Search Results (541)

The bark of Myrica rubra (Lour.) Siebold & Zucc (M. rubra) is a natural remedy widely used in China and other Asian countries to treat tissue and bone injuries, burns, scalds, gastrointestinal ulcers, and diarrhea. Myricanol is an important ingredient in the bark of M. rubra. This review summarizes articles published over the past 26 years on the pharmacological effects and mechanisms of action of myricanol, aiming to advance research and applications of myricanol. Evidence shows that myricanol has multiple bioactive properties, including antioxidant, anticancer, anti-inflammatory, antimicrobial, antidiabetic, and antihyperlipidemic effects. Myricanol improves metabolic abnormalities in mice by activating the AMPK/SIRT1/PGC-1α signaling pathway. It also demonstrates significant anticancer, antioxidant, and anti-inflammatory actions, primarily by regulating Caspase and BCL-2 family proteins, inhibiting iNOS expression, scavenging free radicals, and interacting with Peroxiredoxin 5. Therefore, myricanol shows great potential for the treatment of cancer, metabolic abnormalities, and inflammatory bowel disease. Further research is needed to improve its bioavailability, confirm its pharmacological effects and mechanisms in vivo, and explore its pharmacokinetic properties and safety. Full article

Peucephyllum schottii is an aromatic desert plant of the family Asteraceae, which has little scientific research regarding its phytochemical composition and pharmacological properties. This study aims to evaluate in detail the chemical composition and antioxidant, antibacterial, antidiabetic, and cytotoxic activities of the ethanol extract of P. schottii leaves. The chemical composition of the plant extract was analyzed by GC-MS. Total phenolic (TPC) and flavonoid (TFC) contents of the plant were calculated. An antioxidant assay of the plant material was performed by using the DPPH and ABTS tests. The antibacterial activities of P. schottii plant material against six pathogenic bacteria were studied by using the agar diffusion and MIC/MBC techniques. Colorimetric analysis, for its part, enabled the assessment of its antihyperglycemic activities (α-amylase and α-glucosidase) and its cytotoxic activities (in MCF-7 and HepG2 cells). The expressions of apoptotic proteins (caspases, Bcl2, and Bax), were analyzed by RT-PCR. The GC-MS findings showed the presence of complex phytoconstituents of P. schottii in the form of linoleic acid (19.48%), hexadecanoic acid (15.01%), and vitamin E (12.15%). There is high TPC (118.18 mg of GAE/g) and TFC (75.56 mg of QE/g) in P. schottii plant material. The plant showed significant antioxidant (≈105 μg/mL IC₅₀ in DPPH and ≈80 μg/mL IC₅₀ in ABTS) and broad-spectrum antibacterial activities, mostly against E. coli (MIC = 4.68 μg/mL), as well as antihyperglycemic activities against α-amylase (IC₅₀ = 334 μg/mL) and α-glucosidase (IC₅₀ = 196 μg/mL) enzymes. The plant material showed cytotoxic effects in MCF-7 and HepG2 cells in a concentration-dependent manner (IC₅₀ = 78 ± 1.13 μg/mL and 68.23 ± 2.41 μg/mL, respectively). These findings point to P. schottii leaf extract’s potential as a natural antioxidant, antibacterial, antidiabetic, and chemopreventive agent. Full article

In the spirit of the solution of for modeling price changes in high-volatility markets for univariate commodities, here we generalize an approach to the case of modeling price changes jointly for two related commodities. Often, conditional distributions are more easily understood in financial markets, where the fluctuations in one commodity can shed significant light on the behavior of a related commodity. With this observation, we enhance and characterize the entire family of bivariate joint densities for which both the conditional distributions are specified to be of the Laplace form. Such bivariate distributions will be referred to as bivariate Laplace conditional (BLC) distributions. We study the marginals of the BLC distributions and establish that they are not only sub-Gaussian but also super-Laplacian and, hence, super-Cauchy, i.e., they have heavier tails than Gaussian distributions but lighter tails than the usual Laplace and Cauchy distributions. Distance correlation is suggested as a measure of the association between the two marginal variables, as their product moment correlation is zero but they may be non-linearly dependent. A real-life data set is analyzed to illustrate the use of BCL distributions in practice. We believe that this is the first work using conditional specifications in bivariate financial data analysis. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, and advanced disease continues to show poor prognosis due to therapeutic limitations and drug resistance. Royal jelly (RJ), a natural functional food and dietary supplement, contains 10-hydroxy-2-decenoic acid (10-HDA), a bioactive fatty acid unique to RJ with demonstrated anticancer potential. This study evaluated the anti-CRC effects and underlying mechanisms of 10-HDA through cellular, animal, and transcriptomic approaches. 10-HDA markedly suppressed CRC cell viability with IC₅₀ of 2.07 mM and 3.49 mM against HCT 116 and HT-29 cells, respectively, reduced gap closure by 29.30%, elevated intracellular reactive oxygen species (ROS), and attenuated xenograft tumor growth dose-dependently. Preliminary safety evaluation suggested that 10-HDA was well tolerated under the tested conditions, with no significant changes in body weight, serum AST, ALT, or ALP levels, or organ histology. Transcriptomic analysis showed significant enrichment of apoptosis and Wnt/β-catenin pathways. Molecular assessments indicated that 10-HDA was associated with alterations in apoptosis-related features, including increased caspase-3 activity, changes in Bcl-2 family proteins, and elevated ROS levels, as well as with modulation of the Wnt/β-catenin signaling pathway. These changes were consistent with enhanced β-catenin degradation and reduced nuclear translocation. It suggests that Wnt/β-catenin may be involved in the anti-CRC effects of 10-HDA. This study mechanistically clarifies the anti-CRC activity of 10-HDA as a natural food-derived bioactive compound, suggesting its therapeutic potential for Wnt/β-catenin dysregulated CRC. Full article

Bax, a key member of the B-cell lymphoma 2 (Bcl-2) protein family, is essential for inducing mitochondrial apoptosis. In this study, we employed yeast two-hybrid screening to identify ubiquitin-specific protease 49 (USP49) as a binding partner of Bax. Subsequent immunoprecipitation and glutathione S-transferase (GST) pull-down assays confirmed their direct interaction. Functional assays showed that USP49 reduces Bax polyubiquitination at multiple lysine residues within ubiquitin, with the strongest effects observed on K11, K29, K33, and K63 linkages. In contrast, its effect on K48-linked ubiquitination was weak and insufficient to influence Bax protein stability, indicating that USP49 does not regulate Bax abundance through proteasomal degradation. Instead, RT-qPCR analysis revealed that USP49 overexpression significantly increased Bax mRNA levels, and this effect was maintained under apoptosis stimuli (UV, H₂O₂, and STS), indicating transcriptional regulation largely independent of stress-induced damage, whereas its effect was modest and not statistically significant under starurosporine treatment. Collectively, these findings demonstrate that USP49 regulates Bax primarily through K29/K33/K63-linked ubiquitination and transcriptional upregulation, highlighting its role as a stress-responsive modulator of apoptosis and a potential therapeutic target in cancer. Moreover, under DNA damage condition (UV), USP49 overexpression marked enhanced apoptosis. Full article

Nodal T-follicular helper cell lymphomas comprise a biologically similar but morphologically diverse family of T-cell neoplasms, including angioimmunoblastic T-cell lymphoma, nodal T-follicular helper cell lymphoma, follicular-type, and nodal TFH lymphoma, not otherwise specified. Despite recurrent molecular alterations involving RHOA, IDH2, TET2, and DNMT3A, the diagnosis of TFH lymphomas remains challenging because of their mimicry of other lymphoid neoplasms and reactive lymphadenopathy. A key pitfall is confusion with classical Hodgkin lymphoma, as admixed Epstein–Barr virus-positive large B-cells with Reed–Sternberg cell-like morphology and immunophenotype can be found in TFH lymphomas. Similarly, follicular-type TFH lymphoma is often misclassified as follicular B-cell lymphoma unless T-cell lineage is investigated by immunophenotyping and the absence of BCL2 or BCL6 rearrangement is established. The ‘not otherwise specified’ category should be reserved for cases with proven T-follicular helper immunophenotype but lacks definitive angioimmunoblastic or follicular architecture. Comparing current frameworks, 5th edition of the World Health Organization classification permits rare CD4/CD8 double negative cases, while International Consensus Classification requires CD4 positivity. Some of these distinctions may appear taxonomic as all T-follicular helper T-cell lymphoma subtypes share molecular alterations, prognosis, and treatment approach. However, these classifications are meaningful from the perspective of a histopathologic diagnosis as a wrong diagnosis may lead to ineffective treatment approach. Accurate recognition of these lymphomas prevents misclassification, avoids inappropriate regimens, and ensures eligibility for proper clinical trials. A structured approach integrating morphology, multiparameter immunohistochemistry, flow cytometry, and molecular testing provides the best safeguard against diagnostic pitfalls and refines classification across subtypes. Full article

Dpep is a cell-penetrating peptide that targets transcription factors ATF5, CEBPB and CEBPD to selectively suppress growth and survival of diverse tumor cell types in vitro and in vivo. Due to these actions and its apparent safety, the peptide has potential as a cancer therapeutic. How Dpep might be combined with other anti-cancer agents to achieve synergistic efficacy and to overcome possible peptide resistance has not been assessed in depth. Based on prior work indicating that Dpep promotes apoptotic cancer cell death and up-regulates multiple pro-apoptotic and tumor suppressor genes, we studied combinations of Dpep with ABT-263, a pro-apoptotic BCL2 family inhibitor, and decitabine, a hypomethylating drug. Combining Dpep with each agent alone or together synergistically suppressed the growth of a range of solid and liquid tumor cell types. Moreover, the combinations synergistically inhibited the growth of cells lines that were selected either in vivo or in vitro for Dpep resistance. Finally, we tested the combination of Dpep with ABT-263 in a mouse melanoma xenograft model. The combination more effectively inhibited tumor growth than either agent alone and, in contrast to vehicle or ABT-263, produced a 40% durable survival rate. Taken together, these observations highlight potential drug partners for the therapeutic development of Dpep. Full article

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial inflammation and progressive joint destruction. There is no cure, and patient responses to current therapies vary, reflecting underlying pathogenic heterogeneity. Leveraging single-cell RNA sequencing (scRNA-seq) of RA synovium, we identified a PLAUR/uPAR-high myeloid subset that co-expresses pathogenic mediators, including IL1B and CXCL8. To target these cells, we developed anti-uPAR antibody–drug conjugates (ADCs) and evaluated various payloads in vitro and in vivo. ADCs bearing BCL-2 family inhibitors selectively induced apoptosis in proinflammatory human monocytes and macrophages with elevated uPAR, while sparing unstimulated monocytes with low basal uPAR in vitro. The treatment also reduced CXCL8 secretion. Given that murine myeloid cells exhibited lower uPAR expression and reduced sensitivity to BCL-2 family inhibitors, we used a monomethyl auristatin F (MMAF) payload to demonstrate in vivo proof-of-concept. In an air-pouch model, the anti-uPAR–MMAF conjugate reduced uPAR^highCD11b⁺F4/80⁺ macrophages by 39% compared with the isotype control. Together, our study underscores the potential of ADCs to eliminate disease-relevant cell types with inducible cell surface markers. This work opens new avenues for exploring cytotoxic ADCs as targeted therapies for autoimmune and inflammatory diseases. Full article

Acute lymphoblastic leukemia (ALL) is a clinically diverse cancer in which microRNA (miRNA)-mediated post-transcriptional regulation contributes to leukemogenesis and subtype heterogeneity. In this study, miRNA expression profiling by microarray was performed on ALL cases (B-ALL and T-ALL) and healthy controls. Data were normalized and analyzed for differential expression using false discovery rate (FDR)-adjusted p-values. Differentially expressed miRNAs were further examined using unsupervised visualization to assess overall disease-related expression patterns. To explore their biological significance, experimentally validated miRNA–target interactions were obtained using multiMiR, limited to validated databases (miRTarBase, TarBase, and miRecords) and summarized via target-burden ranking, miRNA–target network analysis, and Circos–style interaction mapping. A unique miRNA expression signature was identified in ALL. Upregulated miRNAs included miR-106a-5p, miR-106b-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-181b-5p, and miR-128-3p, while miR-127-3p, miR-139-5p, miR-433-3p, and miR-584-5p were downregulated. Validated targets concentrated on key leukemia-related genes like PTEN, BCL2L11, CDKN1A, CCND1, RB1, E2F1, and TGFBR2. KEGG pathway analysis highlighted pathways associated with leukemic cell survival and growth, including MAPK, cell cycle, autophagy, Hippo, ubiquitin-mediated proteolysis, and mTOR signaling pathways. These findings reveal a concise ALL-associated miRNA panel predominantly comprising the miR-17/20/106 family and provide a prioritized set of candidate regulatory networks for subtype-specific validation and functional follow-up studies. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase (PARP) inhibition, and epigenetic or metabolic targets including histone deacetylases (HDACs), bromodomain and extra-terminal proteins (BET), and mutant isocitrate dehydrogenases (IDH1/2). Across these areas, we summarize recurrent resistance mechanisms and the rationale for combination or sequential approaches. Biologic targeted therapy is discussed in parallel, including immune checkpoint blockade, antibody–drug conjugates, bispecific antibodies (BsAb), and cell therapies such as chimeric antigen receptor T cells, with emphasis on biomarker-guided patient stratification. Finally, we outline emerging directions beyond canonical nodes, including modulation of the p53-MDM2/MDM4 axis, ferroptosis control through AIFM2/FSP1, and innate immune pathways such as CD47-SIRPa and the stimulator of interferon genes (STING). Overall, the field is shifting from single-target inhibition toward integrated strategies that combine precise molecular targeting with an understanding of signaling network dynamics, resistance evolution, and therapeutic vulnerabilities. Full article

Background/Objectives: Drug repurposing offers a time- and cost-efficient strategy for accelerating the development of anticancer therapies by leveraging the established safety profiles of existing pharmaceuticals. This study aimed to investigate the anticancer potential of three tetracycline analogues chemically modified tetracycline-3 (COL-3), doxycycline (DOX), and minocycline (MIN) in leukemia models, with a particular focus on their cytotoxic effects and modulation of the JAK2/STAT3 signaling pathway. Methods: Cytotoxicity was evaluated in K562, KG-1a and Jurkat cell lines using luminescence-based viability assays, whereas the mechanisms of cell death were analyzed by Annexin-V/7-AAD staining and Western blotting. Results: COL-3 displayed the highest cytotoxic potency across all cell lines, with Jurkat cells showing the greatest overall sensitivity. Flow cytometry revealed that tetracycline analogues primarily induced apoptosis, although the molecular mechanisms differed between cell lines. In K562 and KG-1a cells, apoptosis occurred largely through JAK2/STAT3-independent mechanisms, involving differential regulation of BCL-2 family proteins: COL-3 reduced BCL-2 expression, whereas DOX and MIN increased BAX expression. In contrast, Jurkat cell apoptosis correlated with suppression of phosphorylated JAK2 and STAT3 and downregulation of BCL-2, implicating a JAK2/STAT3-dependent mechanism. Conclusions: Taken together, these findings demonstrate that tetracycline analogues exert cell line-specific anticancer activities through distinct molecular pathways. Among them, COL-3 emerges as the most potent analogue and acts through both JAK/STAT-dependent and -independent mechanisms. This work supports further investigation of COL-3 as a candidate for drug repurposing strategies in hematological malignancies. Full article

Background/Objectives: Epstein–Barr virus (EBV) is associated with a subset of gastric carcinomas characterized by latency programs that promote survival of infected cells. EBV-encoded BamH I A rightward transcript (BART) microRNAs contribute to apoptosis resistance in infected epithelial cells. This study investigated whether dasatinib, a Src family kinase (SFK) inhibitor, selectively targets EBV-positive gastric epithelial cells and examined the molecular mechanisms underlying this effect. Methods: EBV-positive and EBV-negative gastric epithelial cell models were analyzed to evaluate cell viability, apoptosis induction, signaling pathways, and viral gene regulation. BART miRNA expression was quantified by RT-qPCR, and promoter activity was examined using luciferase reporter assays. Downstream target gene expression was analyzed at both the transcript and protein levels. Recombinant EBV lacking BZLF1 or LMP2A was used to assess the contributions of lytic activation and LMP2A-associated signaling. Results: Dasatinib preferentially reduced viability and induced apoptosis in EBV-positive gastric epithelial cells compared with EBV-negative counterparts. Treatment suppressed phosphorylation of Src and ERK and reduced expression of the anti-apoptotic proteins BCL-xL and MCL1. Apoptosis was also observed in cells infected with LMP2A-deficient EBV, suggesting that the effect cannot be fully explained by inhibition of LMP2A-associated signaling. Dasatinib inhibited BART miRNA promoter activity and reduced pri-, pre-, and mature miR-BART levels, accompanied by increased expression of pro-apoptotic target genes including CASZ1a, OCT1, ARID2, TP53INP1, and DAB2. In parallel, dasatinib suppressed BZLF1 promoter activity without evidence of lytic reactivation. Conclusions: Dasatinib promotes apoptosis in EBV-positive gastric epithelial cells in association with coordinated suppression of SFK signaling and EBV-encoded BART miRNA expression, accompanied by derepression of pro-apoptotic cellular genes. These findings reveal a previously underappreciated vulnerability of EBV-positive epithelial cells and suggest that targeting host kinase signaling pathways that regulate viral microRNAs may represent a potential therapeutic strategy for EBV-associated malignancies. Full article

Introduction: PMBCL is an aggressive type of lymphoma characterized by high heterogeneity in clinical, molecular, and genetic features. In PMBCL, disturbances in the NFkB pathway and deregulation of BCL-2 and mTOR family proteins are observed, which may contribute to impaired apoptosis. Therefore, many strategies have been established to target the functioning of these pathways. Early clinical trials of mTOR, NFkB and Bcl-2 inhibitors suggest their activity in many hematological cancers, but their activity as monotherapy agents may still be insufficient; therefore, combinations of these compounds with other molecules acting on those active in a given cancer subtype are being sought. Materials and Methods: In vitro studies were conducted on a single PMBCL cell line, Karpas 1106P. We administered three novel drugs: AZD2014 (vistusertib), an inhibitor of the serine-threonine kinase mTOR; IMD-0354, an NFκB inhibitor; and ABT-199 (venetoclax), a highly selective inhibitor for BCL-2. Drugs were administered alone, in pairs and in combination of all three agents. Results: Based on the results of our own research, for the Karpas cell line individually, ABT-199 had the strongest pro-apoptotic effect on cancer cells, while in pairs the most potent induction of apoptosis occurred following treatment with AZD2014+ABT-199. The combination of three drugs did not have a stronger effect than either a single drug used alone or any two-drug combination. Conclusions: These results provide preliminary in vitro evidence that targeting the BCL-2 and mTOR pathways may enhance pro-apoptotic activity in a PMBCL cell model; however, further validation in additional cell lines and in vivo models is needed before translational implications can be considered. Full article

Eriodictyol, a naturally occurring flavanone, has appeared as a biologically versatile compound with increasing relevance in biomedical research, especially in cancers. Evidence over the past few decades indicates that eriodictyol influences cancer cell fate through coordinated modulation of cell-cycle control, survival, and regulated cell death pathways. Eriodictyol appears to reshape oncogenic signaling networks, including PI3K/Akt/mTOR and associated kinase cascades, thereby restricting proliferative capacity and lowering resistance thresholds. Studies consistently report cell-cycle arrest at critical checkpoints, accompanied by activation of both mitochondrial- and death-receptor-mediated apoptotic pathways through disruption of BCL-2 family balance, caspase engagement, and mitochondrial destabilization. Furthermore, eriodictyol alters intracellular redox dynamics in a dose-dependent manner, selectively sensitizing cancer cells to oxidative and metabolic stress. More recent findings extend its significance to inflammation-driven tumor progression and to the regulation of ferroptosis. Beyond intrinsic pharmacological activity, advances in nanocarrier-based delivery and balanced combination strategies have started to address critical challenges and limitations regarding solubility and bioavailability, while allowing precise therapeutic applications. In this review, we have discussed the plausible mechanisms, experimental evidence, and translational insights of eriodictyol as a systems-level modulator of cancer biology. We also outlined research priorities essential for progressing its clinical relevance as future perspectives. Full article