The Efficiency of Brain-Derived Neurotrophic Factor Secretion by mRNA-Electroporated Regulatory T Cells Is Highly Impacted by Their Activation Status.

Genetic engineering of regulatory T cells (Tregs) presents a promising avenue for advancing immunotherapeutic strategies, particularly in autoimmune diseases and transplantation. This study explores the modification of Tregs via mRNA electroporation, investigating the influence of T-cell activation status on transfection efficiency, phenotype, and functionality. For this CD45RA Tregs were isolated, expanded, and modified to overexpress brain-derived neurotrophic factor (BDNF).

Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice.

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter.

Neurotrophic Factors as Regenerative Therapy for Neurodegenerative Diseases: Current Status, Challenges and Future Perspectives.

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has recently focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases.

Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis.

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD) and Alzheimer's disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase.

Engineering of regulatory T cells by means of mRNA electroporation in a GMP-compliant manner.

Regulatory T cells (Tregs) are crucial in inducing and maintaining tolerance. This unique capacity of Tregs, in combination with proof-of-principle in preclinical studies, highlights the potential clinical use of Tregs for the treatment of autoimmunity and transplant rejection. Although proven to be safe and well tolerated in the first clinical trials, only modest clinical results were observed.

Cells to the Rescue: Emerging Cell-Based Treatment Approaches for NMOSD and MOGAD.

Cell-based therapies are gaining momentum as promising treatments for rare neurological autoimmune diseases, including neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease. The development of targeted cell therapies is hampered by the lack of adequate animal models that mirror the human disease. Most cell-based treatments, including HSCT, CAR-T cell, tolerogenic dendritic cell and mesenchymal stem cell treatment have entered early stage clinical trials or have been used as rescue treatment in treatment-refractory cases.

Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies.

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS.

Safety and immunological proof-of-concept following treatment with tolerance-inducing cell products in patients with autoimmune diseases or receiving organ transplantation: A systematic review and meta-analysis of clinical trials.

In the past years, translational approaches have led to early-stage clinical trials assessing safety and efficacy of tolerance-inducing cell-based treatments in patients. This review aims to determine if tolerance-inducing cell-based therapies, including dendritic cells, regulatory T cells and mesenchymal stem cells, are safe in adult patients who underwent organ transplantation or in those with autoimmune diseases, including multiple sclerosis, diabetes mellitus type 1, Crohn's disease and rheumatoid arthritis. Immunological and clinical outcomes were reviewed, to provide evidence for proof-of-concept and efficacy.

Endurance Exercise Intervention Is Beneficial to Kidney Function in a Rat Model of Isolated Abdominal Venous Congestion: a Pilot Study.

In this study, the effects of moderate intense endurance exercise on heart and kidney function and morphology were studied in a thoracic inferior vena cava constricted (IVCc) rat model of abdominal venous congestion. After IVC surgical constriction, eight sedentary male Sprague-Dawley IVCc rats (IVCc-SED) were compared to eight IVCc rats subjected to moderate intense endurance exercise (IVCc-MOD). Heart and kidney function was examined and renal functional reserve (RFR) was investigated by administering a high protein diet (HPD).

Impact of Exercise-Nutritional State Interactions in Patients with Type 2 Diabetes.

Introduction: This study examines the role of nutritional status during exercise training in patients with type 2 diabetes mellitus by investigating the effect of endurance-type exercise training in the fasted versus the fed state on clinical outcome measures, glycemic control, and skeletal muscle characteristics in male type 2 diabetes patients.

Methods: Twenty-five male patients (glycated hemoglobin (HbA1c), 57 ± 3 mmol·mol (7.4% ± 0.

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration.

Introduction: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains.

Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA.

Background: Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent.

Exercise-induced lactate responses in Multiple Sclerosis: A retrospective analysis.

Background: Persons with Multiple Sclerosis have elevated resting serum lactate concentrations compared to healthy controls (HC).

Objective: To evaluate lactate concentrations during acute exercise and/or following training in MS compared to HC.

Methods: In this retrospective study, blood lactate concentrations (mmol/l) originating from two previous studies were analyzed.

Effects of Rehabilitation on Gait Pattern at Usual and Fast Speeds Depend on Walking Impairment Level in Multiple Sclerosis.

Background: Physical rehabilitation can improve walking capacity in persons with multiple sclerosis (MS). However, changes in spatiotemporal gait parameters after rehabilitation are not frequently evaluated, and it is unknown to what extent potential effects depend on baseline disability level. The objective was to investigate the effectiveness of rehabilitation programs on gait parameters at usual and fastest speeds in persons with MS categorized according to walking speed.

Walking endurance and perceived symptom severity after a single maximal exercise test in persons with mild disability because of multiple sclerosis.

People with multiple sclerosis (PwMS) are less physically active compared with the general population. This might also be because of the perception of temporary worsening of symptoms during physical activity. Forty-two PwMS with a mild level of disability underwent a maximal exercise test on a bicycle ergometer.

Adrenergically and non-adrenergically mediated human adipose tissue lipolysis during acute exercise and exercise training.

Obesity-related adipose tissue (AT) dysfunction, in particular subcutaneous AT (SCAT) lipolysis, is characterized by catecholamine resistance and impaired atrial natriuretic peptide (ANP) responsiveness. It remains unknown whether exercise training improves (non-)adrenergically mediated lipolysis in metabolically compromised conditions. We investigated the effects of local combined α-/β-adrenoceptor blockade on abdominal SCAT lipolysis in lean insulin sensitive (IS) (=10), obese IS (=10), and obese insulin resistant (IR) (=10) men.

Muscle carnosine in experimental autoimmune encephalomyelitis and multiple sclerosis.

Background: Muscle carnosine is related to contractile function (Ca handling) and buffering of exercise-induced acidosis. As these muscular functions are altered in Multiple Sclerosis (MS) it is relevant to understand muscle carnosine levels in MS.

Methods: Tibialis anterior muscle carnosine was measured in an animal MS model (EAE, experimental autoimmune encephalomyelitis, n = 40) and controls (CON, n = 40) before and after exercise training (EAE, CON, 10d, 1 h/d, 24 m/min treadmill running) or sedentary conditions (EAE, CON).

Twelve Weeks of Medium-Intensity Exercise Therapy Affects the Lipoprotein Profile of Multiple Sclerosis Patients.

Multiple sclerosis (MS) is an inflammatory auto-immune disease of the central nervous system (CNS). Serum glucose alterations and impaired glucose tolerance (IGT) are reported in MS patients, and are commonly associated with the development of cardio-metabolic co-morbidities. We previously found that a subgroup of MS patients shows alterations in their lipoprotein profile that are similar to a pre-cardiovascular risk profile.

Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.

Background: Exercise therapy studies in persons with multiple sclerosis (pwMS) primarily focused on motor outcomes in mid disease stage, while cognitive function and neural correlates were only limitedly addressed.

Objectives: This pragmatic randomized controlled study investigated the effects of a remotely supervised community-located "start-to-run" program on physical and cognitive function, fatigue, quality of life, brain volume, and connectivity.

Method: In all, 42 pwMS were randomized to either experimental (EXP) or waiting list control (WLC) group.

Impact of high-intensity concurrent training on cardiovascular risk factors in persons with multiple sclerosis - pilot study.

Purpose: High-intensity concurrent training positively affects cardiovascular risk factors. Because this was never investigated in multiple sclerosis, the present pilot study explored the impact of this training on cardiovascular risk factors in this population.

Methods: Before and after 12 weeks of high-intense concurrent training (interval and strength training, 5 sessions per 2 weeks, n = 16) body composition, resting blood pressure and heart rate, 2-h oral glucose tolerance (insulin sensitivity, glycosylated hemoglobin, blood glucose and insulin concentrations), blood lipids (high- and low-density lipoprotein, total cholesterol, triglyceride levels) and C-reactive protein were analyzed.

Elevated cardiovascular risk factors in multiple sclerosis.

Background: Multiple sclerosis (MS) is associated with elevated cardiovascular mortality. To prevent this a better understanding of their CVD risk factors and interrelations is necessary.

Methods: MS patients (n = 52) and healthy controls (HC, n = 24) were matched for age, height, weight, body mass index and physical activity.

Muscle Strength, But Not Muscle Oxidative Capacity, Varies Between the Morning and the Afternoon in Patients with Multiple Sclerosis: A Pilot Study.

Despite frequent muscle strength or muscle oxidative capacity (based on exercise-onset oxygen uptake [VO2] kinetics) assessments in patients with multiple sclerosis, the impact of time of day on these parameters is often not taken into account. Based on observations in healthy subjects, it remains to be studied whether muscle strength, and/or exercise-onset VO2 kinetics, varies between the morning and the afternoon in patients with multiple sclerosis. In this prospective observational pilot study, walking capacity, exercise-onset VO2 kinetics, isometric knee extension/flexion strength (dynamometry), and self-reported fatigue were measured in 11 patients with multiple sclerosis (age, 51.

Muscular, cardiac, ventilatory and metabolic dysfunction in patients with multiple sclerosis: Implications for screening, clinical care and endurance and resistance exercise therapy, a scoping review.

In the treatment of multiple sclerosis (MS), exercise training is now considered a cornerstone. However, most clinicians tend to focus on neurologic deficits only, and thus prefer to prescribe rehabilitation programs specifically to counteract these deficits. However, the present comprehensive review shows that patients with MS (pwMS) also experience significant muscular, cardiac, ventilatory and metabolic dysfunction, which significantly contribute, next to neurologic deficits, to exercise intolerance.

High Intensity Aerobic and Resistance Exercise Can Improve Glucose Tolerance in Persons With Multiple Sclerosis: A Randomized Controlled Trial.

Introduction: The prevalence of impaired glucose tolerance (IGT) is higher in persons with multiple sclerosis (MS) compared to healthy controls, indicating metabolic deficits that may increase comorbidity. In other populations, IGT can, at least partly, be reversed by intense physical exercise, but this is never investigated before in MS.

Aim: To investigate the effect of high intensity aerobic and resistance training on glucose tolerance and skeletal muscle GLUT4 content in MS.

High Intensity Training May Reverse the Fiber Type Specific Decline in Myogenic Stem Cells in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is associated with loss of skeletal muscle mass and function. The myogenic stem cells (satellite cells-SCs) are instrumental to accretion of myonuclei, but remain to be investigated in MS. The present study aimed to compare the SC and myonuclei content between MS patients (n = 23) and age matched healthy controls (HC, n = 18).