Management and Rehabilitative Treatment in Osteoarthritis with a Novel Physical Therapy Approach: A Randomized Control Study.

Knee osteoarthritis (KOA) is a chronic degenerative disease characterized by progressive joint damage leading to significant disability. Although rehabilitative treatment methods for KOA have been widely implemented, the optimal integrated instrumental physical therapy approach remains unclear. Therefore, this study aimed to analyze the effect of Quantum Molecular Resonance (QMR) on pain reduction as the primary outcome and the functional improvement in activity daily living (ADL) as a secondary outcome. The study was designed as a double-blind, randomized, controlled trial in an outpatient setting. Fifty-four (N = 54) patients were enrolled and then randomized into three groups according to a simple randomization list: Group 1 (intensive protocol, N = 22), Group 2 (extensive protocol, N = 21), and a Sham group (N = 11). Patients were evaluated over time with scales assessing pain and function. Treatment was performed with the QMR model electro-medical device, which generates alternating electric currents characterized by high frequency (4-64 MHz). The results showed that QMR had a positive effect with respect to the Sham group in terms of pain and function (p < 0.01), and intensive treatment was more effective than the extensive treatment in terms of "speed of response" to the treatment (p < 0.05). In conclusion, QMR in KOA could be effective in slowing the progression of clinical symptoms and improving patients' pain and functionality and thus quality of life. Future studies will be necessary to investigate further treatment algorithms and therapeutic associations with rehabilitative exercise.

Polystyrene nanoplastics mediate oxidative stress, senescence, and apoptosis in a human alveolar epithelial cell line.

Background: Nanoplastics, an emerging form of pollution, are easily consumed by organisms and pose a significant threat to biological functions due to their size, expansive surface area, and potent ability to penetrate biological systems. Recent findings indicate an increasing presence of airborne nanoplastics in atmospheric samples, such as polystyrene (PS), raising concerns about potential risks to the human respiratory system. Methods: This study investigates the impact of 800 nm diameter-PS nanoparticles (PS-NPs) on A549, a human lung adenocarcinoma cell line, examining cell viability, redox balance, senescence, apoptosis, and internalization. We also analyzed the expression of hallmark genes of these processes. Results: We demonstrated that PS-NPs of 800 nm in diameter significantly affected cell viability, inducing oxidative stress, cellular senescence, and apoptosis. PS-NPs also penetrated the cytoplasm of A549 cells. These nanoparticles triggered the transcription of genes comprised in the antioxidant network [SOD1 (protein name: superoxide dismutase 1, soluble), SOD2 (protein name: superoxide dismutase 2, mitochondrial), CAT (protein name: catalase), Gpx1 (protein name: glutathione peroxidase 1), and HMOX1 (protein name: heme oxygenase 1)], senescence-associated secretory phenotype [Cdkn1a (protein name: cyclin-dependent kinase inhibitor 1A), IL1A (protein name: interleukin 1 alpha), IL1B (protein name: interleukin 1 beta), IL6 (protein name: interleukin 6), and CXCL8 (protein name: C-X-C motif chemokine ligand 8)], and others involved in the apoptosis modulation [BAX (protein name: Bcl2 associated X, apoptosis regulator), CASP3 (protein name: caspase 3), and BCL2 (protein name: Bcl2, apoptosis regulator)]. Conclusion: Collectively, this investigation underscores the importance of concentration (dose-dependent effect) and exposure duration as pivotal factors in assessing the toxic effects of PS-NPs on alveolar epithelial cells. Greater attention needs to be directed toward comprehending the risks of cancer development associated with air pollution and the ensuing environmental toxicological impacts on humans and other terrestrial mammals.

Quantum Molecular Resonance Inhibits NLRP3 Inflammasome/Nitrosative Stress and Promotes M1 to M2 Macrophage Polarization: Potential Therapeutic Effect in Osteoarthritis Model In Vitro.

This study aimed to investigate the anti-inflammatory effects of Quantum Molecular Resonance (QMR) technology in an in vitro model of osteoarthritis-related inflammation. The study used THP-1-derived macrophages stimulated with lipopolysaccharide and hyaluronic acid fragments to induce the expression of inflammatory cytokines and nitrosative stress. QMR treatment inhibited COX-2 and iNOS protein expression and activity and reduced NF-κB activity. Furthermore, QMR treatment led to a significant reduction in peroxynitrite levels, reactive nitrogen species that can form during inflammatory conditions, and restored tyrosine nitration values to those similar to sham-exposed control cells. We also investigated the effect of QMR treatment on inflammasome activation and macrophage polarization in THP-1-derived macrophages. Results showed that QMR treatment significantly decreased NLRP3 and activated caspase-1 protein expression levels and downregulated IL-18 and IL-1ß protein expression and secretion. Finally, our findings indicate that QMR treatment induces a switch in macrophage polarization from the M1 phenotype to the M2 phenotype.

Combined Rehabilitation Protocol in the Treatment of Osteoarthritis of the Knee: Comparative Study of Extremely Low-Frequency Magnetic Fields and Soft Elastic Knee Brace Effect.

The investigation of this observational case-control study aimed at determining the effectiveness of a combined treatment of extremely low-frequency electromagnetic fields (ELF) with a soft elastic knee brace versus ELF alone in knee osteoarthritis (KOA) with respect to a reduction in pain and functional recovery. We hypothesized that the combined use of ELF and a soft elastic knee brace may provide better results. Thirty-five patients (N = 35, divided into Group 1 = ELF and Group 2 = ELF with the soft elastic knee brace) were analyzed. The rehabilitative protocol consisted of 10 sessions of antiphlogistic and antiedema programs (first cycle) for 2 weeks, followed by twelve sessions of bone repair and connective tissue repair programs (second cycle) in patients with knee osteoarthritis (KOA) for 4 weeks. Patient evaluations were conducted at baseline (T0) and after 2 (T1) and 4 (T2) weeks of treatment. A follow-up evaluation was conducted 6 weeks after treatment (T3). The LIMFA© Therapy System was used to create multifrequency magnetoelectric fields with an intensity of 100 µT and a low-frequency field. The Incrediwear Cred 40 knee sleeve (Incred) was used for alleviating knee pain. The Visual Analogue Scale (VAS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Lysholm score (Ls) were used as outcome measures. The results showed that pain at rest (Vr), pain in motion (Vm), KOOS, and Ls were significantly affected by ELF over time. In conclusion, Group 2 had a better response in terms of pain resolution at rest (p < 0.05) and a concurrent better response at T3 in terms of functional recovery (p < 0.05).

Rapid Detection of Brettanomyces bruxellensis in Wine by Polychromatic Flow Cytometry.

Brettanomyces bruxellensis is found in several fermented matrices and produces relevant alterations to the wine quality. The methods usually used to identify B. bruxellensis contamination are based on conventional microbiological techniques that require long procedures (15 days), causing the yeast to spread in the meantime. Recently, a flow cytometry kit for the rapid detection (1-2 h) of B. bruxellensis in wine has been developed. The feasibility of the method was assessed in a synthetic medium as well as in wine samples by detecting B. bruxellensis in the presence of other yeast species (Saccharomyces cerevisiae and Pichia spp.) and at the concentrations that produce natural contaminations (up to 105 cells/mL), as well as at lower concentrations (103-102 cells/mL). Wine samples naturally contaminated by B. bruxellensis or inoculated with four different strains of B. bruxellensis species together with Saccharomyces cerevisiae and Pichia spp., were analyzed by flow cytometry. Plate counts were carried out in parallel to flow cytometry. We provide evidence that flow cytometry allows the rapid detection of B. bruxellensis in simple and complex mixtures. Therefore, this technique has great potential for the detection of B. bruxellensis and could allow preventive actions to reduce wine spoilage.

Characterization and Valorization of 'Sulmona Red Garlic' Peels and Small Bulbs.

'Sulmona red garlic' is an Italian variety characterized by a red tunica surrounding a white bulb. Red tunicae and non-commercial small bulbs are food wastes that must be studied for their added value. Hydroalcoholic extracts, obtained by separated inner and outer tunicae and peeled bulbs of small commercial 'Sulmona red garlic' bulbs, harvested at two different years, were first characterized with respect to their color, polyphenolic content, and antiradical activity. Then, an untargeted metabolic profile by means of electrospray ionization Fourier transform ion cyclotron resonance (ESI FT-ICR) mass spectrometry led to a comparative evaluation of the chemical diversity of six different samples. The study was completed by biological tests aiming to evaluate the associated health potential. Data on monocytes/macrophages showed good biocompatibility and a promising cytoprotective effect under oxidative stress conditions of all the extracts. At a molecular level, all the garlic extracts were able to downregulate the hydrogen peroxide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression through the modulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) and peroxynitrite intracellular amounts, at different extents depending on the extract, the cell type, and the concentration. On the whole, data highlight an associated health potential of the extracts of this waste plant material both in terms of cytoprotection and of anti-inflammatory activity.

Telerehabilitation proposal of mind-body technique for physical and psychological outcomes in patients with fibromyalgia.

Fibromyalgia (FM) syndrome is characterized by the close correlation of chronic widespread pain and other non-pain related symptoms. Aim of this study was to investigate whether telerehabilitation that provides physical and psychological support services of the mind-body techniques can affect the clinical profile and pain relief of FM patients. The study included twenty-eight female FM patients, mean aged 56.61 ± 8.56 years. All patients underwent a rehabilitation treatment (8 sessions, 1/week, 1 h/each) through Zoom platform, with the following principles of rehabilitation treatment: Anchoring to a positive emotion; listen and perceive your "own" body; conscious breathing; improve interoceptive awareness; relax. All patients then underwent clinical assessment of the physical distress and fear of movement for the Numeric Rating Scale (NRS); the Fatigue Assessment Scale (FAS); the Fear Avoidance Belief Questionnaire (FABQ); with measures of physical and mental disability for the Fibromyalgia Impact Questionnaire (FIQ); the 12-Items Short Form Survey; the Resilience Scale for Adults and the Coping Strategies Questionnaire-Revised. The evaluations were performed at T0 (baseline), T1 (after 8 weeks of treatment), and T2 (after 1 month of follow-up). The main finding was that telerehabilitation reduced physical and mental distress, fear, and disability (p < 0.001). Resilience and coping ability were less affected by the rehabilitative treatment. Our attempt of mind-body technique telerehabilitation has shown good results in the improvement of painful symptoms and quality of life for the FM patients but showed fewer positive impacts for the resilience and coping abilities aspects.

Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection.

Like other organs, brain functions diminish with age. Furthermore, for a variety of neurological disorders-including Alzheimer's disease-age is one of the higher-risk factors. Since in many Western countries the average age is increasing, determining approaches for decreasing the effects of aging on brain function is taking on a new urgency. Neuroinflammation and oxidative stress are two convoluted key factors in brain aging and chronic neurodegenerative diseases. The diverseness of factors, causing an age-related decrease in brain functions, requires identifying small molecules that have multiple biological activities that can affect all these factors. One great source of these small molecules is related to polyphenolic flavonoids. Recently, 3,3',4',7-tetrahydroxyflavone (fisetin) has been reported as a potent senotherapeutic capable of extending lifespan by reducing peroxidation levels and enhancing antioxidant cell responses. The neuroprotective effects of fisetin have been shown in several in vitro and in vivo models of neurological disorders due to its actions on multiple pathways associated with different neurological disorders. The present work aims to collect the most recent achievements related to the antioxidant and neuroprotective effects of fisetin. Moreover, in silico pharmacokinetics, pharmacodynamics, and toxicity of fisetin are also comprehensively described along with emerging novel drug delivery strategies for the amelioration of this flavonol bioavailability and chemical stability.

Flow Cytometry Detection of Anthracycline-Treated Breast Cancer Cells: An Optimized Protocol.

The use of anthracycline derivatives was approved for the treatment of a broad spectrum of human tumors (i.e., breast cancer). The need to test these drugs on cancer models has pushed the basic research to apply many types of in vitro assays, and, among them, the study of anthracycline-induced apoptosis was mainly based on the application of flow cytometry protocols. However, the chemical structure of anthracycline derivatives gives them a strong autofluorescence effect that must be considered when flow cytometry is used. Unfortunately, the guidelines on the analysis of anthracycline effects through flow cytometry are lacking. Therefore, in this study, we optimized the flow cytometry detection of doxorubicin and epirubicin-treated breast cancer cells. Their autofluorescence was assessed both by using conventional and imaging flow cytometry; we found that all the channels excited by the 488 nm laser were affected. Anthracycline-induced apoptosis was then measured via flow cytometry using the optimized setting. Consequently, we established a set of recommendations that enable the development of optimized flow cytometry settings when the in vitro assays of anthracycline effects are analyzed, with the final aim to reveal a new perspective on the use of those in vitro tests for the further implementation of precision medicine strategies in cancer.

Salivary oxytocin, cognitive anxiety and self-confidence in pre-competition athletes.

It is well known that soccer sport has the potential for high levels of stress and anxiety and that these are linked to Cortisol (C) variations. To date, much research has been devoted to understanding how Oxytocin (OT) can affect anxiety in response to a challenge. The aim of this study was to investigate, in 56 young male soccer players, the psychophysiological stress response 96 and 24 h before one soccer match of a tournament, in order to establish whether athletes who won or lost, show different levels of C and OT or expressions of competitive state anxiety subcomponents. We found that winners had significantly lower Cognitive anxiety and higher Self-confidence scores than losers. Also, significant differences between winners and losers in C and OT concentrations were observed, with higher OT levels in who has won and higher C levels in who has lost. Our results showed interesting associations between OT, C, anxiety feelings, and the outcome of competition.

A Review of Plant Extracts and Plant-Derived Natural Compounds in the Prevention/Treatment of Neonatal Hypoxic-Ischemic Brain Injury.

Neonatal hypoxic-ischemic (HI) brain injury is one of the major drawbacks of mortality and causes significant short/long-term neurological dysfunction in newborn infants worldwide. To date, due to multifunctional complex mechanisms of brain injury, there is no well-established effective strategy to completely provide neuroprotection. Although therapeutic hypothermia is the proven treatment for hypoxic-ischemic encephalopathy (HIE), it does not completely chang outcomes in severe forms of HIE. Therefore, there is a critical need for reviewing the effective therapeutic strategies to explore the protective agents and methods. In recent years, it is widely believed that there are neuroprotective possibilities of natural compounds extracted from plants against HIE. These natural agents with the anti-inflammatory, anti-oxidative, anti-apoptotic, and neurofunctional regulatory properties exhibit preventive or therapeutic effects against experimental neonatal HI brain damage. In this study, it was aimed to review the literature in scientific databases that investigate the neuroprotective effects of plant extracts/plant-derived compounds in experimental animal models of neonatal HI brain damage and their possible underlying molecular mechanisms of action.

Valproic acid alters nitric oxide status in neurulating mouse embryos.

The molecular bases of the teratogenic effects elicited by valproic acid (VPA) are not fully defined. It was previously shown that inhibition of nitric oxide (NO) synthesis is associated with an enhancement of the teratogenic effects of VPA, while amplification of NO signal by sildenafil prompted a dose-dependent reduction of VPA-induced neural tube defects. In this study, for the first time, the effect of VPA on the NO synthesis was evaluated in mouse embryos during early organogenesis. On gestation day 8, ICR-CD1 mice received 600 mg/kg of VPA. Eight and 24 h later embryos were collected and analyzed for NO synthase (NOS) isoform expression, and for molecular mechanisms involved in their modulation. As main finding, in utero embryonic exposure to VPA determined a time-dependent shift of NOS isoforms expression, with a down regulated expression and activity of constitutive NOS (cNOS) and an increased expression and activity of inducible NOS (iNOS). The teratological relevance of this information remains to be established.

Medicinal plants for diabetes associated neurodegenerative diseases: A systematic review of preclinical studies.

Diabetes mellitus is a metabolic defect with many complications for the patients. Deaths due to diabetes and its complications are increasing, and one of the most serious consequences are the neurological disorders. Chemical treatments have irreversible side effect and therefore the aim of this study is to evaluate the medicinal plants used for treatment of cognitive impairments and neurodegenerative diseases associated with diabetes in 2004-2020 period. Electronic databases used were PubMed, Scopus and Cochrane library. The keywords used were "diabetes," "plant," "herb," "neurodegenerative," "neurodegeneration," "cognitive," "cognition," "Alzheimer," "dementia." The non-English articles, repetitive articles and review studies were excluded. From total of 3,590 results, 58 articles are included in the study. The results show that many chemical treatments considered for this disease simply control hyperglycemia, but cannot improve the complications of diabetes. Herbal medicine could be more effective due to the high antioxidant activity of some medicinal plants. Biologically active substances of medicinal plants can improve the neurological disorders caused by diabetes via several pathways. The most important pathway is related to antioxidant properties. Other pathways include antiinflammatory, anti-apoptotic, neurotoxicity inhibition, neuronal death, increasing the uptake of glucose by cells and improve neurotransmitters levels involved in learning and memory.

Short ELF-EMF Exposure Targets SIRT1/Nrf2/HO-1 Signaling in THP-1 Cells.

Extremely low frequency electromagnetic fields (ELF-EMFs) have been known to modulate inflammatory responses by targeting signal transduction pathways and influencing cellular redox balance through the generation of oxidants and antioxidants. Here, we studied the molecular mechanism underlying the anti-oxidative effect of ELF-EMF in THP-1 cells, particularly with respect to antioxidant enzymes, such as heme oxygenase-1 (HO-1), regulated transcriptionally through nuclear factor E2-related factor 2 (Nrf2) activation. Cells treated with lipopolysaccharides (LPS) were exposed to a 50 Hz, 1 mT extremely low frequency electromagnetic fields for 1 h, 6 h and, 24 h. Our results indicate that ELF-EMF induced HO-1 mRNA and protein expression in LPS-treated THP-1 cells, with peak expression at 6 h, accompanied with a concomitant migration to the nucleus of a truncated HO-1 protein form. The immunostaining analysis further verified a nuclear enrichment of HO-1. Moreover, ELF-EMF inhibited the protein expressions of the sirtuin1 (SIRT1) and nuclear factor kappa B (NF-kB) pathways, confirming their anti-inflammatory/antioxidative role. Pretreatment with LY294002 (Akt inhibitor) and PD980559 (ERK inhibitor) inhibited LPS-induced Nrf2 nuclear translocation and HO-1 protein expression in ELF-EMF-exposed cells. Taken together, our results suggest that short ELF-EMF exposure exerts a protective role in THP-1 cells treated with an inflammatory/oxidative insult such as LPS, via the regulation of Nrf-2/HO-1 and SIRT1 /NF-kB pathways associated with intracellular glutathione (GSH) accumulation.

Irisin and Autophagy: First Update.

Aging and sedentary life style are considered independent risk factors for many disorders. Under these conditions, accumulation of dysfunctional and damaged cellular proteins and organelles occurs, resulting in a cellular degeneration and cell death. Autophagy is a conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This process is a part of the molecular underpinnings by which exercise promotes healthy aging and mitigate age-related pathologies. Irisin is a myokine released during physical activity and acts as a link between muscles and other tissues and organs. Its main beneficial function is the change of subcutaneous and visceral adipose tissue into brown adipose tissue, with a consequential increase in thermogenesis. Irisin modulates metabolic processes, acting on glucose homeostasis, reduces systemic inflammation, maintains the balance between resorption and bone formation, and regulates the functioning of the nervous system. Recently, some of its pleiotropic and favorable properties have been attributed to autophagy induction, posing irisin as an important regulator of autophagy by exercise. This review article proposes to bring together for the first time the "state of the art" knowledge regarding the effects of irisin and autophagy. Furthermore, treatments on relation between exercise/myokines and autophagy have been also achieved.

Attenuation of Nrf2/Keap1/ARE in Alzheimer's Disease by Plant Secondary Metabolites: A Mechanistic Review.

Alzheimer's disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.

Anti-Migratory Effects of 4'-Geranyloxyferulic Acid on LPS-Stimulated U937 and HCT116 Cells via MMP-9 Down-Regulation: Involvement of ROS/ERK Signaling Pathway.

Matrix metalloproteinases (MMPs) play a crucial role in tumor angiogenesis, and metastasis. 4'-geranyloxyferulic acid (GOFA) has anti-tumor and anti-inflammatory proprieties. Herein, we aimed to determine whether this compound affects cell survival, invasion, and migration through reactive oxygen species (ROS)-mediated MMPs activation of extracellular signal-regulated kinases (ERKs) and p38 signaling in lymphocytic histiocytoma (U937) and colorectal cancer (HCT116) cells. We observed that lipopolysaccharide (LPS) stimulated U937 and HCT116 cells presented abnormal cell proliferation and increased metalloproteinase (MMP-9) activity and expression. Non-cytotoxic doses of GOFA blunted matrix invasive potential by reducing LPS-induced MMP-9 expression and cell migration via inhibiting ROS/ ERK pathway. GOFA also attenuated apoptosis and cell senescence. Our findings indicate that GOFA, inhibiting cancer cell proliferation and migration, could be therapeutically beneficial to prevent tumor metastasis.

Erythropoietin induces miRNA-210 by JAK2/STAT5 signaling in PBMCs of End-stage Renal Disease patients.

Anemia of chronic kidney disease is associated with blunted response/resistance to erythropoietin-stimulating agents (ESAs) in hemodialysis (HD) patients. Several molecules have been successfully associated with ESA responsiveness; however, none of them is now considered a valid therapeutic biomarker of erythropoietin resistance in these patients. We performed an evaluation of the level of specific plasma circulating miRNAs in blood samples of HD patients, in relation to ESA treatment, with a follow-up of 1 year (T0-T3). We found significantly lower circulating levels of all miRNAs analyzed at baseline (T0) in HD patients vs. healthy control (HC). The plasmatic levels of miRNA-210 resulted significantly and negatively associated with Erythropoietin Resistance Index (ERI), and the variance of ΔmiRNA-210 (miRNA-210T3 minus miRNA-210T0 ) explained significant percentage of ΔERI (ERIT3 minus ERIT0 ) variance. The receiver operating characteristic analysis at T0 showed that the plasmatic level of miRNA-210 could distinguish HD patients with positive or negative trend in ERI at T3. In vitro, recombinant human erythropoietin (EPO) induced significant release of miRNA-210 from cultured peripheral blood mononuclear cells, through the activation of Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 5 (STAT5) signaling, but not by the activation of the MAPK protein 38α and extracellular signal-regulated kinase ½. Accordingly, HD patients with negative ΔERI showed higher level of phosphor-Janus kinase 2 and nuclear translocation of phosphor-signal transducer and activator of transcription 5. vs. patients with positive ΔERI or HC. Our data highlighted that chronic HD significantly reduces the circulating level of the miRNAs evaluated; within the targets analyzed, the miRNA-210 could be considered as a prognostic indicator of ESA responsiveness and index for anemia management.

Modulation of Apoptotic Cell Death and Neuroprotective Effects of Glutathione-L-Dopa Codrug Against H2O2-Induced Cellular Toxicity.

The L-3,4-dihydroxyphenylalanine (LD) is the gold standard drug currently used to manage Parkinson's disease (PD) and to control its symptoms. However, LD could cause disease neurotoxicity due to the generation of pro-oxidant intermediates deriving from its autoxidation. In order to overcome this limitation, we have conjugated LD to the natural antioxidant glutathione (GSH) to form a codrug (GSH-LD). Here we investigated the effect of GSH-LD on H2O2-induced cellular toxicity in undifferentiated and differentiated lymphoma U-937 and dopaminergic neuroblastoma SH-SY5Y cell lines, used respectively as models to study the involvement of macrophages/microglia and dopaminergic neurons in PD. We analyzed the effect of GSH-LD on apoptosis and cellular oxidative stress, both considered strategic targets for the prevention and treatment of neurodegenerative diseases. Compared to LD and GSH, GSH-LD had a stronger effect in preventing hydrogen peroxide (H2O2) induced apoptosis in both cell lines. Moreover, GSH-LD was able to preserve cell viability, cellular redox status, gluthation metabolism and prevent reactive oxygen species (ROS) formation, in a phosphinositide 3-kinase (PI3K)/kinase B (Akt)-dependent manner, in a neurotoxicity cellular model. Our findings indicate that the GSH-LD codrug offers advantages deriving from the additive effect of LD and GSH and it could represent a promising candidate for PD treatment.

Modulation of CAT-2B-Mediated l-Arginine Uptake and Nitric Oxide Biosynthesis in HCT116 Cell Line Through Biological Activity of 4'-Geranyloxyferulic Acid Extract from Quinoa Seeds.

Chenopodium quinoa Wild is a "pseudocereal" grain which attracts a lot of attention in the scientific community as it has a positive effect on health. Here, we investigate the presence of biologically active O-prenylated phenylpropanoids in the ethanol extract of commercially available quinoa seeds. We claim that 4'-Geranyloxyferulic acid (GOFA) was the only phytochemical product found that belongs to quinoa's group secondary metabolites. We studied the changes in the oxidative and inflammatory status of the cellular environment in HCT 116 cell line processed with quinoa extract and its component GOFA; the implementation was done through the analysis of the antioxidant enzymes (SOD and CAT), the pro-inflammatory components (iNOS, IL-6 and TNF-α), and the products of intermediary metabolism (ONOO-, O2-). Moreover, the l-arginine uptake was proposed as a target of the tested compounds. We demonstrated that the GOFA, through a decrease of the CAT-2B expression, leads to a reduction of the l-arginine uptake, downregulating the harmful iNOS and restoring the altered redox state. These results propose a new molecular target involved in the reduction of the critical inflammatory process responsible for the cancer progression.