Astaxanthin Rescues Memory Impairments in Rats with Vascular Dementia by Protecting Against Neuronal Death in the Hippocampus.

Vascular dementia (VaD) is a cognitive disorder characterized by a decline in cognitive function resulting from cerebrovascular disease. The hippocampus is particularly susceptible to ischemic insults, leading to memory deficits in VaD. Astaxanthin (AST) has shown potential therapeutic effects in neurodegenerative diseases. However, the mechanisms underlying its protective effects in VaD and against hippocampal neuronal death remain unclear. In this study, We used the bilateral common carotid artery occlusion (BCCAO) method to establish a chronic cerebral hypoperfusion (CCH) rat model of VaD and administered a gastric infusion of AST at 25 mg/kg per day for 4 weeks to explore its therapeutic effects. Memory impairments were assessed using Y-maze and Morris water maze tests. We also performed biochemical analyses to evaluate levels of hippocampal neuronal death and apoptosis-related proteins, as well as the impact of astaxanthin on the PI3K/Akt/mTOR pathway and oxidative stress. Our results demonstrated that AST significantly rescued memory impairments in VaD rats. Furthermore, astaxanthin treatment protected against hippocampal neuronal death and attenuated apoptosis. We also observed that AST modulated the PI3K/Akt/mTOR pathway, suggesting its involvement in promoting neuronal survival and synaptic plasticity. Additionally, AST exhibited antioxidant properties, mitigating oxidative stress in the hippocampus. These findings provide valuable insights into the potential therapeutic effects of AST in VaD. By elucidating the mechanisms underlying the actions of AST, this study highlights the importance of protecting hippocampal neurons and suggests potential targets for intervention in VaD. There are still some unanswered questions include long-term effects and optimal dosage of the use in human. Further research is warranted to fully understand the therapeutic potential of AST and its application in the clinical treatment of VaD.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

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Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

Palladium-catalyzed synthesis and anti-AD biological activity evaluation of N-aryl-debenzeyldonepezil analogues.

A series of novel N-aryl-debenzeyldonepezil derivatives (1-26) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. In vitro cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue 13 possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Furthermore, Compound 13 did not show significant cytotoxicity on SH-SY5Y. These results suggest that 13 is a potential multifunctional active molecule for treating Alzheimer's disease.

[Platelet-rich Plasma Induces M2 Macrophage Polarization via Regulating AMPK Singling Pathway].

OBJECTIVE: To investigate the role of platelet-rich plasma (PRP) in inducing the M2 macrophage polarization via regulating AMPK singling pathway. METHODS: The expressions of M1 marker CD11c and M2 marker CD206 in macrophages of blank control group, LPS group, LPS+PRP group, and LPS+PRP+Compound C group were detected by flow cytometry. Western blot was used to observe the effects of PRP on the expression of AMPK-mTOR signaling pathway-related proteins at different times (12 h, 18 h and 24 h) after LPS treatment. RNA interference technology was used to silence the expression of AMPK in macrophages, and the expression of TGF-ß protein was subsequently examined by Western blot. RESULTS: LPS significantly reduced the expression of CD206 and increased the expression of CD11c (P <0.05). After the addition of PRP, the expression of CD206 was significantly increased (P <0.05), while the expression of CD11c was significantly decreased (P <0.05). Compared with LPS group, PRP treatment significantly increased the expressions of p-AMPK and p-ULK1 proteins at 12 h, 18 h and 24 h, while significantly decreased the expression of p-mTOR protein (P <0.05). After the addition of AMPK inhibitor Compound C, the expression of CD206 was significantly reduced (P <0.05) and the expression of CD11c was significantly increased compared with LPS+PRP group (P <0.05). After silencing the expression of AMPK in macrophages, the promotion effect of PRP on TGF-ß was significantly reduced (P <0.05). CONCLUSION: PRP can stimulate the transformation of macrophages to M2 type via AMPK signalling pathway.

Prolonging dual antiplatelet therapy improves the long-term prognosis in patients with diabetes mellitus undergoing complex percutaneous coronary intervention.

OBJECTIVE: To investigate the optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) requiring complex percutaneous coronary intervention (PCI). METHODS: A total of 2403 patients with DM who underwent complex PCI from January to December 2013 were consecutively enrolled in this observational cohort study and divided according to DAPT duration into a standard group (11-13 months, n = 689) and two prolonged groups (13-24 months, n = 1133; > 24 months, n = 581). RESULTS: Baseline characteristics, angiographic findings, and complexity of PCI were comparable regardless of DAPT duration. The incidence of major adverse cardiac and cerebrovascular event was lower when DAPT was 13-24 months than when it was 11-13 months or > 24 months (4.6% vs. 8.1% vs. 6.0%, P = 0.008), as was the incidence of all-cause death (1.9% vs. 4.6% vs. 2.2%, P = 0.002) and cardiac death (1.0% vs. 3.0% vs. 1.2%, P = 0.002). After adjustment for confounders, DAPT for 13-24 months was associated with a lower risk of major adverse cardiac and cerebrovascular event [hazard ratio (HR) = 0.544, 95% CI: 0.373-0.795] and all-cause death (HR = 0.605, 95% CI: 0.387-0.944). DAPT for > 24 months was associated with a lower risk of all-cause death (HR = 0.681, 95% CI: 0.493-0.942) and cardiac death (HR = 0.620, 95% CI: 0.403-0.952). The risk of major bleeding was not increased by prolonging DAPT to 13-24 months (HR = 1.356, 95% CI: 0.766-2.401) or > 24 months (HR = 0.967, 95% CI: 0.682-1.371). CONCLUSIONS: For patients with DM undergoing complex PCI, prolonging DAPT might improve the long-term prognosis by reducing the risk of adverse ischemic events without increasing the bleeding risk.

Characterization of Arabidopsis thaliana Coq9 in the CoQ Biosynthetic Pathway.

Coenzyme Q, also known as ubiquinone, is a fat-soluble isoprene quinone that serves as a cofactor for numerous enzymes across all domains of life. However, the biosynthetic pathway for this important molecule in plants has been examined in only a limited number of studies. In yeast and mammals, Coq9, an isoprenoid-lipid-binding protein, is essential for CoQ biosynthesis. Previous studies showed that Arabidopsis thaliana Coq9 failed to complement the fission yeast Schizosaccharomyces pombe coq9 null mutant, and its function in plants remains unknown. In this study, we demonstrated that expression of Arabidopsis Coq9 rescued the growth of a yeast temperature-sensitive coq9 mutant and increased CoQ content. Phylogenetic analysis revealed that Coq9 is widely present in green plants. Green fluorescent protein (GFP) fusion experiments showed that Arabidopsis Coq9 is targeted to mitochondria. Disruption of the Coq9 gene in Arabidopsis results in lower amounts of CoQ. Our work suggests that plant Coq9 is required for efficient CoQ biosynthesis. These findings provide new insights into the evolution of CoQ biosynthesis in plants. The identification of Coq9 as a key player in CoQ biosynthesis in plants opens up new avenues for understanding the regulation of this important metabolic pathway.

Impact of heart failure on outcomes in patients with sepsis: A systematic review and meta-analysis.

BACKGROUND: Heart failure (HF) often affects the progress of sepsis patients, although its impact on outcomes is inconsistent and inconclusive. AIM: To conduct a systematic review and meta-analysis of the impact of HF on mortality in patients with sepsis. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library databases were searched to compare the outcomes of sepsis patients with HF. A random effect model was used to summarize the mortality data, and the odds ratio (OR) and 95% confidence interval (CI) were calculated as effect indicators. RESULTS: Among 18001 records retrieved in the literature search, 35712 patients from 10 separate studies were included. The results showed that sepsis patients with HF were associated with increased total mortality (OR = 1.80, 95%CI: 1.34-2.43; I2 = 92.1%), with high heterogeneity between studies. Significant subgroup differences according to age, geographical location, and HF patient sample were observed. HF did not increase the 1-year mortality of patients (OR = 1.11, 95%CI: 0.75-1.62; I2 = 93.2%), and the mortality of patients with isolated right ventricular dysfunction (OR=2.32, 95%CI: 1.29-4.14; I2 = 91.5%) increased significantly. CONCLUSION: In patients with sepsis, HF is often associated with adverse outcomes and mortality. Our results call for more high-quality research and strategies to improve outcomes for sepsis patients with HF.

ZnO Nanoparticles Modified by Carbon Quantum Dots for the Photocatalytic Removal of Synthetic Pigment Pollutants.

Synthetic pigment pollutants caused by the rapid development of the modern food industry have become a serious threat to people's health and quality of life. Environmentally friendly ZnO-based photocatalytic degradation exhibits satisfactory efficiency, but some shortcomings of large band gap and rapid charge recombination reduce the removal of synthetic pigment pollutants. Here, carbon quantum dots (CQDs) with unique up-conversion luminescence were applied to decorate ZnO nanoparticles to effectively construct the CQDs/ZnO composites via a facile and efficient route. The ZnO nanoparticles with a spherical-like shape obtained from a zinc-based metal organic framework (zeolitic imidazolate framework-8, ZIF-8) were coated by uniformly dispersive quantum dots. Compared with single ZnO particles, the obtained CQDs/ZnO composites exhibit enhanced light absorption capacity, decreased photoluminescence (PL) intensity, and improved visible-light degradation for rhodamine B (RhB) with the large apparent rate constant (k app). The largest k app value in the CQDs/ZnO composite obtained from 75 mg of ZnO nanoparticles and 12.5 mL of the CQDs solution (∼1 mg·mL-1) was 2.6 times that in ZnO nanoparticles. This phenomenon may be attributed to the introduction of CQDs, leading to the narrowed band gap, an extended lifetime, and the charge separation. This work provides an economical and clean strategy to design visible-light-responsive ZnO-based photocatalysts, which is expected to be used for the removal of synthetic pigment pollutants in food industry.

Identification of Sodium- and Chloride-Sensitive Sites in the Slack Channel.

The Slack channel (KCNT1, Slo2.2) is a sodium-activated and chloride-activated potassium channel that regulates heart rate and maintains the normal excitability of the nervous system. Despite intense interest in the sodium gating mechanism, a comprehensive investigation to identify the sodium-sensitive and chloride-sensitive sites has been missing. In the present study, we identified two potential sodium-binding sites in the C-terminal domain of the rat Slack channel by conducting electrophysical recordings and systematic mutagenesis of cytosolic acidic residues in the rat Slack channel C terminus. In particular, by taking advantage of the M335A mutant, which results in the opening of the Slack channel in the absence of cytosolic sodium, we found that among the 92 screened negatively charged amino acids, E373 mutants could completely remove sodium sensitivity of the Slack channel. In contrast, several other mutants showed dramatic decreases in sodium sensitivity but did not abolish it altogether. Furthermore, molecular dynamics (MD) simulations performed at the hundreds of nanoseconds timescale revealed one or two sodium ions at the E373 position or an acidic pocket composed of several negatively charged residues. Moreover, the MD simulations predicted possible chloride interaction sites. By screening predicted positively charged residues, we identified R379 as a chloride interaction site. Thus, we conclude that the E373 site and the D863/E865 pocket are two potential sodium-sensitive sites, while R379 is a chloride interaction site in the Slack channel.SIGNIFICANCE STATEMENT The research presented here identified two distinct sodium and one chloride interaction sites located in the intracellular C-terminal domain of the Slack (Slo2.2, KCNT1) channel. Identification of the sites responsible for the sodium and chloride activation of the Slack channel sets its gating property apart from other potassium channels in the BK channel family. This finding sets the stage for future functional and pharmacological studies of this channel.

Effects of Particulate Matter on the Risk of Gestational Hypertensive Disorders and Their Progression.

Associations between particulate matter (PM) and gestational hypertensive disorders (GHDs) are well documented, but there is no evidence on the associations between PM and GHD progression, especially among those with assisted reproductive technology (ART) conceptions. To explore the effects of PM on the risk of GHDs and their progression among pregnant women with natural or ART conception, we enrolled 185,140 pregnant women during 2014-2020 in Shanghai and estimated the associations during different periods using multivariate logistic regression. During the 3 months of preconception, 10 µg/m3 increases in PM concentrations were associated with increased risks of gestational hypertension (GH) (PM2.5: aOR = 1.076, 95% CI: 1.034-1.120; PM10: aOR = 1.042, 95% CI: 1.006-1.079) and preeclampsia (PM2.5: aOR = 1.064, 95% CI: 1.008-1.122; PM10: aOR = 1.048, 95% CI: 1.006-1.092 ) among women with natural conception. Furthermore, for women with ART conceptions who suffered current GHD, 10 µg/m3 increases in PM concentrations in the third trimester elevated the risk of progression (PM2.5: aOR = 1.156, 95% CI: 1.022-1.306 ; PM10: aOR = 1.134, 95% CI: 1.013-1.270). In summary, women with natural conception should avoid preconceptional PM exposure to protect themselves from GH and preeclampsia. For women with ART conceptions suffering from GHD, it is necessary to avoid PM exposure in late pregnancy to prevent the disease from progressing.

Prolonged dual antiplatelet therapy after drug-eluting stent implantation improves long-term prognosis for acute coronary syndrome: five-year results from a large cohort study.

BACKGROUND: To investigate the most appropriate dual antiplatelet therapy (DAPT) duration for patients with acute coronary syndrome (ACS) after drug-eluting stent (DES) implantation in the largest cardiovascular center of China. METHODS: We enrolled 5,187 consecutive patients with ACS who received DES from January to December 2013. Patients were divided into four groups based on DAPT duration: standard DAPT group (11-13 months, n=1,568) and prolonged DAPT groups (13-18 months [n=308], 18-24 months [n=2,125], and >24 months [n=1,186]). Baseline characteristics and 5-year clinical outcomes were recorded. RESULTS: Baseline characteristics were similar across the four groups. Among the four groups, those with prolonged DAPT (18-24 months) had the lowest incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) (14.1% vs. 11.7% vs. 9.6% vs. 24.2%, P<0.001), all-cause death (4.8% vs. 3.9% vs. 2.1% vs. 2.6%, P<0.001), cardiac death (3.1% vs. 2.6% vs. 1.4% vs. 1.9%, P=0.004), and myocardial infarction (MI) (3.8% vs. 4.2% vs. 2.5% vs. 5.8%, P<0.001). The incidence of bleeding was not different among the four groups (9.9% vs. 9.4% vs. 11.0% vs. 9.4%, P=0.449). Cox multivariable analysis showed that prolonged DAPT (18-24 months) was an independent protective factor for MACCEs (hazard ratio [HR] 0.802, 95% confidence interval [CI] 0.729-0.882, P<0.001), all-cause death (HR 0.660, 95% CI 0.547-0.795, P<0.001), cardiac death (HR 0.663, 95% CI 0.526-0.835, P<0.001), MI (HR 0.796, 95% CI 0.662-0.957, P=0.015), and target vessel revascularization (HR 0.867, 95% CI 0.755-0.996, P=0.044). Subgroup analysis for high bleeding risk showed that prolonged DAPT remained an independent protective factor for all-cause death and MACCEs. CONCLUSION: For patients with ACS after DES, appropriately prolonging the DAPT duration may be associated with a reduced risk of adverse ischemic events without increasing the bleeding risk.

Associations between short-term and long-term exposure to particulate matter and preterm birth.

Despite the longstanding evidence on the effect of air pollutants on preterm birth (PTB), few studies have focused on its subtypes, including spontaneous preterm birth (sPTB) and medically indicated preterm birth (miPTB). Most studies evaluated only the short-term or long-term effects of particulate matter (PM) on PTB. Thus, we designed this study, based on a cohort of 179,385 women, to evaluate both short- and long-term effects of PM with diameters ≤2.5 µm and ≤10 µm (PM2.5 and PM10) on PTB, sPTB and miPTB in Shanghai. Generalized additive models (GAMs) were applied to evaluate short-term effects. Lagged effects were identified using different lag structures. Exposure-response correlation curves were plotted using GAMs after adjustment for confounders. ORs and 95% CIs were calculated using logistic regression to estimate the long-term effect after adjustment for confounders. There was 5.67%, 3.70% and 1.98% daily incidence of PTB, sPTB, and miPTB on average. Every 10 µg/m3 increase in PM2.5 and PM10 was positively associated with PTB and sPTB at lag 2 day. The exposure-response curves (lag 2 day) indicated a rapid increase in sPTB for PM2.5 and a linear increase for PM10, in PTB for PM2.5 and PM10 at concentrations over 100 µg/m3. Regarding long-term exposure, positive associations were found between 10 µg/m3 increases in PM2.5 and PM10 in 3rd trimester and greater odds of sPTB (aOR: 1.042, 95% CI: 1.018-1.065, and 1.018, 95% CI:1.002-1.034), and during the 3 months before conception and miPTB (aOR: 1.023, 95% CI: 1.003-1.042, and 1.017, 95% CI: 1.000-1.036). Acute exposure to PM2.5 and PM10 at lag 2 day and chronic exposure in 3rd trimester was significantly associated with sPTB, while miPTB was related to chronic exposure during the 3 months before pregnancy. These findings indicate that susceptibility windows of PM exposure can be influenced by different underlying etiologies of PTB.

Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion.

Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue (cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.

Combined robot motor assistance with neural circuit-based virtual reality (NeuCir-VR) lower extremity rehabilitation training in patients after stroke: a study protocol for a single-centre randomised controlled trial.

INTRODUCTION: Improving lower extremity motor function is the focus and difficulty of post-stroke rehabilitation treatment. More recently, robot-assisted and virtual reality (VR) training are commonly used in post-stroke rehabilitation and are considered feasible treatment methods. Here, we developed a rehabilitation system combining robot motor assistance with neural circuit-based VR (NeuCir-VR) rehabilitation programme involving procedural lower extremity rehabilitation with reward mechanisms, from muscle strength training, posture control and balance training to simple and complex ground walking training. The study aims to explore the effectiveness and neurological mechanisms of combining robot motor assistance and NeuCir-VR lower extremity rehabilitation training in patients after stroke. METHODS AND ANALYSIS: This is a single-centre, observer-blinded, randomised controlled trial. 40 patients with lower extremity hemiparesis after stroke will be recruited and randomly divided into a control group (combined robot assistance and VR training) and an intervention group (combined robot assistance and NeuCir-VR training) by the ratio of 1:1. Each group will receive five 30 min sessions per week for 4 weeks. The primary outcome will be Fugl-Meyer assessment of the lower extremity. Secondary outcomes will include Berg Balance Scale, Modified Ashworth Scale and functional connectivity measured by resting-state functional MRI. Outcomes will be measured at baseline (T0), post-intervention (T1) and follow-ups (T2-T4). ETHICS, REGISTRATION AND DISSEMINATION: The trial was approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Chinese Traditional Medicine (Grant No. 2019-014). The results will be submitted to a peer-reviewed journal or at a conference. TRIAL REGISTRATION NUMBER: ChiCTR2100052133.

Three-Dimensional Encoding Approach for Wearable Tactile Communication Devices.

In this work, we presented a novel encoding method for tactile communication. This approach was based on several tactile sensory characteristics of human skin at different body parts, such as the head and neck, where location coordinates in the three-dimensional (3D) space were clearly mapped in the brain cortex, and gentle stimulations of vibrational touching with varied strengths were received instantly and precisely. For certain applications, such as playing cards or navigating walk paths for blinded people, we demonstrated specifically designed code lists with different patterns of tactile points in varied temporal sequences. By optimizing these codes, we achieved excellent efficiency and accuracy in our test experiments. As this method matched well with the natural habits of tactile sensory, it was easy to learn in a short training period. The results of the present work have offered a silent, efficient and accurate communication solution for visually impaired people or other users.

A PPARG Splice Variant in Granulosa Cells Is Associated with Polycystic Ovary Syndrome.

BACKGROUND: We explored whether there are splice variants (SVs) of peroxisome proliferator-activated receptor-gamma (PPARG) in polycystic ovary syndrome (PCOS) patients and its relationship with clinical features and KGN cell functions. METHODS: We performed a study involving 153 women with PCOS and 153 age-matched controls. One type of PPARG SV was detected by SMARTer RACE. The correlations between PPARG SV expression levels, clinical features, and KGN cell functions were analyzed. The effect of the PPARG SV on the expression of important genes in metabolism-related pathways was explored by PCR array. RESULTS: The expression of the PPARG SV in PCOS patients was significantly higher than that in the controls. Clinical features were more significant in the PCOS group with the SV. Compared with overexpression of PPARG, the overexpression of the PPARG SV inhibited the proliferation, migration, and apoptosis of KGN cells in vitro. The genes related to the PPARG SV were mainly involved in lipid metabolism. CONCLUSION: While granulosa cells contribute greatly to the development of follicles, our results suggest that the identified PPARG SV may regulate cell proliferation, migration, and apoptosis in granulosa cells, which could partially explain the mechanisms of ovulation dysfunction in PCOS. Further investigation of the utility of this PPARG SV as a biomarker for PCOS is warranted.

Long-term outcome of percutaneous or surgical revascularization with and without prior stroke in patients with three-vessel disease.

OBJECTIVE: To determine whether high-risk patients with three-vessel disease (TVD) with and without prior stroke preferentially benefit from three strategies [percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) and medical therapy (MT)]. METHODS: A total of 8943 patients with TVD were included in the study. Patients enrolled were stratified into two categories according to the presence or absence of prior stroke history. The primary endpoint was all-cause death. Secondary endpoints included stroke and major adverse cardiac and cerebrovascular event (MACCE), a composite of death, myocardial infarction (MI), unplanned revascularization and stroke. RESULTS: Prior stroke was present in 888 patients (9.9%). These patients were older and had higher rates of comorbidities. During a median follow-up of 7.5 years, patients with prior stroke were strongly associated with increased risks of all-cause death, cardiac death, stroke and MACCE, even after adjusting for confounding variables and results been consistent across either treatment subgroup (PCI, CABG and MT) (all adjusted P < 0.01). Notably, there was a significant interaction between prior stroke history and treatment strategies. Revascularization strategy (PCI or CABG) was associated with a lower incidence of all-cause death and MACCE compared with MT alone, and favorable rates of MACCE, MI and unplanned revascularization in the CABG group compared with the PCI group, but with similar rate of all-cause death regardless of prior stroke history. The prevalence of stroke was significantly higher after CABG when compared with PCI or MT in no prior stroke patients [hazard ratio (HR) = 1.429, 95% CI: 1.132-1.805 for CABG vs. MT; HR = 1.703, 95% CI: 1.371-2.116 for CABG vs. PCI]. CONCLUSIONS: Patients with TVD and prior stroke have poor clinical outcomes. It is essential to balance benefit and risk when determining the optimal treatment strategy for TVD with and without prior stroke.

Paeoniae Radix Rubra can enhance fatty acid ß-oxidation and alleviate gut microbiota disorder in α-naphthyl isothiocyanate induced cholestatic model rats.

Cholestasis is the most destructive pathological manifestation of liver disease and available treatments are very limited. Paeoniae Radix Rubra (PRR) is an important traditional Chinese drug used to treat cholestasis. This study combined targeted metabonomics, PCR array analysis, and 16S rRNA sequencing analysis to further clarify the mechanisms of PRR in the treatment of cholestasis. PRR conspicuously reversed the elevation of fatty acids (FFA 14:0 and other 14 fatty acids) and the decrease of organic acids (pyruvic acid and citric acid) in a cholestatic model induced by α-naphthyl isothiocyanate (ANIT). Eight elevated amino acids (L-proline, etc.) and five elevated secondary bile acids (taurohyodeoxycholic acid, etc.) in model rats were also reduced by PRR. Pathway analysis revealed that PRR significantly alleviated eight pathways (ß-alanine metabolism). Furthermore, we found that PRR significantly reversed the decrease of Cpt1a, Hadha, Ppara, and Slc25a20 (four genes relevant to fatty acid ß-oxidation) mRNAs caused by ANIT, and PRR conspicuously decreased nine acylcarnitines (the forms of fatty acids into mitochondria for ß-oxidation) that increased in model rats. These results indicate that PRR could enhance fatty acid ß-oxidation, which may be the way for PRR to reduce the levels of 15 fatty acids in the serum of model rats. 16S rRNA sequencing analysis revealed that PRR alleviated gut microbiota disorders in model rats, including upregulating four genera (Coprococcus, Lactobacillus, etc.) and downregulating four genera (Bacteroides, Escherichia, etc.). As the relative abundance of these eight genera was significantly correlated with the levels of the five secondary bile acids (deoxycholic acid, taurolithocholic acid, etc.) reduced by PRR, and Bacteroides and Escherichia were reported to promote the production of secondary bile acid, we inferred that the downregulation of PRR on five secondary bile acids in model rats was inseparable from gut microbiota. Thus, the gut microbiota also might be a potential pharmacological target for the anticholestatic activity of PRR. In conclusion, we consider that the mechanisms of PRR in treating cholestasis include enhancing fatty acid ß-oxidation and alleviating gut microbiota disorders.

Metabolism of Paeoniae Radix Rubra and its 14 constituents in mice.

Objective: Paeoniae Radix Rubra (PRR) is a commonly used traditional Chinese medicine with the effects of clearing away heat, cooling the blood, and relieving blood stasis. To 1) elucidate the metabolites and metabolic pathways of PRR and its 14 main constituents in mice and 2) reveal the possible origins of the known effective forms of PRR and their isomers, the metabolism of PRR in mice was systematically studied for the first time. Methods: PRR and its 14 constituents were administered to mice by gavage once a day for seven consecutive days, respectively. All urine and feces were collected during the 7 days of dosing, and blood was collected at 1 h after the last dose. Metabolites were detected and identified using high performance liquid chromatography with diode array detector and combined with electrospray ionization ion trap time-of-flight multistage mass spectrometry (HPLC-DAD-ESI-IT-TOF-MSn). Results: In total, 23, 16, 24, 17, 18, 30, 27, 17, 22, 17, 33, 3, 8, 24, and 31 metabolites of paeoniflorin, albiflorin, oxypaeoniflorin, benzoylpaeoniflorin, hydroxybenzoylpaeoniflorin, benzoyloxypaeoniflorin, galloylpaeoniflorin, lactiflorin, epicatechin gallate, catechin gallate, catechin, ellagic acid, 3,3'-di-O-methylellagic acid, methylgallate, and PRR were respectively identified in mice; after eliminating identical metabolites, a total of 195 metabolites remained, including 8, 11, 25, 17, 18, 30, 27, 17, 21, 17, 1, 2, 8, 20, and 20 newly identified metabolites, respectively. The metabolic reactions of PRR and its 14 main constituents in mice were primarily methylation, hydrogenation, hydrolysis, hydroxylation, glucuronidation, and sulfation. Conclusion: We elucidated the metabolites and metabolic pathways of PRR and its 14 constituents (e.g., paeoniflorin, catechin, ellagic acid, and gallic acid) in mice and revealed the possible origins of the 10 known effective forms of PRR and their isomers. The findings are of great significance to studying the mechanism of action and quality control of PRR.