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Pharmaceuticals (Basel, Switzerland) May 2024Recently, there has been great interest in plant-derived compounds known as phytochemicals. The pentacyclic oleanane-, ursane-, and lupane-type triterpenes are...
Recently, there has been great interest in plant-derived compounds known as phytochemicals. The pentacyclic oleanane-, ursane-, and lupane-type triterpenes are phytochemicals that exert significant activity against diseases like cancer. Lung cancer is the leading cause of cancer-related death worldwide. Although chemotherapy is the treatment of choice for lung cancer, its effectiveness is hampered by the dose-limiting toxic effects and chemoresistance. Herein, we investigated six pentacyclic triterpenes, oleanolic acid, ursolic acid, asiatic acid, betulinic acid, betulin, and lupeol, on NSCLC A549 cells. These triterpenes have several structural variations that can influence the activation/inactivation of key cellular pathways. From our results, we determined that most of these triterpenes induced apoptosis, S-phase and G2/M-phase cycle arrest, the downregulation of ribonucleotide reductase (RR), reactive oxygen species, and caspase 3 activation. For chemoresistance markers, we found that most triterpenes downregulated the expression of MAPK/PI3K, STAT3, and PDL1. In contrast, UrA and AsA also induced DNA damage and autophagy. Then, we theoretically determined other possible molecular targets of these triterpenes using the online database ChEMBL. The results showed that even slight structural changes in these triterpenes can influence the cellular response. This study opens up promising perspectives for further research on the pharmaceutical role of phytochemical triterpenoids.
PubMed: 38931361
DOI: 10.3390/ph17060694 -
Nutrients Jun 2024Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the...
Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We found that OC ascites-derived cells contained significantly more intracellular taurine than cell culture-modeled OC. In culture, elevation of intracellular taurine concentration to OC ascites-cell-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse-phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant or wild-type p53 binding to DNA, activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine's suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage-sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine's ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine's cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth and metabolism, and activate cell protective mechanisms involving mTOR and DNA damage-sensing signal transducti.
Topics: Taurine; Humans; TOR Serine-Threonine Kinases; Female; Ovarian Neoplasms; DNA Damage; Cisplatin; Tumor Suppressor Protein p53; Cell Line, Tumor; Cell Proliferation; Signal Transduction; Glycolysis; Extracellular Signal-Regulated MAP Kinases; Antineoplastic Agents
PubMed: 38931171
DOI: 10.3390/nu16121816 -
Plants (Basel, Switzerland) Jun 2024To better understand the mechanism of action of the compounds in the ethanolic extracts of leaves and green husks, their binding to CT-DNA was investigated. This study...
To better understand the mechanism of action of the compounds in the ethanolic extracts of leaves and green husks, their binding to CT-DNA was investigated. This study was conducted to elucidate the in vitro protective effect of extracts against chromosomal damage in mitogen-induced human lymphocytes and investigate the possible application of selec+ted extracts as a natural source of polyphenolic compounds. Using HPLC-MS analysis, 103 different compounds were identified as having a higher number of active species, which is consistent with their activity. The frequency of micronuclei (MN) was scored in binucleated cells, and the nuclear proliferation index was calculated. Cyclic voltammetry experiments demonstrate that the nature of the interaction between extracts and CT-DNA is a synergy of electrostatic and intercalative modes, where leaves extracts showed a higher ability to bind to DNA. Extracts showed excellent antioxidant activity. At a concentration of only 4 µg/mL, extract of leaves and the green husks reduced the incidence of MN by 58.2% and 64.5%, respectively, compared to control cell cultures.
PubMed: 38931101
DOI: 10.3390/plants13121669 -
Plants (Basel, Switzerland) Jun 2024Lemon essential oil, derived from , possesses diverse health-promoting properties, including antioxidant, antimicrobial, and mood-enhancing effects. Despite its...
Lemon essential oil, derived from , possesses diverse health-promoting properties, including antioxidant, antimicrobial, and mood-enhancing effects. Despite its traditional use in aromatherapy and complementary medicine, there is a need for comprehensive investigations into its therapeutic potential, particularly in mitigating DNA damage and supporting health in palliative care settings. This study aimed to evaluate the antigenotoxic effects of lemon essential oil in human peripheral blood mononuclear cells and to explore its potential applications in palliative care. Treatment with lemon essential oil significantly reduced DNA damage, with 1% w/v with 3.13% DNA in tail demonstrating greater efficacy. Furthermore, lemon essential oil attenuated streptonigrin-induced DNA damage, suggesting a potential protective effect against oxidative stress, especially at 3% w/v, with 11.81% DNA in tail. Compared to olive oil treatment, the DNA damage was significantly lower with streptonigrin treatment alone, which had 47.06% DNA in tail, while the olive oil treatment resulted in 36.88% DNA in tail. These results can be attributed to the main constituents: limonene in lemon essential oil and oleic acid in olive oil. These results suggest a potential role in mitigating oxidative stress and supporting genomic stability. Further research is warranted to elucidate the mechanisms of action and clinical applications in palliative care.
PubMed: 38931055
DOI: 10.3390/plants13121623 -
Molecules (Basel, Switzerland) Jun 2024The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the...
The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the effectiveness of targeting the metabolism of nicotinamide adenine dinucleotide (NAD), a pivotal molecule crucial for cancer cell survival and growth, as a promising anticancer strategy. Within mammalian cells, sustaining optimal NAD concentrations relies on two key enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymer 1 (PARP1). Recent studies have accentuated the potential benefits of combining NAMPT inhibitors and PARP1 inhibitors to enhance therapeutic outcomes, particularly in breast cancer. In this study, we designed and synthesized eleven novel NAMPT/PARP1 dual-target inhibitors. Among them, compound DDY02 exhibited acceptable inhibitory activities against both NAMPT and PARP1, with IC values of 0.01 and 0.05 µM, respectively. Moreover, in vitro evaluations revealed that treatment with DDY02 resulted in proliferation inhibition, NAD depletion, DNA damage, apoptosis, and migration inhibition in MDA-MB-468 cells. These results posit DDY02, by targeting NAD metabolism through inhibiting both NAMPT and PARP1, as a promising lead compound for the development of breast cancer therapy.
Topics: Nicotinamide Phosphoribosyltransferase; Humans; NAD; Breast Neoplasms; Poly (ADP-Ribose) Polymerase-1; Antineoplastic Agents; Female; Cell Proliferation; Cell Line, Tumor; Apoptosis; Drug Design; Cytokines; Enzyme Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Molecular Docking Simulation
PubMed: 38930900
DOI: 10.3390/molecules29122836 -
Molecules (Basel, Switzerland) Jun 2024The genome-the source of life and platform of evolution-is continuously exposed to harmful factors, both extra- and intra-cellular. Their activity causes different types...
The genome-the source of life and platform of evolution-is continuously exposed to harmful factors, both extra- and intra-cellular. Their activity causes different types of DNA damage, with approximately 80 different types of lesions having been identified so far. In this paper, the influence of a clustered DNA damage site containing imidazolone (Iz) or oxazolone (Oz) and 7,8-dihydro-8-oxo-2'-deoxyguanosine (dG) on the charge transfer through the double helix as well as their electronic properties were investigated. To this end, the structures of , d[AIzAGA]*d[TCTCT], and , d[AOzAGA]*d[TCTCT], were optimized at the M06-2X/6-D95**//M06-2X/sto-3G level of theory in the aqueous phase using the ONIOM methodology; all the discussed energies were obtained at the M06-2X/6-31++G** level of theory. The non-equilibrated and equilibrated solvent-solute interactions were taken into consideration. The following results were found: (A) In all the discussed cases, dG showed a higher predisposition to radical cation formation, and B) the excess electron migration toward Iz and Oz was preferred. However, in the case of , the electron transfer from Oz to complementary C was noted during vertical to adiabatic anion relaxation, while for , it was settled exclusively on the Iz moiety. The above was reflected in the charge transfer rate constant, vertical/adiabatic ionization potential, and electron affinity energy values, as well as the charge and spin distribution. It can be postulated that imidazolone moiety formation within the CDL ds-oligo structure and its conversion to oxazolone can significantly influence the charge migration process, depending on the C2 carbon hybridization or . The above can confuse the single DNA damage recognition and removal processes, cause an increase in mutagenesis, and harm the effectiveness of anticancer therapy.
Topics: DNA Damage; Imidazoles; Oxazolone; 8-Hydroxy-2'-Deoxyguanosine; DNA; Models, Molecular; Deoxyguanosine; Thermodynamics
PubMed: 38930820
DOI: 10.3390/molecules29122754 -
Molecules (Basel, Switzerland) Jun 2024Ultraviolet B (UVB) exposure can contribute to photoaging of skin. is rich in ursolic acid (UA), which is beneficial to the prevention of photoaging. Because UA is...
Ultraviolet B (UVB) exposure can contribute to photoaging of skin. is rich in ursolic acid (UA), which is beneficial to the prevention of photoaging. Because UA is hardly soluble in water, the extract (COE) was obtained using water as the antisolvent to separate the components containing UA from the crude extract of . The effect of COE on UVB damage was assessed using . The results showed that COE could increase the lifespan and enhance the antioxidant enzyme activity of exposed to UVB while decreasing the reactive oxygen species (ROS) level. At the same time, COE upregulated the expression of antioxidant-related genes and promoted the migration of SKN-1 to the nucleus. Moreover, COE inhibited the expression of the downstream gene and the extension of the lifespan in mutants exposed to UVB, indicating that SKN-1 was required for COE to function. Our findings indicate that COE mainly ameliorates the oxidative stress caused by UVB in via the SKN-1/Nrf2 pathway.
Topics: Animals; Caenorhabditis elegans; Triterpenes; Ursolic Acid; Ultraviolet Rays; Plant Extracts; Caenorhabditis elegans Proteins; Oxidative Stress; Cornus; Antioxidants; Reactive Oxygen Species; Skin Aging; Transcription Factors; DNA-Binding Proteins; Longevity; NF-E2-Related Factor 2
PubMed: 38930783
DOI: 10.3390/molecules29122718 -
Microorganisms May 2024Colorectal cancer (CRC) stands as a significant global health concern, ranking second in mortality and third in frequency among cancers worldwide. While only a small... (Review)
Review
Colorectal cancer (CRC) stands as a significant global health concern, ranking second in mortality and third in frequency among cancers worldwide. While only a small fraction of CRC cases can be attributed to inherited genetic mutations, the majority arise sporadically due to somatic mutations. Emerging evidence reveals gut microbiota dysbiosis to be a contributing factor, wherein polyketide synthase-positive (pks+ ) plays a pivotal role in CRC pathogenesis. pks+ bacteria produce colibactin, a genotoxic protein that causes deleterious effects on DNA within host colonocytes. In this review, we examine the role of the gut microbiota in colon carcinogenesis, elucidating how colibactin-producer bacteria induce DNA damage, promote genomic instability, disrupt the gut epithelial barrier, induce mucosal inflammation, modulate host immune responses, and influence cell cycle dynamics. Collectively, these actions foster a microenvironment conducive to tumor initiation and progression. Understanding the mechanisms underlying pks+ bacteria-mediated CRC development may pave the way for mass screening, early detection of tumors, and therapeutic strategies such as microbiota modulation, bacteria-targeted therapy, checkpoint inhibition of colibactin production and immunomodulatory pathways.
PubMed: 38930493
DOI: 10.3390/microorganisms12061111 -
Materials (Basel, Switzerland) Jun 2024The paper presents the study concerning the preparation and physio-chemical and biological properties of wool-copper (WO-Cu) materials obtained by the sputter deposition...
The paper presents the study concerning the preparation and physio-chemical and biological properties of wool-copper (WO-Cu) materials obtained by the sputter deposition of copper onto the wool fibers. The WO-Cu material was subjected to physio-chemical and biological investigations. The physio-chemical investigations included the elemental analysis of materials (C, N, O, S, and Cu), their microscopic analysis, and surface properties analysis (specific surface area and total pore volume). The biological investigations consisted of the antimicrobial activity tests of the WO-Cu materials against colonies of Gram-positive () bacteria, Gram-negative () bacteria, and fungal mold species (). Biochemical-hematological tests included the evaluation of the activated partial thromboplastin time and pro-thrombin time. The tested wool-copper demonstrated the ability to interact with the DNA in a time-dependent manner. These interactions led to the DNA's breaking and degradation. The antimicrobial and antifungal activities of the WO-Cu materials suggest a potential application as an antibacterial/antifungal material. Wool-copper materials may be also used as customized materials where the blood coagulation process could be well controlled through the appropriate copper content.
PubMed: 38930247
DOI: 10.3390/ma17122878 -
Journal of Clinical Medicine Jun 2024Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper... (Review)
Review
Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as (). Hence, identifying HR-deficiencies by genomic analysis-for instance, used in triple-negative breast cancer-should be a part of the selection process for PARP inhibitor therapy. Published data suggest germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available analysis. In this review, we discuss [F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.
PubMed: 38929955
DOI: 10.3390/jcm13123426