Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, confers properties of ‘stemness’, such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system, as a well-established paradigm of stem cell biology, to evaluate Zeb1 mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knockout (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid onset thymic atrophy and apoptosis driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multi-lineage differentiation block was observed in Zeb1 KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multi-lineage differentiation genes, and of cell polarity, consisting of cytoskeleton, lipid metabolism/lipid membrane and cell adhesion related genes. Notably, Epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1 KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients and Zeb1 KO in the malignant counterparts of HSCs - leukemic stem cells (LSCs) - accelerated MLL-AF9 and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically co-ordinating HSC self-renewal, apoptotic and multi-lineage differentiation fates required to suppress leukemic potential in AML

Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, confers properties of ‘stemness’, such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system, as a well-established paradigm of stem cell biology, to evaluate Zeb1 mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knockout (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid onset thymic atrophy and apoptosis driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multi-lineage differentiation block was observed in Zeb1 KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multi-lineage differentiation genes, and of cell polarity, consisting of cytoskeleton, lipid metabolism/lipid membrane and cell adhesion related genes. Notably, Epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1 KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients and Zeb1 KO in the malignant counterparts of HSCs - leukemic stem cells (LSCs) - accelerated MLL-AF9 and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically co-ordinating HSC self-renewal, apoptotic and multi-lineage differentiation fates required to suppress leukemic potential in AML

Bioactive brominated oxindole alkaloids from the Red Sea sponge Callyspongia siphonella

In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents

Knowledge, attitudes and practices with regard to prophetic medicine during the COVID-19 pandemic in Saudi Arabia

OBJECTIVE: The current study explores the impact of Prophetic medicine’s knowledge, attitudes, and practices on the Saudi population during the COVID-19 pandemic. SUBJECTS AND METHODS: This study used a web-based cross-sectional design. A self-selected nonprobability sampling technique was utilized to recruit social media users in Saudi Arabia aged ≥18. RESULTS: Four statements were used to evaluate participants’ knowledge of the role of prophetic medicine in preventing and treating COVID-19. The participants had significant levels of knowledge, with an average of 90.3% correct answers. They strongly agreed with prophetic advice, including quarantine, travel bans and hand washing to prevent COVID-19 infection, with a mean of 4.3. In addition, the participants followed prophetic advice, including walking for half an hour, keeping social distance, wearing masks, and taking vaccines to prevent COVID-19 infection, with a mean of 4.2. CONCLUSIONS: The current study was conducted to evaluate the knowledge, attitudes, and practices of Muslim residents of Saudi Arabia concerning prophetic medicine during the COVID-19 pandemic. The study revealed that participants had good knowledge of prophetic medicine, including the use of natural products such as honey, ginger, garlic, and olive oil, as well as herbal products such as black seeds, and practices such as cupping. The study also showed that participants strongly believed that COVID-19 preventative measures – including quarantine, travel bans, and handwashing – were introduced by prophetic medicine. Practices including self-isolation, hand washing, and travel bans help prevent, treat and control diseases. They assist in maintaining good health and developing resistance to diseases

Isolation of anticancer constituents from Cucumis prophetarum var. prophetarum through bioassay-guided fractionation

Abstract Background Cucumis prophetarum var. prophetarum is used in Saudi folk medicine for treating liver disorders and grows widely between Abha and Khamis Mushait City, Saudi Arabia. Methods Bioassay-guided fractionation and purification were used to isolate the main active constituents of Cucumis prophetarum var. prophetarum fruits. These compounds were structurally elucidated using NMR spectroscopy, mass spectral analyses and x-ray crystallography. All fractions, sub-fractions and pure compounds were screened for their anticancer activity against six cancer cell lines. Results The greatest cytotoxic activity was found to be in the ethyl acetate fraction, resulting in the isolation of five cucurbitacin compounds [E, B, D, F-25 acetate and Hexanorcucurbitacin D]. Among the cucurbitacins that were isolated and tested cucurbitacin B and E showed potent cytotoxicity activities against all six human cancer cell lines. Conclusion Human breast cancer cell lines were found to be the most sensitive to cucurbitacins. Preliminary structure activity relationship (SAR) for cytotoxic activity of Cucurbitacins against human breast cancer cell line MDA-MB-231 has been reported

Colonic Mucosal Microbiota in Colorectal Cancer: A Single-Center Metagenomic Study in Saudi Arabia

Background and Aim. Because genetic and geographic variations in intestinal microbiota are known to exist, the focus of this study was to establish an estimation of microbiota in colorectal cancer (CRC) patients in Saudi Arabia by means of metagenomic studies. Methods. From July 2010 to November 2012, colorectal cancer patients attending our hospital were enrolled for the metagenomic studies. All underwent clinical, endoscopic, and histological assessment. Mucosal microbiota samples were collected from each patient by jet-flushing colonic mucosa with distilled water at unified segments of the colon, followed by aspiration, during colonoscopy. Total purified dsDNA was extracted and quantified prior to metagenomic sequencing using an Illumina platform. Satisfactory DNA samples (n=29) were subjected to metagenomics studies, followed by comprehensive comparative phylogenetic analysis. An equal number of healthy age-matched controls were also examined for colonic mucosal microbiota. Results. Metagenomics data on 29 patients (14 females) in the age range 38–77 years were analyzed. The majority 11 (37%) of our patients were overweight (BMI = 25–30). Rectal bleeding was the presenting symptom in 18/29 (62%), while symptomatic anemia was the presenting symptom in 11/29 (37%). The location of colon cancer was rectal in 14 (48%), while cecal growth was observed in 8 (27%). Hepatic flexure growth was found in 1 (3%), descending colonic growth was found in 2 (6%), and 4 (13%) patients had transverse colon growth. The metagenomics analysis was carried out, and a total of 3.58G reads were sequenced, and about 321.91G data were used in the analysis. This study identified 11 genera specific to colorectal cancer patients when compared to genera in the control group. Bacteroides fragilis and Fusobacterium were found to be significantly prevalent in the carcinoma group when compared to the control group. Conclusion. The current study has given an insight into the microbiota of colorectal cancer patients in Saudi Arabia and has identified various genera significantly present in these patients when compared to those of the control group

The associations between the credibility of the tobacco control regulatory body and smoking behavior change among Saudi smokers

Introduction Recently, Saudi Arabia has extensively reformed its tobacco control policies and extended its smoking cessation services. A public outrage on social media among smokers was witnessed, especially after the implementation of plain cigarette packaging, which might have discredited the significant efforts of tobacco treatment services and tobacco control policies. However, it is not known how the credibility of the tobacco control regulatory body among Saudi smokers might affect their smoking behavior. Methods Saudi tobacco smokers (n=511) were recruited using a convenience sampling technique. A cross-sectional survey was conducted comprising questions related to the credibility of the tobacco control regulatory body (modified Food and Drug Administration Tobacco Credibility Scale), quit attempts, use of nicotine replacement therapy (NRT), and motivation to change smoking behavior in the future. Logistic and linear regression models were used for the analysis. Results The public interest subscale of the credibility of the tobacco control regulatory body, was positively associated with confidence in changing smoking behavior (β=0.204; 95% CI: 0.078–0.713; t=2.449, p=0.015) and readiness to change smoking behavior (β=0.237; 95% CI: 0.127–0.727; t=2.802, p=0.005). Moreover, the subscale of expertise was positively associated with confidence in changing smoking behavior (β=0.190; 95% CI: 0.006–0.697; t=1.999, p=0.046) and readiness to change smoking behavior (β=0.225; 95% CI: 0.063–0.710; t=2.352, p=0.019). However, public interest in the credibility of the tobacco control regulatory body was negatively associated with NRT use among smokers who tried to quit (adjusted odds ratio, AOR=0.691; 95% CI: 0.526–0.909). The credibility of the tobacco control regulatory body, however, was not associated with the last month’s or ever quit attempts. Conclusions The credibility of the tobacco control regulatory body was positively associated with motivation to change smoking behavior but negatively associated with NRT use. Optimizing communication tools with the public is a potential avenue for improving smoking treatment and prevention in Saudi Arabia

Anti-Tumor Potential of <i>Gymnema sylvestre</i> Saponin Rich Fraction on In Vitro Breast Cancer Cell Lines and In Vivo Tumor-Bearing Mouse Models

Gymnema sylvestre (GS) is a perennial woody vine native to tropical Asia, China, the Arabian Peninsula, Africa and Australia. GS has been used as a medicinal plant with potential anti-microbial, anti-inflammatory and anti-oxidant properties. This study was conceptualized to evaluate the cytotoxicity potential of Gymnema sylvestre saponin rich fraction (GSSRF) on breast cancer cell lines (MCF-7 and MDA-MB-468) by SRB assay. The anti-tumor activity of GSSRF was assessed in tumor-bearing Elrich ascites carcinoma (EAC) and Dalton’s lymphoma ascites (DLA) mouse models. The anti-oxidant potential of GSSRF was assessed by DPPH radical scavenging assay. The acute toxicity of GSSRF was carried out according to OECD guideline 425. The yield of GSSRF was around 1.4% and the presence of saponin content in GSSRF was confirmed by qualitative and Fourier transform infrared spectroscopic (FTIR) analysis. The in vitro cytotoxic effects of GSSRF on breast cancer cell lines were promising and found to be dose-dependent. An acute toxicity study of GSSRF was found to be safe at 2000 mg/kg body weight. GSSRF treatment has shown a significant increase in the body weight and the life span of EAC-bearing mice in a dose-dependent manner when compared with the control group. In the solid tumor model, the doses of 100 and 200 mg/kg body weight per day have shown about 46.70% and 60.80% reduction in tumor weight and controlled the tumor weight until the 30th day when compared with the control group. The activity of GSSRF in both models was similar to the cisplatin, a standard anticancer agent used in the study. Together, these results open the door for detailed investigations of anti-tumor potentials of GSSRF in specific tumor models, mechanistic studies and clinical trials leading to promising novel therapeutics for cancer therapy

The Intersection of Health Rehabilitation Services with Quality of Life in Saudi Arabia: Current Status and Future Needs

Quality of life (QoL) is essential for maintaining a healthy, balanced lifestyle, especially among individuals with chronic diseases. Saudi Arabia (SA) launched a health sector transformation program as part of the nationwide Vision 2030 initiative to ensure the sustainable development of efficient healthcare services, aiming to improve health by increasing well-being and QoL. More investigation into the current status of health rehabilitation services provided to individuals with chronic diseases and future needs to optimize services and improve QoL is needed. This was narratively discussed by experts from different health rehabilitation services in SA. Comprehensive health rehabilitation services including orthopedic, occupational, cardiac, pulmonary, critical care, perioperative, hearing and speech, substance use disorders, and vocational rehabilitation services were addressed. Health rehabilitation services in SA, as in other countries, are suboptimal for individuals in health rehabilitation programs. To optimize the QoL of individuals with chronic diseases, health rehabilitation services should be tailored based on the unique requirements of each service and its serving patients. The shared need to improve health rehabilitation services includes the adoption of home-based and telehealth services, the integration of multi-governmental sectors, the empowerment and allocation of health rehabilitation specialists, public awareness campaigns, policy legislation and guideline development, and the implementation of a long-term follow-up system. This review is one of the first to address the intersection of health rehabilitation services and QoL in SA; urgent and holistic actions are paramount to address the pressing need to optimize SA&rsquo;s health rehabilitation services. The experts&rsquo; recommendations in this study may be applicable to other countries&rsquo; health systems, as health rehabilitation services are not well optimized globally