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Biological Trace Element Research Jun 2024In recent years, increasing attention has been paid to research on diseases related to the deposition of misfolded proteins (amyloids) in various organs. Moreover,...
In recent years, increasing attention has been paid to research on diseases related to the deposition of misfolded proteins (amyloids) in various organs. Moreover, modern scientists emphasise the importance of selenium as a bioelement necessary for the proper functioning of living organisms. The inorganic form of selenium-sodium selenite (redox-active)-can prevent the formation of an insoluble polymer in proteins. It is very important to undertake tasks aimed at understanding the mechanisms of action of this element in inhibiting the formation of various types of amyloid. Furthermore, yeast cells play an important role in this matter as a eukaryotic model organism, which is intensively used in molecular research on protein amyloidosis. Due to the lack of appropriate treatment in the general population, the problem of amyloidosis remains unsolved. This extracellular accumulation of amyloid is one of the main factors responsible for the occurrence of Alzheimer's disease. The review presented here contains scientific information discussing a brief description of the possibility of amyloid formation in cells and the use of selenium as a factor preventing the formation of these protein aggregates. Recent studies have shown that the yeast model can be successfully used as a eukaryotic organism in biotechnological research aimed at understanding the essence of the entire amyloidosis process. Understanding the mechanisms that regulate the reaction of yeast to selenium and the phenomenon of amyloidosis is important in the aetiology and pathogenesis of various disease states. Therefore, it is imperative to conduct further research and analysis aimed at explaining and confirming the role of selenium in the processes of protein misfolding disorders. The rest of the article discusses the characteristics of food protein amyloidosis and their use in the food industry. During such tests, their toxicity is checked because not all food proteins can produce amyloid that is toxic to cells. It should also be noted that a moderate diet is beneficial for the corresponding disease relief caused by amyloidosis.
PubMed: 38829477
DOI: 10.1007/s12011-024-04245-x -
Hepatology (Baltimore, Md.) May 2024New guidelines for the definitions of steatotic liver disease have named the entity of MetALD as an overlap condition of metabolic-dysfunction associated steatotic liver...
New guidelines for the definitions of steatotic liver disease have named the entity of MetALD as an overlap condition of metabolic-dysfunction associated steatotic liver disease (MASLD) and alcohol-related liver disease. There is a broad range of therapeutics in all stages of development for MASLD but these therapeutics in general have not been studied in patients with significant ongoing alcohol use. In this review we discuss the current understanding of the endogenous and exogenous risks for MASLD and MetALD. Rational strategies for therapeutic intervention in MetALD include biopsychosocial interventions, alcohol use cessation strategies including the use of medications for alcohol use disorder and judicious use of therapeutics for steatotic liver disease. Therapeutics with promise for MetALD include incretin-based therapies, fibroblast growth factor 21 (FGF21) agonists, thyroid hormone receptor beta (THR- β) agonists, sodium-glucose co-transporter 2 (SGLT2) inhibitors and agents to modify de-novo lipogenesis (DNL). Currently glucagon like peptide 1 receptor agonists (GLP-1ra) and peroxisome proliferator-activated receptor (PPAR) γ agonists have the largest body of literature supporting their use in MASLD and there is a paucity of agents in trials for alcohol-related liver disease. From existing studies, it is not clear if unique therapeutics or a combinatorial approach are needed for MetALD. Further elucidation of the safety and benefits of MASLD-related therapies are of paramount importance for advancing therapeutics for MetALD in carefully designed inclusive clinical trials.
PubMed: 38820071
DOI: 10.1097/HEP.0000000000000935 -
Journal of Parkinson's Disease 2024The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well...
BACKGROUND
The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood.
OBJECTIVE
To determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants.
METHODS
Participants of the Parkinson's Progression Markers Initiative (PPMI) with a LRRK2-G2019 S or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure.
RESULTS
378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019 S (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7-18.5, p < 0.01). People with a LRRK2 variant and a history of occupational pesticide exposure had non-significantly elevated odds of PD (aOR 1.3, 95% CI 0.4-4.6, p = 0.7). Among those with PD, pesticide exposure was associated with a higher risk of balance problems and cognitive impairment in LRRK2-PD and functional impairment in GBA-PD, although associations were not statistically significant.
CONCLUSIONS
Occupational pesticide exposure may increase penetrance of GBA-PD and may be associated with faster symptom progression. Further studies in larger cohorts are necessary.
Topics: Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Female; Parkinson Disease; Male; Glucosylceramidase; Occupational Exposure; Pesticides; Aged; Middle Aged; Penetrance; Activities of Daily Living; Cognitive Dysfunction
PubMed: 38820021
DOI: 10.3233/JPD-240015 -
Frontiers in Veterinary Science 2024Recently, herpesvirus of turkeys (HVT), which was initially employed as a vaccine against Marek's disease (MD), has been shown to be a highly effective viral vector for...
Simultaneous construction strategy using two types of fluorescent markers for HVT vector vaccine against infectious bursal disease and H9N2 avian influenza virus by NHEJ-CRISPR/Cas9.
Recently, herpesvirus of turkeys (HVT), which was initially employed as a vaccine against Marek's disease (MD), has been shown to be a highly effective viral vector for producing recombinant vaccines that can simultaneously express the protective antigens of multiple poultry diseases. Prior to the development of commercial HVT-vectored dual-insert vaccines, the majority of HVT-vectored vaccines in use only contained a single foreign gene and were often generated using time-consuming and inefficient traditional recombination methods. The development of multivalent HVT-vectored vaccines that induce simultaneous protection against several avian diseases is of great value. In particular, efficacy interference between individual recombinant HVT vaccines can be avoided. Herein, we demonstrated the use of CRISPR/Cas9 gene editing technology for the insertion of an IBDV (G2d) VP2 expression cassette into the UL45/46 region of the recombinant rHVT-HA viral genome to generate the dual insert rHVT-VP2-HA recombinant vaccine. The efficacy of this recombinant virus was also evaluated in specific pathogen-free (SPF) chickens. PCR and sequencing results showed that the recombinant virus rHVT-VP2-HA was successfully constructed. Vaccination with rHVT-VP2-HA produced high levels of specific antibodies against IBDV (G2d) and H9N2/Y280. rHVT-VP2-HA can provide 100% protection against challenges with IBDV (G2d) and H9N2/Y280. These results demonstrate that rHVT-VP2-HA is a safe and highly efficacious vaccine for the simultaneous control of IBDV (G2d) and H9N2/Y280.
PubMed: 38812565
DOI: 10.3389/fvets.2024.1385958 -
PLoS Pathogens May 2024Marek's disease virus (MDV) vaccines were the first vaccines that protected against cancer. The avirulent turkey herpesvirus (HVT) was widely employed and protected...
Marek's disease virus (MDV) vaccines were the first vaccines that protected against cancer. The avirulent turkey herpesvirus (HVT) was widely employed and protected billions of chickens from a deadly MDV infection. It is also among the most common vaccine vectors providing protection against a plethora of pathogens. HVT establishes latency in T-cells, allowing the vaccine virus to persist in the host for life. Intriguingly, the HVT genome contains telomeric repeat arrays (TMRs) at both ends; however, their role in the HVT life cycle remains elusive. We have previously shown that similar TMRs in the MDV genome facilitate its integration into host telomeres, which ensures efficient maintenance of the virus genome during latency and tumorigenesis. In this study, we investigated the role of the TMRs in HVT genome integration, latency, and reactivation in vitro and in vivo. Additionally, we examined HVT infection of feather follicles. We generated an HVT mutant lacking both TMRs (vΔTMR) that efficiently replicated in cell culture. We could demonstrate that wild type HVT integrates at the ends of chromosomes containing the telomeres in T-cells, while integration was severely impaired in the absence of the TMRs. To assess the role of TMRs in vivo, we infected one-day-old chickens with HVT or vΔTMR. vΔTMR loads were significantly reduced in the blood and hardly any virus was transported to the feather follicle epithelium where the virus is commonly shed. Strikingly, latency in the spleen and reactivation of the virus were severely impaired in the absence of the TMRs, indicating that the TMRs are crucial for the establishment of latency and reactivation of HVT. Our findings revealed that the TMRs facilitate integration of the HVT genome into host chromosomes, which ensures efficient persistence in the host, reactivation, and transport of the virus to the skin.
Topics: Animals; Chickens; Telomere; Virus Integration; Marek Disease; Virus Latency; Genetic Vectors; Herpesvirus 1, Meleagrid; Marek Disease Vaccines; Genome, Viral; Herpesvirus 2, Gallid; Repetitive Sequences, Nucleic Acid; Poultry Diseases
PubMed: 38805555
DOI: 10.1371/journal.ppat.1012261 -
Frontiers in Veterinary Science 2024MicroRNAs (miRNAs) serve as key regulators in gene expression and play a crucial role in immune responses, holding a significant promise for diagnosing and managing... (Review)
Review
MicroRNAs (miRNAs) serve as key regulators in gene expression and play a crucial role in immune responses, holding a significant promise for diagnosing and managing diseases in farm animals. This review article summarizes current research on the role of miRNAs in various farm animal diseases and mycotoxicosis, highlighting their potential as biomarkers and using them for mitigation strategies. Through an extensive literature review, we focused on the impact of miRNAs in the pathogenesis of several farm animal diseases, including viral and bacterial infections and mycotoxicosis. They regulate gene expression by inducing mRNA deadenylation, decay, or translational inhibition, significantly impacting cellular processes and protein synthesis. The research revealed specific miRNAs associated with the diseases; for instance, gga-miR-M4 is crucial in Marek's disease, and gga-miR-375 tumor-suppressing function in Avian Leukosis. In swine disease such as Porcine Respiratory and Reproductive Syndrome (PRRS) and swine influenza, miRNAs like miR-155 and miR-21-3p emerged as key regulatory factors. Additionally, our review highlighted the interaction between miRNAs and mycotoxins, suggesting miRNAs can be used as a biomarker for mycotoxin exposure. For example, alterations in miRNA expression, such as the dysregulation observed in response to Aflatoxin B1 (AFB1) in chickens, may indicate potential mechanisms for toxin-induced changes in lipid metabolism leading to liver damage. Our findings highlight miRNAs potential for early disease detection and intervention in farm animal disease management, potentially reducing significant economic losses in agriculture. With only a fraction of miRNAs functionally characterized in farm animals, this review underlines more focused research on specific miRNAs altered in distinct diseases, using advanced technologies like CRISPR-Cas9 screening, single-cell sequencing, and integrated multi-omics approaches. Identifying specific miRNA targets offers a novel pathway for early disease detection and the development of mitigation strategies against mycotoxin exposure in farm animals.
PubMed: 38803799
DOI: 10.3389/fvets.2024.1372961 -
Viruses May 2024Marek's disease (MD), caused by (GaAHV2) or Marek's disease herpesvirus (MDV), is a devastating disease in chickens characterized by the development of lymphomas...
Marek's disease (MD), caused by (GaAHV2) or Marek's disease herpesvirus (MDV), is a devastating disease in chickens characterized by the development of lymphomas throughout the body. Vaccine strains used against MD include 3 (GaAHV3), a non-oncogenic chicken alphaherpesvirus homologous to MDV, and homologous meleagrid alphaherpesvirus 1 (MeAHV1) or turkey herpesvirus (HVT). Previous work has shown most of the MDV gC produced during in vitro passage is secreted into the media of infected cells although the predicted protein contains a transmembrane domain. We formerly identified two alternatively spliced gC mRNAs that are secreted during MDV replication in vitro, termed gC104 and gC145 based on the size of the intron removed for each (gC) transcript. Since gC is conserved within the subfamily, we hypothesized GaAHV3 (strain 301B/1) and HVT also secrete gC due to mRNA splicing. To address this, we collected media from 301B/1- and HVT-infected cell cultures and used Western blot analyses and determined that both 301B/1 and HVT produced secreted gC. Next, we extracted RNAs from 301B/1- and HVT-infected cell cultures and chicken feather follicle epithelial (FFE) skin cells. RT-PCR analyses confirmed one splicing variant for 301B/1 gC (gC104) and two variants for HVT gC (gC104 and gC145). Interestingly, the splicing between all three viruses was remarkably conserved. Further analysis of predicted and validated mRNA splicing donor, branch point (BP), and acceptor sites suggested single nucleotide polymorphisms (SNPs) within the 301B/1 transcript sequence resulted in no gC145 being produced. However, modification of the 301B/1 gC145 donor, BP, and acceptor sites to the MDV sequences did not result in gC145 mRNA splice variant, suggesting mRNA splicing is more complex than originally hypothesized. In all, our results show that mRNA splicing of avian herpesviruses is conserved and this information may be important in developing the next generation of MD vaccines or therapies to block transmission.
Topics: Animals; Chickens; RNA Splicing; Viral Envelope Proteins; RNA, Messenger; Marek Disease; Mardivirus; Viral Proteins; Herpesvirus 2, Gallid; Alternative Splicing; Antigens, Viral
PubMed: 38793663
DOI: 10.3390/v16050782 -
Poultry Science Jul 2024Marek's disease virus (MDV) is a significant tumorigenic virus that causes severe immunosuppression in chickens. Lentinan (LNT) is an immunomodulator containing...
Marek's disease virus (MDV) is a significant tumorigenic virus that causes severe immunosuppression in chickens. Lentinan (LNT) is an immunomodulator containing β-glucans and is widely used in areas such as antiviral, anticancer, and immune regulation. To investigate the immunomodulatory effects of LNT on specific pathogen-free (SPF) chicks and its potential to inhibit MDV infection, we conducted an MDV challenge experiment and observed the immune-enhancing effect of LNT on SPF chicks. The results showed that LNT promoted the growth and development of SPF chicks and induced the upregulation of cytokines such as Mx protein, interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), and interleukin-2 (IL-2). The specific gravity of CD4 T-lymphocytes and CD8 T-lymphocytes and their ratios were also significantly upregulated. Prophylactic use of LNT inhibited MDV replication in lymphocytes, liver, and spleen. It also alleviated MDV-induced weight loss and hepatosplenomegaly in SPF chicks. The present study confirms that LNT can enhance the levels of innate and cellular immunity in SPF chicks and contributes to the inhibition of MDV replication in vivo and mitigation of immune organ damage in chicks due to MDV infection. This provides an adjunctive measure for better control of MDV infection.
Topics: Animals; Chickens; Marek Disease; Lentinan; Poultry Diseases; Herpesvirus 2, Gallid; Specific Pathogen-Free Organisms; Animal Feed; Immunologic Factors; Diet; Random Allocation
PubMed: 38772093
DOI: 10.1016/j.psj.2024.103840 -
Neurologia I Neurochirurgia Polska 2024To investigate the relationship between serum lipoprotein (a) [Lp(a)] concentration and the risk of ischaemic stroke (IS) and its subtypes.
AIM OF THE STUDY
To investigate the relationship between serum lipoprotein (a) [Lp(a)] concentration and the risk of ischaemic stroke (IS) and its subtypes.
CLINICAL RATIONALE FOR THE STUDY
Lp(a) plays a role in atherogenic, pro-thrombotic, and antifibrinolytic processes. Elevated plasma Lp(a) is a strong independent risk factor for the development and progression of atherosclerotic disease. The association between lipoproteins and IS is more complex than that reported for cardiovascular diseases, with inconsistent and contradictory results from epidemiological studies.
MATERIAL AND METHODS
231 patients with acute IS (defined as cases) and 163 age- and sex-matched control subjects were included in this prospective case-control study. Demographic and clinical variables (i.e. age, sex, smoking, presence of chronic diseases and concomitant medication) and laboratory data (i.e. concentrations of total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Lp(a), apolipoprotein A1, apolipoprotein B) were recorded.
RESULTS
The mean age and the percentage of men did not significantly differ between groups. Compared to controls, there was a significantly higher percentage of cases reported with concomitant diseases: diabetes mellitus, myocardial infarction, ischaemic heart disease, peripheral arterial disease, and atrial fibrillation. The study showed a significantly higher serum Lp(a) concentration in cases than in control subjects (81.81 nmol/L [c.32.7 mg/dL] vs. 59.75 nmol/L [c.23.9 mg/dL]; p = 0.036) and found an association between Lp(a) levels stratified by quartiles and the risk for ischaemic stroke (Q1 [Lp(a) < 13 nmol/L] vs. Q4 [Lp(a) > 117 nmol/L]: OR 2.23; 95% CI 1.23-4.03; p = 0.008). A subgroup analysis based on the TOAST classification of IS also showed a significant association between Lp(a) value of more than 75 nmol/L (30 mg/dL) and the risk of large-artery atherosclerosis stroke compared to the controls (OR 2.4; 95% CI 1.39-3.93; p = 0.001), as well as a statistically non-significant association with other subtypes of IS. The influence of Lp(a) remained significant even after adjusting for established risk factors for IS (OR 1.99; 95% CI 1.05-3.76; p = 0.04; respectively for the large-artery atherosclerotic subtype: OR 2.54; 95% CI 1.39-4.67; p = 0.003).
CONCLUSION
We found that Lp(a) is an independent risk factor for ischaemic stroke, and for the large-artery atherosclerotic subtype of ischaemic stroke.
Topics: Humans; Male; Lipoprotein(a); Female; Risk Factors; Case-Control Studies; Ischemic Stroke; Middle Aged; Aged; Prospective Studies
PubMed: 38767133
DOI: 10.5603/pjnns.98343 -
Lancet (London, England) Jun 2024Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.
BACKGROUND
Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear.
METHODS
RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.
FINDINGS
Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths.
INTERPRETATION
Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population.
FUNDING
Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Prostatectomy; Aged; Tosyl Compounds; Anilides; Middle Aged; Nitriles; Oligopeptides; Gonadotropin-Releasing Hormone; Combined Modality Therapy; Prostate-Specific Antigen
PubMed: 38763154
DOI: 10.1016/S0140-6736(24)00548-8