Short-term Administration Research Articles

Short-Term Introduction of Fullerene C60 Nanoparticles in Rat Small Intestine Induces the Rapid Development of Hepatocyte Pathology

Fullerenes C60 are used in various fields of industry; therefore, issues of studying their biosafety for living organisms, their biodistribution in organs and tissues organs and tissues of laboratory animals, and their induction of cellular pathologies are very important. In recent years, analytical and transmission electron microscopy (TEM) have proven their efficiency in detecting carbon nanoparticles in biological samples. Combining these methods can reveal pathological changes in cells induced by nanoparticles and detect accumulations of nanoparticles in them. The aim of the study was to reveal cellular pathologies upon direct short-term administration of fullerene C60 nanoparticles into the gastrointestinal tract (GIT) of rats and to detect nanoparticles in samples of the small intestine and liver. The histological and ultrastructural analysis did not reveal pathological changes in the small intestine, but degenerative changes in hepatocytes were indicated in the form of accumulation of lipid inclusions. High-performance liquid chromatography and analytical TEM revealed no accumulations of fullerene C60 nanoparticles in the studied samples. Probably, hepatosteatosis may be a consequence of the indirect influence of C60 nanoparticles on liver cells. Apparently, the surface of fullerene C60 undergoes modifications in the GIT, and its contact with the cells of the small intestine induces the synthesis of proinflammatory cytokines, with their subsequent entry into the liver, leading to the rapid development of fatty degeneration. Revealing and identifying modified C60 nanoparticles and their metabolites, in turn, is a complex problem, which in the future can be solved using radiotracers, mass spectrometry, and modern metabolomic technologies.

Short-term treatment with imetelstat sensitizes hematopoietic malignant cells to a genotoxic agent via suppression of the telomerase-mediated DNA repair process

Imetelstat is a specific and competitive inhibitor of telomerase enzymatic activity. We demonstrated that imetelstat could interfere with the DNA repair process and enhance the effect of DNA damaging agents using hematological tumor cell lines. Short-term administration of imetelstat enhanced growth suppression by anticancer agents and radiation. It also upregulated γH2AX expression induced by irradiation. Immunofluorescence staining showed that both human telomerase reverse transcriptase (hTERT) and γH2AX were upregulated and co-localized in the nucleus of peripheral blood mononuclear cells after irradiation, suggesting that hTERT was involved in the DNA-DSB repair process. Imetelstat enhanced growth inhibitory effect of cytotoxic agents in short-term culture without shortening of telomeres, indicating that this effect was attributed by telomere length independent mechanism. Our results suggest that the combination of short-term treatment with imetelstat and cytotoxic agent is a promising strategy to treat a wide variety of hematopoietic malignancies.

Anticancer bioactive peptide combined with docetaxel and its mechanism in the treatment of breast cancer.

Breast cancer remains a worldwide public-health issue. Novel drugs that increase the sensitivity and reduce the toxic side effects of chemotherapeutic agents are urgently required. The present study investigated the effect and mechanism of the short-term intermittent administration of an anticancer bioactive peptide (ACBP), docetaxel (DTX), ACBP combined with DTX (MIX) and ACBP combined with low dose DTX (L-MIX) to nude mice bearing human breast cancer tumors. The body weight, tumor length, tumor diameter, diet and water consumption of the tumor-bearing nude mice were calculated. The protein and mRNA expression levels of p53, p21 and Ki67 were detected via immunohistochemistry and reverse transcription-quantitative PCR, respectively. The results revealed that the activity level of each group of mice was consistent. However, the food and water consumption of the ACBP group was significantly increased compared with the NS group. Compared with the normal saline group, the tumor weights and volumes of the treatment groups were significantly decreased, indicating an inhibitory effect of the treatment. However, the MIX group exhibited lower tumor weights and volumes compared with the ACBP and DTX groups. Furthermore, no significant cell necrosis, edema or inflammatory cell infiltration was observed upon hematoxylin & eosin staining of the liver and spleen in all groups. The results also revealed that the p21, p53 and Ki67 protein and mRNA levels were decreased in the ACBP, DTX and MIX groups compared with the control group. Additionally, when compared with those in the MIX and L-MIX groups, the p21 and Ki67 protein, and p53 and Ki67 mRNA levels in the ACBP and DTX groups were significantly increased. The results suggested that the short-term intermittent use of ACBP alone had an inhibitory effect on tumor growth and improved the food and water consumption of tumor-bearing nude mice. Furthermore, the combination of ACBP and DTX reduced toxic side effects and the dosage requirement of drugs to achieve therapeutic effects on the tumor-bearing nude mice. Therefore, the antitumor effect of ACBP may be associated with the improvement of immune function in tumor-bearing nude mice and ACBP may serve an antitumor role via the p53-p21 signaling pathway in breast cancer.

Safety of repository corticotropin injection as an adjunctive therapy for the treatment of rheumatoid arthritis

ABSTRACT Introduction Disease-modifying antirheumatic drugs (DMARDs) have significantly improved clinical symptoms and quality of life with reduced disease progression in many patients with rheumatoid arthritis (RA). Short-term glucocorticoid therapy is often used initially in combination with DMARDs, but some patients still have difficulty reaching treatment goals. Repository corticotropin injection (RCI, Acthar® Gel) is approved as adjunctive therapy for short-term administration in patients with continued RA disease activity. Areas covered To determine the safety of RCI in the treatment of RA, adverse events (AEs) from a recent clinical trial of RCI as an adjunctive therapy along with DMARDs and glucocorticoids (ClinicalTrials.gov identifier NCT02919761) were compared with AEs reported in randomized clinical trials of DMARDs and glucocorticoids alone. A systematic review of the literature yielded 4 articles describing the detailed safety results of DMARD/glucocorticoid combination therapy used in the treatment of RA for comparison. Expert opinion There were no clinically significant differences between the AE profiles of RCI/DMARD/glucocorticoid treatment in the RCI clinical trial and those in the DMARD/glucocorticoid safety profile compiled from the reviewed clinical trials; this was supported by pharmacovigilance data. These results support the short-term safety of RCI as an adjunctive therapy for patients with persistently active RA.

Long-term administration of intranasal insulin improves peripheral glucose concentration in diabetic male rats

Introduction: Experiments in rodents and humans suggest that short-term intranasal insulin administration, which is known to reach the brain, does not affect peripheral glucose concentration under diabetic conditions. Methods: In this work, we provide evidence for the effect of intranasal insulin (10 IU/rat/day for 3 or 10 days) on serum insulin and glucose in streptozotocin-diabetic male rats using insulin measurements in the brain and periphery and a serum glucose assay 18 hours after three or ten days of nasal insulin administration. Results: Our findings revealed peripheral insulin increased and glucose level decreased in the diabetic male rats. Based on insulin kinetics, it seems that brain insulin directly or indirectly regulates serum insulin and glucose metabolism under diabetic conditions. Conclusion: Our results may suggest an insight into the therapeutic benefits of nasal insulin in diabetes.

Further Evidence of Benefits to Mood and Working Memory from Lipidated Curcumin in Healthy Older People: A 12-Week, Double-Blind, Placebo-Controlled, Partial Replication Study.

Curcumin (a flavonoid isolated from turmeric) affects several processes involved in neurocognitive aging. We have previously reported that short term (4-weeks) administration of a highly bioavailable curcumin preparation (Longvida©) improved working memory and reduced fatigue and stress reactivity in a healthy older cohort. The present trial (ACTRN12616000484448) was a partial replication study, evaluating similar effects at 4 and 12-weeks Longvida© supplementation. A double-blind, placebo-controlled, parallel-groups trial was conducted. Eighty participants aged 50–80 years (mean = 68.1, SD = 6.34) were randomised to receive Longvida© (400 mg daily containing 80 mg curcumin) or a matching placebo. Assessment took place at baseline then following 4 and 12 weeks treatment. Outcome measures included cognitive performance, mood and biomarkers. Compared with placebo, curcumin was associated with several significant effects. These included better working memory performance at 12-weeks (Serial Threes, Serial Sevens and performance on a virtual Morris Water Maze), and lower fatigue scores on the Profile of Mood States (POMS) at both 4 and 12-weeks, and of tension, anger, confusion and total mood disturbance at 4-weeks only. The curcumin group had significantly elevated blood glucose. These results confirm that Longvida© improves aspects of mood and working memory in a healthy older cohort. The pattern of results is consistent with improvements in hippocampal function and may hold promise for alleviating cognitive decline in some populations.

Improvement of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use.

Background and Aims:It is currently unclear whether sodium–glucose co-transporter 2 (SGLT2) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation.Methods and ResultsThis single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients’ metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulinemic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment, while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity, were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment.ConclusionSGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.

Short-term intermittent parathyroid hormone (1-34) administration increased angiogenesis and matrix metalloproteinase 9 in femora of mature and middle-aged C57BL/6 mice.

What is the central question of this study? We sought to assess the effects of intermittent parathyroid hormone (1-34) administration on bone angiogenesis, the redistribution of bone marrow blood vessels, and matrix metalloproteinase9 as a function of advancing age in mice. What is the main finding and its importance? Short-term (i.e. 10 days) intermittent parathyroid hormone (1-34) administration increased the number of small (≤29-µm-diameter) bone marrow blood vessels and augmented matrix metalloproteinase9. These changes occurred before alterations in trabecular bone. Given the rapid response in bone angiogenesis, this investigation highlights the impact of intermittent parathyroid hormone (1-34) administration on the bone vascular network. Intermittent parathyroid hormone (PTH) administration augments bone, stimulates the production of matrix metalloproteinase9 (Mmp9) and relocates bone marrow blood vessels closer to osteoid seams. Discrepancies exist, however, regarding bone angiogenesis. Given that Mmp9 participates in cellular homing and migration, it might aid in blood vessel relocation. We examined the influence of short-term intermittent PTH administration on angiogenesis, Mmp9 secretion and the distance between blood vessels and bone. Mature (6- to 8-month-old) and middle-aged (10- to 12-month-old) male and female C57BL/6 mice were divided into three groups: control (CON), and 5 (5dPTH) and 10days (10dPTH) of intermittent PTH administration. Mice were given PBS (50µlday-1 ) or PTH(1-34) (43µgkg-1 day-1 ). Frontal sections (5µm thick) of the right distal femoral metaphysis were triple-immunolabelled to identify endothelial cells (anti-CD31), vascular smooth muscle cells (anti-αSMA) and Mmp9 (anti-Mmp9). Vascular density, Mmp9 density, area and localization, and blood vessel distance from bone were analysed. Blood vessels were analysed according to diameter: 1-29, 30-100 and 101-200µm. Trabecular bone microarchitecture and bone static and dynamic properties were assessed. No main effects of age were observed for any variable. The density of CD31-labelled blood vessels 1-29 and 30-100µm in diameter was higher (P<0.05) and tended (P=0.055) to be higher, respectively, in 10dPTH versus 5dPTH and CON. Mmp9 was augmented (P<0.05) in 10dPTH versus the other groups. Mmp9 was closer (P<0.05) to blood vessels 1-29µm in diameter and furthest (P<0.05) from bone. In conclusion, bone angiogenesis occurred by day10 of intermittent PTH administration, coinciding with augmented Mmp9 secretion near the smallest blood vessels (1-29µm in diameter).

Efficacy and safety of letrozole in treatment of male children with disorders of sex development

To investigate the efficacy and safety of aromatase inhibitor letrozole in treatment of male children with disorders of sex development (DSD). Clinical data of 12 male DSD children with a mean age of 14.6±2.5 years admitted to Peking Union Medical College Hospital from January 2014 to January 2016 were retrospectively analyzed. The patients were treated with letrozole (1.25-2.5 mg, once a day) for 3 months or longer, and followed up for 0.5-2.5 years. Clinical manifestation and laboratory test findings were documented, and the efficacy and safety were evaluated. After half-year treatment, the blood luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone levels of patients increased (all P &lt; 0.05), and estrogen levels decreased from baseline ( P &lt; 0.05). After 1 year of treatment, the blood testosterone level was significantly higher ( P &lt; 0.05); the LH and FSH levels tended to increase and the estrogen level tended to decrease, but there was no significant statistical difference ( P&gt;0.05). Semen was routinely detected in 8 patients, and sperms were detected in semen of 3 patients with hypospadias. There were no significant changes in biochemical results after treatment, and no significant adverse event was observed during the treatment. Letrozole can effectively increase testosterone levels in patients with disorders of sex development and promote spermatogenesis, it has no significant adverse effects in short-term administration.

Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH.

In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and pro-apoptotic sphingolipid metabolites, implicated in regulating fatty acid oxidation and inflammation. Importantly, inhibition of de novo ceramide biosynthesis or knock-down of ceramide synthases reverse some of the pathology of NASH. In contrast, cell permeable, short chain ceramides have shown anti-inflammatory actions in multiple models of inflammatory disease. Here, we investigated non-apoptotic doses of a liposome containing short chain C6-Ceramide (Lip-C6) administered to human hepatic stellate cells (hHSC), a key effector of hepatic fibrogenesis, and an animal model characterized by inflammation and elevated liver fat content. On the basis of the results from unbiased liver transcriptomic studies from non-alcoholic fatty liver disease patients, we chose to focus on adenosine monophosphate activated kinase (AMPK) and nuclear factor-erythroid 2-related factor (Nrf2) signaling pathways, which showed an abnormal profile. Lip-C6 administration inhibited hHSC proliferation while improving anti-oxidant protection and energy homeostasis, as indicated by upregulation of Nrf2, activation of AMPK and an increase in ATP. To confirm these in vitro data, we investigated the effect of a single tail-vein injection of Lip-C6 in the methionine-choline deficient (MCD) diet mouse model. Lip-C6, but not control liposomes, upregulated phospho-AMPK, without inducing liver toxicity, apoptosis, or exacerbating inflammatory signaling pathways. Alluding to mechanism, mass spectrometry lipidomics showed that Lip-C6-treatment reversed the imbalance in hepatic phosphatidylcholines and diacylglycerides species induced by the MCD-fed diet. These results reveal that short-term Lip-C6 administration reverses energy/metabolic depletion and increases protective anti-oxidant signaling pathways, possibly by restoring homeostatic lipid function in a model of liver inflammation with fat accumulation.

Role of Long Noncoding RNA Gas5 in Cocaine Action

BackgroundLong noncoding RNAs (lncRNAs) are a class of transcribed RNA molecules greater than 200 nucleotides in length. Although lncRNAs do not encode proteins, they play numerous functional roles in gene expression regulation. lncRNAs are notably abundant in brain; however, their neural functions remain largely unknown. MethodsWe examined the expression of the lncRNA Gas5 in nucleus accumbens (NAc), a key brain reward region, of adult male mice after cocaine administration. We then performed viral-mediated overexpression of Gas5 in NAc neurons to determine its role in addiction-related behaviors. We also carried out RNA sequencing to investigate Gas5-mediated transcriptomic changes. ResultsWe demonstrated that repeated short-term or long-term cocaine administration decreased expression of Gas5 in NAc. Viral-mediated overexpression of Gas5 in NAc neurons decreased cocaine-induced conditioned place preference. Likewise, Gas5 overexpression led to decreased cocaine intake, decreased motivation, and compulsive-like behavior to acquire cocaine, and it facilitated extinction of cocaine-seeking behavior. Transcriptome profiling identified numerous Gas5-mediated gene expression changes that are enriched in relevant neural function categories. Interestingly, these Gas5-regulated gene expression changes significantly overlap with chronic cocaine-induced transcriptome alterations, suggesting that Gas5 may serve as an important regulator of transcriptional responses to cocaine. ConclusionsAltogether, our study demonstrates a novel lncRNA-based molecular mechanism of cocaine action.

Stimulatory effects of short-term calcitonin administration on plasma calcium, magnesium, phosphate, and glucose in juvenile Siberian sturgeon Acipenser baerii.

Calcitonin (CT) has a potential function in calcium (Ca) regulation, but there are conflicting observations in fishes. Because of the lack of calcified endoskeleton, sturgeons have low Ca circulating compared with teleost fish and the function of CT on Ca in sturgeon is very less understood. The purpose of this study was to investigate the impact of injection of salmon CT on plasma Ca, magnesium (Mg), phosphate (PHO), and glucose levels of juvenile Siberian sturgeon Acipenser baerii. Sixteen-month-old fish (429.6 ± 12.1g) were intraperitoneally injected with a single dose of CT (5μgkg-1 BW) and saline solution as a control group. Thereafter, blood sampling was performed at 0, 1, 2, 4, 6, 12, 24, and 48h after injection. CT produced marked increases in all variables measured. The highest levels of Ca (6.77 ± 0.53mgdL-1), Mg (9.79 ± 0.16mgdL-1) and PHO (1.74 ± 0.05mgdL-1) were recorded at 2h after CT injection and showed significant difference compared with control treatment (Ca 4.75 ± 0.12mgdL-1; Mg 5.47 ± 0.16mgdL-1 and PHO 1.23 ± 0.06mgdL-1). It also likely produced hyperglycemia. However, the differences with the controls were not statistically significant, possibly due to interference with the hyperglycemia induced by the stress of injection. Our results showed that the injection of 5μgkg-1 BW CT to Siberian sturgeon has an incremental effect on plasma Ca, Mg, and PHO. The increase in plasma Ca level indicated that CT has a potent hypercalcemic effect in sturgeon under laboratory condition, in contrast to the hypocalcemic effects reported for teleosts.

Prevention of Type 1 Diabetes via a lipid Nanoparticle-Based Oral Immunotherapy that Targets Selective Lymphoid Tissues

Abstract Type 1 diabetes (T1D) is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Antigen presenting cells (APCs) malfunctions and aberrant accumulation of type 1 interferons contribute to T1D, and the inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of the disease. However, maintenance of a therapeutic concentration of these drugs is challenging and their prolonged use leads to significant side effects. Our objective was to design a controlled and localized delivery of Tofa via biocompatible lipid nanoparticles, Nanostructured Lipid Carrier (NLC), and assess if, via this strategy, a short-term administration would impact T1D development. We identified a formulation of NLC that had negligible toxicity, could be readily taken up by multiple immune cells, and had a favorable Tofa encapsulation efficiency. Live animal imaging confirmed these particles have the unique property of accumulating in lymphoid tissues, particularly in spleen, pancreatic and mesenteric lymph nodes when administrated via oral gavage. Ex-vivo, Tofa-NLC rapidly delivered Tofa to mouse APCs preventing their maturation and the release of inflammatory cytokines. Importantly, short-term administration of Tofa-NLC via oral gavage at early (3-week-old) or late (10-week-old) stage in disease prone NOD mice promoted a significant delay of T1D onset. Cell profiling and in vivo challenges indicated that this therapeutic effect is likely due to localized inhibition of APCs maturation and promotion of anergy in diabetogenic T cells. These results highlight the versatility of this lipid nanoparticle-based drug delivery strategy.

High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model.

Chemotherapy infusions directly into the fourth ventricle may play a role in treating malignant fourth-ventricular tumors. This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma) into the fourth ventricle of nonhuman primates. Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In group I (n = 2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for 5 consecutive days. Serial CSF and serum panobinostat levels were measured. In group II (n = 2), fourth-ventricle catheters were connected to a subcutaneously placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 μM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and postmortem histological analyses. No neurological deficits occurred after intraventricular MTX110 infusions. MRI scans showed catheter placement within the fourth ventricle in all 4 animals, with extension to the cerebral aqueduct in 1 animal and into the third ventricle in 1 animal. There were no MRI signal changes in the brainstem, cerebellum, or elsewhere in the brains of any of the animals. Histologically, normal brain cytoarchitecture was preserved with only focal mild postsurgical changes in all animals. Panobinostat was undetectable in serum samples collected 2 and 4 hours after infusions in all samples in both groups. In group I, the mean peak panobinostat level in the fourth-ventricle CSF (6242 ng/ml) was significantly higher than that in the lumbar CSF (9 ng/ml; p < 0.0001). In group II, the mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than the mean trough CSF panobinostat level (33 ng/ml; p < 0.0001). MTX110 can be safely infused into the fourth ventricle in nonhuman primates at supratherapeutic doses. Postinfusion CSF panobinostat levels peak immediately in the fourth ventricle and then rapidly decrease over 24 hours. Panobinostat is detectable at low levels in CSF measured from the lumbar cistern up to 4 hours after infusions. These results will provide background data for a pilot clinical trial in patients with recurrent medulloblastoma.

Atherosclerosis-related biomarkers in women with endometriosis: The effects of dienogest and oral contraceptive therapy.

ObjectiveChronic inflammation in endometriosis is associated with increased risk of future cardiovascular disease; however, no studies have investigated the cardiovascular risk of women who have undergone hormonal therapy for endometriosis. We investigated atherosclerosis-related biomarkers in women with and without endometriosis and the effects of dienogest (DNG) and oral contraceptive (OC) therapies.Study designIn this cross-sectional study, 109 women with endometriosis and 42 control women without endometriosis were enrolled. The endometriosis group was divided into the untreated (n = 34), DNG therapy (n = 33), and OC therapy (n = 42) groups. Lipid profile serum levels, inflammatory marker such as high-sensitivity C-reactive protein, oxidative stress markers such as oxidized low-density lipoprotein and diacron-reactive oxygen metabolites, and atherosclerosis indicators (cardio-ankle vascular index [CAVI] and ankle-brachial pressure index [ABI]) were measured.ResultsThe median treatment duration was 28 months in the DNG group and 32.5 months in the OC group. Triglyceride levels were higher in the OC group than in the other three groups (P < 0.05). Regarding markers of inflammation and oxidative stress, log high-sensitivity C-reactive protein and diacron-reactive oxygen metabolites levels were higher in the untreated group than in the control group (P < 0.05), and these markers were further increased in the OC group (log high-sensitivity C-reactive protein: P < 0.05; diacron-reactive oxygen metabolites: P < 0.01), but not in the DNG group. There was no difference in the CAVI and ABI among all groups. Spearman correlation revealed a positive correlation between duration of OC therapy and CAVI (ρ = +0.49; P = 0.002), but no correlation between the duration of DNG therapy and CAVI (ρ = –0.04; P = 0.81).ConclusionsInflammation and oxidative stress markers are increased in women with untreated endometriosis. Treatment with OC, but not with DNG, further increases these levels. There was a positive association between the duration of OC administration and atherosclerosis risk for women with endometriosis. Our results suggest that DNG could be administered to endometriosis without the increased atherosclerosis risk and short-term OC administration for endometriosis is not harmful, however, atherosclerosis risk should be strictly observed.

Examining the Early Period Effect of Nilotinib on Hearing: An Experimental Study.

Nilotinib has very few side effects, including neutropenia, thrombocytopenia, cardiotoxicity, high pancreatic lipase, ischemia, and vascular occlusion. We aimed to investigate whether short-term administration of nilotinib had ototoxic effects in rats. Wistar-albino rats were categorized into three groups: group C (administered 0.25 mL of distilled water, no nilotinib), group N-20 (administered 20 mg/kg/day of nilotinib dissolved in distilled water), and group N-50 (administered 50 mg/kg/day of nilotinib dissolved in distilled water). A single dose was administered once per day, at the same hour, over 21 days. Auditory brainstem response (ABR) thresholds were recorded on day 0 and day 21. There were no changes in ABR threshold values obtained on day 0 (baseline) and on day 21 across all three groups. A statistically significant difference was not found in terms of the mean latency of waves V and III, interpeak latency values of waves III-V, and amplitude ratios of waves III-V and V/Va at baseline and on day 21 across all three groups on within-group or between-group evaluation. Consequently, further studies are needed that involve different drug doses, prolonged administration of drugs, as well as distortion otoacoustic emission test for the evaluation of cochlear activation and ABR. Furthermore, histopathological studies are needed to indicate whether the cochlea is affected to prove that nilotinib has definitively no ototoxic effect.

Evaluation of dose-response effects of short-term oral prednisone administration on clinicopathologic and hemodynamic variables in healthy dogs.

To determine whether a dose-response relationship exists between short-term oral prednisone administration and common clinicopathologic variables, cardiovascular biomarkers, and systolic arterial blood pressure (SAP) in healthy dogs. 8 healthy Beagles. Dogs underwent five 5-day experiments (no prednisone treatment [control condition] and prednisone administration at 0.5, 1, 2, and 4 mg/kg, PO, q 24 h), with a 9-day washout period between protocols. Analyses performed before and after treatments included a CBC, serum biochemical analysis, and determination of SAP, fractional excretion of electrolytes, urine protein-to-creatinine ratio, glomerular filtration rate (GFR), serum N-terminal pro B-type natriuretic peptide (NT-proBNP) and plasma cortisol concentrations, and plasma renin activity. Linear mixed-effects modeling was used to compare changes in variables from baseline (day 1 for the same experiment) among treatment conditions. Changes in serum glucose concentration and GFR were significantly greater after administration of prednisone at 4 mg/kg than for the control condition. Fractional excretion of sodium was decreased from baseline when dogs received 0.5, 1, or 4 mg of prednisone/kg, compared with results for the control condition. Several expected changes in clinicopathologic values were observed after prednisone administration at any dose. Changes in serum NT-proBNP concentration, plasma renin activity, and SAP did not differ from changes for the control condition at any prednisone dose. Oral prednisone administration did not affect SAP, NT-proBNP concentration, or measures of renin-angiotensin-aldosterone system activation in healthy laboratory-housed dogs but was associated with relative increases in GFR and serum glucose concentration.

Homeopathic medicines as a means of non-specific prophylaxis and therapy of influenza and acute respiratory diseases

Many years of experience in the use of homeopathic medicines in the treatment and prevention of respiratory diseases has been accumulated in Russia; it testifies to the effectiveness of their use in pediatrics. Materials and methods. The results of a multicenter open randomized observation on the effectiveness of the homeopathic medicine Oscillococcinum® in the treatment of influenza and other acute respiratory diseases in children aged 6 to 12 years are presented. Results. It was shown that short-term (within 4 days from the onset of the disease) administration of the drug according to the standard scheme leads to a persistent improvement in clinical symptoms already on the 4th day of illness in most children (88.66%). Symptoms of intoxication, such as weakness, headache, temperature reaction are recorded by the 14th day of the disease in only 2—4% of cases. Catarrhal symptoms stop by the end of the second week of the disease in most children. Only 1 adverse event was identified associated with the course of the underlying disease.

Administration of Nicotinamide Mononucleotide (NMN) Reduces Metabolic Impairment in Male Mouse Offspring from Obese Mothers.

Maternal obesity impacts offspring metabolism. We sought to boost mitochondrial energy metabolism using the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) to treat metabolic impairment induced by maternal and long-term post weaning over-nutrition. Male offspring of lean or obese mothers, fed chow or high fat diet (HFD) for 30 weeks post-weaning, were given NMN injection, starting at 31 weeks of age, daily for 3 weeks before sacrifice. Glucose tolerance was tested at 10, 29 and 32 weeks of age to measure short and long term effects of post-weaning HFD, and NMN treatment. Plasma insulin and triglycerides, liver triglycerides and expression of mitochondrial metabolism-related genes were measured at 34 weeks. Impaired glucose tolerance due to maternal and post weaning HFD was significantly improved by only 8 days of NMN treatment. Furthermore, in offspring of obese mothers hepatic lipid accumulation was reduced due to NMN treatment by 50% and 23% in chow and HFD fed offspring respectively. Hepatic genes involved in fat synthesis, transport and uptake were reduced, while those involved in fatty acid oxidation were increased by NMN. Overall this finding suggests short term administration of NMN could be a therapeutic approach for treating metabolic disease due to maternal and post weaning over-nutrition, even in late adulthood.

The Prophylactic Use of Bovine Colostrum in a Murine Model of TNBS-Induced Colitis

Simple SummaryColostrum is the first milk secreted by the mammary glands, and it is very rich in bioactive components. Recently, the importance of bovine colostrum (BC) as a nutraceutical product has been emerging with regards to gastrointestinal diseases. One of the most widespread gastrointestinal disorders is the inflammatory bowel disease (IBD), a multifactorial chronic condition that has a powerful impact on the social life of millions of people. Because current therapy protocols neither ensure complete recovery from IBD nor are free of secondary side effects, the present study assessed the impact of a short-term prophylactic oral administration of BC in a murine model of TNBS-induced colitis. BC administration was both well tolerated and did not induce any pathological symptoms. It considerably modulated the response to inflammation through modifications of the TLR4 and cytokines gene expression profiles as well as that of the intestinal microbiota. Although further studies are needed to develop a precise therapeutic protocol of BC administration, it seems to have the potential to be used as a natural supplement in the treatment of IBD.This study investigated the effects of a short-term administration of bovine colostrum (BC) in a TNBS model of induced colitis. Colitis was induced by TNBS treatment after seven days of BC (BC group, n = 12) or saline (control group, n = 12) administration in mice. Clinical signs, histopathological characteristics, expression levels of Toll-like receptor 4 (TLR4), pro- and anti-inflammatory cytokines, and microbial composition were assessed. BC was well tolerated and did not induce any histological damage or clinical symptoms. After TNBS treatment, the BC group showed a reduction in body weight (BW) loss compared to Control (p < 0.05). Moreover, expression levels of TLR4 (p < 0.01), Interleukin-1β (IL-1β; p < 0.001), Interleukin-8 (IL-8; p < 0.001), and Interleukin-10 (IL-10; p < 0.001) were lower in mice administered with BC. Finally, Escherichia coli were higher (p < 0.05), while Enterococci (p < 0.001), Lactobacillus spp. (p < 0.001), and Bifidobacterium spp. (p < 0.05) were lower in Control than BC group. This study confirms that pre-treatment with BC modulates the expression of genes and the count of microbes involved in the etiopathogenesis of colitis.