p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function

Alzheimer’s disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies. We previously demonstrated that extracellular soluble tau triggers p38 MAPK activation in microglia. Given the activation of this signaling pathway in AD and its involvement in neuroinflammation processes, here we evaluated the effect of p38 inhibition on primary microglia cultures subjected to tau treatment. Our data showed that the toxic effect driven by tau in microglia was diminished through p38 inhibition. Furthermore, p38 blockade enhanced microglia-mediated tau phagocytosis, as reflected by an increase in the number of lysosomes. In conclusion, these results contribute to our understanding of the functions of p38 in the central nervous system (CNS) beyond tau phosphorylation in neurons and provide further insights into the potential of p38 inhibition as a therapeutic strategy to halt neuroinflammation in tauopathies.

Disorders of the Sclera

Episcleritis and scleritis are the most common diseases among disorders of sclera. Episcleritis is a relatively common condition in the Middle Eastern population. The true incidence is difficult to determine, as episcleritis are self-limited conditions and patients generally do not seek professional advice. Scleritis is characterized by a chronic inflammatory response located in the sclera, which can spillover and involve adjacent ocular structures, mainly the cornea and the uvea. Scleritis can be seen at any age, but most commonly occurs in the fourth to sixth decades. It has a small female preponderance (1.6:1), and the condition is bilateral in 52% of cases. This chapter includes a severe infectious scleritis case with before and after treatment photos. The disease responded to antibiotic treatment, but later the patient presented with immune disease recurrence which responded to oral immunosuppressive treatment. Treatment photos are shown chronologically.

The Impact of Microplastic on Human Health

Background: Microplastics are considered an emerging contaminant due to their wide distribution and production in the environment, representing constant exposure to humans. However, little is known about the effects it can trigger in the body. Objective: To establish a concrete relationship between microplastics and the human body, their means of production, exposure, systemic responses, and diseases caused by their presence Methods: In this context, a review article of foreign and national literature was developed, through the PubMed and Scielo Indexers, where studies were found that address the production of plastic, the paths that lead to the production of microplastics and the exposure and damage that it represents to human health, being possible to exclude the literary sums with a publication date before 2017 Results: hey showed that translocation of the residues occurs to the circulatory and lymphatic system via the respiratory and gastrointestinal tracts. Once in the body, microplastic can stimulate a chronic inflammatory response that functions as a precursor to neoplasia and fibrosis, or carry toxic compounds such as heavy metals, endogenous disruptors, biofilms, and persistent organic pollutants. In addition, lung biopsies have shown plastic fibers in patients with respiratory diseases, highlighting a potentially dangerous accumulation. Conclusion: The present moment demonstrates that experimental research to prove the effect of microplastics is extremely necessary, since the controversy among authors and the repetition of information already described affirm that the research done so far is not sufficient.

Chronic inflammatory response modulation against Leishmania (L.) amazonensis by homeopathic thymulin and antimonium crudum inBalb/c mice

In previous studies it was found that thymulin 5cH (thymic hormone) can modulate immune processes in several diseases. Additionally, the Antimonium crudum has used in dogs bearing leishmaniosis, according to the similia principle. We studied the inflammatory and immune modulation by thymulin 5CH and Antimonium crudum 30CH treatment in mice experimentally inoculated with Leishmania (L.) amazonensis. Male adult Balb/c mice were inoculated with Leishmania (2x105 promastigotes) into the footpad to induce inflammatory response and peritoneum and spleen cells were evaluated by flow cytometry after 60 days. Animals were divided in 3 groups (n=10): thymulin 5cH, Antimonium crudum 30cH and vehicle /control. Treatment was made in blind, daily, in water/alcohol 30% diluted 1:2500 in drinking water, during all experimental period. CD11b (activated phagocytes and B1 cells), CD19 (B1 cells and B2), CD4 and CD8 (effective T lymphocytes) markers were used to identify immune cells subsets in peritoneal washing fluid and spleen cell suspension. Mice treated with thymulin 5cH presented increase in peritoneal and spleen B1 stem cells (X2=0.0001) and higher CD8+/CD4+ ratio in spleen, regarding to the control. Also, Antimonium crudum 30CH induced a mild increase in B1 cells in peritoneum and spleen ( both X2, p=0.0001). Further histological analysis of the primary lesion will be done in the next step, to elucidate the impact of these findings in the disease evolution. The results show that both treatments stimulate B1 stem cell proliferation and suggest the cooperation of T spleen lymphocytes in the process.

Deficiency of MMP-10 Aggravates the Diseased Phenotype of Aged Dystrophic Mice

Matrix metalloproteinases (MMPs) have been implicated in the progression of muscular dystrophy, and recent studies have reported the role of MMP-10 in skeletal muscle pathology of young dystrophic mice. Nevertheless, its involvement in dystrophin-deficient hearts remains unexplored. Here, we aimed to investigate the involvement of MMP-10 in the progression of severe muscular dystrophy and to characterize MMP-10 loss in skeletal and cardiac muscles of aged dystrophic mice. We examined the histopathological effect of MMP-10 ablation in aged mdx mice, both in the hind limb muscles and heart tissues. We found that MMP-10 loss compromises survival rates of aged mdx mice, with skeletal and cardiac muscles developing a chronic inflammatory response. Our findings indicate that MMP-10 is implicated in severe muscular dystrophy progression, thus identifying a new area of research that could lead to future therapies for dystrophic muscles.

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-β, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets.

Deficiency of MMP-10 Aggravates the Diseased Phenotype of Aged Dystrophic Mice

Matrix metalloproteinases have been implicated in muscular dystrophy progression and recent studies described the role of MMP-10 in skeletal muscle pathology of young dystrophic mice. Nevertheless, its implication in dystrophin deficient hearts is still missing. Here, we aimed at investigating MMP-10 implication in severe muscular dystrophic progression and characterize MMP-10 loss in skeletal and cardiac muscles of aged dystrophic mice. We examined the histopathological effect of MMP-10 ablation in aged mdx mice, both in the hind limb muscles and heart tissues. We have found that MMP-10 loss compromises survival rates of aged mdx mice, with skeletal and cardiac muscles developing a chronic inflammatory response. Our findings indicate that MMP-10 is implicated in severe muscular dystrophy progression, identifying a new area of investigation that could lead to future therapies for dystrophic muscles.

An Enriched Environment Alters DNA Repair and Inflammatory Responses After Radiation Exposure

After the Fukushima Daiichi Nuclear Power Plant accident, there is growing concern about radiation-induced carcinogenesis. In addition, living in a long-term shelter or temporary housing due to disasters might cause unpleasant stress, which adversely affects physical and mental health. It’s been experimentally demonstrated that “eustress”, which is rich and comfortable, has beneficial effects for health using mouse models. In a previous study, mice raised in the enriched environment (EE) has shown effects such as suppression of tumor growth and enhancement of drug sensitivity during cancer treatment. However, it’s not yet been evaluated whether EE affects radiation-induced carcinogenesis. Therefore, to evaluate whether EE suppresses a radiation-induced carcinogenesis after radiation exposure, in this study, we assessed the serum leptin levels, radiation-induced DNA damage response and inflammatory response using the mouse model. In brief, serum and tissues were collected and analyzed over time in irradiated mice after manipulating the raising environment during the juvenile or adult stage. To assess the radiation-induced DNA damage response, we performed immunostaining for phosphorylated H2AX which is a marker of DNA double-strand break. Focusing on the polarization of macrophages in the inflammatory reaction that has an important role in carcinogenesis, we performed analysis using tissue immunofluorescence staining and RT-qPCR. Our data confirmed that EE breeding before radiation exposure improved the responsiveness to radiation-induced DNA damage and basal immunity, further suppressing the chronic inflammatory response, and that might lead to a reduction of the risk of radiation-induced carcinogenesis.

Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia.