Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive. Methods: Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The 'in vivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2SR and Huh7SR xenografts. Molecular docking was done with Swiss dock and Auto Dock Vina. Results: PH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3Tyr705 level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway. Conclusion: Our data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1-mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations. Graphical abstract: [Figure not available: see fulltext]. - 2019 The Author(s).The publication of this article was funded by the Qatar National Library, Qatar. The graphical abstract was created with BioRender.comScopu

Camel Milk Modulates the Expression of Aryl Hydrocarbon Receptor-Regulated Genes, Cyp1a1, Nqo1, and Gsta1, in Murine hepatoma Hepa 1c1c7 Cells

There is a traditional belief in the Middle East that camel milk may aid in prevention and treatment of numerous cases of cancer yet, the exact mechanism was not investigated. Therefore, we examined the ability of camel milk to modulate the expression of a well-known cancer-activating gene, Cytochrome P450 1a1 (Cyp1a1), and cancer-protective genes, NAD(P)H:quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase a1 (Gsta1), in murine hepatoma Hepa 1c1c7 cell line. Our results showed that camel milk significantly inhibited the induction of Cyp1a1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent Cyp1a1 inducer and known carcinogenic chemical, at mRNA, protein, and activity levels in a concentration-dependent manner. In addition, camel milk significantly decreased the xenobiotic responsive element (XRE)-dependent luciferase activity, suggesting a transcriptional mechanism is involved. Furthermore, this inhibitory effect of camel milk was associated with a proportional increase in heme oxygenase 1. On the other hand, camel milk significantly induced Nqo1 and Gsta1 mRNA expression level in a concentration-dependent fashion. The RNA synthesis inhibitor, actinomycin D, completely blocked the induction of Nqo1 mRNA by camel milk suggesting the requirement of de novo RNA synthesis through a transcriptional mechanism. In conclusion, camel milk modulates the expression of Cyp1a1, Nqo1, and Gsta1 at the transcriptional and posttranscriptional levels

Mesenchymal Stem Cells for Cardiac Regeneration: Translation to Bedside Reality

Cardiovascular disease (CVD) is the leading cause of death worldwide. According to the World Health Organization (WHO), an estimate of 17.3 million people died from CVDs in 2008 and by 2030, the number of deaths is estimated to reach almost 23.6 million. Despite the development of a variety of treatment options, heart failure management has failed to inhibit myocardial scar formation and replace the lost cardiomyocyte mass with new functional contractile cells. This shortage is complicated by the limited ability of the heart for self-regeneration. Accordingly, novel management approaches have been introduced into the field of cardiovascular research, leading to the evolution of gene- and cell-based therapies. Stem cell-based therapy (aka, cardiomyoplasty) is a rapidly growing alternative for regenerating the damaged myocardium and attenuating ischemic heart disease. However, the optimal cell type to achieve this goal has not been established yet, even after a decade of cardiovascular stem cell research. Mesenchymal stem cells (MSCs) in particular have been extensively investigated as a potential therapeutic approach for cardiac regeneration, due to their distinctive characteristics. In this paper, we focus on the therapeutic applications of MSCs and their transition from the experimental benchside to the clinical bedside

Camel Milk Triggers Apoptotic Signaling Pathways in Human Hepatoma HepG2 and Breast Cancer MCF7 Cell Lines through Transcriptional Mechanism

Few published studies have reported the use of crude camel milk in the treatment of stomach infections, tuberculosis and cancer. Yet, little research was conducted on the effect of camel milk on the apoptosis and oxidative stress associated with human cancer. The present study investigated the effect and the underlying mechanisms of camel milk on the proliferation of human cancer cells using an in vitro model of human hepatoma (HepG2) and human breast (MCF7) cancer cells. Our results showed that camel milk, but not bovine milk, significantly inhibited HepG2 and MCF7 cells proliferation through the activation of caspase-3 mRNA and activity levels, and the induction of death receptors in both cell lines. In addition, Camel milk enhanced the expression of oxidative stress markers, heme oxygenase-1 and reactive oxygen species production in both cells. Mechanistically, the increase in caspase-3 mRNA levels by camel milk was completely blocked by the transcriptional inhibitor, actinomycin D; implying that camel milk increased de novo RNA synthesis. Furthermore, Inhibition of the mitogen activated protein kinases differentially modulated the camel milk-induced caspase-3 mRNA levels. Taken together, camel milk inhibited HepG2 and MCF7 cells survival and proliferation through the activation of both the extrinsic and intrinsic apoptotic pathways

Date Palm (Phoenix dactylifera) Fruits as a Potential Cardioprotective Agent: The Role of Circulating Progenitor Cells

Date palms, along with their fruits' dietary consumption, possess enormous medicinal and pharmacological activities manifested in their usage in a variety of ailments in the various traditional systems of medicine. In recent years, the identification of progenitor cells in the adult organ systems has opened an altogether new approach to therapeutics, due to the ability of these cells to repair the damaged cells/tissues. Hence, the concept of developing therapeutics, which can mobilize endogenous progenitor cells, following tissue injury, to enhance tissue repair process is clinically relevant. Objectives: The present study investigates the potential of date of palm fruit extracts in repairing tissue injury following myocardial infarction (MI) potentially by mobilizing circulating progenitor cells. Methods: Extracts of four different varieties of date palm fruits common in Saudi Arabia eastern provision were scrutinized for their total flavonoid, total phenolic, in vitro antioxidant capacity, as well as their effects on two different rodent MI models. Results: High concentrations of phenolic and flavonoid compounds were observed in date palm fruit extracts, which contributed to the promising antioxidant activities of these extracts and the observed high protective effect against various induced in vivo MI. The extracts showed ability to build up reserves and to mobilize circulating progenitor cells from bone marrow and peripheral circulation to the site of myocardial infraction. Conclusion: Date palm fruit extracts have the potential to mobilize endogenous circulating progenitor cells, which can promote tissue repair following ischemic injury.University College DublinDate Palm Research Cente

Effectiveness of Educational and Vaccination Interventions in Preventing Monkeypox: Case of Low- and Middle-Income Countries (LMICs)

Preventing the spread of Monkeypox in endemic countries in low-resource settings is important to address the prevalence of this disease and avoid outbreaks in other regions, mostly in the Central African countries and Northern Europe. The concepts covered in this area are educational and vaccination interventions to prevent Monkeypox transmission as a vital public health priority. The aim of this dissertation is to review evidence about the effectiveness of educational and vaccination interventions in low- and-middle-income countries (LMICs) and to examine factors affecting successful implementation of these interventions. A critical review of current literature enabled to evaluate the preventative interventions and factors affecting their implementation to address Monkeypox incidence. The range of evidence included comprised nine studies, eight of which provided evidence from LMICs, while one study was from a high-resource economy, namely the United States. This paper on a high-resource setting was included to assist in establishing factors that have enabled the effective implementation of an intervention in this context to promote public health and suggest ways in which low-income settings could manage implementation challenges. LMICs have differing abilities to handle the factors that affect the successful implementation of intervention efforts. The educational intervention activities increase the ability to identify and address suspected and confirmed Monkeypox cases, while vaccination intervention approaches reduce vulnerability to Monkeypox virus exposure among community members and health care workers. A major finding revealed is that vaccination interventions increased the safety levels among the health care workers infected by Monkeypox virus over a period of four years, with an incidence of 17.4 cases per 10,000 people compared to a range of 0.6-1.8% by year. Corrective and concentrated intervention efforts by the government, health workers, and community members through relaying information and providing follow-up programs is an opportunity to cushion against vulnerability to Monkeypox in low-and-middle-income countries

AI-Guided Repurposing of FDA-Approved Anti-Leukemic Molecularly Targeted Therapies for Fatal Blast Crisis Chronic Myeloid Leukemia: Integrative Genomics for Precision Medicine of Relapsed/Refractory Cancers in the Post-Pandemic Era

Background: The COVID-19 pandemic accelerated the paradigm of drug repurposing, leading to the rapid identification of new uses for existing therapeutics under urgent clinical need. This success story has ignited a broader movement towards leveraging repurposing strategies for relapsed, refractory, and traditionally difficult-to-treat diseases, specifically cancers. Chronic myeloid leukemia (CML), although treatable in the chronic phase (CP), is usually fatal in the blast crisis phase (BC-CML), exemplifying a pressing challenge to oncology, where standard tyrosine kinase inhibitor (TKI) therapies often fail, resulting in poor survival outcomes. Methods and Results: In a multi-institutional cohort of 141 CML patients, we performed WES across disease phases (123 CP-CML, 6 AP-CML, 12 BC-CML). Mutational landscapes were interrogated using the AI-driven PanDrugs2 platform to identify druggable targets and repurposable FDA-approved anti-leukemic therapies. A 54% surge in mutational burden was observed transitioning from AP-CML to BC-CM, revealing 67 recurrent pan-leukemic gene mutations. Notably, actionable alterations were found in NPM1, DNMT3A, PML, AKT1, CBL, JAK2, TET2, IDH1, and BCL2, with therapeutic opportunities using existing agents such as venetoclax, ivosidenib, decitabine, and azacitidine. Emerging vulnerabilities, including RPTOR and BCR mutations, suggest further avenues for mTOR and BTK inhibitor applications beyond traditional TKI paradigms. Conclusions: Our integrated genomic and AI-guided approach demonstrates the transformative potential of drug repurposing for BC-CML, highlighting immediate actionable options where conventional therapies fail. This strategy not only offers hope for patients with BC-CML but also paves a visionary path toward precision medicine frameworks for relapsed, refractory, and otherwise intractable cancers in the post-pandemic clinical era. Prospective multi-omics studies and tailored clinical trials are urgently warranted to expand these opportunities across the oncology landscape