Synthesis, Antimicrobial - Cytotoxic Evaluation, and Molecular Docking Studies of Quinolin-2-one Hydrazones Containing Nitrophenyl or Isonicotinoyl/Nicotinoyl Moiety.

By applying the hybrid molecular strategy, in this study, we reported the synthesis of fifteen quinolin-2-one hydrazones containing nitrophenyl or nicotinonyl/isonicotinoyl moiety, followed by in vitro and in silico evaluations of their potential antimicrobial and anticancer activities. In vitro antimicrobial evaluation of the target compounds on seven pathogenic strains, applying the broth microdilution method, revealed that compound 4a demonstrated the most potential antifungal activity against C. albicans (MIC 512 µg.mL-1) and C. krusei (MIC 128 µg.mL-1). In vitro cytotoxic evaluation of the target compounds on three human cancer cell lines, employing the MTT method, suggested that compound 5c exhibited the most potential cytotoxicities against HepG2 (IC50 10.19 µM), A549 (IC50 20.43 µM), and MDA-MB-231 (IC50 16.82 µM) cells. Additionally, molecular docking studies were performed to investigate the binding characteristics of compounds 4a and 5c with fungal lanosterol 14α-demethylase and human topoisomerase I-II, respectively, thereby contributing to the elucidation of their in vitro antifungal and cytotoxic properties. Furthermore, compounds 4a and 5c, via SwissADME prediction, could exhibit favorable physicochemical and pharmacokinetic properties. In conclusion, this study provides valuable insights into the potential of quinolin-2-one hydrazones as promising candidates for the development of novel antimicrobial and anticancer agents in the future.

Phytochemistry and Cytotoxic Activity of Aquilaria crassna Pericarp on MDA-MB-468 Cell Lines.

The extracts of Aquilaria crassna pericarp were investigated on the MDA-MB-468, a breast cancer cell line, at desired concentration (1-50 µg/mL). The results showed that the dichloromethane (DCM) extract exhibited the strongest toxicity and was carried out subsequently. A total of nine compounds were isolated from the DCM extract using column chromatography and recrystallization, of which their structures were determined. Intriguingly, in addition to the previously reported compounds, neocucurbitacin A, a cucurbitacin triterpenoid aglycone with a lactone in ring A, was reported for the first time in the Aquilaria genus. Among the isolated compounds, cucurbitacin E highly inhibited MDA-MB-468 cell growth in a dose-dependent manner. Owing to binding abilities with the SH2 domain in the molecular docking study, cucurbitacin E, neocucurbitan A, neocucurbitan B, and cucurbitacin E 2-O-ß-d-glucopyranoside act as STAT3 inhibitors and are suitable for further research. This study suggests thatAquilaria crassnafruits could serve as a promising source of natural compounds with potential anticancer effects, particularly against breast cancer.

Design, synthesis, in vitro and in silico evaluation of anti-colorectal cancer activity of curcumin analogues containing 1,3-diphenyl-1H-pyrazole targeting EGFR tyrosine kinase.

Recent studies have shown that monocarbonyl analogues of curcumin (MACs) and 1H-pyrazole heterocycle both demonstrated promising anticancer activities, in which several compounds containing these scaffolds could target EGFR. In this research, 24 curcumin analogues containing 1H-pyrazole (a1-f4) were synthesized and characterized by using modern spectroscopic techniques. Firstly, synthetic MACs were screened for cytotoxicity against human cancer cell lines such as SW480, MDA-MB-231 and A549, from which the 10 most potential cytotoxic compounds were identified and selected. Subsequently, the selected MACs were further screened for their inhibition against tyrosine kinases, which showed that a4 demonstrated the most significant inhibitory effects on EGFRWT and EGFRL858R. Based on the results, a4 further demonstrated its ability to cause morphological changes, to increase the percentage of apoptotic cells, and to increase caspase-3 activity, suggesting its apoptosis-inducing activity on SW480 cells. In addition, the effect of a4 on the SW480 cell cycle revealed its ability to arrest SW480 cells at G2/M phase. In subsequent computer-based assessments, a4 was predicted to possess several promising physicochemical, pharmacokinetic, and toxicological properties. Via molecular docking and molecular dynamics simulation, a reversible binding mode between a4 and EGFRWT, EGFRL858R, or EGFRG719S, remained stable within the 100-ns simulation due to effective interactions especially the hydrogen bonding with M793. Finally, free binding energy calculations suggested that a4 could inhibit the activity of EGFRG719S more effectively than other EGFR forms. In conclusion, our work would provide the basis for the future design of promising synthetic compounds as anticancer agents targeting EGFR tyrosine kinase.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of 1-Aryl-1H-pyrazole-Fused Curcumin Analogues as Anticancer Agents.

Addressing the growing burden of cancer and the shortcomings of chemotherapy in cancer treatment are the current research goals. Research to overcome the limitations of curcumin and to improve its anticancer activity via its heterocycle-fused monocarbonyl analogues (MACs) has immense potential. In this study, 32 asymmetric MACs fused with 1-aryl-1H-pyrazole (7a-10h) were synthesized and characterized to develop new curcumin analogues. Subsequently, via initial screening for cytotoxic activity, nine compounds exhibited potential growth inhibition against MDA-MB-231 (IC50 2.43-7.84 µM) and HepG2 (IC50 4.98-14.65 µM), in which seven compounds showing higher selectivities on two cancer cell lines than the noncancerous LLC-PK1 were selected for cell-free in vitro screening for effects on microtubule assembly activity. Among those, compounds 7d, 7h, and 10c showed effective inhibitions of microtubule assembly at 20.0 µM (40.76-52.03%), indicating that they could act as microtubule-destabilizing agents. From the screening results, three most potential compounds, 7d, 7h, and 10c, were selected for further evaluation of cellular effects on breast cancer MDA-MB-231 cells. The apoptosis-inducing study indicated that these three compounds could cause morphological changes at 1.0 µM and could enhance caspase-3 activity (1.33-1.57 times) at 10.0 µM in MDA-MB-231 cells, confirming their apoptosis-inducing activities. Additionally, in cell cycle analysis, compounds 7d and 7h at 2.5 µM and 10c at 5.0 µM also arrested MDA-MB-231 cells in the G2/M phase. Finally, the results from in silico studies revealed that the predicted absorption, distribution, metabolism, excretion, and the toxicity (ADMET) profile of the most potent MACs might have several advantages in addition to potential disadvantages, and compound 7h could bind into (ΔG -10.08 kcal·mol-1) and access wider space at the colchicine-binding site (CBS) than that of colchicine or nocodazole via molecular docking studies. In conclusion, our study serves as a basis for the design of promising synthetic compounds as anticancer agents in the future.

Transgenerational exposure to marine heatwaves ameliorates the lethal effect on tropical copepods regardless of predation stress.

Marine heatwaves (MHWs) are emerging as a severe stressor in marine ecosystems. Extreme warm sea surface temperatures during MHWs often exceed the optimal thermal range for more than one generation of tropical coastal zooplankton. However, it is relatively unknown whether transgenerational plasticity (TGP) to MHWs may shape the offspring's fitness, particularly in an ecologically relevant context with biotic interactions such as predation stress. We addressed these novel research questions by determining the survival, reproductive success, and grazing rate of the copepod Pseudodiaptomus incisus exposed to MHW and fish predator cues (FPC) for two generations (F1 and F2). The experiment was designed in a full orthogonal manner with 4 treatments in F1 and 16 treatments in F2 generation. In both generations, MHW reduced P. incisus survival, reproductive parameters, and grazing by 10%-62% in MHW, but these parameters increased by 2%-15% with exposure to FPC, particularly at control temperature. F2 reproductive success and grazing rate as indicated by cumulative fecal pellets were reduced by 20%-30% in F1-MHW, but increased by ~2% in F1-FPC. Strikingly, MHW exposure reduced 17%-18% survival, but transgenerational exposure to MHWs fully ameliorated its lethal effect and this transgenerational effect was independent of FPC. Increased survival came with a cost of reduced reproductive success, constrained by reduced grazing. The rapid transgenerational MHW acclimation and its associated costs are likely widespread and crucial mechanisms underlying the resilience of coastal tropical zooplankton to MHWs in tropical coastal marine ecosystems.

Parental exposures increase the vulnerability of copepod offspring to copper and a simulated marine heatwave.

Extreme temperatures from marine heatwaves (MHWs) and pollution are dominant stressors in tropical marine ecosystems. However, we know little about the role of transgenerational effects of metals and MHWs in shaping the offspring's vulnerability to these stressors. We addressed this fundamental knowledge gap by exposing the planktonic copepod Pseudodiaptomus incisus to copper (Cu: control, 15 and 60 µg L-1) under 2 temperatures (30 and a simulated marine heatwave at 34 °C) in the first generation (F1) and 16 treatments in F2: offspring from each of 4 F1 conditions (control or 15 µg Cu L-1 × 30 or 34 °C) was reared in 4 F2 conditions (control or 15 µg Cu L-1 × 30 or 34 °C). We assessed changes in copepod performance, particularly survival, adult size, grazing, and reproduction. In F1, Cu or marine heatwave (MHW) exposures reduced all fitness traits of F1; the effects were particularly strong when both stressors were present. Transgenerational effects of Cu or MHW also strongly reduced F2 performance. Direct Cu and MHW effects on the offspring were further strengthened by transgenerational effects, resulting in more substantial reductions in F2 performance when both generations were exposed to these stressors. As copepods are major food resources for corals, shrimps, or fish larvae and juveniles, strong transgenerational and direct effects of Cu and MHW can have a cascading effect on entire coastal food webs. These results highlight the importance of considering the interaction of transgenerational and direct effects of multiple stressors, particularly relevant for short-lived organisms in tropical marine ecosystems.

Molecular Docking Studies of Glycyrrhetinic Acid Derivatives as Anti- Colorectal Cancer Agents.

BACKGROUND: In this study, the anti-colorectal cancer (CRC) activities of 40 glycyrrhetinic acid derivatives were proposed and evaluated by the molecular docking method, which allowed the flexibility of both ligand-receptor, with twelve CRC-related targets. METHODS: The proposed derivatives, which clearly distinguish isomers at position 18 as well as the different tautomers, were divided into five groups, including (1) glycyrrhetinic acid and its oxidation derivatives, (2) glycoside derivatives, (3) 3ß-amine derivatives, (4) five-membered heterocyclic ring-combined derivatives, and (5) six-membered heterocyclic ring-combined derivatives. RESULTS: Finally, four out of twelve proposed targets related to CRC with good binding affinities to the proposed glycyrrhetinic acid derivatives were selected, including Epidermal Growth Factor Receptor (EGFR), Focal Adhesion Kinase (FAK), Lactate Dehydrogenase A (LDHA), and Thymidylate Synthase (TS). CONCLUSION: From there, 9/40 derivatives for EGFR (pKd ≥ 9); 10/40 derivatives for FAK (pKd ≥ 10); 9/40 derivatives for LDHA (pKd ≥ 10), and 6/40 derivatives for TS (pKd ≥ 9) were also obtained. The glycoside derivatives showed the best binding affinity (especially the glucuronide derivative 5b), followed by the 3ß-amino derivatives (especially the 3ß-(phenylamino) derivative 8b) and the five-membered heterocyclic ring-combined derivatives (especially the pyrrole derivative 10a or pyrazole derivative 11.2a), while the six-membered heterocyclic ring-combined derivatives had less potential to inhibit the 4 selected targets.

Interactive effects of extreme temperature and a widespread coastal metal contaminant reduce the fitness of a common tropical copepod across generations.

Tropical coastal areas are increasingly exposed to temperature extremes from marine heatwaves and contaminants from anthropogenic activities. The interactive effects of these environmental changes on marine life are understudied. We investigated the direct and cross-generational effects of copper (Cu) on F0 and F1 generations of the common tropical copepod Pseudodiaptomus annandalei under extreme temperatures (30 and 34 °C). In F0, Cu exposure reduced survival and nauplii production; these patterns were more pronounced at 34 °C and in females. F0 Copepods produced more faecal pellets at 34 °C than 30 °C, indicating a higher energetic demand. In F1, the number of F1 adults was lower in CuF0 and at 34 °C. Cu-exposed F0 produced larger adult F1, while exposure to 34 °C resulted in smaller adult F1. Our results show that tropical copepods are highly vulnerable to the interactive effects of contaminants and extreme temperatures.

Author Correction: Extreme temperature impairs growth and productivity in a common tropical marine copepod.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Extreme temperature impairs growth and productivity in a common tropical marine copepod.

Shallow, tropical marine ecosystems provide essential ecosystem goods and services, but it is unknown how these ecosystems will respond to the increased exposure to the temperature extremes that are likely to become more common as climate change progresses. To address this issue, we tracked the fitness and productivity of a key zooplankton species, the copepod Pseudodiaptomus annandalei, acclimated at two temperatures (30 and 34 °C) over three generations. 30 °C is the mean temperature in the shallow water of the coastal regions in Southeast Asia, while 34 °C simulated a temperature extreme that occurs frequently during the summer period. For each generation, we measured the size at maturity and reproductive success of individuals. In all three generations, we found strong negative effects of warming on all measured fitness-related parameters, including prolonged development time, reduced size at maturity, smaller clutch sizes, lower hatching success, and reduced naupliar production. Our results suggest that P. annandalei are already exposed to temperatures that exceed their upper thermal optimum. Increased exposure to extreme temperatures may reduce the abundance of these tropical marine copepods, and thus reduce the availability of resources to higher trophic levels.

Attitudes of Canadian psychiatry residents if mentally ill: awareness, barriers to disclosure, and help-seeking preferences.

BACKGROUND: The medical culture is defined by mental illness stigma, non-disclosure, and avoidance of professional treatment. Little research has explored attitudes and help-seeking behaviors of psychiatry trainees if they were to become mentally ill. METHOD: Psychiatry residents (n = 106) from training centres across Ontario, Canada completed a postal survey on their attitudes, barriers to disclosure, and help-seeking preferences in the context of hypothetically becoming mentally ill. RESULTS: Thirty-three percent of respondents reported personal history of mental illness and the frequency of mental illness by year of training did not significantly differ. The most popular first contact for disclosure of mental illness was family and friends (n = 61, 57.5%). Frequent barriers to disclosure included career implications (n = 39, 36.8%), stigma (n = 11, 10.4%), and professional standing (n = 15, 14.2%). Personal history of mental illness was the only factor associated with in-patient treatment choice, with those with history opting for more formal advice versus informal advice. CONCLUSIONS: At the level of residency training, psychiatrists are reporting barriers to disclosure and help-seeking if they were to experience mental illness. A majority of psychiatry residents would only disclose to informal supports. Those with a history of mental illness would prefer formal treatment services over informal services.

A fast seed detection using local geometrical feature for automatic tracking of coronary arteries in CTA.

We propose a fast seed detection for automatic tracking of coronary arteries in coronary computed tomographic angiography (CCTA). To detect vessel regions, Hessian-based filtering is combined with a new local geometric feature that is based on the similarity of the consecutive cross-sections perpendicular to the vessel direction. It is in turn founded on the prior knowledge that a vessel segment is shaped like a cylinder in axial slices. To improve computational efficiency, an axial slice, which contains part of three main coronary arteries, is selected and regions of interest (ROIs) are extracted in the slice. Only for the voxels belonging to the ROIs, the proposed geometric feature is calculated. With the seed points, which are the centroids of the detected vessel regions, and their vessel directions, vessel tracking method can be used for artery extraction. Here a particle filtering-based tracking algorithm is tested. Using 19 clinical CCTA datasets, it is demonstrated that the proposed method detects seed points and can be used for full automatic coronary artery extraction. ROC (receiver operating characteristic) curve analysis shows the advantages of the proposed method.