Search Results (1,711)

Background: A protein called ‘apoptosis inhibitor of macrophage (AIM)’ is involved in the pathogenesis of obesity-associated disease. Although it is widely recognized that concurrent obesity affects the disease progression of chronic liver disease, as does concurrent type 2 diabetes mellitus (T2DM), the involvement of AIM in the pathogenesis of obesity or insulin resistance is not yet understood in patients with primary biliary cholangitis (PBC). Methods: Obesity was defined as a body mass index (BMI) exceeding 25, and insulin resistance was defined as a homeostasis model assessment for insulin resistance (HOMA-IR) value exceeding 2.0, respectively. Hepatic steatosis was estimated based on the classification proposed by Brunt and colleagues. The histological stage was determined by Scheuer’s classification. Results: Twelve (25.0%) of the forty-eight PBC patients had concurrent obesity, and seven (14.6%) had concurrent T2DM. The PBC patients with obesity had significantly higher frequency of hepatic steatosis. Compared to the patients without T2DM, those with concurrent T2DM had significantly higher serum ALT levels and more advanced histological stages. The patients’ serum AIM levels were not associated with concurrent obesity or concurrent T2DM. Our analyses identified the following as the factors that significantly affected the patients’ AIM levels: serum immunoglobulin G, albumin, tumor necrosis factor-α levels, and the histological stages. Conclusions: These results indicate that AIM may not be involved in obesity or insulin resistance, but it may be associated with the disease severity of PBC. Full article

Elderly patients often experience multimorbidity and long-term polypharmacy, making medication safety a critical challenge in disease management. In China, the concurrent use of Western medicines and proprietary Chinese medicines (PCMs) further complicates this issue, as potential drug interactions are often implicit, increasing risks for physiologically vulnerable older adults. Although large language model-based medical question-answering systems have been widely adopted, they remain prone to unsafe outputs in medication-related contexts. Existing retrieval-augmented generation (RAG) frameworks typically rely on static retrieval strategies, limiting their ability to appropriately allocate retrieval and verification efforts across different question types. This paper proposes FusionGraphRAG, an adaptive RAG framework for geriatric disease management. The framework employs query classification-based routing to distinguish questions by complexity and medication relevance; integrates dual-granularity knowledge alignment to connect fine-grained medical entities with higher-level contextual knowledge across diseases, medications, and lifestyle guidance; and incorporates explicit contradiction detection for high-risk medication scenarios. Experiments on the GeriatricHealthQA dataset (derived from the Huatuo corpus) indicate that FusionGraphRAG achieves a Safety Recall of 71.7%. Comparative analysis demonstrates that the framework improves retrieval accuracy and risk interception capabilities compared to existing graph-enhanced baselines, particularly in identifying implicit pharmacological conflicts. The results indicate that the framework supports more reliable geriatric medical question answering while providing enhanced safety verification for medication-related reasoning. Full article

Background/Objectives: Migraine and diabetes mellitus are highly prevalent chronic diseases, and their comorbidity presents management challenges, particularly when wearable medical technologies are used concurrently. Remote electrical neuromodulation (REN; Nerivio^®) is an FDA-cleared non-pharmacological migraine therapy, and continuous glucose monitoring (CGM) systems are widely used in diabetes care. However, the safety and compatibility of simultaneous co-use have not yet been evaluated. This technical compatibility study aimed to assess whether REN operation affects CGM performance or interferes with glucose measurement integrity in diabetic adults. Methods: Twenty-one adults with diabetes using Dexcom G6/G7 or FreeStyle Libre 2/3 participated in a single-arm interventional study. During a 45 min session, participants operated the REN and CGM devices simultaneously on their smartphones, and the REN device was paused three times to compare CGM readings between REN ON and RED OFF conditions. The primary outcome was the mean absolute relative difference (MARD_{REN ON/OFF}), evaluated against a prespecified 5% threshold. Statistical analysis included the Wilcoxon test, with subgroup analysis by the CGM device family. Results: The median MARD_{REN ON/OFF} across all participants was 1.61% (IQR 0.84–2.44%), significantly below the 5% threshold (p < 0.001). All participants achieved MARD_{REN ON/OFF} < 5%. Subgroup analyses were consistent: the median MARD_{REN ON/OFF} was 1.70% (IQR 0.90–2.45%) for Dexcom and 1.05% (IQR 0.83–1.50%) for Abbott. No technical interference, Bluetooth disruptions, missed data transmission, or adverse events were observed. Conclusions: Simultaneous use of Nerivio^® REN and CGM systems in adults with diabetes is compatible and safe, with no evidence of interference or significant deviations in glucose readings. These findings support the integrated and reliable use of REN and CGM wearables in adults with diabetes managing comorbid conditions. Full article

Background/Objectives: Mild Traumatic Brain Injury (mTBI) is a prevalent form of cranial trauma that can elicit a range of acute and chronic neuropsychiatric symptoms, and may increase the risk of neurodegenerative diseases. Its accurate identification remains a significant challenge in the field of forensic medicine. This study aimed to identify differential gut microbiota as potential biomarkers following mTBI and to preliminarily explore the association between alterations in gut microbiota and brain metabolites. Methods: An animal model was used to induce mTBI in male Sprague-Dawley (SD) rats. Dynamic changes in the gut microbiota and brain metabolites were analyzed via 16S rRNA sequencing and untargeted metabolomics. Results: Key discriminative taxa included Staphylococcus, Streptococcus, and Aeromonadaceae. Concurrently, brain metabolites, such as C24:1 Sphingomyelin and Thioetheramide PC, exhibited significant alterations. Multi-omics integration revealed that these changes were strongly correlated; in addition, a pathway analysis implicated disruptions in short-chain fatty acid and glycerophospholipid metabolism, which were linked to the regulation of inflammatory factors. Conclusions: This study demonstrates that mTBI induces distinct, time-dependent alterations in both the gut microbiota and brain metabolome, thereby providing a novel direction for research into the forensic diagnosis and mechanistic investigation of mTBI. Future studies are warranted to validate these potential biomarkers in human cohorts and to further elucidate the causal mechanisms underlying gut–brain axis interactions. Full article

Objectives: To synthesize current evidence and emerging data on systemic treatment strategies for early-stage and locally advanced human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), with emphasis on treatment de-escalation and the integration of immunotherapy. Data Sources: We searched PubMed/MEDLINE, Scopus, and EMBASE for English-language studies published from 2010 to 2025 using terms related to HPV-positive disease, oropharyngeal carcinoma, de-escalation, chemoradiation, and immunotherapy. Review Methods: Peer-reviewed clinical trials, meta-analyses, and key translational studies addressing systemic therapy, biomarkers, and immunotherapeutic strategies in HPV-positive OPSCC were included. Emphasis was placed on phase II–III trials evaluating cisplatin-sparing regimens, cetuximab substitution, radiation dose reduction, and early-phase immunotherapy combinations. Evidence was synthesized qualitatively. Results: Cisplatin-based concurrent chemoradiation remains the standard of care for locally advanced HPV-positive OPSCC. De-intensification trials suggest that reduced-intensity regimens may be feasible in carefully selected low-risk patients; however, replacing cisplatin with cetuximab results in inferior survival. PD-1 inhibitors (e.g., pembrolizumab, nivolumab) provide durable responses in recurrent/metastatic disease and are under active evaluation in earlier stages and in combination with therapeutic vaccines, bispecific antibodies, and viral-vector platforms. Conclusions: Systemic therapy for HPV-positive OPSCC is moving toward biomarker-informed personalization. Cisplatin-based chemoradiation remains the curative backbone, while rational de-escalation and immunotherapy integration may preserve high cure rates while reducing long-term toxicity. Ongoing phase III trials will clarify which patient subsets are most suitable for de-intensified or immunotherapeutic approaches, guiding future standards of care. Full article

Resilience is commonly framed as a psychological trait, yet clinical and experimental evidence demonstrates that resilience failures emerge concurrently across metabolic, endocrine, immune, and cognitive domains. This review examines resilience as a bioenergetic property constrained by how organisms allocate finite metabolic resources under stress. We synthesize evidence from endocrinology, mitochondrial biology, immunometabolism, and stress physiology to propose a parsimonious, hypothesis-driven Energy Allocation System (EAS) in which the hypothalamic-pituitary-adrenal (HPA), thyroid (HPT), and gonadal (HPG) axes are conceptualized as a coordinated energy-governance network. Despite extensive investigation within these individual fields, the literature lacks an integrative physiological framework explaining why multisystem stress responses co-occur in predictable endocrine and metabolic patterns. Within this framework, mitochondrial reserve capacity serves as the limiting substrate through which hormonal signals regulate mobilization, metabolic pacing, immune tolerance, and recovery. The reviewed literature supports predictable patterns of endocrine reorganization during energetic strain, including prioritization of glucocorticoid-mediated mobilization, constrained thyroid hormone activation, suppression of long-term anabolic investment, and impaired recovery following stress. These configurations reflect adaptive energy-conserving strategies rather than isolated organ dysfunction. The novelty of this review lies in organizing established biological mechanisms into a unified, energy-allocation-based framework that generates falsifiable predictions linking endocrine coordination to bioenergetic capacity and recovery dynamics. We further discuss how routinely available biomarkers and validated psychometric measures can be interpreted as functional readouts of energetic allocation rather than static disease markers. Framing resilience through coordinated energy governance offers a unifying mechanistic lens for interpreting multisystem stress responses and generates testable predictions for future experimental and clinical investigation. Full article

Background/Objectives: Primary progressive aphasia (PPA) is a clinical syndrome associated with gradual language impairment caused by neurodegenerative disease. While people with post-stroke aphasia often depend on visual and prosodic cues to facilitate language, we hypothesized that people with PPA may have difficulty using such cues due to degeneration in the right hemisphere (albeit less than in the left hemisphere) in PPA. Methods: Eighty-eight outpatients diagnosed with PPA received the Hopkins Auditory Comprehension with Context Assessment (HACCA), a recently developed instrument that systematically titrates both acoustic (prosody) and visual (speaker image) cues in a four-item forced-choice sentence picture matching paradigm assessing comprehension. Patients were grouped based on the effects of cues on accuracy and were examined both by the PPA variant and individually. Results: There was a significant difference between performance classifications across the three cueing conditions as a function of PPA variant (p = 0.014). When individuals with distinct complementary profiles of performance across conditions were examined separately, a small number with logopenic PPA uniquely benefitted from the inclusion of video, while certain patients performed more poorly given any additional cues. HACCA performance across cueing conditions had a strong positive association with other concurrent measures of communication and cognition. Conclusions: Individual patterns of response to prosodic and visual cues provide important insights valuable in refining therapeutic approaches that target the retention of function and support a more robust understanding of the individual variability among patients with this uncommon neurodegenerative syndrome. Full article

The increasing and global distribution of microplastics and nanoplastics (MPs/NPs) in the environment has led to concern about their potential influence on human health, especially on the gastrointestinal tract, as well as the brain. MPs/NPs could traverse epithelial and endothelial barriers, disrupt the gut microbiota, and perturb the microbiota–gut–brain axis, leading to systemic inflammation and possibly extending neurodegenerative processes. Experimental models now demonstrate that MPs/NPs reprogram nuclear and mitochondrial epigenetics—DNA methylation, histone modifications, non-coding RNAs, and mitochondrial DNA regulation—in gut, immune, and neural cells with downstream effects on synaptic function, neuronal survival, and protein aggregation. This mechanistic narrative review integrates preclinical and emerging human evidence of how MPs/NPs compromise intestinal barrier integrity, modulate gut microbiota composition, affect the blood–brain barrier, and converge on oxidative stress, neuroinflammatory signaling, and cell death pathways within the central nervous system across key neurodegenerative diseases. Overall, the review offers an integrated model in which environmental exposure to chronic MPs/NPs disrupts the microbiota–gut–brain axis and drives concurrent nuclear and mitochondrial epigenetic remodeling, lowering the threshold for neurodegeneration in susceptible individuals, while outlining candidate mechanistic readouts that require exposure-specific validation in human-relevant models and longitudinal cohorts. Full article

Background/Objectives: The combination of chemotherapy and radiotherapy represents a standard adjuvant treatment for patients with high-risk endometrial cancer. However, limited access to radiotherapy in many healthcare systems frequently results in treatment delays, potentially compromising outcomes. The aim of this study was to evaluate the oncologic outcomes and toxicity profile of an inverted treatment sequence consisting of upfront chemotherapy followed by concurrent chemoradiotherapy. Methods: We conducted a retrospective single-center study including patients with non-metastatic high-risk endometrial cancer. Eligible patients had FIGO stage I grade 3 disease with lymphovascular space invasion, stage II–III disease, or non-endometrioid histology. All patients received four cycles of paclitaxel–carboplatin followed by pelvic radiotherapy with concurrent cisplatin. Survival outcomes, including local recurrence-free survival, disease-free survival, metastasis-free survival, and overall survival, were analyzed using the Kaplan–Meier method and Cox proportional hazards models. Acute hematologic toxicity was graded according to CTCAE v5.0. Bone marrow dose–volume parameters were evaluated, and receiver operating characteristic curve analysis was performed to identify thresholds associated with grade ≥ 2 hematologic toxicity. Results: Fifty-two patients were included, with a median follow-up of 31.4 months. Five-year overall survival and disease-free survival rates were 86.1% and 77.5%, respectively. Ten patients relapsed, with distant metastases observed in all cases and synchronous local recurrence in one. Delays between surgery and radiotherapy of 20 weeks or more, as well as delays exceeding 10 weeks before initiation of chemotherapy, were associated with significantly reduced disease-free survival. Grade ≥ 2 hematologic toxicity was frequent, and neutropenia was associated with inferior overall survival. Bone marrow dose–volume thresholds predictive of hematologic toxicity included V40 Gy < 20–25% and V30 Gy < 40%. Conclusions: A chemotherapy-first adjuvant strategy provides favorable oncologic outcomes and excellent locoregional control in high-risk endometrial cancer when radiotherapy is delayed. However, increased hematologic toxicity highlights the importance of optimized bone marrow sparing. Full article

Pseudorabies virus (PRV), an alphaherpesvirus, causes severe neurological and respiratory diseases in multiple mammalian species and poses an emerging threat to public health. Increasing evidence suggests that virus-induced inflammatory cell death plays a pivotal role in shaping host immune responses and disease outcomes. PANoptosis, a newly defined inflammatory programmed cell death pathway integrating pyroptosis, apoptosis, and necroptosis, has been implicated in host defense against diverse pathogens. However, whether PRV infection induces PANoptosis and contributes to inflammatory pathology remains largely unexplored. In this study, we demonstrate that PRV efficiently replicates in Human Acute Monocytic Leukemia Cells (THP-1)-derived macrophages and robustly induces PANoptosis, characterized by the concurrent activation of Gasdermin D, caspase-3, and Mixed Lineage Kinase Domain-Like (MLKL). Pharmacological inhibition of PANoptosis markedly attenuated PRV-induced inflammatory cytokine production in vitro. Furthermore, intranasal inoculation of PRV in Balb/c mice resulted in productive lung infection accompanied by pronounced pulmonary inflammation. Lung tissues from PRV-challenged mice exhibited molecular and histopathological hallmarks of PANoptosis. Importantly, drug-mediated suppression of PANoptosis significantly reduced lung inflammation and inflammatory cytokine expression in vivo. Collectively, our findings identify PANoptosis as a critical mechanism underlying PRV-induced inflammatory responses and suggest that targeting PANoptosis may represent a promising therapeutic strategy for PRV-associated inflammatory diseases. Full article

The evolving tumor microenvironment (TME) plays a critical role in breast cancer tumorigenesis, growth, and metastatic potential. This study focuses on two key components of the TME: tumor-associated neutrophils (TANs) and the desmoplastic reaction (DR). We will analyze their multifaceted functions, emphasizing the significant mutual relationships among them, which dramatically affect disease outcomes and the effectiveness of treatments. TANs can either suppress or promote tumors, demonstrating notable functional flexibility in response to signals from their immediate environment. Concurrently, the proliferation of myofibroblasts and the extensive deposition of extracellular matrix (ECM), which characterize the DR, substantially alter the tumor’s physical properties, increasing its stiffness. This increased stiffness significantly obstructs immune system cells from accessing the tumor, ultimately limiting the effectiveness of therapies and contributing to a more clinically aggressive tumor behavior. A comprehensive understanding of the interactions among TANs, the desmoplastic stroma, and other elements of the TME is critical for developing new predictive biomarkers and establishing more effective targeted therapies. Full article

Zinc homeostasis is fundamental to metabolic health, orchestrated by the coordinated actions of two major zinc transporter families: ZIP (Zrt- and Irt-like proteins) and ZnT (zinc transporters). ZIP transporters facilitate zinc influx into the cytosol from the extracellular space or from the lumen of intracellular organelles, whereas ZnT transporters control zinc efflux from the cytosol to the extracellular space or facilitate its sequestration into intracellular vesicles and organelles, concurrently harboring the meticulous intracellular zinc homeostasis. This equilibrium is essential for all critical functions like cellular response, metabolic control, and immune pathway alteration. Disruption of this homeostasis is a driver of different pathological alterations like metabolic inflammation, a chronic low-grade inflammatory state underlying obesity; type 2 diabetes; and nonalcoholic fatty liver disease. Recent studies revealed that ZIP and ZnT transporters dynamically regulate metabolic and inflammatory cues, with their tissue-specific expression varying by tissue and acclimating to different physiological and pathological conditions. Recent advanced research in molecular and genetic understanding has helped to deepen our knowledge of the interplay of activity between ZIP and ZnT transporters and their crosstalk in metabolic tissues, underscoring the potential therapeutic prospect for restoring zinc balance and ameliorating metabolic inflammation. This review provides a comprehensive overview that covers the function, regulation, and interactive crosstalk of ZIP and ZnT zinc transporters in metabolic tissues and their pathological conditions. Full article

This study aimed to identify metabolomic biomarkers for diabetes progression and validate their response to lifestyle intervention. A two-phase design was employed: first, untargeted metabolomics distinguished normoglycemic, prediabetic (PDM), and diabetic (DM) individuals, identifying 1,5-anhydroglucitol (1,5-AG) as the most significant biomarker for differentiating PDM from DM (apparent AUC = 0.97, 95% CI: 0.95–1.00; corrected AUC = 0.94, 95% CI: 0.83–1.00; q < 0.001). Second, in a 3-month randomized controlled trial involving 300 adults with PDM, the combined diet and exercise intervention significantly improved fasting blood glucose and glycated hemoglobin levels, while concurrently elevating serum 1,5-AG levels compared with the control group, though it did not yield significant improvements in other cardiovascular disease-related risk factors including body mass index, waist circumference, systolic blood pressure, and diastolic blood pressure. The intervention also showed a trend toward reduced diabetes incidence. Integrated analysis establishes 1,5-AG as a sensitive biomarker of dysglycemia that is responsive to lifestyle modification, supporting its potential as a mechanistic tool for monitoring intervention efficacy in diabetes prevention. Full article

Background/Objectives: Nutraceuticals, including short-chain fatty acids (SCFAs) and antioxidants (AOXs), are nutrient-derived bioactive compounds considered as potential treatments for metabolic-associated steatotic liver disease (MASLD). However, in vitro studies of their effects are limited by inconsistent experimental conditions, including differences in cell lines, methods of steatosis induction, and culture media, and by reliance on qualitative rather than quantitative assessments. Here, we systematically evaluate the anti-steatotic potential of eight commonly used nutraceuticals—three SCFAs (butyrate, acetate, and propionate) and five AOXs (resveratrol, curcumin, berberine, chlorogenic acid, and vitamin E)—using a standardized in vitro approach. Methods: Following a systematic literature review to identify common experimental conditions, we developed an assay to validate steatosis induction and quantified the effects of the nutraceuticals. For our studies we used the HepG2 liver cancer cell line and the Fa2N-4 immortalized hepatocyte cell line. Steatosis was modeled by stimulating cells with free fatty acids and fructose for 48 h. Nutraceuticals were added either concurrently with steatotic stimulation, to assess preventive effects, or after 24 h to assess therapeutic effects. Anti-steatotic drugs (resmetirom, semaglutide, obeticholic acid, and a DGAT2 inhibitor) were included as positive controls. Intracellular triglyceride levels were measured to quantify steatosis. Results: A systematic review of 46 studies revealed large differences in culture conditions, steatosis induction, and nutraceutical assessment. In our experiments, most nutraceuticals did not reduce intracellular triglycerides, with the exception of vitamin E. Surprisingly, butyrate, berberine, and curcumin increased triglyceride accumulation. Resmetirom was the only drug that significantly decreased triglycerides, while obeticholic acid, semaglutide, and the DGAT2 inhibitor showed minimal or inconsistent effects. Fa2N-4 cells were generally more sensitive than HepG2 cells, showing larger absolute changes in triglyceride levels in response to both nutraceuticals and resmetirom. Conclusions: We established a standardized in vitro assay to evaluate the anti-steatotic potential of nutraceuticals. Using this system, we found that SCFAs and AOXs did not consistently reduce intracellular triglycerides, highlighting the need for quantitative assessments and careful validation when studying anti-steatotic interventions in vitro. Full article

Cocoa production in West Africa supplies most of the global demand but is increasingly constrained by yield stagnation, soil degradation, disease pressure, and climate variability. This review examines how integrating regenerative agriculture (RA) with unmanned aerial systems (UAS) and artificial intelligence (AI) can support more precise and resilient cocoa management across heterogeneous smallholder landscapes. A PRISMA-guided systematic review of peer-reviewed literature published between 2000 and 2024 was conducted, yielding 49 core studies analyzed alongside supporting evidence. The synthesis evaluates regenerative agronomic outcomes, UAV-derived multispectral, thermal, and structural diagnostics, and AI-based analytical approaches for stress detection, yield estimation, and management zoning. Results indicate that regenerative practices consistently improve soil health and yield stability, while UAS data enhance spatial targeting of rehabilitation, shade management, and stress interventions. AI models further improve predictive capacity and decision relevance when aligned with data availability and institutional context, although performance varies across systems. Reported yield stabilization or improvement typically ranges from 12–30% under integrated approaches, with concurrent reductions in fertilizer and water inputs where spatial targeting is applied. The review concludes that effective scaling of RA–UAS–AI systems depends less on technical sophistication than on governance arrangements, extension integration, and cooperative service models, positioning these tools as enabling components rather than standalone solutions for sustainable cocoa intensification. Full article