key: cord-0963259-06b3xsy4
authors: Li, Zhenlin; Paulin, Denise; Lacolley, Patrick; Coletti, Dario; Agbulut, Onnik
title: Vimentin as a target for the treatment of COVID-19
date: 2020-09-09
journal: BMJ Open Respir Res
DOI: 10.1136/bmjresp-2020-000623
sha: dafe58505de3b0221cf5c55c53032092c191894e
doc_id: 963259
cord_uid: 06b3xsy4

We and others propose vimentin as a possible cellular target for the treatment of COVID-19. This innovative idea is so recent that it requires further attention and debate. The significant role played by vimentin in virus-induced infection however is well established: (1) vimentin has been reported as a co-receptor and/or attachment site for SARS-CoV; (2) vimentin is involved in viral replication in cells; (3) vimentin plays a fundamental role in both the viral infection and the consequent explosive immune-inflammatory response and (4) a lower vimentin expression is associated with the inhibition of epithelial to mesenchymal transition and fibrosis. Moreover, the absence of vimentin in mice makes them resistant to lung injury. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentin-targeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin. Consequently, we speculate here that drugs which decrease the expression of vimentin can be used for the treatment of patients with COVID-19 and advise that several Food and Drug Administration-approved drugs be immediately tested in clinical trials against SARS-CoV-2, thus broadening therapeutic options for this type of viral infection.

The COVID-19 has triggered a global public health crisis with more than 10 million infected people up to date (30 June 2020) worldwide and a global incidence rate which is still growing. 1 SARS-CoV-2 infection causes an explosive immune response, characterised by a cytokine storm, a subsequent progression to lung injury and an acute respiratory distress syndrome leading to death. 2 3 Despite many promising therapeutic options for the treatment of COVID-19, anti-SARS-CoV-2 drugs or vaccines are still under investigation. 4 Vimentin, known as a cytoskeletal protein belonging to the intermediate filament (IF) family, plays an important role in stabilising intracellular architecture through its mechanical role in cell plasticity and organelle anchoring, in the metabolism of lipids and in cell remodelling through its interaction with signalling molecules and components of gene regulatory networks. [5] [6] [7] [8] [9] [10] At cellular level, vimentin has been shown to be implicated in cell proliferation, stiffness, adhesion, migration, differentiation, senescence and apoptosis. [7] [8] [9] [10] Vimentin also plays a role in inflammation and immune responses, as well as in the epithelial to mesenchymal transition (EMT); the latter, in turn, being involved in the opening of epithelial barriers and cell migration. 11 12 Strikingly, intracellular vimentin has been shown to be implicated in the processes of virus fusion, replication and assembly (for a review, see Ramos et al 8 ) . Vimentin was additionally found to be located outside of the cell, where it serves as an attachment site for viral proteins, in the majority of cases favouring viral binding/entry. [13] [14] [15] [16] One possible exception was reported for the human papillomavirus type infection, in which vimentin actually had the opposite effect. 17 In this case, the authors reported that cell surface vimentin interfered with viral binding to its receptor, thus having a protective effect against viral infection. However, the role of vimentin for this specific virus is debated and contradictory reports have been published. As evidence to the contrary, Jacobs et al 18 experimentally reduced the level of vimentin on the surface of cervical cancer cells by exposing the cells to the hookworm Nippostrongylus brasiliensis, with the result of decreasing the internalisation of the HPV-16 in these cells. 18 One of the proposed mechanisms underlying this observation was the production of T helper-derived cytokines (eg, interleukin (IL)-4) associated with the helminth infection, which could, in turn, have modified the expression of HPV receptors in cancer cells.

During the submission period of the present manuscript in which we propose vimentin as a potential therapeutic target against viral infection, another two papers were written advocating the same hypothesis. 8 9 Vimentin was also been previously proposed as a potential therapeutic target in cancer treatment and other disease conditions such as fibrosis. The upregulation of vimentin typically observed in oncogenic transformation and Open access its involvement in cancer cell migration highlighted the possibility that vimentin is not only a marker but also a player in the development of cancer (reviewed in Refs 10 and 19) . Therefore, molecules such as withaferin A, FiVe1 and simvastatin were used to perturb the expression and/or the assembly of vimentin filament and led to the downregulation of soluble vimentin, accompanied by decreased fibrosis, the disruption of mitotic cells, filament disorganisation and cell death. [20] [21] [22] This paper summarises the scientific evidence indicating that reducing the expression of vimentin could be a powerful therapeutic option for COVID-19, since it could hamper SARS-CoV-2 infection and, at the same time, decrease the immunological response that is ultimately responsible for the often lethal acute respiratory distress syndrome. This hypothesis can be readily tested through clinical trials since Food and Drug Administration (FDA)-approved pharmacological treatments targeting vimentin for other pathologies are already available.

Vimentin is a co-receptor for SARS-CoV and possibly for SARS-CoV-2 ACE 2 (ACE2) is a cellular receptor for the SARS-CoV spike protein. 23 However, it has been shown that ACE2 is not sufficient to make host cells susceptible to infection [24] [25] [26] and vimentin has been proposed as a co-receptor for the entry of SARS-CoV into cells. 13 Indeed, the authors reported that the SARS-CoV virus enhances cell surface vimentin expression and, importantly, showed the existence of a direct interaction between vimentin and the SARS-CoV spike protein during viral entry. 13 Moreover, SARS-CoV and SARS-CoV-2 share similar spike protein sequences and the same cell entry route. 27 Interestingly, it has been recently reported that two proteins that are well known to be involved in the entry of SARS-CoV-2 into the cell-ACE2 and TMPRSS2-are both expressed by two cell types, that is, lung type II pneumocytes and nasal goblet secretory cells 28 ; it is worth noting these two cell types also express high levels of vimentin. [28] [29] [30] In addition, a potential interaction between vimentin and the SARS-CoV-2 spike protein is revealed in a SARS-CoV-2 protein-protein interaction map (see supplemental data). 31 Vimentin starts being expressed in the early stages of embryonic development by highly plastic precursor cells, whereas in postnatal life it is found in fibroblasts, endothelial cells, smooth muscle cells and in the lining epithelial cells of the lung, gut and other mucosae. 29 30 32 33 Here vimentin expression is quickly increased in response to viral infection and inflammatory stimuli [34] [35] [36] since vimentin belongs to the 'immediate early genes' family, a group of genes which are quickly activated in the presence of infection and inflammation. In this condition, due to its translocation to the cell surface, vimentin works as a co-receptor or attachment site for several viruses, including the Japanese encephalitis virus, 37 the porcine reproductive and respiratory syndrome virus, 38 the enterovirus 71, 39 cowpea mosaic virus, 14 dengue virus 16 as well as the coronavirus. 13 Interestingly, an upsurge of vimentin expression accompanies, and favours, viral entry of the majority of viruses including SARS-CoV 13 with the exception of HPV-16 in which viral entry is actually hampered by an increase in vimentin expression. 17 Consistently, interfering with vimentin expression or treating cells with the neutralising 'anti-vimentin' antibodies attenuates some types of viral infection. 8 9 18 37 38 However, it is unknown if vimentin is involved in the infection of the Middle East respiratory syndrome coronavirus (MERS-CoV) which uses dipeptidyl peptidase 4 as the host cell receptor. 40 Vimentin is involved in different steps of viral replication or assembly since it colocalises with viral capsid proteins in the endoplasmic reticulum of the infected cells, 41 cooperating to produce virus particles. 42 It is reported that vimentin is implicated-through the control of lysosomal trafficking and reduced translocation of viral ribonucleoproteins-in the progression of the influenza A virus, acting as a restriction factor for viral replication. 43 44 In addition, vimentin influences the hepatitis C virus (HCV) and Theiler's virus replication through its interaction with virus core proteins. 45 46 A strong reduction of HIV-1 replication was reported in vimentin knockdown cells, showing that vimentin is necessary for viral replication. 47 Vimentin contributes to EMT, a process by which epithelial cells, including those lining the lung mucosa, lose their polarity and adhesion. EMT thus confers migratory and invasive properties to the cells in a variety of pathological conditions such as viral infections, angiogenesis, chronic autoimmune inflammatory diseases, inflammatory bowel diseases, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Overall, EMT promotes the creation of a suitable environment for viral infection and inflammation.

Vimentin expression is regulated by a plethora of transcription factors such as NF-κB (nuclearfactor-kappa B), Stat3 (signal transducer and activator of transcription 3), ZBP-89 (Kruppel-type zinc-finger family transcription factor), Smads (smallmothers against decapentaplegic transcription factors), AP-1 (activator protein 1), Sp1 (proximal specificity protein 1) and PEA3 (polyomaenhancer activator 3)-see figure 1 . In response to viral infection or other insults, vimentin expression quickly increases. There are other transcription factors, such as Snail, Twist, ZEB2 and Slug, 12 48-52 that regulate vimentin expression during EMT so that the overexpression of vimentin and N-cadherin in epithelial cells leads to the loss of the epithelial phenotype.

In addition, vimentin expression is also regulated epigenetically through the chromatin modifications of its promoter. 53 These modifications have been studied in cancer cells since they promote EMT-a crucial event in the formation of tumour metastases. In particular, the methylation level of the vimentin promoter inversely correlates with the expression of vimentin in gastric Open access cancer. 54 Finally, vimentin expression is also regulated by post-transcriptional mechanisms including that of noncoding microRNAs. 12 Vimentin actively participates in inflammation and immune response Targeting vimentin could have additional effects against the progression of COVID-19 by directly modulating the inflammatory response of patients with COVID-19. Indeed, a subgroup of these patients suffer from a cytokine storm syndrome, that is, an excessive cytokine production sustained by a positive feedback loop producing an inflammatory response, often leading to respiratory failure from acute respiratory distress syndrome. 2 3 The NLRP3 inflammasome (nucleotide-binding and oligomerisation domain-like receptor protein 3 inflammasome) is an intracellular multiprotein complex that triggers the immune response of the host against pathogens including viruses and is implicated in acute lung injury. 55 It has been demonstrated that vimentin is a key regulator of the NLRP3 inflammasome by direct interaction. 11 Important events in lung inflammation and the onset of injury are the increase in IL-1β levels, the permeability of the endothelial-alveolar epithelium barrier and irreversible fibrosis. The relevance of vimentin in these responses was demonstrated in animal models in which the inflammatory response of vimentin-knockout mice to lipopolysaccharide (LPS), bleomycin or asbestos treatment was considerably lower, entailing a less significant lung injury. 11 Leucocyte adhesion to vascular endothelium and platelets is an early step in acute inflammatory response and attenuation of this adhesion may be beneficial in acute lung injury. By increasing circulating IL-1β-the major proinflammatory cytokine-vimentin is responsible for activating and recruiting inflammatory cells. In this context, it was shown that the vimentin IFs of both endothelial cells and lymphocytes form an anchoring structure between these two cell types. 56 Further evidence of the importance of vimentin for leucocyte extravasation comes from the report that the transendothelial migration of blood T and B lymphocytes is markedly reduced in vimentin-deficient lymphocytes and endothelial cells. 56 On the other hand, the presence of vimentin on the platelet and endothelial cell surface also serves as an adhesive receptor for the von Willebrand factor (VWF) and causes the binding of platelets to the subendothelial collagen and the subsequent intravascular generation of thrombin. 57 58 The latter being responsible (4) inflammation. 11 56-60 Therefore, decreasing the expression of vimentin would contribute to hampering viral infection and, in parallel, reducing the inflammatory response ultimately leading to COVID-19 lung injury, acute respiratory distress syndrome and fatalities. Worth noting, several transcription factors (including NF-kB, AP1 and Sp1) are implicated in the regulation of vimentin expression. 34 Open access for microthrombus formation and contributing to a nonhaemostatic effect, that is, the inflammatory response.

The inhibition of the vimentin-VWF interaction, by anti-vimentin antibodies, is effective in interfering with the VWF-mediated platelet adhesion to different matrices. 57 58 The administration of exogenous recombinant human vimentin, binding specifically to P-selectin, stops leucocyte adhesion to platelets and endothelium by blocking P-selectin interaction with P-selectin glycoprotein ligand, ultimately decreasing endotoxin-induced acute lung injury. 59 The oxidised form of membranebound vimentin is a marker of senescent cells, 60 which, as such, produce a plethora of potentially harmful proinflammatory cytokines, chemokines and growth factors. Virus incubation times in senescent cells is longer, as observed in the case of HPV-16 61 and studying coronavirus infection in aged cells has been proposed, since this important issue for this virus is still unexplored. 9 As shown above, vimentin is expressed by many cell types, it has multiple cellular localisations, it plays multiple roles in cell behaviour by interacting with a plethora of molecular partners. The complexity of the functions exercised by vimentin, especially as concerns viral infection, is exemplified by contradictory reports in the literature showing opposite roles for vimentin, depending on the type of virus and the specific partners involved in its direct or indirect interactions. In the following paragraph and in table 1, we report and comment on a list of vimentin-targeting drugs, which are globally known to downregulate vimentin expression, since we think that such a downregulation would be beneficial. However, we decided to provide only a few significant case by case comments. Each single drug, depending on the type of virus and host cell type concerned, should be further investigated.

Based on the fact that vimentin is important for viral infection and the associated inflammatory response, we have searched the literature for compounds targeting vimentin so as to select drugs that may treat COVID-19. Some of these drugs are as common and as easily available as melatonin, which makes our hypothesis immediately verifiable through clinical trials on COVID-19 specifically.

Some of the 49 compounds that we have identified (table 1) are completely new molecules that have recently started to be studied, others have never been employed in clinical practice although they are referenced by the FDA, while others are already being tested in clinical trials. However, all these molecules in table 1 affect vimentin levels, as demonstrated by western blot and/or real-time PCR analysis. Several of these compounds have been identified and characterised in in vitro experiments only, while others have been validated in vivo against cell growth and dispersion in cancer, and for their capacity to inhibit EMT which, as mentioned, amounts to fighting inflammation.

Interestingly, a significant fraction (16 out of 49) of the drugs listed in table 1 have been reported to play a role in acute lung injury and are briefly discussed below for this reason. Melatonin markedly reduces pulmonary injury and decreases the infiltration of macrophages and neutrophils into the lungs of LPS-treated mice, by inhibiting the NLRP3 inflammasome, in a model of acute lung injury. 62 Worth noting, it has already been speculated that melatonin would be beneficial in patients with COVID-19. 63 Niclosamide, a cheap antihelminthic drug, is effective against several viruses such as SARS-CoV, MERS-CoV, Zika virus, HCV and human adenovirus. 64 In particular, niclosamide has been shown to be an inhibitor of SARS-CoV 3CL protease, involved in viral replication. 64 Endogenous hydrogen sulfide participates in the regulation of important biological processes in the respiratory tract, such as airway tone, pulmonary circulation, cell proliferation and apoptosis, fibrosis, oxidative stress and inflammation. 65 Since hydrogen sulfide exerts a broad-spectrum antiviral activity, as well as having an anti-inflammatory action, the controlled release of hydrogen sulfide from chemical donors has been proposed as a treatment in lung diseases. 65 Simvastatin has protective vascular effects in the lungs since it improves the function of the endothelial barrier. The efficacy of simvastatin against LPSinduced lung injury involves the stabilisation of the cell cytoskeleton and adherent junctions. 66 The ability of triptolide to inhibit the proinflammatory NF-κB signalling pathway makes it another promising therapeutic agent for acute lung injury. 67 Sinomenine attenuates septic shockdependent acute lung injury, probably thanks to the inhibition of inflammation and oxidative stress. 68 Tanshinone IIA inhibits the production of proinflammatory factors in LPS-induced acute lung injury through the regulation of calcium in pulmonary interstitial macrophages. 69 Ginsenoside Rg3 attenuates LPS-induced acute lung injury by decreasing the production of proinflammatory factors and increasing the synthesis of anti-inflammatory cytokines, through the activation of the PI3K/AKT/mTOR pathway downstream of the Mer receptor. 70 Icariin reduces acute lung injury by enhancing the expression of the glucocorticoid receptor alpha in lung tissues and by inhibiting the expression of p65, c-Jun, Stat3, IL-6 and tumour necrosis factor-alpha. 71 The therapeutic window of Valproic acid is narrower but interesting, since it is effective in a mouse model of Gram-negative bacteriainduced pneumonia. 72 Apigenin C-glycosides inhibit acute inflammation and apoptosis by suppressing the activation of the TLR4/TRPC6 signalling pathway in a murine model of acute lung injury. 73 Inositol derivatives present in surfactant preparations diminish the activation of key inflammatory pathways in lung diseases. 74 Pterostilbene 4′-β-glucoside, the glycosylated form of the antioxidant pterostilbene, diminishes intracellular and mitochondrial reactive oxygen species production, thus reducing the inflammatory response to LPS. 75 Osthole exerts Open access Open access of blocking the interaction between vimentin and viral proteins.

Vimentin functions as a co-receptor for SARS-CoV-and likely for SARS-CoV-2-thus contributing to viral infection. Evidence of the significant role played by vimentin in virus-induced infection comes from the following observations: vimentin expression increases during viral infection in several clinical settings, while the absence of vimentin in knockout mice makes them more resistant to inflammation and acute lung injury than wild-type mice. Therefore, vimentin can be a target for the treatment of COVID-19-related pneumonia. It is a matter of fact that drugs that have proven efficient against viral infection downregulate vimentin expression. While the correlative nature of this evidence does not yet prove a causative role for vimentin downregulation in diminishing viral infection, it indicates that establishing whether drugs which decrease vimentin expression can be used for the treatment of patients with COVID-19 is the point at issue. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentintargeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin.

In particular: (1) the decreased amount of vimentin on the cell surface would decrease its interaction with SARS-CoV-2 spike protein, thus interfering with viral entry; (2) the decreased amount of vimentin within the cell would affect virus replication; (3) the lesser amount of vimentin within inflammatory cells would exert negative effects on the inflammasome. This in turn would avoid the cytokine storm and curb the arrival of infiltrating inflammatory cells; (4) lower vimentin expression in epithelial cells and fibroblasts would decrease EMT and fibrosis. Taken together, all these considerations strongly suggest that vimentin represents a valuable therapeutic target at the early stages of the SARS-CoV infection, may help avoid the progression to serious complications and indicate that several FDA-approved drugs (such as melatonin, niclosamide, selenium, hydrogen sulfide, inositol) should be tested in clinical trials against SARS-CoV-2.

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Japanese encephalitis virus interacts with vimentin to facilitate its entry into porcine kidney cell line

Superficial vimentin mediates DENV-2 infection of vascular endothelial cells

Vimentin modulates infectious internalization of human papillomavirus 16 pseudovirions

Hookworm exposure decreases human papillomavirus uptake and cervical cancer cell migration through systemic regulation of epithelial-mesenchymal transition marker expression

Vimentin intermediate filaments as potential target for cancer treatment

Withaferin a effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis

A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers

An image-based smallmolecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells

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Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke

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A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Initial expression of neurofilaments and vimentin in the central and peripheral nervous system of the mouse embryo in vivo

Vimentin knockout results in increased expression of sub-endothelial basement membrane components and carotid stiffness in mice

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Endoplasmic reticulum-Golgi intermediate compartment membranes and vimentin filaments participate in vaccinia virus assembly

Vimentin plays a role in the release of the influenza a viral genome from endosomes

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Cellular vimentin content regulates the protein level of hepatitis C virus core protein and the hepatitis C virus production in cultured cells

Interaction of Theiler's virus with intermediate filaments of infected cells

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PEA3 transactivates vimentin promoter in mammary epithelial and tumor cells

Regulatory elements of the human vimentin gene: activation during proliferation

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Stat3 enhances vimentin gene expression by binding to the antisilencer element and interacting with the repressor protein, ZBP-89

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Regulation of epithelial-mesenchymal transition through epigenetic and posttranslational modifications

DNA hypermethylation of the vimentin gene inversely correlates with vimentin expression in intestinal-and diffuse-type gastric cancer

NLRP3 (NALP3/CIAS1/ Cryopyrin) mediates key innate and healing responses to influenza A virus via the regulation of caspase-1

Vimentin function in lymphocyte adhesion and transcellular migration

Vimentin exposed on platelets serves as an adhesive receptor for Von Willebrand factor

Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress

Recombinant human vimentin binds to P-selectin and blocks neutrophil capture and rolling on platelets and endothelium

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

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Simvastatin attenuates acute lung injury via regulating CDC42-PAK4 and endothelial microparticles

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Sinomenine attenuates septicassociated lung injury through the Nrf2-Keap1 and autophagy

Tanshinone IIA alleviates lipopolysaccharide-induced acute lung injury by downregulating TRPM7 and pro-inflammatory factors

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D-4F, an apolipoprotein A-I mimetic, inhibits TGF-β1 induced epithelial-mesenchymal transition in human alveolar epithelial cell

DHEA increases epithelial markers and decreases mesenchymal proteins in breast cancer cells and reduces xenograft growth

Dictamnine promotes apoptosis and inhibits epithelial-mesenchymal transition, migration, invasion and proliferation by downregulating the HIF-1α and Slug signaling pathways

Ginsenoside Rg3 inhibits epithelialmesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4

Ginsenoside Rg3 inhibits cell growth, migration and invasion in Caco-2 cells by downregulation of lncRNA CCAT1

Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway

Icariin inhibits cell proliferation, migration and invasion by down-regulation of microRNA-625-3p in thyroid cancer cells

Icariside II inhibits the EMT of NSCLC cells in inflammatory microenvironment via down-regulation of Akt/NF-κB signaling pathway

Inositol induces mesenchymal-epithelial reversion in breast cancer cells through cytoskeleton rearrangement

The potential therapeutic effect of melatonin on human ovarian cancer by inhibition of invasion and migration of cancer stem cells

Melatonin inhibits lung metastasis of gastric cancer in vivo

Metapristone (RU486 derivative) inhibits cell proliferation and migration as melanoma metastatic chemopreventive agent

Caffeic acid and metformin inhibit invasive phenotype induced by TGF-β1 in C-4I and HTB-35/SiHa human cervical squamous carcinoma cells by acting on different molecular targets

The regulatory effects of metformin on the

Moscatilin inhibits epithelial-to-mesenchymal transition and sensitizes anoikis in human lung cancer H460 cells

N-Acetylcysteine tiherapeutically protects against pulmonary fibrosis in a mouse model of silicosis

The antihelminthic niclosamide inhibits cancer stemness, extracellular matrix remodeling, and metastasis through dysregulation of the nuclear β-catenin/c-Myc axis in

Norcantharidin suppresses colon cancer cell epithelial-mesenchymal transition by inhibiting the αvβ6-ERK-Ets1 signaling pathway

In vitro anticancer activities of osthole against renal cell carcinoma cells

PAC exhibits potent anti-colon cancer properties through targeting cyclin D1 and suppressing epithelial-to-mesenchymal transition

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Inhibition of LSD1 by Pargyline inhibited process of EMT and delayed progression of prostate cancer in vivo

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Pterostilbene inhibits triplenegative breast cancer metastasis via inducing microRNA-205 expression and negatively modulates epithelial-to-mesenchymal transition

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A short-term intervention with selenium affects expression of genes implicated in the epithelial-to-mesenchymal transition in the prostate

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Sinomenine inhibits proliferation, migration, invasion and promotes apoptosis of prostate cancer cells by regulation of miR-23a

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Tanshinone IIA inhibits epithelial-mesenchymal transition in bladder cancer cells via modulation of STAT3-CCL2 signaling

Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy

Tetrandrine reverses epithelialmesenchymal transition in bladder cancer by downregulating gli-1

A natural product toosendanin inhibits epithelial-mesenchymal transition and tumor growth in pancreatic cancer via deactivating Akt/mTOR signaling

Protective effects of triptolide on TLR4 mediated autoimmune and inflammatory response induced myocardial fibrosis in diabetic cardiomyopathy

Valproic acid (VPA) inhibits the epithelialmesenchymal transition in prostate carcinoma via the dual suppression of Smad4

Up-Regulation of TIF1γ by valproic acid inhibits the epithelial mesenchymal transition in prostate carcinoma through TGF-β/Smad signaling pathway

Wogonin suppresses human alveolar adenocarcinoma cell A549 migration in inflammatory microenvironment by modulating the IL-6/STAT3 signaling pathway

Acknowledgements The authors are grateful to Anna Luisa Mazzotti and Lydia