One of the pathological hallmarks of Alzheimer’s disease (AD) associated with its progression that contributes to β-amyloid (Aβ) generation is oxidative stress (OS). Clinical data suggest that ...melatonin is a potent antioxidant that might be effective in the adjunctive therapy of this neurodegenerative disease. The present study aimed to explore the role of melatonin on behavioral changes and markers of OS in three rat models, namely, pinealectomy (pin) model of melatonin deficit, intracerebroventricular (icv)Aβ1-42 model of AD, and combination of both pin and Aβ1-42 model (pin+icvAβ1-42). The chronic injection with vehicle/melatonin (50 mg/kg, i.p. for 40 days) started on the same day of sham/pin and icv vehicle/Aβ1-42 infusion procedures. Anxiety in the open field and the elevated plus-maze test and cognitive responses in the object recognition test were tested between the 30th–35th day after the surgical procedures. Markers of OS in the frontal cortex (FC) and hippocampus were detected by the ELISA method. Melatonin treatment corrected the exacerbated anxiety response only in the pin+icvAβ1-42 model while it alleviated the cognitive impairment in the three models. Pinealectomy disturbed the antioxidant system via enhanced SOD activity and decreased GSH levels both in the FC and hippocampus. The Aβ1-42 model decreased the SOD activity in the FC and elevated the MDA level in the two brain structures. The pin+icvAβ1-42 model impaired the antioxidant system and elevated lipid peroxidation. Melatonin supplementation restored only the elevated MDA level of icvAβ1-42 and pin+icvAβ1-42 model in the hippocampus. In conclusion, our study reveals that the pin+icvAβ1-42 rat model triggers more pronounced anxiety and alterations in markers of OS that may be associated with melatonin deficit concomitant to icvAβ1-42-induced AD pathology.
The partial efficacy and high toxicity of the current anticancer chemotherapeutics as well as the development of multiple drug resistance are the major problems in cancer therapy. Therefore, there is ...an emergency need for the development of novel well-tolerated anticancer agents with different mode of action that could be successfully used in combination with other drugs as an adjuvant therapy. The inhibition of intracellular signaling pathways associated with cancer growth and invasiveness is a main therapeutic approach in cancer treatment. It is well known that lipid metabolism is involved in the regulation of key cellular processes such as proliferation, differentiation and apoptosis. Statins and alkylphospholipids are both relatively new synthetic agents with considerable anticancer properties that disturb lipid metabolism and subsequently modulate proliferation and cell survival signaling pathways, leading to apoptosis. Numerous in vitro and in vivo studies have shown promising results for the use of statins and alkylphospholipids as potential therapeutic agents in the treatment of various human malignancies. However, more investigations and clinical trials are needed to assess their optimal safe dose and maximal efficacy and better understand the molecular mechanisms underlying the antitumor effects of these drugs.
Betulinic acid (BA) is a natural pentacyclic triterpene with diverse biological activities. However, its low water solubility limits its pharmaceutical application. The conversion of pharmaceutically ...active molecules into ionic liquids (ILs) is a promising strategy to improve their physicochemical properties, stability, and/or potency. Here, we report the synthesis and characterization of 15 novel ILs containing a cation ethyl ester of a polar, non-polar, or charged amino acid AAOEt and an anion BA. Except for ValOEtBA, we observed preserved or up to 2-fold enhanced cytotoxicity toward hormone-dependent breast cancer cells MCF-7. The estimated IC50 (72 h) values within the series varied between 4.8 and 25.7 µM. We found that the most cytotoxic IL, LysOEtBA
, reduced clonogenic efficiency to 20% compared to that of BA. In addition, we evaluated the effect of a 72 h treatment with BA or LysOEtBA
, the most cytotoxic compound, on the thermodynamic behavior of MCF-7 cells. Based on our data, we suggest that the charged amino acid lysine included in the novel ILs provokes cytotoxicity by a mechanism involving alteration in membrane lipid organization, which could be accompanied by modulation of the visco-elastic properties of the cytoplasm.
Fluorescent micellar carriers with controlled release of a novel anticancer drug were developed to enable intracellular imaging and cancer treatment simultaneously. The nanosized fluorescent micellar ...systems were embedded with a novel anticancer drug via the self-assembling behavior of well-defined block copolymers based on amphiphilic poly(acrylic acid)-block-poly(n-butyl acrylate) (PAA-b-PnBA) copolymer obtained by Atom Transfer Radical Polymerization (ATRP) and hydrophobic anticancer benzimidazole-hydrazone drug (BzH). Through this method, well-defined nanosized fluorescent micelles were obtained consisting of a hydrophilic PAA shell and a hydrophobic PnBA core embedded with the BzH drug due to the hydrophobic interactions, thus reaching very high encapsulation efficiency. The size, morphology, and fluorescent properties of blank and drug-loaded micelles were investigated using dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescent spectroscopy, respectively. Additionally, after 72 h of incubation, drug-loaded micelles released 3.25 μM of BzH, which was spectrophotometrically determined. The BzH drug-loaded micelles were found to exhibit enhanced antiproliferative and cytotoxic effects on MDA-MB-231 cells, with long-lasting effects on microtubule organization, with apoptotic alterations and preferential localization in the perinuclear space of cancer cells. In contrast, the antitumor effect of BzH alone or incorporated in micelles on non-cancerous cells MCF-10A was relatively weak.
Common butterbur (
L.) is a traditional medicinal plant with numerous therapeutic properties among which is its recently uncovered anti-tumor activity. The present study aims to examine the activity ...of a standardized Bulgarian
L. root extract, containing the active ingredients petasins, on the human breast cancer cell line MDA-MB-231 and non-cancerous MCF-10A cells. Specifically, we examined cell death, oxidative stress, and nuclear factor kappa-B (NF-κB) signaling.
A standardized butterbur powdered extract containing a minimum of 15% petasins was used. A lipophilic extract was obtained from subterranean portion of the plant of Bulgarian populations of
using liquid-liquid extraction after completely removing pyrrolizidine alkaloids. The induction of apoptosis and necrosis was analyzed by flow cytometry, and oxidative stress biomarkers and NF-κB were measured using enzyme-linked immunosorbent assay (ELISA).
L. root extract triggered apoptosis in a cancer-specific fashion and induced a moderate oxidative stress characterized by diminished glutathione (GSH) levels and elevated malondialdehyde (MDA) levels in MDA-MB-231 72 h after treatment. NF-κB levels were higher in cancer cells after treatment with IC50 and IC75 doses, this suggested that the NF-κB pathway was activated in response to oxidative stress leading to the induction of apoptosis. MCF-10A cells were affected to a lesser extent by the
extract, and the adaptive response of their antioxidant defense system halted oxidative stress.
Overall, these results indicate that
L. root extract selectively acts as a pro-oxidant in breast cancer cells and thus represents a potential therapeutic option for cancer treatment with fewer side effects.
Previous studies have explored the antinociceptive effects of riboflavin (vitamin B2) across various experimental models. However, there remains a gap in the literature regarding its potential to ...alleviate neuropathic pain in diabetes. This study aims to investigate the effects of riboflavin on hyperalgesia and serum glutamine-to-glutamate ratio in rats with painful diabetic neuropathy. In fasted rats, a model of painful diabetic neuropathy was induced through intraperitoneal injection of streptozotocin. In the fifth week post-injection, diabetic rats experiencing neuropathic pain were administered daily doses of riboflavin (25 or 50 mg), dissolved in their drinking water, for a duration of two weeks. Results demonstrate that riboflavin significantly reduced mechanical and cold-induced hyperalgesia in diabetic rats compared to controls. Formalin-induced hyperalgesia was alleviated by riboflavin in the second phase. Additionally, riboflavin supplementation increased the serum glutamine-to-glutamate ratio in these animals. These findings highlight the therapeutic potential of riboflavin in managing neuropathic pain associated with diabetes.
Replication of a damaged DNA template can threaten the integrity of the genome, requiring the use of various mechanisms to tolerate DNA lesions. The Smc5/6 complex, together with the Nse2/Mms21 SUMO ...ligase, plays essential roles in genome stability through undefined tasks at damaged replication forks. Various subunits within the Smc5/6 complex are substrates of Nse2, but we currently do not know the role of these modifications. Here we show that sumoylation of Smc5 is targeted to its coiled-coil domain, is upregulated by replication fork damage, and participates in bypass of DNA lesions. smc5-KR mutant cells display defects in formation of sister chromatid junctions and higher translesion synthesis. Also, we provide evidence indicating that Smc5 sumoylation modulates Mph1-dependent fork regression, acting synergistically with other pathways to promote chromosome disjunction. We propose that sumoylation of Smc5 enhances physical remodeling of damaged forks, avoiding the use of a more mutagenic tolerance pathway.
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•Smc5-SUMO is a specific read-out for damaged replication forks•SUMO preferentially targets lysines in the coiled-coil domain of Smc5•smc5-KR is epistatic to MPH1, upregulating TLS and reducing strand exchange•Defects in Smc5 sumoylation are normally backed up by the Mms4-Mus81 nuclease
Zapatka et al. show that sumoylation of Smc5 helps cells tolerate DNA lesions at damaged replication forks in an error-free mode. Using unsumoylatable smc5-KR mutants, they show that this modification operates through Mph1 in fork regression, working in parallel with several nucleases and helicases to promote chromosome segregation.
Diabetes mellitus is one of the most common chronic diseases in the world. Metabolomic studies have demonstrated altered blood levels of glutamate and glutamine during type 1 diabetes and type 2 ...diabetes. Riboflavin is a precursor of flavin adenine dinucleotide and flavin mononucleotide, which are coenzymes necessary for the function of enzymes involved in various biochemical reactions, including those affecting amino acid metabolism. In this study, we investigated the effects of riboflavin on serum glutamate and glutamine levels in rats with streptozotocin-induced type 1 diabetes. Diabetic rats received riboflavin (25 mg, 50 mg, or 100 mg) dissolved in the drinking water daily for 2 weeks. Our results showed that riboflavin supplementation did not affect serum glutamate levels but increased serum glutamine levels in diabetic rats. We speculate that increased serum glutamine levels resulting from riboflavin supplementation may have beneficial effects during diabetes.
One of the pathological hallmarks of Alzheimer's disease (AD) associated with its progression that contributes to β-amyloid (Aβ) generation is oxidative stress (OS). Clinical data suggest that ...melatonin is a potent antioxidant that might be effective in the adjunctive therapy of this neurodegenerative disease. The present study aimed to explore the role of melatonin on behavioral changes and markers of OS in three rat models, namely, pinealectomy (pin) model of melatonin deficit, intracerebroventricular (icv)Aβ
model of AD, and combination of both pin and Aβ
model (pin+icvAβ
). The chronic injection with vehicle/melatonin (50 mg/kg, i.p. for 40 days) started on the same day of sham/pin and icv vehicle/Aβ
infusion procedures. Anxiety in the open field and the elevated plus-maze test and cognitive responses in the object recognition test were tested between the 30th-35th day after the surgical procedures. Markers of OS in the frontal cortex (FC) and hippocampus were detected by the ELISA method. Melatonin treatment corrected the exacerbated anxiety response only in the pin+icvAβ
model while it alleviated the cognitive impairment in the three models. Pinealectomy disturbed the antioxidant system via enhanced SOD activity and decreased GSH levels both in the FC and hippocampus. The Aβ
model decreased the SOD activity in the FC and elevated the MDA level in the two brain structures. The pin+icvAβ
model impaired the antioxidant system and elevated lipid peroxidation. Melatonin supplementation restored only the elevated MDA level of icvAβ
and pin+icvAβ
model in the hippocampus. In conclusion, our study reveals that the pin+icvAβ
rat model triggers more pronounced anxiety and alterations in markers of OS that may be associated with melatonin deficit concomitant to icvAβ
-induced AD pathology.
This is the first study on the surface modification of a hemocyanin from marine snail Rapana thomasiana (RtH) with series of imidazolium-based amino acid ionic liquids emimAA. We monitored the ...induced by emimAA conformational changes in RtH molecule and evaluated the effect of these ionic liquids (ILs) on the protein thermal stability. The cytotoxicity of all obtained RtH-emimAA complexes was assessed toward breast cancer cells (MCF-7) and murine fibroblasts (3T3).
As a whole, even small amounts of the tested ILs altered the secondary structure of RtH. The thermal denaturation of RtH in presence of emimAA displayed multi-component transitions, which were shifted toward lower temperatures in comparison to those estimated for the native RtH. The profiles of the RtH-IL calorimetric curves show a clear dependence on the structure of the added salts. In addition, all RtH-emimAA complexes exhibited an enhanced antiprofilerative activity of toward MCF-7 cells in comparison to that of the native RtH. The best results are observed for RtH-emimLeu, RtH-emimTrp or RtH-emimIle, which applied in concentration of 700μg/mL inhibited the MCF-7 cell viability (for 24h) by 66, 63 and 53%, respectively. In addition, these IL-RtH complexes were less cytotoxic to 3T3 cells, i.e. they exhibited some cell specificity.
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