Background: This study addresses a particular aspect of the biological behavior of the Spike subunit S1 of SARS-CoV-2. Researchers observed S1 acting freely in the human organism during and after COVID-19 and vaccination. One of its properties is that it interacts one-to-one with human proteins. S1 interacts with 12 specific human proteins in the liver. Methods: We used these proteins as seeds to extract their functional relationships from the human proteome through enrichment. The interactome representing the set of metabolic activities in which they are involved shows several molecular processes (KEGG), including some linked to HBV (hepatitis B) and HCC (hepatocellular carcinoma) with many genes/proteins involved. Reports show that, in some COVID patients, HBV reactivated or progressed to cancer. Results: We analyzed the interactome with several approaches to understand whether the two pathologies have independent progressions or a common progression. All our efforts consistently showed that the molecular processes involving both HBV and HCC are significantly present in all approaches we used, making it difficult to extract any useful information about their fate. Through BioGRID, we extracted experimental data in vivo but derived it from model cell systems. The lack of patient data in STRING results prevents diagnosis or prediction of real disease progression; therefore, we can consider them “aseptic” model data. Conclusion: The interactome tells us that genes involved in HCC and HVB-related pathways have the potential to activate disease processes. We can consider them as a gold standard. It is the comparison with similar molecular interactions found in individual human phenotypes that shows us whether the phenotype favors or hinders their progression. This also suggests how to use these features. These sets of proteins constitute a molecular “toolkit”. In fact, if we compare them with similar molecular sets of the patient, they will provide us with information on the level of the phenotypic state that is driving the disease. The information derived from the composition of an entire group of proteins is broader and more detailed than a single marker. Therefore, these protein compositions can serve as a reference system with which doctors can compare specific cases for personalized molecular medicine diagnoses.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has surged as a major cause of liver transplants in the United States. Existing studies have presented conflicting findings regarding the association between liver characteristics (specifically steatosis and fibrosis) and mortality. This study investigates the relationship between the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) and all-cause mortality in MASLD patients. Methods: Using the NHANES 2017-2018 database, 3821 individuals representing the United States population with MASLD underwent VCTE for liver stiffness measurement. Exclusion criteria were applied, eliminating ineligible cases, incomplete examinations, underage individuals, and those with hepatitis B or C, along with significant alcohol consumption history. Cox proportional hazard models assessed the hazard ratio (HR) for all-cause mortality in CAP and LSM. Cox regression analysis with interaction terms was employed for deeper exploration. Results: The study unveiled a strong, independent correlation between LSM and all-cause mortality. However, the CAP failed to demonstrate a significant association with mortality in both univariate and adjusted analyses, contrary to recent findings. The analysis underscores the importance of accurately measuring liver stiffness via VCTE in predicting adverse outcomes in MASLD patients, emphasizing the pivotal role of fibrosis in assessing mortality risk. Conclusion: This study reaffirms the robust link between liver fibrosis (measured through VCTE) and mortality among MASLD individuals. The absence of a significant association between steatosis (indicated by CAP) and mortality challenges recent research, urging further comprehensive investigations with larger cohorts to delineate steatosis’ precise impact on MASLD-related mortality.

Background: The use of natural hepatoprotective remedies represents an important path in modern phytotherapy. Objectives: In this context, our research aims to evaluate the phytochemical composition and the hepatoprotective and oxidative stress reduction potential of an Arctium tomentosum Mill. root extract. Methods: The phenolic profile of the tested extract, prepared by the subcritical fluid-assisted method were qualitatively and quantitatively analyzed by spectrophotometrical and HPLC/DAD/ESI methods. In vitro antioxidant capacity was assessed using DPPH and FRAP assays. Hepatoprotective activity of the extract was assessed on a model of CCl4 experimentally induced hepatotoxicity in mice. Results: Phytochemical assays revealed the presence of important polyphenols, such as chlorogenic acid (17.20 ± 0.65 μg/mL) and acacetin 7-O-glucoside (56.80 ± 1.66 μg/mL). In vitro, the tested extract exhibited a significant oxidative stress reduction capacity, while in vivo it showed a dose-dependent hepatoprotective effect indicated by an improvement in plasma proteins profile and down-regulation of plasma transaminase activity (ALAT, ASAT, GGT). In liver tissue, the extract partially restored the activity of GPx, CAT, and SOD and attenuated lipid peroxidation. The protective effect of the A. tomentosum root extract was supported by the alleviation of histological injuries of the liver (centrilobular necrosis, granulocytic infiltrate, and fibrosis). Conclusions: The A. tomentosum subcritical fluid-assisted root extract proved to be able to provide a significant hepatoprotective effect mainly through an antioxidant mechanism.

Background: Unlike other chronic liver disorders, in primary biliary cholangitis (PBC), systemic oxidative stress (SOS) worsens along with liver disease progression status (DPS), influencing muscle metabolism, muscle quantity (MQ), and itch pathways. Synergistically, cholestasis contributes to reduced vitamin D absorption, with a negative impact on MM and SOS. Despite this evidence, the prevalence of sarcopenia in PBC, and the SOS-MQ relationship comparing PBC with other CLDs, has never been investigated. Moreover, the relationship between vitamin D and MQ-SOS, and the correlation between SOS and pruritus severity, remains unexplored in PBC. Methods: A total of 40 MASLD, 52 chronic HBV infections, 50 chronic HCV infections, and 41 ursodeoxycholic acid/antioxidant-naïve PBC patients were enrolled. Biochemical, nutritional, and liver stiffness (LSM) data were collected, and sarcopenia was assessed after a normalizing 3-month dietetic–physical exercise regimen. The d-ROMs/BAP tests evaluated SOS. The validated “PBC-40 questionnaire” estimated pruritus and quality of life (QoL). Results: Unlike other CLDs, in PBC patients, sarcopenia was more prevalent in initial mild fibrosis (PBC: 57.10% vs. MASLD: 30.76%, HBV: 22.60%, HCV: 20.70%, all p < 0.0001), and SOS significantly correlated with MQ (dROMs-ASM/h2, p: 0.0002; BAP-ASM/h2: p: 0.0092). PBC patients presented lower vitamin D levels and a significant correlation of these with SOS and MQ (all p < 0.0001). SOS also correlated with pruritus severity (dROMs, R: 0.835; BAP, R: −0.775, p < 0.0001). QoL impairment was significantly more represented in PBC individuals with sarcopenia, SOS imbalance, and relevant pruritus (p: 0.0228). Conclusions: In PBC, SOS correlates with MQ impairment and pruritus severity, configuring two independent relationships simultaneously impacting QoL.

Hepatocellular carcinoma (HCC) is one of the leading causes of death in which the molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations in oncogenes, DNA repair genes, and tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory of harmful epigenetic modifications in DNA and chromatin—impacting the expression of genes involved in cellular proliferation, differentiation, genome stability, cell-cycle control, and DNA repair—are now acknowledged across various biological contexts that contribute to cancer etiology. Notably, the dynamic hypermethylation and hypomethylation in enhancer and promoter regions that promote activation or silencing of the master regulatory genes of the epigenetic programs is often altered in tumor cells due to mutation. Genome instability is one of the cancer hallmarks that contribute to transdifferentiation and intratumoral heterogeneity. Thus, it is broadly accepted that tumor tissue is dominated by genetically and epigenetically distinct sub-clones which display a set of genetic and epigenetic mutations. Here we summarize some functions of key genetic and epigenetic players and biochemical pathways leading to liver cell transformation. We discuss the role of the potential epigenetic marks in target genes thought to be involved in sequential events following liver lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, and finally hepatocellular carcinoma. We also briefly describe new findings showing how epigenetic drugs together with chemotherapy and immunotherapy can improve overall responses in patients with hepatic tumors.

Background/Objectives: The approval of direct-acting antiviral (DAA) therapy for hepatitis C (HCV) resulted in a highly effective oral treatment for patients. The primary objective of this study was to identify reasons that patients were not treated versus why patients were treated. Identifying potential reasons for the failure to treat can provide a pathway to interventions using evidence-based data. Methods: The electronic medical records in an urban predominately African American (AA) population were searched for all patients with HCV seen at least once in a Gastroenterology or Infectious Disease clinic in 2019. Data collected included demographics, treatment visits, laboratory data, insurance and ZIP codes for median income. Results: Of the 441 patients who were not yet treated at the first 2019 visit, only 43% were treated by July 2020. Insurance and median income were not factors in failure to treat. Patients with an average of four visits were more likely to be treated than those with two or less, suggesting that failure to follow up was a significant factor for patient treatment (42% vs. 8% p < 0.0001). Confirmation of viral infection at first visit was an important factor with respect to treatment (treated 38% vs. not treated 25% p < 0.02). Conclusions: Significant numbers of our patients (57%) failed to be treated after at least one clinic visit. The two critical factors were PCR confirmation prior to the initial visit and the requirement for multiple visits before the initiation of treatment. Since the degree of fibrosis had no impact on treatment, initiating treatment immediately after confirming infection with HCV should improve patient treatment rates and outcomes.

Infection of hepatitis B (HBV) patients with hepatitis D (HDV) can cause the most severe form of viral hepatitis, leading to liver fibrosis, liver failure, and hepatocellular carcinoma. HDV relies on simultaneous infection with HBV for the generation of infectious viral particles. The innate immune response, which is weakly induced in HBV infection, becomes strongly activated upon HDV co-infection. In HBV/HDV co-infection, the immune system comprises a cell-intrinsic strong IFN response, which leads to the induction of interferon-stimulated genes (ISGs), the local activation of liver-resident innate immune cells, and additional immune cell recruitment from the blood. Efficient innate immune responses are indispensable for successful viral control and spontaneous viral clearance. Despite this fact, innate immune cell activation can also contribute to adaptive immune cell inhibition and accelerate liver damage in HBV/HDV infection. While the intrinsic IFN response in HDV-infected cells is well characterized, far less is known about the cellular innate immune cell compartment. In this review, we summarize HBV/HDV replication characteristics and decipher the role of innate immune cell subsets in the anti-viral response in HBV/HDV infections. We further review the impact of epigenetic and metabolic changes in infected heptatocytes on the innate anti-viral response. Moreover, we discuss the potential of exploiting the innate immune response for improving vaccination strategies and treatment options, which is also discussed in this review.

Background: Pediatric hepatitis B virus (HBV) serostatus remains variably characterized, hardly determined at times, or documented as part of national monitoring of the Extended Programs for Immunization (EPI). Methods: We cross-sectionally characterized the seroprevalence of HBV vaccine and/or infection status among 501 and 288 children <5 and 15–17 years old, respectively, in Kawempe Division, Kampala, Uganda, between May and August 2023. These children received HBV vaccination under the Uganda National Extended Program on Immunizations (UNEPI). Samples were qualitatively screened for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb or anti-HBs), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb or anti-HBe), and for hepatitis B core antibody (HBcAb or anti-HBc) using three different HBV Combo test rapid immunochromatographic diagnostic tests: Nova, Fastep, and Beright. Results: The seroprevalence of HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc was 1.52%, 27.75%, 0.88%, 0.63%, and 0.76%, respectively, for the combined study age groups. The HBsAg seroprevalence of 2.78% was almost 3.5-fold higher among adolescents when compared to the 0.8% observed in the under-5-year-olds. The qualitative seroprevalence of anti-HBs was 33.1% and 18.4% in the under-5 and among the 15–17-year-old study groups, respectively. Conclusions: The proportion of qualitatively detectable anti-HBs in both groups of vaccinated children is low and probably indicates reduced seroprotection. Consequently, a large proportion of children who received the hepatitis B vaccine under UNEPI may be at risk of HBV infection, especially adolescents. A booster dose of the Hepatitis B Vaccine may be required for adolescents.