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Human Cell May 2024Polycystic ovary syndrome (PCOS) is a complex gynaecological endocrine disease that occurs in women of childbearing age. The pathogenesis of PCOS is still unclear and...
Polycystic ovary syndrome (PCOS) is a complex gynaecological endocrine disease that occurs in women of childbearing age. The pathogenesis of PCOS is still unclear and further exploration is needed. Here, proteomic analysis indicated that the expression of farnesyl diphosphate synthase (FDPS) protein in ovarian tissue of PCOS mice was significantly decreased. The purpose of this study is to investigate the relationship between potential biomarkers of PCOS and granulosa cells (GCs) function. The mechanisms by which FDPS affected the proliferation of granulosa cells were also explored both in vitro and in vivo. We found that knockdown of FDPS inhibited the proliferation of KGN (human ovarian granulosa cell line), while overexpression of FDPS had the opposite effect. FDPS activated Rac1 (Rac Family Small GTPase 1) activity and regulated MAPK/ERK signalling pathway, which affecting the proliferation of KGN cells significantly. In addition, treatment with the adeno-associated virus (AAV)-FDPS reverses the dehydroepiandrosterone (DHEA)-induced PCOS-phenotype in mice. Our data indicated that FDPS could regulate the proliferation of ovarian GCs by modulating MAPK/ERK (mitogen-activated protein kinase/extracellular regulated protein kinases) pathway via activating Rac1 activity. These findings suggest that FDPS could be of great value for the regulation of ovarian granulosa cell function and the treatment of PCOS.
Topics: Humans; Female; Mice; Animals; Polycystic Ovary Syndrome; Geranyltranstransferase; Proteomics; Granulosa Cells; Cell Proliferation; MicroRNAs; Apoptosis; rac1 GTP-Binding Protein
PubMed: 38551774
DOI: 10.1007/s13577-024-01050-5 -
Molecular Therapy : the Journal of the... Jun 2024Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia,...
Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in EIF2B5. Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated EIF2B5 gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter-AAV9-gfaABC(1)D-EIF2B5-thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure.
Topics: Animals; Dependovirus; Mice; Disease Models, Animal; Leukoencephalopathies; Genetic Therapy; Genetic Vectors; Astrocytes; Eukaryotic Initiation Factor-2B; Glial Fibrillary Acidic Protein; Humans
PubMed: 38549375
DOI: 10.1016/j.ymthe.2024.03.034 -
Transplant Infectious Disease : An... Apr 2024
Topics: Humans; BK Virus; Polyomavirus Infections; Kidney Transplantation; Immunosuppression Therapy; Inflammation; Tumor Virus Infections; Kidney Diseases
PubMed: 38547004
DOI: 10.1111/tid.14272 -
Transplant Infectious Disease : An... Apr 2024As there is no specific antiviral treatment currently available for BK polyomavirus associated nephropathy (BKVAN), its management relies on immunosuppression reduction...
INTRODUCTION
As there is no specific antiviral treatment currently available for BK polyomavirus associated nephropathy (BKVAN), its management relies on immunosuppression reduction in kidney transplant patients. Data on efficacy of steroid pulses in this indication are lacking.
METHODS
We performed a retrospective monocenter study on 64 patients diagnosed with biopsy-proven BKVAN. Patients within the "pulse group" (n = 37) received IV methylprednisolone 10 mg/kg 3 days consecutively. In the "low dose" steroid group (n = 27), patients were continued oral prednisone 5 mg daily.
RESULTS
Mean follow up was 78 months in the steroid pulse group and 56 months in the low dose group (p = 0.15). Mean eGFR values at diagnosis were comparable, as well as other demographic characteristics. Mean BK plasma viral load was higher in "pulse" than in "low dose" steroid group. Pulse group had higher inflammation and tubulitis (p < 0.05). Graft loss reached 57% in the "pulse" group versus 41% in the "low dose" group, p = 0.20. Rejection events were similar. No major adverse event was statistically associated with steroid pulse, including infections, cancer, and de novo diabetes.
CONCLUSION
No significant differences were found in the evolution of both groups of patients, despite patients receiving "pulse" steroids were identified as the most severe sharing higher BK viral load and more frequent active lesions on histology.
Topics: Humans; BK Virus; Retrospective Studies; Nephritis, Interstitial; Allografts; Inflammation; Steroids; Polyomavirus Infections; Tumor Virus Infections; Kidney Diseases; Graft Rejection
PubMed: 38547002
DOI: 10.1111/tid.14260 -
Asian Pacific Journal of Cancer... Mar 2024Breast cancer, a pervasive invasive carcinoma among women globally, afflicts approximately 12% of women worldwide. Previous studies have indicated that certain viruses,...
INTRODUCTION
Breast cancer, a pervasive invasive carcinoma among women globally, afflicts approximately 12% of women worldwide. Previous studies have indicated that certain viruses, including oncogenic viruses such as polyomaviruses BK and JC, may play a role in the development of breast cancer. In light of this, the present study endeavors to assess the incidence of BKV and JCV virus in breast cancer patients.
MATERIALS AND METHODS
One hundred formalin-fixed paraffin-embedded tissue samples were procured and subjected to deparaffinize by xylene, followed by DNA extraction through the phenol-chloroform methodology. Detection and genotyping of BKV and JCV were carried out utilizing specific primers via PCR analysis.
RESULTS
Merely 2 out of 100 (2%) ductal carcinoma in situ with grade 2 specimens exhibited positivity for BK virus genotype IV, whereas JC virus DNA was not discerned across all the samples.
DISCUSSION
The findings of the current investigation demonstrate that there was an absence of JC virus detection in the breast biopsy. Additionally, a small fraction of patients diagnosed with ductal carcinoma exhibited a low prevalence of genotype IV polyomavirus BK at a rate of 2%. However, in order to gain a more comprehensive understanding of the incidence of BKV and JCV in breast cancer, a substantial number of breast samples must undergo investigation.
Topics: Humans; Female; JC Virus; Breast Neoplasms; Prevalence; Polyomavirus Infections; DNA, Viral; BK Virus; Carcinoma, Intraductal, Noninfiltrating; Tumor Virus Infections
PubMed: 38546065
DOI: 10.31557/APJCP.2024.25.3.821 -
Clinical Transplantation Apr 2024There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19...
Safety and efficacy of a reduced frequency viral monitoring strategy for Epstein-Barr virus, cytomegalovirus, and BK polyomavirus post-kidney transplant: A quality assurance initiative.
BACKGROUND
There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19 pandemic, the Transplant Manitoba Adult Kidney Program updated its monitoring protocols for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) to a reduced frequency.
METHODS
This single-center nested case-control study evaluated 252 adult kidney transplant recipients transplanted from 2015 to 2021, with the updated protocols effective on March 19 2020. Cases included recipients transplanted after the protocol update who developed CMV, EBV, and BKV DNAemia and were matched to controls with DNAemia transplanted prior to the protocol update. The primary outcome was the difference in maximum DNA load titers between cases and matched controls. Secondary outcomes included time to initial DNAemia detection and DNAemia clearance. Safety outcomes of tissue-invasive viral disease were described.
RESULTS
There were 216 recipients transplanted preupdate and 36 recipients postupdate. There was no difference between cases and controls in maximum or first DNA load titers for EBV, CMV, or BKV. Cases experienced earlier EBV DNAemia detection (26 (IQR 8, 32) vs. 434 (IQR 96, 1184) days, p = .005). Median follow-up was significantly longer for recipients transplanted preupdate (4.3 vs. 1.3 years, p < .0001). After adjusting for follow-up time, there was no difference in DNAemia clearance or tissue-invasive viral disease.
CONCLUSION
Our findings suggest that reduced frequency viral monitoring protocols may be safe and cost-effective. This quality assurance initiative should be extended to detect longer-term and tissue-invasive disease outcomes.
Topics: Adult; Humans; Herpesvirus 4, Human; Cytomegalovirus; Kidney Transplantation; Epstein-Barr Virus Infections; BK Virus; Case-Control Studies; Pandemics; Cytomegalovirus Infections; DNA; DNA, Viral; Transplant Recipients
PubMed: 38545888
DOI: 10.1111/ctr.15292 -
Viruses Mar 2024African swine fever (ASF) is a highly contagious and hemorrhagic disease caused by infection with the African swine fever virus (ASFV), resulting in a mortality rate of...
The Accumulation of Phenyllactic Acid Impairs Host Glutamine Metabolism and Inhibits African Swine Fever Virus Replication: A Novel Target for the Development of Anti-ASFV Drugs.
African swine fever (ASF) is a highly contagious and hemorrhagic disease caused by infection with the African swine fever virus (ASFV), resulting in a mortality rate of up to 100%. Currently, there are no effective treatments and commercially available vaccines for ASF. Therefore, it is crucial to identify biochemicals derived from host cells that can impede ASFV replication, with the aim of preventing and controlling ASF. The ASFV is an acellular organism that promotes self-replication by hijacking the metabolic machinery and biochemical resources of host cells. ASFV specifically alters the utilization of glucose and glutamine, which are the primary metabolic sources in mammalian cells. This study aimed to investigate the impact of glucose and glutamine metabolic dynamics on the rate of ASFV replication. Our findings demonstrate that ASFV infection favors using glutamine as a metabolic fuel to facilitate self-replication. ASFV replication can be substantially inhibited by blocking glutamine metabolism. The metabolomics analysis of the host cell after late-stage ASFV infection revealed a significant disruption of normal glutamine metabolic pathways due to the abundant expression of PLA (phenyllactic acid). Pretreatment with PLA also inhibited ASFV proliferation and glutamine consumption following infection. The metabolomic analysis also showed that PLA pretreatment greatly slowed down the metabolism of amino acids and nucleotides that depend on glutamine. The depletion of these building blocks directly hindered the replication of ASFV by decreasing the biosynthetic precursors produced during the replication of ASFV's progeny virus. These findings provide valuable insight into the possibility of pursuing the development of antiviral drugs against ASFV that selectively target metabolic pathways.
Topics: Swine; Animals; African Swine Fever Virus; African Swine Fever; Glutamine; Glucose; Polyesters; Virus Replication; Mammals; Lactates
PubMed: 38543813
DOI: 10.3390/v16030449 -
Biomolecules Mar 2024Mitochondria are essential organelles that possess their own DNA. Mitochondrial dysfunction has been revealed in many kidney diseases, including BK...
Mitochondria are essential organelles that possess their own DNA. Mitochondrial dysfunction has been revealed in many kidney diseases, including BK polyomavirus-associated nephropathy (BKPyVAN). In this study, we introduce an innovative approach for non-invasive monitoring of mitochondrial impairment through urinary donor-derived cell-free mitochondrial DNA (ddcfmtDNA), addressing the crucial challenge of BKPyVAN diagnosis. Urinary samples were collected at the time of biopsy from a total of 60 kidney transplant recipients, comprising 12 with stable function, 22 with T cell-mediated rejection, and 21 with biopsy-proven BKPyVAN. Our findings reveal that the ddcfmtDNA-to-ddcfDNA ratio exhibits superior capability in distinguishing BKPyVAN from other conditions, with a cutoff value of 4.96% (area under curve = 0.933; sensitivity: 71.4%; and specificity: 97.1%). Notably, an elevation of ddcfmtDNA levels is associated with mitochondrial damage, as visualized through electron microscopy. These results underscore the promise of non-invasive monitoring for detecting subtle mitochondrial damage and its potential utility in BKPyVAN diagnosis. Further investigations are required to advance this field of research.
Topics: Humans; Kidney Transplantation; BK Virus; Tumor Virus Infections; Graft Rejection; Polyomavirus Infections; Mitochondria; DNA, Mitochondrial
PubMed: 38540767
DOI: 10.3390/biom14030348 -
Biomedicines Feb 2024Our previous study showed that the Epstein-Barr virus (EBV) may be the etiology for some patients with interstitial cystitis/bladder pain syndrome (IC/BPS); hence, the...
Our previous study showed that the Epstein-Barr virus (EBV) may be the etiology for some patients with interstitial cystitis/bladder pain syndrome (IC/BPS); hence, the current study aimed to investigate the urinary viral spectrum in patients with IC/BPS and the clinical efficacy of valacyclovir. Twenty-eight patients were prospectively enrolled for valacyclovir 500 mg twice a day for 4 weeks. Urine samples were collected from IC/BPS patients and 30 controls. The primary outcome was the difference in the visual analog scale (VAS) pain score, and secondary outcomes included changes in the urinary viral spectrum and urinary inflammatory cytokine level (ClinicalTrials.gov Identifier: NCT05094414). Urinary EBV was detected in 14.2% IC/BPS patients but not in the controls. Urinary John Cunningham virus and BK virus were detected in 18 (64.3%) and 2 (7.1%) patients with IC/BPS, respectively, with similar prevalences noted for the controls. No cytomegalovirus, varicella-zoster virus, or herpes simplex virus was detected in the urine samples. The VAS pain score in patients with IC/BPS significantly decreased after 4 weeks (from 7.5 [5.52-9.0] to 5 [1.5-6.0], = 0.0003). Urinary EBV was undetectable in any sample after valacyclovir treatment, and the decreases in urinary interleukin (IL)-1β (from 0.66 [0.55-0.82] pg/mL to 0.58 [0.55-0.64] pg/mL, = 0.0034), IL-8 (from 6.81 [2.38 to 29.1] pg/mL to 4.33 [1.53-11.04] pg/mL, = 0.0361), IL-10 (from 1.06 [0.94-1.18] pg/mL to 0.92 [0.88-1.02], = 0.0086), and tumor necrosis factor-α (from 1.61 [1.50-1.72] pg/mL to 1.50 [1.44-1.55] pg/mL, = 0.0079) were significant. Valacyclovir could relieve bladder pain, eliminate urinary EBV, and reduce bladder inflammation.
PubMed: 38540138
DOI: 10.3390/biomedicines12030522 -
Journal of Clinical Microbiology Apr 2024BK virus (BKV) infection or reactivation in immunocompromised individuals can lead to adverse health consequences including BKV-associated nephropathy (BKVAN) in kidney...
UNLABELLED
BK virus (BKV) infection or reactivation in immunocompromised individuals can lead to adverse health consequences including BKV-associated nephropathy (BKVAN) in kidney transplant patients and BKV-associated hemorrhagic cystitis (BKV-HC) in allogeneic hematopoietic stem cell transplant recipients. Monitoring BKV viral load plays an important role in post-transplant patient care. This study evaluates the performance of the Alinity m BKV Investigational Use Only (IUO) assay. The linearity of the Alinity m BKV IUO assay had a correlation coefficient of 1.000 and precision of SD ≤ 0.25 Log IU/mL for all panel members tested (2.0-7.3 Log IU/mL). Detection rate at 50 IU/mL was 100%. Clinical plasma specimens tested comparing Alinity m BKV IUO to ELITech MGB Alert BKV lab-developed test (LDT) on the Abbott 2000 platform using specimen extraction protocols for DNA or total nucleic acid (TNA) resulted in coefficient of correlation of 0.900 and 0.963, respectively, and mean bias of 0.03 and -0.54 Log IU/mL, respectively. Alinity m BKV IUO compared with Altona RealStar BKV and Roche cobas BKV assays demonstrated coefficient of correlation of 0.941 and 0.980, respectively, and mean bias of -0.47 and -0.31 Log IU/mL, respectively. Urine specimens tested on Alintiy m BKV IUO and ELITech BKV LDT using TNA specimen extraction had a coefficient of correlation of 0.917 and mean bias of 0.29 Log IU/mL. The Alinity m BKV IUO assay was performed with high precision across the dynamic range and correlated well with other available BKV assays.
IMPORTANCE
BK virus (BKV) in transplant patients can lead to adverse health consequences. Viral load monitoring is important in post-transplant patient care. This study evaluates the Alinity m BKV assay with currently available assays.
Topics: Humans; BK Virus; Kidney Transplantation; Polyomavirus Infections; Viral Load; Nucleic Acids; Tumor Virus Infections
PubMed: 38526061
DOI: 10.1128/jcm.01354-23