Pharmacology and Toxicology Metabolism of Synthetic and Natural Compounds

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (10 July 2023) | Viewed by 13492

Special Issue Editors


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Guest Editor
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Interests: experimental therapeutics in drugs dependence research; metabolomic profile of drug dependence models; role of neurotransmitters and neurometabolites in neurological diseases; metabolomic pathway involved in drug dependence research

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Guest Editor
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Interests: extraction, fractionation, isolation, and purification of bioactive secondary metabolites with particular emphasis on anticancer agents and herb-drug interaction assessment; de novo structure elucidation and characterization of natural product compounds; biosynthetic pathways of chemical classes derived from natural products; synthesis of natural product derivatives based on molecular docking studies; developing validated analytical methods using the isolated markers and hyphenated UPLC-PDA-MS technique for chemical finger-printing and standardization of nutraceuticals and herbal supplements

Special Issue Information

Dear Colleagues,

Metabolic alterations have been observed in several diseases/disorders. These alterations are linked to the toxicological and pharmacological effects of synthetic and natural products. It is important to establish metabolomics profiling of drugs-induced diseases and/or toxicity. This will provide beneficial information about the effects of synthetic and natural compounds on amino acids, sugars, fatty acids and other metabolites as well as metabolic signaling in different systems in the body. Moreover, drugs-induced disease models such as substances use disorders models have altered metabolomic profiles. This alteration in metabolites might be resulted from pharmacological or toxicological effects of these substances of abuse. In addition, conducting metabolic studies on natural products is critical to report the potential toxicity effects of the plant metabolites. Moreover, secondary metabolites of toxic natural products can be extracted, fractionated, isolated and purified using appropriate techniques. These secondary metabolites might have unknown toxicological and pharmacological effects. It is also important to study the molecular docking of the metabolites with the proteins using available software.    

The aim of this special issue is to highlight the potential metabolic pathways and metabolites that can be modulated by synthetic and natural compounds. We are pleased to invite you to submit your original research, literature and systematic reviews, meta-analysis, and case reports to be published in this special issue.

Dr. Fawaz Alasmari
Dr. Omer Ibrahim Fantoukh
Guest Editors

Manuscript Submission Information

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Keywords

  • metabolites
  • metabolism of drugs
  • metabolomic profile of drugs-induced diseases and/or toxicity
  • metabolomics profile of natural and synthetic products
  • metabolites analysis
  • isolation, and purification of bioactive secondary metabolites
  • metabolomic pathway involved in pharmacological research

Published Papers (8 papers)

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Research

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20 pages, 4456 KiB  
Article
Liver Metabolomics and Inflammatory Profiles in Mouse Model of Fentanyl Overdose Treated with Beta-Lactams
by Fawaz Alasmari, Mohammed S. Alasmari, Mohammed A. Assiri, Mohammed Alswayyed, Syed Rizwan Ahamad, Abdulrahman I. Alhumaydhi, Bandar I. Arif, Sahar R. Aljumayi, Abdullah F. AlAsmari, Nemat Ali, Wayne E. Childers, Magid Abou-Gharbia and Youssef Sari
Metabolites 2023, 13(8), 965; https://doi.org/10.3390/metabo13080965 - 21 Aug 2023
Viewed by 1435
Abstract
Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several [...] Read more.
Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have demonstrated the efficacy of beta-lactams in modulating the expression of glutamate transporter-1 (GLT-1) in different body organs, including the liver. The upregulation of GLT-1 by beta-lactams is associated with the attenuation of hyperglutamatergic state, which is a characteristic feature of opioid use disorders. A novel experimental beta-lactam compound with no antimicrobial properties, MC-100093, has been developed to attenuate dysregulation of glutamate transport, in part by normalizing GLT-1 expression. A previous study showed that MC-100093 modulated hepatic GLT-1 expression with subsequent attenuation of alcohol-increased fat droplet content in the liver. In this study, we investigated the effects of fentanyl overdose on liver metabolites, and determined the effects of MC-100093 and ceftriaxone in the liver of a fentanyl overdose mouse model. Liver samples from control, fentanyl overdose, and fentanyl overdose ceftriaxone- or MC-100093-treated mice were analyzed for metabolomics using gas chromatography–mass spectrometry. Heatmap analysis revealed that both MC-100093 and ceftriaxone attenuated the effects of fentanyl overdose on several metabolites, and MC-100093 showed superior effects. Statistical analysis showed that MC-100093 reversed the effects of fentanyl overdose in some metabolites. Moreover, enrichment analysis revealed that the altered metabolites were strongly linked to the glucose-alanine cycle, the Warburg effect, gluconeogenesis, glutamate metabolism, lactose degradation, and ketone body metabolism. The changes in liver metabolites induced by fentanyl overdose were associated with liver inflammation, an effect attenuated with ceftriaxone pre-treatments. Ceftriaxone normalized fentanyl-overdose-induced changes in liver interleukin-6 and cytochrome CYP3A11 (mouse homolog of human CYP3A4) expression. Our data indicate that fentanyl overdose impaired liver metabolites, and MC-100093 restored certain metabolites. Full article
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17 pages, 5269 KiB  
Article
Anti-Pyretic, Analgesic, and Anti-Inflammatory Activities of Meloxicam and Curcumin Co-Encapsulated PLGA Nanoparticles in Acute Experimental Models
by Bilal Aslam, Asif Hussain, Muhammad Usman Bari, Muhammad Naeem Faisal, Zia ud Din Sindhu, Rasha Alonaizan, Rasha K. Al-Akeel, Shabana Naz and Rifat Ullah Khan
Metabolites 2023, 13(8), 935; https://doi.org/10.3390/metabo13080935 - 10 Aug 2023
Cited by 4 | Viewed by 1099
Abstract
Herein, we evaluated the in vivo effects of meloxicam and curcumin co-encapsulated PLGA nanoparticles in experimental acute models of pyrexia, nociception, and inflammation. Seven groups (n = 6) were designed for each investigation and pretreated intraperitoneally (i.p.): the control group, meloxicam (4 [...] Read more.
Herein, we evaluated the in vivo effects of meloxicam and curcumin co-encapsulated PLGA nanoparticles in experimental acute models of pyrexia, nociception, and inflammation. Seven groups (n = 6) were designed for each investigation and pretreated intraperitoneally (i.p.): the control group, meloxicam (4 mg/kg b.w.), curcumin (15 mg/kg b.w.), and equivalent content containing PLGA capped nanoparticles of meloxicam (Mlx-NP) and curcumin (Cur-NP) alone and in combination (Mlx-Cur-NP; at two doses). The results showed that PLGA encapsulation significantly (p ≤ 0.05) improved the in vivo activities of each compound. Furthermore, co-encapsulation of meloxicam and curcumin potentiated the anti-pyretic effect on yeast-induced pyretic rats, anti-nociceptive effect on nociception induced in rats by formalin and heat, and anti-edematogenic activity in xylene-induced ear edema in rats in a dose-dependent manner. In carrageenan-induced paw inflammation in rats, meloxicam and curcumin co-loading (Mlx-Cur-NP) resulted in significant (p ≤ 0.05) inhibition of paw inflammation, reduction in TNF-α and PGE2 levels, downregulation of expressions of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), as well as a decrease in histopathological changes and TNF-α immunoexpression in paw tissues. Moreover, Mlx-Cur-NP demonstrated noteworthy potentiation in pharmacological effects compared to free compounds and mono-compound-loaded nanoparticles. Thus, the association of meloxicam with curcumin in a biodegradable nanocarrier system could provide a promising anti-pyretic, anti-nociceptive, and anti-inflammatory therapeutic approach for acute conditions. Full article
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19 pages, 2616 KiB  
Article
Pseudobombax parvifolium Hydroalcoholic Bark Extract: Chemical Characterisation and Cytotoxic, Mutagenic, and Preclinical Aspects Associated with a Protective Effect on Oxidative Stress
by Tiago Felipe de Senes-Lopes, Jefferson Romáryo Duarte da Luz, Zaira da Rosa Guterres, Eder A. Barbosa, Débora Batista, Ony Araújo Galdino, Marcela Abbott Galvão Ururahy, Elizabeth Cristina Gomes dos Santos, Jorge A. López, Gabriel Araujo-Silva and Maria das Graças Almeida
Metabolites 2023, 13(6), 748; https://doi.org/10.3390/metabo13060748 - 13 Jun 2023
Cited by 1 | Viewed by 1135
Abstract
Plants have long been used in traditional medicine to treat illnesses. Nevertheless, their chemical diversity requires studies to establish the extract dosage and its safe use. Pseudobombax parvifolium, an endemic species of the Brazilian Caatinga biome, is commonly used in folk medicine, [...] Read more.
Plants have long been used in traditional medicine to treat illnesses. Nevertheless, their chemical diversity requires studies to establish the extract dosage and its safe use. Pseudobombax parvifolium, an endemic species of the Brazilian Caatinga biome, is commonly used in folk medicine, due to its anti-inflammatory properties related to cellular oxidative stress; however, its biological properties have scarcely been studied. In this study, we chemically characterized the P. parvifolium hydroalcoholic bark extract (EBHE) and evaluated its cytotoxic, mutagenic, and preclinical aspects, as well as its antioxidant effect. Our phytochemical analysis revealed a significative total polyphenol content and identified loliolide for the first time in this species. Cytotoxicity, mutagenicity, and acute oral and repeated dose indicated no toxic effects on cell culture, Drosophila melanogaster, and Wistar rat exposure to different EBHE concentrations, respectively. Furthermore, we observed a significant decrease in lipid peroxidation and a mild hypoglycemic and hypolipidemic effect with repeated oral dosing of EBHE. Although there were no significant changes in glutathione content, we did observe a significant increase in superoxide dismutase at a dose of 400 mg/kg and in glutathione peroxidase at doses of 100, 200, and 400 mg/kg. These findings suggest that EBHE has potential as a source of bioactive molecules, and it can be used safely in traditional medicine and in the development of herbal medicines for application in the public health system. Full article
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24 pages, 7275 KiB  
Article
Metabolomics Analysis as a Tool to Measure Cobalt Neurotoxicity: An In Vitro Validation
by Ibrahim M. Alanazi, Abdullah R. Alzahrani, Torki A. Zughaibi, Ahmed I. Al-Asmari, Shams Tabrez, Catherine Henderson, David Watson and Mary Helen Grant
Metabolites 2023, 13(6), 698; https://doi.org/10.3390/metabo13060698 - 27 May 2023
Viewed by 1351
Abstract
In this study, cobalt neurotoxicity was investigated in human astrocytoma and neuroblastoma (SH-SY5Y) cells using proliferation assays coupled with LC–MS-based metabolomics and transcriptomics techniques. Cells were treated with a range of cobalt concentrations between 0 and 200 µM. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay [...] Read more.
In this study, cobalt neurotoxicity was investigated in human astrocytoma and neuroblastoma (SH-SY5Y) cells using proliferation assays coupled with LC–MS-based metabolomics and transcriptomics techniques. Cells were treated with a range of cobalt concentrations between 0 and 200 µM. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed cobalt cytotoxicity and decreased cell metabolism in a dose and time-dependent manner was observed by metabolomics analysis, in both cell lines. Metabolomic analysis also revealed several altered metabolites particularly those related to DNA deamination and methylation pathways. One of the increased metabolites was uracil which can be generated from DNA deamination or fragmentation of RNA. To investigate the origin of uracil, genomic DNA was isolated and analyzed by LC–MS. Interestingly, the source of uracil, which is uridine, increased significantly in the DNA of both cell lines. Additionally, the results of the qRT-PCR showed an increase in the expression of five genes Mlh1, Sirt2, MeCP2, UNG, and TDG in both cell lines. These genes are related to DNA strand breakage, hypoxia, methylation, and base excision repair. Overall, metabolomic analysis helped reveal the changes induced by cobalt in human neuronal-derived cell lines. These findings could unravel the effect of cobalt on the human brain. Full article
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16 pages, 1087 KiB  
Article
Metabolites of Geum aleppicum and Sibbaldianthe bifurca: Diversity and α-Glucosidase Inhibitory Potential
by Nina I. Kashchenko, Daniil N. Olennikov and Nadezhda K. Chirikova
Metabolites 2023, 13(6), 689; https://doi.org/10.3390/metabo13060689 - 25 May 2023
Cited by 5 | Viewed by 1110
Abstract
α-Glucosidase inhibitors are essential in the treatment of diabetes mellitus. Plant-derived drugs are promising sources of new compounds with glucosidase-inhibiting ability. The Geum aleppicum Jacq. and Sibbaldianthe bifurca (L.) Kurtto & T.Erikss. herbs are used in many traditional medical systems to treat diabetes. [...] Read more.
α-Glucosidase inhibitors are essential in the treatment of diabetes mellitus. Plant-derived drugs are promising sources of new compounds with glucosidase-inhibiting ability. The Geum aleppicum Jacq. and Sibbaldianthe bifurca (L.) Kurtto & T.Erikss. herbs are used in many traditional medical systems to treat diabetes. In this study, metabolites of the G. aleppicum and S. bifurca herbs in active growth, flowering, and fruiting stages were investigated using high-performance liquid chromatography with photodiode array and electrospray ionization triple quadrupole mass spectrometric detection (HPLC-PDA-ESI-tQ-MS/MS). In total, 29 compounds in G. aleppicum and 41 components in S. bifurca were identified including carbohydrates, organic acids, benzoic and ellagic acid derivatives, ellagitannins, flavonoids, and triterpenoids. Gemin A, miquelianin, niga-ichigoside F1, and 3,4-dihydroxybenzoic acid 4-O-glucoside were the dominant compounds in the G. aleppicum herb, while guaiaverin, miquelianin, tellimagrandin II2, casuarictin, and glucose were prevailing compounds in the S. bifurca herb. On the basis of HPLC activity-based profiling of the G. aleppicum herb extract, the most pronounced inhibition of α-glucosidase was observed for gemin A and quercetin-3-O-glucuronide. The latter compound and quercetin-3-O-arabinoside demonstrated maximal inhibition of α-glucosidase in the S. bifurca herb extract. The obtained results confirm the prospects of using these plant compounds as possible sources of hypoglycemic nutraceuticals. Full article
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14 pages, 2073 KiB  
Article
Revisiting the Flora of Saudi Arabia: Phytochemical and Biological Investigation of the Endangered Plant Species Euphorbia saudiarabica
by Omer I. Fantoukh, Gadah A. Al-Hamoud, Fahd A. Nasr, Omer M. Almarfadi, Mohammed F. Hawwal, Zulfiqar Ali, Waleed A. Alobaid, Abdulaziz Binawad, Menwer Alrashidi, Fawaz Alasmari, Mohammad Z. Ahmed and Omar M. Noman
Metabolites 2023, 13(4), 556; https://doi.org/10.3390/metabo13040556 - 13 Apr 2023
Cited by 1 | Viewed by 1786
Abstract
Euphorbia plants have a significant place in traditional medicine due to their numerous therapeutic properties, including their anti-tumor effects, which have been observed in several species. In the current study, a phytochemical investigation of Euphorbia saudiarabica methanolic extract led to the isolation and [...] Read more.
Euphorbia plants have a significant place in traditional medicine due to their numerous therapeutic properties, including their anti-tumor effects, which have been observed in several species. In the current study, a phytochemical investigation of Euphorbia saudiarabica methanolic extract led to the isolation and characterization of four secondary metabolites from the chloroform (CHCl3) and ethyl acetate (EtOAc) fractions, which are reported for the first time in this species. One of the constituents, saudiarabicain F (2), is a rare C-19 oxidized ingol-type diterpenoid that has not been previously reported. The structures of these compounds were determined by extensive spectroscopic (HR-ESI-MS, 1D and 2D NMR) analyses. The anticancer properties of the E. saudiarabica crude extract, its fractions and its isolated compounds were examined against several cancer cells. The active fractions were evaluated for their effects on cell-cycle progression and apoptosis induction using flow cytometry. Furthermore, RT-PCR was employed to estimate the gene-expression levels of the apoptosis-related genes. It was demonstrated that the E. saudiarabica CHCl3 and EtOAc fractions suppressed the proliferation of the cancer cells. The MCF-7 cells were the most sensitive to both fractions, with IC50 values of 22.6 and 23.2 µg/mL, respectively. Notably, both fractions caused cell-cycle arrest in the G2/M phase of the treated MCF-7 cells. The inhibition of the MCF-7 cells’ proliferation was also linked with apoptosis induction by flow-cytometry analysis. Additionally, the activation of apoptosis by both fractions was demonstrated by an increase in the ratio of Bax to Bcl-2, with an increase in the expression of caspase-7. Among the isolated compounds, glutinol (1) showed potent activity against the MCF-7 cell line, with an IC50 value of 9.83 µg/mL. Our findings suggest that E. saudiarabica has apoptosis-inducing effects and shows promise as a potential source of new chemotherapeutic drugs. Full article
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13 pages, 2216 KiB  
Article
Effect of Cigarette Smoke Exposure and Aspirin Treatment on Neurotransmitters’ Tissue Content in Rats’ Hippocampus and Amygdala
by Alaa M. Hammad, Ala A. Alhusban, Lujain F. Alzaghari, Fawaz Alasmari and Youssef Sari
Metabolites 2023, 13(4), 515; https://doi.org/10.3390/metabo13040515 - 04 Apr 2023
Cited by 4 | Viewed by 2300
Abstract
Cigarette smoke withdrawal can cause anxiety-like behavior and modulate neurotransmitter-related proteins in the brain. We examined the effects of cigarette smoke with and without aspirin treatment on the concentrations of neurotransmitters, including dopamine, serotonin, glutamate, glutamine, and GABA in the amygdala and hippocampus. [...] Read more.
Cigarette smoke withdrawal can cause anxiety-like behavior and modulate neurotransmitter-related proteins in the brain. We examined the effects of cigarette smoke with and without aspirin treatment on the concentrations of neurotransmitters, including dopamine, serotonin, glutamate, glutamine, and GABA in the amygdala and hippocampus. Sprague-Dawley rats were randomly assigned to four different groups: (1) control group exposed only to standard room air, (2) cigarette smoke exposed group treated with saline vehicle, (3) cigarette smoke exposed group treated with aspirin (30 mg/kg), and (4) control group treated only with aspirin (30 mg/kg). Cigarette smoke exposure was performed for 2 h/day, 5 days/week, for 31 days. Behavioral testing was carried out weekly, 24 h after cigarette smoke exposure, during acute withdrawal. At the end of week 4, rats were given either distilled water (1 mL) or aspirin 45 min before cigarette exposure for 11 days. Dopamine, serotonin, glutamate, glutamine, and GABA were extracted from both the amygdala and hippocampus and were separated and quantified using a developed and validated HPLC-MS/MS method. Cigarette smoke withdrawal induced anxiety behaviors, and aspirin treatment reduced this effect. Cigarette smoke exposure increased tissue content of dopamine, serotonin, glutamate, glutamine, and GABA, and aspirin treatment reversed this effect. Cigarette smoke caused an increase in tissue content of several neurotransmitters as well as anxiety-like behavior, and these effects were normalized by aspirin treatment. Full article
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Review

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17 pages, 1562 KiB  
Review
Pharmacokinetic and Pharmacodynamic Drug–Drug Interactions: Research Methods and Applications
by Lei Sun, Kun Mi, Yixuan Hou, Tianyi Hui, Lan Zhang, Yanfei Tao, Zhenli Liu and Lingli Huang
Metabolites 2023, 13(8), 897; https://doi.org/10.3390/metabo13080897 - 29 Jul 2023
Cited by 5 | Viewed by 2516
Abstract
Because of the high research and development cost of new drugs, the long development process of new drugs, and the high failure rate at later stages, combining past drugs has gradually become a more economical and attractive alternative. However, the ensuing problem of [...] Read more.
Because of the high research and development cost of new drugs, the long development process of new drugs, and the high failure rate at later stages, combining past drugs has gradually become a more economical and attractive alternative. However, the ensuing problem of drug–drug interactions (DDIs) urgently need to be solved, and combination has attracted a lot of attention from pharmaceutical researchers. At present, DDI is often evaluated and investigated from two perspectives: pharmacodynamics and pharmacokinetics. However, in some special cases, DDI cannot be accurately evaluated from a single perspective. Therefore, this review describes and compares the current DDI evaluation methods based on two aspects: pharmacokinetic interaction and pharmacodynamic interaction. The methods summarized in this paper mainly include probe drug cocktail methods, liver microsome and hepatocyte models, static models, physiologically based pharmacokinetic models, machine learning models, in vivo comparative efficacy studies, and in vitro static and dynamic tests. This review aims to serve as a useful guide for interested researchers to promote more scientific accuracy and clinical practical use of DDI studies. Full article
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