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International Journal of Molecular... May 2024Friedreich's Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and...
Friedreich's Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.
Topics: Humans; Frataxin; Friedreich Ataxia; Iron-Binding Proteins; Molecular Dynamics Simulation; Mutation, Missense; Computer Simulation; Genetic Variation
PubMed: 38891993
DOI: 10.3390/ijms25115796 -
Scientific Reports Jun 2024Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute...
Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to "leukotriene production involved in inflammatory response", "lipoxygenase pathway", "metabolic pathways", and "regulation of lipolysis in adipocytes" pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.
Topics: Myocardial Infarction; Lipid Metabolism; Humans; 5-Lipoxygenase-Activating Proteins; Gene Expression Profiling; Animals; Arachidonate 5-Lipoxygenase; Gene Expression Regulation; Mice; Male; Coenzyme A Ligases
PubMed: 38890389
DOI: 10.1038/s41598-024-65022-3 -
Journal For Immunotherapy of Cancer Jun 2024Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and...
BACKGROUND
Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.
METHODS
Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.
RESULTS
EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.
CONCLUSIONS
MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
Topics: Animals; Mice; Humans; Matrix Metalloproteinase 9; Macrophages; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Receptors, Cell Surface; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Receptors, Antigen, T-Cell; Tumor Microenvironment; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 38886114
DOI: 10.1136/jitc-2023-008375 -
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 -
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 -
Cell Jun 2024Microbial hydrogen (H) cycling underpins the diversity and functionality of diverse anoxic ecosystems. Among the three evolutionarily distinct hydrogenase superfamilies...
Microbial hydrogen (H) cycling underpins the diversity and functionality of diverse anoxic ecosystems. Among the three evolutionarily distinct hydrogenase superfamilies responsible, [FeFe] hydrogenases were thought to be restricted to bacteria and eukaryotes. Here, we show that anaerobic archaea encode diverse, active, and ancient lineages of [FeFe] hydrogenases through combining analysis of existing and new genomes with extensive biochemical experiments. [FeFe] hydrogenases are encoded by genomes of nine archaeal phyla and expressed by H-producing Asgard archaeon cultures. We report an ultraminimal hydrogenase in DPANN archaea that binds the catalytic H-cluster and produces H. Moreover, we identify and characterize remarkable hybrid complexes formed through the fusion of [FeFe] and [NiFe] hydrogenases in ten other archaeal orders. Phylogenetic analysis and structural modeling suggest a deep evolutionary history of hybrid hydrogenases. These findings reveal new metabolic adaptations of archaea, streamlined H catalysts for biotechnological development, and a surprisingly intertwined evolutionary history between the two major H-metabolizing enzymes.
Topics: Hydrogenase; Phylogeny; Hydrogen; Archaea; Models, Molecular; Iron-Sulfur Proteins; Genome, Archaeal; Archaeal Proteins
PubMed: 38866018
DOI: 10.1016/j.cell.2024.05.032 -
Redox Biology Aug 2024Hydrogen sulfide (HS) has recently been recognized as an important gaseous transmitter with multiple physiological effects in various species. Previous studies have...
Hydrogen sulfide (HS) has recently been recognized as an important gaseous transmitter with multiple physiological effects in various species. Previous studies have shown that HS alleviated heat-induced ganoderic acids (GAs) biosynthesis, an important quality index of Ganoderma lucidum. However, a comprehensive understanding of the physiological effects and molecular mechanisms of HS in G. lucidum remains unexplored. In this study, we found that heat treatment reduced the mitochondrial membrane potential (MMP) and mitochondrial DNA copy number (mtDNAcn) in G. lucidum. Increasing the intracellular HS concentration through pharmacological and genetic means increased the MMP level, mtDNAcn, oxygen consumption rate level and ATP content under heat treatment, suggesting a role for HS in mitigating heat-caused mitochondrial damage in G. lucidum. Further results indicated that HS activates sulfide-quinone oxidoreductase (SQR) and complex III (Com III), thereby maintaining mitochondrial homeostasis under heat stress in G. lucidum. Moreover, SQR also mediated the negative regulation of HS to GAs biosynthesis under heat stress. Furthermore, SQR might be persulfidated under heat stress in G. lucidum. Thus, our study reveals a novel physiological function and molecular mechanism of HS signalling under heat stress in G. lucidum with broad implications for research on the environmental response of microorganisms.
Topics: Hydrogen Sulfide; Reishi; Triterpenes; Mitochondria; Homeostasis; Heat-Shock Response; Membrane Potential, Mitochondrial; Quinone Reductases; DNA, Mitochondrial; Electron Transport Complex III
PubMed: 38865903
DOI: 10.1016/j.redox.2024.103227 -
Science Advances Jun 2024Nitrogenase plays a key role in the global nitrogen cycle; yet, the evolutionary history of nitrogenase and, particularly, the sequence of appearance between the...
Nitrogenase plays a key role in the global nitrogen cycle; yet, the evolutionary history of nitrogenase and, particularly, the sequence of appearance between the homologous, yet distinct NifDK (the catalytic component) and NifEN (the cofactor maturase) of the extant molybdenum nitrogenase, remains elusive. Here, we report the ability of NifEN to reduce N at its surface-exposed L-cluster ([FeSC]), a structural/functional homolog of the M-cluster (or cofactor; [(-homocitrate)MoFeSC]) of NifDK. Furthermore, we demonstrate the ability of the L-cluster-bound NifDK to mimic its NifEN counterpart and enable N reduction. These observations, coupled with phylogenetic, ecological, and mechanistic considerations, lead to the proposal of a NifEN-like, L-cluster-carrying protein as an ancient nitrogenase, the exploration of which could shed crucial light on the evolutionary origin of nitrogenase and related enzymes.
Topics: Nitrogenase; Phylogeny; Nitrogen; Molybdoferredoxin; Models, Molecular; Bacterial Proteins; Nitrogen Fixation
PubMed: 38865457
DOI: 10.1126/sciadv.ado6169 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's...
OBJECTIVE
To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's disease (PD) the gut-brain axis.
METHODS
Thirty-nine 7-week-old male C57BL/6J mice were randomized equally into control group, PD model group, and NaB treatment group. In the latter two groups, PD models were established by intraperitoneal injection of 30 mg/kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) once daily for 5 consecutive days, and normal saline was injected in the control group. After modeling, the mice received daily gavage of NaB (300 mg/kg) or an equal volume of saline for 14 days. Behavioral tests were carried out to assess the changes in motor function of the mice, and Western blotting was performed to detect the expressions of tyrosine hydroxylase (TH) and -synuclein (-syn) in the striatum and nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-), interleukin 6 (IL-6), and the tight junction proteins ZO-1, Occludin, and Claudinin the colon. HE staining was used to observe inflammatory cell infiltration in the colon of the mice. RNA sequencing analysis was performed to identify the differentially expressed genes in mouse colon tissues, and their expressions were verified using qRT-PCR and Western blotting.
RESULTS
The mouse models of PD with NaB treatment showed significantly increased movement speed and pulling strength of the limbs with obviously upregulated expressions of TH, Occludin, and Claudin and downregulated expressions of -syn, NF-κB, TNF-, and IL-6 (all < 0.05). HE staining showed that NaB treatment significantly ameliorated inflammatory cell infiltration in the colon of the PD mice. RNA sequencing suggested that Bmal1 gene probably mediated the neuroprotective effect of NaB in PD mice ( < 0.05).
CONCLUSION
NaB can improve motor dysfunction, reduce dopaminergic neuron loss in the striatum, and ameliorate colonic inflammation in PD mice possibly through a mechanism involving Bmal1.
Topics: Animals; Mice; Butyric Acid; Male; Mice, Inbred C57BL; Neuroprotective Agents; Disease Models, Animal; Parkinson Disease; alpha-Synuclein; Tumor Necrosis Factor-alpha; NF-kappa B; Interleukin-6; Tyrosine 3-Monooxygenase; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Corpus Striatum; Occludin; Brain-Gut Axis
PubMed: 38862445
DOI: 10.12122/j.issn.1673-4254.2024.05.09 -
BMJ Open Jun 2024This systematic review and meta-analysis aimed to comprehensively assess the impact of weekly iron-folic acid supplementation (WIFAS) on the nutrition, health and... (Meta-Analysis)
Meta-Analysis
Weekly iron-folic acid supplementation and its impact on children and adolescents iron status, mental health and school performance: a systematic review and meta-analysis in sub-Saharan Africa.
OBJECTIVE
This systematic review and meta-analysis aimed to comprehensively assess the impact of weekly iron-folic acid supplementation (WIFAS) on the nutrition, health and educational outcomes of children and adolescents in sub-Saharan Africa.
DESIGN
A systematic review and meta-analysis was used.
DATA SOURCES
Five databases, namely, MEDLINE, Scopus, Web of Science, Cochrane Library and Google Scholar, were systematically searched for relevant articles up to 23 August 2023.
ELIGIBILITY CRITERIA
It was focused on randomised controlled trials involving children and adolescents in sub-Saharan Africa, exploring the effects of iron supplementation on various outcomes, such as serum ferritin and haemoglobin levels, anaemia, mental health and school performance.
DATA EXTRACTION AND SYNTHESIS
The Joanna Briggs Institute Critical Appraisal tools were used for quality assessment, with two independent reviewers thoroughly evaluating each paper. Using the Cochrane risk of bias tool, we evaluated the certainty of evidence such as the risk of bias, inconsistency, indirectness, imprecision and publication bias.
RESULTS
A systematic review of 10 articles revealed that WIFAS significantly increased serum ferritin levels in adolescent girls (Hedge's g=0.53, 95% CI 0.28 to 0.78; heterogeneity I=41.21%, p<0.001) and haemoglobin levels in school-aged children (Hedge's g=0.37, 95% CI 0.01 to 0.73; heterogeneity I=91.62%, p<0.001). The analysis further demonstrated a substantial reduction in the risk of anaemia by 20% (risk ratio=0.8, 95% CI 0.69 to 0.93; heterogeneity I=28.12%, p<0.001).
CONCLUSION
WIFAS proved effective in enhancing serum ferritin and haemoglobin concentrations and lowering the risk of anaemia in school-aged children and adolescents compared with a placebo. Similarly, there are not enough studies to examine the effects of WIFAS on school performance. However, information regarding mental health problems, mortality and potential side effects remains insufficient.
PROSPERO REGISTRATION NUMBER
CRD42023397898.
Topics: Humans; Child; Adolescent; Dietary Supplements; Africa South of the Sahara; Mental Health; Iron; Folic Acid; Ferritins; Anemia, Iron-Deficiency; Hemoglobins; Randomized Controlled Trials as Topic; Female; Nutritional Status
PubMed: 38862227
DOI: 10.1136/bmjopen-2024-084033