Enzyme-Triggered Polyelectrolyte Complex for Responsive Delivery of α-Helical Polypeptides to Optimize Antibacterial Therapy.

Responsive nanomaterials hold significant promise in the treatment of bacterial infections by recognizing internal or external stimuli to achieve stimuli-responsive behavior. In this study, we present an enzyme-responsive polyelectrolyte complex micelles (PTPMN) with α-helical cationic polypeptide as a coacervate-core for the treatment of Escherichia coli (E. coli) infection. The complex was constructed through electrostatic interaction between cationic poly(glutamic acid) derivatives and phosphorylation-modified poly(ethylene glycol)-b-poly(tyrosine) (PEG-b-PPTyr) by directly dissolving them in aqueous solution. The cationic polypeptide adopted α-helical structure and demonstrated excellent broad-spectrum antibacterial activity against both Gram-negative and Gram-positive bacteria, with a minimum inhibitory concentration (MIC) as low as 12.5 µg mL-1 against E. coli. By complexing with anionic PEG-b-PPTyr, the obtained complex formed ß-sheet structures and exhibited good biocompatibility and low hemolysis. When incubated in a bacterial environment, the complex cleaved its phosphate groups triggered by phosphatases secreted by bacteria, exposing the highly α-helical conformation and restoring its effective bactericidal ability. In vivo experiments confirmed accelerated healing in E. coli-infected wounds.

Effect of GABAa-receptors on neuronal discharge and ion activity in focal seizures.

Focal seizures are a type of epileptic event that has plagued the medical community for a long time, and the existing drug treatment is mainly based on the modulation of ${GABA}_a$-receptors to affect GABAergic signaling to achieve the therapeutic purpose. The majority of research currently focuses on the impact of ${GABA}_a$-receptors on neuronal firing, failing to analyze the molecular and ionic mechanisms involved. Specifically, the research on deeper-level mechanisms on how ${GABA}_a$-receptors affect neuronal firing by altering ion activity has not been addressed. This research aimed to study the effects of different ${GABA}_a$-receptor structures on ion activity in focal seizures model by adjusting parameters of the ${GABA}_a$-receptors: the rise time constant (${tau}_1$) and decay time constant (${tau}_2$). The research indicates that as the values of ${tau}_1$ and ${tau}_2$ of the ${GABA}_a$-receptor change, the ion concentration will vary based on the change of the ${GABA}_a$-receptor potential. To a certain extent, the duration of epileptic activity will also be affected to a certain extent. In conclusion, the alteration of ${GABA}_a$-receptor structure will affect the inhibitory effect of interneurons on pyramidal neurons, and different parameters of the ${GABA}_a$-receptor will directly impact the therapeutic effect.

Functional connectivity key feature analysis of cognitive impairment patients based on microstate brain network.

Mild cognitive impairment (MCI) is the initial phase of Alzheimer's disease (AD). The cognitive decline is linked to abnormal connectivity between different regions of the brain. Most brain network studies fail to consider the changes in brain patterns and do not reflect the dynamic pathological characteristics of patients. Therefore, this paper proposes a method for constructing brain networks based on microstate sequences. It also analyzes the microstate temporal parameters and introduces a new feature, the brain homeostasis coefficient (Bhc), to quantify the stability of patient brain connections. The results showed that microstate class B parameters were higher in the MCI than in the HC group. Additionally, the Bhc values in most channels of the MCI and AD groups were lower than those of the HC group, with the most significant differences observed in the right frontal lobe. These differences were statistically significant (P < 0.05). The findings indicate that connectivity in the right frontal lobe may be most severely disrupted in patients with cognitive impairment. Furthermore, the Montreal Cognitive Assessment score showed a strong positive correlation with Bhc. This suggests that Bhc could be a novel biomarker for evaluating cognitive function in patients with cognitive impairment.

Comparative Efficacy of Augmenting Escitalopram with Modified Electroconvulsive Therapy or High-Frequency Repetitive Transcranial Magnetic Stimulation on Depressive Symptoms, Quality of Life, and Cognitive Function in Treatment-Resistant Depression.

Treatment-resistant depression (TRD) poses significant therapeutic challenges despite available interventions. Escitalopram (ESC) is a highly selective antidepressant. This study aimed to compare ESC alone and ESC combined with modified electroconvulsive therapy (MECT) or high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in TRD patients. Ninety participants were randomized into ESC alone, ESC + MECT, and ESC + HF-rTMS groups. Notable differences were observed in Hamilton Depression Rating Scale (HDRS-17) scores at 12 weeks among ESC (14.37), ESC + MECT (10.27), and ESC + HF-rTMS (10.77) groups (P = 0.006). In terms of overall quality of life (QoL) evaluated using the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) at 12 weeks, the ESC, ESC + MECT, and ESC + HF-rTMS groups scored 2, 3, and 3.5, respectively. ESC + MECT/HF-rTMS groups showed reduced depressive symptoms compared to the ESC group, accompanied by higher overall QoL scores and increased satisfaction with health. Patients receiving ESC + MECT demonstrated no significant alterations in short-term memory and orientation, as measured by the Montreal Cognitive Assessment (MoCA), before and after treatment. Moreover, a decline in language was observed compared to baseline (12 weeks: median 2, IQR 2-3; baseline: median 1, IQR 1-3; P = 0.022). The positive impact of ESC with HF-rTMS on cognitive function was evidenced by improvements in all domines MoCA.Combining ESC with MECT or HF-rTMS exhibited enhanced effectiveness in alleviating depressive symptoms and enhancing QoL compared to ESC monotherapy. Specifically, the ESC + HF-rTMS combination displayed potential as a comprehensive treatment strategy for TRD, addressing both emotional and cognitive aspects.

Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma.

Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.

Astaxanthin alleviates fine particulate matter (PM2.5)-induced lung injury in rats by suppressing ferroptosis and apoptosis.

Objectives: Fine particulate matter (PM2.5), a small molecule particulate pollutant, can reach the lungs via respiration and cause lung damage. Currently, effective strategies and measures are lacking to prevent and treat the pulmonary toxicity of PM2.5. Astaxanthin (ASX), a natural xanthophyll carotenoid, has attracted attention due to its unique biological activity. Our research aims to probe into the prevention and treatment of ASX on PM2.5-induced lung injury and clarify its potential mechanism. Methods: Sprague-Dawley (SD) rats were given olive oil and different concentrations of ASX orally daily for 21 days. PM2.5 suspension was instilled into the trachea of rats every two days for one week to successfully develop the PM2.5 exposure model in the PM2.5-exposed and ASX-treated groups of rats. The bronchoalveolar lavage fluid (BALF) was collected, and the content of lung injury-related markers was detected. Histomorphological changes and expression of markers associated with oxidative stress, inflammation, iron death, and apoptosis were detected in lung tissue. Results: PM2.5 exposure can cause changes in lung histochemistry and increase the expression levels of TP, AKP, ALB, and LDH in the BALF. Simultaneously, inflammatory responses and oxidative stress were promoted in rat lung tissue after exposure to particulate matter. Additionally, ASX preconditioning can alleviate histomorphological changes, oxidative stress, and inflammation caused by PM2.5 and reduce PM2.5-related ferroptosis and apoptosis. Conclusion: ASX preconditioning can alleviate lung injury after PM2.5 exposure by inhibiting ferroptosis and apoptosis.

Astaxanthin alleviates PM2.5-induced cardiomyocyte injury via inhibiting ferroptosis.

BACKGROUND: Long-term exposure of humans to air pollution is associated with an increasing risk of cardiovascular diseases (CVDs). Astaxanthin (AST), a naturally occurring red carotenoid pigment, was proved to have multiple health benefits. However, whether or not AST also exerts a protective effect on fine particulate matter (PM2.5)-induced cardiomyocyte damage and its underlying mechanisms remain unclear. METHODS: In vitro experiments, the H9C2 cells were subjected to pretreatment with varying concentrations of AST, and then cardiomyocyte injury model induced by PM2.5 was established. The cell viability and the ferroptosis-related proteins expression were measured in different groups. In vivo experiments, the rats were pretreated with different concentrations of AST for 21 days. Subsequently, a rat model of myocardial PM2.5 injury was established by intratracheal instillation every other day for 1 week. The effects of AST on myocardial tissue injury caused by PM2.5 indicating by histological, serum, and protein analyses were examined. RESULTS: AST significantly ameliorated PM2.5-induced myocardial tissue injury, inflammatory cell infiltration, the release of inflammatory factors, and cardiomyocyte H9C2 cell damage. Mechanistically, AST pretreatment increased the expression of SLC7A11, GPX4 and down-regulated the expression of TfR1, FTL and FTH1 in vitro and in vivo. CONCLUSIONS: Our study suggest that ferroptosis plays a significant role in the pathogenesis of cardiomyocyte injury induced by PM2.5. AST may serve as a potential therapeutic agent for mitigating cardiomyocyte injury caused by PM2.5 through the inhibition of ferroptosis.

Mechanistic photophysics of tellurium-substituted cytosine: Electronic structure calculations and nonadiabatic dynamics simulations.

Previously, the MS-CASPT2 method was performed to study the static and qualitative photophysics of tellurium-substituted cytosine (TeC). To get quantitative information, we used our recently developed QTMF-FSSH dynamics method to simulate the excited-state decay of TeC. The CASSCF method was adopted to reduce the calculation costs, which was confirmed to provide reliable structures and energies as those of MS-CASPT2. A detailed structural analysis showed that only 5% trajectories will hop to the lower triplet or singlet state via the twisted (S2 /S1 /T2 )T intersection, while 67% trajectories will choose the planar intersections of (S2 /S1 /T3 /T2 /T1 )P and (S2 /S1 /T2 /T1 )P but subsequently become twisted in other electronic states. By contrast, ~28% trajectories will maintain in a plane throughout dynamics. Electronic population revealed that the S2 population will ultrafast transfer to the lower triplet or singlet state. Later, the TeC system will populate in the spin-mixed electronic states composed of S1 , T1 and T2 . At the end of 300 fs, most trajectories (~74%) will decay to the ground state and only 17.4% will survive in the triplet states. Our dynamics simulation verified that tellurium substitution will enhance the intersystem crossings, but the very short triplet lifetime (ca. 125 fs) will make TeC a less effective photosensitizer.

Understanding the Excited-State Relaxation Mechanisms of Xanthophyll Lutein by Multi-configurational Electronic Structure Calculations.

The contradictory behaviors in light harvesting and non-photochemical quenching make xanthophyll lutein the most attractive functional molecule in photosynthesis. Despite several theoretical simulations on the spectral properties and excited-state dynamics, the atomic-level photophysical mechanisms need to be further studied and established, especially for an accurate description of geometric and electronic structures of conical intersections for the lowest several electronic states of lutein. In the present work, semiempirical OM2/MRCI and multi-configurational restricted active space self-consistent field methods were performed to optimize the minima and conical intersections in and between the 1Ag-, 2Ag-, 1Bu+, and 1Bu- states. Meanwhile, the relative energies were refined by MS-CASPT2(10,8)/6-31G*, which can reproduce correct electronic state properties as those in the spectroscopic experiments. Based on the above calculation results, we proposed a possible excited-state relaxation mechanism for lutein from its initially populated 1Bu+ state. Once excited to the optically bright 1Bu+ state, the system will propagate along the key reaction coordinate, i.e., the stretching vibration of the conjugated carbon chain. During this period of time, the 1Bu- state will participate in and forms a resonance state between the 1Bu- and 1Bu+ states. Later, the system will rapidly hop to the 2Ag- state via the 1Bu+/2Ag- conical intersection. Finally, the lutein molecule will survive in the 2Ag- state for a relatively long time before it internally converts to the ground state directly or via a twisted S1/S0 conical intersection. Notably, though the photophysical picture may be very different in solvents and proteins, the current theoretical study proposed a promising calculation protocol and also provided many valuable mechanistic insights for lutein and similar carotenoids.

Modulating Cation Migration and Deposition with Xylitol Additive and Oriented Reconstruction of Hydrogen Bonds for Stable Zinc Anodes.

Highly reversible plating/stripping in aqueous electrolytes is one of the critical processes determining the performance of Zn-ion batteries, but it is severely impeded by the parasitic side reaction and dendrite growth. Herein, a novel electrolyte engineering strategy is first proposed based on the usage of 100 mM xylitol additive, which inhibits hydrogen evolution reaction and accelerates cations migration by expelling active H2 O molecules and weakening electrostatic interaction through oriented reconstruction of hydrogen bonds. Concomitantly, xylitol molecules are preferentially adsorbed by Zn surface, which provides a shielding buffer layer to retard the sedimentation and suppress the planar diffusion of Zn2+ ions. Zn2+ transference number and cycling lifespan of Zn∥Zn cells have been significantly elevated, overwhelmingly larger than bare ZnSO4 . The cell coupled with a NaV3 O8 cathode still behaves much better than the additive-free device in terms of capacity retention.

The protective effects of procyanidin supplementation on PM2.5-induced acute cardiac injury in rats.

OBJECTIVE: Numerous epidemiological and experimental studies have indicated that ambient fine particulate matter (PM2.5) exposure can lead to myocardial injury by inhibiting oxidative stress and apoptosis. The effects of procyanidin (PC) on PM2.5-induced cardiovascular diseases (CVDs) are still unknown. The purpose of this study was to explore the protective effect of PC supplementation on PM2.5-induced oxidative stress and cardiomyocyte apoptosis in rats. METHOD: Rats were treated by gavage with three different PC concentrations (50, 100 and 200 mg/kg) for 21 days prior to exposure to 10 mg/kg PM2.5 suspension liquid by intratracheal instillation every other day for three times. We determined myocardial reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the myocardium were measured. The expression levels of apoptosis-related proteins, including p-Akt/Akt, Bcl-2, caspase-3 and Bax, were determined. In addition, histopathological examination was used to evaluate cardiac injury. RESULTS: PM2.5 exposure noticeably elevated the contents of MDA and ROS and decreased the activities of GSH-Px and SOD. PM2.5 exposure inhibited Bcl-2 expression and up-regulated caspase-3 and Bax expression in the myocardium of rats. The anti-apoptosis-related index p-Akt/Akt was reduced. Moreover, pretreatment with PC could attenuate these PM2.5-induced changes. However, remarkable differences in the protective effect of different PC doses did not exist. CONCLUSIONS: The results indicated that PC supplementation could effectively attenuate the oxidative stress and apoptosis induced by PM2.5 in rat myocardial tissue.

Randomized controlled trial for time-restricted eating in overweight and obese young adults.

Time-restricted eating (TRE) is known to improve metabolic health, whereas very few studies have compared the effects of early and late TRE (eTRE and lTRE) on metabolic health. Overweight and obese young adults were randomized to 6-h eTRE (eating from 7 a.m. to 1 p.m.) (n = 21), 6-h lTRE (eating from 12 p.m. to 6 p.m.) (n = 20), or a control group (ad libitum intake in a day) (n = 19). After 8 weeks, 6-h eTRE and lTRE produced comparable body weight loss compared with controls. Compared with control, 6-h eTRE reduced systolic blood pressure, mean glucose, fasting insulin, insulin resistance, leptin, and thyroid axis activity, whereas lTRE only reduced leptin. These findings shed light on the promise of 6-h eTRE and lTRE for weight loss. Larger studies are needed to assess the promise of eTRE to yield better thyroid axis modulation and overall cardiometabolic health improvement.

Sesamin Ameliorates Fine Particulate Matter (PM2.5)-Induced Lung Injury via Suppression of Apoptosis and Autophagy in Rats.

Lung damage can be caused by fine particulate matter (PM2.5). Thus, effective prevention strategies for PM2.5-induced lung injury are urgently required. Sesamin (Ses) is a natural polyphenolic compound that has attracted considerable attention of researchers because of its wide range of pharmacological activities. The present study aims to elucidate whether Ses pretreatment could alleviate PM2.5-induced lung damage and identify its possible mechanisms. Sprague-Dawley rats were orally dosed with 0.5% carboxymethylcellulose (CMC) and different concentrations of Ses once a day for 21 days. Then, the rats of the PM2.5 exposure group and Ses-treated group were exposed to PM2.5 by intratracheal instillation every 2 days for 1 week. Biomarkers associated with lung injury were detected in bronchoalveolar lavage fluid (BALF). Lung tissue was collected for histology, inflammation, oxidative stress, immunohistochemistry, and Western blot. Our results showed that PM2.5 exposure could cause pathological changes in lung tissue and increase levels of TP, AKP, and ALB in BALF. Meanwhile, exposure to PM2.5 can cause oxidative stress and inflammation in the lungs. In addition, Ses pretreatment could ameliorate histopathological injury, oxidative stress, and inflammation caused by PM2.5 exposure. It could also inhibit PM2.5-induced apoptosis and upregulation of autophagy-associated proteins. Collectively, our study indicated that Ses pretreatment could ameliorate PM2.5-induced lung damage via inhibiting apoptosis and autophagy in rats.

Vascular benefits of vitamin C supplementation against fine particulate air pollution in healthy adults: A double-blind randomised crossover trial.

Evidence on the health benefits of vitamin C supplementation in highly polluted areas has not been evaluated. We aimed to evaluate whether dietary vitamin C supplementation can improve vascular health linked to particulate matter (PM) exposure. A randomised double-blind crossover trial involving 58 health young adults was performed in Shijiazhuang, China in 2018. All subjects were randomly assigned to the vitamin C supplementation group (2000 mg/d) or placebo group for a week alternating with a 2 week washout period. Fifteen circulating biomarkers were measured. Linear mixed-effect model was applied to evaluate the effect of vitamin C supplementation on health outcomes. The average concentrations of PM2.5 and PM10 were 164.91 and 327.05 µg/m3, respectively. Vitamin C supplementation was significantly associated with a 19.47% decrease in interleukin-6 (IL-6), 17.30% decrease in tumour necrosis factor-a (TNF-α), 34.01% decrease in C-reactive protein (CRP), 3.37% decrease in systolic blood pressure (SBP) and 6.03% decrease in pulse pressure (PP). Furthermore, glutathione peroxidase (GSH-Px) was significantly increased by 7.15%. Sex-subgroup analysis showed that vitamin C significantly reduced TNF-α by 27.85% in male participants and significantly increased APOB by 6.28% and GSH-Px by 14.47% only in female participants. This study indicated that vitamin C supplementation may protect vascular vessels against PM exposure among healthy young adults in China.

Altered non-coding RNA profiles and potential disease marker identification in peripheral blood mononuclear cells of patients with NMOSD.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelination disorder, and dysregulation of RNAs contributes to its pathogenesis. We aimed to reveal the expression profiles of RNAs, including messenger RNA (mRNA), circular RNA (circRNA) and long non-coding RNA (lncRNA), in the peripheral blood mononuclear cells (PBMCs) of patients with NMOSD. Seven NMOSD patients and seven healthy controls (HCs) were enrolled in the competitive endogenous RNA (ceRNA) microarray analysis. Bioinformatics analysis was then performed on the microarray data. Selected RNAs were validated by RT-qPCR. Differentially expressed (DE) RNA profiles of patients and HCs were related to NK cell mediated cytotoxicity, the IL-17 signaling pathway, and the B cell receptor signaling pathway. Moreover, DE non-coding RNAs (DE ncRNAs) including DE circRNAs and DE lncRNAs, may participate in the transforming growth factor beta (TGF-ß) signaling pathway, leukocyte migration and neutrophil chemotaxis. Immune cell infiltration analysis showed that the abundance of M1 macrophages and plasma cells significantly increased, while that of M2 macrophages significantly decreased in the NMOSD group. Finally, through RT-qPCR validation, lnc-HELZ-7:1 (95% confidential interval of area under curve [95%CI of AUC] = 0.6633-1.0000), ring finger protein-LIM domain interacting (RLIM; 95%CI of AUC = 0.6980-1.0000), and hsa_circ_0026993 (95%CI of AUC = 0.7550-1.0000) could discriminate NMOSD from HCs by receiver operating characteristic curve analysis. To our knowledge, this is the first study to preliminarily investigate the RNA profiles, especially circRNA profiles in PBMCs of NMOSD patients from North China. We identified lnc-HELZ-7:1, RLIM, and hsa_circ_0026993 as the potential disease markers for NMOSD.

The Effects of Sesamin Supplementation on Obesity, Blood Pressure, and Lipid Profile: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Aims: Sesamin, the main lignin constituent of sesame, plays a pivotal role in regulating physical state. Some studies have evidenced that the supplementation of sesamin may decrease cardiovascular disease risk. The goal of this systematic review was to summarize evidence of the effects of sesamin supplementation on obesity, blood pressure, and lipid profile in humans by performing a meta-analysis of randomized controlled trials. Data Synthesis: Five databases (PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus) were searched electronically from inception to July 2021 to identify randomized controlled trials that assessed the impact of sesamin on obesity, blood pressure, and lipid profile. Weighted mean difference (WMD) and standard deviation (SD) were used to present the major outcomes. Conclusions: Seven trials (n = 212 participants) were included in the overall analysis. Results showed that sesamin supplementation caused a great reduction in TC (WMD: -10.893 mg/dl, 95% CI: -19.745 to -2.041, p = 0.016), LDL-c (WMD: -8.429 mg/dl, 95% CI: -16.086 to -0.771, p = 0.031), and SBP (WMD: -3.662 mmHg, 95% CI: -6.220 to -1.105, p = 0.005), whereas it had no effect on HDL-c, TG, DBP, or weight. Subgroup analysis showed that duration, parallel design, and unhealthy status can affect TC, LDL-c, and SBP evidently. We did not discover a strong link between indicators' changes and duration of supplementation. Sesamin can be used as an obtainable dietary supplement to improve blood pressure and blood lipids, and further as a health product to prevent cardiovascular diseases.

Liraglutide attenuate central nervous inflammation and demyelination through AMPK and pyroptosis-related NLRP3 pathway.

AIMS: Multiple sclerosis (MS) still maintains increasing prevalence and poor prognosis, while glucagon-like peptide-1 receptor (GLP-1R) agonists show excellent neuroprotective capacities recently. Thus, we aim to evaluate whether the GLP-1R agonist liraglutide (Lira) could ameliorate central nervous system demyelination and inflammation. METHODS: The therapeutic effect of Lira was tested on experimental autoimmune encephalitis (EAE) in vivo and a microglia cell line BV2 in vitro. RESULTS: Lira administration could ameliorate the disease score of EAE mice, delay the disease onset, ameliorate pathological demyelination and inflammation score in lumbar spinal cord, reduce pathogenic T helper cell transcription in spleen, restore phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) level, autophagy level, and inhibit pyroptosis-related NLR family, pyrin domain-containing protein 3 (NLRP3) pathway in lumbar spinal cord. Additionally, cell viability test, lactate dehydrogenase release test, and dead/live cell staining test for BV2 cells showed Lira could not salvage BV2 from nigericin-induced pyroptosis significantly. CONCLUSION: Lira has anti-inflammation and anti-demyelination effect on EAE mice, and the protective effect of Lira in the EAE model may be related to regulation of pAMPK pathway, autophagy, and NLRP3 pathway. However, Lira treatment cannot significantly inhibit pyroptosis of BV2 cells in vitro. Our study provides Lira as a potential candidate for Multiple Sclerosis treatment.

The antithrombosis effect of dehydroandrographolide succinate: in vitro and in vivo studies.

CONTEXT: Dehydroandrographolide succinate (DAS) is mainly used in the clinical treatment of various infectious diseases. Its potential effects on platelet aggregation and blood coagulation systems have not been reported systematically. OBJECTIVE: To explore whether DAS exerts an antithrombotic effect and its internal mechanism. MATERIALS AND METHODS: Human blood samples and Sprague-Dawley (SD) rats divided into control, aspirin (30 mg/kg), and DAS groups (200, 400 and 600 mg/kg) were used to measure the platelet aggregation rate, coagulation function, coagulation factor activity, and contents of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α). The histopathology of the SD rat gastric mucosa was also observed. All rats were administered intragastric or intraperitoneal injections once a day for 3 consecutive days. RESULTS: Compared to control group, DAS significantly inhibited the platelet aggregation rate (ED50 = 386.9 mg/kg) by decreasing TXB2 levels (1531.95 ± 649.90 pg/mL to 511.08 ± 411.82 pg/mL) and activating antithrombin III (AT-III) (103.22 ± 16.22% to 146.46 ± 8.96%) (p < 0.05). In addition, DAS significantly enhanced the coagulation factors FV (304.12 ± 79.65% to 443.44 ± 75.04%), FVII (324.19 ± 48.03% to 790.66 ± 225.56%), FVIII (524.79 ± 115.47% to 679.92 ± 143.34%), FX (34.90 ± 7.40% to 102.76 ± 29.41%) and FXI (38.12 ± 10.33% to 65.47 ± 34.08%), increased the content of Fg (2.18 ± 0.39 to 3.61 ± 0.37 g/L), shorten the PT (10.42 ± 0.44 to 9.22 ± 0.21 s), APTT (16.43 ± 1.4 to 14.07 ± 0.75 s) and TT time (37.04 ± 2.13 to 32.68 ± 1.29 s) (p < 0.05), while the aspirin group showed no such effect on these items but showed reduced activity of FII (89.21 ± 21.72% to 61.83 ± 8.95%) and FVIII (524.79 ± 115.47% to 306.60 ± 29.96%) (p < 0.05). Histopathological changes showed aspirin-induced gastric mucosa haemorrhage and the protective effect of DAS in the gastric mucosa. CONCLUSIONS: DAS is more suitable than aspirin in thromboprophylaxis treatment, which provides a reliable theoretical and experimental basis for its clinical application.

Sesamin attenuates PM2.5-induced cardiovascular injury by inhibiting ferroptosis in rats.

Objective: This study aimed to elucidate the pharmacological effects of sesamin (Ses) and its mechanism of action towards PM2.5-induced cardiovascular injuries. Method: Forty Sprague Dawley (SD) rats were randomly divided into five groups: a saline control group; a PM2.5 exposure group; and low-, middle-, and high-dose Ses pretreatment groups. The SD rats were pretreated with different concentrations of Ses for 21 days. Afterward, the rats were exposed to ambient PM2.5 by intratracheal instillation every other day for a total of three times. The levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), and interleukin-6 (IL-6), and indicators related to oxidative responses, such as total superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), were measured in the blood and heart. The expression of ferroptosis-related proteins in heart tissues was determined via western blot and immunohistochemistry. Results: Ses pretreatment substantially ameliorated cardiovascular injuries in rats as evidenced by the decrease in the pathological score and collagen area. The decreased levels of SOD, GSH, and GSH-Px in the heart and serum were inhibited by Ses. In addition, Ses not only notably increased the activity of antioxidant enzymes but also reduced the levels of MDA, CK, LDH, CK-MB, IL-6, TNF-α, IL-1ß, and IL-6. Furthermore, Ses pretreatment upregulated the expression levels of GPX4, SLC7A11, TFRC, and FPN1 and inhibited the expression levels of FTH1 and FTL. Conclusion: Ses pretreatment could ameliorate PM2.5-induced cardiovascular injuries perhaps by inhibiting ferroptosis. Therefore, Ses pretreatment may be a novel strategy for the prevention and treatment of PM2.5-induced cardiovascular injury.

BLK polymorphisms and expression level in neuromyelitis optica spectrum disorder.

AIM: This study aimed to determine the correlation between B-lymphoid tyrosine kinase (BLK) polymorphism, mRNA gene expression of BLK, and NMOSD in a Chinese Han population. BACKGROUND: B-lymphoid tyrosine kinase gene expressed mainly in B cells plays a key role in various autoimmune disorders. However, no studies have investigated the association of BLK polymorphisms with neuromyelitis optica spectrum disorder (NMOSD). METHODS: Han Chinese population of 310 subjects were recruited to analyze three single nucleotide polymorphisms (rs13277113, rs4840568, and rs2248932) under allele, genotype, and haplotype frequencies, followed by clinical characteristics stratified analysis. Real-time PCR was used to analyze mRNA expression levels of BLK in the peripheral blood mononuclear cells of 64 subjects. RESULTS: Patients with NMOSD showed lower frequencies of the minor allele G of rs2248932 than healthy controls (odds ratio (OR) =0.57, 95% confidence intervals (CI) 0.39-0.83, p = 0.003). The association between minor allele G of rs2248932 and reduced NMOSD susceptibility was found by applying genetic models of inheritance (codominant, dominant, and recessive) and haplotypes analysis. Subsequently, by stratification analysis for AQP4-positivity, the minor allele G frequencies of rs2248932 in AQP4-positive subgroup were significantly lower than in the healthy controls (OR =0.46, 95% CI 0.30-0.72, p = 0.001). Notably, the genotype GG of rs2248932 was more frequent in AQP4-negative subgroup (n = 14) than in AQP4-positive subgroup (n = 93) (p = 0.003, OR =0.05, 95% CI =0.01-0.57). BLK mRNA expression levels in the NMOSD patients (n = 36) were lower than in healthy controls (n = 28) (p < 0.05). However, the acute non-treatment (n = 7), who were untreated patients in the acute phase from the NMOSD group, showed BLK mRNA expression levels 1.8-fold higher than healthy controls (n = 8) (p < 0.05). CONCLUSION: This study evaluated that the minor allele G of rs2248932 in BLK is associated with reduced susceptibility to NMOSD and protected the risk of AQP4-positive. BLK mRNA expression in NMOSD was lower as compared to healthy controls while significantly increased in acute-untreated patients.