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This study investigates the effects of artificial in vitro polyploidisation of Astragalus membranaceus, focusing specifically on gene expression and metabolic pathway associated with the biosynthesis of calycosin and calycosin-7-O-β-D-glucoside. Using oryzalin as an antimitotic agent, we have systematically investigated different genotypic lines, under both in vitro and ex vitro conditions. Amid cases of reduced gene expression in certain lines, results showed a significant upregulation in specific lines, particularly in genotypes 16, 54, and 74. Genotype 54 showed an exceptional response, manifesting a statistically significant upregulation in all investigated genes studied under in vitro conditions (i.e. AmPAL, AmC4H and AmI3′H). Interestingly, even under ex vitro conditions after two years of greenhouse cultivation, certain lines showed significant variations in gene expression. The genotype 16, although no longer tetraploid, exhibited the highest expression levels among the examined genotypes, with statistically significant upregulation of both the AmPAL and AmC4H genes. In addition, the induced autotetraploid genotype 74 showed a significant upregulation of the AmI3′H gene and a concomitant downregulation of the AmC4H gene. These results highlight the complex regulatory mechanisms affected by the polyploidisation of A. membranaceus and provide promising avenues for manipulating gene expression to enhance the production of pharmacologically significant compounds. Key message: This study investigates the effects of artificial polyploidisation on gene expression of Astragalus membranaceus, suggesting diverse regulatory influences for potential plant bioactive compound production. [ABSTRACT FROM AUTHOR]

Our previous study found that 2-phenyl-4-quinolone (2-PQ) derivatives are antimitotic agents, and we adopted the drug design concept of scaffold hopping to replace the 2-aromatic ring of 2-PQs with a 4-aromatic ring, representing 4-phenyl-2-quinolones (4-PQs). The 4-PQ compounds, whose structural backbones also mimic analogs of podophyllotoxin (PPT), maybe a new class of anticancer drugs with simplified PPT structures. In addition, 4-PQs are a new generation of anticancer lead compounds as apoptosis stimulators. On the other hand, previous studies showed that 4-arylcoumarin derivatives with 5-, 6-, and 7-methoxy substitutions displayed remarkable anticancer activities. Therefore, we further synthesized a series of 5-, 6-, and 7-methoxy-substituted 4-PQ derivatives (19–32) by Knorr quinoline cyclization, and examined their anticancer effectiveness. Among these 4-PQs, compound 22 demonstrated excellent antiproliferative activities against the COLO205 cell line (50% inhibitory concentration (IC50) = 0.32 μM) and H460 cell line (IC50 = 0.89 μM). Furthermore, we utilized molecular docking studies to explain the possible anticancer mechanisms of these 4-PQs by the docking mode in the colchicine-binding pocket of the tubulin receptor. Consequently, we selected the candidate compounds 19, 20, 21, 22, 25, 27, and 28 to predict their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. Pharmacokinetics (PKs) indicated that these 4-PQs displayed good drug-likeness and bioavailability, and had no cardiotoxic side effects or carcinogenicity, but we detected risks of drug–drug interactions and AMES toxicity (mutagenic). However, structural modifications of these 4-PQs could improve their PK properties and reduce their side effects, and their promising anticancer activities attracted our attention for further studies. [ABSTRACT FROM AUTHOR]

Polyploidy induction plays a significant role in hybridizing and improving orchids (Orchidaceae). Induction of polyploidy can help to restore fertility by doubling of chromosomes and thus leading to the creation of allotetraploids which can help breeders develop improved hybrids and novel types by contributing beautiful floral or growth characteristics unobtainable from the diploid forms. The objective of the present study was to investigate the effective colchicine concentration and duration of exposure for the polyploidy induction in Dendrobium crumenatum via in vivo method, thus improving the flower characteristics. For the in vivo induction of polyploidy, D. crumenatum plantlets were chosen and subjected to eight different colchicine treatments. Treatments were based on colchicine concentration (0.05 and 0.1%) and the duration of exposure of plantlets to these doses of colchicine (24, 48, 72 and 96 h). The morphological characters, like shoot length, diameter of pseudobulb, number of leaves and width of leaves showed treatment mean values greater than their corresponding control plantlets. After analyzing the histogram peaks of in vivo treated samples, it was observed that the highest tetraploid induction (50%) was achieved with the treatment of 0.05% colchicine for 96 hours. Moreover, the maximum mixoploids (66.67%) were obtained from two different treatments; first, with 0.05% colchicine for 72 hours and second, with 0.05% colchicine for 48 hours. These results suggest that a longer treatment duration of 96 hours with 0.05% colchicine leads to higher tetraploid induction while shorter durations of 72 and 48 hours with the same concentration of colchicine are more effective for producing mixoploids. Stomatal observations exhibited a lower stomatal density but increased stomatal size in polyploids than in diploids. [ABSTRACT FROM AUTHOR]

Abstract Background The aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells. In contrast, decreased cytotoxic effects against non-neoplastic blood cells, chondrocytes, and fibroblasts were observed. However, the actual FX-9 molecular mode of action is currently not fully understood. Methods In this study, microarray gene expression analysis comparing FX-9 exposed and unexposed prostate cancer cells (PC-3 representing castration-resistant prostate cancer), followed by pathway analysis and gene annotation to functional processes were performed. Immunocytochemistry staining was performed with selected targets. Results Expression analysis revealed 0.83% of 21,448 differential expressed genes (DEGs) after 6-h exposure of FX-9 and 0.68% DEGs after 12-h exposure thereof. Functional annotation showed that FX-9 primarily caused an activation of inflammatory response by non-canonical nuclear factor-kappa B (NF-κB) signaling. The 6-h samples showed activation of the cell cycle inhibitor CDKN1A which might be involved in the secondary response in 12-h samples. This secondary response predominantly consisted of cell cycle-related changes, with further activation of CDKN1A and inhibition of the transcription factor E2F1, including downstream target genes, resulting in G1-phase arrest. Matching our previous observations on cellular level senescence signaling pathways were also found enriched. To verify these results immunocytochemical staining of p21 Waf1/Cip1 (CDKN1A), E2F1 (E2F1), PAI-1 (SERPNE1), and NFkB2/NFkB p 100 (NFKB2) was performed. Increased expression of p21 Waf1/Cip1 and NFkB2/NFkB p 100 after 24-h exposure to FX-9 was shown. E2F1 and PAI-1 showed no increased expression. Conclusions FX-9 induced G1-phase arrest of PC-3 cells through activation of the cell cycle inhibitor CDKN1A, which was initiated by an inflammatory response of noncanonical NF-κB signaling.

Our previous study found that 2-phenyl-4-quinolone (2-PQ) derivatives are antimitotic agents, and we adopted the drug design concept of scaffold hopping to replace the 2-aromatic ring of 2-PQs with a 4-aromatic ring, representing 4-phenyl-2-quinolones (4-PQs). The 4-PQ compounds, whose structural backbones also mimic analogs of podophyllotoxin (PPT), maybe a new class of anticancer drugs with simplified PPT structures. In addition, 4-PQs are a new generation of anticancer lead compounds as apoptosis stimulators. On the other hand, previous studies showed that 4-arylcoumarin derivatives with 5-, 6-, and 7-methoxy substitutions displayed remarkable anticancer activities. Therefore, we further synthesized a series of 5-, 6-, and 7-methoxy-substituted 4-PQ derivatives (19–32) by Knorr quinoline cyclization, and examined their anticancer effectiveness. Among these 4-PQs, compound 22 demonstrated excellent antiproliferative activities against the COLO205 cell line (50% inhibitory concentration (IC50) = 0.32 μM) and H460 cell line (IC50 = 0.89 μM). Furthermore, we utilized molecular docking studies to explain the possible anticancer mechanisms of these 4-PQs by the docking mode in the colchicine-binding pocket of the tubulin receptor. Consequently, we selected the candidate compounds 19, 20, 21, 22, 25, 27, and 28 to predict their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. Pharmacokinetics (PKs) indicated that these 4-PQs displayed good drug-likeness and bioavailability, and had no cardiotoxic side effects or carcinogenicity, but we detected risks of drug–drug interactions and AMES toxicity (mutagenic). However, structural modifications of these 4-PQs could improve their PK properties and reduce their side effects, and their promising anticancer activities attracted our attention for further studies.

Background: The aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells. In contrast, decreased cytotoxic effects against non-neoplastic blood cells, chondrocytes, and fibroblasts were observed. However, the actual FX-9 molecular mode of action is currently not fully understood.Methods: In this study, microarray gene expression analysis comparing FX-9 exposed and unexposed prostate cancer cells (PC-3 representing castration-resistant prostate cancer), followed by pathway analysis and gene annotation to functional processes were performed. Immunocytochemistry staining was performed with selected targets.Results: Expression analysis revealed 0.83% of 21,448 differential expressed genes (DEGs) after 6-h exposure of FX-9 and 0.68% DEGs after 12-h exposure thereof. Functional annotation showed that FX-9 primarily caused an activation of inflammatory response by non-canonical nuclear factor-kappa B (NF-κB) signaling. The 6-h samples showed activation of the cell cycle inhibitor CDKN1A which might be involved in the secondary response in 12-h samples. This secondary response predominantly consisted of cell cycle-related changes, with further activation of CDKN1A and inhibition of the transcription factor E2F1, including downstream target genes, resulting in G1-phase arrest. Matching our previous observations on cellular level senescence signaling pathways were also found enriched. To verify these results immunocytochemical staining of p21 Waf1/Cip1 (CDKN1A), E2F1 (E2F1), PAI-1 (SERPNE1), and NFkB2/NFkB p 100 (NFKB2) was performed. Increased expression of p21 Waf1/Cip1 and NFkB2/NFkB p 100 after 24-h exposure to FX-9 was shown. E2F1 and PAI-1 showed no increased expression.Conclusions: FX-9 induced G1-phase arrest of PC-3 cells through activation of the cell cycle inhibitor CDKN1A, which was initiated by an inflammatory response of noncanonical NF-κB signaling. [ABSTRACT FROM AUTHOR]

The tubulin colchicine binding site has been recognized as an attractive drug target to combat cancer, but none of the candidate drugs have been approved for medical treatment. We recently identified a structurally distinct small molecule S-40 as an oral potent tubulin destabilizing agent. Crystal structure analysis of S-40 in a complex with tubulin at a resolution of 2.4 Å indicated that S-40 occupies all 3 zones in the colchicine pocket with interactions different from known microtubule inhibitors, presenting unique effects on assembly and curvature of tubulin dimers. S-40 overcomes paclitaxel resistance and lacks neurotoxicity, which are the main obstacles limiting clinical applications of paclitaxel. Moreover, S-40 harbors the ability to inhibit growth of cancer cell lines as well as patient-derived organoids, induce mitotic arrest and cell apoptosis. Xenograft mouse models of human prostate cancer DU145, non-small cell lung cancer NCI-H1299 and paclitaxel-resistant A549 were strongly restrained without apparent side effects by S-40 oral administration once daily. These findings provide evidence for the development of S-40 as the next generation of orally effective microtubule inhibitors for cancer therapy. [ABSTRACT FROM AUTHOR]

Cancer drugs which are specifically targeted at mitosis have generally under-delivered as a class. One likely reason is that only a small percentage of cancer cells in a tumor are actually dividing at any moment. If this is the case, then prolonged bioavailability in the tumor should significantly increase the efficacy of antimitotic agents. Here, we show that if the Plk1 inhibitor BI 2536 is co-encapsulated in a liposome with a pair of anions, its release rate is dependent on both the identity and stoichiometry of the anions. We created a library of liposomes with varying release rates using this approach and found that liposomal drug release rates correlated inversely with in vitro cancer cell killing. Xenografted mice treated with a single dose of slow-releasing liposomal BI 2536 experienced tumor volume decreases lasting 12 days and complete responses in 20% of mice. Treatment with two doses a week apart increased the response rate to 75%. This approach, which we termed Paired Anion Calibrated Release (PACeR), has the potential to revive the clinical utility of antimitotic cancer drugs which have failed clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Recurrence is the most common problem with pterygium excision. Various adjunctive methods have been described to decrease the recurrence rate of pterygium. Mitomycin C (MMC) and limbal Conjunctival Autograft (CAG) are most commonly used methods to reduce its recurrence. Aim: To compare the recurrence rate of pterygium and the complications with MMC eyedrops after bare sclera pterygium excision versus sutureless and glue free CAG. Materials and Methods: Total 104 eyes were divided into two groups (A and B) of 52 eyes each. Group A patients underwent bare sclera excision of pterygium followed by 0.01% MMC eye drops BD (twice a day) for five days and Group B patients had sutureless and glue free CAG using oozing blood as tissue adhesive after pterygium excision. The patients were followed-up postoperatively on day 1, day 3, day 7, one month, three months, six months and one year. All the patients were examined for recurrence and complications. Statistical analysis was done by using Statistical Package for the Social Sciences (SPSS) version 16 and student’s t-test was applied for comparison. Results: A total of 104 eyes of 92 patients were divided into two groups (A and B) of 52 each. The mean age of Group A was around 45 year and group B was around 43 years and the difference was statistically insignificant (p>0.05). Total three patients had recurrence in one year of follow-up in group A, out of which first case appeared before the end of 1st month, second before the completion of 3rd month and the third case at the last follow-up. In group B only one case presented with recurrence at 6th month follow-up. The difference between the recurrences in both the groups was statistically insignificant (p>0.05). Short term complications were observed in five patients in group A. One patient had corneal thinning; one had scleral thinning, two patients presented with avascular sclera and one patient with granuloma. In group B, 18 patients with graft retraction, eight with graft oedema, five with sub-conjunctival graft haemorrhage and one with granuloma were observed. All these complications resolved by the time. Long term complications were not observed in any patient of both the groups. Conclusion: This study concluded that the use of MMC eye drops (0.01%) BD or glue free and sutureless CAG after pterygium excision is safe and effective treatment modalities for pterygium.

Introduction: Recurrence is the most common problem with pterygium excision. Various adjunctive methods have been described to decrease the recurrence rate of pterygium. Mitomycin C (MMC) and limbal Conjunctival Autograft (CAG) are most commonly used methods to reduce its recurrence. Aim: To compare the recurrence rate of pterygium and the complications with MMC eyedrops after bare sclera pterygium excision versus sutureless and glue free CAG. Materials and Methods: Total 104 eyes were divided into two groups (A and B) of 52 eyes each. Group A patients underwent bare sclera excision of pterygium followed by 0.01% MMC eye drops BD (twice a day) for five days and Group B patients had sutureless and glue free CAG using oozing blood as tissue adhesive after pterygium excision. The patients were followed-up postoperatively on day 1, day 3, day 7, one month, three months, six months and one year. All the patients were examined for recurrence and complications. Statistical analysis was done by using Statistical Package for the Social Sciences (SPSS) version 16 and student’s t-test was applied for comparison. Results: A total of 104 eyes of 92 patients were divided into two groups (A and B) of 52 each. The mean age of Group A was around 45 year and group B was around 43 years and the difference was statistically insignificant (p>0.05). Total three patients had recurrence in one year of follow-up in group A, out of which first case appeared before the end of 1st month, second before the completion of 3rd month and the third case at the last follow-up. In group B only one case presented with recurrence at 6th month follow-up. The difference between the recurrences in both the groups was statistically insignificant (p>0.05). Short term complications were observed in five patients in group A. One patient had corneal thinning; one had scleral thinning, two patients presented with avascular sclera and one patient with granuloma. In group B, 18 patients with graft retraction, eight with graft oedema, five with sub-conjunctival graft haemorrhage and one with granuloma were observed. All these complications resolved by the time. Long term complications were not observed in any patient of both the groups. Conclusion: This study concluded that the use of MMC eye drops (0.01%) BD or glue free and sutureless CAG after pterygium excision is safe and effective treatment modalities for pterygium. [ABSTRACT FROM AUTHOR]

Green plants provide food, fuel, materials, and medicine for humans. Amongst these, medicinal plants contain unique molecules with therapeutic applications. However, our understanding of these organisms is in its infancy. Landscaping plants also have a great impact on the human soul and emotional perception. These two groups of plants are part of natural wealth and have great economic value. One of the remarkable breeding strategies to improve the valuable properties of plants is artificial polyploidy induction. Medicinal and ornamental plants with duplicated whole sets of chromosomes, although not always, have more distinctive characteristics such as modified phytochemical profile, higher content of desired pharma molecules, plant form, flower color, size and style, fragrance, vase life, and prolonged flowering period. Therefore, artificial chromosome doubling (ACD) of ornamental and medicinal plants could have significant economic consequences. In medicinal plants with an ornamental flower/inflorescence, and/or in ornamental plants bearing essential oils, ACD is a dual beneficial breeding strategy. Working with both in vitro and in vivo chromosome doubling pathways, researchers are able to produce custom-designed plants with higher marketability. Some critical factors must be considered to establish a successful ACD protocol. The plant genotype and explant type are important parameters in this procedure. Type, dosage and duration of application (exposure time) of antimitotic agent (AMA) should also be considered as the main factors. Antimitotic agents can be classified according to their efficacy and toxicity. Although colchicine is the most applied and well-known AMA, there are other alternative mitotic spindle inhibitors with higher specificity for tubulin binding sites in plant materials and possessing less toxicity for animal tubulin. Testing the interaction effects of plant and AMA parameters is necessary for establishing an ACD breeding program and promoting the economic values of medicinal and ornamental plants. This paper reviews significant developments in polyploidization using different antimitotic agents over the last decade in the field of ornamental and medicinal plants. Key message: Artificial polyploidy induction is one of the applicable breeding methods in ornamental and medicinal plants. Increasing the efficiency of chromosome doubling and fast-reliable screening of desired phenotypes are prerequisites for production of custom-designed medicinal and ornamental plants through artificial polyploidy induction. [ABSTRACT FROM AUTHOR]

Microtubules play a dynamic role during cell division. In our early studies 4‐phenyl‐1‐(1‐acylindoline‐5‐sulfonylimidazolones were thoroughly explored and found that the indoline bicyclic system next to the sulfonyl group is very important for cytotoxicity. In this research, imidazolone motif was replaced with pyrrolidin‐2‐one and this isosteric replacement led to show some promising activity. Thus, the structure activity relationship of 4‐phenyl‐1‐(1‐acylindolin‐5‐ylsulfonyl)pyrrolidin‐2‐ones with the various acyl group at the indoline NH was explored. The presence of benzoyl groups with electron donating group was the more favorable for cytotoxicity while less bulky alkanoyl groups led to decrease cytotoxicity. [ABSTRACT FROM AUTHOR]

New target compounds were designed as inhibitors of tubulin polymerization relying on using two types of ring B models (cyclohexenone and indazole) to replace the central ring in colchicine. Different functional groups (R1) were attached to manipulate their physicochemical properties and/or their biological activity. The designed compounds were assessed for their antitumor activity on HCT-116 and MCF-7 cancer cell lines. Compounds 4b, 5e and 5f exhibited comparable or higher potency than colchicine against colon HCT-116 and MCF-7 tumor cells. The mechanism of the antitumor activity was investigated through evaluating the tubulin inhibition potential of the active compounds. Compounds 4b, 5e and 5f showed percentage inhibition of tubulin in both cell line homogenates ranging from 79.72% to 89.31%. Cell cycle analysis of compounds 4b, 5e and 5f revealed cell cycle arrest at G2/M phase. Molecular docking revealed the binding mode of these new compounds into the colchicine binding site of tubulin.

Highlights • Colchicine is a potent antimitotic agent that induce polyploidization in plants. • Induced polyploids provides genetic variation that is important to plant improvement and breeding program. • This paper seeks to provide an overview on an array of current best practices in polyploidization. Abstract Polyploidization of plants occurs in nature but it is a slow and gradual process that has driven evolution and speciation throughout the ages. As time is important, polyploidization can be induced in a shorter period by using colchicine that interferes with mitosis of cells. To develop an efficient polyploidization protocol of a species, up to date research is paramount. The efficiency of polyploidization induction system depends on the advancement of propagation techniques of the species which consist of in vitro , ex vitro and in vivo systems. During polyploidization induction, several parameters can be manipulated to obtain highest percentage of polyploids. These parameters include colchicine concentration, treatment duration and explant type. Several other factors that enhance these parameters include usage of shaker, DMSO (Dimethyl sulfoxide) and medium types. Induced putative polyploids are selected indirectly based on morphological parameters, anatomical parameters and flow cytometry. Selected putative polyploid can be verified directly and accurately using chromosome counting. Polyploidization has been practised for decades with notable breakthrough recently in terms of polyploidization system and polyploid identification. Current trend in polyploidization has included polyploid characterization in their protocol in terms of polyploid ultrastructure, bioactive compounds, photosynthetic capabilities and metabolomics studies. Establishment of methodologies in polyploid characterization will help the plant breeder to assess noble phenotype among polyploids which can be beneficial for commercial purpose. This paper seeks to provide an overview on an array of current best practices in polyploidization using colchicine. [ABSTRACT FROM AUTHOR]

An effective chromosome doubling protocol was established in essential garden crop of cucumber (Cucumis sativus L.) Cv. Hi Power. The different concentrations of colchicine (0, 250, 500, 750, and 1500 mg/L), oryzalin (0, 5, 15, 25, 50, 75, and 150 mg/L) and trifluralin (0, 5, 15, 25, 50, 75, and 150 mg/L) were applied on parthenogenesis-induced haploid nodal and shoot tip explants of cucumber for 18 and 38 h in three independent factorial experiments. Increasing concentrations of applied antimitotic agents led to the significant reduction in the survival rate of both shoot tip and nodal explants, especially in longer exposure duration. Three ploidy levels including haploid, mixoploid, and doubled haploid were regenerated form both explant types treated with colchicine, oryzalin, and trifluralin. Flow cytometry analysis proved successful chromosome doubling of haploid plants. Based on the results obtained, the highest number of regenerated doubled haploid plants (92.31%) and fruit set (86.21%) were related to immersion of nodal explants in 50 mg/L oryzalin for 18 h. The highest doubled haploid regeneration for colchicine and trifluralin antimitotic agents were 58.33 and 83.33%, respectively. The leaf size of doubled haploid plants was larger than their correspond haploids. The optimized chromosome doubling protocol would be applicable for doubled haploid production in garden crops of Cucurbitaceae family, which is recalcitrant to the spontaneous doubling, and also for in vitro polyploidy induction studies. [ABSTRACT FROM AUTHOR]

Marine-derived microorganisms are a valuable source of novel bioactive natural products. Asperphenin A is a lipopeptidyl benzophenone metabolite isolated from large-scale cultivation of marine-derived Aspergillus sp. fungus. The compound has shown potent antiproliferative activity against various cancer cells. However, the underlying mechanism of action remained to be elucidated. In this study, we demonstrated the antitumor activity and molecular mechanism of asperphenin A in human colon cancer cells for the first time. Asperphenin A inhibited the growth of colon cancer cells through G2/M cell cycle arrest followed by apoptosis. We further discovered that asperphenin A can trigger microtubule disassembly. In addition to its effect on cell cycle, asperphenin A-induced reactive oxygen species. The compound suppressed the growth of tumors in a colon cancer xenograft model without any overt toxicity and exhibited a combination effect with irinotecan, a topoisomerase I inhibitor. Moreover, we identified the aryl ketone as a key component in the molecular structure responsible for the biological activity of asperphenin A using its synthetic derivatives. Collectively, this study has revealed the antiproliferative and antitumor mechanism of asperphenin A and suggested its possibility as a chemotherapeutic agent and lead compound with a novel structure.

Profound behavioral changes occur in the mother at parturition, a time when the maternal brain undergoes extensive remodeling of neural circuits, especially in olfactory structures. Adult neurogenesis, a form of brain plasticity, could constitute an adaptive response to motherhood. The present study hypothesized that chemical disruption of olfactory neurogenesis would impair the establishment of maternal behavior in sheep. In addition, because ewes are able to learn the olfactory signature of their offspring, we also examined whether disruption of olfactory neurogenesis altered recognition of the familiar lamb. At one month of gestation, ewes received either infusion of the antimitotic drug Ara-C or saline into the lateral ventricles via one-month-long osmotic minipumps. Ara-C infusion dramatically decreased olfactory neurogenesis but spared hippocampal neurogenesis. Mothers exhibiting more than a 70% reduction in olfactory neurogenesis emitted fewer maternal bleats during the first hours after parturition. Reduction of olfactory neurogenesis also negatively affected discrimination of the familiar lamb. Differences in ewes’ aggressive behavior toward familiar and alien lambs were observed in sham mothers, but not in mothers with reduced olfactory neurogenesis. In addition, when ewes were given the choice between familiar and unfamiliar anesthetized lambs, so that only olfactory cues were available, mothers with a reduction in neurogenesis greater than 70% were not able to discriminate their own lamb from an alien lamb. These results indicate that adult-born olfactory neurons are to some extent involved in the establishment of maternal behavior in sheep by contributing to the processing of offspring odors. [ABSTRACT FROM AUTHOR]

For confirming the role of five membered ring of imidazolidinone moiety of N-arylsulfonylimidazolidinones (7) previously reported with highly potent anticancer agent, a series of N-arylsulfonylpyrimidones (10a-g) and N-arylsulfonyltetrahydropyrimidones (11a-e) were prepared and their anti-proliferating activity was measured against human cancer cell lines (renal ACHN, colon HCT-15, breast MDA-MB-231, lung NCI-H23, stomach NUGC-3, and prostate PC-3) using XTT assay. Among them, 1-(1-acetylindolin-5-ylsulfonyl)-4-phenyltetrahydropyrimidin-2(1H)-one (11d, mean GI50 = 3.50 µM) and ethyl 5-(2-oxo-4-phenyltetrahydropyrimidin-1(2H)-ylsulfonyl)-indoline-1-carboxylate (11e, mean GI50 = 0.26 µM) showed best growth inhibitory activity against human cancer cell lines. Considering the activity results, N-arylsulfonyltetrahydropyrimidones (11) exhibited more potent activity compared to N-arylsulfonylpyrimidones (10) and comparable activity to N-arylsulfonylimidazolidinones (7). Especially, tetrahydropyrimidin-2(1H)-one analogs containing acylindolin-5-ylsulfonyl moiety at position 1 demonstrated their strong growth inhibitory activity against human cancer cell lines. [ABSTRACT FROM AUTHOR]

4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), an active polar metabolite of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR), was shown to exert promising antitumor activity through at least two independent mechanisms of action. Specifically, differently from 4-HPR and other retinoids, 4-oxo-4-HPR targets microtubules and inhibits tubulin polymerization causing mitotic arrest and on the other hand, analogously to the parent drug, it induces apoptosis through the activation of a signaling cascade involving the generation of reactive oxygen species (ROS). However, the potential in vivo use of 4-oxo-4-HPR is impaired by its poor solubility. By chemical modification of 4-oxo-4-HPR, a new class of compounds with improved solubility and in vivo bioavailability was obtained. We demonstrated here that, among them, the most promising molecule, sodium 4-carboxymethoxyimino-(4-HPR), was endowed with in vitro antitumor efficacy and entirely preserved the double mechanism of action of the parent drug in cancer cells of different histotypes. In fact, the retinoid induced the activation of the apoptotic cascade related to the generation of ROS through endoplasmic reticulum stress response and upregulation of phospho c-Jun N-terminal kinases and PLAcental Bone morphogenetic protein, leading to cell death through caspase-3 cleavage. Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization. To assess the compound antitumor activity, in vivo experiments were performed in three mouse xenograft models (ovarian and breast cancers and mesothelioma). The in vivo results demonstrated that retinoid administration as single agent significantly increased the survival in ovarian cancer xenografts, induced a statistically significant decrease in tumor growth in breast cancer xenografts, and caused a 30% reduction in tumor growth in a mesothelioma mouse model. Even though further studies investigating sodium 4-carboxymethoxyimino-(4-HPR) toxicity and in vitro and in vivo activities in combination with other drugs are required, the double mechanism of action of the retinoid coupled with its in vivo antitumor efficacy and potential low toxicity suggest a promising therapeutic potential for the compound in different solid tumors.

The root of Chinese sage (Salvia miltiorrhiza Bunge) was regarded as top-grade Chinese medicine two thousand years ago, according to Shen Nong Materia Medica. The aim of this study is to develop an easy and reliable means for obtaining tetraploids (4x plants) via thidiazuron-induced direct organogenesis in the presence of colchicine. The resulting 4x plants showed significantly enhanced agronomic traits, including the size of stomata, leaflet, pollen, and seed as well as shoot length, root diameter, number of leaves, and fresh weight of plant. In addition, an obvious reduction of length to width ratio was found in the 4x plants, including stomata, leaflets, pollens, seeds, and roots. The 4x ploidy state of the plants was stable as was proved by evaluation of selection indicators as well as consistent ploidy level at 10th generation plantlets and also on 4x seedlings obtained via self-pollination. The major bioactive compounds, salvianolic acid B, tanshinone I, tanshinone IIA, dihydrotanshinone I and cryptotanshinone, as well as total tanshinones were determined by high performance liquid chromatography (HPLC). The concentrations of dihydrotanshinone I and total tanshinones in the root extract of the 4x plants were significantly higher when compared with the 2x plants. This present study developed a simple and efficient system for inducing and subculture of tetrapolids which have stable ploidy level, enhanced growth characteristics as well as the content of dihydrotanshinone I in the root of S. miltiorrhiza.

Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.

Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.

Cryptophycins are a class of 16-membered highly cytotoxic macrocyclic depsipeptides isolated from cyanobacteria. The biological activity is based on their ability to interact with tubulin. They interfere with microtubule dynamics and prevent microtubules from forming correct mitotic spindles, which causes cell-cycle arrest and apoptosis. Their strong antiproliferative activities with 100-fold to 1000-fold potency compared with those of paclitaxel and vinblastine have been observed. Cryptophycins are highly promising drug candidates, as their biological activity is not negatively affected by P-glycoprotein, a drug efflux system commonly found in multidrug-resistant cancer cell lines and solid tumors. Cryptophycin-52 had been investigated in phase II clinical trials but failed because of its high neurotoxicity. Recently, cryptophycin conjugates with peptides and antibodies have been developed for targeted delivery in tumor therapy. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), an active polar metabolite of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR), was shown to exert promising antitumor activity through at least two independent mechanisms of action. Specifically, differently from 4-HPR and other retinoids, 4-oxo-4-HPR targets microtubules and inhibits tubulin polymerization causing mitotic arrest and on the other hand, analogously to the parent drug, it induces apoptosis through the activation of a signaling cascade involving the generation of reactive oxygen species (ROS). However, the potential in vivo use of 4-oxo-4-HPR is impaired by its poor solubility. By chemical modification of 4-oxo-4-HPR, a new class of compounds with improved solubility and in vivo bioavailability was obtained. We demonstrated here that, among them, the most promising molecule, sodium 4-carboxymethoxyimino-(4-HPR), was endowed with in vitro antitumor efficacy and entirely preserved the double mechanism of action of the parent drug in cancer cells of different histotypes. In fact, the retinoid induced the activation of the apoptotic cascade related to the generation of ROS through endoplasmic reticulum stress response and upregulation of phospho c-Jun N-terminal kinases and PLAcental Bone morphogenetic protein, leading to cell death through caspase-3 cleavage. Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization. To assess the compound antitumor activity, in vivo experiments were performed in three mouse xenograft models (ovarian and breast cancers and mesothelioma). The in vivo results demonstrated that retinoid administration as single agent significantly increased the survival in ovarian cancer xenografts, induced a statistically significant decrease in tumor growth in breast cancer xenografts, and caused a 30% reduction in tumor growth in a mesothelioma mouse model. Even though further studies investigating sodium 4-carboxymethoxyimino-(4-HPR) toxicity and in vitro and in vivo activities in combination with other drugs are required, the double mechanism of action of the retinoid coupled with its in vivo antitumor efficacy and potential low toxicity suggest a promising therapeutic potential for the compound in different solid tumors. [ABSTRACT FROM AUTHOR]

The potent kinesin spindle protein inhibitor CPUYJ039 and a set of analogues were prepared by a target-oriented approach based on a Ugi reaction that uses 2-nitrophenyl isocyanides as key building blocks. The herein documented strategy provides straightforward and atom economical access to potent benzimidazole-based antimitotic agents by exploring the versatility and exploratory power of the Ugi reaction. The results of docking studies and biological activity evaluations of the benzimidazole compounds are also reported. [ABSTRACT FROM AUTHOR]

Medicinal plants are in huge demand since the consumption is widespread and ever-increasing globally. The conventional breeding programs are generally environmental dependent; prone to different biotic and abiotic stresses as well as the secondary metabolite content is too low to harvest. In this context, developing polyploid individuals artificially would be a remarkable approach to increase vigor and attain this objective. Polyploids often exhibit some morphological features that are different or greater in forms than their diploid progenies. Polyploidization can be induced by quite a few antimitotic agents. The most frequently used antimitotic chemicals are colchicine, trifluralin, and oryzalin. The whole method of induced chromosome doubling consists of a series of steps, including an induction phase, regrowth phase, and a confirmation technique to evaluate the rate of achievement. The induction phase depends on different factors, such as explant types, antimitotic agents, its different concentrations, and exposure durations. To evaluate the accomplishment of polyploidization, morphological or anatomical observations are recorded as a rapid method. However, chromosome count and flow cytometry are the most eminent method for absolute confirmation. Despite significant prospects of polyploidization, there has been very little research on medicinal plants. The current review gives an overview of the different parameters of in vitro chromosome doubling, the history of the technique, and progress made over the last two decades. [ABSTRACT FROM AUTHOR]

New target compounds were designed as inhibitors of tubulin polymerization relying on using two types of ring B models (cyclohexenone and indazole) to replace the central ring in colchicine. Different functional groups (R1) were attached to manipulate their physicochemical properties and/or their biological activity. The designed compounds were assessed for their antitumor activity on HCT-116 and MCF-7 cancer cell lines. Compounds4b,5eand5fexhibited comparable or higher potency than colchicine against colon HCT-116 and MCF-7 tumor cells. The mechanism of the antitumor activity was investigated through evaluating the tubulin inhibition potential of the active compounds. Compounds4b,5eand5fshowed percentage inhibition of tubulin in both cell line homogenates ranging from 79.72% to 89.31%. Cell cycle analysis of compounds4b,5eand5frevealed cell cycle arrest at G2/M phase. Molecular docking revealed the binding mode of these new compounds into the colchicine binding site of tubulin. [ABSTRACT FROM AUTHOR]

Procedures to arrest metaphase chromosomes are used for determining chromosome numbers, chromosomal aberrations, and natural chromosome variation, as well as chromosome sorting. Here is described a technique of nitrous oxide gas treatment of freshly harvested root tips that is highly effective at producing an excellent mitotic index together with well-spread chromosomes. The details of the treatment and equipment used are provided. The metaphase spreads can be used directly for determining chromosome numbers or for in situ hybridization to reveal chromosomal features., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

To explore the possibility of isosteric replacement of imidazolidinone moiety of ( S)-1-(1-(4-aminobenzoyl)indolin-5-ylsulfonyl)-4-phenylimidazolidin-2-one ( 1) for the anticancer activity, novel 1-(1-acyl substituted indolin-5-sulfonyl)-4-phenyl-1 H-imidazoles 2 were prepared with varying the N-acyl group on the indoline ring and evaluated for their in vitro anticancer activity against six human cancer cell lines (renal ACHN, colon HCT-15, breast MDA-MB-231, lung NCI-H23, stomach NUGC-3, and prostrate PC-3). Among the analogs prepared, imidazoles with hydrophobic acyl substituents on indoline like cyclohexanecarbonyl ( 2e, mean 50% growth inhibition [ GI50 ] = 2.29 μM) or benzoyl with electron-donating groups like 4-methoxybenzoyl ( 2g, mean GI50 = 4.11 μM) and 4-aminobenzoyl ( 2a, mean GI50 = 4.45 μM) exhibited relatively good cytotoxicity. Although imidazole moiety of arylsulfonylphenylimidazole 2 contains only hydrogen bonding acceptor property without a stereogenic center unlike imidazolidinone analogs, the high level of the activity of 2 proved that the imidazole motif is obviously good isostere of imidazolidinone moiety of arylsulfonylphenylimidazolidinone 1 for the anticancer activity. [ABSTRACT FROM AUTHOR]

In order to create more potent anticancer agents, a series of five structurally different derivatives of Colchicine have been synthesised. These compounds were characterised spectroscopically and structurally and their antiproliferative activity against four human tumour cell lines (HL-60, HL-60/vinc, LoVo, LoVo/DX) was evaluated. Additionally the activity of the studied compounds was calculated using computational methods involving molecular docking of the Colchicine derivatives to β-tubulin. The experimental and computational results are in very good agreement indicating that the antimitotic activity of Colchicine derivatives can be readily predicted using computational modeling methods. [ABSTRACT FROM AUTHOR]