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Subclinical inflammation is linked to comorbidities and risk factors, consolidating the diagnosis of chronic non-communicable diseases, such as insulin resistance, atherosclerosis, hepatic steatosis, and some types of cancer. In this context, the role of macrophages is highlighted as a marker of inflammation as well as for the high power of plasticity of these cells. Macrophages can be activated in a wide range between classical or proinflammatory, named M1, and alternative or anti-inflammatory, also known as M2 polarization. All nuances between M1 and M2 macrophages orchestrate the immune response by secreting different sets of chemokines, while M1 cells promote Th1 response, the M2 macrophages recruit Th2 and Tregs lymphocytes. In turn, physical exercise has been a faithful tool in combating the proinflammatory phenotype of macrophages. This review proposes to investigate the cellular and molecular mechanisms in which physical exercise can help control inflammation and infiltration of macrophages within the non-communicable diseases scope. During obesity progress, proinflammatory macrophages predominate in adipose tissue inflammation, which reduces insulin sensitivity until the development of type 2 diabetes, progression of atherosclerosis, and diagnosis of non-alcoholic fatty liver disease. In this case, physical activity restores the balance between the proinflammatory/anti-inflammatory macrophage ratio, reducing the level of meta-inflammation. In the case of cancer, the tumor microenvironment is compatible with a high level of hypoxia, which contributes to the advancement of the disease. However, exercise increases the level of oxygen supply, favoring macrophage polarization in favor of disease regression. [ABSTRACT FROM AUTHOR]

The capacity of the liver to regenerate is an important clinical issue after major hepatectomies and makes the difference between life and death in some cases of post-operative malfunction when the liver remnant is too small or has an impaired regenerative capacity. Several approaches have been tested to stimulate hepatic regeneration after post-operative hepatic failure syndrome; however, they have produced controversial results. A quick, simple, and harmless method that can be used intraoperatively and capable of promoting an increased regenerative capacity of the remaining liver would be very welcome. Thus, based on the data in the literature, we presented low-power laser irradiation (LPLI) as a quick, simple, and harmless method to improve liver regeneration after major hepatectomies. This article highlights the current evidence about the effects of LPLI on liver regeneration, and also suggests laser therapy as an important tool for regenerative stimulation in clinical practice. [ABSTRACT FROM AUTHOR]

Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest of scientists in using adipose-derived mesenchymal stem cells (ADMSC) in repair processes seems to be mostly due to their paracrine and immunomodulatory effects in stimulating specific cellular events. ADMSC activity can be influenced by GDF-5, which has been successfully used to drive tenogenic differentiation of ADMSC in vitro. Thus, we hypothesized that the application of ADMSC in isolation or in association with GDF-5 could improve Achilles tendon repair through the regulation of important remodeling genes expression. Lewis rats had tendons distributed in four groups: Transected (T), transected and treated with ADMSC (ASC) or GDF-5 (GDF5), or with both (ASC+GDF5). In the characterization of cells before application, ADMSC expressed the positive surface markers, CD90 (90%) and CD105 (95%), and the negative marker, CD45 (7%). ADMSC were also differentiated in chondrocytes, osteoblast, and adipocytes. On the 14th day after the tendon injury, GFP-ADMSC were observed in the transected region of tendons in the ASC and ASC+GDF5 groups, and exhibited and/or stimulated a similar genes expression profile when compared to the in vitro assay. ADMSC up-regulated Lox, Dcn, and Tgfb1 genes expression in comparison to T and ASC+GDF5 groups, which contributed to a lower proteoglycans arrangement, and to a higher collagen fiber organization and tendon biomechanics in the ASC group. The application of ADMSC in association with GDF-5 down-regulated Dcn, Gdf5, Lox, Tgfb1, Mmp2, and Timp2 genes expression, which contributed to a lower hydroxyproline concentration, lower collagen fiber organization, and to an improvement of the rats' gait 24 h after the injury In conclusion, although the literature describes the benefic effect of GDF-5 for the tendon healing process, our results show that its application, isolated or associated with ADMSC, cannot improve the repair process of partial transected tendons, indicating the higher effectiveness of the application of ADMSC in injured Achilles tendons. Our results show that the application of ADMSC in injured Achilles tendons was more effective in relation to its association with GDF-5. [ABSTRACT FROM AUTHOR]

Brachial plexus lesion results in loss of motor and sensory function, being more harmful in the neonate. Therefore, this study evaluated neuroprotection and regeneration after neonatal peripheral nerve coaptation with fibrin sealant. Thus, P2 neonatal Lewis rats were divided into three groups: AX: sciatic nerve axotomy (SNA) without treatment; AX+FS: SNA followed by end-to-end coaptation with fibrin sealant derived from snake venom; AX+CFS: SNA followed by end-to-end coaptation with commercial fibrin sealant. Results were analyzed 4, 8, and 12 weeks after lesion. Astrogliosis, microglial reaction, and synapse preservation were evaluated by immunohistochemistry. Neuronal survival, axonal regeneration, and ultrastructural changes at ventral spinal cord were also investigated. Sensory-motor recovery was behaviorally studied. Coaptation preserved synaptic covering on lesioned motoneurons and led to neuronal survival. Reactive gliosis and microglial reaction decreased in the same groups (AX+FS, AX+CFS) at 4 weeks. Regarding axonal regeneration, coaptation allowed recovery of greater number of myelinated fibers, with improved morphometric parameters. Preservation of inhibitory synaptic terminals was accompanied by significant improvement in the motor as well as in the nociceptive recovery. Overall, the present data suggest that acute repair of neonatal peripheral nerves with fibrin sealant results in neuroprotection and regeneration of motor and sensory axons. [ABSTRACT FROM AUTHOR]

Guyana and Suriname have made important progress in reducing the burden of malaria. While both countries use microscopy as the primary tool for clinical diagnosis, malaria rapid diagnostic tests (RDTs) are useful in remote areas of the interior where laboratory support may be limited or unavailable. Recent reports indicate that histidine-rich protein 2 (PfHRP2)-based diagnostic tests specific for detection of P. falciparum may provide false negative results in some parts of South America due to the emergence of P. falciparum parasites that lack the pfhrp2 gene, and thus produce no PfHRP2 antigen. Pfhrp2 and pfhrp3 genes were amplified in parasite isolates collected from Guyana and Suriname to determine if there were circulating isolates with deletions in these genes. Pfhrp3 deletions were monitored because some monoclonal antibodies utilized in PfHRP2-based RDTs cross-react with the PfHRP3 protein. We found that all 97 isolates from Guyana that met the inclusion criteria were both pfhrp2- and pfhrp3-positive. In Suriname (N = 78), 14% of the samples tested were pfhrp2-negative while 4% were pfhrp3-negative. Furthermore, analysis of the genomic region proximal to pfhrp2 and pfhrp3 revealed that genomic deletions extended to the flanking genes. We also investigated the population substructure of the isolates collected to determine if the parasites that had deletions of pfhrp2 and pfhrp3 belonged to any genetic subtypes. Cluster analysis revealed that there was no predominant P. falciparum population substructure among the isolates from either country, an indication of genetic admixture among the parasite populations. Furthermore, the pfhrp2-deleted parasites from Suriname did not appear to share a single, unique genetic background. [ABSTRACT FROM AUTHOR]

We recently proposed a new surgical approach to treat ventral root avulsion, resulting in motoneuron protection. The present work combined such a surgical approach with bone marrow mononuclear cells (MC) therapy. Therefore, MC were added to the site of reimplantation. Female Lewis rats (seven weeks old) were subjected to unilateral ventral root avulsion (VRA) at L4, L5 and L6 levels and divided into the following groups (n = 5 for each group): Avulsion, sealant reimplanted roots and sealant reimplanted roots plus MC. After four weeks and 12 weeks post-surgery, the lumbar intumescences were processed by transmission electron microscopy, to analyze synaptic inputs to the repaired a motoneurons. Also, the ipsi and contralateral sciatic nerves were processed for axon counting and morphometry. The ultrastructural results indicated a significant preservation of inhibitory pre-synaptic boutons in the groups repaired with sealant alone and associated with MC therapy. Moreover, the average number of axons was higher in treated groups when compared to avulsion only. Complementary to the fiber counting, the morphometric analysis of axonal diameter and "g" ratio demonstrated that root reimplantation improved the motor component recovery. In conclusion, the data herein demonstrate that root reimplantation at the lesion site may be considered a therapeutic approach, following proximal lesions in the interface of central nervous system (CNS) and peripheral nervous system (PNS), and that MC therapy does not further improve the regenerative recovery, up to 12 weeks post lesion. [ABSTRACT FROM AUTHOR]

The present work compared the local injection of mononuclear cells to the spinal cord lateral funiculus with the alternative approach of local delivery with fibrin sealant after ventral root avulsion (VRA) and reimplantation. For that, female adult Lewis rats were divided into the following groups: avulsion only, reimplantation with fibrin sealant; root repair with fibrin sealant associated with mononuclear cells; and repair with fibrin sealant and injected mononuclear cells. Cell therapy resulted in greater survival of spinal motoneurons up to four weeks post-surgery, especially when mononuclear cells were added to the fibrin glue. Injection of mononuclear cells to the lateral funiculus yield similar results to the reimplantation alone. Additionally, mononuclear cells added to the fibrin glue increased neurotrophic factor gene transcript levels in the spinal cord ventral horn. Regarding the motor recovery, evaluated by the functional peroneal index, as well as the paw print pressure, cell treated rats performed equally well as compared to reimplanted only animals, and significantly better than the avulsion only subjects. The results herein demonstrate that mononuclear cells therapy is neuroprotective by increasing levels of brain derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF). Moreover, the use of fibrin sealant mononuclear cells delivery approach gave the best and more long lasting results. [ABSTRACT FROM AUTHOR]

Objective It has become clear that exercise may be a useful therapy in the insulin resistance treatment, as it has anti-inflammatory effects and improves insulin sensitivity. However, it remains uncertain whether exercise affects the adipocytes or infiltrated macrophages. Thus, the aim was to investigate the effects of acute exercise on the inflammatory status and insulin signaling of the white adipose tissue (WAT) fractions (stromal-vascular fraction [SVF] and adipocytes). Design and Methods The effect of acute swimming exercise was investigated on insulin sensitivity, insulin signaling, inflammatory pathways in the WAT fractions of high-fat fed Wistar rats. Additionally, macrophage infiltration and polarization were analyzed in the WAT. Results Acute exercise can improve insulin signaling in WAT fractions, along with a phenotypic switch from M1- to M2-macrophages in obese rats, as indicated by a marked increase in macrophage galactose-type C-type lectin 1-positive cells in WAT was observed. Additionally, exercise promoted a reduction in circulating levels of lipopolysaccharide, and toll-like receptor 4 activity along with TNF-alpha, IL-1-beta and MCP-1 mRNA levels in WAT fractions. Conclusions These data suggest that acute exercise improves insulin signaling in the WAT, at least in part by inducing macrophage polarization toward the M2-state. [ABSTRACT FROM AUTHOR]

In neonatal rats, the transection of a peripheral nerve leads to an intense retrograde degeneration of both motor and sensory neurons. Most of the axotomy-induced neuronal loss is a result of apoptotic processes. The clinical use of neurotrophic factors is difficult due to side effects and elevated costs, but other molecules might be effective and more easily obtained. Among them, some are derived from Cannabis sativa. Cannabidiol ( CBD) is the major non-psychotropic component found on the surface of such plant leaves. The present study aimed to investigate the neuroprotective potential of CBD. Thus, 2-day-old Wistar rats were divided into the following experimental groups: sciatic nerve axotomy + CBD treatment ( CBD group), axotomy + vehicle treatment (phosphate buffer group) and a control group (no-treatment group). The results were analysed by Nissl staining, immunohistochemistry and terminal deoxynucleotidyl transferase d UTP nick end labeling at 5 days post-lesion. Neuronal counting revealed both motor and sensory neuron rescue following treatment with CBD (15 and 30 mg/kg). Immunohistochemical analysis (obtained by synaptophysin staining) revealed 30% greater synaptic preservation within the spinal cord in the CBD-treated group. CBD administration decreased the astroglial and microglial reaction by 30 and 27%, respectively, as seen by glial fibrillary acidic protein and ionised calcium binding adaptor molecule 1 immunolabeling quantification. In line with such results, the terminal deoxynucleotidyl transferase d UTP nick end labeling reaction revealed a reduction of apoptotic cells, mostly located in the spinal cord intermediate zone, where interneurons promote sensory-motor integration. The present results show that CBD possesses neuroprotective characteristics that may, in turn, be promising for future clinical use. [ABSTRACT FROM AUTHOR]

Aortobronchial fistula is an abnormal passage between the aorta and the bronchus, and even when recognized and treated promptly, it carries a high risk of fatality. It can develop after aortic operations, and it is usually the result of a pseudoaneurysm. Massive or intermittent hemoptysis is the main symptom. Conventional treatment of aortobronchial fistula is open surgery of the thoracic aorta with tracheobronchial reconstruction. Recently, endovascular repair has been proposed as an alternative. The authors report a case of successful endovascular treatment of thoracic aortic pseudoaneurysm with aortobronchial fistula, 22 years after surgical correction of the aortic coarctation. [ABSTRACT FROM AUTHOR]

The present study investigates the effects of xenotransplantation of Adipose Tissue Mesenchymal Stem Cells (AT-MSCs) in animals after ventral root avulsion. AT-MSC has similar characteristics to bone marrow mesenchymal stem cells (BM-MSCs), such as immunomodulatory properties and expression of neurotrophic factors. In this study, Lewis rats were submitted to surgery for unilateral avulsion of the lumbar ventral roots and received 5 × 105 AT-MSCs via the lateral funiculus. Two weeks after cell administration, the animals were sacrificed and the moto neurons, T lymphocytes and cell defense nervous system were analyzed. An increased neuronal survival and partial preservation of synaptophysin-positive nerve terminals, related to GDNF and BDNF expression of AT-MSCs, and reduction of pro-inflammatory reaction were observed. In conclusion, AT-MSCs prevent second phase neuronal injury, since they suppressed lymphocyte, astroglia and microglia effects, which finally contributed to rat motor-neuron survival and synaptic stability of the lesioned motor-neuron. Moreover, the survival of the injected AT- MSCs lasted for at least 14 days. These results indicate that neuronal survival after lesion, followed by mesenchymal stem cell (MSC) administration, might occur through cytokine release and immunomodulation, thus suggesting that AT-MSCs are promising cells for the therapy of neuronal lesions. [ABSTRACT FROM AUTHOR]

• Dimethyl fumarate (DMF) improves motoneuron survival following axotomy. • DMF downregulates astroglial reaction. • DMF enhances anti-inflammatory cytokines expression following lesion. • Sensorymotor recovery is significantly improved by DMF treatment. CNS lesions usually result in permanent loss of function and are an important problem in the medical field. In order to investigate neuroprotection/degeneration mechanisms and the synaptic plasticity of motoneurons, in addition to the potential for a variety of treatments, different experimental models of axonal injury have been proposed. Recent studies have tested the immunomodulatory drug dimethyl fumarate (DMF) for the treatment of neurodegenerative diseases and have shown promising outcomes. Therefore, in this work, we investigated the effects of DMF with regard to neuroprotection and its influence on the glial response in C57BL/6J animals subjected to crushing of the motor roots in the lumbar intumescence of the spinal cord. The animals were divided into a vehicle-treated injury group (0.08 % methylcellulose solution control group, n = 7) and injured groups treated with DMF at different doses (15, 30, 45, 90 and 180 mg/kg; n = 6–7 per dose). The 90 mg/kg dose showed the best neuroprotective results, so it was used for treatment over a period of eight weeks. Neuronal survival was assessed through Nissl staining, and functional recovery was evaluated with the CatWalk system (walking track test) and the von Frey test (mechanoreception). Immunohistochemistry was used to assess synaptic coverage and astroglial and microglial reactivity using the primary antibodies anti-synaptophysin (pre-synaptic terminal pan marker), GAD65 (GABAergic pre-synaptic terminations - inhibitory), and VGLUT1 (glutamatergic pre-synaptic terminations - excitatory). Glial reactions were evaluated with anti-IBA1 (microglia) and GFAP (astrocytes). Gene transcript levels of IL-3, IL-4, TNF-α, IL-6, TGF-β, iNOS-M1, and arginase-M2 were quantified by RT-qPCR. The results indicated that treatment with DMF, at a dose of 90 mg/kg, promoted neuroprotection and immunomodulation towards an anti-inflammatory response. It also resulted in greater preservation of inhibitory synapses and reduced astroglial reactivity, providing a more favorable environment for sensorimotor recovery. [ABSTRACT FROM AUTHOR]

Ventral root avulsion (VRA) triggers a strong glial reaction which contributes to neuronal loss, as well as to synaptic detachment. To overcome the degenerative effects of VRA, treatments with neurotrophic factors and stem cells have been proposed. Thus, we investigated neuroprotection elicited by human embryonic stem cells (hESC), modified to overexpress a human fibroblast growth factor 2 (FGF-2), on motoneurons subjected to VRA. Lewis rats were submitted to VRA (L4-L6) and hESC/FGF-2 were applied to the injury site using a fibrin scaffold. The spinal cords were processed to evaluate neuronal survival, synaptic stability, and glial reactivity two weeks post lesion . Then, qRT-PCR was used to assess gene expression of β2-microglobulin (β2m), TNFα, IL1β, IL6 and IL10 in the spinal cord in vivo and FGF2 mRNA levels in hESC in vitro . The results indicate that hESC overexpressing FGF2 significantly rescued avulsed motoneurons, preserving synaptic covering and reducing astroglial reactivity. The cells were also shown to express BDNF and GDNF at the site of injury. Additionally, engraftment of hESC led to a significant reduction in mRNA levels of TNFα at the spinal cord ventral horn, indicating their immunomodulatory properties. Overall, the present data suggest that hESC overexpressing FGF2 are neuroprotective and can shift gene expression towards an anti-inflammatory environment. [ABSTRACT FROM AUTHOR]

Introduction Injuries to peripheral nerves generate disconnection between spinal neurons and the target organ. Due to retraction of the nerve stumps, end-to-end neurorrhaphy is usually unfeasible. In such cases, autologous grafts are widely used, nonetheless with some disadvantages, such as mismatching of donor nerve dimensions and formation of painful neuromas at the donor area. Tubulization, using bioresorbable polymers, can potentially replace nerve grafting, although improvements are still necessary. Among promising bioresorbable synthetic polymers, poly( l-lactic acid) ( PLLA) and poly(ε-caprolactone) ( PCL) are the most studied. Carbon nanotubes and graphene sheets have been proposed, however, as adjuvants to improve mechanical and regenerative properties of tubular prostheses. Thus, the present work evaluated nerve tubulization repair following association of PCL with nanoparticles of carbon ( NPC) and graphene ( NPG). Methods For that, adult Lewis rats were subjected to unilateral sciatic nerve tubulization and allowed to survive for up to 8 and 12 weeks postsurgery. Results Nanocomposites mechanical/chemical evaluation showed that nanoparticles do not alter PCL crystallinity, yet providing reinforcement of polymer matrix. Thus, there was a decrease in the enthalpy of melting when the mixture of PCL + NPC + NPG was used. Nanocomposites displayed positive changes in molecular mobility in the amorphous phase of the polymer. Also, the loss modulus (E') and the glass transition exhibited highest values for PCL + NPC + NPG. Scanning electron microscopy analysis revealed that PCL + NPC + NPG prostheses showed improved cell adhesion as compared to PCL alone. Surgical procedures with PCL + NPC + NPG were facilitated due to improved flexibility of the prosthesis, resulting in better stump positioning accuracy. In turn, a twofold increased number of myelinated axons was found in such repaired nerves. Consistent with that, target muscle atrophy protection has been observed. Conclusion Overall, the present data show that nanocomposite PCL tubes facilitate nerve repair and result in a better regenerative outcome, what may, in turn, represent a new alternative to pure PCL or PLLA prostheses. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury in newborn rats triggers extensive neuronal death within the spinal cord. Because most neurodegeneration is related to oxidative stress and apoptosis, the use of antioxidants may be of therapeutic interest. Tempol is promising because of its ability to chelate reactive oxygen species and to minimize or even prevent tissue damage. Here, we evaluated neuroprotective effects of tempol following neonatal sciatic nerve transection. Two-day-old pups underwent sciatic nerve axotomy followed by tempol (12, 24 and 48mg/kg) treatment (i.p.) at 10min, 6h, and every 24h up to 1 week after injury. The rats were then killed for lumbar intumescence analysis. Nissl staining, TUNEL, synaptophysin immunolabeling and qRT-PCR (Caspase 3, Bax and Bcl2) were carried out. The results indicated that tempol treatment, at 24mg/kg, increased up to 21% spinal cord motoneuron survival (p<0.001), also preserving pre-synaptic terminals in the neuropile. Likewise, the TUNEL-positive cell number decreased in tempol-treated animals. qRT-PCR results indicated differential increase in Caspase 3 (3-fold), Bax (13-fold) and Bcl2 (28-fold) gene expression, after 12h following axotomy and tempol treatment. In conclusion, tempol administration has proven to be neuroprotective after neonatal nerve injury, leading to improved motoneuron survival, synapse preservation and minimizing apoptosis. [ABSTRACT FROM AUTHOR]