Biomedical subjects

Axel M Gressner

Publications and source records attributed to Axel M Gressner.

At least 19 recordsLinked to original sources

PubMed2006

Connective tissue growth factor in serum as a new candidate test for assessment of hepatic fibrosis.

BACKGROUND: No reliable, cost-effective serum test is available for assessment of liver fibrogenesis, the most serious complication of chronic inflammatory liver diseases (CLD). In sera of patients with CLD, we determined the concentration of connective tissue growth factor (CTGF), a secreted downstream mediator of the potent fibrogenic cytokine transforming growth factor beta (TGF-beta). PATIENTS AND METHODS: We studied 83 patients with CLD (17 with chronic hepatitis, 16 with histologically proven fibrosis, and 50 with cirrhosis) and 74 healthy individuals. Serum CTGF was measured by use of a sandwich immunoassay. RESULTS: The mean concentration of CTGF was highest in the fibrosis group (5.2-fold) and in the chronic viral hepatitis group (4.3-fold) but lower in those patients with fully developed cirrhosis. The area under the ROC curve (AUC) of CTGF for fibrosis vs control was 0.955 (95% confidence interval, 0.890-0.987). The CTGF/platelet ratio increased the detection limit for cirrhosis from 84% to 92% and the specificity from 85% to 87.5% (cutoff for CTGF was 364 microg/L, ratio 2.05). CONCLUSION: CTGF in serum is a candidate marker of ongoing fibrogenesis in chronic liver diseases.

Connective Tissue Growth Factor↗

PubMed2006

The expression of CSRP2 encoding the LIM domain protein CRP2 is mediated by TGF-beta in smooth muscle and hepatic stellate cells.

Transforming growth factor-beta (TGF-beta) is a cytokine implicated in differentiation of smooth muscle cells and other mesenchymal-derived cells. During hepatic fibrogenesis, TGF-beta has a pivotal role in the initiation, promotion, and progression of transdifferentiation of hepatic stellate cells into myofibroblasts that play a central role in the synthesis of extracellular matrix components. Both, smooth muscle and activated hepatic stellate cells, express smooth muscle alpha-actin, the calponin-related protein SM22alpha, and CSRP2 encoding the cysteine- and glycine-rich LIM domain protein 2 (CRP2). The aim of the present study was to determine whether the expression of CSRP2 is influenced by TGF-beta. Stimulation as well as sequestering experiments demonstrated that TGF-beta markedly influences CSRP2 gene activity. Inhibition experiments using the ALK5 inhibitor SB-431542 further reveal that the transcriptional stimulation of the CSRP2 gene is mediated via the ALK5/Smad2/Smad3 signalling pathway. By use of bisulfite genomic analysis of CpG islands within the 5' regulatory regions we could exclude methylation-associated silencing, previously found to be responsible for the transcriptional inactivity of CSRP2 in a variety of human cancer cells and in a multistage carcinogenesis model, as a cause for CSRP2 inactivity in hepatocytes or fully transdifferentiated myofibroblasts.

Activin Receptors, Type I↗

PubMed2006

Gc-globulin: roles in response to injury.

BACKGROUND: Gc-globulin (vitamin D-binding protein) appears to have important functions in addition to its role as a carrier of vitamin D. APPROACH: We reviewed recent studies focusing on the pathophysiologic functions and clinical significance of Gc-globulin. RESULTS: Serum concentrations of Gc-globulin, as determined by immunoassay techniques, are decreased in severe injury. The extent of the decrease may have prognostic significance for patient outcomes. Clinical studies and animal models have shown that Gc-globulin has an important role in the clearance of procoagulant actin from the circulation after its release during cell necrosis and tissue injury. Gc-globulin has other potential roles in responses to acute tissue injury through conversion to a macrophage-activating factor, neutrophil chemotactic activity, and enhancement of C5a-mediated signaling. CONCLUSION: Considering the important physiologic roles of Gc-globulin in responses to tissue injury, such as clearance of actin, measurement of Gc-globulin may have value in directing the care of patients in many clinical disorders.

Actins↗

PubMed2006

Primary biliary cirrhosis is not a clinical condition for increased carbohydrate-deficient transferrin: experience with four independent CDT analysis methods.

BACKGROUND: Primary biliary cirrhosis (PBC) is considered as an important cause for increased carbohydrate-deficient transferrin (CDT). The underlying pathomechanism is difficult to explain by the pathogenesis and/or consequences of PBC. We tested whether PBC causes increased CDT results with current CDT analysis methods and, if so, whether this depends on the CDT analysis principle. METHODS: 48 serum samples from PBC patients were analyzed by HPLC, microcolumn CDT and non-CDT fractionation followed by a turbidimetric immunoassay, particle-enhanced immunonephelometry with monoclonal CDT antibodies, and capillary electrophoresis. The test-specific decision limits were used for categorization of the CDT analysis results into normal and increased values. RESULTS: HPLC: 47 normal/1 increased, microcolumn+TIA: 46 normal/2 increased, particle-enhanced immunonephelometry: 41 normal/7 increased, capillary electrophoresis: 48 normal CDT results. After combining an immunological CDT test (microcolumn+TIA or particle-enhanced immunonephelometry) as the screening method with a physico-chemical CDT test (HPLC or electrophoresis) as the confirmatory method, 1 case remained with increased CDT values by the screening (value 2.6%, cut-off 2.5%, particle-enhanced immunonephelometry) and confirmatory (value 1.8%, cut-off 1.75%, HPLC) analysis. CONCLUSIONS: PBC should no longer be overstressed as an important cause for false-positive CDT results regarding chronic alcohol abuse. In the presence of odd CDT results, PBC should be considered in the anamnestic exploration. However, PBC is not by itself a cause for increased CDT values.

Adult↗

PubMed2006

Variable expression of cystatin C in cultured trans-differentiating rat hepatic stellate cells.

AIM: To study the expression of cystatin C (CysC), its regulation by transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor (PDGF) and the potential interference of CysC with TGF-beta1 signaling in this special cell type. METHODS: We evaluated the CysC expression in cultured, profibrogenic hepatic stellate cells and trans-differentiated myofibroblasts by Northern and Western blotting and confocal laser scanning microscopy. RESULTS: CysC was increased significantly in the course of trans-differentiation. Both TGF-beta1 and PDGF-BB suppressed CysC expression. Furthermore, CysC secretion was induced by the treatment with TGF-beta1. Although CysC induced an increased binding affinity of TGF-beta receptor type III (beta-glycan) as assessed by chemical cross-linking with [125I]-TGF-beta1, it did not modulate TGF-beta1 signal transduction as shown by evaluating the Smad2/3 phosphorylation status and [CAGA]-MLP-luciferase reporter gene assay. Interestingly, the shedding of type III TGF-beta receptor beta-glycan was reduced in CysC-treated cells. Our data indicated that CysC expression was upregulated during trans-differentiation. CONCLUSION: Increased CysC levels in the serum of patients suffering from liver diseases are at least partially due to a higher expression in activated hepatic stellate cells. Furthermore, TGF-beta1 influences the secretion of CysC, highlighting a potentially important role of cysteine proteases in the progression of hepatic fibrogenesis.

Animals↗

PubMed2006

Global analysis of host tissue gene expression in the invasive front of colorectal liver metastases.

Host cell reactions are a crucial determinant for tumor invasion. We analyzed on a genomewide scale gene expression differences between microdissected tissues taken from unaffected liver tissue of a human colorectal tumor (LS174) growing in the livers of nude mice and tissue from the host part of the invasive front. Due to the low degree of interspecies cross-hybridization of 15% as determined on Affymetrix microarrays, our xenograft model allowed for the distinction of genes of murine versus human origin even if the respective tissues could not be isolated separately. Using the gene ontology (GO) classification, we were able to determine patterns of up- and downregulated genes in the liver part of the invasive front. We observed a pronounced overrepresentation, e.g., of the GO terms "extracellular matrix," "cell communication," "response to biotic stimulus," "structural molecule activity" and "cell growth," indicating a very pronounced host cell response to tumor invasion. On the single gene level, hepatic stellate cell (HSC) activation markers were overrepresented in the liver part of the invasion front. Immunohistochemistry and qPCR confirmed an activation of HSC as well as an increased number of HSC in the invasive front as compared to the noninvaded liver tissue. In summary, our data demonstrate the feasibility of an interspecies differential gene expression approach on a genomewide scale.

Adenocarcinoma↗

PubMed2006

Elevation of Nepsilon-(carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis.

OBJECTIVES: Progression of liver fibrosis to cirrhosis is a dire consequence of chronic liver diseases (CLD). Nepsilon-(carboxymethyl)lysine (CML)-modified advanced glycation end products (AGEs) in patients with CLD could reflect the degree of severity of the disease. DESIGN AND METHODS: In 110 patients with CLD and 124 healthy controls, CML serum levels and their diagnostic sensitivity and specificity were determined and compared to hyaluronan (HA). RESULTS: Serum levels of CML were significantly affected by the stage of liver cirrhosis and were closely associated with liver function capacity. CML correlated positively with HA (r = 0.639, P < 0.0001). In ROC analysis, the diagnostic sensitivity and specificity in distinguishing healthy controls from liver disease patients for CML (AUC 0.908; 95%-CI 0.863-0.942, cut-off 640 ng/mL, sensitivity 74.5% and specificity 97.6%) resembled HA (AUC 0.948; 95%-CI 0.907-0.974; cut-off 50 ng/mL, sensitivity 80.7% and specificity 97.9%). The combination of CML and HA shows an AUC of 0.932; 95%-CI 0.888-0.962; sensitivity 82.6%; and specificity 95.8%. CONCLUSIONS: Our data suggest that serum levels of CML could provide a supplementary diagnostic marker for advanced stages of liver cirrhosis. However, the quality of interaction needs further investigation.

Adolescent↗

PubMed2006

Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a crucial role in the pathogenesis of hepatic fibrosis and thus may represent an important therapeutic target in the design of anti-fibrotic strategies for chronic liver disease. We present an innovative therapy based on the assignment of inactivated enzymes acting as scavengers for TIMP-1. Hepatic fibrosis was induced in BALB/c mice by repetitive intraperitoneal CCl4 injection. The animals were treated with proteolytic inactive matrix metalloproteinase-9 mutants (E402Q, H401A, E402H/H411E) using adenovirus-mediated gene transfer. Application of these MMP-9 mutants inhibited fibrogenesis, which was indicated by decreasing portal and periportal accumulation of collagen. Total hydroxyproline of liver tissue, the morphometric stage of fibrosis as well as mRNA expression of marker proteins for hepatic fibrosis in livers of E402Q- and H401A-treated mice were significantly reduced. MMP-9 mutants suppressed transdifferentiation of hepatic stellate cells to the myofibroblast like phenotype in vitro and in vivo. Moreover, adenoviral application of the mutants MMP-9-H401A and -E402Q led to increased apoptosis of activated hepatic stellate cells, thought to be the main promoters of hepatic fibrosis. Application of MMP-9 mutants as TIMP-1 scavengers may provide a new therapeutic strategy for hepatic fibrosis.

Adenoviridae↗

PubMed2006

Resistin serum levels are associated with insulin resistance, disease severity, clinical complications, and prognosis in patients with chronic liver diseases.

OBJECTIVES: Hyperinsulinemia and insulin resistance are present in nearly all patients with liver cirrhosis. Resistin, a mainly adipose-derived peptide hormone, reduces insulin sensitivity in adipocytes, skeletal muscles, and hepatocytes. In experimental cirrhosis models, resistin expression is upregulated. We aimed to evaluate the potential clinical value of resistin in chronic liver diseases (CLD). METHODS: Serum resistin was measured in 82 non-diabetic CLD patients during evaluation for potential liver transplantation and 76 age- and sex-matched healthy controls. Patients were followed for 6 yr. RESULTS: Resistin serum levels were significantly elevated in patients with liver cirrhosis compared with healthy controls (p<0.001). Resistin increased with stage of liver cirrhosis as defined by Child-Pugh or model for end-stage liver disease (MELD) score. Serum resistin correlated with insulin secretion (C-peptide, p<0.001) and inversely with insulin sensitivity (HOMA-index, p=0.008) in CLD patients. Resistin also correlated inversely with markers of hepatic biosynthetic capacity and positively with markers of inflammation such as tumor necrosis factor alpha (TNF-alpha) or C-reactive protein (CRP), as well as with clinical complications, e.g., portal hypertension. Patients with elevated resistin had increased mortality in 6-yr-survival (p=0.005, Cox regression model). CONCLUSION: Resistin offers novel application potential as a clinical biomarker in the assessment of liver cirrhosis. Elevated resistin may contribute to insulin resistance in advanced liver dysfunction.

Adult↗

PubMed2006

Technical evaluation of the Beckman Coulter OV-Monitor (CA 125 antigen) immunoassay.

BACKGROUND: The CA 125 antigen is a large (200-1000 kDa) glycoprotein, present within normal and benign ovarian tissue. We evaluated the analytical performance of the newly available Beckman Coulter OV-Monitor (CA 125 antigen) immunoassay on the Beckman Coulter UniCel DxI 800 analyzer. METHODS: The evaluation was performed according to NCCLS recommendations. RESULTS: The lowest level of CA 125 antigen detectable was 0.374 U/mL. Serial dilution of two pooled CA 125 antigen-rich samples provided a linear response (p<0.0001). For total CV% the following results were obtained: pool sera, 11.7 U/mL (2.70%), 56.3 U/mL (2.41%), 108.43 U/mL (2.31%); and QC sera, 29.4 U/mL (2.57%), 101.1 U/mL (3.26%). Comparison of the OV-Monitor on the UniCel DxI 800 showed linear regression values of r=0.961 vs. the Bayer ADVIA Centaur system and r=0.981 vs. the Abbott AxSYM system. CONCLUSION: Considering the limited number of serum samples analyzed, our data indicate that the Beckman Coulter OV-Monitor immunoassay has excellent analytical performance and shows satisfactory correlation with automated immunoassays on the Abbott AxSYM and Bayer ADVIA Centaur systems. It is easy to perform, accurate and suitable for measurements in routine clinical laboratories.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed2005

Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects.

Y-box protein-1 (YB-1) is a known negative regulator of collagen (Col) expression by two different mechanisms, acting directly through binding to an interferon-gamma response element within the col1A2 promoter and/or by physically interacting with p300/Smad3, thereby abrogating the stimulatory effect of transforming growth factor-beta (TGF-beta). Here, we report that YB-1 activation via the Jak1 signaling pathway is required and sufficient to confer interferon-gamma-dependent activation of the smad7 gene. By binding to a bona fide recognition site within the smad7 promoter, YB-1 up-regulates smad7 transcription, which was additively enhanced by autoinhibitory TGF-beta signaling. Importantly, the anti-TGF-beta effect was not only supplied by induced Smad7 expression but was recapitulated in the context of the col1A2 promoter, where YB-1 overexpression abolished the trans-stimulatory TGF-beta effect in a dominant fashion. In conclusion, YB-1 is the main target of interferon-gamma signaling via Jak1 that exerts antifibrotic action by both interference with TGF-beta signaling and direct down-regulation of collagen expression.

Animals↗

PubMed2005

Disruption of intermolecular disulfide bonds in PDGF-BB dimers by N-acetyl-L-cysteine does not prevent PDGF signaling in cultured hepatic stellate cells.

Oxidative stress is important in the pathogenesis of liver fibrosis through its induction of hepatic stellate cell (HSC) proliferation and enhancement of collagen synthesis. Reactive oxygen species have been found to be essential second messengers in the signaling of both major fibrotic growth factors, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), in cultured HSC and liver fibrosis. The non-toxic aminothiol N-acetyl-L-cysteine (NAC) inhibits cellular activation and attenuates experimental fibrosis in liver. Prior reports show that NAC is capable of reducing the effects of TGF-beta in biological systems, in cultured endothelial cells, and HSC through its direct reducing activity upon TGF-beta molecules. We here analyzed the effects of NAC on PDGF integrity, receptor binding, and downstream signaling in culture-activated HSC. We found that NAC dose-dependently induces disintegration of PDGF in vitro. However, even high doses (>20mM) were not sufficient to prevent the phosphorylation of the PDGF receptor type beta, extracellular signal-regulated kinase, or protein kinase B (PKB/Akt). Therefore, we conclude that the PDGF monomer is still active. The described antifibrotic effects are therefore mainly attributable to the structural impairment of TGF-beta signaling components reported previously.

Acetylcysteine↗

PubMed2005

Fibroblast growth factor 3, a protein with a dual subcellular fate, is interacting with human ribosomal protein S2.

The secreted isoform of fibroblast growth factor 3 (FGF3) induces a mitogenic cell response, while the nuclear form inhibits cell proliferation. Recently, we identified a nucleolar FGF3-binding protein which is implicated in processing of pre-rRNA as a possible target of nuclear FGF3 signalling. Here, we report a second candidate protein identified by a yeast two-hybrid screen for nuclear FGF3 action, ribosomal protein S2, rpS2. Recombinant rpS2 binds to in vitro translated FGF3 and to nuclear FGF3 extracted from transfected COS-1 cells. Characterization of the FGF3 binding domain of rpS2 showed that both the Arg-Gly-rich N-terminal region and a short carboxyl-terminal sequence of rpS2 are necessary for FGF3 binding. Mapping the S2 binding domains of FGF3 revealed that these domains are important for both NoBP and rpS2 interaction. Transient co-expression of rpS2 and nuclear FGF3 resulted in a reduced nucleolar localization of the FGF. These findings suggest that the nuclear form of FGF3 inhibits cell proliferation by interfering with ribosomal biogenesis.

Amino Acid Sequence↗

PubMed2005

N-acetyl-L-cysteine suppresses TGF-beta signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug.

The interrelated signaling via TGF-beta1 and reactive oxygen species has a profound impact on fibrogenesis and is therefore selected as target for antifibrotic therapies. This prompted us to investigate the influence of the antioxidant N-acetyl-L-cysteine on TGF-beta signaling in culture-activated hepatic stellate cells, the most relevant pro-fibrogenic cell type in liver. Dissection of the molecular steps involved in TGF-beta signaling revealed that N-acetyl-L-cysteine dose-dependently abrogated the induction of the TGF-beta1 signaling reporter gene activation, the phosphorylation of Smad2 and Smad3, and the up-regulation of Smad7 mRNA. By means of Western blot analysis and cross-linking experiments, it was demonstrated that these effects are based on disintegration of TGF-beta1 and the TGF-beta receptor endoglin, as well as a reduced ligand binding capacity of betaglycan. We conclude that N-acetyl-L-cysteine is a specific inhibitor of TGF-beta signaling targeting different components of the TGF-beta signaling machinery. In conclusion, these findings suggest that this non-toxic aminothiol downregulates TGF-beta signal transduction thereby mediating beneficial effects on experimental liver fibrosis characterized by TGF-beta hyperactivity.

Acetylcysteine↗

PubMed2005

Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC).

The platelet-derived growth factor (PDGF) family, which regulates many physiological and pathophysiological processes has recently been enlarged by two new members, the isoforms PDGF-C and -D. Little is known about the expression levels of these new members in hepatic fibrosis. We therefore investigated by quantitative real time PCR (Taqman) the mRNA expression profiles of all four PDGF isoforms in transdifferentiating primary cultured hepatic stellate cells (HSC), an in vitro model system of hepatic fibrogenesis, either with or without stimulation of the cells with PDGF-BB or TGF-beta1. All four isoforms were expressed in HSC transdifferentiating to myofibroblast-like cells (MFB) albeit with different profiles: while PDGF-A mRNA exhibited minor fluctuations only, PDGF-B was rapidly down-regulated. In contrast, both PDGF-C and -D mRNA were strongly induced: PDGF-C up to 5 fold from day 2 to day 8 and PDGF-D up to 8 fold from day 2 to day 5 of culture. Presence of PDGF-DD in activated HSC was confirmed at the protein level by immunocytochemistry. Stimulation of HSC and MFB with PDGF-BB led to down-regulation of the new isoforms, whereas TGF-beta1 upregulated PDGF-A only. We further show that PDGF receptor-beta (PDGFR-beta) mRNA was rapidly upregulated within the first day of culture and was constantly expressed from day 2 on while the expression profile of PDGFR-alpha mRNA was very similar to that of PDGF-A during transdifferentiation. Given the dramatic changes in PDGF-C and -D expression, which may compensate for down-regulation of PDGF-B, we hypothesize that the new PDGF isoforms may fulfil specific functions in hepatic fibrogenesis.

Animals↗

PubMed2005

Cryopreservation of hepatic stellate cells.

BACKGROUND/AIMS: Isolated rat hepatic stellate cells (HSC) are taken as a valuable in vitro model to study hepatic fibrogenesis, biotransformation of pharmaceutics, gene expression, transcription factors controlling HSC behaviour, and for the establishment of long-term cultures. Consequently, methods for the isolation and maintenance of HSC cultures are well documented. However, there is ongoing controversial discussion directed on the existence and cellular origin of different HSC subpopulations. Thus, there is a continuing need for developing methods allowing the exchange of HSC isolates between different laboratories. A practical solution to this problem is cryopreservation and banking of HSC. METHODS: We here describe for the first time the successful establishment of a methodology for long-term cryopreservation and recovery of primary, non-activated HSC from rats. We have optimised critical factors for HSC-banking including prefreeze processing, freezing rate, freezing medium, final cooling temperature, and thawing conditions. We found that DMSO gave far superior attachment and viability on thawing than other cryoprotectants. The viability and cellular characteristics of thawed cells was comparatively analysed by light- and electron microscopic analysis, proliferation assay, Oil Red O-staining, apoptosis testing, and evaluation of marker proteins for fibrogenic activities. RESULTS: In summary, our data reveal no significant differences in the biochemical and cellular properties between cryopreserved/thawed and freshly isolated HSC. CONCLUSIONS: According to these results, we suggest that cryoprotected HSC retain functional integrity thereby allowing banking and comfortable exchange of these cells between different laboratories.

Animals↗

PubMed2005

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.

Animals↗

PubMed2005

Abrogation of transforming growth factor-beta signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts.

Human fibroproliferative disorders like hypertrophic scarring of the skin are characterized by increased contractility and excess extracellular matrix synthesis. A beneficial role of transforming growth factor (TGF)-beta in wound healing was proposed; however, chronic stimulation by this cytokine leads to fibrosis. In the present report, the intracellular TGF-beta signaling in fibroblasts derived from hypertrophic scars and normal skin was examined. In an attempt to intervene in profibrogenic TGF-beta functions, ectopic expression of Smad7 or dominant negative Smads3/4 completely inhibited contractility of scar-derived and normal fibroblasts after suspension in collagen gels. Both cell types displayed constitutive Smad2/3 phosphorylation and (CAGA)9-MLP-Luc activity with expression and phosphorylation of Smad3 being predominant in hypertrophic scar-derived fibroblasts. Down-regulation of intrinsic signaling with various TGF-beta antagonists, e.g. soluble TGF-beta receptor, latency-associated peptide, and anti-TGF-beta1 antibodies, confirms autocrine TGF-beta stimulation of both cell populations. Further, Smad7 expression inhibited alpha1 (I) collagen and alpha-smooth muscle actin expression. In summary, our data indicate that autocrine TGF-beta/Smad signaling is involved in contractility and matrix gene expression of fibroblasts from normal and hypertrophic scars. Smad7 inhibits these processes and may exert beneficial effects on excessive scar formation.

Actins↗