PMID: 

Photomed Laser Surg. 2016 Nov ;34(11):556-563. Epub 2016 May 31. PMID: 27244220

Abstract Title: 

Mesenchymal Stem Cells Synergize with 635, 532, and 405 nm Laser Wavelengths in Renal Fibrosis: A Pilot Study.

Abstract: 

OBJECTIVE: To address whether a single treatment of one of three visible light wavelengths, 635, 532, and 405 nm (constant wave, energy density 2.9 J/m), could affect the hallmarks of established renal fibrosis and whether these wavelengths could facilitate mesenchymal stem cell (MSC) beneficence.BACKGROUND DATA: Chronic kidney disease is a global health problem with only 20% receiving care worldwide. Kidneys with compromised function have ongoing inflammation, including increased oxidative stress and apoptosis, peritubular capillary loss, tubular atrophy, and tubulointerstitial fibrosis. Promising studies have highlighted the significant potential of MSC-based strategies to mitigate fibrosis; however, reversal of established fibrosis has been problematic, suggesting that methods to potentiate MSC effects require further development. Laser treatments at visible wavelengths have been reported to enhance mitochondrial potential and available cellular ATP, facilitate proliferation, and inhibit apoptosis. We hypothesized that laser-delivered energy might provide wavelength-specific effects in the fibrotic kidney and enhance MSC responses.MATERIALS AND METHODS: Renal fibrosis, established in C57BL6 mice following 21 days of unilateral ureter obstruction (UUO), was treated with one of three wavelengths alone or with autologous MSC. Mitochondrial activity, cell proliferation, apoptosis, and cytokines were measured 24 h later.RESULTS: Wavelengths 405, 532, and 635 nm all significantly synergized with MSC to enhance mitochondrial activity and reduce apoptosis. Proliferative activity was observed in the renal cortices following combined treatment with the 532 nm laser and MSC; endothelial proliferation increased in response to the 635 nm laser alone andto the combined effects of MSC and the 405 nm wavelength. Reductions of transforming growth factor-β were observed with 532 nm alone and when combined with MSC.CONCLUSIONS: Specific wavelengths of laser energy appear to induce different responses in renal fibrotic tissue. These findings support further study in the development of a customized laser therapy program of combined wavelengths to optimize MSC effects in the treatment of renal fibrosis.

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PMID: 

J Integr Med. 2016 May ;14(3):165-73. PMID: 27181123

Abstract Title: 

Interventional mechanisms of herbs or herbal extracts on renal interstitial fibrosis.

Abstract: 

Renal interstitial fibrosis (RIF) is a common development in chronic renal diseases that can lead to uremia and be life-threatening. The RIF pathology has complicated extracellular and intercellular mechanisms, involving many cells and cytokines, resulting in an incomplete mechanistic understanding of the disease. Finding effective herbs or herbal extracts for prevention and treatment of RIF is crucial because current medical approaches do not reliably slow or reverse RIF. In recent years, many experts have worked to identify herbs or herbal extracts to combat RIF both in vivo and in vitro, with some success. This review attempts to summarize the possible interventional mechanisms of herbs or herbal extracts involved in protecting and reversing RIF. The authors found some herbs and their extracts that may ameliorate renal impairments through anti-inflammation, anti-fibrogenesis and stabilization of extra cellular matrix. Among them, tetramethylpyrazine/ligustrazine, curcumin and polyglucoside of Tripterygium have experimentally shown good potential for improving RIF. However, conclusive evidence is still needed, especially in randomized controlled clinical trials. We expect that herbs or herbal extracts will play an important role in RIF treatment and reversal in the future.

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PMID: 

Biofactors. 2017 Mar ;43(2):272-282. Epub 2016 Nov 1. PMID: 27801960

Abstract Title: 

Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells.

Abstract: 

The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different pathological processes, including fibrogenesis. Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl) 5μL gbody wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg kg dayi.p, beginning 2 weeks after the start of CCladministration. At both 4 and 6 weeks following CCltreatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression ofα-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β and collagen (Col) Ι. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3, and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, asevidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole revealsnovel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis. © 2016 BioFactors, 43(2):272-282, 2017.

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PMID: 

J Int Med Res. 2019 Feb ;47(2):884-892. Epub 2019 Jan 11. PMID: 30632430

Abstract Title: 

Reversal effect of Zhigancao decoction on myocardial fibrosis in a rapid pacing-induced atrial fibrillation model in New Zealand rabbits.

Abstract: 

OBJECTIVE: To evaluate the effect of Zhigancao decoction on reversal of right atrial myocardial fibrosis after rapid atrial pacing (RAP)-induced atrial fibrillation (AF).METHODS: New Zealand white rabbits were randomly divided into four groups: sham operation group (Group A: implanted electrodes, no RAP), pacing group (Group B: RAP-induced AF), Zhigancao soup water decoction Yin group (Group C: RAP-induced AF followed by Zhigancao soup Yin prescription twice a day for 30 days), and Zhigancao soup group (Group D: RAP-induced AF followed by Zhigancao water decoction twice a day for 30 days). The atrial myocardium was then examined for myocardial fibrosis by Masson staining, and protein expression of matrix metalloproteinase-9 (MMP-9) was immunohistochemically assessed. The right atrial appendage tissue field action potential duration (fAPD) was measured by microelectrode arrays.RESULTS: RAP successfully induced AF. Myocardial fibrosis was more severe in Groups B and C and less severe in Group D. Protein expression of MMP-9 was strongly positive in Groups B and C and weakly positive in Group D. The fAPD was significantly decreased in Groups B and C, but the decrease in Group D was not significant.CONCLUSION: Zhigancao decoction can reverse AF-induced myocardial fibrosis in rabbits and shorten the fAPD.

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PMID: 

BMC Complement Altern Med. 2019 Oct 30 ;19(1):290. Epub 2019 Oct 30. PMID: 31666058

Abstract Title: 

Effect of Nigella sativa and its bioactive compound on type 2 epithelial to mesenchymal transition: a systematic review.

Abstract: 

BACKGROUND: Nigella sativa or commonly known as black seed or black cumin is one of the most ubiquitous complementary medicine. Epithelial to mesenchymal transition (EMT) of type 2 is defined by the balance between wound healing and tissue fibrosis, which is dependent to the state of inflammation. This systematic review is conducted to provide an overview regarding the reported effect of Nigella sativa and its bioactive compound on the type 2 EMT.METHODS: A search was done in EBSCOHOST, OVID and SCOPUS database to obtain potentially relevant articles that were published between 1823 and August 2019. This review includes studies that focus on the effect of Nigella sativa and its bioactive compound on the events related to type 2 EMT.RESULTS: A total of 1393 research articles were found to be potentially related to the effect of Nigella sativa and its bioactive compound, thymoquinone on Type 2 EMT. After screening was done, 22 research articles met inclusion criteria and were included in this review. Majority of the studies, reported better wound healing rate or significant prevention of tissue inflammation and organ fibrosis following Nigella sativa or thymoquinone treatments. In terms of wound healing, studies included reported progression of EMT related pathological changes after treatment with Nigella sativa or thymoquinone. Alternatively, in terms of fibrosis and inflammation, studies included reported reversal of pathological changes related to EMT after treatment with Nigella sativa or thymoquinone.CONCLUSION: Through this review, Nigella sativa and thymoquinone have been associated with events in Type 2 EMT. They have been shown to promote wound healing, attenuate tissue inflammation, and prevent organ fibrosis via regulation of the EMT process.

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PMID: 

Lasers Med Sci. 2019 Feb ;34(1):1-10. Epub 2018 Oct 26. PMID: 30367294

Abstract Title: 

Adipose-derived mesenchymal stem cells treatments for fibroblasts of fibrotic scar via downregulating TGF-β1 and Notch-1 expression enhanced by photobiomodulation therapy.

Abstract: 

[n/a]

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PMID: 

Mol Cell Biochem. 2015 Sep ;407(1-2):263-79. Epub 2015 Jun 16. PMID: 26077659

Abstract Title: 

Troxerutin reverses fibrotic changes in the myocardium of high-fat high-fructose diet-fed mice.

Abstract: 

A previous study from our laboratory showed that troxerutin (TX) provides cardioprotection by mitigating lipid abnormalities in a high-fat high-fructose diet (HFFD)-fed mice model of metabolic syndrome (MS). The present study aims to investigate the reversal effect of TX on the fibrogenic changes in the myocardium of HFFD-fed mice. Adult male Mus musculus mice were grouped into four and fed either control diet or HFFD for 60 days. Each group was divided into two, and the mice were either treated or untreated with TX (150 mg/kg bw, p.o) from the 16th day. HFFD-fed mice showed marked changes in the electrocardiographic data. Increased levels of myocardial superoxide, p22phox subunit of NADPH oxidase, transforming growth factor (TGF), smooth muscle actin (α-SMA), and matrix metalloproteinases (MMPs)-9 and -2, and decreased levels of tissue inhibitors of MMPs-1 and -2 were observed. Furthermore, degradation products of troponin I and myosin light chain-1 were observed in the myocardium by immunoblotting. Rise in collagen was observed by hydroxyproline assay, while fibrotic changes were noticed by histology and Western blotting. Hypertrophy of cardiomyocytes and myocardial calcium accumulation were also observed in HFFD-fed mice. TX treatment exerted cardioprotective and anti-fibrotic effects in HFFD-fed miceby improving cardiac contractile function, reducing superoxide production and by favorably modifying the fibrosis markers. These findings suggest that TX could be cardioprotective through its antioxidant and antifibrogenic actions. This new finding could pave way for translation studies to human MS.

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PMID: 

Biomed Res Int. 2015 ;2015:935903. Epub 2015 Dec 31. PMID: 26881209

Abstract Title: 

Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells.

Abstract: 

Activation of hepatic stellate cells (HSCs) depending on epithelial-to-mesenchymal transition (EMT) reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET) of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY) recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-β 1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-β 1 at both transcription and translation levels. Restoration of TGF-β 1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) as characterized by the abolishment of EMT markers (α-SMA and desmin) and reoccurrence of MET marker (E-cadherin). In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activatedHSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4-) induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs.

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PMID: 

Int J Mol Sci. 2015 Nov 25 ;16(12):27988-8000. Epub 2015 Nov 25. PMID: 26602917

Abstract Title: 

Application of Green Tea Catechin for Inducing the Osteogenic Differentiation of Human Dedifferentiated Fat Cells in Vitro.

Abstract: 

Despite advances in stem cell biology, there are few effective techniques to promote the osteogenic differentiation of human primary dedifferentiated fat (DFAT) cells. We attempted to investigate whether epigallocatechin-3-gallate (EGCG), the main component of green tea catechin, facilitates early osteogenic differentiation and mineralization on DFAT cells in vitro. DFAT cells were treated with EGCG (1.25-10μM) in osteogenic medium (OM) with or without 100 nM dexamethasone (Dex) for 12 days (hereafter two osteogenic media were designated as OM(Dex) and OM). Supplementation of 1.25 μM EGCG to both the media effectively increased the mRNA expression of collagen 1 (COL1A1) and runt-related transcriptionfactor 2 (RUNX2) and also increased proliferation and mineralization. Compared to OM(Dex) with EGCG, OM with EGCG induced earlier expression for COL1A1 and RUNX2 at day 1 and higher mineralization level at day 12. OM(Dex) with 10 μM EGCG remarkably hampered the proliferation of the DFAT cells. These results suggest that OM(without Dex) with EGCG might be a preferable medium to promote proliferation and to induce osteoblast differentiation of DFAT cells. Our findings provide an insight for the combinatory use of EGCG and DFAT cells for bone regeneration and stem cell-based therapy.

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PMID: 

Epigenetics. 2018 ;13(2):156-162. Epub 2018 Mar 7. PMID: 28055298

Abstract Title: 

Vitamin D limits inflammation-linked microRNA expression in adipocytes in vitro and in vivo: A new mechanism for the regulation of inflammation by vitamin D.

Abstract: 

Inflammation of adipose tissue is believed to be a contributing factor to many chronic diseases associated with obesity. Vitamin D (VD) is now known to limit this metabolic inflammation by decreasing inflammatory marker expression and leukocyte infiltration in adipose tissue. In this study, we investigated the impact of VD on microRNA (miR) expression in inflammatory conditions in human and mouse adipocytes, using high-throughput methodology (miRNA PCR arrays). Firstly, we identified three miRs (miR-146a, miR-150, and miR-155) positively regulated by TNFα in human adipocytes. Interestingly, the expression of these miRs was strongly prevented by 1,25(OH)D preincubation. These results were partly confirmed in 3T3-L1 adipocytes (for miR-146a and miR-150). The ability of VD to control the expression of these miRs was confirmed in diet-induced obese mice: the levels of the three miRs were increased following high fat (HF) diet in epididymal white adipose tissue and reduced in HF diet fed mice supplemented with VD. The involvement of NF-κB signaling in the induction of these miRs was confirmed in vitro and in vivo using aP2-p65 transgenic mice. Finally, the ability of VD to deactivate NF-κB signaling, via p65 and IκB phosphorylation inhibition in murine adipocyte, was observed and could constitute a driving molecular mechanism.This study demonstrated for the first time that VD modulates the expression of miRs in adipocytes in vitro and in adipose tissue in vivo through its impact on NF-κB signaling pathway, which could represent a new mechanism of regulation of inflammation by VD.

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