Corrigendum: Oral ultramicronized palmitoylethanolamide: plasma and tissue levels and spinal antihyperalgesic effect.

[This corrects the article DOI: 10.3389/fphar.2018.00249.].

Impaired mitochondrial quality control in fibromyalgia: Mechanisms involved in skeletal muscle alteration.

Fibromyalgia (FMS) is a persistent syndrome marked by widespread musculoskeletal pain and behavioural symptoms. Given the hypothesis linking FMS aetiology to mitochondrial dysfunction and oxidative stress, we examined the biochemical correlation among these factors by studying specific proteins associated with mitochondrial homeostasis in muscle. Additionally, this study investigated the role of Boswellia serrata gum resin extract (BS), known for its various functions, including the potent induction of antioxidant enzymes, in determining protective or reparative mechanisms in the muscle cells. Sprague-Dawley rats were injected with reserpine to induce FMS. These animals exhibited moderate changes in hind limb skeletal muscles, experiencing mobility difficulties. Additionally, there were noteworthy morphological and ultrastructural alterations, along with the expression of myogenin, mitochondrial enzymes and oxidative stress markers in the gastrocnemius muscle. Interestingly, BS demonstrated a reduction in spontaneous motor activity difficulties. Moreover, BS showed a positive impact on musculoskeletal morphostructural aspects, as well as a decrease in oxidative stress and mitochondrial alterations. In particular, BS restored the mRNA expression of citrate synthase and cytochrome-c oxidase subunit II and the activity of electron transfer chain complexes. BS also influenced mitochondrial biogenesis, upregulating PGC-1α expression and the related transcription factors (Nrf1, Tfam, Nrf2, FOXO3a, SIRT3, GCLC, NQO1, SOD2 and GPx4), oxidative stress (lipid peroxidation, GSH levels and GSH-Px activity) and mitochondrial dynamics and function (Mnf2 expression and CoQ10 levels). Overall, this study underlined the key role of the mitochondrial alteration in FMS and that BS had a very high antioxidant effect in these organelles and also in the cells.

Role of mitochondrial dysfunction and biogenesis in fibromyalgia syndrome: Molecular mechanism in central nervous system.

A critical role for mitochondrial dysfunction has been shown in the pathogenesis of fibromyalgia. It is a chronic pain syndrome characterized by neuroinflammation and impaired oxidative balance in the central nervous system. Boswellia serrata (BS), a natural polyphenol, is a well-known able to influence the mitochondrial metabolism. The objective of this study was to evaluate the mitochondrial dysfunction and biogenesis in fibromyalgia and their modulation by BS. To induce the model reserpine (1 mg/Kg) was subcutaneously administered for three consecutive days and BS (100 mg/Kg) was given orally for twenty-one days. BS reduced pain like behaviors in reserpine-injected rats and the astrocytes activation in the dorsal horn of the spinal cord and prefrontal cortex that are recognized as key regions associated with the neuropathic pain. Vulnerability to neuroinflammation and impaired neuronal plasticity have been described as consequences of mitochondrial dysfunction. BS administration increased PGC-1α expression in the nucleus of spinal cord and brain tissues, promoting the expression of regulatory genes for mitochondrial biogenesis (NRF-1, Tfam and UCP2) and cellular antioxidant defence mechanisms (catalase, SOD2 and Prdx 3). According with these data BS reduced lipid peroxidation and the GSSG/GSH ratio and increased SOD activity in the same tissues. Our results also showed that BS administration mitigates cytochrome-c leakage by promoting mitochondrial function and supported the movement of PGC-1α protein into the nucleus restoring the quality control of mitochondria. Additionally, BS reduced Drp1 and Fis1, preventing both mitochondrial fission and cell death, and increased the expression of Mfn2 protein, facilitating mitochondrial fusion. Overall, our results showed important mitochondrial dysfunction in central nervous system in fibromyalgia syndrome and the role of BS in restoring mitochondrial dynamics.

Correction: D'Amico et al. Toxic Exposure to Endocrine Disruptors Worsens Parkinson's Disease Progression through NRF2/HO-1 Alteration. Biomedicines 2022, 10, 1073.

Errors in Figures [...].

Redox Homeostasis and Antioxidant Strategies in the Pathophysiology.

The molecular mechanisms underlying oxidative stress, and pathophysiological consequences in cell and tissue function, are frequently described as the imbalance between the production of reactive species and the ability to defend through sophisticated antioxidant machinery (Contributions 1-3) [...].

Oxidative stress and mitochondrial dysfunction in brain of vinclozolin exposed animals.

Vinclozolin (VCZ) is a widely used fungicide in agriculture, especially in fruits and wine. Various studies have detailed the effects of VCZ exposure on different organs, but no information is available on its effects on brain tissues. This paper investigated the effects of VCZ exposure on the oxidative stress and mitochondrial dysfunction in brain tissue. C57BL/6 mice were exposed to VCZ (100 mg/kg) by oral gavage for 28 days. Mitochondrial homeostasis, often known as mitochondrial quality control, involves a range of processes, including mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy and autophagy. VCZ administration modified the mRNA expression levels of Sirt1, Sirt3, PGC-1α, TFAM, Nrf1, VDAC-1 and Cyt c in brain tissue, as compared to control animals (CTR). The analyses also showed increased oxidative stress, in particular VCZ administration reduced SOD and CAT activities and GSH levels while increased T-AOC levels and lipid peroxidation. Additionally, brain tissues from VCZ group showed DNA oxidation (increased PARP-1 immunostaining) and apoptosis (increased TUNEL+ cells, increased expression of Bax mRNA level and reduced Bcl-2 levels). Western blot and immunohistochemical analyses showed increased mitophagic pathway with the accumulation of PINK1 and Parkin in mitochondria. Additionally, autophagic pathway was also increased with the increased expression and colocalization of LC3 with Neun and GFAP. Overall, this study showed that chronic VCZ exposure impaired mitochondrial homeostasis and increased oxidative stress in brain tissues.

Molecular targets for anti-oxidative protection of açaí berry against diabetes myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion injury (MIRI) is the principal cause of death and occurs after prolonged blockage of the coronary arteries. Diabetes represents one of the main factors aggravating myocardial injury. Restoring blood flow is the first intervention against a heart attack, although reperfusion process could cause additional damage, such as the overproduction of reacting oxygen species (ROS). In recent years, açaí berry has gained international attention as a functional food due to its antioxidant and anti-inflammatory properties; not only that but this fruit has shown glucose-lowering effects. Therefore, this study was designed to evaluate the cardioprotective effects of açaí berry on the inflammatory and oxidative responses associated with diabetic MIRI. Diabetes was induced in rats by a single intravenous inoculation of streptozotocin (60 mg/kg) and allowed to develop for 60 days. MIRI was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. Açaí (200 mg/kg) was administered 5 min before the end of ischemia and 1 h after reperfusion. In this study, we clearly demonstrated that açaí treatment was able to reduce biomarkers of myocardial damage, infarct size, and apoptotic process. Moreover, açaí administrations reduced inflammatory and oxidative response, modulating Nf-kB and Nrf2 pathways. These results suggest that açai berry supplementation could represent a useful strategy for pathological events associated to MIRI.

Açaí berry ameliorates cognitive impairment by inhibiting NLRP3/ASC/CASP axis in STZ-induced diabetic neuropathy in mice.

Diabetes complications such as diabetic peripheral neuropathy (DPN) are linked to morbidity and mortality. Peripheral nerve damages in DPN are accompanied by discomfort, weakness, and sensory loss. Some drugs may demonstrate their therapeutic promise by reducing neuroinflammation, but they have side effects. Based on these considerations, the objective of this study was to examine the beneficial properties of açaí berry in a mouse model of DPN generated by injection of streptozotocin (STZ). Açaí berry was given orally to diabetic and control mice every day beginning 2 wk after STZ injection. The animals were euthanized after 16 wk, and tissues from the spinal cord and sciatic nerve and urine were taken. Our findings showed that daily treatment of açaí berry at a dose of 500 mg/kg was able to prevent behavioral changes as well as mast cell activation and nerve deterioration via NOD-like receptor family pyrin-domain-containing-3 (NLRP3)/apoptosis-associated speck-like protein containing a card (ASC)/caspase (CASP) regulation after diabetes induction.NEW & NOTEWORTHY Our research shows that açaí berry reduces mast cells degranulation and histological damage in diabetic neuropathy, improves physiological defense against reactive oxygen species, modulates the NLRP3/ASC/CASP axis, and ameliorates inflammation and oxidative stress. Diet could help treatment for diabetic peripheral neuropathy.

Antioxidant Activity of a Sicilian Almond Skin Extract Using In Vitro and In Vivo Models.

Almond skins are known for their antioxidative and anti-inflammatory properties, which are mainly due to the presence of polyphenols. The aim of the present study was to evaluate the antioxidant and anti-inflammatory effects of almond skin extract (ASE) obtained from the Sicilian cultivar "Fascionello" and to evaluate the possible mechanisms of action using an in vitro model of human monocytic U937 cells as well as an in vivo model of carrageenan (CAR)-induced paw edema. The in vitro studies demonstrated that pretreatment with ASE inhibited the formation of ROS and apoptosis. The in vivo studies showed that ASE restored the CAR-induced tissue changes; restored the activity of endogenous antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione; and decreased neutrophil infiltration, lipid peroxidation, and the release of proinflammatory mediators. The anti-inflammatory and antioxidant effects of ASE could be associated with the inhibition of the pro-inflammatory nuclear NF-κB and the activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) antioxidant pathways. In conclusion, almond skin could reduce the levels of inflammation and oxidative stress and could be beneficial in the treatment of several disorders.

Modulation of TLR4/NFκB Pathways in Autoimmune Myocarditis.

Myocarditis is an inflammatory and oxidative disorder characterized by immune cell recruitment in the damaged tissue and organ dysfunction. In this paper, we evaluated the molecular pathways involved in myocarditis using a natural compound, Coriolus versicolor, in an experimental model of autoimmune myocarditis (EAM). Animals were immunized with an emulsion of pig cardiac myosin and complete Freund's adjuvant supplemented with mycobacterium tuberculosis; thereafter, Coriolus versicolor (200 mg/Kg) was orally administered for 21 days. At the end of the experiment, blood pressure and heart rate measurements were recorded and the body and heart weights as well. From the molecular point of view, the Coriolus versicolor administration reduced the activation of the TLR4/NF-κB pathway and the levels of pro-inflammatory cytokines (INF-γ, TNF-α, IL-6, IL-17, and IL-2) and restored the levels of anti-inflammatory cytokines (IL-10). These anti-inflammatory effects were accompanied with a reduced lipid peroxidation and nitrite levels and restored the antioxidant enzyme activities (SOD and CAT) and GSH levels. Additionally, it reduced the histological injury and the immune cell recruitment (CD4+ and CD68+ cells). Moreover, we observed an antiapoptotic activity in both intrinsic (Fas/FasL/caspase-3) and extrinsic (Bax/Bcl-2) pathways. Overall, our data showed that Coriolus versicolor administration modulates the TLR4/NF-κB signaling in EAM.

Modulation of the Proliferative Pathway, Neuroinflammation and Pain in Endometriosis.

Endometriosis is a chronic disease characterized by pelvic inflammation. This study aimed at investigating the molecular mechanisms underlying the pathology and how they can be modulated by the administration of a natural compound, Actaea racemosa (AR). We employed an in vivo model of endometriosis in which rats were intraperitoneally injected with uterine fragments from donor animals. During the experiment, rats were monitored by abdominal high-frequency ultrasound analysis. AR was able to reduce the lesion's size and histological morphology. From a molecular point of view, AR reduced hyperproliferation, as shown by Ki-67 and PCNA expression and MAPK phosphorylation. The impaired apoptosis pathway was also restored, as shown by the TUNEL assay and RT-PCR for Bax, Bcl-2, and Caspase levels. AR also has important antioxidant (reduced Nox expression, restored SOD activity and GSH levels, and reduced MPO activity and MDA levels) and anti-inflammatory (reduced cytokine levels) properties. Moreover, AR demonstrated its ability to reduce the pain-like behaviors associated with the pathology, the neuro-sensitizing mediators (c-FOS and NGF) expression, and the related central astrogliosis (GFAP expression in the spinal cord, brain cortex, and hippocampus). Overall, our data showed that AR was able to manage several pathways involved in endometriosis suppression.

Targeting Nrf2 and NF-κB Signaling Pathways in Inflammatory Pain: The Role of Polyphenols from Thinned Apples.

Diet can modulate the different stages of inflammation due to the presence of bioactive compounds such as polyphenols. Apples are a great source of phenolic compounds that show anti-inflammatory and antioxidant properties, and these might be used as a dietary supplement and/or functional element in the treatment of chronic inflammatory illnesses. The aim of our study was to evaluate the anti-inflammatory and antioxidant actions of thinned apple polyphenol (TAP) extracts in a model of paw edema. The experimental model was induced in rats via subplantar injections of 1% λ-Carrageenan (CAR) in the right hind leg, and TAP extract was administered via oral gavage 30 min before and 1 h after the CAR injection at doses of 5 mg/kg and 10 mg/kg, respectively. The inflammatory response is usually quantified by the increase in the size of the paw (edema), which is maximal about 5 h after the injection of CAR. CAR-induced inflammation generates the release of pro-inflammatory mediators and reactive oxygen species (ROS). Furthermore, the inflammatory state induces the pain that involves the peripheral nociceptors, but above all it acts centrally at the level of the spinal cord. Our results showed that the TAP extracts reduced paw histological changes, neutrophil infiltration, mast cell degranulation, and oxidative stress. Additionally, the oral administration of TAP extracts decreased thermal and mechanical hyperalgesia, along with a reduction in spinal microglia and the markers of nociception. In conclusion, we demonstrate that TAP extract is able to modulate inflammatory, oxidative, and painful processes, and is also useful in the treatment of the symptoms associated with paw edema.

Aggravation of TGFß1-Smad Pathway and Autoimmune Myocarditis by Fungicide (Tebuconazole) Exposure.

Myocarditis is an inflammatory cardiac disorder and the primary cause of heart failure in young adults. Its origins can be attributed to various factors, including bacterial or viral infections, exposure to toxins or drugs, endocrine disruptors (EDs), and autoimmune processes. Tebuconazole (TEB), which is a member of the triazole fungicide family, is utilized to safeguard agricultural crop plants against fungal pathogens. Although TEB poses serious threats to mammal health, the information about how it induces toxic effects through various pathways, particularly in autoimmune diseases, are still limited. Thus, the aim of this paper was to evaluate the effect of TEB exposure in autoimmune myocarditis (AM). To induce AM, rats were immunized with porcine cardiac myosin and exposed to TEB for 21 days. Thereafter, animals were sacrificed, and histological, biochemical, and molecular analyses were performed. TEB exposure increased heart weight, systolic blood pressure and heart rate already augmented by AM. Additionally, it significantly increased creatine phosphokinase heart (CK-MB), creatine phosphokinase (CPK), cardiac troponin T (cTnT), and cardiac troponin I (cTnI), as compared to the control. From the histological perspective, TEB exacerbates the histological damage induced by AM (necrosis, inflammation and cell infiltration) and increased fibrosis and collagen deposition. TEB exposure strongly increased pro-inflammatory cytokines and prooxidant levels (O2-, H2O2, NO2-, lipid peroxidation) and reduced antioxidant enzyme levels, which were already dysregulated by AM. Additionally, TEB increased NOX-4 expression and the TGFß1-Smads pathway already activated by AM. Overall, our results showed that TEB exposure strongly aggravated the cardiotoxicity induced by AM.

Inhibition of Fatty Acid Amide Hydrolase (FAAH) Regulates NF-kb Pathways Reducing Bleomycin-Induced Chronic Lung Inflammation and Pulmonary Fibrosis.

The deadly interstitial lung condition known as idiopathic pulmonary fibrosis (IPF) worsens over time and for no apparent reason. The traditional therapy approaches for IPF, which include corticosteroids and immunomodulatory drugs, are often ineffective and can have noticeable side effects. The endocannabinoids are hydrolyzed by a membrane protein called fatty acid amide hydrolase (FAAH). Increasing endogenous levels of endocannabinoid by pharmacologically inhibiting FAAH results in numerous analgesic advantages in a variety of experimental models for pre-clinical pain and inflammation. In our study, we mimicked IPF by administering intratracheal bleomycin, and we administered oral URB878 at a dose of 5 mg/kg. The histological changes, cell infiltration, pro-inflammatory cytokine production, inflammation, and nitrosative stress caused by bleomycin were all reduced by URB878. Our data clearly demonstrate for the first time that the inhibition of FAAH activity was able to counteract not only the histological alteration bleomycin-induced but also the cascade of related inflammatory events.

Bioactive Compounds of the Mediterranean Diet as Nutritional Support to Fight Neurodegenerative Disease.

Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress, and neuronal depletion. They include selective malfunction and progressive loss of neurons, glial cells, and neural networks in the brain and spinal cord. There is an urgent need to develop new and more effective therapeutic strategies to combat these devastating diseases because, today, there is no treatment that can cure degenerative diseases; however, we have many symptomatic treatments. Current nutritional approaches are beginning to reflect a fundamental change in our understanding of health. The Mediterranean diet may have a protective effect on the neurodegenerative process because it is rich in antioxidants, fiber, and omega-3 polyunsaturated fatty acids. Increasing knowledge regarding the impact of diet on regulation at the genetic and molecular levels is changing the way we consider the role of nutrition, resulting in new dietary strategies. Natural products, thanks to their bioactive compounds, have recently undergone extensive exploration and study for their therapeutic potential for a variety of diseases. Targeting simultaneous multiple mechanisms of action and a neuroprotection approach with the diet could prevent cell death and restore function to damaged neurons. For these reasons, this review will be focused on the therapeutic potential of natural products and the associations between the Mediterranean-style diet (MD), neurodegenerative diseases, and markers and mechanisms of neurodegeneration.

Inhibiting IL-6 in medicine: a new twist to sustain inhibition of his cytokine tin the therapy of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a chronic, progressive disease characterized by an increase in blood pressure in the lungs' arteries. It can occur in a variety of species, including humans, dogs, cats, and horses. To date, PAH has a high mortality rate in both veterinary and human medicine, often due to complications such as heart failure. The complex pathological mechanisms of PAH involve multiple cellular signalling pathways at various levels. IL-6 is a powerful pleiotropic cytokine that regulates several phases of immune response, inflammation, and tissue remodelling. The hypothesis of this study was that the use of an IL-6 antagonist in PAH could interrupt or mitigate the cascade of events that leads to the progression of the disease and the worsening of clinical outcome, as well as tissue remodelling. In this study, we used two pharmacological protocols with an IL-6 receptor antagonist in a monocrotaline-induced PAH model in rats. Our results showed that the use of an IL-6 receptor antagonist had a significant protective effect, ameliorating both haemodynamic parameters, lung and cardiac function, tissue remodelling, and the inflammation associated with PAH. The results of this study suggest that the inhibition IL-6 could be a useful pharmacological strategy in PAH, in both human and veterinary medicine.