Search Results (723)

Background/Objectives: Mechanisms underlying treatment resistance in hematopoietic malignancies such as acute lymphoblastic leukemia (ALL) include (1) enhanced activity of anticancer drug efflux mechanisms (MRP1); (2) suppressed activity of anticancer drug influx mechanisms (ENT-1); (3) enhanced drug detoxification activity (AKR1B10, AKR1C3, CYP3A4); (4) influence of the tumor microenvironment (GRP94), etc. We conducted this study to comprehensively and clinically examine treatment resistance due primarily to a decrease in the tumor intracellular anticancer drug concentrations. Methods: The subjects were 19 ALL patients who underwent initial induction therapy with alternating Hyper CVAD/MA therapy. Antibodies against 23 types of treatment resistance-associated proteins were used for immunohistochemical analysis of tumor specimens obtained from the patients, and correlations between the results of immunohistochemistry and the overall survival (OS) were retrospectively analyzed using the Kaplan–Meier method. Results: Based on the patterns of expression of the enzymes involved in treatment resistance, we classified the patients (Urayasu classification for ALL, which we believe would be very useful for accurately stratifying patients with ALL according to the predicted prognosis), as follows: Good prognosis group, n = 1, 5%: AKR1B1(+)/AKR1B10(−), 5-year overall survival (OS), 100%; Intermediate prognosis-1 group, n = 9, 5%: AKR1B1(−)/AKR1B10(−) plus MRP1(−), 5-year OS, 68%; Intermediate-2 prognosis group, n = 6.3%: AKR1B1(−)/AKR1B10(−) plus MRP1(+), median survival, 17 months, 5-year OS, 20%; and Poor prognosis group, n = 3, 16%: AKR1B1(−)/AKR1B10(+), median survival, 18 months, 5-year OS, 0%. n = 2. Conclusions: The Urayasu classification for ALL is considered reliable for predicting the prognosis of patients with ALL after the initial Hyper CVAD/MA remission induction therapy. Full article

This paper analyzes the impact of COVID-19 on the supply chain and production, investigating countermeasures for industrial recovery. In particular, the study examines how COVID-19 has affected the raw material supply chain, production, and outages on a real case study, that is, Turkey’s Glass-Reinforced Plastic (GRP) pipe industry. Using two- and three-way analysis of variance (ANOVA), significant negative impacts on the raw material supply chain are identified with 95% confidence. To enhance decision-making, the fuzzy q-rung orthopair set (FQROPS) and entropy-based multi-criteria decision-making (MCDM) methods are integrated in the baseline method. Specifically, ANOVA-identified factors, such as cost, supply continuity, production capacity, and risk level, are used as criteria in the MCDM analysis. Entropy determined criteria weights and FQROPS evaluate alternatives based on their proximity to the ideal solution. Findings show that significant disruptions occurred due to the pandemic. In addition, the MCDM analysis reveals that pre-pandemic conditions for key materials, such as fiberglass and resin, were significantly more favorable in terms of cost, supply continuity, production capacity, and risk levels. This integrated approach provides strategic insights for managing supply chains and production in the GRP pipe industry during and after pandemic events. Full article

The COVID-19 outbreak has made it evident that the nature and behavior of SARS-CoV-2 requires constant research and surveillance, owing to the high mutation rates that lead to variants. This work focuses on the statistical analysis of energy measures as biomarkers of SARS-CoV-2. The main purpose of this study is to determine which energy measure can differentiate between SARS-CoV-2 variants, human cell receptors (GRP78 and ACE2), and their combinations. The dataset includes energy measures for different biological structures categorized by variants, receptors, and combinations, representing the sequence of variants and receptors. A multiple analysis of variance (ANOVA) test for equality of means and a Bartlett test for equality of variances are applied to energy measures. Results from multiple ANOVA show (a) the presence of significant differences in energy across variants, receptors, and combinations, (b) that average energy is significant only for receptors and combinations, but not for variants, and (c) the absence of significant differences observed for standard deviation across variants or combinations, but that there are significant differences across receptors. The results from the Bartlett tests show that (a) there is a presence of significant differences in the variances in energy across the variants and combinations, but no significant differences across receptors, (b) there is an absence of significant differences in variances across any group (variants, receptors, combinations), and (c) there is an absence of significant differences in variances for standard deviation of energy across variants, receptors, or combinations. In summary, it is concluded that energy and mean energy are the key biomarkers used to differentiate receptors and combinations. In addition, energy is the primary biomarker where variances differ across variants and combinations. These findings can help to implement tailored interventions, address the SARS-CoV-2 issue, and contribute considerably to the global fight against the pandemic. Full article

This study examines the use of electronic waste (e-waste) as an alternative material in concrete for sustainability and natural resource conservation. Various e-wastes, such as Polyvinyl Chloride (PVC), Glass-Reinforced Plastic (GRP), Glass Fiber-Reinforced Polymer (GFRP), cross-linked polyethylene (XLPE), polyethylene (PE), electronic cable waste (ECW), Waste Electrical Cable Rubber (WECR), copper fiber (Cu Fib.), aluminum Fibers (Al fib.), steel fibers, basalt fibers, glass fibers, aramid−carbon fibers, Kevlar fibers, jute fibers, and optical fibers, were tested for influence on compressive, flexural, tensile strength, modulus of elasticity, and water absorption. Outcomes show that fine particle waste at low levels (0.2–1.5%) can improve mechanical performance, while higher levels of replacement or coarse particles generally reduce performance. Mechanical and physical properties are highly sensitive to material type, particle size, and dose. Life cycle assessment (LCA) and predictive modeling are recommended as validation for sustainability benefits. Full article

Epithelial ovarian cancer is one of the most lethal gynecological malignancies worldwide. Its development strongly depends on several genetic and environmental factors, with metabolic components and cellular redox homeostasis alterations playing a significant a role in its development and disease progression. In this review, we summarize the contribution of mitochondrial and endoplasmic reticulum (ER) stress in the pathogenesis of epithelial ovarian cancer along with their role as potential biomarkers and therapeutic targets, including proteins of glucose metabolism, mitochondrial fission and fusion, mitophagy, membrane-associated ring-CH-type finger 5 (MARCH5), A-kinase anchoring proteins (AKAPs), proteins regulating mitochondrial Ca²⁺ homeostasis, mitochondrial unfolded protein response (UPRmt) proteins, activating transcription factors (ATFs), CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP), ‘mitokines’, GRP75, and GRP78. Although many of these potential targets are in preclinical phase, they have a high potential to become valuable alternative or additive treatments for epithelial ovarian cancers. Full article

This study presents a novel hybrid intelligent framework integrating fuzzy logic and artificial neural networks (ANN) to model the erosion-corrosion behavior of glass-fiber-reinforced pipes (GRP) under harsh operating conditions. Experimental data encompassing multiple operational parameters—including abrasive sand concentrations (250 g, 400 g, 500 g), flow rates (0.0067 m³/min, 0.01 m³/min, 0.015 m³/min), chlorine content (0–10 wt.%), and exposure times (1–5 h)—were utilized to develop the computational models. The fuzzy logic system effectively captured qualitative expert knowledge and uncertainty in material degradation processes, while ANN models provided quantitative predictions of erosion and corrosion rates. Results demonstrated good prediction accuracy, with R² values of 0.81 for corrosion rate and moderate prediction accuracy 0.56 for erosion rate. The analysis revealed that flow rate (correlation: 0.6) and fuzzy severity (0.6) were the most influential parameters, followed by chlorine content (0.41) and sand concentration (0.32). The hybrid model identified optimal operating conditions to minimize material degradation: low sand concentration (250 g), low flow rate (0.0067 m³/min), absence of chlorine, and shorter exposure times. This intelligent modeling approach provides a powerful tool for predictive maintenance, operational optimization, and service life prediction of GRP systems in aggressive environments, bridging the gap between experimental data and computational intelligence for enhanced material performance assessment. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse event triggered by antiresorptive and/or anti-angiogenic agents, characterized by bone destruction, sequestrum formation, and refractory mucosal defects. Effective mucosal healing can be a critical factor for MRONJ prevention and treatment. While endoplasmic reticulum stress (ER stress) has been implicated in tissue repair, its role in MRONJ-associated mucosal healing impairment remains undefined. This study investigated the effects of the anti-angiogenic drug sunitinib on oral mucosal healing and its underlying mechanisms. A mouse model of palatal mucosal defects was established, RNA-seq, transmission electron microscopy, and morphological analyses were used to assess how sunitinib affects ER function during mucosal repair. Using human oral keratinocytes (HOKs), we further elucidated the subcellular mechanisms through which sunitinib influences cell proliferation, migration, cell cycle progression, tight junctions, and apoptosis via techniques such as qPCR, Western blotting, immunofluorescence, and flow cytometry. Our findings demonstrated that sunitinib might induce significant alterations in the morphology of the ER and mitochondria. Both in vivo and in vitro experiments revealed that sunitinib persistently activates the GRP78 (BIP)/PERK/ATF4/CHOP axis in HOKs. This sustained ER stress can inhibit keratinocytes migration and proliferation, disrupt tight junctions, and trigger the intrinsic mitochondrial apoptotic pathway, ultimately leading to impaired oral mucosal healing and barrier dysfunction. Critically, pharmacological inhibition of ER stress was shown to restore keratinocytes’ function and promote effective mucosal healing. These results indicated that targeting sunitinib-induced persistent ER stress might represent a promising therapeutic strategy to prevent and treat oral mucosal toxicity associated with this drug. Full article

Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, we used hepatocyte-specific BAP31 knockout mice (BAP31-LKO) and wild-type (WT) littermates exposed to ethanol to assess BAP31′s biochemical and metabolic impact. Following ethanol exposure, BAP31-LKO mice exhibited elevated serum alanine transaminase (23.2%, p < 0.05) and aspartate transaminase (31.4%, p < 0.05) levels compared to WT mice. Increased malondialdehyde (8.5%, p < 0.05) and reduced superoxide dismutase (22.8%, p < 0.05) in BAP31-LKO mice indicate exacerbated liver injury. Furthermore, BAP31 deficiency increased triglyceride (35.7%, p < 0.05) and free fatty acid (16.2%, p < 0.05) accumulation following ethanol treatment, while the expression of fatty acid oxidation-related genes, including Pparα, Cd36, Fatp2, Cpt2, and Acox1, was reduced in BAP31-LKO mice. The mRNA levels of Xbp1, Xbp1s, and Chop, as well as protein levels of p-eIF2α, IRE1α, GRP78, and CHOP, were increased in BAP31-LKO mice compared to WT controls, indicating aggravated ethanol-induced ER stress. Hepatic glycogen content was also reduced in BAP31-LKO mice, along with reduced Ppp1r3c expression, demonstrating impaired glycogen synthesis. Consistently, BAP31 knockdown amplified ethanol-induced lipid accumulation, inflammation, impaired glycogen storage, ER stress, and suppression of Pparα signaling in HepG2 cells. Together, these findings demonstrate that BAP31 deficiency exacerbates ethanol-induced liver steatosis, inflammation, and liver injury by impairing fatty acid oxidation and glycogen synthesis, and by amplifying ER stress responses. Full article

This paper establishes a comprehensive framework for the hereditary transfer of categorical completeness and cocompleteness to categories of internal group objects in D-modules. We prove that while completeness of $\mathbf{Grp}\left(\mathbf{D}\text{-}\mathbf{Mod}\right)$ follows unconditionally from the completeness of the base category $\mathbf{D}\text{-}\mathbf{Mod}$, cocompleteness requires $\mathbf{D}\text{-}\mathbf{Mod}$ to be regular, cocomplete, and admit a free group functor left adjoint to the forgetful functor. Explicit constructions are provided for limits via componentwise operations and for colimits through coequalizers of relations induced by group axioms over free group objects. The theory reveals fundamental geometric obstructions: differentially constrained subcategories such as holonomic D-modules fail to be cocomplete due to characteristic variety constraints that prevent free group constructions. Applications demonstrate cocompleteness in topological D-module groups and D-module sheaves, while counterexamples in differential geometric groups exhibit necessary analytic constraints. Additional results include regularity inheritance under product-preserving free group functors, internal hom-object constructions in locally Cartesian closed settings yielding Tannaka-type dualities, and monadicity criteria for locally presentable base categories. This work unifies categorical algebra with differential geometric obstruction theory, resolving fundamental questions on exactness transfer while enabling new constructions in homotopical algebra and internal representation theory for D-modules. Full article

The oral cavity acts as the anatomical gateway to the respiratory tract, sharing both microbiological and pathophysiological links with the lower airways. Although radiotherapy is a cornerstone treatment for lung cancer, reliable oral microbiome biomarkers for predicting patient outcomes remain lacking. We analyzed the oral microbiome of 136 lung cancer patients and 199 healthy controls across discovery and two validation cohorts via 16S rRNA sequencing. Healthy controls exhibited a significantly higher abundance of Streptococcus compared to patients (p = 0.049, p < 0.001, p < 0.001, respectively). The structure of the microbial community exhibited substantial dynamic changes during treatment. Responders showed enrichment of Rothia aeria (p = 0.027) and Prevotella salivae (p = 0.043), associated with prolonged overall survival (OS) and progression-free survival (PFS), whereas non-responders exhibited elevated Porphyromonas endodontalis (p = 0.037) correlating with shorter OS and PFS. According to Analysis of Compositions of Microbiomes with Bias Correction 2 (ANCOM-BC2) analysis, Akkermansia and Alistipes were nearly absent in non-responders, while Desulfovibrio and Moraxella were virtually absent in responders. A diagnostic model based on Streptococcus achieved area under the curve (AUC) values of 0.85 (95% CI: 0.78–0.91) and 0.99 (95% CI: 0.98–1) in the validation cohorts, and a response prediction model incorporating Prevotella salivae and Neisseria oralis yielded an AUC of 0.74 (95% CI: 0.58–0.90). Furthermore, in small cell lung cancer, microbiota richness and diversity were inversely correlated with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.008, p < 0.001, respectively) and pro-gastrin-releasing peptide (ProGRP) levels (p = 0.065, p = 0.084, respectively). These results demonstrate that lung cancer-associated oral microbiota signatures dynamically reflect therapeutic response and survival outcomes, supporting their potential role as non-invasive biomarkers for diagnosis and prognosis. Full article

Background/Objectives: Postbiotics derived from lactic acid bacteria are emerging as promising antimicrobial agents due to their antibacterial, antibiofilm, and immunomodulatory properties. Among their metabolites, lactic acid (LA) is thought to play a major role in antimicrobial activity. This study investigated the proteomic response of Pseudomonas aeruginosa and Staphylococcus aureus to Lacticaseibacillus rhamnosus cell-free supernatant (CFS) and compared it with that elicited by LA alone. Methods: Overnight bacterial cultures were exposed to sub-MIC LA or CFS (1:10 for P. aeruginosa and 1:8 for S. aureus; ~12.5–15.6 mM LA) for 6 h at 37 °C. Intracellular proteins were harvested and subsequently quantified and purified to be analysed by HPLC–MS/MS, for quantitative label-free proteomics. Results: Proteomic analysis revealed clear separation of treated samples from controls, with largely overlapping responses to CFS and LA. Hallmark acid-stress adaptations were observed, including urease-mediated pH buffering, confirming that part of the response was driven by mild organic acid. In P. aeruginosa, treatments suppressed virulence pathways (phenazines, T3SS), while shifting metabolism toward lactate utilisation and reinforcing the outer membrane (lipid A, polyamine). In S. aureus, decreased abundance of the SaeRS-regulated immune-evasion factor Sbi, together with changes in envelope, ROS and translation-related proteins, suggested a bacteriostatic-like state. S. aureus differences between CFS and LA were more pronounced; CFS uniquely increased cell-wall defences, oxidative stress (SodA, SodM) and chaperone expression (GroS, GrpE), suggesting stress beyond acidification alone. Conclusions: These findings shed light on the molecular mechanisms underlying bacterial adaptation to CFS and highlight their potential as a novel antimicrobial approach. Full article

Previous studies have identified oxidative stress and inflammatory responses in granulosa cells (GCs) of periparturient dairy cows. However, whether non-esterified fatty acids (NEFA)-induced endoplasmic reticulum (ER) stress is involved in GC apoptosis remains unclear. In this study, treatment with NEFA (0.9 mM, 24 h) activated the ER stress pathway. This was evidenced by increased expression of both CHOP and GRP78. Furthermore, upregulation of pro-apoptotic factors BAX and Caspase-3 and downregulation of the anti-apoptotic factor Bcl-2 were observed. Pretreatment of GCs with 4-phenylbutyric acid (4-PBA, 2.5 mM, 2 h) reversed the ER stress and apoptotic effects. This suggests that NEFA-induced apoptosis is mediated through activation of the PERK pathway of ER stress, and that 4-PBA alleviates this effect. Furthermore, targeted metabolomics revealed disruptions in lipid and hormone metabolism in GCs following NEFA treatment. Analysis revealed an increase in the levels of 26 types of fatty acids, while a decrease was detected in the levels of 3 types of fatty acids. In summary, NEFA induces ER stress and disrupts intracellular fatty acid, ultimately leading to cell apoptosis. Our findings offer valuable insights for developing strategies to regulate follicular development in dairy cows and mitigate the impacts of postpartum negative energy balance (NEB). Full article

Background and Objectives: ADAM17, a sheddase that regulates cytokine and receptor ectodomains, amplifies inflammatory signaling. Acute liver injury (ALI) is driven by dysregulated inflammation, accompanied by both oxidative and endoplasmic reticulum (ER) stress responses. We investigated whether pharmacological inhibition of ADAM17 with GW280264X mitigates lipopolysaccharide (LPS)-induced acute liver injury by targeting these pathways. Methods: Male C57BL/6J mice received intraperitoneal LPS (10 mg/kg). GW280264X (500 µg/kg, i.p.) was administered at one and three hours post-LPS treatment. At the fifth hour, serum and liver samples were collected to determine serum ALT/AST levels and to perform hematoxylin and eosin (H&E) staining. Inflammatory (TNF-α), oxidative (MDA, 4-HNE, Fe²⁺, GSH; NRF2/KEAP1), endoplasmic reticulum (ER) stress (GRP78, ATF6, CHOP), and ferroptosis-related (GPX4, SLC7A11) markers, along with ADAM17 protein levels, were analyzed using ELISA, colorimetric assays, and Western blotting. Results: LPS triggered hepatic injury. This was accompanied by marked elevations in TNF-α, oxidative indices (MDA, 4-HNE, Fe²⁺) and ER stress proteins (GRP78, ATF6, CHOP), together with depletion of hepatic GSH. GW280264X significantly reduced AST levels, attenuated inflammatory, oxidative, and ER stress responses, and improved hepatic histopathology. GPX4 and SLC7A11 tended to increase following treatment, but the changes did not reach statistical significance and should be interpreted cautiously due to the limited sample size (n = 5). Similarly, ADAM17 protein levels tended to decrease, although the change was not statistically significant. Conclusions: Pharmacological inhibition of ADAM17 with GW280264X may confer early hepatoprotection in LPS-induced ALI by attenuating inflammatory, oxidative and ER stress pathways. ADAM17 inhibition yielded partial and statistically non-significant protective effects at this early stage; therefore, these findings should be considered exploratory. Future studies with larger sample sizes and longer observation periods are warranted to confirm the durability and mechanistic basis of this response. Full article

Castration-resistant prostate cancer presents radiotherapeutic challenges, especially in optimizing the cytosolic internalization of therapeutic radiopharmaceuticals. This research aimed to design and evaluate in vitro, a new dimeric radiopharmaceutical, [¹⁷⁷Lu]Lu–iPSMA–iGRP78, which combines PSMA and GRP78 inhibitors in a heterodimeric radioligand to improve the radionuclide internalization and cytotoxicity efficacy. Molecular docking showed that the dimer iPSMA–iGRP78 presents a higher affinity for GRP78 (CNN-docking score: −14.0 kcal·mol⁻¹, pKi: 10) and for PSMA (CNN-docking score: −17.0 kcal·mol⁻¹, pKi: 11.5) compared to the monomers iGRP78 (CNN-docking score: −11.0 kcal·mol⁻¹, pKi: 9.4) and iPSMA (CNN-docking score: −13.9 kcal·mol⁻¹, pKi: 10.2). The saturation binding assay using LNCaP cells (PSMA+, CS-GRP78+) showed an affinity (K_d) of 1.883 nM for [¹⁷⁷Lu]Lu–iPSMA–iGRP78 and 2.245 nM for [¹⁷⁷Lu]Lu–iPSMA. The dimeric radiopharmaceutical achieved 10.44 ± 2.43% cytosolic internalization and 4.81 ± 0.94% nuclear internalization, while the [¹⁷⁷Lu]Lu–iPSMA monomer showed 6.45 ± 0.60% cytosolic internalization and no uptake in the cell nucleus. In PC3 cells (PSMA–, CS-GRP78–), [¹⁷⁷Lu]Lu–iPSMA–iGRP78 uptake was negligible, demonstrating specificity. Treatment with the dimeric radiopharmaceutical reduced cell viability (69.93 ± 4.85% of dead cells) significantly more than [¹⁷⁷Lu]Lu–iPSMA (38.63 ± 6.13% of dead cells). In conclusion, conjugation of a GRP78 inhibitor to [¹⁷⁷Lu]Lu–iPSMA improves the radionuclide internalization and cytotoxicity in prostate cancer cells, suggesting that the bispecific radiopharmaceutical is a promising strategy in prostate cancer treatment. Full article

Background/Objectives: Mitophagy, the selective removal of damaged mitochondria, plays a pivotal role in regulating cardiac hypertrophy and fibrosis under pressure overload. Targeting mitophagy may help mitigate adverse cardiac remodeling. This preclinical study examined the effects of cafestol, a coffee-derived diterpene, on pressure overload-induced cardiac hypertrophy and fibrosis in mice, with emphasis on mitophagy modulation and mitochondrial ultrastructure. Methods: Male normotensive mice underwent transverse aortic constriction (TAC) and received cafestol at 2, 10, or 50 mg/kg/day via oral gavage for 28 days. Cardiac function was assessed by echocardiography. Histological and molecular analyses quantified fibrosis, inflammation, and apoptosis. Protein expression of CD68, CTGF, DDR2, α-SMA, CD44, galectin-3 (Gal3), collagen I, GAPDH, Bcl-2, Bax, cleaved caspase-3, GRP78, p-ERK/ERK, ATF4, p-mTOR/mTOR, and p62 was evaluated. Transmission electron microscopy (TEM) was used to assess autophagosome formation and mitochondrial morphology. Results: TAC induced significant cardiac hypertrophy and fibrosis, accompanied by elevated expression of fibrotic (CTGF, DDR2, α-SMA, collagen I), inflammatory (CD68, CD44, Gal3), apoptotic (Bax, cleaved caspase-3), and endoplasmic reticulum stress markers (GRP78, ATF4). TEM revealed increased autophagosome accumulation and disrupted mitochondrial architecture. Cafestol treatment reduced collagen deposition, immune cell infiltration, and apoptotic signaling; enhanced Bcl-2 expression; and restored p62 levels. TEM findings demonstrated decreased autophagosome burden and preserved mitochondrial structure, consistent with improved mitophagic flux and mitochondrial homeostasis. Conclusions: Cafestol mitigated pressure overload-induced cardiac remodeling in mice by modulating mitophagy, suppressing fibrotic and inflammatory responses, and preserving mitochondrial integrity. These findings support further investigation of cafestol’s mechanisms and safety profile in preclinical models of cardiovascular disease. Full article