Melatonin actions in the heart; more than a hormone

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.

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Intracerebroventricular injection of prostaglandin E2 increases splenic sympathetic nerve activity in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.269.3.r662 ◽

1995 ◽

Vol 269 (3) ◽

pp. R662-R668 ◽

Cited By ~ 5

Author(s):

T. Ando ◽

T. Ichijo ◽

T. Katafuchi ◽

T. Hori

Keyword(s):

Prostaglandin E2 ◽

Sympathetic Nerve ◽

Time Course ◽

Sympathetic Nerve Activity ◽

Dependent Manner ◽

Central Administration ◽

Nerve Activity ◽

High Doses ◽

Alpha Chloralose ◽

Dose Dependent

The effects of central administration of prostaglandin E2 (PGE2) and its selective agonists on splenic sympathetic nerve activity (SNA) were investigated in urethan- and alpha-chloralose-anesthetized rats. An intra-third-cerebroventricular (13V) injection of PGE2 (0.1-10 nmol/kg) increased splenic SNA in a dose-dependent manner. An I3V injection of an EP1 agonist, 17-phenyl-omega-trinor PGE2 (1-30 nmol/kg), also resulted in a dose-dependent increase in splenic SNA, with a time course similar to that of PGE2-induced responses. In contrast, EP2 agonists, butaprost (10-100 nmol/kg I3V) and 11-deoxy-PGE1 (10-100 nmol/kg I3V), had no effect on splenic SNA. An I3V injection of M & B-28767 (an EP3/EP1 agonist, EP3 >> EP1) increased splenic SNA only at high doses (10-100 nmol/kg). Pretreatment with an EP1 antagonist, SC-19220 (200 and 500 nmol/kg), completely blocked the responses of splenic SNA to PGE2 (0.1 nmol/kg) and M & B-28767 (10 nmol/kg), respectively. These findings indicate that brain PGE2 increases splenic SNA through its action on EP1 receptors.

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

Toxins ◽

10.3390/toxins13100723 ◽

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.

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

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.01012 ◽

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.

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

Human & Experimental Toxicology ◽

10.1177/0960327120930125 ◽

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.

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Effect of ethyl alcohol on motor function in canine stomach

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1992.262.2.g223 ◽

1992 ◽

Vol 262 (2) ◽

pp. G223-G230

Author(s):

L. C. Knight ◽

A. H. Maurer ◽

R. Wikander ◽

B. Krevsky ◽

L. S. Malmud ◽

...

Keyword(s):

Gastric Emptying ◽

Solid Food ◽

Blood Levels ◽

Lag Phase ◽

Dependent Manner ◽

Solid Meal ◽

The Mean ◽

High Doses ◽

Mean Time ◽

Dose Dependent

The aim of this study was to elucidate the effects of ethanol on gastric emptying and the trituration of solid food. With the use of a noninvasive physiological imaging technique, gastric processing of a radiolabeled solid meal was evaluated in unanesthetized dogs which ingested 6-8% ethanol solutions or received intravenous alcohol before the meal. Oral alcohol (resulting in blood levels up to 174 mg/dl) decreased the amplitude of antral contractions or completely abolished them. Alcohol did not significantly affect the fundamental frequency of contractions except at high doses, at which contractions were abolished. Alcohol lengthened the mean time to 50% of gastric emptying in a dose-dependent manner, from 132 +/- 3 min without alcohol to 160 +/- 10 min with oral alcohol at blood levels of 80-120 mg/dl (P less than 0.05). This was manifested by a lengthening of the lag phase, but there was no effect on the terminal slope of emptying (emptying rate) of the processed meal. At equal blood levels up to 120 mg/dl, orally administered alcohol had a more pronounced effect than intravenous alcohol. These data suggest that even low doses of dilute alcohol affect the ability of the antrum to process solid food and thereby contribute to impairment of gastric emptying.

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

BioMed Research International ◽

10.1155/2016/5398730 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 7

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.

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Biphasic Dose–Response Induced by PCB150 and PCB180 in HeLa Cells and Potential Molecular Mechanisms

Dose-Response ◽

10.1177/1559325820910040 ◽

2020 ◽

Vol 18 (1) ◽

pp. 155932582091004

Author(s):

Ainy Zehra ◽

Muhammad Zaffar Hashmi ◽

Abdul Majid Khan ◽

Tariq Malik ◽

Zaigham Abbas

Keyword(s):

Hela Cells ◽

Molecular Mechanisms ◽

Dependent Manner ◽

Genotoxic Effects ◽

Species Formation ◽

Low Concentrations ◽

Extracellular Signal ◽

High Concentrations ◽

High Doses ◽

Dose Dependent

The polychlorinated biphenyls (PCBs) are persistent and their dose-dependent toxicities studies are not well-established. In this study, cytotoxic and genotoxic effects of PCB150 and PCB180 in HeLa cells were studied. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that the cell proliferation was stimulated at low doses (10−3 and 10−2 µg/mL for 12, 24, 48, and 72 hours) and inhibited at high doses (10 and 15 µg/mL for 24, 48, and 72 hours) for both PCBs. Increase in reactive oxygen species formation was observed in the HeLa cells in a time- and dose-dependent manner. Malondialdehyde and superoxide dismutase showed increased levels at high concentrations of PCBs over the time. Glutathione peroxidase expression was downregulated after PCBs exposure, suggested that both PCB congeners may attributable to cytotoxicity. Comet assay elicited a significant increase in genotoxicity at high concentrations of PCBs as compared to low concentrations indicating genotoxic effects. PCB150 and PCB180 showed decrease in the activity of extracellular signal–regulated kinase 1/2 and c-Jun N-terminal kinase at high concentrations after 12 and 48 hours. These findings may contribute to understanding the mechanism of PCBs-induced toxicity, thereby improving the risk assessment of toxic compounds in humans.

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Effect of Noni (Morinda citrifoliaLinn.) Fruit and Its Bioactive Principles Scopoletin and Rutin on Rat Vas Deferens Contractility: AnEx VivoStudy

The Scientific World JOURNAL ◽

10.1155/2014/909586 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 22

Author(s):

Vijayapandi Pandy ◽

Megala Narasingam ◽

Thubasni Kunasegaran ◽

Dharmani Devi Murugan ◽

Zahurin Mohamed

Keyword(s):

Vas Deferens ◽

Contractile Response ◽

Rat Vas Deferens ◽

Morinda Citrifolia ◽

Dependent Manner ◽

Per Se ◽

High Doses ◽

Dose Dependent ◽

Higher Doses ◽

Agonistic Effect

This study examined the effect of methanolic extract ofMorinda citrifoliaLinn. (MMC) and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1–40 mg/mL), scopoletin (1–200 μg/mL), and rutin hydrate (0.6–312.6 μg/mL) dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, andα1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMCper seat higher doses (60–100 mg/mL) showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (<40 mg/mL) and dopaminergic agonistic effect at higher concentrations (>60 mg/mL). However, similar contractile response at high doses of scopoletin (0.5–5 mg/mL) and rutin hydrate (0.5–5 mg/mL)per sewas not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC.

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Parathyroid Hormone (1-34) Counteracts the Suppression of Interleukin-11 Expression by Glucocorticoid in Murine Osteoblasts: A Possible Mechanism for Stimulating Osteoblast Differentiation Against Glucocorticoid Excess

Endocrinology ◽

10.1210/en.2013-1915 ◽

2013 ◽

Vol 154 (3) ◽

pp. 1156-1167 ◽

Cited By ~ 7

Author(s):

Rika Kuriwaka-Kido ◽

Shinsuke Kido ◽

Yuka Miyatani ◽

Yuji Ito ◽

Takeshi Kondo ◽

...

Keyword(s):

Bone Formation ◽

Gene Transcription ◽

Osteoblast Differentiation ◽

Mechanical Strain ◽

Dependent Manner ◽

Rapid Induction ◽

Kinase C ◽

High Doses ◽

Interfering Rna ◽

Dose Dependent

Abstract Glucocorticoid (GC) excess causes a rapid loss of bone with a reduction in bone formation. Intermittent PTH (1-34) administration stimulates bone formation and counteracts the inhibition of bone formation by GC excess. We have previously demonstrated that mechanical strain enhances interleukin (IL)-11 gene transcription by a rapid induction of ΔFosB expression and protein kinase C (PKC)-δ-mediated phosphorylation of phosphorylated mothers against decapentaplegic (Smad)-1. Because IL-11 suppresses the expression of dickkopf-1 and -2 and stimulates Wnt signaling, IL-11 appears to mediate at least a part of the effect of mechanical strain on osteoblast differentiation and bone formation. The present study was undertaken to examine the effect of PTH(1-34) and GCs on IL-11 expression in murine primary osteoblasts (mPOBs). PTH(1-34) treatment of mPOBs enhanced IL-11 expression in a time- and dose-dependent manner. PTH(1-34) also stimulated ΔFosB expression and Smad1 phosphorylation, which cooperatively stimulated IL-11 gene transcription. PTH(1-34)-induced Smad1 phosphorylation was mediated via PKCδ and was abrogated in mPOBs from PKCδ knockout mice. Dexamethasone suppressed IL-11 gene transcription enhanced by PTH(1-34) without affecting ΔFosB expression or Smad1 phosphorylation, and dexamethasone-GC receptor complex was bound to JunD, which forms heterodimers with ΔFosB. High doses of PTH(1-34) counteracted the effect of dexamethasone on apoptosis of mPOBs, which was blunted by neutralizing anti-IL-11 antibody or IL-11 small interfering RNA. These results demonstrate that PTH(1-34) and GCs interact to regulate IL-11 expression in parallel with osteoblast differentiation and apoptosis and suggest that PTH(1-34) and dexamethasone may regulate osteoblast differentiation and apoptosis via their effect on IL-11 expression.

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Clerodendrum Chinensis Extracts; AeC and EeC Exerts Rapid Antihypertensive Effects in L-NAME Hypertensive Experimental Models

10.1101/2020.07.18.210070 ◽

2020 ◽

Author(s):

Joy I. Odimegwu ◽

Tolulope F. Okanlawon ◽

Obumneme Noel ◽

Ismail Ishola

Keyword(s):

Blood Pressure ◽

Communicable Disease ◽

Scientific Basis ◽

Experimental Models ◽

Dependent Manner ◽

Arterial Blood ◽

High Doses ◽

Mean Differences ◽

Antihypertensive Properties ◽

Dose Dependent

ABSTRACTBackgroundThe rise in occurrence of hypertension, a non-communicable disease and a major factor for chronic renal failure, cardiovascular disease, and stroke, which most times lead to sudden death is worrisome. Resistant hypertension is more common and may have no symptoms at all for months or years, but then can cause heart attack, stroke, and vision and kidney damage. Prevention and quick management of hypertension are therefore essential in reducing the risk of these debilitating ailments. Aqueous and ethanolic extracts of the leaves of Clerodendrum chinensis (AeC and EeC) are used by local communities of West Africa as medicine for rapid antihypertensive actions. We aim to discover the scientific basis for the use of the herb as medicine.MethodsThis work investigates the antihypertensive effects of AeC and EeC in L-Arginine Methyl Ester Hydrochloride (L-NAME)-induced hypertensive rats Acetylcholine, L-Arginine and Sodium Nitroprusside were used as standards. All results were expressed as means ± standard error of mean. Differences were considered significant at p <0.05.ResultsIntravenous administration of the extracts caused a significant decrease in the Mean Arterial Blood Pressure (MABP) in a dose-dependent manner. AeC at 100mg/kg caused a significant decline in blood pressure in a dose-related manner. Likewise at 100mg/kg, EeC reduced MABP steadily from 103.9± 2.55 to 34.1± 0.95mmHg. The two extracts; possess significant antihypertensive properties.ConclusionsBoth extracts show significant antihypertensive effects and at high doses could lead to hypotension and so should be used with care. Further research is necessary to determine safe dosage forms.

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