Potentiating Effect Research Articles

ZnO nanoparticles impregnated with Hibiscus sabdariffa L. extract: Characterization and antimicrobial activity

Zinc oxide can be a vehicle for the encapsulation of bioactive compounds obtained from Hibiscus sabdariffa L by-products due to its mesoporous structure. The nanoparticles obtained with zinc nitrate showed an average particle size of 120 mn, when impregnated with ultrasound-assisted extract of Jamaican by-product did not show morphological alterations, however; it was observed that there is a modification of the ZnO energy bands attributed to the interactions between ZnO and the extract molecules. T1.0% and T1.5% presented higher inhibition on Listeria Monocytogenes, Staphylococcus aureus, Escherichia coli and Staphylococcus mutans compared to T0.5% and EUSJ. The results show that the synthesis process and the impregnation of Jamaican by-product extracts have interesting antibacterial properties associated with the potentiating effect of ZnO and extract, which can be a starting point for further studies on some applications or other types of microorganisms

Prebiotics Modulate Gut Microbiota-mediated T-cell Immunity to Enhance the Inhibitory Effect of Sintilimab in Lewis Lung Adenocarcinoma Model Mice.

Sintilimab (Sin) helps the body to restore the anti-tumor response of T lymphocytes. However, in clinical use, the treatment process is more complicated due to adverse effects and different dosing regimens. It is not clear whether prebiotics (PREB) have a potentiating effect on Sin for lung adenocarcinoma, and this study intends to investigate the inhibitory effect, safety and possible mechanism of Sin combined with PREB on lung adenocarcinoma from animal experiments. Lewis lung adenocarcinoma cells were inoculated into the right axilla of mice subcutaneously to prepare the Lewis lung cancer mouse model and treated in groups. The volume of transplanted tumors was measured, the histopathology of the liver and kidney of mice was observed by H&E staining, the levels of ALT, AST, UREA, CREA, WBC, RBC, and HGB in blood were analyzed biochemically; the ratio of T-cell subpopulations in blood, spleen, and bone marrow was detected by flow cytometry, the expression of PD-L1 in tumor tissue was detected by immunofluorescence staining, and 16S rRNA to analyze the diversity of fecal flora. Sin inhibited tumor growth and regulated immune cell homeostasis in lung adenocarcinoma mice, but liver and kidney histopathology showed different degrees of damage after Sin treatment, while the addition of PREB reduced liver and kidney damage in lung adenocarcinoma mice and promoted Sin's regulation of immune cells. In addition, the beneficial effects of Sin were associated with changes in intestinal flora diversity. The mechanism by which Sintilimab combined with prebiotics inhibits tumor volume and regulates immune cell subpopulation balance in lung adenocarcinoma mice may be related to gut microbes.

The role of ozone and its potentiating effect on steroids and vesicosupplement injections for knee osteoarthritis

The role of ozone and its potentiating effect on steroids and vesicosupplement injections for knee osteoarthritis

Nedaplatin/Peganum harmala Alkaloids Co-Loaded Electrospun, Implantable Nanofibers: A Chemopreventive Nano-Delivery System for Treating and Preventing Breast Cancer Recurrence after Tumorectomy.

Currently, the main pillars in treating breast cancer involve tumorectomy pursued by hormonal, radio, or chemotherapies. Nonetheless, these approaches exhibit severe adverse effects and might suffer from tumor recurrence. Therefore, there is a considerable demand to fabricate an innovative controlled-release nano-delivery system to be implanted after tumor surgical removal to guard against cancer recurrence. In addition, combining platinum-based drugs with phytochemicals is a promising approach to improving the anticancer activity of the chemotherapeutics against tumor cells while minimizing their systemic effects. This study designed polycaprolactone (PCL)-based electrospun nanofiber mats encapsulating nedaplatin (N) and Peganum harmala alkaloid-rich fraction (L). In addition to physicochemical characterization, including average diameters, morphological features, degradation study, thermal stability, and release kinetics study, the formulated nanofibers were assessed in terms of cytotoxicity, where they demonstrated potentiated effects and higher selectivity towards breast cancer cells. The dual-loaded nanofiber mats (N + L@PCL) demonstrated the highest antiproliferative effects against MCF-7 cells with a recorded IC50 of 3.21 µg/mL, as well as the topmost achieved selectivity index (20.45) towards cancer cells amongst all the tested agents (N, L, N@PCL, and L@PCL). This indicates that the dual-loaded nanofiber excelled at conserving the normal breast epithelial cells (MCF-10A). The combined therapy, N + L@PCL treatment, resulted in a significantly higher percent cell population in the late apoptosis and necrosis quartiles as compared to all other treatment groups (p-value of ≤0.001). Moreover, this study of cell cycle kinetics revealed potentiated effects of the dual-loaded nanofiber (N + L@PCL) at trapping more than 90% of cells in the sub-G1 phase and reducing the number of cells undergoing DNA synthesis in the S-phase by 15-fold as compared to nontreated cells; hence, causing cessation of the cell cycle and confirming the apoptosis assay results. As such, our findings suggest the potential use of the designed nanofiber mats as perfect implants to prevent tumor recurrence after tumorectomy.

Ultrastructural Changes in Hippocampal Region CA1 Neurons After Exposure to Permissive Hypercapnia and/or Normobaric Hypoxia.

Isolated exposure to intermittent hypoxia and permissive hypercapnia activates signaling mechanisms that induce ultrastructural changes in mitochondria and endoplasmic reticulum, accompanied by the development of maximal ischemic tolerance in neurons under the combined influence of these factors. However, there are a lack of data on the combined impact of these factors on the ultrastructure of neuronal organelles. The present study aims to comparatively assess the ultrastructural changes in neurons following isolated and combined exposure to hypoxia and hypercapnia, as well as to correlate these changes with the neuroprotective potential previously observed for these factors. Following a 15-session course of 30-min exposures to permissive hypercapnia (PCO2≈50mmHg) and/or normobaric hypoxia (PO2≈150mmHg), morphometric assessment was conducted to evaluate the extent of ultrastructural changes in hippocampal neurons (mitochondria, perinuclear space, and granular endoplasmic reticulum). It was found that in hippocampal neurons from the CA1 region, permissive hypercapnia resulted in increased mitochondrial size, expansion of membranous compartments of the granular endoplasmic reticulum, and perinuclear space. Normobaric hypoxia affected only mitochondrial size, while hypercapnic hypoxia specifically widened the perinuclear space. These ultrastructural changes objectively reflect varying degrees of the influence of hypoxia and hypercapnia on organelles responsible for energy metabolism, anti-apoptotic, and synthetic functions of neurons. This confirms the effect of potentiation of their neuroprotective effects under combined exposure and highlights the dominant role of the hypercapnic component in this mechanism.

The Effects of Drop Jump Height on Post-Activation Performance Enhancement at Different Ambient Temperatures

This study aimed to determine whether drop jump height will affect the post-activation performance enhancement (PAPE) effect at room temperature (RT) and low temperature (LT) conditions. Twelve male strength-trained males participated in this study. Prior to warm-up, subjects underwent a 30 min period of environmental adaptation. Different warm-up protocols were used at different ambient temperatures to help subjects achieve a level of muscle activity and body temperature similar to their daily training. After the pre-test, each subject participated in six experimental sessions at either RT or LT conditions, respectively, which were separated by at least 72 h and conducted at the same time of day to control for circadian influences on metabolism. After the conditioning activities, vertical jump (VJ) performance was re-tested at 4 min, 8 min, and 12 min of passive recovery to assess transient potentiation effects. Under RT conditions, 60 cm and 90 cm drop jumps could induce PAPE, with the PAPE effect being most significant at 4 min (p < 0.01) and 8 min (p < 0.01), respectively, while a 30 cm drop jump could not induce PAPE. Under LT conditions, 30 cm and 90 cm drop jumps could not induce PAPE, and VJ performance gradually declined over time (p < 0.01). However, although a 60 cm drop jump could not induce PAPE, VJ performance was not affected by LT at 8 min and declined at 12 min (p < 0.05). This study demonstrated that 60 cm and 90 cm drop jumps can be used to induce PAPE at RT conditions. LT can impair PAPE induction, while a 60 cm drop jump can be utilized for warm-up at LT conditions to counteract the effects of LT on athletic performance.

Co-delivery of beta-caryophyllene and indomethacin in the oily core of nanoemulsions potentiates the anti-inflammatory effect in LPS-stimulated macrophage model

The potentiation of pharmacological effects can be achieved through several strategies, such as the association of substances and delivery in nanostructured systems. In practice, potentiation can be measured by the law of mass action and joint evaluation of the combination index (CI) and dose–response curves. In this context, this study aimed to evaluate the anti-inflammatory effect of the association of β-caryophyllene and indomethacin in the free form and delivered in nanoemulsions using the in vitro model of LPS-stimulated murine macrophage. The results indicated potentiation of the anti-inflammatory effect of nanoemulsified substances compared to free substances, as well as synergistic action between the sesquiterpene and the selected NSAID. In comparison, the association of β-caryophyllene and indomethacin in the free form inhibited the production of nitric oxide by 50% at 48.60 µg/mL (CI = 0.21), while the nanoemulsified association of these substances resulted in an IC50 of 1.45 µg/mL (CI = 0.14). In parallel, cytotoxicity assays on HaCaT and MRC-5 cell lines demonstrated the safety of IC50-equivalent concentrations of the anti-inflammatory action, and no irritating effects on the chorioallantoic membrane of embryonated eggs were observed (HET-CAM assay). The results suggest that β-caryophyllene may be an alternative to replace an inert oily core in nanoemulsion systems when anti-inflammatory effects are desirable.

Crop protection potential of the leaves of Juglans mandshurica Maxim.: The phenoloxidase promoting related insecticidal effect of its ethanolic extract

Juglans mandshurica Maxim. (JM) is cultivated for timber production, food, and the pharmaceutical industry. Although its leaves (JML) are usually discarded as agricultural waste, they have attracted researchers’ attention for reutilization. The present research was therefore carried out to investigate the crop protection potential of JML. First, phenoloxidase-related insecticidal effects were predicted according to in vitro tyrosinase-potentiating property of JML extracts using its 70% and 90% ethanolic extracts from different collection dates (June, July, and August). This was subsequently verified by using diverse bioassay experiments to evaluate its in vivo bioactivity against Plutella xylostella Linnaeus, Aphis gossypii Glover, and Pieris rapae Linne. The results showed that, 90% ethanolic JML extract (20 mg/mL) had the strongest selective anti-feeding activity, with 87.74% and 79.35% deterrence against A. gossypii and P. rapae, respectively. After four days of oral administration, the 70% ethanolic JML extract (50 mg/mL) showed ∼100% corrected mortality in all test insects. Furthermore, regarding contact toxicities, the JML extracts (25 mg/mL) induced ∼71%, 56%, and 82% corrected mortalities against P. xylostella, P. rapae, and A. gossypii, respectively. Among them, JML extracts showed the strongest growth inhibition against P. xylostella (34.12%) and P. rapae (41.23%) after 24 h treatment. Second, the insecticidal mechanism of JML was investigated by targeting the phenoloxidase (PO) of P. xylostella. The insect’s PO activity was promoted in vitro with the maximum efficacy of 35.09% from 9 mg/mL of JML extract, and this increasing potential could also be observed in the in vivo evaluation. For instance, after the administration of LC70 of JML extract till the 4th instar of the insect, stronger PO activity was detected compared to the control group (77.3% vs. 58.0%). The level of L-Dopa, a key intermediate of PO, significantly increased (31.11 μg/mL) in the hemolymph of insects when treated with the LC70 of JML extract compared with the control group (4.29 μg/mL). The qRT-PCR-mediated mRNA expression analysis confirmed increased PO expression in P. xylostella compared to the control group after JML extract administration. Finally, UPLC-Q-TOF-MS coupled with partial least squared discriminant analysis (PLS-DA) was used to rapidly profile and characterize the 18 compounds as the index ingredients that were related to PO enzymatic activity potentiation or insecticidal effects in the JML extracts. Therefore, our research highlights the potential of J. mandshurica for insecticide development and demonstrates that JML’s abnormal promotion of insect PO activity contributes to its toxicity against pests.

Free Radical Scavenging Activity of Boron and Vitamin C in Nitrite-Induced Hemoglobin Oxidation Model: In vitro and in vivo Studies

Objective: To investigate the dose-response relationship of the free radical-scavenging activities of boron and vitamin C in nitrite-induced hemoglobin oxidation in vitro and in vivo. Method: Different concentrations of boron and vitamin C were added to a hemolysate challenged with nitrite to induce methemoglobinemia (MetHb), and the most effective dose of boron and vitamin C was used before and after different intervals of inducing Hb oxidation, and the production of MetHb was monitored using a spectrophotometer. The effective doses of boron and vitamin C, alone and in combination, were administered to rats before challenging them with an oral dose of 100 mg/kg sodium nitrite. Results: In vitro results indicated that different concentrations of boron and vitamin C attenuated MetHb formation, with the maximum effect achieved at 0.08mg/L and 10mg/L, respectively. Moreover, when these doses were used at different time intervals, a maximum effect was achieved when added 10 min before nitrite. The in vivo results demonstrated a significant reduction in methemoglobin formation in rats treated with boron and vitamin C alone. The hematological markers were not changed except for the platelet levels, which increased in the boron-treated and combination groups. The monocyte-to-lymphocyte ratio decreased significantly in all treatment groups compared with the positive control group. Conclusion: Boron protects against Hb oxidation induced by nitrite, and a potentiated effect has been achieved with the combination of vitamin C.

Benzodiazepines Reduce Blood Pressure in Short Term: A Systematic Review and Meta-analysis.

Benzodiazepines, due to their anxiolytic properties, are prescribed to reduce anxiety and insomnia. They might have hypotensive effect via potentiation of the inhibitory effect of gamma-amino butyric acid (GABA) in the central nervous system and vasodilatory properties. However, studies comparing the effect of benzodiazepines in lowering blood pressure (BP) are equivocal. This systematic review and meta-analysis was planned to assess the efficacy of benzodiazepines in reducing blood pressure in short term among hypertensive patients. Various trials and retrospective analysis conducted previously have reported that benzodiazepines cause short- as well as long-term BP reduction in patients with increased anxiety with hypertension. On the other hand, several studies investigating the efficacy of benzodiazepines in patients with hypertension have reported inconclusive results. The primary question about the effect of benzodiazepines in lowering BP remains unanswered. In this meta-analysis of seven studies, benzodiazepines were found comparable to standard drugs in reducing systolic and diastolic BP in patients having hypertension. Although, the mean difference in systolic BP with benzodiazepines and placebo was statistically not significant, the difference can be considered as clinically meaningful. The current review offers preliminary evidence that benzodiazepines may have antihypertensive properties and may be used as add-on antihypertensive in a subset of patients in short term. The existing data are encouraging, but more clinical trials and mechanistic research are required to ascertain the long-term benefits.

Combined effect of methotrexate and bifidobacteria metabolites on TNFα AND IFNγ production by human peripheral blood mononuclears

Methotrexate (Mtx) is a first-line drug for the treatment of numerous rheumatic and non-rheumatic disorders, including oncological disdiseases. However, therapeutic efficacy of Mtx is limited by severe toxicity to many organs (myelo-, hepato-, nephrotoxicity, mucositis, enteritis, dysbiosis at various human biotopes, etc.). Recently, a number of studies showed that some metabolites of Bifidobacteria and Lactobacilli are able to enhance effect of chemotherapeutic drugs and limit their toxic properties. The aim of the present work was to study the possible potentiating action of Bifidobacteria cell-free supernatants and methotrexate upon secretion of pro-inflammatory TNF and IFN cytokines by human peripheral blood mononuclear cells (PBMCs). The immunoregulatory effects upon production of TNF and IFNg was evaluated in the in vitro model of cultured PBMC supplemented with Bifidobacteria metabolites, methotrexate, or their combination. Analysis of the combined effect of Bifidobacteria metabolites and Mtx on the cytokine production revealed their synergism towards the key pro-inflammatory cytokines (TNF and IFN). We found an increase against the control cultures (with Mtx only), inhibition of the early pro-inflammatory cytokine TNF production. On the contrary, we revealed an increased secretion of IFN which regulates the effector cells. The results obtained with these cytokines suggest the presence of a potentiating effect of Bifidobacteria metabolites upon anti-inflammatory and immunoregulatory properties of methotrexate. Thus, Bifidobacteria metabolites can be considered a promising agent which potentiates the therapeutic action of methotrexate by suppressing TNF secretion and stimulating IFN by immunocompetent cells. Further studies of the combined effects of Mtx and metabolites from the intestinal microbiota upon the cytokine production by effector cells could be recommended, aiming to enhance therapeutic effect of methotrexate and limit its toxic properties using the Bifidobacteria metabolites.

Neonatal phencyclidine as a model of sex-biased schizophrenia symptomatology in adolescent mice.

Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.

Antibacterial potential and modes of action of the methanol extracts of Elephantopus mollis Kunth (Asteraceae) against multidrug-resistant Gram-negative bacteria overexpressing efflux pumps

Background: Bacterial drug resistance still constitutes a major clinical issue. In the present study, the in vitro antibacterial potential, and modes of action of Elephantopus mollis were investigated. Methods: The antibacterial activity of methanol extracts of the various parts of E. mollis, their association with an efflux pump inhibitor, phenylalanine-arginine β-naphthylamide (PAβN) and the potentiating effect of several standard antibiotics were determined using the broth microdilution method. The effects of E. mollis leaf extract on H+ proton pump/ATPase function and bacterial growth kinetics were determined using standard methods. Phytochemical screening of the extracts was carried out using standard qualitative methods. Results: The crude extract (botanicals) from E. mollis leaf and flower had antibacterial activity with a 100% inhibition spectrum against bacterial strains and isolates with MICs ranging from 16 to 256 µg/mL and 64 to 1024 µg/mL respectively. Botanicals from the leaf extract showed excellent activity with a MIC of 16 µg/mL against K. pneumoniae KP55, a MIC of 32 µg/mL against K. pneumoniae (K2), and P. stuartti (NEA16). Botanicals from the leaf extract inhibited the exponential growth phase and H+-proton pump/ATPases of K. pneumoniae ATCC11296. In the presence of PAβN, the activity of E. mollis extracts was improved on 90% (leaves and flowers) and 63% (roots) of multidrug-resistant (MDR) bacterial strains and isolates. The various extracts of E. mollis potentiated the activities of the antibiotics: doxycycline, levofloxacin, vancomycin, imipenem, ceftriaxone, and ciprofloxacin against at least 70% of bacterial strains and isolates, with factors of increase in activity ranging from 2 to 128. Extracts from all parts of E. mollis contained alkaloids, flavonoids, tannins, and phenols. Conclusion: The results show that E. mollis is a source of antibacterial phytomedicine that can be used to treat bacterial infections caused by Gram-negative bacteria expressing MDR phenotypes. Keywords: Antibiotics; Asteraceae; bacteria; efflux pumps; Elephantopus mollis; multidrug resistance.

Exploring Antibiotic-Potentiating Effects of Tobramycin-Deferiprone Conjugates in Pseudomonas aeruginosa.

Metal ions, including Fe3+, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including Pseudomonas aeruginosa. To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of P. aeruginosa. While all TOB-DEF conjugates were inactive against P. aeruginosa, the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, 1c containing a C12 tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant P. aeruginosa isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe3+ concentration.

Rational Engineering of a Mitochondrial‐Mimetic Therapy for Targeted Treatment of Dilated Cardiomyopathy by Precisely Regulating Mitochondrial Homeostasis

AbstractDilated cardiomyopathy (DCM) is a leading cause of heart failure and the most common indication for heart transplantation. Currently, there is still an unmet clinical need in effective therapies for DCM. Herein a mitochondrial‐mimetic therapy capable of efficiently targeting the heart, cardiomyocytes, and myocardial mitochondria as well as effectively regulating mitochondrial homeostasis for targeted treatment of DCM is reported. A bioactive conjugate TPT is first synthesized by integrating three functional moieties onto a scaffold, which can assemble into small‐size nanomicelles (i.e., TPTN). Intravenously delivered TPTN efficiently accumulates in the heart and mainly localizes in cardiomyocytes and myocardial mitochondria of DCM mice, thereby alleviating DCM. Mechanistically, TPTN inhibits intracellular oxidative stress, alleviates mitochondrial injury, improves mitochondrial dynamics, regulates mitochondrial oxidative phosphorylation, and reduces calpain‐1 and NLRP3 inflammasome activation, thus restoring mitochondrial homeostasis and inhibiting adverse cardiac remodeling. By packaging TPTN into outer mitochondrial membrane‐derived vesicles, a mitochondrial‐mimetic therapy is engineered, which displays significantly enhanced three‐level targeting capability to the heart, cardiac cells, and myocardial mitochondria, thereby affording notably potentiated therapeutic effects in DCM mice. Accordingly, the three‐level targeting mimetics is promising for targeted treatment of DCM. The findings provide new insight into rational design of precision therapies for mitochondrial dysfunction‐associated diseases.

Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome.

Rett syndrome (RTT), a severe X-linked neurodevelopmental disorder, is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). Over 35% RTT patients carry nonsense mutation in MECP2, making it a suitable candidate disease for nonsense suppression therapy. In our previous study, gentamicin was found to induce readthrough of MECP2 nonsense mutations with modest efficiency. Given the recent discovery of readthrough enhancers, CDX compounds, we herein evaluated the potentiation effect of CDX5-1, CDX5-288, and CDX6-180 on gentamicin-mediated readthrough efficiency in transfected HeLa cell lines bearing the four most common MECP2 nonsense mutations. We showed that all three CDX compounds potentiated gentamicin-mediated readthrough and increased full-length MeCP2 protein levels in cells expressing the R168X, R255X, R270X, and R294X nonsense mutations. Among all three CDX compounds, CDX5-288 was the most potent enhancer and enabled the use of reduced doses of gentamicin, thus mitigating the toxicity. Furthermore, we successfully demonstrated the upregulation of full-length Mecp2 protein expression in fibroblasts derived from Mecp2R255X/Y mice through combinatorial treatment. Taken together, findings demonstrate the feasibility of this combinatorial approach to nonsense suppression therapy for a subset of RTT patients.

Assessing radonotherapy effectiveness and modulated steroidogenesis in experimental chronic endometritis model

Aim: to evaluate therapeutic efficacy and modulated steroidogenesis after radon therapy in experimental chronic endometritis model.Materials and Мethods. A therapeutic effect related to radon mineral waters was studied experimentally. The water radon concentration was 5.4–6.2 nCi/dm3. The experimental endometritis was induced in laboratory Wistar line rats (n = 40) inoculated with intra-uterine self-fecal suspension. Experimental group animals (n = 10) received a wide-spectrum antibiotic Ceftriaxone within 7 days followed by applying 10 procedures of radon therapy one a day and from day 41, the first procedure lasting 5 minutes, the second – 8 minutes, the third – 10 minutes, with all other procedures – for 15 minutes. Comparison group I animals (n = 10) received antibacterial therapy, radon therapy and 10 procedures of peloid therapy with natural salt-saturated medium sulfide silt therapeutic mud according to a radon therapy regimen. Сomparison group II (n = 10) received antibacterial and peloid therapy according to comparison group I regimen. Control group (n = 10) received no treatment. Inflammatory signs were assessed by endometrium histology study. The venous steroid hormones levels were analyzed by enzyme-linked immunosorbent assay.Results. In experimental vs. control group, it was found that endometrial diffuse infiltrate was of lower density comprising 125.4 ± 8.1 vs. 180.7 ± 9.0 immunocompetent cells (by 30.7%; p = 0.002), whereas in comparison group I, density of inflammatory infiltration was minimal (reduced by 88.7 % compared to control group; p < 0.001) and reached 20.5 ± 1.8 cells. In the experimental group as well as comparison groups I and II vs. control group, a significant increased level of serum progesterone was observed after treatment (p = 0.008). When using a radon therapy in experimental group, it resulted in a more prominent rise in progesterone level compared to peloid therapy in comparison group II. Radon balneotherapy was found in main control group to elicit a significant declined estradiol level (p = 0.008), but not in comparison groups I and II featured with no significant change in estradiol level compared to control group.Conclusion. Radon therapy exerts an anti-inflammatory effect in experimental chronic endometritis model. Radon therapy combined with peloid therapy has a potentiated effect. The use of radon balneotherapy is accompanied by significantly increased progesterone and decreased estradiol level suggesting to conduct clinical trials for confirming its effectiveness in patients with reproductive dysfunction including diseases accompanied by hyperestrogenism.

Manipulable objects can potentiate pointing and unusual grasping besides habitual grasping behaviors.

People are faster to perform a precision grip when they see a cherry (i.e., a small graspable object) than to perform a power grip, and the reverse holds true when they see an apple (i.e., a large graspable object). This potentiation effect supports that object representations could include motor components that would be simulated when a graspable object is seen. However, the nature of these motor components remains unclear. The embodied account posits that seeing an object only potentiates the most frequent actions associated with it (i.e., usual actions). In contrast, the size-coding account posits that seeing an object potentiates any actions associated to spatial codes compatible with those associated to the objects. We conducted three experiments to disentangle these two alternative accounts. We especially varied the nature of the responses while participants saw either large or small graspable objects. Our results showed a potentiation effect when participants performed the usual grasping actions (Experiment 1: power and precision grip) but also when they performed unusual grasping actions (Experiment 2: grasping between the thumb and little finger) and even when they had to perform non-grasping actions (Experiment 3: pointing actions). By supporting the size-coding account, our contribution underlines the need for a better understanding of the nature of the motor components of object representations and for using a proper control condition (i.e., pointing action) before arguing that the embodied account convincingly explains the potentiation effect of grasping behaviors.

Triggering the Amphotericin B Pore-Forming Activity by Phytochemicals.

The macrolide polyene antibiotic amphotericin B (AmB), remains a valuable drug to treat systemic mycoses due to its wide antifungal activity and low probability of developing resistance. The high toxicity of AmB, expressed in nephropathy and hemolysis, could be partially resolved by lowering therapeutic AmB concentration while maintaining efficacy. This work discusses the possibility of using plant polyphenols and alkaloids to enhance the pore-forming and consequently antifungal activity of AmB. We demonstrated that phloretin, phlorizin, naringenin, taxifolin, quercetin, biochanin A, genistein, resveratrol, and quinine led to an increase in the integral AmB-induced transmembrane current in the bilayers composed of palmitoyloleoylphosphocholine and ergosterol, while catechin, colchicine, and dihydrocapsaicin did not practically change the AmB activity. Cardamonin, 4'-hydroxychalcone, licochalcone A, butein, curcumin, and piperine inhibited AmB-induced transmembrane current. Absorbance spectroscopy revealed no changes in AmB membrane concentration with phloretin addition. A possible explanation of the potentiation is related to the phytochemical-produced changes in the elastic membrane properties and the decrease in the energy of formation of the lipid mouth of AmB pores, which is partially confirmed by differential scanning microcalorimetry. The possibility of AmB interaction with cholesterol in the mammalian cell membranes instead of ergosterol in fungal membranes, determines its high toxicity. The replacement of ergosterol with cholesterol in the membrane lipid composition led to a complete loss or a significant decrease in the potentiating effects of tested phytochemicals, indicating low potential toxicity of these compounds and high therapeutic potential of their combinations with the antibiotic. The discovered combinations of AmB with plant molecules that enhance its pore-forming ability in ergosterol-enriched membranes, seem to be promising for further drug development in terms of the toxicity decrease and efficacy improvement.

Effects of conditioning activity mode, rest interval and effort to pause ratio on post-activation performance enhancement in taekwondo: a randomized study.

Introduction: The present study assessed the effects of conditioning activities, using different effort-to-pause ratios and rest intervals, on taekwondo physical performance. Methods: Twenty-one athletes (13 males and 8 females) (Mean ± SD; age = 20.4 ± 1.4years) performed a control (CC) and twelve experimental conditions. Each condition contained a standard warm-up (i.e., CC: running at 9km/h for 10min) and conditioning activities comprising plyometrics P) or repeated high-intensity techniques (RT) using 1:6, 1:9 and self-selected rest (SSR) ratios, and two rest intervals (3 and 7min). Athletes then performed a battery of fitness tests: countermovement jump (CMJ), taekwondo specific agility (TSAT), 10s and multiple frequency speed kick test (FSKT-10s and FSKT-mult, respectively). Results: All of the preloads provided higher performance outputs compared to the control trial (all p < 0.05). For CMJ, 1:6 ratio with 3min induced lower values with RT compared to P (p = 0.037) and 1:9 ratio using 3min induced higher values with RT compared to P (p = 0.027). Additionally, 1:6 ratio using 7min induced higher values with RT compared to P (p = 0.016). For FSKT-10, 3min using 1:6 induced higher values with P compared to RT, while RT induced higher values with 7min using 1:6 ratio compared to P (both p < 0.001). Moreover, 3min using 1:9 ratio induced higher values with P compared to RT (p = 0.034), while RT induced higher values with 1:9 ratio using 7min compared to P (p < 0.001). Finally, 3min using SSR ratio induced higher values with RT compared to P (p = 0.034). Conclusion: Plyometrics and RT activities improved performance with plyometrics requiring shorter rest interval to induce potentiation effects compared to RT, which required longer interval.