scholarly journals Advances in the Preclinical Study of Some Flavonoids as Potential Antidepressant Agents

Scientifica ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
León Jesús German-Ponciano ◽  
Gilberto Uriel Rosas-Sánchez ◽  
Eduardo Rivadeneyra-Domínguez ◽  
Juan Francisco Rodríguez-Landa
Keyword(s):  
Mechanism Of Action ◽  
Depressive Disorders ◽  
Biological Effects ◽  
Preclinical Study ◽  
Monoamine Oxidase A ◽  
Therapeutic Effects ◽  
Negative Effects ◽  
Preclinical Research ◽  
Antidepressant Agents ◽  
Antioxidant Agents

Flavonoids are phenolic compounds found commonly in plants that protect them against the negative effects of environmental insults. These secondary metabolites have been widely studied in preclinical research because of their biological effects, particularly as antioxidant agents. Diverse flavonoids have been studied to explore their potential therapeutic effects in the treatment of disorders of the central nervous system, including anxiety and depression. The present review discusses advances in the study of some flavonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical effects and the apparent mechanism of action of their preclinical antidepressant-like effects. Natural flavonoids produce antidepressant-like effects in validated behavioral models of depression. The mechanism of action of these effects includes the activation of serotonergic, dopaminergic, noradrenergic, andγ-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant effects of some natural flavonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans.

PRECLINICAL STUDY OF THE VETERINARY DRUGS TOXICITY

1970 ◽  
pp. 61-64
Author(s):  
E. K. Rakhmatullin ◽  
O. D. Sklyarov
Keyword(s):  
Lethal Dose ◽  
Clinical Manifestations ◽  
Preclinical Study ◽  
Veterinary Drugs ◽  
Toxic Effects ◽  
Laboratory Animals ◽  
Therapeutic Effects ◽  
Significant Information ◽  
Important Indicator ◽  
Organ Systems

Preclinical study of the drugs toxicity was analysed it allows predicting the safety of veterinary drugs in laboratory animals. The fundamental normative instruments in the field of preclinical study of drugs for veterinary medicine and animal husbandry are Order of the Ministry of Agriculture of the Russian Federation dated 06.03.2018 N 101 and GOST 33044-2014 Principles of Good Laboratory Practice. An important indicator of the preclinical study of the veterinary drugs is the determination (calculation) of median lethal dose value (lethal dose for half of the animals tested) or concentration (LD50 or LC50). Existing methods for determining this indicator make it possible at the initial study stage to determine the degree and class the drug of toxicity. Studying the symptoms of intoxication in the analysis of pharmacological substances one obtains significant information about the nature of the action of the future drug. The clinical manifestations of intoxication with damage to various organ systems are presented. As criteria for assessing the toxic effects of veterinary drugs it is recommended to determine LD50, cumulation coefficient, latitude index of therapeutic effects, dose level of toxic effects in the experiment which allows predicting the nature and degree of toxic effects of the drug even at the stage of preclinical veterinary drugs study.

Therapeutic Perspectives of Food Bioactive Peptides: A Mini Review

2019 ◽  
Vol 26 (9) ◽  
pp. 664-675
Author(s):  
Sulochana Priya
Keyword(s):  
Bioactive Peptides ◽  
Marine Organism ◽  
Biological Effects ◽  
Amide Bond ◽  
Therapeutic Effects ◽  
Specific Sequence ◽  
The Past ◽  
Cancer Immunity ◽  
Microbial Infections ◽  
Diverse Origin

Bioactive peptides are short chain of amino acids (usually 2-20) that are linked by amide bond in a specific sequence which have some biological effects in animals or humans. These can be of diverse origin like plant, animal, fish, microbe, marine organism or even synthetic. They are successfully used in the management of many diseases. In recent years increased attention has been raised for its effects and mechanism of action in various disease conditions like cancer, immunity, cardiovascular disease, hypertension, inflammation, diabetes, microbial infections etc. Bioactive peptides are more bioavailable and less allergenic when compared to total proteins. Food derived bioactive peptides have health benefits and its demand has increased tremendously over the past decade. This review gives a view on last two years research on potential bioactive peptides derived from food which have significant therapeutic effects.

Cucurbitacins as Anticancer Agents: A Patent Review

2019 ◽  
Vol 14 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Hidayat Hussain ◽  
Ivan R. Green ◽  
Muhammad Saleem ◽  
Khanzadi F. Khattak ◽  
Muhammad Irshad ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Wide Spectrum ◽  
Biological Effects ◽  
Therapeutic Effects ◽  
Cytotoxic Effects ◽  
Natural Sources ◽  
Oh Groups ◽  
Drug Candidates ◽  
The Past ◽  
Wide Range

Background: Cucurbitacins belong to a group of tetracyclic triterpenoids that display a wide range of biological effects. In the past, numerous cucurbitacins have been isolated from natural sources and many active compounds have been synthesized using the privileged scaffold in order to enhance its cytotoxic effects. Objective: his review covers patents on the therapeutic effects of natural cucurbitacins and their synthetic analogs published during the past decade. By far, the majority of patents published are related to cancer and Structure-Activity Relationships (SAR) of these compounds are included to lend gravitas to this important class of natural products. Methods: The date about the published patents was downloaded via online open access patent databases. Results: Cucurbitacins display significant cytotoxic properties, in particular cucurbitacins B and D which possess very potent effects towards a number of cancer cells. Numerous cucurbitacins isolated from natural sources have been derivatized through chemical modification at the C(2)-OH and C(25)- OH groups. Most importantly, an acyl ester of the C(25)-OH and, iso-propyl, n-propyl and ethyl ether groups of the C(2)-OH demonstrated the most increased cytotoxic activity. Conclusion: The significant cytotoxic effects of natural and semi-synthetic cucurbitacins make them attractive as new drug candidates. Moreover, cucurbitacins have the capability to form conjugates with other anticancer drugs which will synergistically enhance their anticancer effects. The authors believe that in order to get lead compounds, there should be a greater focus on the synthesis of homodimers, heterodimers, and halo derivatives of cucurbitacins. In the opinion of the authors the analysis of the published patents on the cucurbitacins indicates that these compounds can be developed into a regimen to treat a wide spectrum of cancers.

The Genetics of Impulsivity

2012 ◽  
Author(s):  
David A. Nielsen ◽  
Dmitri Proudnikov ◽  
Mary Jeanne Kreek
Keyword(s):  
Drug Addiction ◽  
Hpa Axis ◽  
Gaba Receptor ◽  
Depressive Disorders ◽  
Tryptophan Hydroxylase ◽  
Monoamine Oxidase A ◽  
Receptor Type ◽  
Melanocortin Receptor ◽  
Receptor Subunit ◽  
Impulsive Behavior

Impulsivity is a complex trait that varies across healthy individuals, although when excessive, it is generally regarded as dysfunctional. Impulsive behavior may lead to initiation of drug addiction that interferes with inhibitory controls, which may in turn result in facilitation of the individual’s impulsive acts. Although environmental factors play a considerable role in impulsive behavior, a body of evidence collected in twin studies suggests that about 45% of the variance in impulsivity is accounted for by genetic factors. Genetic variants studied in association with impulsivity include those fortryptophan hydroxylase 1 and 2 (TPH1 and TPH2), the serotonintransporter (SERT), serotonin receptors, and genes of the monoamine metabolism pathway (e.g., monoamine oxidase A, MAOA). Other systems may also play a role in these behaviors, such as the dopaminergic system (the dopamine receptors DRD2, DRD3, and DRD4, and the dopamine transporter, DAT), the catecholaminergic system (catechol-O-methyltransferase, COMT), and the GABAergic system (GABAreceptor subunit alpha-1, GABRA1; GABA receptor subunit alpha-6, GABRA6; and GABA receptor subunit beta-1, GABRB1). Taking into account involvement of the hypothalamic-pituitary-adrenal (HPA) axis, the number of candidate genes implicated in impulsivity may be increased significantly and, therefore, may go far beyond those of serotonergic and dopaminergic systems. For a number of years, our group has conducted studies of the association of genes involved in the modulation of the stress-responsive HPA axis and several neurotransmitter systems, all involved in the pathophysiology of anxiety and depressive disorders, impulse control and compulsive disorders, with drug addiction. These genes include those of the opioid system: the mu- and kappa-opioid receptors (OPRM1 and OPRK1) and the nociceptin/orphaninFQ receptor (OPRL1); the serotonergic system: TPH1 and TPH2 and the serotonin receptor 1B (5THR1B); the catecholamine system: COMT; the HPA axis: themelanocortin receptor type 2 (MC2R or adrenocorticotropic hormone, ACTHR); and the cannabinoid system: the cannabinoid receptor type 1 (CNR1). In this chapter we will focus on these findings.

scholarly journals Epigallocatechin-3-Gallate Protects Pro-Acinar Epithelia Against Salivary Gland Radiation Injury

2021 ◽  
Vol 22 (6) ◽  
pp. 3162
Author(s):  
Erni Sulistiyani ◽  
James M. Brimson ◽  
Ajjima Chansaenroj ◽  
Ladawan Sariya ◽  
Ganokon Urkasemsin ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Ex Vivo ◽  
Biological Effects ◽  
Branching Morphogenesis ◽  
Epithelial Proliferation ◽  
Expression Arrays ◽  
Gene Expression Arrays ◽  
Antioxidant Agents ◽  
Bright Field Microscopy ◽  
Injury Models

Antioxidant agents are promising pharmaceuticals to prevent salivary gland (SG) epithelial injury from radiotherapy and their associated irreversible dry mouth symptoms. Epigallocatechin-3-gallate (EGCG) is a well-known antioxidant that can exert growth or inhibitory biological effects in normal or pathological tissues leading to disease prevention. The effects of EGCG in the various SG epithelial compartments are poorly understood during homeostasis and upon radiation (IR) injury. This study aims to: (1) determine whether EGCG can support epithelial proliferation during homeostasis; and (2) investigate what epithelial cells are protected by EGCG from IR injury. Ex vivo mouse SG were treated with EGCG from 7.5–30 µg/mL for up to 72 h. Next, SG epithelial branching morphogenesis was evaluated by bright-field microscopy, immunofluorescence, and gene expression arrays. To establish IR injury models, linear accelerator (LINAC) technologies were utilized, and radiation doses optimized. EGCG epithelial effects in these injury models were assessed using light, confocal and electron microscopy, the Griess assay, immunohistochemistry, and gene arrays. SG pretreated with EGCG 7.5 µg/mL promoted epithelial proliferation and the development of pro-acinar buds and ducts in regular homeostasis. Furthermore, EGCG increased the populations of epithelial progenitors in buds and ducts and pro-acinar cells, most probably due to its observed antioxidant activity after IR injury, which prevented epithelial apoptosis. Future studies will assess the potential for nanocarriers to increase the oral bioavailability of EGCG.

scholarly journals Preliminary Pharmacogenetic Study to Explore Putative Dopaminergic Mechanisms of Antidepressant Action

2021 ◽  
Vol 11 (8) ◽  
pp. 731
Author(s):  
Taichi Ochi ◽  
Natalya M. Vyalova ◽  
Innokentiy S. Losenkov ◽  
Diana Z. Paderina ◽  
Ivan V. Pozhidaev ◽  
...  
Keyword(s):  
Depressive Disorders ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Sufficient Evidence ◽  
Therapeutic Effects ◽  
Pharmacogenetic Study ◽  
Dopaminergic Mechanisms ◽  
Major Depressive Disorders ◽  
Related Proteins ◽  
Antidepressant Action

Background: There is sufficient evidence that interference of dopaminergic neurotransmission contributes to the therapeutic effects of antidepressants in unipolar and bipolar depression. Methods: Hamilton depression rating scale (HAMD 17) scores of 163 at least moderately ill patients with major depressive disorders were used to establish treatment response. HAMD 17 score status was measured before initiation, after two weeks, and after four weeks of treatment with various antidepressants. The possible association between response and genotype in a total of 14 variants of dopamine neurotransmission-related proteins was investigated. Results: DRD4 rs11246226 CA heterozygous patients were found with a greater improvement of HAMD 17 score when compared to homozygous C patients during 0–2 weeks and 0–4 weeks. Patients with MAOB rs1799836 heterozygous GA and homozygous A also demonstrated improved scores during 2–4 weeks and 0–4 weeks. Conclusions: The results are preliminary due to the limited population size and the small number of variants. Further research into the involvement of habenular dopamine D4 receptors in the antidepressant response is desirable.

scholarly journals Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes

Leukemia ◽  
2021 ◽  
Author(s):  
Nanni Schmitt ◽  
Johann-Christoph Jann ◽  
Eva Altrock ◽  
Johanna Flach ◽  
Justine Danner ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Preclinical Study ◽  
Preclinical Research ◽  
Individual Level ◽  
Specific Effects ◽  
Pdx Model ◽  
Whole Exome ◽  
Thrombopoietin Receptor ◽  
Therapeutic Concepts

AbstractPreclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

scholarly journals Comparative study on the antituberculous effect and mechanism of the traditional Chinese medicines NiuBeiXiaoHe extract and JieHeWan

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Li-Yao Duan ◽  
Yan Liang ◽  
Wen-Ping Gong ◽  
Yong Xue ◽  
Jie Mi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chinese Medicine ◽  
Treatment Group ◽  
Mechanism Of Action ◽  
Cell Damage ◽  
Control Group ◽  
Therapeutic Effects ◽  
Model Group ◽  
Lung Histopathology ◽  
Th17 Cytokines

Abstract Background The traditional Chinese medicine NiuBeiXiaoHe (NBXH) extract and Chinese medicine preparation JieHeWan (JHW) exhibit anti-tuberculosis effects. The anti- tuberculosis effect of NBXH was compared with that of JHW to elucidate the mechanism of action of NBXH. Methods BALB/c mice aged 6-8 weeks were randomly divided into a normal control group, Tuberculosis (TB) model group, JHW treatment group, and NBXH treatment group. After 3 and 13 weeks of treatment, the therapeutic effect in each group was evaluated by comparing lung histopathology, lung and liver colony counts, the number of spots representing effector T cells secreting IFN-γ in an ELISPOT, and the levels of Th1, Th2, and Th17 cytokines, which were measured by a cytometric bead array (CBA). Mouse RNA samples were subjected to transcriptome sequencing. Results After 13 weeks of treatment, the mean histopathological lesion area of the NBXH group was significantly smaller than that of the TB model group (P < 0.05). Compared with those in the TB model group, the lung colony counts in the JHW and NBXH groups were significantly decreased (P < 0.05), and the IL-2 and IL-4 levels in the NBXH group were significantly increased (P < 0.05). NBXH partly restored significant changes in gene expression caused by Mycobacterium tuberculosis (M. tuberculosis) infection. According to GO and KEGG analyses, the changes in biological process (BP), cell composition (CC) and molecular function (MF) terms and in signaling pathways caused by NBXH and JHW treatment were not completely consistent, but they were mainly related to the immune response and inflammatory response in the mouse TB model. Conclusions NBXH had therapeutic effects similar to those of JHW in improving lung histopathology, reducing lung colony counts, and regulating the levels of cytokines. NBXH restored significant changes in gene expression and repaired cell damage caused by M. tuberculosis infection by regulating immune-related pathways, which clarified the mechanism of action of NBXH.

Screening of Synthetic Heterocyclic Compounds as Antiplatelet Drugs

2021 ◽  
Vol 17 ◽  
Author(s):  
Marcel Hrubša ◽  
Khondekar Nurjamal ◽  
Alejandro Carazo ◽  
Nayana Nayek ◽  
Jana Karlíčková ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Biological Effects ◽  
Antiplatelet Drugs ◽  
Antiplatelet Drug ◽  
Breast Adenocarcinoma ◽  
Antiplatelet Activity ◽  
Major Mechanism ◽  
Treatment And Prevention ◽  
Impedance Aggregometry ◽  
Thromboxane Receptors

Background: Antiplatelet drugs represent the keystone in the treatment and prevention of diseases of ischemic origin, including coronary artery disease. The current palette of drugs represents efficient modalities in most cases, but their effect can be limited in certain situations or associated with specific side effects. In this study, representatives of compounds selected from series having scaffolds with known or potential antiplatelet activity were tested. These compounds were previously synthetized by us, but their biological effects have not yet been reported. Objective: The aim of this study was to examine the antiplatelet and anticoagulation properties of selected compounds and determine their mechanism of action. Methods: Antiplatelet activity of compounds and their mechanisms of action were evaluated using human blood by impedance aggregometry and various aggregation inducers and inhibitors and compared to appropriate standards. Cytotoxicity was tested using breast adenocarcinoma cell cultures and potential anticoagulation activity was also determined. Results: In total, four of 34 compounds tested were equally or more active than the standard antiplatelet drug acetylsalicylic acid (ASA). In contrast to ASA, all 4 active compounds decreased platelet aggregation triggered not only by collagen, but also partly by ADP. The major mechanism of action is based on antagonism at thromboxane receptors. In higher concentrations, inhibition of thromboxane synthase was also noted. In contrast to ASA, the tested compounds did not block cyclooxygenase-1. Conclusion: The most active compound, 2-amino-4-(1H-indol-3-yl)-6-nitro-4H-chromene-3-carbonitrile (2-N), which is 4-5x times more potent than ASA, is a promising compound for the development of novel antiplatelet drugs.

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