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Biomolecules Jun 2024The Ebola virus (EBOV) is a lethal pathogen causing hemorrhagic fever syndrome which remains a global health challenge. In the EBOV, two multifunctional proteins, VP35...
The Ebola virus (EBOV) is a lethal pathogen causing hemorrhagic fever syndrome which remains a global health challenge. In the EBOV, two multifunctional proteins, VP35 and VP40, have significant roles in replication, virion assembly, and budding from the cell and have been identified as druggable targets. In this study, we employed in silico methods comprising molecular docking, molecular dynamic simulations, and pharmacological properties to identify prospective drugs for inhibiting VP35 and VP40 proteins from the myxobacterial bioactive natural product repertoire. Cystobactamid 934-2, Cystobactamid 919-1, and Cittilin A bound firmly to VP35. Meanwhile, 2-Hydroxysorangiadenosine, Enhypyrazinone B, and Sorangiadenosine showed strong binding to the matrix protein VP40. Molecular dynamic simulations revealed that, among these compounds, Cystobactamid 919-1 and 2-Hydroxysorangiadenosine had stable interactions with their respective targets. Similarly, molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations indicated close-fitting receptor binding with VP35 or VP40. These two compounds also exhibited good pharmacological properties. In conclusion, we identified Cystobactamid 919-1 and 2-Hydroxysorangiadenosine as potential ligands for EBOV that target VP35 and VP40 proteins. These findings signify an essential step in vitro and in vivo to validate their potential for EBOV inhibition.
Topics: Ebolavirus; Molecular Docking Simulation; Biological Products; Molecular Dynamics Simulation; Antiviral Agents; Myxococcales; Humans; Viral Regulatory and Accessory Proteins; Viral Matrix Proteins; Nucleocapsid Proteins
PubMed: 38927063
DOI: 10.3390/biom14060660 -
Transplantation Proceedings Jun 2024Kidney transplant recipients are vulnerable to infections, especially cytomegalovirus (CMV) disease. It is recommended that clinicians plan their prophylaxis and...
BACKGROUND
Kidney transplant recipients are vulnerable to infections, especially cytomegalovirus (CMV) disease. It is recommended that clinicians plan their prophylaxis and therapeutic regimens based on viral load testing.
OBJECTIVE
CMV viral load monitoring testing provides useful information for identifying virologic response and possible antiviral resistance. Due to the paucity of medical literature on guiding viral therapy in cases of CMV tissue disease with nondetectable serum viral load, we intend to provide physicians with evidence on how to guide medical therapy in these cases.
CASE REPORT
A 49-year-old Hispanic male recipient of a kidney transplant from a cadaver donor presented to the emergency department with anorexia, asthenia, diarrhea, weight loss, and supraclavicular and mediastinal adenomegalies at 2 months post-transplantation. Both patients were serum IgG- and IgM-positive for CMV, which classified them as intermediate risk for developing CMV disease or tissue-invasive disease (donor-positive/recipient-positive [D+/R+]). The patient was induced with basiliximab and methylprednisolone and received maintenance therapy with tacrolimus, mycophenolic acid, and prednisone. Real-time polymerase chain reaction analyses were performed due to suspicion for BK virus, B19 parvovirus, Epstein-Barr virus, and CMV, with an undetectable viral load for all. A biopsy specimen taken from the gastrointestinal tract confirmed CMV infection, which was corroborated through immunocytochemistry.
CONCLUSIONS
Histopathologic testing is a possible option for patients with CMV tissue disease symptoms but no detectable serum viral load. Clinical observation is fundamental when viral monitoring is difficult.
PubMed: 38908954
DOI: 10.1016/j.transproceed.2024.05.005 -
Iranian Journal of Kidney Diseases May 2024Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect...
INTRODUCTION
Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect graft function by predisposing patients to rejection or nephrotoxicity. We conducted this study with the aim of assessing the influence of Tac-IPV on 2-year graft function, biopsy-proven rejection, and infections in compliant renal recipients.
METHODS
In this single-center retrospective analytic cross-sectional study, 250 patients who underwent transplantation from March 21, 2018, to March 20, 2020 and had at least three outpatient tacrolimus trough levels on the same daily dose 6 to 12 months after transplantation were recruited. Tac-IPV was defined as a coefficient variation of > 15%. Graft function, biopsy-proven rejection, cytomegalovirus (CMV) and BK virus viremia, and calcineurin inhibitor (CNI) toxicity were evaluated.
RESULTS
Of 202 transplant recipients, 128 were included with a mean age of 45.48 ± 13.14 years. The median Tac-IPV was 13.28% with 43.75% of patients with Tac-IPV > 15%. There were no significant differences in graft function, rejection, CNI toxicity, and CMV viremia among the groups during the 24-month study (P > .05). However, BK viremia was significantly higher among patients with Tac-IPV > 15% (13 vs. 2.9%, P = .042). The risk of antibody mediated rejection alone (22.7 vs. 2.9%) or any kind of rejection (22.7 vs. 11.8%) was significantly higher in patients with higher Tac-IPV, and in those who had mean trough levels below 7 ng/mL (P = .015, .032; respectively).
CONCLUSION
Tac-IPV is low in adherent patients (with the median of 13.28%) and maintaining tacrolimus trough level above 7 ng/mL can overcome the adverse graft outcome of Tac-IPV in compliant kidney transplant recipients. DOI: 10.52547/ijkd.7815.
Topics: Humans; Kidney Transplantation; Tacrolimus; Female; Male; Cross-Sectional Studies; Middle Aged; Immunosuppressive Agents; Retrospective Studies; Adult; Graft Rejection; Cytomegalovirus Infections; Graft Survival; Medication Adherence; Polyomavirus Infections; Calcineurin Inhibitors; Viremia
PubMed: 38904339
DOI: 10.52547/54drw293 -
Kidney International Reports Jun 2024Earlier reports suggest that patients after ABO-incompatible kidney transplantation (ABOi) are at enhanced risk of developing BK-virus (BKV, also known as BK...
INTRODUCTION
Earlier reports suggest that patients after ABO-incompatible kidney transplantation (ABOi) are at enhanced risk of developing BK-virus (BKV, also known as BK polyomavirus [BKPyV]) nephropathy (BKPyVAN). It remains elusive whether this is a result of more intense immunosuppression or an ABOi-associated "intrinsic attribute." To address this question, we measured Torque Teno virus (TTV) loads as a quantitative proxy for immunosuppressive depth in ABOi recipients and compared them to human leukocyte antigen-incompatible (HLAi, i.e. pretransplant donor-specific antibody-positive) and standard-risk transplant recipients.
METHODS
Our retrospective study screened 2256 consecutive kidney transplantations performed between 2007 and 2020 at the Medical University of Vienna. Out of 629 in-principle eligible transplantations, we were able to include 465 patients: 42 ABOi, 106 HLAi, and 317 control recipients. Longitudinal TTV- polymerase chain reaction (PCR) and BKV-PCR was carried out at predefined timepoints and ranged from pretransplant until month 24 posttransplantation. TTV loads and immunosuppression were evaluated in the context of BKV-associated complications.
RESULTS
ABOi recipients had a higher TTV load compared to HLAi and controls both at month 3 (median 1.5 × 10 vs. 2.4 × 10 vs. 9.1 × 10; = 0.010) and at month 6 (3.1 × 10 vs. 1.4 × 10 vs. 6.4 × 10; = 0.014) posttransplantation. Tacrolimus exposure was significantly higher in ABOi patients compared to HLAi and control patients (ABOi vs. HLAi: = 0.007; ABOi vs. controls: < 0.0001). Biopsy-proven BKPyVAN was more frequent in ABOi recipients when compared to HLAi and control recipients (11.9% vs. 2.8% vs. 4.1%; = 0.046).
CONCLUSION
Our data support the assumption that ABOi patients are indeed at higher risk to develop BKPyVAN. A higher TTV load and immunosuppressive burden suggest that intense immunosuppression, rather than an "intrinsic attribute" conferred by ABOi, may contribute to this finding.
PubMed: 38899213
DOI: 10.1016/j.ekir.2024.04.003 -
International Journal of Molecular... May 2024Cigarette smoking is a primary contributor to mortality risks and is associated with various diseases. Among these, COPD represents a significant contributor to global...
Cigarette smoking is a primary contributor to mortality risks and is associated with various diseases. Among these, COPD represents a significant contributor to global mortality and disability. The objective of this study is to investigate the effect of smoking on a selected battery of variables, with an emphasis on DNA damage. A total of 87 elderly patients diagnosed with COPD, divided into three groups based on their smoking history (current, former, never-smokers), were evaluated using a cross-sectional approach. Clinical features including mortality and inflammatory/oxidative parameters (Lymphocytes/Monocytes, Neutrophils/Lymphocytes, Platelets/Lymphocytes ratio), SII, MDA, 8-Oxo-dG, and IL6 (ELISA assay), as well as DNA damage (comet assay), were investigated. Virus infection, i.e., influenza A virus subtype H1N1, JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), and Torquetenovirus (TTV), was also tested. Current smokers exhibit higher levels of comorbidity (CIRS; < 0.001), Platelets/Lymphocytes ratio ( < 0.001), systemic immune inflammation ( < 0.05), and DNA damage ( < 0.001). Former smokers also showed higher values for parameters associated with oxidative damage and showed a much lower probability of surviving over 5 years compared to never- and current smokers ( < 0.0017). This study showed a clear interaction between events which are relevant to the oxidative pathway and cigarette smoking. A category of particular interest is represented by former smokers, especially for lower survival, possibly due to the presence of more health problems. Our findings raise also the attention to other parameters which are significantly affected by smoking and are useful to monitor COPD patients starting a program of pulmonary rehabilitation (DNA damage, inflammation parameters, and selected viral infections).
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Female; Aged; Cigarette Smoking; DNA Damage; Oxidative Stress; Cross-Sectional Studies; Middle Aged; Biomarkers; Inflammation
PubMed: 38892022
DOI: 10.3390/ijms25115834 -
Journal of Medical Virology Jun 2024Polyomaviruses BK (BKPyV) and JC (JCPyV), belonging to the Polyomaviridae, are responsible for human pathologies. In kidney transplant recipients, BKPyV replication can...
Polyomaviruses BK (BKPyV) and JC (JCPyV), belonging to the Polyomaviridae, are responsible for human pathologies. In kidney transplant recipients, BKPyV replication can lead to irreversible nephron damage whereas JCPyV replication remains asymptomatic. Concomitant replication is rare and potential competition between the infections has been described. The aim of this retrospective case-control study was to describe the molecular epidemiology and risk factors associated with BKPyV and JCPyV replication in a cohort of kidney transplant recipients. In total, 655 urine samples from 460 patients were tested for BKPyV and JCPyV DNA. Positive samples were submitted to strain genotyping. Demographic and clinical characteristics were also compared. Isolated JCPyV and BKPyV was found in 16.5% and 23.3% of patients, respectively; co-replication was rare (3.9%). BKPyV strains Ib-2, Ib-1, and IVc-2 were the most prevalent. JCPyV strains mostly belonged to genotypes 4 and 1B. During follow-up, JCPyV shedding significantly reduced the risk of BKPyV DNAuria, with an odds ratio of 0.57 (95% confidence interval: 0.35-0.99), and was associated with better prognosis than BKPyV replication, based on the estimated glomerular filtration rate. Molecular epidemiology of BKPyV and JCPyV strains in our region was similar to previous studies. This study suggests that JCPyV is benign and appears to limit damaging BKPyV replication. JCPyV DNAuria screening could thus be a useful strategy to predict BKPyV-related outcomes.
Topics: Humans; BK Virus; Polyomavirus Infections; Kidney Transplantation; Male; Female; Middle Aged; Retrospective Studies; Risk Factors; JC Virus; Case-Control Studies; Adult; Genotype; Molecular Epidemiology; Virus Shedding; Aged; Transplant Recipients; Tumor Virus Infections; DNA, Viral; Allografts
PubMed: 38874263
DOI: 10.1002/jmv.29742 -
Journal of Cellular and Molecular... Jun 2024As an important protein encoded by hepatitis B virus (HBV), HBV X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). It has been...
As an important protein encoded by hepatitis B virus (HBV), HBV X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). It has been shown that seven in absentia homologue 1 (SIAH1) could regulates the degradation of HBx through the ubiquitin-proteasome pathway. However, as a member of SIAH family, the regulatory effects of SIAH2 on HBx remain unclear. In this study, we first confirmed that SIAH2 could reduce the protein levels of HBx depending on its E3 ligase activity. Moreover, SIAH2 interacted with HBx and induced its K48-linked polyubiquitination and proteasomal degradation. Furthermore, we provided evidence that SIAH2 inhibits HBx-associated HCC cells proliferation by regulating HBx. In conclusion, our study identified a novel role for SIAH2 in promoting HBx degradation and SIAH2 exerts an inhibitory effect in the proliferation of HBx-associated HCC through inducing the degradation of HBx. Our study provides a new idea for the targeted degradation of HBx and may have great huge significance into providing novel evidence for the targeted therapy of HBV-infected HCC.
Topics: Humans; Viral Regulatory and Accessory Proteins; Carcinoma, Hepatocellular; Trans-Activators; Ubiquitination; Liver Neoplasms; Ubiquitin-Protein Ligases; Cell Proliferation; Nuclear Proteins; Proteolysis; Hepatitis B virus; Cell Line, Tumor; Signal Transduction; Hep G2 Cells
PubMed: 38842124
DOI: 10.1111/jcmm.18484 -
Virology Journal Jun 2024The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored...
BACKGROUND
The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA.
METHODS
Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log IU/mL ≤ HBV DNA < 7 log IU/mL), moderate (7 log IU/mL ≤ HBV DNA < 8 log IU/mL), and high (HBV DNA ≥ 8 log IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis.
RESULTS
The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis.
CONCLUSION
Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.
Topics: Humans; Hepatitis B, Chronic; Male; Female; Adult; Liver Cirrhosis; DNA, Viral; Alanine Transaminase; Hepatitis B e Antigens; Hepatitis B virus; Middle Aged; Viral Load; Young Adult; Liver; Biopsy
PubMed: 38835029
DOI: 10.1186/s12985-024-02368-0 -
Scientific Reports Jun 2024BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols... (Comparative Study)
Comparative Study
A comparative analysis of clinical outcomes between conversion to mTOR inhibitor and calcineurin inhibitor reduction in managing BK viremia among kidney transplant patients.
BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3-4 and 4-5). In the iVL 4-5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3-4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.
Topics: Humans; Kidney Transplantation; Male; Female; BK Virus; Middle Aged; Calcineurin Inhibitors; Viremia; Polyomavirus Infections; Tacrolimus; Adult; TOR Serine-Threonine Kinases; Immunosuppressive Agents; Viral Load; Treatment Outcome; Tumor Virus Infections; Graft Rejection; Sirolimus; Republic of Korea; Retrospective Studies; Aged
PubMed: 38834615
DOI: 10.1038/s41598-024-60695-2 -
Applied Microbiology and Biotechnology May 2024The African swine fever virus (ASFV) has the ability to infect pigs and cause a highly contagious acute fever that can result in a mortality rate as high as 100%. Due to...
The African swine fever virus (ASFV) has the ability to infect pigs and cause a highly contagious acute fever that can result in a mortality rate as high as 100%. Due to the viral epidemic, the pig industry worldwide has suffered significant financial setbacks. The absence of a proven vaccine for ASFV necessitates the development of a sensitive and reliable serological diagnostic method, enabling laboratories to effectively and expeditiously detect ASFV infection. In this study, four strains of monoclonal antibodies (mAbs) against p72, namely, 5A1, 4C4, 8A9, and 5E10, were generated through recombinant expression of p72, the main capsid protein of ASFV, and immunized mice with it. Epitope localization was performed by truncated overlapping polypeptides. The results indicate that 5A1 and 4C4 recognized the amino acid 20-39 aa, 8A9 and 5E10 are recognized at 263-282 aa, which is consistent with the reported 265-280 aa epitopes. Conserved analysis revealed 20-39 aa is a high conservation of the epitopes in the ASFV genotypes. Moreover, a blocking ELISA assay for detection ASFV antibody based on 4C4 monoclonal antibody was developed and assessed. The receiver-operating characteristic (ROC) was performed to identify the best threshold value using 87 negative and 67 positive samples. The established test exhibited an area under the curve (AUC) of 0.9997, with a 95% confidence interval ranging from 99.87 to 100%. Furthermore, the test achieved a diagnostic sensitivity of 100% (with a 95% confidence interval of 95.72 to 100%) and a specificity of 98.51% (with a 95% confidence interval of 92.02 to 99.92%) when the threshold was set at 41.97%. The inter- and intra-batch coefficient of variation were below 10%, demonstrating the exceptional repeatability of the method. This method can detect the positive standard serum at a dilution as high as 1:512. Subsequently, an exceptional blocking ELISA assay was established with high diagnostic sensitivity and specificity, providing a novel tool for detecting ASFV antibodies. KEY POINTS: • Four strains of ASFV monoclonal antibodies against p72 were prepared and their epitopes were identified. • Blocking ELISA method was established based on monoclonal antibody 4C4 with an identified conservative epitope. • The established blocking ELISA method has a good effect on the detection of ASFV antibody.
Topics: Animals; Antibodies, Monoclonal; African Swine Fever Virus; Epitope Mapping; Enzyme-Linked Immunosorbent Assay; Antibodies, Viral; Swine; African Swine Fever; Mice; Capsid Proteins; Mice, Inbred BALB C; Sensitivity and Specificity; Epitopes
PubMed: 38809284
DOI: 10.1007/s00253-024-13146-x