Search Results (64)

Rat hepatitis E virus (rat HEV, Rocahepevirus genotype C1) represents a potential zoonotic threat, but its epidemiological and evolutionary characteristics in small mammals remain poorly understood, especially in regions with complex geography. Between 2022 and 2024, we collected 818 small mammals from seven border counties and cities in Yunnan, China. Rat HEV RNA was detected by RT-PCR, risk factors were assessed using binary logistic regression, and full genomes were sequenced for phylogenetic and molecular clock analysis. The overall prevalence of rat HEV was 6.23% (51/818), with significantly higher odds observed in Gengma and Heqing counties, in oriental house rat (Rattus tanezumi) and Chevrieri’s field mouse (Apodemus chevrieri), in residential habitats, and at mid-high altitudes (all p < 0.001). The 51 partial genomic sequences (RdRp gene) obtained in this study clustered within Rocahepevirus, forming two distinct subclades associated with host species. The two complete genomes, GS188 and GS197 from Rattus tanezumi, were classified as subtypes C1b and C1d, respectively. Bayesian analysis estimated that GS197 diverged from a closely related Rattus tanezumi-derived strain around 1998, while GS188 diverged from a lineage containing shrew and human strains around 1931. These findings reveal a relatively high prevalence and substantial genetic diversity of Rochepevirus in southwestern Yunnan, suggesting human-influenced transmission dynamics and a potential for cross-species infection. Full article

Viral hepatitis constitutes a substantial global public health challenge. The etiological agents, referred to as hepatitis viruses, are primarily categorized into five types: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Among the various preventive strategies, vaccination is widely acknowledged as the most cost-effective and efficient method for controlling viral hepatitis and its related hepatic complications. To date, numerous countries have initiated extensive vaccination programs targeting hepatitis A and hepatitis B. Advances in biotechnology have facilitated substantial progress in vaccine formulation design, the development of innovative adjuvants, and the utilization of novel vectors. However, significant challenges persist, including inadequate vaccination coverage, inconsistent immune responses among vulnerable populations, and concerns regarding vaccine safety. This article presents a systematic review of recent advancements, the current status of vaccination efforts, and ongoing challenges associated with hepatitis vaccines, with the objective of providing critical insights to support the World Health Organization’s goal of eliminating viral hepatitis as a public health threat by 2030. Full article

If the number of viral hepatitis infections is to be decreased worldwide, and the World Health Organization (WHO) elimination targets are to be achieved by 2030, this requires determining the burden of infection according to the WHO’s test-and-treat approach. In 2014, the introduction of Direct-Acting Antivirals (DAAs) revolutionized the management of Hepatitis C Virus (HCV); another improvement came in 2020, when the use of bulevirtide (BLV) was authorized as a treatment for chronic Hepatitis D Virus (HDV) infection, showing good efficacy. The present observational study was carried out between 2019 and 2024. The diagnosis of viral hepatitis was carried out by routine assays. HDV typing was performed by Sanger sequencing and phylogenetic analysis. Overall, the HCV antibody prevalence was 3.4% in the studied time span, and it was higher in males than in females (59% vs. 41%). In viremic patients, HCV1b (33%) and HCV2a/2c (25%) were the most common subtypes. The overall HCV viremic rate declined in 2022 (2.8%). Unlike HCV, 71.4% of HDV viremic patients were females, and they had a median age of 58 years. The viral load of HDV RNA ranged from 20 IU/mL to 8 million IU/mL. Viral genotypes were classified as HDV1c and HDV1e. In this study, we highlight the prevalence of HCV/HDV infections and their genotype evolution in Southern Italy, underscoring the urgent need to enhance screening and linkage to care. Finally, we quantify the burden of active infections in order to provide data from real-life settings, and we describe the virological status of people living with HCV or HBV/HDV, who may experience significant benefits in terms of liver-related mortality after DAA or BLV treatment. Full article

Background/Objectives: In pregnancy threatened by preterm birth, antenatal corticosteroids (ACS) are administered to accelerate fetal lung maturation. However, they have side effects, including the production of reactive oxygen species that can impact cytochrome P450 (CYP) activity. We hypothesised that antioxidants could protect a fetus treated with ACS during gestation and prevent the programming of altered hepatic CYP activity in the offspring. The primary outcome of our study was the impact of different maternal treatments on the activity of hepatic drug-metabolising enzymes in offspring. Methods: At 100 ± 1 days gestational age (dGA, term = 147 dGA), 73 ewes were randomly allocated to the following: saline (5 mL IV daily 105–137 ± 2 dGA, n = 17), ACS (Dexamethasone (Dex); 12 mg IM at 115 and 116 dGA; n = 25), MitoQ (6 mg/kg MS010 IV, daily bolus 105–137 ± 2 dGA; n = 17) or Dex and MitoQ (Dex+MitoQ; n = 14). CYP activity and protein abundance were assessed using functional assays and Western blot. Results: Dex decreased the hepatic activity of fetal CYP3A (−56%, P_Dex = 0.0322), and 9 mo lamb CYP1A2 (−22%, P_Dex = 0.0003), CYP2B6 (−36%, P_Dex = 0.0234), CYP2C8 (−34%, P_Dex = 0.0493) and CYP2E1 (−57%, P_Dex = 0.0009). For all, except CYP1A2, activity returned to control levels with Dex+MitoQ in 9 mo lambs. In 9 mo lambs, MitoQ alone increased activity of CYP2B6 (+16%, P_MitoQ = 0.0011) and CYP3A (midazolam, +25%, P_MitoQ = 0.0162) and increased CAT expression (P_MitoQ = 0.0171). Dex+MitoQ increased CYP3A4/5 activity (testosterone, +65%, P_Intx < 0.0003), decreased CYP1A2 activity (−14%, P_Intx = 0.0036) and decreased mitochondrial abundance (P_Intx = 0.0051). All treatments decreased fetal hepatic DRP1, a regulator of mitochondrial fission (P_Dex = 0.0055, P_MitoQ = 0.0006 and P_Intx = 0.0034). Conclusions: Antenatal Dex reduced activity of only one CYP in the fetus but programmed the reduced activity of several hepatic CYPs in young adult offspring, and this effect was ameliorated by combination with MitoQ. Full article

The emergence of RNA viruses driven by global population growth and international trade highlights the urgent need for effective antiviral agents that can inhibit viral replication. Nucleoside analogs, which mimic natural nucleotides, have shown promise in targeting RNA-dependent RNA polymerases (RdRps). Starting from protected 5-iodouridine, we report the synthesis of hitherto unknown C5-substituted-(1,3-diyne)-uridines nucleosides and their phosphoramidate prodrugs. The modifications at C5 include 4-(trifluoromethyl)benzene (a), 4-pentyl-benzene (b), 3,5-dimethoxy-benzene (c), 4-(trifluoromethoxy)benzene (d), 3-aniline (e), 4-pyridine (f), 3-thiophene (g), C₆H₁₃ (h), 2-pyrimidine (i), cyclopropyl (j), and phenyl (k) groups. These compounds were synthesized using Sonogashira palladium-catalyzed reactions and nickel–copper-catalyzed C-H activation between various alkynes, yielding between 25% and 67%. The antiviral activities of obtained compounds were measured through HTS against RNA viruses including influenza H1N1 and H3N2, human respiratory syncytial virus (RSV), SARS-CoV-2, Zika, hepatitis C virus (HCV), Hepatitis E virus (HEV), as well as against coronavirus (HCoV-229E). Unfortunately, none of them showed promising antiviral activity, with less than 85% inhibition observed in the cell viability screening of infected cells. Full article

Background/Objectives: Perillyl alcohol (POH), a monoterpene natural product derived from the essential oils of plants such as perilla (Perilla frutescens), is currently in phase I and II clinical trials as a chemotherapeutic agent. In this study, we investigated the effect of POH on cytochrome P450 (CYP) activity for evaluating POH–drug interaction potential. Methods: The investigation was conducted using pooled human liver microsomes (HLMs), recombinant CYP3A4 (rCYP3A4) enzymes, and human pluripotent stem cell-derived hepatic organoids (hHOs) employing liquid chromatography-tandem mass spectrometry. Results: POH inhibited the activities of CYP2A6 and CYP2B6 with K_i of 6.35 and 3.78 μM, respectively, whereas it stimulated CYP3A4 activity in pooled HLMs incubated with midazolam (MDZ). In a direct CYP inhibition assay using HLMs, activities of CYP2C9, CYP2C19, and CYP2E1 were also inhibited by POH, with IC₅₀ values greater than 50 μM, but those of CYP1A2, CYP2C8, CYP2D6, and CYP3A4 (testosterone) were not significantly inhibited. In pooled HLMs, the V_max/K_m value of 1′-hydroxy MDZ, but not that of 4-hydroxy MDZ, was increased 2.7-fold by 100 μM POH compared with that in the absence of POH. Moreover, stimulation of MDZ 1′-hydroxylation by CYP3A4 was observed in hHOs and rCYP3A4 with cytochrome b₅ but not rCYP3A4 without cytochrome b₅. Furthermore, activation of CYP3A4-mediated metabolism by POH was observed in HLMs incubated with fimasartan but not atorvastatin, buspirone, donepezil, nifedipine, or tadalafil, suggesting a substrate-dependent activation of CYP3A4 by POH. Conclusions: POH inhibits CYP2A6 and CYP2B6, but it activates CYP3A4. These findings underscore the need for further evaluation of the interactions of clinical drugs with POH. Full article

Viral hepatitis (A–E) presents a major global health challenge. In 2015, the World Health Organization (WHO) launched an initiative to eliminate viral hepatitis, with the aim of reducing new infections by 90% and deaths by 65% by 2030. Mexico is one of 38 focus countries identified by the WHO, collectively accounting for 80% of global infections and deaths. While hepatitis B and C are commonly diagnosed in Mexico, routine diagnosis for hepatitis D and E is lacking, with no specific epidemiological data available. In 2020, Mexico implemented the National Hepatitis C Elimination Program, focusing on preventing new infections, reducing complications like cirrhosis and hepatocellular carcinoma, ensuring access to treatment, and improving patient care. However, this program has not been extended to hepatitis B and E. Addressing the challenges of viral hepatitis control in Mexico requires increased resource allocation, expanded diagnosis, vaccination for hepatitis A and B, and treatment coverage for hepatitis B and C, along with multisectoral engagement. This work provides an overview of Mexico’s response to the global initiative, highlighting its progress, challenges, and areas of opportunity. Full article

Viral hepatitis is a major cause of liver illness worldwide. Despite advances in the understanding of these infections, the pathogenesis of hepatitis remains a complex process driven by intricate interactions between hepatitis viruses and host cells at the molecular level. This paper will examine in detail the dynamics of these host–pathogen interactions, highlighting the key mechanisms that regulate virus entry into the hepatocyte, their replication, evasion of immune responses, and induction of hepatocellular damage. The unique strategies employed by different hepatitis viruses, such as hepatitis B, C, D, and E viruses, to exploit metabolic and cell signaling pathways to their advantage will be discussed. At the same time, the innate and adaptive immune responses put in place by the host to counter viral infection will be analyzed. Special attention will be paid to genetic, epigenetic, and environmental factors that modulate individual susceptibility to different forms of viral hepatitis. In addition, this work will highlight the latest findings on the mechanisms of viral persistence leading to the chronic hepatitis state and the potential implications for the development of new therapeutic strategies. Fully understanding the complex host–pathogen interactions in viral hepatitis is crucial to identifying new therapeutic targets, developing more effective approaches for treatment, and shedding light on the mechanisms underlying progression to more advanced stages of liver damage. Full article

Cystic echinococcosis (CE) is a zoonotic disease caused by the parasite Echinococcus granulosus (E. granulosus), which can lead to the formation of liver lesions. Research indicates that E. granulosus releases both Toll-like receptor 2 (TLR2) and Interleukin-9 (IL-9), which can potentially impair the body’s innate immune defenses and compromise the liver’s ability to fight against diseases. To investigate the role of TLR2 and IL-9 in liver damage caused by E. granulosus infection, samples were initially collected from individuals diagnosed with CE. Subsequently, BALB/c mice were infected with E. granulosus at multiple time points (4 weeks, 12 weeks, 32 weeks) and the expression levels of these markers was then assessed at each of these phases. Furthermore, a BALB/c mouse model was generated and administered anti-IL-9 antibody via intraperitoneal injection. The subsequent analysis focused on the TLR2/MyD88/NF-κB signaling pathway and the expression of IL-9 in E. granulosus was examined. A co-culture experiment was conducted using mouse mononuclear macrophage cells (RAW264.7) and hepatic stellate cells (HSCs) in the presence of E. granulosus Protein (EgP). The findings indicated elevated levels of IL-9 and TLR2 in patients with CE, with the activation of the signaling pathway significantly increased as the duration of infection progressed. Administration of anti-IL-9 in mice reduced the activation of the TLR2/MyD88/NF-κB signaling pathway, exacerbating liver injury. Moreover, EgP stimulates the TLR2/MyD88/NF-κB signaling pathway, resulting in the synthesis of α-SMA and Collagen I. The data suggest that infection with E. granulosus may stimulate the production of IL-9 through the activation of the TLR2/MyD88/NF-κB signaling pathway, which is mediated by TLR2. This activation stimulates RAW264.7 and HSCs, exacerbating liver injury and fibrosis. Full article

Viral hepatitis is a systemic infectious diseases caused by various hepatitis viruses, primarily leading to liver damage. It is widely prevalent worldwide, with hepatitis viruses categorized into five types: hepatitis A, B, C, D, and E, based on their etiology. Currently, the detection of hepatitis viruses relies on methods such as enzyme-linked immunosorbent assay (ELISA), immunoelectron microscopy to observe and identify viral particles, and in situ hybridization to detect viral DNA in tissues. However, these methods have limitations, including low sensitivity, high error rates in results, and potential false negative reactions due to occult serum infection conditions. To address these challenges, we have designed an AuNPs-DNA walker method that uses gold nanoparticles (AuNPs) and complementary DNA strands for detecting viral DNA fragments through a colorimetric assay and fluorescence detection. The DNA walker, attached to gold nanoparticles, comprises a long walking strand with a probe sequence bound and stem-loop structural strands featuring a modified fluorescent molecule at the 3′ end, which contains the DNAzyme structural domain. Upon the addition of virus fragments, the target sequence binds to the probe chains. Subsequently, the long walking strand is released and continuously hybridizes with the stem-loop structural strand. The DNAzyme undergoes hydrolytical cleavage by Mg²⁺, breaking the stem-loop structural strand into linear single strands. As a result of these structural changes, the negative charge density in the solution decreases, weakening spatial repulsion and rapidly reducing the stability of the DNA walker. This leads to aggregation upon the addition of a high-salt solution, accompanied by a color change. Virus typing can be performed through fluorescence detection. The innovative method can detect DNA/RNA fragments with high specificity for the target sequence, reaching concentrations as low as 1 nM. Overall, our approach offers a more convenient and reliable method for the detection of hepatitis viruses. Full article

In sub-Saharan Africa (SSA), the (sub)genotypes A1, D3, and E of the hepatitis B virus (HBV) prevail. Individuals infected with subgenotype A1 have a 4.5-fold increased risk of HCC compared to those infected with other (sub)genotypes. The effect of (sub)genotypes on protein expression and host signalling has not been studied. Mass spectrometry was used to analyse the proteome of Huh7 cells transfected with replication-competent clones. Proteomic analysis revealed significantly differentially expressed proteins between SSA (sub)genotypes. Different (sub)genotypes have the propensity to dysregulate specific host signalling pathways. Subgenotype A1 resulted in dysregulation within the Ras pathway. Ras-associated protein, RhoC, was significantly upregulated in cells transfected with subgenotype A1 compared to those transfected with other (sub)genotypes, on both a proteomic (>1.5-fold) and mRNA level (p < 0.05). Two of the main cellular signalling pathways involving RHOC, MAPK and PI3K/Akt/mTOR, regulate cell growth, motility, and survival. Downstream signalling products of these pathways have been shown to increase MMP2 and MMP9 expression. An extracellular MMP2 and MMP9 ELISA revealed a non-significant increase in MMP2 and MMP9 in the cells transfected with A1 compared to the other (sub)genotypes (p < 0.05). The upregulated Ras-associated proteins have been implicated as oncoproteins in various cancers and could contribute to the increased hepatocarcinogenic potential of A1. Full article

Non-alcoholic fatty liver disease (NAFLD) is a condition in which the pathological cumulation of fat with coexisting inflammation and damage of hepatic cells leads to progressive dysfunctions of the liver. Except for the commonly well-known major causes of NAFLD such as obesity, dyslipidemia, insulin resistance, or diabetes, an unbalanced diet and imbalanced nutritional status should also be taken into consideration. In this narrative review, we summarized the current knowledge regarding the micro- and macronutrient status of patients suffering from NAFLD considering various diets and supplementation of chosen supplements. We aimed to summarize the knowledge indicating which nutritional impairments may be associated with the onset and progression of NAFLD at the same time evaluating the potential therapy targets that could facilitate the healing process. Except for the above-mentioned objectives, one of the most important aspects of this review was to highlight the possible strategies for taking care of NAFLD patients taking into account the challenges and opportunities associated with the micronutrient status of the patients. The current research indicates that a supplementation of chosen vitamins (e.g., vitamin A, B complex, C, or D) as well as chosen elements such as zinc may alleviate the symptoms of NAFLD. However, there is still a lack of sufficient data regarding healthy ranges of dosages; thus, further research is of high importance in this matter. Full article

The indigenous populations of the Arctic regions of Russia experience the lowest coverage of health-related services. We assessed the prevalence of hepatitis A, B, C, D and E viruses (HAV, HBV, HCV, HDV and HEV) among 367 healthy adult Native people of the Arctic zone of Yakutia. The HAV seroprevalence was above and increased with age. The anti-HEV IgM and IgG antibody detection rates were 4.1% and 2.5%, respectively. The average HBsAg detection rate was 4.6%, with no positive cases identified in participants aged under 30 years, confirming the effectiveness of the newborn vaccination program that began in 1998. Anti-HDV antibodies were detected in 29.4% of HBsAg-positive cases. The anti-HCV and HCV RNA detection rates peaked in the age cohort of 50–59 years (10.8% and 3.9%). No statistically significant gender differences in the prevalence of different viral hepatitis were observed. The time-scaled phylogenetic analysis demonstrated that all HBV genotype A and D strains isolated in this study were autochthonous and had an estimated most common recent ancestor (MCRA) age of around the 11th to 14th century. Unlike HBV, the HCV strains of subtypes 1b, 2a and 2k/1b were introduced from other regions of Russia in the 1980s and 1990s. The HCV 1b sequence analysis revealed a series of transmission events. In conclusion, these data emphasize the urgent need for expanded viral hepatitis screening and care programs in the indigenous populations of the Arctic zone of Yakutia. Full article

Hepatitis is an inflammatory liver disease primarily caused by hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV) viruses. The chronic forms of hepatitis resulting from HBV and HCV infections can progress to cirrhosis or hepatocellular carcinoma (HCC), while acute hepatitis can lead to acute liver failure, sometimes resulting in fatality. Viral hepatitis was responsible for over 1 million reported deaths annually. The treatment of hepatitis caused by viral infections currently involves the use of interferon-α (IFN-α), nucleoside inhibitors, and reverse transcriptase inhibitors (for HBV). However, these methods do not always lead to a complete cure for viral infections, and chronic forms of the disease pose significant treatment challenges. These facts underscore the urgent need to explore novel drug developments for the treatment of viral hepatitis. The discovery of the CRISPR/Cas9 system and the subsequent development of various modifications of this system have represented a groundbreaking advance in the quest for innovative strategies in the treatment of viral infections. This technology enables the targeted disruption of specific regions of the genome of infectious agents or the direct manipulation of cellular factors involved in viral replication by introducing a double-strand DNA break, which is targeted by guide RNA (spacer). This review provides a comprehensive summary of our current knowledge regarding the application of the CRISPR/Cas system in the regulation of viral infections caused by HAV, HBV, and HCV. It also highlights new strategies for drug development aimed at addressing both acute and chronic forms of viral hepatitis. Full article