A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women, Menopause, and “Medical Cannabinoids”

Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E2) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E2 treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions.

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Effect of Osteoporosis on Well-Integrated Bone Implants

Applied Sciences ◽

10.3390/app11020723 ◽

2021 ◽

Vol 11 (2) ◽

pp. 723

Author(s):

Amani M. Basudan ◽

Marwa Y. Shaheen ◽

Abdurahman A. Niazy ◽

Jeroen J.J.P. van den Beucken ◽

John A. Jansen ◽

...

Keyword(s):

Dental Implants ◽

Femoral Condyle ◽

Bone Implants ◽

Bone Implant ◽

Ovx Rats ◽

Bone Response ◽

Significant Difference ◽

Female Wistar Rats ◽

Edentulous Patients

The installation of dental implants has become a common treatment for edentulous patients. However, concern exists about the influence of osteoporosis on the final implant success. This study evaluated whether an ovariectomy (OVX)-induced osteoporotic condition, induced eight weeks postimplantation in a rat femoral condyle, influences the bone response to already-integrated implants. The implants were inserted in the femoral condyle of 16 female Wistar rats. Eight weeks postimplantation, rats were randomly ovariectomized (OVX) or sham-operated (SHAM). Fourteen weeks later, animals were sacrificed, and implants were used for histological and histomorphometric analyses. A significant reduction in the quantity and quality of trabecular bone around dental implants existed in OVX rats in comparison to the SHAM group. For histomorphometric analysis, the bone area (BA%) showed a significant difference between OVX (34.2 ± 4.3) and SHAM (52.6 ± 12.7) groups (p < 0.05). Bone–implant contact (BIC%) revealed significantly lower values for all implants in OVX (42.5 ± 20.4) versus SHAM (59.0 ± 19.0) rats. Therefore, induction of an osteoporotic condition eight weeks postimplantation in a rat model negatively affects the amount of bone present in close vicinity to bone implants.

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Targeted Regulation Of Cgrp Gene Expression

The Scientific World JOURNAL ◽

10.1100/tsw.2001.438 ◽

2001 ◽

Vol 1 ◽

pp. 5-5 ◽

Cited By ~ 1

Author(s):

A. F. Russo ◽

P. L. Durham

Keyword(s):

Map Kinase ◽

Therapeutic Strategy ◽

Adenoviral Vectors ◽

Calcium Signal ◽

Trigeminal Ganglia ◽

Cerebral Vasculature ◽

Trigeminal Neuron ◽

Calcitonin Gene ◽

Gene Enhancer ◽

A Cell

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent regulator of cerebral vascular tone and contributes to neurogenic inflammation. Clinical studies have shown that CGRP levels are elevated during the painful phase of migraine headache, then restored to baseline by antimigraine 5-HT1 drugs. Conversely, CGRP is depleted in perivascular nerve terminals from patients who have suffered vasospasm following subarachnoid hemorrhage. We have investigated the mechanisms controlling CGRP expression in the trigeminal ganglia neurons, which provide virtually all of the CGRP innervation to the cerebral vasculature. We found that nerve depolarization, inflammatory compounds, and nitric oxide can increase CGRP synthesis and secretion. Using both adenoviral vectors and transfection approaches, we have shown that the increased synthesis is due to activation of a cell-specific MAP kinase-responsive enhancer upstream of the CGRP gene. Interestingly, the 5-HT1 migraine drugs are able to block this up-regulation by a mechanism that involves a very prolonged elevation of calcium. We have shown that the duration of the calcium signal is a key determinant for whether a MAP kinase responsive gene will be stimulated or repressed by calcium-activated pathways. This observation supports the importance of a finely tuned balance of calcium in the trigeminal neuron, which is intriguing in light of genetic evidence for calcium channel mutations in a rare form of inherited migraine. These studies suggest that modulation of MAP kinase control of the cell-specific CGRP gene enhancer may be a useful therapeutic strategy for neurovascular disorders.

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Targeting Mitochondria as Therapeutic Strategy for Metabolic Disorders

The Scientific World JOURNAL ◽

10.1155/2014/604685 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 25

Author(s):

Daniela Sorriento ◽

Antonietta Valeria Pascale ◽

Rosa Finelli ◽

Anna Lisa Carillo ◽

Roberto Annunziata ◽

...

Keyword(s):

Metabolic Syndrome ◽

Mitochondrial Dysfunction ◽

Small Molecules ◽

Metabolic Disorders ◽

Therapeutic Strategy ◽

Cell Metabolism ◽

Therapeutic Interventions ◽

Mtdna Mutations ◽

Pathological Conditions ◽

Mitochondria Targeting

Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.

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Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms

Cephalalgia ◽

10.1177/0333102416678000 ◽

2016 ◽

Vol 37 (13) ◽

pp. 1272-1284 ◽

Cited By ~ 23

Author(s):

Rosaria Greco ◽

Chiara Demartini ◽

Anna Maria Zanaboni ◽

Elisa Redavide ◽

Selena Pampalone ◽

...

Keyword(s):

Kynurenic Acid ◽

Formalin Injection ◽

Major Mechanism ◽

Trigeminal Nociception ◽

Acid Analogue ◽

Calcitonin Gene ◽

Pain Models ◽

Increased Sensitivity ◽

Kynurenic Acid Analogue ◽

Oxide Synthase

Background Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.

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Immunohistochemical characterisation of neurons in the mandibular ganglion and nerve fibres supplying the porcine mandibular gland

Veterinární Medicína ◽

10.17221/221/2015-vetmed ◽

2017 ◽

Vol 61 (No. 7) ◽

pp. 361-373 ◽

Cited By ~ 1

Author(s):

M. Klimczuk ◽

P. Podlasz ◽

W. Sienkiewicz ◽

A. Franke-Radowiecka ◽

A. Dudek ◽

...

Keyword(s):

Mandibular Gland ◽

Double Labelling ◽

Nerve Terminals ◽

Rt Pcr ◽

Nerve Fibres ◽

Chemical Coding ◽

Pcr Product ◽

Calcitonin Gene ◽

Oxide Synthase ◽

Cryostat Sections

The present study was designed to investigate the chemical coding of neurons in the mandibular ganglion (MGn) and nerve fibres supplying the porcine mandibular gland (MGl) with the use of immunofluorescence and RT-PCR. The cryostat sections from MGn and MGl were processed for double-labelling immunohistochemistry using antisera against vesicular acetylcholine transporter (VAChT), choline acetyltransferase (ChAT), dopamine β-hydroxylase (DβH), neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), galanin (GAL), substance P (SP) and calcitonin gene-related peptide (CGRP). The MGl was found to be richly supplied by VAChT-positive nerve fibres that surrounded intra- and interlobular salivary ducts. A large number of VAChT-immunoreactive (VAChT-IR) nerve terminals were also observed around acini. Many periductal and periacinar nerve fibres stained positive for DβH. Immunoreactivity to GAL, NPY or VIP was observed in an intermediate number of nerve terminals which were associated with both salivary ducts and acini. Double-immunostaining revealed that in MGn nearly all neurons stained positive for VAChT/ChAT (98.45 ± 0.59%, mean ± SEM) and nNOS (99.71 ± 0.18%). An intermediate number of the nerve cell bodies displayed immunoreactivity to NPY or VIP (18.67 ± 0.52% and 8.11 ± 0.36%, respectively). Single GAL-IR and CGRP-positive neurons were also observed. RT-PCR revealed the presence of transcripts of ChAT, VAChT, nNOS, NPY, VIP and GAL. For SP and DβH very weak signals were observed. RT-PCR with primers targeting CGRP did not generate any PCR product.

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Phytoestrogenic Effects of Blackcurrant Anthocyanins Increased Endothelial Nitric Oxide Synthase (eNOS) Expression in Human Endothelial Cells and Ovariectomized Rats

Molecules ◽

10.3390/molecules24071259 ◽

2019 ◽

Vol 24 (7) ◽

pp. 1259 ◽

Cited By ~ 5

Author(s):

Kayo Horie ◽

Naoki Nanashima ◽

Hayato Maeda

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Endothelial Nitric Oxide Synthase ◽

Mrna Levels ◽

Human Endothelial Cells ◽

Enos Expression ◽

Ovx Rats ◽

Enos Mrna ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Phytoestrogens are plant-derived chemicals that are found in many foods and have estrogenic activity. We previously showed that blackcurrant extract (BCE) and anthocyanins have phytoestrogenic activity mediated via estrogen receptors (ERs), and anthocyanins may improve vascular function. BCE contains high levels of anthocyanins, but their health-promoting effects are unclear. This study examined the effects of BCE on the regulation of endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis in human endothelial cells as key regulators in cardiovascular disease. The results showed that eNOS mRNA levels were significantly upregulated in BCE- or anthocyanin-treated human vascular endothelial cells but decreased in cells treated with fulvestrant, an ER antagonist. These results corresponded with NO levels, suggesting that BCE and anthocyanin may regulate NO synthesis via eNOS expression. Thus, the phytoestrogenic effects exerted by BCE via ERs influenced eNOS mRNA expression and NO synthesis. In vivo, we investigated whether anthocyanin-rich BCE upregulated eNOS protein expression in ovariectomized (OVX) rats, a widely used animal model of menopause. Our results showed that anthocyanin-rich BCE significantly upregulated eNOS mRNA levels and NO synthesis through phytoestrogenic activity and therefore promoted blood vessel health in OVX rats as a postmenopausal model.

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Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21165645 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5645

Author(s):

Joseph Wai-Hin Leung ◽

Kwok-Kuen Cheung ◽

Shirley Pui-Ching Ngai ◽

Hector Wing-Hong Tsang ◽

Benson Wui-Man Lau

Keyword(s):

Therapeutic Strategy ◽

Molecular Mechanisms ◽

Neural Progenitor Cells ◽

Neurological Diseases ◽

Protective Effects ◽

Neurological Outcomes ◽

Pathological Conditions ◽

Neurological Illnesses ◽

Neurological Conditions ◽

Traditional Understanding

Neurogenesis is the process by which functional new neurons are generated from the neural stem cells (NSCs) or neural progenitor cells (NPCs). Increasing lines of evidence show that neurogenesis impairment is involved in different neurological illnesses, including mood disorders, neurogenerative diseases, and central nervous system (CNS) injuries. Since reversing neurogenesis impairment was found to improve neurological outcomes in the pathological conditions, it is speculated that modulating neurogenesis is a potential therapeutic strategy for neurological diseases. Among different modulators of neurogenesis, melatonin is a particularly interesting one. In traditional understanding, melatonin controls the circadian rhythm and sleep–wake cycle, although it is not directly involved in the proliferation and survival of neurons. In the last decade, it was reported that melatonin plays an important role in the regulation of neurogenesis, and thus it may be a potential treatment for neurogenesis-related disorders. The present review aims to summarize and discuss the recent findings regarding the protective effects of melatonin on the neurogenesis impairment in different neurological conditions. We also address the molecular mechanisms involved in the actions of melatonin in neurogenesis modulation.

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Age and Sex-Dependent Differences in the Neurochemical Characterization of Calcitonin Gene-Related Peptide-Like Immunoreactive (CGRP-LI) Nervous Structures in the Porcine Descending Colon

International Journal of Molecular Sciences ◽

10.3390/ijms20051024 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1024 ◽

Cited By ~ 5

Author(s):

Krystyna Makowska ◽

Slawomir Gonkowski

Keyword(s):

Calcitonin Gene Related Peptide ◽

Colonic Wall ◽

Related Peptide ◽

Calcitonin Gene ◽

Adaptive Processes ◽

Descending Colon ◽

And Gender ◽

Oxide Synthase

Neurons of the enteric nervous system (ENS) may undergo changes during maturation and aging, but knowledge of physiological stimuli-dependent changes in the ENS is still fragmentary. On the other hand, the frequency of many ENS-related intestinal illnesses depends on age and/or sex. The double immunofluorescence technique was used to study the influence of both of these factors on calcitonin gene-related peptide (CGRP)—positive enteric nervous structures—in the descending colon in young and adult female and castrated male pigs. The influence of age and gender on the number and neurochemical characterization (i.e., co-localization of CGRP with substance P, nitric oxide synthase, galanin, cocaine- and amphetamine-regulated transcript peptide and vesicular acetylcholine transporter) of CGRP-positive nerve structures in the colonic wall has been shown. These observations strongly suggest the participation of CGRP in adaptive processes in the ENS during GI tract maturation. Moreover, although the castration of males may mask some aspects of sex-dependent influences on the ENS, the sex-specific differences in CGRP-positive nervous structures were mainly visible in adult animals. This may suggest that the distribution and exact role of this substance in the ENS depend on the sex hormones.

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The Aqueous Extract of Dacryodes edulis (Burseraceae) Leaves Inhibits Cell Proliferation Induced by Estradiol on the Uterus and Vagina of Ovariectomized Female Wistar Rats

Advances in Pharmacological and Pharmaceutical Sciences ◽

10.1155/2020/8869281 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Marius Trésor Wego Kamgaing ◽

Marie Alfrede Mvondo ◽

Sylviane Laure Poualeu Kamani ◽

Stéphane Minko Essono ◽

Sylvie Lea Wansi Ngnokam

Keyword(s):

Cell Proliferation ◽

Aqueous Extract ◽

Wistar Rats ◽

Estradiol Valerate ◽

Control Groups ◽

Natural Substances ◽

Ovx Rats ◽

Female Wistar Rats ◽

Potential Alternative ◽

Dacryodes Edulis

Proliferation is a cellular process strongly linked to the genesis of cancer. Natural substances with antiproliferative activities are currently potential alternatives in the treatment of cancers. Dacryodes edulis, for instance, is a medicinal plant traditionally used in the treatment of cancer. Scientific studies have reported the antioxidant activity of this plant. In addition, the presence of prostate cancer chemopreventive polyphenols was reported in D. edulis extracts. Therefore, this study was aimed to evaluate the effects of the aqueous extract of D. edulis leaves on cell proliferation induced by estradiol in ovariectomized female Wistar rats. In this regard, ovariectomized (OVX) rats were cotreated with estradiol valerate (E2V) (0.75 mg/kg) and the aqueous extract of D. edulis leaves. Control groups received either the vehicle (sham-operated animals and the OVX control), E2V (0.75 mg/kg) only, or E2V (0.75 mg/kg) and tamoxifen (10 mg/kg). Treatments were administered orally for 3 consecutive days, and animals were sacrificed thereafter. Epithelial heights of the uterus and vagina were assessed. Uterine levels of total cholesterol and estradiol were determined as well. Results showed that the aqueous extract of D. edulis leaves reversed the effects of estradiol as it reduced uterine weight ( p < 0.05 ), uterine ( p < 0.05 ), and vaginal ( p < 0.001 ) epithelium heights. This antiproliferative effect of D. edulis was associated with reduced tissue (uterine) levels of estradiol ( p < 0.001 ). These results suggest that the aqueous extract of D. edulis leaves could be a potential alternative treatment for proliferation-related diseases.

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Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation

Cephalalgia ◽

10.1177/0333102413502735 ◽

2013 ◽

Vol 34 (2) ◽

pp. 136-147 ◽

Cited By ~ 48

Author(s):

Roshni Ramachandran ◽

Deepak Kumar Bhatt ◽

Kenneth Beri Ploug ◽

Anders Hay-Schmidt ◽

Inger Jansen-Olesen ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Femoral Vein ◽

Calcitonin Gene Related Peptide ◽

Human Model ◽

Neuronal Activation ◽

Related Peptide ◽

Calcitonin Gene ◽

Pre Treatment ◽

Oxide Synthase

Background and aim Infusion of glyceryltrinitrate (GTN), a nitric oxide (NO) donor, in awake, freely moving rats closely mimics a universally accepted human model of migraine and responds to sumatriptan treatment. Here we analyse the effect of nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) systems on the GTN-induced neuronal activation in this model. Materials and methods The femoral vein was catheterised in rats and GTN was infused (4 µg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP and Western blot for measuring nNOS protein expression. The effect of olcegepant, L-nitro-arginine methyl ester (L-NAME) and neurokinin (NK)-1 receptor antagonist L-733060 were analysed on Fos activation. Results GTN-treated rats showed a significant increase of nNOS and CGRP in dura mater and CGRP in the trigeminal nucleus caudalis (TNC). Upregulation of Fos was observed in TNC four hours after the infusion. This activation was inhibited by pre-treatment with olcegepant. Pre-treatment with L-NAME and L-733060 also significantly inhibited GTN induced Fos expression. Conclusion The present study indicates that blockers of CGRP, NOS and NK-1 receptors all inhibit GTN induced Fos activation. These findings also predict that pre-treatment with olcegepant may be a better option than post-treatment to study its inhibitory effect in GTN migraine models.

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