Role of Escin in breast cancer therapy: potential mechanism for inducing ferroptosis and synergistic antitumor activity with cisplatin.

Breast cancer (BC) has threatened women worldwide for a long time, and novel treatments are needed. Ferroptosis is a new form of regulated cell death that is a potential therapeutic target for BC. In this study, we identified Escin, a traditional Chinese medicine, as a possible supplement for existing chemotherapy strategies. Escin inhibited BC cell growth in vitro and in vivo, and ferroptosis is probable to be the main cause for Escin-induced cell death. Mechanistically, Escin significantly downregulated the protein level of GPX4, while overexpression of GPX4 could reverse the ferroptosis triggered by Escin. Further study revealed that Escin could promote G6PD ubiquitination and degradation, thus inhibiting the expression of GPX4 and contributing to the ferroptosis. Moreover, proteasome inhibitor MG132 or G6PD overexpression could partially reverse Escin-induced ferroptosis, when G6PD knockdown aggravated that. In vivo study also supported that downregulation of G6PD exacerbated tumor growth inhibition by Escin. Finally, our data showed that cell apoptosis was dramatically elevated by Escin combined with cisplatin in BC cells. Taken together, these results suggest that Escin inhibits tumor growth in vivo and in vitro via regulating the ferroptosis mediated by G6PD/GPX4 axis. Our findings provide a promising therapeutic strategy for BC.

Isoliquiritigenin from licorice flavonoids attenuates NLRP3-mediated pyroptosis by SIRT6 in vascular endothelial cells.

ETHNOPHARMACOLOGIC RELEVANCE: Licorice is a traditional Chinese medicine that has been used for cardiovascular diseases. Recent studies found that supplementation with licorice extracts attenuated the development of atherosclerosis (AS) in hypercholesterolemic patients. Many studies have shown that licorice flavonoids, the main active components of licorice, have a variety of pharmacological effects, including anti-inflammation, regulation of lipid metabolism, and antioxidation. However, the key active components against AS in licorice flavonoids are still unclear. AIM OF THE STUDY: The aim of this paper is to investigate the active components of licorice flavonoids that exert anti-atherosclerotic effects and the underlying mechanisms. MATERIALS AND METHODS: Network pharmacology was used to screen the active components of licorice flavonoids that have anti-atherosclerotic effects. Combining bioinformatics analysis and in vitro studies, the effects and underlying mechanisms of the active component isoliquiritigenin (ISL) on cell pyroptosis were further investigated in tumor necrosis factor (TNF)-α-treated human umbilical vein endothelial cells (HUVECs). RESULTS: We constructed a compound-target network and screened 3 active components, namely, ISL, glabridin, and naringenin in licorice flavonoids. The half maximal effective concentration values of these 3 components suggested that ISL was the key active component against TNF-α-induced endothelial cell injury. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that ISL could potentially treat AS via the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway. An in vitro study verified that ISL suppressed TNF-α-induced NLRP3 activation and pyroptosis in HUVECs. The molecular docking and cellular thermal shift assay showed good compatibility between ISL and class III histone deacetylase sirtuin 6 (SIRT6). Moreover, we found that ISL upregulated the expression of SIRT6 in TNF-α-treated HUVECs. Further study found that SIRT6 knockdown reduced the inhibitory effect of ISL on pyroptosis, whereas the NLRP3 inhibitor reversed this process in TNF-α-treated HUVECs. CONCLUSIONS: Our results demonstrate that ISL is a key active component of licorice flavonoids. ISL attenuates NLRP3-mediated vascular endothelial cell pyroptosis via SIRT6, and SIRT6 may be a potential target of ISL for the treatment of AS.

Rhaponticum carthamoides improved energy metabolism and oxidative stress through the SIRT6/Nrf2 pathway to ameliorate myocardial injury.

BACKGROUND: Rhaponticum carthamoides (Willd.) Iljin (Rha) is a member of the family Compositae that is widely used in folk medicine as a dietary supplement to treat cardiovascular diseases (CVDs), such as senile cardiac insufficiency, and to restore myocardial function after surgery. Sirtuin 6 (SIRT6), an NAD+-dependent class III histone deacetylase, plays a considerable role in the administration of CVDs. However, the specific effects and mechanism of Rha on myocardial injury remain unknown. PURPOSE: This study aimed to explore the therapeutic potential of Rha against myocardial injury as well as its underlying mechanisms in vivo and in vitro. METHODS: A myocardial ischaemia model was established in male SD rats by subcutaneously injecting ISO. The rats were gavaged with Rha (40, 80, 160 mg/kg) or Rho (6 ml/kg) for 14 successive days and then injected subcutaneously with ISO or saline solution on the 13th and 14th days. The positive effects of Rha against myocardial injury in rats were evaluated by ECG assessment, BP measurements, H&E staining, and myocardial enzyme detection. Biochemical indicators of energy metabolism and oxidative stress, such as NAD+/NADH, ATP, and MDA, were analysed by assay kits to assess the effects of Rha. The protein and mRNA expression levels of SIRT6 and Nrf2 in the myocardium were determined by western blotting and real-time PCR. RESULTS: Our results showed that Rha ameliorated myocardial ischaemia and inhibited energy metabolism disorders (NAD+/NADH ratio, ATP, and LD) and oxidative stress (SOD, ROS, etc.) in rat myocardial tissue and H9c2 cells. In addition, Rha upregulated SIRT6 and Nrf2 expression in myocardial injury. Mechanistic studies then found that SIRT6 knockdown reduced the expression of Nrf2 as well as the effects of Rha on the levels of ATP, LD, and ROS, whereas activation of Nrf2 improved the effects of Rha in cells. In summary, Rha might exert its cardioprotective effects via the SIRT6-mediated Nrf2 signaling pathway. CONCLUSION: The results suggest that Rha regulates energy metabolism and oxidative stress through the SIRT6/Nrf2 signaling pathway to play a protective role in myocardial injury.

Comparison of ureteroscopy (URS) complementary treatment after extracorporeal shock wave lithotripsy failure with primary URS lithotripsy with holmium laser treatment for proximal ureteral stones larger than10mm.

BACKGROUND: To compare ureteroscopy (URS) complementary treatment following extracorporeal shock wave lithotripsy (SWL) failure with primary URS lithotripsy for proximal ureteral stones > 10 mm, and try to find out acceptable number of SWL sessions followed by safe URS. METHODS: This was a retrospective study following approval from Medical Ethics Committee of People's Hospital of Chongqing Banan District. Patients (n = 340) who received URS in our hospital for stones > 10 mm from Jan 2015 to June 2020 were divided into two groups according to their previous SWL history. Group 1 consisted of 160 patients that underwent unsuccessful SWL before URS. Group 2 encompassed 180 patients without SWL before URS. Patient's operative outcomes were compared. A logistic regression and receiver operator characteristics (ROC) were used to identify the acceptable number of SWL sessions prior to URS, regarding the intra-operative complications of URS. RESULTS: The group 1 required more surgery time (41.38 ± 11.39 min vs. 36.43 ± 13.36 min, p = 0.01). At the same time, more intra-operative (68.1% VS 22.8%, p < 0.05) and post-operative (35% VS 18.0%, p = 0.001) complications occurred in group 1. Need more hospital stay in group 1 (2.7 ± 1.2 days vs 1.6 ± 1.1 days, p < 0.05). More patients in group 1 need further URS (16.3% VS 8.9%, p = 0.029). After second URS, the SFR of URS in two groups was insignificant differences (82.5% VS 88.9%, p > 0.05). The median (25-75%) of SWL sessions before URS was 2 (1-3) in group 1. According to the results of logistic regression analysis, patients suffered more SWL failure have an increased risk of complications during URS (OR = 1.995, 95% CI: 1.636-2.434). ROC showed that the optimal number of SWL session followed by URS were 0.5, with a sensitivity of 67.7% and specificity of 71.5%. Intra-operative complication rates of URS treatment were higher in patients who suffered > 1 SWL failure (72.6% vs 57.4%, p = 0.047). CONCLUSION: There was no acceptable number of SWL sessions that could be followed by URS with fewer intra-operative complications. Patients who underwent previous SWL were likely to suffer more intra-operative complications, the average operating time, hospitalization time, and needing further treatment, during URS treatment for proximal ureteral stones larger than 10 mm.

Inhibition of NLRP3 Inflammasome Activation and Pyroptosis in Macrophages by Taraxasterol Is Associated With Its Regulation on mTOR Signaling.

Taraxasterol (TAS) is an active ingredient of Dandelion (Taraxacum mongolicum Hand. -Mazz.), a medicinal plant that has long been used in China for treatment of inflammatory disorders. But the underlying mechanism for its therapeutic effects on inflammatory disorders is not completely clear. Inflammasome activation is a critical step of innate immune response to infection and aseptic inflammation. Among the various types of inflammasome sensors that has been reported, NLR family pyrin domain containing 3 (NLRP3) is implicated in various inflammatory diseases and therefore has been most extensively studied. In this study, we aimed to explore whether TAS could influence NLPR3 inflammasome activation in macrophages. The results showed that TAS dose-dependently suppressed the activation of caspase-1 in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin treatment, resulting in reduced mature interleukin-1ß (IL-1ß) release and gasdermin D (GSDMD) cleavage. TAS greatly reduced ASC speck formation upon the stimulation of nigericin or extracellular ATP. Consistent with reduced cleavage of GSDMD, nigericin-induced pyroptosis was alleviated by TAS. Interestingly, TAS time-dependently suppressed the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 signaling induced by LPS priming. Like TAS, both INK-128 (inhibiting both mTORC1 and mTORC2) and rapamycin (inhibiting mTORC1 only) also inhibited NLRP3 inflammasome activation, though their effects on mTOR signaling were different. Moreover, TAS treatment alleviated mitochondrial damage by nigericin and improved mouse survival from bacterial infection, accompanied by reduced IL-1ß levels in vivo. Collectively, by inhibiting the NLRP3 inflammasome activation, TAS displayed anti-inflammatory effects likely through regulation of the mTOR signaling in macrophages, highlighting a potential action mechanism for the anti-inflammatory activity of Dandelion in treating inflammation-related disorders, which warrants further clinical investigation.

Berberine augments hypertrophy of colonic patches in mice with intraperitoneal bacterial infection.

Colonic patches, the counterparts of Peyer's patches in the small intestine, are dynamically regulated lymphoid tissues in the colon that have an important role in defensing against microbial infections. Berberine is an isoquinoline alkaloid extracted from medicinal herbs including Rhizoma coptidis and has long been used for the treatment of infectious gastroenteritis, but its impact on the colonic lymphoid tissues (such as colonic patches) is unknown. In this study, we aimed to investigate whether berberine had any influences on the colonic patches in mice with bacterial infection. The results showed that oral berberine administration in bacterial infected mice substantially enhanced the hypertrophy of colonic patches, which usually possessed the features of two large B-cell follicles with a separate T-cell area. Moreover, the colonic patches displayed follicular dendritic cell networks within the B-cell follicles, indicative of mature colonic patches containing germinal centers. Concomitant with enlarged colonic patches, the cultured colon of infected mice treated with berberine secreted significantly higher levels of interleukin-1ß (IL-1ß), IL-6, TNF-α, and CCL-2, while NLRP3 inhibitor MMC950 or knockout of NLRP3 gene abrogated berberine-induced hypertrophy of colonic patches, suggesting the involvement of the NLRP3 signaling pathway in this process. Functionally, oral administration of berberine ameliorated liver inflammation and improved formed feces in the colon. Altogether, these results indicated that berberine was able to augment the hypertrophy of colonic patches in mice with bacterial infection probably through enhancing local inflammatory responses in the colon.

The potential role of Annexin 3 in diapause embryo restart of Artemia sinica and in response to stress of low temperature.

Annexins are highly conserved and ubiquitous in various somatic cell types. They are involved in membrane transport and a range of calcium-regulated activities on the cell membrane surface, including vesicular transport, membrane fusion in exocytosis, signal transduction, and formation of calcium channels. They also regulate inflammatory response, cell differentiation, and interaction between cytoskeletal proteins. In this study, for the first time, an ANX3 gene from Artemia sinica ( As-anx3) was cloned. The As-anx3 full-length complementary DNA comprises 1,024 bp and has a 948 bp open reading frame encoding a 315-amino-acid polypeptide with four ANX domains. The profiles of both As-ANX3 mRNA and protein expression exhibited peaks at the 0 hr stage and had the same significant downregulation trend throughout the post-diapause embryo development stage. The ERK1/2, the phosphorylation levels of ERK1/2, and cell cycle-related protein (CDK4) expressions were analyzed by western blot analysis. The results showed that CDK4 presented a significantly ascending trend from 0 and 40 hr, although the phosphorylation levels of ERK1/2 did not increase significantly. The transcriptional and protein expressions of As-ANX3 were highly upregulated when the temperature was lowered from 25 to 15°C, but the expressions showed a gradual downward trend when the temperature was further lowered to 5°C. These results indicated that As-ANX3 plays a crucial role in restarting diapause and low-temperature stress in A. sinica.

Hydroxytyrosol NO regulates oxidative stress and NO production through SIRT1 in diabetic mice and vascular endothelial cells.

BACKGROUND: Vascular complications are major causes of disability and death in people with diabetes mellitus (DM). Nitric oxide (NO) supplement may help prevent vascular complications and is an attractive treatment option for DM. Hydroxytyrosol (HT) is a major polyphenol in olive oil. It is mainly used as a dietary supplement because of its antioxidant effect. PURPOSE: We aimed to determine the effects of hydroxytyrosol nitric oxide (HT-NO) on oxidative stress and NO level as well as related mechanisms. STUDY DESIGN/METHODS: The effects of HT-NO on oxidative stress and NO level were examined by using diabetic mouse model and HUVECs. RESULTS: Our results showed that HT-NO has antioxidant and NO-releasing activities in vitro and in DM mice. HT-NO not only decreased blood glucose and oxidative stress but also increased NO level and deacetylase Sirtuin 1 (SIRT1) expression in DM mice and high glucose (HG)-stimulated HUVECs. Further studies found that SIRT1 activation augmented the effect of HT-NO on eNOS phosphorylation in HG-stimulated HUVECs. However, the promotive effect of HT-NO on eNOS phosphorylation was abolished by SIRT1 knockdown. Most importantly, HT-NO inhibited reactive oxygen species (ROS) production through SIRT1 in HUVECs. The ROS scavenger enhanced the effect of HT-NO on eNOS phosphorylation. CONCLUSION: These results suggest that HT-NO regulates oxidative stress and NO production partly through SIRT1 in DM mice and HG-stimulated HUVECs.

Screening of Antitumor Active Components and Key Targets of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma Based on PI3K/Akt Pathway / 中国实验方剂学杂志

Objective:Screen out the antitumor constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma base on system pharmacology with chemical constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma as study objects, in order to provide the theoretical basis for the development of antitumor and nontoxic activities of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma. Method:The small molecule ligand library of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma was built based on Traditional Chinese Medicine Systems Pharmacology(TCMSP), energy of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma was matched with the key protein targets of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signal pathway by molecular docking (SYBYL2.1, Tripos), the Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma-targets network model was established based on Cytoscape 3.5.1, and the physicochemical properties of the antitumor activity in Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma were predicted by using SwissADME and admetSAR. Result:There were 25 small molecule constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma. Through the energy match, key antitumor constituents of Pinelliae Rhizoma were gondoic acid, 10,13-eicosadienoic, baicalin, 12,13-epoxy-9-hydroxynonadeca-7,10-dienoic acid. Key antitumor constituents of Aconiti Lateralis Radix Praeparata were deltoin, sitosterol, neokadsuranic acid B, 11,14-eicosadienoic acid. Phosphatidylinositol 3-kinase (PI3Kα), phosphatase and tensin homolog deleted on chromosome ten (PTEN), phosphoinositide dependent protein kinase 1 (PDK1) were key antitumor targets of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma. There were 8 key antitumor constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, which had a low CYP450 inhibition and basically followed the Lipinski rule. Conclusion:Antitumor nontoxic constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma and key targets are screened out from the molecular level, which provides the new ideas for the effective use of nontoxic traditional Chinese medicine(TCM) and breaks the restrictions in using nontoxic TCM.

Neuronal dynamics in HfOx/AlOy-based homeothermic synaptic memristors with low-power and homogeneous resistive switching.

We studied the pseudo-homeothermic synaptic behaviors by integrating complimentary metal-oxide-semiconductor-compatible materials (hafnium oxide, aluminum oxide, and silicon substrate). A wide range of temperatures, from 25 °C up to 145 °C, in neuronal dynamics was achieved owing to the homeothermic properties and the possibility of spike-induced synaptic behaviors was demonstrated, both presenting critical milestones for the use of emerging memristor-type neuromorphic computing systems in the near future. Biological synaptic behaviors, such as long-term potentiation, long-term depression, and spike-timing-dependent plasticity, are developed systematically, and comprehensive neural network analysis is used for temperature changes and to conform spike-induced neuronal dynamics, providing a new research regime of neurocomputing for potentially harsh environments to overcome the self-heating issue in neuromorphic chips.

Scaling Effect on Silicon Nitride Memristor with Highly Doped Si Substrate.

A feasible approach is reported to reduce the switching current and increase the nonlinearity in a complementary metal-oxide-semiconductor (CMOS)-compatible Ti/SiNx /p+ -Si memristor by simply reducing the cell size down to sub-100 nm. Even though the switching voltages gradually increase with decreasing device size, the reset current is reduced because of the reduced current overshoot effect. The scaled devices (sub-100 nm) exhibit gradual reset switching driven by the electric field, whereas that of the large devices (≥1 µm) is driven by Joule heating. For the scaled cell (60 nm), the current levels are tunable by adjusting the reset stop voltage for multilevel cells. It is revealed that the nonlinearity in the low-resistance state is attributed to Fowler-Nordheim tunneling dominating in the high-voltage regime (≥1 V) for the scaled cells. The experimental findings demonstrate that the scaled metal-nitride-silicon memristor device paves the way to realize CMOS-compatible high-density crosspoint array applications.

Comparison in executive function in Chinese preterm and full-term infants at eight months / 医学前沿

Executive function (EF) is increasingly recognized as being responsible for adverse developmental outcomes in preterm-born infants. Several perinatal factors may lead to poor EF development in infancy, and the deficits in EF can be identified in infants as young as eight months. A prospective cohort study was designed to study the EF in Chinese preterm infants and examine the relationship between EF in preterm infants and maternal factors during perinatal period. A total of 88 preterm infants and 88 full-term infants were followed from birth to eight months (corrected age). Cup Task and Planning Test was applied to assess the EF of infants, and the Bayley Scale of Infant Development (BSID-III) was used to evaluate cognitive (MDI) and motor abilities (PDI) of infants. In comparison with full-term infants, the preterm infants performed more poorly on all measures of EF including working memory, inhibition to prepotent responses, inhibition to distraction, and planning, and the differences remained after controlling the MDI and PDI. Anemia and selenium deficiency in mothers during pregnancy contributed to the differences in EF performance. However, maternal depression, hypertension, and diabetes during pregnancy were not related to the EF deficits in preterm infants. Future research should focus on the prevention of anemia and selenium deficiency during pregnancy and whether supplementing selenium in mothers during pregnancy can prevent further deterioration and the development of adverse outcomes of their offspring.

Analog Synaptic Behavior of a Silicon Nitride Memristor.

In this paper, we present a synapse function using analog resistive-switching behaviors in a SiNx-based memristor with a complementary metal-oxide-semiconductor compatibility and expandability to three-dimensional crossbar array architecture. A progressive conductance change is attainable as a result of the gradual growth and dissolution of the conducting path, and the series resistance of the AlOy layer in the Ni/SiNx/AlOy/TiN memristor device enhances analog switching performance by reducing current overshoot. A continuous and smooth gradual reset switching transition can be observed with a compliance current limit (>100 µA), and is highly suitable for demonstrating synaptic characteristics. Long-term potentiation and long-term depression are obtained by means of identical pulse responses. Moreover, symmetric and linear synaptic behaviors are significantly improved by optimizing pulse response conditions, which is verified by a neural network simulation. Finally, we display the spike-timing-dependent plasticity with the multipulse scheme. This work provides a possible way to mimic biological synapse function for energy-efficient neuromorphic systems by using a conventional passive SiNx layer as an active dielectric.

Xuebijing Injection Promotes M2 Polarization of Macrophages and Improves Survival Rate in Septic Mice.

Xuebijing (XBJ) injection, a concoction of several Chinese herbs, has been widely used as an immunomodulator for the treatment of severe sepsis in China. However, the precise mechanisms responsible for its efficacy have not been fully elucidated. In our study, we determined the flow cytometry markers (F4/80, CD11c, and CD206), the levels of secreted cytokines (TNF-α, IL-6, and IL-10), and the expression of specific proteins of M2 (Ym1, Fizz1, and Arg1) to assess macrophage polarization. Treatment with XBJ lowered M1 associated cytokine levels and increased the level of M2 associated cytokine level. The percentage of M2 phenotype cells of XBJ group was much higher than that of the control group. Expressions of phosphorylated Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6) were markedly enhanced after the administration of XBJ; on the other hand, the M2 associated cytokines and proteins were decreased following treatment with JAK1 or STAT6 inhibitor. In addition, the treatment of XBJ significantly improved the survival rate of septic mice. These studies demonstrate that XBJ can markedly promote M2 polarization and improve the survival rate of septic mice, thereby contributing to therapeutic effect in the treatment of septic complications.

[Effects of biochar on soil nutrients leaching and potential mechanisms: A review].

Controlling soil nutrient leaching in farmland ecosystems has been a hotspot in the research field of agricultural environment. Biochar has its unique physical and chemical properties, playing a significant role in enhancing soil carbon storage, improving soil quality and increasing crop yield. As a kind of new exogenous material, biochar has the potential in impacting soil nutrient cycling directly or indirectly, and has profound influences on soil nutrient leaching. This paper analyzed the intrinsic factors affecting how biochar affects soil nutrient leaching, such as the physical and chemical properties of biochar, and the interaction between biochar and soil organisms. Then the latest literatures regarding the external factors, including biochar application rates, soil types, depth of soil layer, fertilization conditions and temporal dynamics, through which biochar influences soil nutrient (especially nitrogen and phosphorus) leaching were reviewed. On that basis, four related action mechanisms were clarified, including direct adsorption of nutrients by biochar due to its micropore structure or surface charge, influencing nutrient leaching through increasing soil water- holding capacity, influencing nutrient cycling through the interaction with soil microbes, and preferential transport of absorbed nutrients by fine biochar particles. At last future research directions for better understanding the interactions between biochar and nutrient leaching in the soil were proposed.

Effects of electroacupuncture of different intensities on energy metabolism of mitochondria of brain cells in rats with cerebral ischemia-reperfusion injury.

OBJECTIVE: To observe the effects of electroacupuncture (EA) of different intensities on lactate dehydrogernase (LDH), succinate dehydrogenase (SDH) and ATPase in brain tissue of rats with cerebral ischemia-reperfusion injury (CI/R). METHODS: Forty male SD rats were uniformly randomized into sham operation group (group A), CI/R group (group B), CI/R+5 mA EA (group C), CI/R+3 mA EA (group D) and CI/R+1 mA EA (group E) groups with eight rats in each group. Transient general brain ischemia was induced by four-vessel occlusion and reperfusion. The rats in group C, group D and group E were punctured and stimulated at Baihui (GV20), Mingmen (GV4) and Zusanli (ST36) with the same intermittent and rarefaction-dense wave (30 to 50 Hz) and different electric current intensities: 5 mA, 3 mA and 1 mA for 20 min after CI/R. Then the activities of Na(+)-K(+)-ATPase, SDH and LDH in mitochondria of brain tissue were measured by spectrophotometry. The ischemic cerebral cortex tissue was taken for observing the ultrastructure changes of impaired nerve cells. RESULTS: Compared with group A, the activities of LDH, SDH and Na(+)-K(+)-ATPase were lowerer in the group B (P<0.05 or P<0.01). However, the activities of LDH, SDH and Na(+)-K(+)-ATPase were higher in the group D than those in the group B (P<0.05 orP<0.01). In group A, the anatomical structure of the cerebral cortex cells was basically normal; in group B, the neuronal cellular structures were severely damaged, the neuronal mitochondria got swelling, the mitochondrial cristae were broken, the medullated nerve fifibers were not integrated. In group C, group D and group E, the ultrastructure of impaired neuron were improved. Group D was the best among three groups above. CONCLUSION: EA of 3 mA intensity could strengthen aerobic metabolism by elevating the activities of SDH and LDH, meanwhile maintaining the ionic equilibrium in the exterior and interior brain cell and relieving the cellular edema by reinforcing the activities of Na(+)-K(+)-ATPase.

Effects of Nardostachys chinensis on spontaneous ventricular arrhythmias in rats with acute myocardial infarction.

OBJECTIVES: To investigate the effects and mechanisms of Nardostachys chinensis (NC) on spontaneous ventricular arrhythmias in rats with hyper-acute myocardial infarction (AMI). METHODS: Seventy-two rats were randomly divided into the control group (n = 24), metoprolol group (n = 24), and the NC group (n = 24). Premature ventricular contractions (PVCs), ventricular tachycardias (VTs), ventricular fibrillations (VFs), and blood pressure were monitored for 4 hours after coronary artery ligation. The connexin 43 (Cx43) expression in ventricular myocardium was measured by immunohistochemistry, Western blot, and real-time RT-PCR. RESULTS: Compared with the control, metoprolol and NC decreased the VF incidence (50% vs. 4.2%, P < 0.001, and 50% vs. 12.5%, P = 0.005, respectively). There was a steady decrease in the cumulative number of PVCs and VTs within 4 hours from ligating in 3 groups. Compared with the control, metoprolol and NC reduced the cumulative number of VTs and PVCs. Compared with control, metoprolol and NC decreased the infarct size of the left ventricular tissue (55.98% ± 6.20% vs. 39.13% ± 4.53%, P < 0.001, and 55.98% ± 6.20% vs. 42.39% ± 3.44%, P < 0.001, respectively). The results from immunohistochemistry, Western blot, and real-time RT-PCR showed that the protein expression of Cx43 in the control group was significantly lower than that in the metoprolol and NC groups in the infarcted zone. CONCLUSIONS: NC decreased the incidence of spontaneous ventricular arrhythmias (especially VF), reduced Cx43 degradation, and improved Cx43 redistribution in myocardial infarcted zone in rats with hyper-AMI. The data of the present study indicated that NC may be a promising drug in the future to prevent patients with AMI from lethal ventricular arrhythmias in prehospital setting.

Tertiary-butylhydroquinone upregulates expression of ATP-binding cassette transporter A1 via nuclear factor E2-related factor 2/heme oxygenase-1 signaling in THP-1 macrophage-derived foam cells.

BACKGROUND: Tert-butylhydroquinone (tBHQ), a synthetic phenolic antioxidant, is commonly used as a food preservative because of its potent antilipid peroxidation activity. Several lines of evidence have demonstrated that dietary supplementation with antioxidants has an antiatherogenic function through reducing cholesterol uptake or promoting reverse cholesterol transport. In this study, we investigated whether tBHQ affects expression of ATP-binding cassette transporter A1 (ABCA1) and the potential subsequent effect on cellular cholesterol homeostasis. METHODS AND RESULTS: tBHQ increased ABCA1 protein levels and markedly enhanced cholesterol efflux from THP-1 macrophage-derived foam cells. Furthermore, tBHQ reduced calpain-mediated ABCA1 proteolysis via activation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Inhibition of HO-1 with a pharmacological inhibitor or siRNA and knockdown of Nrf2 suppressed the stimulatory effects of tBHQ on ABCA1 expression and calpain activity. CONCLUSIONS: Nrf2/HO-1 signaling is required for the regulation by tBHQ of ABCA1 expression and cholesterol efflux in macrophage-derived foam cells and an antiatherogenic role of tBHQ is suggested.

[Formulation optimization and drug release in vitro of membrane controlled tablets of puerarin inclusion compound].

OBJECTIVE: To prepare membrane controlled tablets of puerarin sinclusion compound and to investigate the drug release in vitro. METHOD: The single factors affecting drug release in vitro were investigated. Then, uniform design was used to optimize the formulation of controlled osmotic-pump tablets. RESULT: Drug release profiles in vitro were affected obviously by membrane thickness, penetrating agents and porogen. CONCLUSION: Membrane controlled tablets of puerarin inclusion compound were prepared according to the optimal formulation with zero-order kinetics.