Search Results (18,518)

Ovarian cancer is one of the deadliest gynecological malignancies, where most patients become clinically symptomatic at advanced stages of disease due to the lack of effective diagnostic screening. Despite recent advances in surgical resection and chemotherapy, recurrent ovarian cancer remains largely refractory to treatment, resulting in poor prognosis. The ovarian cancer tumor microenvironment (TME) is highly abnormal and presents a significant barrier to successful therapy. A combination of abnormal vasculature, desmoplastic extracellular matrix, and aberrantly activated hypoxic and immune-suppressive pathways culminates in promoting tumor growth, dissemination, chemoresistance, and immunosuppression. Whilst immune checkpoint inhibitors have shown success in other cancers, their application in ovarian cancer, particularly at advanced stages, remains limited. In this review, we discussed the application of tumor extracellular matrix normalizing therapies in preclinical models of advanced ovarian cancer, and their synergistic benefit to chemotherapy and immunotherapy. Collectively, these insights underscore TME normalization as a promising therapeutic strategy with the potential to improve ovarian cancer management. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by motor dysfunction and non-motor symptoms, including cognitive decline. Animal models that replicate PD’s clinical features are essential for therapeutic research. The widely used subacute 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced mouse model effectively mimics motor deficits but fails to fully represent aging-related non-motor symptoms. In this study, we established an aging-associated PD mouse model by combining MPTP with D-galactose treatment. Compared to mice treated with MPTP alone, MPTP + D-galactose-treated mice exhibited typical motor impairments alongside cognitive deficits in the Morris water maze and Y-maze tests. D-galactose alone induced cognitive impairment without motor dysfunction. Pathological analysis showed that the MPTP + D-galactose treatment caused tyrosine hydroxylase-positive neuron loss similar to MPTP, while D-galactose did not damage these neurons. Additionally, Micro-CT revealed bone loss in both the MPTP + D-galactose and D-galactose groups. This model recapitulates both the motor and aging-related non-motor symptoms of PD, including cognitive impairment and bone loss, providing a more comprehensive tool for studying PD pathogenesis and evaluating potential therapies. Full article

Background/Objectives: Malaria remains a major global health burden, increasingly complicated by resistance to artemisinin-based therapies. Because artemisinin activation depends on heme and porphyrin chemistry, we sought to exploit host red blood cell (RBC) heme metabolism as a therapeutic vulnerability. This study aims to develop and evaluate a host-directed “bait-and-kill” strategy that selectively sensitizes malaria-infected RBCs to artemisinin. Methods: We integrated quantitative proteomics, erythropoiesis transcriptomic analyses, flow cytometry, and in vitro malaria culture assays to characterize heme metabolism in mature RBCs and Plasmodium falciparum-infected RBCs (iRBCs). The heme precursor 5-aminolevulinic acid (ALA) was used to induce porphyrin accumulation, and dihydroartemisinin (DHA) was applied as the killing agent. Drug synergy, porphyrin accumulation, reactive oxygen species (ROS) induction, and parasite survival were assessed, including ring-stage survival assays using artemisinin-resistant clinical isolates. Results: Mature RBCs retain a truncated heme biosynthesis pathway capable of accumulating porphyrin intermediates, while uninfected RBCs are impermeable to ALA. In contrast, iRBCs exhibit increased membrane permeability, allowing selective ALA uptake and porphyrin accumulation. ALA alone did not induce cytotoxicity or ROS, whereas DHA induced ROS and parasite killing. The ALA + DHA combination resulted in synergistic parasite elimination, including complete clearance of artemisinin-resistant P. falciparum isolates from the Greater Mekong Subregion, with no recrudescence observed over three weeks of culture. Evidence supports a predominant role for host-derived heme metabolites in mediating this synergy. Conclusions: The bait-and-kill strategy selectively exploits host RBC heme metabolism to restore and enhance artemisinin efficacy while sparing uninfected cells. Using clinically safe compounds, this host-directed approach provides a promising, resistance-bypassing framework for malaria treatment and combination drug development. Full article

Background: Acquired brain injury (ABI) affects manual dexterity (MD) and cognitive functions, limiting daily activity performance. Occupational therapy aims to improve functionality and quality of life. Objective: To examine and describe the available evidence on the impact of MD training on cognitive processes and functional performance in adults with stroke, as well as to identify the most commonly used assessment tools and intervention techniques. Methods: Scoping review. A systematic literature search was conducted in PubMed and Scopus to identify experimental studies from the last 10 years involving adults with ABI who participated in interventions targeting upper-limb, MD, and cognitive function. A three-phase screening was carried out by two authors with duplicates removed using Zotero version 7.0. Results: Ten articles published between 2016 and 2023 were included. The most frequent interventions involved robotics and virtual reality. Eight studies were conducted by occupational therapists or included occupational therapy involvement, while two were conducted by physiotherapists. Training MD and upper-limb motor skills led to improvements in attention, memory, and executive functions. Conclusions: Findings support combined motor–cognitive interventions carried out by occupational therapists or physiotherapists to optimize rehabilitation outcomes, although further research is needed to strengthen the evidence. Full article

Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder characterized by hepatic lipid accumulation, oxidative stress, and disturbance of lysosomal degradation. Central to these processes is glutathione (GSH), a key antioxidant regulating redox balance and cellular homeostasis. This study aimed to evaluate the therapeutic potential of two dietary antioxidants—astaxanthin and Garcinia indica (kokum)—in modulating hepatic redox status, lysosomal function, and metabolic gene expression in a murine model of diet-induced NAFLD. A total of 120 male Swiss Webster mice were allocated into control and steatotic groups, followed by a 90-day supplementation period with astaxanthin, kokum, or their combination. Liver tissue was collected post-supplementation for biochemical, antioxidant, and qRT-PCR analyses. Outcomes included lysosomal enzymes activities, superoxide dismutase (SOD), GSH, vitamin C, total polyphenols, DPPH radical-scavenging activity, and total antioxidant capacity (TAC). NAFLD induced marked oxidative stress, lysosomal overactivation, and alteration of antioxidant-related gene expression. Combined supplementation restored GSH, enhanced TAC, reduced lysosomal stress markers, and significantly upregulated nuclear factor erythroid 2-related factor 2 (Nfe2l2) while downregulating fatty acid synthase (FASN) and partially rescuing lipoprotein lipase (LpL). Correlation analyses revealed strong associations between antioxidant capacity, lysosomal function, and transcriptional regulation, supporting the therapeutic relevance of combined antioxidant therapy for concurrent redox and lysosomal dysregulation in NAFLD. These findings underscore the therapeutic potential of targeting redox and cellular degradation pathways with antioxidant-based interventions to re-establish hepatic metabolic balance in NAFLD and related disorders. Full article

Atherosclerosis remains a leading cause of cardiovascular mortality despite advances in pharmacological and interventional therapies. Current treatment approaches face limitations including systemic side effects, inadequate local drug delivery, and restenosis following vascular interventions. Gel-based technologies offer unique advantages through tunable mechanical properties, controlled degradation kinetics, high drug-loading capacity, and potential for stimuli-responsive therapeutic release. This review examines gel platforms across multiple scales and applications in atherosclerosis research and intervention. First, gel-based in vitro models are discussed. These include hydrogel matrices simulating plaque microenvironments, three-dimensional cellular culture platforms, and microfluidic organ-on-chip devices. These devices incorporate physiological flow to investigate disease mechanisms under controlled conditions. Second, therapeutic strategies are addressed through macroscopic gels for localized treatment. These encompass natural polymer-based, synthetic polymer-based, and composite formulations. Applications include stent coatings, adventitial injections, and catheter-delivered depots. Natural polymers often possess intrinsic biological activities including anti-inflammatory and immunomodulatory properties that may contribute to therapeutic effects. Third, nano- and microgels for systemic delivery are examined. These include polymer-based nanogels with stimuli-responsive drug release responding to oxidative stress, pH changes, and enzymatic activity characteristic of atherosclerotic lesions. Inorganic–organic composite nanogels incorporating paramagnetic contrast agents enable theranostic applications by combining therapy with imaging-guided treatment monitoring. Current challenges include manufacturing consistency, mechanical stability under physiological flow, long-term safety assessment, and regulatory pathway definition. Future opportunities are discussed in multi-functional integration, artificial intelligence-guided design, personalized formulations, and biomimetic approaches. Gel technologies demonstrate substantial potential to advance atherosclerosis management through improved spatial and temporal control over therapeutic interventions. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article

Background/Objectives: To improve the response rate of immune checkpoint inhibitors (ICIs), inducing immunogenic cell death (ICD) is a promising approach. Photothermal therapy (PTT) induces immunogenic cell death and activates anti-tumor immunity. While there are various ICD inducers, the difference in ICD induction by various modalities is poorly understood. In this study, we found previously unrecognized advantages of PTT compared to anti-cancer drugs and showed the usefulness of PTT as an anti-cancer drug-free approach to be combined with immunotherapy. Methods: Gold nanorods were synthesized as photothermal agents and added to culture medium or locally administered to tumor tissues. Mitoxantrone (MIT), an ICD inducer, and cisplatin (CDDP), a non-ICD inducer, were compared with PTT. To assess the induction of ICD, the subcellular localization and amounts of high mobility group box 1 (HMGB1) and calreticulin (CRT) were observed using immunofluorescent staining. FM3A tumor-bearing mice were treated with PTT or anti-cancer drugs, and cell death and DAMPs localization in tumor tissues were analyzed. Also, the supra-additive effect of PTT on ICI was observed. Tumor-infiltrating CD8⁺ T cells were examined to evaluate the immune status in tumor tissues. Results: In vivo assays showed that PTT induces HMGB1 release and increased expression of CRT on the cell membrane. Moreover, PTT showed a supra-additive effect in terms of therapeutic effect and anti-tumor activation when combined with an immune checkpoint inhibitor. Conclusions: In this study, we demonstrated that PTT induced ICD-related signaling and improved the response rate of ICI, which means PTT is a promising combination therapy with ICI. Full article

The intensification of aquaculture practices has been accompanied by an increased incidence of bacterial diseases, leading to a greater reliance on antibiotics for disease control. Consequently, the widespread and often indiscriminate use of these compounds has contributed to the emergence and dissemination of antibiotic-resistant bacteria within aquaculture systems, posing a serious threat to animal health, environmental sustainability, and public health. In this regard, research efforts have focused on developing alternative strategies to reduce antibiotic use. Natural compounds have gained particular attention due to their well-documented antimicrobial and antibiofilm activities. In this context, the combined application of antibiotics and natural compounds has emerged as a promising approach to enhance antimicrobial efficacy while potentially mitigating the development of resistance. This review synthesizes the current knowledge on antibiotic resistance in aquaculture, highlights the role of biofilm formation as a key resistance mechanism, and critically examines the potential of antibiotic–natural compound combinations against major aquaculture pathogens, with particular emphasis on bacterial growth inhibition, biofilm disruption, and virulence attenuation. Collectively, the evidence discussed underscores the potential of synergistic strategies as a sustainable tool for improving disease management in aquaculture while supporting efforts to limit antibiotic resistance. Full article

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an extremely rare autosomal recessive disorder, with only a few hundred affected individuals worldwide. Since its initial recognition in the 1980s, only a limited number of studies have described its ocular manifestations. The aim of this review was to summarize and organize the available published evidence regarding ocular findings in LCHADD and their classification. A PubMed search was conducted for studies describing ocular findings associated with LCHADD, using combinations of the following keywords: LCHADD, chorioretinopathy, ocular findings, vision, therapy, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The review included studies published within the past 20 years that reported at least six cases. The search identified 11 eligible studies. Findings were grouped into three categories: LCHADD-associated chorioretinopathy, macular neovascularization (MNV), and the effects of dietary therapy on visual function. Chorioretinopathy emerged as the major pathognomonic ocular feature of LCHADD. MNV was reported in approximately 20% of eyes, often bilaterally but not simultaneously. Progressive myopia was observed in most patients. Newborn screening and early initiation of dietary therapy appear critical and may slow the progression of chorioretinopathy. A strong correlation between patient age and chorioretinopathy severity was consistently demonstrated, and visual deterioration occurred even in individuals with good metabolic control. LCHADD is a life- and vision-threatening disorder characterized by a distinctive chorioretinopathy present in nearly all patients. Early detection through newborn screening and regular ophthalmic follow-up is essential for the optimal management of affected individuals. Full article

Grape pomace is a major byproduct of winemaking and a rich source of bioactive anthocyanins with potential functional value. This study aimed to optimize anthocyanin extraction from Tannat grape pomace and evaluate its antioxidant and anti-aging activities. Ultrasonic-assisted extraction combined with a Box–Behnken design identified optimal conditions of 51.27 °C, 53.46% ethanol, 20.10 min ultrasonication, and a 1:24.05 solid-to-liquid ratio, yielding 186.21 ± 1.03 mg/100 g (R² = 0.9798, p < 0.0001). Tannat Grape Pomace Anthocyanins showed strong antioxidant capacity, with 2,2-Diphenyl-1-picrylhydrazyl scavenging of 89.44% ± 0.87% at 0.2 mg/mL (IC₅₀ = 0.09 mg/mL) and 2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) scavenging of 95.83% ± 0.54% at 0.75 mg/mL (IC₅₀ = 0.26 mg/mL). In Caenorhabditis elegans, TGPA extended lifespan, improved motility, and increased heat and oxidative stress resistance without reducing reproductive capacity. Lifespan is a key indicator of aging. This study holds significant implications for advancing our understanding of the mechanisms underlying lifespan regulation, the connection between aging and disease, as well as the development of anti-aging therapies for humans. In conclusion, these findings indicate that Tannat Grape Pomace Anthocyanins possess promising antioxidant and anti-aging potential and support the sustainable, high-value utilization of grape pomace. This approach directly aligns with the core principles of sustainable agriculture by transforming an agricultural byproduct into a valuable resource. Full article

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: We describe a 31-year-old woman with H3K27-altered DMG who, after standard chemoradiotherapy, was treated with a personalized, mechanism-guided combination regimen based on her tumor’s molecular profile. Next-generation sequencing identified pathogenic alterations in ATRX, H3F3A, and NF1, with a high NF1 mutation allelic fraction indicating RAS/MAPK pathway activation. Immunohistochemistry demonstrated elevated phosphorylated mTOR consistent with PI3K/AKT/mTOR pathway upregulation. The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. At seven months, MRI showed approximately a 60% volumetric reduction in the enhancing tumor component, accompanied by marked T2-weighted signal regression. Clinically, the patient remained neurologically intact with a Karnofsky Performance Score of 100%. Conclusions: This case illustrates the potential clinical value of a genomics-guided, multimodal treatment strategy in H3K27-altered DMG. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks. Full article

Background: The introduction of tyrosine kinase inhibitors has revolutionised the treatment of gastrointestinal stromal tumours (GISTs), yet the role of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal GISTosis remains controversial. Methods: A retrospective analysis was conducted on patients with peritoneal GISTosis who underwent CRS plus HIPEC in an 18-year period. We analysed the clinicopathological characteristics and evaluated the perioperative and long-term outcomes based on the extent of disease (peritoneal cancer index, PCI), the resection (completeness of cytoreduction score) and the IM-administration. The survival factors were also analysed and the Kaplan–Meier estimator to model and estimate overall (OS) and progression-free survival (PFS). The median follow-up period was 72 months (range, 12–146). Results: A total of 25 patients (M:F = 15:10) with a median age of 57 years (range, 32–69) underwent CRS with HIPEC for peritoneal GIST metastases, detected either synchronously (n = 11) or metachronously (n = 14). The media PCI score was 9 (range, 4–20) and complete cytoreduction was achieved in 80%. Grade III complications were observed in two patients, whereas there was no postoperative mortality. Neoadjuvant imatinib-mesylate (IM) therapy was administered in 60% of patients who detected with metachronous metastases (n = 8/14), whereas adjuvant IM therapy was administered in 19 of 25 patients. Median OS was 62 months (95% CI = 22.8–101.2). Median OS and DFS for patients with PCI scores ≤ 10 were significantly longer compared to those with PCI scores > 10 (p = 0.009 and p = 0.024, respectively). Patients with CC scores of 0–1 had a significantly longer OS compared to those with CC scores of 2 (p = 0.005) and 3 (p = 0.002) and longer PFS compared to those with CC scores of 3 (p = 0.005). The need for imatinib did not significantly impact OS (p = 0.240) or PFS (p = 0.243). Conclusions: CRS combined with HIPEC shows promising results in peritoneal GISTosis, especially in patients with lower PCI and CC scores. Until larger studies validate its safety and efficacy, it should be primarily performed in expert hands in specialised peritoneal surface oncology centres. Full article

Toe-in (inward) and toe-out (outward) foot alignments significantly affect gait, posture, and joint stress, causing issues like abnormal gait, joint strain, and foot conditions such as plantar fasciitis and high arches. Addressing these alignments is crucial for improving mobility and comfort. This study introduces IoTToe, a wearable IoT device designed to detect and monitor gait patterns by using six ADXL345 sensors positioned on the foot, allowing healthcare providers to remotely monitor alignment via a webpage, reducing the need for physical tests. Tested on 45 participants aged 20–25 years with diverse BMIs, IoTToe proved suitable for both children and adults, supporting therapy and diagnostics. Statistical tests, including ICC, DFA, and ANOVA, confirmed the device’s effectiveness in detecting gait and postural control differences between legs. Gait variability results indicated that left leg showed more adaptability (DFA close to 0.5), compared to the right leg which was found more consistent (DFA close to 1). Postural control showed stable and agile standing with values between 0.5 and 1. Sensor combinations revealed that removing sensor B (on the gastrocnemius muscle) did not affect data quality. Moreover, taller individuals displayed smaller ankle angle changes, highlighting challenges in balance and upper body stability. IoTToe offers accurate data collection, reliability, portability, and significant potential for gait monitoring and injury prevention. Future studies would expand participation, especially among women and those with alignment issues, to enhance the system’s applicability for foot health management, safety and rehabilitation, further supporting telemetric applications in healthcare. Full article