Emerging Therapeutic Potential of Polyphenols from Geranium sanguineum L. in Viral Infections, Including SARS-CoV-2.

The existing literature supports the anti-inflammatory, antioxidant, and antiviral capacities of the polyphenol extracts derived from Geranium sanguineum L. These extracts exhibit potential in hindering viral replication by inhibiting enzymes like DNA polymerase and reverse transcriptase. The antiviral properties of G. sanguineum L. seem to complement its immunomodulatory effects, contributing to infection resolution. While preclinical studies on G. sanguineum L. suggest its potential effectiveness against COVID-19, there is still a lack of clinical evidence. Therefore, the polyphenols extracted from this herb warrant further investigation as a potential alternative for preventing and treating COVID-19 infections.

Evaluation of Cell-Specific Alterations in Alzheimer's Disease and Relevance of In Vitro Models.

Alzheimer's disease (AD) is a neurodegenerative disorder classically characterized by two neuropathological hallmarks: ß-amyloid plaques and tau tangles in the brain. However, the cellular and molecular mechanisms involved in AD are still elusive, which dampens the possibility of finding new and more effective therapeutic interventions. Current in vitro models are limited in modelling the complexity of AD pathogenesis. In this study, we aimed to characterize the AD expression signature upon a meta-analysis of multiple human datasets, including different cell populations from various brain regions, and compare cell-specific alterations in AD patients and in vitro models to highlight the appropriateness and the limitations of the currently available models in recapitulating AD pathology. The meta-analysis showed consistent enrichment of the Rho GTPases signaling pathway among different cell populations and in the models. The accuracy of in vitro models was higher for neurons and lowest for astrocytes. Our study underscores the particularly low fidelity in modelling down-regulated genes across all cell populations. The top enriched pathways arising from meta-analysis of human data differ from the enriched pathways arising from the overlap. We hope that our data will prove useful in indicating a starting point in the development of future, more complex, 3D in vitro models.

Exploring the Role of CD74 and D-Dopachrome Tautomerase in COVID-19: Insights from Transcriptomic and Serum Analyses.

The COVID-19 pandemic has posed a significant threat to public health worldwide. While some patients experience only mild symptoms or no symptoms at all, others develop severe illness, which can lead to death. The host immune response is believed to play a crucial role in determining disease severity. In this study, we investigated the involvement of CD74 and D-DT in COVID-19 patients with different disease severities, by employing an in silico analysis of a publicly available transcriptomic dataset and by measuring their serum levels by ELISA. Our results showed a significant increase in MIF levels in PBMCs from COVID-19 patients, as well as a significant increase in the D-DT levels in PBMCs. However, we observed no modulation in the serum levels of D-DT. We also observed a concordant reduction in the serum levels and PBMCs expression levels of CD74. Furthermore, we found a negative correlation between CD74 serum levels and IL-13. In conclusion, our study sheds light on the involvement of CD74 and D-DT in COVID-19, with potential implications for disease severity and treatment. Further studies are needed to fully elucidate the mechanisms underlying these observations and to explore the potential therapeutic value of targeting CD74 and IL-13 in COVID-19.

Transcriptional upregulation of galectin-3 in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune, demyelinating disorder of the central nervous system (CNS) affecting approximately 2.5 million people worldwide. The mechanisms underlying the pathogenesis of MS are still only partially elucidated. Galectins are a family of ß-galactoside-binding lectins that are involved in the regulation of immune and inflammatory responses and have been shown to exert a role in the maintenance of central nervous system (CNS) homeostasis. There has been an increasing interest in the role of galectin-3 in neuroinflammation and neurodegeneration. In the current study, we have evaluated the expression levels of galectin-3 in different cellular populations involved in the etiopathogenesis of MS. We have observed dramatically higher transcriptomic levels of galectin-3 in encephalitogenic CD4+ T cells in a preclinical model of MS, the MOG-induced experimental allergic encephalomyelitis (EAE). Also, significantly higher levels of galectin-3 were found in microglial cells, astrocytes, and oligodendrocytes isolated from the spinal cord of EAE mice, as well as in human MS-related white matter lesions. Modular co-expression analysis revealed that galectin-3 is co-expressed with genes involved in the regulation of microglia, cytokine production, and chemotaxis. This is the first comprehensive analysis of the expression of galectin-3 in MS, further strengthening its potential pathogenetic role in the etiopathogenesis of this CNS autoimmune disorder.

Anti-COVID-19 Potential of Ellagic Acid and Polyphenols of Punica granatum L.

Pomegranate (Punica granatum L.) is a rich source of polyphenols, including ellagitannins and ellagic acid. The plant is used in traditional medicine, and its purified components can provide anti-inflammatory and antioxidant activity and support of host defenses during viral infection and recovery from disease. Current data show that pomegranate polyphenol extract and its ellagitannin components and metabolites exert their beneficial effects by controlling immune cell infiltration, regulating the cytokine secretion and reactive oxygen and nitrogen species production, and by modulating the activity of the NFκB pathway. In vitro, pomegranate extracts and ellagitannins interact with and inhibit the infectivity of a range of viruses, including SARS-CoV-2. In silico docking studies show that ellagitannins bind to several SARS-CoV-2 and human proteins, including a number of proteases. This warrants further exploration of polyphenol-viral and polyphenol-host interactions in in vitro and in vivo studies. Pomegranate extracts, ellagitannins and ellagic acid are promising agents to target the SARS-CoV-2 virus and to restrict the host inflammatory response to viral infections, as well as to supplement the depleted host antioxidant levels during the stage of recovery from COVID-19.

Preventive and Therapeutic Effects of Punica granatum L. Polyphenols in Neurological Conditions.

Pomegranate (Punica granatum L.) is a polyphenol-rich food and medicinal plant containing flavonols, anthocyanins, and tannins. Ellagitannins (ETs) are the most abundant polyphenols in pomegranate. A growing body of research shows that polyphenol-rich pomegranate extracts and their metabolites target multiple types of brain cell and support their redox balance, proliferation and survival, as well as cell signaling. Independent studies have demonstrated that the significant neuroprotective effects of ETs are mediated by their antioxidant and anti-inflammatory effects, their chelating properties, by their ability to activate various signaling pathways, as well as the ability to influence mitochondrial damage, thus regulating autophagy, apoptosis and neurotransmitter signaling. The multitude of in vitro and in vivo studies summarized in the present review suggest that pomegranate polyphenols act on both neuronal and glial cells directly, and also affect blood-brain barrier function, restoring redox balance in the blood and brain and increasing blood flow to the brain.

Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy.

Due to the key role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of immunoinflammatory diseases, TNF-α inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. Currently, five anti-TNF-α drugs have been approved: infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. Anti-TNF-α biosimilars are also available for clinical use. Here, we will review the historical development as well as the present and potential future applications of anti-TNF-α therapies, which have led to major improvements for patients with several autoimmune diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PS) and chronic endogenous uveitis. Other therapeutic areas are under evaluation, including viral infections, e.g., COVID-19, as well as chronic neuropsychiatric disorders and certain forms of cancer. The search for biomarkers able to predict responsiveness to anti-TNF-α drugs is also discussed.

Failures in Reflective Functioning and Reported Symptoms of Anxiety and Depression in Bereaved Individuals: A Study on a Sample of Family Caregivers of Palliative Care Patients.

Introduction. This study aims at examining the role of failures in reflective functioning in predicting anxiety and depression among family caregivers of palliative care patients deceased for at least one year. Methods. A sample of 157 bereaved participants (77.1% females, mean age = 43.50 ± 14.04 years) completed the Hospital Anxiety and Depression Scale (HADS) and the Reflective Functioning Questionnaire (RFQ). Results. Results of the correlational analysis showed that anxiety was positively correlated with uncertainty about mental states, indicating one type of impairment in reflective functioning. Anxiety was also negatively correlated with the certainty about mental states. Depression was negatively correlated with certainty but not with uncertainty about mental states. The results of regression analysis indicated that gender and certainty about mental states were statistically significant predictors of anxiety, with the final model explaining 23% of the variance. The results also showed that gender, the condition of being the main caregiver, and the certainty about mental states were significant predictors of depression, with the final model predicting 14% of the variance. Conclusions. Overall, the results of this study point out that the bereaved individuals who scored low on certainty about mental states reported more symptoms of anxiety and depression. Psychological interventions to prevent mental disorders and to promote psychological health in the context of palliative care should carefully consider these findings.

Gene Co-Expression Network Modular Analysis Reveals Altered Immune Mechanisms in HIV-HAND.

Although the introduction of HAART has completely changed the natural course of HIV infection, the number of chronic forms of HIV-associated neurocognitive disorder (HAND) has risen. It is estimated that up to half of subjects undergoing HAART therapy exhibit mild cognitive impairments. In the current study, we apply the gene co-expression network modular analysis, a well-established system biology approach, to the gene expression profiles of cases from the National NeuroAIDS Tissue Consortium (NNTC). We observed a negative enrichment for genes associated with the control of immune responses and putatively regulated by the transcription factors IRF8 and SPI1 and by both type I and II interferons. Our study provides evidence of altered immune responses, which are likely associated with the occurrence of HAND in the absence of HIV encephalitis (HIVE).

Computational Analysis of Pathogenetic Pathways in Alzheimer's Disease and Prediction of Potential Therapeutic Drugs.

BACKGROUND: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease which affects more than 50 million patients and represents 60-80% of all cases of dementia. Mutations in the APP gene, mostly affecting the γ-secretase site of cleavage and presenilin mutations, have been identified in inherited forms of AD. METHODS: In the present study, we performed a meta-analysis of the transcriptional signatures that characterize two familial AD mutations (APPV7171F and PSEN1M146V) in order to characterize the common altered biomolecular pathways affected by these mutations. Next, an anti-signature perturbation analysis was performed using the AD meta-signature and the drug meta-signatures obtained from the L1000 database, using cosine similarity as distance metrics. RESULTS: Overall, the meta-analysis identified 1479 differentially expressed genes (DEGs), 684 downregulated genes, and 795 upregulated genes. Additionally, we found 14 drugs with a significant anti-similarity to the AD signature, with the top five drugs being naftifine, moricizine, ketoconazole, perindopril, and fexofenadine. CONCLUSIONS: This study aimed to integrate the transcriptional profiles associated with common familial AD mutations in neurons in order to characterize the pathogenetic mechanisms involved in AD and to find more effective drugs for AD.

Characterization of Altered Molecular Pathways in the Entorhinal Cortex of Alzheimer's Disease Patients and In Silico Prediction of Potential Repurposable Drugs.

Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterized by a progressive decline in cognitive functions. Accumulation of amyloid-ß plaques and neurofibrillary tangles are a typical feature of AD neuropathological changes. The entorhinal cortex (EC) is the first brain area associated with pathologic changes in AD, even preceding atrophy of the hippocampus. In the current study, we have performed a meta-analysis of publicly available expression data sets of the entorhinal cortex (EC) in order to identify potential pathways underlying AD pathology. The meta-analysis identified 1915 differentially expressed genes (DEGs) between the EC from normal and AD patients. Among the downregulated DEGs, we found a significant enrichment of biological processes pertaining to the "neuronal system" (R-HSA-112316) and the "synaptic signaling" (GO:0099536), while the "regulation of protein catabolic process" (GO:00042176) and "transport of small molecules" (R-HSA-382551) resulted in enrichment among both the upregulated and downregulated DEGs. Finally, by means of an in silico pharmacology approach, we have prioritized drugs and molecules potentially able to revert the transcriptional changes associated with AD pathology. The drugs with a mostly anti-correlated signature were: efavirenz, an anti-retroviral drug; tacrolimus, a calcineurin inhibitor; and sirolimus, an mTOR inhibitor. Among the predicted drugs, those potentially able to cross the blood-brain barrier have also been identified. Overall, our study found a disease-specific set of dysfunctional biological pathways characterizing the EC in AD patients and identified a set of drugs that could in the future be exploited as potential therapeutic strategies. The approach used in the current study has some limitations, as it does not account for possible post-transcriptional events regulating the cellular phenotype, and also, much clinical information about the samples included in the meta-analysis was not available. However, despite these limitations, our study sets the basis for future investigations on the pathogenetic processes occurring in AD and proposes the repurposing of currently used drugs for the treatment of AD patients.

Neuroprotective Effects of Myrtenal in an Experimental Model of Dementia Induced in Rats.

There is growing attention on natural substances capable of stimulating the cholinergic system and of exerting antioxidant effects, as potential therapeutic agents in Alzheimer's disease (AD). The aim of the present study is to evaluate the expected neuroprotective mechanisms of myrtenal (M) in an experimental model of dementia in rats. Dementia was induced in male Wistar rats by scopolamine (Sc) administration (0.1 mg/kg for 8 days and 20.0 mg/kg on day 9). The animals were divided into 5 groups (1) Controls; (2) Sc; (3) Sc + Myrtenal (40 mg/kg), (4) Sc + Galantamine (1 mg/kg); (5) Sc + Lipoic acid (30 mg/kg). Changes in recognition memory and habituation were evaluated via the Novel Object Recognition and Open Field tests. Acetylcholinesterase (AChE) activity, ACh levels, and changes in oxidative status of the brain were measured biochemically. The histological changes in two brain regions-cortex and hippocampus, were evaluated qualitatively and quantitatively. Myrtenal improved recognition memory and habituation, exerted antioxidant effects and significantly increased ACh brain levels. Histologically, the neuroprotective capacity of myrtenal was also confirmed. For the first time, we have demonstrated the neuroprotective potential of myrtenal in an experimental model of dementia. Our study provides proof-of-concept for the testing of myrtenal, in association with standard of care treatments, in patients affected by cognitive decline.

Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus.

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of ß-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 (Galectin-8) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

Identification of Common Pathogenetic Processes between Schizophrenia and Diabetes Mellitus by Systems Biology Analysis.

Schizophrenia (SCZ) is a psychiatric disorder characterized by both positive symptoms (i.e., psychosis) and negative symptoms (such as apathy, anhedonia, and poverty of speech). Epidemiological data show a high likelihood of early onset of type 2 diabetes mellitus (T2DM) in SCZ patients. However, the molecular processes that could explain the epidemiological association between SCZ and T2DM have not yet been characterized. Therefore, in the present study, we aimed to identify underlying common molecular pathogenetic processes and pathways between SCZ and T2DM. To this aim, we analyzed peripheral blood mononuclear cell (PBMC) transcriptomic data from SCZ and T2DM patients, and we detected 28 differentially expressed genes (DEGs) commonly modulated between SCZ and T2DM. Inflammatory-associated processes and membrane trafficking pathways as common biological processes were found to be in common between SCZ and T2DM. Analysis of the putative transcription factors involved in the regulation of the DEGs revealed that STAT1 (Signal Transducer and Activator of Transcription 1), RELA (v-rel reticuloendotheliosis viral oncogene homolog A (avian)), NFKB1 (Nuclear Factor Kappa B Subunit 1), and ERG (ETS-related gene) are involved in the expression of common DEGs in SCZ and T2DM. In conclusion, we provide core molecular signatures and pathways that are shared between SCZ and T2DM, which may contribute to the epidemiological association between them.

Cognitive Decline in Rheumatoid Arthritis: Insight into the Molecular Pathogenetic Mechanisms.

Cognitive decline refers to a deterioration of intellectual and learning abilities and related memory problems, and is often associated with behavioral alterations, which prevents sufferers from carrying out the most common daily activities, such as maintaining normal productive interpersonal relationships, communicating, and leading an autonomous life. Numerous studies have highlighted the association between cognitive decline and autoimmune disorders, including rheumatoid arthritis (RA). RA is a chronic, inflammatory, autoimmune disease that involves systems and organs other than the bones and joints, with varying severity among patients. Here, we review the studies investigating the link between cognitive decline and RA, focusing on the main molecular pathogenetic mechanisms involved. The emerging body of data suggests that clinical, psychological, and biological factors may contribute to the pathogenesis of cognitive decline in RA, including cardiovascular complications, chronic pain, depression, inflammatory factors, changes in hormone levels, drug side effects, and genetics. Further studies are warranted in order to fully clarify the basis underlying the association between cognitive decline and RA and to find new possible diagnostic strategies and therapeutic targets for RA patients.

The Interplay of Attachment Styles and Defense Mechanisms on Eating Disorders Risk: Cross-Sectional Observation in the Community Population.

OBJECTIVE: Eating Disorders (Eds) are considered a broad group of pathological conditions characterized by dysregulated eating-related behaviors and habits. Attachment styles and defense mechanisms appear to be linked to the development of EDs-related unhealthy behaviors; however, these factors have been seldom investigated jointly. This study aimed at exploring the shared association between attachment styles, defense mechanisms, and EDs-related behaviors; additionally, we aimed at investigating whether defense mechanisms might be potential mediators of the association between attachment and Eds behaviors. METHOD: A community-based sample was recruited (88% females, mean age= 22.33 ± 4.81 years) and underwent a comprehensive evaluation protocol assessing attachment styles, defense mechanisms, and risk of eating disorders. RESULTS: Several shared associations between attachment styles, defense mechanisms, and eating disorders scores were found. Additionally, a maladaptive defense style appeared to be a significant mediator of the association between attachment styles and EDs-related symptoms. CONCLUSIONS: The integrated evaluation of attachment and defense mechanisms could generate a more comprehensive framework of the psychological antecedents related to Eating Disorders, and it could be a beneficial factor involved in therapies.

Reactive Oxygen Species and Their Impact in Neurodegenerative Diseases: Literature Landscape Analysis.

Significance: The excessive production of reactive oxygen species (ROS) has been linked to neurodegenerative diseases (NDs), and, therefore, many scientific works were published on the impact of ROS on the development of prevalent NDs, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Since quantitative and qualitative bibliometric analyses in this research area have not yet been done, the aim of this work is to explore the scientific literature implying ROS in NDs and to identify the major contributors, mainstream research themes, and topics on the rise. Recent Advances: Overall, 22,885 publications were identified and analyzed within the Web of Science (WoS) Core Collection electronic database (Clarivate Analytics, Philadelphia, PA). Most of the manuscripts were published in the 21st century. The publications were mainly related to the WoS categories Neurosciences and Biochemistry molecular biology. The United States is the major contributor, harboring the most productive authors and institutions. China, South Korea, and India have emerged as upcoming major contributors in the 2010s. Two most productive journals were Journal of Neurochemistry and Free Radical Biology and Medicine. Critical Issues: AD, PD, and amyotrophic lateral sclerosis were much more investigated than multiple sclerosis and Huntington's disease. Vitamin E and curcumin were frequently mentioned as potential antioxidant therapeutics, but their efficacy in treating NDs requires more clinical studies, since the existing evidence was mainly from in vitro experiments and in vivo animal studies. Future Directions: Mitochondrial dysfunction, autophagy, and nuclear factor erythroid 2-related factor 2 were among the author keywords with rising prevalence. Further research in these directions should advance our understanding of the mechanism and treatment of NDs. Antioxid. Redox Signal. 34, 402-420.

Emerging Neurological and Psychobiological Aspects of COVID-19 Infection.

The SARS-CoV-2 virus, first reported in December 2019 in China, is the causative agent of the current COVID-19 pandemic that, at the time of writing (1 November 2020) has infected almost 43 million people and caused the death of more than 1 million people. The spectrum of clinical manifestations observed during COVID-19 infection varies from asymptomatic to critical life-threatening clinical conditions. Emerging evidence shows that COVID-19 affects far more organs than just the respiratory system, including the heart, kidneys, blood vessels, liver, as well as the central nervous system (CNS) and the peripheral nervous system (PNS). It is also becoming clear that the neurological and psychological disturbances that occur during the acute phase of the infection may persist well beyond the recovery. The aim of this review is to propel further this emerging and relevant field of research related to the pathophysiology of neurological manifestation of COVID-19 infection (Neuro-COVID). We will summarize the PNS and CNS symptoms experienced by people with COVID-19 both during infection and in the recovery phase. Diagnostic and pharmacological findings in this field of study are strongly warranted to address the neurological and psychological symptoms of COVID-19.

Comprehensive Analysis of RNA-Seq Gene Expression Profiling of Brain Transcriptomes Reveals Novel Genes, Regulators, and Pathways in Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with deficits in social communication ability and repetitive behavior. The pathophysiological events involved in the brain of this complex disease are still unclear. METHODS: In this study, we aimed to profile the gene expression signatures of brain cortex of ASD patients, by using two publicly available RNA-seq studies, in order to discover new ASD-related genes. RESULTS: We detected 1567 differentially expressed genes (DEGs) by meta-analysis, where 1194 were upregulated and 373 were downregulated genes. Several ASD-related genes previously reported were also identified. Our meta-analysis identified 235 new DEGs that were not detected using the individual RNA-seq studies used. Some of those genes, including seven DEGs (PAK1, DNAH17, DOCK8, DAPP1, PCDHAC2, and ERBIN, SLC7A7), have been confirmed in previous reports to be associated with ASD. Gene Ontology (GO) and pathways analysis showed several molecular pathways enriched by the DEGs, namely, osteoclast differentiation, TNF signaling pathway, complement and coagulation cascade. Topological analysis of protein-protein interaction of the ASD brain cortex revealed proteomics hub gene signatures: MYC, TP53, HDAC1, CDK2, BAG3, CDKN1A, GABARAPL1, EZH2, VIM, and TRAF1. We also identified the transcriptional factors (TFs) regulating DEGs, namely, FOXC1, GATA2, YY1, FOXL1, USF2, NFIC, NFKB1, E2F1, TFAP2A, HINFP. CONCLUSION: Novel core genes and molecular signatures involved with ASD were identified by our meta-analysis.

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis.

Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.