Anti-fibrotic effects of valproic acid in experimental peritoneal fibrosis

Costalonga, Elerson Carlos; Freitas, Luiza J. de; Aragone, Deise da S. P.; Silva, Filipe Miranda Oliveira; Noronha, Irene L.

doi:10.1371/journal.pone.0184302

Cited by 15 publications

(10 citation statements)

References 41 publications

(60 reference statements)

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“…In our study, as expected, the induction of fibrosis in rats promoted the increase of gene expression of the pro-fibrotic markers fibronectin, FSP-1, TGF-β, SMAD3 and VEGF, that favours angiogenesis and thereby assists the perfusion of the newly formed fibrotic tissue [12,13,19]. It is noteworthy that LDE-PTX treatment pronouncedly diminished the gene expression of all those molecular factors, thus interfering with diverse mechanisms of fibrogenesis.…”

Section: Discussionsupporting

confidence: 86%

“…Over recent years, transforming growth factor-β (TGF-β) has been pointed out as a key fibrogenic factor involved in peritoneal fibrosis [11][12][13]. Activation of TGF-β by receptors on cell surface leads to downstream activation of SMAD proteins so that TGF-β/SMAD signalling has been recognized as an important pathway in the development of peritoneal fibrosis [14].…”

Section: Introductionmentioning

confidence: 99%

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Use of paclitaxel carried in solid lipid nanoparticles to prevent peritoneal fibrosis in rats

et al. 2022

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Background Progressive fibrous thickening of peritoneal membrane (PM) is a major complication of long-term peritoneal dialysis. TGF-β/SMAD pathway activation, inflammation and neoangiogenesis have an important role in PM changes induced by peritoneal dialysis. Here, we investigated the effects of paclitaxel (PTX) carried in lipid core nanoparticles (LDE) on the development of peritoneal fibrosis (PF) in rats. Methods To induce PF, 21 male Wistar rats (300-350g) were injected with chlorhexidine gluconate for 15 consecutive days and randomly assigned to three groups: 1)PF, n = 5: no treatment; 2)LDE, n = 8: treated with LDE only, 3/3 days during 15 days; 3)LDE-PTX, n = 8: treated with PTX (4mg/kg) associated with LDE, 3/3 days during 15 days. A Control group without PF induction (n = 5) was designed, received saline solution, 3/3 days. Peritoneum function tests were performed, and anterior abdominal wall samples of the PM were collected for analyses of peritoneal thickness, immunohistochemitry, and gene expression. Results LDE-PTX treatment preserved the membrane function, maintaining the ultrafiltration rate and mass transfer of glucose at normal levels. LDE-PTX also prevented PM thickening induced by chlorhexidine gluconate injections. LDE-PTX treatment reduced the number of myofibroblasts infiltrating PM and inhibited the cell proliferation. Gene expression of fibronectin, FSP-1, VEGF, TGF-β, and SMAD3 were reduced by LDE-PTX. Conclusions LDE-PTX was effective to prevent development of PF and preserve the PM filtration capacity in this rat model, with clear-cut actions on pro-fibrotic mechanisms. Thus, LDE-PTX can be candidate for future clinical trials as adjuvant to peritoneal dialysis to prevent PF development, since this preparation is devoid of toxicity as shown previously.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Use of paclitaxel carried in solid lipid nanoparticles to prevent peritoneal fibrosis in rats

et al. 2022

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“…CG injected intraperitoneally (IP) induces aseptic peritonitis with PM damage, leading to inflammation and tissue fibrosis (Suga et al 1995; Hoff 2005). To avoid models that require surgery for CKD induction, as the 5/6 ablation model (Guo et al 2007; Mortier et al 2005; Zareie et al 2005), in the present study CKD was accessed by subjecting the rats to an adenine rich diet (Yokozawa et al 1986; Costalonga et al 2017; Santana et al 2013). This model is characterized by remarkable uremia and elevated levels of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 (Santana et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen and bone morphogenic protein-7 modulate fibrosis and inflammation in the peritoneal fibrosis model developed in uremic rats

Silva

Costalonga

Silva

et al. 2019

Mol Med

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Background Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats. Methods To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 μg/Kg, IP). Animals were followed up for 30 days. Results CG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFβ/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression. Conclusions In conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process. Electronic supplementary material The online version of this article (10.1186/s10020-019-0110-5) contains supplementary material, which is available to authorized users.

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“…Unfortunately, since clinical trials typically demand a great deal of resources, further research in this direction has not been continued. Incidentally or not, VPA also possesses anti-platelet and anti-fibrotic capabilities (Larsson et al 2016, Costalonga et al 2017.…”

Section: Development Of Novel Therapeuticsmentioning

confidence: 99%

Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology

Guo

2022

Reproduction

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Traditionally considered as an enigmatic disease, adenomyosis is a uterine disease that affects many women of reproductive age, and is a contributing factor for pelvic pain, heavy menstrual bleeding (HMB), and subfertility. In this review, the new development on the pathogenesis and pathophysiology of adenomyosis has been summarized, along with their clinical implications. After reviewing the progress on our understanding of the pathogenesis and describing the prevailing theories, in conjunction with their deficiencies, a new hypothesis, called endometrial-myometrial interface disruption (EMID), which is backed by extensive epidemiologic data and demonstrated by a mouse model, is reviewed, along with recent data implicating the role of Schwann cells in the EMI area in the genesis of adenomyosis. Additionally, the natural history of adenomyotic lesions is elaborated and underscores that, ] in essence, adenomyotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR), which progress to fibrosis through epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia. Increasing lesional fibrosis propagates into the neighboring the EMI and endometrium. The increased endometrial fibrosis, with ensuing greater tissue stiffness, results in attenuated prostaglandin E2 (PGE2) and hypoxia signaling, impairing endometrial repair and causing HMB. Compared with adenomyosis-associated HMB, the mechanisms underlying adenomyosis-associated pain is less understood, but presumably involves increased uterine contractility, hyperinnervation, increased lesional production of pain mediators, and central sensitization. Viewed through the prism of ReTIAR, new imaging technique can be used to diagnosis adenomyosis and possibly help to choose the best treatment modality.

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Anti-fibrotic effects of valproic acid in experimental peritoneal fibrosis

Cited by 15 publications

References 41 publications

Use of paclitaxel carried in solid lipid nanoparticles to prevent peritoneal fibrosis in rats

Use of paclitaxel carried in solid lipid nanoparticles to prevent peritoneal fibrosis in rats

Tamoxifen and bone morphogenic protein-7 modulate fibrosis and inflammation in the peritoneal fibrosis model developed in uremic rats

Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology

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