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A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment.

The gastric milieu, because of its very low acidic pH, is very harsh for bacterial growth. The discovery of Helicobacter pylori (H.p.) has opened a new avenue for studies on the gastric microbiota, thus indicating that the stomach is not a sterile environment. Nowadays, new technologies of bacterial identification have demonstrated the existence of other microorganisms in the gastric habitat, which play an important role in health and disease. This bacterium possesses an arsenal of compounds which enable its survival but, at the same time, damage the gastric mucosa. Toxins, such as cytotoxin-associated gene A, vacuolar cytotoxin A, lipopolysaccharides, and adhesins, determine an inflammatory status of the gastric mucosa which may become chronic, ultimately leading to a gastric carcinoma. In the initial stage, H.p. persistence alters the gastric microbiota with a condition of dysbiosis, predisposing to inflammation. Probiotics and prebiotics exhibit beneficial effects on H.p. infection, and, among them, anti-inflammatory, antioxidant, and antibacterial activities are the major ones. Moreover, the association of probiotics with prebiotics (synbiotics) to conventional anti-H.p. therapy contributes to a more efficacious eradication of the bacterium. Also, polyphenols, largely present in the vegetal kingdom, have been demonstrated to alleviate H.p.-dependent pathologies, even including the inhibition of tumorigenesis. The gastric microbiota composition in health and disease is described. Then, cellular and molecular mechanisms of H.p.-mediated damage are clarified. Finally, the use of probiotics, prebiotics, and polyphenols in experimental models and in patients infected with H.p. is discussed.

Background: Tirzepatide (TZP) is a once-weekly glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic-polypeptide (GIP) receptor co-agonist approved for T2D. TZP provides promising evidence in improving glucose control and weight loss in T2D and obesity across preclinical and human studies, including data from the SURPASS program. Aims: The goal of this paper was to review the evidence on TZP in terms of glucose control, body weight, and the progression of chronic diabetes-related complications and comorbidities. Results: The mean change in HbA1c ranged from −1.6% to −2.06% over placebo, from −0.29% to −0.92% over each GLP-1RAs, and from −0.7% to −1.09% over basal insulins. In SURPASS-6, TZP was more effective than insulin lispro U100 added to basal insulin in reducing HbA1c levels at the study end (−2.1% vs. −1.1%, respectively). Compared to placebo, TZP induces a significant weight loss: 7.5 (5 mg/week); 11 (10 mg/week); and 12 kg (15 mg/week). Compared to GLP-1RAs, TZP reduces body weight from −1.68 kg to −7.16 kg depending on the dose (5 to 15 mg, respectively). Compared to basal insulin alone rigorously titrated, TZP added onto basal-insulin results in the best strategy for the composite endpoint of improvement of glucose control and weight loss. In SURPASS-6, TZP compared to insulin lispro U100 in add-on to insulin glargine U100 reduced body weight by 9 kg in mean (versus weight gain in basal-bolus users: +3.2 kg). TZP has pleiotropic effects potentially dampening the individual cardiovascular risk, including a reduction in systolic arterial pressure by 4 to 6 mmHg and total cholesterol by 4–6% compared to baseline. A post hoc analysis of SURPASS-4 revealed that TZP, compared to glargine U100, delayed the rate of glomerular filtration decline (−1.4 mL/min vs. −3.6 mL/min, respectively), reduced the rate of urinary albumin excretion (−6.8% vs. +36.9%, respectively), and was associated with a lower occurrence of the composite renal endpoint (HR 0.58 [0.43; 0.80]). Conclusions: Consistent evidence indicates that TZP dramatically changes the clinical course of T2D in different clinical scenarios. The efficacy and safety of TZP on chronic diabetes-related comorbidities and complications seem promising, but ongoing trials will clarify the real benefits.

For a long time, urine has been considered sterile in physiological conditions, thanks to the particular structure of the urinary tract and the production of uromodulin or Tamm–Horsfall protein (THP) by it. More recently, thanks to the development and use of new technologies, i.e., next-generation sequencing and expanded urine culture, the identification of a microbial community in the urine, the so-called urobiota, became possible. Major phyla detected in the urine are represented by Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Particularly, the female urobiota is largely represented by Lactobacillus spp., which are very active against urinary pathogenic Escherichia (E.) coli (UPEC) strains via the generation of lactic acid and hydrogen peroxide. Gut dysbiosis accounts for recurrent urinary tract infections (UTIs), so-called gut–bladder axis syndrome with the formation of intracellular bacterial communities in the course of acute cystitis. However, other chronic urinary tract infections are caused by bacterial strains of intestinal derivation. Monomicrobial and polymicrobial infections account for the outcome of acute and chronic UTIs, even including prostatitis and chronic pelvic pain. E. coli isolates have been shown to be more invasive and resistant to antibiotics. Probiotics, fecal microbial transplantation, phage therapy, antimicrobial peptides, and immune-mediated therapies, even including vaccines for the treatment of UTIs, will be described.

Superantigens, i.e., staphylococcal enterotoxins and toxic shock syndrome toxin-1, interact with T cells in a different manner in comparison to conventional antigens. In fact, they activate a larger contingent of T lymphocytes, binding outside the peptide-binding groove of the major histocompatibility complex class II. Involvement of many T cells by superantigens leads to a massive release of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma. Such a storm of mediators has been shown to account for tissue damage, multiorgan failure and shock. Besides conventional drugs and biotherapeutics, experiments with natural and biological products have been undertaken to attenuate the toxic effects exerted by superantigens. In this review, emphasis will be placed on polyphenols, probiotics, beta-glucans and antimicrobial peptides. In fact, these substances share a common functional denominator, since they skew the immune response toward an anti-inflammatory profile, thus mitigating the cytokine wave evoked by superantigens. However, clinical applications of these products are still scarce, and more trials are needed to validate their usefulness in humans.

Nowadays, infectious diseases of bacterial and viral origins represent a serious medical problem worldwide. In fact, the development of antibiotic resistance is responsible for the emergence of bacterial strains that are refractory even to new classes of antibiotics. Furthermore, the recent COVID-19 pandemic suggests that new viruses can emerge and spread all over the world. The increase in infectious diseases depends on multiple factors, including malnutrition, massive migration of population from developing to industrialized areas, and alteration of the human microbiota. Alternative treatments to conventional antibiotics and antiviral drugs have intensively been explored. In this regard, plants and marine organisms represent an immense source of products, such as polyphenols, alkaloids, lanthipeptides, and terpenoids, which possess antibacterial and antiviral activities. Their main mechanisms of action involve modifications of bacterial cell membranes, with the formation of pores, the release of cellular content, and the inhibition of bacterial adherence to host cells, as well as of the efflux pump. Natural antivirals can interfere with viral replication and spreading, protecting the host with the enhanced production of interferon. Of note, these antivirals are not free of side effects, and their administration to humans needs more research in terms of safety. Preclinical research with natural antibacterial and antiviral compounds confirms their effects against bacteria and viruses, but there are still only a few clinical trials. Therefore, their full exploitation and more intensive clinical studies represent the next steps to be pursued in this area of medicine.

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-kβ) 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.

Background: Individuals with metabolic syndrome exhibit simultaneously pro-thrombotic and pro-inflammatory conditions which more probably can lead to cardiovascular diseases progression, type 2 diabetes mellitus, and some types of cancer. The present scoping review is aimed at highlighting the association between cancer risk, inflammation, and metabolic syndrome. Methods: A search strategy was performed, mixing keywords and MeSH terms, such as “Cancer Risk”, “Inflammation”, “Metabolic Syndrome”, “Oncogenesis”, and “Oxidative Stress”, and matching them through Boolean operators. A total of 20 manuscripts were screened for the present study. Among the selected papers, we identified some associations with breast cancer, colorectal cancer, esophageal adenocarcinoma, hepatocellular carcinoma (HCC), and cancer in general. Conclusions: Cancer and its related progression may also depend also on a latent chronic inflammatory condition associated with other concomitant conditions, including type 2 diabetes mellitus, metabolic syndrome, and obesity. Therefore, prevention may potentially help individuals to protect themselves from cancer.

Résumé Contexte La fonction érectile dépend d’une interaction complexe entre les facteurs démographiques, métaboliques, vasculaires, hormonaux et psychologiques qui déclenchent la dysfonction érectile (DE). Dans la présente étude, nous avons mené ici une étude transversale évaluant l’impact des maladies chroniques non transmissibles (MNT), de l’hypogonadisme masculin et des facteurs démographiques dans la caractérisation des hommes atteints de dysfonction érectile. Quatre cent trente-trois patients externes consécutifs présentant une dysfonction érectile ont été extraits de la base de données électronique de janvier 2017 à décembre 2019. Le score de l’indice international de la fonction érectile (IIEF) 5 a été utilisé pour diagnostiquer la dysfonction érectile et stratifier sa gravité, les valeurs normalisées de la testostérone sérique (10,5 nM/L) et de l’hormone lutéinisante (LH 9,4 UI/L) pour diagnostiquer et classer l’hypogonadisme masculin, et l’indice de comorbidité de Charlson (ICC) pour évaluer le rôle de chaque MNT sur la DE. Résultats Quarante-six pour cent des participants étaient eugonadiques (EuG), 13% avaient un hypogonadisme organique (OrH) et les 41% restants avaient un hypogonadisme fonctionnel (FuH). Les hommes hypogonadiques avaient un score IIEF 5 significativement plus faible (p < 0,0001) que EuG. Les hommes FuH avait un ICC plus élevé que les hommes OrH et EuG (tous p < .0001). Dans un modèle multivariable, seules la T libre (TL) et la globuline liant les hormones sexuelles (SHBG) ont montré une corrélation directe avec le score IIEF 5 (tous p

Sarcopenia is an age-related clinical complaint characterized by the progressive deterioration of skeletal muscle mass and strength over time. Type 2 diabetes (T2D) is associated with faster and more relevant skeletal muscle impairment. Both conditions influence each other, leading to negative consequences on glycemic control, cardiovascular risk, general health status, risk of falls, frailty, overall quality of life, and mortality. PubMed/Medline, Scopus, Web of Science, and Google Scholar were searched for research articles, scientific reports, observational studies, clinical trials, narrative and systematic reviews, and meta-analyses to review the evidence on the pathophysiology of di-abetes-induced sarcopenia, its relevance in terms of glucose control and diabetes-related outcomes, and diagnostic and therapeutic challenges. The review comprehensively addresses key elements for the clinical definition and diagnostic criteria of sarcopenia, the pathophysiological correlation be-tween T2D, sarcopenia, and related outcomes, a critical review of the role of antihyperglycemic treatment on skeletal muscle health, and perspectives on the role of specific treatment targeting myokine signaling pathways involved in glucose control and the regulation of skeletal muscle metabolism and trophism. Prompt diagnosis and adequate management, including lifestyle inter-vention, health diet programs, micronutrient supplementation, physical exercise, and pharmaco-logical treatment, are needed to prevent or delay skeletal muscle deterioration in T2D.

The female genital tract (FGT) performs several functions related to reproduction, but due to its direct exposure to the external environment, it may suffer microbial infections. Both the upper (uterus and cervix) and lower (vagina) FGT are covered by an epithelium, and contain immune cells (macrophages, dendritic cells, T and B lymphocytes) that afford a robust protection to the host. Its upper and the lower part differ in terms of Lactobacillus spp., which are dominant in the vagina. An alteration of the physiological equilibrium between the local microbiota and immune cells leads to a condition of dysbiosis which, in turn, may account for the outcome of FGT infection. Aerobic vaginitis, bacterial vaginosis, and Chlamydia trachomatis are the most frequent infections, and can lead to severe complications in reproduction and pregnancy. The use of natural products, such as probiotics, polyphenols, and lactoferrin in the course of FGT infections is an issue of current investigation. In spite of positive results, more research is needed to define the most appropriate administration, according to the type of patient.

Tirzepatide, a dual agonist of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide 1 (GLP-1) receptors, improved glucose control and reduced body weight in different therapeutic approaches. Herein, we overviewed the role of GIP and GLP-1 in the pathophysiology of type 2 diabetes and systematically reviewed the efficacy and safety of injectable incretin-based therapy added to basal insulin in light of the results of the SURPASS-5 trial. We identified eleven randomized clinical trials. GLP-1 receptor agonists (GLP-1RAs) or Tirzepatide added to basal insulin than rigorously titrated basal insulin significantly ameliorates glucose control (Δ HbA1c = -1%, 95% CI -1.25; -0.74, I2 94%; Δ FPG = -14.6 mg/dL, 95% CI -21.6-; -7.6, I2 90%; chance to achieve HbA1c

Fever represents an elevation of body temperature, that exerts a protective effect against pathogens. Innate immune cells and neurons are implicated in the regulation of body temperature. Pathogen-associated molecular patterns, i.e., lipopolysaccharides from Gram-negative bacteria and peptidoglycan and lipoteichoic acid from Gram-positive bacteria are exogenous pyrogens, that bind to Toll-like receptors on immune and non-immune cells. The subsequent release of pro-inflammatory cytokines [interleukin-1 (IL-1), IL-6 and Tumor necrosis factor-alpha] and their passage through the brain trigger the febrile response. In fact, neurons of the pre-optic area produce prostaglandin E2 (PGE2), that, in turn, bind to the PGE2 receptors; thus, generating fever. Apart from classical non-steroidal anti-inflammatory drugs, i.e., aspirin and acetaminophen, various botanicals are currently used as antipyretic agents and, therefore, their mechanisms of action will be elucidated.

Background: Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). TB treatment is based on the administration of three major antibiotics: isoniazid, rifampicin, and pyrazinamide. However, multi-drug resistant (MDR) Mtb strains are increasing around the world, thus, allowing TB to spread around the world. The stringent response is demonstrated by Mtb strains in order to survive under hostile circumstances, even including exposure to antibiotics. The stringent response is mediated by alarmones, which regulate bacterial replication, transcription and translation. Moreover, the Mtb cell wall contributes to the mechanism of antibiotic resistance along with efflux pump activation and biofilm formation. Immunity over the course of TB is managed by M1-macrophages and M2-macrophages, which regulate the immune response against Mtb infection, with the former exerting inflammatory reactions and the latter promoting an anti-inflammatory profile. T helper 1 cells via secretion of interferon (IFN)-gamma, play a protective role in the course of TB, while T regulatory cells secreting interleukin 10, are anti-inflammatory. Alternative therapeutic options against TB require further discussion. In view of the increasing number of MDR Mtb strains, attempts to replace antibiotics with natural and biological products have been object of intensive investigation. Therefore, in this review the anti-Mtb effects exerted by probiotics, polyphenols, antimicrobial peptides and IFN-gamma will be discussed. All the above cited compounds are endowed either with direct antibacterial activity or with anti-inflammatory and immunomodulating characteristics.

Reproduction is a complex process, which is based on the cooperation between the endocrine–immune system and the microbiota. Testicular immunity is characterized by the so-called immune privilege, a mechanism that avoids autoimmune attacks against proteins expressed by spermatozoa. Testicular microbiota is connected with the gut microbiota, the most prevalent site of commensals inthe body. Both microbiotas take part inthe development of the immune system and protection againstpathogen invasion. Dysbiosis is caused by concurrent pathologies, such as obesity, diabetes, infections and trauma. The substitution of beneficial bacteria with pathogens may lead to destruction of spermatozoa directly or indirectly and, ultimately, to male infertility. Novel therapeutic interventions, i.e., nutritional interventions and supplementation of natural products, such as, probiotics, prebiotics, antioxidants and polyphenols, may lead to the restoration of the otherwise-impaired male reproductive potential, even if experimental and clinical results are not always concordant. In this review, the structure and immune function of the testis will be described with special reference to the blood–testisbarrier. The regulatory role of both the gut and testicular microbiota will be illustrated in health and disease, also emphasizing therapeutic attempts with natural products for the correction of male infertility, in the era of personalized medicine.

Abstract Immunotherapy has matured into standard treatment for several cancers, but much remains to be done to extend the reach of its effectiveness particularly to cancers that are resistant within each indication. This review proposes that nutrition can affect and potentially enhance the immune response against cancer. The general mechanisms that link nutritional principles to immune function and may influence the effectiveness of anticancer immunotherapy are examined. This represents also the premise for a research project aimed at identifying the best diet for immunotherapy enhancement against tumours (D.I.E.T project). Particular attention is turned to the gut microbiota and the impact of its composition on the immune system. Also, the dietary patterns effecting immune function are discussed including the value of adhering to a healthy diets such as the Mediterranean, Veg, Japanese, or a Microbiota-regulating diet, the very low ketogenic diet, which have been demonstrated to lower the risk of developing several cancers and reduce the mortality associated with them. Finally, supplements, as omega-3 and polyphenols, are discussed as potential approaches that could benefit healthy dietary and lifestyle habits in the context of immunotherapy.

In this study the mechanisms are explored, which modulate expression and function of cell surface adhesive glycoproteins of the Immunoglobulin Supergene Family (IgSF), and in particular of its Contactin subset, during neuronal precursor developmental events. In this context, a specific topic concerns the significance of the expression profile of such molecules and their ability to modulate signaling pathways activated through nutraceuticals, in particular polyphenols, administration. Both in vitro and in vivo approaches are chosen. As for the former, by using as a model the human SH-SY5Y neuroblastoma line, the effects of grape seed polyphenols are evaluated on proliferation and commitment/differentiation events along the neuronal lineage. In SH-SY5Y cell cultures, polyphenols were found to counteract precursor proliferation while promoting their differentiation, as deduced by studying their developmental parameters through the expression of cell cycle and neuronal commitment/differentiation markers as well as by measuring neurite growth. In such cultures, Cyclin E expression and BrdU incorporation were downregulated, indicating reduced precursor proliferation while increased neuronal differentiation was inferred from upregulation of cell cycle exit (p27–Kip) and neuronal commitment (NeuN) markers as well as by measuring neurite length through morphometric analysis. The polyphenol effects on developmental parameters were also explored in vivo, in cerebellar cortex, by using as a model the TAG/F3 transgenic line, which undergoes delayed neural development as a consequence of Contactin1 adhesive glycoprotein upregulation and premature expression under control of the Contactin2 gene (Cntn-2) promoter. In this transgenic line, a Notch pathway activation is known to occur and polyphenol treatment was found to counteract such an effect, demonstrated through downregulation of the Hes-1 transcription factor. Polyphenols also downregulated the expression of adhesive glycoproteins of the Contactin family themselves, demonstrated for both Contactin1 and Contactin2, indicating the involvement of changes in the expression of the underlying genes in the observed phenotype. These data support the hypothesis that the complex control exerted by polyphenols on neural development involves modulation of expression and function of the genes encoding cell adhesion molecules of the Contactin family and of the associated signaling pathways, indicating potential mechanisms whereby such compounds may control neurogenesis.

In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82–190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (β-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.

In this review, special emphasis will be placed on red grape polyphenols for their antioxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of proinflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Additionally, the effects of red grape polyphenols will be analyzed in obesity, as a low-grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood−brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great antioxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites, and interaction with microbiota, deserve deeper studies.

It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert antioxidant and anti-inflammatory activities switching on some important signaling pathways such as toll-like receptor 4/nuclear factor κB/signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial NO synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal, and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit.

Background: In mice, postnatal immune development has previously been investigated, and evidence of a delayed maturation of the adaptive immune response has been detected. Methods: In this study, the effects of red grape polyphenol oral administration on the murine immune response were explored using pregnant mice (TAG/F3 transgenic and wild type (wt) mice) as the animal model. The study was performed during pregnancy as well as during lactation until postnatal day 8. Suckling pups from polyphenol-administered dams as well as day 30 post-weaning pups (dietary-administered with polyphenols) were used. Polyphenol effects were evaluated, measuring splenic cytokine secretion. Results: Phorbol myristate acetate-activated splenocytes underwent the highest cytokine production at day 30 in both wt and TAG/F3 mice. In the latter, release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was found to be higher than in the wt counterpart. In this context, polyphenols exerted modulating activities on day 30 TAG/F3 mice, inducing release of interleukin (IL)-10 in hetero mice while abrogating release of IL-2, IFN-γ, TNF-α, IL-6, and IL-4 in homo and hetero mice. Conclusion: Polyphenols are able to prevent the development of an inflammatory/allergic profile in postnatal TAG/F3 mice.

Background and Aims. Inflammatory mediators that cross-talk in different metabolically active organs are thought to play a crucial role in the pathogenesis of Nonalcoholic Steatohepatitis (NASH). This study was aimed at investigating the CD4+RORγt+ T-helper cells and their counterpart, the CD4+CD25+FOXP3+ regulatory T cells in the liver, subcutaneous adipose tissue (SAT), and abdominal adipose tissue (AAT) in a high fat diet (HFD) mouse model. Methods. C57BL6 mice were fed a HFD or a normal diet (ND). Liver enzymes, metabolic parameters, and liver histology were assessed. The expression of CD4+RORγt+ cells and regulatory T cells in different organs (blood, liver, AAT, and SAT) were analyzed by flow cytometry. Cytokine and adipokine tissue expression were studied by RT-PCR. Results. Mice fed a HFD developed NASH and metabolic alterations compared to normal diet. CD4+RORγt++ cells were significantly increased in the liver and the AAT while an increase of regulatory T cells was observed in the SAT of mice fed HFD compared to ND. Inflammatory cytokines were also upregulated. Conclusions. CD4+RORγt++ cells and regulatory T cells are altered in NASH with a site-specific pattern and correlate with the severity of the disease. These site-specific differences are associated with increased cytokine expression.

Haemodynamic impairment, inflammatory mediators and glucose metabolism disturbances have been implicated in the pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD).To investigate the cytokine profile in NAFLD patients in peripheral (P) and hepatic venous (HV) blood and to compare with histology, haemodynamic and metabolic parameters.40 obese patients with an indication for a transjugular liver biopsy were enrolled. Besides an extended liver and metabolic work-up, interleukin (IL) 1B, IL4, IL6, IL10, IL23, tumour necrosis factor (TNF) α and interferon (INF) γ were measured in plasma obtained from P and HV blood by means of multiplex immunoassay. The T helper (Th)1/Th2, the macrophage M1/M2 and the IL10/IL17a ratios were calculated.A decrease of the P-IL10/IL17-ratio and an increase of the P-M1/M2-ratio (p

In vivo treatment with parenterally administered hypoxanthine derivatives, notably ST 789, was able to protect cyclophosphamide-immunosuppressed mice against experimental infections with both bacterial and fungal pathogens. However, the mechanisms accounting for these effects of hypoxanthine derivatives remain to be fully established. In fact, only the treatment with ST 789 resulted in a clear enhancement of the primary antibody production as well as macrophage phagocytic activity, whereas T lymphocyte responsiveness to mitogens and both macrophage- and natural killer-dependent cytotoxicity were not significantly affected. These data, together with the recently shown ability of ST 789 to increase interleukin-6 production, suggest that monocyte/macrophages are likely to be the main cellular target of the immunomodulating activity of ST 789. Finally, in the presentln vivo study, hypoxanthine derivatives did not enhance the mean survival time of tumour-bearing immunosuppressed mice.

Tuberculosis (TBC) is characterized by a complex immune response which parallels the clinical course of the disease. In this respect, acquired resistance, delayed hypersensitivity reaction and anergy are the main types of immune reactivity to mycobacterial antigens. In view of the presence of nonspecific and specific immune deficits in TBC patients, a clinical trial was carried out in a group of 20 individuals with active pulmonary TBC by oral administration of acetyl-L-carnitine (ALC). This drug, which has been shown to possess immunomodulating activities, was able to upregulate the T-dependent antibacterial activity in TBC patients after 30 days' treatment, while the same activity decreased in patients receiving placebo only. On the other hand, ALC did not modify serum levels of tumour necrosis factor-α, in the same individuals. This cytokine plays a detrimental rather than beneficial role in TBC pathogenesis. In the light of these data, ALC seems to be a powerful immunomodulator in the course of Mycobacterium tuberculosis infection and other mycobacteriosis.

Both anaesthetics and surgical trauma could strongly affect the production of tumour necrosis factor α (TNFα). During in vitro experiments the authors found that anaesthetics modulate the production of TNFα by peripheral blood mononuclear cells. Notably, Pentothal strongly increased the production of the cytokine as compared to both lipopolysacchride treated and control mononuclear cells, whereas in supernatants from Leptofen driven mononuclear cells TNFα was strongly reduced. On the other hand, Pavulon did not significantly affect the cytokine production. In the in vivo study, in an attempt to ameliorate the metabolic response to surgical trauma, L-carnitine was administered to 20 surgical patients, then the circulating TNFα was measured. The results indicate that the levels of circulating TNFα were strongly increased following surgery and that L-carnitine administration resulted in a strong reduction of TNFα. Thus, the data suggest that L-carnitine could be helpful in protecting surgical patients against dysmetabolism dependent on dysregulated production of TNFα.