scholarly journals Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole–Protein Adducts

Toxins ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 723
Author(s):  
Jiang Ma ◽  
Mi Li ◽  
Na Li ◽  
Wood Yee Chan ◽  
Ge Lin
Keyword(s):  
Natural Products ◽  
Pyrrolizidine Alkaloids ◽  
Pyrrolizidine Alkaloid ◽  
Protein Adducts ◽  
Dependent Manner ◽  
Histological Changes ◽  
Histological Results ◽  
Dose Dependent ◽  
Different Doses ◽  
Alt Activity

Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole–protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of Crotalaria sessiliflora (containing one PA: monocrotaline) and Gynura japonica (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole–protein adducts formed in the rats’ livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole–protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole–protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole–protein adducts—which directly correlated with the elevation of serum ALT activity—was a common insult leading to PA-ILI, suggesting a potential for using pyrrole–protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures.

Melatonin actions in the heart; more than a hormone

2018 ◽  
Vol 1 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Darío Acuña-Castroviejo ◽  
Maria T Noguiera-Navarro ◽  
Russel J Reiter ◽  
Germaine Escames
Keyword(s):  
Cell Membranes ◽  
Myocardial Cell ◽  
Rat Tissues ◽  
Dependent Manner ◽  
Broad Distribution ◽  
Multiple Organs ◽  
High Doses ◽  
Extrapineal Melatonin ◽  
Dose Dependent ◽  
Different Doses

Due to the broad distribution of extrapineal melatonin in multiple organs and tissues, we analyzed the presence and subcellular distribution of the indoleamine in the heart of rats. Groups of sham-operated and pinealectomized rats were sacrificed at different times along the day, and the melatonin content in myocardial cell membranes, cytosol, nuclei and mitochondria, were measured. Other groups of control animals were treated with different doses of melatonin to monitor its intracellular distribution. The results show that melatonin levels in the cell membrane, cytosol, nucleus, and mitochondria vary along the day, without showing a circadian rhythm. Pinealectomized animals trend to show higher values than sham-operated rats. Exogenous administration of melatonin yields its accumulation in a dose-dependent manner in all subcellular compartments analyzed, with maximal concentrations found in cell membranes at doses of 200 mg/kg bw melatonin. Interestingly, at dose of 40 mg/kg b.w, maximal concentration of melatonin was reached in the nucleus and mitochondrion. The results confirm previous data in other rat tissues including liver and brain, and support that melatonin is not uniformly distributed in the cell, whereas high doses of melatonin may be required for therapeutic purposes.

Evaluation of Hepatoprotective activity of Methanol extract of Persicaria hydropiper: An in vivo screening

2021 ◽  
pp. 5819-5824
Author(s):  
Pooja Kamra ◽  
Mahaveer Singh ◽  
Hardarshan Singh Lamba ◽  
Birendra Srivastava
Keyword(s):  
Carbon Tetrachloride ◽  
Intraperitoneal Administration ◽  
Hepatoprotective Activity ◽  
Dependent Manner ◽  
Standard Drug ◽  
Whole Plant ◽  
Dose Dependent ◽  
Histopathological Investigation ◽  
Different Doses

The present study aimed to evaluate the hepatoprotective potential of methanolic whole plant extract of Persicaria hydropiper in carbon tetrachloride (CCl4) induced hepatotoxicity model. Hepatotoxicity was induced in rats by intraperitoneal administration of carbon tetrachloride (CCl4) for seven days. The extract was thereafter administered at two different doses of 200 mg/kg and 400 mg/kg body weight for next seven days. Silymarin was used as a reference standard. The extract revealed hepatoprotective activity in dose dependent manner. The dose of 400 mg/kg exhibited maximum hepatoprotective ability as apparent from several evaluation parameters including liver function profile, bilirubin, antioxidant enzymes as well as histopathological investigation which was comparable to the standard drug Silymarin respectively. These findings sustenance the use of the extract as an adjuvant with existing therapy for treatment of liver ailments.

Cinnamomum cassia ameliorates Ni-NPs-induced liver and kidney damage in male Sprague Dawley rats

2020 ◽  
Vol 39 (11) ◽  
pp. 1565-1581
Author(s):  
S Iqbal ◽  
F Jabeen ◽  
C Peng ◽  
MU Ijaz ◽  
AS Chaudhry
Keyword(s):  
Dependent Manner ◽  
Sprague Dawley ◽  
Cinnamomum Cassia ◽  
Preliminary Information ◽  
Sprague Dawley Rats ◽  
Liver And Kidney ◽  
Altered Blood ◽  
Biochemical Analyses ◽  
Dose Dependent ◽  
Different Doses

Nickel nanoparticles (Ni-NPs) have been widely used in various industries related to electronics, ceramics, textiles, and nanomedicine. Ambient and occupational exposure to Ni-NPs may bring about potential detrimental effects on animals and humans. Thus, there is a growing effort to identify compounds that can ameliorate NPs-associated pathophysiologies. The present study examined Cinnamomum cassia ( C. cassia) bark extracts (CMBE) for its ameliorative activity against Ni-NPs-induced pathophysiological and histopathological alterations in male Sprague Dawley rats. The biochemical analyses revealed that dosing rats with Ni-NPs at 10 mg/kg/body weight (b.w.) significantly altered the normal structural and biochemical adaptations in the liver and kidney. Conversely, supplementations with CMBE at different doses (225, 200, and 175 mg/kg/b.w. of rat) ameliorated the altered blood biochemistry and reduced the biomarkers of liver and kidney function considerably ( p < 0.05) in a dose-dependent manner. However, the best results were at 225 mg/kg/b.w. of rat. The study provided preliminary information about the protective effect of C. cassia against Ni-NPs indicated liver and kidney damages. Future investigations are needed to explore C. cassia mechanism of action and isolation of single constituents of C. cassia to assess their pharmaceutical importance accordingly.

scholarly journals Evaluation of Hepatotoxicity with Treatment Doses of Flucytosine and Amphotericin B for Invasive Fungal Infections

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Alexandra Folk ◽  
Coralia Cotoraci ◽  
Cornel Balta ◽  
Maria Suciu ◽  
Hildegard Herman ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Target Genes ◽  
Fungal Infections ◽  
Combined Therapy ◽  
Hepatic Tissue ◽  
Dependent Manner ◽  
Liver Injuries ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Different Doses

Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 μg/kg amphotericin B; 100 mg/kg flucytosine and 600 μg/kg amphotericin B; 150 mg/kg flucytosine and 900 μg/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-α, IL-6, and NF-κB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-αand IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-κB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-κB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.

Endogenous cholecystokinin drives gallbladder emptying in dogs

1986 ◽  
Vol 251 (4) ◽  
pp. G553-G558
Author(s):  
K. Shiratori ◽  
S. Watanabe ◽  
W. Y. Chey ◽  
K. Y. Lee ◽  
T. M. Chang
Keyword(s):  
Corn Oil ◽  
Venous Blood ◽  
Gallbladder Emptying ◽  
Dependent Manner ◽  
Gallbladder Volume ◽  
Dose Dependent ◽  
Intraduodenal Administration ◽  
Different Doses ◽  
Cck Release

We investigated the effect of fat in the duodenum on the gallbladder emptying in seven dogs prepared with gastric, duodenal, and gallbladder cannulas. Gallbladder volume was measured at 15-min intervals, and venous blood samples were obtained at regular intervals for 2.5 h. Intraduodenal administration of Lipomul (pH 5.0, corn oil) in three different doses (1.1, 2.2, and 4.4 mmol/10 min) resulted in significant increases in gallbladder emptying in a dose-dependent manner (r = 0.8668, P less than 0.001). Likewise, the increase in integrated cholecystokinin (CCK) release in response to Lipomul was also dose dependent (r = 0.7334, P less than 0.001). A statistically significant correlation was found between integrated CCK release and gallbladder emptying in response to Lipomul (P less than 0.001). To determine the role of circulating endogenous CCK on gallbladder emptying effects of intravenous administration of proglumide and a rabbit anti-CCK serum on gallbladder emptying were studied. Gallbladder emptying was virtually abolished by the antiserum. Proglumide not only abolished the emptying but also increased gallbladder volume. Thus we conclude that in dogs the gallbladder emptying in response to fat in the upper small intestine depends on increased circulating endogenous CCK.

scholarly journals EFFICACY OF AN ACTIVE COMPOUND OF THE HERB, ASHWAGANDHA IN PREVENTION OF STRESS INDUCED HYPERGLYCEMIA

2018 ◽  
Vol 10 (10) ◽  
pp. 44 ◽  
Author(s):  
Sarjan H. N. ◽  
Yajurvedi H. N.
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Ethanolic Extract ◽  
Dependent Manner ◽  
Stress Exposure ◽  
In Vitro Experiment ◽  
Isolated Compound ◽  
Dose Dependent ◽  
Different Doses

Objective: To find out whether an isolated compound (IC) from the ethanolic extract of roots of ashwagandha prevents stress-induced hyperglycemia by direct interference with the action of increased concentration of corticosterone on hepatocytes or by preventing hyper-secretion of corticosterone or both.Methods: A group of rats served as controls, and those in another group were subjected to restraint (1 h) and forced swimming exercise (15 min), after a gap of 4 h daily for 4 w. The third group of rats received orally IC (5 mg/kg bw/rat) 1 h prior to exposure to stressors. After the last treatment period, a blood sample was collected and serum was separated for the estimation of corticosterone and glucose. In in vitro experiment, hepatocytes were treated with different concentrations of corticosterone (100, 200, 300, 400 and 500 ng/ml). In another set of experiment, hepatocytes were treated with different doses of IC (1, 10, 100, 1000 and 10 000 μg/ml of medium) along with corticosterone (400ng/ml). The concentration of glucose and activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were determined after the treatment.Results: Stress exposure caused a significant increase in serum concentration of corticosterone and glucose whereas, administration of IC did not result in similar changes. Further, treatment of corticosterone in in vitro significantly increased the activities of PEPCK and G6Pase and concentration of glucose in a dose-dependent manner in hepatocytes. However, treatment with IC did not interfere with the corticosterone-induced an increase in the activities of PEPCK and G6Pase as well as the concentration of glucose in hepatocytes.Conclusion: The in vivo and in vitro results put together reveal that IC does not directly interfere with the action of corticosterone on hepatocytes. However, it prevents stress-induced hyperglycemia by suppressing hyper-secretion of corticosterone. 

Involvement of mitochondrial pathway in benzo[a]pyrene-induced neuron apoptosis

2013 ◽  
Vol 33 (3) ◽  
pp. 240-250 ◽  
Author(s):  
J-S Nie ◽  
H-M Zhang ◽  
J Zhao ◽  
H-J Liu ◽  
Q Niu
Keyword(s):  
Cytochrome C ◽  
Learning And Memory ◽  
B Cell Lymphoma ◽  
Mitochondrial Pathway ◽  
Dependent Manner ◽  
Cerebral Neurons ◽  
Induced Neuron ◽  
Induced Apoptosis ◽  
Dose Dependent ◽  
Different Doses

Benzo[a]pyrene (B[a]P), a well-known carcinogen, is widespread in the environment. Although the neurotoxic effect of B[a]P has not drawn much attention, toxic effects of B[a]P on learning and memory have been reported. Since it is well known that neuronal apoptosis plays a major role in impairment of learning and memory triggered by many stimuli, an effort has been made to examine whether the B[a]P-induced neurotoxicity occurs through mitochondria-mediated apoptosis. Cultured newborn rat cerebral neurons were used to clarify the apoptosis induced by B[a]P in the study. After incubating with different doses of B[a]P in presence of S9 for 40 h, the apoptotic rates of B[a]P-treated neurons increased in a dose-dependent manner. Further analysis showed that B[a]P-induced apoptosis was accompanied by loss of mitochondrial membrane potential, release of cytochrome c from mitochondria to the cytosol, downregulation of antiapoptotic protein B-cell lymphoma-2 (Bcl-2) levels with concurrent upregulation in proapoptotic Bcl-2-associated X protein (Bax) levels, and increase in the levels and activities of caspases-9 and -3. However, there was no difference in the activity of caspase-8 between B[a]P-exposed neurons and controls. Collectively, these results showed that B[a]P upregulates Bax and downregulates Bcl-2 expression in cultured cerebral neurons, which leads to mitochondrial release of cytochrome c, caspase-3 activation and neuronal apoptotic death.

Immunomodulating capacity of kefir

2005 ◽  
Vol 72 (2) ◽  
pp. 195-202 ◽  
Author(s):  
Celso G Vinderola ◽  
Jairo Duarte ◽  
Deepa Thangavel ◽  
Gabriela Perdigón ◽  
Edward Farnworth ◽  
...  
Keyword(s):  
Acetic Acid Bacteria ◽  
Fermented Milk ◽  
Mucosal Immune Response ◽  
Dependent Manner ◽  
Tnf Α ◽  
Translocation Assay ◽  
Feeding Trials ◽  
Dose Dependent ◽  
Different Doses

Kefir is a fermented milk produced by the action of lactic acid bacteria, yeasts and acetic acid bacteria, trapped in a complex matrix of polysaccharides and proteins. Beyond its inherent high nutritional value as a source of proteins and calcium, kefir has a long tradition of being regarded as good for health in countries where it is a staple in the diet. However, published human or animal feeding trials to substantiate this view are not numerous. The aim of this work was to determine the immunomodulating capacity of kefir on the intestinal mucosal immune response in mice and to demonstrate the importance of dose and cell viability on this response. BALB/c mice were fed with commercial kefir ad libitum (diluted 1/10, 1/50, 1/100 or 1/200) or pasteurized kefir (diluted 1/6, 1/10, 1/50, 1/100) for 2, 5 or 7 consecutive days. At the end of each feeding period, the bacterial translocation assay was performed in the liver. Small intestine structure was studied by haematoxilin-eosin staining and light microscopy. The number of IgA+ and IgG+ cells was also determined. For the functional doses chosen, cytokines (IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α and IFN-γ) were determined. Kefir and pasteurized kefir were able to modulate the mucosal immune system in a dose-dependent manner. Kefir was administred 10-times more diluted than pasteurized kefir, but it induced an immunomodulation of similar magnitude, indicating the importance of cell viabilty. The results suggest that a Th1 response was controlled by Th2 cytokines induced by kefir feeding. Pasteurized kefir would induce both Th2 and Th1 responses. This is the first study in vivo regarding the mechanisms involved in the immunomodulating capacity of the oral administration of kefir containing viable or heat-inactivated bacteria at different doses.

Chronic GnRH administration in prepubertal male pigs

1988 ◽  
Vol 118 (1) ◽  
pp. 109-118 ◽  
Author(s):  
Grietje Dijkstra ◽  
J. Martje Fentener van Vlissingen ◽  
C. J. G. Wensing ◽  
P. M. M. van Dorst-Bruijns ◽  
H.J. Degenhart ◽  
...  
Keyword(s):  
Low Dose ◽  
The Other ◽  
Testicular Descent ◽  
Dependent Manner ◽  
Cremaster Muscle ◽  
Histological Changes ◽  
Treatment Dose ◽  
Basal Plasma ◽  
Plasma Hormone ◽  
Dose Dependent

Abstract. The effect of chronic pulsatile low-dose GnRH treatment on the juvenile testis and associated structures was evaluated in relation to hormonal parameters in the peripheral blood in the pig. Starting at 8 weeks of age, male pigs (crossbreds of Dutch Landrace and Yorkshire breeds) were injected 6 times daily im with 0, 75 or 250 ng GnRH/kg body weight during 4 weeks. Immediately after the treatment period, a GnRH stimulation test with 750 ng GnRH/kg iv was carried out. Samples for plasma LH, FSH, testosterone and 5αDHT measurement were obtained weekly (basal level) and after GnRH stimulation. The pigs were castrated at 12 weeks of age and the weights and lengths of the testis, epididymis and cremaster muscle were recorded. Intratesticular testosterone and 5αDHT concentrations were determined, and the testis and epididymis were evaluated for histological changes. Basal plasma hormone concentrations, intratesticular androgen concentrations and the response of the pituitary gland to stimulation had not been affected by GnRH treatment. Pigs receiving the higher treatment dose of GnRH showed less increase in testosterone levels in response to the stimulation dose at 12 weeks of age than the other pigs. Morphologically, no changes were observed in the epididymis and cremaster muscle after GnRH treatment and no signs of reactivation of structures that can provoke testicular descent could be seen. The development of the seminiferous epithelium was more advanced in the GnRH-treated groups, apparently in a dose-dependent manner.

scholarly journals Curcumin Mediated Attenuation of Carbofuran Induced Oxidative Stress in Rat Brain

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sunil Kumar Jaiswal ◽  
Ashish Sharma ◽  
Vivek Kumar Gupta ◽  
Rakesh Kumar Singh ◽  
Bechan Sharma
Keyword(s):  
Oxidative Stress ◽  
Brain Stem ◽  
Rat Brain ◽  
Herbal Product ◽  
Crop Productivity ◽  
Dependent Manner ◽  
Significant Protection ◽  
Sublethal Doses ◽  
Dose Dependent ◽  
Different Doses

The indiscriminate use of carbofuran to improve crop productivity causes adverse effects in nontargets including mammalian systems. The objective of this study was to evaluate carbofuran induced oxidative stress in rat brain stem and its attenuation by curcumin, a herbal product. Out of 6 groups of rats, 2 groups received two different doses of carbofuran, that is, 15 and 30% of LD50, respectively, for 30 days. Out of these, 2 groups receiving same doses of carbofuran were pretreated with curcumin (100 mg/kg body weight). The levels of antioxidants, TBARS, GSH, SOD, catalase, and GST were determined in rat brain stem. The 2 remaining groups served as placebo and curcumin treated, respectively. The data suggested that carbofuran at different doses caused significant alterations in the levels of TBARS and GSH in dose dependent manner. The TBARS and GSH contents were elevated. The activities of SOD, catalase, and GST were significantly inhibited at both doses of carbofuran. The ratio of P/A was also found to be sharply increased. The pretreatment of curcumin exhibited significant protection from carbofuran induced toxicity. The results suggested that carbofuran at sublethal doses was able to induce oxidative stress in rat brain which could be attenuated by curcumin.

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