Exploitation of Natural By-Products for the Promotion of Healthy Outcomes in Humans: Special Focus on Antioxidant and Anti-Inflammatory Mechanisms and Modulation of the Gut Microbiota.

Daily, a lot of food is wasted, and vegetables, fruit, and cereals as well as marine products represent the major sources of unwanted by-products. The sustainability, waste recovery, and revalorization of food by-products have been proposed as the main goals of the so-called circular economy. In fact, food wastes are enriched in by-products endowed with beneficial effects on human health. Grape, olives, vegetables, and rice contain different compounds, such as polyphenols, dietary fibers, polysaccharides, vitamins, and proteins, which exert antioxidant and anti-inflammatory activities, inhibiting pro-oxidant genes and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kß) pathway, as demonstrated by in vitro and in vivo experiments. Dietary fibers act upon the gut microbiota, expanding beneficial bacteria, which contribute to healthy outcomes. Furthermore, marine foods, even including microalgae, arthropods, and wastes of fish, are rich in carotenoids, polyphenols, polyunsaturated fatty acids, proteins, and chitooligosaccharides, which afford antioxidant and anti-inflammatory protection. The present review will cover the major by-products derived from food wastes, describing the mechanisms of action involved in the antioxidant and anti-inflammatory activities, as well as the modulation of the gut microbiota. The effects of some by-products have also been explored in clinical trials, while others, such as marine by-products, need more investigation for their full exploitation as bioactive compounds in humans.

Biomolecular Actions by Intestinal Endotoxemia in Metabolic Syndrome.

Metabolic syndrome (MetS) is a combination of metabolic disorders that concurrently act as factors promoting systemic pathologies such as atherosclerosis or diabetes mellitus. It is now believed to encompass six main interacting conditions: visceral fat, imbalance of lipids (dyslipidemia), hypertension, insulin resistance (with or without impairing both glucose tolerance and fasting blood sugar), and inflammation. In the last 10 years, there has been a progressive interest through scientific research investigations conducted in the field of metabolomics, confirming a trend to evaluate the role of the metabolome, particularly the intestinal one. The intestinal microbiota (IM) is crucial due to the diversity of microorganisms and their abundance. Consequently, IM dysbiosis and its derivate toxic metabolites have been correlated with MetS. By intervening in these two factors (dysbiosis and consequently the metabolome), we can potentially prevent or slow down the clinical effects of the MetS process. This, in turn, may mitigate dysregulations of intestinal microbiota axes, such as the lung axis, thereby potentially alleviating the negative impact on respiratory pathology, such as the chronic obstructive pulmonary disease. However, the biomolecular mechanisms through which the IM influences the host's metabolism via a dysbiosis metabolome in both normal and pathological conditions are still unclear. In this study, we seek to provide a description of the knowledge to date of the IM and its metabolome and the factors that influence it. Furthermore, we analyze the interactions between the functions of the IM and the pathophysiology of major metabolic diseases via local and systemic metabolome's relate endotoxemia.

Current Views About the Link between SARS-CoV-2 and the Liver: Friends or Foe?

The emergence of the novel coronavirus and the pandemic resulting from its spread have led to significant negative impacts on health, economy, relationships, and others. Particularly in the field of hospital care, the need for a greater number of patients has led to a breakdown of the system. Gastrointestinal manifestations are common in SARS-COV 2 patients, while 10% of those who are sick exhibit symptoms only from gastrointestinal without any manifestation on the part of the respiratory tract. The main manifestations are nausea, vomiting, diarrhoea, and anorexia. It is also interesting to note that biochemical liver disorder is a frequent finding and is associated with a worse prognosis and higher probability admission to intensive care. It was also observed that RNA from the virus was found in the stool several days after the tests came back negative pulmonary secretions, while rectal swab virus detection methods were used with a lower but comparable sensitivity to that of nasal swabs. Gastrointestinal symptoms in SARS-COV 2 infection are common and their search should be part of the initial diagnosis approach and have a connection with the gut microbiota dysbiosis and this can lead to an alteration of the gut/liver axis.

Microenvironmental stress drives tumor cell maladaptation and malignancy through regulation of mitochondrial and nuclear cytochrome c oxidase subunits.

After decades of focus on molecular genetics in cancer research, the role of metabolic and environmental factors is being reassessed. Here, we investigated the role of microenvironment in the promotion of malignant behavior in tumor cells with a different reliance on oxidative phosphorylation (OXPHOS) versus lactic acid fermentation/Warburg effect. To this end, we evaluated the effects of microenvironmental challenges (hypoxia, acidity, and high glucose) on the expression of mitochondrial-encoded cytochrome c oxidase 1 (COX I) and two nuclear-encoded isoforms 4 (COX IV-1 and COX IV-2). We have shown that tumor cells with an "OXPHOS phenotype" respond to hypoxia by upregulating COX IV-1, whereas cells that rely on lactic acid fermentation maximized COX IV-2 expression. Acidity upregulates COX IV-2 regardless of the metabolic state of the cell, whereas high glucose stimulates the expression of COX I and COX IV-1, with a stronger effect in fermenting cells. Our results uncover that "energy phenotype" of tumor cells drives their adaptive response to microenvironment stress.NEW & NOTEWORTHY How microenvironmental stress (hypoxia, acidity, and high glucose) supports tumor growth has not yet been fully elucidated. Here, we demonstrated that these stressors promote malignancy by controlling the expression of cytochrome c oxidase I (COX I), and COX IV-1 and COX IV-2 based on the "energy phenotype" of cancer cells (OXPHOS vs. fermentation). Our results uncover a novel process by which the "energy phenotype" of cancer cells drives the adaptive response to microenvironment stress.

Update on COVID-19 and Effectiveness of a Vaccination Campaign in a Global Context.

The COVID-19 pandemic caused by SARS-CoV-2 remains a significant issue for global health, the economy, and society. When SARS-CoV-2 began to spread, the most recent serious infectious disease of this century around the world, with its high morbidity and mortality rates, it is understandable why such infections have generally been spread in the past, mainly from international travel movements. This perspective review aimed to provide an update for clinicians on the recent developments related to the microbiological perspectives in pandemics, diagnostics, prevention (such as the spread of a virus), vaccination campaigns, treatment options, and health consequences for COVID-19 based on the current literature. In this way, the authors attempt to raise awareness on the transversal nature of these challenges by identifying the main risk/vulnerability factors that the scientific community must face including our current knowledge on the virus capacity of the mechanism of entry into the cells, the current classifications of viral variants, the knowledge of the mathematical model on the spread of viruses (the possible routes of transmission), and the effectiveness of vaccination campaigns in a global context of pandemic, particularly from COVID-19, with a look at new or future vaccines.

Treatment of liver cancer cells with ethyl acetate extract of Crithmum maritimum permits reducing sorafenib dose and toxicity maintaining its efficacy.

OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most frequent tumours worldwide and available drugs are inadequate for therapeutic results and tolerability. Hence, novel effective therapeutic tools with fewer side effects are of paramount importance. We have previously shown that Crithmum maritimum ethyl acetate extract exerts a cytostatic effect in HCC cells. Here, we tested whether C. maritimum ethyl acetate extract in combination with half sorafenib IC50 dose ameliorated efficacy and toxicity of sorafenib in inhibiting liver cancer cell growth. Moreover, we investigated the mechanisms involved. METHODS: Two HCC cell lines (Huh7 and HepG2) were treated with C. maritimum ethyl acetate extract and half IC50 sorafenib dose usually employed in vitro. Then, cell proliferation, growth kinetics and cell toxicity were analysed together with an investigation of the cellular mechanisms involved, focusing on cell cycle regulation and apoptosis. KEY FINDINGS: Results show that combined treatment with C. maritimum ethyl acetate extract and half IC50 sorafenib dose decreased cell proliferation comparably to full-dose sorafenib without increasing cell toxicity as confirmed by the effect on cell cycle regulation and apoptosis. CONCLUSIONS: These results provide scientific support for the possibility of an effective integrative therapeutic approach for HCC with fewer side effects on patients.

1H-NMR metabolomics reveals a multitarget action of Crithmum maritimum ethyl acetate extract in inhibiting hepatocellular carcinoma cell growth.

Hepatocellular carcinoma (HCC) is nowadays the sixth cause of tumour-related deceases worldwide, estimated to become the third in Western countries by 2030. New drugs for HCC treatment still have many adverse effects. Several lines of evidence indicate that plant metabolites offer concrete opportunities for developing new therapeutic strategies for many diseases, including cancer. We previously reported that ethyl acetate extract of a spontaneous edible plant harvested in Apulia, Crithmum maritimum, significantly inhibited cell growth in HCC cells. By 1H-NMR spectroscopy, here we show that Crithmum maritimum ethyl acetate extract counteracts the Warburg effect, by reducing intracellular lactate, inhibits protein anabolism, by decreasing amino acid level, and affects membrane biosynthesis by lowering choline and phosphocholine. Also, we observed an effect on lipid homeostasis, with a reduction in triglycerides, cholesterol, monounsaturated fatty acids (MUFA), and diunsaturated fatty acids (DUFA), and an increase in polyunsaturated fatty acids (PUFA). Taken together, these data demonstrate that Crithmum maritimum-induced cytostasis is exerted through a multi-effect action, targeting key metabolic processes in HCC cells. Overall, our findings highlight the role of Crithmum maritimum as a promising tool for the prevention and the improvement of the therapeutic options for HCC and other types of tumours.

Historical Anecdotes and Breakthroughs of Histamine: From Discovery to Date.

AIM: Investigating about the history of allergies and discovery of the histamine's role in the immune response through historical references, starting with ancient anecdotes, analysing the first immunization attempts on animals to understand its importance as the anaphylaxis mediator. Moreover, we shortly resume the most recent discoveries on mast cell role in allergic diseases throughout the latest updates on its antibody-independent receptors. METHODS: Publications, including reviews, treatment guidelines, historical and medical books, on the topic of interest were found on Medline, PubMed, Web of Knowledge, Web of Science, Google Scholar, Elsevier's (EMBASE.comvarious internet museum archives. Texts from the National Library of Greece (Stavros Niarchos Foundation), from the School of Health Sciences of the National and Kapodistrian University of Athens (Greece). We selected key articles which could provide ahistorical and scientific insight into histamine molecule and its mechanism of action's discovery starting with Egyptian, Greek and Chinese antiquity to end with the more recent pharmacological and molecular discoveries. RESULTS: Allergic diseases were described by medicine since ancient times, without exactly understanding the physio-pathologic mechanisms of immuno-mediated reactions and of their most important biochemical mediator, histamine. Researches on histamine and allergic mechanisms started at the beginning of the 20th century with the first experimental observations on animals of anaphylactic reactions. Histamine was then identified as their major mediator of many allergic diseases and anaphylaxis, but also of several physiologic body's functions, and its four receptors were characterized. Modern researches focus their attention on the fundamental role of the antibody-independent receptors of mast cells in allergic mechanisms, such as MRGPRX2, ADGRE2 and IL-33 receptor. CONCLUSION: New research should investigate how to modulate immunity cells activity in order to better investigate possible multi-target therapies for host's benefits in preclinical and clinical studies on allergic diseases in which mast cells play a major role.

The "Scourge of the Renaissance". A Short Review About Treponema pallidum infection.

BACKGROUND: There is not a time in the history when epidemics did not loom large: infectious diseases have always had civilisation and evolution-altering consequences. Throughout history, there have been a number of pandemics: cholera, bubonic plague, influenza, smallpox are some of the most brutal killers in human history. Historical accounts of pandemics clearly demonstrate that war, unhygienic conditions, social and health inequality create conditions for the transmission of infectious diseases, and existing health disparities can contribute to unequal morbidity and mortality. The Renaissance was a period of European cultural, artistic, political and economic "rebirth" following the Middle Ages, but it was also the time when new infectious disease appeared, such as Syphilis. The epidemic spread of Syphilis began between the late 15th century and early 16th century due to the increased migration of peoples across Europe. The rapid spread of venereal syphilis throughout Europe suggests the introduction of a disease into a population that had not previously been exposed. Syphilis is a type of treponematosis, which includes syphilis, bejel, yaws, and pinta, but, while syphilis is venereal disease, the others are nonvenereal. Syphilis was, at the beginning, a disease of great severity due to its novelty, as the population had no time to gain any immunity against this venereal disease. METHODS: The purpose of this study is to investigate the origin of syphilis and the evolution of the treatments from the empiric means to the discovery of penicillin, but also to understand how this venereal disease has largely influenced human lifestyle and evolution. CONCLUSION: The first of the three hypotheses about its origins is the Columbian hypothesis, which states that Columbus's crew acquired syphilis from Native Americans and carried it back to Europe in 1493 A. D. On the contrary, the second hypothesis (pre-Columbian) asserts that syphilis was present in Europe long before Columbus's voyage and was transferred to the New World by Columbus's men. The Unitarian theory argues that syphilis, bejel, yaws, and pinta are not separate diseases but they represent syndromes caused by slightly different strains of one organism. Nowadays, Syphilis' origin is still uncertain and remains controversial. However, the large impact on the social behavior and international public health is an important reason to investigate about its origins and how to prevent the transmission.

The Preoperative Inflammatory Status Affects the Clinical Outcome in Cardiac Surgery.

AIMS: There are many reasons for the increase in post-operative mortality and morbidity in patients undergoing surgery. In fact, an activated inflammatory state before cardiac surgery, can potentially worsen the patient's prognosis and the effects of this preoperative inflammatory state in the medium-term remains unknown. METHODS: There were 470 consecutive patients who underwent cardiac surgery, and were divided in three groups according to the median values of preoperative C-reactive protein (CRP) and fibrinogen (FBG): The first group was the low inflammatory status group (LIS) with 161 patients (CRP < 0.39 mg/dL and FBG < 366 mg/dL); the second was the medium inflammatory status group (MIS) with 150 patients (CRP < 0.39 mg/dL and FBG ≥ 366 mg/dL or CRP ≥ 0.39 mg/dL and FBG < 366 mg/dL,); and the third was the high inflammatory status group (HIS) with 159 patients (CRP ≥ 0.39 mg/dL and FBG ≥ 366 mg/dL,). RESULTS: The parameters to be considered for the patients before surgery were similar between the three groups except, however, for age, left ventricular ejection fraction (LVEF) and the presence of arterial hypertension. The operative mortality was not significantly different between the groups (LIS = 2.5%, MIS = 6%, HIS = 6.9%, p = 0.16) while mortality for sepsis was significantly different (LIS = 0%, MIS = 1.3%, HIS = 3.7%, p = 0.03). The infections were more frequent in the HIS group (p = 0.0002). The HIS group resulted in an independent risk factor for infections (relative risk (RR) = 3.1, confidence interval (CI) = 1.2-7.9, p = 0.02). During the 48-months follow-up, survival was lower for the HIS patients. This HIS group (RR = 2.39, CI = 1.03-5.53, p = 0.05) and LVEF (RR = 0.96, CI = 0.92-0.99, p = 0.04) resulted in independent risk factors for mortality during the follow-up. CONCLUSIONS: The patients undergoing cardiac surgery with a preoperative highly activated inflammatory status are at a higher risk of post-operative infections. Furthermore, during the intermediate follow-up, the preoperative highly activated inflammatory status and LVEF resulted in independent risk factors for mortality.

Current Issues and Perspectives in Patients with Possible Sepsis at Emergency Departments.

In the area of Emergency Room (ER), many patients present criteria compatible with a SIRS, but only some of them have an associated infection. The new definition of sepsis by the European Society of Intensive Care Medicine and the Society of Critical Care Medicine (2016), revolutionizes precedent criteria, overcoming the concept of SIRS and clearly distinguishing the infection with the patient's physiological response from the symptoms of sepsis. Another fundamental change concerns the recognition method: The use of SOFA (Sequential-Sepsis Related-Organ Failure Assessment Score) as reference score for organ damage assessment. Also, the use of the qSOFA is based on the use of three objective parameters: Altered level of consciousness (GCS <15 or AVPU), systolic blood pressure ≤ 100 mmHg, and respiratory rate ≥ 22/min. If patients have at least two of these altered parameters in association with an infection, then there is the suspicion of sepsis. In these patients the risk of death is higher, and it is necessary to implement the appropriate management protocols, indeed the hospital mortality rate of these patients exceeds 40%. Patients with septic shock can be identified by the association of the clinical symptoms of sepsis with persistent hypotension, which requires vasopressors to maintain a MAP of 65 mmHg, and serum lactate levels >18 mg/dL in despite of an adequate volume resuscitation. Then, patient first management is mainly based on: (1) Recognition of the potentially septic patient (sepsis protocol-qSOFA); (2) Laboratory investigations; (3) Empirical antibiotic therapy in patients with sepsis and septic shock. With this in mind, the authors discuss the most important aspects of the sepsis in both adults and infants, and also consider the possible treatment according current guidelines. In addition, the possible role of some nutraceuticals as supportive therapy in septic patient is also discussed.