Neurotensin(8–13) analogs as dual NTS1 and NTS2 receptor ligands with enhanced effects on a mouse model of Parkinson's disease

: The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of PD. In this study, we used a virtually guided molecular modeling approach to predict the activity of NT(8-13) analogs by investigating the docking models of ligands designed for binding to the human NTS1 and NTS2 receptors. The importance of the residues at positions 8 and/or 9 for hNTS1 and hNTS2 receptor binding affinity was experimentally confirmed by radioligand binding assays. Further in vitro ADME profiling and in vivo studies revealed that, compared to the parent peptide NT(8-13), compound 10 exhibited improved stability and BBB permeability combined with a significant enhancement of the motor function and memory in a mouse model of PD. The herein reported NTS1/NTS2 dual-specific NT(8-13) analogs represent an attractive tool for the development of therapeutic strategies against PD and potentially other CNS disorders

Apple polyphenols in human and animal health*

Apples contain substantial amounts of polyphenols, and diverse phenolics mainly flavonoids and phenolic acids, have been identified in their flesh and skins. This work aimed to analyze the overall landscape of the research literature published to date on apple phenolic compounds in the context of human and animal health. The Web of Science Core Collection electronic database was queried with (apple* polyphenol*) AND (health* OR illness* OR disease* OR medic* OR pharma*) to identify relevant papers covering these words and their derivatives in the titles, abstracts, and keywords. The resulted 890 papers were bibliometrically analyzed. The VOSviewer software was utilized to produce term maps that illustrate how the frequent phrases fared in terms of publication and citation data. The apple polyphenol papers received global contributions, particularly from China, Italy, the United States, Spain, and Germany. Examples of frequently mentioned chemicals/chemical classes are quercetin, anthocyanin, catechin, epicatechin, and flavonol, while examples of frequently mentioned medical conditions are cardiovascular disease, atherosclerosis, diabetes, Alzheimers disease, and obesity. The potential health benefits of apple polyphenols on humans and animals are diverse and warrant further study.Authors acknowledge the support from The National Centre for Research and Development (NCBR) of Poland (project number POIR.01.01.01-00-0593/18).info:eu-repo/semantics/publishedVersio

Resveratrol, a popular dietary supplement for human and animal health: Quantitative research literature analysis - a review

Resveratrol is a stilbene-type bioactive molecule with a broad spectrum of reported biological effects. In this sense, the current work provides a comprehensive literature analysis on resveratrol, representing a highly-researched commercially available dietary ingredient. Bibliometric data were identified by means of the search string TOPIC=(resveratrol*) and analyzed with the VOSviewer software, which yielded 17,561 publications extracted from the Web of Science Core Collection electronic database. The ratio of original articles to reviews was 9.5:1. More than half of the overall manuscripts have been published since 2013. Major contributing countries were USA, China, Italy, South Korea, and Spain. Most of the publications appeared in journals specialized in biochemistry and molecular biology, pharmacology and pharmacy, food science technology, cell biology, or oncology. The phytochemicals or phytochemical classes that were frequently mentioned in the keywords of analyzed publications included, in descending order: resveratrol, trans-resveratrol, polyphenols, flavonoids, quercetin, stilbenes, curcumin, piceatannol, cis-resveratrol, and anthocyanins.Atanas G. Atanasov and Dongdong Wang acknowledge the support by the Polish KNOW (Leading National Research Centre) Scientific Consortium “Healthy Animal - Safe Food,” decision of Ministry of Science and Higher Education No. 05-1/KNOW2/2015 and the European Union under the European Regional Development Fund (Homing/2017-4/41). Antoni Sureda was supported by the Institute of Health Carlos III (Project CIBEROBN CB12/03/30038).info:eu-repo/semantics/publishedVersio

Resveratrol, a popular dietary supplement for human and animal health: Quantitative research literature analysis-a review

Resveratrol is a stilbene-type bioactive molecule with a broad spectrum of reported biological effects. In this sense, the current work provides a comprehensive literature analysis on resveratrol, representing a highly-researched commercially available dietary ingredient. Bibliometric data were identified by means of the search string TOPIC=(“resveratrol*”) and analyzed with the VOSviewer software, which yielded 17,561 publications extracted from the Web of Science Core Collection electronic database. The ratio of original articles to reviews was 9.5:1. More than half of the overall manuscripts have been published since 2013. Major contributing countries were USA, China, Italy, South Korea, and Spain. Most of the publications appeared in journals specialized in biochemistry and molecular biology, pharmacology and pharmacy, food science technology, cell biology, or oncology. The phytochemicals or phytochemical classes that were frequently mentioned in the keywords of analyzed publications included, in descending order: resveratrol, trans-resveratrol, polyphenols, flavonoids, quercetin, stilbenes, curcumin, piceatannol, cis-resveratrol, and anthocyanins

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial

Background: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. Methods: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. Findings: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference −1·1% [95% CI −14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI −9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. Interpretation: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. Funding: Cidara Therapeutics and Mundipharma