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Free fatty acid (FFA) receptors FFA1 and FFA4 are omega-3 molecular targets in metabolic diseases; however, their function in cancer cachexia remains unraveled. We assessed the role of FFA1 and FFA4 receptors in the mouse model of cachexia induced by Lewis lung carcinoma (LLC) cell implantation. Naturally occurring ligands such as α-linolenic acid (ALA) and docosahexaenoic acid (DHA), the synthetic FFA1/FFA4 agonists GW9508 and TUG891, or the selective FFA1 GW1100 or FFA4 AH7614 antagonists were tested. FFA1 and FFA4 expression and other cachexia-related parameters were evaluated. GW9508 and TUG891 decreased tumor weight in LLC-bearing mice. Regarding cachexia-related end points, ALA, DHA, and the preferential FFA1 agonist GW9508 rescued body weight loss. Skeletal muscle mass was reestablished by ALA treatment, but this was not reflected in the fiber cross-sectional areas (CSA) measurement. Otherwise, TUG891, GW1100, or AH7614 reduced the muscle fiber CSA. Treatments with ALA, GW9508, GW1100, or AH7614 restored white adipose tissue (WAT) depletion. As for inflammatory outcomes, ALA improved anemia, whereas GW9508 reduced splenomegaly. Concerning behavioral impairments, ALA and GW9508 rescued locomotor activity, whereas ALA improved motor coordination. Additionally, DHA improved grip strength. Notably, GW9508 restored abnormal brain glucose metabolism in different brain regions. The GW9508 treatment increased leptin levels, without altering uncoupling protein-1 downregulation in visceral fat. LLC-cachectic mice displayed FFA1 upregulation in subcutaneous fat, but not in visceral fat or gastrocnemius muscle, whereas FFA4 was unaltered. Overall, the present study shed new light on FFA1 and FFA4 receptors' role in metabolic disorders, indicating FFA1 receptor agonism as a promising strategy in mitigating cancer cachexia. [ABSTRACT FROM AUTHOR]

Polypyrrole (PPy) nanoparticles doped with p -toluene sulfonic acid ((p -TSA); PPy/ p -TSA) were synthesized and characterized, to evaluate the effects of 6-day exposure on zebrafish development. Dose-dependent envelopment of embryo chorion and early hatching were identified in all exposed groups, while additional toxic effect including heart rate, morphological parameters and behavioral locomotion were also altered in higher concentrations. This highlights, for the very first time, adverse effects caused by PPy/ p -TSA exposure in zebrafish embryogenesis and early development. • All PPy/ p -TSA-exposed embryos showed expressive early hatching. • PPy/ p -TSA adhered to and enveloped the embryos chorion dose-dependently. • Embryos exposed to higher concentrations of PPy/ p -TSA showed morphological changes. • Exposed animals showed hypolocomotor-consistent behavioral alterations. Nanomaterials have been attracting attention due to the wide range of applications in nanomedicine. Polypyrrole (PPy), a conductive polymer, has been employed in the biomedical field due to its stimulus-responsive properties, although in vivo studies to assess its potential undesirable effects are limited. This study evaluated the effects of PPy doped with p -toluene sulfonic acid ((p -TSA); PPy/ p -TSA) exposure (at 25, 100, 250 and 500 μg/mL) during six consecutive days on mortality, hatching, spontaneous movement, heart rate, morphology and locomotion behavior of zebrafish embryos/larvae. Additionally, PPy/ p -TSA envelopment of developing embryo chorions and gene expression of a hypoxia-related marker in this context were also evaluated. No significant mortality was found; however, altered heart rate and early hatching was identified in all exposed groups at 48 hours post-fertilization (hpf). Surprisingly, with the 500 μg/mL dose, hatching initiated as early as 24 hpf. PPy/ p -TSA adhered to and enveloped the chorion of embryos in a time- and dose-dependent fashion; morphological changes in body length and ocular distance were found with higher concentrations. PPy/ p -TSA-exposed animals showed locomotor behavioral alterations compatible with hypoactivity. A significant increase in the turn angle with a concomitant reduction in meander was also verified at higher concentrations. Taken together, these results emphasize the adverse effects of PPy/ p -TSA on zebrafish development and behavior. Some effects of PPy/ p -TSA exposure were dose-dependent, and indicate specific adverse effects of PPy/ p -TSA on zebrafish development and behavior. [ABSTRACT FROM AUTHOR]

This study further investigated the mechanisms underlying the rat model of tooth pulp inflammatory pain elicited by complete Freund’s adjuvant (CFA), in comparison to other pulpitis models. Pulps of the left maxillary first molars were accessed. In the CFA group, the pulps were exposed, and CFA application was followed by dental sealing. In the open group, the pulps were left exposed to the oral cavity. For the closed group, the pulps were exposed, and the teeth were immediately sealed. Naïve rats were used as negative controls. Several parameters were evaluated at 1, 2, 3 and 8 days. There was no statistical significant difference among the groups when body weight variation, food or water consumption were compared. Analysis of serum cytokines (IL-1β, TNF or IL-6) or differential blood cell counts did not reveal any evidence of systemic inflammation. The CFA group displayed a significant reduction in the locomotor activity (at 1 and 3 days), associated with an increased activation of satellite glial cells in the ipsilateral trigeminal ganglion (TG; for up to 8 days). Amygdala astrocyte activation was unaffected in any experimental groups. We provide novel evidence indicating that CFA-induced pulp inflammation impaired the locomotor activity, with persistent activation of ipsilateral TG satellite cells surrounding sensory neurons, without any evidence of systemic inflammation or amygdala astrogliosis. [ABSTRACT FROM AUTHOR]

This study investigated the effects of the long-term dietary fish oil supplementation or the acute administration of the omega-3 fatty acid docosahexaenoic acid (DHA) in the mouse hemorrhagic cystitis (HC) induced by the anticancer drug cyclophosphamide (CYP). HC was induced in mice by a single CYP injection (300mg/kg ip). Animals received four different diets containing 10% and 20% of corn or fish oil, during 21days. Separated groups received DHA by ip (1μmol/kg) or intrathecal (i.t.; 10μg/site) routes, 1h or 15min before CYP. The behavioral tests (spontaneous nociception and mechanical allodynia) were carried out from 1h to 6h following CYP injection. Bladder inflammatory changes, blood cell counts and serum cytokines were evaluated after euthanasia (at 6h). Immunohistochemistry analysis was performed for assessing spinal astrocyte and microglia activation or GPR40/FFAR1 expression. Either fish oil supplementation or DHA treatment (ip and i.t.) markedly prevented visceral pain, without affecting CYP-evoked bladder inflammatory changes. Moreover, systemic DHA significantly prevented the neutrophilia/lymphopenia caused by CYP, whereas this fatty acid did not significantly affect serum cytokines. DHA also modulated the spinal astrocyte activation and the GPR40/FFAR1 expression. The supplementation with fish oil enriched in omega-3 fatty acids or parenteral DHA might be interesting nutritional approaches for cancer patients under chemotherapy schemes with CYP. [ABSTRACT FROM AUTHOR]

Abstract: Paraquat (PQ) is an agrochemical agent commonly used worldwide, which is allied to potential risks of intoxication. This herbicide induces the formation of reactive oxygen species (ROS) that ends up compromising various organs, particularly the lungs and the brain. This study evaluated the deleterious effects of paraquat on the central nervous system (CNS) and peripherally, with special attempts to assess the putative protective effects of the selective CXCR2 receptor antagonist SB225002 on these parameters. PQ-toxicity was induced in male Wistar rats, in a total dose of 50 mg/kg, and control animals received saline solution at the same schedule of administration. Separate groups of animals were treated with the selective CXCR2 antagonist SB225002 (1 or 3 mg/kg), administered 30 min before each paraquat injection. The major changes found in paraquat-treated animals were: decreased body weight and hypothermia, nociception behavior, impairment of locomotor and gait capabilities, enhanced TNF-α and IL-1β expression in the striatum, and cell migration to the lungs and blood. Some of these parameters were reversed when the antagonist SB225002 was administered, including recovery of physiological parameters, decreased nociception, improvement of gait abnormalities, modulation of striatal TNF-α and IL-1β expression, and decrease of neutrophil migration to the lungs and blood. Taken together, our results demonstrate that damage to the central and peripheral systems elicited by paraquat can be prevented by the pharmacological inhibition of CXCR2 chemokine receptors. The experimental evidence presented herein extends the comprehension on the toxicodynamic aspects of paraquat, and opens new avenues to treat intoxication induced by this herbicide. [ABSTRACT FROM AUTHOR]