A Novel Cochlioquinone Derivative, CoB1, Regulates Autophagy in Pseudomonas aeruginosa Infection through the PAK1/Akt1/mTOR Signaling Pathway.

Owing to multiple antibiotic resistance, Pseudomonas aeruginosa causes the most intractable infections to human beings worldwide, thus exploring novel drugs to defend against this bacterium remains of great importance. In this study, we purified a novel cochlioquinone B derivative (CoB1) from Salvia miltiorrhiza endophytic Bipolaris sorokiniana and reveal its role in host defense against P. aeruginosa infection by activating cytoprotective autophagy in alveolar macrophages (AMs) both in vivo and in vitro. Using a P. aeruginosa infection model, we observed that CoB1-treated mice manifest weakened lung injury, reduced bacterial systemic dissemination, decreased mortality, and dampened inflammatory responses, compared with the wild type littermates. We demonstrate that CoB1-induced autophagy in mouse AMs is associated with decreased PAK1 expression via the ubiquitination-mediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, blocks the Akt/mTOR signaling pathway, and promotes the release of ULK1/2-Atg13-FIP200 complex from mTOR to initiate autophagosome formation, resulting in increased bacterial clearance capacity. Together, our results provide a molecular basis for the use of CoB1 to regulate host immune responses against P. aeruginosa infection and indicate that CoB1 is a potential option for the treatment of infection diseases.

Impact of COVID-19 pandemic on the professional intention of medical and related students.

BACKGROUND: The outbreak of COVID-19 has led to increased workload and infection risks among medical staff. This situation may influence current medical and health-related students' decision on the choices of their future careers. Hence, this study investigated the impact of COVID-19 on their future career intentions. METHODS: This is a cross-sectional observational study that included medical and health-related students from three universities between October 2020 and January 2021. The study questionnaire was divided into two main sections: Section 1, which comprised students' basic information. And section 2 focused mainly on the impact of COVID-19 pandemic on students' professional intentions. The chi-squared χ2 test was used to compare the responses before and after the pandemic outbreak among Chinese and non-Chinese students. RESULTS: In overall, 1253 students completed the questionnaires. The responses showed that the number of students who preferred clinical medicine, public health, pharmacy and oral medicine increased significantly after the pandemic outbreak. In contrast, the number of students who chose nursing and medical technology decreased significantly. The change mainly occurred in Chinese students, predominantly females. Half of students (50.35%) were more willing to engage in medical and health work after completing their current program. Also, 36.39% of students felt that knowledge was too limited in the pandemic's face and would like to continue studying after graduation to gain more knowledge. Due to the pandemic, 34.18% of students would like a future workplace near their hometown, and 19.63% preferred to work in urban areas. CONCLUSION: The COVID-19 outbreak impacted current medical and health-related students' career planning on their future workplaces and employment time choices. Additionally, the pandemic influenced the intention of Chinese students in choosing their future careers. This study provided the basis for the policymaking, specialty setting of colleges and supplied the medical health department's talent reserve information.

Anthocyanin Extract from Purple Sweet Potato Exacerbate Mitophagy to Ameliorate Pyroptosis in Klebsiella pneumoniae Infection.

Given the rise of morbidity and mortality caused by Klebsiella pneumoniae (KP), the increasing number of strains resistant to antibiotics, and the emergence of hypervirulent Klebsiella pneumonia, treatment of KP infection becomes difficult; thus, novel drugs are necessary for treatment. Anthocyanins, or natural flavonoids, have an extensive effect against bacterial infection. However, few studies on anti-KP are identified. Here, we evaluated the therapeutic effect of purple sweet potato anthocyanins (PSPAs) on KP, containing 98.7% delphinidin 3-sambubioside. Results showed that KP-infected mice after PSPAs treatment manifested decreased mortality, weakened lung injury, dampened inflammatory responses, and reduced bacterial systemic dissemination in vivo. In Vitro, PSPAs significantly suppressed pyroptosis and restricted NLRP3 inflammasome activation in alveolar macrophages infected with KP. As for the mechanism, PSPAs promote mitophagy by recruiting Parkin to the mitochondria. PSPAs-conferred mitophagy increased mitochondrial membrane potential and decreased mitochondrial reactive oxygen species and mitochondrial DNA, resulting in impaired NLRP3 inflammasome activation. In addition, the promotion of mitophagy by PSPAs required the Nrf2 signaling pathway. Collectively, these findings suggest that PSPAs are a potential option for the treatment of KP infection.

Cardioprotection by Low-dose of Estrogen and Testosterone at the Physiological Ratio on Ovariectomized Rats During Ischemia/Reperfusion Injury.

Although estrogen and testosterone deficiency have often been associated with the development of cardiac diseases in postmenopausal women, the benefits of estrogen or testosterone therapy are controversial. Supplementation with high dose of estrogen or testosterone alone has been associated with many side effects, especially estrogen. This study was aimed to investigate whether supplementation of testosterone in combination with low-dose estrogen conferred stronger cardioprotective effects on ovariectomized rats subjected to ischemia/reperfusion injury. Female Sprague Dawley rats were subjected to sham operation (Sham) or bilateral ovariectomy (OVX). Two weeks after ovariectomy, OVX rats were treated with one of the following: (1) vehicle (OVX), (2) testosterone (100 µg·kg·d) (OVX+T), (3) estrogen (20 µg·kg·d) (OVX+E), (4) testosterone (100 µg·kg·d) + estrogen (20 µg·kg·d) (OVX+T+E) for 4 weeks. The hearts were mounted on the Langendorff apparatus and subjected to ischemia/reperfusion injury subsequent to the determination of hemodynamic parameters. We examined the release of lactate dehydrogenase, serum estrogen, and testosterone levels and the expression of pAkt/Akt and bax/bcl-2. Testosterone supplementation alone improved the heart function, increased p-Akt/Akt and bcl-2 expression, and decreased the release of lactate dehydrogenase. Accordingly, these effects of testosterone were more pronounced when low-dose estrogen was administered simultaneously, whereas estrogen alone at the dose of the experiment had no significant effects. These effects might be partially orchestrated by the Akt signaling pathway.

Spinal anaesthesia with low-dose bupivacaine in marginally hyperbaric solutions for caesarean section: A randomised controlled trial.

BACKGROUND: Conventional hyperbaric spinal anaesthesia solution (SAS) with 8% glucose and low-dose bupivacaine may reduce the incidence of hypotension in caesarean section compared to standard doses, and marginally hyperbaric SAS (≤0.8% glucose) can induce a lower block level and a lower incidence of hypotension in nonobstetric patients than conventional 8% glucose SAS. OBJECTIVE: The objective of this study was to evaluate the clinical efficacy of marginally hyperbaric low-dose bupivacaine solutions used for spinal anaesthesia during caesarean section. DESIGN: A randomised, controlled clinical trial. SETTING: Single medical centre. PATIENTS: One hundred twenty women scheduled for elective caesarean section were randomised into four groups. INTERVENTIONS: Caesarean section after combined spinal-epidural anaesthesia using hyperbaric preparations of low-dose SAS (7.2 mg bupivacaine and 2 µg 1.6 ml sufentanil in one of the following: 8%, 0.8%, 0.5% or 0.33% glucose solution. MAIN OUTCOME MEASURES: The dermatomal sensory block and degree of motor block of the lower extremities and adverse effects of anaesthesia were recorded. RESULTS: The maximum cephalad sensory block level and the incidence of hypotension decreased as the density of SAS fell (T1, T2, T4 and T6, P < 0.001; 48.3, 30, 13.3 and 10.3%, P = 0.003). The incidence of shivering reduced with decreasing density of SAS (P < 0.05). There was no significant difference in the quality of anaesthesia (efficacy of motor block and sensory block) between the groups (P > 0.05). CONCLUSION: Compared with conventional 8% glucose hyperbaric SAS, marginally hyperbaric (0.5 or 0.33% glucose) low-dose bupivacaine solutions led to a significantly lower height of cephalad spread and incidence of hypotension with no impact on the efficacy of spinal anaesthesia for caesarean section.

Daidzein ameliorates doxorubicin-induced cardiac injury by inhibiting autophagy and apoptosis in rats.

Backgrounds: Doxorubicin (Dox) is a classical antitumor antibiotic widely restricted for use due to its cardiotoxicity. Daidzein (Daid) is a soy isoflavone that enhances antioxidant enzyme systems and inhibits apoptosis to prevent cardiovascular diseases. In this study, we intended to assess whether Daid protects against Dox-induced cardiotoxicity and explored its underlying mechanisms. Methods: Male Sprague-Dawley (SD) rats were divided into five groups: control (Ctrl), 40 mg per kg per day Daidzein (Daid), 3 mg per kg per week doxorubicin (Dox), 20 mg per kg per day Daidzein + 3 mg per kg per week doxorubicin (Daid20 + Dox) and 40 mg per kg per day Daidzein + 3 mg per kg per week doxorubicin (Daid40 + Dox) groups. Cardiac function assessments, immunohistochemistry (IHC) and immunofluorescence (IF) analyses were initially performed in each group of rats. Secondly, the cell proliferative capacity analysis, AO staining, and LC3 puncta analysis were employed to evaluate the cellular response to Dox in H9c2 cells. Ultimately, the protein expressions of cleaved caspase3, LC3 II, Bcl-2, Bax, Akt, p-Akt, and cyclin D1 were examined by western blotting. Results: Pretreatment with a low dose of Daid rather than a high dose significantly enhanced cardiac function and alleviated histopathological deterioration of cardiomyocytes induced by Dox. Daid downregulated the protein levels of Bax, LC3 II, cleaved caspase3 and p-Akt, while up-regulating Bcl-2 and cyclin D1. The Akt agonist SC79 could invalidate all the protective effects of Daid both in vivo and in vitro. Conclusions: Daid reduced autophagy and apoptosis by inhibiting the PI3K/Akt pathway, thereby protecting the hearts from Dox-induced cardiac damage.

A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation.

The metabolic alterations of amino acid metabolism are closely associated with inflammatory response. However, relatively little is known about the roles of phenylalanine (Phe)/tyrosine (Tyr) catabolites during inflammation. Nitisinone (NTBC) is an orphan drug used to treat hereditary tyrosinemia type I potentially by changing Phe/Tyr metabolic flow. In this study, we used NTBC as a tool to investigate the potential role of the Phe/Tyr catabolic pathway in inflammatory responses. We found that NTBC was effective in tempering the bacterial endotoxin lipopolysaccharide (LPS)-induced septic shock in mice. Mechanistically, the protective effect was related to the accumulation of a Phe/Tyr catabolic intermediate, 4-hydroxyphenylpyruvate (4-HPP), induced by the NTBC treatment. 4-HPP could inhibit NLRP3 inflammasome priming and activation processes and therefore reduce IL-1ß release and pyroptosis. Like NTBC, 4-HPP was also effective in attenuating endotoxic shock in mice. Our results suggest the Phe/Tyr catabolic pathway as a potential immunoregulatory hub that may be exploited therapeutically to alleviate inflammation.

Purple sweet potato delphinidin-3-rutin represses glioma proliferation by inducing miR-20b-5p/Atg7-dependent cytostatic autophagy.

Glioma is the most common primary malignant intracranial tumor. Owing to highly aggressive invasiveness and metastatic properties, the prognosis of this disease remains poor even with surgery, radiotherapy, and chemotherapy. Rutin is a glycoside natural flavonoid that modulates microglia inflammatory profile and improves anti-glioma activity. Here, a glycoside flavonoid was extracted and named purple sweet potato delphinidin-3-rutin (PSPD3R). In an experiment using the subcutaneous xenograft model of human glioblastoma (GBM) and alamar blue assay, we found that PSPD3R suppressed the glioma proliferation both in vitro and in vivo. Flow cytometry assay and transmission electron microscopy observation revealed that PSPD3R stimulated glioma cell autophagy and apoptosis. High-throughput microRNA (miRNA) sequencing showed that PSPD3R substantially affected the miRNA expression of U251 cells. Acridine orange staining and immunoblotting indicated that PSPD3R regulated autophagy via Akt/Creb/miR-20b-5p in glioma cells. Luciferase reporter assays showed that autophagy-related gene 7 (Atg7) mRNA was the target gene of miR-20b-5p. The downregulation of miR-20b-5p inhibited glioma proliferation in vivo. In summary, PSPD3R regulated autophagy in glioma via the Akt/Creb/miR-20b-5p/Atg7 axis. This work unraveled the molecular mechanism of PSPD3R-induced autophagy in glioma and revealed its potential as a therapeutic agent for glioma treatment.

Fluorescence imaging-guided cancer photothermal therapy using polydopamine and graphene quantum dot-capped Prussian blue nanocubes.

In recent years, imaging-guided photothermal tumor ablation has attracted intense research interest as one of the most exciting strategies for cancer treatment. Herein, we prepared polydopamine and graphene quantum dot-capped Prussian blue nanocubes (PB@PDA@GQDs, PBPGs) with high photothermal conversion efficiency and excellent fluorescence performance for imaging-guided cancer treatment. Transmission electron microscopy (TEM), UV-vis absorption spectroscopy (UV-vis), fluorescence spectroscopy, and X-ray photoelectron spectroscopy (XPS) were employed to characterize their morphology and structures. The photothermal conversion efficiency and therapeutic effect were evaluated in vitro and in vivo. Results revealed that this nanoagent had excellent biocompatibility and enhanced the photothermal effect compared to blue nanocubes (PBs) and polydopamine-capped Prussian blue nanocubes (PB@PDA, PBPs). Therefore, our study may open a new path for the production of PB-based nanocomposites as theranostic nanoagents for imaging-guided photothermal cancer treatment.

Cochlioquinone derivative CoB1 induces cytostatic autophagy in lung cancer through miRNA-125b and Foxp3.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide, yet no effective medication for this disease is available. Cochlioquinone B derivative (CoB1), purified from Salvia miltiorrhiza endophytic Bipolaris sorokiniana, affects the defense against pulmonary pathogens by regulating inflammatory responses. However, the effect of CoB1 on lung cancer and the underlying molecular mechanisms remain unknown. In the present study, we investigate the protective effects of CoB1 on lung cancer and explore its underlying mechanism. METHOD: We examined the inhibitory effect of CoB1 on lung cancer cells (A549 cells) by MTT and colony formation assay. The effect of CoB1 on cytostatic autophagy in lung cancer cells was verified by Western blot, transmission electron microscopy, and confocal microscopy. The differentially expressed miRNAs were identified using quantitative RT-PCR. Luciferase assay and Northern blot were performed to verify the correlation between miRNA-125b and Foxp3. Protein expression in autophagy-related pathways was detected by Western blot. Xenograft tumor models were constructed to explore the inhibitory effect of CoB1 and the role of miRNA-125b as a suppressor in lung cancer in vivo. RESULT: CoB1 inhibited lung cancer cell proliferation by inducing cytostatic autophagy both in vitro and in vivo. CoB1-induced autophagy was related to blocking of the PI3K/Akt1/mTOR signaling pathway. In addition, CoB1 induced miR-125b expression via activating the TAK1/MKK4/JNK/Smad axis, thereby reducing Foxp3 expression and further inducing autophagy. CONCLUSION: This study is the first to report the specific inhibitory function of CoB1 purified from Salvia miltiorrhiza endophytic Bipolaris sorokiniana in lung cancer, which may be due to the induction of autophagy. This study provides evidence and novel insights into the anticancer efficacy of CoB1.

Therapeutic potential of IBP as an autophagy inducer for treating lung cancer via blocking PAK1/Akt/mTOR signaling.

Lung cancer is the most frequent and fatal malignancy in humans worldwide, yet novel successful drugs for control of this disease are still lacking. Ipomoea batatas polysaccharides (IBPs) have been implicated in inhibiting diverse cancer types, but their functions in mitigating lung cancer are largely unknown. In this study, we identify a role of IBP in inhibiting lung cancer proliferation. We found that IBP significantly impedes the proliferation of lung cancer cells by inducing cytostatic macroautophagy both in vitro and in vivo. Mechanistically, IBP specifically promotes ubiquitination-mediated degradation of PAK1 (p21-activated kinase 1) and blocks its downstream Akt1/mTOR signaling pathway, leading to increased autophagic flux. In lung cancer xenografts in mice, IBP-induced cytostatic autophagy suppresses tumor development. Through site-directed mutational analysis, the underlying signaling augments ubiquitination via PAK1-ubiquitin interaction. Collectively, this work unravels the molecular mechanism underpinning IBP-induced cytostatic autophagy in lung cancer and characterizes IBP as a potential therapeutic agent for lung cancer treatment.

Polydatin attenuates ischemia/reperfusion-induced apoptosis in myocardium of the rat.

The aim of the present study was to investigate the effect of polydatin on apoptosis induced by ischemia/reperfusion (I/R) in rat myocardium and to explore the underlying mechanism. Adult male Sprague-Dawley (SD) rats were randomly divided into control, I/R and polydatin (50 mumol/L) groups. On the Langendorff apparatus, isolated rat heart was subjected to 30-min global ischemia followed by 60-min reperfusion. TUNEL labeling and flow cytometric techniques were used for the measurement of apoptosis and the expression of Bcl-2 and Bax protein in cardiomyocytes of rat. The results showed: (1) Compared with those in the control group, the number of TUNEL-positive cells and apoptosis rate were increased in I/R group; (2) Compared with that in the I/R group, the number of TUNEL-positive cells was significantly decreased in the polydatin group [(18.1+/-4.0)% vs (35.1+/-5.4)%, P<0.01]; (3) Apoptosis rate assayed by flow cytometry in I/R group was significantly higher than that in polydatin group [(15.43+/-4.55)% vs (8.66+/-3.18)%, P<0.01]; (4) Expression level of Bax protein was higher in I/R group than that in polydatin group (P<0.05), while the level of Bcl-2 protein and Bcl-2/Bax ratio were higher in polydatin group than those in I/R group (P<0.05, P<0.01), respectively. The results obtained suggest that polydatin exerts an inhibitory effect on I/R-induced apoptosis through increasing Bcl-2 protein expression and decreasing Bax protein expression in myocardium of the rat.

Effects of different doses of cisatracurium besilate on hemodynamics and postoperative cognitive function in patients undergoing radical resection of lung cancer.

The effects of different doses of cisatracurium besilate on perioperative hemodynamics and early postoperative cognitive function in patients undergoing radical resection of lung cancer were investigated. One hundred and thirty-six patients who underwent radical resection of lung cancer from June 2013 to June 2016 in Dongying People's Hospital were retrospectively analyzed. Patients who were not given atracurium were selected as the control group (n=35). According to the different anesthetic doses, patients in the experimental group were separated into low dose (0.15 mg/kg cisatracurium besilate) group (LD group, n=34), medium dose (0.2 mg/kg cisatracurium besilate) group (MD group, n=36) and high dose (0.3 mg/kg cisatracurium besilate) group (HD group, n=31). The mean arterial pressure and heart rate (HR) were recorded before induction of anesthesia (T0), at the time of entering pleural cavity (T1), at the end of surgery (T2), and 1 day after surgery (T3). The Mini-Mental State Examination (MMSE) was used to evaluate the postoperative cognitive function scores of the 4 groups 1 day before operation and on the 1st, 3rd and 7th day after surgery. The agitation of patients at 6 and 12 h after operation was evaluated by Ramsay sedation score. There was no significant difference in arterial pressure among the four groups at T2 and T3 (P>0.05). There was no significant difference in terms of MMSE among the four groups 1 day before operation, 3 days after operation and 7 days after operation, but the MMSE score of the control group was significantly lower than that of the LD, MD and HD groups 1 day after surgery (P<0.05). Therefore, cisatracurium besilate can stabilize hemodynamics during radical operation of lung cancer and reduce the incidence of postoperative cognitive dysfunction, and it has no close association with the dose.

Effects of Exercise Training on the Autophagy-Related Muscular Proteins Expression in Ovariectomized Rats.

Ovariectomy disrupts estrogen production and homeostasis. However, whether exercise training (ET) could counteract the ovariectomy-induced effect on muscular autophagy has remained elusive. This study examined muscular autophagy in ovariectomized (OVX) rats following 8 weeks of swimming ET. Here, 40 6-month-old female Sprague-Dawley rats were randomly divided into five groups: sham-operated control (Sham), OVX control (OVX), OVX with 60-min ET (OVX-60ET), 90-min ET (OVX-90ET), and 120-min ET (OVX-120ET) for 6 days/week. According to the results of Western blotting, the expression levels of autophagy-related proteins in the OVX gastrocnemius muscle, including mammalian target of rapamycin, uncoordinated 51-like kinase 1, Beclin-1, autophagy-related gene (Atg-7), and microtubule-associated protein light chains 3 were significantly decreased (all P < 0.05), while there was an elevation on the p62 level. ET appreciably mitigated the OVX-induced negative effects on muscle quality and the autophagy pathway, which seemed to be dependent on ET volume. The most optimal outcomes were observed in the OVX-90ET group. The OVX-120 group had an adversely augmented catabolic process associated with gastrocnemius muscle atrophy. In conclusion, the expression levels of autophagy proteins are decreased in OVX rats, which can be appreciably mitigated following 8 weeks of swimming ET.

Comparison of the effects of chronic intermittent hypobaric hypoxia and continuous hypobaric hypoxia on hemodynamics in rats.

The aim of this study is to investigate the effects of chronic intermittent hypobaric hypoxia (IHH) and chronic continuous hypobaric hypoxia (CHH) on hemodynamics under basic normoxia and acute hypoxia conditions and to find the difference of two types of chronic hypoxia. Forty adult male Sprague-Dawley (SD) rats were randomly divided into 5 groups: Control group (CON), 28 days IHH group (IHH28), 42 days IHH group (IHH42), 28 days CHH group (CHH28) and 42 days CHH group (CHH42). The rats in IHH groups were treated with intermittent hypoxia (11.1% O2) mimicking 5 000 m altitude in a hypobaric chamber for 28 or 42 d, 6 h a day, respectively. The rats in CHH groups lived in the hypobaric chamber with the same degree of hypoxia like IHH rats except half an hour in normoxia each day for feeding and cleaning. The body weight of rats was measured once a week. The parameters in hemodynamics, such as mean artery blood pressure (MAP), heart rate (HR), left ventricular systolic pressure (LVSP), maximum change rate of left ventricular pressure (+/-LVdP/dt(max)) were recorded under basic normoxia and acute hypoxia conditions through catheterization technique. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in myocardium of rats were measured by biochemical method. The weights of whole heart, left and right ventricles were measured separately. The results showed: (1) The basic HR and MAP in CHH42 rats were lower than those in CON, IHH and CHH28 rats (P<0.05). (2) IHH showed a cardioprotection against acute hypoxia and reoxygenation injury, manifested as the result that the changes of HR, MAP, LVSP, and +/- LVdP/dt(max) were smaller than those in CON rats during acute hypoxia and reoxygenation. CHH showed a rather strong cardioprotection during acute hypoxia, manifested as the result that the decreases of HR, MAP, LVSP, and +/- LVdP/dt(max)were much smaller, but it did damage during reoxygenation, manifested as the result that the recovery of hemodynamics was the worst among three groups (P<0.05). (3) The antioxygenation of heart was increased in both IHH and CHH rats compared with that in CON rats manifested by the increased SOD activity and decreased MDA content (P<0.05, P<0.01). (4) IHH had no effect on heart weight, but CHH rats showed an obvious right ventricular hypertrophy compared with CON and IHH animals (P<0.01). The result indicates that IHH can induce a more effective cardioprotection with no much side effect, which might have a potential value for practical use.

MEG3-4 is a miRNA decoy that regulates IL-1ß abundance to initiate and then limit inflammation to prevent sepsis during lung infection.

Long noncoding RNAs (lncRNAs) regulate gene expression. We investigated the role of lncRNAs in the inflammatory response to bacterial infection in the lungs. We identified the lncRNA MEG3 as a tissue-specific modulator of inflammatory responses during bacterial infection. Among the 10 transcript isoforms of MEG3, transcript 4 (referred to as MEG3-4) encodes the isoform with the lowest abundance in mouse lungs. Nonetheless, we found that MEG3-4 bound to the microRNA miR-138 in a competitive manner with mRNA encoding the proinflammatory cytokine interleukin-1ß (IL-1ß), thereby increasing IL-1ß abundance and intensifying inflammatory responses to bacterial infection in alveolar macrophages and lung epithelial cells in culture and in lung tissue in mice. MEG3-4-mediated sponging of miR-138 in the cytoplasm increased the autocrine activity of IL-1ß that subsequently induced a negative feedback mechanism mediated by nuclear factor κB that decreased MEG3-4 abundance and inflammatory cytokine production. This timely reduction in MEG3-4 abundance tempered proinflammatory responses in mice with pulmonary bacterial infection, preventing the progression to sepsis. Together, these findings reveal that MEG3-4 dynamically modulates pulmonary inflammatory responses through transcriptional regulation of immune response genes, extending the decoy and sponge mechanism associated with lncRNAs to antibacterial immunity, which affects both response and disease progression.

K(ATP) channels and MPTP are involved in the cardioprotection bestowed by chronic intermittent hypobaric hypoxia in the developing rat.

The aim of this study was to explore the mechanism underlying the cardioprotection bestowed by chronic intermittent hypobaric hypoxia (CIHH) against ischemia/reperfusion (I/R) injury in developing rats. Neonatal male rats were subjected to CIHH treatments that simulated an altitude of 3000 m a.s.l. for 28 days (CIHH28) and 42 days (CIHH42), respectively, or no treatment (control). The left ventricular function of isolated hearts was evaluated. The ultra-microstructure, superoxide dismutase (SOD) activity and total anti-oxidation capacity (TAC) of the myocardium were determined. The basic left ventricular function remained unchanged in CIHH rats, except for an increased coronary flow. The recovery of cardiac function from I/R, however, was much better in CIHH rats than in control rats. Compared to control rats, CIHH rats had much higher SOD levels and TAC, and the ultra-microstructure damage to mitochondria was considerably less. The cardiac protection of CIHH was canceled out by glibenclamide, an inhibitor of the ATP-sensitive potassium (K(ATP)) channel, 5-hydroxydecanoate, an inhibitor of mitochondrial K(ATP) (mitoKATP), and atractyloside, an opener of the mitochondrial permeability transition pore (MPTP). To the contrary, diazoxide, an opener of mitoKATP, and cyclosporin A, a blocker of MPTP opening, induced cardioprotection in control rats. These results suggest that CIHH protects the heart against I/R injury in developing rats through opening of the K(ATP) channel and inhibiting of opening of the MPTP.

High concentration of epigallocatechin-3-gallate increased the incidences of arrhythmia and diastolic dysfunction via ß2-adrenoceptor.

Epigallocatechin-3-gallate (EGCG) is the major and most potent representative in green tea, which has been proved to modulate myocardial contractility. Whether EGCG has some negative effects on cardiac function is not known. In the present study, we investigated the effects of EGCG at different doses on cardiac contraction and explored whether ß2 -adrenoceptor (ß2 AR) was involved in EGCG-induced cardiac effects. Isolated rat hearts were mounted on the Langendorff system and perfused with different concentrations of EGCG in low or normal calcium Krebs-Henseleit (KH) buffer. The contraction of hearts was measured. Ventricular myocytes were cultured with EGCG and isoprenaline (ISO, 10(-7) M) for 12 h. ICI118,551 (55 nM) was used to inhibit ß2 AR. Cardiomyocyte shortening, viability, and responsiveness to ISO (10(-9) M) were measured. EGCG dose dependently enhanced contractility of perfused heart in low calcium KH buffer. In the normal calcium KH buffer, EGCG at low dose (20 µM) increased heart contraction, while at high dose (50 µM), it increased the incidences of arrhythmia and diastolic dysfunction. In isolated ventricular myocytes, EGCG at the concentration of 0.001 to 1.0 µΜ did not affect their contraction. However, the responsiveness to ISO and the survival of myocytes were increased by EGCG (0.01 µM). The increased responsiveness was partially abolished by ICI118,551. The data obtained in this study demonstrated that EGCG at low dose conferred cardioprotection, yet at high dose increased the incidences of arrhythmia and diastolic dysfunction. ß2 AR was involved in EGCG-induced cardiac effects.