Quercetin, Main Active Ingredient of Moutan Cortex, Alleviates Chronic Orofacial Pain via Block of Voltage-Gated Sodium Channel.

BACKGROUND: Chronic orofacial pain (COP) therapy is challenging, as current medical treatments are extremely lacking. Moutan Cortex (MC) is a traditional Chinese medicine herb widely used for chronic inflammatory diseases. However, the mechanism behind MC in COP therapy has not been well-established. The purpose of this study was to identify the active ingredients of MC and their specific underlying mechanisms in COP treatment. METHODS: In this study, the main active ingredients and compound-target network of MC in COP therapy were identified through network pharmacology and bioinformatics analysis. Adult male Sprague-Dawley rats received oral mucosa lipopolysaccharide (LPS) injection to induce COP. Pain behaviors were evaluated by orofacial mechanical nociceptive assessment after intraganglionar injection. In vitro inflammatory cytokines in LPS-pretreated human periodontal ligament stem cells (hPDLSCs) and rat primary cultural trigeminal ganglion (TG) neurons were quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Schrödinger software was used to verify the molecular docking of quercetin and critical targets. Whole-cell recording electrophysiology was used to evaluate the effect of quercetin on voltage-gated sodium (Na v ) channel in rat TG neurons. RESULTS: The assembled compound-target network consisted of 4 compounds and 46 targets. As 1 of the active components of MC correlated with most related targets, quercetin alleviated mechanical allodynia in LPS-induced rat model of COP (mechanical allodynia threshold median [interquartile range (IQR) 0.5 hours after drug administration: vehicle 1.3 [0.6-2.0] g vs quercetin 7.0 [6.0-8.5] g, P = .002). Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that immune response and membrane functions play essential roles in MC-COP therapy. Five of the related targets were identified as core targets by protein-protein interaction analysis. Quercetin exerted an analgesic effect, possibly through blocking Na v channel in TG sensory neurons (peak current density median [IQR]: LPS -850.2 [-983.6 to -660.7] mV vs LPS + quercetin -589.6 [-711.0 to -147.8] mV, P = .006) while downregulating the expression level of proinflammatory cytokines-FOS (normalized messenger RNA [mRNA] level mean ± standard error of mean [SEM]: LPS [2. 22 ± 0.33] vs LPS + quercetin [1. 33 ± 0.14], P = .034) and TNF-α (normalized mRNA level mean ± SEM: LPS [8. 93 ± 0.78] vs LPS + quercetin [3. 77 ± 0.49], P < .0001). CONCLUSIONS: Identifying Na v as the molecular target of quercetin clarifies the analgesic mechanism of MC, and provides ideas for the development of novel selective and efficient chronic pain relievers.

Arylcarboxylation of unactivated alkenes with CO2 via visible-light photoredox catalysis.

Photocatalytic carboxylation of alkenes with CO2 is a promising and sustainable strategy to synthesize high value-added carboxylic acids. However, it is challenging and rarely investigated for unactivated alkenes due to their low reactivities. Herein, we report a visible-light photoredox-catalyzed arylcarboxylation of unactivated alkenes with CO2, delivering a variety of tetrahydronaphthalen-1-ylacetic acids, indan-1-ylacetic acids, indolin-3-ylacetic acids, chroman-4-ylacetic acids and thiochroman-4-ylacetic acids in moderate-to-good yields. This reaction features high chemo- and regio-selectivities, mild reaction conditions (1 atm, room temperature), broad substrate scope, good functional group compatibility, easy scalability and facile derivatization of products. Mechanistic studies indicate that in situ generation of carbon dioxide radical anion and following radical addition to unactivated alkenes might be involved in the process.

Coupled oscillator cooperativity as a control mechanism in chronobiology.

Control of dynamical processes is vital for maintaining correct cell regulation and cell-fate decisions. Numerous regulatory networks show oscillatory behavior; however, our knowledge of how one oscillator behaves when stimulated by two or more external oscillatory signals is still missing. We explore this problem by constructing a synthetic oscillatory system in yeast and stimulate it with two external oscillatory signals. Letting model verification and prediction operate in a tight interplay with experimental observations, we find that stimulation with two external signals expands the plateau of entrainment and reduces the fluctuations of oscillations. Furthermore, by adjusting the phase differences of external signals, one can control the amplitude of oscillations, which is understood through the signal delay of the unperturbed oscillatory network. With this we reveal a direct amplitude dependency of downstream gene transcription. Taken together, these results suggest a new path to control oscillatory systems by coupled oscillator cooperativity.

Ulinastatin alleviates pulmonary edema by reducing pulmonary permeability and stimulating alveolar fluid clearance in a rat model of acute lung injury.

Objectives: Previous studies have shown that ulinastatin (UTI) alleviates pulmonary edema in acute lung injury (ALI) caused by lipopolysaccharide (LPS), although the mechanism behind this action is uncertain. This research aimed to identify the fundamental mechanism by which UTI alleviates pulmonary edema. Materials and Methods: We established a model of acute lung injury (ALI) in rats by using LPS as the inciting agent.The control, LPS, and LPS+UTI groups were each comprised of a specific number of randomly selected Wistar rats. We evaluated lung injury and determined pulmonary edema. The concentrations of TNF-α, IL-1ß and IL-6 in BALF and the expression levels of α1Na, k-ATPase, ß1Na, K-AtPase, α-ENaC, ß-ENaC, γ-ENaC, Zonula occludens (ZO)-1, Occludin, Caludin-5, PI3K, Akt, TLR4, MyD88 and NF-ƘBwere identified in lung tissues. Results: The presence of UTI was associated with a reduction in lung pathological alterations, lung injury scores, the lung W/D ratio, and MPO activity, in addition to the improved gas exchange (P<0.01). Furthermore, UTI alleviated EB leakage and stimulated AFC (P<0.01). Importantly, UTI increased the expression of ZO-1, Occludin, Caludin-5, α1Na, K-ATPase, ß1Na, K-AtPase, α-ENaC, ß-ENaC, and γ-ENaC (P<0.01). Furthermore, UTI inhibited the inflammatory response, enhanced the expression of PI3K and Akt and hindered TLR4, MyD88, and NF-ƘB expression (P<0.01) in lung tissues. Conclusion: Our results demonstrated that UTI attenuated pulmonary edema by reducing pulmonary permeability and promoting AFC through inhibiting the inflammatory response, and the mechanism is related to promoting PI3K/Akt signaling pathways and suppressing TLR4/MyD88/NF-ƘB signaling pathways.

OVOL2 inhibits macrophage M2 polarization by regulating IL-10 transcription, and thus inhibits the tumor metastasis by modulating the tumor microenvironment.

Invasion and metastasis of breast cancer cells is an important cause of death in breast cancer patients. In the tumor microenvironment, M2 polarization of macrophages can promote the invasion and metastasis of tumor cells. OVOL2 is an evolutionarily conserved transcription regulator, but its effect in macrophages has not been described previously. The aim of this study was to investigate the effects of OVOL2 on macrophage polarity and the role of these effects in the tumor metastasis. We found that overexpression of OVOL2 in macrophages significantly inhibited M2 polarization and thus inhibits breast cancer metastasis. We propose a novel mechanism in which OVOL2 inhibits M2 polarization of macrophages and thus reduces their ability to induce invasion and metastasis of breast cancer. By shedding new light on the regulation of metastasis in cancers, our study provides a new strategy for the targeted therapy of cancer.

Sevoflurane-Remifentanil Versus Propofol-Remifentanil Anesthesia During Noncardiac Surgery for Patients with Coronary Artery Disease - A Prospective Study Between 2016 and 2017 at a Single Center.

BACKGROUND Volatile anesthesia possesses cardioprotective properties, and it is widely used in patients undergoing coronary artery bypass surgery, but no randomized controlled trials (RCTs) are available on the use of sevoflurane-remifentanil versus propofol-remifentanil anesthesia for patients with coronary artery disease (CAD) during noncardiac surgery. This study was designed to compare the 2 different types of general anesthesia in patients with CAD undergoing noncardiac surgery at a single center. MATERIAL AND METHODS Patients with CAD undergoing noncardiac surgery were enrolled in an RCT conducted between March 2016 and December 2017. The participants were randomized to receive either sevoflurane-remifentanil or propofol-remifentanil anesthesia. The primary endpoint was occurrence of in-hospital cardiovascular events. The secondary endpoints included delirium, postoperative nausea and vomiting (PONV), Intensive Care Unit (ICU) length of stay (LOS), in-hospital morbidity and mortality, and hospital LOS. RESULTS A total of 164 participants completed the study (sevoflurane: 81; propofol: 83). The occurrence of in-hospital cardiovascular events did not differ between the 2 groups (42.6% vs 39.4%, P=0.86). The occurrence of delirium did not differ between the 2 groups after the operation. PONV had a higher frequency after sevoflurane anesthesia at 48 h compared with propofol. In-hospital morbidity and mortality, ICU LOS, and hospital LOS were similar between the 2 groups (all P>0.05). At 30 days after surgery, no between-group differences in cardiac morbidity and mortality were observed. CONCLUSIONS In this study, anesthesia using sevoflurane-remifentanil did not provide additional postoperative cardioprotection in comparison with propofol-remifentanil in patients with CAD undergoing noncardiac surgery.

Effects of Apolipoprotein Ε Îµ4 allele on early postoperative cognitive dysfunction after anesthesia.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is one of the main causes of morbidity after noncardiac surgery; however, the pathogenic mechanisms of POCD have remained unclear until now. In this study, we performed a pilot study to investigate the association between apolipoprotein E (ApoE) ε4 and POCD in older patients undergoing intravenous anesthesia (IVA) and inhalation anesthesia (IAA). METHODS: In total, 180 patients from Shenzhen People's Hospital were recruited and randomly divided into an IVA group and an IAA group. The IVA group and IAA group received propofol and sevoflurane treatment, respectively. Within 7 days after surgery, the mini-mental state examination (MMSE) was used daily to assess the cognitive function of both groups of patients. The genotypes of the ApoE gene were detected using the restriction fragment length polymorphism technique. In addition, the serum levels of (soluble protein-100ß) S­100ß and (Interleukin- 6) L­6 were also analyzed. RESULTS: Compared to the preoperative and IVA groups, the MMSE score in the IAA group significantly decreased at 3 days after surgery. Furthermore, the IAA group had a higher percentage of patients who scored less than 25 points than the IVA group at 3 days after surgery. The decrease in the MMSE score was closely related to the ApoE ε4 allele in the IAA group, but this correlation was not observed in the IVA group. The levels of S­100ß and IL­6 were increased sharply in patients with the ε4/ε4 genotype who received IAA compared with IVA at 1 day after surgery. CONCLUSION: The results of the study indicated that the ApoΕ Îµ4/ε4 genotype was a risk factor for early POCD in older patients undergoing sevoflurane anesthesia.

Etomidate vs propofol in coronary heart disease patients undergoing major noncardiac surgery: A randomized clinical trial.

BACKGROUND: The ideal depth of general anesthesia should achieve the required levels of hypnosis, analgesia, and muscle relaxation while minimizing physiologic responses to awareness. The choice of anesthetic strategy in patients with coronary heart disease (CHD) undergoing major noncardiac surgery is becoming an increasingly important issue as the population ages. This is because general anesthesia is associated with a risk of perioperative cardiac complications and death, and this risk is much higher in people with CHD. AIM: To compare hemodynamic function and cardiovascular event rate between etomidate- and propofol-based anesthesia in patients with CHD. METHODS: This prospective study enrolled consecutive patients (American Society of Anesthesiologists grade II/III) with stable CHD (New York Heart Association class I/II) undergoing major noncardiac surgery. The patients were randomly allocated to receive either etomidate/remifentanil-based or propofol/remifentanil-based general anesthesia. Randomization was performed using a computer-generated random number table and sequentially numbered, opaque, sealed envelopes. Concealment was maintained until the patient had arrived in the operating theater, at which point the consulting anesthetist opened the envelope. All patients, data collectors, and data analyzers were blinded to the type of anesthesia used. The primary endpoints were the occurrence of cardiovascular events (bradycardia, tachycardia, hypotension, ST-T segment changes, and ventricular premature beats) during anesthesia and cardiac troponin I level at 24 h. The secondary endpoints were hemodynamic parameters, bispectral index, and use of vasopressors during anesthesia. RESULTS: The final analysis included 40 patients in each of the propofol and etomidate groups. The incidences of bradycardia, hypotension, ST-T segment changes, and ventricular premature beats during anesthesia were significantly higher in the propofol group than in the etomidate group (P < 0.05 for all). The incidence of tachycardia was similar between the two groups. Cardiac troponin I levels were comparable between the two groups both before the induction of anesthesia and at 24 h after surgery. When compared with the etomidate group, the propofol group had significantly lower heart rates at 3 min after the anesthetic was injected (T1) and immediately after tracheal intubation (T2), lower systolic blood pressure at T1, and lower diastolic blood pressure and mean arterial pressure at T1, T2, 3 min after tracheal intubation, and 5 min after tracheal intubation (P < 0.05 for all). Vasopressor use was significantly more in the propofol group than in the etomidate group during the induction and maintenance periods (P < 0.001). CONCLUSION: In patients with CHD undergoing noncardiac major surgery, etomidate-based anesthesia is associated with fewer cardiovascular events and smaller hemodynamic changes than propofol-based anesthesia.

α-Amino Acids and Peptides as Bifunctional Reagents: Carbocarboxylation of Activated Alkenes via Recycling CO2.

Carboxylic acids, including amino acids (AAs), have been widely used as reagents for decarboxylative couplings. In contrast to previous decarboxylative couplings that release CO2 as a waste byproduct, herein we report a novel strategy with simultaneous utilization of both the alkyl and carboxyl components from carboxylic acids. Under this unique strategy, carboxylic acids act as bifunctional reagents in the redox-neutral carbocarboxylation of alkenes. Diverse, inexpensive, and readily available α-AAs take part in such difunctionalizations of activated alkenes via visible-light photoredox catalysis, affording a variety of valuable but otherwise difficult to access γ-aminobutyric acid derivatives (GABAs). Additionally, a series of dipeptides and tripeptides also participate in this photocatalytic carbocarboxylation. Although several challenges exist in this system due to the low concentration and quantitative amount of CO2, as well as unproductive side reactions such as hydrodecarboxylation of the carboxylic acids and hydroalkylation of the alkenes, excellent regioselectivity and moderate to high chemoselectivity are achieved. This process features low catalyst loading, mild reaction conditions, high step and atom economy, and good functional group tolerance, and it is readily scalable. The resulting products are subject to efficient derivations, and the overall process is amenable to applications in the late-stage modification of complex compounds. Mechanistic studies indicate that a carbanion is generated catalytically and it acts as the key intermediate to react with CO2, which is also generated catalytically in situ and thus remains in low concentration. The overall transformation represents an efficient and sustainable system for organic synthesis, pharmaceutics, and biochemistry.

Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury.

Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor (α2AR) agonist, has an anti-inflammatory property and can alleviate pulmonary edema in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the mechanism is still unclear. In this study, we attempted to investigate the effect of Dex on alveolar epithelial sodium channel (ENaC) in the modulation of alveolar fluid clearance (AFC) and the underlying mechanism. Lipopolysaccharide (LPS) was used to induce acute lung injury (ALI) in rats and alveolar epithelial cell injury in A549 cells. In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC, prevented LPS-induced downregulation of α-, ß-, and γ-ENaC expression, attenuated inflammatory cell infiltration in lung tissue, reduced the concentrations of TNF-α, IL-1ß, and IL-6, and increased concentrations of IL-10 in bronchoalveolar lavage fluid (BALF). In A549 cells stimulated with LPS, Dex attenuated LPS-mediated cell injury and the downregulation of α-, ß-, and γ-ENaC expression. However, all of these effects were blocked by the PI3K inhibitor LY294002, suggesting that the protective role of Dex is PI3K-dependent. Additionally, Dex increased the expression of phosphorylated Akt and reduced the expression of Nedd4-2, while LY294002 reversed the effect of Dex in vivo and in vitro. Furthermore, insulin-like growth factor (IGF)-1, a PI3K agonists, promoted the expression of phosphorylated Akt and reduced the expression of Nedd4-2 in LPS-stimulated A549 cells, indicating that Dex worked through PI3K, and Akt and Nedd4-2 are downstream of PI3K. In conclusion, Dex alleviates pulmonary edema by suppressing inflammatory response in LPS-induced ALI, and the mechanism is partly related to the upregulation of ENaC expression via the PI3K/Akt/Nedd4-2 signaling pathway.

Visible-Light Photoredox-Catalyzed Ring-Opening Carboxylation of Cyclic Oxime Esters with CO2.

The carboxylation of cyclic oxime esters with carbon dioxide via visible-light photoredox catalysis is demonstrated for the first time. A variety of cyclic oxime esters undergo ring-opening C-C bond cleavage and carboxylation to give cyanoalkyl-containing carboxylic acids in moderate to good yields. Moreover, this methodology features mild reaction conditions (room temperature, 1 atm), wide substrate scope, good functional group tolerance as well as facile derivations of products. Mechanistic studies indicate that the benzylic radicals and anions might be the key intermediates.

Visible-Light Photoredox-Catalyzed Remote Difunctionalizing Carboxylation of Unactivated Alkenes with CO2.

Remote difunctionalization of unactivated alkenes is challenging but a highly attractive tactic to install two functional groups across long distances. Reported herein is the first remote difunctionalization of alkenes with CO2 . This visible-light photoredox catalysis strategy provides a facile method to synthesize a series of carboxylic acids bearing valuable fluorine- or phosphorus-containing functional groups. Moreover, this versatile protocol shows mild reaction conditions, broad substrate scope, and good functional-group tolerance. Based on DFT calculations, a radical adds to an unactivated alkene to smoothly form a new carbon radical, followed by a 1,5-hydrogen atom-transfer process, the rate-limiting step, generating a more stable benzylic radical. The reduction of the benzylic radicals by an IrII species generates the corresponding benzylic carbanions as the key intermediates, which further undergo nucleophilic attack with CO2 to generate carboxylates.

Reductive dearomative arylcarboxylation of indoles with CO2 via visible-light photoredox catalysis.

Catalytic reductive coupling of two electrophiles and one unsaturated bond represents an economic and efficient way to construct complex skeletons, which is dominated by transition-metal catalysis via two electron transfer. Herein, we report a strategy of visible-light photoredox-catalyzed successive single electron transfer, realizing dearomative arylcarboxylation of indoles with CO2. This strategy avoids common side reactions in transition-metal catalysis, including ipso-carboxylation of aryl halides and ß-hydride elimination. This visible-light photoredox catalysis shows high chemoselectivity, low loading of photocatalyst, mild reaction conditions (room temperature, 1 atm) and good functional group tolerance, providing great potential for the synthesis of valuable but difficultly accessible indoline-3-carboxylic acids. Mechanistic studies indicate that the benzylic radicals and anions might be generated as the key intermediates, thus providing a direction for reductive couplings with other electrophiles, including D2O and aldehyde.

CO2 = CO + [O]: recent advances in carbonylation of C-H bonds with CO2.

Carbon dioxide (CO2) is an ideal one-carbon source owing to its nontoxicity, abundance, availability, and recyclability. Although the thermodynamic stability and kinetic inertness of CO2 bring its utilization challenges, many groups have achieved significant progress in the utilization of CO2 to synthesize valuable carbonyl-containing compounds, which could be also generated via oxidative carbonylation of C-H bonds with CO. As CO2 has a higher oxidation state than CO, it could be considered as a combination of CO and oxidant (CO2 = CO + [O]), thus providing a safe, redox-neutral and economic strategy. In this Feature Article, we have summarized the recent advances in carbonylation of C-H bonds with CO2 based on this concept. The plausible mechanisms of such reactions and future of this field are also discussed.

DNA Hypomethylation of miR-30a Mediated the Protection of Hypoxia Postconditioning Against Aged Cardiomyocytes Hypoxia/Reoxygenation Injury Through Inhibiting Autophagy.

BACKGROUND: Ischemic postconditioning (IPostC) is an endogenous protective mechanism to reduce ischemia-reperfusion (I/R) injury. However, whether IPostC protects aged cardiomyocytes against I/R injury is not fully understood. Considering the protective function of microRNA 30a (miR-30a) against ischemia-induced injury in H9C2 cells, its role in the protective effects of IPostC on I/R injury of aged cardiomyocytes was investigated further.Methods and Results:To mimic I/R and IPostC in vitro, the aged cardiomyocyte model for hypoxia postconditioning (HPostC) treatment was established by 9 days of incubation with 8 mg/mL D-galactose and then followed by exposure to hypoxic environment. HPostC significantly alleviated hypoxia/reoxygenation (H/R) injury and reduced autophagy of aged cardiomyocytes, as evidenced by decreased LC3B-II expression and increased p62 by Western blot. Quantified by quantitative real-time polymerase chain reaction (qRT-PCR), miR-30a was increased in aged cardiomyocytes treated with HPostC compared with I/R injury group. Overexpression of miR-30a by LV3-rno-miR-30a mimic promoted cardioprotective effect of HPostC in aged cardiomyocytes by suppressing BECN1-mediated autophagy, all of which was abrogated by knockdown of miR-30a expression. Epigenetic analyses demonstrated that HPostC reduced DNA methyltransferase 3b-mediated DNA hypomethylation levels at miR-30a promoter, leading to upregulation of miR-30a. CONCLUSIONS: HPostC protected aged cardiomyocytes survival against H/R injury via DNMT3b-dependent activation of miR-30a. miR-30a could be a potential therapeutic target for ischemic myocardial infarction.

Highly Selective and Catalytic Generation of Acyclic Quaternary Carbon Stereocenters via Functionalization of 1,3-Dienes with CO2.

The catalytic asymmetric functionalization of readily available 1,3-dienes is highly important, but current examples are mostly limited to the construction of tertiary chiral centers. The asymmetric generation of acyclic products containing all-carbon quaternary stereocenters from substituted 1,3-dienes represents a more challenging, but highly desirable, synthetic process for which there are very few examples. Herein, we report the highly selective copper-catalyzed generation of chiral all-carbon acyclic quaternary stereocenters via functionalization of 1,3-dienes with CO2. A variety of readily available 1,1-disubstituted 1,3-dienes, as well as a 1,3,5-triene, undergo reductive hydroxymethylation with high chemo-, regio-, E/Z-, and enantioselectivities. The reported method features good functional group tolerance, is readily scaled up to at least 5 mmol of starting diene, and generates chiral products that are useful building blocks for further derivatization. Systemic mechanistic investigations using density functional theory calculations were performed and provided the first theoretical investigation for an asymmetric transformation involving CO2. These computational results indicate that the 1,2-hydrocupration of 1,3-diene proceeds with high π-facial selectivity to generate an (S)-allylcopper intermediate, which further induces the chirality of the quaternary carbon center in the final product. The 1,4-addition of an internal allylcopper complex, which differs from previous reports involving terminal allylmetallic intermediates, to CO2 kinetically determines the E/Z- and regioselectivity. The rapid reduction of a copper carboxylate intermediate to the corresponding silyl-ether in the presence of Me(MeO)2SiH provides the exergonic impetus and leads to chemoselective hydroxymethylation rather than carboxylation. These results provide new insights for guiding further development of asymmetric C-C bond formations with CO2.

Protective effect of dexmedetomidine against organ dysfunction in a two-hit model of hemorrhage/resuscitation and endotoxemia in rats.

Dexmedetomidine (DEX), a selective agonist of α2-adrenergic receptors, has anti-inflammation properties and potential beneficial effects against trauma, shock, or infection. Therefore, this study aimed to investigate whether DEX might protect against multiple-organ dysfunction in a two-hit model of hemorrhage/resuscitation (HS) and subsequent endotoxemia. Eighty Wistar rats were randomized into four groups: NS (normal saline), HS/L (HS plus lipopolysaccharide), HS/L+D (HS/L plus dexmedetomidine), and HS/L+D+Y (HS/L+D plus yohimbine). Six hours after resuscitation, blood gas (PaO2) and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urine nitrogen (BUN), creatinine (Cr), TNF-α, IL-ß, IL-6, IL-8, IL-10, and nitric oxide (NO) were measured. The histopathology was assayed by staining. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels and heme oxygenase-1 (HO-1) were assayed. The PaO2 levels in HS/L rats were lower whereas the ALT, AST, BUN, Cr, TNF-α, IL-ß, IL-6, IL-8, IL-10, and NO levels were higher compared to the control group. The HS/L+D increased PaO2 and further increased IL-10 and decreased ALT, AST, BUN, Cr, TNF-α, IL-ß, IL-6, IL-8, and NO levels of the HS/L groups. In addition, the MDA in the HS/L groups increased whereas SOD activity decreased compared to the control group. Moreover, the HO-1 expression levels were increased by DEX administration in lung, liver, and kidney tissues. Lungs, livers, and kidneys of the HS/L group displayed significant damage, but such damage was attenuated in the HS/L+D group. All of the above-mentioned effects of DEX were partly reversed by yohimbine. DEX reduced multiple organ injury caused by HS/L in rats, which may be mediated, at least in part, by α2-adrenergic receptors.

Protective effect of dexmedetomidine against organ dysfunction in a two-hit model of hemorrhage/resuscitation and endotoxemia in rats

Dexmedetomidine (DEX), a selective agonist of α2-adrenergic receptors, has anti-inflammation properties and potential beneficial effects against trauma, shock, or infection. Therefore, this study aimed to investigate whether DEX might protect against multiple-organ dysfunction in a two-hit model of hemorrhage/resuscitation (HS) and subsequent endotoxemia. Eighty Wistar rats were randomized into four groups: NS (normal saline), HS/L (HS plus lipopolysaccharide), HS/L+D (HS/L plus dexmedetomidine), and HS/L+D+Y (HS/L+D plus yohimbine). Six hours after resuscitation, blood gas (PaO2) and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urine nitrogen (BUN), creatinine (Cr), TNF-α, IL-β, IL-6, IL-8, IL-10, and nitric oxide (NO) were measured. The histopathology was assayed by staining. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels and heme oxygenase-1 (HO-1) were assayed. The PaO2 levels in HS/L rats were lower whereas the ALT, AST, BUN, Cr, TNF-α, IL-β, IL-6, IL-8, IL-10, and NO levels were higher compared to the control group. The HS/L+D increased PaO2 and further increased IL-10 and decreased ALT, AST, BUN, Cr, TNF-α, IL-β, IL-6, IL-8, and NO levels of the HS/L groups. In addition, the MDA in the HS/L groups increased whereas SOD activity decreased compared to the control group. Moreover, the HO-1 expression levels were increased by DEX administration in lung, liver, and kidney tissues. Lungs, livers, and kidneys of the HS/L group displayed significant damage, but such damage was attenuated in the HS/L+D group. All of the above-mentioned effects of DEX were partly reversed by yohimbine. DEX reduced multiple organ injury caused by HS/L in rats, which may be mediated, at least in part, by α2-adrenergic receptors.

3-Methyladenine and dexmedetomidine reverse lipopolysaccharide-induced acute lung injury through the inhibition of inflammation and autophagy.

The aim of the present study was to investigate the effects of 3-methyladenine (3-MA) and dexmedetomidine (DEX) pretreatment on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the potential mechanism underlying the effects. LPS was instilled into the trachea of BALB/c mice to induce the ALI model. Solutions of 3-MA or DEX were intravenously injected into the mice 1 h later to establish the 3-MA and DEX groups. On days 1, 3 and 5 after the injections, arterial blood gas analysis was conducted, and the lung wet-dry weight ratio (W/D) was determined. In addition, albumin, cytokine and myeloperoxidase (MPO) contents were evaluated using ELISAs, and hematoxylin and eosin (H&E) staining was conducted. Furthermore, western blot analysis was used to evaluate the protein expression levels of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, LC3-II, autophagy protein 5 (ATG5), Rab7 and lysosome-associated membrane protein 1 (LAMP1), and reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression levels of nuclear factor-κB (NF-κB) and Toll-like receptor 4 (TLR4). Treatment with 3-MA or DEX increased the blood partial pressure of oxygen level compared with that in the model group, and restored the W/D and blood partial pressure of carbon dioxide to normal levels. The content of tumor necrosis factor-α, interleukin-6 and albumin in bronchoalveolar fluid and MPO in lung tissue was significantly decreased in the 3-MA and DEX groups compared with the model group (P<0.05). H&E staining demonstrated that 3-MA and DEX each reversed the ALI. In addition, 3-MA and DEX reduced the protein expression levels of LC3-I, LC3-II, ATG5, Rab7 and LAMP1. Also, RT-qPCR results revealed that NF-κB and TLR4 mRNA expression levels were clearly decreased in the 3-MA and DEX groups compared with the model group. In conclusion, LPS-induced ALI was effectively reversed by treatment with 3-MA and DEX through the reduction of inflammation and autophagy and inhibition of the TLR4-NF-κB pathway.

In renal hypertension, Cirsium japonicum strengthens cardiac function via the intermedin/nitric oxide pathway.

Cirsium japonicum, a constituent of traditional Chinese medicine, has been shown to exert inflammatory effects as well as to improve the circulation and thus to counteract hematologic stasis. Studies have demonstrated that intermedin (IMD) has protective effects on hypertension in rats by regulating the Ang/NO metabolic pathway. In this study, we investigated whether by regulating the expression of IMD, Cirsium japonicum could improve cardiac function in rats with 2k1c-induced renal hypertension. Renal hypertension was induced in Sprague-Dawley rats by occluding the renal artery. The rats were maintained on a normal diet and randomly divided into four groups: sham, 2k1c, 2k1c with Cirsium japonicum (1.8 g/kg per day) and 2k1c with IMD (n = 10 in each group). Cardiac function, plasma angiotensin II (Ang II), IMD, serum nitric oxide (NO) and nitric oxide synthase (NOS), as well as the expression of IMD and adrenomedullin (ADM) in the aorta and left ventricle were analyzed. Administration of Cirsium japonicum or IMD significantly strengthened cardiac function in 2k1c-induced rats, increased serum NO and NOS levels, reduced plasma Ang II, and upregulated IMD expression in the aorta and left ventricle. These results demonstrate that Cirsium japonicum has cardioprotective effects on 2k1c-induced renal hypertension in rats via the IMD/NO pathway.