Effect of vitamin D metabolites and gene expression of vitamin D receptor, and 1-alpha-hydroxylase related to the sperm quality.

The incidence of male fertility disorders has increased greatly due to various genetic and lifestyle factors. Recently, it has been hypothesized that vitamin D may be involved with idiopathic infertility. The goal of the study was to determine the effect and relationship between blood vitamin D metabolites, intracellular sperm vitamin D levels, and gene expression of 1-α-hydroxylase and VDR, with regard to semen quality. Seventy volunteers aged 25-45 were involved in the study. According to spermogram analysis, participants were stratified into normozoospermic control group, non-normozoospermic target group, and oligoasthenoteratozoospermic group. Vitamin D metabolites (total 25-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol) in blood and spermatozoa were determined by ELISA. Free and bioavailable 25-hydroxycholecalciferol were calculated using the Vermeulen equation. mRNA expression of VDR and 1-α hydroxylase was evaluated by qPCR. Free and bioavailable 25-hydroxycholecalciferol were significantly higher in the control group compared to the target group and compared to the oligoasthenoteratozoospermic group . Intracellular sperm 1,25-dihydroxycholecalciferol was higher in the control group compared to the target group. The mRNA levels of 1- α-hydroxylase were significantly higher in the control samples, while VDR expression was significantly higher in the target group. Significant positive correlations were established between free and bioavailable 25-hydroxycholecalciferol with sperm motility and morphology. Vitamin D metabolites in blood and intracellular sperm 1,25-dihydroxycholecalciferol seem to exert beneficial effects on sperm motility and morphology. Regarding sperm quality, these effects are more pronounced in the free and bioavailable 25OHD compared to the total 25OHD in blood. Higher expression of 1-α-hydroxylase likely leads to higher intracellular levels of 1,25-dihydroxycholecalciferol, which could contribute to sperm motility and morphology. Higher VDR expression may be a compensatory mechanism related to lower intracellular sperm 1,25-dihydroxycholecalciferol.

KRAS Mutation Status in Bulgarian Patients with Advanced and Metastatic Colorectal Cancer.

RAS somatic variants are predictors of resistance to anti-EGFR therapy for colorectal cancer (CRC) and affect the outcome of the disease. Our study aimed to evaluate the frequency of RAS, with a focus on KRAS variants, and their association with tumor location and some clinicopathological characteristics in Bulgarian CRC patients. We prospectively investigated 236 patients with advanced and metastatic CRC. Genomic DNA was extracted from FFPE tumor tissue samples, and commercially available kits were used to detect RAS gene somatic mutations via real-time PCR. A total of 115 (48.73%) patients tested positive for RAS mutations, with 106 (44.92%) testing positive for KRAS mutations. The most common mutation in exon 2 was c.35G>T p.Gly12Val (32.56%). We did not find a significant difference in KRAS mutation frequency according to tumor location. However, patients with a mutation in exon 4 of KRAS were 3.23 times more likely to have a tumor in the rectum than in other locations (95% CI: 1.19-8.72, p = 0.021). Studying the link between tumor location and KRAS mutations in exon 4 is crucial for better characterizing CRC patients. Further research with larger cohorts, especially in rectal cancer patients, could provide valuable insights for patient follow-up and treatment selection.

Sambucus ebulus (Elderberry) Fruits Modulate Inflammation and Complement System Activity in Humans.

Sambucus ebulus (SE) fruits are used for immune stimulation and amelioration of gastrointestinal inflammatory conditions. Currently, there is no scientific evidence of their effects on various aspects of the immune response mechanisms in humans. The purpose of this study was to evaluate the immunomodulatory potential of SE fruit infusion intake in healthy humans. Anthocyanin content was determined with UPLC-ESI-MS/MS. Fifty-three volunteers enrolled in a 4-week SE infusion intake intervention. Blood count, serum total protein, Interleukin 1 beta (IL-1ß), Interleukin 6 (IL-6), Tumor Necrosis Factor Alpha (TNFα), High-sensitivity C-reactive protein (hs-CRP), C3, and C4 levels were measured on automatic analyzers, and Interleukin 8 (IL-8) was measured manually with an ELISA kit. Cyanidin-3-O-galactoside (48.15 mg/g DW), followed by cyaniding-3-sambubioside (43.41 ± 1.07 mg/g DW), were the most abundant anthocyanins in SE samples. A significant decrease in total protein (2.82%), IL-6 (20.15%), TNFα (5.38%), IL-8 (5.50%), C3 (4.16%), and C4 (14.29%) was established in the whole group. Total protein, IL-8, TNFα, and C4 decreased in women (3.11%, 4.76%, 5.09%, and 11.11%), and IL-6 decreased (40.61%) in men. Hb (1.20%) and hematocrit (1.55%) levels decreased in the whole group and in the women group (1.61% and 2.20%). SE fruits exert immune-modulatory activity as revealed by decreased pro-inflammatory status and complement activity markers in healthy volunteers after a 4-week intervention.

Association between Nfr2, HO-1, NF-kB Expression, Plasma ADMA, and Oxidative Stress in Metabolic Syndrome.

Endothelial dysfunction is one of the major factors in the pathogenesis of metabolic syndrome (MetS), and its molecular mechanisms are not completely understood. The present study aimed to examine the connection between nuclear factor2-related factor2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), heme oxygenase 1 (HO-1), and plasma asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) in people with MetS. Participants in the study were as follows: with MetS (n = 30) and without MetS (Control) (n = 14). Expression of Nrf2, NF-kB, and HO-1 was measured in peripheral blood mononuclear cells (PBMCs). Plasma ADMA was determined using the ELISA technique and MDA via the thiobarbituric acid method. Our study showed that mRNA of NF-kB, Nrf2, and HO-1 levels in PBMCs in the MetS group were significantly higher than in the controls by 53%, 130%, and 185% (p < 0.05), respectively. Similarly, elevated levels of MDA (by 78%, p < 0.001) and ADMA (by 18.7%, p < 0.001) were established in the MetS group. Our findings show the importance of transcription factor Nrf2, playing an integral role in the protection of the endothelium, and of NF-κB, a transcription factor mediating the inflammatory response in MetS. Knowledge of complex cellular-molecular mechanisms would allow the use of biomarkers such as Nrf2, NF-kB, HO-1, and ADMA for the assessment of endothelial dysfunction in clinical practice.

Ferrum phosphoricum D12 Treatment Affects J774A.1 Cell Proliferation, Transcription Levels of Iron Metabolism, Antioxidant Defense, and Inflammation-related Genes.

BACKGROUND: Ferrum phosphoricum (FP) is prescribed as a homeopathic remedy to treat the early stages of fever and inflammation in cases of colds or flu, muscle fatigue and anemia. We aimed to analyze the molecular mechanisms of action of FP D12 on cell proliferation and mRNA expression of iron metabolism, antioxidant defense and inflammation-related genes in mouse J774A.1 macrophages. METHODS: Cell proliferation was examined using the MTT test. RT-qPCR analyses were performed to estimate gene expression changes. Relative gene expression levels were calculated using the 2-ΔΔCt method. The effect of treatment using FP D12 tablets was compared with that using placebo tablets (PT). RESULTS: FP D12 in low concentrations (0.0125 mg/mL to 0.025 mg/mL) significantly stimulated proliferation of J774A.1 cells by up to 11% (p < 0.01) versus control untreated cells and by up to 40% (p < 0.01) versus PT-treated cells in the respective concentration. FP D12 versus PT induced a significant increase in mRNA expression of ferritin light chain (Ftl1) (by 8-fold, p < 0.01), ß-2-microglobulin (B2m) (by 2.5-fold, p < 0.05) and iron-responsive element binding protein 2 (Ireb2) (by 4-fold, p < 0.05), and induced a slight decrease in myosin IE (Myo1e) mRNA expression levels (by 0.4-fold, p < 0.01) in macrophages. A highly significant (r2 = 0.99, p < 0.05) correlation was observed between Ireb2 and B2m transcription levels. Significant stimulation of antioxidant enzyme Gpx-1 (by 1.27-fold, p < 0.01) in cells by 0.025 mg/mL FP D12, but a slight decrease (by 0.12-fold, p < 0.05) in 0.0125 mg/mL-treated cells, was observed. A significant increase in the gene expression of IL-1ß (by 3.5-fold, р < 0.05) in macrophages was also detected. CONCLUSION: Ferrum phosphoricum in D12 dilution potentially exhibits iron retention, antioxidant and immunomodulation activities, possibly by modulating transcription levels of related genes in non-stimulated mouse macrophages.

The onset of nausea and vomiting of pregnancy: a prospective cohort study.

BACKGROUND: Nausea and vomiting are experienced by most women during pregnancy. The onset is usually related to Last Menstrual Period (LMP) the date of which is often unreliable. This study describes the time to onset of nausea and vomiting symptoms from date of ovulation and compares this to date of last menstrual period METHODS: Prospective cohort of women seeking to become pregnant, recruited from 12 May 2014 to 25 November 2016, in the United Kingdom. Daily diaries of nausea and vomiting were kept by 256 women who were trying to conceive. The main outcome measure is the number of days from last menstrual period (LMP) or luteinising hormone surge until onset of nausea or vomiting. RESULTS: Almost all women (88%) had Human Chorionic Gonadotrophin rise within 8 to 10 days of ovulation; the equivalent interval from LMP was 20 to 30 days. Many (67%) women experience symptoms within 11 to 20 days of ovulation. CONCLUSIONS: Onset of nausea and vomiting occurs earlier than previously reported and there is a narrow window for onset of symptoms. This indicates that its etiology is associated with a specific developmental stage at the foetal-maternal interface. TRIAL REGISTRATION: NCT01577147 . Date of registration 13 April 2012.

New Circulating Circular RNAs with Diagnostic and Prognostic Potential in Advanced Colorectal Cancer.

Circular RNAs (circRNAs) are a group of special endogenous long non-coding RNAs which are highly stable in the circulation, and, thus, more suitable as new biomarkers of colorectal cancer (CRC). The aim of our study was to explore the plasma expression levels of four circRNAs: has_circ_0001445, hsa_circ_0003028, hsa_circ_0007915 and hsa_circ_0008717 in patients with CRC and to evaluate their associations with clinicopathological characteristics and the clinical outcome of the patients. CircRNAs were extracted from patients' plasma obtained prior to chemotherapy. Their expression levels were measured by qPCR and calculated applying the 2-ΔΔCt method. The levels of all four circRNAs were significantly increased in the plasma of CRC patients. At the optimal cut-off values hsa_circ_0001445 and hsa_circ_0007915 in plasma could significantly distinguish between patients with or without metastatic CRC with 92.56% sensitivity and 42.86% specificity, and with 86.07% sensitivity and 57.14% specificity, respectively. The mean overall survival (OS) of patients with high/intermediate expression of hsa_circ_0001445 was 30 months, significantly higher in comparison with the mean OS of the patients with low expression-20 months (log-rank test, p = 0.034). In multivariate Cox regression analysis, the low levels of hsa_circ_0001445 were also associated with shorter survival (HR = 1.59, 95% CI: 1.02-2.47, p = 0.040). A prognostic significance of hsa_circ_0001445 for patients with metastatic CRC was established.

Junipers of Various Origins as Potential Sources of the Anticancer Drug Precursor Podophyllotoxin.

Juniper representatives are natural sources of plenty of bioactive metabolites and have been used since ancient times as folk remedies against tapeworms, warts, cancer, etc. The antiproliferative activities of junipers are attributed to podophyllotoxin (PPT), which is a precursor for the synthesis of efficient anticancer drugs. However, the natural sources of PPT, Sinopodophyllum hexandrum (Royle) T. S. Ying and Podophyllum peltatum L., are already endangered species because of their intensive industrial exploitation. Therefore, identification of other sources of PPT is necessary. This study is a broad comparative investigation of junipers, for which original sources have been accessed from different continents of the world. The present research is aimed at the identification of species, producing PPT and other lignans at concentrations that are sufficient for the high antiproliferative activity of the corresponding extracts. Cytotoxic juniper leaf extracts demonstrated a broad spectrum of activity on a panel of cancer cell lines. The antiproliferative properties of junipers were attributed to the combined activity of great diversity of lignans (podophyllotoxin, deoxypodophyllotoxin, ß-peltatin, yatein, matairesinol, anhydropodorhizol, etc.), detected by UHPLC-HRMS and LC-ESI-MS/MS in the corresponding extracts. Several species of the genus Juniperus L. were outlined as perspective sources of drug precursors with potential pharmaceutical applications.

Metronomic capecitabine combined with aromatase inhibitors for new chemoendocrine treatment of advanced breast cancer: a phase II clinical trial.

PURPOSE: This study was designed to determine the safety and clinical efficacy of metronomic chemotherapy combined with aromatase inhibitors (AIs) for hormone receptor (HR)-positive advanced breast cancer (ABC) patients who cannot tolerate conventional-dose chemotherapy. METHODS: Postmenopausal patients with HR-positive ABC, who exhibited disease progression after first-line AIs treatment and who could not tolerate or rejected conventional chemotherapy, were enrolled in this study. Patients received capecitabine 500 mg PO TID (could be reduced to 500 mg QD in case of adverse effects) and exemestane 25 mg QD (after PD with letrozole) or letrozole 2.5 mg QD (after PD with exemestane). The primary endpoints were safety and tolerance, the secondary endpoints were objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and time to treatment failure (TTF). RESULTS: In our analysis of 44 patients, the median age was 64 years (range 38-90) and 68.2% patients had at least two recurrences or metastatic lesions. Grade 3 toxicities (hand-foot syndrome) were observed only in 4 of the patients. Most patients exhibited no or mild toxicities. After a median follow-up of 14.8 months, ORR was 70.5%, CBR-77.3%, PFS-16.2 months, and TTF-14.4 months. CONCLUSIONS: Metronomic oral capecitabine combined with AIs showed good efficacy, minimal toxicities, and good tolerance in HR-positive patients with ABC. It is a potential treatment option especially for postmenopausal HR-positive ABC patients in poor general condition who cannot tolerate conventional chemotherapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT01924078.

Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements.

Health has been defined as the capability of the organism to adapt to challenges. In this study, we tested to what extent comprehensively phenotyped individuals reveal differences in metabolic responses to a standardized mixed meal tolerance test (MMTT) and how these responses change when individuals experience moderate weight loss. Metabolome analysis was used in 70 healthy individuals. with profiling of ∼300 plasma metabolites during an MMTT over 8 h. Multivariate analysis of plasma markers of fatty acid catabolism identified 2 distinct metabotype clusters (A and B). Individuals from metabotype B showed slower glucose clearance, had increased intra-abdominal adipose tissue mass and higher hepatic lipid levels when compared with individuals from metabotype A. An NMR-based urine analysis revealed that these individuals also to have a less healthy dietary pattern. After a weight loss of ∼5.6 kg over 12 wk, only the subjects from metabotype B showed positive changes in the glycemic response during the MMTT and in markers of metabolic diseases. Our study in healthy individuals demonstrates that more comprehensive phenotyping can reveal discrete metabotypes with different outcomes in a dietary intervention and that markers of lipid catabolism in plasma could allow early detection of the metabolic syndrome.-Fiamoncini, J., Rundle, M., Gibbons, H., Thomas, E. L., Geillinger-Kästle, K., Bunzel, D., Trezzi, J.-P., Kiselova-Kaneva, Y., Wopereis, S., Wahrheit, J., Kulling, S. E., Hiller, K., Sonntag, D., Ivanova, D., van Ommen, B., Frost, G., Brennan, L., Bell, J. Daniel, H. Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements.

Association of mRNA Levels of IL6, MMP-8, GSS in Saliva and Pyelonephritis in Children.

Nowadays, saliva is a subject of growing scientific interest because of its definite advantages as diagnostic medium. The aim of our study was to investigate the diagnostic potential and reliability of messenger RNAs (mRNAs) of selected genes-interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glutathione synthetase (GSS)-as salivary markers in children with diagnosed pyelonephritis and to correlate their levels with typical urine para-clinical indicators of the disease. Analysis of the mRNA levels for IL-6, MMP-8 and GSS in 28 children hospitalized with the diagnosis of pyelonephritis was conducted applying the method of quantitative reverse transcription polymerase chain reaction (RT-qPCR). In the study group (n = 28), IL-6 mRNA levels demonstrated 64-fold increase (p < 0.001). MMP-8 and GSS mRNA levels were increased in 12 samples in patients with pyelonephritis 3.27 (p < 0.01) and 1.94 (p < 0.001) times, respectively. We found a strong and significant correlation (p < 0.001) between the investigated mRNA for IL-6 and MMP-8, IL-6 and GSS, MMP-8 and GSS. Moderate degree of correlation was established between IL-6 and the typical para-clinical indicator of leucocytes (0.43, p < 0.05) and between GSS and leucocytes (0.54, p < 0.01). Salivary IL-6, MMP-8 and GSS mRNA levels in combination with urine test analysis could be useful diagnostic tool for the very distributed disorder of pyelonephritis in childhood.

Adiponectin, Leptin, and Leptin Receptor in Obese Patients with Type 2 Diabetes Treated with Insulin Detemir.

The aim of the present study is to quantitatively assess the expression of selected regulatory molecules, such as leptin, leptin receptor, and adiponectin in the blood of obese patients with type 2 diabetes both before treatment and after six months of pharmacological therapy with the long-lasting insulin analogue, insulin detemir. A significant decrease in the analysed regulatory molecules, i.e., leptin receptor and adiponectin, was found in blood plasma of the patients with untreated type 2 diabetes. These changes were accompanied by an increase in plasma leptin concentrations. Insulin treatment resulted in the normalization of plasma leptin receptor and adiponectin concentrations. The circulating leptin level did not change following anti-diabetic therapy with insulin detemir. Gender was a significant factor modifying the circulating level of all the analysed regulatory active compounds. Bioinformatic analysis was performed using Matlab with the Signal Processing Toolbox. The conducted discriminant analysis revealed that the leptin receptor, Δw(19), and adiponectin, Δw(21), were the parameters undergoing the most significant quantitative changes during the six-month therapy with insulin detemir. The conducted examinations indicated the contribution of adipocytokines-the biologically-active mediators of systemic metabolism, such as leptin and adiponectin in the pathomechanism of disorders being the basis for obesity which leads to development of insulin resistance, which, in turn, results in the occurrence of type 2 diabetes.

Improved lipid profile and increased serum antioxidant capacity in healthy volunteers after Sambucus ebulus L. fruit infusion consumption.

This study aimed to establish the effect of Sambucus ebulus L. (SE) ripe fruit infusion on body weight, blood pressure, glucose levels, lipid profile and antioxidant markers in healthy volunteers in respect of its possible protective activity against cardiovascular diseases and other oxidative stress-related diseases. The study involved 21 healthy volunteers, aged between 20 and 59, BMI 23.12 ± 1.31, who consumed 200 ml SE infusion/day for a period of 30 d. Blood samples were collected before and at the end of the intervention. Significant decrease in triglycerides (14.92%), total cholesterol (15.04%) and LDL-C (24.67%) was established at the end of the study. In addition, HDL-C/LDL-C ratio increased by 42.77%. Improved serum antioxidant capacity and total thiol levels were also established. The results presented in this first human intervention study with SE fruit infusion indicate the potential of the plant to improve lipid profile and serum antioxidant capacity in humans.

Estimation of phloem conductance at tree level in young, middle-aged and old-aged Scots pine trees growing in different climatic conditions in boreal forests.

In forests, a significant proportion of the carbon fixed by trees during photosynthesis is transported belowground along the conducting phloem, so variations in phloem anatomy can lead to variations in transport capacity. Phloem conductance at tree level (Ktree) is also affected by tree height. Both the phloem anatomy and the tree size change during ontogeny, and also differ under different environmental conditions. The goal of our work was to identify the main drivers of variation in Ktree in Scots pine trees growing in natural boreal forests. We conducted a phloem anatomical study and calculated Ktree in trees of three age groups growing in different climatic conditions along a latitudinal gradient from south to north. We found that Ktree was maintained at the same level in actively growing pine trees (25-80-years-old) but increased in old-aged trees (180-190-years-old), possibly reflecting the shift in source-sink relationships of aboveground and belowground parts of trees. Trees of the same age group growing in different climatic conditions demonstrated similar values of Ktree due to coordinated changes in the phloem anatomy and the tree height. In general, the negative influence of tree height on Ktree is offset by the positive influence of phloem width (or trunk diameter) and sieve cell diameter. The exception was young trees growing in the transition zone of the northern taiga subzone to the tundra, where Ktree was the highest in its age group and even exceeded Ktree of middle-aged trees.

Application of electron paramagnetic resonance spectroscopy to examine free radicals formed in indapamide and torasemide storage under UV irradiation and at the higher temperatures which appear under light exposition.

Free radical formation in two diuretics: indapamide and torasemide was examined during UV irradiation and storage at higher temperatures using X-band (9.3 GHz) electron paramagnetic resonance spectroscopy (EPR). The aim of this study was to investigate the possibility of storing indapamide and torasemide under UV irradiation and at higher temperatures, which may occur during exposure to light. The diuretic samples were exposed to UVA irradiation for 15, 30 and 45 minutes, and stored at temperatures of 40 °C and 50 °C by 30 minutes. The EPR spectra were analyzed to determine the amplitudes (A), linewidths (ΔBpp), and integral intensities (I) and g factors. The concentrations of free radical (N) in the diuretic samples were also determined. The influence of microwave power on amplitudes, linewidths and the asymmetry parameter were evaluated. The result showed that the tested indapamide and torasemide samples exhibited high free radical concentrations in the range of 1018-1019 spin/g after UV irradiation and heat treatment. Therefore, due to the significant free radical formation indapamide and torasemide should not be stored under UV light and at temperatures of 40 °C and 50 °C. The complex character of free radical systems in the diuretic samples was proved as evidenced by the changes of the asymmetry parameters of the EPR lines with increasing microwave power. Fast spin-lattice relaxation processes were observed in all tested diuretic samples, regardless of the storage conditions. Electron paramagnetic resonance spectroscopy is proposed as a useful method in pharmacy to determine the appropriate storage conditions for diuretics.

Tissue Regeneration and Remodeling in Rat Models after Application of Hypericum perforatum L. Extract-Loaded Bigels.

The wound-healing effect of St. John's Wort (SJW) is mainly attributed to hyperforin (HP), but its low stability restricts its topical administration. This study investigates how "free" HP-rich SJW extract (incorporated into a bigel; B/SJW) and extract "protected" by nanostructured lipid carriers (also included in a biphasic semisolid; B/NLC-SJW) affect tissue regeneration in a rat skin excision wound model. Wound diameter, histological changes, and tissue gene expression levels of fibronectin (Fn), matrix metalloproteinase 8 (MMP8), and tumor necrosis factor-alpha (TNF-α) were employed to quantify the healing progress. A significant wound size reduction was achieved after applying both extract-containing semisolids, but after a 21-day application period, the smallest wound size was observed in the B/NLC-SJW-treated animals. However, the inflammatory response was affected more favorably by the bigel containing the "free" SJW extract, as evidenced by histological studies. Moreover, after the application of B/SJW, the expression of Fn, MMP8, and TNF-α was significantly higher than in the positive control. In conclusion, both bigel formulations exhibited beneficial effects on wound healing in rat skin, but B/SJW affected skin restoration processes in a comprehensive and more efficient way.

Polycarbonate-Based Copolymer Micelles as Biodegradable Carriers of Anticancer Podophyllotoxin or Juniper Extracts.

Podophyllotoxin (PPT) is used in the industrial production of efficient anticancer, antiviral and other drugs. Sinopodophyllum hexandrum or Podophyllum peltatum are natural sources of PPT, but at present they are considered as endangered species. Their PPT content is variable, depending on the growing conditions. Searching for new sources of PPT, some representatives of the genus Juniperus were found to exhibit efficient PPT biosynthesis. However, PPT is highly toxic and poorly soluble in water compound, which limits its clinical applications. In this connection, amphiphilic polymer micelles are considered to be suitable PPT carriers, aimed at increase in water solubility and decrease in toxicity. The present research deals with the evaluation of MPEG-polycarbonate block copolymer micelles loaded with PPT or juniper extracts. The active component-loaded polymer nanocarriers were characterized by dynamic and electrophoretic light scattering, as well as by transmission electron microscopy. The active component loading efficiency and loading capacity were also determined. Highly efficient antiproliferative activity of the loaded micelles was determined in a panel of cancer cell lines. The obtained amphiphilic nanocarriers, loaded with PPT-containing bioactive components, have application in future in vivo preclinical trials of their pharmacokinetics and pharmacodynamics as potential therapeutical agents in the prospective nanomedicine.

Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells.

The aim of this study was to identify valproic acid (VPA) analogs with a broad spectrum of anti-cancer activities and an increased apoptosis-inducing potential compared with the parent VPA, which is enrolled as histone deacetylase (HDAC) inhibitor in a large number of clinical trials. We identified a chiral VPA derivative, (S)-2-pentyl-4-pentynoic acid, previously characterized as HDAC inhibitor that induced massive programmed cell death in a strongly enantioselective manner in U937 histiocytic lymphoma cells and NB4 acute promyelocytic leukemia cells. By performing fluorescence-activated cell sorting and Western blotting analyses, we established that enantiomer (S)-2-pentyl-4-pentynoic acid has higher apoptosis-inducing potential than VPA itself. The optic antipode (R)-2-pentyl-4-pentynoic acid and VPA caused under the same conditions only a weak growth inhibition without inducing cell differentiation and apoptosis. (S)-2-pentyl-4-pentynoic acid is more apoptogenic than VPA and displays enantioselective anti-cancer properties that warrant further research regarding the mechanistic basis of its activity and its potential use in cancer therapy.

The free radical theory of aging in search of a strategy for increasing life span.

This overview is an attempt to throw a fresh look at the popular free radical theory of aging (referred to also as oxidative stress theory) which holds that the progressive decline in physiological functions is a result of accumulation of diverse deleterious changes caused by reactive oxygen species (ROS). We discuss the role of mitochondria as a major source of ROS in the cell and how these link accumulation of oxidative damage to the age-related changes in physiologic functions. The free radical theory of aging is analysed here from two different views of aging--one (the pessimistic view) that regards aging as the inevitable result of life activity the consequences of which are accumulation of errors in the genome and damage of the biomolecules, and the other (the optimistic view) which considers that it is the changes in mitochondrial pathways of apoptosis with age that cause the functional tissue changes and aging. We also discuss the possibility of delaying the aging process by appropriate diet or drug therapy, which includes also calorie restriction as a mechanism of modifying the generation of free radicals and body metabolism and thus extending lifespan as a result.

Barriers and enablers around radical sharing.

Multiple social and ecological crises are currently unfolding, the tackling of which requires a thorough understanding of their interlinkages and root causes. More sharing of essential resources while increasing access to valuable goods and services, especially for the most vulnerable in society, has been proposed as an effective strategy to reduce environmental and social damage. However, a more reflective approach to sharing is needed to make sure that it does not worsen some of the issues that it aims to address. In this Personal View, we outline the principles of radical sharing, which highlight the salience of environmental limits, access to essential goods and services, and non-exploitative relationships. Furthermore, we discuss key enablers and barriers to radical sharing and a more successful integration into sharing practices that prioritise needs satisfaction for all within planetary boundaries. Critical perspectives on the sharing economy need to account for the role of power, politics, capitalism, and citizenship alongside the more widely discussed issues around exploitation, discrimination, and greenwashing.