Perfluorinated and polyfluorinated alkyl substances (PFAS), more than 4700 in number, are a group of widely used man-made chemicals that accumulate in living things and the environment over time. They are known as “forever chemicals” because they are extremely persistent in our environment and body. Because PFAS have been widely used for many decades, their presence is evident globally, and their persistence and potential toxicity create concern for animals, humans and environmental health. They can have multiple adverse health effects, such as liver damage, thyroid disease, obesity, fertility problems, and cancer. The most significant source of living exposure to PFAS is dietary intake (food and water), but given massive industrial and domestic use, these substances are now punctually present not only domestically but also in the outdoor environment. For example, livestock and wildlife can be exposed to PFAS through contaminated water, soil, substrate, air, or food. In this review, we have analyzed and exposed the characteristics of PFAS and their various uses and reported data on their presence in the environment, from industrialized to less populated areas. In several areas of the planet, even in areas far from large population centers, the presence of PFAS was confirmed, both in marine and terrestrial animals (organisms). Among the most common PFAS identified are undoubtedly perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA), two of the most widely used and, to date, among the most studied in terms of toxicokinetics and toxicodynamics. The objective of this review is to provide insights into the toxic potential of PFAS, their exposure, and related mechanisms.

Background: Anacardium occidentale L. is a tropical plant used for the treatment of inflammatory diseases. The goal of the present work was to investigate the anti-inflammatory and anti-oxidant potential of oral administration of cashew nuts (from Anacardium occidentale L.) in a mouse model of colitis. Methods: Induction of colitis was performed by intrarectally injection of dinitrobenzene sulfonic acid (DNBS). Cashew nuts were administered daily orally (100 mg/kg) in DNBS-injected mice. Results: Four days after DNBS, histological and macroscopic colon alterations as well as marked clinical signs and increased cytokine production were observed. Neutrophil infiltration, measured by myeloperoxidase (MPO) positive immunostaining, was correlated with up-regulation of adhesion molecules ICAM-1 and P-selectin in colons. Oxidative stress was detected with increased malondialdehyde (MDA) levels, nitrotyrosine, and poly ADP-ribose polymerase (PARP) positive staining in inflamed colons. Oral treatment with cashew nuts reduced histological, macroscopic damage, neutrophil infiltration, pro-inflammatory cytokines and MDA levels, as well as nitrotyrosine, PARP and ICAM-1, and P-selectin expressions. Colon inflammation could be related to nuclear factor (NF)-kB pathway activation and reduced manganese superoxide dismutase (MnSOD) antioxidant activity. Cashew nuts administration inhibited NF-kB and increased MnSOD antioxidant expressions. Conclusions: The results suggested that oral assumption of cashew nuts may be beneficial for the management of colitis.

Background: Anacardium occidentale L. is a medicinal plant with powerful anti-oxidative and anti-inflammatory properties. Acute inflammatory events cause tissue alterations, decrease of anti-oxidative endogenous enzymes such as superoxide dismutase, catalase and glutathione, neutrophils infiltration, increase in the activities of myeloperoxidase, malondialdehyde, and pro-inflammatory release. Methods: Paw edema was induced by subplantar injection of carrageenan into the right hind paw in rats, but 30 min before a group of animals were orally treated with 100 mg/kg of cashew nuts to evaluate the anti-inflammatory and anti-oxidative response. Results: In the present work, we found that (1) cashew nuts reduced the development of carrageenan-induced paw edema limiting the formation of edema and pain; (2) cashew nuts ameliorated the diminutions of the anti-oxidative enzymes caused by carrageenan injection; (3) cashew nuts decreased myeloperoxidase malondialdehyde activity induced by carrageenan; and (4) cashew nuts acted by blocking pro-inflammatory cytokines response and nitrate/nitrite formation stimulated by carrageenan injection. Conclusions: The mechanisms of anti-inflammatory and analgesic effects exerted by cashew nuts were relevant to oxygen free radical scavenging, anti-lipid peroxidation, and inhibition of the formation of inflammatory cytokines.

Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti-inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naïve (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naïve PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [¹³C]₄-PEA-um or naïve [¹³C]₄-PEA by oral gavage, and [¹³C]₄-PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [¹³C]₄-PEA-um as compared to those receiving naïve [¹³C]₄-PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [¹³C]₄-PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down-regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain.

Acute pancreatitis is a severe abdominal pathology often associated with several complications including gut dysfunction. Oxidative stress is one of the most important pathways involved in this pathology. Hydroxytyrosol (HT), a phenolic compound obtained from olive oil, has shown anti-inflammatory and antioxidant properties. We evaluated the effects of HT administration on pancreatic and intestinal injury induced by caerulein administration. CD1 female mice were administered caerulein (50 μg/kg) for 10 h. HT treatment (5 mg/kg) was performed 30 min after the first caerulein injection and for two consecutive hours afterwards. One hour after the last caerulein injection, mice were sacrificed and serum, colon and pancreatic tissue samples were collected. HT was able to reduce the serum hallmarks of pancreatitis (amylase and lipase), histological damage score in both pancreas and colon tissue, inflammatory cells recruitment (mast cells) in both injured tissues, intrapancreatic trypsin activity and overexpression of the adhesion molecules (Intercellular Adhesion Molecule-1 (ICAM-1) and P-selectin) in colon. Additionally, HT reduced cytokine (interleukin 1 beta (IL- 1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α)) levels in serum, pancreas and colon tissue and chemokine release (monocyte chemotactic protein-1 (MCP1/CCL2)) in pancreas and colon tissue. HT decreased lipid peroxidation and oxidative stress (superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) activity) by enhancing the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in both injured tissues. Moreover, HT preserved intestinal barrier integrity, as shown by the diamine oxidase (DAO) serum levels and tight junction (zonula occludens (ZO) and occludin) expression in pancreas and colon. Our findings demonstrated that HT would be an important therapeutic tool against pancreatitis-induced injuries in the pancreas and gut.

Background: Fibromyalgia is a chronic condition characterized by increased sensory perception of pain, neuropathic/neurodegenerative modifications, oxidative, and nitrosative stress. An appropriate therapy is hard to find, and the currently used treatments are able to target only one of these aspects. Methods: The aim of this study is to investigate the beneficial effects of melatonin plus folic acid administration in a rat model of reserpine-induced fibromyalgia. Sprague–Dawley male rats were injected with 1 mg/kg of reserpine for three consecutive days and later administered with melatonin, folic acid, or both for twenty-one days. Results: Administration of reserpine led to a significant decrease in the nociceptive threshold as well as a significant increase in depressive-like symptoms. These behavioral changes were accompanied by increased oxidative and nitrosative stress. Lipid peroxidation was significantly increased, as well as nitrotyrosine and PARP expression, while superoxide dismutase, nonprotein thiols, and catalase were significantly decreased. Endogenously produced oxidants species are responsible for mast cell infiltration, increased expression pro-inflammatory mediators, and microglia activation. Conclusion: Melatonin plus acid folic administration is able to ameliorate the behavioral defects, oxidative and nitrosative stress, mast cell infiltration, inflammatory mediators overexpression, and microglia activation induced by reserpine injection with more efficacy than their separate administration.