Role of Oxidative Stress in Peyronie’s Disease: Biochemical Evidence and Experiences of Treatment with Antioxidants

Background: Peyronie’s disease (PD) is a chronic inflammatory condition affecting adult males, involving the tunica albuginea of the corpora cavernosa of the penis. PD is frequently associated with penile pain, erectile dysfunction, and a secondary anxious–depressive state. The etiology of PD has not yet been completely elucidated, but local injury is generally recognized to be a triggering factor. It has also been widely proven that oxidative stress is an essential, decisive component in all inflammatory processes, whether acute or chronic. Current conservative medical treatment comprises oral substances, penile injections, and physical therapy. Aim: This article intends to show how antioxidant therapy is able to interfere with the pathogenetic mechanisms of the disease. Method: This article consists of a synthetic narrative review of the current scientific literature on antioxidant therapy for this disease. Results: The good results of the antioxidant treatment described above also prove that the doses used were adequate and the concentrations of the substances employed did not exceed the threshold at which they might have interacted negatively with the mechanisms of the redox regulation of tissue. Conclusions: We believe new, randomized, controlled studies are needed to confirm the efficacy of treatment with antioxidants. However, we consider the experiences of antioxidant treatment which can already be found in the literature useful for the clinical practice of urologists in the treatment of this chronic inflammatory disease.     

Neuroprotective properties of mildronate, a small molecule, in a rat model of Parkinson's disease

Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson's disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.     

Neuroprotective Effects of Erucin against 6-Hydroxydopamine-Induced Oxidative Damage in a Dopaminergic-like Neuroblastoma Cell Line

Oxidative stress (OS) contributes to the cascade leading to the dysfunction or death of dopaminergic neurons during Parkinson’s disease (PD). A strategy to prevent the OS of dopaminergic neurons may be the use of phytochemicals as inducers of endogenous antioxidants and phase 2 enzymes. In this study, we demonstrated that treatment of the dopaminergic-like neuroblastoma SH-SY5Y cell line with isothiocyanate erucin (ER), a compound of cruciferous vegetables, resulted in significant increases of both total glutathione (GSH) levels and total antioxidant capacity at the cytosolic level. The increase of GSH levels was associated with an increase in the resistance of SH-SY5Y cells to neuronal death, in terms of apoptosis, induced by 6-hydroxydopamine (6-OHDA). The pretreatment of SH-SY5Y cells with ER was also shown to prevent the redox status impairment, in terms of intracellular ROS and O₂^•− formation, and loss of mitochondrial membrane potential, early events that are initiators of the apoptotic process, induced by 6-OHDA. Last, the antiapoptotic and antioxidant effects of ER were abolished by buthionine sulfoximine, supporting the main role of GSH in the neuroprotective effects recorded by ER. These results suggest that ER may prevent the oxidative damage induced by 6-OHDA.     

Erythropoietin: New Directions for the Nervous System

New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer’s disease, Parkinson’s disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control β-catenin, glycogen synthase kinase-3β, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.     

Oxidant Stress and Signal Transduction in the Nervous System with the PI 3-K,Akt, and mTOR Cascade

Oxidative stress impacts multiple systems of the body and can lead to some of the most devastating consequences in the nervous system especially during aging. Both acute and chronic neurodegenerative disorders such as diabetes mellitus, cerebral ischemia, trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and tuberous sclerosis through programmed cell death pathways of apoptosis and autophagy can be the result of oxidant stress. Novel therapeutic avenues that focus upon the phosphoinositide 3-kinase (PI 3-K), Akt (protein kinase B), and the mammalian target of rapamycin (mTOR) cascade and related pathways offer exciting prospects to address the onset and potential reversal of neurodegenerative disorders. Effective clinical translation of these pathways into robust therapeutic strategies requires intimate knowledge of the complexity of these pathways and the ability of this cascade to influence biological outcome that can vary among disorders of the nervous system.     

Oxidative Stress in Malaria: Potential Benefits of Antioxidant Therapy

Malaria is an infectious disease and a serious public health problem in the world, with 3.3 billion people in endemic areas in 100 countries and about 200 million new cases each year, resulting in almost 1 million deaths in 2018. Although studies look for strategies to eradicate malaria, it is necessary to know more about its pathophysiology to understand the underlying mechanisms involved, particularly the redox balance, to guarantee success in combating this disease. In this review, we addressed the involvement of oxidative stress in malaria and the potential benefits of antioxidant supplementation as an adjuvant antimalarial therapy.     

Isothiocyanates Are Promising Compounds against Oxidative Stress,Neuroinflammation and Cell Death that May Benefit Neurodegeneration in Parkinson’s Disease

Parkinson’s disease (PD) is recognized as the second most common neurodegenerative disorder and is characterized by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra. Despite intensive research, the mechanisms involved in neuronal loss are not completely understood yet; however, misfolded proteins, oxidative stress, excitotoxicity and inflammation play a pivotal role in the progression of the pathology. Neuroinflammation may have a greater function in PD pathogenesis than initially believed, taking part in the cascade of events that leads to neuronal death. To date, no efficient therapy, able to arrest or slow down PD, is available. In this context, the need to find novel strategies to counteract neurodegenerative progression by influencing diseases’ pathogenesis is becoming increasingly clear. Isothiocyanates (ITCs) have already shown interesting properties in detoxification, inflammation, apoptosis and cell cycle regulation through the induction of phase I and phase II enzyme systems. Moreover, ITCs may be able to modulate several key points in oxidative and inflammatory evolution. In view of these considerations, the aim of the present review is to describe ITCs as pleiotropic compounds capable of preventing and modulating the evolution of PD.     

Oleuropein Prevents Neuronal Death,Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE), the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA). We also investigated OLE’s ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model.     

Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

Due to its localization and function, the cornea is regularly exposed to sunlight and atmospheric oxygen, mainly dioxygen, which produce reactive oxygen species (ROS). Therefore, corneal cells are particularly susceptible to oxidative stress. The accumulation of ROS in the cornea may affect signal transduction, proliferation and may also promote cell death. The cornea has several enzymatic and non-enzymatic antioxidants involved in ROS scavenging, but in certain conditions they may not cope with oxidative stress, leading to diseases of the eye. Keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD) are multifactorial diseases of the cornea, in which pathogenesis is not fully understood. However, increased levels of oxidative stress markers detected in these disorders indicate that oxidative stress may play an important role in their development and progression. These markers are: (i) decreased levels of non-enzymatic antioxidants, and (ii) decreased expression of genes encoding antioxidative enzymes, including thioredoxin reductase, peroxiredoxins, superoxide dismutase, glutathione S-transferase, and aldehyde dehydrogenase. Moreover, the FECD endothelium displays higher levels of oxidative DNA damage, especially in mitochondrial DNA (mtDNA), whereas KC cornea shows abnormal levels of some components of oxidative phosphorylation encoded by mtDNA. In this review we present some considerations and results of experiments supporting the thesis on the important role of oxidative stress in KC and FECD pathology.     

Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation

Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.     

Human Adipose Tissue Conditioned Media from Lean Subjects Is Protective against H2O2 Induced Neurotoxicity in Human SH-SY5Y Neuronal Cells

Adipose tissue secretes numerous hormone-like factors, which are known as adipokines. Adipokine receptors have been identified in the central nervous system but the potential role of adipokine signaling in neuroprotection is unclear. The aim of this study is to determine (1) Whether adipokines secreted from cultured adipose tissue of lean humans is protective against oxidative stress-induced neurotoxicity in human SH-SY5Y neuronal cells; and (2) To explore potential signaling pathways involved in these processes. Adipose tissue conditioned media (ATCM) from healthy lean subjects completely prevented H₂O₂ induced neurotoxicity, while this effect is lost after heating ATCM. ATCM activated the phosphorylation of ERK1/2, JNK and Akt at serine 308 in SH-SY5Y cells. PD98059 (25 µM), SP600125 (5 µM) and LY29400 (20 µM) partially blocked the protective effects of ATCM against H₂O₂ induced neurotoxicity. Findings demonstrate that heat-sensitive factors secreted from human adipose tissue of lean subjects are protective against H₂O₂ induced neurotoxicity and ERK1/2, JNK, and PI3K signaling pathways are involved in these processes. In conclusion, this study demonstrates preliminary but encouraging data to further support that adipose tissue secreted factors from lean human subjects might possess neuroprotective properties and unravel the specific roles of ERK1/2, JNK and PI3K in these processes.     

Therapeutic Effects of Hydrogen Gas Inhalation on Trimethyltin-Induced Neurotoxicity and Cognitive Impairment in the C57BL/6 Mice Model

Oxidative stress (OS) is one of the causative factors in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s disease (AD) and cognitive dysfunction. In the present study, we investigated the effects of hydrogen (H₂) gas inhalation in trimethyltin (TMT)-induced neurotoxicity and cognitive dysfunction in the C57BL/6 mice. First, mice were divided into the following groups: mice without TMT injection (NC), TMT-only injection group (TMT only), TMT injection + lithium chloride-treated group as a positive control (PC), and TMT injection + 2% H₂ inhalation-treated group (H₂). The TMT injection groups were administered a single dosage of intraperitoneal TMT injection (2.6 mg/kg body weight) and the H₂ group was treated with 2% H₂ for 30 min once a day for four weeks. Additionally, a behavioral test was performed with Y-maze to test the cognitive abilities of the mice. Furthermore, multiple OS- and AD-related biomarkers such as reactive oxygen species (ROS), nitric oxide (NO), calcium (Ca²⁺), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase, inflammatory cytokines, apolipoprotein E (Apo-E), amyloid β (Aβ)-40, phospho-tau (p-tau), Bcl-2, and Bcl-2- associated X (Bax) were investigated in the blood and brain. Our results demonstrated that TMT exposure alters seizure and spatial recognition memory. However, after H₂ treatment, memory deficits were ameliorated. H₂ treatment also decreased AD-related biomarkers, such as Apo-E, Aβ-40, p-tau, and Bax and OS markers such as ROS, NO, Ca²⁺, and MDA in both serum and brain. In contrast, catalase and GPx activities were significantly increased in the TMT-only group and decreased after H₂ gas treatment in serum and brain. In addition, inflammatory cytokines such as granulocyte colony-stimulating factors (G-CSF), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) were found to be significantly decreased after H₂ treatment in both serum and brain lysates. In contrast, Bcl-2 and vascular endothelial growth factor (VEGF) expression levels were found to be enhanced after H₂ treatment. Taken together, our results demonstrated that 2% H₂ gas inhalation in TMT-treated mice exhibits memory enhancing activity and decreases the AD, OS, and inflammatory-related markers. Therefore, H₂ might be a candidate for repairing neurodegenerative diseases with cognitive dysfunction. However, further mechanistic studies are needed to fully clarify the effects of H₂ inhalation on TMT-induced neurotoxicity and cognitive dysfunction.     

Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex and variable interplay between elements including age, genetic, and environmental risk factors that manifest as the loss of dopaminergic neurons. Contemporary treatments for PD do not prevent or reverse the extent of neurodegeneration that is characteristic of this disorder and accordingly, there is a strong need to develop new approaches which address the underlying disease process and provide benefit to patients with this debilitating disorder. Mitochondrial dysfunction, oxidative damage, and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons seen in PD. However, results of studies aiming to inhibit these pathways have shown variable success, and outcomes from large-scale clinical trials are not available or report varying success for the interventions studied. Overall, the available data suggest that further development and testing of novel therapies are required to identify new potential therapies for combating PD. Herein, this review reports on the most recent development of antioxidant and anti-inflammatory approaches that have shown positive benefit in cell and animal models of disease with a focus on supplementation with natural product therapies and selected synthetic drugs.     

Lymphocytes of Patients with Alzheimer’s Disease Display Different DNA Damage Repair Kinetics and Expression Profiles of DNA Repair and Stress Response Genes

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by loss of memory and cognitive capacity. Given the limitations to analyze brain cells, it is important to study whether peripheral lymphocytes can provide biological markers for AD, an interesting approach, once they represent the overall condition of the organism. To that extent, we sought to find whether lymphocytes of AD patients present DNA damage and repair kinetics different from those found in elderly matched controls (EC group) under in vitro treatment with hydrogen peroxide. We found that AD patient cells indeed showed an altered DNA repair kinetics (comet assay). Real-time quantitative analysis of genes associated with DNA stress response also showed that FANCG and CDKN1A are upregulated in AD, while MTH1 is downregulated, compared with the control group. In contrast, the expression of ATM, ATR and FEN1 genes does not seem to differ between these groups. Interestingly, TP53 protein expression was increased in AD patients. Therefore, we found that kinetics of the stress response in the DNA were significantly different in AD patients, supporting the hypothesis that repair pathways may be compromised in AD and that peripheral lymphocytes can reveal this condition.     

Free radicals, oxidative stress, and antioxidants in human health and disease

Free radicals and other reactive oxygen species (ROS) are constantly formed in the human body. Free-radical mechanisms have been implicated in the pathology of several human diseases, including cancer, atherosclerosis, malaria, and rheumatoid arthritis and neurodegenerative diseases. For example, the superoxide radical (O ₂ ^·− ) and hydrogen peroxide (H₂O₂) are known to be generated in the brain and nervous system in vivo, and several areas of the human brain are rich in iron, which appears to be easily mobilizable in a form that can stimulate free-radical reactions. Antioxidant defenses to remove O ₂ ^·− and H₂O₂ exist. Superoxide dismutases (SOD) remove O ₂ ^·− by greatly accelerating its conversion to H₂O₂. Catalases in peroxisomes convert H₂O₂ into water and O₂ and help to dispose of H₂O₂ generated by the action of the oxidase enzymes that are located in these organelles. Other important H₂O₂-removing enzymes in human cells are the glutathione peroxidases. When produced in excess, ROS can cause tissue injury. However, tissue injury can itself cause ROS generation (e.g., by causing activation of phagocytes or releasing transition metal ions from damaged cells), which may (or may not, depending on the situation) contribute to a worsening of the injury. Assessment of oxidative damage to biomolecules by means of emerging technologies based on products of oxidative damage to DNA (e.g., 8-hydroxydeoxyguanosine), lipids (e.g., isoprostanes), and proteins (altered amino acids) would not only advance our understanding of the underlying mechanisms but also facilitate supplementation and intervention studies designed and conducted to test antioxidant efficacy in human health and disease.     

Loliolide,a New Therapeutic Option for Neurological Diseases? In Vitro Neuroprotective and Anti-Inflammatory Activities of a Monoterpenoid Lactone Isolated from Codium tomentosum

Parkinsons Disease (PD) is the second most common neurodegenerative disease worldwide, and is characterized by a progressive degeneration of dopaminergic neurons. Without an effective treatment, it is crucial to find new therapeutic options to fight the neurodegenerative process, which may arise from marine resources. Accordingly, the goal of the present work was to evaluate the ability of the monoterpenoid lactone Loliolide, isolated from the green seaweed Codium tomentosum, to prevent neurological cell death mediated by the neurotoxin 6-hydroxydopamine (6-OHDA) on SH-SY5Y cells and their anti-inflammatory effects in RAW 264.7 macrophages. Loliolide was obtained from the diethyl ether extract, purified through column chromatography and identified by NMR spectroscopy. The neuroprotective effects were evaluated by the MTT method. Cells’ exposure to 6-OHDA in the presence of Loliolide led to an increase of cells’ viability in 40%, and this effect was mediated by mitochondrial protection, reduction of oxidative stress condition and apoptosis, and inhibition of the NF-kB pathway. Additionally, Loliolide also suppressed nitric oxide production and inhibited the production of TNF-α and IL-6 pro-inflammatory cytokines. The results suggest that Loliolide can inspire the development of new neuroprotective therapeutic agents and thus, more detailed studies should be considered to validate its pharmacological potential.     

Mitochondrial Dysfunction and Oxidative Stress Promote Apoptotic Cell Death in the Striatum via Cytochrome c/Caspase-3 Signaling Cascade Following Chronic Rotenone Intoxication in Rats

Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration. Evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of different pathways, including free-radical generation and dysfunction of the mitochondrial Complex I activity. In Lewis rats, chronic systemic administration of a specific mitochondrial Complex I inhibitor, rotenone (3 mg/kg/day) produced parkinsonism-like symptoms. Increased oxidized proteins and peroxynitrite, and mitochondrial or cytosol translocation of Bim, Bax or cytochrome c in the striatum was observed after 2-4 weeks of rotenone infusion. After 28 days of systemic rotenone exposure, imunohistochemical staining for tyrosine hydroxylase indicated nigrostriatal dopaminergic neuronal cell degeneration. Characteristic histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were present in the striatal neuronal cell after chronic rotenone intoxication. We conclude that chronic rotenone intoxication may enhance oxidative and nitrosative stress that induces mitochondrial dysfunction and ultrastructural damage, resulting in translocation of Bim and Bax from cytosol to mitochondria that contributes to apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade.     

Neuroprotective Effects of Thiamine and Precursors with Higher Bioavailability: Focus on Benfotiamine and Dibenzoylthiamine

Thiamine (vitamin B1) is essential for brain function because of the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. In order to compensate thiamine deficiency, several thiamine precursors with higher bioavailability were developed since the 1950s. Among these, the thioester benfotiamine (BFT) has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. BFT has no adverse effects and improves cognitive outcome in patients with mild Alzheimer’s disease (AD). Recent in vitro studies show that another thiamine thioester, dibenzoylthiamine (DBT) is even more efficient that BFT, especially with respect to its anti-inflammatory potency. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified metabolites in particular open thiazole ring derivatives. The identification of the active neuroprotective derivatives and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental and psychiatric conditions.