MDPI - Publisher of Open Access Journals

8 pages, 619 KiB

Open AccessBrief Report

Metabolic Reprogramming in Toll-like Receptor-Mediated Platelet Activation

by Lih T. Cheah, Jawad S. Khalil, Mary McKay, Mohammad Ali, Cedric Duval, Amanda J. Unsworth and Khalid M. Naseem

Cells 2025, 14(12), 906; https://doi.org/10.3390/cells14120906 - 16 Jun 2025

Viewed by 441

Abstract

Beyond haemostasis and thrombosis, platelets are increasingly recognized for playing a crucial role in modulating immunoinflammation. Toll-like receptors (TLRs) constitute the first line of defence against infection and injury, with their engagement stimulating thrombotic and immune responses in platelets. Hence, anti-platelet drugs have [...] Read more.

Beyond haemostasis and thrombosis, platelets are increasingly recognized for playing a crucial role in modulating immunoinflammation. Toll-like receptors (TLRs) constitute the first line of defence against infection and injury, with their engagement stimulating thrombotic and immune responses in platelets. Hence, anti-platelet drugs have been used to treat patients with infections and inflammation. However, due to the increased risk of bleeding with current anti-platelet drugs, alternative therapeutic targets need to be identified to ameliorate the consequences of inflammation-driven platelet hyperactivation. Previously, we demonstrated that resting platelets exhibit a metabolic plasticity that facilitates fuel selection flexibility, while in contrast, thrombin-stimulated platelets become highly glycolytic. Since multiple aspects of platelet activation require energy in terms of ATP, we investigated metabolic alterations in TLR1/TLR2-activated platelets. In this study, we have demonstrated that TLR1/TLR2-induced platelet activation reprogrammed platelets to upregulate glycolysis via CD36-linked mechanisms. In addition, we showed that this glycolytic flux is controlled by hexokinase (HK), which plays a crucial role in TLR1/TLR2-induced platelet aggregation. Targeting platelet metabolism plasticity may offer a novel strategy to inhibit platelet function in TLR-initiated diseases. Full article

► Show Figures

Figure 1

18 pages, 20269 KiB

Open AccessArticle

Immunomodulation by 4-Hydroxy-TEMPO (TEMPOL) and Dimethyl Fumarate (DMF) After Ventral Root Crush (VRC) in C57BL/6J Mice: A Flow Cytometry Analysis

by Maria Fernanda Vannucci Balzani, Lilian de Oliveira Coser and Alexandre Leite Rodrigues de Oliveira

Biology 2025, 14(5), 473; https://doi.org/10.3390/biology14050473 - 25 Apr 2025

Cited by 1 | Viewed by 546

Abstract

Spinal motor nerve root lesions can happen after avulsion or crush, generating acute motoneuron death and synaptic loss, consequently, causing motor and sensory dysfunctions. Local response is mediated by astroglial and microglial cells, giving rise to a pro-inflammatory profile. TEMPOL and DMF are [...] Read more.

Spinal motor nerve root lesions can happen after avulsion or crush, generating acute motoneuron death and synaptic loss, consequently, causing motor and sensory dysfunctions. Local response is mediated by astroglial and microglial cells, giving rise to a pro-inflammatory profile. TEMPOL and DMF are drugs that have been studied in our laboratory after spinal cord nerve root injuries and have demonstrated significant results in terms of neuroprotection and immunomodulation, decreasing the inflammation process. In the present work, a flow cytometry approach was used to evaluate cellular responses to injury and immunomodulation. For this, injured animals received TEMPOL, DMF or vehicle once a day for 7, 14 or 28 days of treatment. Flow cytometry multiparametric analysis allowed the quantification of different pro- and anti-inflammatory glial, macrophage and lymphocyte markers. Contrasting with the vehicle treated counterpart, TEMPOL and DMF led to downregulation of pro-inflammatory cytokines in astrocytes and microglia subpopulations, but did not show significant results in increasing anti-inflammatory phenotypes. As for macrophage and lymphocyte subpopulations, both treatments showed a balance between pro- and anti-inflammatory phenotypes. Therefore, it was concluded that both drugs exhibit immunomodulatory action, contributing to a pro-regenerative profile in the tissue. Full article

(This article belongs to the Special Issue Regenerative Biology: Regeneration After Spinal Cord and Peripheral Nerve Injury)

► Show Figures

Figure 1

10 pages, 1943 KiB

Open AccessArticle

Prognostic Value of Systemic Inflammatory Markers in Malignant Tumors of Minor Salivary Glands: A Retrospective Analysis of a Single Center

by Maria Giulia Cristofaro, Francesco Ferragina, Samuel Staglianò, Antonella Arrotta, Marianna D’Amico and Ida Barca

Cancers 2025, 17(8), 1373; https://doi.org/10.3390/cancers17081373 - 21 Apr 2025

Cited by 2 | Viewed by 781

Abstract

Background: Malignant tumors of minor salivary glands (MGSTs) are rare and exhibit significant heterogeneity in terms of etiology, histology and prognosis. Methods: This retrospective analysis of 48 resected MGSTs employed Receiver Operating Characteristic (ROC) curves and logistic regression models to evaluate the association [...] Read more.

Background: Malignant tumors of minor salivary glands (MGSTs) are rare and exhibit significant heterogeneity in terms of etiology, histology and prognosis. Methods: This retrospective analysis of 48 resected MGSTs employed Receiver Operating Characteristic (ROC) curves and logistic regression models to evaluate the association between the systemic inflammatory response index (SIRI), the systemic immuno-inflammation index (SII), the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR) with overall survival (OS). Although these biomarkers showed some correlation with OS, none were statistically significant when considered individually. Results: Significant correlation was observed between the SIRI, SII, and NLR with overall survival (OS). Among these, SIRI was the most reliable predictor, with an area under the curve (AUC) of 0.713, 80% sensitivity, and 70% specificity. Conclusions: While these inflammatory biomarkers correlate with the prognosis and risk stratification of MGSTs, there is currently no clinical utility in decision making due to the lack of standardization and their limited application in clinical practice. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies in Salivary Gland Tumor)

► Show Figures

Figure 1

10 pages, 1497 KiB

Open AccessFeature PaperArticle

Low Serum Methylglyoxal Levels Correlate with Psoriasis Severity and Inflammatory Response Indices

by Aleksandra Damasiewicz-Bodzek, Agnieszka Nowak, Maciej Maciejczyk, Sławomir Waligóra and Brygida Przywara-Chowaniec

Pathophysiology 2025, 32(1), 8; https://doi.org/10.3390/pathophysiology32010008 - 3 Feb 2025

Cited by 1 | Viewed by 1175

Abstract

Psoriasis is a multifactorial inflammatory disease. Methylglyoxal (MG) is a highly reactive dicarbonyl compound responsible for dicarbonyl stress in some inflammatory conditions, and it may play a role in the etiopathogenesis of psoriasis. Methods: A total of 50 patients with psoriasis and 35 [...] Read more.

Psoriasis is a multifactorial inflammatory disease. Methylglyoxal (MG) is a highly reactive dicarbonyl compound responsible for dicarbonyl stress in some inflammatory conditions, and it may play a role in the etiopathogenesis of psoriasis. Methods: A total of 50 patients with psoriasis and 35 healthy individuals participated in this study. The following indices were assessed in patients: Body Surface Area (BSA), Psoriasis Area and Severity Index (PASI), and Dermatology Life Quality Index (DLQI). MG concentration was evaluated in blood samples. The following inflammatory response indices were calculated: Systemic Inflammation Response Index (SIRI), Systemic Immuno-inflammation Index (SII), and Aggregate Index of Systemic Inflammation (AISI). Results: An analysis of the obtained data showed a statistically significant decrease in the mean serum MG concentration in patients with psoriasis when compared to the healthy individuals (1.19 ± 0.4 μg/mL vs. 1.75 ± 0.6 μg/mL; p = 0.000002). In the patients, MG concentration correlated negatively with psoriasis disease severity indicators (BSA and PASI), C-reactive protein (CRP) concentration, and inflammatory response indicators (SII and AISI). Conclusions: The decreased concentration of MG may be attributed to an increased accumulation of its derivatives (advanced glycation end-products) in the inflamed skin and/or scavenging by polyamines. Full article

► Show Figures

Figure 1

16 pages, 4354 KiB

Open AccessArticle

Impact of Microbiota Depletion by Antibiotics on SARS-CoV-2 Infection of K18-hACE2 Mice

by Patrícia Brito Rodrigues, Giovanni Freitas Gomes, Monara K. S. C. Angelim, Gabriela F. Souza, Stefanie Primon Muraro, Daniel A. Toledo-Teixeira, Bruna Amanda Cruz Rattis, Amanda Stephane Passos, Laís Passarielo Pral, Vinícius de Rezende Rodovalho, Arilson Bernardo dos Santos P. Gomes, Valquíria Aparecida Matheus, André Saraiva Leão Marcelo Antunes, Fernanda Crunfli, Krist Helen Antunes, Ana Paula Duarte de Souza, Sílvio Roberto Consonni, Luiz Osório Leiria, José Carlos Alves-Filho, Thiago M. Cunha, Pedro M. M. Moraes-Vieira, José Luiz Proença-Módena and Marco Aurélio R. Vinolo Show full author list Hide full author list

Cells 2022, 11(16), 2572; https://doi.org/10.3390/cells11162572 - 18 Aug 2022

Cited by 6 | Viewed by 3151

Abstract

Clinical and experimental data indicate that severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection is associated with significant changes in the composition and function of intestinal microbiota. However, the relevance of these effects for SARS-CoV-2 pathophysiology is unknown. In this study, we analyzed the [...] Read more.

Clinical and experimental data indicate that severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection is associated with significant changes in the composition and function of intestinal microbiota. However, the relevance of these effects for SARS-CoV-2 pathophysiology is unknown. In this study, we analyzed the impact of microbiota depletion after antibiotic treatment on the clinical and immunological responses of K18-hACE2 mice to SARS-CoV-2 infection. Mice were treated with a combination of antibiotics (kanamycin, gentamicin, metronidazole, vancomycin, and colistin, Abx) for 3 days, and 24 h later, they were infected with SARS-CoV-2 B lineage. Here, we show that more than 80% of mice succumbed to infection by day 11 post-infection. Treatment with Abx had no impact on mortality. However, Abx-treated mice presented better clinical symptoms, with similar weight loss between infected–treated and non-treated groups. We observed no differences in lung and colon histopathological scores or lung, colon, heart, brain and kidney viral load between groups on day 5 of infection. Despite some minor differences in the expression of antiviral and inflammatory markers in the lungs and colon, no robust change was observed in Abx-treated mice. Together, these findings indicate that microbiota depletion has no impact on SARS-CoV-2 infection in mice. Full article

(This article belongs to the Special Issue Nucleic Acid Sensing in Respiratory Diseases)

► Show Figures

Figure 1

30 pages, 993 KiB

Open AccessReview

Extracellular Vesicles as Drivers of Immunoinflammation in Atherothrombosis

by Rosa Suades, Maria Francesca Greco, Teresa Padró and Lina Badimon

Cells 2022, 11(11), 1845; https://doi.org/10.3390/cells11111845 - 5 Jun 2022

Cited by 23 | Viewed by 4746

Abstract

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality all over the world. Extracellular vesicles (EVs), small lipid-bilayer membrane vesicles released by most cellular types, exert pivotal and multifaceted roles in physiology and disease. Emerging evidence emphasizes the importance of EVs [...] Read more.

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality all over the world. Extracellular vesicles (EVs), small lipid-bilayer membrane vesicles released by most cellular types, exert pivotal and multifaceted roles in physiology and disease. Emerging evidence emphasizes the importance of EVs in intercellular communication processes with key effects on cell survival, endothelial homeostasis, inflammation, neoangiogenesis, and thrombosis. This review focuses on EVs as effective signaling molecules able to both derail vascular homeostasis and induce vascular dysfunction, inflammation, plaque progression, and thrombus formation as well as drive anti-inflammation, vascular repair, and atheroprotection. We provide a comprehensive and updated summary of the role of EVs in the development or regression of atherosclerotic lesions, highlighting the link between thrombosis and inflammation. Importantly, we also critically describe their potential clinical use as disease biomarkers or therapeutic agents in atherothrombosis. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

► Show Figures

Figure 1

20 pages, 4053 KiB

Open AccessArticle

A New Zebrafish Model to Measure Neuronal α-Synuclein Clearance In Vivo

by Ana Lopez, Alena Gorb, Nuno Palha, Angeleen Fleming and David C. Rubinsztein

Genes 2022, 13(5), 868; https://doi.org/10.3390/genes13050868 - 12 May 2022

Cited by 12 | Viewed by 9121

Abstract

The accumulation and aggregation of α-synuclein (α-SYN) is a common characteristic of synucleinopathies, such as Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA). Multiplications of the wildtype gene of α-SYN (SNCA) and most point mutations make [...] Read more.

The accumulation and aggregation of α-synuclein (α-SYN) is a common characteristic of synucleinopathies, such as Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA). Multiplications of the wildtype gene of α-SYN (SNCA) and most point mutations make α-SYN more aggregate-prone, and are associated with mitochondrial defects, trafficking obstruction, and impaired proteostasis, which contribute to elevated neuronal death. Here, we present new zebrafish models expressing either human wildtype (wt), or A53T mutant, α-SYN that recapitulate the above-mentioned hallmarks of synucleinopathies. The appropriate clearance of toxic α-SYN has been previously shown to play a key role in maintaining cell homeostasis and survival. However, the paucity of models to investigate α-SYN degradation in vivo limits our understanding of this process. Based on our recently described imaging method for measuring tau protein clearance in neurons in living zebrafish, we fused human SNCA to the photoconvertible protein Dendra2 which enabled analyses of wt and A53T α-SYN clearance kinetics in vivo. Moreover, these zebrafish models can be used to investigate the kinetics of α-SYN aggregation and to study the mechanisms, and potential new targets, controlling the clearance of both soluble and aggregated α-SYN. Full article

(This article belongs to the Special Issue Zebrafish Models for Human Genetic Disease Studies)

► Show Figures

Figure 1

15 pages, 2982 KiB

Open AccessArticle

Model Identifies Genetic Predisposition of Alzheimer’s Disease as Key Decider in Cell Susceptibility to Stress

by Ioanna C. Stefani, François-Xavier Blaudin de Thé, Cleo Kontoravdi and Karen M. Polizzi

Int. J. Mol. Sci. 2021, 22(21), 12001; https://doi.org/10.3390/ijms222112001 - 5 Nov 2021

Cited by 2 | Viewed by 2593

Abstract

Accumulation of unfolded/misfolded proteins in neuronal cells perturbs endoplasmic reticulum homeostasis, triggering a stress cascade called unfolded protein response (UPR), markers of which are upregulated in Alzheimer’s disease (AD) brain specimens. We measured the UPR dynamic response in three human neuroblastoma cell lines [...] Read more.

Accumulation of unfolded/misfolded proteins in neuronal cells perturbs endoplasmic reticulum homeostasis, triggering a stress cascade called unfolded protein response (UPR), markers of which are upregulated in Alzheimer’s disease (AD) brain specimens. We measured the UPR dynamic response in three human neuroblastoma cell lines overexpressing the wild-type and two familial AD (FAD)-associated mutant forms of amyloid precursor protein (APP), the Swedish and Swedish-Indiana mutations, using gene expression analysis. The results reveal a differential response to subsequent environmental stress depending on the genetic background, with cells overexpressing the Swedish variant of APP exhibiting the highest global response. We further developed a dynamic mathematical model of the UPR that describes the activation of the three branches of this stress response in response to unfolded protein accumulation. Model-based analysis of the experimental data suggests that the mutant cell lines experienced a higher protein load and subsequent magnitude of transcriptional activation compared to the cells overexpressing wild-type APP, pointing to higher susceptibility of mutation-carrying cells to stress. The model was then used to understand the effect of therapeutic agents salubrinal, lithium, and valproate on signalling through different UPR branches. This study proposes a novel integrated platform to support the development of therapeutics for AD. Full article

(This article belongs to the Section Macromolecules)

► Show Figures

Figure 1

17 pages, 364 KiB

Open AccessReview

Repurposing Peroxisome Proliferator-Activated Receptor Agonists in Neurological and Psychiatric Disorders

by Claudia Sagheddu, Miriam Melis, Anna Lisa Muntoni and Marco Pistis

Pharmaceuticals 2021, 14(10), 1025; https://doi.org/10.3390/ph14101025 - 8 Oct 2021

Cited by 21 | Viewed by 4648

Abstract

Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors [...] Read more.

Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors modulating, among others, anti-inflammatory and neuroprotective genes in diverse tissues. Both endogenous and synthetic PPAR agonists are approved treatments for metabolic and systemic disorders, such as diabetes, fatty liver disease, and dyslipidemia(s), showing high tolerability and safety profiles. Considering that some PPAR-acting drugs permeate through the blood–brain barrier, the possibility to extend their scope from the periphery to central nervous system has gained interest in recent years. Here, we review preclinical and clinical evidence that PPARs possibly exert a neuroprotective role, thereby providing a rationale for repurposing PPAR-targeting drugs to counteract several diseases affecting the central nervous system. Full article

(This article belongs to the Special Issue Repurposing Drug Strategies for CNS Disorders)

14 pages, 627 KiB

Open AccessReview

Genetic Aspects of Inflammation and Immune Response in Stroke

by Dejan Nikolic, Milena Jankovic, Bojana Petrovic and Ivana Novakovic

Int. J. Mol. Sci. 2020, 21(19), 7409; https://doi.org/10.3390/ijms21197409 - 8 Oct 2020

Cited by 27 | Viewed by 6011

Abstract

Genetic determinants play important role in the complex processes of inflammation and immune response in stroke and could be studied in different ways. Inflammation and immunomodulation are associated with repair processes in ischemic stroke, and together with the concept of preconditioning are promising [...] Read more.

Genetic determinants play important role in the complex processes of inflammation and immune response in stroke and could be studied in different ways. Inflammation and immunomodulation are associated with repair processes in ischemic stroke, and together with the concept of preconditioning are promising modes of stroke treatment. One of the important aspects to be considered in the recovery of patients after the stroke is a genetic predisposition, which has been studied extensively. Polymorphisms in a number of candidate genes, such as IL-6, BDNF, COX2, CYPC19, and GPIIIa could be associated with stroke outcome and recovery. Recent GWAS studies pointed to the variant in genesPATJ and LOC as new genetic markers of long term outcome. Epigenetic regulation of immune response in stroke is also important, with mechanisms of histone modifications, DNA methylation, and activity of non-coding RNAs. These complex processes are changing from acute phase over the repair to establishing homeostasis or to provoke exaggerated reaction and death. Pharmacogenetics and pharmacogenomics of stroke cures might also be evaluated in the context of immuno-inflammation and brain plasticity. Potential novel genetic treatment modalities are challenged but still in the early phase of the investigation. Full article

(This article belongs to the Special Issue Immunoinflammatory Background of Neuronal Damage in Stroke)

► Show Figures

Figure 1

9 pages, 736 KiB

Open AccessReview

The Emerging Role of the Microbial-Gastrointestinal-Neural Axis

by Peter G. McLean, Andrew R. Calver, David H. Alpers, Stephen M. Collins, Fergus Shanahan and Kevin Lee

Gastroenterol. Insights 2009, 1(1), e3; https://doi.org/10.4081/gi.2009.e3 - 13 Oct 2009

Cited by 6 | Viewed by 1

Abstract

The gastrointestinal tract and its associated mucosal immune system have been extensively studied in the context of their involvement in disease processes, both within the tract itself and in its associated organs. However, historically a number of aspects of both gastrointestinal physiology and [...] Read more.

The gastrointestinal tract and its associated mucosal immune system have been extensively studied in the context of their involvement in disease processes, both within the tract itself and in its associated organs. However, historically a number of aspects of both gastrointestinal physiology and pathophysiology have been to some extent overlooked. In particular, the relationship of the gastrointestinal tract with its indigenous microbiota, and also the influence of the tract on behavior and neural systems and vice versa. Here, we describe recent advances in our knowledge and understanding of these areas, and attempt to put these advances in perspective with regard to potential therapeutic strategies. Full article

Search Results (11)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI

Saved Queries

Search Filter Reset All

Years

Feature Papers

Subjects

Journals

Article Types

Countries / Regions

Search Results (11)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI