Search

Non-alcoholic fatty liver disease (NAFLD), redefined as Metabolic Associated Fatty Liver Disease (MAFLD), is characterized by an extensive multi-organ involvement. MAFLD-induced systemic inflammatory status and peripheral metabolic alteration lead to an impairment of cerebral function. Herein, we investigated a panel of leptin-related inflammatory mediators as predictive biomarkers of neuroinflammation and evaluated the possible role of Bergamot Polyphenolic Fraction (BPF) in counteracting this MAFLD-induced inflammatory cascade. Male DIAMOND mice were randomly assigned to fed chow diet and tap water or high fat diet with sugar water. Starting from week 16, mice were further divided and treated with vehicle or BPF (50 mg/kg/day), via gavage, until week 30. Magnetic resonance imaging was performed at the baseline and at week 30. Correlation and regression analyses were performed to discriminate the altered lipid metabolism in the onset of cerebral alterations. Steatohepatitis led to an increase in leptin levels, resulting in a higher expression of proinflammatory mediators. The inflammatory biomarkers involved in leptin/CCL3-CCL4 axes were correlated with the altered thalamus energetic metabolism and the white matter degeneration. BPF administration restored leptin level, improved glucose and lipid metabolism, and reduced chronic low-grade inflammatory mediators, resulting in a prevention of white matter degeneration, alterations of thalamus metabolism and brain atrophy. The highlighted positive effect of BPF, mediated by the downregulation of the inflammatory biomarkers involved in leptin/CCL3-CCL4 axes, affording novel elements to candidate BPF for the development of a therapeutic strategy aimed at counteracting MAFLD-related brain inflammation.

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.

Growing epidemiological studies highlight a bi-directional relationship between depressive symptoms and diabetes mellitus. However, the detrimental impact of their co-existence on mental health suggests the need to treat this comorbidity as a separate entity rather than the two different pathologies. Herein, we characterized the peculiar mechanisms activated in mouse hippocampus from the concurrent development of hyperglycaemia, characterizing the different diabetes subtypes, and chronic stress, recognized as a possible factor predisposing to major depression. Our work demonstrates that kynurenine overproduction, leading to apoptosis in the hippocampus, is triggered in a different way depending on hyperglycaemia or chronic stress. Indeed, in the former, kynurenine appears produced by infiltered macrophages whereas, in the latter, peripheral kynurenine preferentially promotes resident microglia activation. In this scenario, QA, derived from kynurenine catabolism, appears a key mediator causing glutamatergic synapse dysfunction and apoptosis, thus contributing to brain atrophy. We demonstrated that the coexistence of hyperglycaemia and chronic stress worsened hippocampal damage through alternative mechanisms, such as GLUT-4 and BDNF down-expression, denoting mitochondrial dysfunction and apoptosis on one hand and evoking the compromission of neurogenesis on the other. Overall, in the degeneration of neurovascular unit, hyperglycaemia and chronic stress interacted each other as the partners of a “West Coast Swing” in which the leading role can be assumed alternatively by each partner of the dance. The comprehension of these mechanisms can open novel perspectives in the management of diabetic/depressed patients, but also in the understanding the pathogenesis of other neurodegenerative disease characterized by the compromission of hippocampal function.

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.

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

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.

Evidence exists that heart failure (HF) has an overall impact of 1–2 % in the global population being often associated with comorbidities that contribute to increased disease prevalence, hospitalization, and mortality. Recent advances in pharmacological approaches have significantly improved clinical outcomes for patients with vascular injury and HF. Nevertheless, there remains an unmet need to clarify the crucial role of nitric oxide/cyclic guanosine 3',5'-monophosphate (NO/cGMP) signalling in cardiac contraction and relaxation, to better identify the key mechanisms involved in the pathophysiology of myocardial dysfunction both with reduced (HFrEF) as well as preserved ejection fraction (HFpEF). Indeed, NO signalling plays a crucial role in cardiovascular homeostasis and its dysregulation induces a significant increase in oxidative and nitrosative stress, producing anatomical and physiological cardiac alterations that can lead to heart failure. The present review aims to examine the molecular mechanisms involved in the bioavailability of NO and its modulation of downstream pathways. In particular, we focus on the main therapeutic targets and emphasize the recent evidence of preclinical and clinical studies, describing the different emerging therapeutic strategies developed to counteract NO impaired signalling and cardiovascular disease (CVD) development.

Nowadays, old-generation pesticides are released into ecosystems alongside new formulations, giving rise to pharmacological interactions (additive, synergistic, and antagonistic effects). The aim of this study was to evaluate the impact that simultaneous exposure to DMT and FLU doses has on bee health. Groups of twenty honeybees were housed in cages to compose six macro-groups. One group consisted of experimental replicates treated orally with a toxic dose of deltamenthrin (DMT 21.6 mg/L); two other groups were subjected to the oral administration of two toxic doses of flupyradifurone (FLU 50 mg/L and FLU 100 mg/L); and two other groups were intoxicated with a combination of the two pesticides (DMT 21.6 + FLU 50 and DMT 21.6 + FLU 100). The consequences of the pesticides’ interactions were highlighted by measuring and comparing data on survival, food consumption, and abnormal behavior. Generally speaking, antagonism between the two pesticides has been demonstrated. The bees were able to survive for up to three days at the lowest dosage of FLU (50 mg/L), with 46% of the subjects still alive; however, the maximum dose (100 mg/L) caused all treated animals to die as early as the second day. When DMT and FLU 50 were administered together, the group that received DMT alone had a lower survival rate. When comparing the survival rates produced by the DMT and FLU 50 combination to those of the group receiving FLU 50 alone, the same was clearly visible. While there was no statistically significant improvement observed when the survival indices of the DMT and FLU 100 combination were compared to those of the group intoxicated with DMT alone, an improvement in survival indices was observed when these were compared with the group intoxicated with FLU 100 alone.

Flupyradifurone (FLU) is a butenolide insecticide that has come onto the market relatively recently. It is used in agriculture to control aphids, psyllids, and whiteflies. Toxicity studies have decreed its low toxicity to honeybees. However, recent research has challenged these claims; oral exposure to the pesticide can lead to behavioral abnormalities and in the worst cases, lethal phenomena. Compounds with antioxidant activity, such as flavonoids and polyphenols, have been shown to protect against the toxic effects of pesticides. The aim of this research was to evaluate the possible protective effect of the bergamot polyphenolic fraction (BPF) against behavioral abnormalities and lethality induced by toxic doses of FLU orally administered to honeybees under laboratory conditions. Honeybees were assigned to experimental groups in which two toxic doses of FLU, 50 mg/L and 100 mg/L were administered. In other replicates, three doses (1, 2 and 5 mg/kg) of the bergamot polyphenolic fraction (BPF) were added to the above toxic doses. In the experimental groups intoxicated with FLU at the highest dose tested, all caged subjects (20 individuals) died within the second day of administration. The survival probability of the groups to which the BPF was added was compared to that of the groups to which only the toxic doses of FLU were administered. The mortality rate in the BPF groups was statistically lower (p < 0.05) than in the intoxicated groups; in addition, a lower percentage of individuals exhibited behavioral abnormalities. According to this research, the ingestion of the BPF attenuates the harmful effects of FLU. Further studies are needed before proposing BPF incorporation into the honeybees’ diet, but there already seem to be beneficial effects associated with its intake.

Antimicrobial resistance (AMR) is a complex and somewhat unpredictable phenomenon. Historically, the utilization of avoparcin in intensive farming during the latter part of the previous century led to the development of resistance to vancomycin, a crucial antibiotic in human medicine with life-saving properties. Currently, in the European Union, there is a growing reliance on the ionophore antibiotic monensin (MON), which acts both as a coccidiostat in poultry farming and as a preventative measure against ketosis in lactating cows. Although many researchers claim that MON does not induce cross-resistance to antibiotics of clinical relevance in human medicine, some conflicting reports exist. The numerous applications of MON in livestock farming and the consequent dissemination of the compound and its metabolites in the environment require further investigation to definitively ascertain whether MON represents a potential vector for the propagation of AMR. It is imperative to emphasize that antibiotics cannot substitute sound animal husbandry practices or tailored dietary regimens in line with the different production cycles of livestock. Consequently, a rigorous evaluation is indispensable to assess whether the economic benefits associated with MON usage justify its employment, also considering its local and global environmental ramifications and the potential risk of instigating AMR with increased costs for its control.

Cerebral metabolites are associated with different physiological and pathological processes in brain tissue. Among them, the concentrations of N-acetylaspartate (NAA) and choline-containing compounds (Cho) in the thalamic region are recognized and analyzed as important predictive markers of brain impairment. The relationship among hypertension, modulation of brain metabolite levels and cerebral diseases is of recent investigation, leaving many unanswered questions regarding the origin and consequences of the metabolic damage caused in grey and white matter during hypertension. Here we provide evidence for the influence of hypertension on NAA and Cho ratios in hypertensive rat thalamus and how the use of natural occurring compounds ameliorates the balance of thalamic metabolites.

Obesity is one of the world’s most serious public health issues, with a high risk of developing a wide range of diseases. As a result, focusing on adipose tissue dysfunction may help to prevent the metabolic disturbances commonly associated with obesity. Nutraceutical supplementation may be a crucial strategy for improving WAT inflammation and obesity and accelerating the browning process. The aim of this study was to perform a preclinical “proof of concept” study on Bergacyn®, an innovative formulation originating from a combination of bergamot polyphenolic fraction (BPF) and Cynara cardunculus (CyC), for the treatment of adipose tissue dysfunction. In particular, Bergacyn® supplementation in WD/SW-fed mice at doses of 50 mg/kg given orally for 12 weeks, was able to reduce body weight and total fat mass in the WD/SW mice, in association with an improvement in plasma biochemical parameters, including glycemia, total cholesterol, and LDL levels. In addition, a significant reduction in serum ALT levels was highlighted. The decreased WAT levels corresponded to an increased weight of BAT tissue, which was associated with a downregulation of PPARγ as compared to the vehicle group. Bergacyn® was able to restore PPARγ levels and prevent NF-kB overexpression in the WAT of mice fed a WD/SW diet, suggesting an improved oxidative metabolism and inflammatory status. These results were associated with a significant potentiation of the total antioxidant status in WD/SW mice. Finally, our data show, for the first time, that Bergacyn® supplementation may be a valuable approach to counteract adipose tissue dysfunction and obesity-associated effects on cardiometabolic risk.

Abstract Metabolic associated fatty liver disease (MAFLD), commonly known as non-alcoholic fatty liver disease, represents a continuum of events characterized by excessive hepatic fat accumulation which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some severe cases hepatocellular carcinoma. MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included. The present study aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo. DIAMOND (Diet-induced animal model of non-alcoholic fatty liver disease) mice were fed a chow diet and tap water (NC NW) or fat Western Diet (WD SW) for up to 28 weeks. At the baseline and weeks 4, 8, 20, 28 the thalamic neurochemical profile and total cerebral brain volume were evaluated longitudinally in both diet groups using 1H-MRS. To confirm the disease progression, at each time point, a subgroup of animals was sacrificed, the livers excised and placed in formalin. Liver histology was assessed and reviewed by an expert liver pathologist. MAFLD development significantly increases the thalamic levels of total N-acetylaspartate, total creatine, total choline, and taurine. Furthermore, in the WD SW group a reduction in total cerebral brain volume has been observed (p

Salvia rosmarinus Spenn. is a native Mediterranean shrub belonging to the Lamiaceae family and is well-known as a flavoring and spicing agent. In addition to its classical use, it has drawn attention because its biological activities, due particularly to the presence of polyphenols, including carnosic acid and rosmarinic acid, and phenolic diterpenes as carnosol. In this study, the aerial part of rosemary was extracted with a hydroalcoholic solution through maceration, followed by ultrasound sonication, to obtain a terpenoids-rich Salvia rosmarinus extract (TRSrE) and a polyphenols-rich Salvia rosmarinus extract (PRSrE). After phytochemical characterization, both extracts were investigated for their antioxidant activity through a classical assay and with electron paramagnetic resonance (EPR) for their DPPH and hydroxyl radicals scavenging. Finally, their potential beneficial effects to reduce lipid accumulation in an in vitro model of NAFLD were evaluated.

The clinical use of anthracycline Doxorubicin as an antineoplastic drug in cancer therapy is limited by cardiotoxic effects that can lead to congestive heart failure. Recent studies have shown several promising activities of different species of the genus Ferula belonging to the Apiaceae Family. Ferula communis is the main source of Ferutinin—a bioactive compound isolated from many species of Ferula—studied both in vitro and in vivo because of their different effects, such as estrogenic, antioxidant, anti-inflammatory, and also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. However, the potential protective role of Ferutinin in myocardium impairment, caused by chemotherapeutic drugs, still represents an unexplored field. The aim of this study was to test the effects of Ferutinin rich-Ferula communis L. root extract (FcFE) at different concentrations on H9C2 cells. Moreover, we evaluated its antioxidant properties in cardiomyocytes in order to explore new potential therapeutic activities never examined before in other experimental works. FcFE, at a concentration of 0.25 µM, in the H9C2 line, significantly reduced the ROS production induced by H2O2 (50 µM and 250 µM) and traced the cell mortality of the H9C2 co-treated with Ferutinin 0.25 µM and Doxorubicin (0.5 µM and 1 µM) to control levels. These results showed that FcFE could protect against Doxorubicin-induced cardiotoxicity. Further molecular characterization of this natural compound may open the way for testing FcFE at low concentrations in vivo and in clinical studies as an adjuvant in cancer therapy in association with anthracyclines to prevent side effects on heart cells.

Evidence exists that the gut microbiota contributes to the alterations of lipid metabolism associated with high-fat diet (HFD). Moreover, the gut microbiota has been found to modulate the metabolism and absorption of dietary lipids, thereby affecting the formation of lipoproteins occurring at the intestinal level as well as systemically, though the pathophysiological implication of altered microbiota composition in HFD and its role in the development of atherosclerotic vascular disease (ATVD) remain to be better clarified. Recently, evidence has been collected indicating that supplementation with natural polyphenols and fibres accounts for an improvement of HFD-associated intestinal dysbiosis, thereby leading to improved lipidaemic profile. This study aimed to investigate the protective effect of a bergamot polyphenolic extract (BPE) containing 48% polyphenols enriched with albedo and pulp-derived micronized fibres (BMF) in the gut microbiota of HFD-induced dyslipidaemia. In particular, rats that received an HFD over a period of four consecutive weeks showed a significant increase in plasma cholesterol, triglycerides and plasma glucose compared to a normal-fat diet (NFD) group. This effect was accompanied by body weight increase and alteration of lipoprotein size and concentration, followed by high levels of MDA, a biomarker of lipid peroxidation. Treatment with a combination of BPE plus BMF (50/50%) resulted in a significant reduction in alterations of the metabolic parameters found in HFD-fed rats, an effect associated with increased size of lipoproteins. Furthermore, the effect of BPE plus BMF treatment on metabolic balance and lipoprotein size re-arrangement was associated with reduced gut-derived lipopolysaccharide (LPS) levels, an effect subsequent to improved gut microbiota as expressed by modulation of the Gram-negative bacteria Proteobacteria, as well as Firmicutes and Bacteroidetes. This study suggests that nutraceutical supplementation of HFD-fed rats with BPE and BMP or with their combination product leads to restored gut microbiota, an effect associated with lipoprotein size re-arrangement and better lipidaemic and metabolic profiles.

The Varroa destructor parasite is the main obstacle to the survival of honey bee colonies. Pest control mainly involves the use of synthetic drugs which, used with the right criteria and in rotation, are able to ensure that infestation levels are kept below the damage threshold. Although these drugs are easy to use and quick to apply, they have numerous disadvantages. Their prolonged use has led to the emergence of pharmacological resistance in treated parasite populations; furthermore, the active ingredients and/or their metabolites accumulate in the beehive products with the possibility of risk for the end consumer. Moreover, the possibility of subacute and chronic toxicity phenomena for adult honeybees and their larval forms must be considered. In this scenario, eco-friendly products derived from plant species have aroused great interest over the years. In recent decades, several studies have been carried out on the acaricidal efficacy of plant essential oils (EOs). Despite the swarming of laboratory and field studies, however, few EO products have come onto the market. Laboratory studies have often yielded different results even for the same plant species. The reason for this discrepancy lies in the various study techniques employed as well as in the variability of the chemical compositions of plants. The purpose of this review is to take stock of the research on the use of EOs to control the V. destructor parasite. It begins with an extensive discussion of the characteristics, properties, and mechanisms of action of EOs, and then examines the laboratory and field tests carried out. Finally, an attempt is made to standardize the results and open up new lines of study in future.

Ferula L., belonging to the Apiaceae family, is represented by about 170 species predominantly present in areas with a mild–warm–arid climate, including the Mediterranean region, North Africa and Central Asia. Numerous beneficial activities have been reported for this plant in traditional medicine, including antidiabetic, antimicrobial, antiproliferative, anti-dysentery, stomachache with diarrhea and cramps remedies. FER-E was obtained from the plant F. communis, and precisely from the root, collected in Sardinia, Italy. A total of 25 g of root was mixed with 125 g of acetone (ratio 1:5, room temperature). The solution was filtered, and the liquid fraction was subjected to high pressure liquid chromatographic separation (HPLC). In particular, 10 mg of dry root extract powder, from F. communis, was dissolved in 10.0 mL of methanol, filtered with a 0.2 µm PTFE filter and subjected to HPLC analysis. The net dry powder yield obtained was 2.2 g. In addition, to reduce the toxicity of FER-E, the component ferulenol was removed. High concentrations of FER-E have demonstrated a toxic effect against breast cancer, with a mechanism independent of the oxidative potential, which is absent in this extract. In fact, some in vitro tests were used and showed little or no oxidizing activity by the extract. In addition, we appreciated less damage on the respective healthy cell lines (breast), assuming that this extract could be used for its potential role against uncontrolled cancer growth. The results of this research have also shown that F. communis extract could be used together with tamoxifen, increasing its effectiveness, and reducing side effects. However, further confirmatory experiments should be carried out.

High salt load is a known noxious stimulus for vascular cells and a risk factor for cardiovascular diseases in both animal models and humans. The stroke-prone spontaneously hypertensive rat (SHRSP) accelerates stroke predisposition upon high-salt dietary feeding. We previously demonstrated that high salt load causes severe injury in primary cerebral endothelial cells isolated from SHRSP. This cellular model offers a unique opportunity to test the impact of substances toward the mechanisms underlying high-salt-induced vascular damage. We tested the effects of a bergamot polyphenolic fraction (BPF) on high-salt-induced injury in SHRSP cerebral endothelial cells. Cells were exposed to 20 mM NaCl for 72 h either in the absence or the presence of BPF. As a result, we confirmed that high salt load increased cellular ROS level, reduced viability, impaired angiogenesis, and caused mitochondrial dysfunction with a significant increase in mitochondrial oxidative stress. The addition of BPF reduced oxidative stress, rescued cell viability and angiogenesis, and recovered mitochondrial function with a significant decrease in mitochondrial oxidative stress. In conclusion, BPF counteracts the key molecular mechanisms underlying high-salt-induced endothelial cell damage. This natural antioxidant substance may represent a valuable adjuvant to treat vascular disorders.

Skeletal muscle atrophy is a condition characterized by a loss of muscle mass and muscle strength caused by an imbalance between protein synthesis and protein degradation. Muscle atrophy is often associated with a loss of bone mass manifesting as osteoporosis. The aim of this study was to evaluate if chronic constriction injury (CCI) of the sciatic nerve in rats can be a valid model to study muscle atrophy and consequent osteoporosis. Body weight and body composition were assessed weekly. Magnetic resonance imaging (MRI) was performed on day zero before ligation and day 28 before sacrifice. Catabolic markers were assessed via Western blot and Quantitative Real-time PCR. After the sacrifice, a morphological analysis of the gastrocnemius muscle and Micro-Computed Tomography (Micro-CT) on the tibia bone were performed. Rats that underwent CCI had a lower body weight increase on day 28 compared to the naive group of rats (p < 0.001). Increases in lean body mass and fat mass were also significantly lower in the CCI group (p < 0.001). The weight of skeletal muscles was found to be significantly lower in the ipsilateral hindlimb compared to that of contralateral muscles; furthermore, the cross-sectional area of muscle fibers decreased significantly in the ipsilateral gastrocnemius. The CCI of the sciatic nerve induced a statistically significant increase in autophagic and UPS (Ubiquitin Proteasome System) markers and a statistically significant increase in Pax-7 (Paired Box-7) expression. Micro-CT showed a statistically significant decrease in the bone parameters of the ipsilateral tibial bone. Chronic nerve constriction appeared to be a valid model for inducing the condition of muscle atrophy, also causing changes in bone microstructure and leading to osteoporosis. Therefore, sciatic nerve constriction could be a valid approach to study muscle–bone crosstalk and to identify new strategies to prevent osteosarcopenia.

Non-alcoholic fatty liver disease (NAFLD) is considered one of the leading causes of liver-related morbidity and mortality. NAFLD is a cluster of liver disorders that includes the accumulation of fat in the liver, insulin resistance, diffuse steatosis, lobular inflammation, fibrosis, cirrhosis and, in the latter stages, liver cancer. Due to the complexity of the disease and the multifactorial basis for the development of liver dysfunction, there is currently no unique drug treatment for NAFLD and the pharmacological options are inconclusive. In recent years, natural products have been studied for their potential beneficial effect in both preventing and treating fatty liver and its consequences in both local and systemic effects related to NAFLD. In particular, bergamot polyphenolic fraction (BPF), which is rich in natural polyphenols, and Cynara cardunculus wild type (which contains large quantities of sesquiterpenes, caffeic acid derivatives and luteolin) have both been investigated in both pre-clinical settings and clinical studies showing their effect in counteracting NAFLD-related health issues. In the present review we summarize the experimental and clinical evidence on the effect of BPF and Cynara extract alone or in their combination product (Bergacyn®) in NAFLD. In particular, data reported show that both extracts may synergize in counteracting the pathophysiological basis of NAFLD by inhibiting lipid accumulation in liver cells, oxidative stress and inflammation subsequent to liver syeatosis and, in the latter stages, liver fibrosis and tissue degeneration. Moreover, due to its powerful vasoprotective effect, the combination of BPF and Cynara extract (Bergacyn®) leads to improved endothelial dysfunction and cardioprotective response in both animal models of NAFLD, in veterinary medicine and in humans. Thus, supplementation with BPF and Cynara cardunculus extract and their combination product (Bergacyn®) represent a novel and potentially useful approach in preventing and treating NAFLD-associated complications.

Background and aim: Non-Alcoholic Fatty Liver Disease (NAFLD) represents a risk factor for cardiovascular diseases. NAFLD is worsened by the simultaneous occurrence of type 2 diabetes mellitus (T2DM) causing an enhancement of inflammatory and fibrotic processes. Although insulin resistance appears the link between NAFLD and T2DM, current pharmacological treatments of T2DM failed to produce relevant benefits in preventing T2DM-related liver dysfunction. In this randomized, double blind, placebo-controlled clinical study, we evaluated the effect of Bergacyn, an innovative formulation originating from the combination of Bergamot Polyphenolic Fraction (BPF) and Cynara cardunculus (CyC). Experimental procedure: 80 adult patients with a history of at least 12 months of T2DM and NAFLD received orally BPF (300 mg/daily) Cyc (300 mg/daily), separately or formulated in combination 50/50% (Bergacyn; 300 mg/daily), or placebo all containing 300 mg of bergamot albedo fibers micronized and co-grinded as excipients. Results and conclusion: Serum measurements and liver ultrasound analyses showed that concomitant administration of BPF and CyC produced significant improvement of NAFLD biomarkers in patients with T2DM. This effect was associated with a substantial reduction of oxidative stress/inflammatory biomarkers, thus contributing to a significant improvement of NO-mediated reactive vasodilation. Furthermore, the effect of Bergacyn showed a synergistic effect of both extracts, thus suggesting that this peculiar formulation represents a novel therapeutic strategy to counteract vascular inflammation and endothelial dysfunction in patients suffering from T2DM and NAFLD. Further studies in larger cohort of diabetic patients are required to better identify the potential of Bergacyn on metabolic disorders accompanying T2DM and NAFLD.

Reduced bioavailability of the nitric oxide (NO) signaling molecule has been associated with the onset of cardiovascular disease. One of the better-known and effective therapies for cardiovascular disorders is the use of organic nitrates, such as glyceryl trinitrate (GTN), which increases the concentration of NO. Unfortunately, chronic use of this therapy can induce a phenomenon known as “nitrate tolerance”, which is defined as the loss of hemodynamic effects and a reduction in therapeutic effects. As such, a higher dosage of GTN is required in order to achieve the same vasodilatory and antiplatelet effects. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a cardioprotective enzyme that catalyzes the bio-activation of GTN to NO. Nitrate tolerance is accompanied by an increase in oxidative stress, endothelial dysfunction, and sympathetic activation, as well as a loss of the catalytic activity of ALDH2 itself. On the basis of current knowledge, nitrate intake in the diet would guarantee a concentration of NO such as to avoid (or at least reduce) treatment with GTN and the consequent onset of nitrate tolerance in the course of cardiovascular diseases, so as not to make necessary the increase in GTN concentrations and the possible inhibition/alteration of ALDH2, which aggravates the problem of a positive feedback mechanism. Therefore, the purpose of this review is to summarize data relating to the introduction into the diet of some natural products that could assist pharmacological therapy in order to provide the NO necessary to reduce the intake of GTN and the phenomenon of nitrate tolerance and to ensure the correct catalytic activity of ALDH2.

Varroatosis is an important parasitic disease of Apis mellifera caused by the mite Varroa destructor (V. destructor). The parasite is able to transmit numerous pathogens to honeybees which can lead to colony collapse. In recent years, the effectiveness of authorized drug products has decreased due to increasing resistance phenomena. Therefore, the search for alternatives to commercially available drugs is mandatory. In this context, essential oils (EOs) prove to be a promising choice to be studied for their known acaricide properties. In this research work, the acaricide activity of EO vapours isolated from the epigeal part (whole plant) of fennel (Foeniculum vulgare sbps. piperitum) and its three fractions (leaves, achenes and flowers) against V. destructor was evaluated. The effectiveness of fumigation was studied using two methods. The first involved prolonged exposure of mites to oil vapour for variable times. After exposure, the five mites in each replicate were placed in a Petri dish with an Apis mellifera larva. Mortality, due to chronic toxicity phenomena, was assessed after 48 h. The second method aimed to translate the results obtained from the in vitro test into a semi-field experiment. Therefore, two-level cages were set up. In the lower compartment of the cage, a material releasing oil vapours was placed; in the upper compartment, Varroa-infested honeybees were set. The results of the first method showed that the increase in mortality was directly proportional to exposure time and concentration. The whole plant returned 68% mortality at the highest concentration (2 mg/mL) and highest exposure time (48 h control), while the leaves, achenes and flowers returned 64%, 52% and 56% mortality, respectively. In the semi-field experiment, a concentration up to 20 times higher than the one used in the in vitro study was required for the whole plant to achieve a similar mite drop of >50%. The results of the study show that in vitro tests should only be used for preliminary screening of EO activity. In vitro tests should be followed by semi-field tests, which are essential to identify the threshold of toxicity to bees and the effective dose to be used in field studies.

Eye health is crucial, and the onset of diseases can reduce vision and affect the quality of life of patients. The main causes of progressive and irreversible vision loss include various pathologies, such as cataracts, ocular atrophy, corneal opacity, age-related macular degeneration, uncorrected refractive error, posterior capsular opacification, uveitis, glaucoma, diabetic retinopathy, retinal detachment, undetermined disease and other disorders involving oxidative stress and inflammation. The eyes are constantly exposed to the external environment and, for this reason, must be protected from damage from the outside. Many drugs, including cortisonics and antinflammatory drugs have widely been used to counteract eye disorders. However, recent advances have been obtained via supplementation with natural antioxidants and nutraceuticals for patients. In particular, evidence has accumulated that polyphenols (mostly deriving from Citrus Bergamia) represent a reliable source of antioxidants able to counteract oxidative stress accompanying early stages of eye diseases. Luteolin in particular has been found to protect photoreceptors, thereby improving vision in many disease states. Moreover, a consistent anti-inflammatory response was found to occur when curcumin is used alone or in combination with other nutraceuticals. Additionally, Coenzyme Q10 has been demonstrated to produce a consistent effect in reducing ocular pressure, thereby leading to protection in patients undergoing glaucoma. Finally, both grape seed extract, rich in anthocyanosides, and polynsatured fatty acids seem to contribute to the prevention of retinal disorders. Thus, a combination of nutraceuticals and antioxidants may represent the right solution for a multi-action activity in eye protection, in association with current drug therapies, and this will be of potential interest in early stages of eye disorders.

Olea europaea L. is a plant belonging to the Oleaceae family, widely grown around the Mediterranean Basin and its leaves are a source of phenolic compounds with antioxidant and anti-inflammatory capacity. Among these, oleuropein and luteolin-7-O-glucoside represent two major polyphenolic compounds in olive-leaf extract. Herein, a polystyrene resin was used to recover the polyphenolic fraction from the acetone-water leaf extract from Nocellara del Belice cultivar, which showed the higher level of analysed bioactive compounds, compared to Carolea cultivar. The antioxidant activity of the extract concentrated in phenolic compounds (OLECp) was evaluated through a classical assay and electron paramagnetic resonance (EPR) for DPPH and hydroxyl radicals scavenging. Thus, the anti-inflammatory activity and the potential beneficial effects in reducing lipid accumulation in an in vitro model of NAFLD using McA-RH7777 cells exposed to oleic acid (OA) were evaluated. Nile Red and Oil Red O have been used to stain the lipid accumulation, while the inflammatory status was assessed by Cytokines Bioplex Assay. OLECp (TPC: 92.93 ± 9.35 mg GAE/g, TFC: 728.12 ± 16.04 mg RE/g; 1 g of extract contains 315.250 mg of oleuropein and 17.44 mg of luteolin-7-O-glucoside) exerted a good radical scavenging capability (IC50: 2.30 ± 0.18 mg/mL) with a neutralizing power against DPPH and hydroxyl radicals, as confirmed by the decreased signal area of the EPR spectra. Moreover, OLECp at concentration of 25, 50 and 100 μg/mL counteracted the intracellular inflammatory status, as result of decreased intracellular lipid content. Our results highlighted the multiple properties and applications of an O. europaea extract concentrated in polyphenols, and the possibility to formulate novel nutraceuticals with antioxidant properties, destined to ameliorate human health.

Both clinical and experimental evidence shows that iron deficiency (ID) correlates with an increased incidence of heart failure (HF). Moreover, data on iron supplementation demonstrating a beneficial effect in subjects with HF have mostly been collected in patients undergoing HF with reduced ejection fraction (HFrEF). Relatively poor data, however, exist on the potential of iron supplementation in patients with HF with preserved ejection fraction (HFpEF). Here, we report on data emerging from a multicentric, double-blind, randomized, placebo-controlled study investigating the effect of IV supplementation with a placebo or ferric carboxymaltose (FCM) on 64 subjects with HFpEF. ID was detected by the measurement of ferritin levels. These data were correlated with cardiac performance measurements derived from a 6 min walking test (6MWT) and with echocardiographic determinations of diastolic function. Moreover, an EndoPAT analysis was performed to correlate cardiac functionality with endothelial dysfunction. Finally, the determination of serum malondialdehyde (MDA) was performed to study oxidative stress biomarkers. These measurements were carried out before and 8 weeks after starting treatment with a placebo (100 mL of saline given i.v. in 10 min; n = 32) or FCM at a dose of 500 mg IV infusion (n = 32), which was given at time 0 and repeated after 4 weeks. Our data showed that a condition of ID was more frequently associated with impaired diastolic function, worse 6MWT and endothelial dysfunction, an effect that was accompanied by elevated MDA serum levels. Treatment with FCM, compared to the placebo, improved ferritin levels being associated with an improved 6MWT, enhanced cardiac diastolic function and endothelial reactivity associated with a significant reduction in MDA levels. In conclusion, this study confirmed that ID is a frequent comorbidity in patients with HFpEF and is associated with reduced exercise capacity and oxidative stress-related endothelial dysfunction. Supplementation with FCM determines a significant improvement in diastolic function and the exercise capacity of patients with HFpEF and is associated with an enhanced endothelial function and a reduced production of oxygen radical species.

Parasites, in particular, gastrointestinal nematodes (GINs) represent one of the main burdens affecting small ruminant farming and pose a serious threat to their health, welfare, productivity, and reproduction. The correct management of animals and the correct use of anthelmintic drugs are the pillars of the GIN control programs for small ruminants. However, globally due to the indiscriminate use of synthetic anthelmintics, there is a significant increase in anthelmintic resistance phenomena to one or more classes of drugs. Even if such a problem never represented a serious threat in southern Italy because of the favourable environmental conditions and because of the good farm management, the phenomenon is actually showing a steep increasing trend and requires alternative treatment measures and constant monitoring. The use of phytotherapies is considered a valuable alternative approach for GIN control in small ruminants and could help with reducing the amount of synthetic drugs used and the forthcoming anthelmintic resistance. From this perspective, the Calabria territory offers a wide number of plants with anthelmintic efficacy that could be helpful for this purpose. The aim of this study was to evaluate the anthelmintic efficacy of aqueous pomegranate (Punica granatum L.) macerate compared to the treatment with Ivermectin and Albendazole in sheep naturally infected with GINs. The pomegranate macerate derives from the ethnoveterinary knowledge of the Calabria region, Southern Italy. The anthelmintic efficacy was evaluated according to the faecal egg count reduction test (FECRt) using the FLOTAC techniques in two sheep farms in Southern Italy. The FECR was calculated from individual samples using the formula FECR = 100 × (1 − [T2/C2]). The treatment with Albendazole in the first farm showed an efficacy of 99.8% after 14 days and 94.8% after 21 days, while the treatment with Ivermectin in the second farm showed an efficacy of 99.9% after 14 days and 96.5% after 21 days of treatment. The pomegranate macerate, in both farms, showed a value of efficacy of around 50% from day 7 to day 21 after the treatment. Previous studies highlighted the presence of gallic acid as the main component in the pomegranate macerate, and its efficacy in nematode control has been as well previously demonstrated in other plant extracts. This in vivo study demonstrated the unequivocal efficacy of plant macerate in easily reducing 50% of the number of GIN eggs in sheep faeces. These results, obtained without the use of synthetic anthelmintics, indicate the use of green veterinary pharmacology as a sustainable alternative to the use of synthetic drugs to reduce the increase in drug resistance phenomena and the environmental impact.

Diabetes is a complex chronic disease, and among the affected patients, cardiovascular disease (CVD)is the most common cause of death. Consequently, the evidence for the cardiovascular benefit of glycaemic control may reduce long-term CVD rates. Over the years, multiple pharmacological approaches aimed at controlling blood glucose levels were unable to significantly reduce diabetes-related cardiovascular events. In this view, a therapeutic strategy combining SGLT2 inhibitors and plant extracts might represent a promising solution. Indeed, countering the main cardiometabolic risk factor using plant extracts could potentiate the cardioprotective action of SGLT2 inhibitors. This review highlights the main molecular mechanisms underlying these beneficial effects that could contribute to the better management of diabetic patients.

Varroa destructor is the most dangerous pest that poses a threat to honey bee survival. In recent years, increasingly worrying phenomena of drug resistance have occurred to various active ingredients of pharmaceutical formulations used to control this parasitosis. Determining the level of infestation is essential to preventing the inappropriate use and abuse of veterinary medicines, and to choose the most appropriate time for treatment. This comparative study investigates the sensitivity and diagnostic accuracy of two field techniques for diagnosing V. destructor infestations in hives. The EasyCheck device (Véto-pharma) was used in two of its application modes, namely, the sugar roll test and carbon dioxide (CO2) injection. The experiments were conducted on 15 samples of 300 bees each taken from the same frame and checked for the presence of mites using standard and modified field techniques in both uncaged and caged queen hive conditions. The results demonstrate that the sugar roll technique is significantly more effective and safer than CO2 injection, allowing for a higher accuracy in diagnosing a V. destructor infestation. Furthermore, the evaluation of mites present on bees in brood block conditions has proven to be particularly reliable. Considering the number of mites on the filter of the device as an additional step helps to implement the diagnostic accuracy of the CO2 injection technique, however, not achieving the efficacy results of the sugar roll.

Abstract Background Experimental and epidemiological studies show that bergamot polyphenolic fraction (BPF) ameliorates the serum lipemic profile, normalizes blood pressure and improves non alcoholic fatty liver disease in patients suffering from metabolic syndrome. Despite this evidence, the molecular mechanisms responsible for these beneficial effects remain unclear. The aim of our study is to clarify the effects of BPF on the lipoprotein assembly and to identify oxidative stress biomarkers correlating hyperlipidaemia and BPF-induced metabolic changes. Methods Male Wistar rats (180–200 g) were randomly assigned to receive a standard diet, a hypercholesterolemic diet or a hypercholesterolemic diet+BPF (20 mg/Kg/rat daily, gavage), respectively, for 90 days. Total cholesterol (tChol), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and fasting plasma glucose were evaluated at the baseline as well as at the end of the treatment. To assess the effect of BPF on the Lipid Transfer Protein System, detection of ACAT, LCAT, CETP, PON1, Apo A1 and Apo B have also been carried out. Finally, the lipid peroxidation biomarker (TBARS) and oxyLDL were also measured. Results BPF prevented tChol, LDL-C, TG and fasting plasma glucose enhancement and improved HDL-C. Treatment of hyperlipæmic rats with BPF significantly restored altered the serum concentration of lipemic biomarkers and the activity of ACAT, LCAT, CETP and PON1, an effect accompanied by the concomitant normalization of Apo A1 and APO B levels. In addition, TBARS levels were reduced significantly by the treatment with BPF. Conclusions BPF prevents diet-induced alteration of the lipid profile in rats, counteracting oxidative stress and improving the dysregulation of the Lipid Transfer Protein System. These data add new insights into the molecular mechanisms underlying the beneficial role of BPF in the therapy of hyperlipidaemia, thus suggesting a novel approach in the prevention of cardiovascular disease.

Multiple sclerosis (MS) is a neurological and inflammatory autoimmune disease of the Central Nervous System in which selective activation of T and B lymphocytes prompts a reaction against myelin, inducing demyelination and axonal loss. Although MS is recognized to be an autoimmune pathology, the specific causes are many; thus, to date, it has been considered a disorder resulting from environmental factors in genetically susceptible individuals. Among the environmental factors hypothetically involved in MS, nutrition seems to be well related, although the role of nutritional factors is still unclear. The gut of mammals is home to a bacterial community of about 2000 species known as the “microbiota”, whose composition changes throughout the life of each individual. There are five bacterial phylas that make up the microbiota in healthy adults: Firmicutes (79.4%), Bacteroidetes (16.9%), Actinobacteria (2.5%), Proteobacteria (1%) and Verrucomicrobia (0.1%). The diversity and abundance of microbial populations justifies a condition known as eubiosis. On the contrary, the state of dysbiosis refers to altered diversity and abundance of the microbiota. Many studies carried out in the last few years have demonstrated that there is a relationship between the intestinal microflora and the progression of multiple sclerosis. This correlation was also demonstrated by the discovery that patients with MS, treated with specific prebiotics and probiotics, have greatly increased bacterial diversity in the intestinal microbiota, which might be otherwise reduced or absent. In particular, natural extracts of Aloe vera and bergamot fruits, rich in polyphenols and with a high percentage of polysaccharides (mostly found in indigestible and fermentable fibers), appear to be potential candidates to re-equilibrate the gut microbiota in MS patients. The present review article aims to assess the pathophysiological mechanisms that reveal the role of the microbiota in the development of MS. In addition, the potential for supplementing patients undergoing early stages of MS with Aloe vera as well as bergamot fibers, on top of conventional drug treatments, is discussed.

Cancer is one of the most widespread diseases globally and one of the leading causes of death. Known cancer treatments are chemotherapy, surgery, radiation therapy, targeted hormonal therapy, or a combination of these methods. Antitumor drugs, with different mechanisms, interfere with cancer growth by destroying cancer cells. However, anticancer drugs are dangerous, as they significantly affect both cancer cells and healthy cells. In addition, there may be the onset of systemic side effects perceived and mutagenicity, teratogenicity, and further carcinogenicity. Many polyphenolic extracts, taken on top of common anti-tumor drugs, can participate in the anti-proliferative effect of drugs and significantly reduce the side effects developed. This review aims to discuss the current scientific knowledge of the protective effects of polyphenols of the genera Vaccinium, Citrus, Olea, and Cynara on the side effects induced by four known chemotherapy, Cisplatin, Doxorubicin, Tamoxifen, and Paclitaxel. In particular, the summarized data will help to understand whether polyphenols can be used as adjuvants in cancer therapy, although further clinical trials will provide crucial information.

Metabolic syndrome is not a single pathology, but a constellation of cardiovascular disease risk factors including: central and abdominal obesity, systemic hypertension, insulin resistance (or type 2 diabetes mellitus), and atherogenic dyslipidemia. The global incidence of Metabolic syndrome is estimated to be about one quarter of the world population; for this reason, it would be desirable to better understand the underlying mechanisms involved in order to develop treatments that can reduce or eliminate the damage caused. The effects of Metabolic syndrome are multiple and wide ranging; some of which have an impact on the central nervous system and cause neurological and neurodegenerative diseases. Autophagy is a catabolic intracellular process, essential for the recycling of cytoplasmic materials and for the degradation of damaged cellular organelle. Therefore, autophagy is primarily a cytoprotective mechanism; even if excessive cellular degradation can be detrimental. To date, it is known that systemic autophagic insufficiency is able to cause metabolic balance deterioration and facilitate the onset of metabolic syndrome. This review aims to highlight the current state of knowledge regarding the connection between metabolic syndrome and the onset of several neurological diseases related to it. Furthermore, since autophagy has been found to be of particular importance in metabolic disorders, the probable involvement of this degradative process is assumed to be responsible for the attenuation of neurological disorders resulting from metabolic syndrome.

Different bacterial families colonize most mucosal tissues in the human organism such as the skin, mouth, vagina, respiratory, and gastrointestinal districts. In particular, the mammalian intestine hosts a microbial community of between 1,000 and 1,500 bacterial species, collectively called “microbiota.” Co-metabolism between the microbiota and the host system is generated and the symbiotic relationship is mutually beneficial. The balance that is achieved between the microbiota and the host organism is fundamental to the organization of the immune system. Scientific studies have highlighted a direct correlation between the intestinal microbiota and the brain, establishing the existence of the gut microbiota–brain axis. Based on this theory, the microbiota acts on the development, physiology, and cognitive functions of the brain, although the mechanisms involved have not yet been fully interpreted. Similarly, a close relationship between alteration of the intestinal microbiota and the onset of several neurological pathologies has been highlighted. This review aims to point out current knowledge as can be found in literature regarding the connection between intestinal dysbiosis and the onset of particular neurological pathologies such as anxiety and depression, autism spectrum disorder, and multiple sclerosis. These disorders have always been considered to be a consequence of neuronal alteration, but in this review, we hypothesize that these alterations may be non-neuronal in origin, and consider the idea that the composition of the microbiota could be directly involved. In this direction, the following two key points will be highlighted: (1) the direct cross-talk that comes about between neurons and gut microbiota, and (2) the degree of impact of the microbiota on the brain. Could we consider the microbiota a valuable target for reducing or modulating the incidence of certain neurological diseases?

Background: The inappropriate use of antibiotics has increased selective pressure and the spread of multi-drug-resistant (MDR) pathogens, which reduces the possibility of effective treatment. A potential alternative therapeutic approach may be represented by essential oils, such as the distilled extract of bergamot (Citrus bergamia Risso et Poiteau). Such natural products exercise numerous biological activities, including antimicrobial effects. Methods: This work aimed to evaluate the kinetics of the bactericidal and fungicidal activity of the distilled extract of bergamot on MDR bacteria and fungi from clinical specimens using the time-kill assay. Furthermore, the antimicrobial activity of the distilled extract of bergamot on the morphology and cellular organization of clinical pathogens was evaluated by confocal laser scanning microscopy. Results: Our results demonstrated that the distilled extract of bergamot exhibited significant antimicrobial activity and a specific bactericidal effect against the bacterial and fungal strains tested. Furthermore, confocal microscope images clearly showed compromised membrane integrity, damage and cell death in bacterial samples treated with the distilled extract of bergamot. In addition, progressive alterations in cell-wall composition, cytoplasmic material and nucleus structure triggered by exposure to the distilled extract of bergamot were identified in the fungal samples considered. Conclusions: Our data suggest that the use of essential oils, such as distilled extract of bergamot (Citrus bergamia Risso et Poiteau), can represent a valid alternative therapeutic strategy to counteract antibiotic resistance of pathogens.

Varroatosis, caused by the Varroa destructor mite, is currently the most dangerous parasitic disease threatening the survival of honey bees worldwide. Its adverse effect on the welfare and health of honey bees requires the regular use of specific acaricides. This condition has led to a growing development of resistance phenomena towards the most frequently used drugs. In addition, another important aspect that should not be understated, is the toxicity and persistence of chemicals in the environment. Therefore, the identification of viable and environmentally friendly alternatives is urgently needed. In this scenario, essential oils are promising candidates. The aim of this study was to assess the contact toxicity, the fumigation efficacy and the repellent effect of Origanum heracleoticum L. essential oil (EO) against V. destructor mite. In the contact tests, each experimental replicate consisted of 15 viable adult female mites divided as follows: 5 treated with EO diluted in HPLC grade acetone, 5 treated with acetone alone (as negative control) and 5 treated with Amitraz diluted in acetone (as positive control). The EO was tested at concentrations of 0.125, 0.25, 0.5, 1 and 2 mg/mL. For each experimental replicate, mortality was manually assessed after one hour. The efficacy of EO fumigation was evaluated through prolonged exposure at different time intervals. After each exposure, the 5 mites constituting an experimental replicate were transferred to a Petri dish containing a honey bee larva and mortality was assessed after 48 h. The repellent action was investigated by implementing a directional choice test in a mandatory route. During the repellency tests the behavior of the mite (90 min after its introduction in the mandatory route) was not influenced by the EO. In contact tests, EO showed the best efficacy at 2 and 1 mg/mL concentrations, neutralizing (dead + inactivated) 90.9% and 80% of the mites, respectively. In fumigation tests, the mean mortality rate of V. destructor at maximum exposure time (90 min) was 60% and 84% at 24 and 48 h, respectively. Overall, these results demonstrate a significant efficacy of O. heracleoticum EO against V. destructor, suggesting a possible alternative use in the control of varroatosis in honey bee farms in order to improve Apis mellifera welfare and health and, consequently, the hive productions.

The maintenance of the physiological values of blood pressure is closely related to unchangeable factors (genetic predisposition or pathological alterations) but also to modifiable factors (dietary fat and salt, sedentary lifestyle, overweight, inappropriate combinations of drugs, alcohol abuse, smoking and use of psychogenic substances). Hypertension is usually characterized by the presence of a chronic increase in systemic blood pressure above the threshold value and is an important risk factor for cardiovascular disease, including myocardial infarction, stroke, micro- and macro-vascular diseases. Hypertension is closely related to functional changes in the endothelium, such as an altered production of vasoconstrictive and vasodilator substances, which lead to an increase in vascular resistance. These alterations make the endothelial tissue unresponsive to autocrine and paracrine stimuli, initially determining an adaptive response, which over time lead to an increase in risk or disease. The gut microbiota is composed of a highly diverse bacterial population of approximately 1014 bacteria. A balanced intestinal microbiota preserves the digestive and absorbent functions of the intestine, protecting from pathogens and toxic metabolites in the circulation and reducing the onset of various diseases. The gut microbiota has been shown to produce unique metabolites potentially important in the generation of hypertension and endothelial dysfunction. This review highlights the close connection between hypertension, endothelial dysfunction and gut microbiota.

Elevated serum cholesterol levels, either associated or not with increased triglycerides, represent a risk of developing vascular injury, mostly leading to atherothrombosis-related diseases including myocardial infarction and stroke. Natural products have been investigated in the last few decades as they are seen to offer an alternative solution to counteract cardiometabolic risk, due to the occurrence of side effects with the use of statins, the leading drugs for treating hyperlipidemias. Red yeast rice (RYR), a monacolin K-rich natural extract, has been found to be effective in counteracting high cholesterol, being its use accompanied by consistent warnings by regulatory authorities based on the potential detrimental responses accompanying its statin-like chemical charcateristics. Here we compared the effects of RYR with those produced by bergamot polyphenolic fraction (BPF), a well-known natural extract proven to be effective in lowering both serum cholesterol and triglycerides in animals fed a hyperlipidemic diet. In particular, BPF at doses of 10 mg/Kg given orally for 30 consecutive days, counteracted the elevation of both serum LDL cholesterol (LDL-C) and triglycerides induced by the hyperlipidemic diet, an effect which was accompanied by significant reductions of malondialdehyde (MDA) and glutathione peroxidase serum levels, two biomarkers of oxidative stress. Furthermore, the activity of BPF was associated to increased HDL cholesterol (HDL-C) levels and to strong reduction of Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels which were found increased in hyperlipidemic rats. In contrast, RYR at doses of 1 and 3 mg/Kg, produced only significant reduction of LDL-C with very poor effects on triglycerides, HDL-C, glutathione peroxidase, MDA and PCSK9 expression. This indicates that while BPF and RYR both produce serum cholesterol-lowering benefits, BPF produces additional effects on triglycerides and HDL cholesterol compared to RYR at the doses used throughout the study. These additional effects of BPF appear to be related to the reduction of PCSK9 expression and to the antioxidant properties of this extract compared to RYR, thereby suggesting a more complete protection from cardiometabolic risk.

Low-dose aspirin represents the best option in the secondary prevention of coronary artery disease, but its extensive use in primary prevention is limited by the occurrence of gastric mucosal lesions and increased risk of bleeding. We investigated the safety profile of a novel sublingual aspirin formulation in 200 healthy volunteers, randomly assigned to ten (n = 20 each) different 7-day once-daily treatment regimens. Gastric mucosal injury based on the modified Lanza score (MLS), the histopathology of gastric mucosa and the serum determination of thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 levels were evaluated at basal as well as after 7 days of each placebo or aspirin treatment regimen. In Groups A and B (placebo—oral and sublingual, respectively), no changes in MLS and in gastric mucosal micro-vessel diameter were found at day 7. In contrast, in Groups C and D (oral standard aspirin—100 and 50 mg daily, respectively), the median MLS was significantly increased. Very few changes were found in Groups E and F (standard sublingual aspirin—100 and 50 mg, respectively). Groups G and H (oral administration of micronized collagen-cogrinded aspirin) showed gastric protection compared to Groups C and D. Moreover, Groups I and L (sublingual collagen-cogrinded aspirin—100 and 50 mg, respectively) showed a significant reduction (Group I) or total abolition (Group L) of gastric mucosal lesions and no difference compared to the standard one in serum TXB2 and urinary 11-dehydro-TXB2 levels. In conclusion, our data show that the new formulation leads to a better safety profile compared to standard aspirin, representing a better therapeutic option for extended use in primary and secondary prevention of cardiovascular diseases.

Doxorubicin (Doxo) is a widely used antineoplastic drug which often induces cardiomyopathy, leading to congestive heart failure through the intramyocardial production of reactive oxygen species (ROS). Icariin (Ica) is a flavonoid isolated from Epimedii Herba (Berberidaceae). Some reports on the pharmacological activity of Ica explained its antioxidant and cardioprotective effects. The aim of our study was to assess the protective activities of Ica against Doxo-detrimental effects on rat heart-tissue derived embryonic cardiac myoblasts (H9c2 cells) and to identify, at least in part, the molecular mechanisms involved. Our results showed that pretreatment of H9c2 cells with 1 μM and 5 μM of Ica, prior to Doxo exposure, resulted in an improvement in cell viability, a reduction in ROS generation, the prevention of mitochondrial dysfunction and mPTP opening. Furthermore, for the first time, we identified one feasible molecular mechanism through which Ica could exerts its cardioprotective effects. Indeed, our data showed a significant reduction in Caveolin-1(Cav-1) expression levels and a specific inhibitory effect on phosphodiesterase 5 (PDE5a) activity, improving mitochondrial function compared to Doxo-treated cells. Besides, Ica significantly prevented apoptotic cell death and downregulated the main pro-autophagic marker Beclin-1 and LC3 lipidation rate, restoring physiological levels of activation of the protective autophagic process. These results suggest that Ica might have beneficial cardioprotective effects in attenuating cardiotoxicity in patients requiring anthracycline chemotherapy through the inhibition of oxidative stress and, in particular, through the modulation of Cav-1 expression levels and the involvement of PDE5a activity, thereby leading to cardiac cell survival.

Cancer is one of the leading causes of death globally, associated with multifactorial pathophysiological components. In particular, genetic mutations, infection or inflammation, unhealthy eating habits, exposition to radiation, work stress, and/or intake of toxins have been found to contribute to the development and progression of cancer disease states. Early detection of cancer and proper treatment have been found to enhance the chances of survival and healing, but the side effects of anticancer drugs still produce detrimental responses that counteract the benefits of treatment in terms of hospitalization and survival. Recently, several natural bioactive compounds were found to possess anticancer properties, capable of killing transformed or cancerous cells without being toxic to their normal counterparts. This effect occurs when natural products are associated with conventional treatments, thereby suggesting that nutraceutical supplementation may contribute to successful anticancer therapy. This review aims to discuss the current literature on four natural bioactive extracts mostly characterized by a specific polyphenolic profile. In particular, several activities have been reported to contribute to nutraceutical support in anticancer treatment: (1) inhibition of cell proliferation, (2) antioxidant activity, and (3) anti-inflammatory activity. On the other hand, owing to their attenuation of the toxic effect of current anticancer therapies, natural antioxidants may contribute to improving the compliance of patients undergoing anticancer treatment. Thus, nutraceutical supplementation, along with current anticancer drug treatment, may be considered for better responses and compliance in patients with cancer. It should be noted, however, that when data from studies with bioactive plant preparations are discussed, it is appropriate to ensure that experiments have been conducted in accordance with accepted pharmacological research practices so as not to disclose information that is only partially correct.

Heart failure (HF) characterized by cardiac remodeling is a condition in which inflammation and fibrosis play a key role. Dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) seems to produce good results. In fact, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory and antioxidant properties and different cardioprotective mechanisms. In particular, following their interaction with the nuclear factor erythropoietin 2 related factor 2 (NRF2), the free fatty acid receptor 4 (Ffar4) receptor, or the G-protein coupled receptor 120 (GPR120) fibroblast receptors, they inhibit cardiac fibrosis and protect the heart from HF onset. Furthermore, n-3 PUFAs increase the left ventricular ejection fraction (LVEF), reduce global longitudinal deformation, E/e ratio (early ventricular filling and early mitral annulus velocity), soluble interleukin-1 receptor-like 1 (sST2) and high-sensitive C Reactive protein (hsCRP) levels, and increase flow-mediated dilation. Moreover, lower levels of brain natriuretic peptide (BNP) and serum norepinephrine (sNE) are reported and have a positive effect on cardiac hemodynamics. In addition, they reduce cardiac remodeling and inflammation by protecting patients from HF onset after myocardial infarction (MI). The positive effects of PUFA supplementation are associated with treatment duration and a daily dosage of 1–2 g. Therefore, both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) define dietary supplementation with n-3 PUFAs as an effective therapy for reducing the risk of hospitalization and death in HF patients. In this review, we seek to highlight the most recent studies related to the effect of PUFA supplementation in HF. For that purpose, a PubMed literature survey was conducted with a focus on various in vitro and in vivo studies and clinical trials from 2015 to 2021.

Cardiovascular disease is the leading cause of death and disability in the Western world. In order to safeguard the structure and the functionality of the myocardium, it is extremely important to adequately support the cardiomyocytes. Two cellular organelles of cardiomyocytes are essential for cell survival and to ensure proper functioning of the myocardium: mitochondria and the sarcoplasmic reticulum. Mitochondria are responsible for the energy metabolism of the myocardium, and regulate the processes that can lead to cell death. The sarcoplasmic reticulum preserves the physiological concentration of the calcium ion, and triggers processes to protect the structural and functional integrity of the proteins. The alterations of these organelles can damage myocardial functioning. A proper nutritional balance regarding the intake of macronutrients and micronutrients leads to a significant improvement in the symptoms and consequences of heart disease. In particular, the Mediterranean diet, characterized by a high consumption of plant-based foods, small quantities of red meat, and high quantities of olive oil, reduces and improves the pathological condition of patients with heart failure. In addition, nutritional support and nutraceutical supplementation in patients who develop heart failure can contribute to the protection of the failing myocardium. Since polyphenols have numerous beneficial properties, including anti-inflammatory and antioxidant properties, this review gathers what is known about the beneficial effects of polyphenol-rich bergamot fruit on the cardiovascular system. In particular, the role of bergamot polyphenols in mitochondrial and sarcoplasmic dysfunctions in diabetic cardiomyopathy is reported.

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 μg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 μg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.

Doxorubicin is an anthracycline that is commonly used as a chemotherapy drug due to its cytotoxic effects. The clinical use of doxorubicin is limited due to its known cardiotoxic effects. Treatment with anthracyclines causes heart failure in 15–17% of patients, resulting in mitochondrial dysfunction, the accumulation of reactive oxygen species, intracellular calcium dysregulation, the deterioration of the cardiomyocyte structure, and apoptotic cell death. Polyphenols have a wide range of beneficial properties, and particular importance is given to Bergamot Polyphenolic Fraction; Oleuropein, one of the main polyphenolic compounds of olive oil; and Cynara cardunculus extract. These natural compounds have particular beneficial characteristics, owing to their high polyphenol contents. Among these, their antioxidant and antoproliferative properties are the most important. The aim of this paper was to investigate the effects of these three plant derivatives using an in vitro model of cardiotoxicity induced by the treatment of rat embryonic cardiomyoblasts (H9c2) with doxorubicin. The biological mechanisms involved and the crosstalk existing between the mitochondria and the endoplasmic reticulum were examined. Bergamot Polyphenolic Fraction, Oleuropein, and Cynara cardunculus extract were able to decrease the damage induced by exposure to doxorubicin. In particular, these natural compounds were found to reduce cell mortality and oxidative damage, increase the lipid content, and decrease the concentration of calcium ions that escaped from the endoplasmic reticulum. In addition, the direct involvement of this cellular organelle was demonstrated by silencing the ATF6 arm of the Unfolded Protein Response, which was activated after treatment with doxorubicin.

Atherothrombosis, a multifactorial and multistep artery disorder, represents one of the main causes of morbidity and mortality worldwide. The development and progression of atherothrombosis is closely associated with age, gender and a complex relationship between unhealthy lifestyle habits and several genetic risk factors. The imbalance between oxidative stress and antioxidant defenses is the main biological event leading to the development of a pro-oxidant phenotype, triggering cellular and molecular mechanisms associated with the atherothrombotic process. The pathogenesis of atherosclerosis and its late thrombotic complications involve multiple cellular events such as inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells (SMCs), extracellular matrix (ECM) alterations, and platelet activation, contributing to chronic pathological remodeling of the vascular wall, atheromatous plague formation, vascular stenosis, and eventually, thrombus growth and propagation. Emerging studies suggest that clotting activation and endothelial cell (EC) dysfunction play key roles in the pathogenesis of atherothrombosis. Furthermore, a growing body of evidence indicates that defective autophagy is closely linked to the overproduction of reactive oxygen species (ROS) which, in turn, are involved in the development and progression of atherosclerotic disease. This topic represents a large field of study aimed at identifying new potential therapeutic targets. In this review, we focus on the major role played by the autophagic pathway induced by oxidative stress in the modulation of EC dysfunction as a background to understand its potential role in the development of atherothrombosis.

The high incidence of obesity is associated with an increasing risk of several chronic diseases such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Sustained obesity is characterized by a chronic and unsolved inflammation of adipose tissue, which leads to a greater expression of proinflammatory adipokines, excessive lipid storage and adipogenesis. The purpose of this review is to clarify how inflammatory mediators act during adipose tissue dysfunction in the development of insulin resistance and all obesity-associated diseases. In particular, we focused our attention on the role of inflammatory signaling in brown adipose tissue (BAT) thermogenic activity and the browning of white adipose tissue (WAT), which represent a relevant component of adipose alterations during obesity. Furthermore, we reported the most recent evidence in the literature on nutraceutical supplementation in the management of the adipose inflammatory state, and in particular on their potential effect on common inflammatory mediators and pathways, responsible for WAT and BAT dysfunction. Although further research is needed to demonstrate that targeting pro-inflammatory mediators improves adipose tissue dysfunction and activates thermogenesis in BAT and WAT browning during obesity, polyphenols supplementation could represent an innovative therapeutic strategy to prevent progression of obesity and obesity-related metabolic diseases.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease that affects about 1% of the global population, with a female–male ratio of 3:1. RA preferably affects the joints, with consequent joint swelling and deformities followed by ankylosis. However, evidence has accumulated showing that patients suffering from RA can also develop extra-articular manifestations, including cardiovascular disease states, neuropathies, and multiorgan dysfunction. In particular, peripheral nerve disorders showed a consistent impact in the course of the disease (prevalence about 20%) mostly associated to vasculitis of the nerve vessels leading to vascular ischemia, axonal degeneration, and neuronal demyelination. The pathophysiological basis of this RA-associated microvascular disease, which leads to impairment of assonal functionality, is still to be better clarified. However, endothelial dysfunction and alterations of the so-called brain-nerve barrier (BNB) seem to play a fundamental role. This review aims to assess the potential mechanisms underlying the impairment of endothelial cell functionality in the development of RA and to identify the role of dysfunctional endothelium as a causative mechanism of extra-articular manifestation of RA. On the other hand, the potential impact of lifestyle and nutritional interventions targeting the maintenance of endothelial cell integrity in patients with RA will be discussed as a potential option when approaching therapeutic solutions in the course of the disease.