Daunorubicin and its hydroxy metabolite in cardiomyocytes: insights into cellular kinetics, toxicity, DNA damage, and dexrazoxane-induced cardioprotection.

Anthracycline anticancer agents, such as daunorubicin and doxorubicin, rank among the most effective and widely used anticancer drugs. However, their benefit is markedly reduced by the risk of severe cardiotoxicity. Anthracyclines undergo metabolic reduction of the side chain carbonyl group, producing hydroxy metabolites implicated in the cardiotoxicity.

Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection.

Topoisomerase II alpha and beta (TOP2A and TOP2B) isoenzymes perform essential and non-redundant cellular functions. Anthracyclines induce their potent anti-cancer effects primarily via TOP2A, but at the same time they induce a dose limiting cardiotoxicity through TOP2B. Here we describe the development of the obex class of TOP2 inhibitors that bind to a previously unidentified druggable pocket in the TOP2 ATPase domain to act as allosteric catalytic inhibitors by locking the ATPase domain conformation with the capability of isoform-selective inhibition.

Phytohormone and Amino Acid Changes in Cherry Radish as Metabolic Adaptive Response to Arsenic Single and Multi-Contamination.

This study investigated the metabolic adaptive responses to As contamination and As co-contamination with cadmium, lead, and zinc in the leaves and tubers of cherry radish ( var. Pers.).

Changes in Secondary Metabolites Content and Antioxidant Enzymes Activity in Leaves of Two L. Genotypes During Various Phenological Phases.

In addition to its fruit, the sweet cherry ( L.) has other parts that can be used as a source of compounds with beneficial biological activity. The content of these metabolites is affected by different inner and outer factors, often as a response to plant defense against various stresses.

Zinc oxide nanoparticles application alleviates salinity stress by modulating plant growth, biochemical attributes and nutrient homeostasis in L.

Salt stress poses a significant challenge to global agriculture, adversely affecting crop yield and food production. The current study investigates the potential of Zinc Oxide (ZnO) nanoparticles (NPs) in mitigating salt stress in common beans. Salt-stressed bean plants were treated with varying concentrations of NPs (25 mg/L, 50 mg/L, 100 mg/L, 200 mg/L) using three different application methods: foliar application, nano priming, and soil application.

Exploring the effects of topoisomerase II inhibitor XK469 on anthracycline cardiotoxicity and DNA damage.

Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However, cardiotoxicity remains the main limitation of their clinical use. Topoisomerase IIβ has recently been identified as a plausible target of anthracyclines in cardiomyocytes.

Hydrophobicity-enhanced ferritin nanoparticles for efficient encapsulation and targeted delivery of hydrophobic drugs to tumor cells.

Ferritin, a naturally occurring iron storage protein, has gained significant attention as a drug delivery platform due to its inherent biocompatibility and capacity to encapsulate therapeutic agents. In this study, we successfully genetically engineered human H ferritin by incorporating 4 or 6 tryptophan residues per subunit, strategically oriented towards the inner cavity of the nanoparticle. This modification aimed to enhance the encapsulation of hydrophobic drugs into the ferritin cage.

Effect of Arsenic Soil Contamination on Stress Response Metabolites, 5-Methylcytosine Level and CDC25 Expression in Spinach.

Experimental spinach plants grown in soil with (5, 10 and 20 ppm) arsenic (As) contamination were sampled in 21 days after As(V) contamination. Levels of As in spinach samples (from 0.31 ± 0.

2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1.

Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC of 4 μM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed.

Arsenic Soil Contamination and Its Effects on 5-Methylcytosine Levels in Onions and Arsenic Distribution and Speciation.

Arsenic represents a serious health threat in localities with a high arsenic-polluted environment and can easily get into the human food chain through agronomy production in areas affected by arsenic contamination. Onion plants that were grown in controlled conditions in arsenic-contaminated soil (5, 10, and 20 ppm) were harvested 21 days after contamination. Arsenic levels (from 0.

Primary prevention of chronic anthracycline cardiotoxicity with ACE inhibitor is temporarily effective in rabbits, but benefits wane in post-treatment follow-up.

Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline (ANT)-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent ANT-induced cardiac damage and provide long-lasting cardioprotection. The present study aimed to examine the cardioprotective effects of perindopril on chronic ANT cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane (DEX) with focus on post-treatment follow-up (FU).

Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation.

Background: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept.

Prodrug of ICRF-193 provides promising protective effects against chronic anthracycline cardiotoxicity in a rabbit model in vivo.

The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer survivors. A bisdioxopiperazine agent dexrazoxane (DEX) has been developed as a cardioprotective drug to prevent these adverse events, but it is uncertain whether it is the best representative of the class. The present study used a rabbit model of chronic ANT cardiotoxicity to examine another bisdioxopiperazine compound called GK-667 (meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,1-diyl))bis(methylene)-bis(2-aminoacetate) hydrochloride), a water-soluble prodrug of ICRF-193 (meso-4,4'-(butan-2,3-diyl)bis(piperazine-2,6-dione)), as a potential cardioprotectant.

Ornamental Plant Efficiency for Heavy Metals Phytoextraction from Contaminated Soils Amended with Organic Materials.

Accumulation of heavy metals (HMs) by ornamental plants (OPs) from contaminated agriculture soils is a unique technique that can efficiently reduce the metal load in the food chain. L. has attractive characteristics acquiring a higher growth rate and large biomass when grown at heavy metal contaminated soils.

Structure-Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions.

Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability.

Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity.

The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs).

COVID-19 Prophylaxis Efforts Based on Natural Antiviral Plant Extracts and Their Compounds.

During the time of the novel coronavirus disease 2019 (COVID-19) pandemic, it has been crucial to search for novel antiviral drugs from plants and well as other natural sources as alternatives for prophylaxis. This work reviews the antiviral potential of plant extracts, and the results of previous research for the treatment and prophylaxis of coronavirus disease and previous kinds of representative coronaviruses group. Detailed descriptions of medicinal herbs and crops based on their origin native area, plant parts used, and their antiviral potentials have been conducted.

Effect of Gibberellic Acid on Growing-Point Development of Non-Vernalized Wheat Plants under Long-Day Conditions.

The goal of this study was to determine whether the application of gibberellic acid (GA) to seeds of common wheat varieties with different vernalization and photoperiod requirements affects the transition from vegetative to generative stage. Three varieties of wheat with different photoperiod sensitivities and vernalization were selected for the experiment-the winter varieties, Mironovskaya and Bezostaya, and the spring variety, Sirael. Seeds were treated with different concentrations of GA and plants were grown under long-day conditions with monitoring of their photosynthetic activity (F/F, P, E, g).

Effect of Acetaminophen (APAP) on Physiological Indicators in .

This study analyzes the effects of acetaminophen (APAP) as a contaminant on physiological characteristics of lettuce plants ( L.). Experiments were provided in an experimental greenhouse with semi-controlled conditions.

Betacyanins and Betaxanthins in Cultivated Varieties of L. Compared to Weed Beets.

There are 11 different varieties of L. that are used in the food industry, including sugar beets, beetroots, Swiss chard, and fodder beets. The typical red coloration of their tissues is caused by the indole-derived glycosides known as betalains that were analyzed in hypocotyl extracts by UV/Vis spectrophotometry to determine the content of betacyanins (betanin) and of betaxanthins (vulgaxanthin I) as constituents of the total betalain content.

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase II Interaction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity.

Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase II (Top2B) activity in chronic anthracycline cardiotoxicity.

and investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline.

Although proteasome inhibitors (PIs) are modern targeted anticancer drugs, they have been associated with a certain risk of cardiotoxicity and heart failure (HF). Recently, PIs have been combined with anthracyclines (ANTs) to further boost their anticancer efficacy. However, this raised concerns regarding cardiac safety, which were further supported by several studies on immature cardiomyocytes.

Changes in Content of Polyphenols and Ascorbic Acid in Leaves of White Cabbage after Pest Infestation.

Crops, such as white cabbage ( L. var. (L.

Vanadium elicitation of Trifolium pratense L. cell culture and possible pathways of produced isoflavones transport across the plasma membrane.

Vanadium compounds increased the content and release of distinct isoflavones in a Trifolium pratense suspension culture. Regarding transport-mechanism inhibitors, the process was mostly facilitated by ABC proteins and vesicular transport. The transport of isoflavones and other secondary metabolites is an important part of metabolism within plants and cultures in vitro regarding their role in defence against various abiotic and biotic stressors.

2,6-Dihydroxybenzaldehyde Analogues of the Iron Chelator Salicylaldehyde Isonicotinoyl Hydrazone: Increased Hydrolytic Stability and Cytoprotective Activity against Oxidative Stress.

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a small molecule and lipophilic chelating agent that firmly binds ferric ions from the cellular labile iron pool and is able to protect various tissues against oxidative damage. Previously, SIH possessed the best ratio of cytoprotective efficiency to toxicity among various iron chelators, including the desferrioxamine, deferiprone, and deferasirox used in clinical practice. Here, we prepared a series of 2,6-dihydroxybenzaldehyde aroylhydrazones as SIH analogues with an additional hydroxyl group that can be involved in the chelation of metal ions.