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Acta Neuropathologica Jun 2024Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel...
Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.
Topics: Humans; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; Spinal Cord; Motor Cortex; Male; Female; Aged; Middle Aged; C9orf72 Protein; Mutation
PubMed: 38884646
DOI: 10.1007/s00401-024-02752-8 -
The Journal of the Association of... May 2024Acute undifferentiated fever (AUF) is defined as any febrile illness with a duration of ≤14 days without evidence of localized infection. Most outpatient services and... (Observational Study)
Observational Study
BACKGROUND
Acute undifferentiated fever (AUF) is defined as any febrile illness with a duration of ≤14 days without evidence of localized infection. Most outpatient services and a significant inpatient load in India are contributed by AUF. COVID-19 has recently added to the existing list of common etiologies of AUF. While the rapid diagnostic test (RDT) kits, which are widely used for the detection of common etiologies of AUF, are unreliable, the rise of various inflammatory markers may help identify the probable etiology. This not only results in better diagnosis but also prepares the physician for close monitoring and pooling of resources.
AIM
To identify the probable etiology of AUF through inflammatory markers.
OBJECTIVE
To understand the clinical and biochemical parameters as possible predictors of adverse outcomes in AUF.
MATERIALS AND METHODS
This was a prospective observational study carried out in the Department of Medicine in a tertiary care hospital. The total duration of the study was 1 year. A total of 400 AUF patients [both outpatient department (OPD) and inpatient department (IPD)] fulfilling the eligibility criteria were taken up for the study after consent. Various inflammatory markers, namely erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-dimer, ferritin, and procalcitonin levels along with basic blood and biochemical tests were measured in all qualifying patients at their first visit. The level of rise of all the measured inflammatory markers was analyzed for clues toward identifying the etiology. Also, the possible predictors of adverse outcomes, as defined in the study, were analyzed. Outcome variables are described as mean ± standard deviation. All statistical calculations were done using computer programs Microsoft Excel 2007 (Microsoft Corporation, New York, United States of America) and SPSS (Statistical Product and Service Solutions; SPSS Inc., United States of America) version 21.
RESULTS
The common etiologies in our study contributing to AUF were dengue (31.5%), COVID-19 (18.5%), enteric fever (12.7%), scrub typhus (9.0%), and malaria (6.0%). In 76 cases (19%), the fever was undiagnosed. Enteric fever had highly elevated CRP (>30 mg/L) and moderately elevated D-dimer, ferritin, and procalcitonin. Both nonsevere dengue and COVID-19 had highly elevated D-dimer (>750 ng/mL), but in nonsevere dengue, CRP, ferritin, and procalcitonin were only mildly elevated, whereas in COVID-19, CRP and ferritin were moderately elevated with mildly elevated procalcitonin. Scrub typhus had highly elevated CRP and ferritin [more than four times the upper limit of normal (ULN)], but D-dimer and procalcitonin were only mildly elevated. The mean serum procalcitonin level in enteric fever is significantly higher than the other etiologies of AUF. Our study was correctly able to identify 90.8% of nonsevere dengue, 87.8% of typhoid, 83.6% of COVID-19, and 91.4% of scrub typhus patients based on the inflammatory markers level. Obesity, diabetes (both types 1 and 2), hypertension, coronary artery disease (CAD), malignancy, chronic kidney disease (CKD), and chronic lung disease were significantly associated with adverse outcomes. A significant delay in visiting the hospital after the onset of fever was found in all etiologies of AUF, which had adverse outcomes.
CONCLUSION
Our study is one of the few studies comparing the rise in the level of various inflammatory markers among the common etiologies of AUF. The novelty of the study is that it aids in identifying the probable etiology of AUF with good confidence through the levels of inflammatory markers. Also, our study highlights the high-risk factors associated with adverse outcomes in AUF.
Topics: Humans; Biomarkers; Male; Female; C-Reactive Protein; Prospective Studies; Adult; Fibrin Fibrinogen Degradation Products; Ferritins; Blood Sedimentation; Middle Aged; Procalcitonin; COVID-19; India; Fever of Unknown Origin; Fever; Inflammation
PubMed: 38881103
DOI: 10.59556/japi.72.0523 -
Clinical Biochemistry Jul 2024The goal of this review was to investigate the levels of pro-inflammatory markers such as Tumour necrosis factor-α (TNF-α) Interlukin-6 (IL-6), C-reactive protein... (Meta-Analysis)
Meta-Analysis
The goal of this review was to investigate the levels of pro-inflammatory markers such as Tumour necrosis factor-α (TNF-α) Interlukin-6 (IL-6), C-reactive protein (CRP), Transforming growth factor-β1 (TGF-β1) and ferritin in pre-eclamptic and normotensive pregnant women. Using PubMed, ProQuest and Google Scholar databases, a literature search was carried out and case-control studies showing associations between inflammatory markers and preeclampsia in pregnancy published between 2010 and 2023 were included. The risk of bias was assessed by using the Newcastle Ottawa quality assessment scale. A random effect meta-analysis was performed and pooled difference in means with 95 % CI were reported. All statistical analyses were performed using R software. Out of 660 articles, 25 articles were included in the systematic review. The differences in means for TGF-β1, CRP, ferritin and TNF-α levels between the preeclamptic women and normotensive women were 2.37 pg/mL [95 % CI: -1.66,6.39], 5.62 mg/L [95 % CI: -4.11,15.36], 32.93 ng/mL [95 % CI: -7.66,58.19] and 13.67 pg/mL [95 % CI: 4.20,23.14] respectively which showed moderate increase. The pooled differences in means for hs-CRP and IL-6 levels between the preeclamptic and normotensive women were 3.20 mg/L [95 % CI: 0.27,6.12] and 17.64 pg/mL [95 % CI: -8.36,43.64] respectively which showed significant increase. Sub-group analysis showed significant differences for CRP, ferritin and TNF-α levels across ethnicities. Meta-analysis demonstrates an increase in the maternal circulating levels of inflammatory markers such as hs-CRP, IL-6 and showed moderate increase in TGF-β1, CRP, ferritin, TNF-α markers among women affected by preeclampsia compared to those with normotensive pregnancies.
Topics: Female; Humans; Pregnancy; Biomarkers; C-Reactive Protein; Ferritins; Inflammation; Interleukin-6; Pre-Eclampsia; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha
PubMed: 38876455
DOI: 10.1016/j.clinbiochem.2024.110778 -
Biomaterials Advances Sep 2024Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution...
Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.
Topics: Humans; Animals; Drug Carriers; Lactoferrin; Alendronate; Ivermectin; K562 Cells; Nanoparticles; Mice; Antineoplastic Agents; Bone and Bones; Lipids; Apoptosis
PubMed: 38875802
DOI: 10.1016/j.bioadv.2024.213924 -
Molecular Medicine Reports Aug 2024Chronic low‑grade inflammation defines obesity as a metabolic disorder. Alterations in the structure of gut flora are strongly associated with obesity. Lactoferrin...
Chronic low‑grade inflammation defines obesity as a metabolic disorder. Alterations in the structure of gut flora are strongly associated with obesity. Lactoferrin (LF) has a biological function in regulating intestinal flora. The present study aimed to investigate the therapeutic and anti‑-inflammatory effects of LF in obese mice based on intestinal flora. A total of 30 C57BL/6 mice were divided into three groups consisting of 10 mice each. Subsequently, one group was fed a normal diet (Group K), another group was fed a high‑fat diet (Group M) and the remaining group switched from regular drinking to drinking 2% LF water (Group Z2) after 2 weeks of high‑fat diet; all mice were fed for 12 weeks. After the experiment, the mouse blood lipid and lipopolysaccharide levels, levels of inflammatory factors and intestinal tight junction proteins were assessed. Mouse stool samples were analyzed using 16S ribosomal RNA sequencing. The results showed that LF reduced serum total cholesterol, triglycerides and low‑density lipoprotein levels, elevated high‑density lipoprotein levels, suppressed metabolic endotoxemia and attenuated chronic low‑grade inflammatory responses in obese mice. In addition, LF upregulated zonula occludens‑1 and occludin protein expression levels in the intestine, thereby improving intestinal barrier integrity. LF altered the intestinal microbial structure of obese mice, reduced the ratio of and an elevated ratio of , modifying the bacterial population to the increased relative abundance of and .
Topics: Animals; Lactoferrin; Gastrointestinal Microbiome; Mice; Obesity; Male; Inflammation; Mice, Inbred C57BL; Diet, High-Fat; Mice, Obese; Occludin; Lipopolysaccharides
PubMed: 38873986
DOI: 10.3892/mmr.2024.13262 -
Dalton Transactions (Cambridge, England... Jun 2024Physiological or pathophysiological changes lead to posttranslational changes in the sialic acid content of human serum transferrin (hTf), an essential mediator of iron...
Physiological or pathophysiological changes lead to posttranslational changes in the sialic acid content of human serum transferrin (hTf), an essential mediator of iron transport in the human body, resulting in a significantly increased concentration of desialylated hTf. The intrinsic fluorescence quenching upon binding of iron to hTf was successfully modeled using the binding polynomial for two iron-binding sites, allowing measurements in a high-throughput format. Removal of sialic acid residues resulted in a 3-fold increase in iron binding affinity for both sites of hTf at pH 7.4. The pH-dependence of iron binding showed significant differences in equilibrium constants, resulting in a 10-fold increase in binding affinity for desialylated hTf at pH 5.9. The changes in hTf sialylation apparently result in tuning of the stability of the conformational state, which in turn contributes to the stability of the diferric hTf. The observed differences in the conditional thermodynamic equilibrium constants suggest that the desialylated protein has a higher preference for diferric hTf over monoferric hTf species down to pH 6.5, which may also influence the interaction with transferrin receptors that preferentially bind to diferric hTf. The results suggest a link between changes in hTf glycan structure and alterations in iron binding equilibrium associated with tissue acidosis.
Topics: Transferrin; Humans; Hydrogen-Ion Concentration; Protein Binding; Iron; N-Acetylneuraminic Acid; Ferric Compounds; Binding Sites; Thermodynamics
PubMed: 38873789
DOI: 10.1039/d4dt01311e -
Science (New York, N.Y.) Jun 2024Respiratory complex I is an efficient driver for oxidative phosphorylation in mammalian mitochondria, but its uncontrolled catalysis under challenging conditions leads...
Respiratory complex I is an efficient driver for oxidative phosphorylation in mammalian mitochondria, but its uncontrolled catalysis under challenging conditions leads to oxidative stress and cellular damage. Ischemic conditions switch complex I from rapid, reversible catalysis into a dormant state that protects upon reoxygenation, but the molecular basis for the switch is unknown. We combined precise biochemical definition of complex I catalysis with high-resolution cryo-electron microscopy structures in the phospholipid bilayer of coupled vesicles to reveal the mechanism of the transition into the dormant state, modulated by membrane interactions. By implementing a versatile membrane system to unite structure and function, attributing catalytic and regulatory properties to specific structural states, we define how a conformational switch in complex I controls its physiological roles.
Topics: Animals; Cryoelectron Microscopy; Electron Transport Complex I; Ischemia; Lipid Bilayers; Mitochondria; Oxidative Phosphorylation; Cattle; Ubiquinone; Protein Conformation, alpha-Helical
PubMed: 38870289
DOI: 10.1126/science.ado2075 -
ACS Nano Jul 2024The smaller size fraction of plastics may be more substantially existing and detrimental than larger-sized particles. However, reports on nanoplastics (NPs), especially...
The smaller size fraction of plastics may be more substantially existing and detrimental than larger-sized particles. However, reports on nanoplastics (NPs), especially their airborne occurrences and potential health hazards to the respiratory system, are scarce. Previous studies limit the understanding of their real respiratory effects, since sphere-type polystyrene (PS) nanoparticles differ from NPs occurring in nature with respect to their physicochemical properties. Here, we employ a mechanical breakdown method, producing NPs directly from bulk plastic, preserving NP properties in nature. We report that among four relatively high abundance NP materials PS, polyethylene terephthalate (PET), polyvinyl chloride (PVC), and polyethylene (PE) with a size of 100 nm, PVC induced slightly more severe lung toxicity profiles compared to the other plastics. The lung cytotoxicity of NPs is higher than that of commercial PS NPs and comparable to natural particles silicon dioxide (SiO) and anatase titanium dioxide (TiO). Mechanistically, BH3-interacting domain death agonist (Bid) transactivation-mediated mitochondrial dysfunction and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy or ferroptosis are likely common mechanisms of NPs regardless of their chemical composition. This study provides relatively comprehensive data for evaluating the risk of atmospheric NPs to lung health.
Topics: Humans; Mitochondria; Animals; Nanoparticles; Ferritins; Mice; Lung; Microplastics; Particle Size; Polystyrenes; Ferroptosis
PubMed: 38869479
DOI: 10.1021/acsnano.4c02335 -
Physical Chemistry Chemical Physics :... Jun 2024Transition metal ions play crucial roles in the structure and function of numerous proteins, contributing to essential biological processes such as catalysis, electron... (Review)
Review
Transition metal ions play crucial roles in the structure and function of numerous proteins, contributing to essential biological processes such as catalysis, electron transfer, and oxygen binding. However, accurately modeling the electronic structure and properties of metalloproteins poses significant challenges due to the complex nature of their electronic configurations and strong correlation effects. Multiconfigurational quantum chemistry methods are, in principle, the most appropriate tools for addressing these challenges, offering the capability to capture the inherent multi-reference character and strong electron correlation present in bio-inorganic systems. Yet their computational cost has long hindered wider adoption, making methods such as density functional theory (DFT) the method of choice. However, advancements over the past decade have substantially alleviated this limitation, rendering multiconfigurational quantum chemistry methods more accessible and applicable to a wider range of bio-inorganic systems. In this perspective, we discuss some of these developments and how they have already been used to answer some of the most important questions in bio-inorganic chemistry. We also comment on ongoing developments in the field and how the future of the field may evolve.
Topics: Metalloproteins; Density Functional Theory; Transition Elements; Chemistry, Bioinorganic; Quantum Theory
PubMed: 38868993
DOI: 10.1039/d4cp01297f -
Journal of Agricultural and Food... Jun 2024Thymol has efficient bactericidal activity against a variety of pathogenic bacteria, but the bactericidal mechanism against () has rarely been reported. In the current...
Thymol has efficient bactericidal activity against a variety of pathogenic bacteria, but the bactericidal mechanism against () has rarely been reported. In the current study, we investigated the bactericidal mechanism of thymol against . The Results revealed that 150 μg/mL of thymol had 99.9% bactericidal activity on . Intracellular bursts of reactive oxygen species (ROS), Feaccumulation, lipid peroxidation, and DNA breakage were checked by cell staining. The exogenous addition of HO and catalase promoted and alleviated thymol-induced cell death to a certain extent, respectively, and the addition of the ferroptosis inhibitor Liproxstatin-1 also alleviated thymol-induced cell death, confirming that thymol induced Fenton-reaction-dependent ferroptosis in . Proteomic analysis revealed that relevant proteins involved in ROS production, lipid peroxidation accumulation, and DNA repair were significantly upregulated after thymol treatment. Molecular docking revealed two potential binding sites (amino acids 46H and 42F) between thymol and ferritin, and thymol could promote the release of Fe from ferritin proteins through in vitro interactions analyzed. Therefore, we hypothesized that ferritin as a potential target may mediate thymol-induced ferroptosis in . This study provides new ideas for the development of natural inhibitors for controlling in aquatic products.
Topics: Ferroptosis; Thymol; Reactive Oxygen Species; Vibrio parahaemolyticus; Hydrogen Peroxide; Anti-Bacterial Agents; Lipid Peroxidation; Iron; Molecular Docking Simulation; Ferritins; Bacterial Proteins
PubMed: 38867141
DOI: 10.1021/acs.jafc.4c01584