Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma

Being the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the disease, toxicity to healthy cells, and the potential for drug resistance. There is ample evidence that coumarin-based compounds are potent anticancer agents, with numerous analogues currently being investigated in preclinical and clinical studies. The current study aimed to explore the antitumor potency of a new class of 8-methoxycoumarin-3-carboxamides against liver cancer. Toward this aim, we have designed, synthesized, and characterized a new set of N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamide analogues. The assessment of antitumor activity revealed that the synthesized class of compounds possesses substantial cytotoxicity toward Hep-G2 cells when compared to staurosporine, without significant impact on normal cells. Out of the synthesized compounds, compound 7 demonstrated the most potent cytotoxic effect against Hep-G2 cells with an IC50 of 0.75 µM, which was more potent than the drug staurosporine (IC50 = 8.37 µM). The investigation into the mechanism behind the antiproliferative activity of compound 7 revealed that it interferes with DNA replication and induces DNA damage, leading to cell cycle arrest as demonstrated by a significant decrease in the percentage of cells in the G1 and G2/M phases, along with an increase in the percentage of cells in the S phase. Flow cytometric analysis further revealed that compound 7 has the ability to trigger programmed cell death by inducing necrosis and apoptosis in HepG-2 cells. Further explorations into the mechanism of action demonstrated that compound 7 displays a potent dual-inhibitory activity toward cytochrome P450 and vascular endothelial growth factor receptor-2 (VEGFR-2) proteins, as compared to sorafenib drug. Further, detailed computational studies revealed that compound 7 displays a considerable binding affinity toward the binding cavity of VEGFR2 and CYP450 proteins. Taken together, our findings indicate that the newly synthesized class of compounds, particularly compound 7, could serve as a promising scaffold for the development of highly effective anticancer agents against liver cancer

Functional conservation of a male germline regulatory module in crop plants

The formation of two sperm cells by the angiosperm male gametophyte is essential for seed production and ultimately for plant productivity. The MYB transcription factor DUO1 POLLEN 1 (DUO1) is a key regulator of male gametogenesis in Arabidopsis thaliana and forms a germline-specific regulatory module with the functionally redundant genes DUO1-ACTIVATED ZINC FINGER1 (DAZ1) and DAZ2. This regulatory module is conserved in some bryophytes, but its wider role among angiosperms remains unexplored. Here the DUO1-DAZ1 regulatory module is investigated in tomato (Solanum lycopersicum L.), wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.). Two DUO1 orthologues and a single DAZ1 orthologue were identified in the genomes of tomato and barley, while three DUO1 and three DAZ1 homoeologues are present in the bread wheat genome. Analysis of RNA-seq data revealed that transcripts for DUO1 and DAZ1 are expressed in male reproductive tissues in each of these crops. Plants carrying knockout alleles disrupting SlDUO1 or SlDAZ1 function in tomato were shown to block generative cell division and the transmission of SlDUO1 or SlDAZ1 mutant alleles through pollen. Further, the generative cell was round in mutant alleles compared to elongated generative cell in wild type. Quantitative analysis of RNA expression in loss of function mutants also indicated that regulatory interactions of the DUO1-DAZ1 module are conserved in tomato. Preliminary analysis of knockout alleles disrupting TaDUO1 function in wheat indicate that generative cell division and sperm cell formation are affected. Plants homozygous for knock out alleles in one of two barley DUO1 orthologues were fertile and showed no generative cell defects. In summary, the data presented demonstrate an essential role for the DUO1-DAZ1 module in tomato and support the hypothesis that this regulatory module is more widely conserved in some key crop plants.</p

Epidemiological Trends of Acute Chemical Poisoning among Children over a Recent Three-Year Period in Saudi Arabia

Acute intoxication from chemicals is a major medical emergency that can result in illness and mortality. This retrospective study aims to evaluate acute chemical poisoning incidents among children in Saudi Arabia from 2019 to 2021. A total of 3009 children were recorded as being chemically intoxicated. The SPSS/PC statistics package was used for the statistical analysis. The acute chemical poisoning incidents that occurred in the age groups were &lt;1 year: 237 (7.8%), 1&ndash;5 years: 2301 (76.4%), 6&ndash;12 years: 214 (7.1%), and 13&ndash;19 years: 257 (8.5%). The mean rate of acute chemical poisoning in the northern region was 40.1%. The most common poisonous agents were organic solvents (20.4%) and disinfection agents (22.7%). Interestingly, there is a significant relationship between the different types of acute chemical poisoning and various factors, including gender, age, the location where acute chemical intoxication occurred, the type of exposure, and whether these were intentional or unintentional events. The data suggest that the northern region of Saudi Arabia has had the highest number of recorded incidents of acute chemical poisoning over the last three years (2019&ndash;2021). Individuals between 1&ndash;5 years old were the worst hit. Organic solvents and detergents were to blame for the acute unintentional chemical poisonings that took place in homes. Therefore, educating the public about chemical poisoning and reducing children&rsquo;s exposure to toxic chemicals requires educational programs, which may help to reduce chemical poisoning occurrence

Epidemiological Trends of Acute Chemical Poisoning among Children over a Recent Three-Year Period in Saudi Arabia

Acute intoxication from chemicals is a major medical emergency that can result in illness and mortality. This retrospective study aims to evaluate acute chemical poisoning incidents among children in Saudi Arabia from 2019 to 2021. A total of 3009 children were recorded as being chemically intoxicated. The SPSS/PC statistics package was used for the statistical analysis. The acute chemical poisoning incidents that occurred in the age groups were <1 year: 237 (7.8%), 1–5 years: 2301 (76.4%), 6–12 years: 214 (7.1%), and 13–19 years: 257 (8.5%). The mean rate of acute chemical poisoning in the northern region was 40.1%. The most common poisonous agents were organic solvents (20.4%) and disinfection agents (22.7%). Interestingly, there is a significant relationship between the different types of acute chemical poisoning and various factors, including gender, age, the location where acute chemical intoxication occurred, the type of exposure, and whether these were intentional or unintentional events. The data suggest that the northern region of Saudi Arabia has had the highest number of recorded incidents of acute chemical poisoning over the last three years (2019–2021). Individuals between 1–5 years old were the worst hit. Organic solvents and detergents were to blame for the acute unintentional chemical poisonings that took place in homes. Therefore, educating the public about chemical poisoning and reducing children’s exposure to toxic chemicals requires educational programs, which may help to reduce chemical poisoning occurrence