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OBJECTIVE: Fluxonorm® is a dietary supplement that includes water-soluble extracts of Solidago virga-aurea, Phyllantus niruri, Epilobium angustifolium, Peumus boldus and Ononis spinosa. The aim of the present study was to evaluate the tolerability and efficacy of Fluxonorm® in improving lower urinary tract symptoms in patients with benign prostatic hyperplasia (BPH) in combination with standard of care. PATIENTS AND METHODS: Lower urinary tract symptoms can be improved by a marked anti-inflammatory action on the lower urinary tract (irritative symptoms) and/or by an anti-proliferative action (obstructive symptoms) on the prostate. Thirty patients were enrolled to evaluate the effect of Fluxonorm® on improving lower urinary tract symptoms. All patients complained of lower urinary tract symptoms (LUTS), such as hesitancy, poor flow, intermittent flow, incomplete voiding (obstructive symptoms), as well as increased frequency, nocturia and urgency (storage symptoms). All patients were treated with one tablet of Fluxonorm® (1200 mg) daily for 30 days to corroborate the results of our observation in which the food supplement (800 µg/mL) was also studied on the human prostate cancer PC3 cell line (antiproliferative activity) and on prostaglandin (PG)E2 production (anti- inflammatory activity). In addition, the effect of this compound on cyclooxygenase-2 (COX-2) gene expression was investigated. Finally, a bioinformatic analysis was conducted with the aim of unravelling the mechanism of action underlying the observed bio-pharmacological effects. RESULTS: As hypothesized in our preclinical research, adding Fluxonorm® to the therapy of enrolled patients improved all studied clinical parameters, including maximum flow (Qmax), after one month of treatment. In the preclinical evaluation, this formulation reduced PC3 cell viability and PGE2 production. The effects were also paralleled by reduced COX-2 gene expression and Fluxonorm®'s partly related content of catechin. While docking studies pointed out to the putative inhibition of matrix metalloproteinse-2 by gallic acid, as a further mechanism underlying the observed anti-proliferative effects, in PC3 cells exposed to Fluxonorm®. CONCLUSIONS: Fluxonorm® improved the efficacy of standard therapy, in terms of antioxidant/anti-inflammatory effects, for the management of lower urinary tract symptoms (LUTS). This could be related, albeit partially, to the blunting effect of this compound on PGE2 production. [ABSTRACT FROM AUTHOR]

Multiple studies demonstrated biological activities of aged black garlic, including anti-inflammatory, antioxidant, and cardioprotective effects. We aimed to investigate the protective effects of an aged black garlic water extract (ABGE) alone or in association with multivitamins consisting of combined Vitamins D, C, and B12, on mouse heart specimens exposed to E. coli lipopolysaccharide (LPS). Moreover, we studied the hydrogen sulphide (H 2 S) releasing properties and the membrane hyperpolarization effect of the Formulation composed by ABGE and multivitamins, using Human Aortic Smooth Muscle Cells (HASMCs). ABGE, vitamins D and C, and the Formulation suppressed LPS-induced gene expression of cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, nuclear factor-kB (NF-kB), and inducible nitric oxide synthase (iNOS) on mouse heart specimens. The beneficial effects induced by the extract could be related to the pattern of polyphenolic composition, with particular regard to gallic acid and catechin. The Formulation also increased fluorescence values compared to the vehicle, and it caused a significant membrane hyperpolarization of HASMCs compared to ABGE. To conclude, our present findings showed that ABGE, alone and in association with multivitamins, exhibited protective effects on mouse heart. Moreover, the Formulation increased intracellular H 2 S formation, further suggesting its potential use on cardiovascular disease.

Cannabis sativa L. belongs to the Cannabaceae family and includes annual, robust, fast-growing and generally dioecious plants. Industrial hemp, and particularly the inflorescences, has been recently recognized as important source of bioactive extracts with antioxidant and antimicrobial effects. The goal of the present study was to explore botanical, phytochemical, and biological properties of water and hydroalcoholic hemp pollen extracts from male inflorescences. The extracts from hemp pollen were found rich in phenolic compounds, such as hydroxytyrosol, coumaric acid, and hesperitin. The phenolic profile was also consistent with the observed scavenging/reducing, enzyme inhibitory, and antimicrobial properties of the extracts. Regarding the antimicrobial effects, Escherichia coli, Trycophyton rubrum, and T. tonsurans were the most sensitive to growth inhibitory effects (MIC values: 9.92-79.37 µg/mL) of the extracts. Whereas, null effects on prostate PC3 and myocyte C2C12 cell viability, in the range 1-1000 µg/mL, are consistent with MIC values and suggest extracts' biocompatibility. The experimental data obtained, which are not reflected in the literature as the topic of hemp pollen is almost completely unexplored, confirm the innovativeness of a product obtained directly from bees, which in the face of greater variability and complexity can reserve promising applications in food, pharmaceutical, and cosmetic sectors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

MOMAST ® GR25 is a polyphenolic granular complex from olive pressing juice with high total content in polyphenols. In this work, we evaluated the possible anti-inflammatory effects of MOMAST ® GR25 in both acute and chronic inflammatory models. MOMAST ® GR25 decreased the levels of prostaglandin (PG) E 2 and 8-iso-PGF 2α in isolated rat colon, liver, and heart specimens stimulated with lipopolysaccharide (LPS). In vivo, compared to controls, rats treated with MOMAST ® GR25 (100 mg/kg to 1 g/kg) showed a significant reduction in both licking/biting time in the formalin test. In a rat model of osteoarthritis by monoiodoacetate (MIA) injection, MOMAST ® GR25 showed pain-relieving properties when acutely administered, reducing mechanical hyperalgesia and spontaneous pain. Moreover, a repeated daily treatment with MOMAST ® GR25 (300 mg/kg) fully counteracted osteoarticular pain without the development of tolerance to the antinociceptive effect. Taken together, our present findings showed that MOMAST ® GR25 could represent a potential strategy for the treatment of inflammation and pain.

Novel 3(2 H )-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity in vivo and anti-proliferative effects against HCT116 cell lines in vitro . Artemia salina lethality test provided LC 50 values >100 µg/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model in vivo of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC 50 values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm.

Industrial hemp ( Cannabis sativa ) is traditionally cultivated as a valuable source of fibers and nutrients. Multiple studies also demonstrated antimicrobial, anti-proliferative, phytotoxic and insecticide effects of the essential oil from hemp female inflorescences. On the other side, only a few studies explored the potential pharmacological application of polar extracts from inflorescences. In the present study, we investigated the water extract from inflorescences of industrial hemp Futura 75 variety, from phytochemical and pharmacological point of view. The water extract was assayed for phenolic compound content, radical scavenger/reducing, chelating and anti-tyrosinase effects. Through an ex vivo model of toxicity induced by lipopolysaccharide (LPS) on isolated rat colon and liver, we explored the extract effects on serotonin, dopamine and kynurenine pathways and the production of prostaglandin (PG)E 2 . Anti-proliferative effects were also evaluated against human colon cancer HCT116 cell line. Additionally, antimycotic effects were investigated against Trichophyton rubrum, Trichophyton interdigitale, Microsporum gypseum. Finally, in silico studies, including bioinformatics, network pharmacology and docking approaches were conducted in order to predict the putative targets underlying the observed pharmacological and microbiological effects. Futura 75 water extract was able to blunt LPS-induced reduction of serotonin and increase of dopamine and kynurenine turnover, in rat colon. Additionally, the reduction of PGE 2 levels was observed in both colon and liver specimens, as well. The extract inhibited the HCT116 cell viability, the growth of T. rubrum and T. interdigitale and the activity of tyrosinase, in vitro, whereas in silico studies highlighting the inhibitions of cyclooxygenase-1 (induced by carvacrol), carbonic anhydrase IX (induced by chlorogenic acid and gallic acid) and lanosterol 14-α-demethylase (induced by rutin) further support the observed pharmacological and antimycotic effects. The present findings suggest female inflorescences from industrial hemp as high quality by-products, thus representing promising sources of nutraceuticals and cosmeceuticals against inflammatory and infectious diseases.

The stem bark (SB) of Piptadeniastrum africanum (PA) has been extensively used in African traditional medicinal systems. However, there is a dearth of scientific information regarding its possible activity in the management of type II diabetes, Alzheimer's disease, and skin hyperpigmentation disorders. This study therefore attempted to elucidate the in vitro inhibitory action of ethyl acetate, methanol, and water extracts of P. africanum stem bark (PA-SB) on α-amylase, α-glucosidase, acetylcholinesterase, butyrylcholinesterase, and tyrosinase. Cell viability, catecholamine, and 3-hydroxykynurenine levels of hypothalamic HypoE22 cells exposed to PA-SB extracts were also investigated. The phytochemical profiles of the extracts were determined by high performance liquid chromatography (HPLC) and antioxidant properties were investigated. Saponin (867.42 mg quillaja equivalent/g) and tannin (33.81 mg catechin equivalent/g) contents were higher in the methanol extract. Multiple dihydroxy-trimethoxy(iso)flavone isomers, loliolide, eriodictyol, naringenin, luteolin, chrysoeriol, apigenin, and liquiritigenin, were characterized from PA-SB extracts using HPLC. The methanol extract of PA-SB showed highest inhibitory activity against acetylcholinesterase (4.88 mg galantamine equivalent (GALAE)/g extract), butyrylcholinesterase (5.37 mg GALAE/g extract), and tyrosinase (154.86 mg kojic acid equivalent/g extract) while α-glucosidase was effectively inhibited by the ethyl acetate extract (15.22 mmol acarbose equivalent/g extract). The methanol extract of PA-SB also showed potent antioxidant properties (493.87, 818.12, 953.07, and 732.19 mg Trolox equivalent/g extract, for 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS), cupric reducing antioxidant capacity (CUPRAC), and ferric reducing antioxidant power (FRAP) assays, respectively). PA-SB extracts exhibited antioxidant activity and promising inhibition against key enzymes related to type II diabetes, Alzheimer's disease, and skin hyperpigmentation disorders. Additionally, all extracts were able to contrast hydrogen peroxide-induced oxidative stress, in HypoE22 cells, thus restoring basal catecholamine and 3-hydroxykinurenine levels, whereas only methanol and water extracts stimulated basal dopamine release. Overall, data from the present study contribute to the biological assessment of P. africanum that appears to be a promising source of natural compounds with protective and neuromodulatory effects., Competing Interests: The authors declare no conflict of interest.

In the present study, we investigated the water extract of Harpagophytum procumbens DC. ex Meisn. in an experimental model of inflammatory bowel diseases (IBDs). Additionally, a microbiological investigation was carried out to discriminate the efficacy against bacterial and fungal strains involved in IBDs. Finally, an untargeted proteomic analysis was conducted on more than one hundred colon proteins involved in tissue morphology and metabolism. The extract was effective in blunting the production of oxidative stress and inflammation, including serotonin, prostaglandins, cytokines, and transcription factors. Additionally, the extract inhibited the growth of Candida albicans and C. tropicalis . The extract was also able to exert a pro-homeostatic effect on the levels of a wide plethora of colon proteins, thus corroborating a protective effect. Conversely, the supraphysiological downregulation of cytoskeletal-related proteins involved in tissue morphology and antimicrobial barrier function suggests a warning in the use of food supplements containing H. procumbens extracts., Competing Interests: The authors declare no conflict of interest.

Phlomis fruticosa L. and P. herba-venti are species belonging to the Lamiaceae family, which have been traditionally used to prepare tonic and digestive drinks. Multiple studies also demonstrated the inhibitory effects of P. fruticosa extracts and essential oil against oxidative/proinflammatory pathways and bacterial strains deeply involved in ulcerative colitis. Considering these findings, the present study evaluated the effects of alcoholic P. fruticosa and P. herba-venti leaf extracts in isolated rat colon challenged with Escherichia coli lipopolysaccharide (LPS), an ex vivo experimental paradigm of ulcerative colitis. In this context, we assayed colon levels of pro-oxidant and proinflammatory biomarkers, including nitrites, malondialdehyde (MDA), lactate dehydrogenase (LDH), and serotonin (5-HT). Additionally, the extracts have been tested in order to evaluate possible inhibitory effects on specific bacterial and fungal strains involved in ulcerative colitis. Alcoholic P. fruticosa and P. herba-venti extracts were able to blunt LPS-induced nitrite, MDA, 5-HT, and LDH levels in isolated rat colon. The same extracts also inhibited the growth of Pseudomonas aeruginosa, E. coli, Staphylococcus aureus, Candida albicans and Candida tropicalis. In conclusion, our findings show a potential role exerted by alcoholic P. fruticosa and P. herba-venti in managing the clinical symptoms related to ulcerative colitis., (© 2019 John Wiley & Sons, Ltd.)

Ethyl acetate (EA), methanol (MeOH), and aqueous extracts of aerial parts of Anthemis tinctoria var. pallida (ATP) and A. cretica subsp. tenuiloba (ACT) were investigated for their phenol and flavonoid content, antioxidant, and key enzyme inhibitory potentials. All extracts displayed antiradical effects, with MeOH and aqueous extracts being a superior source of antioxidants. On the other hand, EA and MeOH extracts were potent against AChE and BChE. Enzyme inhibitory effects against tyrosinase and α-glucosidase were observed, as well. We also studied Anthemis extracts in an ex vivo experimental neurotoxicity paradigm. We assayed extract influence on oxidative stress and neurotransmission biomarkers, including lactate dehydrogenase (LDH) and serotonin (5-HT), in isolated rat cortex challenged with K + 60 mM Krebs-Ringer buffer (excitotoxicity stimulus). An untargeted proteomic analysis was finally performed in order to explore the putative mechanism in the brain. The pharmacological study highlighted the capability of ACT water extract to blunt K + 60 mM increase in LDH level and 5-HT turnover, and restore physiological activity of specific proteins involved in neuron morphology and neurotransmission, including NEFMs, VAMP-2, and PKCγ, thus further supporting the neuroprotective role of ACT water extract.

Multiple studies revealed the potential application of high quality saffron byproducts as cheap sources of bioactive compounds endowed with antioxidant activity. In the present study, we analyzed the total fatty acids of the anthers, and explored the pharmacological and toxicological potential of anthers, by evaluating genotoxic and protective effects in multiple cell lines, brine shrimps and isolated rat tissues. The phytochemical analyses showed that anthers are rich in long chain fatty acids most of which are unsaturated (80.51%). Particularly, anther water extract revealed to be well tolerated by multiple cell lines, and able to modulate reactive oxygen species (ROS) levels, without exerting either genotoxic or cytotoxic effects. The same extract was also able to blunt lipopolysaccharide (LPS)-induced nitrite and malondialdehyde (MDA) in isolated rat tissues. On the other hand, considering the concomitant null effect on HCT116 cell migration, in wound healing experimental paradigm, our findings suggest the efficacy of water anther extract as protective agent without any direct reverting effects on lesioned tissues. Concluding, the promising results, deriving from the pharmacological and toxicological evaluations, support the valorization of saffron anthers as a strategy to optimize and develop the productive chain of Abruzzo saffron., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate whether 5 × 5 mm dental implants with a novel nanostructured calcium-incorporated titanium surface could be an alternative to implants at least 10-mm long placed in bone augmented with bone substitutes in posterior atrophic jaws., Materials and Methods: Forty patients with atrophic posterior (premolar and molar areas) mandibles having 5- to 7-mm bone height above the mandibular canal, and 40 patients with atrophic maxillae having 4- to 6-mm bone height below the maxillary sinus, were randomised according to a parallel-group design to receive one to three 5-mm implants or one to three at least 10-mm long implants in augmented bone at two centres. All implants had a diameter of 5 mm. Mandibles were vertically augmented with interpositional bovine bone blocks covered with resorbable barriers. Implants were placed after 4 months. Maxillary sinuses were augmented with particulated porcine bone via a lateral window covered with resorbable barriers and implants were placed simultaneously. All implants were submerged and loaded after 4 months with provisional prostheses. Four months later, definitive screw-retained or provisionally cemented metal-ceramic or zirconia prostheses were delivered. Patients were followed to 5 years post-loading and the outcome measures were: prosthesis and implant failures, any complication and peri-implant marginal bone level changes., Results: Sixteen patients dropped out before the 5-year evaluation (four short mandibles, three short maxillae, six augmented mandibles and three augmented maxillae). In mandibles, two grafted patients were not prosthetically rehabilitated because of multiple complications, and three implants failed in the same patient (one was a replacement implant) versus one patient who lost his short implant and crown 2 years after loading. In maxillae one short implant failed with its provisional crown 3 months post-loading. There were no statistically significant differences in prostheses (difference in proportion = -0.003; 95% CI: -0.14 to 0.13; P = 1.000) and implant failures (difference in proportion = -0.03; 95% CI: -0.17 to 0.09; P = 0.609) up to 5 years after loading. Significantly more complications occurred at mandibular grafted sites: 17 augmented patients were affected by complications versus nine patients treated with short implants in mandibles (difference in proportion = 0.39; 95% CI: 0.10 to 0.62; P = 0.013). In the maxilla seven sinus-elevated patients versus two patients treated with short implants were affected by complications, the difference not being statistically significant (difference in proportion = 0.25; 95% CI: -0.04 to 0.49; P = 0.128). Patients with mandibular short implants lost on average 1.22 mm of peri-implant bone at 5 years and patients with 10-mm or longer mandibular implants lost 1.70 mm. Patients with maxillary short implants lost on average 1.25 mm of peri-implant bone at 5 years and patients with 10-mm or longer maxillary implants lost 1.73 mm. Longer implants showed a greater bone loss up to 5 years after loading than short implants both in maxillae (mean difference: -0.48 mm; 95% CI: -0.89 to -0.07 mm; P = 0.024) and in mandibles (mean difference: -0.48 mm; 95% CI: -0.79 to -0.18 mm; P = 0.004)., Conclusions: Five years after loading, 5 × 5 mm implants achieved similar results to longer implants placed in augmented bone. Short implants might be a preferable choice to bone augmentation especially in posterior mandibles since the treatment is faster, cheaper and associated with less morbidity; however, 10-year post-loading data are necessary before making reliable recommendations., Competing Interests: Conflict of interest statement: MegaGen (Implant, Gyeongbuk, South Korea) partially supported this trial and donated implants and prosthetic components used in this study. Tecnoss (Giaveno, Italy) donated the bone substitutes and the barriers. Data property belonged to the authors and the manufacturers did not interfere with the conduct of the trial or the publication of its results.

The authors describe a case of cutaneous neuroendocrine (Merkell cell) carcinoma in a patient previously treated for Chronic Lymphocytic Leukaemia (CLL). The authors discuss some of the mechanisms concerning the increased frequency of a second tumour in patients with CLL and focus attention on the high incidence in CLL of secondary tumours, especially skin tumours, of which Merkell cell carcinoma is a rare example. The authors consider the possible therapeutic approaches, reported in the literature, for the treatment of this particular skin carcinoma, which on account of its aggressiveness and the preexistence of a leukaemic process requires a particularly careful therapeutic approach.

This study aimed to explore the 24-h patterns of stroke volume, cardiac output, and peripheral vascular resistance along with other correlated variables, such as left ventricular ejection time, ejection velocity index, thoracic fluid index, heart rate, and blood pressure. The study was performed on 12 clinically healthy subjects by means of a noninvasive beat-to-beat monitoring using the thoracic electric bioimpedance technique associated with the automated sphygmomanometric recording. Time data series were analyzed by means of chronobiological procedures. The results documented the occurrence of a circadian rhythm for all the variables investigated, giving relevance to the beat-to-beat bioperiodicity of cardiac output and peripheral vascular resistance. Temporal quantification of the investigated variables may be useful for a better insight of the chronophysiology of the cardiovascular apparatus.

The present study is aimed to investigate the circadian rhythm (CR) of heart rate (HR) in acute rejecting and non-rejecting heart transplanted patients (HTP). The purpose is to provide evidence that an impairment in the HR CR may have a role in predicting episodes of acute rejection in HTP. The study was carried out on 32 Holter monitorings of 13 patients: 9 Holter monitorings were carried out during an episode of acute rejection documented by endomyocardial biopsy. Time data series were analyzed by Cosinor method in order to validate the occurrence of HR CR. The Cosinor analysis found a highly statistically significant HR CR in non-rejecting HTP. The occurrence of the HR CR was not statistically validated in acute rejecting HTP. These findings suggest that the lack of a periodic variability in the 24-hour HR pattern may be useful to diagnose acute heart rejection.

This report deals with three cases of Bartter's syndrome whose symptomatology was associated with indirect hyperbilirubinemia. The bilirubin disorder was suggestive of Gilbert's syndrome, with no pathological findings being detected as far as the liver function was concerned. Furthermore, the unconjugated fraction of bilirubin increased after fasting. The therapy with indomethacin exerted beneficial effects on both electrolytes and bilirubin disorders, and the patients recovered a good healthy state. These findings suggest the possibility that Bartter's syndrome may coexist in a variety associated with indirect hyperbilirubinemia.