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Unfortunately, there is a gap of understanding in the pathophysiology of chronic liver disease due to the lack of experimental models that exactly mimic the human disease. Additionally, the diagnosis of patients is very poor due to the lack of biomarkers than can detect the disease in early stages. Thus, it is of utmost interest the generation of a multidisciplinary consortium from different countries with a direct translation. The present reports the meeting of the 2021 Iberoamerican Consortium for the study of liver Cirrhosis, held online, in October 2021. The meeting, was focused on the recent advancements in the field of chronic liver disease and cirrhosis with a specific focus on cell pathobiology and liver regeneration, molecular and cellular targets involved in non-alcoholic hepatic steatohepatitis, alcoholic liver disease (ALD), both ALD and western diet, and end-stage liver cirrhosis and hepatocellular carcinoma. In addition, the meeting highlighted recent advances in targeted novel technology (-omics) and opening therapeutic avenues in this field of research.

Background & aims Regular consumption of fast-food (FF) as a form of typical Western style diet is associated with obesity and the metabolic syndrome, including its hepatic manifestation nonalcoholic fatty liver disease. Currently, it remains unclear how intermittent excess FF consumption may influence liver metabolism. The study aimed to characterize the effects of a single FF binge on hepatic steatosis, inflammation, bile acid (BA), glucose and lipid metabolism. Methods Twenty-five healthy individuals received a FF meal and were asked to continue eating either for a two-hour period or until fully saturated. Serum levels of transaminases, fasting BA, lipid profile, glucose and cytokine levels as well as transient elastography and controlled attenuation parameter (CAP; to assess hepatic steatosis) were analyzed before (day 0) and the day after FF binge (day 1). Feces was collected prior and after the FF challenge for microbiota analysis. Results The FF meal induced a modest increase in CAP, which was accompanied by a robust increase of fasting serum BA levels. Surprisingly, levels of cholesterol and bilirubin were significantly lower after the FF meal. Differentiating individuals with a relevant delta BA (>1 μmol/l) increase vs. individuals without (delta BA ≤1 μmol/l), identified several gut microbiota, as well as gender to be associated with the BA increase and the observed alterations in liver function, metabolism and inflammation. Conclusion A single binge FF meal leads to a robust increase in serum BA levels and alterations in parameters of liver injury and metabolism, indicating a novel metabolic aspect of the gut–liver axis.

Animal models are crucial for improving our understanding of human pathogenesis, enabling researchers to identify therapeutic targets and test novel drugs. In the current review, we provide a comprehensive summary of the most widely used experimental models of chronic liver disease, starting from early stages of fatty liver disease (non-alcoholic and alcoholic) to steatohepatitis, advanced cirrhosis and end-stage primary liver cancer. We focus on aspects such as reproducibility and practicality, discussing the advantages and weaknesses of available models for researchers who are planning to perform animal studies in the near future. Additionally, we summarise current and prospective models based on human tissue bioengineering.

The epidemic of the century, Diabetes Mellitus (DM) is continuously rising. Intensive research is urgently needed whereby experimental models represent an essential tool to optimise the diagnostic strategy and to improve therapy. In this review, we describe the central principles of the metabolic tests available in order to study glucose and insulin homeostasis in mice, focusing on the most widely used – the glucose and insulin tolerance tests. We provide detailed experimental procedures as well as the practical implementation of these methods and discuss the main factors that should be taken into account when using this methodology.

Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC., This work was supported by the MINECO Retos SAF2016-78711, SAF2017-87919-R, PID2020-117827RB-IOO, PID2020-117941RB-IOO, PID2020-117116RB-I00, EXOHEP-CM S2017/BMD-3727, NanoLiver-CM Y2018/NMT-4949, AMMF 2018/117, COST Action CA17112 and UCM-25/2019, La Caixa Foundation Program HR17-00601; Asociación Española Contra el Cáncer (AECC PROYE20084REGU); the German Research Foundation (SFB1382 Project ID 403224013/A02). FJC and YAN are Ramón y Cajal Researchers RYC-2014-15242 and RYC-2015-17438, respectively. FJC is a Gilead Liver Research Scholar. The research group belongs to the validated Research Groups Ref. 970935 “Liver Pathophysiology”, 920631 “Lymphocyte immunobiology”, 920361 “Inmunogenética e inmunología de las mucosas” and IBL-6 (imas12-associated). FG and KZ are Chinese Scholarship Council (CSC) fellows. O.E.-V is supported by Beca FPI associated to MINECO SAR2017-87919R and R.B.-U by programa de Financiación de Universidad Complutense de Madrid—Banco Santander, CT63/19. DMM contract is supported by CIBEREHD. DMM, MRG, AR, JA and RG receive support from the Andalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018) and from the Instituto de Salud Carlos III (PI16/01842, PI19/01404; PI19/00589). TB is supported by the German Research Foundation (SFB1382 Project ID 403224013/B07).

Simple Summary Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development. Abstract Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.

Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils), 2. HP-WD—high concentration of PA (main fat source—palm oil), 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.

Cells : open access journal 10(5), 1107 (2021). doi:10.3390/cells10051107 special issue: "Special issue "Cellular and molecular mechanisms underlying the pathogenesis of hepatic fibrosis II" / special issue editor: Ralf Weiskirchen, guest editor", Published by MDPI, Basel

Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.

Journal of Clinical Medicine 10(5), 1039 (2021). doi:10.3390/jcm10051039 special issue: "Infectious Diseases / Edited by: Dr. Miguel A. Martín-Acebes, Dr. Jianbing Mu, Dr. Yoshinori Ito [u.a.]", Published by MDPI, Basel

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol‐associated and metabolic‐associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol‐associated liver disease plus metabolic‐associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA‐sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets., DUAL model perfectly mimics all histological, metabolic and transcriptomic gene signatures of human advanced steatohepatitis, and thus serve as a preclinical tool for the development of therapeutic targets.

Background Metabolic diseases are risk factors for severe Coronavirus disease (COVID-19), which have a close relationship with metabolic dysfunction-associated fatty liver disease (MAFLD). Aims To evaluate the presence of MAFLD and fibrosis in patients with COVID-19 and its association with prognosis. Methods Retrospective cohort study. In hospitalized patients with COVID-19, the presence of liver steatosis was determined by computed tomography scan (CT). Liver fibrosis was assessed using the NAFLD fibrosis score (NFS score), and when altered, the AST to platelet ratio index (APRI) score. Mann-Whitney U, Student´s t-test, logistic regression analysis, Kaplan-Meier curves and Cox regression analysis were used. Results 432 patients were analyzed, finding steatosis in 40.6%. No differences in pulmonary involvement on CT scan, treatment, or number of days between the onset of symptoms and hospital admission were found between patients with and without MAFLD. The presence of liver fibrosis was associated with higher severity scores, higher levels of inflammatory markers, requirement of mechanical ventilation, incidence of acute kidney injury (AKI), and higher mortality than patients without fibrosis. Conclusion The presence of fibrosis rather than the presence of MAFLD is associated with increased risk for mechanical ventilation, development of AKI, and higher mortality in COVID-19 patients.

International journal of molecular sciences 21(9), 3267 (2020). doi:10.3390/ijms21093267 special issue: "Special Issue "Pathophysiology of Liver Fibrosis and Its Therapies" / Special Issue Editor: Dr. Pavel Strnad, Guest Editor", Published by Molecular Diversity Preservation International, Basel

Alcoholic liver disease (ALD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. Understanding the pathophysiology and successful treatment for ALD is closely associated with the suitability of the animal model, which fully reflects all aspects of the pathogenesis and typical histological findings. This study reviews one of the most widely used experimental models of ALD in rodents-the Lieber-DeCarli (LDC) liquid diet. It is an easy, accurate, reliable, and inexpensive model to study the pathogenesis of early stages of ALD. Here, we discuss the historical background and provide an overview of the advantages and disadvantages of the classical LDC as well as modified "second-hit" models. We also provide a comprehensive protocol for the application of the LDC diet to perform it successfully, reliably, and reproducibly in mice.

Aim The natural terpenoid compound was explored in vitro and in vivo to investigate the anti-HCC properties. Methods For our study we used Abisilin ® - a novel natural pharmacological terpenoid compound extracted and purified from coniferous Pinaceae trees. Anti-tumorigenic properties of different concentrations of Abisilin ® were tested on murine hepatoma Hepa 1–6 cell lines. The analysis of proliferation and apoptosis was performed using immunofluorescence microscopy, FACS and qPCR. As an in vivo approach, we tested Abisilin ® (400 mg/kg/day, 14 days, orally) in xenograft mouse models of liver cancer and investigated tumor growth, proliferation, apoptosis and angiogenesis by means of Western blotting, immunofluorescence microscopy and qPCR. Results Application of Abisilin ® for 24 h at a dosage ranging from 0.03 to 0.045 mg significantly reduced the number of viable Hepa 1–6 cells and induced apoptotic cell death with microscopic evidence of changes in cell morphology, and positive TUNEL, cleaved caspase 3 and Annexin V/Propidium Iodide (PI) stainings. Furthermore, treatment with Abisilin ® strongly inhibited proliferation, impaired mitosis and prompted cell cycle arrest by down-regulation of the Cyclin D1, E1 and A2 expression levels. In Hepa 1–6 xenograft in vivo model, Abisilin ® considerably decreased the xenograft tumor size and tumor volume. Consistently with in vitro Abisilin ® administration elicited apoptosis and inhibit proliferation in the xenograft tumor. We also found that Abisilin ® remarkably decrease microvessel density, diminished tumor angiogenesis and reduced expression of ICAM-1. Moreover, the expression of pAMPK, a cellular energy sensor, was up-regulated after Abisilin ® application. Conclusions Anti-proliferative, pro-apoptotic activity and anti-angiogenic potential of natural conifer terpenoids might turn these compounds into an attractive drug candidate for combination therapy against liver cancer.

E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.

Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD., Supported by the MINECO Retos, No. SAF2016-78711 and SAF2017-87919R; EXOHEP-CM, No. S2017/BMD-3727; the AMMF Cholangiocarcinoma Charity, No. 2018/117; the COST Action, No. CA17112; Ramón y Cajal, No. RYC-2014-15242 and No. RYC-2015-17438; grant of ERAB, No. EA 14/18; Gilead Liver Research Scholar 2018, No. 44/2018; Ministerio de Sanidad, Servicios Sociales e Igualdad, No. 2017I065; and the UCM group “Lymphocyte Immunobiology”, No. 920631 (imas12-associated, Ref. IBL-6). German Research Foundation (SFB/TRR57/P04 and DFG NE 2128/2-1); Interdisciplinary Center for Clinical Research from the Faculty of Medicine at RWTH Aachen University (IZKF/E8-2).

Liver regeneration is controlled by a complex network of signaling molecules, and a prominent role for c-jun N-terminal kinase has been suggested during this process. In the present study, we aimed to characterize and define the cell-type-specific contribution of JNK1 activation during liver regeneration. We used hepatocyte-specific JNK1 knockout mice (JNK1(Δhepa)) using the cre/lox-P system. We performed partial hepatectomy (PH) in WT, JNK1(Δhepa) and JNK1(-/-) animals and investigated time-points up to 72 h after PH. Additionally, bone marrow transplantation experiments were conducted in order to identify the contribution of hematopoietic cell-derived JNK1 activation for liver regeneration. Our results show that liver regeneration was significantly impaired in JNK1(-/-) compared to JNK1(Δhepa) and WT animals. These data were evidenced by lower BrdU incorporation and decreased cell cycle markers such as Cyclin A, Cyclin D, E2F1 and PCNA 48 h after PH in JNK1(-/-) compared with JNK1(Δhepa) and WT livers. In JNK1(-/-) mice, our findings were associated with a reduced acute phase response as evidenced by a lower activation of the IL-6/STAT3/SAA-1 cascade. Additionally, CD11b(+)Ly6G(+)-cells were decreased in JNK1(-/-) compared with JNK1(Δhepa) and WT animals after PH. The transplantation of bone marrow-derived JNK1(-/-) into WT recipients caused significant reduction in liver regeneration. Interestingly, the transplantation of JNK1(-/-) into mice lacking JNK1 in hepatocytes only partially delayed liver regeneration. In summary, we provide evidence that (1) JNK1 in hematopoietic cells is crucial for liver regeneration, and (2) a synergistic function between JNK1 in hepatocytes and hematopoietic-derived cells is involved in the hepatic regenerative response.

27 páginas, 4 figuras. Contiene material suplementario, método, 6 figuras en: https://doi.org/10.1038/s41586-019-1112-8, The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex1. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease, s We thank S. Bartlett for English editing, D. Engelberg for the constitutively active mutants, the Division of Signal Transduction Therapy for recombinant proteins, and CNIC Advanced Imaging and Vector Units for technical support. G.S. (RYC-2009-04972), F.J.C. (RYC-2014-15242), and Y.A.N. (RYC-2015-17438) are investigators of the Ramón y Cajal Program. E.M. and M.T. were awarded La Caixa fellowships and R.R.-B. was a fellow of the Fundación Ramón Areces-UAM and FPU. B.G.-T. is a fellow of the FPI Severo Ochoa CNIC program (SVP-2013-067639). F.J.C. is a Gilead Liver Research Scholar. This work was funded by grants supported in part by funds from the European Regional Development Fund: the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (InvestigadoresBBVA-2017) IN[17]_BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R, and Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/ BMD-3733 to G.S.; Juan de la Cierva and MINECO SAF2014-61233-JIN to A.T.-L.; the European Community for MSCA-IF-2014-EF-661160-MetAccembly grant to F.F.; Spanish MINECO CTQ2014-59212-P, European Community for CIG project (PCIG14-GA-2013-630978), and European Research Council (ERC) under the European Union’s Horizon 2020 (ERC-2015-StG-679001- NetMoDEzyme) to S.O.; the German Research Foundation (SFB/TRR57/P04 and DFG NE 2128/2-1) and MINECO SAF2017-87919R to Y.A.N.; EXOHEP-CM S2017/BMD-3727 and the COST Action CA17112, MINECO SAF2016-78711, and the AMMF Cholangiocarcinoma Charity 2018/117 to F.J.C.; MINECO (SAF2015-69920-R co-funded by ERDF-EU), the Consolider-Ingenio 2010 Programme (SAF2014-57791-REDC), Excellence Network CellSYS (BFU2014- 52125-REDT), and the iLUNG Programme (B2017/BMD-3884) from the Comunidad de Madrid to M. Malumbres; MINECO SAF2015-67077-R and SAF2017-89901-R to J.B.; MINECO (BIO2015-67580-P), Carlos III Institute of Health-Fondo de Investigación Sanitaria (ProteoRed PRB3, IPT17/0019 - ISCIII-SGEFI/ERDF), Fundación La Marató and ‘La Caixa’ Banking Foundation (HR17-00247) to J.V.; ISCIII and FEDER PI16/01548 and Junta de Castilla y León GRS 1362/A/16 and INT/M/17/17 to M. Marcos; Junta de Castilla y León GRS 1356/A/16 and GRS 1587/A/17 to J.L.-T.; and MCNU (SAF2017- 84494-C2-1-R) to J.R.-C. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

We present a theoretical study of the propagation of three-dimensional extremely short electromagnetic pulses (a.k.a. light bullets) through a Bragg medium containing an immersed array of carbon nanotubes. We demonstrate the possible stable propagation of such light bullets. In particular, our results suggest these light bullets can carry information about the Bragg medium itself., Comment: To appear in Appl. Phys. B

Cysteine-rich protein 61 (CCN1/CYR61) is a CCN ( C YR61, C TGF (connective tissue growth factor), and N OV (Nephroblastoma overexpressed gene)) family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relatively low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose-dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuates TGF-β signaling by scavenging TGF-β thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. Conclusion: In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy.