Transplantation of mesenchymal stem cells (MSCs) derived from bone marrow (BM) is an alternative treatment of acute liver failure (ALF) mainly because of the resulting anti-inflammatory activity. It is not known how MSCs regulate local immune responses and liver regeneration. This study explored the effects of MSCs on hepatic macrophages and the Wnt signaling pathway in ALF.

MSCs were isolated from BM aspirates of C57BL/6J mice, and transplanted in mice with ALF induced by D-galactosamine (D-Gal). The proliferation of hepatocytes was assayed by immunohistochemical (IHC) staining of Ki-67 and proliferating cell nuclear antigen (PCNA). The levels of key proteins in the Wnt signaling pathway were assayed by western blotting and cytokines were determined enzyme-linked immunosorbent assays (ELISAs). A macrophage polarization assay characterized the M1/M2 ratio. The potential role of interleukin-4 (IL-4) in the biological activity of MSCs was determined by silencing of IL-4.

Transplantation of allogeneic MSCs significantly attenuated D-Gal-induced hepatic inflammation and promoted liver regeneration. MSC transplantation significantly promoted a phenotypic switch from proinflamatory M1 macrophages to anti-inflammatory M2 macrophages, leading to significant Wnt-3a induction and activation of the Wnt signaling pathway in mice with D-Gal-induced ALF. Of the paracrine factors secreted by MSCs (G-CSF, IL-6, IL-1 beta, IL-4, and IL-17A), IL-4 was specifically induced following transplantation in the ALF model mice. The silencing of IL-4 significantly abrogated the phenotypic switch to M2 macrophages and the protective effects of MSCs in both the ALF model mice and a co-culture model in an IL-4 dependent manner.

In vivo and in vitro studies showed that MSCs ameliorated ALF through an IL-4-dependent macrophage switch toward the M2 anti-inflammatory phenotype. The findings may have clinical implications in that overexpression of IL-4 may enhance the therapeutic effects of allogeneic MSC transplantation in the treatment of ALF.

Hepatocellular carcinoma (HCC) has become a challenging disease worldwide. There are still limitations in the diagnosis and treatment of HCC, and its high metastatic capacity and high recurrence rate are the main reasons for its poor prognosis. The ability of extracellular vesicles (EVs) to transfer functionally-active substances and their widespread presence in almost all body fluids suggest their unprecedented potential in the study of various cancers. The unique physicochemical properties of EVs determine their potential as antitumor vaccines and drug carriers. In the last decade, the study of EVs in HCC has evolved from a single hot topic to a system with considerable scale. This paper summarizes the role of EVs, especially exosomes, in the occurrence, metastasis and tumor immunity of HCC, reviews their applications in tumor diagnosis, prognosis and treatment, describes the pros and cons of these studies, and looks forward towards the future research directions of EVs in HCC.

Hepatitis B vaccination is the most cost effective way to prevent hepatitis B virus (HBV) infection. Hepatitis B vaccine (HepB) efficacy is usually assessed by anti-hepatitis B surface antigen (HBsAg) level, but there are few reports of humoral and cellular immune responses to HepB in children after neonatal vaccination.

A group of 100 children with a history of primary hepatitis B immunization were included in this study to evaluate the efficacy of HepB. Blood samples were obtained from 80 children before, and 41 children after, a single HepB booster dose. Children with low anti-HBsAg (HBs) titers of <100 mIU/mL received a booster dose after giving their informed consent. Anti-HBsAg, T-cell response and percentage of B-cell subsets were assayed before and after the booster.

Of the 80 children, 81.36% had positive T cell and anti-HBsAg responses at baseline. After the booster dose, the anti-HBsAg titer (p<0.0001), positive HBsAg-specific T-cell response (p=0.0036), and spot-forming cells (p=0.0003) increased significantly. Compared with pre-existing anti-HBsAg titer <10 mIU/mL, the anti-HBsAg (p=0.0005) and HBsAg-specific T-cell responses (p<0.0001) increased significantly in preexisting anti-HBsAg titer between 10 and 100 mIU/mL group. Change of the HBV-specific humoral response was the reverse of the T-cell response with age. Peripheral blood lymphocytes, B cells, and subset frequency decreased.

HBV immunization protection persisted at least 13 years after primary immunization because of the complementary presence of HBV-specific humoral antibodies and a T-cell immune response. One dose of a HepB booster induced protective anti-HBsAg and promoted an HBsAg-specific T-cell response. In HBV endemic regions, a HepB booster is recommended to children without anti-HBsAg because of effectiveness in HBV prevention.

Iron overload can contribute to the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Hepcidin (Hamp), which is primarily synthesized in hepatocytes, is a key regulator of iron metabolism. However, the role of Hamp in NASH remains unclear. Therefore, we aimed to elucidate the role of Hamp in the pathophysiology of NASH.

Male mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for 16 weeks to establish the mouse NASH model. A choline-supplemented amino acid-defined (CSAA) diet was used as the control diet. Recombinant adeno-associated virus genome 2 serotype 8 vector expressing Hamp (rAAV2/8-Hamp) or its negative control (rAAV2/8-NC) was administered intravenously at week 8 of either the CDAA or CSAA diet.

rAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice, accompanied by changes in lipogenesis-related genes and adiponectin expression. Compared with the control group, rAAV2/8-Hamp therapy attenuated liver damage, with mice exhibiting reduced histological NAFLD inflammation and fibrosis, as well as lower levels of liver enzymes. Moreover, α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) and CD68-postive macrophages increased in number in the CDAA-fed mice, which was reversed by rAAV2/8-Hamp treatment. Consistent with the in vivo findings, overexpression of Hamp increased adiponectin expression in hepatocytes and Hamp treatment inhibited HSC activation.

Overexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver steatohepatitis, inflammation, and fibrosis in an animal model of NASH, suggesting a potential therapeutic role for Hamp.

The SARS-CoV-2 virus Spike (S) protein binds to an angiotensin-converting-enzyme 2 receptor (ACE2) on the surface of cells to allow viral DNA entry. Given the plenitude of FDA-approved antiviral drugs, we aimed to screen those that may be repurposed for treating SARS-CoV-2 infections.

Using the crystal structure of SARS-CoV-2 Spike complexed with ACE2 (PDB ID: 6VW1) as a template, we developed a pharmacophore model of functional centers of the SARS-CoV-2 Spike protein inhibitor-binding domain. The conformations of these compounds underwent 3D fingerprint similarity clusterization, followed by docking of possible conformers to the binding site of ACE2. A similar protocol was followed for a set of randomly-selected compounds. Molecular dynamics was performed to confirm the stability of the selected drugs bound to ACE2.

Based on the model, we conducted a pharmacophore search from a conformational database of FDA-approved drugs. From the 379 compounds identified as potential inhibitors of SARS-CoV-2, 152 compounds with the best scores were selected based on maximal hydrogen-bond and hydrophobic interactions. The average free energies of the docking interaction for the selected compounds were better than those of random compounds. The obtained drug list includes inhibitors of HIV, HCV, CMV, ZIKV, HMPV, and RVFV as well as a set of drugs that have demonstrated some activity in MERS, SARS-CoV, and SARS-CoV-2 therapy.

Using a set of computational methods, we predicted the FDA-approved drugs that might bind to the interface of ACE2 protein and Spike protein of SARS-CoV-2 and prevent binding between Spike and ACE2. In further works, we recommend testing the selected compounds for treatment of COVID-19.

NKX3.1 is an emerging marker for tumors of prostatic origin; however, the utility and diagnostic values of NKX3.1 have not been broadly studied in cytology specimens. The purpose of this study is to determine the performance of NKX3.1, compared to prostatic specific antigen (PSA) and prostatic specific alkaline phosphatase (PSAP), as an organ-specific marker of metastatic prostatic adenocarcinoma (MPAC) in cytology specimens.

The cytology specimens, which had been evaluated to include or exclude MPAC, were collected from our pathology database. Immunostains for PSA, PSAP, and NKX3.1 were performed on cell block sections.

A total of 118 cases were collected. In 37 MPACs, NKX3.1 was diffusely positive in 34 cases (92%) and focally positive in 3 cases (8%). PSA indicated diffuse positivity in 16 cases (43%), focal positivity in 13 (35%) cases, and was negative in 8 (22%) cases. PSAP immunostain was performed in only 12 MPACs, showing diffuse positivity in 5 (42%), focal positivity in 3 (25%), and negativity in 4 (33%) cases. Among the 81 non-metastatic prostatic adenocarcinoma cases, NKX3.1 was negative in 80 (99%) cases and focally positive in only 1 (1%) case; all cases with available PSA and PSAP staining were negative. The calculated sensitivities for NKX3.1, PSA, and PSAP were 100%, 78%, and 67%, respectively, while the specificities were 99%, 100%, and 100%, respectively.

Compared to PSA and PSAP, NKX3.1 is more reliable as an individual marker for MPAC in cytology specimens. Combining NKX3.1 and PSA can be useful in some cases to enhance diagnostic utility.

The leading cause of dementia is Alzheimer’s disease (AD), which affects millions worldwide. Aging populations can foretell the worsening burden of the disease in the future. AD is characterised by the following hallmark pathologies: amyloid-β over-production and deposition, abnormal hyperphosphorylation of tau leading to the formation of neurofibrillary tangles, and neuroinflammation. Many potential treatments fail in clinical trials, suggesting that present theories are outdated or lead to therapeutic dead-ends. A gum disease-causing species of bacteria, Porphyromonas gingivalis, is being increasingly linked with AD, given the ubiquity of gum disease amongst older populations, and studies have revealed that the bacteria causes and exacerbates AD pathology both in vitro and in vivo. P. gingivalis produce many neurotoxic molecules, including gingipain enzymes, lipopolysaccharide and phosphoglycerol dihydroceramides, and all of these have been shown to affect AD pathologies. Numerous mechanisms by which these neurotoxic species reach the brain have been proposed, and one of these is the bacteria’s use of outer membrane vesicles. This review presents the present evidence of the effects of P. gingivalis and its outer membrane vesicles, gingipains, lipopolysaccharide and phosphoglycerol dihydroceramides, on neurodegeneration in neuronal cultures, mice models and post-mortem studies, and determines how this evidence can be used to develop new treatments for AD.

Hepatocellular carcinoma (HCC) is listed as one of the most common causes of cancer-related death. Oncolytic therapy has become a promising treatment because of novel immunotherapies and gene editing technology, but biosafety concerns remain the biggest limitation for clinical application. We studied the the antitumor activity and biosafety of the wild-type Newcastle disease virus HK84 strain (NDV/HK84) and 10 other NDV strains.

Cell proliferation and apoptosis were determined by cell counting Kit-8 and fluorescein isothiocyanate Annexin V apoptosis assays. Colony formation, wound healing, and a xenograft mouse model were used to evaluate in vivo and in vitro oncolytic effectiveness. The safety of NDV/HK84 was tested in nude mice by an in vivo luciferase imaging system. The replication kinetics of NDV/HK84 in normal tissues and tumors were evaluated by infectious-dose assays in eggs. RNA sequencing analysis was performed to explore NDV/HK84 activity and was validated by quantitative real-time PCR.

The cell counting Kit-8 assays of viability found that the oncolytic activity of the NDV strains differed with the multiplicity of infection (MOI). At an MOI of 20, the oncolytic activity of all NDV strains except the DK/JX/21358/08 strain was >80%. The oncolytic activities of the NDV/HK84 and DK/JX/8224/04 strains were >80% at both MOI=20 and MOI=2. Only NDV/HK84 had >80% oncolytic activities at both MOI=20 and MOI=2. We chose NDV/HK84 as the candidate virus to test the oncolytic effect of NDV in HCC in the in vitro and in vivo experiments. NDV/HK84 killed human SK-HEP-1 HCC cells without affecting healthy cells.

Intratumor infection with NDV/HK84 strains compared with vehicle controls or positive controls indicated that NDV/HK84 strain specifically inhibited HCC without affecting healthy mice. High-throughput RNA sequencing showed that the oncolytic activity of NDV/HK84 was dependent on the activation of type I interferon signaling.

The percentage of vaccinated people in Ukraine and Israel extensively varies. Based on this large difference, the influence of possible collective immunity on the COVID-19 pandemic dynamics in summer 2021 was evaluated.

To clarify the presence of a natural collective immunity, the visible and actual characteristics of the COVID-19 epidemic in Ukraine were estimated based on the number of laboratory-confirmed cases (accumulated in May and June 2021), using a generalized SIR-model and parameter identification procedure, and considering the difference between registered and real number of cases.

The calculated optimal value of the visibility coefficient shows that most Ukrainians have already been infected with coronavirus, some of whom have been infected more than once. This suggests that Ukrainians have probably achieved a natural collective immunity. Despite the large percentage of fully vaccinated people in Israel (approximately 60%), the emergence of a new epidemic wave after June 15, 2021 was not prevented, and the number of deaths increased after July 5, 2021. A new wave of the pandemic in Ukraine after July 10, 2021 is characterized by a smaller daily number of new COVID-19 cases per capita and new deaths per capita, despite having a much lower number of vaccinated people than in Israel. This can be explained by a much lower level of testing (many cases in Ukraine remain undetected) and possibly by the probable natural immunity of Ukrainians.

High levels of vaccination and natural collective immunity are unlikely to prevent new waves of the COVID-19 pandemic caused by mutated coronavirus strains.

The dietary consumption of fructose has increased in the last five decades, paralleled by an increase in obesity. Excess fructose intake is linked to obesity, metabolic syndrome, non-alcoholic fatty liver disease, diabetes, hypertension, cardiac disease, and several aggressive types of cancer. The incidence of acute myeloid leukemia (AML), a lethal hematologic malignancy, has also increased in parallel. Despite significant advances in our understanding of AML, including molecular genetics and more effective targeted therapies, relapse is frequent and outcomes remain poor. Moreover, except for several known causes for a small proportion of AML cases, virtually nothing is known about the initial causative leukemogenic event. In this study, the author asked and intended to answer the question, “can excess fructose intake lead to the initial cellular event that causes AML?” The author reviewed published literature to answer the above question and, subsequently, to identify novel AML therapies based on fructose metabolism. In this article, fructose metabolism and its relationship with metabolic pathways essential for AML, including regulation by hypoxia inducible factor, are described. Evidence for the potential etiologic role of fructose in AML is summarized for the first time. To conclude, excess fructose can lead to the initial AML-causative cellular event. Based on this study, future studies are warranted to determine if restricting fructose intake can prevent AML. Therapeutically, the development of hypoxia inducible factor and glucose transporter 5 inhibitors should be pursued for the treatment of AML.

Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease (NAFLD). We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism.

The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD. Visceral fat area (VFA) was measured by bioelectrical impedance. Significant liver fibrosis (SF), defined as stage F ≥2 on histology, was the outcome measure of interest.

The distribution of PNPLA3 genotypes was CC: 27.5%, CG: 48.2%, and GG: 24.3%. Higher VFA was associated with greater risk of having SF (adjusted-odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.02–1.04, p<0.05), independent of potential confounders. Among subjects with the same VFA level, the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not. Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF. VFA remained significantly associated with SF only among the rs738409 G-allele carriers (adjusted-OR: 1.05; 95% CI: 1.03–1.08 for the GG group; and adjusted-OR:1.03; 95% CI: 1.01–1.04 for the GC group). There was a significant interaction between VFA and PNPLA3 rs738409 genotype (Pinteraction=0.004).

PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD. Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF.