The Value of Ursodeoxycholic Acid and Mesenchymal Stem Cells in the Treatment of Severe COVID-19.

Objective: The objective of this study was to evaluate the therapeutic efficacy of ursodeoxycholic acid (UDCA) and mesenchymal stem cells (MSCs) in patients with severe COVID-19. Methods: We included severe COVID-19 patients hospitalized at Shulan (Hangzhou) Hospital between December 2022 and June 2023. We used a logistic regression model to compare the use of UDCA and MSCs in the two distinct groups of improved and poor outcomes. It is noteworthy that the deterioration group encompassed instances of both death and abandonment of treatment. The receiver operating characteristic (ROC) curve was plotted to assess the performance of the model. The aim was to assess the therapeutic effect of UDCA and MSCs on the outcome of severe COVID-19 patients. Results: A total of 167 patients with severe COVID-19 were included in this study. The analysis revealed that out of 42 patients (25.1%), 17 patients (10.2%) had taken UDCA, and 17 patients (10.2%) had used MSCs. Following a multivariable logistic regression, the results indicated a negative association between UDCA treatment (OR = 0.38 (0.16-0.91), p = 0.029), MSCs treatment (OR = 0.21 (0.07-0.65), p = 0.007), and the risk of severe COVID-19 mortality. Additionally, age showed a positive association with the risk of mortality (OR = 1.03 (1.01-1.07), p = 0.025). Conclusions: UDCA and MSCs have shown potential in improving the prognosis of severe COVID-19 patients and could be considered as additional treatments for COVID-19 in the future.

Turner syndrome with isochromosome Xq as a cause of granulomatous hepatitis: a case report.

Introduction: Turner syndrome (TS) is the most common sex chromosome abnormality in women, caused by a complete or partial absence of the second sex chromosome. The karyotype 46, X,i(Xq) is the underlying cause in about 10% of the cases of TS. Hepatic abnormalities are frequent in TS. Granulomas are relatively common in liver samples but are very rarely reported in TS. Case presentation: A 15-year-old female with TS attended a consultation for evaluation of elevated liver enzymes. Her chromosomal analysis showed mosaicism 46, X (iso xq)100%. There were no stigmata of chronic liver disease. A liver biopsy showed granulomatous hepatitis. Other causes of hepatic granulomas have been excluded. Ursodeoxycholic acid (UDCA) therapy leads to the normalization of transaminases. Clinical discussion: Although Hepatic involvement is common and mostly asymptomatic in TS, the mechanism of liver injury is not well understood. The hepatic histological changes in these cases are variable and range from minimal abnormalities to nonalcoholic steatohepatitis (NASH), liver architectural changes, and biliary lesions. Hepatic granulomas are associated with a wide range of systemic disorders but are very rarely reported in tuner syndrome. Normalization of liver enzymes after treatment with UDCA was previously reported, but the importance of this approach is to be determined. Conclusion: Granulomatous hepatitis may be associated with TS and may be added to the histological patterns encountered in this disorder.

Probucol-Ursodeoxycholic Acid Otic Formulations: Stability and In Vitro Assessments for Hearing Loss Treatment.

Targeted drug delivery is an ongoing aspect of scientific research that is expanding through the design of micro- and nanoparticles. In this paper, we focus on spray dried microparticles as carriers for a repurposed lipophilic antioxidant (probucol). We characterise the microparticles and quantify probucol prior to assessing cytotoxicity on both control and cisplatin treated hair cells (known as House Ear Institute-Organ of Corti 1; HEI-OC1). The addition of water-soluble polymers to 2% ß-cyclodextrin resulted in a stable probucol formulation. Ursodeoxycholic acid (UDCA) used as formulation excipient increases probucol miscibility and microparticle drug content. Formulation characterisations reveals spray drying results in spherical UDCA-drug microparticles with a mean size distribution of ∼5-12 µm. Probucol microparticles show stable short-term storage conditions accounting for only ∼10% loss over seven days. By mimicking cell culture conditions, both UDCA-probucol (67%) and probucol only (82%) microparticles show drug release in the initial two hours. Furthermore, probucol formulations with or without UDCA preserve cell viability and reduce cisplatin-induced oxidative stress. Mitochondrial bioenergetics results in lower basal respiration and non-mitochondrial respiration, with higher maximal respiration, spare capacity, ATP production and proton leak within cisplatin challenged UDCA-probucol groups. Overall, we present a facile method for incorporating lipophilic antioxidant carriers in polymer-based particles that are tolerated by HEI-OC1 cells and show stable drug release, sufficient in reducing cisplatin-induced reactive oxygen species accumulation.

Evolutionary relationship between antimitochondrial antibody positivity and primary biliary cholangitis in Taiwan: a 16-year hospital cohort study.

Background: How antimitochondrial antibody (AMA)-positive patients evolve to have primary biliary cholangitis (PBC) in viral hepatitis-endemic areas is unknown. Objectives: We aimed to investigate this evolution in Taiwan. Design/methods: A 16-year medical center-based cohort study of 2,095,628 subjects was conducted in Taiwan, an Asian country endemic to viral hepatitis. AMA-positive subjects were those with positive AMA with alkaline phosphatase (ALP) ⩽1.5 times the upper limit of normal (ULN), and PBC was defined as positive AMA with ALP >1.5 × ULN. Results: AMA-positive subjects had a lower average age- and sex-adjusted prevalence than PBC patients (4.68/105 versus 11.61/105, p = 0.0002), but their incidence was comparable (0.99/105 versus 1.12/105, p = 0.36). The former group had a borderline significantly lower mean age (56.59 years versus 58.10 years, p = 0.06) and a lower female-to-male ratio (2.85:1 versus 5.44:1, p < 0.0001). Both AMA-positive subjects (prevalence change: 20.0%, p < 0.01; incidence change: -9.2%, p < 0.01) and PBC patients (prevalence change: 14.6%, p < 0.01; incidence change: -4.7%, p < 0.01) prevalence rate increased but the incidence rate decreased. Among the 423 AMA-positive subjects, 77 (18.2%) developed PBC, for a mean duration of 1.757 years. Compared with AMA-positive subjects, PBC patients had similar concurrent chronic hepatitis B (CHB) rates (2.7% versus 4.3%, p = 0.197) but lower chronic hepatitis C (CHC) rates (3.69% versus 15.60%, p < 0.01). Conclusion: PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects.

Evolutionary relationship between AMA positivity and PBC in Taiwan PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects.

Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron variant by reducing angiotensin-converting enzyme 2.

The SARS-CoV-2 caused COVID-19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS-CoV-2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS-CoV-2 Delta variant infection. UDCA is a well-known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co-housing with an Omicron variant-infected hamster group resulted in spontaneous airborne transmission, the UDCA pre-supplied group was protected from weight loss relative to the non-treated group at 4 days post-infection by more than 5%-10%. Furthermore, UDCA-treated groups had a 3-fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS-CoV-2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug-repositioning of UDCA from liver health supplement to preventive drug of SARS-CoV-2 infection.

Autoantibodes to GP210 are a metric for UDCA responses in primary biliary cholangitis.

Objectives: Antibodies to gp210 and sp100 are specific and unique anti-nuclear autoantibodies (ANAs) associated with primary biliary cholangitis (PBC). Importantly the presence of anti-gp210 and anti-sp100 responses is indicative of poor clinical outcomes. However, the utility of measuring titers of these antibodies remains unclear. Materials and methods: Using the in-house purified gp210 (HSA108-C18) and sp100 (amino acid position 296-386), we quantitatively measured serum autoantibodies to gp210 and sp100 using chemiluminescence immunoassay (CLIA) in a very large cohort of 390 patients with PBC, including 259 cases with no prior ursodesoxycholic acid (UDCA) treatment and 131 cases with UDCA treatment. We also analyzed serial changes in anti-gp210 and anti-sp100 levels in 245 sequential samples from 88 patients. Results: In our cross-sectional analysis, we detected anti-gp210 immunoglobulin G (IgG) and anti-sp100 IgG autoantibodies in 129 out of 390 (33.1%) and 80 out of 390 (20.5%) PBC patients, respectively. Multivariate analysis revealed that serum IgG (st.ß = 0.35, P = 0.003) and gamma-glutamyltransferase (GGT) (st.ß = 0.23, P = 0.042) levels at baseline were independently associated with anti-gp210 concentrations. In serial testing, we observed significant fluctuations in anti-gp210 antibody levels. These fluctuations reflected responsiveness to UDCA therapy, particularly in anti-gp210-positive patients with initially lower concentrations in the stages of disease. Conclusions: Our study reflects that quantitative changes of anti-gp210 antibody are indicative of UDCA responses. There is a great need for newer metrics in PBC and we suggest that a more detailed and longer study of these unique ANAs is warranted.

Ursodeoxycholic acid alleviates atopic dermatitis-associated inflammatory responses in HaCaT and RBL-2H3 cells and DNCB/DFE-treated mice.

AIMS: Ursodeoxycholic acid (UDCA) is a hydrophilic dihydroxy bile acid used for cholestatic liver disease and exhibits antioxidant, antitumor, and anti-inflammatory effects. However, its potential effects on atopic dermatitis (AD) have not been elucidated. This study aimed to evaluate the efficacy of UDCA in inhibiting the inflammatory response and alleviating lesions in AD-like mice. MAIN METHODS: To investigate the efficacy of UDCA in AD-like inflammatory responses, tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-stimulated HaCaT cells and anti-dinitrophenyl immunoglobulin E (DNP-IgE)- and human serum albumin (HSA)-stimulated RBL-2H3 cells were used to investigate the levels of inflammatory factors and their mechanisms. AD-like lesions were induced by applying DNCB/DFE to mice. The effect of UDCA administration in AD-like mice was analyzed by assessing organ weight, serum IgE and inflammatory cytokine levels, and histopathological changes using immunohistochemical and immunofluorescent staining. KEY FINDINGS: In HaCaT cells, UDCA significantly diminished TARC, MDC, MCP-1, and IL-6 expression by inhibiting the phosphorylation of nuclear NF-κB and cytoplasmic IκB, and also increased the levels of skin barrier protein. In RBL-2H3 cells, UDCA reduced ß-hexosaminidase and IL-4 levels. In AD-like mice, UDCA suppressed organ hypertrophy, ear edema, SCORAD index, DFE-specific IgE levels, inflammatory cytokine levels, skin hypertrophy, mast cell invasion, skin barrier loss, and thymic stromal lymphopoietin-positive areas. SIGNIFICANCE: UDCA suppressed the expression of pro-inflammatory cytokines by keratinocytes and mast cells. It also alleviated atopy by suppressing symptoms without organ toxicity in AD-like mice. UDCA may be an effective and safe treatment for AD.

Endoscopic features of low-phospholipid-associated cholelithiasis syndrome: A retrospective cohort study.

BACKGROUND AND OBJECTIVE: LPAC (low phospholipid-associated cholelithiasis) syndrome is a rare genetic form of cholelithiasis. ERCP (endoscopic retrograde cholangiopancreatography) is often used to remove gallstones in the bile duct. No published data is available on the role of ERCP in LPAC syndrome. PATIENTS AND METHODS: In this retrospective cohort study, we included patients diagnosed with LPAC syndrome in a single tertiary referral center between 2009 and 2021. Our aim was to assess the frequency, indications, modalities, results, and complications of ERCP, as well as predictive factors for ERCP, in LPAC syndrome. Independent factors associated with ERCP occurrence were identified using a multivariable Cox regression analysis. RESULTS: ERCP was required in 31.2 % of the 269 patients included for analysis. Among patients who required ERCPs, 78.6 % had the procedure before diagnosis (i.e., starting UDCA). Most common indications were choledocholithiasis (53.6 %) and acute cholangitis (29.5 %). Post ERCP pancreatitis, perforation and bleeding rates were 7.2 %, 2.6 %, and 1.3 %, respectively. Age and history of cholelithiasis in first-degree relatives were associated with a higher risk of ERCP (Hazard-ratio [HR]=1.30 [95 %confidence-interval [CI] 1.04-1.62] and HR=1.88 [95 %CI 1.15-3.07] respectively). Female gender and UDCA intake ≥ 1 year were associated with a lower risk of ERCP (HR=0.49 [95 %CI 0.29-0.82] and HR=0.44 [95 %CI 0.22-0.90] respectively). Median follow-up was 10.8 years. CONCLUSION: One-third of patients with LPAC syndrome undergo sphincterotomy. However, most procedures are performed before diagnosis and UDCA is associated with a lower risk of endoscopic procedure. Earlier diagnosis and treatment with UDCA may further reduce the need for ERCP in patients with LPAC syndrome.

Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.

Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner.

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.

Ursodeoxycholic acid and 18ß-glycyrrhetinic acid alleviate ethinylestradiol-induced cholestasis via downregulating RORγt and CXCR3 signaling pathway in iNKT cells.

Estrogen-induced intrahepatic cholestasis (IHC) is a mild but potentially serious risk and urges for new therapeutic targets and effective treatment. Our previous study demonstrated that RORγt and CXCR3 signaling pathway of invariant natural killer T (iNKT) 17 cells play pathogenic roles in 17α-ethinylestradiol (EE)-induced IHC. Ursodeoxycholic acid (UDCA) and 18ß-glycyrrhetinic acid (GA) present a protective effect on IHC partially due to their immunomodulatory properties. Hence in present study, we aim to investigate the effectiveness of UDCA and 18ß-GA in vitro and verify the accessibility of the above targets. Biochemical index measurement indicated that UDCA and 18ß-GA presented efficacy to alleviate EE-induced cholestatic cytotoxicity. Both UDCA and 18ß-GA exhibited suppression on the CXCL9/10-CXCR3 axis, and significantly restrained the expression of RORγt in vitro. In conclusion, our observations provide new therapeutic targets of UDCA and 18ß-GA, and 18ß-GA as an alternative treatment for EE-induced cholestasis.

Importance of the gut microbiota in mice with a 'humanized' bile acid pool.

Bile acids are signaling mediators, enabling intricate communication between tissues and the gut microbiota, and are involved in the pathophysiology of several immune and metabolic disorders. In this commentary, we discuss the importance of the gut microbiota in the Cyp2c70 knock-out mice, which are considered as a promising 'humanized' experimental resource for studying bile acids and their role in pathological conditions. We also discuss how Cyp2c70-deficient mice contribute to enhancing the translatability of preclinical studies in murine models to humans.

Exploring the impact of ursodeoxycholic acid therapy on COVID-19 in a real-word setting.

Recent data suggest that ursodeoxycholic acid (UDCA) therapy may reduce susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and even improve clinical outcomes when coronavirus disease-2019 (COVID-19) was diagnosed. However, clinical evidence of UDCA's ability to prevent severe forms of COVID-19 remains limited and contradictory. We evaluated the association between UDCA exposure and the risk of hospitalization for COVID-19 in a large multicenter population of patients with chronic liver disease (CLD) followed during the pandemic period before vaccination. An exposed/unexposed cohort study and a nested case-control study were performed. The primary endpoint was severe COVID-19, defined as SARS-CoV2 infection requiring hospitalization. The secondary endpoint was COVID-19-associated intensive care unit (ICU) admission or death. Adjusted odds ratios (aOR) and their confidence intervals (CI) were determined after controlling for age, gender, comorbidities at risk for COVID-19, severity of CLD, and prior hospitalizations. A total of 10 147 patients, including 1322 exposed and 8825 not exposed to UDCA, totaling 21 867 person-years of follow-up, were included in the cohort analysis, while 88 patients hospitalized for COVID-19 and 840 matched controls were eligible for the nested case-control analysis. In both analyses, exposure to UDCA was not associated with a significant reduction in the risk of hospitalization for COVID-19, with aOR (95% confidence interval) values of 0.48 (0.20-1.19) and 0.93 (0.26-3.29), respectively. Furthermore, there was no significant reduction in the risk of ICU admission or death. In this large population of patients with CLD, UDCA exposure was not associated with a reduced risk of severe COVID-19.

Design, synthesis and evaluation of novel UDCA-aminopyrimidine hybrids as ATX inhibitors for the treatment of hepatic and pulmonary fibrosis.

To discover novel anti-fibrotic agents, a series of UDCA-aminopyrimidine hybrids were designed and synthesized as potent ATX inhibitors by molecular hybridization strategy. The ATX inhibitory activities of all synthesized compounds were evaluated using the LPC choline release assay. The preliminary structure-activity relationship was concluded. Among them, 12a and 12h exhibited the strongest ATX inhibitory activities with IC50 values of 7.62 ± 0.62 and 7.51 ± 0.72 nM respectively, which were 9-fold more effective than the positive control drug GLPG-1690. Molecular docking studies revealed that 12a and 12h occupied the hydrophobic pocket and tunnel of the ATX binding site. The cytotoxicity assay of 12a and 12h revealed that they had no obvious toxicity at concentrations up to 80 µM, therefore their anti-hepatic fibrosis and anti-pulmonary fibrosis activities were further investigated. The results suggested that 12a and 12h significantly decreased the gene and protein expression of α-SMA, COL1A1 and FN in both TGF-ß1-induced HSC-LX2 and CCC-HPF-1 cells. In addition, 12a and 12h significantly inhibited cells migration in both TGF-ß1-induced HSC-LX2 and CCC-HPF-1 cells. Preliminary mechanistic studies indicated that 12a and 12h exerted anti-hepatic fibrosis and anti-pulmonary fibrosis effects by inhibiting the TGF-ß/Smad signaling pathway. Overall, our findings suggested that 12a and 12h might be two promising anti-fibrotic agents, or might serve as two new lead compounds for the further development of anti-fibrotic agents.

Ursodeoxycholic acid does not affect the clinical outcome of SARS-CoV-2 infection: A retrospective study of propensity score-matched cohorts.

BACKGROUND: Ursodeoxycholic acid (UDCA) has been recently proposed as a modulator of angiotensin-converting enzyme 2 (ACE2) receptor expression, with potential effects on COVID-19. AIM AND STUDY DESIGN: We retrospectively evaluated the clinical course and outcome of subjects taking UDCA admitted to the hospital for COVID-19 compared with matched infected subjects. Differences regarding the severity and outcome of the disease between treated and non-treated subjects were assessed. The Kaplan-Meier survival analysis and log-rank test were used to evaluate the effect of UDCA on all-cause intra-hospital mortality. RESULTS: Among 6444 subjects with confirmed COVID-19 admitted to the emergency department (ED) from 1 March 2020 to 31 December 2022, 109 subjects were taking UDCA. After matching 629 subjects were included in the study: 521 in the no UDCA group and 108 in the UDCA group. In our matched cohort, 144 subjects (22.9%) died, 118 (22.6%) in the no-UDCA group and 26 (24.1%) in the UDCA group. The Kaplan-Meier analysis showed no significant difference in survival between groups. In univariate regression analysis, the presence of pneumonia, National Early Warning Score (NEWS) score, and Charlson Comorbidity Index (CCI) were significant independent predictors of death. At multivariate Cox regression analysis, age, NEWS, pneumonia and CCI index were confirmed significant independent predictors of death. UDCA treatment was not a predictor of survival both in univariate and multivariate regressions. CONCLUSIONS: UDCA treatment does not appear to have significant effects on the outcome of COVID-19. Specially designed prospective studies are needed to evaluate efficacy in preventing infection and severe disease.

Obeticholic acid as a second-line treatment for low phospholipid-associated cholelithiasis syndrome.

BACKGROUND: Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid-X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context. AIM: To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA. METHODS: This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist. RESULTS: We reviewed the records of five OCA-treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms - three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA. CONCLUSIONS: These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.

Bile acids and bile acid activated receptors in the treatment of Covid-19.

Since its first outbreak in 2020, the pandemic caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has caused the death of almost 7 million people worldwide. Vaccines have been fundamental in disease prevention and to reduce disease severity especially in patients with comorbidities. Nevertheless, treatment of COVID-19 has been proven difficult and several approaches have failed to prevent disease onset or disease progression, particularly in patients with comorbidities. Interrogation of drug data bases has been widely used since the beginning of pandemic to repurpose existing drugs/natural substances for the prevention/treatment of COVID-19. Steroids, including bile acids such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) have shown to be promising for their potential in modulating SARS-CoV-2/host interaction. Bile acids have proven to be effective in preventing binding of spike protein with the Angiotensin Converting Enzyme II (ACE2), thus preventing virus uptake by the host cells and inhibiting its replication, as well as in indirectly modulating immune response. Additionally, the two main bile acid activated receptors, GPBAR1 and FXR, have proven effective in modulating the expression of ACE2, suggesting an indirect role for these receptors in regulating SARS-CoV-2 infectiveness and immune response. In this review we have examined how the potential of bile acids and their receptors as anti-COVID-19 therapies and how these biochemical mechanisms translate into clinical efficacy.

Ursodeoxycholic acid alleviates sepsis-induced lung injury by blocking PANoptosis via STING pathway.

Acute lung injury (ALI), a progressive lung disease mostly caused by sepsis, is characterized by uncontrolled inflammatory responses, increased oxidative stress, pulmonary barrier dysfunction, and pulmonary edema. Ursodeoxycholic acid (UDCA) is a natural bile acid with various pharmacological properties and is extensively utilized in clinical settings for the management of hepatobiliary ailments. Nonetheless, the potential protective effects and mechanism of UDCA on sepsis-induced lung injuries remain unknown. In this study, we reported that UDCA effectively inhibited pulmonary edema, inflammatory cell infiltration, pro-inflammatory cytokines production, and oxidative stress. Furthermore, UDCA treatment significantly alleviated the damage of pulmonary barrier and enhanced alveolar fluid clearance. Importantly, UDCA treatment potently suppressed PANoptosis-like cell death which is demonstrated by the block of apoptosis, pyroptosis, and necroptosis. Mechanistically, UDCA treatment prominently inhibited STING pathway. And the consequential loss of STING substantially impaired the beneficial effects of UDCA treatment on the inflammatory response, pulmonary barrier, and PANoptosis. These results indicate that STING plays a pivotal role in the UDCA treatment against sepsis-induced lung injury. Collectively, our findings show that UDCA treatment can ameliorate sepsis-induced lung injury and verified a previously unrecognized mechanism by which UDCA alleviated sepsis-induced lung injury through blocking PANoptosis-like cell death via STING pathway.

The Conservative Management of Choledocholithiasis With Ursodeoxycholic Acid.

Choledocholithiasis has been defined as the presence of stones within the common bile duct (CBD) with up to one-half of the cases remaining asymptomatic. We report a case of an 84-year-old frail male admitted for the treatment of pneumonia, pleural effusion, and bacteraemia with co-incidental deranged liver function tests (LFTs). Ensuing magnetic resonance cholangiopancreatography (MRCP) noted three CBD stones; however, the patient remained asymptomatic. After discussing the benefits and risks of treatment options with the gastroenterology team, the patient refused endoscopic retrograde cholangiopancreatography (ERCP) and opted for close monitoring in the community whilst taking ursodeoxycholic acid (UDCA). In the months following, his LFTs normalised, and repeat MRCP no longer showed stones. This case demonstrates that UDCA with close monitoring may be considered a non-invasive alternative treatment of CBD stones, particularly in elderly or frail patients with multiple comorbidities.

Ursodeoxycholic Acid Does Not Improve COVID-19 Outcome in Hospitalized Patients.

Ursodeoxycholic acid (UDCA) was demonstrated to reduce susceptibility to SARS-CoV-2 infection in vitro and improve infection course in chronic liver diseases. However, real-life evidence is lacking. We analyzed the impact of UDCA on COVID-19 outcomes in patients hospitalized in a tertiary center. Between January 2020 and January 2023, among 3847 patients consecutively hospitalized for COVID19, 57 (=UDCA group) were taking UDCA. The UDCA and the control groups (n = 3790) did not differ concerning comorbidities including diabetes mellitus type 2 (15.8% vs. 12.8%) and neoplasia (12.3% vs. 9.4%). Liver diseases and vaccination rate were more common in the UDCA group (14.0% vs. 2.5% and 54.4% vs. 30.2%, respectively). Overall mortality and CPAP treatment were 22.8 % and 15.7% in the UDCA, and 21.3% and 25.9% in the control group. Mortality was similar (p = 0.243), whereas UDCA was associated with a lower rate of CPAP treatment (OR = 0.76, p < 0.05). Treatment with UDCA was not an independent predictor of survival in patients hospitalized for COVID-19.