BACKGROUND:Tissue plasminogen activator (tPA)-induced cerebral hemorrhagic transformation (HT) after ischemic stroke limits its clinical use widely. Pachymic acid, a main active component of Poria cocos, mitigates brain ischemia/reperfusion injury, but its effect on tPA-induced HT is unclear. METHODS:A focal middle cerebral artery occlusion/reperfusion model was established and administered with tPA and pachymic acid. Infarct volume and neurological function were assessed at 24 h after reperfusion. Blood-brain barrier (BBB) damage was evaluated using Evans blue leakage, immunofluorescence, and Western blot. Pachymic acid and PI3K protein interaction was identified using molecular docking, molecular dynamics (MD) simulation, and surface plasmon resonance (SPR). RESULTS:Compared with the tPA group, pachymic acid dose-dependently improves neurological and motor functions, reduces infarct volume and hemorrhagic volume, and alleviates permeability and tight junction protein degradation of BBB after ischemic stroke, with the strongest effects observed at the highest dose. Molecular docking, MD simulation, and SPR results indicate that pachymic acid can directly bind to PI3K protein. Further experiments showed that the PI3K inhibitor LY294002 reversed pachymic acid's protective effects. CONCLUSIONS:This study demonstrated that pachymic acid protects the BBB by targeting PI3K to activate the PI3K/Akt signaling pathway, thereby alleviating tPA-induced HT after ischemic stroke.

BACKGROUND:Emerging evidence suggests that ferroptosis, triggered by iron overload, plays a significant role in the resultant brain damage following intracerebral hemorrhage (ICH). Tetramethylpyrazine (TMP) is an alkylpyrazine bicyclic heterocyclic compound and a potent volatile aroma compound found in fermented foods, vinegar, cocoa, and traditional Chinese medicine. It has been extensively employed in the management of ICH; however, its precise mechanism of action remains to be elucidated. PURPOSE:Current work aims to clarify the effects of TMP on neuronal ferritinophagy and ferroptosis in ICH. METHODS:Collagenase VII was used to perform stereotactic injections into the brain of C57BL/6 mice to establish an ICH model. The therapeutic efficacy of TMP in mice with ICH was assessed using behavioral tests and hemorrhage volume measurement. The effect of TMP on neuronal ferroptosis and ferritinophagy following ICH was examined using in vivo and in vitro models. RESULTS:TMP significantly enhanced neurological functions and reduced hemorrhagic volume following ICH. It downregulated ferritinophagy markers, including nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein light chain 3 (LC3), while upregulating Sequestosome-1 (P62) and ferritin levels. Concurrently, TMP decreased malondialdehyde (MDA) and reactive oxygen species (ROS) levels and increased the expression of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), indicating a potent anti-ferroptotic effect. CONCLUSION:TMP protects neurons against ferroptosis after ICH by inhibiting NCOA4-mediated ferritinophagy, an effect associated with activation of the PI3K/AKT pathway. These findings identify the natural product TMP as a promising candidate for ICH therapy and reveal novel mechanistic insights into the autophagy-ferroptosis axis.

OBJECTIVES:The emerging triglyceride-glucose (TyG) related index has attracted attention as a promising predictor of various cardiometabolic conditions. However, their prospective association with different stages of cardiovascular-renal metabolic (CKM) syndrome is still not fully established, and it remains unclear whether TyG related parameters have prognostic effects on mortality outcomes of CKM syndrome. METHODS:The data were derived from the China Health and Retirement Longitudinal Study (CHARLS), and which were determined by the use of a standardised questionnaire during follow-up. TyG and its related parameters (TyG-body mass index, TyG-waist circumference, TyG-waist to height ratio, and TyG-a body shape index (TyG-ABSI) were calculated. Multivariate Cox regression analysis was used to analyze hazard ratios (HRs) and 95% confidence intervals (CI), and Kaplan-Meier survival curve was used to analyze the associations of TyG-ABSI with all-cause mortality and cardiovascular mortality in patients with CKM syndrome. Additionally, the multivariate adjusted restricted cubic spine was employed to examine the dose-response relationship. Mediation analysis was conducted to assess whether white blood cell (WBC) and C-reactive protein (CRP) mediated the associations. Subgroup analyses and interaction tests were conducted to evaluate the risk within various demographics. The National Health and Nutrition Examination Survey (NHANES) was used as validation to improve the reliability of the study results. RESULTS:The study enrolled 11,235 participants with CKM syndrome from the CHARLS database, during the median follow-up of 5 years, a total of 747 (6.65%) all-cause mortality and 84 (0.75) cardiovascular mortality occurred. TyG-ABSI was associated with CKM syndrome (OR 1.55; 95% CI 1.35-1.79). Furthermore, among patients with CKM syndrome, TyG-ABSI was association with all-cause mortality (HR 1.14; 95% CI 1.04-1.35). In which continuous TyG-ABSI were converted to classified variable (tertile), compared to those with T1 group, the risk of advanced CKM syndrome was found to be 2.41-fold higher in those with T3 group (OR 2.41; 95% CI 1.18-3.20). Additionally, individuals in the T3 group had a 55% increased risk of all-cause mortality (HR 1.55; 95% CI 1.10-2.18). The mediation analysis results suggested that the relationship between TyG-ABSI and all-cause mortality risk is partially mediated by WBC, and CRP, the proportion of mediation were 15.16% and 11.83%. Additionally, analyses of 15,054 participants from the NHANES database indicated a significant positive association between TyG-ABSI and all-cause mortality and cardiovascular mortality among individuals diagnosed with CKM syndrome during the 10 years follow-up. CONCLUSION:Higher TyG-ABSI is associated with an increased risk of advanced CKM syndrome and mortality. It further emphasizes the role of TyG-ABSI in the management of CKM syndrome stages and the risk of all-cause mortality and cardiovascular mortality.

Family income to poverty ratio (PIR) may have independent effects on diet and lifestyle factors and the development of prediabetes and diabetes, as well as on mortality. It is unclear how the protective effect of a healthy lifestyle against death differs between individuals with different glucose metabolic profiles and whether PIR mediates this effect. This study aimed to explore whether healthy lifestyle and family PIR reduced the risk of all-cause mortality in participants with different metabolic status and the mediating role of PIR. In total, 21,411 participants from the 2001–2018 National Health and Nutrition Examination Survey (NHANES) and follow-up until 2019 were included. The weighted healthy lifestyle score was constructed based on smoking, alcohol consumption, physical activity, diet (HEI-2015), and body mass index. Generalized linear regression models were used to analyze the association between healthy lifestyle, PIR, and all-cause mortality. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95

Ischemic stroke, characterized by cerebral blood flow disruption, triggers complex pathophysiological responses where neuronal autophagy plays a bidirectional regulation role in neuroprotection and injury. Autophagy, activated by energy deprivation, hypoxia, and endoplasmic reticulum stress, dynamically regulates neuronal survival through selective autophagy (e.g., mitophagy, endoplasmic reticulum-phagy, ferritinophagy) of damaged organelles and protein aggregates. Early-stage moderate autophagy exerts neuroprotection by clearing cytotoxic aggregates and maintaining metabolic homeostasis, while excessive or prolonged autophagy exacerbates neuronal death via energy depletion and activation of apoptosis/ferroptosis pathways. Key regulatory mechanisms involve AMPK/mTOR, PI3K/AKT, HIF-1, and MAPK signaling, which modulate autophagic flux and crosstalk with oxidative stress, inflammation, and mitochondrial dynamics. Notably, selective autophagy pathways exhibit spatiotemporal specificity: mitophagy via PINK1/Parkin and BNIP3/FUNDC1 balances mitochondrial quality control, while ferritinophagy-mediated iron dysregulation drives ferroptosis. Pharmacological interventions targeting autophagy-related pathways (e.g., rapamycin, 3-MA, NCOA4 inhibitors) or natural compounds (e.g., Ginkgolide B, HSYA) demonstrate therapeutic potential by fine-tuning autophagic activity. However, challenges remain in defining optimal autophagy thresholds and translating preclinical findings to clinical applications. This review highlights the critical importance of spatiotemporal regulation of neuronal autophagy to develop precise neuroprotective strategies for ischemic stroke, with a particular focus on the interaction between autophagy modulators and the pathophysiological mechanisms of ischemia.

BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal damage, with poor prognosis and limited therapeutic options. Inhibition of neuronal ferroptosis has shown promise as a potential treatment for AD. Schisandrin B (Sch B), a major active component of Schisandra chinensis, exhibits potential neuroprotective effects. However, whether Sch B inhibits neuronal ferroptosis remains unclear. PURPOSE:To investigate the mechanisms underlying the effects of Sch B on the GSK3β/Nrf2/GPX4 and FSP1 signaling pathways, which are the suppression of neuronal ferroptosis and the potential therapeutic intervention in AD. METHODS:We employed the 3 × Tg mouse model in vivo, and utilized the erastin-induced ferroptosis model in SH-SY5Y/APP695swe cells in vitro. Nissl staining was conducted to facilitate histopathological assessment. Assessment of neuronal ferroptosis was performed utilizing a lipid peroxidation and ferroptosis marker assay kit. Furthermore, bioinformatic analysis was executed with the application of the GEO database. Immunofluorescence and Western blot analyses were performed to quantify protein expression levels within the cellular context. ELISA was utilized to determine cytokine concentrations within the supernatant of cell cultures. RT-PCR was executed to evaluate mRNA expression levels. RESULTS:Sch B suppresses the activation of GSK3β, modulating the Nrf2/GPX4 signaling pathway and consequently inhibiting ferroptosis in neurons, which results in amelioration of cognitive impairment and pathological damage in 3 × Tg mice. Sch B also inhibits GSK3β activation, thereby modulating the Nrf2/GPX4 signaling pathway to prevent erastin-induced ferroptosis in SH-SY5Y695swe cells in vitro. Furthermore, Sch B modulates FSP1, enhancing its synergistic interaction with the GSK3β/Nrf2/GPX4 pathway to suppress neuronal ferroptosis. Sch B can also inhibit TNF-α release from neurons undergoing ferroptosis, thus impeding the activation of M1-type microglia, suggesting a multifaceted neuroprotective strategy against neuroinflammatory processes. CONCLUSION:Sch B modulates the GSK3β/Nrf2/GPX4 pathway in conjunction with FSP1 to inhibit neuronal ferroptosis and the subsequent microglial M1 polarization mediated by neuronal ferroptosis, thereby improving cognitive impairment and pathological damage in AD.

Evidence indicates that Poria cocos polysaccharide (PCP) improves cognitive impairment in Alzheimer's disease (AD); however, its underlying mechanism, particularly its relationship with the gut microbiota, remains unclear. In the current study, we aimed to investigate the mechanism of PCP in improving cognitive impairment in AD. The results demonstrated that PCP markedly enhanced cognitive function and mitigated AD-related pathological alterations in 3 × Tg-AD mice. PCP treatment reversed the age-dependent gut microbiota dysbiosis in 3 × Tg-AD mice by 16S rDNA sequencing. The contents of propanoic acid, butanoic acid and isohexanoic acid were increased by short-chain fatty acid determination. In addition, PCP could restore both the intestinal barrier and the blood-brain barrier, as demonstrated by immunofluorescence staining of tight junction proteins. Furthermore, PCP alleviated systemic inflammation and neuroinflammation, as evidenced by reduced LPS levels in circulation and decreased IL-6 levels in the brain, likely by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, PCP can reshape gut microbiota to regulate short-chain fatty acids and alleviate neuroinflammation-related cognitive impairment in AD mice.

Delayed thrombolytic therapy with tissue plasminogen activator (tPA), the only FDA-approved drug for ischemic stroke, can cause catastrophic hemorrhagic transformation (HT) after ischemic stroke. However, it remains largely unknown how microglial polarization dynamically changes in HT. Poria cocos is a widely used functional edible fungus in Asia and has been used for more than 2000 years as a food and medicine in China. Our preliminary study found that P. cocos extract (PCE) significantly reduced the volume of cerebral infarction. We performed the effects of PCE on tPA-induced HT in rat models of autologous thromboembolism middle cerebral artery occlusion in vivo and BV-2 cells injured by oxygen-glucose deprivation/reperfusion in vitro. Hemorrhage test and triphenyltetrazolium chloride staining were performed to examine the efficiency of PCE. The expression level of proteins associated with microglia polarization was detected using Western blotting and immunofluorescence staining. Small interfering RNA transfection reveals the regulatory mechanism of PCE on microglia polarization. PCE plus tPA reduced hemorrhage and infarct volumes after ischemic stroke. During tPA-induced HT, M1 microglia increased over time from 3 days onward and remained high for at least 7 days, reaching the peak at 7 days, M2 microglia gradually increased after 3 days and continued to increase for at least 14 days. Furthermore, PCE inhibited the secretion of pro-inflammatory cytokines in M1 microglia and improved the secretion of anti-inflammatory cytokines in M2 microglia, which related to the regulation of the IRF5-IRF4 axis. This current study indicates that PCE alleviates tPA-induced HT after ischemic stroke by modulating microglia M1/M2 phenotype polarization.

The macrophage-derived membrane is widely applied in the targeting nanocarrier for its inflammatory tendency and long circulation ability due to the preservation of membrane protein. Few studies reported the application of macrophage membranes as biotherapeutic agents. To verify the ability of macrophage membrane as a biotherapeutic agent, ischemic stroke was selected as the model disease. Inspired by the features of macrophages infiltrating the ischemic core and the talent of M2 macrophages in modulating the inflammatory microenvironment, an M2 macrophage membrane (M2M)-disguised poly lactic-co-glycolic acid nanoparticles loaded with baicalin (BA) (M2M@BANPs) is developed. The results in vivo and in vitro indicate that M2M@BANPs could efficiently and actively target ischemic brain tissue and accumulate in microglia and neurons due to the coating of M2M. Furthermore, M2M and M2M@BANPs exhibit significant therapeutic effects in salvaging brain tissue damage and neurological functional recovery by reprogramming microglia from M1 to M2, reducing neutrophil infiltration and inhibiting neuronal apoptosis. Together, our fabrication provides a new insight and an applicative perspective for M2M in the therapy of ischemic stroke.

Background: The triglyceride-glucose (TyG) index is a surrogate indicator of insulin resistance. Therefore, we aimed to determine the association between TyG index and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with coronary heart disease (CHD) and to explore whether such associations would be modified by different metabolic states. Methods: Among 107,301 CHD patients, 62,794 were included to analyze the relationship between the TyG index and HF. Among them, 8,606 patients who had undergone echocardiography were included to identify different types of HF, including HF with reduced ejection fraction (HFrEF), HF with intermediate-range ejection fraction (HFmrEF), and HFpEF. Among them, 1896 patients were diagnosed with HFpEF. Logistic regression was used to analyze the relationship between the TyG index and HFpEF in CHD patients. In addition, the association between TyG index and HFpEF according to sex, age, blood lipids, and blood pressure was assessed. Results: A baseline analysis of CHD patients divided into four groups according to the tertile level of the TyG index showed significant differences in the related parameters between the groups. In the multi-adjusted models, the TyG index was significantly associated with the risk of HFpEF (odds ratio [OR]: 1.17; 95% confidence interval [CI]: 1.09-1.25). After adjustment for multivariates, TyG index levels for T2 (OR: 1.33; 95% CI: 1.16-1.52) and T3 (OR: 1.52; 95% CI: 1.32-1.74) were associated with increased OR in HFpEF. In addition, the TyG index of CHD patients was significantly associated with HFpEF in older adults aged > 60 years (OR: 1.20; 95% CI: 1.11-1.29), hypertension (OR: 1.27; 95% CI: 1.17-1.37), and dyslipidemia (OR: 1.15; 95% CI: 1.08-1.24). Moreover, the OR (OR: 1.23; 95% CI: 1.11-1.36) in women is higher than in men (OR: 1.17; 95% CI: 1.02-1.22, indicating a stronger association between TyG index and HFpEF in women. Conclusions: Our findings demonstrated a significant association between TyG index and HFpEF in CHD patients. Furthermore, TyG index was independently associated with HFpEF in hypertension, dyslipidemia, and older patients (aged > 60 years). In addition, the association between the TyG index and HFpEF in CHD patients differed according to sex.

Oxidative stress is one of the earlier events causing neuronal dysfunction in Alzheimer's disease (AD). Gomisin N (GN), a lignin isolated from Schisandra chinensis, has anti-oxidative stress effects. There are currently no studies on the neuroprotective potential of GN in AD. In this study, two AD models were treated with GN for 8 weeks. The cognitive functions, amyloid deposition, and neuronal death were assessed. Additionally, the expressions of critical proteins in the GSK3β/Nrf2 signaling pathway were determined in vivo and in vitro. We showed that GN significantly upregulated the expressions of Nrf2, p-GSK3βSer9/GSK3β, NQO1 and HO-1 proteins in SHSY-5Y/APPswe cells after H2O2 injury, whereas the PI3K inhibitor LY294002 reversed the increase in the expressions of Nrf2, p-GSK3βSer9/GSK3β, NQO1 and HO-1 proteins induced by GN administration. In a further study, GN could significantly improve the learning and memory dysfunctions of the rat and mouse AD models, reduce the area of Aβ plaques in the hippocampus and cortex, and increase the number and function of neurons. Here, we first demonstrate the neuroprotective effects of GN on AD in vivo and in vitro. A possible mechanism by which GN prevents AD is proposed: GN significantly increased the expressions of Nrf2, p-GSK3Ser9/GSK3β and NQO1 proteins in the brain of AD animal models and promoted Nrf2 nuclear translocation, then activated Nrf2 downstream genes to combat oxidative stress in AD pathogenesis. GN might be a promising therapeutic agent for AD.

Drug delivery systems (DDS) have recently emerged as a promising approach for the unique advantages of drug protection and targeted delivery. However, the access of nanoparticles/drugs to the central nervous system (CNS) remains a challenge mainly due to the obstruction from brain barriers. Immune cells infiltrating the CNS in the pathological state have inspired the development of strategies for CNS foundation drug delivery. Herein, we outline the three major brain barriers in the CNS and the mechanisms by which immune cells migrate across the blood-brain barrier. We subsequently review biomimetic strategies utilizing immune cell-based nanoparticles for the delivery of nanoparticles/drugs to the CNS, as well as recent progress in rationally engineering immune cell-based DDS for CNS diseases. Finally, we discuss the challenges and opportunities of immune cell-based DDS in CNS diseases to promote their clinical development.

Elderly people over the age of 65 are those most likely to experience Alzheimer’s disease (AD), and aging and AD are associated with apparent metabolic alterations. Currently, there is no curative medication against AD and only several drugs have been approved by the FDA, but these drugs can only improve the symptoms of AD. Many preclinical and clinical trials have explored the impact of adjusting the whole-body and intracellular metabolism on the pathogenesis of AD. The most recent evidence suggests that mitochondria initiate an integrated stress response to environmental stress, which is beneficial for healthy aging and neuroprotection. There is also an increasing awareness of the differential risk and potential targeting strategies related to the metabolic level and microbiome. As the main participants in intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been regarded as potential therapeutic targets for AD. This review summarizes and highlights these advances.

AIM:In order to understand the different processes and mechanisms of cognitive function and resveratrol (RES) as an active participant in pathophysiological events that affect cognitive function.METHODS:First, the Web of Science (core collection) was selected as the data source. To ensure the comprehensiveness and accuracy of the search data, the index was selected as "SCI-EXPANDED", and the search formula was TS = resveratrol AND TS = ("cognitive" OR "memory" OR "cognition" OR "mood"). Next, details of authors, keywords, journals, countries, institutions, references, and more were analyzed by CiteSpace and VOSviewer software. Finally, we explored the mechanism by which RES could improve cognitive impairment, that involves healthy young adults, healthy elderly, post-menopausal women, and diseases involving Alzheimer's disease (AD), diabetes-related cognitive impairment, mental illness, post-stroke cognitive impairment, and neonatal hypoxic-ischemic injury.RESULTS:287 valid papers were obtained. The scientometric results demonstrated 287 papers used in this study came from 1601 authors from 443 organizations in 38 countries, published in 169 journals, and cited 13,680 literatures from 2431 journals. Depression, AD, cerebral ischemia, diabetic cognitive impairment, and cognitive function in the elderly are all keywords of the co-occurrence network.CONCLUSION:This study supports the hypothesis that chronic RES intake may positively affect brain function. But it has become challenging to determine the optimal dose, time and duration of RES and improve the bioavailability of RES, which many researchers need to overcome.

ETHNOPHARMACOLOGICAL RELEVANCE:Intracerebral hemorrhage (ICH) is a major public health issue that leads to elevated rates of death and disability and has few proven treatments. Naoxueshu oral liquid (NXS), a TCM patent drug, is widely used in patients with ICH. Although a series of clinical studies have confirmed the efficacy and safety of NXS, the underlying mechanism of hematoma absorption is unclear. AIM OF THE STUDY:Our work aimed to elucidate the effect and mechanism of NXS on hematoma absorption in rats with ICH. MATERIALS AND METHODS:Induction of ICH model in the rats with intracerebral injection of collagenase VII, followed by treatment with NXS and Edaravone as a control neuroprotection medication. Neural functional recovery was assessed using mNSS, foot fault test, corner test, forelimb grip-traction test, and adhesive removal test. Hematoma absorption was assessed by the spectrophotometric hemoglobin assay with Drabkin's reagent. The protein expression of CD36, M2 microglia marker (CD206 and YM-1) and TLR4/MyD88/NF-κB pathway related proteins were determined by Western blot and immunofluorescence. RESULTS:NXS could significantly ameliorate the ICH recovery of neural and locomotor function as well as reduce hemorrhage volume. NXS could increase the expression of CD36 expressed in M2 microglia and promote M2 microglia polarization. Simultaneously, NXS significantly suppressed protein expressions of TLR4, MyD88, and NF-κB following ICH in rats. The results indicated that lipopolysaccharide (LPS), TLR4 specific agonist, could partially reverse the change in ICH rats administrated with NXS. CONCLUSIONS:NXS promotes hematoma absorption by targeting CD36 expression in M2 microglia via TLR4/MyD88/NF-κB signaling pathway in rats with ICH. Collectively, current research provides a novel theoretical basis for the clinical application of NXS.

BACKGROUND:Ischemic stroke is a major global cause of mortality and permanent disability.  Studies have shown that autophagy is essential to maintain cell homeostasis and inevitably lead to neuronal damage after cerebral ischemia. Gomisin N (GN), lignin isolated from Schisandra chinensis, possesses multiple pharmacological activities. However, there is no research on the potential of GN for neuroprotection in ischemic stroke. PURPOSE:The current work aimed to explore the potential therapeutic possibilities of GN on ischemic stroke and investigate the underlying molecular mechanisms. STUDY DESIGN:The neuroprotective effects of GN on PC12 cells induced by oxygen glucose deprivation/reoxygenation (OGD/R) and mice with middle cerebral artery occlusion/reperfusion (MCAO/R) injury were investigated. METHODS:On day 3 after ischemia, the infarct volume and neurological function were assessed. The level of autophagy was measured in vivo and in vitro using Transmission electron microscopy (TEM) and Monodansylcadaverine (MDC) staining. The interaction between GN and PI3K/AKT/mTOR pathway was investigated by molecular docking. Additionally, the expressions of critical proteins in the PI3K/AKT/mTOR signaling pathway and autophagy markers were determined by western blotting. RESULTS:In compared to the Model group, GN might considerably improve the neurological and locomotor function following a stroke, as well as lower the volume of the cerebral infarct volume and the number of autophagosomes. GN therapy may suppress autophagy by activating the PI3K/Akt/mTOR signaling pathway in the penumbra. In vitro, MDC and TEM results showed that GN treatment obviously suppressed autophagy. Meanwhile, GN downregulated LC3II/LC3I expression ratio while upregulated the p62 expression level. In further studies, GN dramatically boosted the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR proteins in PC12 cells following OGD/R damage. However, the PI3K inhibitor (LY294002) reversed the increase of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR expression ratio induced by GN administration. Also, LY294002 significantly partially attenuated GN induced reduction of autophagy and increase of cell viability compared with GN treatment alone. CONCLUSIONS:Here, we first demonstrate the neuroprotective effects of GN on MCAO mice and OGD/R induced PC12 cells injury. A possible mechanism by which GN prevents ischemic stroke is proposed: GN could restrain autophagy by stimulating the PI3K/AKT/mTOR signaling pathways. More effects and mechanisms of GN on the rehabilitation of ischemic stroke are worthy to be explored in the future.

Background The triglyceride glucose (TyG) index serves as a surrogate indicator of insulin resistance. However, there is limited evidence on the association between the TyG index and heart failure with preserved ejection fraction (HFpEF) in patients with coronary heart disease (CHD). Methods The 62,794 CHD patients were included used to analyze the relationship between the TyG index and heart failure (HF) in CHD patients. Of these, 8,606 patients who underwent echocardiography were included to identify different types of HF, including HF with reduced ejection fraction (HFrEF), HF with intermediate-range ejection fraction (HFmrEF), and HFpEF. Logistic regression was used to analyze the relationship between the TyG index and HFpEF in CHD patients. The relationship between the TyG index and HFpEF according to sex, age, blood lipids and blood pressure states were also assessed. Results A baseline analysis of CHD patients divided into four groups according to the tertile level of the TyG index showed that there were significant differences in related parameters between the groups. In the multi-adjusted modles, the TyG index was significantly associated with the risk of HFpEF (OR: 1.56; 95% CI: 1.08–1.23). In addition, the TyG index of CHD patients was significantly associated with HFpEF in elderly (> 60 years old) patients (OR:1.19; 95% CI: 1.10-1.48), hypertension (OR:1.17; 95% CI: 1.10-1.25) and dyslipidemia (OR:1.16; 95% CI: 1.08-1.23). The association between the TyG index and HFpEF was not affected by sex. And the association between the TyG index of female and HFpEF was (OR:1.21; 95% CI: 1.10-1.34), which was higher than that of male (OR:1.11; 95% CI: 1.02-1.21). Conclusions This study demonstrated a significant association of the TyG index and HFpEF in CHD patients. In this study, the results show that the TyG index was independently associated with HFpEF in hypertension, dyslipidemia, and elder patients (> 60 years old). In addition, the association between the TyG index and HFpEF in CHD patients was higher in female. ![Figure][1] Graphical abstract ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Natural Science Foundation of China (82074140). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the ethics committee of Tianjin University of Traditional Chinese Medicine (TJUTCM-EC20190008) and registered in the Chinese Clinical Trial Registry (ChiCTR-1900024535) and in Clinical Trials.gov ([NCT04026724][2]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request. * TyG : Triglyceride glucose HF : Heart failure HFrEF : Heart failure with reduced ejection fraction HFmrEF : Heart failure with mid-range ejection fraction HFpEF : Heart failure with preserved ejection fraction LVEF : Left ventricle ejection fraction CHD : Coronary heart disease DM : Diabetes mellitus NCD : Non-communicable diseases T2DM : Type 2 diabetes CAD : Coronary artery disease Pre-DM : Prediabetes AS : Atherosclerosis SBP : Systolic blood pressure DBP : Diastolic blood pressure FPG : Fasting plasma glucose TC : Total cholesterol HDL-C : High-density lipoprotein cholesterol TG : Triglycerides LDL-C : Low-density lipoprotein cholesterol CRP : C-reactionprotein HbA1c : Glycated haemoglobin OR : Odds ratios CIs : Confidence intervals HOMA-IR : Homeostasis model assessment of insulin resistance SA : Subclinical atherosclerosis [1]: pending:yes [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04026724&atom=%2Fmedrxiv%2Fearly%2F2023%2F11%2F01%2F2023.10.31.23297884.atom

Intracerebral hemorrhage (ICH), the second most common subtype of stroke, remains a significant cause of morbidity and mortality worldwide. The pathological mechanism of ICH is very complex, and it has been demonstrated that oxidative stress (OS) plays an important role in the pathogenesis of ICH. Previous studies have shown that OS is a therapeutic target after ICH, and antioxidants have also achieved some benefits in the treatment of ICH. This review aimed to explore the promise of natural products therapy to target OS in ICH. We searched PubMed using the keywords "oxidative stress in intracerebral hemorrhage" and "natural products in intracerebral hemorrhage". Numerous animal and cell studies on ICH have demonstrated the potent antioxidant properties of natural products, including polyphenols and phenolic compounds, terpenoids, alkaloids, etc. In summary, natural products such as antioxidants offer the possibility of treatment of OS after ICH. However, researchers still have a long way to go to apply these natural products for the treatment of ICH more widely in the clinic.

Storax is a traditional Chinese herb that is widely applied in stroke treatment. However, its neuroprotective effects and mechanisms are yet to be fully elucidated. This study aimed to elucidate the neuroprotective effects and underlying mechanisms of storax on oxygen-glucose deprivation/reoxygenation (OGD/R) in injured cortical neurons. The cortical neurons of Wistar rats were primarily cultured in vitro. The TUNEL method and CM-H2DCFDA probe were used to detect cell apoptosis and reactive oxygen species (ROS) expression. Enzyme -linked immunosorbent assay, reverse transcription-polymerase chain reaction, and Western blot were used to detect the expression of inflammatory cytokines and proteins of the TLR4/TRAF6/NF-kappa B signaling pathway. Immunofluorescence was used to measure NF-kappa B nuclear translocation. Transfection of TLR4 siRNA was used to detect the potential anti-inflammatory mechanisms of storax. The present results have shown that storax pro-tected primary cortical neurons from OGD/R-induced injury by suppressing ROS generation and cell apoptosis; alleviating HMGB-1, TNF-alpha, IL-1 beta, and ICAM-1 expression; and promoting IL-10 expression. In addition, storax inhibited the activation of TLR4, TRAF6, I kappa B alpha, IKK beta, and NF-kappa Bp65 caused by OGD/R. It is suggested that storax prevents OGD/R-induced primary cortical neuron injury by inhibiting the TLR4/TRAF6/NF-kappa B signaling pathway.