The Influence of Betulin and Its Derivatives EB5 and ECH147 on the Antioxidant Status of Human Renal Proximal Tubule Epithelial Cells

Kruszniewska‐Rajs, Celina; Strzałka‐Mrozik, Barbara; Kimsa-Dudek, Magdalena; Synowiec-Wojtarowicz, Agnieszka; Chrobak, Elwira; Bębenek, Ewa; Boryczka, Stanisław; Głuszek, Stanisław; Gola, Joanna

doi:10.3390/ijms23052524

Cited by 10 publications

(10 citation statements)

References 40 publications

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“…In line with the results of Kruszniewska et al's research [15], we selected the compounds EB5, ECH147, betulin, cisplatin (Sigma-Aldrich, St Louis, MO, USA) and 5-fluorouracil (Sigma-Aldrich, St Louis, MO, USA) at concentrations of 0.1 and 0.5 µg/mL. For the cell treatment, the tested compounds were dissolved in DMSO (Merck, Darmstadt, Germany) and the mixture thus obtained was added to the culture media.…”

Section: Cell Culture Conditions and Treatmentsupporting

confidence: 90%

“…Zehra et al reported the low cytotoxicity of betulin in mouse fibroblasts [49], whereas Małaczewska et al proved that it is highly toxic to these cells [50]. Kruszniewska et al confirmed that betulin and its derivatives EB5 and ECH147 are cytotoxic to RPTECs, except at lower concentrations such as 0.1 and 0.5 µg/mL [15]; therefore, they were chosen for this research.…”

Section: Importance Of Nephrotoxicity Studies and The Use Of Selected...mentioning

confidence: 99%

“…EB5 and ECH147 have been proven to be effective in several studies [11][12][13][14] involving various cancer cell lines. These compounds were also selected in a study that focused on their influence on the antioxidant status of RPTECs [15]. That research proved that betulin and its derivatives EB5 and ECH147 affect the viability of renal proximal tubule epithelial cells through influencing the antioxidant system.…”

Section: Introductionmentioning

confidence: 99%

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The Influence of Betulin Derivatives EB5 and ECH147 on the Expression of Selected TGFβ Superfamily Genes, TGFβ1, GDF15 and BMP2, in Renal Proximal Tubule Epithelial Cells

Kubica,

Szota-Czyż,

Strzałka-Mrozik

et al. 2023

CIMB

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Betulin derivatives are proposed to serve as an alternative to the drugs already established in oncologic treatment. Drug-induced nephrotoxicity leading to acute kidney injury frequently accompanies cancer treatment, and thus there is a need to research the effects of betulin derivatives on renal cells. The objective of our study was to assess the influence of the betulin derivatives 28-propynylobetulin (EB5) and 29-diethoxyphosphoryl-28-propynylobetulin (ECH147) on the expression of TGFβ1, BMP2 and GDF15 in renal proximal tubule epithelial cells (RPTECs) cultured in vitro. The changes in mRNA expression and copy numbers were assessed using real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) and the standard curve method, respectively. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the effect of the betulin derivatives on the protein concentration in the culture media’s supernatant. The assessment of the betulin derivatives’ influence on gene expression demonstrated that the mRNA level and protein concentration did not always correlate with each other. Each of the tested compounds affected the mRNA expression. The RT-qPCR analyses showed that EB5 and ECH147 induced effects similar to those of betulin or cisplatin and resulted in a decrease in the mRNA copy number of all the analyzed genes. The ELISA demonstrated that EB5 and ECH147 elevated the protein concentration of TGFβ1 and GDF15, while the level of BMP2 decreased. The concentration of the derivatives used in the treatment was crucial, but the effects did not always exhibit a simple linear dose-dependent relationship. Betulin and its derivatives, EB5 and ECH147, influenced the gene expression of TGFβ1, BMP2 and GDF15 in the renal proximal tubule epithelial cells. The observed effects raise the question of whether treatment with these compounds could promote the development of renal fibrosis.

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Section: Cell Culture Conditions and Treatmentsupporting

confidence: 90%

Section: Importance Of Nephrotoxicity Studies and The Use Of Selected...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Influence of Betulin Derivatives EB5 and ECH147 on the Expression of Selected TGFβ Superfamily Genes, TGFβ1, GDF15 and BMP2, in Renal Proximal Tubule Epithelial Cells

Kubica,

Szota-Czyż,

Strzałka-Mrozik

et al. 2023

CIMB

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“…6). The presence of free for substitution groups in other positions open up opportunities for further modifications (Kruszniewska-Rajs et al, 2022). Drąg-Zalesińska et al (2019) have demonstrated significant activity of betulin-diamino butanoic ester 12 (Fig.…”

Section: Bioavailability Of the Terpenoidsmentioning

confidence: 99%

Lupane-Type Triterpenoids Biotransformation

Sagatovich,

Abdimanapovich,

Vasilevich

et al. 2024

OnLine Journal of Biological Sciences

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A lot of scientific material has been accumulated in recent years about the biotransformation processes of lupine-type triterpenoids. The novelty of this review is the summary of these works, the analysis and identification of the most suitable biocatalysts for future researchers, and the presentation of development trends for new derivatives. The known biotransformation examples of the most common lupine-type triterpenoid representatives are considered. Analysis of their biosynthesis pathways starting with squalene is included also. Various approaches in this study are discussed to biotransformation using fungi, bacteria, and plant cell cultures. The conversion of betulin to betulinic acid is a process of special, even extreme interest. Cytochromes P450 are responsible for the catalysis of oxidation reactions while air oxygen is the oxidizer. The expression and activity of these enzymes are crucial factors for product yield. Basically, any given lupine-type triterpenoid can be transformed with P450 monooxygenases. Sadly, P450 catalysts are heme and NAD (P) H-dependent thus using isolated enzymes is not an option for biotransformation. So the whole-cell catalytic processes are completed by the formation of acids, ketones, or other oxidized products. Fungi cell cultures especially Cunninghamella blakesleeana, Armillaria luteo-virens, and Rhodotorula mucilaginosa are characterized by one of the highest conversion rates. Also, fungi cells are tolerant to the antibacterial activity of lupinetype triterpenoids. Thus fungi are the most successful biocatalysts for biotransformation. Applications of lupane-type triterpenoids such as pro-drugs and cosmetics are addressed in the final part of this study. It has clearly indicated development prospects for obtaining new useful derivatives.

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“…Additionally, the triterpenes have proven neuroprotective, hepatoprotective, antidiabetic, and antioxidant effects [ 25 , 26 , 27 ]. The major pharmacological properties of BE and its derivatives are summarized in Figure 2 .…”

Section: Properties and Molecular Mechanisms Of Betulin And Its Deriv...mentioning

confidence: 99%

Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers

Madej,

Gola,

Chrobak

2023

Pharmaceutics

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Gastrointestinal (GI) cancers are an increasingly common type of malignancy, caused by the unhealthy lifestyles of people worldwide. Limited methods of treatment have prompted the search for new compounds with antitumor activity, in which betulin (BE) is leading the way. BE as a compound is classified as a pentacyclic triterpene of the lupane type, having three highly reactive moieties in its structure. Its mechanism of action is based on the inhibition of key components of signaling pathways associated with proliferation, migration, interleukins, and others. BE also has a number of biological properties, i.e., anti-inflammatory, hepatoprotective, neuroprotective, as well as antitumor. Due to its poor bioavailability, betulin is subjected to chemical modifications, obtaining derivatives with proven enhanced pharmacological and pharmacokinetic properties as a result. The method of synthesis and substituents significantly influence the effect on cells and GI cancers. Moreover, the cytotoxic effect is highly dependent on the derivative as well as the individual cell line. The aim of this study is to review the methods of synthesis of BE and its derivatives, as well as its pharmacological properties and molecular mechanisms of action in colorectal cancer, hepatocellular carcinoma, gastric cancer, and esophageal cancer neoplasms.

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The Influence of Betulin and Its Derivatives EB5 and ECH147 on the Antioxidant Status of Human Renal Proximal Tubule Epithelial Cells

Cited by 10 publications

References 40 publications

The Influence of Betulin Derivatives EB5 and ECH147 on the Expression of Selected TGFβ Superfamily Genes, TGFβ1, GDF15 and BMP2, in Renal Proximal Tubule Epithelial Cells

The Influence of Betulin Derivatives EB5 and ECH147 on the Expression of Selected TGFβ Superfamily Genes, TGFβ1, GDF15 and BMP2, in Renal Proximal Tubule Epithelial Cells

Lupane-Type Triterpenoids Biotransformation

Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers

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