Research

12 pages, 2953 KiB

Open AccessArticle

Platelet Desialylation Is a Novel Mechanism and Therapeutic Target in Daboia siamensis and Agkistrodon halys Envenomation-Induced Thrombocytopenia

by Cheng Zhang, Zhanfeng Zhang, Enyu Liang, Yunlong Gao, Hui Li, Fangfang Xu, Weiye Chen, Ming Liu and Xianzhang Huang

Molecules 2022, 27(22), 7779; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27227779 - 11 Nov 2022

Cited by 2 | Viewed by 1049

Abstract

Venom-induced thrombocytopenia (VIT) is one of the most important hemotoxic effects of a snakebite, which is often associated with venom-induced consumptive coagulopathy (VICC). Refractory thrombocytopenia without significant coagulation abnormalities has also been reported after envenomation by some viperid snakes; however, the mechanisms are [...] Read more.

Venom-induced thrombocytopenia (VIT) is one of the most important hemotoxic effects of a snakebite, which is often associated with venom-induced consumptive coagulopathy (VICC). Refractory thrombocytopenia without significant coagulation abnormalities has also been reported after envenomation by some viperid snakes; however, the mechanisms are not well understood and therapeutic strategies are lacking. Here, we found that patients injured by Daboia siamensis or Agkistrodon halys snakes, who were resistant to standard antivenom treatment, had developed coagulopathy-independent thrombocytopenia. Venoms from these viperid snakes, rather than from the elapid snake (Bungarus multicinctus), induced platelet surface expression of neuraminidase-1 (NEU-1), and significantly increased the desialylation of the glycoproteins on human platelets. The desialylated platelets caused by viperid snake venoms were further internalized by macrophages, which resulted in reduced platelet numbers in peripheral blood. Importantly, neuraminidase inhibitor significantly decreased viper venom-induced platelet desialylation, therefore inhibiting platelet phagocytosis by macrophages, and alleviating venom-induced thrombocytopenia. Collectively, these findings support an important role for desialylated platelet clearance in the progression of viper envenomation-induced, coagulopathy-independent thrombocytopenia. Our study demonstrates that the neuraminidase inhibitor may be a potential therapy or adjuvant therapy to treat snakebite-induced thrombocytopenia. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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16 pages, 2835 KiB

Open AccessArticle

Essential Oils as a Source of Ecofriendly Insecticides for Drosophila suzukii (Diptera: Drosophilidae) and Their Potential Non-Target Effects

by Michele Trombin de Souza, Mireli Trombin de Souza, Maíra Chagas Morais, Daiana da Costa Oliveira, Douglas José de Melo, Leonardo Figueiredo, Paulo Henrique Gorgatti Zarbin, Maria Aparecida Cassilha Zawadneak and Daniel Bernardi

Molecules 2022, 27(19), 6215; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27196215 - 21 Sep 2022

Cited by 9 | Viewed by 1554

Abstract

The spotted wing drosophila (Drosophila suzukii) is one of the main invasive pests of small fruits in the world. Thus, 19 essential oils (EOs) were selected to analyze the effects through toxicity and repellency on oviposition and D. suzukii adults. In [...] Read more.

The spotted wing drosophila (Drosophila suzukii) is one of the main invasive pests of small fruits in the world. Thus, 19 essential oils (EOs) were selected to analyze the effects through toxicity and repellency on oviposition and D. suzukii adults. In addition, their lethal and sublethal effects on the pupal endoparasitoid Trichopria anastrephae were evaluated. The EOs of C. flexuosus and Mentha spp. had the highest toxicity observed in the topical application bioassay for D. suzukii. In contrast, the EOs of C. verum, C. citratus QT citratus, and C. winterianus showed the highest toxicity in the ingestion bioassay for D. suzukii. The dry residues of C. verum and C. citratus QT citratus reduced the oviposition of D. suzukii. In the repellency bioassays, the 19 EOs analyzed repelled ≅ 90% of the D. suzukii females. All EOs evaluated using the LC₉₀ values of the products provided mortality of less than 20% of T. anastrephae adults and did not cause a reduction in the parasitism of surviving T. anastrephae females. We conclude that the EOs evaluated have the potential to be used in the management of D. suzukii. They can also serve as selective active ingredients for the formulation and synthesis of new biopesticides. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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18 pages, 4115 KiB

Open AccessArticle

Fraxinellone Induces Hepatotoxicity in Zebrafish through Oxidative Stress and the Transporters Pathway

by Shuting Wang, Jie Bao, Jie Li, Wanfang Li, Mengyin Tian, Caixia Qiu, Fei Pang, Xin Li, Jianbo Yang, Yuchi Hu, Sujuan Wang and Hongtao Jin

Molecules 2022, 27(9), 2647; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092647 - 20 Apr 2022

Cited by 5 | Viewed by 2690

Abstract

Fraxinellone (FRA), a major active component from Cortex Dictamni, produces hepatotoxicity via the metabolization of furan rings by CYP450. However, the mechanism underlying the hepatotoxicity of FRA remains unclear. Therefore, zebrafish larvae at 72 h post fertilization were used to evaluate the metabolic [...] Read more.

Fraxinellone (FRA), a major active component from Cortex Dictamni, produces hepatotoxicity via the metabolization of furan rings by CYP450. However, the mechanism underlying the hepatotoxicity of FRA remains unclear. Therefore, zebrafish larvae at 72 h post fertilization were used to evaluate the metabolic hepatotoxicity of FRA and to explore the underlying molecular mechanisms. The results showed that FRA (10–30 μM) induced liver injury and obvious alterations in the metabolomics of zebrafish larvae. FRA induces apoptosis by increasing the level of ROS and activating the JNK/P53 pathway. In addition, FRA can induce cholestasis by down-regulating bile acid transporters P-gp, Bsep, and Ntcp. The addition of the CYP3A inhibitor ketoconazole (1 μM) significantly reduced the hepatotoxicity of FRA (30 μM), which indicated that FRA induced hepatotoxicity through CYP3A metabolism. Targeted metabolomics analysis indicates the changes in amino acid levels can be combined with molecular biology to clarify the mechanism of hepatotoxicity induced by FRA, and amino acid metabolism monitoring may provide a new method for the prevention and treatment of DILI from FRA. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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13 pages, 1260 KiB

Open AccessArticle

Development of an Inhibition Enzyme-Linked Immunosorbent Assay (ELISA) Prototype for Detecting Cytotoxic Three-Finger Toxins (3FTxs) in African Spitting Cobra Venoms

by Ernest Z. Manson, Kyama C. Mutinda, Joseph K. Gikunju, Aleksandra Bocian, Konrad K. Hus, Vladimír Petrílla, Jaroslav Legáth and James H. Kimotho

Molecules 2022, 27(3), 888; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030888 - 28 Jan 2022

Cited by 5 | Viewed by 2780

Abstract

The administration of toxin-specific therapy in snake envenoming is predicated on improved diagnostic techniques capable of detecting specific venom toxins. Various serological tests have been used in detecting snakebite envenoming. Comparatively, enzyme-linked immunosorbent assay (ELISA) has been shown to offer a wider practical [...] Read more.

The administration of toxin-specific therapy in snake envenoming is predicated on improved diagnostic techniques capable of detecting specific venom toxins. Various serological tests have been used in detecting snakebite envenoming. Comparatively, enzyme-linked immunosorbent assay (ELISA) has been shown to offer a wider practical application. We report an inhibition ELISA for detecting three-finger toxin (3FTx) proteins in venoms of African spitting cobras. The optimized assay detected 3FTxs in N. ashei (including other Naja sp.) venoms, spiked samples, and venom-challenged mice samples. In venoms of Naja sp., the assay showed inhibition, implying the detection of 3FTxs, but showed little or no inhibition in non-Naja sp. In mice-spiked samples, one-way ANOVA results showed that the observed inhibition was not statistically significant between spiked samples and negative control (p-value = 0.164). Similarly, the observed differences in inhibition between venom-challenged and negative control samples were not statistically significant (p-value = 0.9109). At an LOD of 0.01 µg/mL, the assay was able to confirm the presence of 3FTxs in the samples. Our results show a proof of concept for the use of an inhibition ELISA model as a tool for detecting 3FTxs in the venoms of African spitting cobra snakes. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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17 pages, 7976 KiB

Open AccessArticle

Cloning, Expression and Inhibitory Effects on Lewis Lung Carcinoma Cells of rAj-Tspin from Sea Cucumber (Apostichopus japonicus)

by Rong Qiao, Rong Xiao, Zhong Chen, Jingwei Jiang, Chenghua Yuan, Shuxiang Ning, Jihong Wang and Zunchun Zhou

Molecules 2022, 27(1), 229; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010229 - 30 Dec 2021

Cited by 2 | Viewed by 1714

Abstract

In recent years, sea cucumber has become a favorite healthcare food due to its characteristic prevention of cardiovascular diseases, suppression of tumors, as well as enhancement of immunity. In order to screen the anti-tumoral proteins or peptides from sea cucumber (Apostichopus japonicus [...] Read more.

In recent years, sea cucumber has become a favorite healthcare food due to its characteristic prevention of cardiovascular diseases, suppression of tumors, as well as enhancement of immunity. In order to screen the anti-tumoral proteins or peptides from sea cucumber (Apostichopus japonicus), its cDNA library was analyzed, and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13)-like was found. ADAMTS13-like contains 10 thrombospondin 1 (TSP1) domains. Based on analysis of bioinformatics, the third TSP1 domain of this protein, which is further named Aj-Tspin, contains an arginine-glycine-aspartate (RGD) motif. Since our previous studies showed that the recombinant RGD-containing peptide from lampreys showed anti-tumoral activity, the third TSP1 domain of ADAMTS13-like was chosen to evaluate it’s effect on tumor proliferation and metastasis, despite the fact it shares almost no homologue with disintegrins from other species. After artificial synthesis, its cDNA sequence, Aj-Tspin, which is composed of 56 amino acids, was subcloned into a pET23b vector and expressed as a recombinant Aj-Tspin (rAj-Tspin) in a soluble form with a molecular weight of 6.976 kDa. Through affinity chromatography, rAj-Tspin was purified as a single protein. Both anti-proliferation and immunofluorescence assays showed that rAj-Tspin suppressed the proliferation of Lewis lung carcinoma (LLC) cells through apoptosis. Adhesion assay also displayed that rAj-Tspin inhibited the adhesion of LLC cells to ECM proteins, including fibronectin, laminin, vitronectin and collagen. Lastly, rAj-Tspin also suppressed the migration and invasion of LLC cells across the filter in transwells. Thus, the above indicates that rAj-Tspin might act as a potential anti-tumoral drug in the future and could also provide information on the nutritional value of sea cucumber. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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22 pages, 6243 KiB

Open AccessFeature PaperArticle

Interactions of Sea Anemone Toxins with Insect Sodium Channel—Insights from Electrophysiology and Molecular Docking Studies

by Beata Niklas, Milena Jankowska, Dalia Gordon, László Béress, Maria Stankiewicz and Wieslaw Nowak

Molecules 2021, 26(5), 1302; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26051302 - 28 Feb 2021

Cited by 4 | Viewed by 2982

Abstract

Animal venoms are considered as a promising source of new drugs. Sea anemones release polypeptides that affect electrical activity of neurons of their prey. Voltage dependent sodium (Nav) channels are the common targets of Av1, Av2, and Av3 toxins from Anemonia viridis and [...] Read more.

Animal venoms are considered as a promising source of new drugs. Sea anemones release polypeptides that affect electrical activity of neurons of their prey. Voltage dependent sodium (Nav) channels are the common targets of Av1, Av2, and Av3 toxins from Anemonia viridis and CgNa from Condylactis gigantea. The toxins bind to the extracellular side of a channel and slow its fast inactivation, but molecular details of the binding modes are not known. Electrophysiological measurements on Periplaneta americana neuronal preparation revealed differences in potency of these toxins to increase nerve activity. Av1 and CgNa exhibit the strongest effects, while Av2 the weakest effect. Extensive molecular docking using a modern SMINA computer method revealed only partial overlap among the sets of toxins’ and channel’s amino acid residues responsible for the selectivity and binding modes. Docking positions support earlier supposition that the higher neuronal activity observed in electrophysiology should be attributed to hampering the fast inactivation gate by interactions of an anemone toxin with the voltage driven S4 helix from domain IV of cockroach Nav channel (NavPaS). Our modelling provides new data linking activity of toxins with their mode of binding in site 3 of NavPaS channel. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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15 pages, 5276 KiB

Open AccessArticle

Modulatory and Toxicological Perspectives on the Effects of the Small Molecule Kinetin

by Eman M. Othman, Moustafa Fathy, Amany Abdlrehim Bekhit, Abdel-Razik H. Abdel-Razik, Arshad Jamal, Yousef Nazzal, Shabana Shams, Thomas Dandekar and Muhammad Naseem

Molecules 2021, 26(3), 670; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26030670 - 28 Jan 2021

Cited by 17 | Viewed by 2700

Abstract

Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) [...] Read more.

Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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14 pages, 4010 KiB

Open AccessArticle

Crystal Structure of Isoform CBd of the Basic Phospholipase A₂ Subunit of Crotoxin: Description of the Structural Framework of CB for Interaction with Protein Targets

by Dorota Nemecz, Maciej Ostrowski, Marc Ravatin, Frederick Saul and Grazyna Faure

Molecules 2020, 25(22), 5290; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25225290 - 13 Nov 2020

Cited by 9 | Viewed by 2162

Abstract

Crotoxin, from the venom of the South American rattlesnake Crotalus durissus terrificus, is a potent heterodimeric presynaptic β-neurotoxin that exists in individual snake venom as a mixture of isoforms of a basic phospholipase A₂ (PLA₂) subunit (CBa₂, CBb, [...] Read more.

Crotoxin, from the venom of the South American rattlesnake Crotalus durissus terrificus, is a potent heterodimeric presynaptic β-neurotoxin that exists in individual snake venom as a mixture of isoforms of a basic phospholipase A₂ (PLA₂) subunit (CBa₂, CBb, CBc, and CBd) and acidic subunit (CA_1–4). Specific natural mutations in CB isoforms are implicated in functional differences between crotoxin isoforms. The three-dimensional structure of two individual CB isoforms (CBa₂, CBc), and one isoform in a crotoxin (CA₂CBb) complex, have been previously reported. This study concerns CBd, which by interaction with various protein targets exhibits many physiological or pharmacological functions. It binds with high affinity to presynaptic receptors showing neurotoxicity, but also interacts with human coagulation factor Xa (hFXa), exhibiting anticoagulant effect, and acts as a positive allosteric modulator and corrector of mutated chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), implicated in cystic fibrosis. Thus, CBd represents a novel family of agents that have potential in identifying new drug leads related to anticoagulant and anti-cystic fibrosis function. We determined here the X-ray structure of CBd and compare it with the three other natural isoforms of CB. The structural role of specific amino acid variations between CB isoforms are analyzed and the structural framework of CB for interaction with protein targets is described. Full article

(This article belongs to the Special Issue Toxins of Natural Origin: From Venom of Animals or Plants)

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