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Manuela De Gregori,1–3 Inna Belfer,2,4 Roberto De Giorgio,5 Maurizio Marchesini,2,3,6 Carolina Muscoli,7 Mariangela Rondanelli,2,8 Daniela Martini,9 Pedro Mena,9 Laura Isabel Arranz,2,10 Silvia Lorente-Cebrián,2,11 Simone Perna,8 Anna Villarini,12 Maurizio Salamone,2,13,14 Massimo Allegri,2,15 Michael E Schatman2,16,17 1 Pain Therapy Service, Fondazione IRCCS Polclinico San Matteo, Pavia, Italy; 2Study in Multidisciplinary Pain Research Group, Parma, Italy; 3Young Against Pain Group, Parma, Italy; 4Faculty of Dentistry, McGill University, Montreal, QC, Canada; 5Department of Clinical Sciences, Nuovo Arcispedale S. Anna, University of Ferrara, Ferrara, Italy; 6Anesthesia, Intensive Care and Pain Therapy Service, Azienda Ospedaliero, Universitaria of Parma, Parma, Italy; 7Department of Health Sciences, Institute of Research for Food Safety and Health, University “Magna Graecia” of Catanzaro, Parma, Italy; 8Department of Public Health, Section of Human Nutrition and Dietetics, Azienda di Servizi alla Persona di Pavia, University of Pavia, Pavia, Italy; 9Human Nutrition Unit, Department of Food & Drugs, University of Parma, Parma, Italy; 10Department of Nutrition, Food Sciences and Gastronomy, University of Barcelona, Barcelona, Spain; 11Department of Nutrition, Food Science and Physiology, Faculty of Pharmacy, Center for Nutrition Research, University of Navarra, Pamplona, Spain; 12Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 13Science department, Metagenics Italia srl, Milano, Italy; 14Società internazionale di Neuropsicocardiologia, Trapani, Italy; 15Anesthesia and Intensive Care Service – IRCCS MultiMedica Hospital, Sesto San Giovanni, Milano, Italy; 16Research and Network Development, Boston Pain Care, Waltham, MA, USA; 17Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA Abstract: This review is aimed to summarize the latest data regarding pain and nutrition, which have emerged during the second edition of Feed Your Destiny (FYD). Theme presentations and interactive discussions were held at a workshop on March 30, 2017, in Florence, Italy, during the 9th Annual Meeting of Study in Multidisciplinary Pain Research, where an international faculty, including recognized experts in nutrition and pain, reported the scientific evidence on this topic from various perspectives. Presentations were divided into two sections. In the initial sessions, we analyzed the outcome variables and methods of measurement for health claims pertaining to pain proposed under Regulation EC No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Moreover, we evaluated how the Mediterranean diet can have a potential impact on pain, gastrointestinal disorders, obesity, cancer, and aging. Second, we discussed the evidence regarding vitamin D as a nutraceutical that may contribute to pain control, evaluating the interindividual variability of pain nature and nurture, and the role of micro-RNAs (miRNAs), polyunsaturated omega 3 fatty acids, and phenolic compounds, with a final revision of the clinical role of nutrition in tailoring pain therapy. The key take-home message provided by the FYD workshop was that a balanced, personalized nutritional regimen might play a role as a synergic strategy that can improve management of chronic pain through a precision medicine approach. Keywords: chronic pain, multidisciplinary pain management, personalized nutrition, nutritional supplements

Manuela De Gregori,1–3 Carolina Muscoli,2,4,5 Michael E Schatman,2,6 Tiziana Stallone,2,7 Fabio Intelligente,2,8 Mariangela Rondanelli,2,9 Francesco Franceschi,2,10 Laura Isabel Arranz,2,11 Silvia Lorente-Cebrián,2,12 Maurizio Salamone,2,13,14 Sara Ilari,2,5 Inna Belfer,2,15 Massimo Allegri2,16,17 1Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2Study in Multidisciplinary Pain Research Group, 3Young Against Pain Group, Parma, Italy; 4Department of Health Sciences, Institute of Research for Food Safety and Health, University “Magna Graecia” of Catanzaro, Parma, Italy; 5IRCCS San Raffaele Pisana, Roccelletta di Borgia, Catanzaro, Italy; 6US Pain Foundation, Bellevue, WA, USA; 7ENPAB, Rome, 8Chronic Pain Service Anestesia Day-Surgery, IRCCS Humanitas Research Hospital, Rozzano, 9Department of Public Health, Section of Human Nutrition and Dietetics, Azienda di Servizi alla Persona di Pavia, University of Pavia, Pavia, 10Institute of Internal Medicine, Catholic University of Rome, Rome, Italy; 11Department of Nutrition, Food Sciences and Gastronomy, University of Barcelona, Barcelona, 12Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, Spain; 13Metagenics Italia srl, Milano, 14Italian Lifestyle Medicine Association, Bari, Italy; 15Faculty of Dentistry, McGill University, Montreal, QC, Canada; 16Department of Surgical Sciences, University of Parma, 17Anesthesia, Intensive Care and Pain Therapy Service, Azienda Ospedaliero, Universitaria of Parma, Parma, Italy Abstract: Recently, attention to the lifestyle of patients has been rapidly increasing in the field of pain therapy, particularly with regard to the role of nutrition in pain development and its management. In this review, we summarize the latest findings on the role of nutrition and nutraceuticals, microbiome, obesity, soy, omega-3 fatty acids, and curcumin supplementation as key elements in modulating the efficacy of analgesic treatments, including opioids. These main topics were addressed during the first edition of the Study In Multidisciplinary Pain Research workshop: “FYD (Feed Your Destiny): Fighting Pain”, held on April 7, 2016, in Rome, Italy, which was sponsored by a grant from the Italian Ministry of Instruction on “Nutraceuticals and Innovative Pharmacology”. The take-home message of this workshop was the recognition that patients with chronic pain should undergo nutritional assessment and counseling, which should be initiated at the onset of treatment. Some foods and supplements used in personalized treatment will likely improve clinical outcomes of analgesic therapy and result in considerable improvement of patient compliance and quality of life. From our current perspective, the potential benefit of including nutrition in personalizing pain medicine is formidable and highly promising. Keywords: pain, personalized nutrition, nutritional supplements

Carmelo Gigliuto,1 Manuela De Gregori,2 Valentina Malafoglia,3 William Raffaeli,3 Christian Compagnone,4 Livia Visai,5,6 Paola Petrini,7 Maria Antonietta Avanzini,9 Carolina Muscoli,8 Jacopo Viganò,11 Francesco Calabrese,11 Tommaso Dominioni,11 Massimo Allegri,2,10 Lorenzo Cobianchi111Anaesthesia and Intensive Care, University of Pavia, Pavia, 2Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, 3ISAL Foundation, Institute for Research on Pain, Torre Pedrera, Rimini, 4Department of Anaesthesia, Intensive Care and Pain Therapy, Azienda Ospedaliera Universitaria Parma, University of Parma, Parma, 5Department of Molecular Medicine, Center for Tissue Engineering (CIT), INSTM UdR of Pavia, University of Pavia, Pavia, 6Department of Occupational Medicine, Ergonomy and Disability, Laboratory of Nanotechnology, Salvatore Maugeri Foundation, IRCCS, Veruno, 7Dipartimento di Chimica, Materiali e Ingegneria Chimica 'G Natta' and Unità di Ricerca Consorzio INSTM, Politecnico di Milano, Milan, 8Department of Health Science, University Magna Grecia of Catanzaro and Centro del Farmaco, IRCCS San Raffaele Pisana, Roma, 9Laboratory of Transplant Immunology/Cell Factory, Fondazione IRCCS Policlinico "San Matteo", Pavia, 10Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, 11University of Pavia, Department of Surgical, Clinical, Paediatric and Diagnostic Science, General Surgery 1, IRCCS Fondazione Policlinico San Matteo, Pavia, ItalyAbstract: In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals.Keywords: pain assessment, experimental model, translational research

Abstract Background Oxidative stress plays a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV-1) infection causing apoptosis of astroglia cells and neurons. Recent data have shown that oxidative stress is also responsible for the acceleration of human fibroblast telomere shortening in vitro. In the present study we analyzed the potential relations occurring between free radicals formation and telomere length during HIV-1 mediated astroglial death. Results To this end, U373 human astrocytoma cells have been directly exposed to X4-using HIV-1IIIB strain, for 1, 3 or 5 days and treated (where requested) with N-acetylcysteine (NAC), a cysteine donor involved in the synthesis of glutathione (GSH, a cellular antioxidant) and apoptosis has been evaluated by FACS analysis. Quantitative-FISH (Q-FISH) has been employed for studying the telomere length while intracellular reduced/oxidized glutathione (GSH/GSSG) ratio has been determined by High-Performance Liquid Chromatography (HPLC). Incubation of U373 with HIV-1IIIB led to significant induction of cellular apoptosis that was reduced in the presence of 1 mM NAC. Moreover, NAC improved the GSH/GSSG, a sensitive indicator of oxidative stress, that significantly decreased after HIV-1IIIB exposure in U373. Analysis of telomere length in HIV-1 exposed U373 showed a statistically significant telomere shortening, that was completely reverted in NAC-treated U373. Conclusion Our results support the role of HIV-1-mediated oxidative stress in astrocytic death and the importance of antioxidant compounds in preventing these cellular damages. Moreover, these data indicate that the telomere structure, target for oxidative damage, could be the key sensor of cell apoptosis induced by oxidative stress after HIV infection.

Abstract Background HIV envelope gp 120 glycoprotein is released during active HIV infection of brain macrophages thereby generating inflammation and oxidative stress which contribute to the development of the AIDS-Dementia Complex (ADC). Gp120 has also been found capable to generate excitotoxic effect on brain tissue via enhancement of glutamatergic neurotransmission, leading to neuronal and astroglial damage, though the mechanism is still to be better understood. Here we investigated on the effect of N-acetylcysteine (NAC), on gp120-induced damage in human cultured astroglial cells and the possible contribution of gp120-related reacting oxygen species (ROS) in the imbalanced activity of glutamine synthase (GS), the enzyme that metabolizes glutamate into glutamine within astroglial cells playing a neuroprotective role in brain disorders. Results Incubation of Lipari human cultured astroglial cells with gp 120 (0.1–10 nM) produced a significant reduction of astroglial cell viability and apoptosis as evaluated by TUNEL reaction and flow cytometric analysis (FACS). This effect was accompanied by lipid peroxidation as detected by means of malondialdehyde assay (MDA). In addition, gp 120 reduced both glutamine concentration in astroglial cell supernatants and GS expression as detected by immunocytochemistry and western blotting analysis. Pre-treatment of cells with NAC (0.5–5 mM), dose-dependently antagonised astroglial apoptotic cell death induced by gp 120, an effect accompanied by significant attenuation of MDA accumulation. Furthermore, both effects were closely associated with a significant recovery of glutamine levels in cell supernatants and by GS expression, thus suggesting that overproduction of free radicals might contribute in gp 120-related dysfunction of GS in astroglial cells. Conclusion In conclusion, the present experiments demonstrate that gp 120 is toxic to astroglial cells, an effect accompanied by lipid peroxidation and by altered glutamine release. All the effects of gp120 on astroglial cells were counteracted by NAC thus suggesting a novel and potentially useful approach in the treatment of glutammatergic disorders found in HAD patients.

Abstract Background Monocytes/Macrophages (M/M) play a pivotal role as a source of virus during the whole course of HIV-1 infection. Enhanced oxidative stress is involved in the pathogenesis of HIV-1 infection. HIV-1 regulatory proteins induce a reduction of the expression and the activity of MnSOD, the mitochondrial isoform leading to a sustained generation of superoxide anions and peroxynitrite that represent important mediators of HIV-1 replication in M/M. MnTBAP (Mn(III)tetrakis(4-benzoic acid)porphrin chloride), a synthetic peroxynitrite decomposition catalyst, reduced oxidative stress subsequent to peroxynitrite generation. Results Virus production was assessed by p24 ELISA, western blot, and electron microscopy during treatment with MnTBAP. MnTBAP treatment showed a reduction of HIV-1 replication in both acutely and chronically infected M/M: 99% and 90% inhibition of p24 released in supernatants compared to controls, respectively. Maturation of p55 and p24 was strongly inhibited by MnTBAP in both acutely and chronically infected M/M. EC50 and EC90 are 3.7 (± 0.05) μM and 19.5 (± 0.5) μM, in acutely infected M/M; 6.3 (± 0.003) μM and 30 (± 0.6) μM, in chronically infected M/M. In acutely infected peripheral blood limphocytes (PBL), EC50 and EC90 are 7.4 (± 0.06) μM and of 21.3 (± 0.6) μM, respectively. Treatment of acutely-infected M/M with MnTBAP inhibited the elevated levels of malonildialdehyde (MDA) together with the nitrotyrosine staining observed during HIV-1 replication. MnTBAP strongly reduced HIV-1 particles in infected M/M, as shown by electron microscopy. Moreover, in presence of MnTBAP, HIV-1 infectivity was reduced of about 1 log compared to control. Conclusion Results support the role of superoxide anions in HIV-1 replication in M/M and suggest that MnTBAP may counteract HIV-1 replication in combination with other antiretroviral treatments.

Abstract Background Oxidative stress has shown to contribute in the mechanisms underlying apoptotic cell death occuring in AIDS-dementia complex. Here we investigated the role of peroxynitrite in apoptosis occurring in astroglial cells incubated with supernatants of HIV-infected human primary macrophages (M/M). Results Flow cytometric analysis (FACS) of human cultured astrocytes shortly incubated with HIV-1-infected M/M supernatants showed apoptotic cell death, an effect accompanied by pronounced staining for nitrotyrosine (footprint of peroxynitrite) and by abnormal formation of malondialdehyde (MDA). Pretreatment of astrocytes with the peroxynitrite decomposition catalyst FeTMPS antagonized HIV-related astrocytic apoptosis, MDA formation and nitrotyrosine staining. Conclusions Taken together, our results suggest that inibition of peroxynitrite leads to protection against peroxidative stress accompanying HIV-related apoptosis of astrocytes. Overall results support the role of peroxynitrite in HIV-related programmed death of astrocytes and suggest the use of peroxynitrite decomposition catalyst to counteract HIV-1-related neurological disorders.

Introduction: Microbiota, composed of micro-organisms like bacteria, viruses, and non-pathogenic fungi, plays a crucial role in digestion, vitamin production, and protection against dangerous microbes. Several factors, including age, diet, alcohol consumption, stress, environmental microorganisms, and therapies (particularly antibiotics), as well as birth and nursing, could modify the microbiota. Recent research has highlighted its alteration and involvement in a various disease, including metabolic syndrome and acne. This systematic review aimed to identify common biomarkers and microbiota alterations shared between metabolic syndrome and acne, and to explore how the potential prebiotic activities of polyphenols may promote intestinal eubiosis. Materials and methods: A comprehensive search in PubMed and EMBASE resulted in 4142 articles, from which nine studies were selected based on specific criteria after removing duplicates and reviewing abstracts and full texts. All studies correlated the microbiota alteration in both pathologies and the activity of polyphenols in metabolic syndrome. Results: This review suggests that acne may be influenced by some of the same microorganisms involved in metabolic syndrome. While the literature highlights the effectiveness of polyphenols in treating metabolic syndrome, no studies have yet demonstrated their specific impact on acne. Conclusions: The research points to the potential benefits of polyphenols in modulating the microbiota, which could be relevant for individuals with metabolic syndrome. However, due to the limited data available, it was not possible to establish a direct correlation between metabolic syndrome and acne.

Peri-menopausal discomfort can have a detrimental effect on the physical health of women due to physiological and behavioral changes. Estrogen and progesterone-based hormone therapy can alleviate menopausal symptoms, but estrogen supplementation may have negative health effects. The effectiveness of hormone replacement therapy using natural compounds for peri-menopausal disorders is still uncertain. Evidence from in vivo experiments indicates that Ferula L. extract in ovariectomized rats leads to better sexual behavior. The effect seems to be linked to the phytoestrogenic properties of ferutinin, the primary bioactive compound in the extract. The purpose of this study was to assess the clinical impact of Ferula communis L. extract (titrated at 20% ferutinin, and given at doses of 100 mg/die for 90 days) on the quality of life of 64 menopausal women. The clinical trial was randomized, double-blind, and placebo controlled. Our data showed that Ferula communis L. extract reduced by 67 + 9% all symptoms associated to postmenopausal discomfort and enhanced significantly sexual behavior. In addition, the supplement led to a significant improvement of BMI and oxidative stress decrease in the women who received it, while also keeping platelet aggregation within normal levels. Overall, these results could point to the potential use of supplementation with Ferula communis L. extract to revert or mitigate menopause dysfunction.

Whole-body vibration (WBV) has been employed for performance-enhancing purposes. WBV may positively affect muscular endurance and its underlying neural mechanisms due to an enhanced muscular blood circulation and oxygen uptake. However, the effects of WBV on endurance-related torque signal complexity have been understudied. This study aims to investigate the acute effects of WBV on i) maximal isometric torque production; ii) isometric knee extensors fatigability and iii) torque signal complexity during an isometric endurance task. Thirty adult males performed an isometric intermittent endurance protocol on their dominant lower limb after performing: static half squat with WBV (WBV), static half squat without WBV (HS), and no exercise protocol (CC). For each repetition the maximal torque was identified. The maximal torque of the first repetition was identified as the PeakT. The Mean torque (MTorque) and fatigue index (pFatigue) were calculated as the mean and the percentage decay in torque across the entire set of eighteen repetitions (MTorque 0-100 % , pFatigue 0-100 % ), and across shorter blocks of six repetitions (MTorque 0-33 % , pFatigue 0-33 % ; MTorque 34-66 % , pFatigue 34-66 % , and MTorque 67-100 % , pFatigue 67-100 % ). Torque fluctuations were analysed computing Sample Entropy (SampEn) and the coefficient of variation (CV). PeakT was significantly higher in CC than in WBV (p < 0.01) and in HS (p < 0.01). PeakT was significantly higher in HS than in WB (p < 0.05). MTorque 0-100 % , MTorque 0-33 % , MTorque 34-66 %, and MTorque 67-100 % were significantly higher in CC than in WBV (all p-values <0.01) and in HS (p < 0.01). MTorque 67-100 % was significantly higher in HS than in WB (p = 0.049). pFatigue 34-66 % was significantly higher in WBV than in CC (p < 0.05) whereas pFatigue 67-100 % was significantly higher in CC than in WB (p < 0.01) and in HS (p < 0.01). No effect of condition was observed for SampEn and CV. Acute WBV does not lead to beneficial effects on maximal torque production and isometric knee extensors fatigability. These acute detrimental effects may be related to long-term WBV-related adaptations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Morphine is an important pain reliever employed in pain management, its extended utilize is hindered by the onset of analgesic tolerance and oxidative stress. Long-term morphine administration causes elevated production of reactive oxygen species (ROS), disrupting mitochondrial function and inducing oxidation. Sirtuin 3 (SIRT3), a mitochondrial protein, is essential in modulating ROS levels by regulating mitochondrial antioxidant enzymes as manganese superoxide dismutase (MnSOD). Our investigation focused on the impact of SIRT3 on hyperalgesia and morphine tolerance in mice, as evaluating the antioxidant effect of the polyphenolic fraction of bergamot (BPF). Mice were administered morphine twice daily for four consecutive days (20 mg/kg). On the fifth day, mice received an acute dose of morphine (3 mg/kg), either alone or in conjunction with BPF or Mn (III)tetrakis (4-benzoic acid) porphyrin (MnTBAP). We evaluated levels of malondialdehyde (MDA), nitration, and the activity of SIRT3, MnSOD, glutamine synthetase (GS), and glutamate 1 transporter (GLT1) in the spinal cord. Our findings demonstrate that administering repeated doses of morphine led to the development of antinociceptive tolerance in mice, accompanied by increased superoxide production, nitration, and inactivation of mitochondrial SIRT3, MnSOD, GS, and GLT1. The combined administration of morphine with either BPF or MnTBAP prevented these effects.

Adhering to a healthy diet has a protective effect on human health, including a decrease in inflammatory diseases due to consuming fiber. The purpose of this manuscript was to obtain and compare two extracts based on fiber (BF and IF-C), derived from two plants particularly present in the Mediterranean region: bergamot ( Citrus bergamia ) and prickly pear ( Opuntia ficus-indica ). The parts used by these plants have been the "pastazzo" for the bergamot and the cladodes for the prickly pear. In addition to in vitro evaluations, the antioxidant activity was also measured on human neurons under inflammatory conditions. Furthermore, the extracts of interest were examined for their effects on the cell cycle and the regulation of pro-apoptotic proteins, caspase 9 and 3, induced by LPS. The results indicated that both extracts had a protective effect against LPS-induced damage, with BF consistently exhibiting superior functionality compared to IF-C. Moreover, the extracts can reduce inflammation, which is a common process of disease. By exploring this avenue, studying the consumption of dietary fiber could enhance our understanding of its positive effects, but additional experiments are needed to confirm this.

The gut microbiota is a diverse bacterial community consisting of approximately 2000 species, predominantly from five phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. The microbiota's bacterial species create distinct compounds that impact the host's health, including well-known short-chain fatty acids. These are produced through the breakdown of dietary fibers and fermentation of undigested carbohydrates by the intestinal microbiota. The main short-chain fatty acids consist of acetate, propionate, and butyrate. The concentration of butyrate in mammalian intestines varies depending on the diet. Its main functions are use as an energy source, cell differentiation, reduction in the inflammatory process in the intestine, and defense against oxidative stress. It also plays an epigenetic role in histone deacetylases, thus helping to reduce the risk of colon cancer. Finally, butyrate affects the gut-brain axis by crossing the brain-blood barrier, making it crucial to determine the right concentrations for both local and peripheral effects. In recent years, there has been a significant amount of attention given to the role of dietary polyphenols and fibers in promoting human health. Polyphenols and dietary fibers both play crucial roles in protecting human health and can produce butyrate through gut microbiota fermentation. This paper aims to summarize information on the key summits related to the negative correlation between intestinal microbiota diversity and chronic diseases to guide future research on determining the specific activity of butyrate from polyphenols and dietary fibers that can carry out these vital functions.

Opuntia ficus-indica (L.) Mill. belongs to the Cactaceae family and the genus Opuntia; it is a succulent plant that adapts to extreme climatic conditions. The aerial part of the plant consists of the cladodes, morphological changes of branches that appear green, are covered with thorns, and are essential to reduce excessive perspiration of water. The composition of cladodes is very varied, and the main constituents are water, fibers, polysaccharides, proteins, fatty acids, vitamins, sterols, minerals, and polyphenols. Polyphenols are responsible for many beneficial activities for human health, such as antioxidant, anti-inflammatory, anticancer, and nutritional properties. The purpose of this manuscript was to compare the properties of cladodes belonging to the same plant but with different stages of maturity. Relative extracts were tested both in vitro and on a cell line and antioxidant and anti-apoptotic properties were found. The antioxidant activity was tested by the Oxygen Radical Absorbance Capacity (ORAC) test, the 1,1-diphenyl-2-picrylhydrazil (DPPH) test, and the measurement of cellular accumulation of reactive oxygen species (ROS). Anti-apoptotic activity was evaluated by the annexin/PI assay and measurement of caspases 9 and 3 expression. The results obtained showed that the extracts considered possess antioxidant and anti-apoptotic properties. However, the different stages of maturity of cladodes are essential for the performance of both functions. In addition, important variations were made in the dissolution of the extracts that brought greater safety in their use. In conclusion, this manuscript provides further information on cladodes of Opuntia ficus-indica , which can be used as adjuvants in many human pathologies.

Opuntia ficus-indica (L.) Miller is a plant belonging to the Cactaceae family adapted to live in environments characterized by long periods of drought and arid or desert climates. This plant is characterized by an aerial part composed of structures transformed by branches, called "cladodes", which are essential to reduce excessive perspiration of water and appear covered with thorns. The composition of the cladodes includes water, polysaccharides, fiber, proteins, vitamins, fatty acids, sterols, polyphenols, and minerals. The main purposes of this scientific work are (a) to compare the insoluble fiber (IF) extracted from the cladodes of O. ficus-indica belonging to the same plant but collected in different seasonal periods (winter and summer) and develop new extraction protocols that are able to improve the yield obtained and (b) evaluate the antioxidant potential of the fiber and study possible variations as a result of the extraction protocol chosen. The first objective was achieved (1) by measuring the amount of IF extracted from cladodes harvested in winter and summer (CW and CS, respectively) and (2) by modifying three variables involved in the fiber extraction protocol. To achieve the second objective, the following experiments were carried out: (1) measurement of the antioxidant potential of IF in CW and CS; (2) measurement of cellular reactive oxygen species; (3) measurement of the activity of some antioxidant enzymes; and (4) comparison of the polyphenol content in CW and CS. In conclusion, the results obtained showed that the IF extraction process can be improved, achieving a uniform yield regardless of seasonality; the antioxidant effect may vary depending on the extraction protocol.

Arterial hypertension represents a leading cause of cardiovascular morbidity and mortality worldwide, and the identification of effective solutions for treating the early stages of elevated blood pressure (BP) is still a relevant issue for cardiovascular risk prevention. The pathophysiological basis for the occurrence of elevated BP and the onset of arterial hypertension have been widely studied in recent years. In addition, consistent progress in the development of novel, powerful, antihypertensive drugs and their appropriate applications in controlling BP have increased our potential for successfully managing disease states characterized by abnormal blood pressure. However, the mechanisms responsible for the disruption of endogenous mechanisms contributing to the maintenance of BP within a normal range are yet to be fully clarified. Recently, evidence has shown that several natural antioxidants containing active ingredients originating from natural plant extracts, used alone or in combination, may represent a valid solution for counteracting the development of arterial hypertension. In particular, there is evidence to show that natural antioxidants may enhance the viability of endothelial cells undergoing oxidative damage, an effect that could play a crucial role in the pathophysiological events accompanying the early stages of arterial hypertension. The present review aims to reassess the role of oxidative stress on endothelial dysfunction in the onset and progression of arterial hypertension and that of natural antioxidants in covering several unmet needs in the treatment of such diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Caminiti, Carresi, Mollace, Macrì, Scarano, Oppedisano, Maiuolo, Serra, Ruga, Nucera, Tavernese, Gliozzi, Musolino, Palma, Muscoli, Rubattu, Volterrani, Federici, Volpe and Mollace.)

To date, the complex pathological interactions between renal and cardiovascular systems represent a real global epidemic in both developed and developing countries. In this context, renovascular hypertension (RVH) remains among the most prevalent, but also potentially reversible, risk factor for numerous reno-cardiac diseases in humans and pets. Here, we investigated the anti-inflammatory and reno-cardiac protective effects of a polyphenol-rich fraction of bergamot (BPF) in an experimental model of hypertension induced by unilateral renal artery ligation. Adult male Wistar rats underwent unilateral renal artery ligation and treatment with deoxycorticosterone acetate (DOCA) (20 mg/kg, s.c.), twice a week for a period of 4 weeks, and 1% sodium chloride (NaCl) water (n = 10). A subgroup of hypertensive rats received BPF (100 mg/kg/day for 28 consecutive days, n = 10) by gavage. Another group of animals was treated with a sub-cutaneous injection of vehicle (that served as control, n = 8). Unilateral renal artery ligation followed by treatment with DOCA and 1% NaCl water resulted in a significant increase in mean arterial blood pressure (MAP; p< 0.05. vs CTRL) which strongly increased the resistive index (RI; p<0.05 vs CTRL) of contralateral renal artery flow and kidney volume after 4 weeks (p<0.001 vs CTRL). Renal dysfunction also led to a dysfunction of cardiac tissue strain associated with overt dyssynchrony in cardiac wall motion when compared to CTRL group, as shown by the increased time-to-peak (T2P; p<0.05) and the decreased whole peak capacity (Pk; p<0.01) in displacement and strain rate (p<0.05, respectively) in longitudinal motion. Consequently, the hearts of RAL DOCA-Salt rats showed a larger time delay between the fastest and the lowest region (Maximum Opposite Wall Delay-MOWD) when compared to CTRL group (p<0.05 in displacement and p <0.01 in strain rate). Furthermore, a significant increase in the levels of the circulating pro-inflammatory cytokines and chemokines (p< 0.05 for IL-12(40), p< 0.01 for GM-CSF, KC, IL-13, and TNF- α) and in the NGAL expression of the ligated kidney (p< 0.001) was observed compared to CTRL group. Interestingly, this pathological condition is prevented by BPF treatment. In particular, BPF treatment prevents the increase of blood pressure in RAL DOCA-Salt rats (p< 0.05) and exerts a protective effect on the volume of the contralateral kidney (p <0.01). Moreover, BPF ameliorates cardiac tissue strain dysfunction by increasing Pk in displacement (p <0.01) and reducing the T2P in strain rate motion (p<0.05). These latter effects significantly improve MOWD (p <0.05) preventing the overt dyssynchrony in cardiac wall motion. Finally, the reno-cardiac protective effect of BPF was associated with a significant reduction in serum level of some pro-inflammatory cytokines and chemokines (p<0.05 for KC and IL-12(40), p<0.01 for GM-CSF, IL-13, and TNF- α) restoring physiological levels of renal neutrophil gelatinase-associated lipocalin (NGAL, p<0.05) protein of the tethered kidney. In conclusion, the present results show, for the first time, that BPF promotes an efficient renovascular protection preventing the progression of inflammation and reno-cardiac damage. Overall, these data point to a potential clinical and veterinary role of dietary supplementation with the polyphenol-rich fraction of citrus bergamot in counteracting hypertension-induced reno-cardiac syndrome., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Vincenzo Mollace reports financial support was provided by Italian Ministry of Research. Prof. Vincenzo Mollace reports financial support was provided by Region of Calabria., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)