Role of Regulatory T Cells in Skeletal Muscle Regeneration: A Systematic Review.

Muscle injuries are frequent in individuals with genetic myopathies and in athletes. Skeletal muscle regeneration depends on the activation and differentiation of satellite cells present in the basal lamina of muscle fibers. The skeletal muscle environment is critical for repair, metabolic and homeostatic function.

Persistent mdx diaphragm alterations are accompanied by increased expression and activity of calcium and muscle-specific proteins.

The mdx mouse model of Duchenne Muscular Dystrophy (DMD) presents sarcolemma instability and develops a mild multi-stage dystrophinopathy characterized by intense myonecrosis with inflammatory infiltrate at 4-weeks; muscular regeneration at 12-weeks and persistent fibrosis onwards. Mdx diaphragm muscle has a more severe phenotype with structural and functional deterioration that closely resembles the diaphragm impairment responsible for DMD human patients' morbidity. Herein, we compared calcium deposits, activity of calcium-related proteases, and expression of muscle-specific proteins in mdx diaphragm at 4-weeks and 12-weeks.

Adjuvant effect of low-carbohydrate diet on outcomes of patients with recurrent glioblastoma under intranasal perillyl alcohol therapy.

Background: Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through its effects on glucose availability, which is a determinant for tumor progression (TP). Low-carbohydrate diet (LCD) reduces the glucose levels needed to drive the Warburg effect.

Methods: To investigate LCD's effect on GB therapy, we have begun a clinical trial using LCD as an addition to intranasal perillyl alcohol (POH) for recurrent GB (rGB) patients.

The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice.

Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflammatory response contributes directly to severity and exacerbation of the diaphragm muscle pathology. The omentum is a lymphoid organ with unique structural and immune functions serving as a sanctuary of hematopoietic and mesenchymal progenitors that coordinate immune responses in the peritoneal cavity. Upon activation, these progenitors expand and the organ produces large amounts of growth factors orchestrating tissue regeneration.

Liver fibrosis improvement in chronic hepatitis C after direct acting-antivirals is accompanied by reduced profibrogenic biomarkers-a role for MMP-9/TIMP-1.

Background And Aims: Disturbances in matrix metalloproteinases (MMPs) and corresponding tissue inhibitors (TIMPs) contribute to hepatitis C virus (HCV)-induced fibrosis. This study aimed to determine MMP-9/TIMP-1 levels in addition to MMP-2 and -9 activities; correlating with the improvement of liver fibrosis in patients under direct-acting antiviral (DAA) therapy.

Methods: Clinical and laboratory follow-up were performed before treatment and after 12 weeks post-treatment, referred as sustained viral response (SVR).

Dihydrofolate Reductase (DHFR) del19bp Polymorphism and Down Syndrome Offspring.

Down syndrome (DS) is the most common form of mental disability of genetic etiology. Nondisjunction of chromosome 21 is the leading cause of the syndrome. In general, free trisomy 21 cases originate from missegregation in maternal meiosis.

Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism.

Background: Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment.

Comparative study of calcium and calcium-related enzymes with differentiation markers in different ages and muscle types in mdx mice.

Sarcolemma instability and increased calcium influx in muscle fibers are characteristics of the Duchenne muscular dystrophy. Excessive calcium activates calcium-dependent enzymes, such as calpains (CAPN) and matrix metalloproteases (MMP). Here, we analyzed calcium deposits, the activity of CAPN and MMP and the expression of Myh, SERCA and myogenic regulatory factors in different skeletal muscles during myonecrosis (4-weeks) and regeneration (12-weeks) phases of the mdx muscular pathology.

Perillyl alcohol and perillic acid exert efficient action upon HSV-1 maturation and release of infective virus.

Background: Infection by herpes simplex type-1 virus (HSV-1) causes several pathological processes, including cutaneous, oral and genital infections, fatal encephalitis and cognitive dysfunction due to grey matter loss. Acyclovir is the reference compound used as HSV-1 antiviral therapy. However, with the emergence of HSV-resistant strains to current antiviral drugs, development of new antiviral agents with distinct modes of action is urgently needed.

Omentum acts as a regulatory organ controlling skeletal muscle repair of mdx mice diaphragm.

Duchenne muscular dystrophy is a lethal X-linked muscle wasting disease due to mutations of the dystrophin gene leading to distinct susceptibility to degeneration and fibrosis among skeletal muscles. This study aims at verifying whether intense mdx diaphragm remodeling could be attributed to influences from the omentum, a lymphohematopoietic tissue rich in progenitor cells and trophic factors. Mdx omentum produces growth factors HGF and FGF and increased amounts of VEGF with pleiotropic actions upon muscular progenitors and myoblast differentiation.

Reduced mitochondrial respiration and increased calcium deposits in the EDL muscle, but not in soleus, from 12-week-old dystrophic mdx mice.

Mitochondria play an important role in providing ATP for muscle contraction. Muscle physiology is compromised in Duchenne muscular dystrophy (DMD) and several studies have shown the involvement of bioenergetics. In this work we investigated the mitochondrial physiology in fibers from fast-twitch muscle (EDL) and slow-twitch muscle (soleus) in the mdx mouse model for DMD and in control C57BL/10J mice.

Circulating Cell-Free DNA as a Prognostic and Molecular Marker for Patients with Brain Tumors under Perillyl Alcohol-Based Therapy.

Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors.

Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma.

It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless of O6-methylguanine-methyltransferase promoter methylation status. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma.

Perillyl alcohol, a pleiotropic natural compound suitable for brain tumor therapy, targets free radicals.

Monoterpenes such as limonene and perillyl alcohol (POH) are promising natural compounds with pro-oxidant properties partly due to endoplasmic reticulum (ER) stress-induced cytotoxicity, and antioxidant activity owing to their activity as free radical scavengers, inhibition of coenzyme Q synthesis, activation of antioxidant-responsive elements (inducing detoxification enzymes) and induction of apoptosis. Activation of ER-stress responses generates reactive oxygen species (ROS), which are highly reactive free radicals mainly produced during mitochondrial electron transfer for adenosine triphosphate (ATP) synthesis. When cells are subjected to oxidative stress conditions, there is an accumulation of ROS that can lead to irreversible cell injury caused primarily by lipid peroxidation, protein aggregation and/or DNA damage.

Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains.

Tissue damage triggers innate immune response mediated by Toll-like receptor 4 (TLR) that recognizes endogenous host danger molecules associated with cell death and tissue inflammation, although the precise role of TLR-4 signaling in muscle tissue repair is still uncertain. Previously, we observed that TLR-4 exerted a protective effect preventing excessive muscular damage induced by Bothrops jararacussu crude venom. This study aimed to evaluate the involvement of TLR-4 at early stages of muscular tissue remodeling in distinct mouse strains after injection of purified snake venom.

Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long-term inhalational chemotherapy for gliomas.

Background: Gliomas display a high degree of intratumor heterogeneity, including changes in physiological parameters and lipid composition of the plasma membrane, which may contribute to the development of drug resistance. Biophysical interactions between therapeutic agents and the lipid components at the outer plasma membrane interface are critical for effective drug uptake. Amphipathic molecules such as perillyl alcohol (POH) have a high partition coefficient and generally lead to altered lipid acyl tail dynamics near the lipid-water interface, impacting the lipid bilayer structure and transport dynamics.

Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice.

Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.

Implant of polymer containing pentacyclic triterpenes from Eugenia punicifolia inhibits inflammation and activates skeletal muscle remodeling.

Sustained chronic inflammation induces activation of genes involved in cellular proliferation and apoptosis, thereby causing skeletal muscle degeneration. To investigate in vitro effects of isolated pentacyclic triterpenes from Eugenia punicifolia (Ep-CM) upon signaling pathways involved in the regulation of skeletal muscle cell line proliferation, and in vivo muscular tissue remodeling. C2C12 cells were seeded on eight-well plates and [(3)H]-thymidine incorporation, TUNEL assays, mitochondria viability, zymography for matrix metalloproteases (MMPs), Western blot analysis for MAPKinase signaling pathway, NFκB activation and HMGB1 production subsequently determined under basal conditions and after Ep-CM treatment.

Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation.

Aim: This retrospective study aimed to evaluate the long-term response and toxicity of recurrent malignant glioma patients to inhalation chemotherapy with perillyl alcohol (POH).

Patients And Methods: The cohort included 117 men and 81 women with primary glioblastoma multiforme (GBM; n=154), grade III astrocytoma (AA; n=26) and anaplastic oligodendroglioma (AO; n=5). POH inhalation schedule 4-times daily started with 66.

Intranasal administration of perillyl alcohol activates peripheral and bronchus-associated immune system in vivo.

Perillyl alcohol (POH) presents antitumoral activity but clinical application is hampered by adverse effects following oral administration. This work aimed to verify the cytotoxic effect of intranasal POH administration in the histology of lung, liver, brain; the cellularity and function of peripheral and bronchoalveolar-associated immune system. C57 adult mice received 1-min inhalation with POH, vehicle 70 % ethanol or saline buffer, once (84 μg/day) or twice (164 μg/day) during five consecutive days, and were killed 72 h after treatment.

Intake of butter naturally enriched with cis9,trans11 conjugated linoleic acid reduces systemic inflammatory mediators in healthy young adults.

A conjugated linoleic acid (CLA) depletion-repletion study was carried out to investigate the effects of dietary c9,t11 CLA on C-reactive protein, transcription factor NFκB, metalloproteinases 2 and 9, inflammatory mediators (adiponectin, TNFα, IL-2, IL-4, IL-8, IL-10), body composition, and erythrocyte membrane composition in healthy normal-weight human adults. CLA depletion was achieved through an 8-week period of restricted dairy fat intake (depletion phase; CLA intake was 5.2±5.

Increased metalloprotease activity in the epileptogenic lesion--Lobectomy reduces metalloprotease activity and urokinase-type uPAR circulating levels.

Inflammation influences the pathogenesis of seizures by boosting neuronal degeneration of temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). This work aimed to determine the activity of metalloproteases (MMPs) in brain tissue fragments of TLE-HS patients and the effect of lobectomy on circulating inflammatory biomarkers. Surgical fragments (n=4) from epileptogenic focus (EF) e perilesion area (PL), and control hippocampus from autopsy (n=5) were processed for glial protein (GFAP), activated microglia (IB4) immunohistochemistry, and metalloprotease activity (MMP-2, -9).

Resection of the epileptogenic lesion abolishes seizures and reduces inflammatory cytokines of patients with temporal lobe epilepsy.

Persistent neuroinflammation is implicated in the pathogenesis of seizures and neuronal degeneration of temporal lobe epilepsy (TLE). Circulating level of inflammatory cytokines was determined during inter-ictal period of 25 non-operated and 10 patients (OP) submitted to anterior temporal lobectomy. OP patients showed marked reduction of IL-1β, TNFα, MIP-1α, but not IL-6 and TGF-β1.

TLR4 signaling protects from excessive muscular damage induced by Bothrops jararacussu snake venom.

Immune cells and skeletal muscle express Toll-like receptors (TLRs) that participate as sensors of tissue injury triggering signals for activation of innate and adaptive immune responses. This study aimed to investigate the involvement of TLR4 in the process of skeletal muscle repair. Muscular injury was induced by injection of 0.

Persistent activation of omentum influences the pattern of muscular lesion in the mdx diaphragm.

The mdx (X chromosome-linked muscular dystrophy) mouse develops a multi-staged disorder characterized by muscle degeneration and reactive fibrosis. Skeletal muscles of mdx mice are not equally susceptible to degeneration. The aim of this study was to verify whether the intense remodeling of the mdx diaphragm could be attributed to influences from the peritoneal microenvironment and omentum, a lymphohematopoietic tissue rich in progenitor cells and trophic factors.