Dose-dependent Positive Effect Research Articles

Sevofluran Maruziyetinin Civciv Embriyo Gelişimi Üzerindeki Ex-Ovo Değerlendirilmesi: Anjiyogenez Etkilerinin Araştırılması

Objective: Angiogenesis, defined as the formation of new blood vessels from pre-existing ones, plays a vital role in both physiological and pathological conditions. Understanding agents that can influence angiogenesis is crucial in managing diseases where angiogenesis is dysregulated. This study focuses on sevoflurane, a commonly used inhalation anesthetic, whose effects on angiogenesis and embryonic development are not well understood. Our objective was to assess the impact of sevoflurane exposure on angiogenesis using the ex-ovo chick chorioallantoic membrane model. Methods: In this model, fertilized chicken eggs were exposed to sevoflurane at concentrations of 2% and 4%, for varying durations of 1, 2, and 4 hours. The embryos were then divided into control and experimental groups for quantitative angiogenesis assessment using Image J software, followed by statistical analysis with one-way analysis of variance. Results: The results indicate that sevoflurane exposure has a dose-dependent positive effect on angiogenesis, with significant increases in vascular density observed in embryos exposed to both concentrations compared to the control group. Additionally, the length of exposure was found to further enhance these angiogenic effects. Conclusion: Despite the dose and duration-dependent impact of sevoflurane on angiogenesis, the existing literature presents mixed findings, highlighting the need for additional research to elucidate sevoflurane’s role in angiogenesis. This is particularly important for understanding its implications in various medical conditions, such as cancer, wound healing, and fetal development. Future investigations into sevoflurane’s effects on placental angiogenesis could also provide valuable insights into its potential consequences on intrauterine growth. Keywords: Angiogenesis, sevoflurane, chicken embryo, model organisms, ex-ovo

Inhaled nitric oxide: well-known and new therapeutic indications

The use of nitric oxide is widespread in medical practice. Inhaled form of NO in patients with respiratory disease is especially interesting. As an inhalation therapy, nitric oxide reaches well-ventilated areas of the lungs, having a negligible systemic effect due to its rapid inactivation in the bloodstream. It has long been known that inhaled NO improves oxygenation in various pathological conditions. Low doses of inhaled nitric oxide are known as a vasodilator in patients with pulmonary hypertension, its use is possible even in newborns with hypoxemic respiratory failure and persistent pulmonary hypertension. In turn, high doses are used in the treatment of infectious lung diseases, besides, another surge of scientific interest in nitric oxide arose during the coronavirus pandemic. Although the antimicrobial potential of nitric oxide is widely known, it is little used in clinical practice. Endogenous antimicrobial activity is largely mediated by high local concentrations of NO. Numerous preclinical studies have demonstrated that NO has general static and bactericidal activity against viruses, bacteria, protozoa and fungi/yeast in vitro. Due to the dose-dependent positive and negative effects of NO, safety and efficacy tests of NO and its donors are needed to assess their role in the prevention and treatment of infections. This review provides information on the chemical structure, features of metabolism and delivery of inhaled NO, and also pays special attention to the antimicrobial effect in various diseases of the pulmonological profile.

THE DILEMMA OF USE OF THE LEVOTHYROXIN IN PATIENTS WITH HEART FAILURE (literature review and own data)

Systematization of literature data on the use of thyroid hormones in patients with heart failure and the results of own research are given. The therapy of levothyroxine in patients with heart failure, at the moment of time, remains still an "open book". Several questions remain unsolved: regimen, doses and schedule of levothyroxine use, consequences of this therapy. It is necessary to conduct large, multicenter, prospective, placebo-controlled studies, which should provide information on the safety and impact of levothyroxine on the long-term prognosis of these patients. Our study shows that the long-term administration of levothyroxine in patients with heart failure and accompanying hypothyroidism has a dose-dependent positive effect on the value of the left ventricular ejection fraction and on the course of heart pathology. The maximum ejection fraction of the left ventricle is observed in patients who took the drug in a dose > 1.2 μg/kg. The use of the drug in a dose > 0.53 μg/kg leads to a probable decrease in the frequency of re-hospitalization within 2 years due to decompensation of heart failure.

Association between smoking cessation and non-alcoholic fatty liver disease using NAFLD liver fat score.

Smoking is well known to be associated with a higher prevalence and incidence of liver diseases such as advanced fibrosis. However, the impact of smoking on developing nonalcoholic fatty liver disease remains controversial, and clinical data on this is limited. Therefore, this study aimed to investigate the association between smoking history and nonalcoholic fatty liver disease (NAFLD). Data from the Korea National Health and Nutrition Examination Survey 2019-2020 were used for the analysis. NAFLD was diagnosed according to an NAFLD liver fat score of >-0.640. Smoking status was classified as into nonsmokers, ex-smokers, and current smokers. Multiple logistic regression analysis was conducted to examine the association between smoking history and NAFLD in the South Korean population. In total, 9,603 participants were enrolled in this study. The odds ratio (OR) for having NAFLD in ex-smokers and current smokers in males was 1.12 (95% confidence interval [CI]: 0.90-1.41) and 1.38 (95% CI: 1.08-1.76) compared to that in nonsmokers, respectively. The OR increased in magnitude with smoking status. Ex-smokers who ceased smoking for <10 years (OR: 1.33, 95% CI: 1.00-1.77) were more likely to have a strong correlation with NAFLD. Furthermore, NAFLD had a dose-dependent positive effect on pack-years, which was 10 to 20 (OR: 1.39, 95% CI: 1.04-1.86) and over 20 (OR: 1.51, 95% CI: 1.14-2.00). This study found that smoking may contribute to NAFLD. Our study suggests cessation of smoking may help management of NAFLD.

Nitric oxide for the prevention and treatment of viral, bacterial, protozoal and fungal infections

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

DOSE-DEPENDENT EFFECTS OF LEVOTHYROXINE IN HEART FAILURE IN PATIENTS WITH CONCOMITANT THYROID PATHOLOGY

Abstract. Currently, the use of thyroid hormones in the setting of heart failure (HF) is still an "open book". There are several unanswered questions: the regimen, doses and schedule of drug use, as well as the consequences of such therapy. Large clinical studies can provide information on the effect of these hormones on the long-term prognosis in patients with heart failure. At the same time, the presence of comorbid thyroid pathology, which requires the prescription of levothyroxine (LT), makes it possible to partially answer these questions. The aim is to study of the dose-dependent effect of LT on the course of HF in patients with autoimmune thyroiditis (AIT). Material and methods. The study included 218 patients with HF on the background of post-infarction cardiosclerosis. 109 (50.0 %) patients with AIT received LT due to hypothyreosis in the past. These patients intake LT during 2 years before included in the study and have euthyreosis. Whether the levels of thyroid stimulating hormone (TSH), free triiodthyronine (FT3) and free thyroxine (FT4) were determined. Results. Patients who used LT, comparing with patients without this drug, had smaller end-diastolic diametr (EDD) and end-systolic diametr (ESD) and end-diastolic volum (EDV) and end-systolic volum (ESV) of left ventricle (LV) and 22.9 % greater LV ejection fraction (EF) (+ 22.9 %, p = 0.0001), as well as higher low serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level (- 26.3 %, p = 0.009). In the subgroup of patients taking LT at a dose of 0.1 to 0.69 μg/kg, ejection fraction of left ventricle (LVEF) did not differ from patients without this tritment. At a dose of 0.7-1.19 μg/kg, LVEF is higher compared with that of patients who did not take LT (+ 37.9 %, p = 0.0001) and patients who took LT at a dose 0.1 - 0.33 μg/kg (+ 36.9 %, p = 0.0001). LVEF was the highest in patients taking LT at a dose of &gt; 1.20 μg/kg. The use of LT for 2 years reduces the risk of re-hospitalization (RH) due to decompensation of heart failure (Odds ratio = 0.490 (0.281-0.857), p = 0.018) and a tendentious decrease in the risk of combined endpiont achieving (- 27.9 %, p = 0.074). The ROC analysis showed that the risk of RH in patients with heart failure due to decompensation of the disease decreases with the use of LT at a dose of &gt; 0.53 μg/kg (sensitivity – 56.62 %, specificity – 60.98 %, p = 0.016). Conclusions. The use of LT in patients has a dose-dependent positive effect on LVEF. The largest LVEF is observed in patients taking the drug at a dose of &gt; 1.2 μg/kg. The use of an LT dose of &gt; 0.53 μg/kg leads to a significant decrease in the frequency of re-hospitalization due to decompensation of heart failure during 2 years. Keywords: heart failure, autoimmune thyroiditis, levothyroxine, left ventricular, ejection fraction.

Role of Gamma-Aminobutyric Acid in the Antiepileptic Activity of Garcinia Mangostana Standardized Extract

Epilepsy is a neurodegenerative disorder characterized by recurrent seizure activity, accompanied by convulsions and loss of consciousness. The aim of the present study was to investigate the antiepileptic activity of GML in mice using MES- and INH-induced models. Estimation of brain GABA levels and in vitro antioxidant potential was also evaluated. Treatment of mice with GML significantly reversed the MES-induced convulsions, which was reflected by the decrease in the duration (in seconds) of all the phases, with an increment in the GABA levels. In the INH model, animals treated with test drug exhibited a significant delay in the onset (in minutes) of clonic convulsions, and a decrease in the duration (in minutes) of clonic convulsions. GML had a dose dependent positive effect on GABAergic neurotransmission that was evident by a significant increase in the brain GABA levels. GML also exhibited significant free radical scavenging (DPPH•), reducing power, and hydroxyl radical scavenging activity. Put together, the data from the current study suggests that GML has significant antiepileptic potential, modulated through positive GABAergic neurotransmission and antioxidant properties.

Nitric oxide for the prevention and treatment ofviral, bacterial,protozoalandfungalinfections.

Although the antimicrobial potential of nitric oxide(NO)is widelypublished, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses.Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite andS-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (includingβ-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trialsshould test dietary inorganic nitrate forpre- or post-exposureprophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment ofmild-to-severe infections, including due to SARS-CoV-2(COVID-19). This review summarises the evidence base from in vitro, in vivoand early phase clinical studies of NO activity inviral, bacterial,protozoalandfungalinfections.

The Role of γc Cytokines (IL-2, IL-7, and IL-15) in Regulation of Activation-Induced Cell Death of Memory T Cells

The role of γc cytokines (IL-2, IL-7, and IL-15) in the regulation of apoptotic death of memory T cells under cultivation conditions in vitro was studied using the method of cytofluorimetry. It was detected that the effect of IL-2 in combination with TCR activator is aimed at increasing the number of mature CD45RO+CD95+ T cells with a simultaneous decrease in the number of viable T cells, which gives reason to assume the proapoptotic effect of IL-2 under restimulation conditions. On the contrary, the effect of IL-7 and IL-15 in the activation model in vitro leads to an increase in the number of living T cells in СD45RO cultures (as compared with the samples, in which only the activator was added) against the background of an increase in the number of CD8+CD95+ T cells with a central memory phenotype (TCM). Changes induced by IL-15 are aimed an decreasing the content of CD4+CD95+ T cells in CD45RО+ cultures of the immune memory T cells. Thus, a dose-dependent positive effect of IL-2 on the clonal expansion and negative effect on the viability of T cells was demonstrated. While IL-7 and IL-15, on the contrary, preserve the viability of T cells, participating in the generation of a pool of long-lived memory T cells.

Effect of Cnidoscolus aconitifolius Leaf Extract on Selected Renal Parameters and Hematological Indices of Carbon Tetrachloride Induced Toxic Rats

Effect of Cnidoscolus aconitifolius leaf extract on selected renal parameters and hematological indices of carbon tetrachloride (CCl4) induced toxic rats was investigated using standard analytical methods. Forty-two (42) wistar rats weighing 91-185g was used for this study. The rats were divided into 7 groups of 6 rats each and allowed to acclimatize for one week with food and water ad libitum. Carbon tetrachloride was prepared in the ratio of 1:5 (v:v) in olive oil and administered subcutaneously at 0.17 mL/kg body weight on the first day after acclimatization. Group I received normal feed and water only, group II received CCl4 only, group III received olive oil only, groups IV, V and VI received 50 mg/kgbw, 75 mg/kgbw and 100 mg/kgbw oral dose of C. aconitifolius respectively in addition to CCl4 while group VII received vitamin C plus CCl4. After oral administration for twenty-one days, the rats were painlessly sacrificed; plasma and blood were collected for renal and hematological analyses respectively. Results showed that CCl4 increased Ca, Na, K and decreased RBC, PCV, Hb and platelet number of rats induced, however oral administration of C. aconitifolius significantly decreased; Ca and Na at 50 mg/kgbw, K in a dose-dependent pattern and significantly increased RBC, PCV, Hb and platelet number at all doses. This study has shown that the leaf extract of Cnidoscolus aconitifolius had a dose-dependent positive effect on the hematological indices as well as the potential to ameliorate kidney parameters of CCl4 treated wistar rats at the given concentrations.

A jaboticaba extract prevents prostatic damage associated with aging and high-fat diet intake.

Aging and overweight are involved in prostatic lesion development, due to their association with cell proliferation, hormonal imbalance and angiogenesis. The jaboticaba fruit is rich in bioactive compounds, showing potential chemopreventive action such as the capacity to modulate hormones and angiogenesis hallmarks. This study aimed to evaluate the jaboticaba extract (PJE) effect on the prostate morphology and on molecules related to hormone signaling and angiogenesis, during aging and/or high-fat diet (HFD) intake. Seventy FVB mice were distributed into experimental groups: YG group (young: 3 month old mice), AG group (aged: 11 month old mice), HfAG group (aged + HFD), JAGI group (aged + 2.9 g kg-1 PJE), JAGII group (aged + 5.8 g kg-1 PJE), HfJAGI group (aged + HFD + 2.9 g kg-1 PJE) and HfJAGII group (aged + HFD + 5.8 g kg-1 PJE). The ventral prostate was collected for morphological, immunohistochemistry and western-blotting analysis after 60 days of treatment. All PJE treatments promoted hormonal signaling balance and inhibited angiogenesis in the prostates of aged or HFD-fed aged mice, leading to the maintenance of healthy prostate morphology. A high dose of the PJE (JAGII and HfJAGII groups) led to the best capacity to reduce AR (58.40% and 74.42%; p = 0.0240 and p = 0.0023), ERα (30.29% and 45.12%; p = 0.0004 and p < 0.0001), aromatase (39.54% and 55.94%; p = 0.0038 and p = 0.0020), and VEGF (50.81% and 67.68%; p < 0.0001) and increase endostatin immunoexpression. Moreover, HFD intake intensified the hormonal and angiogenic alterations in the aged mouse prostates, contributing to the increase in premalignant lesion incidence. The PJE exerted a dose-dependent positive effect on aged or HFD-fed aged mouse prostates, contributing to the gland microenvironment recovery, mainly due to the hormonal and angiogenic balance. Therefore, we suggest that the PJE can be a potential candidate for prostatic lesion prevention.

Bazhu Decoction, a Traditional Chinese Medical Formula, Ameliorates Cognitive Deficits in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with aging. There are currently no effective treatments for AD. Bazhu decoction (BZD), a traditional Chinese medicine (TCM) formula, has been employed clinically to alleviate AD. However, the underlying molecular mechanisms are still unclear. Here we found that middle- and high-doses of BZD ameliorated the behavioral aspects of 5xFAD transgenic mice in elevated plus maze, Y maze and Morris water maze tests. Moreover, BZD reduced the protein levels of BACE1 and PS1, resulting in a reduction of Aβ plaques. We also identified a beneficial effect of BZD on oxidative stress by attenuating MDA levels and SOD activity in the brains of 5xFAD mice. Together, these results indicate that BZD produces a dose-dependent positive effect on 5xFAD transgenic mouse model by decreasing APP processing and Aβ plaques, and by ameliorating oxidative damage. BZD may play a protective role in the cognitive and anxiety impairments and may be a complementary therapeutic option for AD.

The effects of interleukin-10 and fibroblasts growth factor-2 in mice with toxic cuprizone model of demyelination

Cytokines and growth factors exhibit neurotropic, anti-inflammatory and immunomodulatory properties, and therefore can affect the functioning of the nervous system at demyelinating disorders.Purpose. To identify changes in T-lymphocytes, macrophages, oxidative stress and antioxidant defence factors, endocrine thymus function in the brain and behaviour of mice receiving neurotoxin cuprizone and recombinant human proteins: interleukin-10 (rhIL-10) and fibroblast growth factor (rhFGF-2).Materials and methods. 4-6-month-old 129/Sv mice received cuprizone with food every day for 3 weeks. From the 7th day of cuprizone diet, they received different doses of rhIL-10 and rhFGF-2. The content of СD3+ Т-cells, macrophages, malondialdehyde, activity of antioxidant enzymes in the brain and the level of thymulin in the blood were determined. Behavioural reactions were assessed in the “open field” test.Results. In the brain of mice receiving cuprizone and rhIL-10, there was a decrease in the number of СD3+ Т-cells and the activity of macrophages, which significantly increased under the influence of the toxin. After cytokine injection, the activity of superoxide dismutase, catalase and glutathione peroxidase increased significantly in the brain, as well as the level of thymulin in the blood. Motor, emotional and exploratory activity of mice, significantly suppressed by the cuprizone, was increased after the introduction of rhIL-10. The effect of rhIL-10 on the test parameters is more pronounced at a dose of 5 μg/kg than 50 μg/kg. After injection of rhFGF-2 in the mice with cuprizone diet, there is a decrease in the activity of brain macrophages and an increase of the level of thymulin in the blood depending on the dose of this factor; the motor activity of these animals increased regardless of the rhFGF-2 dose.Conclusion. The injections of rhIL-10 and rhFGF-2 provide dose-dependent positive effects on the pathogenetic factors of experimental demyelinating pathology, as well as the functional state of the nervous system. Whereas, the injections of rhIL-10 have more pronounced effects.

Pharmacological and physiological activation of AMPK improves the spliceopathy in DM1 mouse muscles.

Myotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder caused by a triplet repeat expansion in the 3' untranslated region of dystrophia myotonica protein kinase mRNAs. Mutant mRNAs accumulate in the nucleus of affected cells and misregulate RNA-binding proteins, thereby promoting characteristic missplicing events. However, little is known about the signaling pathways that may be affected in DM1. Here, we investigated the status of activated protein kinase (AMPK) signaling in DM1 skeletal muscle and found that the AMPK pathway is markedly repressed in a DM1 mouse model (human skeletal actin-long repeat, HSALR) and patient-derived DM1 myoblasts. Chronic pharmacological activation of AMPK signaling in DM1 mice with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has multiple beneficial effects on the DM1 phenotype. Indeed, a 6-week AICAR treatment of DM1 mice promoted expression of a slower, more oxidative phenotype, improved muscle histology and corrected several events associated with RNA toxicity. Importantly, AICAR also had a dose-dependent positive effect on the spliceopathy in patient-derived DM1 myoblasts. In separate experiments, we also show that chronic treatment of DM1 mice with resveratrol as well as voluntary wheel running also rescued missplicing events in muscle. Collectively, our findings demonstrate the therapeutic potential of chronic AMPK stimulation both physiologically and pharmacologically for DM1 patients.

Protective, repairing and fibrinolytic effects of rivaroxaban on vascular endothelium.

Rivaroxaban, a direct inhibitor of activated factor X (FXa), is the only new oral anticoagulant approved for secondary prevention after acute coronary syndrome. Our objective was to identify the possible molecular mechanisms of rivaroxaban that contribute to endothelial function. Cell viability and growth of human umbilical vein endothelial cells (HUVEC) were registered. Gene expression studies comparing the effects of rivaroxaban and FXa were conducted by a selective RNA array and confirmed by protein quantification. Wound-healing experiments on HUVEC, platelet adhesion, enzymatic activity, and cell-based assays for fibrin formation were performed with rivaroxaban. Rivaroxaban (50nM) only altered (>2 fold change) the expression of matrix metallopeptidase 2 and urokinase plasminogen activator (u-PA), but counteracted the FXa (9nM)-induced upregulation of several pro-inflammatory genes (P<0.05) and FXa-enhanced platelet adhesion over HUVEC. Rivaroxaban increased u-PA protein expression in HUVEC supernatants and enhanced u-PA activity (up to 4IUng-1 of u-PA). Rivaroxaban (1nM-1μM) showed a significant and dose-dependent positive effect on HUVEC growth that was inhibited by BC-11-hydroxibromide, an inhibitor of u-PA. Healing properties after a wound on HUVEC cultures, and fibrinolytic properties were also shown by rivaroxaban. Both effects were reversed by BC-11-hydroxibromide. Rivaroxaban enhanced viability, growth and migration of HUVEC, mainly by u-PA activation and upregulation, which also participate in the rivaroxaban-induced fibrinolytic activity at endothelial level. Rivaroxaban also protected from the pro-inflammatory effects of FXa on HUVEC. Altogether may improve endothelial functionality and could contribute to the cardiovascular benefits of rivaroxaban.

Assessment of Toxicity and Beneficiary Effects of Garcinia pedunculata on the Hematological, Biochemical, and Histological Homeostasis in Rats.

This study was undertaken to investigate the toxicological profile of a methanolic extract of Garcinia pedunculata fruit in rats by conducting hematological, biochemical, and histopathological examinations. Long Evans rats were divided into four groups, each with 6 animals, and were treated with three oral doses (250, 500, and 1000 mg/kg) once daily for 21 days. The extract did not cause significant changes in body and relative organ weight, percent water content, or hematological parameters at any administered doses. However, a significant dose-dependent positive effect in serum lipid profile and all atherogenic indices including the cardiac risk ratio, Castelli's risk index-2, and the atherogenic coefficient were observed. Significant increases in the levels of iron and decreases in serum alkaline phosphatase, alanine transaminase, and lactate dehydrogenase activities and the levels of serum glucose were noted when the extract was administered at the highest dose (1000 mg/kg). Histopathological examination of the target tissues further confirmed that the extract was safe and had no observed toxicological features. Our study indicates that G. pedunculata fruit is nontoxic, has the potential to be effective against atherosclerosis, and may be used as a hepatoprotectant. The fruit extract is also beneficial to those with iron deficiency and hyperglycemia.

First in human study with a prodrug of galantamine: Improved benefit-risk ratio?

IntroductionGln-1062 (Memogain) is a pharmacologically inactive prodrug of galantamine. Owing to its lipophilic nature, it preferentially enters the brain, where it is cleaved into active galantamine. Gln-1062 is expected to have fewer peripheral side effects than other cholinesterase inhibitors, with improved effectiveness. MethodsThis was a double-blind, comparator and placebo-controlled, sequential cohort, single ascending dose study in 58 healthy subjects with Gln-1062 in doses of 5.5, 11, 22, 33, and 44 mg, compared with oral galantamine 16 mg and donepezil 10 mg. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed. ResultsGln-1062 doses up to 33 mg were well tolerated and induced a dose-dependent increase in the plasma concentrations of Gln-1062 and galantamine. Gln-1062 had a dose-dependent positive effect on verbal memory and attention, mainly in the first hours after drug administration. DiscussionGln-1062 was better tolerated than galantamine in doses with the same molarity and led to improved effects in cognitive tests. This is most likely caused by the more favorable distribution ratio between peripheral and central cholinesterase inhibition. These results give reason for further exploration of this compound.

Antioxidant activity and protection against oxidative-induced damage of Acacia shaffneri and Acacia farnesiana pods extracts: in vitro and in vivo assays.

BackgroundObesity is a worldwide public health issue, reaching epidemic condition in developing countries associated to chronic diseases. Oxidative damage is another side effect of obesity. Antioxidant activity from plant components regulates at some extent this imbalance. Main goal of the present study was to determine the antioxidant activity and protection against oxidative-induced damage of Acacia shaffneri (AS) and Acacia farnesiana (AF) pods extracts.MethodsTo evaluated antioxidant activity and radical scavenging capacity of AS and AF extracts, two experiments were performed: 1) pods extracts were challenged against H2O2 using kidney cells in an in vitro assay; and 2) (Meriones unguiculatus) was employed in an in vivo assay to observe the effect of pods extracts on scavenging properties in plasma.ResultsBoth pods extracts presented an important protective effect on radical scavenging capacity against ABTS• + and DPPH+, and also in TBARS formation in vitro. Vegetal pods extracts did not induce any pro-oxidative effect when added to kidney cells in DMEM. Cells damage in DMEM with addition of H2O2 was significantly higher than those when vegetal pods extracts were added at 50 (P < 0.05) or 200 ppm (P < 0.001). Plasma scavenging properties presented an important dose-dependent positive effect in those groups where pods extracts were administered.ConclusionsThe antioxidant protection of the acacia pods extracts reported in this study suggests the possible transference of antioxidant components and protective effects to animal products (milk, meat, and by-products) from Acacia pods when this vegetation is included in the diet. In order to evaluate, the possible transference of theirs antioxidant components to animal products, the incorporation of these non-conventional resources to ruminant feeding is a good opportunity of study. Profiling of Acacia farnesiana pods extract is necessary to identify the responsible bioactive compounds of protective properties.

Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy

Whether glucocorticoids directly enhance or interrupt osteoclastogenesis is still a controversial subject. In this study, we ascertained the dose-dependent positive effects of glucocorticoids on osteoclastogenesis in vivo and in vitro as well as investigated the mechanism in vitro. As the dose of glucocorticoids increased, osteoclastogenesis was stimulated at 0.1μM, a peak was achieved at 1μM and a corresponding decrease occurred at 10μM. Reactive oxygen species (ROS), which play a crucial role in osteoclastogenesis, and autophagy flux activity, a cellular recycling process, were consistently up-regulated along with the dose-dependent effects of the glucocorticoids on osteoclast formation and function. N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of the glucocorticoids on autophagy and osteoclastogenesis. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, interrupted osteoclastogenesis stimulation by the glucocorticoids. These results implied that with glucocorticoid administration, ROS and autophagy, as a downstream factor of ROS, played vital roles in osteoclast formation and function. 3-MA administration did not enhance ROS accumulation, so that autophagy had no effect on ROS induced by glucocorticoids. Our investigation demonstrated that glucocorticoids had dose-dependent positive effects on osteoclast formation and function via ROS and autophagy. These results provide support for ROS and autophagy as therapeutic targets in glucocorticoid-related bone loss diseases such as glucocorticoid-induced osteoporosis.

Effects of Ascorbic Acid Injection in Incubated Eggs Submitted to Heat Stress on Incubation Parameters and Chick Quality

Dose-dependent positive effects on hatchability and hatchling weight have been attributed to ascorbic acid (AA) when eggs were submitted or not to intermittent heat stress during incubation. Fertile breeder (Cobb(r)) eggs were used to determine if the pre-incubation injection of AA in ovo affects the incubation and hatchling quality of egg incubated under thermoneutral or intermittent heat stress conditions. Eggs were not injected or injected with 0, 2,4, or 6% AA/100µL water and incubated at continuous thermoneutral (37.5oC) or hot (39.0oC) temperature. Eggshell temperature (EST) increased in the second half of the incubation period in all experimental groups. The EST of non-injected eggs and of those injected with water was higher when incubated at 39°C than at 37.5°C, but EST was not different among eggs injected with AA. Egg mass loss and eggshell conductance were higher in the eggs incubated at 39°C than at 37.5°C.Hatchability was lower in the eggs injected with AA. Liver and yolk sac weights were higher, whereas heart and liver weights were lower in hatchlings from eggs incubated at 39°C; however, hatchling weight was not affected by incubation temperature. The results showed that AA doses affected egg conductive heat loss and hatchability, and that they did not minimize the effects of high incubation temperature on liver and heart development.