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1.
Cell Rep Med ; 5(7): 101653, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39019009

ABSTRACT

Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.


Subject(s)
Acetaminophen , Cardiolipins , Chemical and Drug Induced Liver Injury , Cyclopentanes , NEDD8 Protein , Pyrimidines , Acetaminophen/adverse effects , Animals , NEDD8 Protein/metabolism , NEDD8 Protein/genetics , Humans , Pyrimidines/pharmacology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/drug therapy , Cardiolipins/metabolism , Mice , Cyclopentanes/pharmacology , Male , Liver/metabolism , Liver/pathology , Liver/drug effects , Mice, Inbred C57BL , Mice, Transgenic , Hepatocytes/metabolism , Hepatocytes/drug effects , Hepatocytes/pathology , Signal Transduction/drug effects , Ubiquitin-Activating Enzymes/metabolism , Ubiquitin-Activating Enzymes/genetics , Ubiquitin-Activating Enzymes/antagonists & inhibitors
2.
Nucleic Acids Res ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38966993

ABSTRACT

Human antigen R (HuR) is an RNA binding protein mainly involved in maintaining the stability and controlling the translation of mRNAs, critical for immune response, cell survival, proliferation and apoptosis. Although HuR is a nuclear protein, its mRNA translational-related function occurs at the cytoplasm, where the oligomeric form of HuR is more abundant. However, the regulation of nucleo-cytoplasmic transport of HuR and its connection with protein oligomerization remain unclear. In this work, we describe the phosphorylation of Tyr5 as a new hallmark for HuR activation. Our biophysical, structural and computational assays using phosphorylated and phosphomimetic HuR proteins demonstrate that phosphorylation of Tyr5 at the disordered N-end stretch induces global changes on HuR dynamics and conformation, modifying the solvent accessible surface of the HuR nucleo-cytoplasmic shuttling (HNS) sequence and releasing regions implicated in HuR dimerization. These findings explain the preferential cytoplasmic accumulation of phosphorylated HuR in HeLa cells, aiding to comprehend the mechanisms underlying HuR nucleus-cytoplasm shuttling and its later dimerization, both of which are relevant in HuR-related pathogenesis.

3.
Pharmaceuticals (Basel) ; 17(5)2024 May 09.
Article in English | MEDLINE | ID: mdl-38794175

ABSTRACT

Neutrophils, which constitute the most abundant leukocytes in human blood, emerge as crucial players in the induction of endothelial cell death and the modulation of endothelial cell responses under both physiological and pathological conditions. The hallmark of preeclampsia is endothelial dysfunction induced by systemic inflammation, in which neutrophils, particularly through the formation of neutrophil extracellular traps (NETs), play a pivotal role in the development and perpetuation of endothelial dysfunction and the hypertensive state. Considering the potential of numerous pharmaceutical agents to attenuate NET formation (NETosis) in preeclampsia, a comprehensive assessment of the extensively studied candidates becomes imperative. This review aims to identify mechanisms associated with the induction and negative regulation of NETs in the context of preeclampsia. We discuss potential drugs to modulate NETosis, such as NF-κß inhibitors, vitamin D, and aspirin, and their association with mutagenicity and genotoxicity. Strong evidence supports the notion that molecules involved in the activation of NETs could serve as promising targets for the treatment of preeclampsia.

4.
Phys Rev E ; 109(4-1): 044152, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38755945

ABSTRACT

This work is devoted to the emergence of a connected network of slots (cracks) on a square grid. Accordingly, extensive Monte Carlo simulations and finite-size scaling analysis have been conducted to study the site percolation of straight slots with length l measured in the number of elementary cells of the grid with the edge size L. A special focus was made on the dependence of the percolation threshold p_{C}(l,L) on the slot length l varying in the range 1≤l≤L-2 for the square grids with edge size in the range 50≤L≤1000. In this way, we found that p_{C}(l,L) strongly decreases with increase of l, whereas the variations of p_{C}(l=const,L) with the variation of ratio l/L are very small. Consequently, we acquire the functional dependencies of the critical filling factor and percolation strength on the slot length. Furthermore, we established that the slot percolation model interpolates between the site percolation on square lattice (l=1) and the continuous percolation of widthless sticks (l→∞) aligned in two orthogonal directions. In this regard, we note that the critical number of widthless sticks per unit area is larger than in the case of randomly oriented sticks. Our estimates for the critical exponents indicate that the slot percolation belongs to the same universality class as standard Bernoulli percolation.

5.
Diabetes Obes Metab ; 26(8): 3110-3118, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38699781

ABSTRACT

AIM: Gestational diabetes (GD) is a global health concern with significant implications for maternal and neonatal outcomes. This study investigates the association between early GD (eGD) diagnosis (<24 weeks), pharmacotherapy requirements and adverse neonatal outcomes. MATERIALS AND METHODS: A cohort of 369 pregnant women underwent a 75-g oral glucose tolerance test. Maternal variables, pharmacotherapy prescriptions and neonatal outcomes were analysed employing t-tests, χ2 tests, and logistic regression. A p < .05 was considered significant. RESULTS: Early GD increased the odds of neonatal hypoglycaemia [odds ratio (OR): 18.57, p = .013] and respiratory distress syndrome (OR: 4.75, p = .034). Nutritional therapy prescription by an accredited nutritionist was the most common treatment in women diagnosed after 24 weeks, but those with eGD required more frequently specialized nutritional consulting + metformin to achieve glycaemic control (p = .027). eGD was associated with a higher requirement of nutritional therapy prescription + metformin (OR: 2.26, 95% confidence interval: 1.25-4.09, p = .007) and with maternal hyperglycaemia during the post-partum period at 2 h of the oral glucose tolerance test (OR: 1.03, 95% confidence interval: 1.02-1.13, p = .024). CONCLUSION: Timely diagnosis and personalized treatment of GD are desirable because an earlier presentation is related to a higher risk of adverse neonatal and maternal outcomes.


Subject(s)
Diabetes, Gestational , Early Diagnosis , Glucose Tolerance Test , Hypoglycemic Agents , Metformin , Humans , Female , Pregnancy , Diabetes, Gestational/drug therapy , Diabetes, Gestational/diagnosis , Diabetes, Gestational/blood , Infant, Newborn , Adult , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Hypoglycemia/chemically induced , Hypoglycemia/prevention & control , Hypoglycemia/epidemiology , Pregnancy Outcome/epidemiology , Cohort Studies , Respiratory Distress Syndrome, Newborn/prevention & control , Respiratory Distress Syndrome, Newborn/epidemiology , Blood Glucose/metabolism , Blood Glucose/analysis
6.
Biochem J ; 481(8): 569-585, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38563463

ABSTRACT

Homocystinuria is a rare disease caused by mutations in the CBS gene that results in a deficiency of cystathionine ß-synthase (CBS). CBS is an essential pyridoxal 5'-phosphate (PLP)-dependent enzyme in the transsulfuration pathway, responsible for combining serine with homocysteine to produce cystathionine, whose activity is enhanced by the allosteric regulator S-adenosylmethionine (SAM). CBS also plays a role in generating hydrogen sulfide (H2S), a gaseous signaling molecule with diverse regulatory functions within the vascular, nervous, and immune systems. In this study, we present the clinical and biochemical characterization of two novel CBS missense mutations that do not respond to pyridoxine treatment, namely c.689T > A (L230Q) and 215A > T (K72I), identified in a Chinese patient. We observed that the disease-associated K72I genetic variant had no apparent effects on the spectroscopic and catalytic properties of the full-length enzyme. In contrast, the L230Q variant expressed in Escherichia coli did not fully retain heme and when compared with the wild-type enzyme, it exhibited more significant impairments in both the canonical cystathionine-synthesis and the alternative H2S-producing reactions. This reduced activity is consistent with both in vitro and in silico evidence, which indicates that the L230Q mutation significantly decreases the overall protein's stability, which in turn, may represent the underlying cause of its pathogenicity.


Subject(s)
Cystathionine beta-Synthase , Homocystinuria , Mutation, Missense , Cystathionine beta-Synthase/genetics , Cystathionine beta-Synthase/chemistry , Cystathionine beta-Synthase/metabolism , Homocystinuria/genetics , Homocystinuria/metabolism , Homocystinuria/enzymology , Humans , Male , Female
7.
Sci Rep ; 14(1): 9364, 2024 04 23.
Article in English | MEDLINE | ID: mdl-38654065

ABSTRACT

The escalating drug resistance among microorganisms underscores the urgent need for innovative therapeutic strategies and a comprehensive understanding of bacteria's defense mechanisms against oxidative stress and antibiotics. Among the recently discovered barriers, the endogenous production of hydrogen sulfide (H2S) via the reverse transsulfuration pathway, emerges as a noteworthy factor. In this study, we have explored the catalytic capabilities and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa (PaCGL), a multidrug-opportunistic pathogen chiefly responsible for nosocomial infections. In addition to a canonical L-cystathionine hydrolysis, PaCGL efficiently catalyzes the production of H2S using L-cysteine and/or L-homocysteine as alternative substrates. Comparative analysis with the human enzyme and counterparts from other pathogens revealed distinct structural features within the primary enzyme cavities. Specifically, a distinctly folded entrance loop could potentially modulate the access of substrates and/or inhibitors to the catalytic site. Our findings offer significant insights into the structural evolution of CGL enzymes across different pathogens and provide novel opportunities for developing specific inhibitors targeting PaCGL.


Subject(s)
Catalytic Domain , Cystathionine gamma-Lyase , Hydrogen Sulfide , Pseudomonas aeruginosa , Pseudomonas aeruginosa/enzymology , Cystathionine gamma-Lyase/metabolism , Cystathionine gamma-Lyase/chemistry , Crystallography, X-Ray , Substrate Specificity , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/chemistry , Models, Molecular , Cysteine/metabolism , Cysteine/chemistry , Protein Conformation , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Humans , Homocysteine/metabolism , Homocysteine/chemistry , Catalysis
8.
Sci Rep ; 14(1): 6917, 2024 03 22.
Article in English | MEDLINE | ID: mdl-38519529

ABSTRACT

Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype-phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.


Subject(s)
Cation Transport Proteins , Intellectual Disability , Humans , Intellectual Disability/genetics , Magnesium/metabolism , Seizures/genetics , Phenotype , Cation Transport Proteins/genetics
9.
Cell Rep ; 43(3): 113924, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38507413

ABSTRACT

The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Humans , Mice , Carcinoma, Hepatocellular/metabolism , Disease Models, Animal , ELAV-Like Protein 1/metabolism , Liver Neoplasms/pathology , RNA/metabolism , Sumoylation
10.
Heliyon ; 10(2): e24645, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38304793

ABSTRACT

Carbon capture, utilization, and storage (CCUS) technology offer promising solution to mitigate the threatening consequences of large-scale anthropogenic greenhouse gas emissions. Within this context, this report investigates the influence of NiO deposition on the Li4SiO4 surface during the CO2 capture process and its catalytic behavior in hydrogen production via dry methane reforming. Results demonstrate that the NiO impregnation method modifies microstructural features of Li4SiO4, which positively impact the CO2 capture properties of the material. In particular, the NiO-Li4SiO4 sample captured twice as much CO2 as the pristine Li4SiO4 material, 6.8 and 3.4 mmol of CO2 per gram of ceramic at 675 and 650 °C, respectively. Additionally, the catalytic results reveal that NiO-Li4SiO4 yields a substantial hydrogen production (up to 55 %) when tested in the dry methane reforming reaction. Importantly, this conversion remains stable after 2.5 h of reaction and is selective for hydrogen production. This study highlights the potential of Li4SiO4 both a support and a captor for a sorption-enhanced dry reforming of methane. To the best of our knowledge, this is the first report showcasing the effectiveness of Li4SiO4 as an active support for Ni-based catalysis in the dry reforming of methane. These findings provide valuable insights into the development of this composite as a dual-functional material for carbon dioxide capture and conversion.

11.
J Clin Med ; 13(2)2024 Jan 05.
Article in English | MEDLINE | ID: mdl-38256447

ABSTRACT

Antepartum fetal surveillance (AFS) is essential for pregnant women with diabetes to mitigate the risk of stillbirth. However, there is still no universal consensus on the optimal testing method, testing frequency, and delivery timing. This review aims to comprehensively analyze the evidence concerning AFS and the most advantageous timing for delivery in both gestational and pregestational diabetes mellitus cases. This review's methodology involved an extensive literature search encompassing international diabetes guidelines and scientific databases, including PubMed, MEDLINE, Google Scholar, and Scopus. The review process meticulously identified and utilized pertinent articles for analysis. Within the scope of this review, a thorough examination revealed five prominent international guidelines predominantly addressing gestational diabetes. These guidelines discuss the utility and timing of fetal well-being assessments and recommendations for optimal pregnancy resolution timing. However, the scarcity of clinical trials directly focused on this subject led to a reliance on observational studies as the basis for most recommendations. Glucose control, maternal comorbidities, and the medical management received are crucial in making decisions regarding AFS and determining the appropriate delivery timing.

12.
JHEP Rep ; 6(1): 100918, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38192540

ABSTRACT

Background & Aims: Current therapies for the treatment of alcohol-related liver disease (ALD) have proven largely ineffective. Patients relapse and the disease progresses even after liver transplantation. Altered epigenetic mechanisms are characteristic of alcohol metabolism given excessive acetate and NAD depletion and play an important role in liver injury. In this regard, novel therapeutic approaches based on epigenetic modulators are increasingly proposed. MicroRNAs, epigenetic modulators acting at the post-transcriptional level, appear to be promising new targets for the treatment of ALD. Methods: MiR-873-5p levels were measured in 23 liver tissue from Patients with ALD, and GNMT levels during ALD were confirmed using expression databases (transcriptome n = 62, proteome n = 68). High-resolution proteomics and metabolomics in mice following the Gao-binge model were used to investigate miR-873-5p expression in ALD. Hepatocytes exposed to 50 mM alcohol for 12 h were used to study toxicity. The effect of anti-miR-873-5p in the treatment outcomes of ALD was investigated. Results: The analysis of human and preclinical ALD samples revealed increased expression of miR-873-5p in the liver. Interestingly, there was an inverse correlation with NNMT, suggesting a novel mechanism for NAD depletion and aberrant acetylation during ALD progression. High-resolution proteomics and metabolomics identified miR-873-5p as a key regulator of NAD metabolism and SIRT1 deacetylase activity. Anti-miR-873-5p reduced NNMT activity, fuelled the NAD salvage pathway, restored the acetylome, and modulated the levels of NF-κB and FXR, two known SIRT1 substrates, thereby protecting the liver from apoptotic and inflammatory processes, and improving bile acid homeostasis. Conclusions: These data indicate that targeting miR-873-5p, a repressor of GNMT previously associated with NAFLD and acetaminophen-induced liver failure. is a novel and attractive approach to treating alcohol-induced hepatoxicity. Impact and implications: The role of miR-873-5p has not been explicitly examined in the progression of ALD, a pathology with no therapeutic options. In this study, inhibiting miR-873-5p exerted hepatoprotective effects against ALD through rescued SIRT1 activity and consequently restored bile acid homeostasis and attenuated the inflammatory response. Targeting hepatic miR-873-5p may represent a novel therapeutic approach for the treatment of ALD.

13.
J Agric Food Chem ; 72(5): 2482-2491, 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38264997

ABSTRACT

In a previously published study, the authors devised a molecular topology QSAR (quantitative structure-activity relationship) approach to detect novel fungicides acting as inhibitors of chitin deacetylase (CDA). Several of the chosen compounds exhibited noteworthy activity. Due to the close relationship between chitin-related proteins present in fungi and other chitin-containing plant-parasitic species, the authors decided to test these molecules against nematodes, based on their negative impact on agriculture. From an overall of 20 fungal CDA inhibitors, six showed to be active against Caenorhabditis elegans. These experimental results made it possible to develop two new molecular topology-based QSAR algorithms for the rational design of potential nematicides with CDA inhibitor activity for crop protection. Linear discriminant analysis was employed to create the two algorithms, one for identifying the chemo-mathematical pattern of commercial nematicides and the other for identifying nematicides with activity on CDA. After creating and validating the QSAR models, the authors screened several natural and synthetic compound databases, searching for alternatives to current nematicides. Finally one compound, the N2-(dimethylsulfamoyl)-N-{2-[(2-methyl-2-propanyl)sulfanyl]ethyl}-N2-phenylglycinamide or nematode chitin deacetylase inhibitor, was selected as the best candidate and was further investigated both in silico, through molecular docking and molecular dynamic simulations, and in vitro, through specific experimental assays. The molecule shows favorable binding behavior on the catalytic pocket of C. elegans CDA and the experimental assays confirm potential nematicide activity.


Subject(s)
Amidohydrolases , Caenorhabditis elegans , Nematoda , Animals , Caenorhabditis elegans/metabolism , Molecular Docking Simulation , Antinematodal Agents/chemistry , Chitin/metabolism
14.
Environ Microbiol ; 25(12): 3364-3386, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37897125

ABSTRACT

Methane-cycling is becoming more important in high-latitude ecosystems as global warming makes permafrost organic carbon increasingly available. We explored 387 samples from three high-latitudes regions (Siberia, Alaska and Patagonia) focusing on mineral/organic soils (wetlands, peatlands, forest), lake/pond sediment and water. Physicochemical, climatic and geographic variables were integrated with 16S rDNA amplicon sequences to determine the structure of the overall microbial communities and of specific methanogenic and methanotrophic guilds. Physicochemistry (especially pH) explained the largest proportion of variation in guild composition, confirming species sorting (i.e., environmental filtering) as a key mechanism in microbial assembly. Geographic distance impacted more strongly beta diversity for (i) methanogens and methanotrophs than the overall prokaryotes and, (ii) the sediment habitat, suggesting that dispersal limitation contributed to shape the communities of methane-cycling microorganisms. Bioindicator taxa characterising different ecological niches (i.e., specific combinations of geographic, climatic and physicochemical variables) were identified, highlighting the importance of Methanoregula as generalist methanogens. Methylocystis and Methylocapsa were key methanotrophs in low pH niches while Methylobacter and Methylomonadaceae in neutral environments. This work gives insight into the present and projected distribution of methane-cycling microbes at high latitudes under climate change predictions, which is crucial for constraining their impact on greenhouse gas budgets.


Subject(s)
Euryarchaeota , Microbiota , Microbiota/genetics , Euryarchaeota/genetics , Wetlands , Soil/chemistry , Methane
15.
J Neurosurg Spine ; 39(5): 700-708, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37728377

ABSTRACT

OBJECTIVE: The current Roussouly classification identifies four groups of "normal" sagittal spine morphology, which has greatly expanded the understanding of normal heterogeneity of the spine. While there has been extensive characterization of the influence of spinopelvic parameters on outcomes after degenerative spine surgery, the influence of spinopelvic parameters on thoracolumbar trauma has yet to be described. The goal of this study was to determine if spinopelvic parameters and global spine morphology influence fracture location, fracture morphology, and rate of neurological deficit in the setting of thoracolumbar trauma. METHODS: Of 2896 patients reviewed in the authors' institutional spine database between January 2014 and April 2020 with an ICD-9/10 diagnosis of thoracolumbar trauma, 514 met the inclusion criteria of acute thoracolumbar fracture on CT and visible femoral heads on sagittal CT. Pelvic incidence (PI) was calculated on sagittal CT. Demographic and clinical data including age, sex, BMI, smoking status, concomitant cervical fracture, mechanism of injury, major fracture location, neurological deficit, AO Spine thoracolumbar injury classification, and management type (operative vs nonoperative) were collected. Patients were stratified into high-PI (≥ 50°) and low-PI (< 50°) groups. RESULTS: Patients with high PI had a lower incidence of fractures in the lower lumbar spine (below L2) compared with patients with low PI (16% vs 8%, p < 0.01). The last lordotic vertebrae were observed between T10 and L4, and of fractures that occurred at these levels, 75% were at the last lordotic vertebrae. Fall from height was the most common cause of neurological deficit, accounting for 47%. Of the patients presenting with a fall from height, AO Spine type B distraction injuries were more common in the high-PI group (41% vs 18%, p = 0.01). Similarly, within the same subgroup, AO Spine type A compression injuries were more common in the low-PI group (73% vs 53%, p = 0.01). CONCLUSIONS: Spinopelvic parameters and sagittal balance influence the location and morphology of thoracolumbar fractures. Fractures of the thoracolumbar junction are strongly associated with the inflection point, which is defined by sagittal alignment. While the importance of considering sagittal balance is known for decision-making in degenerative spinal pathology, further studies are required to determine if spinopelvic parameters and sagittal balance should play a role in the decision-making for management of thoracolumbar fractures.


Subject(s)
Lordosis , Spinal Fractures , Spinal Injuries , Humans , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/surgery , Spinal Fractures/diagnostic imaging , Spinal Fractures/surgery , Lordosis/diagnostic imaging , Spinal Injuries/complications , Radiography , Thoracic Vertebrae/diagnostic imaging , Thoracic Vertebrae/surgery
16.
Curr Issues Mol Biol ; 45(9): 7476-7491, 2023 Sep 13.
Article in English | MEDLINE | ID: mdl-37754256

ABSTRACT

Traumatic spinal cord injury (SCI) causes irreversible damage leading to incapacity. Molecular mechanisms underlying SCI damage are not fully understood, preventing the development of novel therapies. Tamoxifen (TMX) has emerged as a promising therapy. Our aim was to identify transcriptome changes in the acute phase of SCI and the effect of Tamoxifen on those changes in a rat model of SCI. Four groups were considered: (1) Non-injured without TMX (Sham/TMX-), (2) Non-injured with TMX (Sham/TMX+), (3) injured without TMX (SCI/TMX-), and (4) injured with TMX (SCI/TMX+). Tamoxifen was administered intraperitoneally 30 min after injury, and spinal cord tissues were collected 24 h after injury. Clariom S Assays Array was used for transcriptome analysis. After comparing Sham/TMX- versus SCI/TMX-, 708 genes showed differential expression. The enriched pathways were the SCI pathway and pathways related to the inflammatory response. When comparing SCI/TMX- versus SCI/TMX+, only 30 genes showed differential expression, with no pathways enriched. Our results showed differential expression of genes related to the inflammatory response after SCI, and Tamoxifen seems to regulate gene expression changes in Ccr2 and Mmp12. Our study contributes data regarding the potential value of tamoxifen as a therapeutic resource for traumatic SCI during the acute phase.

17.
J Fungi (Basel) ; 9(7)2023 Jul 21.
Article in English | MEDLINE | ID: mdl-37504759

ABSTRACT

Fungal pathogens are significant plant-destroying microorganisms that present an increasing threat to the world's crop production. Chitin is a crucial component of fungal cell walls and a conserved MAMP (microbe-associated molecular pattern) that can be recognized by specific plant receptors, activating chitin-triggered immunity. The molecular mechanisms underlying the perception of chitin by specific receptors are well known in plants such as rice and Arabidopsis thaliana and are believed to function similarly in many other plants. To become a plant pathogen, fungi have to suppress the activation of chitin-triggered immunity. Therefore, fungal pathogens have evolved various strategies, such as prevention of chitin digestion or interference with plant chitin receptors or chitin signaling, which involve the secretion of fungal proteins in most cases. Since chitin immunity is a very effective defensive response, these fungal mechanisms are believed to work in close coordination. In this review, we first provide an overview of the current understanding of chitin-triggered immune signaling and the fungal proteins developed for its suppression. Second, as an example, we discuss the mechanisms operating in fungal biotrophs such as powdery mildew fungi, particularly in the model species Podosphaera xanthii, the main causal agent of powdery mildew in cucurbits. The key role of fungal effector proteins involved in the modification, degradation, or sequestration of immunogenic chitin oligomers is discussed in the context of fungal pathogenesis and the promotion of powdery mildew disease. Finally, the use of this fundamental knowledge for the development of intervention strategies against powdery mildew fungi is also discussed.

18.
J Mol Diagn ; 25(9): 692-701, 2023 09.
Article in English | MEDLINE | ID: mdl-37356622

ABSTRACT

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the presence of hamartomas in multiple organs. At the molecular level, the disease is caused by pathogenic variants in the TSC1 and TSC2 genes, and only 10% to 25% of clinically diagnosed patients remain negative after multiplex ligation-dependent probe amplification and exon sequencing of both genes. Here, to improve the molecular diagnosis of TSC, we developed an integral approach that includes multiplex ligation-dependent probe amplification and deep-coverage next-generation sequencing of the entire TSC1 and TSC2 genes, along with an adapted bioinformatic pipeline to detect variants at low allele frequencies (>1%). Using this workflow, the molecular cause was identified in 29 of 42 patients with TSC, describing here, for the first time, 12 novel pathogenic variants in TSC genes. These variants included seven splicing variants, five of which were studied at the cDNA level, determining their effect on splicing. In addition, 8 of the 29 pathogenic variants were detected in mosaicism, including four patients with previous negative study results who presented extremely low mosaic variants (allele frequency, <16%). We demonstrate that this integral approach allows the molecular diagnosis of patients with TSC and improves the conventional one by adapting the technology to the detection of low-frequency mosaics.


Subject(s)
Mosaicism , Tuberous Sclerosis , Humans , Tuberous Sclerosis Complex 2 Protein/genetics , Tuberous Sclerosis Complex 1 Protein/genetics , Mutation , Tuberous Sclerosis/diagnosis , Tuberous Sclerosis/genetics
20.
Adv Nutr ; 14(4): 739-751, 2023 07.
Article in English | MEDLINE | ID: mdl-37207838

ABSTRACT

Within the organism, the liver is the main organ responsible for metabolic homeostasis and xenobiotic transformation. To maintain an adequate liver weight-to-bodyweight ratio, this organ has an extraordinary regenerative capacity and is able to respond to an acute insult or partial hepatectomy. Maintenance of hepatic homeostasis is crucial for the proper functioning of the liver, and in this context, adequate nutrition with macro- and micronutrient intake is mandatory. Among all known macro-minerals, magnesium has a key role in energy metabolism and in metabolic and signaling pathways that maintain liver function and physiology throughout its life span. In the present review, the cation is reported as a potential key molecule during embryogenesis, liver regeneration, and aging. The exact role of the cation during liver formation and regeneration is not fully understood due to its unclear role in the activation and inhibition of those processes, and further research in a developmental context is needed. As individuals age, they may develop hypomagnesemia, a condition that aggravates the characteristic alterations. Additionally, risk of developing liver pathologies increases with age, and hypomagnesemia may be a contributing factor. Therefore, magnesium loss must be prevented by adequate intake of magnesium-rich foods such as seeds, nuts, spinach, or rice to prevent age-related hepatic alterations and contribute to the maintenance of hepatic homeostasis. Since magnesium-rich sources include a variety of foods, a varied and balanced diet can meet both macronutrient and micronutrient needs.


Subject(s)
Longevity , Magnesium , Humans , Nutritional Status , Liver , Aging
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