Exploring the potential mechanism of WuFuYin against hypertrophic scar using network pharmacology and molecular docking

BACKGROUND Hypertrophic scar(HTS)is dermal fibroproliferative disorder,which may cause physiological and psychological problems.Currently,the potential mechanism of WuFuYin(WFY)in the treatment of HTS remained to be elucidated.AIM To explore the potential mechanism of WFY in treating HTS.METHODS Active components and corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.HTSrelated genes were obtained from the GeneCards,DisGeNET,and National Center for Biotechnology Information.The function of targets was analyzed by performing Gene Ontology and Kyoto Encyclopaedia of Genes and Genome(KEGG)enrichment analysis.A protein+IBM-protein interaction(PPI)network was developed using STRING database and Cytoscape.To confirm the high affinity between compounds and targets,molecular docking was performed.RESULTS A total of 65 core genes,which were both related to compounds and HTS,were selected from multiple databases.PPI analysis showed that CKD2,ABCC1,MMP2,MMP9,glycogen synthase kinase 3 beta(GSK3B),PRARG,MMP3,and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma(PIK3CG)were the hub targets and MOL004941,MOL004935,MOL004866,MOL004993,and MOL004989 were the key compounds of WFY against HTS.The results of KEGG enrichment analysis demonstrated that the function of most genes were enriched in the PI3K-Akt pathway.Moreover,by performing molecular docking,we confirmed that GSK3B and 8-prenylated eriodictyol shared the highest affinity.CONCLUSION The current findings showed that the GSK3B and cyclin dependent kinase 2 were the potential targets and MOL004941,MOL004989,and MOL004993 were the main compounds of WFY in HTS treatment.

Hypertrophic Scar Formation and Wound Healing Modulation Fatty Acids as Modulators of Severe Scars

Scar tissue usually generates severe discomfort in the short and long term. Common symptoms include anesthetics sequelae, pruritus, joint malfunction, new wounds on the scar surface, and pain. There are several treatments for scars, like compression, topical or intralesional steroid infiltration, 5-fluorouracil, dermabrasion, and surgeries with new scar tissue. For adult patients, it is easier to choose the treatment. However, compression is commonly applied in children to prevent treatments that have adverse effects. This study reports the outcomes of 15 patients submitted to abdominoplasty, traumatic wounds and post-burn scar treatments, which showed significant changes after the continuous use of an ointment composed of petrolatum, cod liver oil, BHT, Chamomilla recutita (chamomile) oil, Helianthus annuus (sunflower) oil, and Prunus amygdalus dulcis (sweet almond) oil. As components of the stratum corneum, unsaturated fatty acids influence the cutaneous structural and immune status and permeability. They also interfere with the maturation and differentiation of the stratum corneum and inhibit the production of proinflammatory eicosanoids, reactive species (ROS and RNS), and cytokines, thereby influencing the inflammatory response and possibly wound healing. This article aims to share our experience with the regular use of an ointment in adult and pediatric patients for three months. The increase in proinflammatory cytokine production at wound sites, resulting in a noninvasive, therapeutical, and effective cutaneous wound healing and scarring modulation, may provide a physiopathological explanation for the fast improvement of scars.

A Case Report of Concurrent Acne-Related Occurrence Complications: Telangiectasia, Post-Inflammatory Erythema, Post-Inflammatory Hyperpigmentation, and Atrophic and Hypertrophic Scars

Prior to his initial diagnosis, a 21-year-old male had been experiencing facial acne for two years and had been treated by a doctor in private practice. The patient visited our department because the clinical manifestations of mandibular acne did not improve. At the time of initial examination, telangiectasia (TE), post-inflammatory erythema (PIE), post-inflammatory hyperpigmentation (PIH), atrophic scars (ASs), and a hypertrophic scar (HS) with induration were observed on the right neck. We diagnosed this as an acne vulgaris complication. HS lesions were topically treated by injecting triamcinolone acetonide, and the patient was prescribed 8.1 g/day of oral Saireito (Japanese herb). Adapalene benzoyl peroxide gel and topical tacrolimus hydrate ointment were used to treat PIE and TE. Both HSs and PIE improved;however, TE and AS did not improve. Currently, the patient is under observation. We consider this to be a very rare concurrent occurrence of diverse complications of acne vulgaris, and present the following case study.

DIAGNOSIS AND TREATMENT OF CESAREAN SCAR PREGNANCY

Objective To investigate the early diagnosis and treatment of cesarean scar pregnancy(CSP).Methods Clinical data of 28 patients with CSP in Peking Union Medical College Hospital from January 1994 to April 2007,including age,interval from the last cesarean delivery to diagnosis,clinical presentation,location of the lesion,process of diagnosis and treatment,outcome,and follow-up,were retrospectively analyzed.Results CSP constituted 1.05% of all ectopic pregnancies,and the ratio of CSP to pregnancy was 1∶1221.The mean age of the group was 31.4 years.Twenty-six women had only one prior cesarean delivery.The interval from the last cesarean delivery to diagnosis ranged from 4 months to 15 years.The most common presenting symptoms of CSP were amenorrhoea and vaginal bleeding.Seventeen cases were misdiagnosed as early intrauterine pregnancies and 2 were misdiagnosed as gestational trophoblastic tumor.The other 9 were diagnosed definitely before treatment.The diagnosis was made based on cesarean delivery history,gynecologic examination,ultrasound,and magnetic resonance imaging(MRI).The treatment of CSP included systemic or local methotrexate administration,conservative surgery,and hysterectomy.The conservative treatment was successful in 24 cases.All of the 28 women were cured through individual therapies.Conclusions CSP is rare and usually misdiagnosed as other diseases.Ultrasound is valuable for diagnosing CSP,and MRI can be used as an adjunct to ultrasound scan.Early diagnosis offers the options of conservative treatment and greatly improves the outcome of patients.Individual therapy is strongly recommended.

Inhibition effects of a negative electret 5-FU patch on the growth of a hypertrophic scar

In this study,the hypertrophic scar（HS） model in rats was established.5-fluorouracil（5-FU）patch,-1000 V and-2000 V polypropylene（PP） electret 5-FU patches were prepared and applied onto the wound.The in vitro permeation experiment was performed using the Franz diffusion cell system to determine the permeation cumulative amount and retention amount of5-FU through/in scar skin.The inhibition effect of negative electret on growth of HS was studied by hematoxylin-eosin（HE） staining,Masson staining and the immunohistologicall methods.The permeation study indicated that a negative electret could enhance the permeation and retention of 5-FU through and in scar skin respectively.HE staining and Masson staining indicated a better effect for-1000 V and-2000 V electret 5-FU patches on HS inhibition after28 d post-wounding compared with 5-FU patch.The immunohistological study showed much more reduced expressions of collegan type I,collegan type III,TGF-β1 and HSP47 in scar tissue after application of negative electret 5-FU patches than those of 5-FU patch.A negative electret5-FU patch may be advantageous for HS treatment.

Inflammation and cutaneous nervous system involvement in hypertrophic scarring

This study aimed to use a mouse model of hypertrophic scarring by mechanical loading on the dorsum of mice to determine whether the nervous system of the skin and inflammation participates in hypertrophic scarring. Results of hematoxylin-eosin and immunohistochemical staining demonstrated that inflammation contributed to the formation of a hypertrophic scar and increased the nerve density in scar tissue.Western blot assay verified that interleukin-13 expression was increased in scar tissue. These findings suggest that inflammation and the cutaneous nervous system play a role in hypertrophic scar formation.

Effects of the He-Ne laser with various power densities on the growth of cultured fibroblasts in hypertrophic scar

Objective To explore the relationship between power density of He -Ne laser with the growth of fibroblasts in hypertroph ic scar (HS).Methods The cultured fibroblasts in HS were i rradiated with He -Ne laser(Wavelenth 632.8nm),various power densities such as50mW/cm 2 ,100mW/cm 2 and 150mW/cm 2 were respectively adopted once a day for 10minutes.After 1,3and 5times o f He -Ne laser for dose rate irradiation separatedly ,the cell count and cell circle analysis were counted and examined by trypa n blue staining and flow cytometry .Results The amount of cell after 1times of 50mW /cm 2 laser irradiation was markedly more than teh control(P<0.01).The amount of cells after 5times of 100mW/cm 2 ,3and 5times of 150mW/cm 2 laser irradiation was less than the controls(P <0.05).The result of cell circle analysis was corresponded with that of the cell count.Conclusion Both stimualtion and inhibition of He -Ne laser on the growth of scar fibroblasts can be obtained with vario us power densities.Power density of He -Ne laser associates with the effects on the growth of scar fibroblasts.

Effect of ALA-PDT on the expressions of MMP-9, MMP-13 and TIMP-1 of hypertrophic scar model in rabbit ears

Objective: To investigate the effect of 5-aminolevulinic(ALA)-photodynamic therapy(PDT) on the expressions of MMP-9, MMP-13 and TIMP-1 of hypertrophic scar model in rabbit ears, and analyze the possible therapeutic mechanisms of ALA-PDT treatment to hypertrophic scars of rabbit ears. Methods: The experimental animals were randomly divided into normal control, negative control, high concentration of ALA-PDT, low concentration of ALA-PDT and PDT groups. The latter three groups received ALA-PDT treatment or PDT treatment once a week for 3 weeks. The specimens of the rabbits were collected respectively 1, 2 and 3 months after treatment to be used for RT-PCR and Western-blot test. Results: 1, 2 and 3 months after PDT treatment, the expressions of MMP-9 and MMP-13(including mRNA and protein) in hypertrophic scar tissues of three treatment groups were significantly higher than those of the negative control group(P<0.01), and the expression of TIMP-1 mRNA and protein of three treatment groups were significantly lower than that of the negative control group(P<0.01). There were also significant differences between high-concentration ALA-PDT treatment group and the low one(P<0.05). Conclusion: ALA-PDT is effective in treating hypertrophic scars of rabbit ears, and its possible therapeutic mechanisms are that ALA-PDT treatment generates oxidation activation effect to activate the activity of MMPs and induces the photoaging of fibroblasts of hypertrophic scar tissues of rabbit ears to inhibit the activity of TIMPs, which causes the up-regulation of MMPs and the down-regulation of TIMPs. Because of this, the degradation of collagen and ECM is accelerated and the formation of scars is suppressed.

Inhibitory effects of He-Ne laser repeated irradiation on collagen synthesis in hypertrophic scar-derived fibroblasts in culture

Objective To explore the inhibitory effects of He-Ne laser repeated irradiation on the collagen synthesis of cultured scar fibroblasts. Method Cultured fibroblasts derived from hypertrophic scars(HS) were irradiated with He-Ne laser for 30 minutes at various power densities(10,50,100 and 150 mW/cm2),once a day for 3 consecutive days.In 24 hours after repeated irradiation collagen production and type I procollagen mRNA level of fibroblasts were measured with the incorporation of 3H proline and blot hybridization techniques respectively.Results Collagen synthesis and type I procollagen mRNA level remained unchanged when the laser was irradiated at the power density of 10 mW/cm2 or 50 mW/cm2.Compared with control,collagen synthesis and type I procollagne mRNA level were significantly decreases at the power density of 100 mW/cm2 or 150mW/cm2(P< 0.05).Type I procollagen mRNA level at the power density of 150 mW/cm2 was lower than that at the 100 mW/cm2 (P< 0.05).Conclusion Repeated He-Ne laser irradiation at the power density of 100 mW/cm2 or 150 mW/cm2 can suppress collagen synthesis of cultured fibroblasts in HS.The cause of suppression may be associated with down regulation of type I procollagen mRNA expression.

Novel Elastomeric Fabrics for the Treatment of Hypertrophic Burn Scars Using Polyhexamethylene Biguanide Antimicrobial Agents

In burn treatments,microorganisms on pressure garments during pressure therapy can prevent rehabilitation by causing functional,hygienic,and aesthetic difficulties. As bacterium is one of the most trouble-causing organisms,they can threaten patients causing infection during the long period of use of these garments.Novel burn pressure garments having durable antimicrobial property were developed using polyhexamethylene biguanide( PHMB)antimicrobial agent procedure on highly elastic nylon 66 /spandex fabrics in powernet,flat warp and weft knitted structures using paddry-cure method. Commercial wireless pressure sensors were used to control pressures at an acceptable medical range. Antimicrobial activity,wash durability,Fourier transform infrared spectroscopy(FTIR) and Scanning electron microscopy(SEM) analyses were conducted for the treated samples. Antimicrobial test results following AATCC 100 Test Method showed 99% reduction of bacteria for the fabric samples treated with PHMB. A small but significant decrease in antimicrobial activity was observed even after50 launderings. These treatments also yield good results to prevent odor,decrease infection by preventing and /or blocking microbial growth according to the antimicrobial mechanism and support reducing of scarring by providing a hygienic environment around the scar.

Expression of transforming growth factor-β_1 and its typeⅠ receptor in different phases of post-burn hypertrophic scars

Objective: To analyze and compare the expression pattern of the transforming growth factor-β1(TGF-β1) and its type I receptor (TGF-β RI ) in nounal human skin and various phases of post-burn hypertrophic scars (HTS). Method: The immunohistochemical ABC method was employed. Results: In nounal human skin, no evident immunoreactivity of TGF-β1 and TGF-β R I was observed. In activation phase of post-burn HTS, TGF-β R I and TGF-β1 were highly expressed in most dermal fibroblasts which seemed to be the same subset. However, in remission phase, no staining was seen in der mal fibroblasts. Conclusion: The formation of all may involve the increase of TGF-β responsiveness in fibroblasts The ac cumulation at the wound site and failure of apoptosis of over-resposive fibroblasts may contribute to the formation of HTS.

The Diagnosis and Treatment for a Special Type of Cesarean Scar Pregnancy

Caesarean scar pregnancy (CSP) is a rare form of ectopic pregnancy, and its incidence has been increased due to the increased rate of Cesarean sections performed. A special type of CSP, concealed CSP, was found in the clinical work in our institution. A retrospective review was performed. From September 2011 to June 2014, 208 women were presented with cesarean scar pregnancy by use of transvaginal color Doppler sonography. The medical records were consulted to collect the demographics and pertinent information. Six of them were determined to be concealed CSP. Four women were diagnosed in the first-trimester pregnancy after termination of pregnancy. The initial ultrasound of the other two women displayed that the gestational sacs were located in the lower uterine cavity. Placenta accrete, increta and previa were diagnosed by the following ultrasounds. Concealed CSP is a very unusual form of CSP. Continued pregnancy may be sufficiently evaluated because of subsequently serious complications. Our results indicate that continued pregnancy increases the risk of laparotomy and hysterectomy. Medical abortion in the first-trimester pregnancy should be considered as the optimal choice for the women with prior cesarean sections who want to terminate the gestation.

NON-LINEAR SPECTRAL IMAGING MICROSCOPY STUDIES OF HUMAN HYPERTROPHIC SCAR

Skin scar is unique to humans,the major significant negative outcome sustained after thermal injuries,traumatic injuries,and surgical procedures.Hypertrophic scar in human skin is investigated using non-linear spectral imaging microscopy.The high contrast images and spectroscopic intensities of collagen and elastic fibers extracted from the spectral imaging of normal skin tissue,and the normal skin near and far away from the hypertrophic scar tissues in a 10-year-old patient case are obtained.The results show that there are apparent differences in the morphological structure and spectral characteristics of collagen and elastic fibers when comparing the normal skin with the hypertrophic scar tissue.These differences can be good indicators to differentiate the normal skin and hypertrophic scar tissue and demonstrate that non-linear spectral imaging microscopy has potential to noninvasively investigate the pathophysiology of human hypertrophic scar.

Dynamic changes of autophagy during hypertrophic scar formation and the role of autophagy intervention

Background:The role of autophagy in the formation of hypertrophic scars(HS)remains unclear.This study aimed to explore the role and potential mechanism of autophagy during the development of HS.Methods:RNA and protein expression levels of Beclin-1,p62,and LC3II in normal skin tissues and HS specimens from different patients were examined.Autophagy inducers and inhibitors were used to cure established HS in rabbit ears,and the expression of Beclin-1,p62,and LC3II at the RNA and protein level was determined.Lastly,the effects of autophagy inducers and inhibitors on HS development were analyzed.Results:Compared to normal skin tissues,the expression of LC3II and Beclin-1 was higher(P<0.05),while that of p62 was lower(P<0.05)in HS tissues.In addition,the LC3II/LC3I ratio was increased during HS formation,and the altered expression of the three proteins stabilized after one year.Administration of autophagy inducers enhanced the formation of HS as well as the expression levels of LC3II and Beclin-1 but decreased p62 expression.Meanwhile,administration of autophagy inhibitors increased the expression of LC3II,Beclin-1,and p62,along with reduced HS formation.Conclusion:Autophagic activity increased during HS initiation and subsequent stabilization.In addition,autophagy inhibitors were able to inhibit HS formation by suppressing autophagy,whereas autophagy inducers promoted scar hyperplasia by enhancing autophagy。

The expression of Cyclin A and p21^(cip1)in fibroblast of hypertrophic scar

Objective To study the relation of the mRNA and protein expression of CyclinA and p21cip1 in different stages hypertrophic scar fibroblast (FB) with its cell cycle,so as to provide theoretical evidence for intervention therapy of

STUDY ON FUNCTION OF FOCAL ADHENSIVE KINASE AND INTEGRIN α_1 IN HYPERTROPHIC SCAR FIBROBLASTS

Objective To study the function of focal adhesion kinase (FAK) in the formation of hypertrophic scar and its interrelationship with integrin α1. Methods Original fibroblasts from human hypertrophic scar and human normal dermis were cultured, and immunocytochemistry was applied to detect localization of expression of FAK and integrin α1 in hypertrophic scar and human normal skin fibroblasts. The expression of integrin α1 was detected before and after FAK antibody blocking hypertrophic scar fibroblasts (HSFB) 48 h later. Meanwhile the collagen synthesis was evaluated by [3H]-proline incorporation and HSFB cell proliferation was measured by MTT method. Results The expression of FAK and integrin α1 of hypertrophic scar fibroblasts was higher than that of the normal skin fibroblasts significantly (P<0.01). The expression of integrin α1 was reduced after FAK being blocked (P<0.01). Meanwhile the collagen synthesis of human scar-derived fibroblasts by [3H]-proline incorporation was depressed respectively (P<0.01). The cell proliferation was inhibited by using 1∶100 and 1∶200 FAK antibody with MTT method (P<0.01). Conclusion FAK is the key point of signal transmission pathway mediated by integrin α1, which regulates protein synthesis of integrin α1, it may play an important role in the proliferation and constriction of hypertrophic scar. FAK antibody can inhibit the collagen synthesis and cell proliferation of hypertrophic scar fibroblasts.

Expression of MMP-3 mRNA in hypertrophic scar fibroblasts and MMP-3 gene transfection

To investigate the molecular mechanism of extracellular matrix overdeposition in hypertrophic scar tissues and to explore MMPs gene therapy for hypertrophic scar. Methods: Hypertrophic scarderived and normal skin-derived fibroblasts were cultured and a recombinant retrovirus vector containing MMP-3 gene was constructed and then transfected into hypertrophic scar fibroblasts. Expressive level of MMP-3 mRNA was detected by dot blotting, and the activity of MMPs was determined by DNP-peptide.Results: Lower expression of MMP-3 mRNA and fewer DNP-peptide hydrolyzed fragments were observed in hypertrophic scar-derived fibroblasts compared with normal skin-derived fibroblasts. Transfection of MMP-3gene into hypertrophic scar-derived fibroblasts could enhance the expression of MMP-3 mRNA (3. 4 fold)and the de novo capacity to hydrolyze DNP-peptide (2. 1 fold). Conclusion: Overdeposition of extracellular matrix in hypertrophic scar tissue was related to low expression of MMP-3 due to its down-degradation of extracellular matrix. MMP-3 gene transfection could be a better way to treat hypertrophic scars by degrading extracellular matrix.

WJC 6~th Anniversary Special Issues(3):Cardiomyopathy Hypertrophic cardiomyopathy in 2013:Current speculations and future perspectives

Hypertrophic cardiomyopathy(HCM),the most variable cardiac disease in terms of phenotypic presentation and clinical outcome,represents the most common inherited cardiomyopathic process with an autosomal dominant trait of inheritance.To date,more than 1400 mutations of myofilament proteins associated with the disease have been identified,most of them "private" ones.This striking allelic and locus heterogeneity of the disease certainly complicates the establishment of phenotype-genotype correlations.Additionally,topics pertaining to patients' everyday lives,such as sudden cardiac death(SCD)risk stratification and prevention,along with disease prognosis,are grossly related to the genetic variation of HCM.This review incorporates contemporary research findings and addresses major aspects of HCM,including preclinical diagnosis,genetic analysis,left ventricular outflow tract obstruction and SCD.More specifically,the spectrum of genetic analysis,the selection of the best method for obstruction alleviation and the need for a unique and accuratefactor for SCD risk stratification are only some of the controversial HCM issues discussed.Additionally,future perspectives concerning HCM and myocardial ischemia,as well as atrial fibrillation,are discussed.Rather than enumerating clinical studies and guidelines,challenging problems concerning the disease are critically appraised by this review,highlighting current speculations and recommending future directions.

Can we suppress excessive post-surgical scar formation:A case report

BACKGROUND Hypertrophic scars(HSs)formation is a complication that occurs after wounds heal with secondary intention and sometimes after clean surgical incisions.Many treatments are in vogue now with varying successes.Although the mechanism or mechanisms that cause a HS to form are not clearly understood,one thing that is clear is that once scar tissue matures,any intervention will not be successful.In this paper,we report on a case where a patient who was known to develop HS was treated with a new combination of ingredients(Phyto-chemicals+Silicone JUMI)to suppress HS formation.CASE SUMMARY A 68-year-old female of African descent presented a severe HS post total knee replacement(TKR),which the patient describes as itchy and painful.Due to complications caused by the scar,she was apprehensive about undergoing TKR on her other knee.However,after the TKR of the contralateral side post-removal of skin clips,JUMI anti-scar cream(JASC)was used to suppress excessive scar formation.CONCLUSION JASC appears potent and efficacious at suppressing excessive scar formation.We believe that this warrants further studies on larger patient groups and on different surgical sites.