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.

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.

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.

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.

Correction: D'Amico et al. Consumption of Cashew (Anacardium occidentale L.) Nuts Counteracts Oxidative Stress and Tissue Inflammation in Mild Hyperhomocysteinemia in Rats. Nutrients 2022, 14, 1474.

In the original publication [...].

Natural Compounds Such as Hericium erinaceus and Coriolus versicolor Modulate Neuroinflammation, Oxidative Stress and Lipoxin A4 Expression in Rotenone-Induced Parkinson's Disease in Mice.

BACKGROUND: A growing body of research suggests that oxidative stress and neuroinflammation are early pathogenic features of neurodegenerative disorders. In recent years, the vitagene system has emerged as a potential target, as it has been shown to have a high neuroprotective power. Therefore, the discovery of molecules capable of activating this system may represent a new therapeutic target to limit the deleterious consequences induced by oxidative stress and neuroinflammation, such as neurodegeneration. Lipoxins are derived from arachidonic acid, and their role in the resolution of systemic inflammation is well established; however, they have become increasingly involved in the regulation of neuroinflammatory and neurodegenerative processes. Our study aimed at activating the NF-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) redox system and increasing lipoxin A4 for the modulation of antioxidant stress and neuroinflammation through the action of two fungi in a rotenone-induced Parkinson's model. METHODS: During the experiment, mice received Hericium erinaceus, Coriolus versicolor or a combination of the two (200 mg/kg, orally) concomitantly with rotenone (5 mg/kg, orally) for 28 days. RESULTS: The results obtained highlighted the ability of these two fungi and, in particular, their ability through their association to act on neuroinflammation through the nuclear factor-kB pathway and on oxidative stress through the Nrf2 pathway. This prevented dopaminergic neurons from undergoing apoptosis and prevented the alteration of typical Parkinson's disease (PD) markers and α-synuclein accumulation. The action of Hericium erinaceus and Coriolus versicolor was also able to limit the motor and non-motor alterations characteristic of PD. CONCLUSIONS: Since these two mushrooms are subject to fewer regulations than traditional drugs, they could represent a promising nutraceutical choice for preventing PD.

Chronic Exposure to Vinclozolin Induced Fibrosis, Mitochondrial Dysfunction, Oxidative Stress, and Apoptosis in Mice Kidney.

Vinclozolin is one of the most used fungicides in the control of fungi in fruits, vegetables, and ornamental plants. The effects of its exposure on different organs have been described, but information regarding its relevance to vinclozolin-induced nephrotoxicity is largely missing. This study focuses on the potential mechanism of vinclozolin-induced nephrotoxicity. CD1 male mice were administered vinclozolin (100 mg/kg) by oral gavage for 28 days. Vinclozolin administration decreased body weight over the treatment period and at the end of the experiment, increased the ratio of kidney weight to body weight and increased serum urea nitrogen and creatinine contents. Vinclozolin also induced histopathological alterations, including tubular dilatation and necrosis and impaired the integrity of the renal-tubular architecture and kidney fibrosis. The analyses conducted showed that vinclozolin administration altered the mRNA levels of mitochondrial function-related proteins (SIRT3, SIRT1, PGC-1α, TFAM, NRF1, VDAC-1, and Cyt c) and oxidative stress (increased lipid peroxidation and decreased total antioxidative capacity, catalase, and superoxide dismutase activities, glutathione levels, and glutathione peroxidase activity) in the kidneys. Furthermore, vinclozolin induced toxicity that altered Nrf2 signalling and the related proteins (HO-1 and NQO-1). Vinclozolin administration also affected both the extrinsic and intrinsic apoptotic pathways, upregulating the expression of proapoptotic factors (Bax, Caspase 3, and FasL) and downregulating antiapoptotic factor (Bcl-2) levels. This study suggests that vinclozolin induced nephrotoxicity by disrupting the transcription of mitochondrial function-related factors, the Nrf2 signalling pathway, and the extrinsic and intrinsic apoptotic pathways.

Chronic Exposure to Endocrine Disruptor Vinclozolin Leads to Lung Damage via Nrf2-Nf-kb Pathway Alterations.

Endocrine-disrupting substances (EDS) are common and pervasive in our environment and pose a serious risk to both human and animal health. Endocrine-disrupting compounds (EDCs) have been associated with a variety of detrimental human health effects, including respiratory issues, as a result of their ability to disrupt cell physiology. Vinclozolin ((RS)-3-(3,5-Dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione) is a common dicarboximide fungicide used to treat plant diseases. Several studies have analyzed the effects of vinclozolin exposure on the reproductive system, but less is known about its effect on other organs such as the lung. Mice were exposed for 28 days to orally administered vinclozolin at a dose of 100 mg/kg. Vinclozolin exposure induced histological alterations and collagen depositions in the lung. Additionally, vinclozolin induced inflammation and oxidative stress that led to lung apoptosis. Our study demonstrates for the first time that the toxicological effects of vinclozolin are not limited to the reproductive system but also involve other organs such as the lung.

Aerosol-Administered Adelmidrol Attenuates Lung Inflammation in a Murine Model of Acute Lung Injury.

Acute lung injury (ALI) is a common and devastating clinical disorder with a high mortality rate and no specific therapy. The pathophysiology of ALI is characterized by increased alveolar/capillary permeability, lung inflammation, oxidative stress and structural damage to lung tissues, which can progress to acute respiratory distress syndrome (ARDS). Adelmidrol (ADM), an analogue of palmitoylethanolamide (PEA), is known for its anti-inflammatory and antioxidant functions, which are mainly due to down-modulating mast cells (MCs) and promoting endogenous antioxidant defense. The aim of this study is to evaluate the protective effects of ADM in a mice model of ALI, induced by intratracheal administration of lipopolysaccharide (LPS) at the dose of 5 mg/kg. ADM 2% was administered by aerosol 1 and 6 h after LPS instillation. In this study, we clearly demonstrated that ADM reduced lung damage and airway infiltration induced by LPS instillation. At the same time, ADM counteracted the increase in MC number and the expression of specific markers of MC activation, i.e., chymase and tryptase. Moreover, ADM reduced oxidative stress by upregulating antioxidant enzymes as well as modulating the Nf-kB pathway and the resulting pro-inflammatory cytokine release. These results suggest that ADM could be a potential candidate in the management of ALI.

Açai Berry Mitigates Parkinson's Disease Progression Showing Dopaminergic Neuroprotection via Nrf2-HO1 Pathways.

The current pharmacological treatment for Parkinson's disease (PD) is focused on symptom alleviation rather than disease prevention. In this study, we look at a new strategy to neuroprotection that focuses on nutrition, by a supplementation with Açai berry in an experimental models of PD. Daily orally supplementation with Açai berry dissolved in saline at the dose of 500 mg/kg considerably reduced motor and non-motor symptom and neuronal cell death of the dopaminergic tract induced by 4 injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, Açai berry administration reduced α-synuclein aggregation in neurons, enhanced tyrosine hydroxylase and dopamine transporter activities, and avoided dopamine depletion. Moreover, Açai berry administration was able to reduce astrogliosis and microgliosis as well as neuronal death. Its beneficial effects could be due to its bioactive phytochemical components that are able to stimulate nuclear factor erythroid 2-related factor 2 (Nrf2) by counteracting the oxidative stress and neuroinflammation that are the basis of this neurodegenerative disease.

Açai Berry Mitigates Vascular Dementia-Induced Neuropathological Alterations Modulating Nrf-2/Beclin1 Pathways.

The second-most common cause of dementia is vascular dementia (VaD). The majority of VaD patients experience cognitive impairment, which is brought on by oxidative stress and changes in autophagic function, which ultimately result in neuronal impairment and death. In this study, we examine a novel method for reversing VaD-induced changes brought on by açai berry supplementation in a VaD mouse model. The purpose of this study was to examine the impact of açai berries on the molecular mechanisms underlying VaD in a mouse model of the disease that was created by repeated ischemia-reperfusion (IR) of the whole bilateral carotid artery. Here, we found that açai berry was able to reduce VaD-induced behavioral alteration, as well as hippocampal death, in CA1 and CA3 regions. These effects are probably due to the modulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and Beclin-1, suggesting a possible crosstalk between these molecular pathways. In conclusion, the protective effects of açai berry could be a good supplementation in the future for the management of vascular dementia.

Discovering the Effects of Fisetin on NF-κB/NLRP-3/NRF-2 Molecular Pathways in a Mouse Model of Vascular Dementia Induced by Repeated Bilateral Carotid Occlusion.

Vascular dementia (VaD) is the second leading cause of dementia. The majority of VaD patients have cognitive abnormalities, which are caused by cerebral hypoperfusion-induced ischemia, endothelial dysfunction, oxidative stress, and neuroinflammation. Natural products are receiving increasing attention for the treatment of neuroinflammatory diseases. The aim of this study was to investigate the molecular pathways underlying the protective effects of fisetin, a flavonoid present in many fruits and vegetables, in a mouse model of VaD induced by repeated ischemia-reperfusion (IR) of the total bilateral carotid artery. Here, we found that VaD caused brain injury, lipid peroxidation, and neuronal death in the hippocampus, as well as astrocyte and microglial activation, and reduced BDNF neurotrophic factor expression together with behavioral alterations. In addition, VaD induced the activation of inflammasome components (NLRP-3, ASC, and caspase 1), and their downstream products (IL-1ß and IL-18) release and promote activation of apoptotic cell death. Fisetin attenuated histological injury, malondialdehyde levels, inflammasome pathway activation, apoptosis, as well as increased BDNF expression, reduced astrocyte, microglial activation, and cognitive deficits. In conclusion, the protective effects of fisetin could be due to the inhibition of the ROS-induced activation of NF-κB/NLRP3 inflammasome together with the activation of antioxidant Nrf2/HO-1, suggesting a possible crosstalk between these molecular pathways.

Role of Etanercept and Infliximab on Nociceptive Changes Induced by the Experimental Model of Fibromyalgia.

BACKGROUND: Fibromyalgia is a clinical condition that affects 1% to 5% of the population. No proper therapy has been currently found. It has been described that inflammation plays a central role in the nerve sensitizations that characterize the pathology. METHODS: This paper aimed to evaluate the efficacy of etanercept and infliximab in the management of pain sensitization. Fibromyalgia was induced by three injections once a day of reserpine at the dose of 1 mg/kg. Etanercept (3 mg/kg) and infliximab (10 mg/kg) were administered the day after the last reserpine injection and then 5 days after that. Behavioral analyses were conducted once a week, and molecular investigations were performed at the end of the experiment. RESULTS: Our data confirmed the major effect of infliximab administration as compared to etanercept: infliximab administration strongly reduced pain sensitization in thermal hyperalgesia and mechanical allodynia. From the molecular point of view, infliximab reduced the activation of microglia and astrocytes and the expression of the purinergic P2X7 receptor ubiquitously expressed on glia and neurons. Downstream of the P2X7 receptor, infliximab also reduced p38-MAPK overexpression induced by the reserpine administration. CONCLUSION: Etanercept and infliximab treatment caused a significant reduction in pain. In particular, rats that received infliximab showed less pain sensitization. Moreover, infliximab reduced the activation of microglia and astrocytes, reducing the expression of the purinergic receptor P2X7 and p38-MAPK pathway.

Açaí (Euterpe Oleraceae Mart.) Seeds Regulate NF-κB and Nrf2/ARE Pathways Protecting Lung against Acute and Chronic Inflammation.

BACKGROUND/AIMS: Respiratory diseases are the world's biggest cause of mortality and disability. Specific nutrients have been proposed to positively affect disease progression as novel therapy alternatives to glucocorticosteroids. There has been a lot of attention in the possible health advantages of dietary assumption of Açai Seeds, popular native fruit found in the Amazon region which is rich in bioactive compounds. Until today nobody investigated the beneficial property of Açai Seeds administration in lung disease. METHODS: In our study we use two model of lung disease: for acute lung disease we use an intrapleural injection of Carrageenan; for chronic disease we used an intratracheal instillation of bleomycin. Açai Seeds was administered orally dissolved in saline. RESULTS: We found that Açai Seeds was able to reduce histological alteration, cells infiltration, pro inflammatory cytokine release, inflammation, and oxidative stress in both acute and chronic model of lung disease. CONCLUSION: Our data clearly demonstrate for the first time that Açai Seeds administration was useful against lung disease by the reduction of NF-κB nuclear translocation and by the stimulation of Nrf2/ARE pathways promoting the physiological antioxidant defense.

Toxic Exposure to Endocrine Disruptors Worsens Parkinson's Disease Progression through NRF2/HO-1 Alteration.

Human exposure to endocrine disruptors (EDs) has attracted considerable attention in recent years. Different studies showed that ED exposure may exacerbate the deterioration of the nervous system's dopaminergic capacity and cerebral inflammation, suggesting a promotion of neurodegeneration. In that regard, the aim of this research was to investigate the impact of ED exposure on the neuroinflammation and oxidative stress in an experimental model of Parkinson's disease (PD). PD was induced by intraperitoneally injections of MPTP for a total dose of 80 mg/kg for each mouse. Mice were orally exposed to EDs, starting 24 h after the first MPTP administration and continuing through seven additional days. Our results showed that ED exposure raised the loss of TH and DAT induced by the administration of MPTP, as well as increased aggregation of α-synuclein, a key marker of PD. Additionally, oral exposure to EDs induced astrocytes and microglia activation that, in turn, exacerbates oxidative stress, perturbs the Nrf2 signaling pathway and activates the cascade of MAPKs. Finally, we performed behavioral tests to demonstrate that the alterations in the dopaminergic system also reflected behavioral and cognitive alterations. Importantly, these changes are more significant after exposure to atrazine compared to other EDs. The results from our study provide evidence that exposure to EDs may play a role in the development of PD; therefore, exposure to EDs should be limited.

Molecular and Biochemical Mechanism of Cannabidiol in the Management of the Inflammatory and Oxidative Processes Associated with Endometriosis.

Endometriosis is usually associated with inflammation and chronic pelvic pain. This paper focuses the attention on the anti-inflammatory, anti-oxidant and analgesic effects of cannabidiol (CBD) and on its potential role in endometriosis. We employed an in vivo model of endometriosis and administered CBD daily by gavage. CBD administration strongly reduced lesions diameter, volume and area. In particular, it was able to modify lesion morphology, reducing epithelial glands and stroma. CBD showed anti-oxidant effects reducing lipid peroxidation, the expression of Nox-1 and Nox-4 enzymes. CBD restored the oxidative equilibrium of the endogenous cellular defense as showed by the SOD activity and the GSH levels in the lesions. CBD also showed important antifibrotic effects as showed by the Masson trichrome staining and by downregulated expression of MMP-9, iNOS and TGF-ß. CBD was able to reduce inflammation both in the harvested lesions, as showed by the increased Ikb-α and reduced COX2 cytosolic expressions and reduced NFkB nuclear localization, and in the peritoneal fluids as showed by the decreased TNF-α, PGE2 and IL-1α levels. CBD has important analgesic effects as showed by the reduced mast cells recruitment in the spinal cord and the reduced release of neuro-sensitizing and pro-inflammatory mediators. In conclusion, the collected data showed that CBD has an effective and coordinated effects in endometriosis suppression.