Ali Hafez El-Far

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer deaths among women worldwide. This study investigates the combined effects of tannic acid (TA) and doxorubicin (DOX) on glucose metabolism in estrogen receptor-positive (MCF7) and triple-negative (MDA-MB-231) BC cells by targeting pyruvate kinase M2 (PKM2). Cells were treated with TA, DOX, and their combinations, then analyzed for cytotoxicity, apoptosis, cell cycle progression, migration, and colony formation. PKM2 expression levels and activity were also measured. Results demonstrated that TA, alone and with DOX, effectively induced apoptosis and inhibited migration and colony formation in both cell lines. Notably, PKM2 mRNA expression was significantly reduced, particularly in TA-treated groups. Furthermore, glucose levels in the medium increased significantly following TA treatment, indicating reduced glucose uptake by cancer cells, and indicating that combining TA with DOX can disrupt glucose metabolism and diminish aggressive behaviors in BC cells. By targeting the glycolytic enzyme PKM2, TA lowers its expression, restricts glucose uptake, and enhances chemotherapy-driven apoptosis while limiting migration and colony formation. These findings underscore the potential of metabolic reprogramming through combining TA with DOX as a promising therapeutic strategy to improve BC treatment outcomes.

Chronic rhinosinusitis (CRS) is a condition with a significant healthcare and economic burden, with a prevalence of 12% in the West. The existing therapies mainly attenuate downstream inflammatory mediators but do not address the underlying immune-regulatory abnormalities that drive disease recurrence and lifelong treatment. Evidence has shown that a regulatory axis involving forkhead box P3 (FOXP3) + regulatory T cells (Tregs), the complement component 5a receptor 1 (C5aR1), and leukemia inhibitory factor (LIF) is crucial for regulating immune tolerance in sinonasal tissues. This review discusses the mechanistic basis for modulating FOXP3, C5aR1, and LIF with natural anti-inflammatory products for the treatment of CRS. A comprehensive literature review across PubMed, Scopus, and Web of Science (2000–2026) was conducted to identify research articles on the molecular mechanisms, preclinical evidence, and clinical application of natural compounds in inflammatory disorders and the sinonasal inflammatory pathway. Various studies show that FOXP3+ Tregs are highly depleted in CRS with nasal polyps. Besides, complement signaling via C5aR1 prevents active Treg induction by activating the PI3K-AKT-mTOR pathway. LIF enhances the expression of FOXP3 and opposes Th17 polarization caused by IL-6. Natural products such as epigallocatechin-3-gallate, curcumin, and rosmarinic acid regulate pathways by inhibiting DNA methyltransferases, the complement cascade, and JAK-STAT signaling. Bromelain and cineole have clinical evidence in favor of efficacy in acute sinusitis, and other compounds are showing emerging evidence. The FOXP3-C5aR1-LIF axis is a mechanistic therapeutic target that is largely overlooked by the current biologics. Natural compounds offer potential benefits, including multi-target activity, favorable safety profiles, and the ability to modulate the upstream immune system. Phenotype-based CRS populations should be studied in well-designed trials, bioavailability formulations should be optimized, and synergistic combinations should be systematically explored.

The metabolism of cancer cells is reprogrammed toward aerobic glycolysis (the Warburg effect), which stimulates tumor growth. Phosphofructokinase (PFK) and its isoforms, PFKP, PFKM, and PFKL, are highly conserved central glycolytic controllers and a potential therapeutic intervention. This review discusses the complex functions of PFK in tumor biology, including its roles in regulating proliferation, invasion, metastasis, and therapy resistance. It further discusses the tumor microenvironmental role of PFK, which influences immune evasion, angiogenesis, and stromal interactions, as well as its non-metabolic signaling functions. The therapeutic approaches to PFK, such as synthetic (e.g., PFK15) and natural (e.g., curcumin) compounds, are considered alongside strategies to address specific difficulties. Lastly, the review is based on a combination of expression analysis of PFK isoforms and a closer analysis of synthetic and natural inhibitors, and it suggests a prospective framework for implementing PFK-targeted therapies in clinical practice that incorporates AI-based drug design, nanodelivery, and immune-metabolic modulation.

G-quadruplexes (G4s) are non-canonical DNA structures that are important in gene regulation, telomere repair, and cancer. The G4s in breast cancer (BC) are enriched in the promoters of important oncogenes, such as c-MYC, KRAS, BCL2, HER2, and ESR1, which are good therapeutic targets. Although synthetic G4 stabilizers are well-researched, natural products are a poorly investigated source of selective ligands with good biocompatibility and multi-target properties. This review systematically collects and analyzes natural compounds, such as flavonoids, alkaloids, polyphenols, terpenoids, and organosulfur compounds, which exhibit G4-stabilizing effects, particularly their suitability in BC. We provide a comprehensive landscape approach to define interactions between G4-ligands, discuss how these interactions are stabilized (via π-π stacking, electrostatic interactions, and groove binding), and map these compounds to genomic regions associated with BC G4-formation. We also identify key research gaps that are essential, including limited in vivo validation, subtype-specific efficacy, and pharmacokinetic issues. The available evidence suggests that natural G4 stabilizers have potential as multi-target and biocompatible agents for BC therapy. However, their effectiveness is currently constrained by a shortage of thorough in vivo studies and subtype-specific data. Lastly, to incorporate in silico docking, mechanistic studies, and translational strategies, we present a prospective roadmap for drug discovery to bring natural G4 stabilizers targeting BC.

G-quadruplexes (G4s) are structurally unique, four-stranded nucleic acid formations composed of guanine-rich sequences stabilized by Hoogsteen hydrogen bonds. These highly stable secondary structures have emerged as vital regulatory elements in DNA and RNA metabolism, where they support genomic stability, telomere integrity, and transcriptional control. Their regulation depends on G4 helicases - specialized enzymes that unwind G4 structures using energy derived from nucleoside triphosphate hydrolysis to ensure proper cellular function. Among them, DEAH-box helicase 36 (DHX36) is a principally essential G4 helicase in human cells, capable of resolving G4s in DNA and RNA. Its activity is critical for preserving genomic integrity and regulating broader cellular processes, underscoring its potential impact on human health and disease. This review synthesizes computational and experimental approaches to discuss the interplay within the DHX36-N6-methyladenosine (m6A)-G4 axis and its role in RNA regulation and cancer genetics or epigenetics, where it post-transcriptionally controls the expression of chromatin-modifying enzymes and oncogenic transcripts. It examines the axis’s diverse activities, including roles in spermatogenesis, antiviral defense, and muscle development, and its regulatory effects in both normal physiological and diseased states. The computational identification of DHX36’s target G4 structures, combined with experimental methods, is crucial for advancing our understanding of its biological functions and disease mechanisms. This approach enhances the accuracy of target recognition and provides insights into the complex interactions within cellular processes that DHX36 may influence.

One hazardous heavy metal that causes oxidative stress is cadmium (Cd) and harms male reproductive function. Although various antioxidants have been explored for protection, the potential of Mesembryanthemum crystallinum ( M. crystallinum ) – a flavonoid and phenolic-rich halophyte- remains understudied in this context. According to the United Nations Sustainable Development Goals (SDGs), specifically SDG 3 on Good Health and Well-Being and SDG 12 Responsible Consumption and Production this novel research evaluated the protective potential of M. crystallinum aqueous extract (MAE) to mitigate cadmium chloride (CdCl ₂ )-induced testicular dysfunction. After acclimatization, Eight groups ( n = 5) of forty male rats were allocated into groups: (1) control; (2) CdCl₂ (2 mg/kg); (3) MAE 200 mg/kg; (4) MAE 400 mg/kg; (5) CdCl₂ + MAE 200 mg/kg; (6) CdCl₂ + MAE 400 mg/kg; (7) MAE (200 mg/kg) pre-treatment + CdCl₂; (8) MAE (400 mg/kg) pre-treatment + CdCl₂. For 14 days, oral treatments were administered. HPLC profiling revealed eight major phenolic compounds in M. crystallinum like quercetin and ellagic acid. CdCl ₂ exposure impaired sperm indices, reduced serum LH and testosterone and induced oxidative and histological damage with elevated caspase-3 and TNF- α expression. MAE treatment especially at 400 mg/kg restored hormonal levels, improved sperm quality, normalized antioxidant defense, and preserved testicular architecture. Molecular docking confirmed binding of hesperidin, rutin, and ellagic acid to apoptotic and inflammatory proteins. MAE may exhibit potent anti-inflammatory, antioxidant, and anti-apoptotic activity, protecting against CdCl₂-induced reproductive injury. M. crystallinum represents a sustainable, plant based therapeutic candidate aligned with SDG-driven strategies for combating environmental toxicity-related infertility.

Fipronil (FIP), as a broad-spectrum pesticide, contributes to adverse reproductive effects. Thus, our study aimed to investigate the effect of telmisartan (TEL) as a selective angiotensin 1 receptor (AT1R) blocker on mitochondrial damage induced by FIP intoxication in male rats. Forty healthy male albino rats were allocated into 4 groups (10/ group): the control group, the TEL group received TEL (10 mg/kg b.wt.), the FIP group received FIP (1/10 of the LD50 of 97 mg/kg b.wt.), and the FIP + TEL cotreated group. All treatments were taken orally for 60 days. Before the experiment, in-silico assessments of FIP and TEL were done. FIP administration diminished relative testicular weight, sperm count, and motility, besides significantly increasing sperm abnormalities ( p < 0.05). Biochemically, FIP treatment reduced considerably ( p < 0.05 ) serum testosterone, luteinizing hormone (LH), and follicular-stimulating hormone (FSH) levels related to control animals. Furthermore, FIP administration significantly increased testicular malondialdehyde (MDA), pro-inflammatory markers as tumor necrosis factor- α (TNF- α ), and interleukin-1 β (IL-1 β ) levels. Also, downregulated the activities of antioxidant markers, Nrf2, HO-1, and PCNA immunostaining. Furthermore, FIP significantly upregulated ( p < 0.05) DRP1 and downregulated PGC-1 α , MNF2, TFAM, and mtDNA mRNA transcripts. Histopathologically, FIP induced deterioration in seminiferous tubules' histoarchitecture with upregulation in Cosentino's score and downregulation in Johnson's score. On the contrary, TEL effectively restored the testicular function hormones, testicular and epididymal histoarchitecture, antioxidant indices, PGC-1 α , and TFAM, with downregulation in MDA levels and DRP1 mRNA transcript. In conclusion, TEL protects the testicular mitochondria against damage from FIP toxicosis by modulating the Nrf2/HO-1/PGC-1α/MNF2/DRP1 expressions. Graphical Abstract

The oral microbiota begins to establish at birth and develops over time under the influence of genetic factors, environmental exposures, diet, and individual oral health behaviors. In a healthy state, these microorganisms exist in a balanced ecosystem; however, disruption of this balance, known as oral dysbiosis, can promote oral diseases such as dental caries and periodontitis (PD). Growing scientific evidence indicates that the impact of oral microbial imbalance may extend beyond the oral cavity. With advances in molecular detection techniques, oral bacterial species have been identified in distant body sites, including heart valves, suggesting a possible association between oral dysbiosis and cardiovascular disease. Chronic periodontal inflammation and microbial imbalance may allow bacteria or their inflammatory products to enter the bloodstream, leading to bacteremia via direct invasion or immune-mediated mechanisms. These processes may contribute to systemic inflammation and potentially influence the development and progression of cardiovascular disease. This study aims to review and summarize current evidence on the relationship between oral dysbiosis and cardiovascular disease, with particular focus on the mechanisms by which chronic oral inflammation and microbial imbalance may contribute to bacteremia and systemic inflammatory pathways that influence cardiovascular health.

Cancer is characterized by abnormal cell growth and remains a leading global cause of death despite advances in conventional therapies. Limitations such as lack of selectivity, cytotoxic side effects, and multidrug resistance underscore the need for potent anticancer agents. Topoisomerase II (TOP2) has emerged as a pivotal target for anticancer drugs, categorized as poisons and catalytic inhibitors. While clinically used TOP2-based drugs predominantly act as poisons, concerns regarding their cytotoxicity and DNA-damaging potential persist. In response to these challenges, exploring natural bioactive compounds (NBCs), including small molecules from Chinese herbs, as sources of novel anticancer agents has become a focal point in pharmaceutical research. Recognizing that NBCs alone may not satisfy as anticancer agents, this review aims to comprehensively analyze the current published studies, specifically focusing on the combined applications of TOP2-inhibiting approved chemotherapeutics and natural products. The review explores this approach's potential synergies and challenges, emphasizing the importance of developing effective and targeted anticancer strategies.