Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

Hydrogen sulfide in health and diseases: cross talk with noncoding RNAs.

Hydrogen sulfide (H2S) is previously described as a potentially lethal toxic gas. However, this gasotransmitter is also endogenously generated by the actions of cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in mammalian systems, thus belonging to the family of gasotransmitters after nitric oxide (NO) and carbon monoxide (CO). The physiological or pathological significance of H2S has been extensively expanded for decades. Growing evidence has revealed that H2S exerts cytoprotective functions in the cardiovascular, nervous, and gastrointestinal systems by modulating numerous signaling pathways. With the continuous advancement of microarray and next-generation sequencing technologies, noncoding RNAs (ncRNAs) have gained recognition as key players in human health and diseases due to their considerable potential as predictive biomarkers and therapeutic targets. Coincidentally, H2S and ncRNAs are not independent regulators but interact with each other during the development and progression of human diseases. Specifically, ncRNAs might serve as downstream mediators of H2S or act on H2S-generating enzymes to govern endogenous H2S production. The purpose of this review is to summarize the interactive regulatory roles of H2S and ncRNAs in the initiation and development of various diseases and explore their potential health and therapeutic benefits. This review will also highlight the importance of cross talk between H2S and ncRNAs in disease therapy.

[Effect of Ropivacaine Combined with Dexmedetomidine for Serratus Anterior Plane Block Plus Patient-Controlled Intravenous Analgesia on Postoperative Recovery Quality of Patients Undergoing Thoracoscopic Radical Resection of Lung Cancer].

Objective: To study the postoperative analgesic effect of ropivacaine combined with dexmedetomidine for serratus anterior plane block (SAPB) under ultrasound visualization plus patient-controlled intravenous analgesia (PCIA) in patients undergoing thoracoscopic radical resection of lung cancer. Methods: A total of 129 patients undergoing elective thoracoscopic surgery were enrolled. The patients were randomly assigned to three groups ( n=43 in each group), a normal saline group (control group), a ropivacaine mesylate group (Group R) and a ropivacaine mesylate combined with dexmetomidine hydrochloride group (Group RD). After operation, ultrasound-guided SAPB was performed and patients in the three groups received the injection of 0 mL of 0.9% normal saline, 25 mL of 0.5% ropivacaine, and 25 mL of 0.5% ropivacaine+1 µg/kg dextrometomidine hydrochloride mixture, respectively. In addition, PCIA was used for all the patients. The button on the PCIA pump was pressed when the postoperative pain visual analogue score (VAS)≥4 on coughing, and rescue analgesic of sufentanil was given intravenously at 2.5 µg/bolus. The primary outcome was the VAS scores at rest and on coughing at 10 min (T 1), 6 h (T 2), 12 h (T 3), 24 h (T 4), and 48 h (T 5) after extubation. The secondary outcomes included hemodynamics, the quality of sleep for the first 3 nights after operation, number of times the button on the PCIA pump was pressed, intraoperative and postoperative opioid dosage, time of first postoperative rescue analgesic, duraion of intubation, length of stay at the hospital, adverse reactions, etc. Results: Compared with those of the control group, the VAS scores of the Group R and Group RD were significantly lower at 10 min, 6 h, and 12 h after extubation ( P<0.05). In comparison with Group R, the number of patients requiring rescue analgesia, the time of first postoperative rescue analgesic, the number of times the button on the PCIA pump was pressed, and the total dose of rescue sufentanil were all significantly lower ( P<0.05) in the Group RD. Patients in the Group RD had better sleep quality in the second and third nights after operation and lower incidence of nausea and vomiting ( P<0.05). Conclusion: 0.5% ropivacaine and 1 µg/kg dexmedetomidine SAPB combined with PCIA can significantly reduce postoperative pain and improve postoperative recovery quality in patients undergoing thoracoscopic radical resection of lung cancer.

Extracellular Vesicle-Mediated Vascular Cell Communications in Hypertension: Mechanism Insights and Therapeutic Potential of ncRNAs.

Hypertension, a chronic and progressive disease, is an outstanding public health issue that affects nearly 40% of the adults worldwide. The increasing prevalence of hypertension is one of the leading causes of cardiovascular morbidity and mortality. Despite of the available treatment medications, an increasing number of hypertensive individuals continues to have uncontrolled blood pressure. In the vasculature, endothelial cells, vascular smooth muscle cells (VSMCs), and adventitial fibroblasts play a fundamental role in vascular homeostasis. The aberrant interactions between vascular cells might lead to hypertension and vascular remodeling. Identification of the precise mechanisms of vascular remodeling may be highly required to develop effective therapeutic approaches for hypertension. Recently, extracellular vesicle-mediated transfer of proteins or noncoding RNAs (ncRNAs) between vascular cells holds promise for the treatment of hypertension. Especially, extracellular vesicle-packaging ncRNAs have gained enormous attention of basic and clinical scientists because of their tremendous potential to act as novel clinical biomarkers and therapeutic targets of hypertension. Here we will discuss the current findings focusing on the emerging roles of extracellular vesicle-carrying ncRNAs in the pathologies of hypertension and its associated vascular remodeling. Furthermore, we will highlight the potential of extracellular vesicles and ncRNAs as biomarkers and therapeutic targets for hypertension. The future research directions on the challenges and perspectives of extracellular vesicles and ncRNAs in hypertensive vascular remodeling are also proposed.

LncRNAs and circular RNAs as endothelial cell messengers in hypertension: mechanism insights and therapeutic potential.

Endothelial cells are major constituents in the vasculature, and they act as important players in vascular homeostasis via secretion/release of vasodilators and vasoconstrictors. In healthy arteries, endothelial cells play a key role in the regulation of vascular tone, cellular adhesion, and angiogenesis. A shift in the functions of the blood vessels toward vasoconstriction, proinflammatory state, oxidative stress and deficiency of nitric oxide (NO) might lead to endothelial dysfunction, a key event implicated in the pathophysiology of cardiovascular metabolic diseases, including diabetes, atherosclerosis, arterial hypertension and pulmonary arterial hypertension (PAH). Thus, reversibility of endothelial dysfunction may be beneficial for maintaining vascular homeostasis. In recent years, accumulative evidence has documented that noncoding RNAs (ncRNAs) are critically involved in endothelial homeostasis. Specifically, long noncoding RNAs (lncRNAs) and circular RNAs are highly expressed in endothelial cells where they serve as important mediators in normal endothelial functions. Dysregulation of lncRNAs and circular RNAs has been tightly associated with hypertension-related endothelial dysfunction. In this review, we will summarize the current progression and underlying mechanisms of lncRNA and circular RNA in endothelial cell biology under hypertensive conditions. We will also highlight their potential as biomarkers or therapeutic targets for hypertension and its associated endothelial dysfunction.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization.

Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.

Vaccarin alleviates septic cardiomyopathy by potentiating NLRP3 palmitoylation and inactivation.

BACKGROUND: Sepsis often leads to significant morbidity and mortality due to severe myocardial injury. As is known, the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome crucially contributes to septic cardiomyopathy (SCM) by facilitating the secretion of interleukin (IL)-1ß and IL-18. The removal of palmitoyl groups from NLRP3 is a crucial step in the activation of the NLRP3 inflammasome. Thus, the potential inhibitors that regulate the palmitoylation and inactivation of NLRP3 may significantly diminish sepsis-induced cardiac dysfunction. PURPOSE: The present study sought to explore the effects of the prospective flavonoid compounds targeting NLRP3 on SCM and to elucidate the associated underlying mechanisms. STUDY DESIGN: The palmitoylation and activation of NLRP3 were detected in H9c2 cells and C57BL/6 J mice. METHODS/RESULTS: Echocardiography, histological staining, western blotting, co-immunoprecipitation, qPCR, ELISA and network pharmacology were used to assess the impact of vaccarin (VAC) on SCM in mice subjected to lipopolysaccharide (LPS) injection. From the collection of 74 compounds, we identified that VAC had the strongest capability to suppress NLRP3 luciferase report gene activity in cardiomyocytes, and the anti-inflammatory characteristics of VAC were further ascertained by the network pharmacology. Exposure of LPS triggered apoptosis, inflammation, oxidative stress, mitochondrial disorder in cardiomyocytes. The detrimental alterations were significantly reversed upon VAC treatment in both septic mice and H9c2 cells exposed to LPS. In vivo experiments demonstrated that VAC treatment alleviated septic myocardial injury, indicated by enhanced cardiac function parameters, preserved cardiac structure, and reduced inflammation/oxidative response. Mechanistically, VAC induced NLRP3 palmitoylation to inactivate NLRP3 inflammasome by acting on zDHHC12. In support, the NLRP3 agonist ATP and the acylation inhibitor 2-bromopalmitate (2-BP) prevented the effects of VAC. CONCLUSION: Our findings suggest that VAC holds promise in protecting against SCM by mitigating cardiac oxidative stress and inflammation via priming NLRP3 palmitoylation and inactivation. These results lay the solid basis for further assessment of the therapeutic potential of VAC against SCM.

Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy.

INTRODUCTION: Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined. OBJECTIVES: We aimed to elucidate the potential roles of Metrnl in DCM. METHODS: Gain- andloss-of-function experimentswere utilized to determine the roles of Metrnl in the pathological processes of DCM. RESULTS: We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation. CONCLUSION: Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.

MiRNAs, lncRNAs, and circular RNAs as mediators in hypertension-related vascular smooth muscle cell dysfunction.

Hypertension is a multifactorial disorder that involves complex genetic and environmental factors. Vascular smooth muscle cells (VSMCs) are important components of blood vessels, and their dysregulation has been shown to be involved in vascular remodeling during the development of systemic hypertension and pulmonary arterial hypertension (PAH) via multiple mechanisms, such as aberrant apoptosis, phenotype conversion, proliferation, and migration of VSMCs. With increasing advances in microarrays and next-generation sequencing, nonprotein-coding RNAs (ncRNAs) have attracted much attention due to their numerous functions in health and diseases. Among ncRNAs, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs are emerging as novel modulators in the biological behaviors of VSMCs, especially in systemic hypertension and PAH. Studies have recommended miRNAs, lncRNAs, and circular RNAs as predictive biomarkers and therapeutic targets for systemic hypertension and PAH. In this review, we summarize the current studies focusing on the roles of VSMC-derived miRNAs, lncRNAs and circular RNAs in the pathologies of systemic hypertension and PAH. MiRNAs, lncRNAs, and circular RNAs might serve as attractive targets for the prevention and treatment of VSMC dysfunction-linked systemic hypertension and PAH.

Roles of circular RNAs in diabetic complications: From molecular mechanisms to therapeutic potential.

Diabetes is characterized by changed homeostasis of blood glucose levels, which is associated with various complications, including cardiomyopathy, atherosclerosis, endothelial dysfunction, nephropathy, retinopathy and neuropathy. In recent years, accumulative evidence has demonstrated that circular RNAs are identified as a novel type of noncoding RNAs (ncRNAs) involving in the regulation of various physiological processes and pathologic conditions. Specifically, the emergence of complications response to diabetes is finely controlled by a complex gene regulatory network in which circular RNAs play a critical role. Recently, circular RNAs are emerging as messengers that could influence cellular functions under diabetic conditions. Dysregulation of circular RNAs has been closely linked to the pathophysiology of diabetes-related complications. In this review, we aimed to summarize the current progression and underlying mechanisms of circular RNA in the development of diabetes-related complications. We will also provide an overview of circular RNA-regulated cell communications in different types of cells that have been linked to diabetic complications. We anticipated that the completion of this review will provide potential clues for developing novel circular RNAs-based biomarkers or therapeutic targets for diabetes and its associated complications.

Emerging Role of IL-10 in Hypertrophic Scars.

Hypertrophic scars (HS) arise from traumatic or surgical injuries and the subsequent abnormal wound healing, which is characterized by continuous and histologically localized inflammation. Therefore, inhibiting local inflammation is an effective method of treating HS. Recent insight into the role of interleukin-10 (IL-10), an important anti-inflammatory cytokine, in fibrosis has increased our understanding of the pathophysiology of HS and has suggested new therapeutic targets. This review summarizes the recent progress in elucidating the role of IL-10 in the formation of HS and its therapeutic potential based on current research. This knowledge will enhance our understanding of the role of IL-10 in scar formation and shed new light on the regulation and potential treatment of HS.

Directed modification of l-LcLDH1, an l-lactate dehydrogenase from Lactobacillus casei, to improve its specific activity and catalytic efficiency towards phenylpyruvic acid.

To improve the specific activity and catalytic efficiency of l-LcLDH1, an NADH-dependent allosteric l-lactate dehydrogenase from L. casei, towards phenylpyruvic acid (PPA), its directed modification was conducted based on the semi-rational design. The three variant genes, Lcldh1Q88R, Lcldh1I229A and Lcldh1T235G, were constructed by whole-plasmid PCR as designed theoretically, and expressed in E. coli BL21(DE3), respectively. The purified mutant, l-LcLDH1Q88R or l-LcLDH1I229A, displayed the specific activity of 451.5 or 512.4 U/mg towards PPA, by which the asymmetric reduction of PPA afforded l-phenyllactic acid (PLA) with an enantiomeric excess (eep) more than 99%. Their catalytic efficiencies (kcat/Km) without d-fructose-1,6-diphosphate (d-FDP) were 4.8- and 5.2-fold that of l-LcLDH1. Additionally, the kcat/Km values of l-LcLDH1Q88R and l-LcLDH1I229A with d-FDP were 168.4- and 8.5-fold higher than those of the same enzymes without d-FDP, respectively. The analysis of catalytic mechanisms by molecular docking (MD) simulation indicated that substituting I229 in l-LcLDH1 with Ala enlarges the space of substrate-binding pocket, and that the replacement of Q88 with Arg makes the inlet of pocket larger than that of l-LcLDH1.

Nesfatin-1 promotes VSMC migration and neointimal hyperplasia by upregulating matrix metalloproteinases and downregulating PPARγ.

The dedifferentiation, proliferation and migration of vascular smooth muscle cells (VSMCs) are essential in the progression of hypertension, atherosclerosis and intimal hyperplasia. Nesfatin-1 is a potential modulator in cardiovascular functions. However, the role of nesfatin-1 in VSMC biology has not been explored. The present study was designed to determine the regulatory role of nesfatin-1 in VSMC proliferation, migration and intimal hyperplasia after vascular injury. Herein, we demonstrated that nesfatin-1 promoted VSMC phenotype switch from a contractile to a synthetic state, stimulated VSMC proliferation and migration in vitro. At the molecular level, nesfatin-1 upregulated the protein and mRNA levels, as well as the promoter activities of matrix metalloproteinase 2 (MMP-2) and MMP-9, but downregulated peroxisome proliferator-activated receptor γ (PPARγ) levels and promoter activity in VSMCs. Blockade of MMP-2/9 or activation of PPARγ prevented the nesfatin-1-induced VSMC proliferation and migration. In vivo, knockdown of nesfatin-1 ameliorated neointima formation following rat carotid injury. Taken together, our results indicated that nesfatin-1 stimulated VSMC proliferation, migration and neointimal hyperplasia by elevating MMP2/MMP-9 levels and inhibiting PPARγ gene expression.

Caveolin-1 scaffolding domain peptides enhance anti-inflammatory effect of heme oxygenase-1 through interrupting its interact with caveolin-1.

Caveolin-1(Cav-1) scaffolding domain (CSD) peptides compete with the plasma membrane Cav-1, inhibit the interaction of the proteins and Cav-1, and re-store the functions of Cav-1 binding proteins. Heme oxygenase-1 (HO-1) binds to Cav-1 and its enzymatic activity was inhibited. In this study, we investigated the effect of CSD peptides on interaction between HO-1 and Cav-1, and on the HO-1 activity in vitro and in vivo. Our data showed that CSD peptides decreased the compartmentalization of HO-1 and Cav-1, and increased the HO-1 activity both in LPS-treated alveolar macrophages and in mice. Meanwhile, CSD peptides obviously ameliorated the pathology changes in mice and lowered the following injury indexes: the wet/dry ratio of lung tissues, total cell numbers in bronchoalveolar lavage fluid and lactate dehydrogenase activity in the serum. Mechanistically, it was firstly found that CSD peptides promoted alveolar macrophages polarization to M2 phenotype and inhibited the IκB degeneration. Furthermore, CSD peptides down-regulated the expression of IL-1ß, IL-6, TNF-α, MCP-1, and iNOS in alveolar macrophages and in lung tissue. However, the protective role of CSD peptides on LPS-induced acute lung injury in mice could be abolished by zinc protoporphyrin IX (ZnPP, a HO-1 activity inhibitor). In summary, CSD peptides have beneficial anti-inflammatory effects by restoring the HO-1 activity suppressed by Cav-1 on plasma membrane.

Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects.

BACKGROUND: Biliverdin (BV) has a protective role against ischemia-reperfusion injury (IRI). However, the protective role and potential mechanisms of BV on lung IRI (LIRI) remain to be elucidated. Thus, we aimed to investigate the protective role and potential mechanisms of BV on LIRI. METHODS: Lungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model. After an initial 15 min stabilization period, the isolated lungs were subjected to ischemia for 60 min, followed by 90 min of reperfusion with or without BV treatment. RESULTS: Lungs in the I/R group exhibited significant decrease in tidal volume (1.44 ± 0.23 ml/min in I/R group vs. 2.41 ± 0.31 ml/min in sham group; P< 0.001), lung compliance (0.27 ± 0.06 ml/cmH2O in I/R group vs. 0.44 ± 0.09 ml/cmH2O in sham group; P< 0.001; 1 cmH2O=0.098 kPa), and oxygen partial pressure (PaO2) levels (64.12 ± 12 mmHg in I/R group vs. 114 ± 8.0 mmHg in sham group; P< 0.001; 1 mmHg = 0.133 kPa). In contrast, these parameters in the BV group (2.27 ± 0.37 ml/min of tidal volume, 0.41 ± 0.10 ml/cmH2O of compliance, and 98.7 ± 9.7 mmHg of PaO2) were significantly higher compared with the I/R group (P = 0.004, P< 0.001, and P< 0.001, respectively). Compared to the I/R group, the contents of superoxide dismutase were significantly higher (47.07 ± 7.91 U/mg protein vs. 33.84 ± 10.15 U/mg protein; P = 0.005) while the wet/dry weight ratio (P < 0.01), methane dicarboxylic aldehyde (1.92 ± 0.25 nmol/mg protein vs. 2.67 ± 0.46 nmol/mg protein; P< 0.001), and adenosine triphosphate contents (297.05 ± 47.45 nmol/mg protein vs. 208.09 ± 29.11 nmol/mg protein; P = 0.005) were markedly lower in BV-treated lungs. Histological analysis revealed that BV alleviated LIRI. Furthermore, the expression of inflammatory cytokines (interleukin-1ß, interleukin-6, and tumor necrosis factor-ß) was downregulated and the expression of cyclooxygenase-2, inducible nitric oxide synthase, and Jun N-terminal kinase was significantly reduced in BV group (all P< 0.01 compared to I/R group). Finally, the apoptosis index in the BV group was significantly decreased (P < 0.01 compared to I/R group). CONCLUSION: BV protects lung IRI through its antioxidative, anti-inflammatory, and anti-apoptotic effects.

Gabapentin reduces allodynia and hyperalgesia in painful diabetic neuropathy rats by decreasing expression level of Nav1.7 and p-ERK1/2 in DRG neurons.

It has been confirmed that gabapentin (GBP) induced a inhibition of the voltage-gated persistent sodium current in chronically compressed dorsal root ganglion (DRG) neurons. The persistent sodium current is found in excitable DRG neurons of painful diabetic neuropathy (PDN) rats where it is mediated by tetrodotoxin (TTX) sensitive sodium channels. Recently, many groups have used models of neurological disorder to explore the mechanism of GBP in neuropathic pain. There is no evidence, however, to explain the particular mechanism of GBP, including its analgesic actions in PDN rats. These issues were addressed in the present study. Using behavioral testing, we found that diabetes leads to mechanical allodynia and thermal hyperalgesia and these effects were reversed by a continuous GBP injection. To investigate the mechanism of GBP's reduction in neural excitability, we systematically analyzed the expression of Nav1.7 and p-ERK1/2 and tested the effect of GBP on these proteins. Diabetes significantly increased the excitability of DRG neurons and the expression of Nav1.7 and p-ERK1/2, and GBP significantly inhibited these changes. These results suggest that the inhibitory effect of GBP on the expression of Nav1.7 and p-ERK1/2 might be one of the analgesic mechanisms of action of GBP. This may partially explain the antinociceptive action of GBP in the PDN rats.