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Current Biology : CB Jun 2024The fate of transcribed RNA dictates cellular function. A new study finds that mutations in specific RNA processing machinery genes result in de-silencing of a...
The fate of transcribed RNA dictates cellular function. A new study finds that mutations in specific RNA processing machinery genes result in de-silencing of a transcript encoding a subunit of the mitochondrial electron transport chain and rescue of a mitochondrial respiratory complex I defect.
Topics: Electron Transport Complex I; Mitochondria; Animals; Mutation; Gene Silencing
PubMed: 38889679
DOI: 10.1016/j.cub.2024.05.011 -
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 -
JCO Precision Oncology Jun 2024Highlighting here a patient case with neuroblastoma, renal cancer & GIST from germline SDHA.
Highlighting here a patient case with neuroblastoma, renal cancer & GIST from germline SDHA.
Topics: Humans; Kidney Neoplasms; Neuroblastoma; Germ-Line Mutation; Gastrointestinal Neoplasms; Male; Electron Transport Complex II; Mosaicism; Female; Neoplasms, Multiple Primary
PubMed: 38885448
DOI: 10.1200/PO.23.00455 -
Molecular Biology Reports Jun 2024Parkinson's disease is a neurological disorder caused by the loss of dopaminergic neurons in the midbrain. Various mechanisms are involved in the incidence of the...
BACKGROUND
Parkinson's disease is a neurological disorder caused by the loss of dopaminergic neurons in the midbrain. Various mechanisms are involved in the incidence of the disease including oxidative stress. Several herbs and natural products may interfere with the oxidative-stress pathway due to their antioxidant effects.
OBJECTIVE
Herein, we aimed to investigate the neuroprotective role of F. vaillantii extract on Parkinson's in vitro and in vivo model owing to the presence of the bioactive agents with antioxidant properties.
METHODS
In vitro experments showed that 6-hydroxydopamine could induce toxicity in PC12 cells. The impact of F. vaillantii extract on cell viability was measured by using MTT assay. Nuclear morphological changes were qualitatively evaluated employing Hoechst staining. The antioxidant activity of the extract was determined by ROS and lipid peroxidation assays. Tyrosine hydroxylase protein expression was measured by western blotting in PC12 cells. For in vivo study, movement parameters were evaluated.
RESULTS
The results indicated that 75 µΜ of 6-OHDA induced 50% toxicity in PC12 cells for 24 h. Following post-treatment with F. vaillantii extract (0.1 mg/ml) for 72 h, we observed that the extract effectively prevented cell toxicity induced by 6-OHDA and reduced the apoptotic cell population. Furthermore, the extract attenuated the ROS level, lipid peroxidation and increased protein expression of TH after 72 h of treatment. In addition, oral administration of 300 mg/kg of F. vaillantii extract for 14 days improved locomotor activity, catalepsy, bradykinesia, motor coordination and reduced the apomorphine-caused rotation in 6-OHDA- induced Parkinson's disease-like symptoms in male rats.
CONCLUSION
The present study suggests a protective role for the extract of F. vaillantii against oxidative stress-induced cell damage in the PC12 cells exposed to neurotoxin 6-OHDA which was verified in in vivo model by reducing the motor defects induced by 6-OHDA. This extract could be a promising therapeutic agent for the prevention of PD progression.
Topics: Animals; PC12 Cells; Rats; Oxidopamine; Plant Extracts; Neuroprotective Agents; Oxidative Stress; Cell Survival; Antioxidants; Apoptosis; Reactive Oxygen Species; Parkinson Disease; Lipid Peroxidation; Dopaminergic Neurons; Male; Tyrosine 3-Monooxygenase
PubMed: 38884894
DOI: 10.1007/s11033-024-09673-5 -
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 -
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