Zhenyan Song

Prostaglandin E2 (PGE₂) signalling influences amyloid-β (Aβ) processing, myeloid function, and neuronal injury in Alzheimer’s disease (AD). Although EP2 and EP4 share Gs–cyclic adenosine monophosphate (cAMP) signalling, their cellular effects differ. This review integrates genetic, pharmacological, ageing, and AD-model evidence to assess receptor-selective targeting. EP2 deletion enhances myeloid Aβ handling and reduces microglia-mediated neuronal injury in experimental systems, providing a rationale for selective EP2 inhibition. In aged mice, PGE₂–EP2 signalling redirects glucose towards glycogen storage and restricts myeloid mitochondrial respiration; benefits from a predominantly peripheral antagonist suggest that some age-related outcomes may improve without high brain exposure. Chronic antagonist studies in AD models, however, show variable effects on inflammation, amyloid burden, and behaviour. EP4 exhibits contrasting cell-dependent actions: activation supports microglial Aβ uptake and inflammatory control, whereas signalling in some amyloid precursor protein (APP)-expressing cells promotes APP internalisation and Aβ production. Human AD evidence remains mainly tissue-based; EP2 antagonist testing has involved healthy volunteers, not patients with AD. These findings indicate that receptor selectivity alone is insufficient to predict therapeutic outcomes. Further studies should combine cell-specific receptor manipulation, measurements of central and peripheral exposure, and separate assessments of Aβ production, clearance, tissue injury, and functional outcomes.

Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and chronic neuroinflammation. Increasing evidence suggests that the imbalance between pro-inflammatory Th17 cells and anti-inflammatory regulatory T (Treg) cells plays a critical role in AD pathogenesis. However, a comprehensive synthesis of how natural compounds modulate Th17/Treg balance in AD remains lacking. This review aims to summarize current preclinical evidence on Th17/Treg dysregulation and evaluate the immunomodulatory potential of natural compounds in AD. Methods: This review focuses on preclinical evidence derived from experimental AD models and related inflammatory models to evaluate how natural compounds modulate Th17/Treg balance, neuroinflammation, and cognitive function, with an emphasis on underlying molecular and immunometabolic mechanisms. Results: Th17/Treg imbalance contributes significantly to AD-associated neuroinflammation and disease progression. Representative natural compounds, including paeoniflorin, quercetin, and ganoderic acid A, have demonstrated the ability to rebalance Th17/Treg responses, suppress neuroinflammation, and improve neuronal survival in experimental models. These compounds are highlighted due to their relatively stronger evidence in AD-related models and more clearly defined immunomodulatory mechanisms. These effects are partially mediated through modulation of key signaling pathways and immunometabolic reprogramming. Conclusions: Targeting Th17/Treg balance with natural compounds represents a promising multi-target immunomodulatory strategy for AD. However, most current evidence is derived from preclinical or non-AD models, and clinical validation remains limited. Future studies should prioritize AD-specific models and translational research to evaluate therapeutic potential in humans.

Objective: This study investigates the therapeutic potential of Danggui Shaoyao San (DSS), a traditional Chinese herbal formula, focusing on its effects on Th17/Treg -associated immune regulation and the JAK2/STAT3 signaling pathway. Methods: Forty male Sprague-Dawley rats were randomly divided into five groups: control, AD model, low-dose DSS (12 g/kg/day, raw herbal materials), high-dose DSS (24 g/kg/day, raw herbal materials), and donepezil (0.5 mg/kg/day). AD models were established by intraperitoneal injection of D-galactose (100 mg/kg/day) for 8 consecutive weeks. Behavioral tests, flow cytometry, biochemical assays, histological analyses, qPCR, and Western blotting were used to evaluate DSS’s effects. Untargeted metabolomics profiled metabolic alterations, while network pharmacology and molecular docking were integrated to predict key targets and pathways. Results: DSS treatment significantly alleviated neuronal damage, suppressed neuroinflammation, and improved learning and memory deficits in AD rats. Moreover, DSS was associated with alterations in Th17- and Treg-related immune dysregulation both in the brain and periphery. Serum metabolomic identified disruptions lipid metabolism and amino acid metabolism pathways. Network pharmacology and experimental validation indicated that DSS exerts its anti-neuroinflammatory effects by inhibiting JAK2 and STAT3 phosphorylation, reducing their nuclear translocation, and consequently suppressing Th17 differentiation and pro-inflammatory cytokine production. Conclusion: DSS is a promising candidate for AD treatment, with neuroprotective and cognitive-enhancing properties mediated through immunomodulation and JAK2/STAT3 pathway inhibition.

Background Studies have shown that urinary AD7c-NTP levels are elevated in patients with Alzheimer Disease (AD) and mild cognitive impairment (MCI), suggesting its potential as a novel diagnostic biomarker. However, more comprehensive studies are still required to validate its diagnostic potential for AD and MCI. Methods We systematically reviewed studies reporting urinary AD7c-NTP concentrations in patients with Alzheimer Disease, mild cognitive impairment, and healthy controls. Twelve electronic databases were comprehensively searched for studies evaluating the diagnostic accuracy of urinary AD7c-NTP for detecting AD or MCI from their inception to November 7, 2024. The pooled sensitivity, specificity, and the diagnostic odds ratio were calculated using a hierarchical summary receiver operating characteristic model. Results In the comparative analysis of AD and the controls (26 studys, 4,237 participants), the pooled sensitivity was 0.87 (95%CI:0.84–0.90, I ² = 69.91, p < 0.1) and the pooled specificity was 0.87 (95%CI:0.84–0.89, I²=73.16, p < 0.1). In the comparative analysis of MCI and the controls (11 studys, 1,293 participants), the pooled sensitivity was 0.79 (95%CI:0.70–0.85, I²=80.00, p < 0.1) and the pooled specificity was 0.84 (95%CI:0.78–0.88, I²=64.41, p < 0.1). Conclusion Our study showed that urinary AD7c-NTP had good diagnostic value for Alzheimer Disease and mild cognitive impairment. However, analysis of studies related to mild cognitive impairment revealed model instability, suggesting the need for further research to identify factors that may influence urinary AD7c-NTP levels. (INPLASY registration number: INPLASY202530048).

Background: Mitochondrial oxidative damage in pancreatic β-cells is a key contributor to diabetes pathogenesis, particularly under hyperglycemic conditions. Polygonatum sibiricum polysaccharides (PSP) have demonstrated potential anti-diabetic effects; however, their precise mechanism, particularly through the AMPK-SIRT1 pathway, remains unclear.Methods: A diabetic zebrafish model was established by exposure to 2% glucose for 28 days. Zebrafish were divided into control, model, low-dose PSP (50 μg/mL), medium-dose PSP (100 μg/mL), high-dose PSP (200 μg/mL), and metformin groups. Behavioral, biochemical, and molecular analyses were performed to assess β-cell function, mitochondrial oxidative damage, and inflammation. Network pharmacology analysis was used to predict PSP targets, and molecular docking validated key protein interactions. Immunofluorescence and Western blotting (WB) were conducted to examine apoptosis-related protein expression.Results: Polygonatum sibiricum polysaccharides significantly improved zebrafish swimming behavior, reduced blood glucose and fructosamine levels, and enhanced ATP production (p < 0.01). Antioxidant enzyme activities (SOD, CAT) increased, while oxidative stress markers (MDA) and inflammatory cytokines (IL-1β, IL-6, TNF-α) decreased (p < 0.01). PSP treatment downregulated Cycs expression, alleviating mitochondrial damage. Moreover, PSP upregulated AMPK and SIRT1 expression (p < 0.01), along with downstream regulators PGC-1α and Nrf1/2 (p < 0.01), confirming AMPK-SIRT1 pathway activation. Network pharmacology identified 389 shared targets between PSP and diabetes-related pathways, implicating key mechanisms of inflammation, insulin resistance, and mitochondrial dysfunction. Molecular docking demonstrated strong PSP binding affinities to AMPK and SIRT1. Immunofluorescence and WB analyses showed reduced cleaved caspase-3 levels and apoptosis in pancreatic β-cells following PSP treatment (p < 0.01).Conclusion: Polygonatum sibiricum polysaccharides protects pancreatic β-cell function in diabetic zebrafish by mitigating mitochondrial oxidative stress and apoptosis via AMPK-SIRT1 pathway activation. Network pharmacology and molecular docking further highlight PSP’s potential as a multi-target therapeutic agent for diabetes.

Emerging contaminants refer to chemical substances that have not been widely regulated but possess the potential to cause adverse effects on both the environment and human health. Antibiotics, as emerging contaminants, pose significant threats to ecosystems and human health due to their widespread use and persistence in the environment. Levofloxacin, a broad-spectrum fluoroquinolone antibiotic, is commonly employed in the treatment of bacterial infections, and has been frequently detected in environmental matrices and freshwater systems. In this study, we assessed the effects of levofloxacin on hatchability, mortality rates, malformations, behavioral changes, and cardiac development in zebrafish embryos by exposing them to varying concentrations of levofloxacin (0, 0.5, 1, 2, 4, and 8 mM). Our results demonstrate that levofloxacin exposure significantly impaired the growth and development of zebrafish larvae, particularly at higher concentrations. Notable effects included reduced body length, abnormal yolk sac and swim bladder development, pericardial edema, prolonged distances between the sinus venosus and arteriolar bulb (SV-BA), and disruptions in heart rate. Quantitative PCR analysis further revealed that levofloxacin exposure significantly upregulated the expression of key cardiac development genes in zebrafish larvae, including nppa, myh6, cacna1ab, myl7, gata4, nkx2.5, tbx2b, and tbx5b. These findings indicate that levofloxacin exposure exerts significant toxic effects on both embryonic and larval growth as well as heart development and gene expression in zebrafish. This study provides critical insights into the potential ecological risks posed by levofloxacin along with other antibiotics while laying a foundation for further investigation into their toxicological mechanisms.