scholarly journals Effect of benomyl and diazinon on acquired azole resistance in Aspergillus flavus and expression of mdr1 and cyp51c genes

2019 ◽  
Author(s):  
Maryam Akbari Dana ◽  
Seyed Jamal Hashemi ◽  
Roshanak Daei Ghazvini ◽  
Sadegh Khodavesi ◽  
Mona Modiri ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Aspergillus Flavus ◽  
Morphological Changes ◽  
Agricultural Products ◽  
Sensitive Species ◽  
Agricultural Pesticides ◽  
Expression Of Genes ◽  
Resistant Strains

Background and Purpose: Aspergillus flavus is an important pathogen in immunodeficient patients. Due to the abundance of this fungus in nature, fungicides are commonly used to preserve and maintain agricultural products. Long-term exposure to these pesticides can lead to the induction of drug resistance in this fungus. Materials and Methods: For the purpose of the study, 10 strains of A. flavus ATCC 204304 were cultured in benomyl and diazinon pesticides at the concentrations of 62.5, 125, 250.500, 750, 1000, 1500, 2000, and 2500 mg/L in nine steps. Morphological changes and resistance to voriconazole, itraconazole, and amphotericin B were evaluated at the end of each step. Subsequently, changes in the expression of mdr1 and cyp51C genes were studied in the strains showing drug resistance. Results: The results showed that during the nine stages of the adjacency of strains with benomyl and diazinon at different concentrations, resistance to voriconazole, itraconazole, and amphotericin B in these toxins increased by 30% and 10%, respectively. In addition, the microscopic examination of resistant strains revealed the absence of sporulation, and only mycelium was found. Macroscopically, the color of the colonies changed from green to white. Furthermore, the investigation of the expression of mdr1 and cyp51c genes in these strains showed a decrease and increase in adjacency with diazinon and benomyl, respectively. Conclusion: As the findings indicated, exposure to agricultural pesticides can lead to the incidence of morphological changes and resistance to amphotericin B, itraconazole, and voriconazole in the sensitive species of A. flavus by altering the expression of genes involved in drug resistance.

scholarly journals Antigiardial Effect of Kramecyne in Experimental Giardiasis

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Leticia Eligio-García ◽  
Elida Pontifez-Pablo ◽  
Salúd Pérez-Gutiérrez ◽  
Enedina Jiménez-Cardoso
Keyword(s):  
Side Effects ◽  
High Efficiency ◽  
Morphological Changes ◽  
Lethal Dose ◽  
Expression Of Genes ◽  
Antigiardial Activity ◽  
Resistant Strains ◽  
Polymerase Chain

A variety of drugs are used in giardiasis treatment with different levels of efficiency, presence of side effects, and even formation of resistant strains, so that it is important to search new only-one-dose treatments with high efficiency and less side effects. Kramecyne, an anti-inflammatory compound isolated from methanolic extract ofKrameria cytisoides, does not present toxicity, even at doses of 5,000 mg/kg. The objective was to determine the antigiardial effect of kramecyne overGiardia intestinalis in vitroandin vivoand analyze the expression of genes ERK1, ERK2, and AK on kramecyne treated trophozoites by Real Time Polymerase Chain Reaction (RTPCR). The median lethal dose (LD50) was 40 μg/mL and no morphological changes were observed by staining with blue trypan and light microscopy; experimental gerbil infection was eliminated with 320 μg/Kg of weight. After treatment there were no differences between intestines from treated and untreated gerbils. Kramecyne did not have significant effect over ERK1 and AK, but there are differences in ERK2 expression (p=0.04). Results show antigiardial activity of kramecyne; however the mode of action is still unclear and the evaluation of ultrastructural damage and expressed proteins is an alternative of study to understand the action mechanism.

Alternating anti-prion regimens reduce combination drug resistance but do not further extend survival in scrapie-infected mice

2021 ◽  
Vol 102 (12) ◽  
Author(s):  
Kathryn S. Beauchemin ◽  
Judy R. Rees ◽  
Surachai Supattapone
Keyword(s):  
Drug Resistance ◽  
Prion Diseases ◽  
Disease Free Survival ◽  
Combination Drug ◽  
Free Survival ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Combination Regimens ◽  
Disease Free

Prion diseases are fatal and infectious neurodegenerative diseases in humans and other mammals caused by templated misfolding of the endogenous prion protein (PrP). Although there is currently no vaccine or therapy against prion disease, several classes of small-molecule compounds have been shown to increase disease-free incubation time in prion-infected mice. An apparent obstacle to effective anti-prion therapy is the emergence of drug-resistant strains during static therapy with either single compounds or multi-drug combination regimens. Here, we treated scrapie-infected mice with dynamic regimens that alternate between different classes of anti-prion drugs. The results show that alternating regimens containing various combinations of Anle138b, IND24 and IND116135 reduce the incidence of combination drug resistance, but do not significantly increase long-term disease-free survival compared to monotherapy. Furthermore, the alternating regimens induced regional vacuolation profiles resembling those generated by a single component of the alternating regimen, suggesting the emergence of strain dominance.

scholarly journals PM2.5 can Promote the Alzheimer's Disease-like Changes through Microglia Related Mechanism in Mice

2020 ◽  
Author(s):  
Jiaqi Wang ◽  
Jie Li ◽  
Jia Wang ◽  
Wenping Sun ◽  
Qiuyuan Fang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Complete Blood Count ◽  
Morphological Changes ◽  
Mrna Level ◽  
Air Pollutant ◽  
Whole Genome ◽  
Expression Of Genes

Abstract Background: PM2.5, the main particulate air pollutant, poses serious hazard to human health. Alzheimer's disease (AD) is a major neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles. Recent studies reported that PM could promote AD-like pathologies in human brain. However, the mechanism of PM2.5-induced AD-like changes is still unclear and more investigations are needed for further understanding.Methods: In this study, we established experimental model of long-term PM2.5 exposure with young/old wildtype C57BL/6 and APP/PS transgenic mice. Behavior assessments were monitored after four weeks of exposure. The changes of blood cells were detected by Complete Blood Count and splenic macrophages were detected by flow cytometry. Immunohistochemical staining was used to observe the damage of PM2.5 on neurons, the deposition of Aβ and the changes of microglia. RNA-seq was used to analyze the whole genome changes of hippocampus after PM2.5 exposure. In addition, microglia related genes were analyzed via Real-time PCR. Results: After mice were exposed to PM2.5 for a month, some AD-like behavioral changes, such as learning and memory impairment were detected especially in old and transgenic mice. The histopathological changes, such as β-amyloid (Aβ) deposition, morphological changes of microglia, as well as great impairments of hippocampus neurons but not cortex neurons were observed. The analyze of whole-genome expression in the hippocampus suggested long term PM2.5 exposure changed the expression of genes related with AD process (mouse behavior and microglia differentiation). Furthermore, the mRNA level, which related to microglia, of CD86, CD22, IL-1β was upregulated and CD206, TREM2, TGF-β2 was downregulated. Conclusions: Aged population were more susceptible to long-term PM2.5 exposure and PM2.5 could promote AD-like phenotype through microglia related mechanism.

Comparative assessment of morphological mechanisms of maintaining structural liver homeostasis in the dynamics of exposure to coal-rock dust and sodium fluoride on the body

2020 ◽  
pp. 189-194
Author(s):  
M. S. Bugaeva ◽  
O. I. Bondarev ◽  
N. N. Mikhailova ◽  
L. G. Gorokhova
Keyword(s):  
Sodium Fluoride ◽  
Morphological Changes ◽  
The Body ◽  
System Level ◽  
Production Factor ◽  
Coal Rock ◽  
The Impact ◽  
Structural Homeostasis ◽  
Rock Dust

Introduction. The impact on the body of such factors of the production environment as coal-rock dust and fluorine compounds leads to certain shift s in strict indicators of homeostasis at the system level. Maintaining the relative constancy of the internal environment of the body is provided by the functional consistency of all organs and systems, the leading of which is the liver. Organ repair plays a crucial role in restoring the structure of genetic material and maintaining normal cell viability. When this mechanism is damaged, the compensatory capabilities of the organ are disrupted, homeostasis is disrupted at the cellular and organizational levels, and the development of the main pathological processes is noted.The aim of the study is to compare the morphological mechanisms of maintaining structural homeostasis of the liver in the dynamics of the impact on the body of coal-rock dust and sodium fluoride.Materials and methods. Experimental studies were conducted on adult white male laboratory rats. Features of morphological mechanisms for maintaining structural homeostasis of the liver in the dynamics of exposure to coal-rock dust and sodium fluoride were studied on experimental models of pneumoconiosis and fluoride intoxication. For histological examination in experimental animals, liver sampling was performed after 1, 3, 6, 9, 12 weeks of the experiment.Results. The specificity of morphological changes in the liver depending on the harmful production factor was revealed. It is shown that chronic exposure to coal-rock dust and sodium fluoride is characterized by the development of similar morphological changes in the liver and its vessels from the predominance of the initial compensatory-adaptive to pronounced violations of the stromal and parenchymal components. Long-term inhalation of coal-rock dust at 1–3 weeks of seeding triggers adaptive mechanisms in the liver in the form of increased functional activity of cells, formation of double-core hepatocytes, activation of immunocompetent cells and endotheliocytes, ensuring the preservation of the parenchyma and the general morphostructure of the organ until the 12th week of the experiment. Exposure to sodium fluoride leads to early disruption of liver compensatory mechanisms and the development of dystrophic changes in the parenchyma with the formation of necrosis foci as early as the 6th week of the experiment.Conclusions. The study of mechanisms for compensating the liver structure in conditions of long-term exposure to coal-rock dust and sodium fluoride, as well as processes that indicate their failure, and the timing of their occurrence, is of theoretical and practical importance for developing recommendations for the timely prevention and correction of pathological conditions developing in employees of the aluminum and coal industry.The authors declare no conflict of interests.

scholarly journals Mimosa tenuiflora Aqueous Extract: Role of Condensed Tannins in Anti-Aflatoxin B1 Activity in Aspergillus flavus

Toxins ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 391
Author(s):  
Christopher Hernandez ◽  
Laura Cadenillas ◽  
Anwar El Maghubi ◽  
Isaura Caceres ◽  
Vanessa Durrieu ◽  
...  
Keyword(s):  
Aspergillus Flavus ◽  
Aqueous Extract ◽  
Aflatoxin B1 ◽  
Condensed Tannins ◽  
Fungal Growth ◽  
Oxidation Reactions ◽  
Expression Of Genes ◽  
Dependent Inhibition ◽  
Interesting Candidate ◽  
Mimosa Tenuiflora

Aflatoxin B1 (AFB1) is a potent carcinogenic mycotoxin that contaminates numerous crops pre- and post-harvest. To protect foods and feeds from such toxins without resorting to pesticides, the use of plant extracts has been increasingly studied. The most interesting candidate plants are those with strong antioxidative activity because oxidation reactions may interfere with AFB1 production. The present study investigates how an aqueous extract of Mimosa tenuiflora bark affects both the growth of Aspergillus flavus and AFB1 production. The results reveal a dose-dependent inhibition of toxin synthesis with no impact on fungal growth. AFB1 inhibition is related to a down-modulation of the cluster genes of the biosynthetic pathway and especially to the two internal regulators aflR and aflS. Its strong anti-oxidative activity also allows the aqueous extract to modulate the expression of genes involved in fungal oxidative-stress response, such as msnA, mtfA, atfA, or sod1. Finally, a bio-guided fractionation of the aqueous extract demonstrates that condensed tannins play a major role in the anti-aflatoxin activity of Mimosa tenuiflora bark.

scholarly journals 149. Efficacy of Cochleated Amphotericin B (CAMB) in Mouse and Human Mucocutaneous Candidiasis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S204-S205
Author(s):  
Jigar V Desai ◽  
Amanda Urban ◽  
Doris Z Swaim ◽  
Elise Ferre ◽  
Benjamin Colton ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Clinical Improvement ◽  
Clinical Efficacy ◽  
Chronic Mucocutaneous Candidiasis ◽  
Vaginal Tissue ◽  
Dose Escalation Study ◽  
Fungal Burden ◽  
Mucocutaneous Candidiasis ◽  
Inherited Susceptibility

Abstract Background Candida albicans causes debilitating mucosal infections in patients with inherited susceptibility to chronic mucocutaneous candidiasis (CMC), often requiring long-term azole-based treatment. Due to increasing azole resistance, alternative treatments are desirable. Acquired resistance to amphotericin B (AMB) is rare but AMB use is limited by parenteral administration and nephrotoxicity. Cochleated AMB (CAMB) is a new oral formulation of AMB and thus an attractive option for oropharyngeal candidiasis (OPC), esophageal candidiasis (EC) and vulvovaginal candidiasis (VVC). We assessed the efficacy of CAMB in mouse models of OPC and VVC and in 4 patients with azole resistant CMC manifesting as OPC, EC or VVC. Methods Act1 -/- mice were infected with C. albicans in models of OPC and VVC and were treated once daily via oral gavage with CAMB or vehicle or intraperitoneal AMB-deoxycholate (AMBd) from day 1 through 4 post-infection (pi). At day 5 pi, the tongue or vaginal tissue was harvested to quantify fungal burden. Patients with azole resistant CMC enrolled in a phase 2A CAMB dose escalation study. The primary endpoint was clinical improvement at 2 weeks based on an efficacy scale, followed by optional extension for long-term suppression of CMC to assess safety and efficacy. Results CAMB-treated mice had significantly reduced tongue and vaginal tissue fungal burden compared to vehicle-treated mice, while they exhibited comparable fungal control relative to AMBd-treated mice. Among 4 CAMB-treated patients, 3 reached clinical efficacy by 2 weeks at a dose of 400 mg twice daily and one reached clinical efficacy at 200 mg twice daily. Three of 4 patients continued on the extension phase past 48 months with sustained clinical improvement of OPC and EC; patient #3 had relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical response was not seen for onychomycosis or VVC. CAMB was safe and well-tolerated without renal toxicity. Conclusion Oral administration of CAMB in IL-17-signaling deficient mice resulted in reduced tongue and vaginal tissue fungal burden during mucosal C. albicans infections. A proof-of-concept clinical trial in humans with inherited CMC showed efficacy in OPC and EC with good tolerability and safety. Disclosures Benjamin Colton, PharmD, Merck (Shareholder)Pfizer (Shareholder) Ruying Lu, n/a, Matinas BioPharma Inc. (Employee)Matinas BioPharma Inc. (Employee, Shareholder) Theresa Matkovits, PhD, Matinas BioPharma (Employee, Shareholder) Raphael J. Mannino, n/a, Matinas BioPharma Inc. (Employee, Shareholder) Michail Lionakis, MD, ScD, Matinas BioPharma (Research Grant or Support)

The importance of year-round flea and roundworm prevention in lockdown and beyond

2021 ◽  
Vol 12 (2) ◽  
pp. 54-57
Author(s):  
Ian Wright
Keyword(s):  
Drug Resistance ◽  
Environmental Impact ◽  
Pivotal Role ◽  
Parasite Control ◽  
Treatment Need ◽  
Zoonotic Risk ◽  
Control Protocols

Whether routine preventative deworming regimens for Toxocara spp. in cats and dogs should be used to reduce zoonotic risk, continues to be a subject of much debate. Nurses are on the frontline of giving preventative parasite control advice and it is vital that this is based on the latest evidence to minimise zoonotic risk while ensuring over treatment does not take place. The need for routine year-round flea treatment is also fundamental to parasite control protocols in cats and dogs. The benefits of routine flea treatment need to be considered against the possible environmental impact and drug resistance issues that may be associated with long-term use. Veterinary nurses play a pivotal role in giving accurate parasite control to clients and balancing these factors based on the latest evidence.

scholarly journals Diversity and Drug Resistance of Filamentous Fungi Isolated from the Fresh Raspberries

2021 ◽  
Author(s):  
Ewelina Farian ◽  
Angelina Wójcik-Fatla
Keyword(s):  
Drug Resistance ◽  
Food Safety ◽  
Human Health ◽  
Amphotericin B ◽  
Filamentous Fungi ◽  
Rubus Idaeus ◽  
Disc Diffusion ◽  
Potential Threat ◽  
Fungal Strains ◽  
Strip Method

AbstractFungi are one of the most widely distributed microorganisms in the environment, including food such as fruits, vegetables and other crops, posing a potential threat to food safety and human health. The aim of this study was to determine the diversity, intensity and drug resistance of potentially pathogenic filamentous fungi isolated from the fresh raspberries (Rubus idaeus L.). A total of 50 strains belonging to genera Fusarium, Cladosporium, Alternaria, Penicillium, Mucor, Rhizopus, Aspergillus and Acremonium were tested for drug resistance against 11 antifungals by disc diffusion and gradient strips methods. The average mycological contamination in the examined samples of raspberries amounted to 4.34 log CFU/g. The Cladosporium was isolated from all tested samples, followed by Alternaria and Fusarium with a frequency of 61% and 34%, respectively. The highest level of drug resistance was observed for Acremonium genera and Fusarium strains recorded a wide variation in drug resistance as revealed by susceptibility with amphotericin B and voriconzole with MICs ranged from 0.5–4 µg/ml and posaconazole with MICs ranging from 3–8 µg/ml. All fungal strains showed 100% resistance to caspofungin, fluconazole and flucytosine with both the methods, and 100% resistance to micafungin and anidulafungin in the gradient strip method.

Possible reason for preferential damage to renal tubular epithelial cells evoked by amphotericin B.

1996 ◽  
Vol 40 (5) ◽  
pp. 1116-1120 ◽  
Author(s):  
I Walev ◽  
S Bhakdi
Keyword(s):  
Epithelial Cells ◽  
Amphotericin B ◽  
Important Determinant ◽  
Major Complication ◽  
Toxic Action ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Recovery Mechanisms ◽  
Renal Tubular

An important determinant of nephrotoxicity, which is the major complication of long-term amphotericin B treatment, is dysfunction of distal tubular epithelial cells. The underlying cause for this rather selective damage to the cells is unknown. In the present investigation, it was shown that kidney epithelial cells were initially damaged by amphotericin B at concentrations of 2.5 to 10 micrograms/ml, as demonstrable by a dramatic drop in cellular K+ levels. Cells could recover from the initial toxic action of the polyene if they were kept in medium of neutral pH, and cellular K+ levels returned to normal after 6 h. However, the recovery mechanisms failed at lower pHs of 5.6 to 6.0. At low pHs, cells became progressively depleted of ATP; they leaked lactate dehydrogenase and became irreversibly damaged after approximately 6 h. The possibility that the low pH characteristic of the distal tubulus lumen renders the renal epithelial cells particularly vulnerable to the toxic action of amphotericin B is raised. The concept is in line with an earlier report that alkalization ameliorates amphotericin B nephrotoxicity in rats.

scholarly journals Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

2015 ◽  
Vol 210 (5) ◽  
pp. 771-783 ◽  
Author(s):  
Norbert Bencsik ◽  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Krisztián Tárnok ◽  
Sándor Borbély ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Dendritic Spines ◽  
Morphological Changes ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

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