ABSTRACT
Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Receptors, Virus , Ursodeoxycholic Acid , Animals , Humans , Mice , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/prevention & control , Receptors, Virus/genetics , Receptors, Virus/metabolism , Retrospective Studies , SARS-CoV-2/metabolism , COVID-19 Drug Treatment , Cricetinae , Transcription, Genetic , Ursodeoxycholic Acid/pharmacology , Lung/drug effects , Lung/metabolism , Organoids/drug effects , Organoids/metabolism , Liver/drug effects , Liver/metabolism , Nasal Mucosa/drug effects , Nasal Mucosa/metabolism , Registries , Reproducibility of Results , Liver TransplantationABSTRACT
A borderline Schwann cell tumour with common bile duct compression and jaundice is extremely rare. This paper presents the first report in the Italian literature of a hepatojejunostomy for a symptomatic lesion midway between benign and malignant.
Subject(s)
Bile Duct Neoplasms/surgery , Common Bile Duct , Neurilemmoma/surgery , Anastomosis, Roux-en-Y , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/pathology , Cholangiography , Common Bile Duct/diagnostic imaging , Common Bile Duct/pathology , Common Bile Duct/surgery , Female , Follow-Up Studies , Humans , Jejunum/surgery , Liver/diagnostic imaging , Middle Aged , Neurilemmoma/diagnosis , Neurilemmoma/diagnostic imaging , Neurilemmoma/pathology , Tomography, X-Ray ComputedABSTRACT
Lab-scale tests were set up to investigate different options for achieving sustainability by reducing long-term landfill emissions. The options which have been studied and compared with the traditional anaerobic landfill for unprocessed refuse were: mechanical-biological pretreatment, landfill aeration with forced and with natural advective air flow (semi-aerobic), flushing. Combination of different options have been experimented. The combination of mechanical-biological Pretreatment, Aeration by the semi-aerobic method and Flushing (PAF model) seems to synergize the advantages of the individual options. The research is ongoing and further studies are necessary in order to assess the full-scale applicability of the model.
