Search Results (47,127)

Background: Immune checkpoint inhibitors (ICIs), particularly programmed death-ligand 1 (PD-L1) inhibitors such as atezolizumab, have significantly improved outcomes in cancer therapy. However, these agents may cause immune-related adverse effects, including nephrotoxicity associated with oxidative stress and cellular stress responses. This study aimed to investigate and comparatively evaluate the protective effects of adenosine triphosphate (ATP) and taxifolin against atezolizumab-induced renal tissue injury in rats. Methods: Animals were divided into four groups: healthy (HG), atezolizumab (ATZ), ATP + atezolizumab (ATAZ), and taxifolin + atezolizumab (TXAZ). ATP (4 mg/kg, i.p.) and taxifolin (50 mg/kg, oral) were administered for six days, while atezolizumab (10 mg/kg, i.p.) was given on days 1 and 4. On day 7, renal tissues were collected for biochemical, histopathological, and double immunofluorescence analyses. Results: Atezolizumab significantly increased malondialdehyde (MDA) levels and decreased total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) levels, indicating enhanced oxidative stress and impaired antioxidant defense. These changes were accompanied by tubular degeneration and increased expression of apoptotic markers. Both ATP and taxifolin significantly ameliorated these alterations; however, ATP demonstrated a more pronounced protective effect. Conclusions: In conclusion, ATP and taxifolin attenuated the biochemical, histopathological, and immunofluorescence alterations associated with atezolizumab administration. ATP exhibited a more pronounced protective effect than taxifolin under the conditions of this experimental model. Nevertheless, further experimental studies are required to elucidate the mechanisms underlying these effects. Full article

Background/Objectives: Drug repurposing has emerged as a promising strategy for identifying novel anticancer agents among clinically established drugs. Fexofenadine, a second-generation H1 antihistamine, has been proposed as a candidate for repurposing in oncology; however, the molecular mechanisms underlying its biological activity remain insufficiently characterized. This study investigated the effects of fexofenadine on oxidative stress, mitochondrial function, apoptosis, and pro-survival signaling pathways in cervical and lung cancer cells. Methods: HeLa and A549 cancer cells, as well as non-tumorigenic Beas-2B epithelial cells, were exposed to fexofenadine under in vitro conditions. Cell viability, apoptosis, reactive oxygen species generation, mitochondrial membrane potential, DNA damage, autophagy-associated responses, and PI3K/AKT and MAPK/ERK pathway activation were assessed using flow cytometry, fluorescence microscopy, electron microscopy, and biochemical assays. Three-dimensional spheroid cultures and N-acetyl-L-cysteine rescue experiments were additionally employed to evaluate biological relevance and the contribution of oxidative stress. Results: Fexofenadine induced concentration-dependent accumulation of reactive oxygen species, mitochondrial membrane depolarization, Bcl-2 inactivation, caspase-3/7 activation, DNA damage, and apoptotic cell death in HeLa and A549 cells. Antioxidant pretreatment with N-acetyl-L-cysteine significantly reduced oxidative stress, attenuated mitochondrial dysfunction, and partially suppressed apoptosis. Fexofenadine was associated with reduced PI3K/AKT and MAPK/ERK pathway activation and promoted autophagy-associated responses. In three-dimensional spheroid cultures, treatment disrupted spheroid integrity and increased apoptotic cell death. Non-tumorigenic Beas-2B cells exhibited lower sensitivity to treatment than malignant cells. Conclusions: Fexofenadine disrupts redox homeostasis and is associated with reduced activation of pro-survival signaling pathways, resulting in oxidative stress-associated mitochondrial dysfunction and apoptosis in cancer cells. These findings provide mechanistic support for further evaluation of fexofenadine as a candidate for anticancer drug repurposing, while additional pharmacokinetic and in vivo studies are required to determine its translational relevance. Full article

Carrot processing for juice generates substantial pomace residues rich in bioactive compounds, which represent both an environmental challenge and an unexploited resource. This study investigated the protective effects of a polyphenolic extract derived from carrot pomace (CP) against Escherichia coli lipopolysaccharide (LPS)-induced damage. For that, we used IPEC-1 (Intestinal Porcine Epithelial Cells) as an in vitro model of the intestinal epithelium. The total phenolic content of the CP polyphenolic extract (CPE) was 1.017 mg GAE/mL, with flavan-3-ols (epicatechin, catechin, epigallocatechin) accounting for 71.3% of that value. Before being exposed to LPS (10 μg/mL) for 24 h, the cells were pre-treated with CP extract (20.34 µg and 10.17 µg polyphenols/mL of extract corresponding to 1/50 and 1/100 dilution) for 4 h. Epithelial renewal (cell viability, cell proliferation and apoptosis), monolayer/barrier integrity (TEER, FD4 permeability, LDH release), as well as epithelial functionality (synthesis of pro-inflammatory cytokines: TNF-α, IL-1β, IL-6, reactive oxygen species (ROS), nitric oxide (NO) production), MAPK signalling and mitochondrial morphology and function were assessed. The results showed that CP extract had no cytotoxic effects and successfully counteracted LPS-induced loss of cell viability and proliferation. The pre-treatment with CPE at both dilutions significantly reduced LPS-induced apoptosis and cell death. Barrier integrity was preserved with TEER values maintained near baseline: −0.43% and −0.24% for 1/50 and 1/100 dilutions of CPE vs. −53.47% at 72 h for LPS alone, and paracellular FD4 passage was restored to control levels. At the molecular level, CP extract reduced pro-inflammatory cytokine gene expression (IL-6 by 40%, TNF-α by 50–56%) and suppressed LPS-induced MAPK activation by 62.9% and 46.5%, for 1/50 and 1/100 dilutions of CPE, respectively. The pre-treatment of cells with CP extract normalised LPS-induced ROS production and protected mitochondrial morphology and function. These in vitro findings demonstrate that CP extract exerts a protective effect on intestinal epithelial cells, acting through anti-inflammatory, antioxidant and barrier-preserving mechanisms. This supports the hypothesis for valorisation of carrot agro-industrial by-products as functional feed additives for promoting intestinal health. Further in vivo studies are needed to validate this hypothesis and to establish the concentration/rate of inclusion of carrot by-products to achieve the maximal positive effects. Full article

Background: Several studies reveal an inverse relation between serum 25-hydroxyvitamin D [25(OH)D] concentration and the risk of acute ischemic stroke (AIS). The aim of this study was to determine relationships between 25(OH)D concentration and the course and outcomes of AIS treatment and the level of indices of inflammatory response to brain injury. Patients and Methods: Retrospective analysis of medical documentation of 1381 real-world AIS patients hospitalized in a single center between 1 January 2020 and 31 May 2025. Serum 25(OH)D level, several inflammatory indices, and clinical data were assessed. Results: Compared to patients in the lowest quartile of 25(OH)D concentration, those in the highest quartile had a shorter length of in-hospital stay, a lower risk of all-cause death, and a lower score for disability on a modified Rankin scale (mRS). Along with an increase in 25(OH)D quartiles, we found: a decrease in neutrophil count; a decrease in glucose, HbA1c, albumin, C-reactive protein (CRP), and CRP-to-albumin, -lymphocyte, -neutrophil, and -platelet ratios; lower neutrophil-to-lymphocyte and -albumin ratios, and lower systemic immune inflammation, and systemic inflammation response indices. In multifactorial logistic regression, the quartile of 25(OH)D (OR, 95% CI: 1.52, 1.09–2.12; p = 0.012) was the only variable to have a positive association with a mRS score ≤ 2 at discharge from hospital, and neutrophil-to-lymphocyte ratio, age, diabetes, and treatment with endovascular mechanical thrombectomy were biomarkers of poor functional status at discharge. Conclusions: Higher 25(OH)D concentration in AIS patients is related to better survival and a lower level of inflammatory response indices and disability at discharge. Full article

The rising burden of diabetic kidney disease (DKD) and its associated lipid abnormalities underscores the need for new mechanistic insights. Uromodulin, a kidney-enriched protein, has been associated with metabolic disorders in human studies, yet its functional role in systemic lipid metabolism remains elusive. In this study, transcriptomic datasets were analyzed to investigate uromodulin expression and biological function in DKD. Subsequently, a diabetic model was induced in UMOD^+/+ and UMOD^−/− rats using a combination of a high-fat diet, unilateral nephrectomy, and streptozotocin to assess renal and metabolic phenotypes. Public RNA-seq data indicated that uromodulin expression was downregulated in DKD and was enriched in the fatty acid metabolism pathway. At baseline, UMOD^−/− rats resembled UMOD^+/+ rats in terms of growth, routine serum lipids, and major organ function. However, in diabetes, UMOD^−/− rats exhibited higher mortality and pronounced hyperlipidemia. Hyperlipidemia occurred prior to the onset of renal dysfunction. Of note, this exacerbated lipid dysregulation represented a lipodystrophy-like phenotype rather than secondary changes in the pancreas, liver, or circulating cytokines (IL-6, IL-1β, and TNF-α). Moreover, UMOD^−/− rats displayed exacerbated tubular injury and enhanced renal lipid accumulation in DKD relative to UMOD^+/+ rats. Collectively, uromodulin protects diabetic rats from death, prevents epididymal white adipose tissue from browning, and attenuates kidney injury. Our findings identify uromodulin as a novel regulator of the kidney–adipose axis. Full article

Background: Reliable intraoperative tools for donor liver assessment are needed, particularly in the context of steatotic and extended-criteria grafts. While histology remains the reference standard, it is limited by sampling variability and logistical constraints. Preservation fluid may provide a complementary, whole-organ source of biochemical information. Methods: In this single-center prospective exploratory pilot study, liver tissue and preservation fluid were collected from 30 donation-after-brain-death grafts during the back-table procedure. Biochemical parameters, including arginase activity, β-hydroxybutyrate (βHB), acetoacetate, and total protein, were measured using standard assays. Associations with histological steatosis on wedge biopsy were assessed using nonparametric correlation analyses, and paired preservation fluid samples were compared. Results: Most grafts demonstrated absent or mild steatosis; only two exhibited moderate steatosis, and none were severely steatotic. No preservation fluid biomarker showed a statistically significant association with histological steatosis. Weak, non-significant positive correlations were observed for βHB and arginase activity (Spearman r ≈ 0.33–0.35). Protein concentration and arginase activity decreased between start and end samples, whereas ketone body levels remained relatively stable. Conclusions: Preservation fluid biomarker measurement during routine graft preparation is feasible. Although no significant associations with histological steatosis were identified, the observed weak correlations suggest possible associations requiring validation in larger studies. Larger, adequately powered studies, including a broader spectrum of steatosis and clinically relevant outcomes, are required to determine potential clinical applicability. Full article

Mitochondria-targeting metal complexes (MTMCs) are a mechanistically distinct class of metallopharmaceuticals. Unlike first-generation platinum drugs that form nuclear DNA adducts, MTMCs exploit organelle-specific vulnerabilities such as hyperpolarised mitochondrial membrane potential (ΔΨm), elevated reactive oxygen species (ROS), limited mitochondrial DNA (mtDNA) repair capacity, and redox-dependent enzymes such as thioredoxin reductase (TrxR). We systematically searched PubMed, Web of Science, Scopus, and Google Scholar databases for studies published between 2016 and 2026, applying predefined inclusion criteria that included subcellular localization evidence and functional bioenergetic endpoints. The search identified 147 studies covering Pt(II/IV), Ru(II/III), Au(I/III), Ir(III), Os(II), Re(I), and V(IV/V) complexes and metal–organic framework nanoplatforms. Mechanistic evidence converges on four intramitochondrial target categories: inhibition of ETC (Electron Transport Chain) Complexes I/III with consequent ATP depletion; ROS overproduction, coupled with glutathione and TrxR depletion; outer mitochondrial membrane permeabilization and intrinsic apoptotic cascade activation; and mtDNA damage within a compartment limited to base excision repair. Multi-modal cell death—the co-occurrence of apoptosis, ferroptosis, necroptosis, and autophagic cell death—was a recurrent finding across the reviewed studies. This review thoroughly surveys the latest trends in MTMC drug design (metals, ligand structures, and mechanisms of action) and summarises analytical techniques for speciation, pharmacokinetics, safe monitoring, and resistance, while critically analysing translational barriers and clinical failures. To address the field’s inconsistent terminology, we introduce an explicit localization evidence hierarchy that distinguishes mitochondria-targeting complexes (through quantitative ICP-MS fractionation or co-localization with defined Pearson/Manders coefficients) from simply mitochondria-localising or mitochondria-perturbing agents, and we apply it throughout. We also point out that the idea of selectivity being purely driven by membrane voltage (ΔΨm) and thermodynamics is constrained by membrane and protein binding, as well as the transmembrane pH gradient, kinetic limitations, and demonstrated heterogeneity of cancer-cell membrane potential, and, as such, the functional mitochondrial effects must not be equated with mitochondrial accumulation. Since elemental quantification cannot distinguish intact complex from protein adducts and decomposition products, speciation-aware pharmacokinetics emerges as a prerequisite for a credible exposure–response interpretation. The translational progress will depend less on new chemotypes than on this analytical and pharmacokinetic rigour, together with organelle-level safety monitoring and biomarker-guided patient selection. Full article

Background/Objectives: Healthcare-associated infections (HAIs) are a major and preventable threat to patient safety, yet reported figures in Central and Eastern Europe are widely affected by under-reporting, which can distort both the apparent infection profile and the perceived burden of disease. Patient-level regional surveillance data were analysed to characterise the reported HAI profile, the determinants of in-hospital mortality, and between-hospital surveillance quality in post-pandemic Southeast Romania. Methods: This was a retrospective, cross-sectional analysis of 2878 HAI cases reported across a five-county, multicentre network of 32 hospitals during 2024. Infections were grouped as Clostridioides difficile infection (CDI) versus non-CDI. Logistic regression was applied for in-hospital mortality, Cox and competing-risks models for time to death, negative binomial regression for length of stay, and a Spiegelhalter funnel plot for between-hospital variation. Results:Clostridioides difficile infection accounted for 56.3% of reported cases, a markedly higher proportion than that described in European point-prevalence surveys, although differences in design and denominator preclude direct comparison. CDIs and non-CDIs formed distinct clinical phenotypes. In-hospital mortality was lower in CDI than in non-CDIs (14.9% versus 26.1%) and was independently associated with intensive care admission, age, and immunosuppression, while CDI remained associated with lower mortality. The reported CDI proportion ranged from approximately 1% to 93% between hospitals, with most institutions lying outside the funnel control limits. Conclusions: The predominance of CDI among reported HAIs is best interpreted as a signal of selective ascertainment rather than as direct evidence of a genuinely higher CDI burden. Because the dataset lacked admission or patient-day denominators, the CDI-to-total ratio should be regarded as a simple screening indicator of potential surveillance imbalance, useful for identifying hospitals where non-CDIs may be under-detected. Full article

Despite advances in liver machine perfusion (MP), ischemia–reperfusion injury (IRI) remains a major challenge in liver transplantation, with energetic stress and mitochondrial dysfunction recognized as key drivers of damage exacerbation. We investigated whether fractions enriched with extracellular vesicles (EVs) derived from mesenchymal stromal cells can preserve energetic homeostasis in rat livers undergoing normothermic MP (NMP). An established NMP rat model was used (n = 5 per group). After procurement, livers underwent NMP for 4 h, preceded or not by 30 min cold ischemia (CI). EVs (NMP + EVs and CI + NMP + EVs) or saline (NMP and CI + NMP) were randomly administered to the perfusion fluid. Perfusate samples were collected throughout the procedure, and biopsies were taken at the end of NMP. Ischemic livers exhibited succinate accumulation, flavin mononucleotide (FMN) release, activation of reverse electron transport, and adenosine triphosphate (ATP) depletion. EV treatment effectively counteracted these effects, restoring a metabolic profile comparable to that of non-ischemic livers. Moreover, EVs improved adenosine monophosphate/ATP ratios and prevented AMP-activated protein kinase activation, a key energy-stress sensor. Furthermore, EVs reduced oxidative stress markers, cell death mediators, and pro-inflammatory cytokines, indicating a broad cytoprotective and anti-inflammatory effect. These findings support the potential of EVs to preserve mitochondrial function, restore energy balance, and reduce inflammation, thereby improving liver cell viability during NMP. Full article

Snakebite envenoming is a neglected tropical disease causing approximately 81,410–137,880 deaths globally each year and four-fold more disabilities than mortality rate. Despite the availability of antivenoms for treatment, several in vitro and in vivo preclinical studies have shown that their efficacy is limited by many factors including regional venom variation and poor neutralization of major venom toxins. To address these limitations, the potential of alternatives including aptamers, recombinant monoclonal antibodies, camelid antibodies, small molecule inhibitors, and natural product-based inhibitors targeting key venom proteins have been explored. Among these, small molecule inhibitors targeting key enzymatic snake venom proteins are emerging as adjuvants to antivenom treatment. Most of these small molecules are repurposed drugs with established safety, oral bioavailability, and lower cost compared to antivenoms. In this regard, this review tries to compile available information regarding the use of small molecule inhibitors to counteract envenomation with special emphasis on three major enzymatic snake venom protein families: phospholipase A₂, snake venom metalloproteinases, and snake venom serine proteases. In vitro studies have shown that these small molecule inhibitors used either alone or in combination with antivenom can potentially reduce the adverse effects of venom-induced coagulopathy, neurotoxicity, tissue damage, and inflammation. However, critical gaps remain including limited human clinical trial data, uncertain efficacy across diverse venoms, and undefined dosing strategies. Overall, small molecules represent a mechanistically targeted and clinically promising adjunct to antivenom therapy, warranting further validation through randomized trials, pharmacokinetic studies, and development of field-applicable treatment protocols. Full article

The small heat shock protein HSPB1 is a ubiquitously expressed mechanoresponsive chaperone essential for cytoskeletal remodeling under mechanical load. Mutations in HSPB1, including S135F, cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, yet the mechanisms underlying the selective vulnerability of peripheral nerves remain enigmatic. Here we demonstrate that substrate stiffness is a critical determinant of HSPB1^S135F-mediated neurodegeneration. Using stiffness-tunable polydimethylsiloxane (PDMS) substrates (1 kPa, 10 kPa, 2 MPa) and uniaxial cyclic stretch, we show that primary dorsal root ganglia (DRG) neurons and SH-SY5Y cells expressing HSPB1^S135F exhibit profound deficits in mechanoadaptation. On compliant substrates (10 kPa), HSPB1^S135F causes stretch-induced axon fragmentation and neuronal death, whereas HSPB1^WT confers robust neuroprotection. HSPB1^S135F also disrupts stiffness-directed neuritogenesis in differentiated SH-SY5Y cells: HSPB1^WT-expressing cells show optimal axonal outgrowth and βIII-tubulin expression on 10 kPa substrates mimicking muscle tissue stiffness, while HSPB1^S135F mutants display disorganized focal adhesions and complete differentiation failure. Mechanistically, we uncover that HSPB1^S135F dysregulates stage-specific transglutaminase (TGase) expression—insufficient TGase during early neuritogenesis impairs filopodia stabilization, whereas aberrant TGase persistence at late stages constrains axon extension. Our findings establish HSPB1 as a biomechanical sensor that integrates ECM stiffness signals to coordinate peripheral nerve regeneration, and identify defective mechanoadaptation as a previously unrecognized pathomechanism in CMT. These results open new avenues for stiffness-targeted therapeutic strategies in peripheral neuropathy. Full article

Background/Objectives: Attitudes toward end-of-life care (EOLC) are a key component of nursing practice. This study aimed to assess nursing students’ attitudes toward EOLC and their perceived preparedness to manage end-of-life situations. Methods: A cross-sectional descriptive study was conducted with 593 undergraduate nursing students from a public Spanish university. Data were collected using an online questionnaire, including the validated Spanish version of the Frommelt Attitude Toward Care of the Dying Scale (FATCOD-S). Descriptive and inferential analyses were performed. Results: The median reverse-coded FATCOD-S total score was 125.0 (IQR 119.0–131.0), and 99.7% of students were classified as having positive or very positive attitudes when the descriptive cut-offs were applied. In the exploratory adjusted model, fourth-year status and previous EOLC training were associated with higher FATCOD-S total scores. However, 59.5% of respondents reported feeling unprepared to provide EOLC, and 59.0% perceived EOLC as a significant source of stress for nurses. Additionally, 62.0% of students with positive attitudes reported not feeling prepared to provide such care. Responses related to emotional involvement, communication about death, and ethical aspects showed greater variability. Conclusions: Although most nursing students display favorable attitudes toward EOLC, these coexist with a low perceived level of preparedness, with more than half of students reporting that they do not feel prepared to provide EOLC. Positive attitudes alone may not ensure confidence in clinical practice. Strengthening undergraduate education—particularly in emotional preparation, communication skills, and coping strategies—is essential to better prepare future nurses for the complexities of EOLC. These findings should be interpreted in light of the study’s cross-sectional design and single-university setting. Full article

Background: Respiratory failure (RF) is a frequently fatal complication of chronic liver disease (CLD), yet population-level data on RF-related mortality trends among adults with CLD are lacking. This study characterized temporal trends and demographic disparities in RF-related mortality among U.S. adults with CLD from 1999 to 2024. Methods: Death certificate data were obtained from the CDC WONDER database for adults aged ≥25 years with both RF (ICD-10: J96) and CLD (ICD-10: K70–K76) listed as an underlying or contributing cause of death. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated using the 2000 U.S. standard population. Joinpoint regression identified temporal inflection points and annual percentage change (APC). Results: Among 241,075 deaths, the overall AAMR increased 3.2-fold from 2.237 (1999) to 7.162 (2021) per 100,000, then declined to 6.132 by 2024. Joinpoint analysis identified four segments: moderate increase (1999–2006; APC +2.40%), accelerated increase (2006–2018; APC +5.37%), late acceleration period (2018–2021; APC +13.10%), and post-pandemic decline (2021–2024; APC −4.32%; all p < 0.001). The 2024 AAMR remained 174.2% above baseline. The male-to-female rate ratio narrowed from 2.02 to 1.50, with females showing steeper acceleration (+14.38% vs. +12.36%). American Indian or Alaska Native individuals had the highest AAMRs and the most dramatic surge (APC +26.90%). Rural areas surpassed urban AAMRs by 2020, with steeper post-2007 acceleration (+8.74% vs. +5.51%). The Western U.S. consistently had the highest regional rates. Younger adults aged 25–34 and 35–44 showed 2.96-fold and 2.37-fold increases in crude mortality rates, respectively. Approximately 80% of deaths occurred in inpatient settings. Conclusions: RF-related mortality among U.S. adults with CLD increased more than threefold from 1999 to 2021, with a dramatic surge followed by incomplete decline. Persistent disparities by sex, race/ethnicity, urbanization, and region highlight the need for targeted interventions, including expanded screening for alcohol-associated and metabolic liver disease and improved access to hepatology services in underserved communities. Full article

Background/Objectives: Malignant melanoma is characterized by constitutive PI3K/Akt/mTOR and MAPK activation, driving aggressive behavior and therapeutic resistance. Alpha-lipoic acid (αLA), a naturally occurring dithiol compound with an established clinical safety profile, has shown anticancer potential; however, its integrated molecular mechanisms in melanoma remain poorly defined. This study aimed to comprehensively evaluate the cytotoxic and mechanistic effects of αLA in B16F10 murine melanoma cells. Methods: Antiproliferative effects were assessed by MTT assay at four concentrations (250, 500, 750, 1000 µM) over 48 h. Protein levels of apoptotic markers (Bax, Bcl-2, Caspase-3, AIF), kinase signaling components (p-Akt, p-mTOR, p-ERK, p-JNK), ER stress markers (GRP78, GADD153/CHOP), and cell cycle regulator Wee1 were quantified by ELISA at a specifically selected sub-lethal concentration of 750 µM (inducing ~38% growth inhibition). Results: αLA dose-dependently inhibited B16F10 proliferation. At 750 µM, it triggered robust intrinsic apoptotic signaling, evidenced by a nearly 10-fold shift in the Bax/Bcl-2 ratio and greater than 9-fold Caspase-3 activation. Elevated AIF suggested profound mitochondrial stress and the potential priming of concurrent caspase-independent cell death mechanisms. αLA suppressed survival signaling by reducing p-Akt (44%), p-mTOR, p-ERK, and p-JNK. Treatment triggered lethal ER stress via GRP78 and GADD153/CHOP upregulation and upregulated Wee1, suggesting the induction of stress-responsive checkpoint signaling. The simultaneous CHOP upregulation and p-Akt suppression highlight a concurrent dysregulation of stress and survival pathways, suggesting a potential pro-apoptotic interplay. Conclusions: αLA exerts potent multi-target anticancer effects by inducing a broad spectrum of associated molecular changes, including the suppression of PI3K/Akt/mTOR and MAPK networks, induction of ER stress, engagement of cell cycle checkpoints, and activation of the mitochondrial Bax/Bcl-2/Caspase-3 axis. Importantly, these correlative findings do not establish proven pathway dependencies. Nevertheless, this concurrent dysregulation positions αLA as a potential disruptor of inter-pathway resilience underlying drug resistance. Full article

Glioblastoma multiforme (GBM), isocitrate dehydrogenase (IDH)-wildtype, is the most aggressive primary malignant tumor of the central nervous system, characterized by poor prognosis and high recurrence rates despite standard multimodal treatment. This study investigates the molecular response of glioblastoma cells to 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT), focusing on gene expression changes associated with apoptosis, ferroptosis, and oxidative stress. Human glioblastoma T98G cells were treated with 5-ALA followed by light irradiation, and gene expression was analyzed using RT-qPCR. PDT induced moderate upregulation of pro-apoptotic genes (BAX, CASP3, FAS) alongside increased expression of the anti-apoptotic gene BCL2, indicating simultaneous activation of cell death and survival pathways. Ferroptosis-related genes showed mixed responses, with slight upregulation of ACSL4 and downregulation of GPX4, suggesting increased susceptibility to lipid peroxidation. The most significant change was observed in GCH1 expression, reflecting activation of oxidative stress response mechanisms. However, none of the observed changes reached statistical significance, likely due to the limited sample size. These findings demonstrate that PDT induces a complex and dual biological response in glioblastoma cells, involving both cytotoxic and adaptive mechanisms. This may limit therapeutic efficacy and contribute to treatment resistance. The results support the rationale for combining PDT with targeted molecular therapies aimed at inhibiting antioxidant defenses and anti-apoptotic pathways. Additionally, personalized therapeutic strategies based on tumor molecular profiles may enhance treatment outcomes. Further studies with larger sample sizes and functional validation are required to confirm these preliminary observations. Full article