Oxidative Stress and Neurodegeneration: Insights and Therapeutic Strategies for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative condition marked by the gradual deterioration of dopaminergic neurons in the substantia nigra. Oxidative stress has been identified as a key player in the development of PD in recent studies. In the first part, we discuss the sources of oxidative stress in PD, including mitochondrial dysfunction, dopamine metabolism, and neuroinflammation. This paper delves into the possibility of mitigating oxidative stress as a potential treatment approach for PD. In addition, we examine the hurdles and potential of antioxidant therapy, including the challenge of delivering antioxidants to the brain and the requirement for biomarkers to track oxidative stress in PD patients. However, even if antioxidant therapy holds promise, further investigation is needed to determine its efficacy and safety in PD treatment.

Molecular and Cellular Involvement in CIPN.

Many anti-cancer drugs, such as taxanes, platinum compounds, vinca alkaloids, and proteasome inhibitors, can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a frequent and harmful side effect that affects the sensory, motor, and autonomic nerves, leading to pain, numbness, tingling, weakness, and reduced quality of life. The causes of CIPN are not fully known, but they involve direct nerve damage, oxidative stress, inflammation, DNA damage, microtubule dysfunction, and altered ion channel activity. CIPN is also affected by genetic, epigenetic, and environmental factors that modulate the risk and intensity of nerve damage. Currently, there are no effective treatments or prevention methods for CIPN, and symptom management is mostly symptomatic and palliative. Therefore, there is a high demand for better understanding of the cellular and molecular mechanisms involved in CIPN, as well as the development of new biomarkers and therapeutic targets. This review gives an overview of the current knowledge and challenges in the field of CIPN, focusing on the biological and molecular mechanisms underlying this disorder.

Organoids Modeling Stroke in a Petri Dish.

Stroke is a common neurological disorder, the second leading cause of death, and the third leading cause of disability. Unfortunately, the only approved drug for it is tissue plasminogen, but the therapeutic window is limited. In this context, preclinical studies are relevant to better dissect the underlying mechanisms of stroke and for the drug screening of potential therapies. Brain organoids could be relevant in this setting. They are derived from pluripotent stem cells or isolated organ progenitors that differentiate to form an organ-like tissue, exhibiting multiple cell types that self-organize to form a structure not unlike the organ in vivo. Brain organoids mimic many key features of early human brain development at molecular, cellular, structural, and functional levels and have emerged as novel model systems that can be used to investigate human brain diseases including stroke. Brain organoids are a promising and powerful tool for ischemic stroke studies; however, there are a few concerns that need to be addressed, including the lack of vascularization and the many cell types that are typically present in the human brain. The aim of this review is to discuss the potential of brain organoids as a novel model system for studying ischemic stroke, highlighting both the advantages and disadvantages in the use of this technology.

Brain Organoids: A Game-Changer for Drug Testing.

Neurological disorders are the second cause of death and the leading cause of disability worldwide. Unfortunately, no cure exists for these disorders, but the actual therapies are only able to ameliorate people's quality of life. Thus, there is an urgent need to test potential therapeutic approaches. Brain organoids are a possible valuable tool in the study of the brain, due to their ability to reproduce different brain regions and maturation stages; they can be used also as a tool for disease modelling and target identification of neurological disorders. Recently, brain organoids have been used in drug-screening processes, even if there are several limitations to overcome. This review focuses on the description of brain organoid development and drug-screening processes, discussing the advantages, challenges, and limitations of the use of organoids in modeling neurological diseases. We also highlighted the potential of testing novel therapeutic approaches. Finally, we examine the challenges and future directions to improve the drug-screening process.

Therapeutic potential of saffron in brain disorders: From bench to bedside.

Saffron is a spice derived from the flower of Crocus sativus L., which has been used for centuries as a coloring and flavoring agent, as well as a source of medicinal compounds. Saffron contains various bioactive constituents, such as crocin, crocetin, safranal, picrocrocin, and kaempferol, that have shown potential benefits for human health. Among them, crocin is the most abundant and characteristic constituent of saffron, responsible for its bright red color and antioxidant properties. One of the most promising applications of saffron and its constituents is in the prevention and treatment of neurological disorders, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, and other brain disorders. Saffron and its constituents have been reported to exert neuroprotective effects through various mechanisms, such as modulating neurotransmitters, enhancing neurogenesis, reducing neuroinflammation, regulating oxidative stress, activating the Nrf2 signaling pathway, and modulating epigenetic factors. Several clinical and preclinical studies have demonstrated the efficacy and safety of saffron and its constituents in improving cognitive function, mood, and other neurological outcomes. In this review, we summarize the current evidence on the therapeutic potential of saffron and its constituents in neurological disorders, from bench to bedside. We also discuss the challenges and future directions for the development of saffron-based therapies for brain health.

Therapeutic advances in neural regeneration for Huntington's disease.

Huntington's disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington's disease. From a clinical point of view, Huntington's disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington's disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington's disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington's disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington's disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington's disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington's disease.

Intranasal delivery of NGF rescues hearing impairment in aged SAMP8 mice.

Hearing loss impacts the quality of life and affects communication resulting in social isolation and reduced well-being. Despite its impact on society and economy, no therapies for age-related hearing loss are available so far. Loss of mechanosensory hair cells of the cochlea is a common event of hearing loss in humans. Studies performed in birds demonstrating that they can be replaced following the proliferation and transdifferentiation of supporting cells, strongly pointed out on HCs regeneration as the main focus of research aimed at hearing regeneration. Neurotrophins are growth factors involved in neuronal survival, development, differentiation, and plasticity. NGF has been involved in the interplay between auditory receptors and efferent innervation in the cochlea during development. During embryo development, both NGF and its receptors are highly expressed in the inner ears. It has been reported that NGF is implicated in the differentiation of auditory gangliar and hair cells. Thus, it has been proposed that NGF administration can decrease neuronal damage and prevent hearing loss. The main obstacle to the development of hearing impairment therapy is that efficient means of delivery for selected drugs to the cochlea are missing. Herein, in this study NGF was administered by the intranasal route. The first part of the study was focused on a biodistribution study, which showed the effective delivery in the cochlea; while the second part was focused on analyzing the potential therapeutic effect of NGF in senescence-accelerated prone strain 8 mice. Interestingly, intranasal administration of NGF resulted protective in counteracting hearing impairment in SAMP8 mice, ameliorating hearing performances (analyzed by auditory brainstem responses and distortion product otoacoustic emission) and hair cells morphology (analyzed by microscopy analysis). The results obtained were encouraging indicating that the neurotrophin NGF was efficiently delivered to the inner ear and that it was effective in counteracting hearing loss.

Neuroprotective effects of the PPARß/δ antagonist GSK0660 in in vitro and in vivo Parkinson's disease models.

BACKGROUND: The underlying mechanism of Parkinson's disease are still unidentified, but excitotoxicity, oxidative stress, and neuroinflammation are considered key actors. Proliferator activated receptors (PPARs) are transcription factors involved in the control of numerous pathways. Specifically, PPARß/δ is recognized as an oxidative stress sensor, and we have previously reported that it plays a detrimental role in neurodegeneration. METHODS: Basing on this concept, in this work, we tested the potential effects of a specific PPARß/δ antagonist (GSK0660) in an in vitro model of Parkinson's disease. Specifically, live-cell imaging, gene expression, Western blot, proteasome analyses, mitochondrial and bioenergetic studies were performed. Since we obtained promising results, we tested this antagonist in a 6-hydroxydopamine hemilesioned mouse model. In the animal model, behavioral tests, histological analysis, immunofluorescence and western blot of substantia nigra and striatum upon GSK0660 were assayed. RESULTS: Our findings suggested that PPARß/δ antagonist has neuroprotective potential due to neurotrophic support, anti-apoptotic and anti-oxidative effects paralleled to an amelioration of mitochondria and proteasome activity. These findings are strongly supported also by the siRNA results demonstrating that by silencing PPARß/δ a significative rescue of the dopaminergic neurons was obtained, thus indicating an involvement of PPARß/δ in PD's pathogenesis. Interestingly, in the animal model, GSK0660 treatment confirmed neuroprotective effects observed in the in vitro studies. Neuroprotective effects were highlighted by the behavioural performance and apomorphine rotation tests amelioration and the reduction of dopaminergic neuronal loss. These data were also confirmed by imaging and western blotting, indeed, the tested compound decreased astrogliosis and activated microglia, concomitant with an upregulation of neuroprotective pathways. CONCLUSIONS: In summary, PPARß/δ antagonist displayed neuroprotective activities against 6-hydroxydopamine detrimental effects both in vitro and in vivo models of Parkinson's disease, suggesting that it may represent a novel therapeutic approach for this disorder.

Ketoprofen, lysine and gabapentin co-crystal magnifies synergistic efficacy and tolerability of the constituent drugs: Pre-clinical evidences towards an innovative therapeutic approach for neuroinflammatory pain.

Chronic pain is an enormous public health concern, and its treatment is still an unmet medical need. Starting from data highlighting the promising effects of some nonsteroidal anti-inflammatory drugs in combination with gabapentin in pain treatment, we sought to combine ketoprofen lysine salt (KLS) and gabapentin to obtain an effective multimodal therapeutic approach for chronic pain. Using relevant in vitro models, we first demonstrated that KLS and gabapentin have supra-additive effects in modulating key pathways in neuropathic pain and gastric mucosal damage. To leverage these supra-additive effects, we then chemically combined the two drugs via co-crystallization to yield a new compound, a ternary drug-drug co-crystal of ketoprofen, lysine and gabapentin (KLS-GABA co-crystal). Physicochemical, biodistribution and pharmacokinetic studies showed that within the co-crystal, ketoprofen reaches an increased gastrointestinal solubility and permeability, as well as a higher systemic exposure in vivo compared to KLS alone or in combination with gabapentin, while both the constituent drugs have increased central nervous system permeation. These unique characteristics led to striking, synergistic anti-nociceptive and anti-inflammatory effects of KLS-GABA co-crystal, as well as significantly reduced spinal neuroinflammation, in translational inflammatory and neuropathic pain rat models, suggesting that the synergistic therapeutic effects of the constituent drugs are further boosted by the co-crystallization. Notably, while strengthening the therapeutic effects of ketoprofen, KLS-GABA co-crystal showed remarkable gastrointestinal tolerability in both inflammatory and chronic neuropathic pain rat models. In conclusion, these results allow us to propose KLS-GABA co-crystal as a new drug candidate with high potential clinical benefit-to-risk ratio for chronic pain treatment.

Cell Rearrangement and Oxidant/Antioxidant Imbalance in Huntington's Disease.

Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a CAG triplet repeat in the HTT gene, resulting in the production of an aberrant huntingtin (Htt) protein. The mutant protein accumulation is responsible for neuronal dysfunction and cell death. This is due to the involvement of oxidative damage, excitotoxicity, inflammation, and mitochondrial impairment. Neurons naturally adapt to bioenergetic alteration and oxidative stress in physiological conditions. However, this dynamic system is compromised when a neurodegenerative disorder occurs, resulting in changes in metabolism, alteration in calcium signaling, and impaired substrates transport. Thus, the aim of this review is to provide an overview of the cell's answer to the stress induced by HD, focusing on the role of oxidative stress and its balance with the antioxidant system.

Early-life exposure to environmentally relevant concentrations of triclocarban impairs ocular development in zebrafish larvae.

Triclocarban (TCC), is an antimicrobial component in personal care products and it is one of the emerging contaminants since it has been detected in various environmental matrices. Its presence in human cord blood, breast milk, and maternal urine raised issues about its possible impact on development and increased concerns about the safety of daily exposure. This study aims to provide additional information about the effects of zebrafish early-life exposure to TCC on eye development and visual function. Zebrafish embryos were exposed to two concentrations of TCC (5 and 50 µg/L) for 4 days. TCC-mediated toxicity was assessed in larvae at the end of exposure and in the long term (20 days post fertilization; dpf), through different biological end-points. The experiments showed that TCC exposure influences the retinal architecture. In 4 dpf treated larvae, we found a less organized ciliary marginal zone, a decrease in the inner nuclear and inner plexiform layers, and a decrease in the retinal ganglion cell layer. Photoreceptor and inner plexiform layers showed an increase in 20 dpf larvae at lower and both concentrations, respectively. The expression levels of two genes involved in eye development (mitfb and pax6a) were both decreased at the concentration of 5 µg/L in 4 dpf larvae, and an increase in mitfb was observed in 5 µg/L-exposed 20 dpf larvae. Interestingly, 20 dpf larvae failed to discriminate between visual stimuli, demonstrating notable visual perception impairments due to compound. The results prompt us to hypothesize that early-life exposure to TCC may have severe and potentially long-term effect on zebrafish visual function.

Differential Effects of Nonsteroidal Anti-Inflammatory Drugs in an In Vitro Model of Human Leaky Gut.

The intestinal barrier is the main contributor to gut homeostasis. Perturbations of the intestinal epithelium or supporting factors can lead to the development of intestinal hyperpermeability, termed "leaky gut". A leaky gut is characterized by loss of epithelial integrity and reduced function of the gut barrier, and is associated with prolonged use of Non-Steroidal Anti-Inflammatories. The harmful effect of NSAIDs on intestinal and gastric epithelial integrity is considered an adverse effect that is common to all drugs belonging to this class, and it is strictly dependent on NSAID properties to inhibit cyclo-oxygenase enzymes. However, different factors may affect the specific tolerability profile of different members of the same class. The present study aims to compare the effects of distinct classes of NSAIDs, such as ketoprofen (K), Ibuprofen (IBU), and their corresponding lysine (Lys) and, only for ibuprofen, arginine (Arg) salts, using an in vitro model of leaky gut. The results obtained showed inflammatory-induced oxidative stress responses, and related overloads of the ubiquitin-proteasome system (UPS) accompanied by protein oxidation and morphological changes to the intestinal barrier, many of these effects being counteracted by ketoprofen and ketoprofen lysin salt. In addition, this study reports for the first time a specific effect of R-Ketoprofen on the NFkB pathway that sheds new light on previously reported COX-independent effects, and that may account for the observed unexpected protective effect of K on stress-induced damage on the IEB.

Neurotrophic factor-based pharmacological approaches in neurological disorders.

Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline. This process represents the major risk factor for aging-related diseases such as Alzheimer's disease, Parkinson's disease, and ischemic stroke. The incidence of all these pathologies increases exponentially with age. Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies. Cognitive deficit and neurodegeneration, common features of aging-related pathologies, are related to the alteration of the activity and levels of neurotrophic factors, such as brain-derived neurotrophic factor, nerve growth factor, and glial cell-derived neurotrophic factor. For this reason, treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases. Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors, neurotrophins' binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies. Considering neurotrophins' crucial role in aging pathologies, here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.

Paclitaxel binds and activates C5aR1: A new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions.

Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms-in terms of cold and mechanical allodynia-and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.

Are We What We Eat? Impact of Diet on the Gut-Brain Axis in Parkinson's Disease.

Parkinson's disease is characterized by motor and non-motor symptoms, such as defects in the gut function, which may occur before the motor symptoms. To date, there are therapies that can improve these symptoms, but there is no cure to avoid the development or exacerbation of this disorder. Dysbiosis of gut microbiota could have a crucial role in the gut-brain axis, which is a bidirectional communication between the central nervous system and the enteric nervous system. Diet can affect the microbiota composition, impacting gut-brain axis functionality. Gut microbiome restoration through probiotics, prebiotics, synbiotics or other dietary means could have the potential to slow PD progression. In this review, we will discuss the influence of diet on the bidirectional communication between gut and brain, thus supporting the hypothesis that this disorder could begin in the gut. We also focus on how food-based therapies might then have an influence on PD and could ameliorate non-motor as well as motor symptoms.

An Update on Graphene-Based Nanomaterials for Neural Growth and Central Nervous System Regeneration.

Thanks to their reduced size, great surface area, and capacity to interact with cells and tissues, nanomaterials present some attractive biological and chemical characteristics with potential uses in the field of biomedical applications. In this context, graphene and its chemical derivatives have been extensively used in many biomedical research areas from drug delivery to bioelectronics and tissue engineering. Graphene-based nanomaterials show excellent optical, mechanical, and biological properties. They can be used as a substrate in the field of tissue engineering due to their conductivity, allowing to study, and educate neural connections, and guide neural growth and differentiation; thus, graphene-based nanomaterials represent an emerging aspect in regenerative medicine. Moreover, there is now an urgent need to develop multifunctional and functionalized nanomaterials able to arrive at neuronal cells through the blood-brain barrier, to manage a specific drug delivery system. In this review, we will focus on the recent applications of graphene-based nanomaterials in vitro and in vivo, also combining graphene with other smart materials to achieve the best benefits in the fields of nervous tissue engineering and neural regenerative medicine. We will then highlight the potential use of these graphene-based materials to construct graphene 3D scaffolds able to stimulate neural growth and regeneration in vivo for clinical applications.

Looking for In Vitro Models for Retinal Diseases.

Retina is a layered structure of the eye, composed of different cellular components working together to produce a complex visual output. Because of its important role in visual function, retinal pathologies commonly represent the main causes of visual injury and blindness in the industrialized world. It is important to develop in vitro models of retinal diseases to use them in first screenings before translating in in vivo experiments and clinics. For this reason, it is important to develop bidimensional (2D) models that are more suitable for drug screening and toxicological studies and tridimensional (3D) models, which can replicate physiological conditions, for investigating pathological mechanisms leading to visual loss. This review provides an overview of the most common retinal diseases, relating to in vivo models, with a specific focus on alternative 2D and 3D in vitro models that can replicate the different cellular and matrix components of retinal layers, as well as injury insults that induce retinal disease and loss of the visual function.

S-Carboxymethyl Cysteine Protects against Oxidative Stress and Mitochondrial Impairment in a Parkinson's Disease In Vitro Model.

The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated metabolites generated upon night-time administration. It has been indicated that this drug behaves like a free radical scavenger and that, in this regard, the sulfide is the active species with sulphoxide metabolites (already oxidized) being inactive. Consequently, a night-time consumption of the drug should be more effective upon daytime administration. Still, this diurnal variation in biotransformation (deactivation) is dependent on the genetic polymorphism on which relies the patient population capacities of S-carboxymethyl-L-cysteine sulphoxidation. It has been reported that those cohorts who are efficient sulfur oxidizers will generate inactive oxygenated metabolites. In contrast, those who have a relative deficiency in this mechanism will be subjected to the active sulfide for a more extended period. In this regard, it is noteworthy that 38-39% of Parkinson's disease patients belong to the poor sulphoxide cohort, being exposed to higher levels of active sulfide, the active antioxidant metabolite of S-carboxymethyl-L-cysteine. Parkinson's disease is a neurodegenerative disorder that affects predominately dopaminergic neurons. It has been demonstrated that oxidative stress and mitochondrial dysfunction play a crucial role in the degeneration of dopaminergic neurons. Based on this evidence, in this study, we evaluated the effects of S-carboxymethyl cysteine in an in vitro model of Parkinson's disease in protecting against oxidative stress injury. The data obtained suggested that an S-carboxymethylcysteine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes.

CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling.

Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines' effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.

L-Methionine Protects against Oxidative Stress and Mitochondrial Dysfunction in an In Vitro Model of Parkinson's Disease.

Methionine is an aliphatic, sulfur-containing, essential amino acid that has been demonstrated to have crucial roles in metabolism, innate immunity, and activation of endogenous antioxidant enzymes, including methionine sulfoxide reductase A/B and the biosynthesis of glutathione to counteract oxidative stress. Still, methionine restriction avoids altered methionine/transmethylation metabolism, thus reducing DNA damage and possibly avoiding neurodegenerative processes. In this study, we wanted to study the preventive effects of methionine in counteracting 6-hydroxydopamine (6-OHDA)-induced injury. In particular, we analyzed the protective effects of the amino acid L-methionine in an in vitro model of Parkinson's disease and dissected the underlying mechanisms compared to the known antioxidant taurine to gain insights into the potential of methionine treatment in slowing the progression of the disease by maintaining mitochondrial functionality. In addition, to ascribe the effects of methionine on mitochondria and oxidative stress, methionine sulfoxide was used in place of methionine. The data obtained suggested that an L-methionine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes.