Significant Dose-dependent Increase Research Articles

The Acute Pharmacological Manipulation of Dopamine Receptors Modulates Judgment Bias in Japanese Quail.

We have studied the effects of dopamine antagonists and agonists on Japanese quail behavior in the spatial judgment task. Twenty-four Japanese quail hens were trained in the spatial discrimination task to approach the feeder placed in the rewarded location (Go response, feeder containing mealworms) and to not approach the punished location (No-Go response, empty feeder plus aversive sound). In a subsequent spatial judgment task, the proportion of Go responses as well as approach latencies to rewarded, punished, and three ambiguous locations (near-positive, middle, near-negative, all neither rewarded nor punished) were assessed in 20 quail hens that successfully mastered the discrimination task. In Experiment 1, each bird received five treatments (0.1 and 1.0 mg/kg of dopamine D1 receptor antagonist SCH 23390, 0.05 and 0.5 mg/kg of dopamine D2 receptor antagonist haloperidol, and saline control) in a different order, according to a Latin square design. All drugs were administered intramuscularly 15 min before the spatial judgment test, with 2 days break between the treatments. Both antagonists caused a significant dose-dependent increase in the approach latencies as well as a decrease in the proportion of Go responses. In Experiment 2, with the design analogous to Experiment 1, the hens received again five treatments (1.0 and 10.0 mg/kg of dopamine D1 receptor agonist SKF 38393, 1.0 and 10.0 mg/kg of dopamine D2 receptor agonist bromocriptine, and saline control), applied intramuscularly 2 h before the test. The agonists did not have any significant effect on approach latencies and the proportion of Go responses in the spatial judgment task, as compared to the saline control, except for 10.0 mg/kg SKF 38393, which caused a decrease in the proportion of Go responses. The approach latency and the proportion of Go responses were affected by the cue location in both experiments. Our data suggest that the dopamine D1 and D2 receptor blockade leads to a decrease in the reward expectation and the negative judgment of stimuli. The effect of dopamine receptor activation is less clear. The results reveal that dopamine receptor manipulation alters the evaluation of the reward and punishment in the spatial judgment task.

Effects of polyacrylamide hydrogel used in the treatment of osteoarthritis on mesenchymal stem cells and human osteoblasts

Background/Aim: Adipose-derived mesenchymal stem cells (AD-MSCs) have gained popularity for use in treating osteoarthritis (OA) although their long-term effects remain unsatisfactory for treating the end stages of OA. However, clinically injectable polyacrylamide hydrogels (PAHGs) remain in the joint indefinitely, which could make them ideal candidates as AD-MSC carriers. Our aim was to evaluate whether combinations of PAHG and AD-MSCs have positive effects on cell viability, thereby the potential of this combination prior to clinical use in OA treatment in addition to the effects of PAHG on human osteoblasts (HOBs). Methods: Cell lines of AD-MSCs of canine origin and HOBs were culture-expanded and seeded in 96-well plates (0.5 x 105 cells/well). The PAHG substrate at doses of 2, 6, 10, 20, or 40 µL per 200 µL of sample were added to the wells, and their effects were compared to the positive and negative control groups and among substrate doses for each cell line. The experiments were repeated three times, and cell viability was studied using tetrazolium (MTT) method. Results: Cell viability in all dose groups was significantly greater than that of their negative control groups for both cell lines (P < 0.001). Among the different dose groups, significant dose-dependent viability increases were only observed for the HOB cell line (P < 0.001). The PAHG substrate was not lethal to AD-MSCs or HOBs up to the maximum assayed doses and had positive effects on the viability of these cell lines, including slight increases in proliferation. Conclusion: Combination of PAHG with AD-MSCs may have positive long-term effects for OA treatment. However, further trials are needed.

AMELIORATIVE POTENTIALS OF DICHLOROMETHANE EXTRACT OF Musa paradisiaca BRACT IN INDOMETHACIN ADMINISTERED WISTAR RATS

This study aimed to ascertain the ameliorative potentials of dichloromethane extract of Musa paradisiaca bract in Wistar rats administered indomethacin. The bracts were processed and extracted using dichloromethane and the bioactive components in sample were analysed using gas chromatography-mass spectrometry (GC-MS) methods. Forty five male Wistar rats (120-180g) in five groups of nine rats each were used for in-vivo analysis. A single oral dose of 40mg/kg body weight indomethacin was administered to study groups and faecal occult blood tests (FOB) of animals were carried out using immunochromatographic sandwich methods. Study groups were treated with 200mg, 150mg and 100mg/kg bodyweight of extract for three weeks. The animals were sacrificed and selected biochemical indices, hematological parameters and histopathology of kidney, stomach and liver were determined. GC-MS analyses revealed eleven bioactive compounds; fatty acids, amides and amines in the sample analysed. FOB tests were positive (+) at week 0 and week one, then negative (-) at weeks two and three in all treated groups. Significant dose-dependent increases (p≤ 0.05) in packed cell volume, hemoglobin and red blood count was observed in treated groups (38.80 ± 0.15%, 12.93 ± 0.05g/dl and 5.85 ± 0.05x109/L) respectively compared to untreated control (21.70 ± 0.12%, 7.24 ± 0.04g/dl, and 3.75 ± 0.05x109/L). Serum levels of Aspartate aminotransferase, Alanine aminotransferase, Alkaline phosphatase, creatinine and urea showed a dose-dependent decrease significantly at (p≤ 0.05) in treated groups, compared to untreated control. Kidney, stomach and liver tissues in treated groups showed no cellular degeneration after three weeks of treatment, compared to control. This study revealed that the dichloromethane extract of M. paradisiaca bract showed dose-dependent ameliorative potentials and non-impairment of hepatorenal function in Wistar rats administered indomethacin.

Anthelmintic Effect of Leucaena leucocephala Extract and Its Active Compound, Mimosine, on Vital Behavioral Activities in Caenorhabditis elegans.

Helminth infections continue to be a neglected global threat in tropical regions, and there have been growing cases of anthelmintic resistance reported towards the existing anthelmintic drugs. Thus, the search for a novel anthelmintic agent has been increasing, especially those derived from plants. Leucaena leucocephala (LL) is a leguminous plant that is known to have several pharmacological activities, including anthelmintic activity. It is widely known to contain a toxic compound called mimosine, which we believed could be a potential lead candidate that could exert a potent anthelmintic effect. Hence, this study aimed to validate the presence of mimosine in LL extract and to investigate the anthelmintic effect of LL extract and mimosine on head thrashing, egg-laying, and pharyngeal pumping activities using the animal model Caenorhabditis elegans (C. elegans). Mimosine content in LL extract was confirmed through an HPLC analysis of spiking LL extract with different mimosine concentrations, whereby an increasing trend in peak heights was observed at a retention time of 0.9 min. LL extract and mimosine caused a significant dose-dependent increase in the percentage of worm mortality, which produced LC50s of 73 mg/mL and 6.39 mg/mL, respectively. Exposure of C. elegans to different concentrations of LL extract and mimosine significantly decreased the head thrashing, egg-laying, and mean pump amplitude of pharyngeal pumping activity. We speculated that these behavioral changes are due to the inhibitory effect of LL extract and mimosine on an L-type calcium channel called EGL-19. Our findings provide evidential support for the potential of LL extract and its active compound, mimosine, as novel anthelmintic candidates. However, the underlying mechanism of the anthelmintic action has yet to be elucidated.

Effect of mushroom (Pleurotus djamor var. roseus) meal as feed supplemented on the hematological responses and growth performance of Nile tilapia (Oreochromis niloticus) fingerlings

This study aimed to evaluate the effects of mushroom meal supplementation, Pleurotus djamor var. roseus (Pd), on the diet of Nile tilapia (Oreochromis niloticus), on hematological parameters and growth performance for 60 days. Nile tilapia fingerlings (3.23 ± 0.19 g) were fed with three experimental diets based on the mushroom meal in different percentages: diet 0% control (MM0), diet 15% (MM15), diet 20% (MM20) and diet 25% (MM25). Blood samples from the fish of all treatments were collected at the start of the experiment (day 0), 30 and 60 days. The weight and size of the fish were determined every 15 days (0, 15, 30, 45 and 60 days). The results showed a significant dose-dependent increase in the levels of erythrocytes count and leukocytes count. The groups that showed significant differences in the basal value and the final control result were hematocrit, hemoglobin, and lymphocyte. An increase in lymphocytes proportion and a decrease in neutrophils were found, which was related to the immune response of fish fed the diet. The highest levels of leukocytes, lymphocytes, and low neutrophils were presented in the diet with 15 and 20% (P &lt; 0.05). The growth (weight gain and specific growth rate) of fish fed MM15 and MM20 of Pd in the diet was higher than the control group (P &gt; 0.05). Dietary supplementation (15 and 20%) improved hematological and defense blood cells, as well as the growth of tilapia.

Novel role of the Mu-opioid receptor in pancreatic cancer: potential link between opioid use and cancer progression.

Opioids are the most popular drugs for both acute and chronic pain management. The G protein-coupled mu-opioid receptor (MOR) is the therapeutic target for most clinically used opioids, including morphine. A mounting number of publications suggest a relationship between the MOR and possible cancer progression and recurrence extending to managing chronic cancer pain. In this study, we studied the possible link between opioid use and pancreatic cancer (PC) progression. We found increased MOR expression in murine and human PC cell lines, human PC-derived organoids, and in the undifferentiated or poorly differentiated areas of surgically resected PC tissues. Direct stimulation of MOR by morphine (MOR agonist) caused a significant dose-dependent increase in proliferation, invasion, and levels of stemness markers in PC cells. In a co-culture system, MOR stimulation of macrophages also resulted in increased proliferation of PC cells. MOR overexpression increased proliferation and cancer stemness, whereas knock-down of MOR followed opposite results in the PC cells. Morphine induced chemoresistance to conventional chemotherapeutic agents used for PC treatment. Overall, our results suggest that MOR is expressed in pancreatic cancer and may be involved in tumor progression and chemoresistance.

Adverse physiologic effects of a common food additive potassium metabisulfite (E224) in laboratory rats

Current study investigated the effects of potassium metabisulfite (E224), a common food preservative, in male rats following 28 days of oral exposure at doses: 0.7, 7.0, and 70 mg/kg b.w. Following autopsies, blood and tissues samples (liver, kidney, brain, and testes) were taken. Data were compared statistically at p < .05. Potassium metabisulfite caused significant dose-dependent reduction in most hematological parameters except the white blood cells and platelets that showed elevation. Biochemically, dose-dependent significant increase occurred in the oxidative stress biomarkers, the reactive oxygen species, and thiobarbituric acid reactive substances, while a concomitant significant decrease was noticeable in the antioxidant enzymes, superoxide dismutase, peroxidase, catalase, and non-enzymatic reduced glutathione and as well as total protein content in liver, kidneys, brain, and testes of treated animals. Mild to relatively severe histological alterations were noticeable in all tissues. The study for the first time shows that potassium metabisulfite is toxic even in very small quantity. Novelty impact statement Potassium metabisulphite designated as E224 is a food preservative used in many food items, but its effects on physiological health are lacking. Rats exposed to its oral doses for 28 continuous days demonstrated that it is toxic even at the lowest recommended concentration of 0.7 mg/kg body weight. It produces excessive free radicals and has every potential to damage the cells biochemically and structurally when used in slightly greater amounts.

The Glycemic Control Potential of Some Amaranthaceae Plants, with Particular Reference to In Vivo Antidiabetic Potential of Agathophora alopecuroides.

Natural products continue to provide inspiring moieties for the treatment of various diseases. In this regard, investigation of wild plants, which have not been previously explored, is a promising strategy for reaching medicinally useful drugs. The present study aims to investigate the antidiabetic potential of nine Amaranthaceae plants: Agathophora alopecuroides, Anabasis lachnantha, Atriplex leucoclada, Cornulaca aucheri, Halothamnus bottae, Halothamnus iraqensis, Salicornia persia, Salsola arabica, and Salsola villosa, growing in the Qassim area, the Kingdom of Saudi Arabia. The antidiabetic activity of the hydroalcoholic extracts was assessed using in vitro testing of α-glucosidase and α-amylase inhibitory effects. Among the nine tested extracts, A. alopecuroides extract (AAE) displayed potent inhibitory activity against α-glucosidase enzyme with IC50 117.9 µg/mL noting better activity than Acarbose (IC50 191.4 µg/mL). Furthermore, AAE displayed the highest α- amylase inhibitory activity among the nine tested extracts, with IC50 90.9 µg/mL. Based upon in vitro testing results, the antidiabetic activity of the two doses (100 and 200 mg/kg) of AAE was studied in normoglycemic and streptozotocin (STZ)-induced diabetic mice. The effects of the extract on body weight, food and water intakes, random blood glucose level (RBGL), fasting blood glucose level (FBGL), insulin, total cholesterol, and triglycerides levels were investigated. Results indicated that oral administration of the two doses of AAE showed a significant dose-dependent increase (p < 0.05) in the body weight and serum insulin level, as well as a significant decrease in food and water intake, RBGL, FBGL, total cholesterol, and triglyceride levels, in STZ-induced diabetic mice, compared with the diabetic control group. Meanwhile, no significant differences of both extract doses were observed in normoglycemic mice when compared with normal control animals. This study revealed a promising antidiabetic activity of the wild plant A. alopecuroides.

Optimization of Phyllanthus emblica L. leaf extract-assisted clearance of hyperbilirubinemia in White New Zealand albino rabbits

All parts of Phyllanthus emblica L. are traditionally used for the treatment of jaundice, inflammation, and diarrhea. The present study was planned to evaluate the P. emblica leaf extract (PELE) assisted clearance of bilirubin in artificially-induced hyperbilirubinemic rabbits. Hyperbilirubinemia was induced in White New Zealand albino rabbits by oral administration of phenyl hydrazine solution (10 mg kg−1 body weight) and an intraperitoneal injection of ursodeoxycholic acid solution (10 mg kg−1 bw). PELE-assisted bilirubin clearance from animals was optimized by a bi-factorial response-surface central composite design with five levels of each of the extract dose (0, 25, 50, 75, and 100 mg kg−1 bw) and sampling period (24, 48, 72, 96, and 120 h). The oral administration of PELE showed a significant (p < 0.05) dose-dependent linear increase in bilirubin clearance from hyperbilirubinemic rabbits. However, the sampling period showed no significant effect on bilirubin clearance. The optimum levels of PELE dose and sampling period for maximum clearance of bilirubin (0.658 mg dL−1) were found to be 94.864 mg kg−1 body weight and 51.12 h respectively. PELE was found to be effective in bilirubin clearance at the observed optimum levels of extract dose and would be a good choice for the management of hyperbilirubinemia.

Evaluation of Anticancer Potential of Biogenic Copper Oxide Nanoparticles (CuO NPs) against Breast Cancer

The present study evaluated the anticancer potential of copper oxide nanoparticles (CuO NPs) synthesized from pumpkin seed extract in human breast cancer cell line (MDA‐MB‐231) using a battery of tests such as MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assay, morphological alteration, reactive oxygen species (ROS) generation, and changes in mitochondrial membrane potential (MMP). The biogenic CuO NPs showed a dose‐dependent decline in cell viability with 50% inhibitory concentration (IC50) at 20 μg/ml. Treatment with an IC50 dose of CuO NPs resulted in considerable morphology changes, such as shrinkage, detachment, membrane blebbing, and deformed shape in MDA‐MB‐231 cells. We also observed a significant dose‐dependent increase in ROS production and MMP modulation due to CuO NP treatment. Overall, CuO NPs showed significant anticancer potential in the breast cancer cell line. However, further validation of our data is required in ex vivo and in vivo models before this nanoformulation could be exploited for the treatment/management of human breast cancer.

Mesoporous silica nano-adjuvant triggers pro-inflammatory responses in Caco-2/peripheral blood mononuclear cell (PBMC) co-cultures.

The aim of this study was to evaluate the cytotoxicity and immune-stimulatory effect of Mesoporous silica nanoparticle (MSN) Nano-adjuvant on pro-inflammatory cytokines and pattern recognition receptors (PRR) genes expression in Caco-2/PBMC co-culture model. MSNs were synthesized and characterized by scanning electron microscope (SEM), Brunauer Emmett Teller (BET) and Barrett Joyner Halenda (BJH) techniques. The BET specific surface area of MSNs was around 947 m2/g and the total pore volume and average pore diameter were 1.5 cm3/g and 8.01 nm, respectively. At the concentration of 10 µg/mL, MSN showed a low and time-dependent cytotoxicity on Caco-2 cells, while no cytotoxic effect was observed for 0.1 and 1 µg/mL concentrations after 24, 48 and 72 h. The expression of pro-inflammatory cytokines genes (IL-1, IL-8 and TNF-α) in co-cultures treated with different concentrations of MSN showed a dose-dependent significant increase up to 17.44, 2.722 and 4.34 folds, respectively, while the expression augmentation of IL-1 gene was significantly higher than the others. This indicates slight stimulation of intestinal inflammation. Different concentrations of MSN significantly increased TLR4 and NOD2 expression to 4.14 and 2.14 folds, respectively. NOD1 was not affected significantly. It can be concluded that MSN might increase protective immune responses against antigens as a vaccine adjuvant candidate. It seems that stimulation of TNF-α, IL-1, and IL-8 expression in enterocytes probably transpires through the agonistic activity of MSN for TLRs including TLR4, while NOD2-associated signaling pathways are also involved. This study provides an overall picture of MSN as a novel and potent oral adjuvant for mucosal immunity.

Activation of efficient DNA repair mechanisms after photon and proton irradiation of human chondrosarcoma cells

Although particle therapy with protons has proven to be beneficial in the treatment of chondrosarcoma compared to photon-based (X-ray) radiation therapy, the cellular and molecular mechanisms have not yet been sufficiently investigated. Cell viability and colony forming ability were analyzed after X-ray and proton irradiation (IR). Cell cycle was analyzed using flow cytometry and corresponding regulator genes and key players of the DNA repair mechanisms were measured using next generation sequencing, protein expression and immunofluorescence staining. Changes in metabolic phenotypes were determined with nuclear magnetic resonance spectroscopy. Both X-ray and proton IR resulted in reduced cell survival and a G2/M phase arrest of the cell cycle. Especially 1 h after IR, a significant dose-dependent increase of phosphorylated γH2AX foci was observed. This was accompanied with a reprogramming in cellular metabolism. Interestingly, within 24 h the majority of clearly visible DNA damages were repaired and the metabolic phenotype restored. Involved DNA repair mechanisms are, besides the homology directed repair (HDR) and the non-homologous end-joining (NHEJ), especially the mismatch mediated repair (MMR) pathway with the key players EXO1, MSH3, and PCNA. Chondrosarcoma cells regenerates the majority of DNA damages within 24 h. These molecular mechanisms represent an important basis for an improved therapy.

IL-6 induced enhanced clearance of proANP and ANP by insulin-degrading enzyme in T1DM mice.

Cardiovascular disease (CVD) is a prevalent cause of morbidity and mortality in type I diabetes mellitus (T1DM). However, the pathophysiological mechanisms underlying the relationship between CVD, CVD risk factors, and T1DM have not yet been sufficiently explored. Here, we report that insulin-degrading enzyme (IDE) effectively degrades the precursor of atrial natriuretic peptide (proANP) in HEK293T cells. The pro-inflammatory cytokine IL-6 elicited a significant dose-dependent increase in IDE protein expression. Inhibition of the ERK/MAPK signaling pathway with selumetinib abolished the IL-6-stimulated increase in IDE protein levels and decreased ANP secretion in H9C2 cells. Importantly, the T1DM mouse model displayed lower proANP in the heart and ANP in serum, due to increased IDE expression and activity. Our results suggest a novel role of IL-6 in ANP metabolism via IDE and provide possibilities for new potential therapeutic strategies for diabetes-related cardiovascular complications.

Preclinical Efficacy and Safety Studies of Formulation SSV-003, a Potent Anti-Viral Herbal Formulation.

BackgroundRecent viral pandemics have challenged the global scientific community to immediately develop new therapies. The fastest approach to develop these is to explore natural products for their efficacies and repurposing of already approved molecules. Keeping global emergency in view, researchers at Shreepad Shree Vallabh SSV Phytopharmaceuticals developed the CurvicTM (SSV-003) formulation, comprising of curcumin, vitamin C, vitamin K2-7, selenomethionine and Zinc.MethodsResearchers have systematically studied the SSV-003 formulation for its in vitro efficacy against influenza A virus (H1N1) (ATCC® VR-219™) and human beta coronavirus (ATCC® VR1558™) using MDCK & HCT-8 cell lines, respectively, in vivo efficacy studies of SSV-003 on influenza A virus infected Balb/c mice, and acute toxicity studies as per OECD guidelines.ResultsFormulation SSV-003 showed potent antiviral activities against both the selected virus strains. Its IC50 was significantly lessthan ribavirin against influenza A-H1N1-VR219, with no cytopathic effect. SSV-003 showed IC50 of 2.26 µg/mL against human beta coronavirus, which was near to the IC50 of ribavirin (2.25 µg/mL) and was less than remedisivir (6.23 µg/mL) with no cytopathic effect. In-vivo studies in an influenza A virus infected mice model showed a significantly higher TCID50 value in the infected control group as compared to test groups. Animals treated with SSV-003 showed a dose dependent decrease in TCID50. Formulation SSV-003 at the dose of 500, 1,000, and 1,500 mg/kg body weight showed 85.9%, 94.6%, and 95.1% decreases in infection as compared to the infected control group. Dose-dependent significant increases in CD4+, CD8+ counts, IgG and IgM levels were observed in SSV-003 treated groups as compared to the infected control group and remedisivir treated group. In the acute oral toxicity study, no mortality or morbidity was observed.ConclusionThe data from these preclinical studies provide strong evidence of potent and safe antiviral and immunomodulatory activity of SSV-003.

Effect of Itrifal Muqawwi-e-Dimagh (a polyherbal drug) on the transgenic Drosophila model of Parkinson's Disease

BackgroundParkinson's Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the mid brain which leads to the depletion of dopamine levels. The depletion of dopamine leads to the motor dysfunction characterized by tremors, rigidity, bradykinesia and postural instability. In this context, the effect of unani herbal formulation Itrifal Muqawwi-e-Dimagh (IMD) was studied on the transgenic Drosophila melanogaster expressing human alpha synuclein in the neurons of flies. IMD is recommended for enhancing mental power and to treat mental illness in the Unani system of medicine. IMD was prepared as per the standard procedures and was subjected to various physico-chemical tests. MethodsThe equivalents of recommended dose for human were established for 20 g of fly food i.e. 0.0014, 0.0028, 0.0042 and 0.0056 g per 20 g of diet. The PD flies were allowed to feed on it for 24 days before performing the assays. ResultsThe PD flies exposed to IMD showed increase in the life span and improvement in the activity. A significant dose dependent delay in the loss of climbing ability was observed in PD flies exposed to various doses of IMD. The exposure of PD flies to IMD showed a significant reduction in the oxidative stress and increase in the anti-oxidant enzymes compared to unexposed PD flies. The PD flies exposed to various doses of IMD showed a significant dose dependent increase in the activity of tyrosine hydroxylase as evident by immunohistochemistry. ConclusionIt is concluded that IMD is potent in reducing the PD symptoms being mimicked in the transgenic Drosophila.

Toxic potential of sodium hypochlorite in the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ) Bg9

Sodium hypochlorite (NaOCl) at a final concentrations of 0.025, 0.050, 0.075 and 0.1 M was mixed in the diet and the third instar larvae were allowed to feed on it for 24 h. The larvae exposed to 0.050, 0.075 and 0.1 M of NaOCl showed a dose-dependent significant increase in the activity of β-galactosidase, tissue damage, oxidative stress markers, DNA damage and Caspase-3 and 9 activities. Larvae exposed to 0.025 M of NaOCl did not show any toxic effect in the third instar larvae. The NaOCl is toxic at 0.05, 0.075 and 0.1 M in the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ) Bg9.

In Vitro Assessment of the Genotoxic Potential of Pristine Graphene Platelets.

(1) Background: Graphene is a two-dimensional atomic structure with a wide range of uses, including for biomedical applications. However, knowledge of its hazards is still limited. This work brings new cytotoxic, cytostatic, genotoxic and immunotoxic data concerning the in vitro exposure of human cell line to two types of graphene platelets (GP). It also contributes to the formation of general conclusions about the health risks of GP exposure. (2) Methods: In vitro exposure of a THP-1 cell line to three concentrations of two GP over 40 h. The cytotoxic potential was assessed by the measurement of LDH and glutathione (ROS) and by a trypan blue exclusion assay (TBEA); the cytostatic and genotoxic potential were assessed by the cytokinesis-block micronucleus (CBMN) test; and the immunotoxic potential was assessed by the measurement of IL-6, IL-10 and TNF-α. (3) Results: We found a significant dose-dependent increase in DNA damage (CBMN). The lowest observed genotoxic effect levels (LOGEL) were 5 µg/mL (GP1) and 30 µg/mL (GP2). We found no significant leaking of LDH from cells, increase in dead cells (TBEA), induction of ROS, increased levels of cytostasis, or changes in IL-6, IL-10 and TNF-α levels. (4) Conclusions: The genotoxicity increased during the short-term in vitro exposure of THP-1 to two GP. No increase in cytotoxicity, immunotoxicity, or cytostasis was observed.

Fentanyl-related substances elicit antinociception and hyperlocomotion in mice via opioid receptors

Synthetic opioids have been implicated as the single greatest contributor to rising drug-related fatalities in recent years. This study evaluated mu-opioid receptor (MOR) mediated effects of seven fentanyl-related substances that have emerged in the recreational drug marketplace, and for which there are no existing or only limited in vivo data. Adult male Swiss Webster mice were administered fentanyl-related substances and their effects on nociception and locomotion as compared to MOR agonist standards were observed. In locomotor activity tests, morphine (100, 180 mg/kg), fentanyl (1, 10 mg/kg), beta-methylfentanyl (10 mg/kg), para-methoxyfentanyl (10 mg/kg), fentanyl carbamate (100 mg/kg), and 3-furanylfentanyl (10 mg/kg), elicited significant (p ≤ 0.05) dose-dependent increases in locomotion. However, para-methylfentanyl and beta′-phenylfentanyl did not produce significant effects on locomotion at doses up to 100 mg/kg and phenylfentanyl (100 mg/kg) significantly decreased locomotion. In warm-water tail-withdrawal tests, all substances produced significant dose-dependent increases in antinociception with increasing ED50 values (95% CI) of fentanyl [0.08 mg/kg (0.04–0.16)] > para-methoxyfentanyl [0.43 mg/kg (0.23–0.77)] > 3-furanylfentanyl [0.51 mg/kg (0.36–0.74)] > beta-methylfentanyl [0.74 mg/kg (0.64–0.85)] > para-methylfentanyl [1.92 mg/kg (1.48–2.45)] > fentanyl carbamate [5.59 mg/kg (4.11–7.54)] > morphine [7.82 mg/kg (5.42–11.0)] > beta′-phenylfentanyl [19.4 mg/kg (11.0–34.4)] > phenylfentanyl [55.2 mg/kg (33.5–93.0)]. Naltrexone (1 mg/kg) increased ED50 values several fold with decreasing magnitudes of para-methylfentanyl (63.1×) > para-methoxyfentanyl (22.5×) > beta′-phenylfentanyl (21.0×) > 3-furanylfentanyl (20.6×) > beta-methylfentanyl (19.2×) > phenylfentanyl (5.23×) > fentanyl (3.95×) > fentanyl carbamate (2.21×) > morphine (1.48×). These findings expand upon in vivo results from previous studies and establish that the effects of these fentanyl related-related substances are at least in part mediated by the MOR.

Dose-dependent effects of aerobic exercise on clinically relevant biomarkers among healthy women at high genetic risk for breast cancer: A secondary analysis of a randomized controlled study.

BackgroundExcess adiposity and dysregulated metabolism are associated with increased cancer risk. Triglycerides, cholesterol, glucose, insulin, HOMA‐IR, and VO2max are robust clinical‐metabolic biomarkers of overall health.AimsAerobic exercise may improve clinical‐metabolic biomarkers and decrease cancer risk. This secondary analysis of the WISER Sister randomized controlled trial investigated dose‐dependent effects of aerobic exercise on clinical biomarker levels in women at high genetic risk for breast cancer.Methods and ResultsOne hundred thirty‐nine participants were randomized to: control (<75 min/week), low‐dose (150 min/week), and high‐dose (300 min/week) aerobic exercise intervention groups. Intervention adherence was assessed via heart monitor. Fasting blood draws, cardio‐pulmonary tests, and demographical surveys were taken at baseline and 5 months. Triglyceride, cholesterol, glucose, insulin, and VO2max changes were assessed for 80 of the 122 study completers. Ninety‐six percent of assayed‐completers adhered to >80% of their exercise dose. A significant dose‐dependent increase in VO2max was observed for the low‐dose and high‐dose groups compared to control. No intervention effects were observed for plasma biomarkers. Overweight women (BMI > 25) showed a significant decrease in insulin levels and a trend for decreased triglycerides following exercise intervention. Significant increases in VO2max were independent of BMI stratification.ConclusionWomen at high genetic risk for breast cancer should maintain healthy weights and aerobic capacities through aerobic exercise to achieve measurable benefits on overall health. For overweight women, exercise appears to improve subclinical metabolic dysregulation. However, normal weight women were unaffected by aerobic exercise as their biomarker levels may be below the threshold for improvement. VO2max increases solely quantified the benefits of exercise in already healthy women at high‐risk for breast cancer.

Evaluation of the Laxative Activity of Saponin Enriched Hydroethanolic Pericarp Extract of Sapindus emarginatus in Animal Models

Background: Constipation is a common, predominant, chronic gastrointestinal functional disorder. The drugs available to treat constipation are limited because of their side effects for long term use. Therefore, we need effective drug to treat constipation. Sapindus emarginatus Vahl belongs to the family Sapindaceae, commonly known as soapnut. It is traditionally used as an antipruritic, antifertility, laxative, and anti-inflammatory agent. Objective: The present study was conducted to evaluate the laxative activity of hydroethanolic pericarp extract of Sapindus emarginatus (HESE) in animal models. Methods: The saponin content in the extract was measured by the gravimetric analysis. The laxative activity of hydroethanolic pericarp extract of Sapindus emarginatus was evaluated by the weight of feces matter, charcoal meal hyperperistalsis test, and loperamide induced constipation model. Results: The saponin content of the soapnut pericarp was 13.48% and the extract was found to be 11.92%. The results obtained from these models showed a significant dose-dependent increase in fecal weight, peristalsis index, and moisture content compared to control animals. Conclusion: The present study concluded that the oral administration of HESE showed a significant laxative activity in different animal models. The presence of triterpene saponins is supposed to be responsible for this activity. Further studies are needed to confirm their mechanism behind the laxative effect. The administration of the extract was found to be effective in constipation therapy.