Regulation of microRNAs in cell signaling pathways-mediated vascular remodeling

Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described as converting from a contractile state into a synthetic phenotype,is a crucial event during vascular remodeling.Recently,micro RNAs(mi RNAs)a kind of small non-coding RNA molecules,has been proven to target critical genes of cell signaling pathways to regulate SMC phenotypic change.By searching the Pub Med,Embase,reviews,and reference listsof relevant papers,we systematically carried out a review of the literature to provide an overview of the mi RNAs and their target genes in cell signaling pathways,focus inthe pathways involving in SMC phenotype change.To be specific,mi RNAs that regulate genes involved in the MAPK signaling pathways(such as:mi R-155,mi R-92a,mi R-424/503,mi R-133,mi R-181b,mi R-31,mi R-1298,mi R-132,mi R-200c and mi R-483-3p),mi RNAs target genes involved in the TGF-βsignaling pathways(including mi R-24,mi R-17/92 cluster,mi R-599,mi R-21 and mi R-143/145),mi RNAs target the genes involved in the AMPK signaling pathways including mi R-144/451 and mi R-195,mi RNAs target the genes involved in the PI3K-Akt signaling pathways(including mi R-138,mi R-34c,mi R-223,mi R-761,mi R-10a,mi R-146a),mi R-199a-5ptargets the genes involved in the Wnt signaling pathways mi RNAs(mi R-221/222,mi R-15b,mi R-24/29a,mi R-224)involved in the PDGF signaling pathways and some mi RNAs(mi R-638,mi R-328,mi R-365,mi R-663,mi R-29b,mi R-130,mi R-142-5p,mi R-424/322)which regulate SMC phenotype change by other corresponding targets were in detailed discussed in our review.Exploring the regulation of miR NAs in key cellsignaling pathways-mediatedvascular remodeling wil have momentous impact on identifying novel therapeutic targets for its associated disease.

Research Progress of miRNA Regulating Cell Signaling Pathways Related to Hepatocarcinogenesis

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors in clinical practice.The pathogenesis of HCC is still unclear.Currently,the clinical treatment of HCC is poorly targeted and the therapeutic effect is poor.MicroRNAs(miRNAs)are closely related to the occurrence of HCC,and they are mainly involved in the occurrence and development of HCC through binding to target genes or acting on related signaling pathways.In recent years,studies have shown that miRNA can be used as a potential biomarker for diagnosis and prognosis of HCC.In addition,studies have also shown that miRNA plays a tumorsuppressing or tumor-promoting role in the process of HCC by regulating the biological processes of tumor cell proliferation,migration,invasion and metastasis.In this paper,the recent studies on miRNA signaling pathways related to the occurrence and development of HCC were reviewed,with a view to providing ideas for the clinical diagnosis and treatment of HCC.

Mitogen activated protein kinase signaling pathways participate in the active principle region of Buyang Huanwu decoction-induced differentiation of bone marrow mesenchymal stem cells

Our preliminary studies confirmed that an active principle region of Buyang Huanwu decoction, comprising alkaloid, polysaccharide, aglycon, glucoside and volatile oil, can induce bone marrow mesenchymal stem cell differentiation into neurons. Mitogen-activated protein kinase signaling was identified as one of the key pathways underlying this differentiation process. The present study shows phosphorylated extracellular signal-regulated protein kinase and phosphorylated p38 protein expression was increased after differentiation. Cellular signaling pathway blocking agents, PD98059 and SB203580, inhibited extracellular signal-regulated protein kinase and p38 in mitogen-activated protein kinase signaling pathways respectively, mRNA and protein expression of the neuronal marker, neuron specific enolase, and neural stem cell marker, nestin, were decreased in bone marrow mesenchymal stem cells after treatment with the active principle region of Buyang Huanwu decoction. Experimental findings indicate that, extracellular signal-regulated protein kinase and p38 in mitogen-activated protein kinase signaling pathways participate in bone marrow mesenchymal stem cell differentiation into neuron-like cells, induced by the active principle region of Buyang Huanwu decoction.

Cellular signaling pathways of T cells in giant cell arteritis

Giant cell arteritis(GCA)is a commonly occurring large vacuities characterized by angiopathy of medium and large-sized vessels.GCA granulomatous formation plays an important role in the pathogenesis of GCA.Analysis of T cell lineages and signaling pathways in GCA have revealed the essential role of T cells in the pathology of GCA.T cells are the dominant population present in GCA lesions.CD4+T cell subtypes that are present include Th1,Th2,Th9,Th17,follicular helper T(Tfh)cells,and regulatory T(Treg)cells.CD8 T cells can primarily differentiate into cytotoxic CD8+T lymphocytes and Treg cells.The instrumental part of GCA is the interplay between dendritic cells,macrophages and endothelial cells,which can result in the vascular injury and the characteristics granulomatous infiltrates formation.During the inflammatory loop of GCA,several signaling pathways have been reported to play an essential role in recruiting,activating and differentiating T cells,including T-cell receptor(TCR)signaling,vascular endothelial growth factor(VEGF)-Jagged-Notch signaling and the Janus kinase and signal transducer and activator of transcription(STAT)pathway(JAK-STAT)pathway.In this review,we have focused on the role of T cells and their potential signaling mechanism(s)that are involved in the pathogenesis of GCA.A better understanding of the role of T cells mediated complicated orchestration during the homeostasis and the changes could possibly favor developments of novel treatment strategies against immunological disorders associated with GCA.

B cell receptor signaling pathway involved in benign lymphoepithelial lesions of the lacrimal gland

AIM：To detect the expression of B cell receptor signaling pathway（BCRSP） in lacrimal gland benign lymphoepithelial lesions（LGBLEL）.METHODS：Gene microarray was used to compare whole-genome expression in lacrimal gland tissues from LGBLEL patients to tissues from orbital cavernous hemangioma（control tissues）. Expression of BCRSP was confirmed by polymerase chain reaction（PCR） and immunohistochemistry. RESULTS：The expression of 22 genes of the BCRSP increased significantly in LGBLEL patients. PCR analysis showed that CD22, CR2, and BTK were all highly expressed in LGBLEL tissues. Immunohistochemical analysis showed that CR2 protein was present in LGBLEL, but CD22 and BTK proteins were negative. CR2, CD22, and BTK were not observed in the orbital cavernous hemangiomas with either PCR or immunohistochemistry. CONCLUSION：BCRSP might be involved in the pathogenesis of LGBLEL.

Role of JAK-STAT3 signaling pathway during neuronal differentiation of rat bone marrow mesenchymal stem cells

Recent studies regarding neuronal differentiation of mesenchymal stem cells （MSCs） have primarily focused on induction methods and transplantation in vivo. However, knowledge about the intrinsic regulatory mechanisms underlying neuronal induction of MSCs remains limited and unclear. OBJECTIVE： To elucidate the role of JAK-STAT3 signaling pathway during neuronal differentiation of MSCs using a combination of the JAK-STAT3 signaling inhibitor AG490 and growth factors. DESIGN, TIME AND SETTING： Neural, molecular, biomedical, in vitro experiment was performed at the Laboratory of Pharmacology, School of Pharmacy, Nanjing Medical University between March and December 2008 MATERIALS： An inhibitor of the JAK-STAT3 signaling pathway was purchased from Calbiochem, USA. Antibody kit for total and phosphorylated STAT3 was purchased from Cell Signaling, USA. METHODS： MSCs from passage 3 were assigned to non-induced, growth factor, and AG490 groups. MAIN OUTCOME MEASURE： The number of cells expressing neuron-specific enolase, microtubule-associated protein, and glial fibrillary acidic protein were determined by immunocytochemistry. Total and phosphorylated （Tyr705） expression levels of STAT3 protein were measured by Western blot analysis. RESULTS： MSCs were transdifferentiated into neuronal- and astrocyte-like phenotypes through the induction of epidermal growth factor, basic fibroblast growth factor, and brain-derived neurotrophic factor. In addition, the JAK-STAT3 signaling pathway was significantly activated during neural differentiation. Expression of phosphorylated （Tyr705） STAT3 was inhibited with AG490 （5 pmol/L） prior to neural induction with epidermal growth factor, basic fibroblast growth factor, and brain-derived neurotrophic factor; proportion of astrocyte-like cells was significantly reduced （P 〈 0.01）, and the proportion of neuronal-like phenotypes was significantly increased （P〈 0.01）. CONCLUSION： JAK-STAT3 signaling pathway was shown to regulate neuronal induction of bone marrow MSCs. The proportion of MSC-induced neuronal-like cells was increased following treatment with the JAK-STAT3 signaling inhibitor AG490.

Effect of the Notch signaling pathway on retinal ganglion cells and its neuroprotection in rats with acute ocular hypertension

AIM： To explore the effect of the Notch signaling pathway on retinal ganglion cells（RGCs） and optic nerve in rats with acute ocular hypertension（OH）.METHODS： Totally 48 Sprague-Dawley（SD） rats were included, among which 36 rats were selected to establish acute OH models. OH rats received a single intravitreal injection of 2 μL phosphate buffered solution（PBS） and another group of OH rats received a single intravitreal injection of 10 μmol/L γ-secretase inhibitor（DAPT）. Quantitative real-time polymerase chain reaction（qPCR） and Western blot assay were adopted to determine the mRNA level of Notch and the protein levels of Notch, Bcl-2, Bax, caspase-3, and growth-associated protein 43（GAP-43）. The RGC apoptosis conditions were assessed by TUNEL staining.RESULTS： The OH rats and PBS-injected rats had increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, with severer macular edema and RGCs more loosely aligned, when compared with the normal rats. The DAPT-treated rats displayed increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, in comparison with the OH rats and PBSinjected rats. RGCs were hardly observed and macular edema became severe in the DAPT-treated rat.CONCLUSION： The Notch signaling pathway may suppress the apoptosis of retinal ganglion cells and enhances the regeneration of the damaged optic nerves in rats with acute OH.

Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics

Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells(CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.

Pentoxifylline Inhibits Liver Fibrosis via Hedgehog Signaling Pathway

Infection of schistosomiasis japonica may eventually lead to liver fibrosis, and no effective antifibrotic therapies are available but liver transplantation. Hedgehog（HH） signaling pathway has been involved in the process and is a promising target for treating liver fibrosis. This study aimed to explore the effects of pentoxifylline（PTX） on liver fibrosis induced by schistosoma japonicum infection by inhibiting the HH signaling pathway. Phorbol12-myristate13-acetate（PMA） was used to induce human acute mononuclear leukemia cells THP-1 to differentiate into macrophages. The THP-1-derived macrophages were stimulated by soluble egg antigen（SEA）, and the culture supernatants were collected for detection of activation of macrophages. Cell Counting Kit-8（CCK-8） was used to detect the cytotoxicity of the culture supernatant and PTX on the LX-2 cells. The LX-2 cells were administered with activated culture supernatant from macrophages and（or） PTX to detect the transforming growth factor-β gene expression. The m RNA expression of shh and gli-1, key parts in HH signaling pathway, was detected. The m RNA expression of shh and gli-1 was increased in LX-2 cells treated with activated macrophages-derived culture supernatant, suggesting HH signaling pathway may play a key role in the activation process of hepatic stellate cells（HSCs）. The expression of these genes decreased in LX-2 cells co-cultured with both activated macrophages-derived culture supernatant and PTX, indicating PTX could suppress the activation process of HSCs. In conclusion, these data provide evidence that PTX prevents liver fibrogenesis in vitro by the suppression of HH signaling pathway.

The role of the HGF/c-Met signaling pathway in crizotinib-induced apoptosis in lung cancer with c-Met amplification

Objective This study aimed to study the role of the HGF/c-Met signaling pathway in crizotinib-induced apoptosis of various lung adenocarcinoma cell lines and xenograft tumor models.Methods In vitro, H2228, H1993, and A549 cells were treated with crizotinib. The inhibition of proliferation was quantitated by a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide(MTT) assay. Apoptosis was quantified by flow cytometry. Expression of key proteins of the HGF/c-Met signaling pathway was examined by western blotting. In vivo, H1993 and A549 tumor cell xenograft models were established. Immunohistochemical analysis was used to determine protein expression of HGF and c-MET and the amount of phospho-c-MET(p-c-Met). Real-time quantitative polymerase chain reaction(PCR) was applied to examine the messenger RNA(m RNA) expression of c-MET and serine/threonine protein kinase(AKT). The expression and activation of the key proteins were evaluated by western blotting.Results In vitro, the growth of H1993, H2228, and A549 cells was inhibited after crizotinib treatment for 72 h. Apoptotic rates of H1993 and H2228 cells increased with the crizotinib concentration and exposure time. In vivo, the growth-inhibitory rate of crizotinib for H1993 xenografts was 72.3%. Positive expression rates of HGF and c-MET in H1993 xenografts were higher than those in A549 xenografts; the p-c-MET amount was the largest in H1993 xenograft control but the lowest in the H1993 xenograft with crizotinib treatment. The m RNA expression levels of c-MET and AKT in H1993 xenografts were higher than those of A549 xenografts. The protein levels of c-MET, AKT, and extracellular regulated protein kinases(ERK) in H1993 xenografts were higher than those in A549 xenografts; the p-AKT amount was higher in H1993 xenograft control than in A549 xenografts; the largest amount of p-c-MET was detected in H1993 xenograft control; the amount of p-ERK was the lowest in the H1993 xenograft with crizotinib treatment.Conclusion The HGF/c-Met signaling pathway may mediate crizotinib-induced apoptosis and inhibition of proliferation of lung adenocarcinoma cells.

Core fucosylation and its roles in gastrointestinal glycoimmunology

Glycosylation is a common post-translational modification in eukaryotic cells.It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function.Core fucosylation plays a vital role in the immune response.Most immune system molecules are core fucosylated glycoproteins such as complements,cluster differentiation antigens,immunoglobulins,cytokines,major histocompatibility complex molecules,adhesion molecules,and immune molecule synthesis-related transcription factors.These core fucosylated glycoproteins play important roles in antigen recognition and clearance,cell adhesion,lymphocyte activation,apoptosis,signal transduction,and endocytosis.Core fucosylation is dominated by fucosyltransferase 8(Fut8),which catalyzes the addition ofα-1,6-fucose to the innermost GlcNAc residue of N-glycans.Fut8 is involved in humoral,cellular,and mucosal immunity.Tumor immunology is associated with aberrant core fucosylation.Here,we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.

Osteogenesis stimulation by copper-containing 316L stainless steel via activation of akt cell signaling pathway and Runx2 upregulation

As a metallic orthopedic implant,316L stainless steel(316L SS)is used extensively for its good resistance to corrosion and mechanical properties.However,it takes a long time to achieve osseointegration between 316L SS and adjacent tissues due to its bio-inert characteristic.Hence,the aim is to improve the bio-adaption of 316L SS.A good approach is to add elements to materials to improve their osteogenic capabilities by the appropriate release of ions.Hence copper-containing 316L stainless steel(316L-Cu SS)was investigated in this work,where Cu is an essential trace element that can stimulates osteogenesis.It was found that 316L-Cu SS was bio-safe and did not affect the proliferation of co-cultured osteoblasts in comparison with 316L SS.It increased cell apoptosis on day 1 but inhibited it on day 3,which cooperates with new bone formation processes.Osteoblasts extend themselves more quickly and in a better manner on the surface of 316L-Cu SS,wheneven more pseudopodia are present.Furthermore,the gene expression of alkaline phosphatase,collagen I and runt-related transcription factor 2(Runx2)in osteoblasts cultured with 316L-Cu SS was significantly enhanced.Runx2 protein expression increased,and osteogenesis was stimulated by 316L-Cu SS via an Akt cell signaling pathway.In conclusion,316L-Cu SS stimulates osteogenesis through activation of the Akt cell signaling pathway and the upregulation of Runx2.Thus,316L-Cu SS is a promising material that may be used in surgical implants to stimulate osteogenesis.

COVID-19 liver and gastroenterology findings:An in silico analysis of SARS-CoV-2 interactions with liver molecules

BACKGROUND Coronavirus disease 19(COVID-19)has not only been shown to affect the respiratory system,but has also demonstrated variable clinical presentations including gastrointestinal tract disorders.In addition,abnormalities in liver enzymes have been reported indicating hepatic injury.It is known that severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)might infect cells via the viral receptor angiotensin-converting enzyme 2(ACE2)which is expressed in several organs including the liver.The viral Spike glycoprotein binds to ACE2 and must be cleaved by Furin and Type 2 Serine Protease to enter the cells.After that,the Akt/mTOR signaling pathway is activated and several COVID-19 changes are triggered.AIM To analyze liver and gastrointestinal symptoms and cell signaling pathways triggered by SARS-CoV-2 infection due to virus-liver interactions in silico.METHODS In this in silico study,the three-dimensional structures of the Akt,mTORC1 and Furin(receptors)were selected from the Protein Data Bank(PDB)and the structures of inhibitors(ligands)MK-2206,CC-223 and Naphthofluorescein were selected from PubChem and ZINC databases.Ligand files were downloaded as 2D structures and converted to optimized 3D structures using ViewerLite 4.2 software.Marvin Sketch®software was used to calculate prediction of the protonated form of inhibitors in a physiological environment(pH 7.4).AutoDock Tools(ADT)software was used to calculate and delimit the Grid box used in the molecular docking of each structure selected in the PDB.In addition,protonated ligands were prepared for molecular docking using ADT software.Molecular docking was performed using ADT software tools connected to Vina software.Analysis of the amino acid residues involved in ligand interactions,as well as ligand twists,the atoms involved in interactions,bond type and strength of interactions were performed using PyMol^(■)and Discovery Studio^(■)(BIOVIA)software.RESULTS Molecular docking analysis showed that the mTORC1/CC-223 complex had affinity energy between the receptor and ligand of-7.7 kcal/moL with interactions ranging from 2.7 to 4.99Å.There were four significant chemical bonds which involved two of five polypeptide chains that formed the FKBP12–Rapamycin-Binding(FRB)domain.The strongest was a hydrogen bond,the only polar interaction,and Van der Waals interactions shown to be present in 12 residues of mTORC1’s FRB domain.With regard to the Akt/MK-2206 complex there were three Van der Waals interactions and 12 chemical bonds in which seven residues of Akt were involved with all five rings of the MK-2206 structure.In this way,both ASP 388 and GLN 391 bind to the same MK-2206 ring,the smaller one.However,LYS 386 had four chemical bonds with the inhibitor,one with each structure ring,while LYS 387 binds two distinct rings.One of the MK-2206 inhibitor's rings which binds to LYS 387 also binds simultaneously to ILE 367 and LEU 385 residues,and the fifth ring of the structure was involved in a bond with the ALA 382 residue.The hydrogen bonds were the shortest bonds in the complex(2.61 and 3.08Å)and all interactions had an affinity energy of-8.8 kcal/moL.The affinity energy in the Furin/Naphhofluorescein complex was-9.8 kcal/moL and involved six interactions ranging from 2.57 to 4.98Å.Among them,two were polar and the others were non-polar,in addition to twelve more Van der Waals interactions.Two distinct hydrogen bonds were formed between Furin and its inhibitor involving GLN 388 and ALA 532 residues.ALA 532 also binds to two distinct rings of Naphthofluorescein,while TRP 531 residue has two simultaneous bonds with the inhibitor.CONCLUSION Liver infection and signaling pathways altered by SARS-CoV-2 can be modulated by inhibitors that demonstrate significant interaction affinity with human proteins,which could prevent the development of infection and symptoms.

c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress Induced Neuronal Cell Death

Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. We have defined that the

Targeted suppression of miRNA-21 inhibit K562 cells growth through PTEN-PI3K/AKT signaling pathway

Objective To investigate the K562 cells biological function and related molecular changes in PTEN-PI3K/AKT signaling pathway of leukemia K562 cells by inhibiting the miRNA-21 expression to explore its pathogenesis of leukemia.Methods The chemical synthetic miRNA-

miR-202 contributes to sensitizing MM cells to drug significantly via activing JNK/SAPK signaling pathway

Objective To explore the role of miR-202 in multiple myeloma(MM)cells,and study the regulation of miR-202 on drug sensitivity of MM cells.Methods miR-202 and BAFF mRNA levels were detected by real-time PCR.U266 cells were transfected with miR-202-mimics,miR-202-inhibitor,siB AFF and their negative controls.

An update: the role of Nephrin inside and outside the kidney

Nephrin is a key molecule in podocytes to maintain normal slit diaphragm structure. Nephin interacts with many other podo- cyte and slit diaphragm protein and also mediates important cell signaling pathways in podocytes. Loss of nephrin during the development leads to the congenital nephrotic syndrome in children. Reduction of nephrin expression is often observed in adult kidney diseases including diabetic nephropathy and HIV-associated nephropathy. The critical role of nephrin has been confirmed by different animal models with nepbrin knockout and knockdown. Recent studies demonstrate that knockdown of nephrin expression in adult mice aggravates the progression of＇ unilateral nephrectomy and Adriamycin-induced kidney disease In addition to its critical role in maintaining normal glomerular filtration unit in the kidney, nephrin is also expressed in other organs. However, the exact role of nephrin in kidney and extra-renal organs has not been well characterized. Future studies are required to determine whether nephrin could be developed as a drug target to treat patients with kidney disease.

Prostate cancer： the need for biomarkers and new therapeutic targets

Prostate cancer （PCa） incidence and mortality have decreased in recent years. Nonetheless, it remains one of the most prevalent cancers in men, being a disquieting cause of men＇s death worldwide. Changes in many cell signaling pathways have a predominant role in the onset, development, and progression of the disease. These include prominent pathways involved in the growth, apoptosis, and angiogenesis of the normal prostate gland, such as an- drogen and estrogen signaling, and other growth factor signaling pathways. Understanding the foundations of PCa is leading to the discovery of key molecules that could be used to improve patient management. The ideal scenario would be to have a panel of molecules, preferably detectable in body fluids, that are specific and sensitive biomarkers for PCa In the early stages, androgen deprivation is the gold standard therapy. However, as the cancer progresses, it even- tually becomes independent of androgens, and hormonal therapy fails. For this reason, androgen-independent PCa is still a major therapeutic challenge. By disrupting specific protein interactions or manipulating the expression of some key molecules, it might be possible to regulate tumor growth and metastasis formation, avoiding the systemic side effects of current therapies. Clinical trials are already underway to assess the efficacy of molecules specially designed to target key proteins or protein interactions. In this review, we address that recent progress made towards under- standing PCa development and the molecular pathways underlying this pathology. We also discuss relevant molecular markers for the management of PCa and new therapeutic challenges.

New insights into the pathogenesis of Peyronie’s disease:A narrative review

Peyronie’s disease(PD)is a benign,progressive fibrotic disorder characterized by scar or plaques within the tunica albuginea(TA)of the penis.This study provides new insights into the pathogenesis of PD based on data from different studies regarding the roles of cytokines,cell signaling pathways,biochemical mechanisms,genetic factors responsible for fibrogenesis.A growing body of literature has shown that PD is a chronically impaired,localized,wound healing process within the TA and the Smith space.It is caused by the influence of different pathological stimuli,most often the effects of mechanical stress during sexual intercourse in genetically sensitive individuals with unusual anatomical TA features,imbalanced matrix metalloproteinase/tissue inhibitor of metalloproteinase(MMP/TIMP),and suppressed antioxidant systems during chronic inflammation.Other intracellular signal cascades are activated during fibrosis along with low expression levels of their negative regulators and transforming growth factor-β1 signaling.The development of multikinase agents with minimal side effects that can block several signal cell pathways would significantly improve fibrosis in PD tissues by acting on common downstream mediators.