Liver sinusoidal endothelial inflammation/dysfunction and fibrosis are a crucial part of Metabolic Dysfunction Associated Steatohepatitis (MASH) development. TRC105 and M1043 are anti-endoglin (ENG) monoclonal antibodies that bind ENG. In this study, we hypothesized that treatment with anti-ENG antibodies would prevent the progression of LSECs inflammation and fibrosis in vivo and in vitro. MASH was induced in male C57BL/6 mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) for 4 or 8 weeks. In the rescue study, mice were divided into three groups: a control group (chow diet), a MASH group (CDAA-HFD + IgG), and a rescue group (CDAA-HFD + M1043). Later, two groups received rat IgG1 (10 mg/kg) and M1043 (10 mg/kg). In in vitro experiments, inflammation was induced in human LSECs by ox-LDL (50 μg/mL) and treated with TRC105 (300 μg/mL). Liver sinusoidal endothelial inflammation/dysfunction in MASH animals was characterized by endothelial overexpression of ENG, VCAM-1, and ICAM-1 and reduced VE-cadherin and p-eNOS/eNOS expression. M1043 treatment prevented the overexpression of ENG, VCAM-1, and ICAM-1, the progression of liver fibrosis, and the increase of liver-to-body weight ratio. In vitro experiments with TRC105 confirmed the prevention of LSECs inflammation development by reduced ENG and VCAM-1 expression, as well as decreased THP-1 monocytic cell adhesion in ox-LDL activated LSECs. In conclusion, we demonstrate that anti-ENG antibody treatment can prevent LSECs inflammation and fibrosis progression in a MASH animal model and LSECs inflammation in vitro. Thus, we propose directly targeted ENG may represent a promising pharmacological approach for addressing LSECs inflammation and liver fibrosis.
- Klíčová slova
- Anti-endoglin antibody, Endoglin, Fibrosis, Liver alteration, Liver sinusoidal endothelial inflammation,
- MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- endoglin * metabolismus antagonisté a inhibitory MeSH
- endoteliální buňky účinky léků metabolismus patologie MeSH
- jaterní cirhóza * prevence a kontrola patologie farmakoterapie metabolismus MeSH
- játra * patologie účinky léků metabolismus MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- monoklonální protilátky * farmakologie MeSH
- myši inbrední C57BL * MeSH
- myši MeSH
- nealkoholová steatóza jater farmakoterapie prevence a kontrola patologie metabolismus MeSH
- progrese nemoci MeSH
- zánět * patologie farmakoterapie metabolismus prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- endoglin * MeSH
- monoklonální protilátky * MeSH
This phytochemical study presents the isolation of eight alkaloids from Zephyranthes citrina Baker. The structures of the new alkaloids, zephycitrine (1) and 6-oxonarcissidine (2), were established by analysis of spectroscopic and spectrometric data. Processing the EtOH extract under acid-base conditions yielded the unreported isolation artifacts 3 and 4. This work also provides analytical data for alkaloids not properly described in the literature (5 and 6). The hippeastidine/zephyranine scaffolds in derivatives 3, 4, and 8-10 are also thoroughly discussed. Furthermore, a cytotoxicity screening of 25 Amaryllidaceae alkaloids isolated from Z. citrina was performed. Only the known alkaloids haemanthamine (12), haemanthidine (13), and lycorine (27) showed significant cell growth inhibition.
- MeSH
- alkaloidy amarylkovitých * farmakologie chemie izolace a purifikace MeSH
- Amaryllidaceae * chemie MeSH
- fenantridiny farmakologie chemie MeSH
- fytogenní protinádorové látky farmakologie chemie izolace a purifikace MeSH
- lidé MeSH
- molekulární struktura MeSH
- screeningové testy protinádorových léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkaloidy amarylkovitých * MeSH
- fenantridiny MeSH
- fytogenní protinádorové látky MeSH
- hemanthamine MeSH Prohlížeč
- lycorine MeSH Prohlížeč
The increasing threat of nuclear incidents and the widespread use of ionizing radiation (IR) in medical treatments underscore the urgent need for effective radiation countermeasures. Despite the availability of compounds such as amifostine, their clinical utility is significantly limited by adverse side effects and logistical challenges in administration. This study focuses on the synthesis and evaluation of novel piperazine derivatives as potential radioprotective agents, with the aim of overcoming the limitations associated with current countermeasures. We designed, synthesized, and evaluated a series of 1-(2-hydroxyethyl)piperazine derivatives. The compounds were assessed for cytotoxicity across a panel of human cell lines, and for their radioprotective effects in the MOLT-4 lymphoblastic leukemia cell line and in peripheral blood mononuclear cells (PBMCs) exposed to gamma radiation. The radioprotective efficacy was further quantified using the dicentric chromosome assay (DCA) to measure DNA damage mitigation. Among the synthesized derivatives, compound 6 demonstrated the most significant radioprotective effects in vitro, with minimal cytotoxicity across the tested cell lines. Compound 3 also showed notable efficacy, particularly in reducing dicentric chromosomes, thus indicating its potential to mitigate DNA damage from IR. Both compounds exhibited superior safety profiles and effectiveness compared to amifostine, suggesting their potential as more viable radioprotective agents. This study highlights the development of novel piperazine derivatives with promising radioprotective properties. Compound 6 emerged as the leading candidate, offering an optimal balance between efficacy and safety, with compound 3 also displaying significant potential. These findings support the further development and clinical evaluation of these compounds as safer, and more effective radiation countermeasures.
- Publikační typ
- časopisecké články MeSH
The isoquinoline alkaloids found in Amaryllidaceae are attracting attention due to attributes that can be harnessed for the development of new drugs. The possible molecular mechanisms by which montanine exerts its inhibitory effects against cancer cells have not been documented. In the present study, montanine, manthine and a series of 15 semisynthetic montanine analogues originating from the parent alkaloid montanine were screened at a single test dose of 10 μM to explore their cytotoxic activities against a panel of eight cancer cell lines and one non-cancer cell line. Among montanine and its analogues, montanine and its derivatives 12 and 14 showed the highest cytostatic activity in the initial single-dose screening. However, the native montanine exhibited the greatest antiproliferative activity against cancer cells, with a lower mean IC50 value of 1.39 µM, compared to the displayed mean IC50 values of 2.08 µM for 12 and 3.57 µM for 14. Montanine exhibited the most potent antiproliferative activity with IC50 values of 1.04 µM and 1.09 µM against Jurkat and A549 cell lines, respectively. We also evaluated montanine's cytotoxicity and cell death mechanisms. Our results revealed that montanine triggered apoptosis of MOLT-4 cells via caspase activation, mitochondrial depolarisation and Annexin V/PI double staining. The Western blot results of MOLT-4 cells showed that the protein levels of phosphorylated Chk1 Ser345 were upregulated with increased montanine concentrations. Our findings provide new insights into the mechanisms underlying the cytostatic, cytotoxic and pro-apoptotic activities of montanine alkaloids in lung adenocarcinoma A549 and leukemic MOLT-4 cancer cell types.
- Klíčová slova
- Apoptosis, Cell cycle arrest, Cytotoxicity, DNA damage, Manthine, Montanine, Semisynthetic derivatives,
- MeSH
- alkaloidy amarylkovitých * farmakologie MeSH
- alkaloidy * MeSH
- Amaryllidaceae * MeSH
- apoptóza MeSH
- cytostatické látky * MeSH
- isochinoliny farmakologie MeSH
- lidé MeSH
- nádory plic * MeSH
- protinádorové látky * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkaloidy amarylkovitých * MeSH
- alkaloidy * MeSH
- cytostatické látky * MeSH
- isochinoliny MeSH
- montanine MeSH Prohlížeč
- protinádorové látky * MeSH
Aim: This investigation was designed to synthesize half-sandwich Rh(III) and Ru(II) complexes and study their antiproliferative activity in human cancer cell lines. Materials & methods: Nine compounds were prepared and tested by various assays for their anticancer activity and mechanism of action. Results: Hit Rh(III) complex 6 showed low-micromolar potency in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian carcinoma cell lines, promising selectivity toward these cancer cells over normal lung fibroblasts and an unprecedented mechanism of action in the treated cells. DNA synthesis was decreased and CDKN1A expression was upregulated, but p21 expression was not induced. Conclusion: Rh complex 6 showed high antiproliferative activity, which is induced through a p21-independent mechanism of action.
Nine rhodium(III)and ruthenium(II) complexes were developed and screened for their anticancer activity on a panel of human cancer cell lines. The best-performing rhodium(III) complex (6) showed high activity in ovarian cancer cells, including the variant resistant to the conventional anticancer drug cisplatin, while it was less effective towards non-cancerous lung fibroblasts. In cancer cells, compound 6 induced a modification of the cell cycle connected with a significant decrease in DNA synthesis, which was not observed for cisplatin. The effect of 6 on the expression of proteins related to the cell cycle modification was analysed by quantitative PCR and western blot in cancer cells and the results indicated a p21-independent mode of anticancer action, which is different from cisplatin.
- Klíčová slova
- DNA, PCR, antiproliferative activity, half-sandwich, p21, rhodium, ruthenium, western blot,
- Publikační typ
- časopisecké články MeSH
Ambelline, an alkaloid from the Amaryllidaceae family with a crinane-type skeleton, has not yet demonstrated any outstanding biological activity. However, its analogues prepared by derivatization of the C-11 hydroxyl group show different interesting effects. Continuing our earlier work, twelve novel aromatic esters were developed (10, 14, 16, 17, 22-25, 30-33) and studied, together with previously synthesized derivatives (2-9, 11-13, 15, 18-21, 26-29) in terms of their cytotoxic activity. The cytotoxic potential was determined on a panel of nine human cancer cell lines and one noncancerous cell line to characterize their biological activity spectrum. To describe and foresee the structure-activity relationship for further research, substances synthesized and described in our previous work were also included in this cytotoxicity study. The most significant activity was associated with analogues having methyl (10), methoxy (14-17), or ethoxy (18) substitution on the phenyl condensed to ambelline. However, the 4-chloro-3-nitrobenzoyl derivative (32) showed the most promising IC50 values, ranging from 0.6 ± 0.1 µM to 9.9 ± 0.2 µM. In vitro cytotoxicity studies indicated the most potent antiproliferative activity of 32 in a dose-dependent and time-dependent manner. Besides, 32 was found to be effective in decreasing viability and triggering apoptosis of MOLT-4 T-lymphoblastic leukemia cells.
- Klíčová slova
- 11-O-(4-Chloro-3-nitrobenzoyl)ambelline, Amaryllidaceae alkaloids, Ambelline, Antiproliferative activity, Cytotoxicity, In vitro,
- Publikační typ
- časopisecké články MeSH
Glioblastoma multiforme (GBM) belongs to most aggressive and invasive primary brain tumor in adults whose prognosis and survival remains poor. Potential new treatment modalities include targeting the cytoskeleton. In our study, we demonstrated that repurposed drug flubendazole (FLU) significantly inhibits proliferation and survival of GBM cells. FLU exerted its effect by affecting microtubule structure and our results also suggest that FLU influences tubulins expression to a certain degree. Moreover, FLU effects decreased activation of STAT3 and also partially inhibited its expression, leading to upregulation of p53 signaling pathway and subsequent cell cycle arrest at G2/M phase as well as caspase-dependent cell death in GBM cells. These results suggest FLU as a promising agent to be used in GBM treatment and prompting further testing of its effects on GBM.
- MeSH
- apoptóza MeSH
- buněčný cyklus MeSH
- dospělí MeSH
- glioblastom * patologie MeSH
- kontrolní body buněčného cyklu MeSH
- lidé MeSH
- mebendazol farmakologie terapeutické užití MeSH
- nádorové buněčné linie MeSH
- nádory mozku * patologie MeSH
- proliferace buněk MeSH
- transkripční faktor STAT3 metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- flubendazole MeSH Prohlížeč
- mebendazol MeSH
- STAT3 protein, human MeSH Prohlížeč
- transkripční faktor STAT3 MeSH
Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three highlighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 μM. In contrast, the compound 22, 7-azaindole congener with the most pronounced cytotoxicity profile exceeding CDDP alone or in combination with CDDP, expressed the multi-kinase activity. Highlighted representatives, including compound 29, were also effective alone against primary glioblastoma. Overall, we showed that 7-azaindole, and 2,7-diazaindole scaffolds could be considered novel pharmacophores delivering anticancer activity.
- Klíčová slova
- ATR inhibition, Berzosertib, Cancer, Chemosensitization, Cytotoxicity, Glioblastoma,
- MeSH
- ATM protein MeSH
- cisplatina farmakologie MeSH
- indoly MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- protinádorové látky * farmakologie MeSH
- pyrazoly farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 7-azaindole dimer MeSH Prohlížeč
- ATM protein MeSH
- cisplatina MeSH
- indoly MeSH
- protinádorové látky * MeSH
- pyrazoly MeSH
Endoglin (Eng) is a co-receptor of the transforming growth factor β superfamily playing an important role in endothelial dysfunction. TRC105 (carotuximab) is a monoclonal antibody that blocks Eng and its downstream Smad signaling pathway. Here we have investigated for the first time the effects of TRC105 treatment on the development of endothelial dysfunction induced by 7-ketocholesterol (7K) or high glucose (HG), focusing on Eng expression, signaling, and function. In the hypercholesterolemia study, human aortic endothelial cells (HAoECs) were treated with TRC105 (300 μg/ml) for 1 h, followed by the addition of 7K (10 μg/ml) for another 12 h. In the hyperglycemia study, HAoECs were exposed to HG (45 mM) for 60 h, followed by the addition of TRC105 for another 12 h, and cells treated with 5mM glucose and 40 mM mannitol served as control. Protein levels, adhesion, and transmigration of monocytes were assessed by flow cytometry, mRNA expression was measured by qRT-PCR. 7K and HG treatment increased protein levels of NF-κB and Eng and adhesion and transmigration of monocytes through HAoECs monolayer. TRC105 pretreatment reduced the 7K- or HG-induced Eng protein levels and pSmad1/5 and pSmad2/3 signaling. Despite increased protein levels of P-selectin and VCAM-1, TRC105 mediated blockage of Eng prevented 7K- and HG-induced adhesion and transmigration of monocytes through endothelial monolayers. These results suggest that TRC105-mediated Eng blockage can counteract the hypercholesterolemia- and hyperglycemia-induced endothelial dysfunction in HAoECs, suggesting that Eng might be a potential therapeutic target in disorders associated with elevated cholesterol and glucose levels.
- Klíčová slova
- 7-ketocholesterol, TRC105, endoglin, endothelial dysfunction, high glucose,
- Publikační typ
- časopisecké články MeSH
