[This corrects the article DOI: 10.1371/journal.pone.0240156.].

T apollinea, a medicinal plant native to arid regions, remains underexplored for in vitro plant tissue culture in pharmaceutical applications. This study integrates phytochemical, bioactivity, and GC–MS–based metabolomic analyses to reveal organ-specific temperature-driven metabolic reprogramming in Tephrosia apollinea callus cultures. Calli were induced from root, stem, and leaf explants at 4 °C, 30 °C, and 40 °C. Morphological, moisture, and phytochemical analyses revealed distinct organ and temperature-dependent responses. Stem calli at 30 °C and root calli at 40 °C demonstrated the highest total phenolic content. Root calli also exhibited the strongest antioxidant activity (IC50 = 0.58 ± 0.05 mg/mL), while stem calli at 40 °C exhibited the most potent anti-Candida activity, reducing cell viability by 52.46 ± 0.45%. GC-MS based metabolomics and pathway enrichment analyses revealed organ-specific metabolic reprogramming. Stem calli under heat stress enriched linoleic acid metabolism, steroid biosynthesis, and unsaturated fatty acid biosynthesis, while root calli uniquely enhanced α-linoleic acid metabolism. Shared lipophilic compounds included γ-sitosterol, squalene, and stigmasta-3,5-dien-7-one. Molecular docking studies further supported the biological relevance of these metabolites interacting with C. albicans CYP51 (PDB: 5V5Z), human SOD1 (PDB: 5YTO), and catalase (PDB: 1DGB). Stem calli-derived compounds including 4,8,12,16-tetramethyl heptadecan-4-olide and stigmastanol exhibited strong binding affinity to Candida albicans CYP51, while root-derived antioxidants such as α-tocopherol and scyllo-inositol interacted effectively with SOD1 and catalase. Overall, this study highlights the impact of temperature stress on metabolite accumulation in T. apollinea calli and demonstrates the potential of callus cultures as a source of bioactive metabolites with predicted antioxidant and antifungal activities.

PNP-mediated metabolic and immune reprogramming in breast cancer: mechanisms and therapeutic strategies.

Mucormycosis is an emerging, life-threatening human infection caused by Mucorales fungi1-3. Metabolic disorders uniquely predispose an ever-expanding group of patients to mucormycosis through poorly understood mechanisms1,2,4,5, suggesting that uncharacterized host metabolic effectors may confer protective immunity against this infection. Here we uncover a master regulatory role of albumin in host defence against Mucorales through the modulation of fungal pathogenicity. Our initial studies identified severe hypoalb uminaemia as a prominent metabolic abnormality and an independent biomarker of poor mucormycosis outcome across three distinct cohorts of patients with mucormycosis. Notably, purified albumin selectively inhibits Mucorales growth among a range of pathogens, and albumin-deficient mice display susceptibility specifically to mucormycosis. The antifungal activity of albumin is mediated by the release of bound free fatty acids (FFAs). Albumin prevents FFA oxidation, which otherwise abolishes their antifungal properties, and sera from patients with mucormycosis display high levels of oxidized FFAs. Physiologically, albumin-bound FFAs suppress the expression of key virulence factors by inhibiting protein synthesis, the reby rendering Mucorales avirulent in vivo. Overall, we identify a host defence mechanism that directs the pathogen to suppress its pathogenicity program in response to unfavourable metabolic cues regulated by albumin. These findings have major implications for the pathogenesis and management of mucormycosis.

Chimeric antigen receptor (CAR)-engineered cellular therapies have progressed from early proof of concept into highly programmable platforms capable of mediating potent cytotoxicity and precise immune modulation. In oncology, successive CAR design has incorporated optimized costimulatory domains, cytokine-secreting modules, and gene-editing technologies to enhance efficacy and durability in hematologic malignancies. CD19- and BCMA-directed CAR-T cells induce deep and durable remissions in refractory B-cell leukemias, lymphomas, and multiple myeloma. Emerging strategies, including logic-gated CARs, synthetic Notch (SynNotch) circuits, and modular adaptor-based systems, aim to overcome antigen escape, reduce off-tumor toxicity, and extend efficacy to heterogeneous solid tumors. Concurrently, a conceptual shift has expanded CAR applications beyond cancer toward immune modulation in autoimmune diseases. CD19-directed CAR-T therapy has achieved deep B-cell depletion and clinical improvement in small early-phase studies (typically 5-18 patients) of systemic lupus erythematosus, inducing drug-free remission in some patients; however, randomized controlled trials are lacking and evidence remains preliminary. Antigen-specific approaches, including chimeric autoantibody receptor (CAAR)-T cells and CAR-engineered regulatory T-cells (CAR-Tregs), enable selective depletion of autoreactive B-cell clones or localized restoration of immune tolerance. These strategies are under investigation across systemic sclerosis, multiple sclerosis, myasthenia gravis, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis. Collectively, advances in synthetic receptor engineering and translational application position CAR platforms as versatile, next-generation therapeutics across malignant and immune-mediated diseases.

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine salvage pathway that has recently emerged as a potential therapeutic target in cancer. While its role in hematological malignancies is relatively well established, its contribution to solid tumors, particularly breast cancer, remains insufficiently defined. This review aims to critically evaluate the role of PNP in breast cancer progression, with a focus on its involvement in metabolic reprogramming, tumor aggressiveness, and immune modulation, in addition to therapeutic targeting potential. Current evidence indicates that PNP overexpression supports nucleotide homeostasis, promotes proliferation, and contributes to metastatic phenotypes through metabolites such as hypoxanthine. Structural and computational studies have facilitated the development of diverse PNP inhibitors; however, their clinical translation into breast cancer therapy remains limited. A major research gap lies in the lack of mechanistic integration between PNP-driven metabolism, tumor-immune interactions, and subtype-specific breast cancer biology, as well as insufficient in vivo and clinical validation of candidate inhibitors in solid tumors. To address these limitations, future research should focus on integrating multi-omics approaches, advanced computational modeling, and patient-derived models to elucidate PNP-centered metabolic-immune networks. In parallel, the rational design of selective inhibitors with improved pharmacokinetic profiles, combined with biomarker-driven patient stratification and combination therapy strategies, establishes a strong rationale for the development of clinically effective PNP-targeted therapies for breast cancer.

Cannabis is a chemically diverse plant with bioactive cannabinoids that exert a wide range of therapeutic and psychoactive effects. This review comprehensively explores the botanical, chemical, pharmacological, and regulatory distinctions between hemp and marijuana, focusing particularly on the contrasting actions of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We examine cannabinoid biosynthesis, structure-activity relationships (SARs) in relation to receptor interactions and activation, and metabolic pathways to highlight the scientific basis for their different effects and clinical applications. Additionally, the paper critically evaluates detection techniques and surveys international legal frameworks, highlighting disparities that often reflect cultural rather than scientific understanding. By integrating emerging clinical data and public policy trends, this review underscores the need for evidence-based reform and education, especially regarding non-intoxicating cannabinoids such as CBD. It also offers a scientific foundation to inform both health professionals and regulators in shaping future cannabis policy.

Breast cancer (BC) remains the leading cause of cancer-related death among women in the Middle East and North Africa, with particularly high mortality in the United Arab Emirates (UAE), mainly due to delayed diagnosis. This study aimed to identify metabolic and proteomic biomarkers associated with BC progression in the UAE population. A cohort of 35 BC patients and 30 healthy control (HC) individuals underwent plasma-based untargeted metabolomics and proteomics analyses using LC-QTOF-MS. Multivariate statistical models, including OPLS-DA and AUROC analyses, were employed to assess biomarker performance. Integrated pathway and structural motif analyses were conducted to explore disease-stage-specific signatures. A distinct metabolic signature was identified, featuring disrupted amino acid (particularly arginine), purine/pyrimidine, and steroid hormone metabolism. Key metabolites such as l-arginine, hypoxanthine, uridine, vitamin D3, and estradiol showed stage-specific alterations. Eleven metabolites yielded high diagnostic power (AUROC = 0.954). Structural motif analysis revealed a transition from small, polar metabolites in early-stage BC to complex, lipophilic steroidal, and lipid structures in late-stage disease. Integrated proteomics revealed dysregulated immune and hormonal signaling, highlighting the cross-talk among metabolic, immune, and endocrine pathways. This UAE-based study reveals distinct metabolic and structural features of BC progression, suggesting candidate biomarkers for BC detection and personalized therapy.

Endometriosis is a chronic, inflammatory gynecological condition characterized by the ectopic growth of endometrial-like tissue, with an unclear etiology and limited treatment efficacy. Recent studies implicate the oral and gut commensal bacterium Fusobacterium nucleatum in the pathogenesis of endometriosis, with uterine colonization reported in up to 64% of affected women. This review highlights the potential role of F. nucleatum in disease progression, particularly through its metabolic activation within the endometrial microenvironment. We explore the contribution of key bacterial metabolites (formate, lactate, and hydrogen sulfide), proteins (FadA and Fap2), and lipids (oxidized LDL, lysophosphatidylcholines, and saturated fatty acids) to inflammation, immune evasion, and epithelial-mesenchymal transition (EMT), features that overlap with tumor biology. The review also investigates the preferential triggers of F. nucleatum translocation into the endometrium. Host factors such as hypoxia, estrogen dominance, and retrograde menstruation appear to create a permissive microenvironment that potentially facilitates F. nucleatum colonization and virulence. While current therapeutic strategies largely neglect microbial involvement, emerging approaches including targeted antimicrobials, probiotics, immunomodulators, and microenvironmental modulation offer promising avenues for microbiome-informed endometriosis management. This narrative review also underscores the urgent need for longitudinal, in vivo studies to characterize the relationship between the oral, gut, and endometrial microbiomes and their impact on disease onset and progression.

Fujairah honey, collected from the mountainous regions of the United Arab Emirates, represents promising natural sources of functional food and pharmacological potential. This study aimed to characterise the functional food properties of crude Fujairah honey and to employ fractionation approaches to identify constituents with anticancer potential. Twenty Fujairah honey samples (Samar and Sidr) obtained from distinct locations of Fujairah Emirate were evaluated and compared with Manuka honey. The relationship between cytotoxicity, physicochemical properties, and underlying molecular mechanisms including antioxidant capacity, anti-inflammatory, and antimetastatic effects was investigated. Among the samples, Sample 6 (Samar honey derived from Acacia species) demonstrated selective cytotoxic activity following fractionation. While the crude honey promoted cell proliferation, its dichloromethane (DCM) fraction induced a 20% reduction in Michigan Cancer Foundation-7 (MCF-7) cell viability. Sample 6 DCM exhibits strong antioxidant activity (92.47% 2,2-diphenyl-1-picrylhydrazyl-hydrate radical scavenging), antimetastatic effects, and significant anti-inflammatory effects through Interleukin-6 (IL-6) downregulation (p < .0001) without excessive immune stimulation. Metabolomics profiling revealed elevated levels of fatty acids and monoacylglycerides, and succinic acid (with 28% enhanced cytotoxicity), supporting the unique activity of Samar (particularly Sample 6) honey. Driven by Fujairah's arid climate and unique flora, Fujairah honey emerges as a promising source of novel pharmaceutical and nutritional applications, offering distinctive anticancer and immunomodulatory properties.

Ashwagandha (Withania somnifera), a traditional Ayurvedic adaptogen, is increasingly investigated in hormone-sensitive malignancies such as breast cancer. Its bioactive constituents, particularly withaferin A, exhibit diverse effects relevant to hormonal regulation, tumor suppression, and systemic balance. This review explores Ashwagandha’s tri-axial roles in hormonal modulation, gut microbiota interaction, and direct anticancer activity across breast cancer subtypes. Preclinical findings show that withaferin A suppresses estrogen receptor alpha (ERα), inhibits STAT3 and NF-κB signaling, induces ROS-mediated apoptosis, and alters epigenetic regulators. In HER2-positive and triple-negative models, it reduces cancer stem cell activity, epithelial-to-mesenchymal transition (EMT), and pro-inflammatory mediators. Ashwagandha also influences the hypothalamic–pituitary–gonadal axis, raising LH, FSH, estrogen, and progesterone, while lowering cortisol and normalizing thyroid function. Immunologically, it enhances CD8⁺ T cell activity, reduces myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), and may synergize with checkpoint inhibitors. Effects on gut microbiota suggest additional roles in estrogen metabolism and inflammatory regulation. Toxicity data indicate high tolerability (LD₅₀ > 2000 mg/kg), though rare hepatic and thyroid adverse events occur. Regulatory oversight remains inconsistent, with limited phytochemical standardization. Ashwagandha shows multidimensional promise but requires rigorous, standardized clinical validation.

Polymicrobial infections involving fungal and bacterial pathogens are increasingly recognized ‎as critical determinants of disease severity, particularly in immunocompromised patients. ‎However, the metabolic mechanisms underlying these interactions remain poorly understood. ‎In this study, we investigated the impact of co-culture with Escherichia coli, Staphylococcus ‎aureus, and Candida albicans on the growth dynamics and metabolic profile of Rhizopus ‎delemar. E. coli showed a significant inhibitory effect on the growth of R. delemar, whereas S. ‎aureus and C. albicans exhibited comparatively limited influence. Untargeted metabolomics ‎demonstrated distinct clustering patterns across mono- and co-cultures, indicating substantial ‎metabolic reprogramming in response to microbial interactions. Shared upregulated metabolites ‎across co-cultures included S-benzyl-cysteine, dihydrouracil, urocanic acid, and histidinol, ‎suggesting a conserved metabolic adaptation during microbial competition. In contrast, each co-‎culture displayed unique metabolic signatures, including N-butyryl glycine in the R. delemar–‎E. coli interaction, pyruvic acid in the R. delemar–S. aureus interaction, and multiple ‎metabolites in the R. delemar–C. albicans interaction. Tyramine was uniquely detected in all R. ‎delemar-containing cultures and absent in microbial monocultures, highlighting its potential as ‎a biomarker associated with Rhizopus growth and polymicrobial interaction. Overall, these ‎findings demonstrate that polymicrobial interactions strongly influence the metabolic landscape ‎of R. delemar and provide evidence of metabolic warfare as a key mechanism underlying ‎interspecies competition. Importantly, the identified metabolic signatures offer potential ‎biomarkers for distinguishing polymicrobial infections and may inform targeted therapeutic ‎strategies.‎

Objectives:Breast cancer (BC) is the leading cause of cancer-related mortality in women, largely due to metastasis. This study aims to explore the role of purine nucleoside phosphorylase (PNP), a key enzyme in purine metabolism, in the aggressiveness and metastatic behavior of BC. Methods:A comprehensive analysis was performed using in silico transcriptomic data (n = 2509 patients), immunohistochemical profiling of BC tissues (n = 103), and validation through western blotting in multiple BC cell lines. Gene expression and survival analyses were conducted using Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the cBioPortal for cancer genomics (cBioPortal) platforms. Correlations between PNP and key epithelial-mesenchymal transition (EMT) markers, molecular subtypes, tumor grades, and stages were examined. Results:PNP was significantly overexpressed in human epidermal growth factor receptor 2 (HER-2)-positive and triple-negative BCs compared to luminal subtypes. High PNP levels were strongly associated with advanced BC stages, high-grade tumors, EMT phenotypes, and poor overall survival. Notably, HER-2 inhibition suppressed PNP expression, while PNP gene silencing induced HER-2 upregulation, revealing a reciprocal regulatory loop. Dual inhibition of PNP and HER-2 resulted in a significant reduction in cell viability compared to HER-2 inhibition alone. Conclusion:Collectively, PNP emerges as a promising biomarker of BC aggressiveness and progression. Its reciprocal interaction with HER-2 underscores its potential as a therapeutic target. Dual targeting of PNP and HER-2 may offer a novel strategy for improving outcomes in aggressive BC subtypes.

Calotropis procera is a resilient plant native to arid and semi-arid regions of Asia, Africa, and South America. This review aims to align the geophytochemical variability, and traditional medicinal uses of C. procera from different studies and locations with contemporary pharmacological insights for consensus knowledge and optimum drug discovery. Ethnobotanical records underscore its use across African, Middle Eastern and South Asian healing systems, where different plant parts are traditionally employed for analgesic, anti-inflammatory and wound-healing effects. Modern studies validated these applications, identifying key bioactive compounds such as calotropin, calactin, uscharin and α-amyrin, with notable antimicrobial, anticancer and immunomodulatory activities. Geophytochemical analyses further reveal that the plant's phytochemical profile and therapeutic efficacy are influenced by environmental conditions. However, significant gaps remain in correlating these phytogeographic patterns with pharmacological outcomes. This review calls for integrated ethnopharmacological and geochemical investigations to unlock the discovery of novel natural compounds to combat challenging health conditions.

Polyphyllin VII (PP7), a natural saponin derived from the rhizomes of Paris polyphylla (family: Melanthiaceae), possesses a unique steroidal furostane structure that contributes to its versatile pharmacological profile. It is traditionally used in Chinese medicine for treating pain, insect bites, and bleeding. PP7's unique pharmacophoric features and optimal lipophilic-hydrophilic balance underlie its diverse anticancer therapeutic actions, including cell cycle arrest, apoptosis, ferroptosis, and autophagy activation, alongside metastasis and angiogenesis inhibition. PP7 has gained attention for its potent bioactivity in breast cancer and other pathological conditions. In breast cancer, PP7 demonstrates remarkable efficacy, addressing not only tumor growth but also associated complications such as inflammation and osteoporosis. Additionally, PP7 exhibits synergistic effects with chemotherapeutic agents like cisplatin, bortezomib, and gefitinib, enhancing cancer cell apoptosis and mitigating drug resistance. Beyond its anticancer properties, PP7 also displays broad pharmacological activities, including anti-inflammatory, hepatoprotective, and antimicrobial effects. Thus, PP7 holds significant potential for therapeutic application across breast cancer patients with comorbidities. However, further research is necessary to clarify its specific role in breast cancer subtypes, ensure its safety in clinical applications, and optimize its broad-scale biosynthesis. This review highlights the structure-driven mechanisms underlying PP7 actions and its therapeutic potential as a standalone agent or adjunct in breast cancer therapy.

Periapical abscesses, radicular cysts, and periapical granulomas are among the most frequently identified pathological lesions in the alveolar bone. Although many studies have investigated bacterial metagenomics in periapical abscesses, little is known about the genome mining of abundant bacteria in periapical lesions and its correlation to human transcriptome. This study aims to explore the enriched metabolic environment of periapical lesions associated with microbial diversity and their role in lesion progression. Bacterial DNA and human RNA were isolated from periapical lesions and healthy pulp tissue and sequenced using next-generation sequencing (NGS). The sequences of the most abundant bacteria were then analyzed to identify secondary metabolites, pathogenic proteins, and their associated metabolic pathways. The results revealed that Fusobacterium nucleatum was the predominant bacterium in periapical abscesses and radicular cysts, whereas Porphyromonas endodontalis was the most abundant in periapical granulomas. Integrated bacterial and human metabolic pathways indicated that the augmentation of similar pathways is important in lesions pathogenesis. In periapical abscesses, inflammatory response, humoral immune response, positive regulation of cell migration, and hemopoiesis were enriched. In radicular cysts, pathways linked to NABA matrisome associated, inflammatory response, immune response-regulating signaling pathway, neutrophil degranulation, and P73 pathway were enriched. Meanwhile, periapical granulomas exhibited significant enrichment of pathways related to response to bacterium, regulation of immune effector process, and positive regulation of cell migration. In conclusion, this study is the first to elucidate the interplay between microbial and human metabolic activity associated with inflammation in abscesses, apoptosis in cysts, and inflammatory regulation in granulomas. These findings have significant clinical implications for the early diagnosis, prevention, and treatment of periapical lesions.

Metastasis is the primary cause of death in women with breast cancer, which ranks among the most prevalent malignant diseases. Recently, we identified the significant metastatic role of hypoxanthine (HYP) in cancer cells. HYP is a naturally occurring purine derivative that actively participates in the synthesis of nucleic acids via the nucleotide salvage pathway. To gain a deeper insight onto the metastatic mechanism of HYP, integrated transcriptomics and metabolomics were conducted following the treatment of MCF-7 cells with HYP. HYP significantly activates PI3K/AKT pathway, a hallmark of cancer metastasis. Glycerolipid and fatty acid metabolisms are among the top-upregulated lipid metabolic pathways, while glycolysis is dysregulated. Seahorse real-time ATP rate analysis revealed a significant decrease in ATP production from the glycolysis pathway in HYP-treated cancer cells. On the other hand, genetic information processes including gene transcription and protein translation were downregulated. Collectively, our results highlight the contribution of HYP to cancer cell metastasis through the PI3K/AKT pathway. Consequently, manipulating HYP release could serve as a therapeutic target for the management of breast cancer.