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

Impact of Smoking Exposure on Pregnancy and Perinatal Outcome Among Saudi Women: A Cross-Sectional Study

Objective: To assess the impact of smoking exposure on pregnancy and perinatal outcomes among Saudi women. Methods: This research will employ a cross-sectional study design to assess the impact of smoking exposure on pregnancy and perinatal outcomes among Saudi women. Cross-sectional studies are particularly suitable for examining associations and prevalence within a defined population at a specific point in time. In this case, the study aims to collect data on smoking behavior, pregnancy history, and perinatal outcomes among a representative sample of Saudi women in healthcare facilities across different regions of the country. The cross-sectional design allows for the efficient collection of data from a diverse population, providing insights into the relationship between smoking and perinatal outcomes without the need for long-term follow-up. Results: The study included 450 participants. The most frequent age among them was 35 and more years (n= 309, 68.7%) followed by 30-34 (n= 94, 20.9%). The most frequent educational level among study participants was the university (n= 408, 90.7%) followed by the school (n= 39, 8.7%). The most frequent job among study participants was a Governmental job (n= 159, 35.3%) followed by a housewife (n= 135, 30%). Number of previous births among study participants with most of them having a previous birth (n= 396, 88%) followed by this is the first birth (n= 54, 12%). Number of previous pregnancies among study participants with most of them having a previous pregnancy (n= 408, 90.7%) followed by this is the first pregnancy (n= 42, 9.3%). Number of abortions among study participants with most of them nothing (n= 234, 52%) followed by there is (n= 216, 48%). Participants were asked about smoking. The most frequent were don’t smoke (n= 315, 70%) followed by smoking (n= 135, 30%). The most frequent exposure to smoking among them was yes (n= 333, 74%) followed by no (n= 117, 26%). Conclusion: Study results showed that most of the study participants are the university according to their educational level. Most frequencies of participants had a previous birth. Most of them don’t smoke in another hand most of them were exposed to smoking. In addition, most of the study participants had good social connection

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

Safety and quality of AI chatbots for drug-related inquiries: A real-world comparison with licensed pharmacists

Introduction Pharmacists play a pivotal role in ensuring patients are administered safe and effective medications; however, they encounter obstacles such as elevated workloads and a scarcity of qualified professionals. Despite the prospective utility of large language models (LLMs), such as Generative Pre-trained Transformers (GPTs), in addressing pharmaceutical inquiries, their applicability in real-world cases remains unexplored. Objective To evaluate GPT-based chatbots’ accuracy in real-world drug-related inquiries, comparing their performance to licensed pharmacists. Methods In this cross-sectional study, authors analyzed real-world drug inquiries from a Drug Information Inquiry Database. Two independent pharmacists evaluated the performance of GPT-based chatbots (GPT-3, GPT-3.5, GPT-4) against human pharmacists using accuracy, detail, and risk of harm criteria. Descriptive statistics described inquiry characteristics. Absolute proportion comparative analyses assessed accuracy, detail, and risk of harm. Stratified analyses were performed for different inquiry types. Results Seventy inquiries were included. Most inquiries were received from physicians (41%) and pharmacists (44%). Inquiries type included dosage/administration (34.2%), drug interaction (12.8%) and pregnancy/lactation (15.7%). Majority of inquires included adults (83%) and female patients (54.3%). GPT-4 had 64.3% completely accurate responses, comparable to human pharmacists. GPT-4 and human pharmacists provided sufficiently detailed responses, with GPT-4 offering additional relevant details. Both GPT-4 and human pharmacists delivered 95% safe responses; however, GPT-4 provided proactive risk mitigation information in 70% of the instances, whereas similar information was included in 25.7% of human pharmacists’ responses. Conclusion Our study showcased GPT-4's potential in addressing drug-related inquiries accurately and safely, comparable to human pharmacists. Current GPT-4-based chatbots could support healthcare professionals and foster global health improvements

¹H NMR metabolomics insights into comparative diabesity in male and female zebrafish and the antidiabetic activity of DL-limonene

Zebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene – a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity—and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.</p

Rate and Causes of Unplanned Hospital Returns within 60 Days following Head and Neck Surgery

Introduction Unplanned hospital returns are frequent and may be preventable

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

Unveiling the multifaceted antiproliferative efficacy of Cichorium endivia root extract by dual modulation of apoptotic and inflammatory genes, inducing cell cycle arrest, and targeting COX-2

Chicory (Cichorium endivia L. divaricatum) is a renowned medicinal plant traditionally used for various ailments, yet the pharmacological potential of its roots, particularly in terms of antitumor activity, remains elusive. In the present study, we explore, for the first time, the metabolomic profile of ethanolic extract from Cichorium endivia roots (CIR) and further unveil its antiproliferative potential. The untargeted phytochemical analysis UPLC/T-TOF-MS/MS identified 131 metabolites in the CIR extract, covering acids, amino acids, flavonoids, alkaloids, nucleotides, and carbohydrates. The antiproliferative activity of the CIR extract was tested in 14 cancer cell lines, revealing significant cytotoxicity (IC50: 2.85–29.15 μg mL−1) and a high selectivity index. Among the cells examined, the CIR extract recorded the most potent antiproliferative activity and selectivity toward HepG2 and Panc-1 cells, with an IC50 of 2.85 μg mL−1 and 3.86 μg mL−1, respectively, and SI > 10. Insights into the mode of action of the antiproliferative activity revealed that CIR extract induces cell arrest in the S phase while diminishing cell distribution in the G0/G1 and G2/M phases in HepG-2 and Panc-1 cells. Flow cytometric and RT-PCR analysis revealed that the CIR extract significantly triggers apoptosis and modulates the expression of pro-apoptotic and anti-apoptotic genes. Furthermore, the CIR extract exhibited a pronounced anti-inflammatory activity, as evidenced by down-regulating key cytokines in LPS-induced RAW 264.7 cells and selectively inhibiting the COX-2 enzyme. Finally, the CIR extract showed a robust total antioxidant capacity, together with potent free radicals and metal scavenging properties, highlighting its role in alleviating oxidative stress. Taken together, this study highlights the multifaceted therapeutic potential of CIR extract as a natural-based antitumor supplement.Ministry of Education – Kingdom of Saudi Arabi 10.13039/501100011821Peer Reviewe