previously, we have found that quercetin inhibits cigarette smoke extract-induced adipogenesis in GO fibroblasts by reducing ROS ( 48 ). Additionally, we have reported several molecules with anti-oxidative properties such as resveratrol, caffeine, and curcumin suppress adipogenesis in GO fibroblasts ( 49 – 51 ). Given that oxidative stress contributes to the proliferation of orbital fibroblasts ( 52 ), the impeded proliferation of GO fibroblasts by PCSK9 inhibition demonstrated in this study may be attributed to the anti-oxidative property of the PCSK9 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Role of Proprotein Convertase Subtilisin/Kexin Type 9 in the Pathogenesis of Graves’ Orbitopathy in Orbital Fibroblasts

et al. 2021

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BackgroundThe proprotein convertase subtilisin/kexin type 9 (PCSK9) has been implicated in the pathogenesis of inflammatory diseases. We sought to investigate the role of PCSK9 in the pathogenesis of Graves’ orbitopathy (GO) and whether it may be a legitimate target for treatment.MethodsThe PCSK9 was compared between GO (n=11) and normal subjects (n=7) in orbital tissue explants using quantitative real-time PCR, and in cultured interleukin-1β (IL-1β)-treated fibroblasts using western blot. Western blot was used to identify the effects of PCSK9 inhibition on IL-1β-induced pro-inflammatory cytokines production and signaling molecules expression as well as levels of adipogenic markers and oxidative stress-related proteins. Adipogenic differentiation was identified using Oil Red O staining. The plasma PCSK9 concentrations were compared between patients with GO (n=44) and healthy subjects (n=26) by ELISA.ResultsThe PCSK9 transcript level was higher in GO tissues. The depletion of PCSK9 blunted IL-1β-induced expression of intercellular adhesion molecule 1 (ICAM-1), IL-6, IL-8, and cyclooxygenase-2 (COX-2) in GO and non-GO fibroblasts. The levels of activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphorylated forms of Akt and p38 were diminished when PCSK9 was suppressed in GO fibroblasts. Decreases in lipid droplets and attenuated levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein β (C/EBPβ), and leptin as well as hypoxia-inducible factor 1α (HIF-1α), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), and heme oxygenase-1 (HO-1) were noted when PCSK9 was suppressed during adipocyte differentiation. The plasma PCSK9 level was significantly higher in GO patients and correlated with level of thyrotropin binding inhibitory immunoglobulin (TBII) and the clinical activity score (CAS).ConclusionsPCSK9 plays a significant role in GO. The PCSK9 inhibition attenuated the pro-inflammatory cytokines production, oxidative stress, and fibroblast differentiation into adipocytes. PCSK9 may serve as a therapeutic target and biomarker for GO.

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“…In a clinical setting, it is widely accepted that antioxidant effects are mostly related to age-related diseases [ 65 ], such as cardiovascular disease [ 66 , 67 ], non-alcoholic fatty liver disease [ 67 ], vascular dementia [ 68 ], Graves’ ophthalmopathy [ 69 ], cancer [ 70 , 71 ], diabetes [ 72 ], etc. ROS, including hydrogen peroxide (H 2 O 2 ), hydroxyl radical (•OH), singlet oxygen (1O 2 ), superoxide (O 2 2− ), etc., is a group of unstable molecules produced by various cells in the human body.…”

Section: Research Progress On Pharmacological Activitymentioning

confidence: 99%

The Chemical and Pharmacological Research Progress on a Kind of Chinese Herbal Medicine, Fructus Malvae

Wang

Zhao

et al. 2022

Molecules

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Since the outbreak of the COVID-19 pandemic, traditional Chinese medicine has played an important role in the treatment process. Furthermore, the discovery of artemisinin in Artemisia annua has reduced the incidence of malaria all over the world. Therefore, it is becoming urgent and important to establish a novel method of conducting systematic research on Chinese herbal medicine, improving the medicinal utilization value of traditional Chinese medicine and bringing great benefits to human health all over the world. Fructus Malvae, a kind of Chinese herbal medicine which has been recorded in the “Chinese Pharmacopoeia” (2020 edition), refers to the dry, ripe fruits of Malva verticillata L. Recently, some studies have shown that Fructus Malvae exhibits some special pharmacological activities; for example, it has diuretic, anti-diabetes, antioxidant and anti-tumor properties, and it alleviates hair loss. Furthermore, according to the reports, the active ingredients separated and identified from Fructus Malvae contain some very novel compounds such as nortangeretin-8-O-β-d-glucuronopyranoside and 1-O-(6-deoxy-6-sulfo)-glucopyranosyl-2-O-linolenoyl-3-O-palmitoyl glyceride, which could be screened as important candidate compounds for diabetes- or tumor-treatment drugs, respectively. Therefore, in this research, we take Fructus Malvae as an example and systematically summarize the chemical constituents and pharmacological activity research progress of it. This review will be helpful in promoting the development and application of Fructus Malvae and will also provide an example for other investigations of traditional Chinese medicine.

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Anti-oxidative and anti-adipogenic effects of caffeine in an <i>in vitro</i> model of Graves’ orbitopathy

Cited by 21 publications

References 32 publications

Role of binding immunoglobulin protein (BiP) in Graves’ orbitopathy pathogenesis

Role of binding immunoglobulin protein (BiP) in Graves’ orbitopathy pathogenesis

Role of Proprotein Convertase Subtilisin/Kexin Type 9 in the Pathogenesis of Graves’ Orbitopathy in Orbital Fibroblasts

The Chemical and Pharmacological Research Progress on a Kind of Chinese Herbal Medicine, Fructus Malvae

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