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54 pages, 1275 KB  
Review
Microbiome-Based Therapeutics in Oncology: Expanding Indications Beyond C. difficile
by Ayham Al-Omari, Abdallah Kheshman, Peter Morkos, Katherine Davanzo and Lea Monday
Onco 2026, 6(3), 47; https://doi.org/10.3390/onco6030047 - 14 Sep 2026
Abstract
The intestinal microbiome has emerged as a clinically significant modulator of outcomes across multiple domains of cancer care. In hematopoietic stem cell transplantation (HSCT), loss of microbial diversity and depletion of short-chain fatty acid-producing commensals are independently associated with graft-versus-host disease (GvHD), bloodstream [...] Read more.
The intestinal microbiome has emerged as a clinically significant modulator of outcomes across multiple domains of cancer care. In hematopoietic stem cell transplantation (HSCT), loss of microbial diversity and depletion of short-chain fatty acid-producing commensals are independently associated with graft-versus-host disease (GvHD), bloodstream infections, transplant-related mortality, and overall survival. Mechanistic studies have identified interconnected pathways—including butyrate-mediated epithelial protection, tryptophan-derived aryl hydrocarbon receptor signaling, bile acid metabolism, and Paneth cell–intestinal stem cell interactions—through which microbial communities regulate intestinal barrier integrity and immune homeostasis. These insights have provided the biological rationale for therapeutic strategies aimed at restoring microbial ecology. Fecal microbiota transplantation (FMT) has demonstrated promising clinical activity in steroid-refractory acute GvHD, with one meta-analysis reporting a pooled clinical remission rate of 64% (95% CI, 51–77%) across prospective single-arm studies, and proprietary live biotherapeutic products (LBPs) such as MaaT013 met the primary endpoint of the single-arm phase III ARES trial, achieving a day-28 gastrointestinal overall response rate of 62%; however, the CHMP adopted a negative opinion on its conditional marketing authorization application in June 2026, citing limitations of the single-arm design, and a re-examination is pending. In parallel, gut microbiome composition has been associated with immune checkpoint inhibitor (ICI) response, and early-phase FMT studies suggest that microbiome modulation may restore sensitivity to anti-PD-1 therapy in some patients with refractory melanoma and may enhance treatment responses in first-line ICI settings; however, these findings derive primarily from small, uncontrolled or early-phase studies. Defined single-strain approaches, notably Clostridium butyricum MIYAIRI 588 (CBM588), have shown encouraging secondary clinical efficacy signals in two small, randomized phase I trials in metastatic renal cell carcinoma, including significantly prolonged progression-free survival in one trial and a higher objective response rate in another; however, neither trial met its prespecified primary microbiome endpoint of increased Bifidobacterium spp. abundance. Emerging evidence further links antibiotic-induced dysbiosis to impaired chimeric antigen receptor T-cell (CAR-T) therapy outcomes, while short-chain fatty acids have been identified as direct enhancers of CAR-T cell effector function. This review synthesizes the current evidence for microbiome-based therapeutics across HSCT, GvHD, ICI therapy, CAR-T cell therapy, and infection prevention, and addresses cross-cutting translational challenges including antibiotic stewardship, donor selection, safety in immunocompromised populations, and pharmacomicrobiomics. While randomized controlled trial data remain limited and many approaches are investigational, the convergence of mechanistic, observational, and early interventional evidence positions microbiome restoration as a promising frontier in precision oncology. Full article
104 pages, 4982 KB  
Review
Hyperforin as a Multifunctional Specialized Metabolite of Natural Origin for Chronic Diseases: From Molecular Mechanisms to Clinical Translation
by Efthymios Poulios, Sousana K. Papadopoulou, Exakousti-Petroula Angelakou, Gerasimos Tsourouflis, Aspasia Serdari and Constantinos Giaginis
Curr. Issues Mol. Biol. 2026, 48(9), 937; https://doi.org/10.3390/cimb48090937 - 14 Sep 2026
Abstract
Hyperforin, a polyprenylated acylphloroglucinol and major bioactive constituent of Hypericum perforatum L. (H. perforatum, St. John’s Wort), has attracted considerable interest because of its pleiotropic pharmacological properties. Although historically investigated primarily for its contribution to the antidepressant activity of H. perforatum [...] Read more.
Hyperforin, a polyprenylated acylphloroglucinol and major bioactive constituent of Hypericum perforatum L. (H. perforatum, St. John’s Wort), has attracted considerable interest because of its pleiotropic pharmacological properties. Although historically investigated primarily for its contribution to the antidepressant activity of H. perforatum, experimental studies have identified broader neuroprotective, anti-inflammatory, antioxidant, immunomodulatory, antimicrobial, metabolic, anticancer, and tissue-regenerative actions. However, the evidence remains heterogeneous, and an important distinction exists between findings obtained with purified hyperforin and those derived from multicomponent H. perforatum preparations. Unlike previous reviews that have primarily summarized the pharmacological activities of hyperforin, the present review adopts a translational evidence framework that distinguishes purified hyperforin from multicomponent H. perforatum preparations and evaluates the maturity of evidence from molecular mechanisms and preclinical models through pharmacokinetics, human studies, safety, and clinical development. A comprehensive narrative review was conducted according to the Scale for the Assessment of Narrative Review Articles (SANRA) recommendations. PubMed/MEDLINE, Scopus, Web of Science, Embase, and Google Scholar were searched from database inception through 25 July 2026. Mechanistic, in vitro, animal, translational, pharmacokinetic, and clinical studies, together with relevant systematic reviews and meta-analyses, were critically synthesized according to intervention type, disease-specific evidence, pharmacokinetic and formulation characteristics, safety, and translational relevance. Hyperforin acts as a pleiotropic signaling modulator affecting interconnected pathways involved in neurotransmission and neuroplasticity, inflammatory and redox regulation, mitochondrial and cellular homeostasis, immune function, and metabolism. Extensive cellular and animal evidence supports biological activity across neuropsychiatric, neurodegenerative, inflammatory, immune-mediated, cardiometabolic, oncological, gastrointestinal, infectious, dermatological, and other chronic disease settings. Nevertheless, evidence maturity differs markedly among indications. The strongest human evidence concerns standardized hyperforin-containing H. perforatum preparations for mild-to-moderate depression, whereas most other applications remain preliminary or predominantly preclinical. Adequately powered randomized controlled trials of purified hyperforin are lacking, preventing attribution of the clinical effects of H. perforatum preparations specifically to hyperforin. Translation is further constrained by poor aqueous solubility, chemical instability, variable bioavailability and formulation composition, limited compound-specific pharmacokinetic data, and clinically important herb–drug interactions, particularly through PXR-mediated induction of CYP3A4 and P-glycoprotein. Hyperforin is a pharmacologically promising multifunctional natural compound, but its experimental activity currently exceeds the strength of compound-specific clinical evidence. Future research should prioritize chemically defined and preferably purified formulations, rigorous pharmacokinetic and dose-finding studies, biomarker-supported target-engagement assessment, and adequately powered randomized controlled trials, together with long-term safety, interaction, standardization, and regulatory evaluation. Demonstrating predictable human exposure, biologically relevant target engagement, clinically meaningful efficacy, and an acceptable long-term safety profile will be essential for determining whether hyperforin can progress from experimental promise to evidence-based therapeutic application. Full article
24 pages, 11174 KB  
Review
Phytochemistry and Pharmacological Evidence of East Asian Crowberry Reported as Empetrum nigrum var. japonicum or E. nigrum subsp. asiaticum: A Critical Review of Potential Chemotypic Differentiation
by Theophilus Bhatti and Ji-Yeong Bae
Organics 2026, 7(3), 38; https://doi.org/10.3390/org7030038 - 14 Sep 2026
Abstract
East Asian crowberry has been reported under Empetrum nigrum var. japonicum and E. nigrum subsp. asiaticum. This critical narrative review evaluates taxonomy, phytochemistry, and pharmacological evidence from Korean, Japanese, and Chinese source-reported material in the context of the wider Empetrum literature. Reassessment [...] Read more.
East Asian crowberry has been reported under Empetrum nigrum var. japonicum and E. nigrum subsp. asiaticum. This critical narrative review evaluates taxonomy, phytochemistry, and pharmacological evidence from Korean, Japanese, and Chinese source-reported material in the context of the wider Empetrum literature. Reassessment of primary reports identified a broader East Asian chemical evidence base than previously summarized, including methylated, methoxylated, and hydroxylated chalcone/dihydrochalcone derivatives, bibenzyls, triterpenoids, flavonoids, and related constituents. These reports raise the possibility of East Asian chemotypic differentiation, but direct comparative metabolomics using authenticated populations and standardized methods has not established their geographic specificity or abundance. Reported pharmacological activities include antioxidant and cytoprotective effects, nitric oxide and α-glucosidase inhibition, cancer cell cytotoxicity, anti-angiogenic activity in an in ovo chorioallantoic membrane model, and limited mammalian in vivo evidence, including a Korean carbon tetrachloride-induced hepatotoxicity model and a Chinese alcoholic fatty liver rat model. Evidence strength varies substantially because botanical authentication, extract standardization, dose–response reporting, and independent replication are inconsistent. The available literature therefore provides preliminary evidence consistent with potential East Asian chemotypic differentiation but does not establish a discrete chemotypic boundary. Priority needs are taxonomic authentication, harmonized chemical profiling, quantitative marker validation, extract standardization, compound-level testing, and independent pharmacological replication. Full article
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51 pages, 1307 KB  
Review
Biologically Mediated Nanoparticle Synthesis as a Potential Green Strategy: Principles, Methods, and Pharmaceutical Applications
by Mahmoud M. Mokhtar, Rahma Wael Soliman, Jassy Salim, Shrouk Khaled Mohamed, Lobna Abdelsalam and Rehab Abdelmonem
Pharmaceutics 2026, 18(9), 1151; https://doi.org/10.3390/pharmaceutics18091151 - 14 Sep 2026
Abstract
Nanoparticles have gained considerable attention as important platforms in pharmaceutical and biomedical research due to their size, morphology, surface chemistry, and colloidal behavior, which can affect drug delivery, antimicrobial activity, diagnostics, imaging, and therapeutic performance. However, conventional chemical and physical synthesis routes may [...] Read more.
Nanoparticles have gained considerable attention as important platforms in pharmaceutical and biomedical research due to their size, morphology, surface chemistry, and colloidal behavior, which can affect drug delivery, antimicrobial activity, diagnostics, imaging, and therapeutic performance. However, conventional chemical and physical synthesis routes may require hazardous reagents, high energy demands, and procedures that raise environmental, safety, and scalability concerns. In this context, biologically mediated synthesis has emerged as an approach in which plants, microorganisms, including fungi and algae, and isolated biomolecules contribute to nanoparticle formation by acting as reducing, capping, and stabilizing agents. This narrative review evaluates these routes as potential green strategies, covering formation principles, biological sources, nanoparticle classes, characterization challenges, pharmaceutical applications, comparison with conventional synthesis, and limitations. The reviewed evidence indicates that the composition of biological sources and reaction conditions can shape nanoparticle size, morphology, surface chemistry, stability, and biological activity, highlighting green synthesis as a design-dependent process rather than a simple substitute for chemical reducing agents. Integrated characterization using optical, spectroscopic, diffraction, microscopic, and colloidal techniques is essential for interpreting nanoparticle identity and reproducibility. Biologically mediated nanoparticles show experimental and preclinical potential in drug delivery, antimicrobial therapy, anticancer research, biosensing, imaging, and diagnostics; however, most evidence remains preclinical and model-dependent. Translation remains limited by source variability, batch inconsistency, scale-up and purification challenges, stability, incomplete safety evidence, and regulatory uncertainty. Progress will require standardized process control, comparative life cycle and techno-economic assessment, scalable manufacturing, and rigorous pharmacokinetic, biodistribution, toxicological, and regulatory validation. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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18 pages, 11286 KB  
Article
Basal-like Phenotype Identifies Immunotherapy-Responsive Subset of HR+/HER2- Breast Cancer with Aggressive Clinical Behavior
by Fangyu He, Yu Wu, Lu Pan, Keming Chen, Jiehua He, Jiabin Lu, Mei Li, Xue Chao, Rongzhen Luo, Xi Cai, Ziqing Zhao, Yuxuan Wu, Jinhui Zhang and Peng Sun
Cancers 2026, 18(18), 2965; https://doi.org/10.3390/cancers18182965 - 14 Sep 2026
Abstract
Background: While basal-like markers (BMs), particularly cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR), are traditionally associated with triple-negative breast cancer, their expression in HR+/HER2- tumors defines a clinically distinct subgroup with unique therapeutic vulnerabilities. We comprehensively characterized the clinicopathological features, immune [...] Read more.
Background: While basal-like markers (BMs), particularly cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR), are traditionally associated with triple-negative breast cancer, their expression in HR+/HER2- tumors defines a clinically distinct subgroup with unique therapeutic vulnerabilities. We comprehensively characterized the clinicopathological features, immune microenvironment, and neoadjuvant immunotherapy response of BM-positive HR+/HER2- breast cancer. Methods: We analyzed 150 basal marker-positive (BM+) and 180 BM-negative HR+/HER2- breast cancer patients. Clinicopathological data and survival outcomes were assessed using Kaplan–Meier and Cox regression analyses. The immune microenvironment was characterized by stromal tumor-infiltrating lymphocytes (sTILs) and immunohistochemistry for immune markers (CD3, CD8, FOXP3, CXCL13, CD68, PD-1, PD-L1). An independent cohort of 53 BM+ patients receiving neoadjuvant chemotherapy with anti-PD-1/PD-L1 immunotherapy was evaluated for pathological complete response (pCR). Results: BM+ patients exhibited significantly more aggressive features: younger age at diagnosis, higher histological grade, increased necrosis, and lower hormone receptor expression. BM+ status independently predicted worse disease-free survival (HR = 1.96, p = 0.034) and overall survival (HR = 2.93, p = 0.037), with CK5/6 expression emerging as an independent prognostic factor for both endpoints. These tumors displayed an activated immune microenvironment with significantly higher sTILs, enhanced cytotoxic T-cell infiltration, and elevated PD-L1 expression. Remarkably, the neoadjuvant immunotherapy cohort achieved a pCR rate of 49.1%, comparable to triple-negative breast cancer rates and substantially exceeding historical HR+/HER2- benchmarks. Conclusions: The basal-like phenotype identifies a clinically aggressive subset of HR+/HER2- breast cancer with distinct immune-activated characteristics and remarkable immunotherapy response rates. These findings suggest that the BM status, particularly CK5/6 expression, may serve as a basis for clinicians to decide whether to administer immunotherapy to patients with HR+/HER2-breast cancer. Full article
(This article belongs to the Special Issue Tailoring Neoadjuvant Strategies for Breast Cancer Subtypes)
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25 pages, 4965 KB  
Article
Aporphine Alkaloid N-Nornuciferine from Nelumbo nucifera Induces MAPK-Associated Autophagy Under Nutrient Deprivation in Human Pancreatic Cancer Cells
by Hung Hong Nguyen, Juthamart Maneenet, Ashraf M. Omar, Tomoya Mori, Supawadee Daodee, Orawan Monthakantirat, Chantana Boonyarat, Charinya Khamphukdee, Yaowared Sumanont, Tsutomu Fujii and Suresh Awale
Pharmaceuticals 2026, 19(9), 1454; https://doi.org/10.3390/ph19091454 - 14 Sep 2026
Abstract
Background: Pancreatic cancer cells adapt to nutrient stress by activating metabolic pathways that facilitate survival and proliferation within the tumor microenvironment, a phenomenon known as austerity. Targeting this resilience presents a strategy for developing chemotherapeutic agents with anti-austere properties. Methods: Phytochemical investigation of [...] Read more.
Background: Pancreatic cancer cells adapt to nutrient stress by activating metabolic pathways that facilitate survival and proliferation within the tumor microenvironment, a phenomenon known as austerity. Targeting this resilience presents a strategy for developing chemotherapeutic agents with anti-austere properties. Methods: Phytochemical investigation of Nelumbo nucifera petals led to the isolation of six alkaloids: three benzylisoquinolines (13), two aporphines (4, 5), and one proaporphine (6). Preferential cytotoxicity under nutrient deprivation was evaluated. The most active compound was further analyzed in MIA PaCa-2 cells using proliferation, migration, colony formation, and three-dimensional spheroid growth assays, with additional selective cytotoxicity assessment in KLM-1 cells. Mechanistic studies examined MAPK family signaling, autophagy-associated alterations, and apoptosis. Results: (−)-N-nornuciferine (5) exhibited considerable preferential cytotoxicity against MIA PaCa-2 cells (PC50 = 0.53 µM) and KLM-1 cells (PC50 = 1.11 µM). Under nutrient-rich conditions, 5 suppressed the proliferation, migration, colony formation, and spheroid growth of MIA PaCa-2 cells. Under nutrient deprivation, 5 increased MAPK phosphorylation and LC3-II accumulation while reducing p62/SQSTM1 levels. Chloroquine (CQ) further increased LC3-II accumulation, particularly at 10 µM 5, compared with CQ alone. However, autophagy inhibitors did not rescue 5-induced loss of viability, and the pan-caspase inhibitor Z-VAD-FMK also failed to significantly mitigate cytotoxicity. No detectable PARP or caspase-3 cleavage was observed. Conclusions: (−)-N-nornuciferine (5) exhibits anti-austere and anticancer activities in pancreatic ductal adenocarcinoma (PDAC) models, accompanied by MAPK phosphorylation and autophagy-related changes under nutrient deprivation conditions. Conventional caspase-dependent apoptosis is unlikely to be the main contributor to this process. Full article
(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants—4th Edition)
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42 pages, 3266 KB  
Review
Peganum harmala L.: Essential Oil Composition, Extraction Technologies, Biological Activities and Emerging Applications
by Kawthar El Ahmadi, Khadija Haboubi, Sofia Zazouli, Oussama Khibech, Fahd A. Nasr, Ashraf Ahmed Qurtam, Joe Miantezila Basilua and Phuong Nguyen-Tri
Molecules 2026, 31(18), 3243; https://doi.org/10.3390/molecules31183243 - 14 Sep 2026
Abstract
Peganum harmala L. is a xerophytic medicinal and aromatic plant of considerable ethnopharmacological importance, characterized by a rich diversity of β-carboline alkaloids, phenolic compounds, and essential oil constituents. Despite increasing scientific interest, current knowledge remains fragmented across phytochemistry, essential oils, extraction technologies, biological [...] Read more.
Peganum harmala L. is a xerophytic medicinal and aromatic plant of considerable ethnopharmacological importance, characterized by a rich diversity of β-carboline alkaloids, phenolic compounds, and essential oil constituents. Despite increasing scientific interest, current knowledge remains fragmented across phytochemistry, essential oils, extraction technologies, biological activities, and safety assessments. This review provides an integrated overview of the essential oil composition, extraction methods, analytical characterization, biological properties, toxicological considerations, and emerging applications of P. harmala. Particular emphasis is given to organ-specific chemical variability, geographical and environmental influences on volatile profiles, and the importance of standardized chemical characterization for reliable bioactivity evaluation. Conventional extraction methods, including hydrodistillation and steam distillation, are critically compared with emerging green technologies such as ultrasound-assisted, microwave-assisted, and supercritical CO2 extraction. Advanced analytical tools, including GC-MS, LC-MS/MS, NMR, and chemometric approaches, are highlighted for comprehensive phytochemical profiling. Reported biological activities include antimicrobial, antifungal, antioxidant, anti-inflammatory, antidiabetic, anticancer, and agricultural effects, although their translation requires rigorous chemical standardization, mechanistic validation, and safety evaluation. Overall, this review emphasizes that the sustainable development of P. harmala should rely on quality-by-design strategies integrating botanical authentication, chemotyping, green extraction, and regulatory-oriented toxicological assessment. Full article
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13 pages, 4199 KB  
Article
Engineering Red Blood Cell Membrane-Coated PLGA Nanoparticles for Kahweol Delivery: Formulation Development and Pharmacokinetic Assessment
by Okan Ali Aksoy, Yagmur Okcay, Alperen Enes Solmaz, Kübra Kılıç, Berk Alp Göksel, Burcu Eser, Özgür Eşim, İsmail Mert Vural, Ayhan Savaşer and Yalçın Özkan
Molecules 2026, 31(18), 3239; https://doi.org/10.3390/molecules31183239 - 14 Sep 2026
Abstract
Kahweol is an active diterpene with anti-inflammatory, antioxidant, and anticancer properties; however, its use may be limited by unfavorable pharmacokinetic characteristics. This study aimed to develop kahweol-loaded poly(lactic-co-glycolic acid) (PLGA) and red blood cell membrane-coated PLGA (RBC-PLGA) nanoparticles and evaluate their in vitro [...] Read more.
Kahweol is an active diterpene with anti-inflammatory, antioxidant, and anticancer properties; however, its use may be limited by unfavorable pharmacokinetic characteristics. This study aimed to develop kahweol-loaded poly(lactic-co-glycolic acid) (PLGA) and red blood cell membrane-coated PLGA (RBC-PLGA) nanoparticles and evaluate their in vitro release behavior and in vivo pharmacokinetic profiles. Kahweol-loaded PLGA nanoparticles were prepared using the emulsification-solvent evaporation method and subsequently coated with rabbit erythrocyte membranes, a type of blood cell membrane, to obtain RBC-PLGA nanoparticles. Particle size, zeta potential, morphology, and encapsulation efficiency were characterized. In vitro release studies were performed using the dialysis bag method. Pharmacokinetic profiles of free kahweol, kahweol-loaded PLGA, and kahweol-loaded RBC-PLGA nanoparticles were evaluated in rabbits following intravenous administration (0.5 mg/kg), and plasma kahweol concentrations were analyzed by LC-MS/MS. PLGA and RBC-PLGA nanoparticles showed high encapsulation efficiency (>90%) and sustained biphasic release compared with the rapid burst release of free kahweol. Pharmacokinetic analysis demonstrated that PLGA and RBC-PLGA nanoparticles reduced peak plasma concentrations and prolonged systemic exposure. Among the nanoparticles, RBC-PLGA exhibited the most prolonged pharmacokinetic profile, with delayed time to maximum plasma concentration (Tmax), extended half-life, and increased overall exposure. The nanoparticles improved the pharmacokinetic profile of kahweol by enabling sustained release and prolonged systemic exposure, supporting their potential as delivery platforms for future applications. Full article
(This article belongs to the Special Issue Nanomaterials for Biomedicine: Innovations and Challenges)
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25 pages, 2945 KB  
Article
Design, Synthesis, and Antiproliferative Evaluation of C3/C12-Modified Panaxadiol Derivatives Against Gastric Cancer Cells: Integrated Transcriptomic and Metabolomic Analyses
by Yueru Zhang, Hongqing Xie, Chenggang Shan, Jinlong Han, Fangzhou Zhao, Xianchang Wang, Yinan Qi, Xiaoyang Li, Jianhua Zhang, Feng Zhang and Yun Zhou
Molecules 2026, 31(18), 3225; https://doi.org/10.3390/molecules31183225 - 12 Sep 2026
Abstract
Panaxadiol (PD) is a bioactive dammarane triterpenoid with limited antiproliferative potency, and systematic optimization of its C3 and C12 positions remains underexplored. Here, a stepwise, site-differentiated strategy was established by combining selective C3 esterification with late-stage C12 diversification through a chloroacetyl–piperazine linker, affording [...] Read more.
Panaxadiol (PD) is a bioactive dammarane triterpenoid with limited antiproliferative potency, and systematic optimization of its C3 and C12 positions remains underexplored. Here, a stepwise, site-differentiated strategy was established by combining selective C3 esterification with late-stage C12 diversification through a chloroacetyl–piperazine linker, affording 23 PD derivatives and enabling complementary C3/C12 structure–activity analysis. Antiproliferative screening in AGS gastric cancer cells identified compounds 6, 11, and 17 as the most active analogues, with IC50 values of 8.41, 5.08, and 6.78 μM, respectively, all outperforming 5-fluorouracil under identical conditions. Compound 6 provided a relatively favorable balance between low-micromolar activity and preservation of non-malignant GES-1 cells within a defined concentration range and was therefore selected for mechanistic investigation. Transcriptomic profiling identified 298 differentially expressed genes associated with cellular stress, cytokine signaling, epithelial growth regulation, and extracellular remodeling, whereas metabolomic analysis revealed marked perturbation of glycerophospholipid, choline, polyunsaturated fatty acid, and glutathione metabolism. Integrated analysis highlighted membrane-lipid remodeling, redox dysregulation, and ferroptosis-related processes as central features of the response. These findings establish a modular platform for PD optimization and identify compound 6 as a promising lead for further anti-gastric cancer development. Full article
30 pages, 5979 KB  
Article
Rational Design of Putative Dual-Target Opioid-Dopaminergic Casomorphin–Ranatensin Hybrid Peptides: Computational Modeling and Preliminary Antiproliferative Evaluation
by Krystian Małek, Adrian Górski, Łukasz Szeleszczuk, Anna K. Laskowska, Zuzanna Markowska, Sebastian Granica, Anna Pogorzelska, Piotr Koch, Natalia Pielaszkiewicz, Jagoda Michniewicz, Wojciech Kamysz, Małgorzata Milczarek, Karol Sikora and Patrycja Kleczkowska
Molecules 2026, 31(18), 3221; https://doi.org/10.3390/molecules31183221 - 12 Sep 2026
Abstract
Despite advances in oncology, cancer remains a leading cause of mortality worldwide, and both μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) signaling have been implicated in the regulation of tumor proliferation, survival, and progression, positioning them as attractive targets for multifunctional anticancer [...] Read more.
Despite advances in oncology, cancer remains a leading cause of mortality worldwide, and both μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) signaling have been implicated in the regulation of tumor proliferation, survival, and progression, positioning them as attractive targets for multifunctional anticancer strategies. In the present study, a series of novel casomorphin–ranatensin hybrid peptides were designed, synthesized, and evaluated as putative dual-target anticancer agents combining MOR and D2R pharmacophores. Among the evaluated analogues, KAZO_5.2 and KAZO_7.2 reduced viability of HCT116 colorectal cancer cells in a dose- and time-dependent manner, with a modest selectivity ratio compared to non-tumorigenic MCF 10A cells. Both compounds showed favorable docking scores toward MOR and D2R, while single 100 ns molecular dynamics trajectories showed that the peptides remained associated with their respective receptor models over the simulated timescale. Partial reversal of the viability-reducing effect by naloxone suggested involvement of opioid-sensitive pathways, while only low baseline MOR expression was detected in HCT116 cells under our experimental conditions, consistent with a possible contribution of additional receptor-mediated mechanisms to the observed activity. Neither compound induced pronounced apoptosis or cell cycle arrest, suggesting cytostatic rather than cytotoxic effects. Both peptides exhibited negligible hemolytic activity and high proteolytic stability in human plasma, with intact peptides remaining predominant after 24 h of incubation at 37 °C. These findings identify casomorphin–ranatensin hybrids as a promising scaffold for dual-target anticancer peptide development, warranting further structural optimization and mechanistic investigation. Full article
22 pages, 7441 KB  
Article
Subcellular Localization of CD24 Is Associated with Integrin β1 Signaling, Immune Suppression, and Clinical Outcomes Across Human Cancers
by Bhaumik Patel, Marina Curcic, Mohamed A. Eltokhy, Faizah Alabi and Omar Eltoukhy
Biology 2026, 15(18), 1611; https://doi.org/10.3390/biology15181611 - 12 Sep 2026
Viewed by 35
Abstract
CD24 is an emerging innate immune checkpoint that regulates inflammatory and antiviral immune responses through interactions with Siglec family receptors. Although CD24 has been extensively studied in immune regulation and has recently gained attention as a therapeutic target in infectious and inflammatory diseases, [...] Read more.
CD24 is an emerging innate immune checkpoint that regulates inflammatory and antiviral immune responses through interactions with Siglec family receptors. Although CD24 has been extensively studied in immune regulation and has recently gained attention as a therapeutic target in infectious and inflammatory diseases, its role in cancer remains incompletely understood. CD24 is overexpressed in multiple human malignancies, where accumulating evidence suggests that it promotes tumor progression and immune evasion through activation of diverse intracellular and extracellular signaling pathways. However, the importance of its subcellular localization and associated signaling remains poorly defined. Here, we investigated CD24 expression, localization, signaling associations, immune-cell infiltration, and clinical outcomes using publicly available cancer datasets, focusing on breast cancer (BRCA), cervical squamous cell carcinoma (CESC), and glioblastoma multiforme (GBM). Our analyses revealed prominent membrane-associated CD24 localization in BRCA and CESC, whereas CD24 was predominantly cytoplasmic in GBM. BRCA and CESC exhibited increased integrin β1 expression and distinct associations between CD24 and components of integrin β1/SRC and TGFβ-associated signaling networks, including MEK1 and SMAD7. In addition, we identified a structurally consistent and energetically favorable predicted interface between CD24 and Siglec-10, suggesting a mechanism by which CD24 may suppress anti-tumor immunity. Elevated CD24 expression was associated with immune-infiltration patterns consistent with an immunosuppressive tumor microenvironment in BRCA and CESC, including negative associations with M1 macrophage, CD8+ T-cell, and NK-cell infiltration. Importantly, high CD24 expression was associated with unfavorable overall survival in BRCA and CESC, whereas the opposite relationship was observed in GBM. Collectively, these findings suggest that the subcellular distribution of CD24 may be associated with distinct tumor signaling, the immune microenvironment, and prognostic profiles, highlighting the potential importance of CD24 localization in determining its tumor-type-specific biological functions. Full article
(This article belongs to the Section Immunology)
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29 pages, 3610 KB  
Article
Biological Properties of Eucalyptus globulus Oil and Eucalyptol, Chemical Composition and Molecular Docking
by Ilyass Lkhalidi, Aimad Allali, Hamza Saghrouchni, Mohamed Chebaibi, Rachid Flouchi, Ibrahim Mssillou, Ana Tomić, Asaad Khalid, Abdelkrim Agour, Youness El Abdali, Issam Ghabbour and Moulay Larbi Ouahidi
Biophysica 2026, 6(5), 88; https://doi.org/10.3390/biophysica6050088 - 11 Sep 2026
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Abstract
Background: Moroccans employ Eucalyptus globulus Labill., a medicinal herb, to cure a variety of ailments. This research aimed to evaluate the chemical constituents of Eucalyptus globulus essential oil (EGEO) to determine their composition and potential use as hemolytic, antioxidant, and antimicrobial agents. Methods: [...] Read more.
Background: Moroccans employ Eucalyptus globulus Labill., a medicinal herb, to cure a variety of ailments. This research aimed to evaluate the chemical constituents of Eucalyptus globulus essential oil (EGEO) to determine their composition and potential use as hemolytic, antioxidant, and antimicrobial agents. Methods: GC analysis was utilized to determine the composition of EGEO harvested in the province of Meknes. Using the disk diffusion technique, MIC, MBC, and MFC tests, antibacterial and antifungal activity were assessed against pathogenic microorganisms. DPPH, TAC, and FRAP experiments were used to evaluate the antioxidant potential of EGEO and Eucalyptol. The main chemical binding affinities were predicted by Molecular Docking analysis. GraphPad Prism (v8) was used to evaluate these findings using a Tukey and ANOVA analysis. Results: GC-MS revealed 27 components, including Eucalyptol (1,8-Cineole) (55.07%). Hemolysis recorded the greatest value, 8.16 ± 0.13. Staphylococcus aureus had the highest MIC values (1.25 mg/mL). Bacillus subtilis had a 65 mm inhibitory zone. The fungicidal effectiveness of EGEO and its major component varies according to the studied fungus strain. In terms of antioxidant characteristics, DPPH radical inhibition revealed that 1,8-Cineole has a higher IC50 (4.7 ± 0.5 µg/mL). The Total Antioxidant Capacity was 22 ± 0.02 mg AAE/g. FRAP analysis showed that Eucalyptol is more potent than EGEO. Conclusion: Antimicrobial and antioxidant studies support the use of EGEO and eucalyptol in traditional and therapeutic medicine, and show their numerous possible uses as natural preservatives for perfumes and foods, as well as anticancer agents due to their hemolytic capacity. Full article
(This article belongs to the Special Issue Latest Advances in Molecular Docking Involved in Biophysics)
17 pages, 557 KB  
Review
Effect of Manilkara zapota (L.) P. Royen in Cancer and Inflammation
by Bee Ling Tan and Mohd Esa Norhaizan
Rom. J. Prev. Med. 2026, 4(3), 8; https://doi.org/10.3390/rjpm4030008 - 11 Sep 2026
Viewed by 49
Abstract
As of 2020, liver cancer has emerged as the fifth most common cancer and the third leading cause of cancer death worldwide, following lung and colorectal cancers. The most prevalent type is hepatocellular carcinoma (HCC), originating from hepatocytes. Despite advancements, liver cancer treatment [...] Read more.
As of 2020, liver cancer has emerged as the fifth most common cancer and the third leading cause of cancer death worldwide, following lung and colorectal cancers. The most prevalent type is hepatocellular carcinoma (HCC), originating from hepatocytes. Despite advancements, liver cancer treatment outcomes remain poor due to metastasis and recurrence. Existing anticancer drugs often exhibit narrow therapeutic windows and limited selectivity for cancer cells. Manilkara zapota (L.) P. Royen has attracted significant scientific attention because of its diverse bioactive constituents and potential therapeutic properties. Of particular interest in this review, we explored the molecular connectivity of oxidative stress-induced liver cancer. We discussed the underlying mechanisms of Manilkara zapota (L.) P. Royen involved in cancer and inflammation. The phytochemical constituents were also highlighted in this study. The phytochemicals reported from Manilkara zapota (L.) P. Royen included flavonoids, tannins, saponins, and phenolic compounds. These compounds demonstrated potential anticancer activities through mechanisms such as induction of apoptosis, inhibition of cell proliferation, modulation of oxidative stress, and regulation of PI3K/Akt and NF-κB signaling pathways. Further investigations are required to clarify the benefit–risk profile of Manilkara zapota (L.) P. Royen through large-scale clinical trials. Collectively, the current evidence suggests that this plant may offer a promising strategy for cancer management, provided that such interventions are optimized to minimize adverse effects. Full article
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32 pages, 6125 KB  
Review
Pentacyclic Triterpenoid Acids in the Treatment of Breast Cancer
by Natalia Jankowska, Rostyslav Dudchak, Magdalena Podolak, Marcin Cybulski, Elisabetta Esposito, Olga Michalak, Krzysztof Bielawski, Anna Bielawska and Agnieszka Gornowicz
Molecules 2026, 31(18), 3207; https://doi.org/10.3390/molecules31183207 - 11 Sep 2026
Viewed by 228
Abstract
Despite increasing awareness about cancer, it still remains one of the biggest threats to human life. Breast cancer is among the most commonly diagnosed types of cancer. Pentacyclic triterpenoids are a group of plant compounds commonly known in traditional medicine due to their [...] Read more.
Despite increasing awareness about cancer, it still remains one of the biggest threats to human life. Breast cancer is among the most commonly diagnosed types of cancer. Pentacyclic triterpenoids are a group of plant compounds commonly known in traditional medicine due to their anti-inflammatory, antibacterial, antidiabetic, cardioprotective and anticancer effects. This review examined the potential of pentacyclic triterpenoid acids in the treatment of breast cancer, focusing on research from the past 15 years. Although the subject literature demonstrates that pentacyclic acids show anticancer activity, it also reveals their limitations such as low bioavailability, aqueous solubility, or high IC50 values. Therefore, to overcome these limitations, structural modifications, mostly at the C3 and C28 positions, were made, and several novel derivatives with oleanane, lupane and ursane skeletal types were synthesized. This review not only identified pentacyclic acids derivatives but also evaluated how structural modifications enhanced their biological activity and potential in breast cancer treatment. The findings revealed that even though the obtained derivatives enhanced anticancer potential against breast cancer, the main issues of bioavailability and solubility remain unsolved, suggesting that future research in synthesis should focus not only on improving cytotoxicity but also on the bioavailability of novel compounds. Full article
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16 pages, 18969 KB  
Article
Camel Milk Exosomes Alleviate Doxorubicin-Induced Cardiotoxicity by Regulating Apoptosis and Autophagy via the NF-κB and MAPK Pathways
by Zhihua Wang, Qi Tian, Fanhua Meng, Shenyuan Wang, Lu Li and Junwei Cao
Biology 2026, 15(18), 1604; https://doi.org/10.3390/biology15181604 - 11 Sep 2026
Viewed by 140
Abstract
Doxorubicin (Dox)-induced cardiotoxicity (DIC) is a major clinical challenge in cancer therapy. Camel milk exosomes (CMEs) have been applied in anti-tumor treatments as they have a variety of effects, including on inflammation, oxidative stress, metastasis, and apoptosis. However, their role in DIC treatment [...] Read more.
Doxorubicin (Dox)-induced cardiotoxicity (DIC) is a major clinical challenge in cancer therapy. Camel milk exosomes (CMEs) have been applied in anti-tumor treatments as they have a variety of effects, including on inflammation, oxidative stress, metastasis, and apoptosis. However, their role in DIC treatment remains incompletely understood. This research was designed to evaluate the protection provided by CMEs against DIC. The DIC mice were treated with Dox intraperitoneally and divided into a model group and groups treated with different doses of CMEs. Dox-induced H9c2 cell injury was also established and divided into a model group and groups treated with different concentrations of CMEs. The evaluation parameters in vitro included H9c2 cell viability, reactive oxygen species (ROS), mitochondria, and apoptotic cells. The apoptosis and autophagy markers, as well as the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were assessed via Western blotting both in vivo and in vitro. In addition, transcriptome sequencing of cardiac tissue was also applied to investigate the related mechanisms. Our results indicate that CMEs significantly attenuated the cell viability reduction, apoptosis, and ROS production in H9c2 cells caused by Dox. CMEs also regulated autophagy, inhibited apoptosis, and inhibited the NF-κB and MAPK pathways. In conclusion, our findings demonstrate that CMEs exert a cardiac protective effect against DIC by inhibiting apoptosis and regulating autophagy via NF-κB and MAPK signaling pathways. Full article
(This article belongs to the Section Medical Biology)
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