Search Results (17,747)

Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been demonstrated to improve outcomes when combined with hypomethylating drugs (HMAs) such as azacitidine or decitabine; nonetheless, clinical trials have indicated that resistance and recurrence are prevalent. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection. Full article

Despite rapid advances in anticancer therapy, cancer incidence and mortality remain substantial worldwide. Although immune checkpoint inhibitors (ICIs), including anti-PD-1/PD-L1 and anti-CTLA-4 therapies, have transformed cancer treatment by harnessing host antitumor immunity, their efficacy remains limited to a subset of patients, largely because of the complexity of the tumor microenvironment. This review examines drug-induced immunogenic cell death (ICD) and drug-induced senescence as complementary strategies for overcoming these limitations and enhancing immunotherapeutic responses. We further highlight evidence that agents capable of inducing ICD may instead promote cellular senescence when administered at lower concentrations for prolonged periods, indicating that these distinct cellular outcomes can be determined by drug dose and treatment duration. This dose- and time-dependent relationship suggests that the therapeutic application of the same agent may require optimization according to the patient’s condition and tumor stage. Collectively, this review provides an integrated perspective on the selective use of ICD and senescence induction to enhance antitumor immunity, improve therapeutic outcomes, and potentiate synergistic responses to existing ICIs. Full article

Background/Objectives: Oxidative stress is a key contributor to breast cancer (BC) progression and therapeutic response. Although carboplatin is widely used in BC treatment, the effects of combining carboplatin with metformin and boric acid (BA) on cellular redox homeostasis remain poorly understood. This study investigated the effects of these agents on cell viability, migration, and oxidative stress in BC and normal mammary epithelial cells. Methods: Human BC MCF-7 cells and normal mammary epithelial CRL-4010 cells were treated with carboplatin, metformin, BA, and selected combination regimens. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay following 24, 48, and 72 h of treatment. Cell migration was evaluated using a scratch wound-healing assay, and intracellular oxidative stress responses were assessed by measuring superoxide dismutase (SOD) activity. Statistical analyses were performed using one-way ANOVA followed by Fisher’s least significant difference (LSD) post hoc test. Results: Treatment responses were both time- and treatment-dependent in MCF-7 and CRL-4010 cells. Combination regimens significantly reduced cell viability after 48 and 72 h (all p < 0.0001) and generally exhibited greater inhibitory effects than single-agent treatments. Metformin- and BA-containing combinations also produced more pronounced inhibition of cell migration. Significant treatment-related alterations in SOD activity were observed in both cell lines, indicating treatment-associated changes in antioxidant enzyme activity. While several combination regimens decreased SOD activity, others induced increased SOD activity, suggesting differential oxidative stress responses between malignant and non-malignant cells. Conclusions: Carboplatin, metformin, and BA significantly modulated cell viability, migration, and antioxidant responses in both BC and normal mammary epithelial cells. Combination treatments generally produced greater inhibitory effects on cell viability and migration than selected single-agent treatments, particularly in MCF-7 cells. These findings demonstrate treatment-dependent changes in cell viability, migration, and SOD activity and provide a basis for further investigation of the molecular mechanisms underlying carboplatin-based combination treatments. Full article

Exogenous gonadotropin-based estrus synchronization is widely used in livestock reproduction. However, this hormonal treatment has been associated with adverse reproductive outcomes, suggesting that it may alter the uterine environment and endometrial receptivity, although the underlying molecular mechanism remains poorly understood. Here, we investigated the endometrial responses to gonadotropin-induced estrus synchronization using both in vivo and in vitro models. We found that gonadotropin treatment caused structural and inflammatory changes in the endometrium of both pigs and mice, accompanied by elevated circulating estradiol (E₂) levels and enhanced NLRP3 inflammasome-related signaling. In mice, gonadotropin treatment also altered the expression of MUC1, Hand2, and HoxA11, indicating disruption of molecular features associated with endometrial receptivity. In porcine endometrial epithelial cells, supraphysiological E₂ exposure induced mitochondrial oxidative stress, characterized by increased mitochondrial reactive oxygen species production, loss of mitochondrial membrane potential, increased cellular mtDNA abundance, and oxidative DNA damage. E₂ treatment further promoted NLRP3 inflammasome-associated signaling and ASC speck formation, whereas antioxidant N-acetyl-L-cysteine treatment attenuated ASC speck formation. Collectively, these findings support a link between high E₂ exposure, mitochondrial oxidative stress, and enhanced NLRP3 inflammasome signaling in endometrial epithelial cells. Our results suggest that an E₂–mitochondrial oxidative stress–NLRP3 axis may contribute to gonadotropin-associated endometrial dysfunction and provide a basis for further investigation of antioxidant and inflammasome-targeted strategies in livestock reproduction. Full article

This study evaluated the osteogenic differentiation and paracrine response of dental pulp stem cells (DPSCs) cultured within a 3D-printed alginate/chitosan/cannabidiol (CBD) hydrogel. DPSCs from a single donor (passage 6; n = 3 technical replicates per condition) were cultured as monolayers or on hydrogel constructs (CBD 0–12 mg/mL) in basal or osteogenic medium for 7, 14, and 21 days. Alizarin Red S staining confirmed retention of osteogenic competence. Supernatant osteoprotegerin (OPG) and RANKL were quantified by Luminex immunoassay. Monolayer cultures produced up to 7867.5 ± 676.8 pg/mL OPG, whereas hydrogel cultures yielded 9.7–69.3 pg/mL (98–99.8% reduction; p < 0.001). RANKL remained stable at 9–11 pg/mL across all conditions; neither analyte varied with CBD concentration. The OPG/RANKL ratio collapsed from 215–858 to 1.0–6.3 in hydrogel groups. Since RANKL—co-secreted by the same cells—was unaffected, a generalized cellular or secretory deficit is unlikely to explain the selective OPG decrease. The data are consistent with charge-selective retention of cationic OPG (pI ≈ 8.5–9.0) within the anionic alginate network, although this mechanism remains hypothetical pending direct adsorption and ζ-potential verification. These findings indicate that scaffold fixed charge constitutes an active variable in the apparent secretome of three-dimensional cultures. Full article

Background: The incidence of diabetes-related chronic wounds has been increasing annually, characterized by delayed wound healing due to persistent inflammatory responses. To alleviate patient suffering, there is an urgent need to discover novel wound-healing agents that reduce local inflammatory reactions. Animal peptides emerge as promising candidates due to their low molecular weight, low toxicity, low resistance potential, high sensitivity, potent activity, and ease of transmembrane absorption. However, the precise mechanism by which animal peptides accelerate skin wound healing remains unclear. Method: Scorpion peptides were extracted using ultrafiltration, followed by de novo analysis after library searching with Peaks 8 software and combined LC-MS/MS detection to identify peptide components in scorpions. A full-thickness skin defect model in diabetic mice was established to evaluate the wound-healing promotion capacity of scorpion peptides. In vitro experiments were conducted using mouse monocyte–macrophage leukemia cells (RAW264.7 cells). Enzyme-linked immunosorbent assay (ELISA) evaluated inflammatory cytokine expression, flow cytometry analyzed macrophage phenotypes, Western blotting (WB) measured P-P65 and P65 protein levels, immunofluorescence to observe P-P65 nuclear translocation, molecular docking and molecular dynamics simulations, and the Cellular Thermal Shift Assay (CETSA) to evaluate the binding capacity of scorpion peptides to target proteins, and the TUNEL assay to detect apoptosis, among other methods, to investigate the mechanisms by which scorpion peptides promote wound healing. Result: This study successfully identified 2331 peptides from a scorpion peptide extract. In a full-thickness skin defect model in diabetic mice, treatment with scorpion peptides significantly promoted wound healing and induced M2 polarization of macrophages at the wound site. Further in vitro mechanism studies were conducted using a RAW264.7 cell inflammation model established by combining lipopolysaccharide (LPS) with high glucose. The results showed that scorpion peptide reduced the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), increased the anti-inflammatory cytokine interleukin-10 (IL-10), downregulate the P-P65/P65 protein expression ratio, and reduce the number of TUNEL-positive apoptotic cells, suggesting that the NF-κB pathway may be involved in mediating its anti-inflammatory and anti-apoptotic effects. To further identify the target, molecular docking and molecular dynamics simulations showed that the active peptide segments PPPPPP and GPPPPP adopt stable binding conformations with the P65 protein; CETSA further validated that they enhance the thermal stability of the P-P65 protein. Through repeated validation using active peptide fragments, ELISA, flow cytometry, Western blot, and immunofluorescence assays consistently confirmed that scorpion peptide, PPPPPPP, and GPPPPP not only inhibit P65 phosphorylation but also inhibit the nuclear translocation of P-P65, and exhibit anti-inflammatory, macrophage M2 polarization-promoting, and anti-apoptotic effects. Conclusions: Scorpion peptides and their active peptide fragments block the activation of the NF-κB pathway by interfering with P65 phosphorylation and nuclear translocation, effectively inducing M2 polarization of macrophages, reducing inflammation and apoptosis, and ultimately promoting the healing of diabetic wounds. Full article

Inflammation is a complex protective biological response triggered by harmful stimuli such as pathogens, chemical agents, or physical injury, and is closely associated with the development of pain and various chronic diseases. It involves a coordinated cascade of cellular and molecular events, including activation of pattern recognition receptors, release of pro-inflammatory cytokines, production of reactive oxygen species, and recruitment of immune cells. Acute inflammation is essential for host defense and tissue repair. However, persistent or dysregulated inflammation may lead to chronic inflammation, oxidative stress, and tissue damage. Inflammatory pain, a subtype of nociceptive pain, arises from the sensitization of peripheral and central nociceptive pathways by inflammatory mediators such as cytokines, prostaglandins, and nitric oxide. Herbal products have been traditionally used to manage inflammatory diseases due to their bioactive compounds, which modulate inflammatory pathways and alleviate symptoms, and gaining increasing attention due to their multi-targeted mechanisms and lower adverse effects. Polygonum minus (PM), a medicinal herb widely used in Southeast Asia, is rich in bioactive compounds including flavonoids, phenolics, polygodial and essential oils. Phytochemical studies have identified compounds such as qsiuercetin and myricetin, which exhibit strong antioxidant and anti-inflammatory properties. Experimental evidence suggested that PM exerts its anti-inflammatory effects through the inhibition of key inflammatory pathways, including cyclooxygenase (COX) and lipoxygenase (5-LOX), suppression of pro-inflammatory cytokines, and modulation of nuclear factor-kappa B (NF-κB) signaling. Additionally, its antioxidant activity contributes to the reduction in oxidative stress, thereby limiting inflammation-induced tissue damage. This review highlights the mechanisms the potential therapeutic role of PM in modulating underlying inflammation and inflammatory pain. The evidence suggested that PM may serve as a potential promising natural agent for the management of inflammation and pain. Further studies are warranted to elucidate its molecular mechanisms and to validate its efficacy and safety in clinical settings. Full article

The translocase of the outer membrane (TOM) complex is the primary entry gate for nucleus-encoded mitochondrial proteins and is conserved across eukaryotes; however, parasitic protists exhibit remarkable adaptations. This review synthesizes current knowledge on the composition, structure, and function of TOM and related import systems in apicomplexans, kinetoplastids, and anaerobic protists with reduced mitochondrion-related organelles (MROs). We highlight major evolutionary innovations, including the bacterial-origin ATOM complex in trypanosomes—comprising core channel ATOM40, receptors ATOM46/69, structural subunit ATOM19, and multifunctional pATOM36 linking protein import to mitochondrial DNA inheritance—alongside lineage-specific receptors such as Tom60 in Entamoeba histolytica and extreme reductive streamlining in microsporidian mitosomes. Beyond its canonical role in biogenesis, we explore how parasites co-opt the host TOM complex for intracellular survival and how the import machinery integrates with broader cellular processes, including immune signaling, stress responses, and organelle dynamics. Notably, the essential nature of these adapted systems, coupled with their significant divergence from host machinery, highlights their potential as targets for developing novel therapeutic strategies against major parasitic diseases. This work underscores that understanding the diversity of mitochondrial protein import pathways not only provides insights into eukaryotic evolution but may also open new avenues for the development of antiparasitic drugs. Full article

Lung cancer is classified as either Non-Small Cell (NSCLC) and Small Cell Lung Cancer (SCLC) and still represents the leading cause of cancer-related mortality worldwide. Prognosis of NSCLC and SCLC patients is grim; thus, novel therapies are needed. In this context, plant-derived compounds, such as olive leaf extract (OLE), recently attracted much interest for their anti-cancer properties. We investigated the impact of OLE on cell proliferation and apoptosis (by flow cytometry) and migration (by scratch test and transwell assay) of NSCLC and SCLC cell lines, underlying the mechanisms involved. Synergistic effects with cisplatin were also evaluated. OLE differentially impaired cell proliferation and induced apoptosis in LC cell lines. Notably, such effects were higher in SCLC than in NSCLC cell lines. Further analyses were performed on GLC-1 and SKMES cells, identified as OLE-sensitive and OLE-resistant models, respectively. Indeed, OLE triggered the intrinsic apoptotic pathway by activating cleaved caspase-9, -3 and -7, and induced DNA damage response and cellular stress molecules in GLC-1 cells only. In contrast, OLE affected migratory capacity of SKMES cell line and modulated stress adaptation and survival pathways. Finally, OLE synergized with cisplatin in the induction of apoptosis in GLC-1 cells. OLE exerted multiple anti-tumor effects on LC cells in vitro. Its ability to enhance cisplatin-induced apoptosis supports further investigation of OLE as a potential dietary adjunct to chemotherapy. Although OLE has an established safety profile, in vivo studies are required to validate its efficacy, and assess potential interactions with chemotherapeutic drugs before any clinical application. Full article

Low-altitude unmanned aerial vehicles (UAVs) need environmental evidence for perception and navigation, yet dedicated onboard sensing and prior maps may be unavailable. Existing cellular infrastructure offers persistent signals of opportunity, but a passive UAV observes only scalar RSRP, which conflates transmit power, sector response, and environmental loss. We formulate UAV environmental perception as passive, protocol-assisted sensing using non-cooperative commercial cellular downlinks and propose a protocol-anchored reconstruction of a propagation-equivalent virtual radio environment map (vREM). Decodable nominal reference power and path-loss normalization set the power scale, coarse site bearings constrain antenna directions, and multi-altitude UAV trajectories excite height dependence. A hard height-class Beer–Lambert model recovers occupancy support and a height proxy without building geometry at inference. In a controlled multi-altitude simulation based on Xi’an Bell Tower geometry, the method achieved a held-out ${\mathrm{RMSE}}_{\mathrm{RSRP}}$ of $5.24$ dB, compared with $15.70$ dB for NoProtocol; all metrics improved across 200 paired repetitions. A separate ground-based field collection yielded 1518 observations from 82 LTE/NR sources at 41 sites and reduced relative-power mapping RMSE from $7.27$ to $3.41$ dB. The receiver uses public broadcast fields locally, while the commercial transmitters remain outside the sensing and inversion loop. Full article

Nasopharyngeal carcinoma (NPC) is a geographically distinct malignancy closely associated with Epstein–Barr virus (EBV) infection and characterized by extensive epigenetic reprogramming within a highly immunosuppressive tumor microenvironment (TME). High-mobility group box 1 (HMGB1), a multifunctional chromatin-binding protein that can also act as an extracellular damage-associated molecular pattern (DAMP), has emerged as an important regulator of genome organization, transcriptional control, cellular stress responses, and immune signaling. Increased HMGB1 expression has been reported in NPC and is associated with adverse clinicopathological features and poor patient outcomes. Emerging evidence suggests that the diverse biological functions of HMGB1 are influenced by post-translational modifications (PTMs), which affect its subcellular localization, molecular interactions, and extracellular signaling functions. Through these regulatory mechanisms, HMGB1 may transition from a nuclear chromatin-associated protein to an extracellular mediator of immune and inflammatory responses. PTMs including acetylation, phosphorylation, glycosylation, oxidation, methylation, and lactylation have been implicated in regulating HMGB1 trafficking and function, although the specific roles of many of these modifications in NPC remain incompletely characterized. In this review, we summarize current evidence regarding HMGB1 PTMs and discuss their potential implications for EBV-associated NPC, with emphasis on nuclear regulation, immune crosstalk, and therapeutic response. We explicitly distinguish findings directly demonstrated in NPC from mechanistic insights derived from other malignancies and related disease models, and identify areas where proposed mechanisms remain hypothesis-generating rather than experimentally validated in NPC. By integrating current evidence with emerging mechanistic concepts, we highlight key knowledge gaps, unresolved questions, and priorities for future research. A better understanding of PTM-dependent HMGB1 regulation may facilitate the development of novel biomarker and therapeutic strategies for EBV-associated NPC. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), continues to pose a significant global health challenge despite the existence of effective treatments. The only licensed TB vaccine, Bacillus Calmette–Guérin (BCG), offers inconsistent and generally limited protection against adult pulmonary TB. As a result, the pursuit of more effective TB vaccines has intensified over the past two decades, prompting the evaluation of several immunodominant Mtb antigens as vaccines. Among these, antigen 85B (Ag85B) has emerged as a promising candidate due to its critical roles in mycobacterial cell wall biosynthesis, host cell adhesion, and the induction of immune responses. Ag85B has been incorporated into diverse vaccine platforms, including subunit, recombinant, DNA, and mRNA-based vaccines. Evidence from preclinical and clinical studies indicates that Ag85B-containing vaccine formulations elicit robust cellular immune responses, and in many instances, enhance protection against TB. Collectively, these findings position Ag85B as a central component in the development of next-generation TB vaccines. This review examines the biological properties and immunological significance of Ag85B and provides an overview of recent advances in Ag85B-based vaccine strategies. Full article

Background: combination chemotherapy employing agents with complementary mechanisms of action can enhance therapeutic efficacy and overcome resistance, but mismatched pharmacokinetics and systemic toxicity limit benefit. Methods: We designed reductant-responsive squalene prodrugs of doxorubicin (DOX) and exatecan (EXA) that co-assemble with DSPE-PEG_2k into approximately 76 nm dual-prodrug nanoparticles (doxorubicin prodrug–exatecan prodrug nanoparticles, DP-EP NPs) at a predefined synergistic ratio 1:2. Results: The minimalist, drug-as-carrier formulation achieved high effective loadings with minimal leakage under normoxia, yet synchronously liberated both drugs in reductive, hypoxia-mimicking media (24 h release: DOX ~65% and EXA ~58% at 1 mM Na₂S₂O₄ vs. ~8–11% at 0 mM Na₂S₂O₄). In MCF-7 and 4T1 cells, the nanoparticles enhanced intracellular accumulation, intensified the disruption of DNA damage repair, as evidenced by increased colocalization of 53BP1 and enhanced γ-H2AX foci, and induced markers of immunogenic cell death, including increased CRT-associated cellular fluorescence and reduced intracellular HMGB1 staining. Furthermore, they partially reversed drug resistance in MCF-7/ADR cells. In rats, the formulation prolonged circulation and increased exposure (DOX t_½ ~9×, AUC ~1.8×; EXA t_½ ~5×, AUC ~14.9×) relative to the free-drug mixture. In 4T1 tumor-bearing mice, the nanoparticles produced the greatest tumor-growth inhibition with improved tolerability, supported by stable body weight and benign histopathology. Conclusions: These findings establish a scalable, excipient-lean platform that aligns pharmacokinetics with microenvironment-triggered pharmacodynamics to deliver synchronized Topo II/I inhibition for synergistic chemotherapy. Full article

Cold exposure is a major physiological stimulus that promotes adipose tissue browning and enhances thermogenic capacity. As a cold-tolerant breed, Min pigs may rely on distinct adaptive mechanisms in adipose tissues, but how different adipose depots respond to cold stress remains unclear. This study systematically examines how cold exposure affects adipose tissue morphology, thermogenic gene expression, and the differentiation potential of preadipocytes derived from four adipose depots—cervical, axillary, perirenal, and inguinal—in Min pigs. Adipose tissues from the four depots were collected and analyzed using infrared thermography, histological staining, scanning electron microscopy, real-time quantitative PCR, Western blotting and in vitro differentiation assays. The results demonstrated that cold stress induced depot-specific remodeling patterns. Infrared thermography showed that the subcutaneous adipose depots including inguinal and axillary depots maintained relatively higher surface temperatures following cold exposure. Histological and ultrastructural analyses revealed typical beige-like characteristics in inguinal depots, including the accumulation of small lipid droplets, whereas changes in other depots were minimal. Molecular analyses further confirmed this heterogeneity: inguinal depots exhibited the strongest beiging response, characterized by significant upregulation of key thermogenic markers (PGC1α, UCP3, and DIO2) and lipolytic genes (HSL and ATGL) at the mRNA and/or protein levels. In contrast, visceral adipose depots showed weak or suppressed thermogenic activation. In vitro differentiation assays demonstrated that preadipocytes isolated from inguinal depot had the strongest beiging potential, forming tightly packed small lipid droplets and markedly increasing the expression of beige adipose-related genes upon induction. In conclusion, this study demonstrates that cold stress induces distinct beige remodeling across adipose depots in Min pigs, with the inguinal depot exhibiting the strongest thermogenic response and differentiation potential at morphological, molecular, and cellular levels. These findings identify the inguinal depot as a key site for adaptive thermogenesis and provide novel insights into adipose tissue remodeling and environmental adaptation in large mammals. Full article

Measles virus infection couples nonlinear processes across biological scales, including within-host viral amplification, immune-cell depletion, delayed adaptive control, persistent viral RNA, heterogeneous host severity and vaccination-dependent population spread. A multiscale mathematical framework is developed by coupling a seven-variable within-host ordinary differential equation model to a stochastic cellular automaton. The within-host system extends a four-variable measles immunodynamics core by including IFN-$\gamma$-dominant and IL-17-associated immune responses, persistent viral RNA and neutralizing antibodies. Six host archetypes are represented as structured parameter perturbations of this common dynamical core. The principal novelty is an explicit cross-scale coupling operator that separates genuinely ODE-derived host descriptors from hybrid epidemiological mapping rules and independently specified population-level contact and susceptibility assumptions, allowing within-host heterogeneity to propagate transparently into a spatial stochastic epidemic model. An explicit ODE-to-cellular-automaton map translates within-host trajectories into infectious timing, daily infectivity profiles and an illustrative ODE-informed severity-to-death transition mapping used internally by the cellular automaton. The mortality map depends on viral burden, infectious duration, IFN-$\gamma$ deficit, cumulative infectivity and an immune-deficit–infectivity interaction term. Population simulations show a nonlinear reduction in attack rate with increasing vaccination coverage, reduced modeled death burden under targeted high-risk in silico perturbations and additional suppression under reactive vaccination campaigns. A direct local cellular-automaton secondary-infection estimate is reported instead of interpreting cumulative infectivity burden as a reproduction number. A targeted contact-structure sensitivity further shows that matching the expected local direct-secondary-infection potential does not imply equivalent population-level attack rates, emphasizing that the quantitative CA outcomes are geometry specific. Sobol sensitivity analysis with convergence up to $N_{\mathrm{base}}=4096$ identifies core viral and immune parameters as dominant drivers of within-host and multiscale outputs. The framework provides an explicit dynamical-systems approach for coupling differential-equation immunodynamics to spatial stochastic population models in mathematical biology. Full article