The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.

AIMS:Oxidised lipoproteins-including oxidised high-density lipoprotein cholesterol (ox-HDL-C), oxidised low-density lipoprotein cholesterol (ox-LDL-C) and oxidised lipoprotein(a) [ox-Lp(a)]-are emerging biomarkers of oxidative stress and vascular inflammation. However, their roles in glycometabolic disorders and the progression from prediabetes to type 2 diabetes mellitus (T2DM) remain poorly defined. To prospectively assess the associations between plasma ox-HDL-C, ox-LDL-C and ox-Lp(a) levels and the future risk of T2DM among individuals with prediabetes. MATERIALS AND METHODS:This multi-centre, prospective cohort study enrolled 3056 participants, including 1521 individuals with prediabetes who were followed for 5 years. Baseline levels of ox-HDL-C, ox-LDL-C and ox-Lp(a) were quantified using ELISA. Glycaemic indices, insulin resistance markers and β-cell function were assessed. Associations with incident T2DM were evaluated using logistic regression, Cox proportional hazards models and restricted cubic spline analyses. RESULTS:Elevated baseline levels of ox-HDL-C, ox-LDL-C and ox-Lp(a) were independently associated with increased odds and hazard ratios for progression from prediabetes to T2DM. These associations were dose-dependent and remained significant across sex-specific subgroups. Additionally, oxidised lipoproteins correlated positively with FBG, HbA1c and HOMA-IR, and negatively with HOMA-β and HOMA-IS, suggesting a relationship with β-cell dysfunction and insulin resistance. CONCLUSIONS:Ox-HDL-C, ox-LDL-C and ox-Lp(a) are independent, dose-dependent predictors of T2DM development in individuals with prediabetes. Their close association with impaired β-cell function highlights their potential utility in early risk stratification and targeted prevention strategies for T2DM.

The global burden and serious outcomes of coronary heart disease (CHD) highlight the need for further comprehensive research. This study explored the predictive value of glycated apolipoprotein A-1 (G-apoA1) and glycated low-density lipoprotein cholesterol (G-LDL-C) levels for coronary artery obstruction severity and future major adverse cardiovascular events (MACEs) among patients with type 2 diabetes mellitus (T2DM). This study included 3,292 patients with T2DM who were followed up for 5 years. Patients were stratified into quartiles of G-apoA1 and G-LDL-C, and associations with the incidence of MACEs were assessed by comparing quartile groups. Logistic regression and Spearman's correlation analyses were conducted to evaluate the associations of G‑apoA1 and G‑LDL‑C with CHD risk, while Cox regression was used to estimate the risk of MACEs. G-apoA1 and G-LDL-C levels were significantly higher in patients with T2DM and CHD than in those with T2DM without CHD and were identified as independent risk factors for CHD [G-apoA1: odds ratio (OR) = 2.021, 95%CI: 1.622-2.519, p < 0.001; G-LDL-C: OR = 2.038, 95%CI: 1.616-2.570, p < 0.001]. These levels were also positively correlated with the number of obstructed coronary arteries and the Gensini score (GS). During the 5-year follow-up period, 443 patients experienced MACEs. An analysis using restricted cubic spline models revealed that the incidence of MACEs increased with higher G-apoA1 and G-LDL-C levels. Multivariate Cox regression analysis showed a significantly higher risk of MACEs among patients in the highest quartile than among those in the lowest quartile [G-apoA1: hazard ratio (HR):2.183, 95%CI: 1.630-2.923, p < 0.001; G-LDL-C: HR:2.798, 95%CI: 2.053-3.812, p < 0.001]. This study showed that G-apoA1 and G-LDL-C levels were associated with CHD in patients with T2DM and correlated with the severity of coronary obstruction. Moreover, higher G-apoA1 and G-LDL-C levels were associated with an increased incidence of MACEs.

The synthesis of complex, highly oxidized terpenes remains a central challenge, particularly when oxidation state dictates skeletal architecture. We establish a programmed oxidation strategy that prioritizes oxygen installation by its role in skeletal construction. This logic enabled the first total syntheses of neoanisatin (20 steps), majusanol A (18 steps), and majusanol B (19 steps), and delivered a significantly shorter route to anisatin (20 steps vs prior 40- and 43-step syntheses). Our work provides a generalizable design principle for the efficient and divergent synthesis of skeletally diverse, densely oxidized molecules.

Objective:This meta-analysis and trial sequential analysis (TSA) aimed to evaluate the effects of probiotics on lipid metabolism, oxidative stress, and inflammation in patients with coronary heart disease (CHD). Methods:Six databases were systematically searched for relevant studies published before May 1, 2025. Basic study characteristics, outcome data, and risk of bias were extracted. Meta-analyses were performed using RevMan 5.3, TSA was conducted using TSA 0.9.5.10 beta, and publication bias was assessed using Egger's test. Results:Eight randomized controlled trials involving 296 patients were included. Compared with the placebo, probiotics significantly reduced the low-density lipoprotein cholesterol (LDL-C) [mean difference (MD) -11.07 mg/dL, 95% confidence interval (CI) -19.94 to -2.20], malondialdehyde [standardized mean difference (SMD) -0.57, 95% CI -1.01 to -0.13], high-sensitivity C-reactive protein (MD -0.81 ng/mL, 95% CI -1.31 to -0.30), Toll-like receptor 4 (MD -4.13 ng/mL, 95% CI -5.39 to -2.88), and interleukin-6 (MD -3.22 ng/mL, 95% CI -4.01 to -2.44). Meanwhile, they increased the high-density lipoprotein cholesterol (HDL-C) (MD 2.79 mg/dL, 95% CI 0.95 to 4.63), glutathione (MD 104.66 μmol/L, 95% CI 53.74 to 155.58), and total antioxidant capacity (MD 69.51 mmol/L, 95% CI 44.64 to 94.38). However, the effects on LDL-C and HDL-C were not robust in sensitivity analyses, and neither outcome reached the minimal clinically important difference, indicating that lipid modulation is not clinically meaningful. Additionally, no significant differences were observed in very low-density lipoprotein cholesterol, total cholesterol, triglycerides, tumor necrosis factor-alpha and adverse event rate. TSA confirmed the robustness of all significant outcomes except for malondialdehyde, and Egger's tests revealed no significant publication bias. Conclusion:Probiotics exert moderate anti-inflammatory and antioxidative effects, supporting their potential as an complementary strategy for CHD. In contrast, their influence on lipid metabolism appears uncertain and clinically negligible. Given the limited certainty of evidence and the geographic concentration of available trials, high-quality multicenter studies are required to confirm these findings.

BACKGROUND:With the rapid development of artificial intelligence technology, generative artificial intelligence content (AIGC) is increasingly widely applied in the field of medical education. Large language models (LLMs), such as ChatGPT, are a prominent type of AIGC technology. Critical thinking is a core ability in medical education, but the impact of AIGC technology on the critical thinking ability of medical students remains unclear. Medical students are at a crucial stage in cultivating critical thinking, and the intervention of AIGC technology may have a profound impact on this process. OBJECTIVE:This study aims to systematically review the impact of AIGC technology on the complex mechanisms affecting medical students' critical thinking abilities and to build a corresponding strategic framework. The findings are intended to provide theoretical support and practical guidance for applying AIGC in medical education. METHODS:This study followed 2020 PRISMA guidelines, retrieval scope limited to November 2022 to June 2025 published in the English literature. Through the PubMed database, combined with the search methods of subject terms and free words, relevant studies involving the impact of AIGC on the critical thinking of medical students were screened out around keywords such as "AIGC", "medical students", and "critical thinking". Two independent reviewers screened and evaluated the literature, and ultimately conducted qualitative analysis based on the common themes extracted from the literature. RESULTS:AIGC technology in medical education is two-fold. On the one hand, AIGC's powerful information capabilities provide abundant learning resources and efficient tools. This accelerates knowledge acquisition and broadens learning scope. On the other hand, over-reliance on AIGC may lead to mental inertia, weaken critical thinking skills, and cause academic integrity issues among students.Research has found that strategies such as customized AIGC tools, virtual standardized patients, new models of resource integration, and proactive assessment of AI limitations can effectively make up for the deficiencies of AIGC in cultivating high-level critical thinking, helping medical students maintain and enhance their critical thinking and problem-solving abilities. CONCLUSIONS:AIGC technology application in the medical education needs to carefully weigh the pros and cons. By optimizing the design and usage of AIGC tools and combining them with the guidance and supervision of educators, they can be transformed into powerful tools for promoting the development of critical thinking among medical students. Future research should further expand the scope of study, optimize research methods, pay attention to individual differences, track long-term effects, and deeply explore the influence of ethical and cultural factors to more comprehensively assess the application potential and challenges of AIGC technology in medical education.

The glymphatic system is a critical waste clearance system in the brain, playing an essential role in maintaining homeostasis within the central nervous system. Aquaporin 4 (AQP4), an indispensable component of the glymphatic system, is vital for ensuring the proper function of this system. Melatonin has been proven to be protective in treating hypoxic-ischemic encephalopathy (HIE). The aim of this study was to examine if alterations occur in the glymphatic system function in the brain of HIE model rats, and to determine whether melatonin can enhance the function of the glymphatic system by regulating AQP4, along with elucidating the mechanisms underlying melatonin's effects on AQP4. 10-day-old rat pups were subjected to hypoxic-ischemic (HI) injury; melatonin and roscovitine (an inhibitor of cyclin-dependent kinase 5) were injected intraperitoneally at 10 min following HI induction. At 24 h post-HI, intracisternal tracer infusion, neurobehavioral tests, immunofluorescence staining, western blot analysis, Evans blue (EB) permeability assay, brain water content test, ELISA detection, and co-immunoprecipitation tests were performed. At 28 days post-HI, neurobehavioral tests, intracisternal EB infusion, Nissl staining, and cerebral blood flow (CBF) evaluations were performed. The results showed that melatonin improved neurological function, restored glymphatic function, maintained blood-brain barrier integrity, alleviated brain edema, increased CBF, and reduced brain atrophy; both melatonin and roscovitine inhibited cyclin-dependent kinase 5 (CDK5) activity, enhanced the interaction between AQP4 and alpha-syntrophin (α-Syn), and maintained AQP4 polarity. In conclusion, the current study suggests that melatonin may enhance the interaction between AQP4 and α-Syn by inhibiting CDK5 activity after HI to maintain glymphatic function.

OBJECTIVES:To report a rare pediatric case of ectopic paragonimiasis presenting as isolated massive pericardial effusion and to emphasize key diagnostic clues for early recognition in endemic regions. DESIGN OR METHODS:We describe a 10-year-old boy from an endemic area in China who presented with acute gastrointestinal symptoms and recurrent massive pericardial effusion without respiratory manifestations. Diagnostic evaluation included pericardial fluid analysis, microbiological testing, echocardiography, cardiac magnetic resonance imaging(MRI), serological testing for Paragonimus IgG, therapeutic response assessment, and histopathological examination following surgery. RESULTS:Despite repeated pericardiocenteses and empirical anti-infective therapy, the effusion persisted. Laboratory testing revealed exudative pericardial fluid with negative cytology, acid-fast staining, and metagenomic next-generation sequencing(mNGS), while peripheral eosinophilia and stool ova were absent. Echocardiography showed a characteristic "cocoon-like" pericardial pattern, and serology was positive for Paragonimus IgG.The patient improved after praziquantel and corticosteroids, but progressive pericardial thickening required pericardiectomy, which confirmed necrotizing granulomatous inflammation. The patient recovered with no recurrence during follow-up. CONCLUSION:Paragonimiasis should be considered in children from endemic areas with unexplained or recurrent pericardial effusion, even in the absence of pulmonary involvement or eosinophilia. Epidemiological exposure, characteristic echocardiographic findings, and serology are critical for diagnosis, and timely anti-parasitic therapy with surgical intervention when necessary may prevent constrictive pericarditis.

Mast cells (MCs) degranulation is responsible for the occurrence and development of neuroinflammation after hypoxic-ischemic encephalopathy (HIE). Stromal interaction molecule 1 (STIM1) serves as a Ca2+ sensor on the endoplasmic reticulum. It has been demonstrated that the supression of STIM1 impedes degranulation of MCs in numerous prior investigations. This study aimed to explore the impact of edaravone, an oxygen radical scavenger, on MCs degranulation in HIE rat model, and to explore the contribution of reactive oxygen species (ROS)/STIM1 pathway in mediating MCs degranulation. Nine-day old undetermined gender rat pups were experienced hypoxic-ischemic (HI) injury and edaravone was administered intraperitoneally at 10 min after HI insults. CM4620, an inhibitor of STIM1, was administered intraperitoneally at 10 min after HI insults to elucidate the possible mechanisms. TTC staining, Western blot analysis, immunofluorescence staining, brain water content, cerebral blood flow, toluidine blue staining, Nissl staining, and neurobehavioral test were conducted. The results demonstrated that tryptase, STIM1, tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) were increased after HI, and edaravone significantly improved neurobehavioral outcomes, reduced brain water content, decreased infarct area, reduced the accumulation of ROS, decreased the degranulation of MCs, and downregulated the protein expression of tryptase, STIM1, IL-6 and TNF-α. CM4620 inhibited MCs degranulation and downregulated the expression of STIM1, tryptase, IL-6, TNF-α. In conclusion, the current investigation revealed that edaravone attenuates MCs degranulation and neuroinflammation, at least partially, via ROS/STIM1 pathway after HI injury.

BACKGROUND:Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis, as chemotherapy resistance leads to relapse in many patients. Carboplatin addition improves treatment response, but challenges persist. METHODS:To identify novel targets for TNBC, we analyzed differentially expressed proteins in patients treated with neoadjuvant chemotherapy. Cell viability was assessed using CCK-8 and colony formation assays. In vivo effects were studied in an orthotopic xenograft model using THEM6 overexpression cells. ROS, iron levels, MDA, and mitochondrial ultrastructure were assessed. Protein expression was analyzed by Western blotting and RT-PCR, and FDFT1 ubiquitination was evaluated. RESULTS:We identified THEM6 (co-downregulated) and PGRMC1 (co-upregulated) as survival-associated proteins. THEM6 overexpression enhanced carboplatin sensitivity in vitro and in vivo, reducing tumor weight and volume. THEM6-induced sensitivity was linked to ferroptosis, as the ferroptosis inhibitor Fer-1 reversed the effect, while apoptosis, necrosis, and autophagy inhibitors had no impact. THEM6 overexpression reduced GPX4 and SLC7A11, while increasing ACSL4. TEM revealed mitochondrial damage, and iron, MDA, and ROS levels were elevated in treated cells. Mechanistically, THEM6 stabilized FDFT1 by inhibiting its K48-linked ubiquitination, prolonging its protein half-life, and promoting ferroptosis. FDFT1 knockdown reversed THEM6-induced sensitivity to carboplatin. CONCLUSIONS:Our findings suggest that THEM6 enhances carboplatin sensitivity in TNBC by promoting ferroptosis through regulation of FDFT1. THEM6 may serve as a novel therapeutic target to improve TNBC treatment outcomes.

Background:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis. Methods:Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 (CSRNP1) expression levels in HCC cell lines were assessed via western blot (WB) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of CSRNP1 knockdown or overexpression on cell proliferation, migration, and apoptosis were evaluated using cell counting-8 (CCK-8) assays, Transwell assays, and flow cytometry. Mitochondrial ultrastructure was examined by transmission electron microscopy, and intracellular and mitochondrial reactive oxygen species (mROS) levels were measured using specific fluorescent probes. WB was used to assess activation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and pathway dependence was examined using the ROS scavenger N-Acetylcysteine (NAC) and the JNK inhibitor SP600125. Results:A six-gene prognostic model was established, comprising downregulated genes (NR4A1 and CSRNP1) and upregulated genes (CENPQ, YAE1, FANCF, and POC5) in HCC. Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis. Conversely, CSRNP1 overexpression impaired mitochondrial integrity, increased both mitochondrial and cytoplasmic ROS levels, and activated the JNK/p38 MAPK pathway. Notably, treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis. Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC. It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner. These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.

RATIONALE AND OBJECTIVE:To investigate the cerebral iron content and glymphatic function in newborns with HIE. METHODS:A total of 57 newborns with HIE, aged 1-28 days, were prospectively selected to constitute the HIE group. Meanwhile, 50 healthy newborns were selected as the control group. All the newborns underwent T1 Flair, T2 Flair, 3D-T1, ESWAN, and DTI sequence scans. Subsequently, software processing was performed to obtain the QSM values reflecting iron contents in brain regions and the DTI-ALPS values evaluating the function of glymphatic system. Comparative analysis of the QSM and DTI-ALPS values between the two groups were carried out to identify the characteristic parameters in the brain regions of newborns with HIE. ROC curve analysis was then utilized to detect the sensitivity of QSM value and DTI-ALPS index. RESULTS:In newborns with HIE, the QSM values in the frontal lobe, temporal lobe, and basal ganglia were significantly elevated (P < 0.05). the DTI-ALPS values were notably decreased (P < 0.05). The QSM values in different brain regions such as the frontal lobe, temporal lobe, and basal ganglia were respectively negative correlated with the DTI-ALPS value. The QSM values of the frontal lobe, temporal lobe and basal ganglia, in combination with the DTI-ALPS values, facilitated the discrimination of newborns with HIE from those in the control group (P < 0.05). CONCLUSION:In newborns with HIE, a significant increase in brain iron content was manifested, concomitant with a compromised glymphatic dysfunction. KEY POINTS AND CLINICAL RELEVANCE STATEMENT.

Bilirubin encephalopathy (BE) is a neurological disorder caused by the accumulation of unconjugated bilirubin (UCB) in the brain of newborns, resulting in various degrees of neuronal impairment. BE is characterized by cytotoxic edema and neuronal apoptosis. Aquaporin-4 (AQP4), a water channel abundantly expressed in the central nervous system, plays a critical role in maintaining water homeostasis. Dysregulation of AQP4 expression or trafficking is closely associated with brain edema, suggesting that modulation of AQP4 may offer a potential therapeutic approach for BE. Previous studies have indicated that melatonin (MT) possesses neuroprotective and therapeutic potential against BE; however, its precise mechanisms remain unclear. In this study, we optimized rat BE model to investigate the therapeutic effects of melatonin on AQP4 expression, trafficking, and apoptosis in parietal cortical neurons. Furthermore, we explored the molecular mechanisms underlying melatonin’s neuroprotective actions, including the regulation mechanism of AQP4 expression, brain edema formation, and apoptosis induced by UCB accumulation. The results indicate that in the BE model, pathological injury of parietal cortex was significantly aggravated and AQP4’s expression peaked at 24 h after BE modeling. MT activated PI3K/AKT signaling pathway in rat parietal cortex to downregulate AQP4 expression, apoptosis related proteins, and decreased SNX27’s expression to promote the internalization of AQP4, reducing bilirubin induced cytotoxic edema and cortical apoptosis. This data suggest that MT has a neuroprotective role in BE, by potentially delaying its progression.

Objective The diagnosis and prognosis of hepatocellular carcinoma (HCC) present significant challenges in clinical practice. This study aimed to evaluate the clinical utility of tumor abnormal protein (TAP), Prothrombin induced by vitamin K absence-II (PIVKA-II), and alpha-fetoprotein (AFP) in diagnosing HCC as well as to investigate their prognostic significance in patients with HCC undergoing transarterial chemoembolization.Methods A total of 93 HCC patients were enrolled and 101 healthy individuals served as controls. Fresh venous blood samples were collected, and TAP, PIVKA-II, and AFP levels were measured by chemiluminescence immunoassay.Results Significant differences in TAP, PIVKA-II, and AFP levels were found between HCC patients and healthy individuals. The combined assay of TAP, AFP, and PIVKA-II showed better diagnostic performance for HCC. Patients who underwent transarterial chemoembolization and achieved complete response (CR) had lower levels of prechemotherapy serum TAP, AFP, and PIVKA-II. There are significant differences in levels of TAP, AFP, and PIVKA-II between CR and partial response (PR), CR and stable disease (SD), and CR and progressive disease (PD).Conclusion Combined detection of TAP, PIVKA-II, and AFP has better diagnostic performance for HCC. Higher levels of prechemotherapy serum TAP, AFP, and PIVKA-II are significantly associated with poor clinical chemoresponse.

BACKGROUND:Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver ailment globally, remains a significant concern. Acupuncture has been increasingly utilized for the treatment of NAFLD in recent years. However, current evidence is insufficient to support its efficacy and safety. The aim of this study was to perform a recent and thorough meta-analysis concerning the impacts of acupuncture on NAFLD. METHODS:Randomized controlled trials (RCTs) investigating acupuncture for NAFLD were retrieved from 6 databases. The search encompassed the period from the inception of each database until February 28, 2024. We conducted literature screening based on predefined inclusion and exclusion criteria, resulting in the selection of 30 articles. Analysis of the data was carried out utilizing Review Manager 5.4 and Stata 15.1. RESULTS:The meta-analysis revealed a marked enhancement in the overall clinical effectiveness rate within the acupuncture group in comparison to the control group (OR = 3.36; 95% CI:2.62 to 4.31; P < .00001, I2 = 0%). Acupuncture exhibited positive impact on liver function recovery, blood lipid reduction, glucose regulation, improvement in insulin levels, antiliver fibrosis treatment, and imaging outcomes. Comprehensive analysis revealed that acupoint embedding (OR = 3.14; 95% CI: 2.113 to 4.62; P < .00001, I2 = 0%) demonstrated the most effective and stable therapeutic effect, followed by manual acupuncture (MA) (OR = 3.27; 95% CI: 2.19 to 4.90; P < .00001, I2 = 0%) and electroacupuncture (EA) (OR = 3.32; 95% CI: 1.69 to 6.52; P < .0005, I2 = 0%). In contrast, acupoint injection (AI) (OR = 5.74; 95% CI: 2.23 to 14.883; P < .0003, I2 = 0%) exhibited relatively modest effects, particularly in lipid reduction. No significant adverse reactions were observed with acupuncture treatments. CONCLUSION:Acupuncture has demonstrated safety and efficacy in the treatment of NAFLD, significantly improving hepatic function, lowering glucose and lipid levels, and mitigating liver fibrosis. Nevertheless, these findings necessitate validation through large-scale, rigorously designed randomized controlled trials.

Illicium sesquiterpenes are a large class of highly oxygenated and sterically congested sesquiterpenoids isolated from the genus Illicium. Illisimonin A stands out as one of the most structurally intricate members of this family, featuring a novel bridged tricyclo[5.2.1.01,5]decane carbon framework designated as the "illisimonane" skeleton. This core ring system is further embellished by additional bridging via a γ-lactone and a γ-lactol ring, resulting in a caged pentacyclic scaffold with a 5/5/5/5/5 ring arrangement. The compound demonstrates neuroprotective activity by mitigating oxygen-glucose deprivation-induced cell injury in SH-SY5Y cells. Since its isolation in 2017, illisimonin A has garnered significant interest from the synthetic chemistry community. To date, five research groups have accomplished the total synthesis of illisimonin A. This review offers a comprehensive overview of its isolation, proposed biosynthetic pathway and the synthetic strategies employed in its total synthesis.

Background: Activation of mast cells plays an important role in brain inflammation. CD300a, an inhibitory receptor located on mast cell surfaces, has been reported to reduce the production of pro-inflammatory cytokines and exert protective effects in inflammation-related diseases. Peroxisome proliferator-activated receptor beta/delta (PPAR(beta/delta)), a ligand-activated nuclear receptor, activation upregulates the transcription of CD300a. In this study, we aim to investigate the role of PPAR(beta/delta) in the attenuation of germinal matrix hemorrhage (GMH)-induced mast cell activation via CD300a/SHP1 pathway.Methods: GMH model was induced by intraparenchymal injection of bacterial collagenase into the right hemispheric ganglionic eminence in P7 Sprague Dawley rats. GW0742, a PPAR(beta/delta) agonist, was administered intranasally at 1 h post-ictus. CD300a small interfering RNA (siRNA) and PPAR(beta/delta) siRNA were injected intracerebroventricularly 5 days and 2 days before GMH induction. Behavioral tests, Western blot, immunofluorescence, Toluidine Blue staining, and Nissl staining were applied to assess post-GMH evaluation.Results: Results demonstrated that endogenous protein levels of PPAR(beta/delta) and CD300a were decreased, whereas chymase, tryptase, IL-17A and transforming growth factor beta 1 (TGF-beta 1) were elevated after GMH. GMH induced significant short- and long-term neurobehavioral deficits in rat pups. GW0742 decreased mast cell degranulation, improved neurological outcomes, and attenuated ventriculomegaly after GMH. Additionally, GW0742 increased expression of PPAR(beta/delta), CD300a and phosphorylation of SHP1, decreased phosphorylation of Syk, chymase, tryptase, IL-17A and TGF-beta 1 levels. PPAR(beta/delta) siRNA and CD300a siRNA abolished the beneficial effects of GW0742.Conclusions: GW0742 inhibited mast cell-induced inflammation and improved neurobehavior after GMH, which is mediated by PPAR(beta/delta)/CD300a/SHP1 pathway. GW0742 may serve as a potential treatment to reduce brain injury for GMH patients.