Single-cell RNA landscape of cell heterogeneity and immune microenvironment in ligation-induced vascular remodeling in rat.

BACKGROUND AND AIMS: Vascular remodeling is a common pathological basis for cardiovascular diseases. Although both immune and non-immune cells have been suggested to contribute to this process, the complex cellular heterogeneity and intercellular interactions remain largely uncharacterized. METHODS AND RESULTS: In this study, we simulated early and late vascular remodeling by ligating the rat carotid artery for 1 week and 4 weeks, respectively. Using single-cell RNA-sequencing, we characterized gene expression signatures and driver signals of major cell types involved in vascular remodeling. Focused analysis revealed a novel sub-population of Selenbp1hi smooth muscle cells (SMCs) associated with vascular remodeling. Results of intercellular communication analyses predicted several ligand-receptor pairs between immune cells with SMCs and endothelial cells (ECs), implicating SMCs apoptosis and repair, ECs aging and inflammatory responses. CONCLUSIONS: We present a comprehensive single-cell atlas of vascular cells in early and late stages of ligated rat carotid artery, providing valuable insights into the understanding of the initiation and progression of vascular remodeling.

Adsorption and Degradation of Volatile Organic Compounds by Metal-Organic Frameworks (MOFs): A Review.

Volatile organic compounds (VOCs) are a major threat to human life and health. The technologies currently used to remove VOCs mainly include adsorption and photocatalysis. Adsorption is the most straightforward strategy, but it cannot ultimately eliminate VOCs. Due to the limited binding surface, the formaldehyde adsorption on conventional photocatalysts is limited, and the photocatalytic degradation efficiency is not high enough. By developing novel metal-organic framework (MOF) materials that can catalytically degrade VOCs at room temperature, the organic combination of new MOF materials and traditional purification equipment can be achieved to optimize adsorption and degradation performance. In the present review, based on the research on the adsorption and removal of VOCs by MOF materials in the past 10 years, starting from the structure and characteristics of MOFs, the classification of which was described in detail, the influencing factors and mechanisms in the process of adsorption and removal of VOCs were summarized. In addition, the research progress of MOF materials was summarized, and its future development in this field was prospected.

Pore Structure Characteristics and Their Controlling Factors of Deep Shale: A Case Study of the Lower Silurian Longmaxi Formation in the Luzhou Area, Southern Sichuan Basin.

Recently, deep shale reservoirs are emerging as time requires and commence occupying a significant position in the further development of shale gas. However, the understanding of pore characteristics in deep shale remains poor, prohibiting accurate estimation of the hydrocarbon content and insights into fluid mobility. This study focuses on the Longmaxi Formation from the Luzhou (LZ) region, southern Sichuan. Scanning electron microscopy (SEM), low-temperature N2/CO2 adsorption, X-ray diffraction, and geochemical analysis were performed to investigate the micro-nanopore size distribution, main controlling factors, and unique pore features distinct from other regions. Results showed that the pores can be classified into four categories, organic matter (OM) pores, intergranular pores, intragranular pores, and microfractures, according to SEM images. The total pore volume is overwhelmingly dominated by mesopores and contributed by pores in the range of 0.5-0.6, 2-4, and 10-30 nm. The specific surface area is primarily contributed by micropores and mesopores in the range of 0.5-0.7 and 2-4 nm. By analyzing the influencing factors extensively, it is concluded that the buried depth, geochemical factors, and mineral composition can impact the pore structure in the overmature deep shales. Specifically, the total organic carbon content plays a more effective and positive role in the development of micropores, mesopores, total pores, and the porosity when compared with vitreous reflectance (Ro). The micropores are inferred to be OM-related. On the contrary, clay mineral is detrimental to the development of micropores and mesopores and the petrophysical properties (porosity and permeability), which may be attributed to the occurrence of chlorite and kaolinite instead of illite. The plagioclase conforms to the same law as clay due to their coexistence. Quartz, carbonate minerals, and pyrite can barely contribute to the pores. Eventually, the compared results suggest that the Longmaxi Formation of the LZ region are qualified with a superior pore size distribution, complicated structure, and diverse morphology, implying a potential to generate and store hydrocarbons. Overall, this study improves the understanding of complex pore structures in deep shale and provides significant insights into the development and exploration of unconventional resources in the future.

Single-Cell RNA Sequencing Technology Revealed the Pivotal Role of Fibroblast Heterogeneity in Angiotensin II-Induced Abdominal Aortic Aneurysms.

The mechanism of abdominal aortic aneurysm (AAA) has not been fully elucidated. In this study, we aimed to map the cellular heterogeneity, molecular alteration, and functional transformation of angiotensin (Ang) II-induced AAA in mice based on single-cell RNA sequencing (sc-RNA seq) technology. sc-RNA seq was performed on suprarenal abdominal aorta tissue from male Apoe-/- C57BL/6 mice of Ang II-induced AAA and shame models to determine the heterogeneity and phenotypic transformation of all cells. Immunohistochemistry was used to determine the pathophysiological characteristics of AAA. The single-cell trajectory was performed to predict the differentiation of fibroblasts. Finally ligand-receptor analysis was used to evaluate intercellular communication between fibroblasts and smooth muscle cells (SMCs). More than 27,000 cells were isolated and 25 clusters representing 8 types of cells were identified, including fibroblasts, macrophages, endothelial cells, SMCs, T lymphocytes, B lymphocytes, granulocytes, and natural killer cells. During AAA progression, the function and phenotype of different type cells altered separately, including activation of inflammatory cells, alternations of macrophage polarization, phenotypic transformation of vascular smooth muscle cells, and endothelial to mesenchymal transformation. The alterations of fibroblasts were the most conspicuous. Single-cell trajectory revealed the critical reprogramming genes of fibroblasts mainly enriched in regulation of immune system. Finally, the ligand-receptor analysis confirmed that disorder of collagen metabolism led by fibroblasts was one of the most prominent characteristics of Ang II-induced AAA. Our study revealed the cellular heterogeneity of Ang II-induced AAA. Fibroblasts may play a critical role in Ang II-induced AAA progression according to multiple biological functions, including immune regulation and extracellular matrix metabolic balance. Our study may provide us with a different perspective on the etiology and pathogenesis of AAA.

Naringin Ameliorates Monocrotaline-Induced Pulmonary Arterial Hypertension Through Endothelial-To-Mesenchymal Transition Inhibition.

Pulmonary arterial hypertension (PAH) caused by enhanced arterial pressure increases vessel resistance in the lung. Endothelial-to-mesenchymal transition (EndMT) plays key roles in the vascular remodeling in PAH. Naringin, a protective gaseous mediator is commonly extracted from tomatoes and citrus fruits (such as grapefruits), and demonstrates anti-inflammation, anti-oxidant, anti-proliferation, and anti-tumor effects. Meanwhile, the association of Naringin and the process of EndMT is still unclear. In this study, monocrotaline (MCT) administration (60 mg/kg) was delivered for the induction of PAH in rats. Following this, Naringin (concentrations: 25, 50, and 100 mg/kg/day) was used for treatments. Human Umbilical Vein Endothelial Cells (HUVECs) were stimulated with Naringin and transforming growth factor ß1 (TGFß1, 10 ng/ml). As the result, Naringin was demonstrated to inhibit EndMT and alleviate PAH progression. In particular, in HUVECs, Naringin significantly suppressed the mesenchymal marker expression induced by TGFß1 treatment, enhanced the endothelial marker expression, and inhibited the activation of ERK and NF-κB signaling pathways. To conclude, this study provided novel evidence suggesting the beneficial effects of Naringin in PAH through the inhibition of the ERK and NF-κB signaling pathways and the EndMT progression in pulmonary arteries.

Sodium Selenite Attenuates Balloon Injury-Induced and Monocrotaline-Induced Vascular Remodeling in Rats.

Vascular remodeling (VR), induced by the massive proliferation and reduced apoptosis of vascular smooth muscle cells (VSMCs), is primarily responsible for many cardiovascular conditions, such as restenosis and pulmonary arterial hypertension. Sodium selenite (SSE) is an inorganic selenium, which can block proliferation and stimulate apoptosis of tumor cells; still, its protective effects on VR remains unknown. In this study, we established rat models with carotid artery balloon injury and monocrotaline induced pulmonary arterial hypertension and administered them SSE (0.25, 0.5, or 1 mg/kg/day) orally by feeding tube for 14 consecutive days. We found that SSE treatment greatly ameliorated the development of VR as evidenced by an improvement of its characteristic features, including elevation of the ratio of carotid artery intimal area to medial area, right ventricular hypertrophy, pulmonary arterial wall hypertrophy and right ventricular systolic pressure. Furthermore, PCNA and TUNEL staining of the arteries showed that SSE suppressed proliferation and enhanced apoptosis of VSMCs in both models. Compared with the untreated VR rats, lower expression of PCNA and CyclinD1, but higher levels of Cleaved Caspase-3 and Bax/Bcl-2 were observed in the SSE-treated rats. Moreover, the increased protein expression of MMP2, MMP9, p-AKT, p-ERK, p-GSK3ß and ß-catenin that occurred in the VR rats were significantly inhibited by SSE. Collectively, treatment with SSE remarkably attenuates the pathogenesis of VR, and this protection may be associated with the inhibition of AKT and ERK signaling and prevention of VSMC's dysfunction. Our study suggest that SSE is a potential agent for treatment of VR-related diseases.

Molecular modeling on the pressure-driven methane desorption in illite nanoslits.

Understanding to the pressure-driven desorption of methane in shale formations is crucial for the establishment of predictive models used in shale gas development. Based on the grand canonical Monte-Carlo simulations of methane adsorption in illite slits of 1-5-nm wide, the pressure-driven desorption processes of methane in the nanoslits are studied with non-equilibrium molecular dynamics simulations. External forces are applied to the methane molecules to mimic a pressure drop that releases the adsorbed molecules and pushes them flowing directionally. Effect of pressure drop and slit aperture on the interchange between adsorbed and free phases of methane is investigated by a statistic analysis on the velocity and density distributions of methane molecules in the nanoslits under various conditions. A minimum pressure drop that initiates the methane desorption in the illite slit exists and varies with slit aperture. Our simulations reveal the microscopic mechanism of pressure-driven methane desorption, which would be useful for subsequent studies on the prediction of mineable yields for shale formations. Under pressure drop, adsorbed methane molecules are desorbed to free phase and then transported to wellbore. The criterion of pressure drop for desorption increases with decreasing slit aperture.

Icariin Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension via the Inhibition of TGF-ß1/Smads Pathway in Rats.

BACKGROUND: Pulmonary artery remodeling is important in the development of pulmonary artery hypertension. The TGF-ß1/Smads signaling pathway is activated in pulmonary arterial hypertension (PAH) in rats. Icariin (ICA) suppresses the TGF-ß1/Smad2 pathway in myocardial fibrosis in rats. Therefore, we investigated the role of icariin in PAH by inhibiting the TGF-ß1/Smads pathway. METHODS: Rats were randomly divided into control, monocrotaline (MCT), MCT + ICA-low, and MCT + ICA-high groups. MCT (60 mg/kg) was subcutaneously injected to induce PAH, and icariin (50 or 100 mg/kg.d) was orally administered for 2 weeks. At the end of the fourth week, right ventricular systolic pressure (RVSP) was obtained and the right ventricular hypertrophy index (RI) was determined as the ratio of the right ventricular weight to the left ventricular plus septal weight (RV/LV + S). Western blots were used to determine the expression of TGF-ß1, Smad2/3, P-Smad2/3, and matrix metalloproteinase-2 (MMP2) in lung tissues. RESULTS: Compared to the control group, RVSP and RI were increased in the MCT group (ρ < 0.05). Additionally, TGF-ß1, Smad2/3, P-Smad2/3, and MMP2 expressions were obviously increased (ρ < 0.01). Compared to the MCT group, RVSP and RI were decreased in the MCT + ICA group (ρ < 0.05). TGF-ß1, Smad2/3, P-Smad2/3, and MMP2 expressions were also inhibited in the icariin treatment groups (ρ < 0.05). Conclusions. Icariin may suppress MCT-induced PAH via the inhibition of the TGFß1-Smad2/3 pathway.

PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells.

Transforming growth factor ß (TGFß) signaling plays an important role in regulating tumor malignancy, including in non-small cell lung cancer (NSCLC). The major biological responses of TGFß signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFß-SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGFß signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasion in vitro and lung metastasis in vivo In addition, TGFß signaling and TGFß-induced epithelial-mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGFß-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGFß signaling and NSCLC progression.

Endothelial Scaffolding Protein ENH (Enigma Homolog Protein) Promotes PHLPP2 (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase 2)-Mediated Dephosphorylation of AKT1 and eNOS (Endothelial NO Synthase) Promoting Vascular Remodeling.

OBJECTIVE: A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multiple protein kinases, but whether it regulates eNOS activation and vascular remodeling remains unknown. Approach and Results: ENH was upregulated in injured mouse arteries and human atherosclerotic plaques and was associated with coronary artery disease. Neointima formation in carotid arteries, induced by ligation or wire injury, was greatly decreased in endothelium-specific ENH-knockout mice. Vascular ligation reduced AKT and eNOS phosphorylation and nitric oxide production in the endothelium of control but not ENH-knockout mice. ENH was found to interact with AKT1 and its phosphatase PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2). AKT and eNOS activation were prolonged in VEGF (vascular endothelial growth factor)-induced ENH- or PHLPP2-deficient endothelial cells. Inhibitors of either AKT or eNOS effectively restored ligation-induced neointima formation in ENH-knockout mice. Moreover, endothelium-specific PHLPP2-knockout mice displayed reduced ligation-induced neointima formation. Finally, PHLPP2 was increased in the endothelia of human atherosclerotic plaques and blood cells from patients with coronary artery disease. CONCLUSIONS: ENH forms a complex with AKT1 and its phosphatase PHLPP2 to negatively regulate AKT1 activation in the artery endothelium. AKT1 deactivation, a decrease in nitric oxide generation, and subsequent neointima formation induced by vascular injury are mediated by ENH and PHLPP2. ENH and PHLPP2 are thus new proatherosclerotic factors that could be therapeutically targeted.

Inhibitory effects of formononetin on the monocrotaline­induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is a fatal syndrome resulting from enhanced pulmonary arterial pressure and pulmonary vessel resistance. Perivascular inflammation and extracellular matrix deposition are considered to be the crucial pathophysiologic bases of PAH. Formononetin (FMN), a natural phytoestrogen isolated from red clover (Trifolium pratense), has a variety of proapoptotic, anti­inflammatory and anti­tumor activities. However, the therapeutic effectiveness of FMN for PAH remains unclear. In the present study, 60 mg/kg monocrotaline (MCT) was first used to induce PAH in rats, and then all rats were treated with different concentrations of FMN (10, 30 and 60 mg/kg/day). At the end of this study, the hemodynamics and pulmonary vascular morphology of rats were evaluated. Specifically, matrix metalloproteinase (MMP)2, transforming growth factor ß1 (TGFß1) and MMP9 were measured using western blot and immunohistochemical staining. Collagen type I, collagen type III, fibronectin, monocyte chemotactic protein­1, tumor necrosis factor­α, interleukin­1ß, ERK and NF­κB were quantified using western blotting. The results demonstrated that FMN significantly alleviated the changes of hemodynamics and pulmonary vascular morphology, and decreased the MCT­induced upregulations of TGFß1, MMP2 and MMP9 expression levels. Meanwhile, the expression levels of collagen type I, collagen type III and fibronectin in rat lungs decreased after FMN treatment. Furthermore, the phosphorylated ERK and NF­κB also decreased after FMN treatment. Taken together, the present study indicated that FMN serves a therapeutic role in the MCT­induced PAH in rats via suppressing pulmonary vascular remodeling, which may be partially related to ERK and NF­κB signals.

Salvianolic acid a inhibits platelet activation and aggregation in patients with type 2 diabetes mellitus.

BACKGROUND: Platelets in patients with type 2 diabetes mellitus (DM2) are characterized by increased activation and aggregation, which tends to be associated with a high morbidity and mortality due to cardiovascular disease (CVD). Moreover, a large proportion of DM2 patients show an inadequate response to standard antiplatelet treatments, contributing to recurrent cardiovascular events. In our previous study, we indicated that Salvianolic acid A (SAA) presents an antiplatelet effect in healthy volunteers. However, whether it can inhibit "activated platelets" with a pathologic status has not been explored. Therefore, this study was designed to investigate the antiplatelet effect of SAA and its diabetic complication-related difference in DM2. METHODS: Forty patients diagnosed with DM2 from January 2018 to April 2018 were recruited. Fibrinogen-binding (PAC-1) and P-selectin (CD62p) flow cytometry reagents were measured under resting and stimulated conditions by flow cytometry, while agonist-induced platelet aggregation was conducted by light transmission aggregometry. Before all these measurements were conducted, all platelet samples were preincubated with a vehicle or SAA for 10 min. Additionally, the diabetic complication-related difference in the antiplatelet effect of SAA was further studied in enrolled patients. RESULTS: The expressions of PAC-1 and CD62p were elevated in DM2, as well as the maximal platelet aggregation. In addition, SAA decreased the expressions of PAC-1 and CD62p, which were enhanced by ADP and thrombin (all P < 0.01). It also reduced the platelet aggregation induced by ADP (P < 0.001) and thrombin (P < 0.05). Comparing the antiplatelet effect of SAA on DM2, with and without diabetic complications, no statistically significant difference was found (all P > 0.05). CONCLUSIONS: The present study demonstrated that SAA can inhibit platelet activation and aggregation in patients with DM2, and the inhibition did not abate for the existence of diabetic complications.

Formononetin attenuates monocrotaline­induced pulmonary arterial hypertension via inhibiting pulmonary vascular remodeling in rats.

Pulmonary arterial hypertension (PAH) is a life­threatening disease induced by the excessive proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Formononetin (FMN) is a natural isoflavone with numerous cardioprotective properties, which can inhibit the proliferation and induce the apoptosis of tumor cells; however, whether FMN has a therapeutic effect on PAH remains unclear. In the present study, PAH was induced in rats with monocrotaline (MCT, 60 mg/kg); rats were then administered FMN (10, 30 or 60 mg/kg/day). At the end of the experiment, hemodynamic changes, right ventricular hypertrophy and lung morphological characteristics were evaluated. α­smooth muscle actin (α­SMA), proliferating cell nuclear antigen (PCNA), and TUNEL were detected by immunohistochemical staining. The expression of PCNA, Bcl­2­associated X protein (Bax), Bcl­2 and, cleaved caspase­3, and activation of AKT and ERK were examined by western blot analysis. The results demonstrated that FMN significantly ameliorated the right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling induced by MCT. FMN also attenuated MCT­induced increased expression of α­SMA and PCNA. The ratio of Bax/Bcl­2 and cleaved caspase­3 expression increased in rat lung tissue in response to FMN treatment. Furthermore, reduced phosphorylation of AKT and ERK was also observed in FMN­treated rats. Therefore, FMN may provide protection against MCT­induced PAH by preventing pulmonary vascular remodeling, potentially by suppressing the PI3K/AKT and ERK pathways in rats.

Thymoquinone suppresses platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferation, migration and neointimal formation.

The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are mainly responsible for vascular occlusion diseases, such as pulmonary arterial hypertension and restenosis. Our previous study demonstrated thymoquinone (TQ) attenuated monocrotaline-induced pulmonary arterial hypertension. The aim of the present study is to systematically examine inhibitory effects of TQ on platelet-derived growth factor-BB (PDGF-BB)-induced proliferation and migration of VSMCs in vitro and neointimal formation in vivo and elucidate the potential mechanisms. Vascular smooth muscle cells were isolated from the aorta in rats. Cell viability and proliferation were measured in VSMCs using the MTT assay. Cell migration was detected by wound healing assay and Transwell assay. Alpha-smooth muscle actin (α-SMA) and Ki-67-positive cells were examined by immunofluorescence staining. Reactive oxygen species (ROS) generation and apoptosis were measured by flow cytometry and terminal deoxyribonucleotide transferase-mediated dUTP nick end labelling (TUNEL) staining, respectively. Molecules including the mitochondria-dependent apoptosis factors, matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), PTEN/AKT and mitogen-activated protein kinases (MAPKs) were determined by Western blot. Neointimal formation was induced by ligation in male Sprague Dawley rats and evaluated by HE staining. Thymoquinone inhibited PDGF-BB-induced VSMC proliferation and the increase in α-SMA and Ki-67-positive cells. Thymoquinone also induced apoptosis via mitochondria-dependent apoptosis pathway and p38MAPK. Thymoquinone blocked VSMC migration by inhibiting MMP2. Finally, TQ reversed neointimal formation induced by ligation in rats. Thus, TQ is a potential candidate for the prevention and treatment of occlusive vascular diseases.

Salvianolic acid a attenuates limb ischemia/reperfusion injury in skeletal muscle of rats.

Ischemia and reperfusion(I/R) injury can cause complications in applying blood flow treatment for atherosclerosis occlusion syndrome. Platelet activation and inflammatory reaction play a role in the procession of I/R injury. This study was designed to investigate the effects of Salvianolic Acid A(SAA) on limb I/R injury via inhibition of platelet activation and inflammatory reaction. Rats were divided into sham, I/R, I/R+SAA-Low (5mg/kg) and I/R+SAA-high (10mg/kg) groups with a procession of 6h for ischemia and 24h for reperfusion in the femoral artery of the right hind limb, with the exception of the sham group. SAA was injected into the right jugular vein before reperfusion. Reperfusion recovery was monitored by Laser Doppler. HE staining, electron microscopy examination and MDA were used to evaluate the I/R injury. ELISA, Western Blot and RT-PCR were used to measure the levels of P-selectin, IL-8(KC), ICAM-1, TNF-α, IL-1ß, CK and NF-κB in plasma or tissues. Pretreatment with SAA attenuated skeletal muscle edema and mitochondria changes, and decreased the levels of MDA and CK. Meanwhile, there was significant reduction of P-selectin, KC, ICAM-1, TNF-α, IL-1ß and NF-κB with treatment of SAA. Pretreatment with SAA may attenuate the I/R injury in the skeletal muscle tissues of rats via inhibition of platelet activation and inflammatory reaction.

Schisandrin B protects against myocardial ischemia/reperfusion injury via the PI3K/Akt pathway in rats.

The natural medicinal monomer, schisandrin B (Sch B), has been shown to exert cardioprotective effects; however, the underlying mechanisms of these effects remain to be fully elucidated. Therefore, the aim of the present study was to investigate whether Sch B attenuated myocardial ischemia/reperfusion (I/R) injury via the phosphoinositide 3­kinases (PI3K)/Akt signaling pathway. To confirm this, I/R models were established in rats by ligation of the left anterior descending coronary artery. A group of animals were administered with Sch B (60 mg/kg, lavage) and/or the PI3K inhibitor, LY294002 (0.3 mg/kg, intraperitoneal). Myocardial infarct size, myocardial infarct serum markers, myocardial apoptotic index and the expression of Akt were measured in each group. The results demonstrated that the administration of Sch B reduced the size of the myocardial infarct, and this effect was eliminated following LY294002 treatment. In addition, the administration of Sch B decreased the apoptotic index and the serum markers of myocardial infarction. Sch B administration also increased the expression of phosphorylated Akt, and Sch B treatment decreased the B­cell lymphoma 2 (Bcl­2)­like protein 4/Bcl­2 ratio and the expression of cleaved caspase­3. Therefore, Sch B may protect myocardial tissue from I/R injury via the PI3K/Akt signaling pathway in rats.

Schisandrin B Prevents Hind Limb from Ischemia-Reperfusion-Induced Oxidative Stress and Inflammation via MAPK/NF-κB Pathways in Rats.

Schisandrin B (ScB), isolated from Schisandra chinensis (S. chinensis), is a traditional Chinese medicine with proven cardioprotective and neuroprotective effects. However, it is unclear whether ScB also has beneficial effects on rat hind limb ischemia/reperfusion (I/R) injury model. In this study, ScB (20 mg/kg, 40 mg/kg, and 80 mg/kg) was administered via oral gavage once daily for 5 days before the surgery. After 6 h ischemia and 24 h reperfusion of left hind limb, ScB reduced I/R induced histological changes and edema. ScB also suppressed the oxidative stress through decreasing MDA level and increasing SOD activity. Moreover, above changes were associated with downregulated TNF-α mRNA expression and reduced level of IL-1ß in plasma. Meanwhile, ScB treatment downregulated activation of p38MAPK, ERK1/2, and NF-κB in ischemic skeletal muscle. These results demonstrate that ScB treatment could prevent hind limb I/R skeletal muscle injury possibly by attenuating oxidative stress and inflammation via p38MAPK, ERK1/2, and NF-κB pathways.