Transcriptomics to evaluate the influence mechanisms of ethanol on the ester production of Wickerhamomyces anomalus with the induction of lactic acid.

Wickerhamomyces anomalus is one of the most important ester-producing strains in Chinese baijiu brewing. Ethanol and lactic acid are the main metabolites produced during baijiu brewing, but their synergistic influence on the growth and ester production of W. anomalus is unclear. Therefore, in this paper, based on the contents of ethanol and lactic acid during Te-flavor baijiu brewing, the effects of different ethanol concentrations (3, 6, and 9% (v/v)) combined with 1% lactic acid on the growth and ester production of W. anomalus NCUF307.1 were studied and their influence mechanisms were analyzed by transcriptomics. The results showed that the growth of W. anomalus NCUF307.1 under the induction of lactic acid was inhibited by ethanol. Although self-repair mechanism of W. anomalus NCUF307.1 induced by lactic acid was initiated at all concentrations of ethanol, resulting in significant up-regulation of genes related to the Genetic Information Processing pathway, such as cell cycle-yeast, meiosis-yeast, DNA replication and other pathways. However, the accumulation of reactive oxygen species and the inhibition of pathways associated with carbohydrate and amino acid metabolism may be the main reason for the inhibition of growth in W. anomalus NCUF307.1. In addition, 3% and 6% ethanol combined with 1% lactic acid could promote the ester production of W. anomalus NCUF307.1, which may be related to the up-regulation of EAT1, ADH5 and TGL5 genes, while the inhibition in 9% ethanol may be related to down-regulation of ATF2, EAT1, ADH2, ADH5, and TGL3 genes.

Regeneration of Spent Lithium Manganate Batteries into Al-Doped MnO2 Cathodes toward Aqueous Zn Batteries.

Large quantities of spent lithium-ion batteries (LIBs) will inevitably be generated in the near future because of their wide application in many fields. It will cause not only resource waste but also environmental pollution if these spent batteries are not properly handled. Until now, the recycling of spent lithium manganate batteries has centered on high-valuable elements such as lithium; however, manganese element and current collector Al foil have not yet attracted wide attention. In this work, aluminum-doped manganese dioxide was synthesized by overall recycling cathode active materials and current collector Al foil from a spent lithium manganate battery. Employing such aluminum-doped manganese dioxide as the cathode material of aqueous Zn batteries, it displays better electrochemical performance than manganese dioxide prepared by only recycling the cathode active materials. The overall recycling not only simplifies the recycling process but also realizes high-value recycling of spent lithium manganate batteries. We offer new tactics for overall recycling of cathodes from spent LIBs and designing high-performance manganese dioxide cathodes for aqueous Zn batteries.

Editorial to Special Issue-Food Brewing Technology and Brewing Microorganisms.

Food brewing technology is an important technology in the modern worldwide food industry, which uses the specific traits of microorganisms to produce food by traditional or modern engineering techniques [...].

Effects of bio-augmented Daqu on microbial community, aroma compounds and physicochemical parameters of fermented grains during the brewing of Chinese special-flavor baijiu.

BACKGROUND: Bio-augmented Daqu is used to improve the microbial community and physicochemical parameters of fermented grains, thus affecting the flavor and quality of baijiu. This study investigated the effects of bio-augmented Daqu inoculated with Aspergillus niger NCUF413.1 and Saccharomyces cerevisiae NCUF304.1 on the microbial community, aroma compounds, and physicochemical parameters of fermented grains during special-flavor baijiu brewing. RESULTS: Compared with the control group (CG), the utilization of starch and production of ethanol in the inoculated group (IG) increased by 3.55% and 12.59%, respectively. The use of bio-augmented Daqu changed the bacterial communities. For example, Kroppenstedsia was the dominant bacterial genus (the relative abundance was about 22%) in the CG while Lactobacillus was the main dominant genus (the relative abundance was more than 30%) in the IG on days 20-30. Lactobacillus showed a significant positive correlation with the aroma compounds. The use of bio-augmented Daqu increased the aroma compound content - such as the ethyl heptanoate and ethyl hexanoate content. CONCLUSION: The addition of bio-augmented Daqu with A. niger and S. cerevisiae could change microbial communities, resulting in an increase in the yield of ethanol and the aroma compound content of fermented grains, thus improving the quality of baijiu. © 2022 Society of Chemical Industry.

Increase the Content of Ester Compounds in Blueberry Wine Fermentation with the Ester-Producing Yeast: Candida glabrata, Pichia anomala, and Wickerhamomyces anomalus.

The co-fermentation of Saccharomyces cerevisiae and ester-producing yeasts is considered to be an effective way to improve the flavor and quality of fruit wine. In this study, three kinds of ester-producing yeasts (Candida glabrata NCUF308.1, Pichia anomala NCUF306.1, and Wickerhamomyces anomalus NCUF307.1) and S. cerevisiae NCUF309.2 were used to simulate blueberry wine co-fermentation at different ratios. The results showed that, compared with S. cerevisiae NCUF309.2 fermentation (S), the population of S. cerevisiae NCUF309.2 in co-fermentation samples decreased to varying degrees, and the content of ethanol also decreased. The results also showed that the co-fermentation of C. glabrata NCUF308.1 and S. cerevisiae NCUF309.2 at the ratio of 1:1 (CS1), co-fermentation of P. anomala NCUF306.1 and S. cerevisiae NCUF309.2 at the ratio of 5:1 (PS5), and co-fermentation of W. anomalus NCUF307.1 and S. cerevisiae NCUF309.2 at the ratio of 5:1 (WS5) could significantly increase the content of ester compounds (p < 0.05), which was 3.29, 4.75, and 3.04 times that of the S sample, respectively. Among them, the sample of CS1 was characterized by phenethyl acetate and isoamyl acetate, while the samples of CS5 and PS5 were characterized by propyl octanoate and ethyl decanoate, and the sample of WS5 was characterized by 3-methylbutyl hexanoate. However, the contents of odor active compounds were higher in the CS1 sample. Therefore, the samples of CS1 had the potential to create the distinctive flavor of blueberry wine.

Effects on Cell Membrane Integrity of Pichia anomala by the Accumulating Excessive Reactive Oxygen Species under Ethanol Stress.

Ethanol stress to yeast is well recognized and exists widely during the brewing process of alcohol products. Pichia anomala is an important ester-producing yeast in the brewing process of Chinese Baijiu and other alcohol products. Therefore, it is of great significance for the alcohol products brewing industry to explore the effects of ethanol stress on the growth metabolism of P. anomala. In this study, the effects of ethanol stress on the growth, esters production ability, cell membrane integrity and reactive oxygen species (ROS) metabolism of P. anomala NCU003 were studied. Our results showed that ethanol stress could inhibit the growth, reduce the ability of non-ethyl ester compounds production and destroy the cell morphology of P. anomala NCU003. The results also showed that 9% ethanol stress produced excessive ROS and then increased the activities of antioxidant enzymes (superoxide dismutase, catalase, aseorbateperoxidase and glutathione reductase) compared to the control group. However, these increased antioxidant enzyme activities could not prevent the damage caused by ROS to P. anomala NCU003. Of note, correlation results indicated that high content of ROS could promote the accumulation of malondialdehyde content, resulting in destruction of the integrity of the cell membrane and leading to the leakage of intracellular nutrients (soluble sugar and protein) and electrolytes. These results indicated that the growth and the non-ethyl ester compounds production ability of P. anomala could be inhibited under ethanol stress by accumulating excessive ROS and the destruction of cell membrane integrity in P. anomala.

Insight on Efficacy of Renal Artery Denervation for Refractory Hypertension with Chronic Kidney Diseases: A Long-Term Follow-Up of 24-Hour Ambulatory Blood Pressure.

Aims: To explore the long-term efficacy and safety of renal denervation in patients with RHT and CKD, a post hoc analysis of eGFR subgroups was completed. Methods: Fifty-four patients with refractory hypertension with chronic kidney disease were treated with RDN and enrolled in the study. Patients were divided into three groups according to eGFR: eGFR 46-90 ml/min group, eGFR 15-45 ml/min group, and eGFR <15 ml/min group. The planned follow-up period was 48 months to assess 24 h ambulatory blood pressure, renal function, type of antihypertensive medication, and RDN complications. Results: The ablation sites of the GFR 46-90 ml/min group and GFR 15-45 ml/min group were 32.57 ± 2.99 and 29.53 ± 5.47, respectively. No complications occurred in the GFR 46-90 ml/min group. The GFR<15 ml/min group was treated with 27.07 ± 5.59 ablation. Renal artery dissection occurred in each group of GFR 15-45 ml/min and GFR <15 ml/min. And renal stent implantation artery was performed on these two patients. No severe renal artery stenosis occurred. There were no significant differences in Scr and eGFR between the three groups at each follow-up point. Compared with baseline, SBP was significantly of each group decreased to varying degrees at each follow-up time point. SBP decreased most in the GFR 46-90 ml/min group. Compared with baseline, the type of antihypertensive drugs used in the GFR46-90 ml/min group decreased significantly except for 36 and 48 months. At 48 months' postadmission, there was a significant decrease in the type of antihypertensive medication used in the GFR15-45 ml/min group, and there was no significant decrease in the type of antihypertensive medication used in the GFR<15 ml/min group. Conclusions: RDN can safely reduce SBP in CKD patients combined with RHT for 48 months, with the most pronounced reduction in the GFR15-45 ml/min group. The variety of antihypertensive drugs was significantly reduced after RDN. This was particularly evident in patients with GFR 15-45 ml/min.

Integrated Bioinformatics and Validation of lncRNA-Mediated ceRNA Network in Myocardial Ischemia/Reperfusion Injury.

Background: Myocardial ischemia/reperfusion (MI/R) injury is a common pathology in ischemia heart disease. Long noncoding RNAs (lncRNAs) are significant regulators related to many ischemia/reperfusion conditions. This study is aimed at exploring the molecule mechanism of lncRNA-mediated competing endogenous RNA (ceRNA) network in MI/R. Methods: The dataset profiles of MI/R and normal tissues (GSE130217 and GSE124176) were obtained from the GEO database. Integrated bioinformatics were performed to screen out differentially expressed genes (DEGs). Thereafter, an lncRNA-mediated ceRNA network was constructed by the starBase database. The GO annotations and KEGG pathway analysis were conducted to study action mechanism and related pathways of DEGs in MI/R. A model of hypoxia/reoxygenation- (H/R-) treated HL-1 cell was performed to verify the expression of lncRNAs through qRT-PCR. Results: 2406 differentially expressed- (DE-) mRNAs, 70 DE-lncRNAs, and 156 DE-miRNAs were acquired. These DEGs were conducted to construct an lncRNA-mediated ceRNA network, and a subnetwork including lncRNA Xist/miRNA-133c/mRNA (Slc30a9) was screen out. The functional enrichment analyses revealed that the lncRNAs involved in the ceRNA network might functions in oxidative stress and calcium signaling pathway. The lncRNA Xist expression is reduced under H/R conditions, followed by the increased level of miRNA-133c, thus downregulating the expression of Slc30a9. Conclusion: In sum, the identified ceRNA network which included the lncRNA Xist/miR-133c/Slc30a9 axis might contribute a better understanding to the pathogenesis and development of MI/R injury and offer a novel targeted therapy way.

Research progress of anti-environmental factor stress mechanism and anti-stress tolerance way of Saccharomyces cerevisiae during the brewing process.

Saccharomyces cerevisiae plays a decisive role in the brewing of alcohol products, and the ideal growth and fermentation characteristics can give the pure flavor of alcohol products. However, S. cerevisiae can be affected profoundly by environmental factors during the brewing process, which have negative effects on the growth and fermentation characteristics of S. cerevisiae, and seriously hindered the development of brewing industry. Therefore, we summarized the environmental stress factors (ethanol, organic acids, temperature and osmotic pressure) that affect S. cerevisiae during the brewing process. Their impact mechanisms and the metabolic adaption of S. cerevisiae in response to these stress factors. Of note, S. cerevisiae can increase the ability to resist stress factors by changing the cell membrane components, expressing transcriptional regulatory factors, activating the anti-stress metabolic pathway and enhancing ROS scavenging ability. Meantime, the strategies and methods to improve the stress- tolerant ability of S. cerevisiae during the brewing process were also introduced. Compared with the addition of exogenous anti-stress substances, mutation breeding and protoplast fusion, it appears that adaptive evolution and genetic engineering are able to generate ideal environmental stress tolerance strains of S. cerevisiae and are more in line with the needs of the current brewing industry.

The association between orthostatic blood pressure changes and arterial stiffness.

OBJECTIVE: Although orthostatic hypotension (OH) and orthostatic hypertension (OHT) can independently predict cardiovascular events, the underlying mechanisms remain controversial. Our study aimed to examine the relationships between orthostatic blood pressure (BP) changes and arterial stiffness. METHODS: In this cross-sectional analysis, 1820 participants were divided into three groups according to BP changes within 3 min of orthostatism: the OH group had a decrease of >20 mmHg in SBP or >10 mmHg in DBP, the OHT group had an increase of ≥20 mmHg in SBP, and the orthostatic normotensive (ONT) group had normal changes. Arterial stiffness was assessed by measuring the carotid-femoral pulse wave velocity (cfPWV). RESULTS: OH and OHT were observed in 257 (14.1%) and 62 (3.4%) participants, respectively. Subjects in the OH group were significantly older, were more likely to have hypertension and diabetes, and had higher cfPWV than those in the ONT group ( P < 0.05); however, no differences were found between the ONT and OHT groups. Stepwise multiple regression analysis of the subgroups stratified by hypertension and diabetes revealed that age was related to increased cfPWV in all stratifications, and the change in SBP was significantly positively correlated with cfPWV in hypertensive subjects; however, this association was not observed in nonhypertensive subjects. CONCLUSION: We found that arterial stiffness was closely related to OH but not to OHT. In addition to expanding current knowledge of the relationship between orthostatic BP changes and arterial stiffness, our study underlines the importance of age, SBP changes, and hypertension in evaluating arterial stiffness.

MicroRNA-21-5p acts via the PTEN/Akt/FOXO3a signaling pathway to prevent cardiomyocyte injury caused by high glucose/high fat conditions.

MicroRNAs (miRNAs or miRs) play important roles in cardiovascular disease. miR-21-5p is known to be involved in the regulation of cardiomyocyte injury under high glucose and high fat (HG-HF) conditions, but its mechanism of action remains unclear. In the present study, a cardiomyocyte cell line, H9c2, was treated with 33 mM glucose and 250 µM sodium palmitate for 24, 48, and 72 h to produce HG-HF injury. After treatment, miR-21-5p expression was detected by reverse transcription-quantitative PCR. A miR-21-5p mimic was then constructed and transfected into the cells and the potential molecular mechanism was investigated using Cell Counting Kit-8, TUNEL, flow cytometry and western blot assays. Expression of miR-21-5p was significantly downregulated by HG-HF treatment of H9c2 cells for 24, 48, and 72 h. In subsequent experiments, cells were treated for an intermediate period (48 h). Compared with the control group, HG-HF treatment significantly inhibited H9c2 proliferation and promoted apoptosis, while these effects were significantly reduced in the miR-21-5p mimic. Compared with the control group, HG-HF treatment significantly increased reactive oxygen species, while miR-21-5p mimic significantly reduced this effect. Compared with the control group, HG-HF treatment significantly increased the expression of the pro-apoptotic proteins Bax and phosphorylated (p)-Akt and decreased the expression of the anti-apoptotic proteins Bcl-2, p-PTEN, and p-FOXO3a, while overexpression of miR-21-5p significantly reduced these effects. The results revealed that miR-21-5p inhibited apoptosis and oxidative stress in H9c2 cells induced by HG-HF, likely through the PTEN/Akt/FOXO3a signaling pathway.

Molecular mechanism of high-production tannase of Aspergillus carbonarius NCUF M8 after ARTP mutagenesis: revealed by RNA-seq and molecular docking.

BACKGROUND: Tannase is an enzyme produced by microbial fermentation and is widely used in the food industry; however, the molecular mechanism of tannase production by Aspergillus has not yet been studied. This study was conducted to reveal the differences in Aspergillus carbonarius tannase enzymatic characterization, secondary structures and molecular mechanisms after treatment of the strain with atmospheric and room temperature plasma (ARTP). RESULTS: The results showed that the specific activity of tannase was improved by ARTP treatment, and it showed higher thermostability and tolerance to metal ions and additives. The enzymatic characterization and molecular docking results indicated that tannase had a higher affinity and catalytic rate with tannic acid as a substrate after ARTP treatment. In addition, the docking results indicated that Aspergillus tannases may catalyze tannic acid by forming two hydrogen-bonding networks with neighboring residues. RNA-seq analysis indicated that changes in steroid biosynthesis, glutathione metabolism, glycerolipid metabolism, oxidative phosphorylation pathway and mitogen-activated protein kinase signaling pathways might be crucial reasons for the high production of tannase. CONCLUSION: ARTP enhanced the yield and properties of A. carbonarius tannase by changing the enzyme structure and cell metabolism. This study provides a theoretical basis for elucidating the molecular mechanism underlying high production of Aspergillus tannases. © 2022 Society of Chemical Industry.

Effects of renal denervation on the expression profile of circular RNA in the serum of patients with resistant hypertension.

OBJECTIVE: Renal denervation (RDN) is a new treatment option for resistant hypertension (RH), although it has been shown that reduced sympathetic nerve activity after RDN is the main cause of blood pressure decline. In view of the possible correlation between circRNA and hypertension and the metabolic state of the body after RDN, we investigated the potential role of circRNA in RDN treatment of RH. METHODS: Serum samples of patients with RH were collected before and 48 h after RDN. We explored the mechanism underlying RDN with high-throughput integration of circRNA data. RESULTS: There were 338 circRNAs that were differentiated before and after RDN; 170 were upregulated and 168 were downregulated (≥1.2-fold, P < 0.05), and the expression of five of them changed significantly (≥1.5-fold, P < 0.05). We used reverse transcription-quantitative polymerase chain reaction to confirm these results in 13 other patients with RH. hsa_circRNA_000367 was upregulated and hsa_circRNA_405119 was downregulated after RDN. We predicted their downstream miRNA-mRNA network and analyzed their putative function via the circRNA-miRNA-mRNA pathway. GO/KEGG analysis showed that their functional annotation may be related to nerve injury and hypertension. We used the Venn Diagram Generator to obtain the intersection of predicted target and sympathetic nerve-related genes (from GeneCards website). CONCLUSION: The mechanism underlying RDN may be closely related to upregulated hsa_circRNA_000367 or downregulated hsa_circRNA_405119 and involve regulated multiple pathways and multiple cellular and molecular biological processes. These circRNAs may potentially be used as treatment effect biomarkers in RDN.

Lithium chloride promotes proliferation of neural stem cells in vitro, possibly by triggering the Wnt signaling pathway.

The objective of this study was to clarify the relationship between the effect and associated mechanisms of lithium chloride on neural stem cells (NSCs) and the Wnt signaling pathway. The expression of key molecules proteins related to the Wnt signaling pathway in the proliferation and differentiation of control NSCs and lithium chloride-treated NSCs was detected by Western blot analysis. Flow cytometry analysis was applied to study the cell cycle dynamics of control NSCs and NSCs treated with lithium chloride. The therapeutic concentrations of lithium chloride stimulated NSC proliferation. ß-catenin expression gradually decreased, while Gsk-3ß expression gradually increased (P < 0.01). Furthermore, NSCs treated with lithium chloride showed significantly enhanced ß-catenin expression and inhibited Gsk-3ß expression in a dose-dependent manner. NSCs in the G0/G1-phases were activated with an increased therapeutic concentration of lithium chloride, while NSCs in the S-phase, as well as G2/M-phases, were arrested (P < 0.01). These data confirm that the proliferation of NSCs is remarkably promoted through changes of cell dynamics after treatment with lithium chloride. Our results provide insight into the effects of lithium chloride in promoting the proliferation abilities of NSCs in vitro and preventing the cells from differentiating, which is potentially mediated by activation of the Wnt signaling pathway.

The association of two polymorphisms in adiponectin-encoding gene with hypertension risk and the changes of circulating adiponectin and blood pressure: A meta-analysis.

OBJECTIVES: This meta-analysis was prepared to synthesize published data on the association of two polymorphisms (T45G and G276T) in adiponectin-encoding gene (ADIPOQ) with hypertension risk and the changes of circulating adiponectin and blood pressure. Methodology and Major Findings: Data were collected and corrected by two authors, and were managed with Stata software. In total, 12 articles were synthesized, including 12 studies (3358 cases and 5121 controls) for the association of two study polymorphisms with hypertension risk and 11 studies (3053 subjects) for the between-genotype changes of adiponectin and/or blood pressure. Based on all qualified studies, the risk prediction for hypertension was nonsignificant for both polymorphisms, with significant heterogeneity for G276T polymorphism (I2 = 53.8%). Overall changes in adiponectin and blood pressure were also nonsignificant for T45G, while contrastingly 276GT genotype was associated with significantly higher levels of adiponectin (weighted mean difference [WMD] = 0.72 µg/mL, 95% confidence interval [CI]: 0.04 to 1.41, P = 0.038), systolic (WMD = 5.15 mm Hg, 95% CI: 0.98 to 9.32, P = 0.016) and diastolic (WMD = 3.45 mm Hg, 95% CI: 0.37 to 6.53, P = 0.028) blood pressure with evident heterogeneity (I2 = 72.0%, 78.3% and 80.0%, respectively), and these associations were more obvious in hypertensive patients. Publication bias was a low probability event for overall comparisons. CONCLUSIONS: Our findings suggested that in spite of the nonsignificant association between ADIPOQ T45G or G276T polymorphism and hypertension, the heterozygous mutation of G276T was observed to account for increased levels of circulating adiponectin and blood pressure, especially in hypertensive patients.

Alteration in rectification of potassium channels in perinatal hypoxia ischemia brain damage.

Oligodendrocyte progenitor cells (OPCs) are susceptible to perinatal hypoxia ischemia brain damage (HIBD), which results in infant cerebral palsy due to the effects on myelination. The origin of OPC vulnerability in HIBD, however, remains controversial. In this study, we defined the HIBD punctate lesions by MRI diffuse excessive high signal intensity (DEHSI) in postnatal 7-day-old rats. The electrophysiological functional properties of OPCs in HIBD were recorded by patch-clamp in acute cerebral cortex slices. The slices were intracellularly injected with Lucifer yellow and immunohistochemically labeled with NG2 antibody to identify local OPCs. Passive membrane properties and K(+) channel functions in OPCs were analyzed to estimate the onset of vulnerability in HIBD. The resting membrane potential, membrane resistance, and membrane capacitance of OPCs were increased in both the gray and white matter of the cerebral cortex. OPCs in both the gray and white matter exhibited voltage-dependent K(+) currents, which consisted of the initiated rectified potassium currents (IA) and the sustained rectified currents (IK). The significant alternation in membrane resistance was influenced by the diversity of potassium channel kinetics. These findings suggest that the rectification of IA and IK channels may play a significant role in OPC vulnerability in HIBD.

Regional specific regulation of steroid receptor coactivator-1 immunoreactivity by orchidectomy in the brain of adult male mice.

Androgens including testosterone and dihydrotestosterone play important roles on brain structure and function, either directly through androgen receptor or indirectly through estrogen receptors, which need coactivators for their transcription activation. Steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but how it is regulated by androgens in the brain remains unclear. In this study, we explored the effect of orchidectomy (ORX) on the expression of SRC-1 in the adult male mice using nickel-intensified immunohistochemistry. The results showed that ORX induced dramatic decrease of SRC-1 immunoreactivity in the olfactory tubercle, piriform cortex, ventral pallidum, most parts of the septal area, hippocampus, substantia nigra (compact part), pontine nuclei and nucleus of the trapezoid body (p<0.01). Significant decrease of SRC-1 was noticed in the dorsal and lateral septal nucleus, medial preoptical area, dorsomedial and ventromedial hypothalamic nucleus and superior paraolivary nucleus (p<0.05). Whereas in other regions examined, levels of SRC-1 immunoreactivity were not obviously changed by ORX (p>0.05). The above results demonstrated ORX downregulation of SRC-1 in specific regions that have been involved in sense of smell, learning and memory, cognition, neuroendocrine, reproduction and motor control, indicating that SRC-1 play pivotal role in the mediating circulating androgenic regulation on these important brain functions. It also indicates that SRC-1 may serve as a novel target for the central disorders caused by the age-related decrease of circulating androgens.

Intriguing roles of hippocampus-synthesized 17ß-estradiol in the modulation of hippocampal synaptic plasticity.

Accumulated studies have shown that 17ß-estradiol (E2) can be de novo synthesized in the hippocampus, and its role in the regulation of hippocampal synaptic plasticity, which is the basis of learning and memory, has long been exploring. Steroidogenic enzymes (e.g., aromatase) that are essential to the hippocampus-synthesized synthesis of E2 have been detected in the hippocampus. Inhibition of E2 synthesis by aromatase inhibitors significantly reduces the density of hippocampal spine synapses, levels of some synaptic proteins such as spinopholin and synaptophysin. Moreover, the electrophysiological properties of hippocampal neurons are also changed in response to this inhibition. The influences of gonadal and hippocampal E2 on synaptic plasticity may exist some differences, since some reports showed that gonadal (or circulating) estrogens have no obvious effects in the modulation of hippocampal synaptic proteins as evidenced in some ovariectomized animals and postmenopausal women who suffered from Alzheimer's disease (AD). These evidences leads to a hypothesis that hippocampal E2 may play a more important role in modulation of synaptic plasticity than gonadal E2. The signaling pathways, whereby hippocampal E2 modulates synaptic plasticity, insist of classical chronic genomic pathway and rapid nongenomic pathway, which mediated by nonnuclear estrogen receptor (GPER) and/or nuclear or nonnuclear estrogen receptors, which require coactivators for their transcription activity. Among which steroid receptor coactivator-1 (SRC-1) is the predominant coactivator p160 family members in the brain. Several clues have shown that SRC-1 is expressed in hippocampus and is highly correlated with some key synaptic proteins developmentally or after orchidectomy but not ovariectomy, indicating SRC-1 may be regulated by hippocampus-synthesized E2 and profoundly involved in the mediation of hippocampal E2 regulation of hippocampal synaptic plasticity. Further studies about the exact roles of hippocampus-synthesized E2 and therefore SRC-1 are urgently needed in order to facilitate our understanding of hippocampal E2, which will be very important to the development of novel strategies of estrogen replacement therapy against neurodegenerative deficits such as Alzheimer's disease (AD).

Aromatase inhibitor letrozole downregulates steroid receptor coactivator-1 in specific brain regions that primarily related to memory, neuroendocrine and integration.

As one of the third generation of aromatase inhibitors, letrozole is a favored drug for the treatment of hormone receptor-positive breast cancer with some adverse effects on the nervous system, but the knowledge is limited and the results are controversial, the mechanism underlying its central action is also unclear. Accumulated evidences have demonstrated that estrogens derived from androgens by aromatase play profound roles in the brain through their receptors, which needs coactivator for the transcription regulation, among which steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but whether it is regulated by letrozole is currently unknown. In this study, we examined letrozole regulation on SRC-1 expression in adult mice brain using immunohistochemistry. The results showed that letrozole induced dramatic decrease of SRC-1 in the medial septal, hippocampus, medial habenular nucleus, arcuate hypothalamic nucleus and superior colliculus (p<0.01). Significant decrease was detected in the dorsal lateral septal nucleus, bed nucleus of stria terminalis, ventral taenia tecta, dorsomedial and ventromedial hypothalamic nuclei, dorsomedial periaqueductal gray, superior paraolivary nucleus and pontine nucleus (p<0.05). In the hippocampus, levels of estradiol content, androgen receptor, estrogen receptor α and ß also decreased significantly after letrozole injection. The above results demonstrated letrozole downregulation of SRC-1 in specific regions that are primarily related to learning and memory, cognition and mood, neuroendocrine as well as information integration, indicating that SRC-1 may be one important downstream central target of letrozole. Furthermore, these potential central adverse effects of letrozole should be taken into serious considerations.

Atorvastatin ameliorates contrast medium-induced renal tubular cell apoptosis in diabetic rats via suppression of Rho-kinase pathway.

Contrast medium-induced acute kidney injury (CI-AKI) remains a leading cause of iatrogenic, drug-induced acute renal failure. This study aimed to investigate the protective effects of atorvastatin against renal tubular cell apoptosis in diabetic rats and the related mechanisms. CI-AKI was induced by intravenous administration of iopromide (12ml/kg) in streptozotocin-induced diabetic rats. Atorvastatin (ATO) was administered intragastrically at the dose of 5, 10 and 30mg/kg/d in different groups, respectively, for 5 days before iopromide injection. Renal function parameters, kidney histology, renal tubular cell apoptosis, the expression of apoptosis regulatory proteins, caspase-3 and Rho-associated protein kinase 1 (ROCK-1), and the phosphorylation of myosin phosphatase target subunit -1 (MYPT-1), were determined. Atorvastatin was shown to notably ameliorate contrast medium induced medullary damage, restore renal function, and suppress renal tubular apoptosis. Meanwhile, atorvastatin up-regulated the expression of Bcl-2, down-regulated the expression of Bax, caspase-3 and ROCK-1, restored the ratio of Bcl-2/Bax, and suppressed the phosphorylation of MYPT-1 in a dose-dependent manner. Thus, atorvastatin pretreatment could dose-dependently ameliorate the development of CI-AKI, which was partly attributed to its suppression of renal tubular cell apoptosis by inhibiting the Rho/ROCK pathway.