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Life
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Biological Activities of Natural Products, Antipsychotics, and Their Derivatives
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Biological Activities of Natural Products, Antipsychotics, and Their Derivatives

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Pharmaceutical Science".

Deadline for manuscript submissions: closed (22 September 2021) | Viewed by 19834

Special Issue Editors

Dr. Michał Otręba

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Guest Editor
Department of Drug Technology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, St Jedności 8, 41-200 Sosnowiec, Poland
Interests: anticancer activity; cellular assays; bee products; antioxidant activity; phenothiazine derivatives
Special Issues, Collections and Topics in MDPI journals
Dr. Leon Kosmider

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Co-Guest Editor
Department of General and Inorganic Chemistry, Faculty of Pharmaceutical Sciences, Medical University of Silesia, 41-200 Sosnowiec, Poland
Interests: electronic cigarettes; addiction; public health; toxycology
Special Issues, Collections and Topics in MDPI journals
Dr. Anna Kleczka

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Co-Guest Editor
Department of Pathology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland
Interests: natural bioactive compounds; polyphenols; chemoprevention; cell cycle; ovarian cancer biology; apoptosis; cytopathology; SARS-CoV-2 research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

According to the World Health Organization (WHO) report from 2018, cancer is the second leading cause of death around the world. Global statistics have shown that the total annual economic cost related to cancer rose to US 1.16 trillion in 2010.

The next major problem is viral infections: to date, antiviral drugs are used only for treating less than 10 viral infections. Unfortunately, there are still no drugs that are effective enough against some pathogenic viruses, for example, Zika (ZIKV), Ebola (EBOV), or severe acute respiratory syndrome (SARS). The WHO confirmed that 339,000, 2,058,227, and 13,600–20,400 deaths occur globally last year due to hepatitis C virus, COVID-19, and Japanese encephalitis virus, respectively.

On 29 April 2019, the WHO published a report demanding immediate, coordinated, and ambitious action to avert a potentially disastrous drug-resistance crisis. They estimated that about 10 million deaths will occur each year by 2050 due to drug-resistant diseases, while by 2030, antimicrobial resistance could force up to 24 million people into extreme poverty. The WHO and Eurostat statistics for 2016, as well as the European Heart Network data for 2017, report the global increase in deaths caused by cardiovascular diseases (coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, and pulmonary embolism). Notably, in some cases, the global death percentage is higher than the number of deaths caused by malignant neoplasm cancer (26.0%).

Thus, new and more effective methods of treating cancer; viral, fungal, and bacterial infections; as well as cardiovascular and many other diseases are needed. Drug repurposing/repositioning is an alternative approach to developing new agents. The main idea is to use existing drugs for new therapeutic purposes. Another option is using natural products.

Phenothiazine derivatives (chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine) possess novel antitumor activity, which has been confirmed by several research groups, toward different types of cancer not only in vitro but also in vivo. They have also shown antiviral and antibacterial activities. Polyphenols present in natural products, such as propolis, honey, pollen, bee bread, and wax used in apitherapy, possess anti-inflammatory, neuroprotective, cardioprotective, and chemopreventive activities.

This Special Issue is focused on discussing the future roles of antipsychotic drugs including phenothiazines and their derivatives in cancer, viral, bacterial, and or fungal treatment. We want to discuss the biological activity of natural products, e.g., bee products and others in the treatment of cancer; bacteria, fungal, and viral infections and diseases; and cardiovascular diseases, amongst many other. In this field, in vitro and in vivo studies are needed to determine the precise molecular mechanisms and concentrations required to produce those effects. Research on antipsychotics, phenothiazines (chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine) and their new derivatives as well as natural products, including research on mixtures with other drugs or compounds, are welcome.  The comparison of in vitro results with normal human cell lines and/or in vivo studies are also within the scope of this issue; review papers are welcome. The goal of this Special Issue is to shed light on the molecular mechanisms of the biological activities of antipsychotics, phenothiazines and their derivatives, and natural products, and possible strategies to interfere with these processes.

Dr. Michał Otręba
Dr. Leon Kosmider
Dr. Anna Kleczka
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Human cancer cell lines (brain, breast, colon, lymphoma, lung, skin, liver, pancreas, and others) ;
  • Normal human and animal cell lines, especially in comparison with cancer cell lines;
  • Viability;
  • Antioxidant system;
  • Anticancer, antifungal, antibacterial, antiviral, and other activities;
  • Cardiovascular and other diseases treatment;
  • Antipsychotics and derivatives;
  • Phenothiazines and their new derivatives (chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, and others);
  • Natural products;
  • Cell death (apoptosis, necrosis, autophagy, etc.);
  • Cellular migration;
  • Cell cycle;
  • Protein level;
  • Enzymes activity;
  • Proteins expression;
  • Genes expression;
  • Melanogenesis;
  • Minimal inhibitory concentration;
  • Drug-resistance/multidrug resistance (MDR);
  • Antioxidant activity;
  • Protective activity of natural products;
  • In vitro assays;
  • In vivo assays

Related Special Issue

Published Papers (6 papers)

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Research

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18 pages, 13697 KiB  
Article
Isolation, Characterization and Neuroprotective Activity of Folecitin: An In Vivo Study
by Umar Farooq, Taous Khan, Shahid Ali Shah, Md. Sanower Hossain, Yousaf Ali, Rahim Ullah, Naila Raziq, Muhammad Shahid and Raffaele Capasso
Life 2021, 11(8), 825; https://doi.org/10.3390/life11080825 - 12 Aug 2021
Cited by 27 | Viewed by 3490
Abstract
Neurodegenerative diseases (NDs) extend the global health burden. Consumption of alcohol as well as maternal exposure to ethanol can damage several neuronal functions and cause cognition and behavioral abnormalities. Ethanol induces oxidative stress that is linked to the development of NDs. Treatment options [...] Read more.
Neurodegenerative diseases (NDs) extend the global health burden. Consumption of alcohol as well as maternal exposure to ethanol can damage several neuronal functions and cause cognition and behavioral abnormalities. Ethanol induces oxidative stress that is linked to the development of NDs. Treatment options for NDs are yet scarce, and natural product-based treatments could facilitate ND management since plants possess plenty of bioactive metabolites, including flavonoids, which typically demonstrate antioxidant and anti-inflammatory properties. Hypericum oblongifolium is an important traditional medicinal plant used for hepatitis, gastric ulcer, external wounds, and other gastrointestinal disorders. However, it also possesses multiple bioactive compounds and antioxidant properties, but the evaluation of isolated pure compounds for neuroprotective efficacy has not been done yet. Therefore, in the current study, we aim to isolate and characterize the bioactive flavonoid folecitin and evaluate its neuroprotective activity against ethanol-induced oxidative-stress-mediated neurodegeneration in the hippocampus of postnatal day 7 (PND-7) rat pups. A single dose of ethanol (5 g/kg body weight) was intraperitoneally administered after the birth of rat pups on PND-7. This caused oxidative stress accompanied by the activation of phosphorylated-c-Jun N-terminal kinase (p-JNK), nod-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cysteine-aspartic acid protease-1 (caspase-1) proteins to form a complex called the NLRP3-inflammasome, which converts pro-interleukin 1 beta (IL-1B) to activate IL-1B and induce widespread neuroinflammation and neurodegeneration. In contrast, co-administration of folecitin (30 mg/kg body weight) reduced ethanol-induced oxidative stress, inhibited p-JNK, and deactivated the NLRP3-inflammasome complex. Furthermore, folecitin administration reduced neuroinflammatory and neurodegenerative protein markers, including decreased caspase-3, BCL-2-associated X protein (BAX), B cell CLL/lymphoma 2 (BCL-2), and poly (ADP-ribose) polymerase-1 (PARP-1) expression in the immature rat brain. These findings conclude that folecitin is a flavone compound, and it might be a novel, natural and safe agent to curb oxidative stress and its downstream harmful effects, including inflammasome activation, neuroinflammation, and neurodegeneration. Further evaluation in a dose-dependent manner would be worth it in order to find a suitable dose regimen for NDs. Full article
(This article belongs to the Special Issue Biological Activities of Natural Products, Antipsychotics, and Their Derivatives)
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20 pages, 32668 KiB  
Article
Rutin Mediated Apoptotic Cell Death in Caski Cervical Cancer Cells via Notch-1 and Hes-1 Downregulation
by Fahad Khan, Pratibha Pandey, Niraj Kumar Jha, Mohammad Khalid and Shreesh Ojha
Life 2021, 11(8), 761; https://doi.org/10.3390/life11080761 - 28 Jul 2021
Cited by 17 | Viewed by 3164
Abstract
Natural dietary molecules such as flavonoids have been recognized for their immense potential in cancer therapeutics with several health benefits. Hes-1 and Notch-1 overexpression has been associated with the progression of cervical cancer. However, the apoptosis-inducing potential of one [...] Read more.
Natural dietary molecules such as flavonoids have been recognized for their immense potential in cancer therapeutics with several health benefits. Hes-1 and Notch-1 overexpression has been associated with the progression of cervical cancer. However, the apoptosis-inducing potential of one such potent flavanol against these two key components of the Notch signaling pathway in cervical cancer has not been elucidated to date. Therefore, in this study, we performed several in vitro assays to gain detailed insight about the apoptotic inducing effect of rutin as well as its modulatory effect on Notch-1 and Hes-1 in cervical cancer cells. The results indicated that rutin led to a dose-dependent antiproliferative effects on Caski cervical cancer cells. DAPI and Mitotracker red staining revealed that rutin induced significant apoptotic effects via caspase-3/9 activation, ROS generation, and alteration in Bax/Bcl2 mRNA expression. Cell cycle analysis resulted in the arrest of cell cycle progression in G0/G1 that was associated with a reduced expression of CDK4 and Cyclin D1. The gene expression analysis further revealed that rutin treatment decreases Notch-1 and Hes-1 mRNA expression. Altogether, these results showed that rutin showed potent anticancer effects in human cervical cancer Caski cells by triggering apoptosis, G0/G1 phase arrest, and downregulating the level of Notch-1 and Hes-1 of the Notch signaling pathway. Full article
(This article belongs to the Special Issue Biological Activities of Natural Products, Antipsychotics, and Their Derivatives)
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14 pages, 3488 KiB  
Article
Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells
by Carina Colturato-Kido, Rayssa M. Lopes, Hyllana C. D. Medeiros, Claudia A. Costa, Laura F. L. Prado-Souza, Letícia S. Ferraz and Tiago Rodrigues
Life 2021, 11(4), 365; https://doi.org/10.3390/life11040365 - 20 Apr 2021
Cited by 9 | Viewed by 2463
Abstract
Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve [...] Read more.
Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL. Full article
(This article belongs to the Special Issue Biological Activities of Natural Products, Antipsychotics, and Their Derivatives)
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10 pages, 1393 KiB  
Communication
A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines
by Michał Otręba, Johanna Johansson Sjölander, Morten Grøtli and Per Sunnerhagen
Life 2021, 11(4), 297; https://doi.org/10.3390/life11040297 - 31 Mar 2021
Cited by 3 | Viewed by 1998
Abstract
Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, [...] Read more.
Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, under oxidative stress. To investigate the generality of these findings, we now study the effect of INR119 in human cells under similar conditions. Cells of the established breast cancer line MCF-7 were exposed to H2O2 or phenothiazines, alone or combined with INR119. In line with the previous results in fission yeast, the phosphorylation of the MAPKs ERK and p38 increased substantially more with the combination treatment than by H2O2 or phenothiazines, whereas INR119 alone did not affect phosphorylation. We also measured the mRNA levels of TP53 and BAX, known to be affected by ERK and p38 activity. Similarly, the combination of INR119 and phenothiazines increased both mRNAs to higher levels than for phenothiazines alone. In conclusion, the mechanism of action of INR119 on its target protein kinase may be conserved between yeast and humans. Full article
(This article belongs to the Special Issue Biological Activities of Natural Products, Antipsychotics, and Their Derivatives)
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Review

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23 pages, 1585 KiB  
Review
Bee Venom, Honey, and Royal Jelly in the Treatment of Bacterial Infections of the Oral Cavity: A Review
by Michał Otręba, Łukasz Marek, Natalia Tyczyńska, Jerzy Stojko and Anna Rzepecka-Stojko
Life 2021, 11(12), 1311; https://doi.org/10.3390/life11121311 - 28 Nov 2021
Cited by 6 | Viewed by 4279
Abstract
Oral diseases affect a very large number of people, and the applied pharmacological methods of treatment and/or prevention have serious side effects. Therefore, it is necessary to search for new, safer methods of treatment. Natural bee products, such as honey, royal jelly, and [...] Read more.
Oral diseases affect a very large number of people, and the applied pharmacological methods of treatment and/or prevention have serious side effects. Therefore, it is necessary to search for new, safer methods of treatment. Natural bee products, such as honey, royal jelly, and bee venom, can be a promising alternative in the treatment of oral cavity bacterial infections. Thus, we performed an extensive literature search to find and summarize all articles about the antibacterial activity of honey, royal jelly, and bee venom. Our analysis showed that these bee products have strong activity against the bacterial strains causing caries, periodontitis, gingivitis, pharyngitis, recurrent aphthous ulcers, supragingival, and subgingival plaque. An analysis of average MIC values showed that honey and royal jelly have the highest antimicrobial activity against Porphyromonas gingivalis and Fusobacterium nucleatum. In turn, bee venom has an antibacterial effect against Streptococcus mutans. Streptococcus sobrinus and Streptoccus pyogenes were the most resistant species to different types of honey, and royal jelly, respectively. Moreover, these products are safer in comparison to the chemical compounds used in the treatment of oral cavity bacterial infections. Since the antimicrobial activity of bee products depends on their chemical composition, more research is needed to standardize the composition of these compounds before they could be used in the treatment of oral cavity bacterial infections. Full article
(This article belongs to the Special Issue Biological Activities of Natural Products, Antipsychotics, and Their Derivatives)
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19 pages, 2803 KiB  
Review
Phenothiazines Modified with the Pyridine Ring as Promising Anticancer Agents
by Beata Morak-Młodawska, Małgorzata Jeleń and Krystian Pluta
Life 2021, 11(3), 206; https://doi.org/10.3390/life11030206 - 05 Mar 2021
Cited by 18 | Viewed by 2843
Abstract
Azaphenothiazines are the largest and most perspective group of modified phenothiazines, and they exhibit variety of biological activities. The review sums up the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, which are modified azaphenothiazines with one and two pyridine [...] Read more.
Azaphenothiazines are the largest and most perspective group of modified phenothiazines, and they exhibit variety of biological activities. The review sums up the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, which are modified azaphenothiazines with one and two pyridine rings, respectively, against 10 types of cancer cell lines. Some 10-substituted dipyridothiazines and even 10-unsubstituted parent compounds, such as 10H-1,9-diazaphenothiazine and 10H-3,6-diazaphenothiazine, exhibited very potent action with the IC50 values less than 1 µg/mL and 1 µM against selected cancer cell lines. The strength of the anticancer action depends both on the tricyclic ring scaffolds and the substituents at the thiazine nitrogen atom. The review discusses the kind of the substituents, nature of tricyclic ring scaffolds with the location of the azine nitrogen atoms, the types of the cancer cell lines, and the mechanism of action. Full article
(This article belongs to the Special Issue Biological Activities of Natural Products, Antipsychotics, and Their Derivatives)
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