Polyphenols from berries of Aronia melanocarpa reduce the plasma lipid peroxidation induced by

Background. Oxidative stress in schizophrenia may be caused partially by the treatment of patients with antipsychotics. The aim of the study was to establish the effects of polyphenol compounds derived from berries of Aronia melanocarpa (Aronox) on the plasma lipid peroxidation induced by ziprasidone in vitro. Methods. Lipid peroxidation was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with ziprasidone (40 ng/ml; 139 ng/ml; and 250 ng/ml) alone and with Aronox (5 ug/ml; 50 ug/ml). Results. We observed a statistically significant increase of TBARS level after incubation of plasma with ziprasidone (40 ng/ml; 139 ng/ml; and 250 ng/ml) (after 24 h incubation: = 7.0× 10 −4 , = 1.6× 10 −3 , and = 2.7× 10 −3 , resp.) and Aronox lipid peroxidation caused by ziprasidone was significantly reduced. After 24-hour incubation of plasma with ziprasidone (40 ng/ml; 139 ng/ml; and 250 ng/ml) in the presence of 50 ug/ml Aronox, the level of TBARS was significantly decreased: = 6.5× 10 −8 , = 7.0× 10 −6 , and = 3.0× 10 −5 , respectively. Conclusion. Aronox causes a distinct reduction of lipid peroxidation induced by ziprasidone

CA-170 : a potent small-molecule PD-L1 inhibitor or not?

CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins – important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented. Using well-known in vitro methods: NMR binding assay, HTRF and cell-based activation assays, we clearly show that there is no direct binding between CA-170 and PD-L1. To strengthen our reasoning, we performed control experiments on AUNP-12 – a 29-mer peptide, which is a precursor of CA-170. Positive controls consisted of the well-documented small-molecule PD-L1 inhibitors: BMS-1166 and peptide-57

Discovery of inhibitory fragments that selectively target Spire2−FMN2 interaction

Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2–FMN2 but not the Spire1–FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and 1H–15N HSQC nuclear magnetic resonance. Extensive structure–activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chemical probes targeting the Spire2–FMN2 interaction

Synthesis and in vitro evaluation of anti-inflammatory, antioxidant, and anti-fibrotic effects of new 8-aminopurine-2,6-dione-based phosphodiesterase inhibitors as promising anti-asthmatic agents

Phosphodiesterase (PDE) inhibitors are currently an extensively studied group of compounds that can bring many benefits in the treatment of various inflammatory and fibrotic diseases, including asthma. Herein, we describe a series of novel N’-phenyl- or N’-benzylbutanamide and N’-arylidenebutanehydrazide derivatives of 8-aminopurine-2,6-dione (27–43) and characterized them as prominent pan-PDE inhibitors. Most of the compounds exhibited antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. The most active compounds (32–35 and 38) were evaluated in human bronchial epithelial cells (HBECs) derived from asthmatics. To better map the bronchial microenvironment in asthma, HBECs after exposure to selected 8-aminopurine-2,6-dione derivatives were incubated in the presence of two proinflammatory and/or profibrotic factors: transforming growth factor type β (TGF-β) and interleukin 13 (IL-13). Compounds 32–35 and 38 significantly reduced both IL-13- and TGF-β-induced expression of proinflammatory and profibrotic mediators, respectively. Detailed analysis of their inhibition preferences for selected PDEs showed high affinity for isoenzymes important in the pathogenesis of asthma, including PDE1, PDE3, PDE4, PDE7, and PDE8. The presented data confirm that structural modifications within the 7 and 8 positions of the purine-2,6-dione core result in obtaining preferable pan-PDE inhibitors which in turn exert an excellent anti-inflammatory and anti-fibrotic effect in the bronchial epithelial cells derived from asthmatic patients. This dual-acting pan-PDE inhibitors constitute interesting and promising lead structures for further anti-asthmatic agent discovery

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow 18F labeling that could be used for PET imaging. Radiolabeling, which is used in drug development and diagnosis, was applied to investigate the properties of those ligands and test them against tissue sections with diverse expression levels of PD-L1. We confirmed biological activity toward hPD-L1 for this inhibitor, comparable with BMS1166, while holding enhanced pharmacological properties. </p

Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe — recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency

Wstęp: Wyniki badań z ostatnich lat dokumentują wiele korzyści wynikających z działania witaminy D na organizm człowieka na wszystkichetapach jego życia. Większość badań epidemiologicznych sugeruje, że niedobór witaminy D jest powszechny wśród mieszkańców EuropyŚrodkowej. Naturalną konsekwencją tej sytuacji jest konieczność ciągłego uświadamiania społeczeństwu oraz środowisku medycznemu,jaką rolę odgrywa witamina D w rozwoju i funkcjonowaniu organizmu ludzkiego.Metody: Na podstawie przeglądu danych literaturowych Polski Zespół Wielodyscyplinarny opracował tezy dotyczące zasad suplementacjiwitaminą D, które przesłano do członków Komitetu Naukowego konferencji „Witamina D — minimum, maksimum, optimum”,19–20 Październik, 2012, Warszawa. W trakcie powyższej konferencji z udziałem 550 delegatów oraz Ekspertów różnych dziedzin medycynyomówiono i przedyskutowano propozycje wytycznych suplementacji witaminą D populacji Europy Środkowej.Wyniki: W efekcie przeprowadzonych dyskusji Zespół Ekspertów opracował wytyczne suplementacji witaminą D dla wszystkich grupwiekowych populacji Europy Środkowej. Określono również kryteria diagnostyczne charakteryzujące stan zaopatrzenia organizmu w witaminę D: deficyt witaminy D ustalono jako stężenie 25(OH)D &lt; 20 ng/mL (&lt; 50 nmol/L)], suboptymalne zaopatrzenie jako stężenie25(OH)D wynoszące 20–30 ng/mL (50–75 nmol/L), a stężenie 30–50 ng/mL (75–125 nmol/L) uznano za docelowe dla zapewnienia efektuplejotropowego witaminy D.Wnioski: Poprawa obecnego stanu zaopatrzenia witaminy D w grupach dzieci, młodzieży, osób aktywnych zawodowo i seniorówpowinna zostać włączona do priorytetów polityki zdrowotnej społeczeństw Europy Środkowej.Introduction: Adequate Vitamin D intake and its concentration in serum are important for bone health and calcium–phosphate metabolismas well as for optimal function of many organs and tissues. Documented trends in lifestyle, nutritional habits and physical activityappear to be associated with moderate or severe Vitamin D deficits resulting in health problems. Most epidemiological studies suggest thatVitamin D deficiency is prevalent among Central European populations. Concern about this problem led to the organising of a conferencefocused on overcoming Vitamin D deficiency.Methods: After reviewing the epidemiological evidence and relevant literature, a Polish multidisciplinary group formulated theses onrecommendations for Vitamin D screening and supplementation in the general population. These theses were subsequently sent to ScientificCommittee members of the ‘Vitamin D — minimum, maximum, optimum’ conference for evaluation based on a ten-point scale.With 550 international attendees, the meeting ‘Vitamin D — minimum, maximum, optimum’ was held on October 19–20, 2012 in Warsaw(Poland). Most recent scientific evidence of both skeletal and non-skeletal effects of Vitamin D as well as the results of panellists’ votingwere reviewed and discussed during eight plenary sessions and two workshops.Results: Based on many polemical discussions, including post-conference networking, the key opinion leaders established ranges ofserum 25-hydroxyVitamin D concentration indicating Vitamin D deficiency [&lt; 20 ng/mL (&lt; 50 nmol/L)], suboptimal status [20–30 ng/mL(50–75 nmol/L)], and target concentration for optimal Vitamin D effects [30–50 ng/mL (75–125 nmol/L)]. General practical guidelines regardingsupplementation and updated recommendations for prophylactic Vitamin D intakes in Central European neonates, infants, childrenand adolescents as well as in adults (including recommendations for pregnant and breastfeeding women and the elderly) were developed.Conclusions: Improving the Vitamin D status of children, adolescents, adults and the elderly must be included in the priorities of physicians,healthcare professionals and healthcare regulating bodies. The present paper offers elaborated consensus on supplementationguidance and population strategies for Vitamin D in Central Europe

Changes in disease burden in Poland between 1990-2017 in comparison with other Central European countries : a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND:Systematic collection of mortality/morbidity data over time is crucial for monitoring trends in population health, developing health policies, assessing the impact of health programs. In Poland, a comprehensive analysis describing trends in disease burden for major conditions has never been published. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides data on the burden of over 300 diseases in 195 countries since 1990. We used the GBD database to undertake an assessment of disease burden in Poland, evaluate changes in population health between 1990-2017, and compare Poland with other Central European (CE) countries. METHODS:The results of GBD 2017 for 1990 and 2017 for Poland and CE were used to assess rates and trends in years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life years (DALYs). Data came from cause-of-death registration systems, population health surveys, disease registries, hospitalization databases, and the scientific literature. Analytical approaches have been used to adjust for missing data, errors in cause-of-death certification, and differences in data collection methodology. Main estimation strategies were ensemble modelling for mortality and Bayesian meta-regression for disability. RESULTS:Between 1990-2017, age-standardized YLL rates for all causes declined in Poland by 46.0% (95% UI: 43.7-48.2), YLD rates declined by 4.0% (4.2-4.9), DALY rates by 31.7% (29.2-34.4). For both YLLs and YLDs, greater relative declines were observed for females. There was a large decrease in communicable, maternal, neonatal, and nutritional disease DALYs (48.2%; 46.3-50.4). DALYs due to non-communicable diseases (NCDs) decreased slightly (2.0%; 0.1-4.6). In 2017, Poland performed better than CE as a whole (ranked fourth for YLLs, sixth for YLDs, and fifth for DALYs) and achieved greater reductions in YLLs and DALYs than most CE countries. In 2017 and 1990, the leading cause of YLLs and DALYs in Poland and CE was ischaemic heart disease (IHD), and the leading cause of YLDs was low back pain. In 2017, the top 20 causes of YLLs and YLDs in Poland and CE were the same, although in different order. In Poland, age-standardized DALYs from neonatal causes, other cardiovascular and circulatory diseases, and road injuries declined substantially between 1990-2017, while alcohol use disorders and chronic liver diseases increased. The highest observed-to-expected ratios were seen for alcohol use disorders for YLLs, neonatal sepsis for YLDs, and falls for DALYs (3.21, 2.65, and 2.03, respectively). CONCLUSIONS:There was relatively little geographical variation in premature death and disability in CE in 2017, although some between-country differences existed. Health in Poland has been improving since 1990; in 2017 Poland outperformed CE as a whole for YLLs, YLDs, and DALYs. While the health gap between Poland and Western Europe has diminished, it remains substantial. The shift to NCDs and chronic disability, together with marked between-gender health inequalities, poses a challenge for the Polish health-care system. IHD is still the leading cause of disease burden in Poland, but DALYs from IHD are declining. To further reduce disease burden, an integrated response focused on NCDs and population groups with disproportionally high burden is needed

Local and Systemic Immunity Are Impaired in End-Stage-Renal-Disease Patients Treated With Hemodialysis, Peritoneal Dialysis and Kidney Transplant Recipients Immunized With BNT162b2 Pfizer-BioNTech SARS-CoV-2 Vaccine

Vaccination against COVID-19 in patients with end-stage renal disease (ESRD) on replacement therapy and kidney transplant recipients (KTRs) is particularly important due to the high mortality rate. Here, we tested the local and systemic immunity to the novel Pfizer BioNTech (BNT162b2) messenger RNA (mRNA) in ESRD, KTR patients, and healthy individuals (150 subjects). The ESRD group was divided into: hemodialysis (HD) and peritoneal dialysis (PD). We investigated the local and systemic immunity based on anti-N (nucleoprotein) and anti-S (spike1/2) Immunoglobulin A (IgA) and Immunoglobulin G (IgG) antibodies, respectively. Additionally, we performed an Interferon gamma (IFN-γ) release test Interferon-gamma release assay (IGRA) to monitor the cellular component of vaccine response. The control group had the highest level of anti-S IgG antibodies (153/2,080 binding antibody units (BAU)/ml) among all analyzed patients after the 1st and 2nd dose, respectively. The HD group (48/926 BAU/ml) had a diminished antibody level compared to PD (93/1,607 BAU/ml). Moreover, the seroconversion rate after the 1st dose was lower in HD than PD (56% vs. 86%). KTRs had extremely low seroconversion (33%). IgA-mediated immunity was the most effective in the control group, while other patients had diminished IgA production. We observed a lower percentage of vaccine responders based on the IFN-γ level in all research participants (100% vs. 85% in control, 100% vs. 80% in PD, 97% vs. 64% in HD). 63% of seropositive KTRs had a positive IGRA, while 28% of seronegative patients produced IFN-γ. Collectively, PD patients had the strongest response among ESRD patients. Two doses of the Pfizer vaccine are ineffective, especially in HD and KTRs. A closer investigation of ESRD and KTRs is required to set the COVID-19 vaccine clinical guidance.Clinical Trial Registration Numberwww.ClinicalTrials.gov, identifier: NCT04 905 86