Nonclinical Safety Pharmacology Study of the Herbal Product HAD-B1

HAD-B1 is a Korean herbal formula designed to treat solid tumors, and through cell experiments, it has proven to have an anticancer effect. The current study aims to test the safety of HAD-B1. This experiment is under the regulation of ICH. In order to find if HAD-B1 has any effect on the CNS, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally administered to male and female rats once. To discover any effect on the respiratory system, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally given to male rats followed by measuring the respiratory rate, tidal volume, and minute respiratory volume. To assess the possibility of a delayed QT period as a result of the drug administration, hERG analysis was conducted at 0, 0.1, 0.3, and 1 μg/ml. To assess any effect on the cardiovascular system, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally given to male beagle dogs once followed by temperature, blood pressure, ECG, and heart rate analyses. There were no clinically significant changes in both male and female rats on assessing any effects on the CNS. There were no clinically significant changes in male rats’ respiratory assessment. There were no clinically significant changes in hERG analysis results. There were no clinically significant changes in the cardiovascular system of male beagle dogs. Our results demonstrate that HAD-B1 is a safe herbal formula that does not have a clinically significant effect on the CNS, respiratory, and cardiovascular systems.

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INDUCTION OF GOITRE BY PTU OR KClO4 IN MALE AND FEMALE RATS. EFFECT OF GONADECTOMY

Acta Endocrinologica ◽

10.1530/acta.0.0740088 ◽

1973 ◽

Vol 74 (1) ◽

pp. 88-104 ◽

Cited By ~ 2

Author(s):

T. Jolín ◽

M. J. Tarin ◽

M. D. Garcia

Keyword(s):

Iodine Content ◽

High Plasma ◽

Disc Electrophoresis ◽

Female Rats ◽

Male Rats ◽

Adult Rats ◽

Male And Female ◽

Glucose Levels ◽

Male And Female Rats ◽

Tsh Levels

ABSTRACT Male and female rats of varying ages were placad on a low iodine diet (LID) plus KClO4 or 6-propyl-2-thiouracil (PTU) or on the same diet supplemented with I (control rats). Goitrogenesis was also induced with LID plus PTU in gonadectomized animals of both sexes. The weight of the control and goitrogen treated animals, and the weight and iodine content of their thyroids were determined, as well as the plasma PBI, TSH, insulin and glucose levels. The pituitary GH-like protein content was assessed by disc electrophoresis on polyacrylamide gels. If goitrogenesis was induced in young rats of both sexes starting with rats of the same age, body weight (B.W.) and pituitary growth hormone (GH) content, it was found that both the males and females developed goitres of the same size. On the contrary, when goitrogenesis was induced in adult animals, it was found that male rats, that had larger B.W. and pituitary GH content than age-paired females, developed larger goitres. However, both male and female rats were in a hypothyroid condition of comparable degree as judged by the thyroidal iodine content and the plasma PBI and TSH levels. When all the data on the PTU or KClO4-treated male and female rats of varying age and B.W. were considered together, it was observed that the weights of the thyroids increased proportionally to B.W. However, a difference in the slope of the regression of the thyroid weight over B.W. was found between male and female rats, due to the fact that adult male rats develop larger goitres than female animals. In addition, in the male rats treated with PTU, gonadectomy decreased the B.W., pituitary content of GH-like protein and, concomitantly, the size of the goitre decreased; an opposite effect was induced by ovariectomy on the female animals. However, when goitrogenesis was induced in weight-paired adult rats of both sexes, the male animals still developed larger goitres than the females. Among all the parameters studied here, the only ones which appeared to bear a consistent relationship with the size of the goitres in rats of different sexes, treated with a given goitrogen, were the rate of body growth and the amount of a pituitary GH-like protein found before the onset of the goitrogen treatment. Moreover, though the pituitary content of the GH-like protein decreased as a consequence of goitrogen treatment, it was still somewhat higher in male that in female animals. The present results suggest that GH may somehow be involved in the mechanism by which male and female rats on goitrogens develop goitres of different sizes, despite equally high plasma TSH levels.

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Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis

Biology of Sex Differences ◽

10.1186/s13293-020-00346-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ming Song ◽

Fang Yuan ◽

Xiaohong Li ◽

Xipeng Ma ◽

Xinmin Yin ◽

...

Keyword(s):

Sex Differences ◽

Microbial Activity ◽

Hepatic Steatosis ◽

Female Rats ◽

Male Rats ◽

Calorie Intake ◽

Dietary Copper ◽

Male And Female ◽

Male And Female Rats ◽

Rrna Sequencing

Abstract Background Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. Methods Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS). Results Male and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. Conclusions Our data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.

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Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz050 ◽

2019 ◽

Vol 22 (11) ◽

pp. 710-723 ◽

Cited By ~ 8

Author(s):

Atul P Daiwile ◽

Subramaniam Jayanthi ◽

Bruce Ladenheim ◽

Michael T McCoy ◽

Christie Brannock ◽

...

Keyword(s):

Sex Differences ◽

Nucleus Accumbens ◽

Fixed Ratio ◽

Female Rats ◽

Male Rats ◽

Mrna Levels ◽

Self Administration ◽

Male And Female ◽

Orexin Receptors ◽

Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

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The Preventive Effects of Diminazene Aceturate in Renal Ischemia/Reperfusion Injury in Male and Female Rats

Advances in Preventive Medicine ◽

10.1155/2014/740647 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Maryam Malek ◽

Mehdi Nematbakhsh

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Female Rats ◽

Male Rats ◽

Converting Enzyme ◽

Diminazene Aceturate ◽

Male And Female ◽

Male And Female Rats

Background. Angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor (ACE2/Ang-1-7/MasR) appears to counteract most of the deleterious actions of angiotensin-converting enzyme/angiotensin II/angiotensin II receptor 1 (ACE/Ang II/AT1R) in renal ischemia/reperfusion (I/R) injury but ACE2 activity and its levels are sexually dimorphic in the kidney. This study was designed to evaluate the effects of activation endogenous ACE2 using the diminazene aceturate (DIZE) in renal I/R injury in male and female rats.Methods. 36 Wistar rats were divided into two groups of male and female and each group distinct to three subgroups (n=6). I/R group was subjected to 45 min of bilateral ischemia and 24 h of reperfusion, while treatment group received DIZE (15 mg/kg/day) for three days before the induction of I/R. The other group was assigned as the sham-operated group.Results. DIZE treatment in male rats caused a significant decrease in blood urea nitrogen (BUN), creatinine, liver functional indices, serum malondialdehyde (MDA), and increase kidney nitrite levels (P<0.05), and in female rats a significant increase in creatinine and decrease serum nitrite levels compared to the I/R group (P<0.05).Conclusions. DIZE may protect the male kidney from renal I/RI through antioxidant activity and elevation of circulating nitrite level.

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Gender-based differences in the effect of dietary cholesterol in rats

Open Life Sciences ◽

10.2478/s11535-012-0091-7 ◽

2012 ◽

Vol 7 (6) ◽

pp. 980-986 ◽

Cited By ~ 2

Author(s):

Milan Marounek ◽

Zdeněk Volek ◽

Eva Skřivanová ◽

Marian Czauderna

Keyword(s):

Dietary Cholesterol ◽

Female Rats ◽

Male Rats ◽

Cholesterol Concentration ◽

Hepatic Cholesterol ◽

Bile Acid Concentration ◽

Male And Female ◽

Relative Expression ◽

Male And Female Rats ◽

Cholesterol Supplementation

AbstractMale and female rats were fed diets supplemented with cholesterol and palm fat at 10 and 50 g/kg, respectively; serum, hepatic tissue and faeces were analysed. Cholesterol supplementation significantly increased serum and hepatic cholesterol both in male and female rats. Male and female rats fed the cholesterol-containing diet differed significantly in serum cholesterol concentration (2.48 µmol/mL vs 2.92 µmol/mL), concentration of serum triacylglycerols, but not in hepatic cholesterol concentration. The serum and hepatic cholesterol concentrations correlated non-significantly in male rats (r=0.491; P=0.063) and significantly in female rats (r=0.818; P<0.001). Cholesterol supplementation non-significantly decreased relative expression of the hepatic LDL receptor gene and significantly increased relative expression of the hepatic cholesterol 7α-hydroxylase gene in rats of both genders. The faeces of control rats contained similar amounts of cholesterol and bile acids. Cholesterol supplementation increased cholesterol concentration 10 times in the faeces of male rats and 12 times in faeces of female rats. The corresponding increases of bile acid concentration were much lower (83% in male rats and 108% in female rats). It can be concluded that the effects of cholesterol supplementation were more pronounced in female than in male rats.

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17-β-Estradiol Induces Heat Shock Proteins in Brain Arteries and Potentiates Ischemic Heat Shock Protein Induction in Glia and Neurons

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200202000-00006 ◽

2002 ◽

Vol 22 (2) ◽

pp. 183-195 ◽

Cited By ~ 60

Author(s):

Aigang Lu ◽

Rui-qiong Ran ◽

Joseph Clark ◽

Melinda Reilly ◽

Alex Nee ◽

...

Keyword(s):

Cerebral Ischemia ◽

Heat Shock ◽

Heat Shock Protein ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Female Rats ◽

Male Rats ◽

Western Blots ◽

Male And Female ◽

Male And Female Rats

Estradiol reduces brain injury from many diseases, including stroke and trauma. To investigate the molecular mechanisms of this protection, the effects of 17-β-estradiol on heat shock protein (HSP) expression were studied in normal male and female rats and in male gerbils after global ischemia. 17-β-Estradiol was given intraperitoneally (46 or 460 ng/kg, or 4.6 μg/kg) and Western blots performed for HSPs. 17-β-Estradiol increased hemeoxygenase-1, HSP25/27, and HSP70 in the brain of male and female rats. Six hours after the administration of 17-β-estradiol, hemeoxygenase-1 increased 3.9-fold (460 ng/kg) and 5.4-fold (4.6 μg/kg), HSP25/27 increased 2.1-fold (4.6 μg/kg), and Hsp70 increased 2.3-fold (460 ng/kg). Immunocytochemistry showed that hemeoxygenase-1, HSP25/27,and HSP70 induction was localized to cerebral arteries in male rats, possibly in vascular smooth muscle cells. 17-β-Estradiol was injected intraperitoneally 20 minutes before transient occlusion of both carotids in adult gerbils. Six hours after global cerebral ischemia, 17-β-estradiol (460 ng/kg) increased levels of hemeoxygenase-1 protein 2.4-fold compared with ischemia alone, and HSP25/27 levels increased 1.8-fold compared with ischemia alone. Hemeoxygenase-1 was induced in striatal oligodendrocytes and hippocampal neurons, and HSP25/27 levels increased in striatal astrocytes and hippocampal neurons. Finally, Western blot analysis confirmed that estrogen induced heat shock factor-1, providing a possible mechanism by which estrogen induces HSPs in brain and other tissues. The induction of HSPs may be an important mechanism for estrogen protection against cerebral ischemia and other types of injury.

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Glutathione Conjugates of Ochratoxin a as Biomarkers of Exposure / Glutationski Konjugati Okratoksina A Kao Biomarkeri Izloženosti

Archives of Industrial Hygiene and Toxicology ◽

10.2478/10004-1254-63-2012-2202 ◽

2012 ◽

Vol 63 (4) ◽

pp. 417-427 ◽

Cited By ~ 27

Author(s):

Mariana Tozlovanu ◽

Delphine Canadas ◽

Annie Pfohl-Leszkowicz ◽

Christine Frenette ◽

Robert J. Paugh ◽

...

Keyword(s):

Ochratoxin A ◽

Rat Kidney ◽

Female Rats ◽

Amide Bond ◽

Male Rats ◽

Dark Agouti ◽

Female Rat ◽

Male And Female ◽

Male And Female Rats ◽

Liver And Kidney

AbstractIn the present study the photoreactivity of the fungal carcinogen ochratoxin A (OTA) has been utilised to generate authentic samples of reduced glutathione (GSH) and N-acetylcysteine (NAC) conjugates of the parent toxin. These conjugates, along with the nontoxic OTα, which is generated through hydrolysis of the amide bond of OTA by carboxypeptidase A, were utilised as biomarkers to study the metabolism of OTA in the liver and kidney of male and female Dark Agouti rats. Male rats are more susceptible than female rats to OTA carcinogenesis with the kidney being the target organ. Our studies show that the distribution of OTA in male and female rat kidney is not significantly different. However, the extent of OTA metabolism was greater in male than female rats. Much higher levels of OTα were detected in the liver compared to the kidney, and formation of OTα is a detoxification pathway for OTA. These findings suggest that differences in metabolism between male and female rats could provide an explanation for the higher sensitivity of male rats to OTA toxicity

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Abstract 15602: Sex-differences in Extreme Exercise-induced Adverse Cardiovascular Remodeling

Circulation ◽

10.1161/circ.142.suppl_3.15602 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Gemma Sanguesa ◽

Aline Meza ◽

Anna Alcarraz ◽

Cira Rubies ◽

Lluis Mont ◽

...

Keyword(s):

High Intensity ◽

Female Rats ◽

Male Rats ◽

Mrna Levels ◽

Descending Aorta ◽

Male And Female ◽

Cardiovascular Remodeling ◽

High Intensity Training ◽

Male And Female Rats ◽

Exercise Induced

Introduction: There is emerging evidence in men that sustained high-intensity training promotes an adverse cardiovascular remodeling, thereby increasing the risk of atrial fibrillation, ventricular arrhythmias and coronary calcification. Whether men and women are similarly affected by high intensity exercise-induced harm is unclear. Our aim was to study sex differences in a long-term endurance training rat model. Methods: Male and female Wistar rats were subjected to high intensity training for 16 weeks (INT, 60min 60cm/s, male n=20, female n=15). Sedentary rats (SED, male n=20, female n=18) were used as controls. At the end of the training period, rats had an electrocardiogram and echocardiography performed. Vascular fibrosis was assessed in descending aorta, left carotid, and intramyocardial arteries (IMA), right and left atria, and left ventricle (LV) histological samples. mRNA levels of cardiac hypertrophy, fibrosis, oxidative stress and inflammation genes were assessed in LV samples by Real-Time PCR. Results: INT male rats presented lower heart rate (382±9, 340±10, SED vs INT, p<0.01) and a longer QRS duration (18.8±0.6, 22.4±1.1, SED vs INT, p<0.01), while these were not modified in the INT female group. Echocardiography showed eccentric LV hypertrophy in both trained male and female rats. High intensity exercise induced fibrosis in the descending aorta and carotid in both males and females, but IMA were only affected in trained male rats. In the heart, exercise-induced atrial fibrosis similarly occurred in both trained male and female rats. No training-induced fibrosis was evident in the LV of both INT male and female rats. Regarding LV mRNA analysis, INT males showed a reduction of desmin, TTN and N2BA/N2B ratio, whereas INT females exhibited higher desmin mRNA levels and lower αMHC/βMHC ratio. Intense exercise did not increase LV mRNA levels of fibrosis, oxidative stress and inflammation markers neither in males nor in females. In comparison to males, females had lower LV myocardial fibrosis as well as lower fibrosis markers. Conclusions: Male and female rats exhibit qualitatively different cardiovascular remodeling after extreme exercise. Nevertheless, both sexes might develop exercise-induced adverse vascular and cardiac effects.

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Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00271.2017 ◽

2018 ◽

Vol 314 (1) ◽

pp. R12-R21 ◽

Cited By ~ 14

Author(s):

Hershel Raff ◽

Brian Hoeynck ◽

Mack Jablonski ◽

Cole Leonovicz ◽

Jonathan M. Phillips ◽

...

Keyword(s):

Insulin Resistance ◽

Adult Male ◽

Rat Model ◽

Female Rats ◽

Male Rats ◽

Male And Female ◽

Neonatal Hypoxia ◽

Male And Female Rats ◽

Plasma Leptin ◽

Neonatal Separation

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

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Hydration with Mannitol and Dextrose May Promote Cisplatin-Induced Nephrotoxicity: Test of Five Protocols of Hydration during Cisplatin Therapy in Rat Models

Journal of Toxicology ◽

10.1155/2021/5547341 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Mohammad-Sedigh Khosravi ◽

Alireza Samimiat ◽

Bahar Mazaheri ◽

Farzaneh Ashrafi ◽

Ardeshir Talebi ◽

...

Keyword(s):

Tumor Therapy ◽

Kidney Tissue ◽

Serum Levels ◽

Female Rats ◽

Male Rats ◽

Male And Female ◽

Male And Female Rats ◽

Female Wistar Rats ◽

Solid Tumor Therapy ◽

Cisplatin Therapy

Backgrounds. Cisplatin (CP) still is a novel choice for solid tumor therapy, but it is accompanied with the side effect of nephrotoxicity. Hydration may reduce the risk of CP-induced nephrotoxicity, while the issue is still challenging. In this study, five types of hydration protocols including saline, mannitol, dextrose saline, saline plus furosemide, and saline plus mannitol were examined in both sexes of rats during CP therapy. Methods. Seventy-six male and female Wistar rats in 14 groups of experiments were subjected to CP therapy, and five types of hydration protocols were implemented, and the induced nephrotoxicity was evaluated via biochemical markers, kidney function parameters, and pathology investigation. Results. Male and female rats had different responses to hydration protocol types. The higher mortality rate was seen in female rats that received mannitol or dextrose hydration types. In addition, the serum levels of blood urea nitrogen (BUN) and creatinine (Cr) and sodium excretion fraction (ENa%) increased and the clearance of Cr (ClCr) decreased significantly ( P < 0.05 ) in female rats hydrated with saline plus furosemide or mannitol plus saline-treated groups. The worsened condition in male rats is observed in the mannitol hydration group with a significant decrease of ClCr and significant increase of serum BUN and Cr and ENa% ( P < 0.05 ). The higher kidney tissue damage score (KTDS) in the mentioned groups verified the findings. Conclusion. Hydration with mannitol or dextrose promotes the risk of nephrotoxicity during CP therapy with more intensity on the female.

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