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Scientific Reports Jun 2024In recent decades, the food system has been faced with the significant problem of increasing food waste. Therefore, the feed industry, supported by scientific research,...
In recent decades, the food system has been faced with the significant problem of increasing food waste. Therefore, the feed industry, supported by scientific research, is attempting to valorise the use of discarded biomass as co-products for the livestock sector, in line with EU objectives. In parallel, the search for functional products that can ensure animal health and performances is a common fundamental goal for both animal husbandry and feeding. In this context, camelina cake (CAMC), cardoon cake (CC) and cardoon meal (CM), due valuable nutritional profile, represent prospective alternatives. Therefore, the aim of this work was to investigate the antioxidant activity of CAMC, CC and CM following in vitro digestion using 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), Ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Total phenolic content (TPC) and angiotensin converting enzyme (ACE) inhibitory activity, actively involved in modulating antioxidant properties, were also studied. Further, a peptidomic analysis was adopted to substantiate the presence of bioactive peptides after in vitro digestion. The results obtained confirmed an interesting nutritional profile of CAMC, CC and CM and relevant antioxidant and ACE inhibitory activities. In particular, considering antioxidant profile, CM and CC revealed a significantly higher (10969.80 ± 18.93 mg TE/100 g and 10451.40 ± 149.17 mg TE/100 g, respectively; p < 0.05) ABTS value than CAMC (9511.18 ± 315.29 mg TE/100 g); a trend also confirmed with the FRAP assay (306.74 ± 5.68 mg FeSO/100 g; 272.84 ± 11.02 mg FeSO/100 g; 103.84 ± 3.27 mg FeSO/100 g, for CC, CM and CAMC, respectively). Similar results were obtained for TPC, demonstrating the involvement of phenols in modulating antioxidant activity. Finally, CAMC was found to have a higher ACE inhibitory activity (40.34 ± 10.11%) than the other matrices. Furthermore, potentially bioactive peptides associated with ACE inhibitory, anti-hypertensive, anti-cancer, antimicrobial, antiviral, antithrombotic, DPP-IV inhibitory and PEP-inhibitory activities were identified in CAMC. This profile was broader than that of CC and CM. The presence of such peptides corroborates the antioxidant and ACE profile of the sample. Although the data obtained report the important antioxidant profile of CAMC, CC, and CM and support their possible use, future investigations, particularly in vivo trials will be critical to evaluate and further investigate their effects on the health and performance of farm animals.
Topics: Antioxidants; Cynara; Brassicaceae; Angiotensin-Converting Enzyme Inhibitors; Phenols; Peptides; Animals; Plant Extracts; Animal Feed; Proteomics
PubMed: 38914602
DOI: 10.1038/s41598-024-64989-3 -
Frontiers in Immunology 2024Anti-rods and rings (anti-RR) antibodies have recently been described as a cytoplasmic pattern in IIF-based screening of autoantibodies on HEp-2 cells and ICAP has named...
INTRODUCTION
Anti-rods and rings (anti-RR) antibodies have recently been described as a cytoplasmic pattern in IIF-based screening of autoantibodies on HEp-2 cells and ICAP has named it as AC-23. It is most frequently related to drug-induced antibody generation. This study aimed to investigate the clinical significance of AC-23 positivity and its relevance to the diagnosis and/or follow-up of the associated diseases and/or drug use.
METHODS
A multicenter retrospective study was conducted among 10 hospitals from six different provinces in Türkiye from January 2017 to December 2021. The laboratory data and clinical information of 600 patients with positive anti-RR antibodies out of 547.558 HEp-2 IIF ANA samples were analyzed.
RESULTS
The distribution of AC-23 positive patients by year indicated a steady increase between 2017-2021. Anti-RR prevalence in post-COVID-19 period was significantly higher than that of pre-COVID-19 period (p=0.00). Concomitant ANA positivity was detected in 56.5% of patients, the most common patterns being AC-4 and AC-5 (41.1%). The most frequent pathology among the anti-RR positive patients was an autoimmune disease (19.83%); 28.57% of which had rheumatoid arthritis and 17.65% autoimmune liver disease. Among the 600 patients, 65 (10.83%) were diagnosed as hepatitis C virus (HCV) infection. Available data for 38 of the HCV patients revealed that 71.05% of them had a history of interferon alfa+ribavirin and 28.95% of them had a history of NS3/4/5A/5B polymerase inhibitor or protease inhibitor drug use. Significant increase in the rate of anti-RR positivity was observed in the post-COVID-19 period when compared to pre-COVID-19 period (p:0.00).
DISCUSSION
This is the first multicenter study in Türkiye about the clinical association of anti-RR antibodies which may be ignored during routine HEp-2 IIF testing. Pathologies other than HCV should be taken into consideration in terms of the possible role of anti-RR in autoimmune diseases and other pathologies. The preliminary data obtained in this study suggest that anti-RR antibody development might also be associated to COVID-19, supporting the several previous data related to the potential of viruses triggering the formation of autoantibodies. Large-scale prospective studies should elucidate the clinical significance of RR pattern and determine its role in patient diagnosis and follow-up.
Topics: Humans; Retrospective Studies; Antibodies, Antinuclear; Female; Male; COVID-19; Middle Aged; Fluorescent Antibody Technique, Indirect; Aged; Adult; SARS-CoV-2; Autoimmune Diseases
PubMed: 38911869
DOI: 10.3389/fimmu.2024.1359030 -
ACS Omega Jun 2024New 2-thioxopyrimidinone derivatives (-) were synthesized in 87-96% yields via a simple three-component condensation reaction. These compounds were screened extensively...
New Pyrimidinone Bearing Aminomethylenes and Schiff Bases as Potent Antioxidant, Antibacterial, SARS-CoV-2, and COVID-19 Main Protease M Inhibitors: Design, Synthesis, Bioactivities, and Computational Studies.
New 2-thioxopyrimidinone derivatives (-) were synthesized in 87-96% yields via a simple three-component condensation reaction. These compounds were screened extensively through assays for antioxidant and antibacterial investigations. The DPPH assays resulted in the excellent potency of - as antioxidants with IC values of 0.83 ± 0.125, 0.90 ± 0.77, 0.36 ± 0.063, 1.4 ± 0.07, and 1.18 ± 0.06 mg/mL, which were much better than 1.79 ± 0.045 mg/mL for the reference ascorbic acid. These compounds exhibited better antibacterial potency against with IC values of 2 ± 7, 1.32 ± 8.9, 1.19 ± 11, 1.1 ± 12, and 1.16 ± 11 mg/mL for -. High-throughput screenings (HTS) of these motifs were carried out including investigation of drug-like behaviors, physiochemical property evaluation, and structure-related studies involving DFT and metabolic transformation trends. The radical scavenging ability of the synthesized motifs was validated through molecular docking studies through ligand-protein binding against human inducible nitric oxide synthase (HINOS) PDB ID: 4NOS, and the results were promising. Furthermore, the antiviral capability of the compounds was examined by studies using two viral proteins PDB ID: 6Y84 and PDB ID: 6LU7. Binding poses of ligands were discussed, and amino acids in the protein binding pockets were investigated, where the tested compounds showed much better binding affinities than the standard inhibitors, proving to be suitable leads for antiviral drug discovery. The stabilities of the molecular docked complexes in real systems were validated by molecular dynamics simulations.
PubMed: 38911743
DOI: 10.1021/acsomega.3c09393 -
RSC Medicinal Chemistry Jun 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of January 2024, there has been over 774 million reported cases and 7 million deaths worldwide. While vaccination efforts have been successful in reducing the severity of the disease and decreasing the transmission rate, the development of effective therapeutics against SARS-CoV-2 remains a critical need. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme required for viral replication and has been identified as a promising target for drug development. In this study, we report the identification of novel Mpro inhibitors, using a combination of deep reinforcement learning for drug design with 3D pharmacophore/shape-based alignment and privileged fragment match count scoring components followed by hit expansions and molecular docking approaches. Our experimentally validated results show that 3 novel series exhibit potent inhibitory activity against SARS-CoV-2 Mpro, with IC values ranging from 1.3 μM to 2.3 μM and a high degree of selectivity. These findings represent promising starting points for the development of new antiviral therapies against COVID-19.
PubMed: 38911172
DOI: 10.1039/d4md00106k -
TH Open : Companion Journal To... Apr 2024Agonist-induced platelet activation, with the integrin αIIbβ3 conformational change, is required for fibrinogen binding. This is considered reversible under...
Agonist-induced platelet activation, with the integrin αIIbβ3 conformational change, is required for fibrinogen binding. This is considered reversible under specific conditions, allowing a second phase of platelet aggregation. The signaling pathways that differentiate between a permanent or transient activation state of platelets are poorly elucidated. To explore platelet signaling mechanisms induced by the collagen receptor glycoprotein VI (GPVI) or by protease-activated receptors (PAR) for thrombin that regulate time-dependent αIIbβ3 activation. Platelets were activated with collagen-related peptide (CRP, stimulating GPVI), thrombin receptor-activating peptides, or thrombin (stimulating PAR1 and/or 4). Integrin αIIbβ3 activation and P-selectin expression was assessed by two-color flow cytometry. Signaling pathway inhibitors were applied before or after agonist addition. Reversibility of platelet spreading was studied by microscopy. Platelet pretreatment with pharmacological inhibitors decreased GPVI- and PAR-induced integrin αIIbβ3 activation and P-selectin expression in the target order of protein kinase C (PKC) > glycogen synthase kinase 3 > β-arrestin > phosphatidylinositol-3-kinase. Posttreatment revealed secondary αIIbβ3 inactivation (not P-selectin expression), in the same order, but this reversibility was confined to CRP and PAR1 agonist. Combined inhibition of conventional and novel PKC isoforms was most effective for integrin closure. Pre- and posttreatment with ticagrelor, blocking the P2Y adenosine diphosphate (ADP) receptor, enhanced αIIbβ3 inactivation. Spreading assays showed that PKC or P2Y inhibition provoked a partial conversion from filopodia to a more discoid platelet shape. PKC and autocrine ADP signaling contribute to persistent integrin αIIbβ3 activation in the order of PAR1/GPVI > PAR4 stimulation and hence to stabilized platelet aggregation. These findings are relevant for optimization of effective antiplatelet treatment.
PubMed: 38911141
DOI: 10.1055/s-0044-1786987 -
BMC Medical Research Methodology Jun 2024Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials.
METHODS
We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.
RESULTS
We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).
CONCLUSIONS
Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Cholesterol, LDL; Male; Anticholesteremic Agents; Randomized Controlled Trials as Topic; Female; Treatment Outcome; Middle Aged; Hypercholesterolemia; PCSK9 Inhibitors; Aged; Proprotein Convertase 9
PubMed: 38909176
DOI: 10.1186/s12874-024-02260-z -
Scientific Reports Jun 2024The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants... (Observational Study)
Observational Study
The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants to such patients because of possible harm. The effects of frailty on anticoagulant therapy in older Japanese patients with nonvalvular atrial fibrillation (NVAF) are unclear. Herein, we prescribed rivaroxaban to Japanese patients with NVAF and monitored for a mean of 2.0 years. The primary endpoint was stroke or systemic embolism. The secondary endpoints were all-cause or cardiovascular death, composite endpoint, and major or non-major bleeding. Frailty was assessed using the Japanese long-term care insurance system. A multiple imputation technique was used for missing data. The propensity score (PS) was obtained to estimate the treatment effect of frailty and was used to create two PS-matched groups. Overall, 5717 older patients had NVAF (mean age: 73.9 years), 485 (8.5%) were classified as frail. After PS matching, background characteristics were well-balanced between the groups. Rivaroxaban dosages were 10 and 15 mg/day for approximately 80% and the remaining patients, respectively. Frailty was not associated with the primary endpoint or secondary endpoints. In conclusion, frailty does not affect the effectiveness or safety of rivaroxaban anticoagulant therapy in older Japanese patients with NVAF.Trial registration: UMIN000019135, NCT02633982.
Topics: Humans; Atrial Fibrillation; Aged; Male; Female; Frailty; Rivaroxaban; Aged, 80 and over; Anticoagulants; Japan; Stroke; Frail Elderly; Hemorrhage; Factor Xa Inhibitors; East Asian People
PubMed: 38909144
DOI: 10.1038/s41598-024-65237-4 -
Ecotoxicology and Environmental Safety Jun 2024Paraquat (PQ) is a widely used herbicide that poisons human by accident or intentional ingestion. PQ poisoning causes systemic inflammatory response syndrome (SIRS)...
BACKGROUND
Paraquat (PQ) is a widely used herbicide that poisons human by accident or intentional ingestion. PQ poisoning causes systemic inflammatory response syndrome (SIRS) resulting in acute lung injury (ALI) with an extremely high mortality rate. Blood trematode Schistosoma japonicum-produced cystatin (Sj-Cys) is a strong immunomodulatory protein that has been experimentally used to treat inflammation related diseases. In this study, Sj-Cys recombinant protein (rSj-Cys) was used to treat PQ-induced lung injury and the immunological mechanism underlying the therapeutic effect was investigated.
METHODS
PQ-induced acute lung injury mouse model was established by intraperitoneally injection of 20 mg/kg of paraquat. The poisoned mice were treated with rSj-Cys and the survival rate was observed up to 7 days compared with the group without treatment. The pathological changes of PQ-induced lung injury were observed by examining the histochemical sections of affected lung tissue and the wet to dry ratio of lung as a parameter for inflammation and edema. The levels of the inflammation related cytokines IL-6 and TNF-α and regulatory cytokines IL-10 and TGF-β were measured in sera and in affected lung tissue using ELISA and their mRNA levels in lung tissue using RT-PCR. The macrophages expressing iNOS were determined as M1 and those expressing Arg-1 as M2 macrophages. The effect of rSj-Cys on the transformation of inflammatory M1 to regulatory M2 macrophages was measured in affected lung tissue in vivo (EKISA and RT-PCR) and in MH-S cell line in vitro (flow cytometry). The expression levels of TLR2 and MyD88 in affected lung tissue were also measured to determine their role in the therapy of rSj-Cys on PQ-induced lung injury.
RESULT
We identified that treatment with rSj-Cys significantly improved the survival rate of mice with PQ-induced lung injury from 30 % (untreated) to 80 %, reduced the pathological damage of poisoning lung tissue, associated with significantly reduced levels of proinflammatory cytokines (IL-6 from 1490 to 590 pg/ml, TNF-α from 260 to 150 pg/ml) and increased regulatory cytokines (IL-10 from360 to 550 pg/ml, and TGF-β from 220 to 410 pg/ml) in both sera (proteins) and affected lung tissue (proteins and mRNAs). The polarization of macrophages from M1to M2 type was found to be involved in the therapeutic effect of rSj-Cys on the PQ-induced acute lung injury, possibly through inhibiting TLR2/MyD88 signaling pathway.
CONCLUSIONS
Our study demonstrated the therapeutic effect of rSj-Cys on PQ poisoning caused acute lung injury by inducing M2 macrophage polarization through inhibiting TLR2/MyD88 signaling pathway. The finding in this study provides an alternative approach for the treatment of PQ poisoning and other inflammatory diseases.
PubMed: 38905933
DOI: 10.1016/j.ecoenv.2024.116615 -
Polish Journal of Microbiology Jun 2024Chikungunya virus (CHIKV) causes a debilitating fever and joint pain, with no specific antiviral treatment available. Halogenated secondary metabolites from plants are a...
Chikungunya virus (CHIKV) causes a debilitating fever and joint pain, with no specific antiviral treatment available. Halogenated secondary metabolites from plants are a promising new class of drug candidates against chikungunya, with unique properties that make them effective against the virus. Plants produce these compounds to defend themselves against pests and pathogens, and they are effective against a wide range of viruses, including chikungunya. This study investigated the interactions of halogenated secondary metabolites with nsP2pro, a therapeutic target for CHIKV. A library of sixty-six halogenated plant metabolites screened previously for ADME properties was used. Metabolites without violation of Lipinski's rule were docked with nsP2pro using AutoDock Vina. To find the stability of the pipoxide chlorohydrin-nsP2pro complex, the GROMACS suite was used for MD simulation. The binding free energy of the ligand-protein complex was computed using MMPBSA. Molecular docking studies revealed that halogenated metabolites interact with nsP2pro, suggesting they are possible inhibitors. Pipoxide chlorohydrin showed the greatest affinity to the target. This was further confirmed by the MD simulations, surface accessible area, and MMPBSA studies. Pipoxide chlorohydrin, a halogenated metabolite, was the most potent against nsP2pro in the survey.
Topics: Chikungunya virus; Molecular Docking Simulation; Antiviral Agents; Chikungunya Fever; Secondary Metabolism; Molecular Dynamics Simulation; Halogenation; Plants; Computer Simulation; Viral Nonstructural Proteins
PubMed: 38905281
DOI: 10.33073/pjm-2024-020 -
PloS One 2024The battle against viral drug resistance highlights the need for innovative approaches to replace time-consuming and costly traditional methods. Deep generative models...
The battle against viral drug resistance highlights the need for innovative approaches to replace time-consuming and costly traditional methods. Deep generative models offer automation potential, especially in the fight against Human immunodeficiency virus (HIV), as they can synthesize diverse molecules effectively. In this paper, an application of an LSTM-based deep generative model named "LSTM-ProGen" is proposed to be tailored explicitly for the de novo design of drug candidate molecules that interact with a specific target protein (HIV-1 protease). LSTM-ProGen distinguishes itself by employing a long-short-term memory (LSTM) architecture, to generate novel molecules target specificity against the HIV-1 protease. Following a thorough training process involves fine-tuning LSTM-ProGen on a diverse range of compounds sourced from the ChEMBL database. The model was optimized to meet specific requirements, with multiple iterations to enhance its predictive capabilities and ensure it generates molecules that exhibit favorable target interactions. The training process encompasses an array of performance evaluation metrics, such as drug-likeness properties. Our evaluation includes extensive silico analysis using molecular docking and PCA-based visualization to explore the chemical space that the new molecules cover compared to those in the training set. These evaluations reveal that a subset of 12 de novo molecules generated by LSTM-ProGen exhibit a striking ability to interact with the target protein, rivaling or even surpassing the efficacy of native ligands. Extended versions with further refinement of LSTM-ProGen hold promise as versatile tools for designing efficacious and customized drug candidates tailored to specific targets, thus accelerating drug development and facilitating the discovery of new therapies for various diseases.
Topics: HIV Protease Inhibitors; Drug Design; Humans; HIV Protease; HIV-1; Acquired Immunodeficiency Syndrome; Molecular Docking Simulation
PubMed: 38905197
DOI: 10.1371/journal.pone.0303597