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Clinical Transplantation Jul 2024Hepatitis B virus reactivation (HBVr) can occur in solid organ transplant (SOT) recipients with previously inactive hepatitis B virus (HBV) infection. Previous studies...
INTRODUCTION
Hepatitis B virus reactivation (HBVr) can occur in solid organ transplant (SOT) recipients with previously inactive hepatitis B virus (HBV) infection. Previous studies have reported that HBVr is generally less than 10% in nonliver SOT recipients with past HBV infection.
METHODS
We conducted a retrospective study from January 2018 to August 2023 at Mayo Clinic sites in Arizona, Florida, and Minnesota. We examined the antiviral prophylaxis strategy used and the characteristics of HBVr in hepatitis B core antibody-positive (HBcAb +) nonliver SOT adult recipients. Past HBV infection was defined as HBcAb + / hepatitis B surface antigen (HBsAg) -. Chronic HBV infection was defined as HBcAb + / HBsAg +.
RESULTS
A total of 180 nonliver SOT recipients were identified during the study period. Indefinite antiviral prophylaxis was utilized in 77 recipients, and none developed HBVr after transplantation. In 103 recipients without antiviral prophylaxis, the incidence of HBVr was 12% (12/97) and 33% (2/6) in those with past HBV infection and chronic HBV infection. The incidence of HBVr in patients with past HBV infection is 16% (8/50), 15% (3/20), and 5% (1/22) in kidney, heart, and lungs, respectively. HBVr was more frequent in those who received alemtuzumab. Among 14 recipients with HBVr, none had HBV-associated liver failure or death.
CONCLUSIONS
Our study observed a higher rate of HBVr (12%) in nonliver SOT recipients with past HBV infection compared to the previous studies. Further studies are needed to identify predictors of HBVr in nonliver SOT recipients and optimize antiviral prophylaxis guidance.
Topics: Humans; Retrospective Studies; Male; Female; Hepatitis B virus; Incidence; Middle Aged; Organ Transplantation; Hepatitis B; Follow-Up Studies; Risk Factors; Virus Activation; Antiviral Agents; Prognosis; Adult; Risk Assessment; Postoperative Complications; Aged
PubMed: 38952185
DOI: 10.1111/ctr.15389 -
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi =... Jun 2024Objective To investigate the effects of astragaloside IV(AS-IV) on the balance of T helper type 1 (Th1) and Th2 cells in mice with IgA nephropathy (IgAN) and its...
Objective To investigate the effects of astragaloside IV(AS-IV) on the balance of T helper type 1 (Th1) and Th2 cells in mice with IgA nephropathy (IgAN) and its possible mechanism. Methods The IgAN model of BALB/c mice was established. Successfully modeled mice were randomly divided into four groups: model, AS-IV low dose, AS-IV medium dose and AS-IV high dose groups, with 10 mice in each group. Another 10 mice served as the control group. Mice in the low, medium and high dose groups were administered 12.5, 25 and 50 mg/kg AS-IV suspension (prepared in normal saline) by gavage, while the control and model groups were given an equivalent volume of normal saline. The 24-hour urinary protein (24 h UPr) content and urine red blood cell count were measured in each group. The levels of blood urea nitrogen (BUN), serum creatinine (Scr) and albumin (ALB) were determined. Serum interferon γ (IFN-γ), interleukin 4 (IL-4) and IL-10 levels were detected by ELISA. The ratio of Th1/Th2 cells in peripheral blood of mice was detected using flow cytometry. Histopathological changes in the kidney of mice were observed by HE staining. RT-PCR and Western blot were used to detect the mRNA and protein expressions of T cell immunoglobulin and mucin domain gene 1 (TIM-1), Toll-like receptor 4 (TLR4) in mouse kidney tissue. Results Compared with the model group, in weeks 12 and 15, the urine red blood cell count, 24 h UPr, BUN, Scr, levels of IL-4 and IL-10, the proportion of Th2 cells, as well as the mRNA and protein expression levels of TIM-1 and TLR4 were significantly decreased in the low, medium and high dose groups of AS-IV, and the levels of ALB, IFN-γ, the proportion of Th1 cells and Th1/Th2 cell ratio were increased, with the high-dose group showing the best effects. Conclusion AS-IV can inhibit TIM-1 signaling pathway, increase the Th1/Th2 cell ratio, inhibit the inflammatory reaction, and alleviate the renal injury in IgAN mice.
Topics: Animals; Hepatitis A Virus Cellular Receptor 1; Triterpenes; Glomerulonephritis, IGA; Saponins; Th1 Cells; Signal Transduction; Mice, Inbred BALB C; Th2 Cells; Mice; Toll-Like Receptor 4; Interleukin-4; Kidney; Interleukin-10; Interferon-gamma; Male; Female
PubMed: 38952089
DOI: No ID Found -
BMC Genomics Jun 2024Viperin, also known as radical S-adenosyl-methionine domain containing protein 2 (RSAD2), is an interferon-inducible protein that is involved in the innate immune...
BACKGROUND
Viperin, also known as radical S-adenosyl-methionine domain containing protein 2 (RSAD2), is an interferon-inducible protein that is involved in the innate immune response against a wide array of viruses. In mammals, Viperin exerts its antiviral function through enzymatic conversion of cytidine triphosphate (CTP) into its antiviral analog ddhCTP as well as through interactions with host proteins involved in innate immune signaling and in metabolic pathways exploited by viruses during their life cycle. However, how Viperin modulates the antiviral response in fish remains largely unknown.
RESULTS
For this purpose, we developed a fathead minnow (Pimephales promelas) clonal cell line in which the unique viperin gene has been knocked out by CRISPR/Cas9 genome-editing. In order to decipher the contribution of fish Viperin to the antiviral response and its regulatory role beyond the scope of the innate immune response, we performed a comparative RNA-seq analysis of viperin and wildtype cell lines upon stimulation with recombinant fathead minnow type I interferon.
CONCLUSIONS
Our results revealed that Viperin does not exert positive feedback on the canonical type I IFN but acts as a negative regulator of the inflammatory response by downregulating specific pro-inflammatory genes and upregulating repressors of the NF-κB pathway. It also appeared to play a role in regulating metabolic processes, including one carbon metabolism, bone formation, extracellular matrix organization and cell adhesion.
Topics: Animals; Cyprinidae; Inflammation; Immunity, Innate; Fish Proteins; Cell Line; CRISPR-Cas Systems; Interferon Type I; Gene Editing; Gene Expression Regulation
PubMed: 38951796
DOI: 10.1186/s12864-024-10566-x -
Nature Chemical Biology Jul 2024Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin...
Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin antibiotics. Peptides armed with electrophilic warheads have proven to be particularly effective covalent inhibitors, providing essential antimicrobial, antiviral and anticancer agents. Here we provide a full characterization of the pathways that nature deploys to assemble peptides with β-lactone warheads, which are potent proteasome inhibitors with promising anticancer activity. Warhead assembly involves a three-step cryptic methylation sequence, which is likely required to reduce unfavorable electrostatic interactions during the sterically demanding β-lactonization. Amide-bond synthetase and adenosine triphosphate (ATP)-grasp enzymes couple amino acids to the β-lactone warhead, generating the bioactive peptide products. After reconstituting the entire pathway to β-lactone peptides in vitro, we go on to deliver a diverse range of analogs through enzymatic cascade reactions. Our approach is more efficient and cleaner than the synthetic methods currently used to produce clinically important warhead-containing peptides.
PubMed: 38951647
DOI: 10.1038/s41589-024-01657-7 -
Nature Communications Jun 2024Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is...
Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2 mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.
Topics: Animals; Interferon-gamma; Interleukin-12; Male; Insulin Resistance; Obesity; Mice; Fatty Liver; Mice, Knockout; Macrophages; Signal Transduction; Liver; Mice, Inbred C57BL; Diet, High-Fat; Receptors, Interferon; Interferon gamma Receptor; Liver Cirrhosis
PubMed: 38951527
DOI: 10.1038/s41467-024-49633-y -
Drug Discovery Today Jun 2024Pathogenic viruses are a profound threat to global public health, underscoring the urgent need for the development of efficacious antiviral therapeutics. The advent of... (Review)
Review
Pathogenic viruses are a profound threat to global public health, underscoring the urgent need for the development of efficacious antiviral therapeutics. The advent of RNA-targeting antiviral strategies has marked a significant paradigm shift in the management of viral infections, offering a potent means of control and potential cure. In this review, we delve into the cutting-edge progress in RNA-targeting antiviral agents, encompassing antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and small bifunctional molecules. We provide an in-depth examination of their strategic molecular design and elucidate the underlying mechanisms of action that confer their antiviral efficacy. By synthesizing recent findings, we shed light on the innovative potential of RNA-targeting approaches and their pivotal role in advancing the frontiers of antiviral drug discovery.
PubMed: 38950729
DOI: 10.1016/j.drudis.2024.104074 -
The Journal of the Association of...
Topics: Humans; Female; Black or African American; HIV Infections; Pre-Exposure Prophylaxis; Adult; Community-Based Participatory Research; Anti-HIV Agents; United States; Patient Acceptance of Health Care; Middle Aged
PubMed: 38949909
DOI: 10.1097/JNC.0000000000000456 -
The Journal of the Association of...In the U.S. South, over half of new HIV diagnoses occur among Black Americans with research lagging for women who face increased HIV rates and low PrEP uptake, among...
In the U.S. South, over half of new HIV diagnoses occur among Black Americans with research lagging for women who face increased HIV rates and low PrEP uptake, among other health inequities. Community engaged research is a promising method for reversing these trends with established best practices for building infrastructure, implementing research, and translating evidence-based interventions into clinical and community settings. Using the 5Ws of Racial Equity in Research Framework (5Ws) as a racial equity lens, the following paper models a review of a salon-based intervention to improve PrEP awareness and uptake among Black women that was co-developed with beauty salons, stylists, and Black women through an established community advisory council. In this paper we demonstrate how the 5Ws framework was applied to review processes, practices, and outcomes from a community-engaged research approach. The benefits of and challenges to successful collaboration are discussed with insights for future research and community impact.
Topics: Humans; Female; HIV Infections; Black or African American; Pre-Exposure Prophylaxis; Community-Based Participatory Research; Anti-HIV Agents; Adult; Healthcare Disparities; Health Knowledge, Attitudes, Practice; Patient Acceptance of Health Care; United States; Health Equity
PubMed: 38949908
DOI: 10.1097/JNC.0000000000000453 -
The Journal of the Association of...Black women are essential to ending the HIV epidemic in the United States; yet prevention, access, testing, and structural racism affect how HIV disproportionately...
Black women are essential to ending the HIV epidemic in the United States; yet prevention, access, testing, and structural racism affect how HIV disproportionately affects them. Limited public health research focuses on Black women attending Historically Black Colleges and Universities (HBCUs) and the ability to address HIV prevention, such as pre-exposure prophylaxis (PrEP) uptake. PrEP is a once-daily oral pill used to prevent HIV transmission and has suboptimal uptake within the Black community. This generic qualitative descriptive analysis identifies the barriers and facilitators of PrEP uptake among Black women attending an HBCU using the health belief model. Overall, 22 Black college women participated in a 60-minute focus group. Emergent categories were as follows: (a) Barriers-stigma, cost, and side effects; (b) Facilitators-PrEP's effectiveness, exposure to HIV, and unprotected sex. Our findings can inform future efforts to increase PrEP uptake among Black women attending an HBCU.
Topics: Humans; Female; Pre-Exposure Prophylaxis; HIV Infections; Qualitative Research; Universities; Black or African American; Adult; Anti-HIV Agents; Focus Groups; Young Adult; Social Stigma; Health Services Accessibility; Health Knowledge, Attitudes, Practice; Patient Acceptance of Health Care; Students; Racism; Adolescent
PubMed: 38949902
DOI: 10.1097/JNC.0000000000000470 -
Journal of Medical Virology Jul 2024Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory...
Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.
Topics: Humans; SARS-CoV-2; Mitochondria; COVID-19; A549 Cells; Viral Regulatory and Accessory Proteins; Transcriptome; Open Reading Frames; Viral Proteins; Viroporin Proteins
PubMed: 38949191
DOI: 10.1002/jmv.29752