Study on Plastic Constitutive Relation and Ductile Fracture Criterion of AM60B Magnesium Alloy.

It is currently a challenge to accurately predict the deformation and fracture behavior of metal parts in automobile crashes. Many studies have shown that the deformation and fracture behavior of materials are significantly affected by the stress state during automobile crashes with complex stress state characteristics. In order to further promote the application of die-cast magnesium alloys in automobiles, it is particularly important to study the material deformation and fracture behavior of die-cast magnesium alloys. In this paper, the mechanical properties of the AM60B die-cast magnesium alloy sheet under four stress states (shear, tension, R10 notch tension, and cupping) were designed and tested. Based on the von Mises isotropic constitutive model and Swift weighted Hockett-Sherby hardening model, the plastic constitutive model of die-cast magnesium alloy was established. Based on the plastic model and the fracture model (JC, MMC, and DIEM) considering the influence of three stress states, the deformation and fracture behavior of the AM60B die-cast magnesium alloy front-end members in three-point bending were predicted by experiments and finite element simulation. The experimental results show that the deformation mode and loading-displacement curve trend of the AM60B die-cast magnesium alloy front members are the same, the crack initiation point and crack initiation time are the same, and the crack shape is similar. The results show that the complex stress state constitutive model parameters and the DIEM fracture model obtained in this paper can accurately predict the deformation and fracture failure behavior of the AM60B die-cast magnesium alloy sheet.

Impact of cascade reservoirs on nutrients transported downstream and regulation method based on hydraulic retention time.

Cascade reservoirs construction has modified the nutrients dynamics and biogeochemical cycles, consequently affecting the composition and productivity of river ecosystems. The Jinsha River, as the predominant contributor to runoff, suspended sediment (SS), and nutrients production within the Yangtze River, is a typical cascade reservoir region with unclear transport patterns and retention mechanisms of nutrients (nitrogen and phosphorus). Furthermore, how to regulate nutrients delivery in the cascade reservoirs region is also an urgent issue for basin water environment study. Therefore, we monitored monthly variations in nitrogen and phosphorus concentrations from November 2021 to October 2022 in the cascade reservoirs of the Jinsha River. The results indicated that the concentrations and fluxes of total phosphorus (TP) and particulate phosphorus (PP) decreased along the cascade of reservoirs, primarily due to PP deposited with SS, while opposing trends for total nitrogen (TN) and dissolved total nitrogen (DTN), which might be the consequences of human inputs and the increase of dissolved inorganic nitrogen discharged from the bottom of the reservoirs. Moreover, the positive average annual retention ratios for TP and PP were 10% and 16%, respectively, in contrast to the negative averages of -8 % for TN and -11% for particulate nitrogen (PN). The variability in runoff-sediment and hydraulic retention time (HRT) of cascade reservoirs played crucial roles in the retention of TP and PP. A regulatory threshold of HRT = 5.3 days in the flood season was obtained for controlling the balance of TP based on the stronger relationship between HRT and TP retention ratio. Consequently, the HRT of these reservoirs could be managed to control nutrients delivery, which was of particular significance for basin government institutions. This study enhances our comprehension of how cascade reservoirs influence the distribution and transport patterns of nutrients, offering a fresh perspective on nutrients delivery regulation.

Prognostic value of the systemic immuno-inflammatory index in critically ill patients with vertebral fractures.

Inflammation plays a critical role in vertebral fractures. However, there is a lack of sufficient evidence regarding the prognostic significance of the systemic immuno-inflammatory index (SII), a novel marker of systemic inflammation, in patients with vertebral fractures. In this study, we aimed to assess the predictive value of SII in critically ill patients with vertebral fractures. The data were from the Medical Information Mart for Intensive Care III (MIMIC-III) version 1.4 and Wenzhou Hospital of Traditional Chinese Medicine. The cutoff values for SII were determined using the receiver operating characteristic curve, and the subjects were grouped accordingly. The clinical outcome measured was mortality within 30 days, 90 days, or 1 year. The following formula was used to calculate the SII: SII = (platelet count) × (neutrophil count)/ (lymphocyte count). Cox proportional-hazard models were employed to assess the relationship between SII and survival. Additionally, propensity score matching analysis and COX models were utilized to examine the association between SII and survival outcomes. The Pearson correlation test confirmed the correlation between SII and vertebral T-values measured by bone mineral density and pain indicator. A total of 354 patients were finally included from MIMIC-III in the univariate analysis, for the 30-day mortality, SII ≥ 3164 group, the hazard ratio (HR) (95% confidence interval) was 1.71 (1.01, 2.94). After adjusting for age, gender, race, anion gap, creatinine, systolic blood pressure (SBP), DBP MBP, SOFA, acute physiologic score III, chronic kidney disease, and SAPS II, SII ≥ 3164 was found to be an independent significant risk factor for death in patients (HR = 1.85, 95% CI: 1.06-3.24, P = .0315). A similar trend was observed for 90-day mortality and 1-year mortality. Propensity scores matching analysis further confirmed the association of SII and the prognosis of patients. Our validation results were consistent with it. Besides, the Pearson correlation test confirmed a significant correlation between SII and vertebral T-values measured by bone mineral density and pain indicator. The study findings revealed that SII is an independent predictor of mortality in patients with vertebral fractures. This indicates that SII can serve as a reliable and easily accessible prognostic indicator for newly diagnosed critically ill patients with vertebral fractures.

Madecassoside alleviates acute kidney injury by regulating JNK-mediated oxidative stress and programmed cell death.

BACKGROUND: Acute kidney injury (AKI) has high morbidity and mortality, which is manifested by inflammation and apoptosis. Effective treatment methods for AKI are currently lacking. OBJECTIVE: This study demonstrated the protecting effects of Madecassoside (MA) in the cisplatin- and hypoxia-reoxygenation-induced renal tubular epithelial cells in vitro and AKI mice in vivo. METHODS: In vivo AKI mouse models were established by inducing them with cisplatin and renal ischemia-reperfusion. In vitro injury models of mouse renal tubular epithelial cells were established by inducing them with cisplatin and hypoxia and reoxygenation, respectively. The mechanism of MA effects was further explored using molecular docking and RNA-sequencing. RESULTS: MA could significantly reduce kidney injury in the cisplatin-and renal ischemia-reperfusion (IRI)-induced AKI. Further validation in the two cellular models also showed that MA had protect effects. MA can alleviate AKI in vitro and in vivo by inhibiting inflammation, cell apoptosis, and oxidative stress. MA exhibited high permeability across the Caco-2 cell, can enter cells directly. Through RNA-seq and molecular docking analysis, this study further demonstrated that MA inhibits its activity by directly binding to JNK kinase, thereby inhibiting c-JUN mediated cell apoptosis and improving AKI. In addition, MA has better renal protective effects compared to curcumin and JNK inhibitor SP600125. CONCLUSION: The results demonstrate that MA might be a potential drug for the treatment of AKI and act through the JNK/c-JUN signaling pathway.

Low vitamin B12 levels may predict the risk of ischemic stroke: A cross-sectional study.

BACKGROUND: To examine serum vitamin B12 concentrations in relation to the risk of ischemic stroke among hospitalized patients in the Department of Neurology. METHODS: We performed a cross-sectional study involving 2,212 inpatients discharged from the Department of Neurology of the First Affiliated Hospital of Chongqing Medical University, from January 2020 to January 2022. The results of laboratory assays such as serum vitamin B12, homocysteine, and folate levels were measured. Logistic regression analysis was used to investigate the association between serum vitamin B12 concentrations and ischemic stroke, with adjustment for a number of relevant demographic and lifestyle factors and comorbidities. RESULTS: A total of 961 (43.4%) patients had an ischemic stroke. In the fully adjusted model, logistic regression analysis suggested a positive association between serum vitamin B12 levels<150 pg/mL (aOR: 1.42; 95% CI 1.02-1.97; p = 0.035), serum vitamin B12 150-300 pg/mL (aOR: 1.37; 95% CI 1.11-1.68; p = 0.003) and the prevalence of ischemic stroke. Furthermore, an inverse association was observed between serum vitamin B12 levels ≥ 900 pg/mL (aOR: 0.38; 95% CI: 0.19-0.77; p =0.007) and the prevalence of ischemic stroke. Moreover, the cut-off value of vitamin B12 concentration was 316.4 pg/mL and the discrimination power of the score evaluated by AUC-ROC was 0.71 (95%CI 0.68-0.73, p<0.001) in the vitamin B12 and ischemic stroke. CONCLUSION: Findings suggest that low vitamin B12 levels may predict the risk of ischemic stroke, early and timely supplementation of vitamin B12 can improve the short-term prognosis of ischemic stroke patients.

Combined Amphiphilic Silybin Meglumine Nanosuspension Effective Against Hepatic Fibrosis in Mice Model.

Introduction: Silybin (SLB) as an effective hepatoprotective phytomedicine has been limited by its hydrophobicity, poor bioavailability and accumulation at lesion sites. Additionally, present drug loading methods are impeded by their low drug loading capacity, potential hazard of materials and poor therapeutic effects. Consequently, there is a pressing need to devise an innovative approach for preparing nanosuspensions loaded with both SLB and Silybin Meglumine salt (SLB-M), as well as to investigate the therapeutic effects of SLB nanosuspensions against hepatic fibrosis. Methods: The SLB nanosuspension (NS-SLB) was prepared and further modified with a hyaluronic acid-cholesterol conjugate (NS-SLB-HC) to improve the CD44 targeting proficiency of NS-SLB. To validate the accumulation of CD44 and ensure minimal cytotoxicity, cellular uptake and cytotoxicity assessments were carried out for the nanosuspensions. Western blotting was employed to evaluate the anti-hepatic fibrosis efficacy in LX-2 cells by inhibiting the secretion of collagen I. Hepatic fibrosis mouse models were used to further confirm the effectiveness of NS-SLB and NS-SLB-HC against hepatic fibrosis in vivo. Results: Uniform nanosuspensions were prepared through self-assembly, achieving high drug loading rates of 89.44% and 60.67%, respectively. Both SLB nanosuspensions showed minimal cytotoxicity in cellular environments and mitigated hepatic fibrosis in vitro. NS-SLB-HC was demonstrated to target activated hepatic stellate cells by receptor-ligand interaction between HA and CD44. They can reverse hepatic fibrosis in vivo by downregulating TGF-ß and inhibiting the secretion of α-SMA and collagen I. Conclusion: Designed as a medical excipient analogue, SLB-M was aimed to establish an innovative nanosuspension preparation method, characterized by high drug loading capacity and a notable impact against hepatic fibrosis.

Salidroside suppresses proliferation and migration in prostate cancer via the PI3K/AKT pathway.

BACKGROUND: Prostate cancer (PCa) is one of the most common malignancies in men. PCa is difficult to detect in its early stages, and most patients are diagnosed in the middle to late stages. At present, drug therapy for advanced PCa is still insufficient. Some patients develop drug resistance in the later stage of therapy, which leads to tumor recurrence, metastasis and even treatment failure. Therefore, it is crucial to find new and effective drugs to treat prostate cancer. OBJECTIVE: The aim of this study was to investigate the anti-cancer effect of salidroside, an active ingredient in a traditional Chinese herbal medicine, on PCa. METHODS: Two human PCa cell lines, PC3 and DU145, were cultured and treated with salidroside. Cell viability and proliferation ability were analyzed through CCK-8 and colony assays, and cell migration ability was detected by Transwell and Scratch assays. RT-PCR and WB were used to detected the expression levels of moleculars related to cell proliferation, apoptosis, migration, and AKT signaling pathway. Forthmore, we performed rescue experiments with agonist to verify the affected signaling pathway. RESULTS: Salidroside inhibited the proliferation, colony formation, and migration of PCa cells. Meanwhile, apoptosis of PCa cells was enhanced. Moreover, salidroside inhibited PI3K/AKT pathway in PCa cells. The treatment of AKT agonist 740Y-P abrogated the inhibitory effect of salidroside on the PI3K/AKT signaling pathway. CONCLUSIONS: Our study demonstrated that in PCa cells, salidroside inhibites proliferation and migration and promots apoptosis via inhibiting PI3K/AKT pathway.

Dietary docosahexaenoic acid plays an opposed role in ferroptotic and non-ferroptotic acute kidney injury.

Ferroptosis due to polyunsaturated fatty acid (PUFA) peroxidation has been implicated in the pathogenesis of acute kidney injury (AKI), suggesting the risk of dietary intake of PUFA for people susceptible to AKI. Clinically, however, in addition to ferroptosis, other mechanisms also contribute to different types of AKI such as inflammation associated necroptosis and pyroptosis. Therefore, the role of PUFA, especially ω3 PUFA which is a common food supplement, in various AKIs deserves further evaluation. In this study, rhabdomyolysis- and folic acid-induced AKI (Rha-AKI and FA-AKI) were established in mice fed with different fatty acids Histology of kidney, blood urea nitrogen and creatinine, lipid peroxidation, and inflammatory factors were examined. Results showed that these two types of AKIs had diametrically different pathogenesis indicated by that ferrostatin-1 (Fer-1), a lipid antioxidant, can attenuate FA-AKI rather than Rha-AKI. Further, dietary DHA (provided by fish oil) reduced tubular injury and renal lesion by inhibiting peroxidation and inflammation in mice with Rha-AKI while increasing cell death, tissue damage, peroxidation and inflammation in mice with FA-AKI. In human renal tubular epithelial cell line HK-2, MTT assay and DHE staining showed that both myoglobin and ferroptosis inducers can cause cell death and oxidative stress. Ferroptosis inducer-induced cell death was promoted by DHA, while such result was not observed in myoglobin-induced cell death when adding DHA. This study illustrates that the mechanisms of AKI might be either ferroptosis dependent or -independent and the deterioration effect of dietary DHA depends on whether ferroptosis is involved.

TCM monotherapy achieves significant efficacy in crizotinib-refractory advanced NSCLC with brain metastasis.

RATIONALE: The morbidity and mortality of lung cancer rank the first among all kinds of cancer. In China, anaplastic lymphoma kinase-positive pulmonary tumors account for nearly 5% of non-small cell lung cancer (NSCLC), and these patients are quite likely to develop brain metastases, as high as around 45%. Although anaplastic lymphoma kinase-tyrosine kinase inhibitors crizotinib and alectinib have proved effective for controlling tumor metastases to the brain, drug resistance and disease progression cannot be ignored in the course of treatment. PATIENT CONCERNS: Most of the literature reports that traditional Chinese medicine (TCM) has produced satisfactory results in the treatment of cancer patients as an adjuvant treatment for various malignancies in a 53-year-old male patient who developed advanced NSCLC with brain metastases. As first-line crizotinib and erlotinib treatments were ineffective and the intracranial lesions progressed extensively, the patient chose to receive TCM treatment alone in the hope of prolonging his life and improving his quality of life. DIAGNOSES: A 53-year-old male patient who developed advanced NSCLC with brain metastasis. Because first-line crizotinib and alectinib have failed, and the intracranial lesions progressed in a large area. INTERVENTIONS: The patient requested that the final therapeutic strategy be Chinese medicine as monotherapy for long-term treatment. The patient took 30 mL of the decoction 1 hour after a meal, 3 times a day. The patient was not treated with dehydrating agents or diuretics during the TCM treatment. OUTCOMES: The improvement was obvious after 3 months of treatment, and significant reduction of cranial lesions. During the follow-up period, the patient developed neither severe liver damage nor kidney damage. LESSONS: This case is the first 1 in the world where TCM was introduced as monotherapy for severe conditions with extensive brain metastases and achieved remarkable efficacy.

Vitamin B12 supplementation improves cognitive function in middle aged and elderly patients with cognitive impairment.

Introduction: Objectives: to determine the effects of vitamin B12 supplementation on neuropsychological function and disease progression in middle aged and elderly patients with cognitive impairment. Methods: this was a prospective case-control study. From May 2020 to May 2021, 307 participants clinically diagnosed with cognitive impairment in the Department of Neurology of the First Affiliated Hospital of Chongqing Medical University were enrolled. A total of 115 patients were included in this study. Meanwhile, 115 participants with cognitive impairment were randomly assigned in equal proportions to two groups: vitamin B12 treatment group (n = 58, vitamin B12 500 mg/d intramuscularly for seven days, followed by cobamamide 0.25 mg/d and methylcobalamin 0.50 mg/d) and the control group (n = 57). Demographic characteristics and blood biochemical variables were obtained from all participants. Cognitive performance was measured using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Cognitive performance was measured at baseline and after six months. Results: the vitamin B12 supplementation treatment patients who presented with cognitive impairment showed significant improvement, especially in attention, calculation (p < 0.01) and visual-constructional ability (p < 0.05), in their neuropsychological function compared to their matched group. Conclusion: vitamin B12 supplementation may improve frontal function in patients with cognitive decline. Vitamin B12 levels should be investigated in all patients with cognitive impairment.

Introducción: Objetivos: determinar los efectos de la suplementación con vitamina B12 en la función neuropsicológica y la progresión de la enfermedad en pacientes de mediana edad y adultos mayores con deterioro cognitivo. Métodos: se realizó un estudio prospectivo de casos y controles; se estudiaron 307 participantes, desde mayo de 2020 a mayo de 2021, diagnosticados clínicamente con deterioro cognitivo en el Departamento de Neurología, el Primer Hospital Anexado a la Universidad Médica de Chongqing. En el estudio se incluyeron un total de 115 pacientes con deterioro cognitivo que fueron asignados aleatoriamente en proporciones iguales a dos grupos: un grupo de tratamiento con vitamina B12 (n = 58, vitamina B12 500 mg/d intramuscular durante 7 días, seguido de cobamamida 0,25 mg/d y metilcobalamina 0,50 mg/d) y un grupo de control (n = 57). Se obtuvieron las características demográficas y las variables bioquímicas sanguíneas de todos los participantes. El rendimiento cognitivo se midió mediante el miniexamen del estado mental (MMSE) y la evaluación cognitiva de Montreal (Moca) al inicio del estudio y a los 6 meses. Resultados: los pacientes con deterioro cognitivo que recibieron tratamiento de suplementación con vitamina B12 mostraron una mejora significativa, especialmente en la atención, el cálculo (p < 0,01) y la capacidad visuoespacial (p < 0,05), en su función neuropsicológica en comparación con el grupo control. Conclusión: la suplementación con vitamina B12 puede mejorar la función frontal en pacientes con deterioro cognitivo. Los pacientes con deterioro cognitivo deben conocer sus propios niveles de vitamina B12.

Pollen self-elimination CRISPR-Cas genome editing prevents transgenic pollen dispersal in maize.

This study reports the development of a programmed pollen self-elimination CRISPR-Cas (PSEC) system in which the pollen is infertile when PSEC is present in haploid pollen. PSEC can be inherited through the female gametophyte and retains genome editing activity in vivo across generations. This system could greatly alleviate serious concerns about the widespread diffusion of genetically modified (GM) elements into natural and agricultural environments via outcrossing.

Cajanin stilbene acid: A direct inhibitor of colistin resistance protein MCR-1 that restores the efficacy of polymyxin B against resistant Gram-negative bacteria.

BACKGROUND: The resistance of Gram-negative bacteria to polymyxin B, caused by the plasmid-mediated colistin resistance gene mcr-1, which encodes a phosphoethanolamine transferase (MCR-1), is a serious threat to global public health. Therefore, it is urgent to find new drugs that can effectively alleviate polymyxin B resistance. Through the screening of 78 natural compounds, we found that cajanin stilbene acid (CSA) can significantly restore the susceptibility of polymyxin B to mcr-1 positive Escherichia coli (E. coli). PURPOSE: In this study, we tried to evaluate the ability of CSA to restore the susceptibility of polymyxin B towards the E. coli, and explore the mechanism of sensitivity recovery. STUDY DESIGN AND METHODS: Checkerboard MICs, time-killing curves, scanning electron microscope, lethal and semi-lethal models of infection in mice were used to assess the ability of CSA to restore the susceptibility of polymyxyn to E. coli. The interaction between CSA and MCR-1 was evaluated using surface plasmon resonance (SPR), and molecular docking experiments. RESULTS: Here, we find that CSA, a potential direct inhibitor of MCR-1, effectively restores the sensitivity of E. coli to polymyxin B. CSA can restore the sensitivity of polymyxin B to drug-resistant E. coli, and the MIC value can be reduced to 1 µg/ml. The time killing curve and scanning electron microscopy results also showed that CSA can effectively restore polymyxin B sensitivity. In vivo experiments showed that the simultaneous use of CSA and polymyxin B can effectively reduce the infection of drug-resistant E. coli in mice. SPR and molecular docking experiments confirmed that CSA strongly bound to MCR-1. The 17-carbonyl oxygen and 12- and 18­hydroxyl oxygens of CSA were the key sites binding to MCR-1. CONCLUSION: CSA is able to significantly restore the sensitivity of polymyxin B to E. coli in vivo and in vitro. CSA inhibits the enzymatic activity of the MCR-1 protein by binding to key amino acids at the active center of the MCR-1 protein.

Endogenous n-3 PUFAs Improve Non-Alcoholic Fatty Liver Disease through FFAR4-Mediated Gut-Liver Crosstalk.

The gut-liver axis plays a key role in the development and progression of non-alcoholic fatty liver disease (NAFLD). Due to the complexity and incomplete understanding of the cross-talk between the gut and liver, effective therapeutic targets are largely unknown. Free fatty acid receptors (FFARs) may bridge the cross-talk between the gut and liver. FFAR4 has received considerable attention due to its important role in lipid metabolism. However, the role of FFAR4 in this cross talk in NAFLD remains unclear. In this study, mice with high endogenous n-3 PUFAs but FFAR4 deficiency were generated by crossbreeding Fat-1 and FFAR4 knockout mice. FFAR4 deficiency blocked the protective effects of high endogenous n-3 PUFAs on intestinal barrier dysfunction and hepatic steatosis. In addition, FFAR4 deficiency decreased gut microbiota diversity and enriched Rikenella, Anaerotruncus, and Enterococcus, and reduced Dubosiella, Ruminococcaceae UCG-010, Ruminococcaceae UCG-014, Coriobacteriaceae UCG-002, Faecalibaculum, Ruminococcaceae UCG-009, and Akkermansia. Notably, FFAR4 deficiency co-regulated pantothenic acid and CoA biosynthesis, ß-alanine metabolism, and sphingolipid metabolism pathways in the gut and liver, potentially associated with the aggravation of NAFLD. Together, the beneficial effects of n-3 PUFAs on the gut and liver were mediated by FFAR4, providing insights on the role of FFAR4 in the treatment of NAFLD through the gut-liver axis.

Genome-wide identification of GSK gene family in Senna tora L. and expression analyses / 药学学报

Glycogen synthase kinase 3/SHAGGY-like kinase (GSK3) proteins play important roles in regulating plant growth, development, and stress response. In order to reveal the characteristics of GSK family members in the medicinal plant Senna tora L., in this study, we conducted the identification and expression analyses of GSKs in S. tora based on its whole genome data, combined with bioinformatics and gene expression research methods. The results showed that a total of nine S. tora GSK genes were identified, all of which contained the GSK characteristic kinase domains. All members were distributed on six chromosomes, the encoding amino acid length ranged from 465 to 943 aa, the protein molecular weight was from 33.57 to 88.83 kDa, and the average isoelectric point was 8.2. The StoSKs were divided into four evolutionary branches, and the StoSKs in the same evolutionary branch shared the same exon/intron structure and conserved motifs. The expansion of the StoSKs gene family was mainly due to segment duplication events, and there were 17, 11, 8 and 7 pairs of collinear genes with Glycine max, Medicago truncatula, Arabidopsis thaliana and Oryza sativa, respectively. The promoter regions of StoSKs mostly contained responses elements related to stress stimulation, growth and development, and hormone induction. Transcriptome data analysis showed that StoSKs were expressed in different tissues, with the highest expression level in roots. Quantitative real-time PCR (qRT-PCR) analysis indicated that StoSKs in different evolutionary branches displayed a synergistic expression pattern response to light, and most of StoSKs could rapidly respond to NaCl stress with significantly up-regulated expression. All the results provide a basis for further analysis of the biological functions of the GSKs gene family in S. tora.

Guanxinning tablet inhibits the interaction between leukocyte integrin Mac-1 and platelet GPIbα for antithrombosis without increased bleeding risk.

Recent studies have showed that thrombosis is closely related to leucocytes involved in immunity. Interfering with the binding of leukocyte integrin Mac-1 and platelet GPIbα can inhibit thrombosis without affecting physiological coagulation. Mac-1-GPIbα is proposed as a potential safety target for antithrombotic agents. Guanxinning tablet (GXNT) is an oral Chinese patent medicine used for the treatment of angina pectoris, which contains phenolic acid active ingredients, such as salvianolic acids, ferulic acid, chlorogenic acid, caffeic acid, rosmarinic acid, tanshinol, and protocatechualdehyde. Our previous studies demonstrated that GXN exhibited significant antithrombotic effects, and clinical studies suggested that it did not increase bleeding risk. In addition, GXN exerted a significantly regulatory effect on immune inflammation. In the current study, we intended to evaluate the effects of GXN on bleeding events and explore the safety antithrombotic mechanism of GXN based on leukocyte-platelet interaction. First, we established a gastric ulcer model induced by acetic acid in rats and found that GXN not only did not increase the degree of gastrointestinal bleeding when gastric ulcer occurred, but also had a certain promoting effect on the healing of gastric ulcer. Second, in vitroexperiments showed that after pretreatment with GXN and activation by phorbol 12-myristate-13-acetate (PMA), the adhesion and aggregation of leukocytes with human platelets were reduced. It was also found that GXN reduced the expression and activation of Mac-1 in leucocytes, and inhibited platelet activation due to leukocyte engagement via Mac-1. Overall, the results suggest that GXN may be a safe antithrombotic agent, and its low bleeding risk mechanism is probably related to inhibited leukocyte-platelet aggregation and its interaction target Mac-1-GPIbα.

Bergapten mediated inflammatory and apoptosis through AMPK/eNOS/AKT signaling pathway of isoproterenol-induced myocardial infarction in Wistar rats.

Bergapten (BeG) is explored for its anti-inflammatory and antioxidant properties. Myocardial infarction (MI) is reported to be one of the leading cardiovascular diseases characterized by mitochondrial dysfunction and apoptosis. The main purpose of this study is to assess the cardiopreventive effects of BeG (50 mg/kg) in isoproterenol (ISO)-induced MI in Wistar rats. The increased infarct size after ISO induction was reduced simultaneously on treatment with BeG. Similarly, augmented levels of cardiac biomarkers, namely cardiac troponin T, creatine kinase (CK), cardiac troponin I, and CK-MB were also suppressed by BeG. The increased rate of lipid hydroperoxides and thiobarbituric acid reactive substances owing to the oxidative stress caused by free radical generation in ISO-induced rats were also inhibited by BeG. Antioxidants reduce oxidative stress by scavenging free radicals. ISO induction reduces these antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase, and glutathione, and levels causing oxidative cardiac damage to the heart tissue. BeG supplementation improved these enzymes synthesis preventing potential damage to the myocardium. Inflammation caused by ISO pretreatment increased the secretion of proinflammatory cytokines in ISO-induced rats. Pretreatment with BeG suppressed these inflammatory cytokines to a normal level in ISO + BeG-treated rats. The histopathological examination of the morphological characteristics showed that the intensity of cardiac damage caused by ISO induction was less in BeG pretreated rats with less inflammatory cells and no necrosis. BeG also showed promising results in the molecular alteration of AMP-activated protein kinase/endothelial nitric oxide synthase/protein kinase B signaling molecules. These observations emphasize the cardioprotective effects of BeG and its potential use as a drug in the near future.

Luteolin Induced Hippocampal Neuronal Pyroptosis Inhibition by Regulation of miR-124-3p/TNF-α/TRAF6 Axis in Mice Affected by Breast-Cancer-Related Depression.

Background: Breast-cancer-related depression (BCRD) is associated with an increased mortality rate among breast cancer (BC) survivors. Luteolin has many pharmacological effects, particularly in the treatment of BC. In this study, we aimed to explore the anti-BCRD activity of luteolin and its underlying functional mechanism. Methods: A BCRD mouse model was induced by injecting 4T1 cells and corticosterone (COR). Behavioral test, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Nissl staining, immunofluorescence, reverse-transcription quantitative PCR (RT-qPCR), and western blotting were used to study the effect of luteolin in mice with BCRD in vivo. A COR-induced neuron injury model was established in HT-22 cells in vitro. The role of miR-124-3p in the anti-BCRD effects of luteolin was studied using a miR-124-3p inhibitor. Results: Luteolin significantly reduced the size and weight of the tumor, increased the mice entry frequency in the symmetrical sector, and reduced the duration of immobility in the tail suspension and forced swimming tests of mice affected by BCRD. Simultaneously, apoptosis of hippocampal neurons was inhibited, and the number of Nissl bodies increased with luteolin treatment. In addition, luteolin resulted in the upregulation of miR-124-3p expression in the hippocampus and downregulated the expression of tumor necrosis factor-α (TNF-α) and TNF receptor-associated factor 6 (TRAF6), as well as lowered the phosphorylation levels of nuclear factor-kappa B (NF-κB) and IkappaB (IκB). Luteolin also inhibited pyroptosis of hippocampal neurons in mice affected by BCRD, as revealed by the low protein levels of NOD-like receptor protein 3 (NLRP3), caspase-1, gasdermin D-N (GSDMD-N), interleukin (IL)-1ß, and IL-18. However, the miR-124-3p inhibitor significantly reversed the therapeutic effect of luteolin on COR-induced HT-22 cells. Conclusion: Our study demonstrated that the anti-BCRD function of luteolin was mediated by regulating the miR-124-3p/TNF-α/TRAF6-related pathway and inhibiting neuronal cell pyroptosis and subsequent inflammation. Therefore, luteolin may be a potential drug candidate in the treatments of BCRD.

Resveratrol Inhibits High Glucose-Induced H9c2 Cardiomyocyte Hypertrophy and Damage via RAGE-Dependent Inhibition of the NF-κB and TGF-ß1/Smad3 Pathways.

Hyperglycaemia is associated with the development of cardiac vascular disease. Resveratrol (RES) is a naturally occurring polyphenolic compound that possesses many biological properties, including anti-inflammatory properties and antioxidation functions. Our study aimed to explore the RES's protective roles on high glucose (HG)-induced H9c2 cells and the underlying mechanisms. Small-molecule inhibitors, western blotting (WB), as well as reverse-transcription PCR (RT-PCR) were employed to investigate the mechanisms underlying HG-induced damage in H9c2 cells. RES (40 µg/mL) treatment significantly alleviated HG-induced cardiac hypertrophy and cardiac dysfunction. RES abated the HG-induced increase in the levels of extracellular matrix (ECM) components and inflammatory cytokines, reducing ECM accumulation and inflammatory responses. Additionally, RES administration prevented HG-induced mitochondrion-mediated cardiac apoptosis of myocardial cells. In terms of mechanisms, we demonstrated that RES ameliorated the HG-induced overexpression of receptor for advanced glycation endproducts (RAGE) and downregulation of NF-κB signalling. Moreover, RES inhibited HG-induced cardiac fibrosis by inhibiting transforming growth factor beta 1 (TGF-ß1)/Smad3-mediated ECM synthesis in cultured H9c2 cardiomyocytes. Further studies revealed that the effects of RES against HG-induced upregulation of NF-κB and TGF-ß1/Smad3 pathways were similar to those of FPS-ZM1, a RAGE inhibitor. Collectively, the results implied that RES might help alleviate HG-induced cardiotoxicity via RAGE-dependent downregulation of the NF-κB and TGF-ß/Smad3 pathways. This study provided evidence that RES can be developed as a promising cardioprotective drug.

Plasma Concentrations of Trace Elements Selenium and Cobalt During and After Coronary Artery Bypass Grafting Surgery.

Trace elements selenium (Se) and cobalt (Co) are essential in the human body, and a correlation between Se and cardiac surgery has been suggested. We investigated the plasma concentrations of Se and Co during and after coronary artery bypass grafting (CABG) surgery under cardiopulmonary bypass (CPB). From December 2019 to January 2020, preoperative plasma samples from isolated first-time CABG patients (n=20; 10 males, 10 females) were prospectively collected post-anesthesia and before CPB (T1), 45 min after CPB started (T2), 90 min after CPB started (T3), and postoperative days 1 (T4), and day 4 (T5). The plasma concentrations of Se and Co were measured. The Se concentration was significantly decreased at T2 (105.24±4.08 vs. 68.56±2.42 µg/L, p<0.001) and T3 (105.24±4.08 vs. 80.41±3.40 µg/L, p<0.001). The Co concentration was significantly decreased at T4 (0.35±0.19 vs. 0.26±0.13 µg/L, p<0.01) and T5 (0.35±0.19 vs. 0.23±0.11 µg/L, p<0.001). Five patients developed atrial fibrillation (AF); there was no other operative mortality or major morbidity. This is the first report of alterations of plasma Se and Co concentrations during and after CABG surgery. Our results may indicate that Se supplementation before or during CABG and Co supplementation after CABG may become necessary for patients undergoing CABG.

Atomic-Layer Deposition Processes Applied to Phage λ and a Phage-like Particle Platform Yield Thermostable, Single-Shot Vaccines.

Especially in developing countries, the impact of vaccines can be limited by logistical obstacles associated with multiple dose regimens, pathogen variants, and challenges imposed by requirements for maintaining vaccines at low temperatures during shipping and storage. Thus, there is a need for vaccines that can be flexibly modified to address evolving pathogen landscapes, are stable outside of narrow "cold-chain" temperatures and require administration of only single doses. Here we demonstrate in proof-of-concept studies a vaccine platform that addresses these impediments to more widespread use of vaccines. The platform relies on bacteriophage-derived phage-like-particles (PLPs) that utilize a "plug-and-play" antigen delivery system that allows for fast, easy alteration of antigens on the surface of the PLPs. Thermostability of PLP-based vaccines can be achieved by embedding the PLPs within glassy particles produced by spray drying, and nanoscopic aluminum oxide layers applied using atomic layer deposition (ALD) can serve to control release of antigen in vivo, yielding vaccine formulations that elicit strong immune responses after administration of single doses. Bacteriophage λ was stabilized by spray drying to form powders that were incubated at 37 °C for up to a year without loss of infectious activity. PLPs derived from bacteriophage λ were expressed and purified from E. coli cultures, and an in vitro conjugation strategy was used to decorate specific PLP surface sites with T4-lysozyme, a model vaccine antigen. The resulting T4-lysozyme:PLP complexes (Lys-PLPs) were embedded in glassy dry powders formed by spray drying and coated with nanometer-thick layers of alumina deposited by ALD in a fluidized bed reactor. Alumina-coated Lys-PLP vaccines were stable for a least a month at 50 °C, and single doses of the alumina-coated vaccines elicited immune responses that were indistinguishable from responses generated by conventional two-dose, prime-and-boost dosing regimens of alum-adjuvanted Lys-PLP vaccines.