Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

An overview on recent patents and technologies on nanoparticles for nucleic acid delivery.

INTRODUCTION: Nucleic acid-based therapeutics offer groundbreaking potential for treating genetic diseases and advancing next-generation vaccines. Despite their promise, challenges in efficient delivery persist due to the properties of nucleic acids. Nanoparticles (NPs) serve as vital carriers, facilitating effective delivery to target cells, and addressing these challenges. Understanding the global landscape of patents in this field is essential for fostering innovation and guiding decision-making for researchers, the pharmaceutical industry, and regulatory agencies. AREAS COVERED: This review provides a comprehensive overview of patent compositions, applications, and manufacturing aspects concerning NPs as nucleic acid delivery systems. It delves into temporal trends, protection locations, market dynamics, and the most influential technological domains. In this work, we provide valuable insights into the advancements and potential of NP-based nucleic acid delivery systems, with a special focus on their pivotal role in advancing cutting-edge therapeutic solutions. EXPERT OPINION: Investment in NPs for nucleic acid delivery has significantly surged in recent years. However, translating these therapies into clinical practice faces obstacles, including the need for robust clinical evidence, regulatory compliance, and streamlined manufacturing processes. To address these challenges, our review article summarizes recent advances. We aim to engage researchers worldwide in the development of these promising technologies.

Head-to-Head Intra-Individual Comparison of Biodistribution and Tumor Uptake of [18F]FAPI-74 with [18F]FDG in Patients with PDAC: A Prospective Exploratory Study.

BACKGROUND: Radiolabeled fibroblast activation protein (FAP) ligands, a novel class of tracers for PET/CT imaging, have demonstrated very promising results in various oncological, as well as in some benign, diseases with long-term potential to supplant the current pan-cancer agent [18F]FDG in some cancer types. Pancreatic ductal carcinoma (PDAC) belongs to the group of epithelial malignancies with a strong so-called "desmoplastic reaction", leading to a prominent tumor stroma with cancer-associated fibroblasts that exhibit a marked overexpression of fibroblast activation protein (FAP). The first clinical experiences in PDAC with 68Ga-labeled FAP ligands suggested superior sensitivity to [18F]FDG. However, there is limited data with 18F-labeled FAP derivatives, i.e. [18F]FAPI-74, yet prospective single- and multicenter trials are already ongoing. In this proof-of-concept study, we sought to evaluate the biodistribution, tumor uptake, and lesion detectability in patients with PDAC using [18F]FAPI-74 PET/CT as compared to [18F]FDG PET/CT scans for staging. METHODS: This study includes 7 patients (median age 69) who underwent both [18F]FDG PET/CT with contrast-enhancement and [18F]FAPI-74 PET with low-dose CT for primary staging (n = 3) and therapy response control after neoadjuvant (n = 1) or re-staging after palliative therapy (n = 3). The mean interval between PET scans was 11 ± 4 days (range 1-15 days). The [18F]FDG and [18F]FAPI-74 PET/CT scans were acquired at 64 ± 4.1 min (range 61-91 min) and 66.4 ± 6.3 min (range 60-76 min), respectively, after administration of 200 ± 94 MBq (range 79-318 MBq) and 235 ± 88 MBq (range 90-321 MBq), respectively. Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. RESULTS: Overall, 32 lesions were detected in 7 patients including primary (n = 7), lung (n = 7), bone (n = 3), lymph node (n = 13), and peritoneal metastases (n = 2). [18F]FAPI-74 detected 22% more lesions compared with [18F]FDG with a better TBR and visual lesion delineation. In one patient the primary lesion could be detected unequivocally with [18F]FAPI-74 but was missed by [18F]FDG imaging. Altogether, most of the lesions demonstrated markedly elevated uptake of [18F]FAPI-74 with a simultaneous lower uptake in the background, providing a very high visual contrast. CONCLUSION: To the best of our knowledge, this is the first, prospective, intra-individual investigation comparing [18F]FAPI-74 with [18F]FDG imaging in PDAC with encouraging results. These pivotalresults supporta larger, multicentric, prospective study to determine the value of [18F]FAPI-74 in detecting and staging PDAC in comparison with current standard of care imaging.

c-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer's disease.

Background: Growing evidence suggests that the non-receptor tyrosine kinase, c-Abl, plays a significant role in the pathogenesis of Alzheimer's disease (AD). Here, we analyzed the effect of c-Abl on the cognitive performance decline of APPSwe/PSEN1ΔE9 (APP/PS1) mouse model for AD. Methods: We used the conditional genetic ablation of c-Abl in the brain (c-Abl-KO) and pharmacological treatment with neurotinib, a novel allosteric c-Abl inhibitor with high brain penetrance, imbued in rodent's chow. Results: We found that APP/PS1/c-Abl-KO mice and APP/PS1 neurotinib-fed mice had improved performance in hippocampus-dependent tasks. In the object location and Barnes-maze tests, they recognized the displaced object and learned the location of the escape hole faster than APP/PS1 mice. Also, APP/PS1 neurotinib-fed mice required fewer trials to reach the learning criterion in the memory flexibility test. Accordingly, c-Abl absence and inhibition caused fewer amyloid plaques, reduced astrogliosis, and preserved neurons in the hippocampus. Discussion: Our results further validate c-Abl as a target for AD, and the neurotinib, a novel c-Abl inhibitor, as a suitable preclinical candidate for AD therapies.

c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease.

Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lowers sphingomyelin accumulation in NPA patient fibroblasts and NPA neuronal models and 3) chronic treatment with nilotinib and neurotinib, two c-Abl inhibitors with differences in blood-brain barrier penetrance and target binding mode, show further benefits. While nilotinib treatment reduces neuronal death in the cerebellum and improves locomotor functions, neurotinib decreases glial activation, neuronal disorganization, and loss in hippocampus and cortex, as well as the cognitive decline of NPA mice. Our results support the participation of c-Abl signaling in NPA neurodegeneration and autophagy-lysosomal alterations, supporting the potential use of c-Abl inhibitors for the clinical treatment of NPA patients.

Study of the Epidemiological Profile of Tuberculosis and Coinfection of HIV-Seropositive Patients in a Reference Hospital in the State of Alagoas / Estudo do Perfil Epidemiológico da Tuberculose e Coinfecção de Pacientes Soropositivos para HIV em Hospital de Referência no Estado de Alagoas

Abstract Tuberculosis is a disease that has affected the population for more than centuries, it is caused by Mycobacterium tuberculosis with high incidence and prevalence in the population. In Brazil, active tuberculosis is the condition with the greatest impact on mortality in people living with the human immunodeficiency virus, since this part of the population is more likely to develop the disease. In this sense, in order to elucidate the epidemiological profile of patients coinfected with Tuberculosis/HIV, a retrospective study was carried out with a quantitative approach in a referral hospital in the care of these patients in the State of Alagoas. 956 cases of tuberculosis and HIV co-infection were reported, with a higher incidence in males (63.49%), in mixed race (82.42%) and in the age group corresponding to the economically active population, between 21 and 50 years (84,.08%). In addition, the pulmonary clinical form (73.95%) is predominant among the cases, with the peripheral lymph node (32.12%) being the most frequent among the extrapulmonary forms (19.87%). Regarding the clinical outcome of these patients, it was observed that there was a higher rate of treatment drop-out in patients reported with alcoholism, consequently reducing the cure rate of these patients. Therefore, it is evident that socioeconomic variables directly influence the incidence and outcome of patients co-infected with Tuberculosis/HIV and that despite the therapeutic advances and the existing support network, it is still a disease that generates negative impacts on the social development of the country. (AU)

Resumo A tuberculose é uma enfermidade que afeta a população há mais de séculos, é causada pelo Mycobacterium tuberculosis apresentando elevada incidência e prevalência na população. No Brasil, a tuberculose ativa é a condição de maior impacto na mortalidade em pessoas que vivem com o vírus da imunodeficiência humana, já que essa parcela da população apresenta uma maior probabilidade de desenvolver a doença. Nesse sentindo, a fim de elucidar o perfil epidemiológico dos pacientes coinfectados com Tuberculose/HIV, realizou-se um estudo retrospectivo com abordagem quantitativa em um hospital de referência no atendimento destes pacientes no Estado de Alagoas. Foram notificados 956 casos de coinfecção tuberculose e HIV, apresentando maior incidência no sexo masculino (63,49%), na cor parda (82,42%) e na faixa etária correspondente a população economicamente ativa, entre 21 e 50 anos (84,08%). Além disso, a forma clínica pulmonar (73,95%) é predominante dentre os casos, sendo a ganglionar periférica (32,12%) a mais incidente entre as formas extrapulmonares (19,87%). Em relação ao desfecho clínico desses pacientes, observou-se que houve uma maior taxa de abandono do tratamento em pacientes notificados com agravo por alcoolismo, reduzindo consequentemente a taxa de cura destes pacientes. Portanto, fica evidente que variáveis socioeconômicas influenciam diretamente na incidência e no desfecho de pacientes coinfectados com Tuberculose/HIV e que apesar dos avanços terapêuticos e da rede de suporte já existente, ainda é uma doença que gera impactos negativos para o desenvolvimento social do país. (AU)

Therapeutic effects of dexamethasone-loaded hyaluronan nanogels in the experimental cholestasis.

A major function of the intrahepatic biliary epithelium is bicarbonate excretion in bile. Recent reports indicate that budesonide, a corticosteroid with high receptor affinity and hepatic first pass clearance, increases the efficacy of ursodeoxycholic acid, a choleretic agent, in primary biliary cholangitis patients. We have previously reported that bile ducts isolated from rats treated with dexamethasone or budesonide showed an enhanced activity of the Na+/H+ exchanger isoform 1 (NHE1) and Cl-/HCO3- exchanger protein 2 (AE2) . Increasing the delivery of steroids to the liver may result in three beneficial effects: increase in the choleresis, treatment of the autoimmune or inflammatory liver injury and reduction of steroids' systemic harmful effects. In this study, the steroid dexamethasone was loaded into nanohydrogels (or nanogels, NHs), in order to investigate corticosteroid-induced increased activities of transport processes driving bicarbonate excretion in the biliary epithelium (NHE-1 isoform) and to evaluate the effects of dexamethasone-loaded NHs (NHs/dex) on liver injury induced by experimental cholestatis. Our results showed that NHs and NHs/dex do not reduce cell viability in vitro in human cholangiocyte cell lines. Primary and immortalized human cholangiocytes treated with NHs/dex show an increase in the functional marker expression of NHE1 cholangiocytes compared to control groups. A mouse model of cholangiopathy treated with NHs/dex shows a reduction in markers of hepatocellular injury compared to control groups (NHs, dex, or sham group). In conclusion, we believe that the NHs/dex formulation is a suitable candidate to be investigated in preclinical models of cholangiopathies.

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases.

Autophagy is a "housekeeping" lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

Role of autophagy in cholangiocarcinoma: Pathophysiology and implications for therapy.

Cholangiocarcinoma (CCA) is a malignant tumour of the biliary system that originates from the neoplastic transformation of cholangiocytes. CCA is characterized by late diagnosis and poor outcome, with surgery considered as the last option for management. Autophagy is a physiological lysosomal degradation process, essential for cellular homeostasis and ubiquitous in all eukaryotic cells. Several studies have reported a potential involvement of autophagy in cancer, but it remains unclear whether activation of this process represents a survival mechanism of cancer cells. In the present review, we examine the autophagic process and summarize the current knowledge about the involvement of autophagy in the progression of cancer. The link between autophagy and chemoresistance and the use of autophagic markers in diagnosis are also considered in detail. Preliminary evidence shows that the combination of autophagy modulators (activators or inhibitors) with conventional chemotherapeutic agents offers a possible treatment option against signalling pathways that are hyperactivated or altered in CCA. In vitro evidence suggests that combination of chemotherapy agents, such as cisplatin, under activation or inhibition of autophagic processes, in two different CCA cell lines, may improve chemosensitivity and reduce cell survival, respectively. A deeper understanding of these pathways, in both cancer and non-cancer cells, could unveil possible therapeutic targets to treat CCA patients.

Characterization of an Agarophyton chilense Oleoresin Containing PPARγ Natural Ligands with Insulin-Sensitizing Effects in a C57Bl/6J Mouse Model of Diet-Induced Obesity and Antioxidant Activity in Caenorhabditis elegans.

The biomedical potential of the edible red seaweed Agarophyton chilense (formerly Gracilaria chilensis) has not been explored. Red seaweeds are enriched in polyunsaturated fatty acids and eicosanoids, which are known natural ligands of the PPARγ nuclear receptor. PPARγ is the molecular target of thiazolidinediones (TZDs), drugs used as insulin sensitizers to treat type 2 diabetes mellitus. Medical use of TZDs is limited due to undesired side effects, a problem that has triggered the search for selective PPARγ modulators (SPPARMs) without the TZD side effects. We produced Agarophyton chilense oleoresin (Gracilex®), which induces PPARγ activation without inducing adipocyte differentiation, similar to SPPARMs. In a diet-induced obesity model of male mice, we showed that treatment with Gracilex® improves insulin sensitivity by normalizing altered glucose and insulin parameters. Gracilex® is enriched in palmitic acid, arachidonic acid, oleic acid, and lipophilic antioxidants such as tocopherols and ß-carotene. Accordingly, Gracilex® possesses antioxidant activity in vitro and increased antioxidant capacity in vivo in Caenorhabditis elegans. These findings support the idea that Gracilex® represents a good source of natural PPARγ ligands and antioxidants with the potential to mitigate metabolic disorders. Thus, its nutraceutical value in humans warrants further investigation.

Insulin resistance and liver histopathology in metabolically unhealthy subjects do not correlate with the hepatic abundance of NLRP3 inflammasome nor circulating IL-1ß levels.

INTRODUCTION: Systemic chronic low-grade inflammation has been linked to insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). NOD-like receptor protein 3 (NLRP3) inflammasome and its final product, interleukin (IL)-1ß, exert detrimental effects on insulin sensitivity and promote liver inflammation in murine models. Evidence linking hepatic NLRP3 inflammasome, systemic IR and NASH has been scarcely explored in humans. Herein, we correlated the hepatic abundance of NLRP3 inflammasome components and IR and NASH in humans. RESEARCH DESIGN AND METHODS: Metabolically healthy (MH) (n=11) and metabolically unhealthy (MUH) (metabolic syndrome, n=21, and type 2 diabetes, n=14) subjects were recruited. Insulin sensitivity (homeostatic model assessment of IR (HOMA-IR) and Oral Glucose Sensitivity (OGIS120)), glycemic (glycated hemoglobin), and lipid parameters were determined by standard methods. Plasma cytokines were quantified by Magpix. Hepatic NLRP3 inflammasome components were determined at the mRNA and protein levels by reverse transcription-quantitative PCR and western blot, respectively. Liver damage was assessed by histological analysis (Non-alcoholic Fatty Liver Disease Activity Score (NAS) and Steatosis, Inflammatory Activity, and Fibrosis (SAF) scores). IR and liver histopathology were correlated with NLRP3 inflammasome components as well as with liver and plasma IL-1ß levels. RESULTS: Body Mass Index, waist circumference, and arterial hypertension frequency were significantly higher in MUH subjects. These patients also had increased high-sensitivity C reactive protein levels compared with MH subjects. No differences in the plasma levels of IL-1ß nor the hepatic content of Nlrp3, apoptosis-associated speck-like (Asc), Caspase-1, and IL-1ß were detected between MUH and MH individuals. MUH subjects had significantly higher NAS and SAF scores, indicating more severe liver damage. However, histological severity did not correlate with the hepatic content of NLRP3 inflammasome components nor IL-1ß levels. CONCLUSION: Our results suggest that NLRP3 inflammasome activation is linked neither to IR nor to the inflammatory status of the liver in MUH patients.

Gut-Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology.

The Nlrp3 inflammasome is a multiprotein complex activated by a number of bacterial products or danger signals and is involved in the regulation of inflammatory processes through caspase-1 activation. The Nlrp3 is expressed in immune cells but also in hepatocytes and cholangiocytes, where it appears to be involved in regulation of biliary damage, epithelial barrier integrity and development of fibrosis. Activation of the pathways of innate immunity is crucial in the pathophysiology of hepatobiliary diseases, given the strong link between the gut and the liver. The liver secretes bile acids, which influence the bacterial composition of the gut microbiota and, in turn, are heavily modified by microbial metabolism. Alterations of this balance, as for the development of dysbiosis, may deeply influence the composition of the bacterial products that reach the liver and are able to activate a number of intracellular pathways. This alteration may be particularly important in the pathogenesis of cholangiopathies and, in particular, of primary sclerosing cholangitis, given its strong association with inflammatory bowel disease. In the present review, we summarize current knowledge on the gut-liver axis in cholangiopathies and discuss the role of Nlrp3 inflammasome activation in cholestatic conditions.

Aging and the Biological Response to Liver Injury.

Interest in understanding the aging process has recently risen in the scientific community. Aging, commonly defined as the functional decline in the function of organs and tissues, is indeed the major risk factor for the development of many chronic diseases, such as cardiovascular diseases, pathologies of nervous system, or cancer. To date, the influence of aging in the pathophysiology of liver and biliary diseases is not fully understood. Although liver cells have a high regenerative capacity, hepatocytes and cholangiocytes undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, liver cells initially activate compensatory mechanisms that, if hyperstimulated, may lead to the decline of regenerative capacity and the development of pathologies. A deeper understanding of molecular aging has undoubtedly the potential to improve the clinical management of patients, possibly unveiling new pathways for selective drug treatment.

Guidelines of the Brazilian Society of Oncologic Surgery for pelvic exenteration in the treatment of cervical cancer.

BACKGROUND AND OBJECTIVES: The primary treatment for locally advanced cases of cervical cancer is chemoradiation followed by high-dose brachytherapy. When this treatment fails, pelvic exenteration (PE) is an option in some cases. This study aimed to develop recommendations for the best management of patients with cervical cancer undergoing salvage PE. METHODS: A questionnaire was administered to all members of the Brazilian Society of Surgical Oncology. Of them, 68 surgeons participated in the study and were divided into 10 working groups. A literature review of studies retrieved from the National Library of Medicine database was carried out on topics chosen by the participants. These topics were indications for curative and palliative PE, preoperative and intraoperative evaluation of tumor resectability, access routes and surgical techniques, PE classification, urinary, vaginal, intestinal, and pelvic floor reconstructions, and postoperative follow-up. To define the level of evidence and strength of each recommendation, an adapted version of the Infectious Diseases Society of America Health Service rating system was used. RESULTS: Most conducts and management strategies reviewed were strongly recommended by the participants. CONCLUSIONS: Guidelines outlining strategies for PE in the treatment of persistent or relapsed cervical cancer were developed and are based on the best evidence available in the literature.

Aging-Related Molecular Pathways in Chronic Cholestatic Conditions.

Aging is commonly defined as the time-dependent functional decline of organs and tissues. Average life expectancy has increased considerably over the past century and is estimated to increase even further, consequently also the interest in understanding the aging processes. Although aging is not a disease, it is the major risk factor for the development of many chronic diseases. Pathologies, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) are cholestatic liver diseases characterized by chronic inflammation, biliary damage and ultimately liver fibrosis, targeting specifically cholangiocytes. To date, the influence of aging in these biliary diseases is not fully understood. Currently, liver transplantation is the only solution because of lacking in efficiently therapies. Although liver cells have a high regenerative capacity, they undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, the cells initially activate protective compensatory processes that, if hyperstimulated, can lead to the decline of regenerative ability and the development of pathologies. Recent studies have introduced novel therapeutic tools for cholangiopathies that have showed to have promising potential as novel therapies for PSC and PBC and for the development of new drugs. The recent advancements in understanding of molecular aging have undoubtedly the potential to unveil new pathways for selective drug treatments, but further studies are needed to deepen their knowledge.

Aging-Related Expression of Twinfilin-1 Regulates Cholangiocyte Biological Response to Injury.

Disorders of the biliary tree develop and progress differently according to patient age. It is currently not known whether the aging process affects the response to injury of cholangiocytes. The aim of this study was to identify molecular pathways associated with cholangiocyte aging and to determine their effects in the biological response to injury of biliary cells. A panel of microRNAs (miRs) involved in aging processes was evaluated in cholangiocytes of young and old mice (2 months and 22 months of age, respectively) and subjected to a model of sclerosing cholangitis. Intracellular pathways that are common to elevated miRs were identified by in silico analysis. Cell proliferation and senescence were evaluated in Twinfilin-1 (Twf1) knocked-down cells. In vivo, senescence-accelerated prone mice (Samp8, a model for accelerated aging), Twf1-/- , or their respective controls were subjected to DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine). Cholangiocytes from DDC-treated mice showed up-regulation of a panel of aging-related miRs. Twf1 was identified by in silico analysis as a common target of the up-regulated miRs. Twf1 expression was increased both in aged and diseased cholangiocytes, and in human cholangiopathies. Knock-down of Twf1 in cholangiocytes reduced cell proliferation. Senescence and senescence-associated secretory phenotype marker expression increased in Twf1 knocked-down cholangiocytes following pro-proliferative and pro-senescent (10-day lipopolysaccharide) stimulation. In vivo, Samp8 mice showed increased biliary proliferation, fibrosis, and Twf1 protein expression level, whereas Twf1-/- had a tendency toward lower biliary proliferation and fibrosis following DDC administration compared with control animals. Conclusion: We identified Twf1 as an important mediator of both cholangiocyte adaptation to aging processes and response to injury. Our data suggest that disease and aging might share common intracellular pathways.

Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies.

Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.

Hepatic peroxisome proliferator-activated receptor γ coactivator 1ß drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice.

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1ß (PGC-1 ß) is a master regulator of mitochondrial biogenesis and oxidative metabolism as well as of antioxidant defense. Specifically, in the liver, PGC-1ß also promotes de novo lipogenesis, thus sustaining cellular anabolic processes. Given the relevant pathogenic role of mitochondrial and fatty acid metabolism in hepatocarcinoma (HCC), here we pointed to PGC-1ß as a putative novel transcriptional player in the development and progression of HCC. For this purpose, we generated both hepatic-specific PGC-1ß-overexpressing (LivPGC-1ß) and PGC-1ß knockout (LivPGC-1ßKO) mice, and we challenged them with both chemical and genetic models of hepatic carcinogenesis. Our results demonstrate a pivotal role of PGC-1ß in driving liver tumor development. Indeed, whereas mice overexpressing PGC-1ß show greater tumor susceptibility, PGC-1ß knockout mice are protected from carcinogenesis. High levels of PGC-1ß are able to boost reactive oxygen species (ROS) scavenger expression, therefore limiting the detrimental ROS accumulation and, consequently, apoptosis. Moreover, it supports tumor anabolism, enhancing the expression of genes involved in fatty acid and triglyceride synthesis. Accordingly, the specific hepatic ablation of PGC-1ß promotes the accumulation of ROS-driven macromolecule damage, finally limiting tumor growth. CONCLUSION: The present data elect hepatic PGC-1ß as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. (Hepatology 2018;67:884-898).

Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology.

Cholangiocytes, the epithelial cells lining the bile ducts, are an important subset of liver cells. They are involved in the modification of bile volume and composition, and respond to endogenous and exogenous stimuli. Along the biliary tree, two different kinds of cholangiocytes exist: small and large cholangiocytes. Each type has different features and biological role in physiologic and pathologic conditions, and their immunobiology is important for understanding biliary diseases. Cholangiocytes provide the first line of defence against luminal microbes in the hepatobiliary system. Indeed, they express a variety of pattern recognition receptors and may start an antimicrobial defence activating a set of intracellular signalling cascades. In response to injury, cholangiocytes that are normally quiescent become reactive and acquire a neuroendocrine-like phenotype with the release of proinflammatory mediators and antimicrobial peptides, which support biliary epithelial integrity. These molecules act in an autocrine/paracrine manner to modulate cholangiocyte biology and determine the evolution of biliary damage. Failure or dysregulation of such mechanisms may influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. In this review, we focus on the response of cholangiocytes in inflammatory conditions, with a particular focus on the mechanism driving cholangiocytes adaptation to damage. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Author Correction: Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.