Cardiovascular protective effects of GLP-1: a focus on the MAPK signaling pathway.

Cardiovascular and related metabolic diseases are significant global health challenges. Glucagon-like peptide 1 (GLP-1) is a brain-gut peptide secreted by the ileal endocrine system and is now an established drug target in type 2 diabetes (T2DM). GLP-1 targeting agents have been shown not only to treat T2DM, but also to exert cardiovascular protective effects by regulating multiple signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, a common signal transduction pathway for transmitting extracellular signals to downstream effector molecules, is involved in regulating diverse cellular physiological processes, including cell proliferation, differentiation, stress, inflammation, functional synchronization, transformation, and apoptosis. The purpose of this review is to highlight the relationship between GLP-1 and cardiovascular disease (CVD) and discuss how GLP-1 exerts cardiovascular protective effects through the MAPK signaling pathway. This review also discusses the future challenges in fully characterizing and evaluating the CVD protective effects of GLP-1 receptor agonists (GLP-1RA) at the cellular and molecular levels. A better understanding of the MAPK signaling pathway that is dysregulated in CVD may aid in the design and development of promising GLP-1RA.

Rhizospheric pore-water content predicts the biochar-attenuated accumulation, translocation, and toxicity of cadmium to lettuce.

Metal bioavailability controls its behaviors in soil-plant system, especially involved in biochar amendment. This study compared a rhizospheric pore-water extraction against a BCR sequential extraction method to understand cadmium (Cd) bioavailability in two typical Chinese soils. Soils were spiked with five levels of Cd (CdCl2) and remediated with 3% corn-straw derived biochar. After 60 days of lettuce growth, Cd accumulation and enzyme activities in tissues were analyzed. Results showed that biochar increased soil properties (pH, CEC and SOM) compared to un-amended soils, but decreased contents of bioavailable Cd in soil pore-water (Cdpore-water) and BCR extracted Cd (CdFi+Fii). Contents of Cdpore-water were lower in yellow-brown soils than that in red soils. Pearson analysis showed that bioavailable Cd is negatively correlated with soil pH and CEC (p < 0.05). Cd accumulation in lettuce roots and leaves both were decreased by biochar addition, and the established linear equations proved that soil Cdpore-water is the best predictor for Cd accumulation in lettuce roots (r2 = 0.964) and in leaves (r2 = 0.953), followed by CdFi+Fii. Transfer factor (TF) values of Cd from roots to leaves were lower than 1, and slightly better correlated with soil Cdpore-water (r = -0.674, p < 0.01) than CdFi+Fii (r = -0.615, p < 0.01). Aggregated boosted tree (ABT) analyses indicated that soil properties together with Cdpore-water contribute more than 50% to root enzyme activities. Collectively, soil Cdpore-water is a promising predictor of Cd bioavailability, accumulation and toxicity in soil-plant system with biochar addition.

Lunar rock investigation and tri-aspect characterization of lunar farside regolith by a digital twin.

Yutu-2 rover conducted an exciting expedition on the 41st lunar day to investigate a fin-shaped rock at Longji site (45.44°S, 177.56°E) by extending its locomotion margin on perilous peaks. The varied locomotion encountered, especially multi-form wheel slippage, during the journey to the target rock, established unique conditions for a fin-grained lunar regolith analysis regarding bearing, shear and lateral properties based on terramechanics. Here, we show a tri-aspect characterization of lunar regolith and infer the rock's origin using a digital twin. We estimate internal friction angle within 21.5°-42.0° and associated cohesion of 520-3154 Pa in the Chang'E-4 operational site. These findings suggest shear characteristics similar to Apollo 12 mission samples but notably higher cohesion compared to regolith investigated on most nearside lunar missions. We estimate external friction angle in lateral properties to be within 8.3°-16.5°, which fills the gaps of the lateral property estimation of the lunar farside regolith and serves as a foundational parameter for subsequent engineering verifications. Our in-situ spectral investigations of the target rock unveil its composition of iron/magnesium-rich low-calcium pyroxene, linking it to the Zhinyu crater (45.34°S, 176.15°E) ejecta. Our results indicate that the combination of in-situ measurements with robotics technology in planetary exploration reveal the possibility of additional source regions contributing to the local materials at the Chang'E-4 site, implying a more complicated geological history in the vicinity.

The role of m5C methyltransferases in cardiovascular diseases.

The global leading cause of death is cardiovascular disease (CVD). Although advances in prevention and treatment have been made, the role of RNA epigenetics in CVD is not fully understood. Studies have found that RNA modifications regulate gene expression in mammalian cells, and m5C (5-methylcytosine) is a recently discovered RNA modification that plays a role in gene regulation. As a result of these developments, there has been renewed interest in elucidating the nature and function of RNA "epitranscriptomic" modifications. Recent studies on m5C RNA methylomes, their functions, and the proteins that initiate, translate and manipulate this modification are discussed in this review. This review improves the understanding of m5C modifications and their properties, functions, and implications in cardiac pathologies, including cardiomyopathy, heart failure, and atherosclerosis.

Solid-gas carbonate formation during dust events on Mars.

Electrostatic discharge experiments under simulated martian atmospheric conditions indicate that atmospheric CO2 has been sequestered into carbonate by the Mars dust activities during the Amazonia era.

In situ analysis of surface composition and meteorology at the Zhurong landing site on Mars.

The Zhurong rover of the Tianwen-1 mission landed in southern Utopia Planitia, providing a unique window into the evolutionary history of the Martian lowlands. During its first 110 sols, Zhurong investigated and categorized surface targets into igneous rocks, lithified duricrusts, cemented duricrusts, soils and sands. The lithified duricrusts, analysed by using laser-induced breakdown spectroscopy onboard Zhurong, show elevated water contents and distinct compositions from those of igneous rocks. The cemented duricrusts are likely formed via water vapor-frost cycling at the atmosphere-soil interface, as supported by the local meteorological conditions. Soils and sands contain elevated magnesium and water, attributed to both hydrated magnesium salts and adsorbed water. The compositional and meteorological evidence indicates potential Amazonian brine activities and present-day water vapor cycling at the soil-atmosphere interface. Searching for further clues to water-related activities and determining the water source by Zhurong are critical to constrain the volatile evolution history at the landing site.

Annexin A protein family in atherosclerosis.

Atherosclerosis, a silent chronic vascular pathology, is the cause of the majority of cardiovascular ischaemic events. Atherosclerosis is characterized by a series of deleterious changes in cellularity, including endothelial dysfunction, transmigration of circulating inflammatory cells into the arterial wall, pro-inflammatory cytokines production, lipid accumulation in the intima, vascular local inflammatory response, atherosclerosis-related cells apoptosis and autophagy. Proteins of Annexin A (AnxA) family, the well-known Ca2+ phospholipid-binding protein, have many functions in regulating inflammation-related enzymes and cell signaling transduction, thus influencing cell adhesion, migration, differentiation, proliferation and apoptosis. There is now accumulating evidence that some members of the AnxA family, such as AnxA1, AnxA2, AnxA5 and AnxA7, play major roles in the development of atherosclerosis. This article discusses the major roles of AnxA1, AnxA2, AnxA5 and AnxA7, and the multifaceted mechanisms of the main biological process in which they are involved in atherosclerosis. Considering these evidences, it has been proposed that AnxA are drivers- and not merely participator- on the road to atherosclerosis, thus the progression of atherosclerosis may be prevented by targeting the expression or function of the AnxA family proteins.

Zhurong reveals recent aqueous activities in Utopia Planitia, Mars.

The Mars' climate is cold and dry in the most recent epoch, and liquid water activities are considered extremely limited. Previous orbital data only show sporadic hydrous minerals in the northern lowlands of Mars excavated by large impacts. Using the short-wave infrared spectral data obtained by the Zhurong rover of China's Tianwen-1 mission, which landed in southern Utopia Planitia on Mars, we identify hydrated sulfate/silica materials on the Amazonian terrain at the landing site. These hydrated minerals are associated with bright-toned rocks, interpreted to be duricrust developed locally. The lithified duricrusts suggest that formation with substantial liquid water originates by either groundwater rising or subsurface ice melting. In situ evidence for aqueous activities identified at Zhurong's landing site indicates a more active Amazonian hydrosphere for Mars than previously thought.

[Expression of orexin receptor 1 in rat pancreatic tissue with alimentary obesity].

OBJECTIVE: To identify the presence of orexin receptor 1 (OXR1) in obese rat pancreas and clarify its effect and mechanism on body weight and metabolic index in obese rats. METHODS: The obese rat model was established a high-fat diet. And the serum levels of glucose, triglyceride and insulin were measured by Mini-Blood Glucose meter, biochemical enzymatic method and chemiluminescent immunoassay. The pancreatic expression of OX1R protein was identified by immunohistochemistry. After an intracerebroventricular infusion of orexin receptor 1 antisense oligodeoxynucleotide (OX1R-PS-ODNs), the effect on OX1R protein was detected in rat pancreatic tissue with obesity. RESULTS: After feeding for 8 weeks, high-fat diet rats appear alimentary obesity body weight, serum glucose, insulin, triglyceride and cholesterol of high-diet rats were higher than those in the control group (P < 0.05). The expression of OX1R protein was located in the cytoplasm of pancreas Islet ß-cells. The expression of OX1R protein in obese rat pancreas decreased around 16% versus the normal group (P < 0.05). After the obese rats were treated by OX1R-PS-ODNs for 72 hours, the expression of OX1R protein in pancreas declined from 82 ± 6 to 65 ± 4, reduced about 21% compare with control group (P < 0.01). CONCLUSION: The expression of OX1R protein is found in pancreas Islet ß-cells. Hypothalamic orexin system can intervene the expression of OX1R protein in rat pancreatic tissue with alimentary obesity. And it may participate in the occurrence of obesity and the metabolic regulation of serum glucose and insulin.

Role of Kruppel-like factor 4 in atherosclerosis.

Atherosclerosis is one of the chronic progressive diseases, which is caused by vascular injury and promoted by the interaction of various inflammatory factors and inflammatory cells. In recent years, kruppel-like factor 4 (KLF4), a significant transcription factor that participated in cell growth, differentiation and proliferation, has been proved to cause substantial impacts on regulating cardiovascular disease. This paper will give a comprehensive summary to highlight KLF4 as a crucial regulator of foam cell formation, vascular smooth muscle cells (VSMCs) phenotypic transformation, macrophage polarization, endothelial cells inflammation, lymphocyte differentiation and cell proliferation in the process of atherosclerosis. Recent studies show that KLF4 may be an important "molecular switch" in the process of improving vascular injury and inflammation under harmful stimulation, suggesting that KLF4 is a latent disease biomarker for the therapeutic target of atherosclerosis and vascular disease.

Transcriptional activation of insulin-like growth factor binding protein 6 by 17beta-estradiol in SaOS-2 cells.

Osteoblasts can synthesize the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs), which may either enhance or attenuate IGF-stimulated bone cell proliferation. Since estrogen induced osteoblastic differentiation and proliferation through an estrogen-responsive gene in target cells, we investigated the effects of estrogen on IGFBP-6 expression in the human osteoblastic-like cell line SaOS-2. Expressions of IGFBP-6 protein and mRNA increased 2.8 and 2-fold, respectively, in the presence of 17-beta-estradiol (E2) (0.01 to 1 micronM) and estrogen receptor (ER) in SaOS-2 cells. On the other hand, E2 induced a 2-fold increase in SaOS-2 cell proliferation. To identify genomic sequences associated with estrogen responsiveness, the 5'-promoter region (-44 to +118) of the IGFBP-6 gene was cloned into a chloramphenicol acetyltransferase (CAT) reporter vector. E2 induced a 3-fold increase in CAT activity in SaOS-2 cells transiently transfected with this construct. Identification of the estrogen-responsive element (ERE) [5-CCTTCA CCTG-3] (-9 to +1) in this IGFBP-6 gene promoter region was confirmed using electromobility shift assays and deletion analysis. This functional ERE was important for E2-induced trans-activation of the IGFBP-6 gene. These results demonstrate that E2 exhibits a positive effect on IGFBP-6 gene transcription through estrogen-liganded ER binding to the functional ERE in the IGFBP-6 gene promoter in SaOS-2 cells.

Retinoic acid down-regulates bone morphogenetic protein 7 expression in rat with cleft palate.

OBJECTIVE: To evaluate the effects of retinoic acid (RA) on expression of bone morphogenetic protein 7 (BMP-7) in rat fetus with cleft palate, and the effects of RA on proliferation and apoptosis of osteoblasts. METHODS: All-trans RA (ATRA) was used to induce congenital cleft palate in Wistar rat BMP-7 mRNA expression in maxillary bone tissue of fetal rats was measured by Northern blotting analysis. Flow cytometry and MTT assay were used to measure the apoptosis and proliferation of ATRA-treated MC-3T3-E1 cells. BMP-7 mRNA and protein expressions in ATRA-treated MC-3T3-E1 cells were detected by RT-PCR and Western blotting analysis. RESULTS: ATRA could induce cleft palate of rat fetus. The incidence rate of cleft palate induced by 100 mg/kg AT-RA (45.5%) was significantly higher than 50 mg/kg ATRA (12.5%, P < 0.05). BMP-7 mRNA expression decreased in maxillary bone tissue of rat fetus with cleft palate. MC-3T3-E1 cells proliferation treated with 1 x 10(-6) mol/L ATRA decreased by 60%, the cell apoptosis increased by 2 times. BMP-7 mRNA and protein levels in MC-3T3-E1 cells treated with 1 x 10(-6) mol/L ATRA decreased by 60% and 80%, respectively, compared with ATRA-untreated cells (P < 0.05). CONCLUSIONS: BMP-7 may play an important role in embryonic palate development RA may possess the ability to down-regulate cell proliferation through regulation of BMP-7 gene expression.

[Effect of dioxin on apoptosis of osteogenic sarcoma cells and regulation on gene expression of insulin-like growth factor binding protein 6].

OBJECTIVE: To investigate the effect of the environmental carcinogenic factor-TCDD (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin) on cell apoptosis and gene regulation of insulin-like growth factor binding protein 6 (IGFBP-6) in osteogenic sarcoma (SaOS-2) cells. METHODS: The SaOS-2 cells were cultured with TCDD (1 x 10(-9), 1 x 10(-8), 1 x 10(-7) mol/L) for 24 hours. The MTT reduction assay and flow cytometry were used to measure the cell proliferation and the cell apoptosis in TCDD-treated SaOS-2 cells. The Nitrophenol phosphate salt method was used to measure activity of alkaline phosphatase (ALP) in SaOS-2 cells. The IGFBP-6 mRNA and protein in SaOS-2 cells were detected by reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis. RESULTS: SaOS-2 cell proliferation was up-regulated with TCDD (1 x 10(-9), 1 x 10(-8), and 1 x 10(-7) mol/L) about 20%, 47% and 93% (18.4 +/- 4.5, 22.5 +/- 3.6 and 29.4 +/- 4.2), respectively. The synthesis of ALP was up-regulated about 28%, 95%, and 142% (1.12 +/- 0.28, 1.58 +/- 0.14 and 1.96 +/- 0.17), respectively (P < 0.05). The cell apoptosis was down-regulated in dose-dependent biological manner about 5%, 26% and 52%, respectively (P < 0.05). The expression of IGFBP-6 mRNA and protein was decreased in 1 x 10(-7) mol/L TCDD-treated SaOS-2 cells about 76% and 72% (P < 0.05). CONCLUSION: TCDD at low concentration may have the negative effect on cell apoptosis and down-regulation on gene expression of IGFBP-6 in SaOS-2 cells.

Dalangtan Saline Playa in a Hyperarid Region on Tibet Plateau: II. Preservation of Salts with High Hydration Degrees in Subsurface.

Based on a field expedition to the Dalangtan (DLT) saline playa located in a hyperarid region (Qaidam Basin) on the Tibet Plateau and follow-up investigations, we report the mineralogy and geochemistry of the salt layers in two vertical stratigraphic cross sections in the DLT playa. Na-, Ca-, Mg-, KCaMg-sulfates; Na-, K-, KMg-chlorides; mixed (K, Mg)-chloride-sulfate; and chlorate and perchlorate were identified in the collected samples. This mineral assemblage represents the last-stage precipitation products from Na-K-Mg-Ca-Cl-SO4 brine and the oxychlorine formation from photochemistry reaction similar to other hyperarid regions on Earth. The spatial distributions of these salts in both stratigraphic cross sections suggest very limited brine volumes during the precipitation episodes in the Holocene era. More importantly, sulfates and chlorides with a high degree of hydrations were found preserved within the subsurface salt-rich layers of DLT saline playa, where the environmental conditions at the surface are controlled by the hyperaridity in the Qaidam Basin on the Tibet Plateau. Our findings suggest a very different temperature and relative humidity environment maintained by the hydrous salts in a subsurface salty layer, where the climatic conditions at surface have very little or no influence. This observation bears some similarities with four observations on Mars, which implies not only a large humidity reservoir in midlatitude and equatorial regions on Mars but also habitability potential that warrants further investigation.

Effects of acute hypoglycemia on the orexin system in rat.

OBJECTIVE: To evaluate the effects of acute glucose level changes on expression of prepro-orexin, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) mRNA in rat hypothalamus tissue and pancreatic islets cells. METHODS: Thirty adult male Wistar rats were randomly divided into three equal groups (n = 10). The acute hypoglycemia rat model was induced by a single subcutaneous injection of insulin. Twenty acute hypoglycemia rats were divided into group B and group C. Group B was allowed to eat freely, while group C was food-deprived. Control rats were injected the same volume of saline. The effect of glucose levels (2.8 mmol/L and 8.3 mmol/L) on pancreatic islet cell orexin system was detected in pancreas islet cell cultured in vitro. The expression of prepro-orexin and OXR mRNA was examined in rat hypothalamus tissue and pancreatic islets cell cultured in vitro using reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Expression of orexin mRNA increased about 150% for the food-deprived hypoglycemia rats in comparison with control group (P < 0.01), whereas expression of OX1R mRNA decreased up to 30% (P < 0.01). However, expression of OX2R mRNA was unchanged in comparison with control group. In vitro, after incubation with 2.8 mmol/L glucose for 6 hours, the expression of prepro-orexin mRNA increased 2 times in rat pancreas islet cells in comparison with 8.3 mmol/L glucose group (P < 0.01). But the expression of OX1R mRNA was not sensitive to acute glucose fluctuation. CONCLUSIONS: Orexin in rat hypothalamus is stimulated by decline in blood glucose and inhibited by signals related to feeding. Moreover, glucose plays a role in modulating the gene expression of prepro-orexin in rat pancreatic islet cells.

Toxic effects of TCDD on osteogenesis through altering IGFBP-6 gene expression in osteoblasts.

Since 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has reproductive and developmental toxicity as an estrogen antagonist, we investigated the effects of TCDD on osteogenesis in rat skeleton and the human female-responsive osteoblastic osteosarcoma cell line SaOS-2. Rat fetuses were exposed to 5, 10, or 15 microg/kg TCDD on gestation day (GD) 10. TCDD dose-dependently induced single or multiple rat fetal skeletal development malformations in vivo. In vitro, 10 nM TCDD significantly inhibited cell proliferation in the presence of 1 microM 17-beta-estradiol (E2) in SaOS-2 cells. Insulin-like growth factor binding protein 6 (IGFBP-6), as a crucial regulator in IGF system, plays an important role in osteogenesis and bone function. TCDD (15 microg/kg) induced a dramatic 3-fold increase in IGFBP-6 mRNA expression in rat fetal calvaria on GD 21. On the other hand, the concurrent treatment of 10 nM TCDD and 1 muM E2 resulted in a significant increase in IGFBP-6 mRNA and protein after 24 h in SaOS-2 cells, but TCDD and (or) E2 had no effect on the mRNA level of cytosolic aromatic hydrocarbon receptor. The functional estrogen-responsive element (ERE) [5'-CCT TCA CCT G-3'] (-9 to +1) in the IGFBP-6 promoter region was identified in this study for the first time as the ER genomic binding site. Collectively, these results suggest that TCDD can alter the expression of IGFBP-6 gene and exerts growth-inhibitory effects on osteogenesis. In addition, TCDD exhibits an anti-estrogenic effect through its interference with the binding of activated estrogen-liganded ER to the functional ERE in IGFBP-6 gene promoter.

[Study on heavy metals in soils contaminated by acid mine drainage from Dabaoshan mine, Guangdong].

Mining activities in the Dabaoshan area in the upper reach of the Hengshihe River have caused severe environmental changes, the waste water of milling and refining drained directly into the Hengshihe River, which contaminated the soils along the river severely. It is shown that Pb, Zn, Cd and Cu have contaminated the soil, the Cd contamination was more severe, and the contaminated level of Pb, Zn reached moderately to strongly polluted. The pH value of river and soil affected directly the heavy metals concentration of total and exchangeable ions, and presented negative pertinences. The levels of Pb, Zn, Cu and Cd in the surface soil of Shangbacun village in the lower reach of the river were found as high as 257.762, 350.235, 5.083 and 186.901 mg x kg(-1) respectively, which were relatively higher than those of the background values of soil 1.03, 1.75, 16.9 and 3.7 times respectively, and the result on the soil profiles showed that the contaminations have infiltrated into lower layer soil, ecological environment was harmed severely.