Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom

The voltage-gated K+ channels Kv3.1 display fast activation and deactivation kinetics and are known to have a crucial contribution to the fast-spiking phenotype of certain neurons. AahG50, as a natural product extracted from Androctonus australis hector venom, inhibits selectively Kv3.1 channels. In the present study, we focused on the biochemical and pharmacological characterization of the component in AahG50 scorpion venom that potently and selectively blocks the Kv3.1 channels. We used a combined optimization through advanced biochemical purification and patch-clamp screening steps to characterize the peptide in AahG50 active on Kv3.1 channels. We described the inhibitory effect of a toxin on Kv3.1 unitary current in black lipid bilayers. In silico, docking experiments are used to study the molecular details of the binding. We identified the first scorpion venom peptide inhibiting Kv3.1 current at 170 nM. This toxin is the alpha-KTx 15.1, which occludes the Kv3.1 channel pore by means of the lysine 27 lateral chain. This study highlights, for the first time, the modulation of the Kv3.1 by alpha-KTx 15.1, which could be an interesting starting compound for developing therapeutic biomolecules against Kv3.1-associated diseases.

Download Full-text

Brassinolide Enhances the Level of Brassinosteroids, Protein, Pigments, and Monosaccharides in Wolffia arrhiza Treated with Brassinazole

Plants ◽

10.3390/plants10071311 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1311

Author(s):

Magdalena Chmur ◽

Andrzej Bajguz

Keyword(s):

Plant Growth ◽

Growth And Development ◽

Inhibitory Effect ◽

Dependent Manner ◽

Plant Growth And Development ◽

Concentration Dependent Manner ◽

Spectrophotometric Methods ◽

Synthetic Inhibitor ◽

Wolffia Arrhiza ◽

First Time

Brassinolide (BL) represents brassinosteroids (BRs)—a group of phytohormones that are essential for plant growth and development. Brassinazole (Brz) is as a synthetic inhibitor of BRs’ biosynthesis. In the present study, the responses of Wolffia arrhiza to the treatment with BL, Brz, and the combination of BL with Brz were analyzed. The analysis of BRs and Brz was performed using LC-MS/MS. The photosynthetic pigments (chlorophylls, carotenes, and xanthophylls) levels were determined using HPLC, but protein and monosaccharides level using spectrophotometric methods. The obtained results indicated that BL and Brz influence W. arrhiza cultures in a concentration-dependent manner. The most stimulatory effects on the growth, level of BRs (BL, 24-epibrassinolide, 28-homobrassinolide, 28-norbrassinolide, catasterone, castasterone, 24-epicastasterone, typhasterol, and 6-deoxytyphasterol), and the content of pigments, protein, and monosaccharides, were observed in plants treated with 0.1 µM BL. Whereas the application of 1 µM and 10 µM Brz caused a significant decrease in duckweed weight and level of targeted compounds. Application of BL caused the mitigation of the Brz inhibitory effect and enhanced the BR level in duckweed treated with Brz. The level of BRs was reported for the first time in duckweed treated with BL and/or Brz.

Download Full-text

A novel role for WAVE1 in controlling actin network growth rate and architecture

Molecular Biology of the Cell ◽

10.1091/mbc.e14-10-1477 ◽

2015 ◽

Vol 26 (3) ◽

pp. 495-505 ◽

Cited By ~ 9

Author(s):

Meredith O. Sweeney ◽

Agnieszka Collins ◽

Shae B. Padrick ◽

Bruce L. Goode

Keyword(s):

Actin Filament ◽

Specific Activity ◽

Inhibitory Effect ◽

Actin Network ◽

Inhibitory Effects ◽

Cellular Functions ◽

Network Growth ◽

Assembly Kinetics ◽

Filament Networks ◽

First Time

Branched actin filament networks in cells are assembled through the combined activities of Arp2/3 complex and different WASP/WAVE proteins. Here we used TIRF and electron microscopy to directly compare for the first time the assembly kinetics and architectures of actin filament networks produced by Arp2/3 complex and dimerized VCA regions of WAVE1, WAVE2, or N-WASP. WAVE1 produced strikingly different networks from WAVE2 or N-WASP, which comprised unexpectedly short filaments. Further analysis showed that the WAVE1-specific activity stemmed from an inhibitory effect on filament elongation both in the presence and absence of Arp2/3 complex, which was observed even at low stoichiometries of WAVE1 to actin monomers, precluding an effect from monomer sequestration. Using a series of VCA chimeras, we mapped the elongation inhibitory effects of WAVE1 to its WH2 (“V”) domain. Further, mutating a single conserved lysine residue potently disrupted WAVE1's inhibitory effects. Taken together, our results show that WAVE1 has unique activities independent of Arp2/3 complex that can govern both the growth rates and architectures of actin filament networks. Such activities may underlie previously observed differences between the cellular functions of WAVE1 and WAVE2.

Download Full-text

Characterization of the inositol 1,4,5-trisphosphate-induced calcium release from permeabilized endocrine cells and its inhibition by decavanadate and p-hydroxymercuribenzoate

Biochemical Journal ◽

10.1042/bj2620083 ◽

1989 ◽

Vol 262 (1) ◽

pp. 83-89 ◽

Cited By ~ 48

Author(s):

K J Föhr ◽

J Scott ◽

G Ahnert-Hilger ◽

M Gratzl

Keyword(s):

Endocrine Cells ◽

Calcium Release ◽

Cell Types ◽

Inhibitory Effect ◽

Maximal Effect ◽

Thiol Compounds ◽

Inositol 1,4,5 Trisphosphate ◽

Dependent Inhibition ◽

Pheochromocytoma Pc12 ◽

First Time

The inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ compartment of endocrine cells was studied with alpha-toxin- and digitonin-permeabilized rat insulinoma (RINA2) and rat pheochromocytoma (PC12) cells. The Ca2+ uptake was ATP-dependent, and submicromolar concentrations of IP3 specifically released the stored Ca2+. Half-maximal Ca2+ release was observed with 0.25-0.5 mumol of IP3/l, and the amount of Ca2+ released due to IP3 could be enhanced by additional loading of the Ca2+ compartment. Consecutive additions of the same concentration of IP3 for 1-2 h always released the same amount of Ca2+ without desensitization, providing an ideal basis to further characterize the IP3-induced Ca2+ release. Here we describe for the first time a reversible inhibitory effect of decavanadate on the IP3-induced Ca2+ release. Among the vanadium species tested (decavanadate, oligovanadate and monovanadate), only decavanadate was inhibitory, with a half-maximal effect at 5 mumol/l in both cell types. The effect of decavanadate could be overcome by increasing the amount of sequestered Ca2+ or added IP3. Decavanadate did not affect the ATP-driven Ca2+ uptake but oligovanadate was inhibitory on Ca2+ uptake. p-Hydroxymercuribenzoate (pHMB) at concentrations between 10 and 30 mumol/l also inhibited the Ca2+ release due to IP3. Thiol compounds such as dithiothreitol (DTT; 1 mmol/l) added before pHMB removed all its inhibitory effect on the IP3-induced Ca2+ release, whereas the inhibition caused by decavanadate was unaffected by DTT. Thus, the decavanadate-dependent inhibition functions by a distinctly different mechanism than pHMB and could serve as a specific tool to analyse various aspects of the IP3-induced Ca2+ release within endocrine cells.

Download Full-text

U46619, a thromboxane A2 agonist, inhibits KCa channel activity from pig coronary artery

AJP Cell Physiology ◽

10.1152/ajpcell.1992.262.3.c708 ◽

1992 ◽

Vol 262 (3) ◽

pp. C708-C713 ◽

Cited By ~ 82

Author(s):

F. S. Scornik ◽

L. Toro

Keyword(s):

Smooth Muscle ◽

Coronary Artery ◽

Lipid Bilayers ◽

Thromboxane A2 ◽

Inhibitory Effect ◽

Channel Activity ◽

Open Probability ◽

Control Value ◽

Kca Channels ◽

Internal Side

Thromboxane A2 (TxA2) is a potent vasoconstrictor derived from the metabolism of arachidonic acid. Because potassium channels are involved in the contraction of vascular smooth muscle, their blockade could contribute to the TxA2-induced contraction. To test this possibility, we studied the effect of the TxA2 stable analogue U46619 on calcium-activated potassium (KCa) channels from coronary artery reconstituted into lipid bilayers. Addition of U46619 (50-150 nM) to the external but not to the internal side of the channel decreased the channel open probability (Po) between 15 and 80% of the control value. The inhibitory effect of U46619 affected both the open and closed states of the channel and could be reversed by internal calcium. Thromboxane B2, the inactive hydrolysis derivative of TxA2, did not affect channel activity. SQ 29548, a TxA2 receptor antagonist, was able to prevent the inhibition by U46619. Furthermore, SQ 29548 added after U46619 could restore channel activity to near control values. These results suggest that TxA2 could be a regulatory factor of KCa channels from coronary smooth muscle and that this regulation could be related to its action as a vasoconstrictor.

Download Full-text

In Silico Docking and In Vitro Approaches towards BACE1 and Cholinesterases Inhibitory Effect of Citrus Flavanones

Molecules ◽

10.3390/molecules23071509 ◽

2018 ◽

Vol 23 (7) ◽

pp. 1509 ◽

Cited By ~ 11

Author(s):

Seungeun Lee ◽

Kumju Youn ◽

GyuTae Lim ◽

Jinhyuk Lee ◽

Mira Jun

Keyword(s):

In Silico ◽

Inhibitory Effect ◽

In Silico Docking

Download Full-text

Potential for transmission of Elizabethkingia anophelis by Aedes albopictus and the role of microbial interactions in Zika virus competence

10.1101/702464 ◽

2019 ◽

Author(s):

MG Onyango ◽

AF Payne ◽

J Stout ◽

C Dieme ◽

L Kuo ◽

...

Keyword(s):

Zika Virus ◽

Inhibitory Effect ◽

Microbial Interactions ◽

Morbidity And Mortality ◽

Source Of Infection ◽

Vector Borne ◽

Complex Relationships ◽

The Impact ◽

First Time ◽

Transmission Barrier

AbstractElizabethkingia anophelis has been the cause of four outbreaks with significant morbidity and mortality. Its transmission routes remain unknown and no point source of infection has been identified. Here we show that E. anophelis can be found in the saliva of Aedes mosquitoes, suggesting the novel possibility of vector-borne transmission of this bacterium. We additionally characterized diverse microbial communities in Aedes midguts, salivary glands and saliva. To the best of our knowledge, this represents the first description of the microbiome of Aedes saliva. Further, we demonstrate that increased abundance of E. anophelis is associated with decreased susceptibility and replication of Zika virus (ZIKV) in the midgut of Aedes mosquitoes, suggesting a novel transmission barrier for arboviruses transmitted by Aedes mosquitoes. Together, these results demonstrate the complex relationships between the mosquito, the midgut microbial community and arboviruses and offer insights into the epidemiology and control of emerging bacterial and viral pathogens.Author SummaryElizabethkingia anophelis has in the recent past caused outbreaks different parts of the world resulting both in morbidity and mortality. Until now, to the best of our knowledge, no study has been able to demonstrate that this bacterium can be transmitted by mosquitoes. We have demonstrated for the first time that Elizabethkingia anophelis is present in the saliva of both infected and non-infected Aedes mosquitoes. Further, we have shown that it confers an inhibitory effect on Zika virus establishment in the midguts of Aedes mosquitoes. Together, these results potentially display the potential for vector borne transmission of E. anophelis as well as a novel transmission barrier of ZIKV. Lastly, we have for the first time characterized salivary microbes of Aedes mosquitoes necessitating the investigation of the impact of salivary microbes in severity of disease in vertebrate hosts.

Download Full-text

PPAR-Alpha Agonist Fenofibrate Combined with Octreotide Acetate in the Treatment of Acute Hyperlipidemia Pancreatitis

PPAR Research ◽

10.1155/2021/6629455 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Wen Bao ◽

Rui Kong ◽

Nan Wang ◽

Wei Han ◽

Jie Lu

Keyword(s):

Combined Treatment ◽

Inhibitory Effect ◽

Water Withdrawal ◽

Signal Pathways ◽

Ppar Alpha ◽

Octreotide Acetate ◽

Treatment Measures ◽

Synergistic Inhibitory Effect ◽

First Time ◽

Alpha Agonist

At present, there are more and more patients with acute hypertriglyceridemia pancreatitis in clinical practice. Common treatment measures include fasting and water withdrawal, fluid resuscitation, and somatostatin. In recent years, studies have pointed out that the PPARa agonist fenofibrate may help improve the condition of such patients. Therefore, through clinical research and analysis, we reported for the first time that fenofibrate combined with octreotide acetate has a more excellent effect in the treatment of patients with acute hypertriglyceridemia pancreatitis, and from the perspective of signal pathways, we revealed that the combination of the two drugs has an effect on NF-κB P65. The synergistic inhibitory effect proves that the combined treatment is beneficial to control inflammation, protect liver function, and improve the prognosis of patients. It is worthy of clinical promotion.

Download Full-text

Eﬀect of Zinc(II)-2,4,5-triphenyl-1H-imidazole Complex Against Replication DENV-2 in Vero Cell

Indonesian Journal of Tropical and Infectious Disease ◽

10.20473/ijtid.v8i3.11776 ◽

2020 ◽

Vol 8 (3) ◽

pp. 183

Author(s):

Teguh Hari Sucipto ◽

Aswandi Wibrianto ◽

Fahimah Martak ◽

Siti Churrotin ◽

Ilham Harlan Amarullah ◽

...

Keyword(s):

Dengue Virus ◽

Vero Cell ◽

Complex Compound ◽

Inhibitory Activity ◽

Vero Cells ◽

Inhibitory Effect ◽

Complex Compounds ◽

Antiviral Compound ◽

First Time

Dengue virus (DENV) is a significant pathogen emerging worldwide as a cause of infectious disease. DENVs are transmitted to humans through female mosquitoes from Aedes aegypti and Aedes albopictus species. Indonesia is one of the largest countries in the world in dengue endemic regions worldwide. Dengue fever was occurred for the first time as an outbreak in Surabaya and Jakarta in 1968. Many eﬀorts have been made to prevent and treat DENV infections, and clinical trials of a number of vaccines are currently underway. Antiviral testing of DENV is an important alternative for drug characterization and development. Complex compounds are formed as a result of metal and organic complex reactions. Complex compounds can be used as an anti-inflammatory, antimicrobial antifungal, antibacterial, antivirus. The Zn2+ ion can be used as an antiviral candidate. The purpose of this project was investigated Zinc(II)-2,4,5-triphenyl-1H-imidazole antiviral compound to be further tested for inhibitory eﬀect on the replication of DENV-2 in cell culture. DENV replication was measured by antiviral activity assay and cytotoxicity assay. The inhibitory activity of Zinc(II)-2,4,5-triphenyl-1H-imidazole complex compound was determined by Viral ToxGloTM Assay. The cytotoxicity of Zinc(II)-2,4,5-triphenyl-1H-imidazole complex compound was determined by CellTiter96® AQuoeus assay. The inhibitory concentration (IC50) of Zinc(II)-2,4,5-triphenyl- 1H-imidazole against dengue virus type-2 was 34.42 μg/ml. The cytotoxic concentration (CC50) of compound against Vero cell was <100 μg/ml. The results of this study demonstrate the antidengue serotype 2 inhibitory activity of investigated Zinc(II)-2,4,5-triphenyl-1H-imidazole complex and its high toxicity in Vero cells. Further studies are not required before investigated Zinc(II)-2,4,5-triphenylimidazole can be applied in the treatment of DENV-2 infections

Download Full-text

EFFICIENCY OF SOME PLANT EXTRACTS TO CONTROL OF PENICILLIUM ITALICUM WEHMER CAUSING BLUE MOLD ON LEMON FRUITS IN IRAQ

Pakistan Journal of Phytopathology ◽

10.33866/phytopathol.031.01.0472 ◽

2019 ◽

Vol 31 (1) ◽

pp. 01-05

Author(s):

Ahed A.H. Matloob ◽

Hamid A A. Khafaji

Keyword(s):

Plant Extracts ◽

Water Extract ◽

Inhibitory Effect ◽

Penicillium Italicum ◽

Blue Mold ◽

Lemon Fruit ◽

Water Extracts ◽

Wild Mustard ◽

First Time ◽

High Inhibitory Effect

The study aimed to evaluate the efficacy of the water extract of Propolis, Wild mustard and dates vinegar in the inhibition of Penicillium italicum causal agent of Blue mold on a lemon fruits. The results showed that all tested extracts with concentrations 5, 10 and 15% had a high inhibitory effect against P. italicum. Dates vinegar is highly effective and showed 100% inhibition of P. italicum and protected lemon fruit from infection. First time this type of natural inhibitory water extracts are used in Iraq which resulted that the dates vinegar is the best suitable option for the management of lemon blue mold disease in post-harvest.

Download Full-text

Isoflavones from Camphorosma lessingii Inhibit the Organic Anion Transporters OAT1 and OAT3

Planta Medica ◽

10.1055/a-0740-3255 ◽

2018 ◽

Vol 85 (03) ◽

pp. 225-230 ◽

Cited By ~ 4

Author(s):

Xinhui Wang ◽

Dujuan Wang ◽

Xue Wang ◽

Manana Khutsishvili ◽

Kamilla Tamanyan ◽

...

Keyword(s):

Organic Anion ◽

Inhibitory Effect ◽

Spectroscopic Methods ◽

Organic Anion Transporters ◽

One Dimensional ◽

Anion Transporters ◽

Significant Inhibitory Effect ◽

Phytochemical Investigation ◽

The Family ◽

First Time

AbstractPhytochemical investigation of Camphorosma lessingii has resulted in the isolation of four previously unreported isoflavones (1–4) and eight known compounds (5–12). Nine of these compounds (1–6, 8–10) are reported for the first time from members of the family Amaranthaceae. The structures of all isolated compounds were determined by spectroscopic methods, primarily one-dimensional and two-dimensional nuclear magnetic resonance and mass spectrometry. The absolute configuration of 6 was confirmed by circular dichroism. Inhibition of the organic anion transporters, OAT1 and OAT3, by the isolated compounds was evaluated. Among them, 7, 2′-dihydroxy- 6,8-dimethoxyisoflavone (1), 2′-hydroxy-6,7,8-trimethoxyisoflavone (2), 6,2′-dihydroxy-7,8-dimethoxyisoflavone (3), and 7-methoxyflavone (5) showed a significant inhibitory effect on 6-carboxyfluorescein uptake mediated by OAT1 and OAT3.

Download Full-text