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BACKGROUND: Inflammation-induced testicular damage is a significant contributing factor to the increasing incidence of infertility. Traditional treatments during the inflammatory phase often fail to achieve the desired fertility outcomes, necessitating innovative interventions such as cell therapy. METHODS: We explored the in vivo properties of intravenously administered Sertoli cells (SCs) in an acute lipopolysaccharide (LPS)-induced inflammatory mouse model. Infiltrating and resident myeloid cell phenotypes were assessed using flow cytometry. The impact of SC administration on testis morphology and germ cell quality was evaluated using computer-assisted sperm analysis (CASA) and immunohistochemistry. RESULTS: SCs demonstrated a distinctive migration pattern, importantly they preferentially concentrated in the testes and liver. SC application significantly reduced neutrophil infiltration as well as preserved the resident macrophage subpopulations. SCs upregulated MerTK expression in both interstitial and peritubular macrophages. Applied SC treatment exhibited protective effects on sperm including their motility and kinematic parameters, and maintained the physiological testicular morphology. CONCLUSION: Our study provides compelling evidence of the therapeutic efficacy of SC transplantation in alleviating acute inflammation-induced testicular damage. These findings contribute to the expanding knowledge on the potential applications of cell-based therapies for addressing reproductive health challenges and offer a promising approach for targeted interventions in male infertility.

Asunto(s)

Inflamación , Células de Sertoli , Espermatozoides , Masculino , Animales , Células de Sertoli/metabolismo , Ratones , Inflamación/patología , Inflamación/terapia , Espermatozoides/metabolismo , Lipopolisacáridos/toxicidad , Ratones Endogámicos C57BL , Testículo , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa c-Mer/genética , Motilidad Espermática , Macrófagos/metabolismo

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Chronic inflammation is associated with diabetes and contributes to the development and progression of micro- and macrovascular complications. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to reduce levels of circulating inflammatory cytokines in non-diabetics by activating the cholinergic anti-inflammatory pathway. We investigated the anti-inflammatory potential of tVNS as a secondary endpoint of a randomized controlled trial in people with diabetes (NCT04143269). 131 people with diabetes (type 1: n = 63; type 2: n = 68), gastrointestinal symptoms and various degrees of autonomic neuropathy were included and randomly assigned to self-administer active (n = 63) or sham (n = 68) tVNS over two successive study periods: (1) Seven days with four daily administrations and, (2) 56 days with two daily administrations. Levels of systemic inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α, IFN-γ) were quantified from blood samples by multiplex technology. Information regarding age, sex, diabetes type, and the presence of cardiac autonomic neuropathy (CAN) was included in the analysis as possible confounders. No differences in either cytokine were seen after study period 1 and 2 between active and sham tVNS (all p-values > 0.08). Age, sex, diabetes type, presence of CAN, and baseline levels of inflammatory cytokines were not associated with changes after treatment (all p-values > 0.07). A tendency towards slight reductions in TNF-α levels after active treatment was observed in those with no CAN compared to those with early or manifest CAN (p = 0.052). In conclusion, tVNS did not influence the level of systemic inflammation in people with diabetes.

Asunto(s)

Citocinas , Estimulación Eléctrica Transcutánea del Nervio , Estimulación del Nervio Vago , Humanos , Estimulación del Nervio Vago/métodos , Masculino , Femenino , Persona de Mediana Edad , Estimulación Eléctrica Transcutánea del Nervio/métodos , Citocinas/sangre , Adulto , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Inflamación/terapia , Inflamación/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/sangre , Neuropatías Diabéticas/terapia , Neuropatías Diabéticas/sangre

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Extracellular histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-targeting therapeutic strategies is currently lacking. In this review, we first update our latest understanding of the underlying molecular mechanisms of histone-induced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases.

Asunto(s)

Histonas , Inflamación , Humanos , Histonas/metabolismo , Animales , Inflamación/inmunología , Inflamación/terapia , Enfermedad Crítica , Heparina/uso terapéutico

RESUMEN

Neurodegenerative disorders, including Dementia, Parkinson's disease, various Vision disorders, Multiple sclerosis, and transsynaptic degenerative changes represent a significant challenge in aging populations. This editorial synthesizes and discusses recent advancements in understanding the genetic and environmental factors contributing to these diseases. Central to these advancements is the role of neuroinflammation and oxidative stress, which exacerbate neuronal damage and accelerate disease progression. Emerging research underscores the significance of mitochondrial dysfunction and protein aggregation in neurodegenerative pathology, highlighting shared mechanisms across various disorders. Innovative therapeutic strategies, including gene therapy, CRISPR-Cas technology, and the use of naturally occurring antioxidant molecules, are being investigated to target and manage these conditions. Additionally, lifestyle interventions such as exercise and healthy diet have shown promise in enhancing brain plasticity and reducing neuroinflammation. Advances in neuroimaging and biomarker discovery are necessary to improve early diagnosis, while clinical and preclinical studies are essential for the translation of these novel treatments. This edition aims to bridge the gap between molecular mechanisms and therapeutic applications, offering insights into potential interventions to mitigate the impact of neurodegenerative diseases. By establishing a deeper understanding of these complex processes, we aim to move closer to effective prevention and treatment strategies, ultimately improving the quality of life for those affected by neurodegenerative disorders.

Asunto(s)

Envejecimiento , Encéfalo , Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/terapia , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Envejecimiento/patología , Encéfalo/patología , Encéfalo/metabolismo , Inflamación/genética , Inflamación/terapia , Estrés Oxidativo , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/genética

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Introduction: The immunomodulatory properties of mesenchymal stromal cells (MSC) have been well-characterized in in-vitro and in-vivo models. We have previously shown that liver MSC (L-MSC) are superior inhibitors of T-cell activation/proliferation, NK cell cytolytic function, and macrophage activation compared to adipose (A-MSC) and bone marrow MSC (BM-MSC) in-vitro. Method: To test these observations in-vivo, we infused these types of MSC into mice with unilateral renal artery stenosis (RAS), an established model of kidney inflammation. Unilateral RAS was induced via laparotomy in 11-week-old, male 129-S1 mice under general anesthesia. Control mice had sham operations. Human L-MSC, AMSC, and BM-MSC (5x105 cells each) or PBS vehicle were injected intra-arterially 2 weeks after surgery. Kidney morphology was studied 2 weeks after infusion using micro-MRI imaging. Renal inflammation, apoptosis, fibrosis, and MSC retention were studied ex-vivo utilizing western blot, immunofluorescence, and immunohistological analyses. Results: The stenotic kidney volume was smaller in all RAS mice, confirming significant injury, and was improved by infusion of all MSC types. All MSC-infused groups had lower levels of plasma renin and proteinuria compared to untreated RAS. Serum creatinine improved in micetreated with BM- and L-MSC. All types of MSC located to and were retained within the stenotic kidneys, but L-MSC retention was significantly higher than A- and BM-MSC. While all groups of MSC-treated mice displayed reduced overall inflammation and macrophage counts, L-MSC showed superior potency in-vivo at localizing to the site of inflammation and inducing M2 (reparative) macrophage polarization to reduce inflammatory changes. Discussion: These in-vivo findings extend our in-vitro studies and suggest that L-MSC possess unique anti-inflammatory properties that may play a role in liver-induced tolerance and lend further support to their use as therapeutic agents for diseases with underlying inflammatory pathophysiology.

Asunto(s)

Isquemia , Hígado , Macrófagos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Ratones , Trasplante de Células Madre Mesenquimatosas/métodos , Masculino , Humanos , Hígado/patología , Hígado/inmunología , Isquemia/terapia , Isquemia/inmunología , Macrófagos/inmunología , Modelos Animales de Enfermedad , Inflamación/inmunología , Inflamación/terapia , Activación de Macrófagos , Obstrucción de la Arteria Renal/terapia , Obstrucción de la Arteria Renal/inmunología , Riñón/patología , Riñón/inmunología

RESUMEN

BACKGROUND: Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints. MATERIALS AND METHODS: The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient's hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH. DISCUSSION: Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH. TRIAL REGISTRATION: Clinical Trials Registered, NCT04557618. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021.

Asunto(s)

Hemorragia Subaracnoidea , Estimulación del Nervio Vago , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inflamación/terapia , Estudios Prospectivos , Hemorragia Subaracnoidea/terapia , Hemorragia Subaracnoidea/complicaciones , Resultado del Tratamiento , Estimulación del Nervio Vago/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

Nowadays, regenerative medicine techniques are usually based on the application of mesenchymal stromal cells (MSCs) for the repair or restoration of injured damaged tissues. However, the effectiveness of autologous therapy is limited as therapeutic potential of MSCs declines due to patient's age, health condition and prolonged in vitro cultivation as a result of decreased growth rate. For that reason, there is an urgent need to develop strategies enabling the in vitro rejuvenation of MSCs prior transplantation in order to enhance their in vivo therapeutic efficiency. In presented study, we attempted to mimic the naturally occurring mitochondrial transfer (MT) between neighbouring cells and verify whether artificial MT (AMT) could reverse MSCs aging and improve their biological properties. For that reason, mitochondria were isolated from healthy donor equine adipose-derived stromal cells (ASCs) and transferred into metabolically impaired recipient ASCs derived from equine metabolic syndrome (EMS) affected horses, which were subsequently subjected to various analytical methods in order to verify the cellular and molecular outcomes of the applied AMT. Mitochondria recipient cells were characterized by decreased apoptosis, senescence and endoplasmic reticulum stress while insulin sensitivity was enhanced. Furthermore, we observed increased mitochondrial fragmentation and associated PARKIN protein accumulation, which indicates on the elimination of dysfunctional organelles via mitophagy. AMT further promoted physioxia and regulated autophagy fluxes. Additionally, rejuvenated ASCs displayed an improved anti-inflammatory activity toward LPS-stimulated synoviocytes. The presented findings highlight AMT as a promising alternative and effective method for MSCs rejuvenation, for potential application in autologous therapies in which MSCs properties are being strongly deteriorated due to patients' condition.

Asunto(s)

Senescencia Celular , Lipopolisacáridos , Células Madre Mesenquimatosas , Mitocondrias , Sinoviocitos , Células Madre Mesenquimatosas/metabolismo , Animales , Caballos , Mitocondrias/metabolismo , Sinoviocitos/metabolismo , Inflamación/terapia , Inflamación/patología , Inflamación/metabolismo , Células Cultivadas , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos

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Inflammation is a key pathological feature of many diseases, disrupting normal tissue structure and resulting in irreversible damage. Despite the need for effective inflammation control, current treatments, including stem cell therapies, remain insufficient. Recently, extracellular vesicles secreted by adipose-derived stem cells (ADSC-EVs) have garnered attention for their significant anti-inflammatory properties. As carriers of bioactive substances, these vesicles have demonstrated potent capabilities in modulating inflammation and promoting tissue repair in conditions such as rheumatoid arthritis, osteoarthritis, diabetes, cardiovascular diseases, stroke, and wound healing. Consequently, ADSC-EVs are emerging as promising alternatives to conventional ADSC-based therapies, offering advantages such as reduced risk of immune rejection, enhanced stability, and ease of storage and handling. However, the specific mechanisms by which ADSC-EVs regulate inflammation under pathological conditions are not fully understood. This review discusses the role of ADSC-EVs in inflammation control, their impact on disease prognosis, and their potential to promote tissue repair. Additionally, it provides insights into future clinical research focused on ADSC-EV therapies for inflammatory diseases, which overcome some limitations associated with cell-based therapies.

Asunto(s)

Tejido Adiposo , Vesículas Extracelulares , Inflamación , Humanos , Vesículas Extracelulares/metabolismo , Inflamación/terapia , Inflamación/metabolismo , Inflamación/patología , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Animales , Células Madre/metabolismo , Células Madre/citología , Cicatrización de Heridas

RESUMEN

Pulmonary hypertension (PH) is a progressive cardiovascular disease, which may lead to severe cardiopulmonary dysfunction. As one of the main PH disease groups, pulmonary artery hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Increased pulmonary artery resistance consequently causes right heart failure, which is the major reason for morbidity and mortality in this disease. Although various treatment strategies have been available, the poor clinical prognosis of patients with PAH reminds us that further studies of the pathological mechanism of PAH are still needed. Inflammation has been elucidated as relevant to the initiation and progression of PAH, and plays a crucial and functional role in vascular remodeling. Many immune cells and cytokines have been demonstrated to be involved in the pulmonary vascular lesions in PAH patients, with the activation of downstream signaling pathways related to inflammation. Consistently, this influence has been found to correlate with the progression and clinical outcome of PAH, indicating that immunity and inflammation may have significant potential in PAH therapy. Therefore, we reviewed the pathogenesis of inflammation and immunity in PAH development, focusing on the potential targets and clinical application of anti-inflammatory and immunosuppressive therapy.

Asunto(s)

Inmunoterapia , Hipertensión Arterial Pulmonar , Humanos , Hipertensión Arterial Pulmonar/terapia , Hipertensión Arterial Pulmonar/etiología , Inmunoterapia/métodos , Animales , Inflamación/terapia , Inflamación/patología , Hipertensión Pulmonar/terapia , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/inmunología , Remodelación Vascular

RESUMEN

Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. TNF-α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system's homeostasis and inflammation through different mechanisms from anti-TNF-α therapies. With a single treatment of adeno-associated virus (AAV)-TIPE2 gene delivery in the accelerated aging Zmpste24-/- (Z24-/-) mouse model, we found differences in Safranin O staining intensity within the articular cartilage (AC) region of the knee between TIPE2-treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24-/- cartilage while shown to be restored in the TIPE2-treated Z24-/- cartilage. We also observed that chondrocytes in Z24-/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α-positive cells, ß-galactosidase (ß-gal) activity, and p16 expression seen in Z24-/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α-induced inflammation and senescence, resulting in the prevention or delay of knee OA in our accelerated aging Z24-/- mouse model.

Asunto(s)

Senescencia Celular , Dependovirus , Modelos Animales de Enfermedad , Terapia Genética , Inflamación , Péptidos y Proteínas de Señalización Intracelular , Osteoartritis , Progeria , Animales , Ratones , Osteoartritis/terapia , Osteoartritis/genética , Osteoartritis/metabolismo , Osteoartritis/etiología , Osteoartritis/patología , Senescencia Celular/genética , Inflamación/genética , Inflamación/metabolismo , Inflamación/terapia , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Terapia Genética/métodos , Progeria/genética , Progeria/terapia , Progeria/metabolismo , Dependovirus/genética , Envejecimiento , Cartílago Articular/metabolismo , Cartílago Articular/patología , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Condrocitos/metabolismo , Ratones Noqueados , Factor de Necrosis Tumoral alfa/metabolismo , Humanos

RESUMEN

BACKGROUND: Intestinal inflammation has various causes and leads to some inflammatory diseases, of which autophagy pathway dysfunction could be considered as one of them. Probiotics could have a positive effect on reducing inflammation by activating the autophagy pathway. To evaluate the precise effects of probiotics as preventive and therapeutic agents to control the symptoms of inflammatory diseases, we aimed to investigate the efficacy of Lactobacillus spp. in regulating the autophagy signaling pathway. METHODS: A quantitative real-time polymerase chain reaction assay was used to analyze the expression of autophagy genes involved in the formation of phagophores, autophagosomes, and autolysosomes after exposing the HT-29 cell line to sonicated pathogens and adding Lactobacillus spp. before, after, and simultaneously with inflammation. A cytokine assay was also accomplished to evaluate the interleukin (IL)-6 and IL-1ß level following the probiotic treatment. RESULTS: Lactobacillus spp. generally increased autophagy gene expression and consumption of Lactobacillus spp. before, simultaneously, and after inflammation, ultimately leading to activate autophagy pathways. The proinflammatory cytokines including IL-6 and IL-1ß decreased after probiotic treatment. CONCLUSIONS: Our native probiotic Lactobacillus spp. showed beneficial effects on HT-29 cells by increasing autophagy gene expression and decreasing the proinflammatory cytokines production in all treatments. Therefore, this novel probiotic cocktail Lactobacillus spp. can prevent and treat inflammation-related diseases.

Asunto(s)

Autofagia , Inflamación , Lactobacillus , Probióticos , Transducción de Señal , Autofagia/inmunología , Humanos , Probióticos/uso terapéutico , Probióticos/farmacología , Células HT29 , Inflamación/prevención & control , Inflamación/inmunología , Inflamación/terapia , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo

RESUMEN

INTRODUCTION: Many trauma patients die from hemorrhagic shock in the military and civilian settings. Although two-thirds of hemorrhagic shock victims die of reasons other than exsanguination, such as the consequent cytokine storm, anti-inflammatory therapies failed to be utilized. Apoptotic cell-based treatments enhance innate ability to exert systemic immunomodulation as demonstrated in several clinical applications and hence might present a novel approach in hemorrhagic shock treatment. MATERIALS AND METHODS: Twenty-two rats underwent a pressure-controlled hemorrhagic shock model and followed up for 24 hours. An infusion of apoptotic cells (Allocetra-OTS, Enlivex Therapeutics Ltd, Nes Ziona, Israel) was administered to the treatment group. Hemodynamics, blood counts, biochemistry findings, and cytokine profile were compared to a saline-resuscitated control group. RESULTS: The treatment group's mean arterial pressure decreased from 94.8 mmHg to 28.2 mmHg, resulting in an 8.13 mg/dL increase in lactate and a 1.9 g/L decrease in hemoglobin, similar to the control group. White blood cells and platelets decreased more profoundly in the treatment group. A similar cytokine profile after 24 hours was markedly attenuated in the treatment group 2 hours after bleeding. Levels of pro-inflammatory cytokines such as interleukin (IL)-1a (28.4 pg/mL vs. 179.1 pg/mL), IL-1b (47.4 pg/mL vs. 103.9 pg/mL), IL-6 (526.2 pg/mL vs. 3492 pg/mL), interferon γ (11.4 pg/mL vs. 427.9 pg/mL), and tumor necrosis factor α (19.0 pg/mL vs. 31.7 pg/mL) were profoundly lower in the treatment group. CONCLUSION: In a pressure-control hemorrhagic shock model in rats, apoptotic cell infusion showed preliminary signs of a uniform attenuated cytokine response. Apoptotic cell-based therapies might serve as a novel immunomodulatory therapy for hemorrhagic shock.

Asunto(s)

Apoptosis , Choque Hemorrágico , Choque Hemorrágico/terapia , Choque Hemorrágico/complicaciones , Choque Hemorrágico/inmunología , Animales , Ratas , Masculino , Apoptosis/fisiología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Citocinas/sangre , Citocinas/análisis , Inflamación/terapia

RESUMEN

Mesenchymal stem cells (MSCs) are a promising tool that may be used in regenerative medicine. Thanks to their ability to differentiate and paracrine signaling, they can be used in the treatment of many diseases. Undifferentiated MSCs can support the regeneration of surrounding tissues through secreted substances and exosomes. This is possible thanks to the production of growth factors. These factors stimulate the growth of neighboring cells, have an anti-apoptotic effect, and support angiogenesis, and MSCs also have an immunomodulatory effect. The level of secreted factors may vary depending on many factors. Apart from the donor's health condition, it is also influenced by the source of MSCs, methods of harvesting, and even the banking of cells. This work is a review of research on how the patient's health condition affects the properties of obtained MSCs. The review discusses the impact of the patient's diabetes, obesity, autoimmune diseases, and inflammation, as well as the impact of the source of MSCs and methods of harvesting and banking cells on the phenotype, differentiation capacity, anti-inflammatory, angiogenic effects, and proliferation potential of MSCs. Knowledge about specific clinical factors allows for better use of the potential of stem cells and more appropriate targeting of procedures for collecting, multiplying, and banking these cells, as well as for their subsequent use. This article aims to review the characteristics, harvesting, banking, and paracrine signaling of MSCs and their role in diabetes, obesity, autoimmune and inflammatory diseases, and potential role in regenerative medicine.

Asunto(s)

Enfermedades Autoinmunes , Diabetes Mellitus , Inflamación , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Obesidad , Medicina Regenerativa , Humanos , Medicina Regenerativa/métodos , Inflamación/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Obesidad/terapia , Diabetes Mellitus/terapia , Enfermedades Autoinmunes/terapia , Diferenciación Celular

RESUMEN

Myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a neurological disorder involving multiple pathophysiological mechanisms and etiologies. Symptoms include asthenia, myalgia, post-exertional malaise and neurocognitive disorders. While the numerous patient complaints pose a diagnostic challenge, the advent of new technologies paves the way for innovative methods to reveal ME. The heterogeneity of the disease's mechanisms complicates the search for effective treatments but also offers the prospect of numerous beneficial molecules. Combining treatments targeting mitochondrial dysfunction, oxidative stress, inflammation and immunological disorders appears to be the current optimal therapeutic approach.

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L'encéphalomyélite myalgique (EM), aussi connue sous le nom de syndrome de fatigue chronique (SFC), est une maladie neurologique impliquant des mécanismes physiopathologiques et des étiologies multiples. Les symptômes comprennent une asthénie, des myalgies, un malaise après effort et des troubles neurocognitifs. Si les nombreuses plaintes des patients représentent un défi diagnostique, l'apparition de nouvelles technologies ouvre la voie à des méthodes novatrices pour révéler l'EM. L'hétérogénéité des mécanismes de la maladie complique la recherche de traitements efficaces mais offre également la perspective de nombreuses molécules bénéfiques. Associer des traitements ciblant le dysfonctionnement mitochondrial, le stress oxydatif, l'inflammation et les troubles immunologiques semble être la meilleure démarche thérapeutique actuelle.

Asunto(s)

Síndrome de Fatiga Crónica , Humanos , Síndrome de Fatiga Crónica/diagnóstico , Síndrome de Fatiga Crónica/terapia , Síndrome de Fatiga Crónica/etiología , Estrés Oxidativo/fisiología , Inflamación/diagnóstico , Inflamación/terapia

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Fu's subcutaneous needling (FSN) is a traditional Chinese acupuncture procedure used to treat pain-related neurological disorders. Moreover, the regulation of inflammatory cytokines may provide a favorable environment for peripheral nerve regeneration. In light of this, FSN may be an important novel therapeutic strategy to alleviate pain associated with peripheral neuropathy; however, the underlying molecular mechanisms remain unclear. This study revealed that patients who had osteoarthritis with peripheral neuropathic pain significantly recovered after 1 to 2 weeks of FSN treatment according to the visual analog scale, Western Ontario and McMaster Universities Osteoarthritis Index, Lequesne index, walking speed, and passive range of motion. Similarly, we demonstrated that FSN treatment in an animal model of chronic constriction injury (CCI) significantly improved sciatic nerve pain using paw withdrawal thresholds, sciatic functional index scores, and compound muscle action potential amplitude tests. In addition, transmission electron microscopy images of sciatic nerve tissue showed that FSN effectively reduced axonal swelling, abnormal myelin sheaths, and the number of organelle vacuoles in CCI-induced animals. Mechanistically, RNA sequencing and gene set enrichment analysis revealed significantly reduced inflammatory pathways, neurotransmitters, and endoplasmic reticulum stress pathways and increased nerve regeneration factors in the FSN+CCI group, compared with that in the CCI group. Finally, immunohistochemistry, immunoblotting and enzyme-linked immunosorbent assay showed similar results in the dorsal root ganglia and sciatic nerve. Our findings suggest that FSN can effectively ameliorate peripheral neuropathic pain by regulate inflammation and endoplasmic reticulum stress, thereby determine its beneficial application in patients with peripheral nerve injuries.

Asunto(s)

Axones , Estrés del Retículo Endoplásmico , Inflamación , Regeneración Nerviosa , Remielinización , Animales , Masculino , Inflamación/terapia , Inflamación/patología , Axones/fisiología , Humanos , Terapia por Acupuntura/métodos , Neuralgia/terapia , Nervio Ciático/lesiones , Persona de Mediana Edad , Femenino , Ratas , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Anciano

RESUMEN

Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patients and are associated with side effects that may limit their use. The vagus nerve (VN) provides a direct communication conduit between the CNS and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the VN (VNS) shows efficacy in ameliorating pathology in several CNS and autoimmune disorders. We therefore investigated the impact of VNS in a rat experimental autoimmune encephalomyelitis (EAE) model of MS. In this study, VNS-mediated neuroimmune modulation is demonstrated to effectively decrease EAE disease severity and duration, infiltration of neutrophils and pathogenic lymphocytes, myelin damage, blood-brain barrier disruption, fibrinogen deposition, and proinflammatory microglial activation. VNS modulates expression of genes that are implicated in MS pathogenesis, as well as those encoding myelin proteins and transcription factors regulating new myelin synthesis. Together, these data indicate that neuroimmune modulation via VNS may be a promising approach to treat MS, that not only ameliorates symptoms but potentially also promotes myelin repair (remyelination).

Asunto(s)

Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Estimulación del Nervio Vago , Nervio Vago , Animales , Encefalomielitis Autoinmune Experimental/terapia , Encefalomielitis Autoinmune Experimental/inmunología , Ratas , Esclerosis Múltiple/terapia , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Estimulación del Nervio Vago/métodos , Inflamación/terapia , Inflamación/patología , Modelos Animales de Enfermedad , Femenino , Vaina de Mielina/metabolismo , Barrera Hematoencefálica

RESUMEN

To evaluate the efficacy of SWEEPS mode of the Er: YAG laser(SL) and passive ultrasonic irrigation(PUI) in the eradication of microorganisms and in the inflammation detection by IL-1ß. Thirty patients with chronic apical periodontitis(AP) were allocated into two groups: Group SL-SWEEPS laser activated irrigation(n = 15) and Group PUI-passive ultrasonic irrigation(n = 15). Bacteriological samples were taken before(S1) and after chemomechanical preparation(S2), and then after final irrigation activation(S3). The levels of total bacteria and Streptococci were measured by means of PCR. Blood samples were collected before and 3rd day after treatment. Enzyme-linked immunosorbent assay was used to measure the levels of IL-1ß. The bacterial reduction showed no differences between groups after chemo-mechanical treatment and after irrigant activation(p = 0.590). Post-treatment IL-1ß levels were lower than pretreatment levels in both groups(p < 0.001). SL or PUI application in addition to chemomechanical preparation has similar effects on total bacterial level and inflammation detected by IL-1ß in patients with AP.

Asunto(s)

Interleucina-1beta , Láseres de Estado Sólido , Periodontitis Periapical , Humanos , Periodontitis Periapical/microbiología , Periodontitis Periapical/terapia , Masculino , Femenino , Interleucina-1beta/sangre , Adulto , Láseres de Estado Sólido/uso terapéutico , Persona de Mediana Edad , Irrigación Terapéutica/métodos , Inflamación/microbiología , Inflamación/terapia , Terapia por Ultrasonido/métodos

RESUMEN

Background: Individuals with posttraumatic stress disorder (PTSD) are at heightened risk for cardiovascular disease (CVD) compared to the general population. Inflammation and autonomic dysfunction are candidate mechanisms of CVD risk in PTSD; however, these mechanisms have not been well-characterised in the PTSD-CVD link. Further, these mechanisms may operate through altered stress-related neural activity (SNA). Yet, it remains unknown if changes in PTSD are associated with changes in CVD risk mechanisms.Objective: This manuscript describes the design and procedures of a pilot randomised controlled trial to assess the impact of a first-line treatment for PTSD (Cognitive Processing Therapy; CPT) versus waitlist control on mechanisms of CVD risk. Further, this study will test the hypothesis that CPT reduces CVD risk through its effects on inflammation and autonomic function and that these changes are driven by changes in SNA.Methods: Adults with PTSD and CVD risk (N = 30) will be randomised to CPT or waitlist control. Participants complete two laboratory visits (baseline and post-treatment) that include surveys, brain and peripheral imaging via 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and resting measures of autonomic function. Primary outcomes include arterial inflammation and heart rate variability. Secondary outcomes include leukopoiesis (bone marrow uptake), heart rate, and blood pressure. The indirect effects of PTSD treatment on changes in inflammation and autonomic function through SNA will also be examined.Conclusions: This study seeks to characterise candidate neuroimmune mechanisms of the PTSD-CVD link to identify treatment targets and develop personalised interventions to reduce CVD events in PTSD populations.Trial registration: ClinicalTrials.gov identifier: NCT06429293..

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Individuals with posttraumatic stress disorder (PTSD) have greater risk for cardiovascular disease (CVD) than the general population.Autonomic dysfunction and inflammation are candidate mechanisms of the PTSD-CVD link, which may be driven by changes in neural activity.This pilot randomised controlled trial will test the impact of a first-line PTSD treatment on autonomic dysfunction and inflammation, and whether neural alterations are associated with changes in these mechanisms.

Asunto(s)

Enfermedades Cardiovasculares , Terapia Cognitivo-Conductual , Trastornos por Estrés Postraumático , Humanos , Trastornos por Estrés Postraumático/terapia , Proyectos Piloto , Enfermedades Cardiovasculares/complicaciones , Adulto , Inflamación/terapia , Masculino , Femenino , Biomarcadores , Sistema Nervioso Autónomo/fisiopatología , Persona de Mediana Edad

RESUMEN

Spinal cord injury (SCI) is a severe medical condition resulting in substantial physiological and functional consequences for the individual. People with SCI are characterised by a chronic, low-grade systemic inflammatory state, which contributes to further undesirable secondary injuries. This study aimed to evaluate the effect of adding aquatic therapy to the standard physiotherapy treatment, implemented in two different schedules, on systemic inflammation in SCI patients. Additionally, the relationship between cytokine blood levels and changes in functionality (measured with the 6MWT, 10MWT, WISCI, BBS, and TUG tests) throughout the study was assessed. A quantitative multiplexed antibody assay was performed to measure the expression level of 20 pro- and anti-inflammatory cytokines in blood samples from SCI patients at three time points: baseline, week 6, and immediately post-intervention (week 12). This study identified a complex signature of five cytokines (IL-12p70, IL-8, MCP-1, IL-1α, and IP10) associated with the time course of the two physiotherapy programs. Two other cytokines (IL-4 and TNF-α) were also associated with the functional recovery of patients. These could be important indicators for SCI prognosis and provide a basis for developing novel targeted therapies.

Asunto(s)

Citocinas , Modalidades de Fisioterapia , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Citocinas/sangre , Citocinas/metabolismo , Inflamación/terapia , Inflamación/sangre , Hidroterapia/métodos , Recuperación de la Función

RESUMEN

Purpose: Corneal injury (CI) resulting in corneal opacity remains a clinical challenge. Exosomes (Exos) derived from bone marrow mesenchymal stem cells (BMSCs) have been proven effective in repairing various tissue injuries and are also considered excellent drug carriers due to their biological properties. Recently, microRNA-29b (miR-29b) was found to play an important role in the autophagy regulation which correlates with cell inflammation and fibrosis. However, the effects of miR-29b and autophagy on CI remain unclear. To find better treatments for CI, we used Exos to carry miR-29b and investigated its effects in the treatment of CI. Methods: BMSCs were transfected with miR-29b-3p agomir/antagomir and negative controls (NCs) to obtain Exos-29b-ago, Exos-29b-anta, and Exos-NC. C57BL/6J mice that underwent CI surgeries were treated with Exos-29b-ago, Exos-29b-anta, Exos-NC, or PBS. The autophagy, inflammation, and fibrosis of the cornea were estimated by slit-lamp, hematoxylin and eosin (H&E) staining, immunofluorescence, RT‒qPCR, and Western blot. The effects of miR-29b-3p on autophagy and inflammation in immortalized human corneal epithelial cells (iHCECs) were also investigated. Results: Compared to PBS, Exos-29b-ago, Exos-29b-anta, and Exos-NC all could ameliorate corneal inflammation and fibrosis. However, Exos-29b-ago, which accumulated a large amount of miR-29b-3p, exerted excellent potency via autophagy activation by inhibiting the PI3K/AKT/mTOR pathway and further inhibited corneal inflammation via the mTOR/NF-κB/IL-1ß pathway. After Exos-29b-ago treatment, the expressions of collagen type III, α-smooth muscle actin, fibronectin, and vimentin were significantly decreased than in other groups. In addition, overexpression of miR-29b-3p prevented iHCECs from autophagy impairment and inflammatory injury. Conclusions: Exos from BMSCs carrying miR-29b-3p can significantly improve the therapeutic effect on CI via activating autophagy and further inhibiting corneal inflammation and fibrosis.

Asunto(s)

Autofagia , Lesiones de la Cornea , Portadores de Fármacos , Exosomas , Células Madre Mesenquimatosas , MicroARNs , Animales , Humanos , Masculino , Ratones , Autofagia/efectos de los fármacos , Western Blotting , Células Cultivadas , Lesiones de la Cornea/metabolismo , Lesiones de la Cornea/genética , Lesiones de la Cornea/terapia , Modelos Animales de Enfermedad , Exosomas/química , Exosomas/metabolismo , Inflamación/terapia , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , MicroARNs/administración & dosificación , MicroARNs/genética , MicroARNs/farmacología