The role of initial geometry in experimental models of wound closing

Chemotherapy, targeting not only malignant but also healthy cells, causes many undesirable side effects in cancer patients. Due to this fact, long-term cancer survivors often suffer from late effects, including cognitive impairment and cardiovascular toxicity. Chemotherapy damages the intestinal mucosa and heavily disrupts the gut ecosystem, leading to gastrointestinal toxicity. Animal models and clinical studies have revealed the associations between intestinal dysbiosis and depression, anxiety, pain, impaired cognitive functions, and cardiovascular diseases. Recently, a possible link between chemotherapy-induced gut microbiota disruption and late effects in cancer survivors has been proposed. In this review, we summarize the current understanding of preclinical and clinical findings regarding the emerging role of the microbiome and the microbiota–gut–brain axis in chemotherapy-related late effects affecting the central nervous system (CNS) and heart functions. Importantly, we provide an overview of clinical trials evaluating the relationship between the gut microbiome and cancer survivorship. Moreover, the beneficial effects of probiotics in experimental models and non-cancer patients with neurocognitive disorders and cardiovascular diseases as well as several studies on microbiota modulations via probiotics or fecal microbiota transplantation in cancer patients are discussed.

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Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

Scientific Reports ◽

10.1038/s41598-020-79607-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shinjini Chakraborty ◽

Veronika Eva Winkelmann ◽

Sonja Braumüller ◽

Annette Palmer ◽

Anke Schultze ◽

...

Keyword(s):

Hemorrhagic Shock ◽

Inflammatory Responses ◽

Experimental Models ◽

Lung Damage ◽

C5a Receptor ◽

Cytokine Levels ◽

Vitro Model

AbstractSingular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.

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Diet in Rheumatoid Arthritis versus Systemic Lupus Erythematosus: Any Differences?

Nutrients ◽

10.3390/nu13030772 ◽

2021 ◽

Vol 13 (3) ◽

pp. 772

Author(s):

Alessia Alunno ◽

Francesco Carubbi ◽

Elena Bartoloni ◽

Davide Grassi ◽

Claudio Ferri ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Musculoskeletal Diseases ◽

Normal Subjects ◽

Experimental Models ◽

Systemic Lupus ◽

History Of ◽

Indirect Action

In recent years, an increasing interest in the influence of diet in rheumatic and musculoskeletal diseases (RMDs) led to the publication of several articles exploring the role of food/nutrients in both the risk of developing these conditions in normal subjects and the natural history of the disease in patients with established RMDs. Diet may be a possible facilitator of RMDs due to both the direct pro-inflammatory properties of some nutrients and the indirect action on insulin resistance, obesity and associated co-morbidities. A consistent body of research has been conducted in rheumatoid arthritis (RA), while studies in systemic lupus erythematosus (SLE) are scarce and have been conducted mainly on experimental models of the disease. This review article aims to outline similarities and differences between RA and SLE based on the existing literature.

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A critical role for central vasopressin in regulation of fever during bacterial infection

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.263.6.r1235 ◽

1992 ◽

Vol 263 (6) ◽

pp. R1235-R1240

Author(s):

R. A. Cridland ◽

N. W. Kasting

Keyword(s):

Body Temperature ◽

Arginine Vasopressin ◽

Continuous Measurement ◽

Critical Role ◽

Experimental Models ◽

Bacterial Endotoxins ◽

Chronic Infusion ◽

Live Bacteria ◽

The Brain

Previous investigations on the antipyretic properties of arginine vasopressin have used bacterial endotoxins or pyrogens to induce fever. Because these experimental models of fever fail to mimic all aspects of the responses to infection, we felt it was important to examine the role of endogenously released vasopressin as a neuromodulator in febrile thermoregulation during infection. Therefore the present study examines the effects of chronic infusion of a V1-receptor antagonist or saline (via osmotic minipumps into the ventral septal area of the brain) on a fever induced by injection of live bacteria. Telemetry was used for continuous measurement of body temperature in the awake unhandled rat. Animals infused with the V1-antagonist exhibited fevers that were greater in duration compared with those of saline-infused animals. These results support the hypothesis that vasopressin functions as an antipyretic agent or fever-reducing agent in brain. Importantly, they suggest that endogenously released vasopressin may play a role as a neuromodulator in natural fever.

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The Role of the TGF-β Coreceptor Endoglin in Cancer

The Scientific World JOURNAL ◽

10.1100/tsw.2010.230 ◽

2010 ◽

Vol 10 ◽

pp. 2367-2384 ◽

Cited By ~ 64

Author(s):

Eduardo Pérez-Gómez ◽

Gaelle del Castillo ◽

Juan Francisco Santibáñez ◽

Jose Miguel Lêpez-Novoa ◽

Carmelo Bernabéu ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Tumor Development ◽

Experimental Models ◽

Type I ◽

Type Ii ◽

Invasion And Metastasis ◽

Promising Target ◽

Growth Factor Beta

Endoglin (CD105) is an auxiliary membrane receptor of transforming growth factor beta (TGF-β) that interacts with type I and type II TGF-β receptors and modulates TGF-β signaling. Endoglin is overexpressed in the tumor-associated vascular endothelium, where it modulates angiogenesis. This feature makes endoglin a promising target for antiangiogenic cancer therapy. In addition, recent studies on human and experimental models of carcinogenesis point to an important tumor cell–autonomous role of endoglin by regulating proliferation, migration, invasion, and metastasis. These studies suggest that endoglin behaves as a suppressor of malignancy in experimental and human epithelial carcinogenesis, although it can also promote metastasis in other types of cancer. In this review, we evaluate the implication of endoglin in tumor development underlying studies developed in our laboratories in recent years.

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Neuroactive steroids, their metabolites, and neuroinflammation

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0127 ◽

2012 ◽

Vol 49 (3) ◽

pp. R125-R134 ◽

Cited By ~ 49

Author(s):

Silvia Giatti ◽

Mariaserena Boraso ◽

Roberto Cosimo Melcangi ◽

Barbara Viviani

Keyword(s):

Nervous System ◽

Biomedical Research ◽

Experimental Models ◽

Neuroactive Steroids ◽

Steroid Metabolism ◽

Neuroactive Steroid ◽

Neuroprotective Strategy ◽

Testosterone Metabolites ◽

Inflammatory Effect

Neuroinflammation represents a common feature of many neurodegenerative diseases implicated both in their onset and progression. Neuroactive steroids act as physiological regulators and protective agents in the nervous system. Therefore, the attention of biomedical research has been recently addressed in evaluating whether neuroactive steroids, such as progestagens, androgens, and estrogens may also affect neuroinflammatory pathways. Observations so far obtained suggest a general anti-inflammatory effect with a beneficial relapse on several neurodegenerative experimental models, thus confirming the potentiality of a neuroprotective strategy based on neuroactive steroids. In this scenario, neuroactive steroid metabolism and the sophisticated machinery involved in their signaling are becoming especially attractive. In particular, because metabolism of neuroactive steroids as well as expression of their receptors is affected during the course of neurodegenerative events, a crucial role of progesterone and testosterone metabolites in modulating neuroinflammation and neurodegeneration may be proposed. In the present review, we will address this issue, providing evidence supporting the hypothesis that the efficacy of neuroactive steroids could be improved through the use of their metabolites.

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Pharmacological Rationale for Targeting IL-17 in Asthma

Frontiers in Allergy ◽

10.3389/falgy.2021.694514 ◽

2021 ◽

Vol 2 ◽

Author(s):

Siti Farah Rahmawati ◽

Maurice te Velde ◽

Huib A. M. Kerstjens ◽

Alexander S. S. Dömling ◽

Matthew Robert Groves ◽

...

Keyword(s):

Severe Asthma ◽

Inhaled Corticosteroids ◽

Current Knowledge ◽

Experimental Models ◽

Airflow Limitation ◽

Interleukin 17 ◽

Asthma Phenotype ◽

T Helper 2 ◽

Bronchial Biopsies

Asthma is a respiratory disease that currently affects around 300 million people worldwide and is defined by coughing, shortness of breath, wheezing, mucus overproduction, chest tightness, and expiratory airflow limitation. Increased levels of interleukin 17 (IL-17) have been observed in sputum, nasal and bronchial biopsies, and serum of patients with asthma compared to healthy controls. Patients with higher levels of IL-17 have a more severe asthma phenotype. Biologics are available for T helper 2 (Th2)-high asthmatics, but the Th17-high subpopulation has a relatively low response to these treatments, rendering it a rather severe asthma phenotype to treat. Several experimental models suggest that targeting the IL-17 pathway may be beneficial in asthma. Moreover, as increased activation of the Th17/IL-17 axis is correlated with reduced inhaled corticosteroids (ICS) sensitivity, targeting the IL-17 pathway might reverse ICS unresponsiveness. In this review, we present and discuss the current knowledge on the role of IL-17 in asthma and its interaction with the Th2 pathway, focusing on the rationale for therapeutic targeting of the IL-17 pathway.

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Multiple Disruptions of Glial-Neuronal Networks in Epileptogenesis That Follows Prolonged Febrile Seizures

Frontiers in Neurology ◽

10.3389/fneur.2021.615802 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gary P. Brennan ◽

Megan M. Garcia-Curran ◽

Katelin P. Patterson ◽

Renhao Luo ◽

Tallie Z. Baram

Keyword(s):

Neuronal Networks ◽

Day Treatment ◽

High Mobility ◽

Febrile Seizures ◽

Experimental Models ◽

Normal Brain ◽

Molecular Signaling ◽

Rat Pups ◽

Anti Inflammatory

Background and Rationale: Bi-directional neuronal-glial communication is a critical mediator of normal brain function and is disrupted in the epileptic brain. The potential role of aberrant microglia and astrocyte function during epileptogenesis is important because the mediators involved provide tangible targets for intervention and prevention of epilepsy. Glial activation is intrinsically involved in the generation of childhood febrile seizures (FS), and prolonged FS (febrile status epilepticus, FSE) antecede a proportion of adult temporal lobe epilepsy (TLE). Because TLE is often refractory to treatment and accompanied by significant memory and emotional difficulties, we probed the role of disruptions of glial-neuronal networks in the epileptogenesis that follows experimental FSE (eFSE).Methods: We performed a multi-pronged examination of neuronal-glia communication and the resulting activation of molecular signaling cascades in these cell types following eFSE in immature mice and rats. Specifically, we examined pathways involving cytokines, microRNAs, high mobility group B-1 (HMGB1) and the prostaglandin E2 signaling. We aimed to block epileptogenesis using network-specific interventions as well as via a global anti-inflammatory approach using dexamethasone.Results: (A) eFSE elicited a strong inflammatory response with rapid and sustained upregulation of pro-inflammatory cytokines. (B) Within minutes of the end of the eFSE, HMGB1 translocated from neuronal nuclei to dendrites, en route to the extracellular space and glial Toll-like receptors. Administration of an HMGB1 blocker to eFSE rat pups did not decrease expression of downstream inflammatory cascades and led to unacceptable side effects. (C) Prolonged seizure-like activity caused overall microRNA-124 (miR-124) levels to plunge in hippocampus and release of this microRNA from neurons via extra-cellular vesicles. (D) Within hours of eFSE, structural astrocyte and microglia activation was associated not only with cytokine production, but also with activation of the PGE2 cascade. However, administration of TG6-10-1, a blocker of the PGE2 receptor EP2 had little effect on spike-series provoked by eFSE. (E) In contrast to the failure of selective interventions, a 3-day treatment of eFSE–experiencing rat pups with the broad anti-inflammatory drug dexamethasone attenuated eFSE-provoked pro-epileptogenic EEG changes.Conclusions: eFSE, a provoker of TLE-like epilepsy in rodents leads to multiple and rapid disruptions of interconnected glial-neuronal networks, with a likely important role in epileptogenesis. The intricate, cell-specific and homeostatic interplays among these networks constitute a serious challenge to effective selective interventions that aim to prevent epilepsy. In contrast, a broad suppression of glial-neuronal dysfunction holds promise for mitigating FSE-induced hyperexcitability and epileptogenesis in experimental models and in humans.

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The Role of Immune-Related miRNAs in the Pathology of Kidney Transplantation

Biomolecules ◽

10.3390/biom11081198 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1198

Author(s):

Emanuela Boštjančič ◽

Željka Večerić-Haler ◽

Nika Kojc

Keyword(s):

Immune Response ◽

Kidney Transplantation ◽

Kidney Diseases ◽

Experimental Models ◽

Regulatory Rna ◽

Limited Data ◽

Pathological Conditions ◽

Monitoring Response ◽

Disease Specific

MicroRNAs (miRNAs) are members of the non-coding regulatory RNA family that play pivotal roles in physiological and pathological conditions, including immune response. They are particularly interesting as promising therapeutic targets, prognostic and diagnostic markers due to their easy detection in body fluids and stability. There is accumulating evidence that different miRNAs provide disease-specific signatures in liquid samples of distinct kidney injuries. Using experimental models and human samples, there have been numerous suggestions that immune-related miRNAs are also important contributors to the development of different kidney diseases as well as important markers for monitoring response after kidney transplantation. However, there are limited data for understanding their function in the molecular pathways of allograft pathologies. In our review, we focused on microRNAs that are related to different aspects of immune response after kidney transplantation.

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The role of Nrf2 in acute and chronic muscle injury

10.21203/rs.3.rs-23184/v3 ◽

2020 ◽

Author(s):

Iwona Bronisz-Budzyńska ◽

Magdalena Kozakowska ◽

Paulina Podkalicka ◽

Neli Kachamakova-Trojanowska ◽

Agnieszka Łoboda ◽

...

Keyword(s):

Muscle Damage ◽

Muscle Injury ◽

Experimental Models ◽

Muscle Pathology ◽

Related Factor ◽

Chronic Injury ◽

Inflammatory Infiltration ◽

Genes Encoding ◽

Fibrotic Scar

Abstract The nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes encoding anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, however, due to inconsistent data, we aimed to investigate how Nrf2 transcriptional deficiency (Nrf2tKO) affects muscle functions both in an acute and chronic injury. The acute muscle damage was induced in mice of two genotypes – WT and Nrf2tKO mice by cardiotoxin (CTX) injection. To investigate the role of Nrf2 in chronic muscle pathology, mdx mice that share genetic, biochemical, and histopathological features with Duchenne muscular dystrophy (DMD) were crossed with mice lacking transcriptionally active Nrf2 and double knockouts (mdx/Nrf2tKO) were generated. To worsen the dystrophic phenotype, the analysis of disease pathology was also performed in aggravated conditions, by applying a long-term treadmill test.We have observed slightly increased muscle damage in Nrf2tKO mice after CTX injection. Nevertheless, transcriptional ablation of Nrf2 in mdx mice did not significantly aggravate the most deleterious, pathological hallmarks of DMD related to degeneration, inflammation, fibrotic scar formation, angiogenesis, and the number and proliferation of satellite cells in non-exercised conditions. On the other hand, upon chronic exercises, the degeneration and inflammatory infiltration of the gastrocnemius muscle, but not diaphragm, turned to be increased in Nrf2tKOmdx in comparison to mdx mice. In conclusion, the lack of transcriptionally active Nrf2 influences moderately muscle pathology in acute CTX-induced muscle injury and chronic DMD mouse model, without affecting muscle functionality. Hence, in general, we demonstrated that the deficiency of Nrf2 transcriptional activity has no profound impact on muscle pathology in various models of muscle injury.

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