scholarly journals Effects of Intestinal Microbiota on Pharmacokinetics of Crocin and Crocetin in Male Sprague-Dawley Rats

Metabolites ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 424
Author(s):  
Rajina Shakya ◽  
Mahesh R. Nepal ◽  
Mi Jeong Kang ◽  
Tae Cheon Jeong
Keyword(s):  
Intestinal Microbiota ◽  
Oral Treatment ◽  
Hepatic Metabolism ◽  
Crocus Sativus ◽  
Male Rats ◽  
Sprague Dawley ◽  
Gardenia Jasminoides ◽  
Sprague Dawley Rats

In addition to the hepatic metabolism, the role of intestinal microbiota in drug metabolism has been considered important in the biotransformation of xenobiotics. Crocin and its aglycone, crocetin, isolated from many plants, including the dried stigma of Crocus sativus and the fruit of Gardenia jasminoides, have been used in treatment of inflammation, cancer, and metabolic disorders. In this study, the effect of intestinal microbiota on the pharmacokinetics of crocin was studied following single oral treatment with 600 mg/kg crocin to male rats pre-treated with a mixture of antibiotics, such as cefadroxil, oxytetracycline, and erythromycin, for three consecutive days. Following crocin treatment, blood, urine, and feces were collected at various time points for evaluating pharmacokinetic characteristics of crocin and crocetin by using LC-MS. Results showed that intestinal absorption of crocin was relatively marginal when compared with that of crocetin, and that crocin metabolism to crocetin by intestinal microbiota would be a critical step for absorption. The present results clearly suggested that the in vivo pharmacological effects of crocin might be considered as the effects by its aglycone, crocetin, mainly, and that the metabolism of glycosidic natural products by intestinal microbiota should be considered to understand their pharmacodynamic actions.

scholarly journals Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

2018 ◽  
Vol 49 (4) ◽  
pp. 1420-1430 ◽  
Author(s):  
Lixiong He ◽  
Yujing Huang ◽  
Qiaonan Guo ◽  
Hui Zeng ◽  
Chuanfen Zheng ◽  
...  
Keyword(s):  
Low Dose ◽  
Soft Agar ◽  
Tumor Formation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
L02 Cells ◽  
Insight Into

Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

scholarly journals Sites and sources of sympathoexcitation in obese male rats: role of brain insulin

2020 ◽  
Vol 318 (3) ◽  
pp. R634-R648 ◽  
Author(s):  
Zhigang Shi ◽  
Ding Zhao ◽  
Priscila A. Cassaglia ◽  
Virginia L. Brooks
Keyword(s):  
Insulin Receptors ◽  
Male Rats ◽  
Melanocortin Receptor ◽  
Sprague Dawley ◽  
Intracerebroventricular Infusion ◽  
Sprague Dawley Rats ◽  
Y1 Receptors ◽  
The Brain ◽  
Obese Male

In males, obesity increases sympathetic nerve activity (SNA), but the mechanisms are unclear. Here, we investigate insulin, via an action in the arcuate nucleus (ArcN), and downstream neuropathways, including melanocortin receptor 3/4 (MC3/4R) in the hypothalamic paraventricular nucleus (PVN) and dorsal medial hypothalamus (DMH). We studied conscious and α-chloralose-anesthetized Sprague-Dawley rats fed a high-fat diet, which causes obesity prone (OP) rats to accrue excess fat and obesity-resistant (OR) rats to maintain fat content, similar to rats fed a standard control (CON) diet. Nonspecific blockade of the ArcN with muscimol and specific blockade of ArcN insulin receptors (InsR) decreased lumbar SNA (LSNA), heart rate (HR), and mean arterial pressure (MAP) in OP, but not OR or CON, rats, indicating that insulin supports LSNA in obese males. In conscious rats, intracerebroventricular infusion of insulin increased MAP only in OP rats and also improved HR baroreflex function from subnormal to supranormal. The brain sensitization to insulin may elucidate how insulin can drive central SNA pathways when transport of insulin across the blood-brain barrier may be impaired. Blockade of PVN, but not DMH, MC3/4R with SHU9119 decreased LSNA, HR, and, MAP in OP, but not OR or CON, rats. Interestingly, nanoinjection of the MC3/4R agonist melanotan II (MTII) into the PVN increased LSNA only in OP rats, similar to PVN MTII-induced increases in LSNA in CON rats after blockade of sympathoinhibitory neuropeptide Y Y1 receptors. ArcN InsR expression was not increased in OP rats. Collectively, these data indicate that obesity increases SNA, in part via increased InsR signaling and downstream PVN MC3/4R.

scholarly journals Role of RFRP-3 in the development of cold stress-induced polycystic ovary phenotype in rats

2018 ◽  
Vol 239 (1) ◽  
pp. 81-91 ◽  
Author(s):  
V Squicciarini ◽  
R Riquelme ◽  
K Wilsterman ◽  
G E Bentley ◽  
H E Lara
Keyword(s):  
Cold Stress ◽  
Polycystic Ovary ◽  
Follicular Development ◽  
Sprague Dawley ◽  
Ovarian Steroid ◽  
Sprague Dawley Rats ◽  
Mrna Expression Analysis

RFamide-related peptide (RFRP-3) is a regulator of GnRH secretion from the brain, but it can also act in human ovary to influence steroidogenesis. We aimed to study the putative local role of RFRP-3 in the ovary and its potential participation in the development of a polycystic ovary phenotype induced by chronic sympathetic stress (cold stress). We used adult Sprague–Dawley rats divided into control and stressed groups. In both groups, we studied the effect of intraovarian exposure to RFRP-3 on follicular development and plasma ovarian steroid concentrations. We also tested the effect of RFRP-3 on ovarian steroid production in vitro. Chronic in vivo intraovarian exposure to RFRP-3 decreased basal testosterone concentrations and cold stress-induced progesterone production by the ovary. In vitro, RFRP-3 decreased hCG-induced ovarian progesterone and testosterone secretion. Immunohistochemistry and mRNA expression analysis showed a decrease in Rfrp and expression of its receptor in the ovary of stressed rats, a result which is in line with the increased testosterone levels found in stressed rats. In vivo application of RFRP-3 recovered the low levels of secondary and healthy antral follicles found in stressed rats. Taken together, our data indicate a previously unknown response of hypothalamic and ovarian RFRP-3 to chronic cold stress, influencing ovarian steroidogenesis and follicular dynamics. Thus, it is likely that RFRP-3 modulation in the ovary is a key component of development of the polycystic ovary phenotype.

Metalloendopeptidases EC 3.4.24.15/16 regulate bradykinin activity in the cerebral microvasculature

2003 ◽  
Vol 284 (6) ◽  
pp. H1942-H1948 ◽  
Author(s):  
M. Ursula Norman ◽  
Rebecca A. Lew ◽  
A. Ian Smith ◽  
Michael J. Hickey
Keyword(s):  
Specific Inhibitor ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Cerebral Microvasculature ◽  
Microvessel Permeability ◽  
The Brain ◽  
Cerebral Microvessel

Bradykinin is a vasoactive peptide that has been shown to increase the permeability of the cerebral microvasculature to blood-borne macromolecules. The two zinc metalloendopeptidases EC 3.4.24.15 (EP 24.15) and EC 3.4.24.16 (EP 24.16) degrade bradykinin in vitro and are highly expressed in the brain. However, the role that these enzymes play in bradykinin metabolism in vivo remains unclear. In the present study, we investigated the role of EP 24.15 and EP 24.16 in the regulation of bradykinin-induced alterations in microvascular permeability. Permeability of the cerebral microvasculature was assessed in anesthetized Sprague-Dawley rats by measuring the clearance of 70-kDa FITC dextran from the brain. Inhibition of EP 24.15 and EP 24.16 by the specific inhibitor N-[1-( R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr- p-aminobenzoate (JA-2) resulted in the potentiation of bradykinin-induced increases in cerebral microvessel permeability. The level of potentiation was comparable to that achieved by the inhibition of angiotensin-converting enzyme. These findings provide the first evidence of an in vivo role for EP 24.15/EP 24.16 in brain function, specifically in regulating alterations in microvessel permeability induced by exogenous bradykinin.

scholarly journals Mesangial cells initiate compensatory renal tubular hypertrophy via IL-10-induced TGF-β secretion: effect of the immunomodulator AS101 on this process

2006 ◽  
Vol 291 (2) ◽  
pp. F384-F394 ◽  
Author(s):  
Inna Sinuani ◽  
Zhan Averbukh ◽  
Inna Gitelman ◽  
Micha J. Rapoport ◽  
Judit Sandbank ◽  
...  
Keyword(s):  
Mesangial Cells ◽  
Renal Tissue ◽  
Sprague Dawley ◽  
Compensatory Renal Growth ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Renal Tubular ◽  
Immunohistochemical Studies

The present study investigated the role of IL-10 produced by the mesangial cells in postnephrectomy compensatory renal growth and the effect of the immunomodulator AS101 on this process. One hundred forty unilateral nephrectomized and sham-operated male Sprague-Dawley rats were treated by AS101 or PBS before and after surgery. The results show that secretion of IL-10 and TGF-β by mesangial cells isolated from the remaining kidneys was increased significantly, compared with those of control and sham animals. Moreover, TGF-β secretion by mesangial cells was increased after the addition of exogenous recombinant IL-10 and inhibited in the presence of neutralizing anti-IL-10 antibodies. In vivo, compensatory growth of the remaining kidneys was associated with significant increase in IL-10 content in renal tissues and plasma. Immunohistochemical studies show that IL-10 was produced by mesangial cells. Elevated IL-10 levels were followed by the rise in TGF-β content in plasma and renal tissue. AS101 treatment decreased IL-10 and TGF-β expression in plasma and kidney tissues and results in 25% reduction in the fresh and fractional kidney weight and decreased hypertrophy of tubular cells (protein/DNA ratio, morphometric analysis). Taken together, these data demonstrate that TGF-β production by mesangial cells is IL-10 dependent. Mesangial cells are the major source of IL-10 in kidneys. AS101, by inhibiting the activity of IL-10, decreases TGF-β production by mesangial cells, thus limiting compensatory tubular cell hypertrophy.

scholarly journals A vapor exposure method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats

2020 ◽  
Author(s):  
Arnold Gutierrez ◽  
Kevin M. Creehan ◽  
Michael A. Taffe
Keyword(s):  
Body Temperature ◽  
Spontaneous Activity ◽  
Female Rats ◽  
Male Rats ◽  
Sprague Dawley ◽  
Exposure System ◽  
Male And Female ◽  
Male And Female Rats ◽  
Sprague Dawley Rats

AbstractBackgroundThe ongoing crisis related to non-medical use of opioids makes it of continued importance to understand the risk factors for opioid addiction, the behavioral and neurobiological consequences of opioid exposure and to seek potential avenues for therapy. Pre-clinical rodent models have been critical to advancing understanding of opioid consequences for decades, but have been mostly limited to drug delivery by injection or by oral dosing. Inhalation, a significant route for many human users, has not been as well-established.MethodWe adapted an e-cigarette based exposure system, previously shown efficacious for delivery of other drugs to rats, to deliver heroin vapor. Effects in vivo were assessed in male and female Sprague-Dawley rats using a warm-water assay for anti-nociception and an implanted radiotelemetry system for evaluating changes in body temperature and spontaneous activity rate.ResultsInhalation of vapor created by heroin 100 mg/mL in the propylene glycol (PG) vehicle significantly slowed tail-withdrawal from a 52°C water bath, bi-phasically altered activity, and increased temperature in male and female rats. Inhalation of heroin 50 mg/mL for 15 minutes produced significant effects, as the lower bound on efficacy, whereas inhalation of heroin 100 mg/mL for 30 minutes produced robust effects across all endpoints and groups.ConclusionsThis work shows that e-cigarette devices deliver psychoactive doses of heroin to rats, using concentrations of ∼50-100 mg/mL and inhalation durations of 15-30 minutes. This technique may be useful to assess the health consequences of inhaled heroin and other opioid drugs.

scholarly journals 20-HETE and CYP4A2 ω-hydroxylase contribute to the elevated blood pressure in hyperandrogenemic female rats

2016 ◽  
Vol 311 (1) ◽  
pp. F71-F77 ◽  
Author(s):  
Carolina Dalmasso ◽  
Rodrigo Maranon ◽  
Chetan Patil ◽  
Mohadetheh Moulana ◽  
Damian G. Romero ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Polycystic Ovary ◽  
Female Rats ◽  
Male Rats ◽  
Sprague Dawley ◽  
Hydroxylase Activity ◽  
Sprague Dawley Rats ◽  
Low Salt ◽  
Cytochrome P 450

In male rats, androgen supplements increase 20-hydroxyeicosatetraenoic acid (20-HETE) via cytochrome P-450 (CYP)4A ω-hydroxylase and cause an increase in blood pressure (BP). In the present study, we determined the roles of 20-HETE and CYP4A2 on the elevated BP in hyperandrogenemic female rats. Chronic dihydrotestosterone (DHT) increased mean arterial pressure (MAP) in female Sprague-Dawley rats (96 ± 2 vs. 108 ± 2 mmHg, P < 0.05) and was associated with increased renal microvascular CYP4A2 mRNA expression (15-fold), endogenous renal 20-HETE (5-fold), and ω-hydroxylase activity (3-fold). Chronic DHT also increased MAP in low salt-fed Dahl salt-resistant female rats (81 ± 4 vs. 95 ± 1 mmHg, P < 0.05) but had no effect on MAP in Dahl salt-sensitive female rats (154 ± 3 vs. 153 ± 3 mmHg), which are known to be 20-HETE deficient. To test the role of CYP4A2, female CYP4A2−/− and SS.5Bn (wild type) rats were treated with DHT. DHT increased MAP in SS.5Bn female rats (104 ± 1 vs. 128 ± 1 mmHg, P < 0.05) but had no effect in CYP4A2−/− female rats (118 ± 1 vs. 120 ± 1 mmHg). Renal microvascular 20-HETE was reduced in control CYP4A2−/− female rats and was increased with DHT in SS.5Bn female rats (6-fold) but not CYP4A2−/− female rats. ω-Hydroxylase activity was 40% lower in control CYP4A2−/− female rats than in SS.5Bn female rats, and DHT decreased ω-hydroxylase activity in SS.5Bn female rats (by 50%) but significantly increased ω-hydroxylase activity in CYP4A2−/− female rats (3-fold). These data suggest that 20-HETE via CYP4A2 contributes to the elevation in BP in hyperandrogenemic female rats. The data also suggest that 20-HETE synthesis inhibition may be effective in treating the elevated BP in women with hyperandrogenemia, such as women with polycystic ovary syndrome.

Cytochrome C suppresses renal accumulation and nephrotoxicity of polymyxin B

2018 ◽  
Vol 38 (2) ◽  
pp. 193-200 ◽  
Author(s):  
Z-D Li ◽  
J Luo ◽  
L-H Jia ◽  
X-Y Wang ◽  
Z-K Xun ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Polymyxin B ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
C 30 ◽  
C 50

The receptor megalin plays an important role in the accumulation of polymyxin B (PMB) in renal cells in vitro. This study aimed to examine the effects of cytochrome c (cyto c), a typical megalin ligand, on renal accumulation and nephrotoxicity of PMB in vivo. Thirty Sprague-Dawley rats were randomly divided into the vehicle control group, PMB group, PMB + cyto c 50, 100, or 200 mg/kg group, respectively, and were treated with intravenous cyto c 30 min before the administration of PMB 4.0 mg/kg once a day for consecutive 5 days. On the 4th day after administration, 24 h urine was collected to determine N-acetyl-β-D-glucosaminidase excretion. Six hours after the last injection on the 5th day, kidneys were harvested to assay PMB concentration and observe pathological alterations, and blood samples were collected to assay serum creatinine (SCr), blood urea nitrogen (BUN), and blood β2-microglobulin (β2-MG) levels. Cyto c 50, 100, and 200 mg/kg decreased the accumulation of PMB in the kidney by 18.5%, 39.1% ( p < 0.01), and 36.8% ( p < 0.01), respectively, and reduced 24 h N-acetyl-β-D- glucosaminidase excretion by 22.5% ( p < 0.05), 40.4% ( p < 0.01), and 40.4% ( p < 0.01), respectively. Kidney pathological damage induced by PMB was markedly reduced by cyto c 100 mg/kg and 200 mg/kg. However, there were no significant differences in SCr, BUN, and blood β2-MG levels among the groups. These results indicated that cyto c may inhibit the renal accumulation and nephrotoxicity of PMB in a rat model, further proving the role of megalin in the accumulation of PMB.

scholarly journals Vitamin B12 Conjugation of Peptide-YY3–36 Decreases Food Intake Compared to Native Peptide-YY3–36 Upon Subcutaneous Administration in Male Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (5) ◽  
pp. 1739-1749 ◽  
Author(s):  
Kelly E. Henry ◽  
Clinton T. Elfers ◽  
Rachael M. Burke ◽  
Oleg G. Chepurny ◽  
George G. Holz ◽  
...  
Keyword(s):  
Food Intake ◽  
Vitamin B12 ◽  
Day Treatment ◽  
Subcutaneous Administration ◽  
Male Rats ◽  
Sprague Dawley ◽  
In Vivo Experiments ◽  
Sprague Dawley Rats

Challenges to peptide-based therapies include rapid clearance, ready degradation by hydrolysis/proteolysis, and poor intestinal uptake and/or a need for blood brain barrier transport. This work evaluates the efficacy of conjugation of vitamin B12 (B12) on sc administered peptide tyrosine tyrosine (PYY)3–36 function. In the current experiments, a B12-PYY3–36 conjugate was tested against native PYY3–36, and an inactive conjugate B12-PYYC36 (null control) in vitro and in vivo. In vitro experiments demonstrated similar agonism for the neuropeptide Y2 receptor by the B12-PYY3–36 conjugate (EC50 26.5 nM) compared with native PYY3–36 (EC50 16.0 nM), with the null control having an EC50 of 1.8 μM. In vivo experiments were performed in young adult male Sprague Dawley rats (9 wk). Daily treatments were delivered sc in five 1-hour pulses, each pulse delivering 5–10 nmol/kg, by implanted microinfusion pumps. Increases in hindbrain Fos expression were comparable 90 minutes after B12-PYY3–36 or PYY3–36 injection relative to saline or B12-PYYC36. Food intake was reduced during a 5-day treatment for both B12-PYY3–36- (24%, P = .001) and PYY3–36-(13%, P = .008) treated groups relative to baseline. In addition, reduction of food intake after the three dark cycle treatment pulses was more consistent with B12-PYY3–36 treatment (−26%, −29%, −27%) compared with the PYY3–36 treatment (−3%, −21%, −16%), and B12-PYY3–36 generated a significantly longer inhibition of food intake vs PYY3–36 treatment after the first two pulses (P = .041 and P = .036, respectively). These findings demonstrate a stronger, more consistent, and longer inhibition of food intake after the pulses of B12-PYY3–36 conjugate compared with the native PYY3–36.

Abstract 16473: Loss of the Apelin-Apelin Receptor Signaling Axis Worsens Hemodynamic Alterations and Right Ventricular (rv) Adaptation and Abrogates 17ß-Estradiol (E2)-Mediated Protection in Experimental Pulmonary Arterial Hypertension (PAH)

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Andrea L Frump ◽  
Todd Cook ◽  
Amanda Fisher ◽  
Valerie Nadeau ◽  
Steeve Provencher ◽  
...  
Keyword(s):  
Ring Formation ◽  
Conditioned Media ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Beneficial Effects ◽  
Sprague Dawley Rats ◽  
Signaling Axis ◽  
Rv Function

Introduction: Women are more likely to develop PAH but exhibit more favorable hemodynamics and better survival than men. These improved outcomes have been linked to protective effects of E2. We recently linked RV-protective effects of E2 to regulation of apelin signaling. However, the role of apelin and its receptor APJ in RV failure is unknown. Hypothesis: RV cardiomyocytes (RVCM)-derived apelin exerts beneficial effects on RV endothelial cells (RVECs). Apelin-APJ signaling is necessary for E2’s RV-protective effects. Methods: Apelin and APJ abundance were quantified (Western blot) and immunolocalized in RVs from PAH patients. In vivo , RV failure was induced in male Sprague-Dawley rats by pulmonary artery banding (PAB). A subset of PAB rats were treated with E2 ± APJ inhibitor ML221. Hemodynamics, RV function and molecular changes were assessed. To study the role of RVCM apelin, conditioned media was collected from RVCMs after apelin knockdown and then added to RVECs. In addition, conditioned media from untreated RVCMs was added to RVECs pretreated with ML221. Lastly, RVECs were treated with E2 ± siApelin or ML221. p<0.05 was considered statistically significant. Results: In PAH RVs, apelin and APJ localized to RVCMs and RVECs and were decreased vs controls (p<0.05). In PAB+E2+ML221 rats, inhibition of apelin signaling resulted in more RV hypertrophy and decreased RV function (p<0.05 vs sham or PAB+E2). Conditioned media from RVCMs+siApelin reduced RVEC eNOS phosphorylation, transwell migration and ring formation (p<0.05 vs scrambled control conditioned media). Concomitantly, treatment of RVECs with ML221 blocked transwell migration and ring formation induced by RVCM conditioned media (p<0.05 vs RVEC+veh control). Lastly, treatment of RVECs with siApelin or ML221 abrogated stimulatory effects of E2 on angiogenic function (p<0.05). Conclusions: Apelin and APJ are decreased in PAH-RVs and loss of apelin-APJ signaling results in more severe RV failure and abrogates E2-mediated RV protection. Apelin is secreted by RVCMs and exerts a beneficial paracrine effect on RVECs, where it is required for E2 to stimulate angiogenesis. Apelin-APJ signaling may represent a novel and therapeutically targetable, cell- and sex-specific signaling axis in the RV.

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