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1. Introduction The global burden of liver diseases is responsible for 2 million deaths in a year, of which 1 million are due to liver cirrhosis, an end-stage liver disease, [...], Liver fibrosis is a typical pathological state/stage involved in most chronic liver diseases and its persistence results in cirrhosis. Inflammasomes are cytoplasmic sensors that induce inflammation in response to stress. Glibenclamide (GLB) is an USFDA-approved drug for type 2 diabetes and is reported to possess anti-inflammatory activity by inhibiting inflammatory cytokines. Dimethyl fumarate (DMF) is an USFDA-approved drug for multiple sclerosis and has been reported to activate the Nrf2/ARE pathway to maintain the cellular antioxidant balance. A total of 36 rats were randomized into six groups (n = 6 each). The rats were injected with thioacetamide (TAA) 200 mg/kg, intraperitoneally every third day for eight consecutive weeks to induce liver fibrosis and oral treatment of GLB 0.5 mg/kg/day and DMF 25 mg/kg/day, and their combinations were provided for the last four consecutive weeks. Treatment with GLB, DMF, and GLB+DMF significantly protected against TAA-mediated oxidative stress and inflammatory conditions by improving hepatic function test, triglycerides, hydroxyproline, and histopathological alterations, by inhibiting the NLRP3 inflammasome signaling and fibrogenic markers, and by activating Nrf2/ARE pathway in Wistar rats. The present results suggest that simultaneous Nrf2/ARE activation and NLRP3 inflammasome inhibition could significantly contribute to developing a novel therapy for patients with liver fibrosis. Key words: liver fibrosis, thioacetamide, glibenclamide, dimethyl fumarate, NLRP3

Mariana Noto Guillen Human history was forever changed with the discovery of antibiotics in 1928. Diseases such as pneumonia, tuberculosis, and sepsis were widespread and lethal until antibiotics made them [...]

Introduction Diabetes mellitus is the leading cause of end-stage kidney disease worldwide (Diabetic Kidney Disease 2021). Until 2019, the only known efficacious therapies for diabetic kidney disease (DKD) were renin [...], Two recent clinical trials, using sodium glucose cotransporter (SGLT2) or endothelin-A receptor (ET-A) blocker, reported the first efficacious treatments in 18 years to slow progression of diabetic kidney disease (DKD). We hypothesized that combined inhibition of SGLT2 and ET-A receptor may confer greater protection against renal injury than either agent alone. Uninephrectomized male db/db mice were randomized to four groups: vehicle, SGLT2 inhibitor (dapagliflozin (dapa), 1 mg/kg/day), ET-A blocker (atrasentan (atra), 5 mg/kg/day), or dual treatment from 10 weeks until 22 weeks of age. At 10 weeks of age, no differences were observed in body weight, blood glucose or urinary albumin excretion among the four groups. At 16 and 22 weeks of age, body weight was lower and blood glucose levels higher in the vehicle and atra groups compared with dapa- and dualtreated groups. No notable differences were observed among the four groups in urinary albumin excretion at weeks 16 and 22. Histological analysis showed mild glomerulosclerosis and tubular injury ( Key words: diabetic kidney disease, SGLT2, endothelin-A receptor, combined therapy A l&apos;aide d&apos;inhibiteurs du cotransporteur sodium-glucose (SGLT2) ou du recepteur A de l&apos;endotheline (ET-A), deux essais cliniques recents ont rapporte les premiers traitements efficaces permettant de ralentir l&apos;evolution de l&apos;insuffisance renale diabetique depuis 18 ans. Nous avons formule une hypothese selon laquelle l&apos;inhibition combinee du SGLT2 et des recepteurs ET-A pourrait apporter une meilleure protection contre les lesions renales que chacun des agents pris isolement. Nous avons reparti des souris db/db males nephrectomisees unilateralement dans 4 groupes : vehicule, dapa (dapaglifozine comme inhibiteur du SGLT2 a 1 mg/kg/jour), atra (atrasentane comme inhibiteur des recepteurs ET-A a 5 mg/kg/jour) ou traitement d&apos;association de l&apos;age de 10 a 22 semaines. A l&apos;age de 10 semaines, nous n&apos;avons observe aucune difference entre les 4 groupes en matiere de masse corporelle, de glycemie ou d&apos;excretion urinaire d&apos;albumine. Aux ages de 16 et de 22 semaines, la masse corporelle etait moins elevee et la glycemie etait plus elevee dans les groupes vehicule et atra que dans le groupe dapa et avec le traitement d&apos;association. Aux semaines 16 et 22, nous n&apos;avons pas observe de difference marquee entre les 4 groupes quant a l&apos;excretion urinaire d&apos;albumine. L&apos;etude histologique a revele la presence d&apos;une legere sclerose glomerulaire et de legeres lesions tubulaires (< 5 %) dans chacun des 4 groupes, malgre une sclerose glomerulaire moins importante avec le traitement d&apos;association qu&apos;avec le vehicule. Dans ce modele, les inhibiteurs du SGLT2 et/ou des recepteurs ET-A n&apos;avaient pas d&apos;effets nephropotecteurs isolement ou en association l&apos;un avec l&apos;autre. [Traduit par la Redaction] Mots-cles : insuffisance renale diabetique, SGLT2, recepteurs A de l&apos;endotheline, traitement d&apos;association

Author(s): Jessica Sook Yuin Ho [sup.1] , Zeyu Zhu [sup.1] , Ivan Marazzi [sup.1] [sup.2] Author Affiliations: (1) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, [...], Unlike the human genome that comprises mostly noncoding and regulatory sequences, viruses have evolved under the constraints of maintaining a small genome size while expanding the efficiency of their coding and regulatory sequences. As a result, viruses use strategies of transcription and translation in which one or more of the steps in the conventional gene-protein production line are altered. These alternative strategies of viral gene expression (also known as gene recoding) can be uniquely brought about by dedicated viral enzymes or by co-opting host factors (known as host dependencies). Targeting these unique enzymatic activities and host factors exposes vulnerabilities of a virus and provides a paradigm for the design of novel antiviral therapies. In this Review, we describe the types and mechanisms of unconventional gene and protein expression in viruses, and provide a perspective on how future basic mechanistic work could inform translational efforts that are aimed at viral eradication. This Review outlines the gene and protein expression strategies used by viruses to expand the efficiency of their coding and regulatory sequences, and the implications of these mechanisms for developing antiviral agents.

Author(s): Cristina Lorenzo [sup.1] , Pilar Delgado [sup.1] [sup.6] , Christian E. Busse [sup.2] , Alejandro Sanz-Bravo [sup.1] , Inmaculada Martos-Folgado [sup.1] , Elena Bonzon-Kulichenko [sup.3] [sup.4] , Alessia Ferrarini [...], Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies.sup.1,2, and there is a connection between atherosclerosis and autoimmunity.sup.3. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood.sup.3-5. Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr.sup.-/- and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr.sup.-/- mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD. An autoantibody found in a mouse model of atherosclerosis recognizses ALDH4A1, and infusion of the antibody delays plaque formation in mice.

Author(s): Karuna Ganesh [sup.1] [sup.2] , Joan Massagué [sup.3] Author Affiliations: (1) Molecular Pharmacology Program, Sloan Kettering Institute, New York, USA (2) Department of Medicine, Memorial Hospital, New York, USA [...], Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes. Increased understanding of the biology of metastases allows improved targeting and outcomes for patients with both micro- and macrometastases.

Author(s): Jingyun Yang [sup.1] , Wei Wang [sup.1] , Zimin Chen [sup.1] , Shuaiyao Lu [sup.2] , Fanli Yang [sup.1] , Zhenfei Bi [sup.1] , Linlin Bao [sup.3] , Fei [...], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells.sup.1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain. A recombinant vaccine that targets the receptor-binding domain of the spike protein of SARS-CoV-2 induces a potent antibody response in immunized mice, rabbits and non-human primates, and protects primates from infection with the virus.

Author(s): Toni K. Choueiri [sup.1] , William G. Kaelin Jr [sup.1] [sup.2] Author Affiliations: (1) Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, USA (2) Howard [...], Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2[alpha] inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2[alpha]-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers. Anticancer therapies that target the HIF oxygen-sensing pathways are moving into the clinic, in particular in kidney cancer.