PMID: 

Tissue Eng Regen Med. 2020 Feb 8. Epub 2020 Feb 8. PMID: 32036567

Abstract Title: 

Centella asiatica (L.)-Neurodifferentiated Mesenchymal Stem Cells Promote the Regeneration of Peripheral Nerve.

Abstract: 

BACKGROUND: Centella asiatica (L.) is a plant with neuroprotective and neuroregenerative properties; however, its effects on the neurodifferentiation of mesenchymal stem cells (MSCs) and on peripheral nerve injury are poorly explored. This study aimed to investigate the effects of C. asiatica (L.)-neurodifferentiated MSCs on the regeneration of peripheral nerve in a critical-size defect animal model.METHODS: Nerve conduit was developed using decellularised artery seeded with C. asiatica-neurodifferentiated MSCs (ndMSCs). A 1.5 cm sciatic nerve injury in Sprague-Dawley rat was bridged with reversed autograft (RA) (n = 3, the gold standard treatment), MSC-seeded conduit (MC) (n = 4) or ndMSC-seeded conduit (NC) (n = 4). Pinch test and nerve conduction study were performed every 2 weeks for a total of 12 weeks. At the 12th week, the conduits were examined by histology and transmission electron microscopy.RESULTS: NC implantation improved the rats' sensory sensitivity in a similar manner to RA. At the 12th week, nerve conduction velocity was the highest in NC compared with that of RA and MC. Axonal regeneration was enhanced in NC and RA as shown by the expression of myelin basic protein (MBP). The average number of myelinated axons was significantly higher in NC than in MC but significantly lower than in RA. The myelin sheath thickness was higher in NC than in MC but lower than in RA.CONCLUSION: NC showed promising effects on nerve regeneration and functional restoration similar to those of RA. These findings revealed the neuroregenerative properties of C. asiatica and its potential as an alternative strategy for the treatment of critical size nerve defect.

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PMID: 

Nutrients. 2020 Feb 5 ;12(2). Epub 2020 Feb 5. PMID: 32033291

Abstract Title: 

Inhibitory Effect of Centella asiatica Extract on DNCB-Induced Atopic Dermatitis in HaCaT Cells and BALB/c Mice.

Abstract: 

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused mainly by immune dysregulation. This study explored the anti-inflammatory and immunomodulatory effects of theethanol extract (CA) on an AD-like dermal disorder. Treatment with CA inhibited the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in a dose-dependent manner in inflammatory stimulated HaCaT cells by interferon-γ (IFN-γ) and TNF-α-triggered inflammation. Eight-week-old BALB/c mice treated with 2,4-dinitrochlorobenzene (DNCB) were used as a mouse model of AD. In AD induce model, we had two types treatment of CA; skin local administration (80 µg/cm, AD+CA-80) and oral administration (200 mg/kg/d, AD+CA-200). Interestingly, the CA-treated groups exhibited considerably decreased mast cell infiltration in the ear tissue. In addition, the expression of IL-6 in mast cells, as well as the expression of various pathogenic cytokines, such as TNF-α, IL-4, IL-5, IL-6, IL-10, IL-17, iNOS, COX-2, and CXCL9, was reduced in both AD+CA-80 and AD+CA-200 groups. Collectively, our data demonstrate the pharmacological role and signaling mechanism of CA in the regulation of allergic inflammation of the skin, which supports our hypothesis that CA couldpotentially be developed as a therapeutic agent for AD.

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PMID: 

Nutrients. 2018 Aug 8 ;10(8). Epub 2018 Aug 8. PMID: 30096827

Abstract Title: 

Chrysin Ameliorates Malfunction of Retinoid Visual Cycle through Blocking Activation of AGE-RAGE-ER Stress in Glucose-Stimulated Retinal Pigment Epithelial Cells and Diabetic Eyes.

Abstract: 

Diabetes-associated visual cycle impairment has been implicated in diabetic retinopathy, and chronic hyperglycemia causes detrimental effects on visual function. Chrysin, a naturally occurring flavonoid found in various herbs, has anti-inflammatory, antioxidant, and neuroprotective properties. The goal of the current study was to identify the retinoprotective role of chrysin in maintaining robust retinoid visual cycle-related components. The in vitro study employed human retinal pigment epithelial (RPE) cells exposed to 33 mM of glucose or advanced glycation end products (AGEs) in the presence of 1⁻20 μM chrysin for three days. In the in vivo study, 10 mg/kg of chrysin was orally administrated to db/db mice. Treating chrysin reversed the glucose-induced production of vascular endothelial growth factor, insulin-like growth factor-1, and pigment epithelium-derived factor (PEDF) in RPE cells.The outer nuclear layer thickness of chrysin-exposed retina was enhanced. The oral gavage of chrysin augmented the levels of the visual cycle enzymes of RPE65, lecithin retinol acyltransferase (LRAT), retinol dehydrogenase 5 (RDH5), and rhodopsin diminished in db/db mouse retina. The diabetic tissue levels of the retinoid binding proteins and the receptor of the cellular retinol-binding protein, cellular retinaldehyde-binding protein-1, interphotoreceptor retinoid-binding protein and stimulated by retinoic acid 6 were restored to those of normal mouse retina. The presence of chrysin demoted AGE secretion and AGE receptor (RAGE) induction in glucose-exposed RPE cells and diabetic eyes. Chrysin inhibited the reduction of PEDF, RPE 65, LRAT, and RDH5 in 100 μg/mL of AGE-bovine serum albumin-exposed RPE cells. The treatment of RPE cells with chrysin reduced the activation of endoplasmic reticulum (ER) stress. Chrysin inhibited the impairment of the retinoid visual cycle through blocking ER stress via the AGE-RAGE activation in glucose-stimulated RPE cells and diabetic eyes. This is the first study demonstrating the protective effects of chrysin on the diabetes-associated malfunctioned visual cycle.

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PMID: 

Sci Rep. 2019 Dec 27 ;9(1):20138. Epub 2019 Dec 27. PMID: 31882891

Abstract Title: 

Citrulline prevents age-related LTP decline in old rats.

Abstract: 

The prevalence of cognitive decline is increasing as the ageing population is considerably growing. Restricting this age-associated process has become a challenging public health issue. The age-related increase in oxidative stress plays a major role in cognitive decline, because of its harmful effect on functional plasticity of the brain, such as long-term potentiation (LTP). Here, we show that citrulline (Cit) has powerful antioxidant properties that can limit ex vivo oxidative stress-induced LTP impairment in the hippocampus. We also illustrate that a three-month Cit supplementation has a protective effect on LTP in aged rats in vivo. The identification of a Cit oxidation byproduct in vitro suggests that the antioxidant properties of Cit could result from its own oxidation. Cit supplementation may be a promising preventive nutritional approach to limit age-related cognitive decline.

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PMID: 

J Strength Cond Res. 2020 Jan 22. Epub 2020 Jan 22. PMID: 31977835

Abstract Title: 

Effects of Citrulline Supplementation on Exercise Performance in Humans: A Review of the Current Literature.

Abstract: 

Gonzalez, AM and Trexler, ET. Effects of citrulline supplementation on exercise performance in humans: A review of the current literature. J Strength Cond Res XX(X): 000-000, 2020-L-citrulline, a nonessential amino acid found primarily in watermelon, has recently garnered much attention for its potential to augment L-arginine bioavailability, nitric oxide production, and exercise performance. Over the past decade, L-citrulline has received considerable scientific attention examining potentially ergogenic properties for both aerobic and anaerobic exercise performance. Thus, the purpose of this article is to summarize the theoretical rationale behind L-citrulline supplementation and to comprehensively review the available scientific evidence assessing the potential ergogenic value of L-citrulline supplementation on vascular function and exercise performance in humans. In addition, research that has investigated the potential synergistic effects of L-citrulline with other dietary ingredients (e.g., arginine, antioxidants, nitrates, and branched-chain amino acids) is reviewed. Oral L-citrulline and citrulline malate supplementation have shown to increase plasma citrulline and arginine concentrations, along with total nitrate and nitrite concentrations. Although blood flow enhancement is a proposed mechanism for the ergogenic potential of L-citrulline, evidence supporting acute improvements in vasodilation and skeletal muscle tissue perfusion after supplementation is scarce and inconsistent. Nevertheless, several studies have reported that L-citrulline supplementation can enhance exercise performance and recovery. Given the positive effects observed from some investigations, future studies should continue to investigate the effects of both acute and chronic supplementation with L-citrulline and citrulline malate on markers of blood flow and exercise performance and should seek to elucidate the mechanism underlying such effects.

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PMID: 

J Biochem Mol Toxicol. 2018 Nov ;32(11):e22201. Epub 2018 Oct 1. PMID: 30273961

Abstract Title: 

Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin.

Abstract: 

This study aimed to investigate the effect of chrysin on colistin-induced reproductive toxicity. Twenty-eight adult male Sprague-Dawley rats were divided into four groups of seven rats each. Group I received physiological saline for 7 days. Group II received 50 mg/kg/day chrysin for 7 days. Group III received a total dose of 73 mg/kg colistin for 7 days. Group IV received 50 mg/kg/day chrysin by an oral gavage after the colistin treatment. Colistin causes an increase in oxidative stress (OS) in the testis. Chrysin treatment significantly decreased the OS in the chrysin + colistin group compared with the colistin group. The highest caspase-3 and LC3B expression levels were found in the colistin group and these levels were statistically lower in the chrysin + colistin group. Colistin treatment caused a decrease in sperm motility and an increase in sperm abnormality. Chrysin treatment mitigated these side effects significantly. In conclusion, chrysin treatment can be beneficial against colistin-induced reproductive toxicity.

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PMID: 

J Cell Physiol. 2019 03 ;234(3):2480-2490. Epub 2018 Oct 9. PMID: 30302765

Abstract Title: 

Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level.

Abstract: 

Chrysin is a natural compound derived from honey, propolis, or passion flowers and has many functional roles, such as antiinflammatory and antiangiogenesis effects. Although endometriosis is a benign gynecological disease, there is a need to identify the pathology and develop a therapy for endometriosis. Elucidating the biological mechanism of chrysin on endometriosis will improve the understanding of endometriosis. In this study, we confirmed the apoptotic effects of chrysin in human endometriotic cells using End1/E6E7 (endocervix-derived endometriotic cells) and VK2/E6E7 (vaginal mucosa-derived epithelial endometriotic cells). The results showed that chrysin suppressed the proliferation of endometriosis and induced programmed cell death through changing the cell cycle proportion and increasing the cytosolic calcium level and generation of reactive oxygen species. In addition, chrysin activated endoplasmic reticulum (ER) stress by stimulating the unfolded protein response proteins, especially the 78-kDa glucose-regulated protein-PRKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α) pathway in both endometriotic cell lines. Furthermore, chrysin inactivated the intracellular phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, also known as AKT) signaling pathway in a dose-dependent manner. Collectively, the results of this study indicated that chrysin induced programmed cell death by activating the ER stress response and inactivating the PI3K signaling pathways in human endometriotic cells.

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PMID: 

Nan Fang Yi Ke Da Xue Xue Bao. 2018 Sep 30 ;38(10):1187-1194. PMID: 30377128

Abstract Title: 

[Chrysin promotes SMMC-7721 cell apoptosis by regulating MAPKs signaling pathway].

Abstract: 

OBJECTIVE: To study the effect of chrysin in inducing apoptosis of human hepatic carcinoma cells and explore the possible mechanism.METHODS: Human hepatic carcinoma SMMC-7721 cells treated with DMSO or chrysin at different concentrations (5-200μg/mL) were examined for changes in the cell proliferation using CCK-8 assay. The morphological changes of SMMC-7721 cells were observed in response to treatment with 5, 10, or 20 μg/mL chrysin, and the changes in the cell nuclei were observed using DAPI nuclear staining. Annexin Ⅴ-FITC/PI flowcytometry was used to determine the cell apoptosis rate. The changes in the apoptosis-related proteins (PARP and caspase-3) and MAPKs signal pathway were detected with Western blotting.RESULTS: Chrysin treatment obviously suppressed the proliferation of SMMC-7721 cells in a dose-dependent manner below the concentration of 60μg/mL. Chrysin (20 μg/mL) also caused significantly increased cell apoptosis and significant cleavage of PARP and caspase-3. Chrysin significantly activated MAPKs signaling pathway in a time-and dose-dependent manner, with the peak activation level occurring at 15 min. Pretreatment of the cells with specific inhibitors of the MAPKs pathway obviously inhibited the effect of chrysin in inducing cell apoptosis.CONCLUSIONS: Chrysin inhibits the proliferation and promotes apoptosis of SMMC-7721 cells by regulating the activation of MAPKs signaling.

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PMID: 

J Cardiovasc Pharmacol Ther. 2019 05 ;24(3):278-287. Epub 2018 Nov 29. PMID: 30497287

Abstract Title: 

Chrysin Suppresses Vascular Endothelial Inflammation via Inhibiting the NF-κB Signaling Pathway.

Abstract: 

The vascular endothelium is a continuous layer of flat polygonal cells that are in direct contact with the blood and participate in responses to inflammation. Chrysin is a flavonoid compound extracted from plants of the genus Asteraceae with a wide range of pharmacological activities and physiological activities. Here, we studied the effects of chrysin on the regulation of the proadhesion and pro-inflammatory phenotypes of the endothelium both in vitro and in vivo. Our results revealed that chrysin strongly inhibited Tohoku Hospital Pediatrics-1 (THP-1) cell adhesion to primary human umbilical vein endothelial cells and concentration-dependently attenuated interleukin 1β-induced increases in intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin messenger RNA levels and ICAM-1 and VCAM-1 protein levels. Previous studies reported that nuclear factor κB (NF-κB) is important in the inflammatory response in endothelial cells, particularly in regulating adhesion molecules, and our data shed light on the mechanisms whereby chrysin suppressed endothelial inflammation via the NF-κB signaling pathway. In addition, our in vivo findings demonstrated the effects of chrysin in the permeability and inflammatory responsesof the endothelium to inflammatory injury. Taken together, we conclude that chrysin inhibits endothelial inflammation both in vitro and in vivo, which could be mainly due to its inhibition of NF-κB signaling activation. In conclusion, chrysin may serve as a promising therapeutic candidate for inflammatory vascular diseases.

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PMID: 

Mol Med Rep. 2019 Feb ;19(2):1222-1229. Epub 2018 Dec 4. PMID: 30535473

Abstract Title: 

Chrysin protects human osteoarthritis chondrocytes by inhibiting inflammatory mediator expression via HMGB1 suppression.

Abstract: 

High‑mobility group box chromosomal protein (HMGB‑1) contributes to osteoarthritis (OA) by modulating various oxidative, inflammatory and apoptotic signaling pathways. The effect of chrysin (CH), a natural plant flavonoid, and its functional interaction with HMGB‑1, was investigated in a chondrocyte model of OA. Human chondrocytes were pre‑treated with CH, and then subsequently treated with IL‑1β to induce the formation of chondrocytes similar to those found in OA joints. Next, the expression level of HMGB‑1 was determined by immunofluorescence and western blot analysis. Additionally,inflammatory factor expression was measured by ELISA, and cell apoptosis was analyzed with flow cytometry. To further explore the effects of CH, HMGB‑1 expression was silenced following CH treatment with small interfering (si)RNA. The results demonstrated that CH inhibited cell apoptosis, dose‑dependently reduced matrix metalloproteinase (MMP) 13, collagenase and IL‑6 expression, and increased collagen α‑1 (II) chain (COL2A1) expression in human osteoarthritis chondrocytes. These effects of CH were accompanied by decreased HMGB‑1 expression. Additionally, the expression of MMP13, collagenase, IL‑6 and COL2A1, as well as apoptosis, was significantly reduced by HMGB‑1 siRNA. These results demonstrated that HMGB‑1 is critical for the protective effect of CH on human osteoarthritis chondrocytes, including cell apoptosis and inflammatory factor inhibition, which suggeststhat CH may have potential therapeutic effect in treating OA by protecting human osteoarthritis chondrocytes via HMGB1 suppression.

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