Nicotinamide riboside or IL-17A signaling blockers to prevent liver disorders

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Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing.

Enteroviruses are suspected to contribute to insulin-producing β cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting β cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in β cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in β cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the β cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes.Human diabetic pancreatic samples and data were obtained from the CNIO Biobank thanks to the help of Maria-Jesus Artiga and from Biobanc-Mur, MarBiobank, Vasque Biobank, and Andalusian Public Health System Biobank, integrated in the Spanish Biobank Network and funded by Instituto de Salud Carlos III. We are also thankful to the Biobank of IDIBAPS, Barcelona, for providing samples to A.N. Samples were processed following standard operating procedures with the appropriate approval of the Ethics and Scientific Committees. We also thank the CNIO Mouse Genome Editing Core Unit as well as the CNIO Genomics Unit for their support. We are also thankful to Dr. K. Qvortrup (University of Copenhagen, Denmark) for the electron microscopy. This work was funded by grant to J.P.W. supported by the National Institutes of Health NIAID/NIDDK R01 AI116920, and by grants to N.D. supported by the EFSD/JRDF/Lilly Programme through the European Foundation for the Study of Diabetes (EFSD) and and by the State Research Agency (AEI, 10.13039/501100011033) from the Spanish Ministry of Science and Innovation (projects SAF2016-76598-R, SAF2017-92733-EXP, and RTI2018-094834-B-I00) through the European Regional Development Fund (ERDF). This work was developed at the CNIO, which is funded by the Health Institute Carlos III (ISCIII) and the Spanish Ministry of Science and Innovation.S

Endogenous retroviruses shape pluripotency specification in mouse embryos.

The smooth and precise transition from totipotency to pluripotency is a key process in embryonic development, generating pluripotent stem cells capable of forming all cell types. While endogenous retroviruses (ERVs) are essential for early development, their precise roles in this transition remains mysterious. Using cutting-edge genetic and biochemical techniques in mice, we identify MERVL-gag, a retroviral protein, as a crucial modulator of pluripotent factors OCT4 and SOX2 during lineage specification. MERVL-gag tightly operates with URI, a prefoldin protein that concurs with pluripotency bias in mouse blastomeres, and which is indeed required for totipotency-to-pluripotency transition. Accordingly, URI loss promotes a stable totipotent-like state and embryo arrest at 2C stage. Mechanistically, URI binds and shields OCT4 and SOX2 from proteasome degradation, while MERVL-gag displaces URI from pluripotent factor interaction, causing their degradation. Our findings reveal the symbiotic coevolution of ERVs with their host cells to ensure the smooth and timely progression of early embryo development.acknowledgments: We thank all mouse providers as described in Materials and Methods. We also thank the cniO Animal Facility for mouse maintenance. We acknowledge M. Ko (Keio University, Systems Medicine, Japan) for providing the pZscan4- emerald reporter plasmid. Funding: S.d.l.R. was supported by a fellowship from the comunidad de Madrid and by funds from the Severo Ochoa- cniO. this work was funded by grants to n.d. supported by the State Research Agency (Aei; 10.13039/501100011033) from the Spanish Ministry of Science and innovation (Rti2018- 094834- B- i00 and Pid2021- 122695OB- i00), also including the idiFFeR network of excellence (Red2022- 134792- t), cofunded by european Regional development Fund (eRdF), by the comunidad Autónoma de Madrid (S2017/BMd- 3817), and by the Asociación española contra el cáncer (Aecc) (PRYGn211184dJOU). this work was developed at the cniO funded by the health institute carlos iii (iSciii) and the Spanish Ministry of Science and innovation. Author contributions: S.d.l.R. designed and performed the experiments and analyzed all the data. S.d.l.R. analyzed all the bioinformatics data. M.d.M.R. performed some experiments. P.v. and S.O. performed microinjection in vivo and chimera embryo assay. S.d.l.R and n.d. developed the project and wrote the manuscript. n.d. conceived the project and secured funding. Competing interests:the authors declare that they have no competing interests. Data and materials availability: All data are available in the main text or Materials and Methods. Materials are available upon request to n.d. and the sharing of materials described in this work will be subject to standard material transfer agreementsS

Coxsackievirus B Type 4 Infection in beta Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing

Enteroviruses are suspected to contribute to insulin-producing beta cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting beta cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in beta cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in beta cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the beta cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

A comprehensive analysis of prefoldins and their implication in cancer.

Prefoldins (PFDNs) are evolutionary conserved co-chaperones, initially discovered in archaea but universally present in eukaryotes. PFDNs are prevalently organized into hetero-hexameric complexes. Although they have been overlooked since their discovery and their functions remain elusive, several reports indicate they act as co-chaperones escorting misfolded or non-native proteins to group II chaperonins. Unlike the eukaryotic PFDNs which interact with cytoskeletal components, the archaeal PFDNs can bind and stabilize a wide range of substrates, possibly due to their great structural diversity. The discovery of the unconventional RPB5 interactor (URI) PFDN-like complex (UPC) suggests that PFDNs have versatile functions and are required for different cellular processes, including an important role in cancer. Here, we summarize their functions across different species. Moreover, a comprehensive analysis of PFDNs genomic alterations across cancer types by using large-scale cancer genomic data indicates that PFDNs are a new class of non-mutated proteins significantly overexpressed in some cancer types.The results published in this study are in part based on data generated by The Cancer Genome Atlas project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at https://cancergenome.nih.gov/.We also acknowledge the Genotype-Tissue Expression (GTEx) program. This work was funded by the State Research Agency (AEI, https://doi.org/10.13039/501100011033) from the Spanish Ministry of Science and Innovation (projects SAF2016-76598-R, SAF2017-92733-EXP, RTI2018-094834-B-I00 and RED2018-102723-T), cofunded by European Regional Development Fund (ERDF). This work was developed at the CNIO funded by the Health Institute Carlos III (ISCIII) and the Spanish Ministry of Science and InnovationS

Boosting NAD(+) for the prevention and treatment of liver cancer.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide yet has limited therapeutic options. We recently demonstrated that inhibition of de novo nicotinamide adenine dinucleotide (NAD(+)) synthesis is responsible for DNA damage, thereby initiating hepatocarcinogenesis. We propose that boosting NAD(+) levels might be used as a prophylactic or therapeutic approach in HCC.ThisworkwassupportedbytheSpanishMinistryofEconomyandCompetitiveness(SAF2010-18518), the Association forInternational Cancer Research AICR-UK(11-0242), CNIO (BC1104-08) and theEuropeanFoundationfortheStudyofDia-betes(EFSD).S

Inflammatory and Non-Inflammatory Mechanisms Controlling Cirrhosis Development.

Because the liver is considered to be one of the most important metabolic organs in the body, it is continuously exposed to damaging environmental agents. Upon damage, several complex cellular and molecular mechanisms in charge of liver recovery and regeneration are activated to prevent the failure of the organ. When liver injury becomes chronic, the regenerative response goes awry and impairs the liver function, consequently leading to cirrhosis, a liver disorder that can cause patient death. Cirrhosis has a disrupted liver architecture and zonation, along with the presence of fibrosis and parenchymal nodules, known as regenerative nodules (RNs). Inflammatory cues contribute to the cirrhotic process in response to chronic damaging agents. Cirrhosis can progress to HCC, the most common and one of the most lethal liver cancers with unmet medical needs. Considering the essential role of inflammatory pathways in the development of cirrhosis, further understanding of the relationship between immune cells and the activation of RNs and fibrosis would guide the design of innovative therapeutic strategies to ameliorate the survival of cirrhotic and HCC patients. In this review, we will summarize the inflammatory mechanisms implicated in the development of cirrhosis.This work was funded by grants to N.D. from the Comunidad Autonoma de Madrid (S2017/BMD-3817) and from the State Research Agency (AEI, 10.13039/501100011033) from the Spanish Ministry of Science and Innovation (projects SAF2017-92733-EXP, RTI2018-094834-B-I00 and RED2018-102723-T). This work was developed at the CNIO, funded by the Health Institute Carlos III (ISCIII) and the Spanish Ministry of Science and Innovation. P.S.S. is a recipient of a FPI fellowship and M.M.R. is a recipient of a FPI-Severo Ochoa fellowship; both fellowships are from the Spanish Ministry of Science and Innovation.S

Cirrhosis: A Questioned Risk Factor for Hepatocellular Carcinoma.

The liver is one of the major metabolic organs in the body, susceptible to injury caused by various factors. In response to injury, sophisticated mechanisms are engaged to repair and regenerate the damaged liver, preventing its failure. When the damage is chronic, regeneration goes awry, impairing liver function and causing cirrhosis. Hence, cirrhosis may rather be a protective response to injury, where wound-healing processes are set to primarily repair the damaged liver. Although cirrhosis is clinically considered a risk factor for hepatocellular carcinoma (HCC), comprehensive population-based studies demonstrate a very modest incidence, refuting the idea that cirrhosis progresses to HCC. Here, we discuss and shed light on the provocative question of whether cirrhosis predisposes to HCC.THis work was funded by the European Foundation for the Study of Diabetes (EFSD) award supported by the EFSD/JRDF/Lilly Programme, the Regional Government of Madrid (project B2017/BMD-3817) cofunded by the European Social Fund (ESF), and the State Research Agency (AEI, 10.13039/501100011033) from the Spanish Ministry of Science and Innovation (projects SAF2016-76598-R, SAF2017-92733-EXP, and RTI2018-094834-B-I00), cofunded by the European Regional Development Fund (ERDF). This work was developed at the CNIO funded by the Health Institute Carlos III (ISCIII) and the Spanish Ministry of Science and Innovation.N

Adaptive survival mechanism to glucose restrictions

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