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Advances in Cytoprotective Drug Discovery

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 35255

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Dr. Ekaterina Yurchenko

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G.B. Elyakov Pacific Institute of Bioorganic Chemistry Far Eastern Branch of Russian Academy of Sciences, Vladivostok, Russia
Interests: bioactive compounds; secondary metabolites; marine invertebrates; marine fungi; cytoprotection; cytotoxicity; structure–activity relationships
Special Issues, Collections and Topics in MDPI journals

Dr. Dmitry Aminin

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G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, 690022 Vladivostok, Russia
Interests: biochemistry; cell biology; structure and function of biological membranes; mechanism of biological activity of natural and synthetic biologically active substances; new drug discovery; molecular targets; toxicology; ecotoxicology; biomarkers; biosensors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is well known that cytoprotection is a process by which chemical compounds provide protection to cells against noxious impacts. The mechanisms for protecting cells from various adverse factors, including physical ones, have attracted the steady attention of researchers. The cells have their own evolutionary features in the pathways for decreasing influence of toxins and other stress factors, which has resulted in saving cell viability and functionality. The autophagy, activated C protein (ACP), heat shock proteins (HSPs), glutathione S-transferases (GSTs), and different signaling pathways (such as Keap1-Nrf2-ARE, UCP2-SIRT3, JAK/STAT and others) were reported as cellular cytoprotective mechanisms realised during various disorders. Additionally, natural and synthetic compounds capable of inducing or modulating these protective molecular targets are important for cytoprotective drug discovery. Annualy, more that 200 papers about new as well as known substances are published on their protective activity against oxydative changes, protein aggregation, apoptosis, mitochondrial and endoplasmic reticulum dysfunction, etc. Some of these substances, for example, resveratrol, astaxanthin, melatonin, carbenoxolone, atorvastatin, echinochrome, and others, are now used as officially approved cytoprotective drugs.

With this Special Issue, we wish to offer a platform for papers describing isolation and identification of natural products’ various demonstrated types of cytoprotective effects, as well as studying of cytoprotective synthetic compounds. Moreover, manuscripts describing the molecular mechanism of cytoprotective action of promising drug candidates are also welcome.

Dr. Ekaterina Yurchenko
Dr. Dmitry Aminin
Guest Editors

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Keywords

Natural products
Synthetic compounds
Cell protection
Neuroprotection
Cardiovascular protection
Hepatoprotection
Gastric protection
Renal protection
Skin protection
Oxidative stress protection
New drug discovery

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 182 KiB

Open AccessEditorial

Advances in Cytoprotective Drug Discovery

by Ekaterina A. Yurchenko and Dmitry L. Aminin

Molecules 2023, 28(11), 4510; https://doi.org/10.3390/molecules28114510 - 2 Jun 2023

Viewed by 944

Abstract

This Special Issue was announced as a platform for authors studying the isolation and identification of various natural products with cytoprotective effects and those studying cytoprotective synthetic compounds [...] Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

Research

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16 pages, 3779 KiB

Open AccessArticle

Lipidomic Profiling of Ipsilateral Brain and Plasma after Celastrol Post-Treatment in Transient Middle Cerebral Artery Occlusion Mice Model

by Maozhu Liu, Mengyuan Chen, Ying Luo, Hong Wang, Haifeng Huang, Zhe Peng, Miaomiao Li, Huizhi Fei, Wen Luo and Junqing Yang

Molecules 2021, 26(14), 4124; https://doi.org/10.3390/molecules26144124 - 7 Jul 2021

Cited by 11 | Viewed by 2697

Abstract

Celastrol, a pentacyclic triterpene isolated from the traditional Chinese medicine Tripterygium wilfordii Hook. F., exhibits effectiveness in protection against multiple central nervous system (CNS) diseases such as cerebral ischemia, but its influence on lipidomics still remains unclear. Therefore, in the present study, the efficacy and potential mechanism of celastrol against cerebral ischemia/reperfusion (I/R) injury were investigated based on lipidomics. Middle cerebral artery occlusion (MCAO) followed by reperfusion was operated in mice to set up a cerebral I/R model. TTC staining and TUNEL staining were used to evaluate the therapeutic effect of celastrol. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) was employed for lipidomics analysis in ipsilateral hemisphere and plasma. Celastrol remarkably reduced cerebral infarct volume and apoptosis positive cells in tMCAO mice. Furthermore, lipidomics analysis showed that 14 common differentially expressed lipids (DELs) were identified in brain and five common DELs were identified in plasma between the Sham, tMCAO and Celastrol-treated tMCAO groups. Through enrichment analysis, sphingolipid metabolism and glycerophospholipid metabolism were demonstrated to be significantly enriched in all the comparison groups. Among the DELs, celastrol could reverse cerebral I/R injury-induced alteration of phosphatidylcholine, phosphatidylethanolamine and sulfatide, which may be responsible for the neuroprotective effect of celastrol. Our findings suggested the neuroprotection of celastrol on cerebral I/R injury may be partially associated with its regulation of lipid metabolism. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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14 pages, 1808 KiB

Open AccessArticle

Anacardic Acids from Amphipterygium adstringens Confer Cytoprotection against 5-Fluorouracil and Carboplatin Induced Blood Cell Toxicity While Increasing Antitumoral Activity and Survival in an Animal Model of Breast Cancer

by Jairo Galot-Linaldi, Karla M. Hernández-Sánchez, Elizabet Estrada-Muñiz and Libia Vega

Molecules 2021, 26(11), 3241; https://doi.org/10.3390/molecules26113241 - 28 May 2021

Cited by 9 | Viewed by 3621

Abstract

Amphipterygium adstringens (cuachalalate) contains anacardic acids (AAs) such as 6-pentadecyl salicylic acid (6SA) that show immunomodulatory and antitumor activity with minimal or no secondary adverse effects. By contrast, most chemotherapeutic agents, such as 5-fluorouracil (5-FU) and carboplatin (CbPt), induce myelosuppression and leukopenia. Here, we investigated the myeloprotective and antineoplastic potential of an AA extract or the 6SA as monotherapy or in combination with commonly used chemotherapeutic agents (5-FU and CbPt) to determine the cytoprotective action of 6SA on immune cells. Treatment of Balb/c breast tumor-bearing female mice with an AA mixture or 6SA did not induce the myelosuppression or leukopenia observed with 5-FU and CbPt. The co-administration of AA mixture or isolated 6SA with 5-FU or CbPt reduced the apoptosis of circulating blood cells and bone marrow cells. Treatment of 4T1 breast tumor-bearing mice with the AA mixture or 6SA reduced tumor growth and lung metastasis and increased the survival rate compared with monotherapies. An increased effect was observed in tumor reduction with the combination of 6SA and CbPt. In conclusion, AAs have important myeloprotective and antineoplastic effects, and they can improve the efficiency of chemotherapeutics, thereby protecting the organism against the toxic effects of drugs such as 5-FU and CbPt. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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14 pages, 2781 KiB

Open AccessArticle

Cytoprotective Potential of Aged Garlic Extract (AGE) and Its Active Constituent, S-allyl-l-cysteine, in Presence of Carvedilol during Isoproterenol-Induced Myocardial Disturbance and Metabolic Derangements in Rats

by Syed Mohammed Basheeruddin Asdaq, Obulesu Challa, Abdulhakeem S. Alamri, Walaa F. Alsanie, Majid Alhomrani, Abdulrahman Hadi Almutiri and Majed Sadun Alshammari

Molecules 2021, 26(11), 3203; https://doi.org/10.3390/molecules26113203 - 27 May 2021

Cited by 24 | Viewed by 2536

Abstract

This study was conducted to determine the potential interaction of aged garlic extract (AGE) with carvedilol (CAR), as well as to investigate the role of S-allyl-l-cysteine (SAC), an active constituent of AGE, in rats with isoproterenol (ISO)-induced myocardial dysfunction. At the end of three weeks of treatment with AGE (2 and 5 mL/kg) or SAC (13.1 and 32.76 mg/kg), either alone or along with CAR (10 mg/kg) in the respective groups of animals, ISO was administered subcutaneously to induce myocardial damage. Myocardial infarction (MI) diagnostic predictor enzymes, lactate dehydrogenase (LDH) and creatinine kinase (CK-MB), were measured in both serum and heart tissue homogenates (HTH). Superoxide dismutase (SOD), catalase, and thiobarbituric acid reactive species (TBARS) were estimated in HTH. When compared with other groups, the combined therapy of high doses of AGE and SAC given alone or together with CAR caused a significant decrease in serum LDH and CK-MB activities. Further, significant rise in the LDH and CK-MB activities in HTH was noticed in the combined groups of AGE and SAC with CAR. It was also observed that both doses of AGE and SAC significantly increased endogenous antioxidants in HTH. Furthermore, histopathological observations corroborated the biochemical findings. The cytoprotective potential of SAC and AGE were dose-dependent, and SAC was more potent than AGE. The protection offered by aged garlic may be attributed to SAC. Overall, the results indicated that a high dose of AGE and its constituent SAC, when combined with carvedilol, has a synergistic effect in preventing morphological and physiological changes in the myocardium during ISO-induced myocardial damage. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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15 pages, 2906 KiB

Open AccessArticle

Curcumin Attenuated Neurotoxicity in Sporadic Animal Model of Alzheimer’s Disease

by Ines ELBini-Dhouib, Raoudha Doghri, Amenallah Ellefi, Imen Degrach, Najet Srairi-Abid and Asma Gati

Molecules 2021, 26(10), 3011; https://doi.org/10.3390/molecules26103011 - 18 May 2021

Cited by 33 | Viewed by 5238

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood–brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl₃), which mimics the sporadic form of Alzheimer’s disease. Our results showed that treatment with CUR enhances pro-oxidant levels, antioxidant enzymes activities and anti-inflammatory cytokine production and decreases apoptotic cells in AlCl₃-exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl₃-induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl₃-exposed rats. Taken together, our data presented CUR as a nutraceutical potential through its protective effects that are more interesting than recovery ones in sporadic model of AD. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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18 pages, 15385 KiB

Open AccessArticle

Chemical Composition, Antioxidant and Enzyme Inhibitory Activities of Onosma bourgaei and Onosma trachytricha and in Silico Molecular Docking Analysis of Dominant Compounds

by Erman Salih Istifli

Molecules 2021, 26(10), 2981; https://doi.org/10.3390/molecules26102981 - 18 May 2021

Cited by 11 | Viewed by 3071

Abstract

The aim of this study was to investigate the chemical composition, antioxidant and enzyme inhibitory activities of methanol (MeOH) extracts from Onosma bourgaei (Boiss.) and O. trachytricha (Boiss.). In addition, the interactions between phytochemicals found in extracts in high amounts and the target enzymes in question were revealed at the molecular scale by performing in silico molecular docking simulations. While the total amount of flavonoid compounds was higher in O. bourgaei, O. trachytricha was richer in phenolics. Chromatographic analysis showed that the major compounds of the extracts were luteolin 7-glucoside, apigenin 7-glucoside and rosmarinic acid. With the exception of the ferrous ion chelating assay, O. trachytricha exhibited higher antioxidant activity than O. bourgaei. O. bourgaei exhibited also slightly higher activity on digestive enzymes. The inhibitory activities of the Onosma species on tyrosinase were almost equal. In addition, the inhibitory activities of the extracts on acetylcholinesterase (AChE) were stronger than the activity on butyrylcholinesterase (BChE). Molecular docking simulations revealed that luteolin 7-glucoside and apigenin 7-glucoside have particularly strong binding affinities against ChEs, tyrosinase, α-amylase and α-glucosidase when compared with co-crystallized inhibitors. Therefore, it was concluded that the compounds in question could act as effective inhibitors on cholinesterases, tyrosinase and digestive enzymes. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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15 pages, 4826 KiB

Open AccessArticle

Contribution of Attenuation of TNF-α and NF-κB in the Anti-Epileptic, Anti-Apoptotic and Neuroprotective Potential of Rosa webbiana Fruit and Its Chitosan Encapsulation

by Anum Firdous, Sadia Sarwar, Fawad Ali Shah, Sobia Tabasum, Alam Zeb, Humaira Nadeem, Abir Alamro, Amani Ahmed Alghamdi, Arooj Mohsin Alvi, Komal Naeem and Muhammad Sohaib Khalid

Molecules 2021, 26(8), 2347; https://doi.org/10.3390/molecules26082347 - 17 Apr 2021

Cited by 22 | Viewed by 2984

Abstract

Rosa webbiana L. (Rosaceae) is one of the least reported and most understudied members of this family. It is native to the Himalayan regions of Pakistan and Nepal. The anti-convulsant effect of n-hexane extract of fruit of Rosa webbiana was investigated in a pentylenetetrazole (PTZ)-induced animal model of epilepsy. Male Sprague-Dawley rats were divided into six groups (n = 7) including control, PTZ (40 mg/kg), diazepam (4 mg/kg) and n-hexane extract (at 50, 150 and 300 mg/kg). Convulsive behavior was observed and resultant seizures were scored, animals sacrificed and their brains preserved. Chitosan nanoparticles were prepared using the ionic gelation method and characterized by UV-analysis, zeta potential and Fourier transform infrared spectroscopy (FTIR). The effects of all the treatments on the expression of phosphorylated cytokine tumor necrosis factor α (p-TNF-α) and phosphorylated transcription factor nuclear factor kappa B (p-NF-κB) expression in the cortex and hippocampus of the brains of treated rats were studied through enzyme linked immunosorbent assay (ELISA) and morphological differences and surviving neuronal number were recorded through hematoxylene and eosin (H&E) staining. Significant changes in seizures score and survival rate of rats were observed. Downregulation of neuro-inflammation, p-TNF-α and p-NF-κB was evident. Gas Chromatography-Mass Spectrometry (GC-MS) analysis of this fraction showed multiple constituents of interest, including esters, alkanes and amines. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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14 pages, 5302 KiB

Open AccessArticle

Inhibitory Effect of LGS and ODE Isolated from the Twigs of Syringa oblata subsp. dilatata on RANKL-Induced Osteoclastogenesis in Macrophage Cells

by Ga-Ram Kim, Eun-Nam Kim, Kyoung Jin Park, Ki Hyun Kim and Gil-Saeng Jeong

Molecules 2021, 26(6), 1779; https://doi.org/10.3390/molecules26061779 - 22 Mar 2021

Cited by 6 | Viewed by 2342

Abstract

Osteoblasts and osteoclasts play a pivotal role in maintaining bone homeostasis, of which excessive bone resorption by osteoclasts can cause osteoporosis and various bone diseases. However, current osteoporosis treatments have many side effects, and research on new treatments that can replace these treatments is ongoing. Therefore, in this study, the roles of ligustroside (LGS) and oleoside dimethylester (ODE), a natural product-derived compound isolated from Syringa oblata subsp. dilatata as a novel, natural product-derived osteoporosis treatments were investigated. In the results of this study, LGS and ODE inhibited the differentiation of receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced RAW264.7 cells into osteoclasts without cytotoxicity, and down-regulated the activity of TRAP, a specific biomarker of osteoclasts. In addition, it inhibited bone resorption and actin ring formation, which are important functions and features of osteoclasts. Also, the effects of LGS and ODE on the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and phosphoinositide 3-kinases (PI3K)/ protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathways that play important roles in osteoclast differentiation were evaluated. In the results, LGS and ODE downregulated the phosphorylation of RANKL-induced MAPK and PI3K/Akt/mTOR proteins in a concentration-dependent manner, translocation of NF-κB into the nucleus was inhibited. As a result, the compounds LGS and ODE isolated from S. oblate subsp. dilatata effectively regulated the differentiation of RANKL-induced osteoclasts and inhibited the phosphorylation of signaling pathways that play a pivotal role in osteoclast differentiation. Therefore, these results suggest the possibility of LGS and ODE as new natural product treatments for bone diseases caused by excessive osteoclasts. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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14 pages, 2831 KiB

Open AccessArticle

Lanostane Triterpenoid Metabolites from a Penares sp. Marine Sponge Protect Neuro-2a Cells against Paraquat Neurotoxicity

by Ekaterina A. Yurchenko, Sophia A. Kolesnikova, Ekaterina G. Lyakhova, Ekaterina S. Menchinskaya, Evgeny A. Pislyagin, Ekaterina A. Chingizova and Dmitry L. Aminin

Molecules 2020, 25(22), 5397; https://doi.org/10.3390/molecules25225397 - 18 Nov 2020

Cited by 9 | Viewed by 2482

Abstract

The results of an investigation of the protective effects of five lanostane triterpenoids: 3β-acetoxy-7β,8β-epoxy-5α-lanost-24-en-30,9α-olide (1), 3β-hydroxy-7β,8β-epoxy-5α-lanost-24-en- 30,9α-olide (2), 29-nor-penasterone (3), penasterone (4), and acetylpenasterol (5), from a marine sponge, Penares sp., against paraquat-induced neuroblastoma Neuro-2a cell damage, are described. The influence of all compounds on viability of the Neuro-2a cells treated with paraquat (PQ) was studied with MTT and fluorescein diacetate assays as well as propidium iodide straining. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity of the compounds as well as their influence on reactive oxygen species (ROS) level and mitochondrial membrane potential in PQ-treated neuronal cells were analyzed. Finally, the effect of the compounds on intracellular level of heat shock protein 70 kDa (Hsp70) and neurite outgrowth in PQ-treated Neuro-2a cells were studied. Studied triterpenoids demonstrated protective effects against PQ-induced neurotoxicity associated with the ability to reduce ROS intracellular level and diminish mitochondrial dysfunction. Acetylpenasterol (5), as a more promising neuroprotective compound, significantly increased the viability of Neuro-2a cells incubated with PQ as well as decreased intracellular ROS level in these cells. Moreover, acetylpenasterol induced Hsp70 expression in PQ-treated cells. It was also shown to inhibit PQ-induced neurite loss and recovered the number of neurite-bearing cells. The relationship between neuroprotective activity of the investigated compounds 1–5 and their chemical structure was also discussed. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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Review

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17 pages, 1353 KiB

Open AccessReview

Natural Cryoprotective and Cytoprotective Agents in Cryopreservation: A Focus on Melatonin

by Giada Marcantonini, Desirée Bartolini, Linda Zatini, Stefania Costa, Massimiliano Passerini, Mario Rende, Giovanni Luca, Giuseppe Basta, Giuseppe Murdolo, Riccardo Calafiore and Francesco Galli

Molecules 2022, 27(10), 3254; https://doi.org/10.3390/molecules27103254 - 19 May 2022

Cited by 26 | Viewed by 4646

Abstract

Cryoprotective and cytoprotective agents (Cytoprotective Agents) are fundamental components of the cryopreservation process. This review presents the essentials of the cryopreservation process by examining its drawbacks and the role of cytoprotective agents in protecting cell physiology. Natural cryoprotective and cytoprotective agents, such as antifreeze proteins, sugars and natural deep eutectic systems, have been compared with synthetic ones, addressing their mechanisms of action and efficacy of protection. The final part of this article focuses melatonin, a hormonal substance with antioxidant properties, and its emerging role as a cytoprotective agent for somatic cells and gametes, including ovarian tissue, spermatozoa and spermatogonial stem cells. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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Other

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8 pages, 1367 KiB

Open AccessBrief Report

Cytoprotective Activity of p-Terphenyl Polyketides and Flavuside B from Marine-Derived Fungi against Oxidative Stress in Neuro-2a Cells

by Ekaterina A. Yurchenko, Ekaterina S. Menchinskaya, Evgeny A. Pislyagin, Ekaterina A. Chingizova, Elena V. Girich, Anton N. Yurchenko, Dmitry L. Aminin and Valery V. Mikhailov

Molecules 2021, 26(12), 3618; https://doi.org/10.3390/molecules26123618 - 13 Jun 2021

Cited by 8 | Viewed by 3038

Abstract

The influence of p-terphenyl polyketides 1–3 from Aspergillus candidus KMM 4676 and cerebroside flavuside B (4) from Penicillium islandicum (=Talaromyces islandicus) against the effect of neurotoxins, rotenone and paraquat, on Neuro-2a cell viability by MTT and LDH release assays and intracellular ROS level, as well as DPPH radical scavenging activity, was investigated. Pre-incubation with compounds significantly diminished the ROS level in rotenone- and paraquat-treated cells. It was shown that the investigated polyketides 1–3 significantly increased the viability of rotenone- and paraquat-treated cells in two of the used assays but they affected only the viability of paraquat-treated cells in the LDH release assay. Flavuside B statistically increased the viability of paraquat-treated cells in both MTT and LDH release assays, however, it increased the viability of rotenone-treated cells in the LDH release assay. Structure–activity relationships for p-terphenyl derivatives, as well as possible mechanisms of cytoprotective action of all studied compounds, were discussed. Full article

(This article belongs to the Special Issue Advances in Cytoprotective Drug Discovery)

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