Chemical and Geological Properties of Shale Gas: In Situ Desorption of Lower Cambrian Niutitang Shale in the Micangshan Tectonic Zone of South Shaanxi, China.

Shale gas was recently found in the Lower Cambrian Niutitang Formation (LCNF) of the Micangshan tectonic zone of south Shaanxi (MTZSS), but not in commercial quantities. To determine the laws governing the generation, enrichment, and desorption of shale gases in overmatured shale strata in the LCNF of MTZSS, we carried out in situ desorption experiments on nine shale core samples and got 168 desorbed gas samples at different phases of desorption. Also measured were the chemical and carbon isotopic compositions of these desorbed gas samples and the geochemical parameters of the shale core samples. CH4 was the predominant hydrocarbon shale gas identified in the 82.06-98.48% range, suggesting that the gases were mainly dry. The nonhydrocarbon gases found were CO2 and H2. The CH4 content of the desorbed gas samples dropped continuously during desorption, lowering the dryness index to 98.48 and 92.26% of the first and last desorbed shale gas, respectively. The change in the gas ratio during shale gas desorption proved that the adsorbability of the LCNF to the various gases follows the trend H2 > CO2 > C2H6 > CH4 > He. Further, δ13C2H6 and δ13CH4 become heavier during desorption, showing isotopic fractionation arising from the desorption-diffusion coeffect. As the desorption temperature increases, the value of δ13CH4 increases because 12CH4 is more sensitive to temperature than 13CH4, so it is with the ethane. Similar to the LCNF shale gas in other areas of China, the desorbed shale gases are characteristic of carbon isotope reversal (CIR) (δ13CH4 > δ13C2H6). The cracking of the residual soluble organic matter at the high overmaturity stage mixed with the cracking of kerogen at the early stage of maturation, causing CIR. Furthermore, the desorbed gas content was proportionally and inversely related to the CIR degree and final dryness index of the desorbed gas, respectively. Moreover, the carbon isotope fractionation degree of CH4 and δ13C1 of the last desorbed gas correlated positively with the desorbed gas content and the desorbed time of the gas. In conclusion, the four parameters are effective parameters for identifying shale gas sweet spots.

The identity of Bupleurumjeholense (Apiaceae).

Bupleurumjeholense Nakai (Apioideae, Apiaceae), originally found in the Wuling Mountain of China, was initially described as a species but later treated as a variety of B.sibiricum Vest ex Spreng. However, researchers have recently found that it is more closely related to B.chinense DC. In this study, we conducted morphological and phylogenetic analyses as well as chromosome counting to determine the taxonomic status of B.sibiricumvar.jeholense (Nakai) Chu. Our results showed that B.sibiricumvar.jeholense and B.chinense share common features (i.e., bracteoles 5 and stem solid) that distinguish both from B.sibiricumvar.sibiricum. The chromosome number of B.sibiricumvar.jeholense was found to be the same as in B.chinense (i.e., 2n = 12), whereas the chromosome number of B.sibiricumvar.sibiricum was 64. A phylogenetic tree based on complete chloroplast genome data revealed a close relationship between B.sibiricumvar.jeholense and B.chinense. Finally, B.sibiricumvar.jeholense and B.chinense were mainly found to differ in plant height, number of stems, and middle stem leaves. Based on this evidence, we propose a new combination: Bupleurumchinensevar.jeholense (Nakai) Q.R.Liu & L.H.Wang.

Phylogeny, biogeography, and character evolution of Anaphalis (Gnaphalieae, Asteraceae).

The HAP clade, mainly including Helichrysum Mill, Anaphalis DC., and Pseudognaphalium Kirp., is a major component of tribe Gnaphalieae (Asteraceae). In this clade, Anaphalis represents the largest genus of Asian Gnaphalieae. The intergeneric relationships among Anaphalis and its related genera and the infrageneric taxonomy of this genus are complex and remain controversial. However, there are few studies that have focused on these issues. Herein, based on the current most comprehensive sampling of the HAP clade, especially Anaphalis, we conducted phylogenetic analyses using chloroplast (cp) genome and nuclear ribosomal DNA (nrDNA) to evaluate the relationships within HAP clade, test the monophyly of Anaphalis, and examine the infrageneric taxonomy of this genus. Meanwhile, the morphological characters were verified to determine the circumscription and infrageneric taxonomy system of Anaphalis. Additionally, the biogeographical history, diversification processes, and evolution of crucial morphological characters were estimated and inferred. Our phylogenetic analyses suggested that Anaphalis is polyphyletic because it nested with Helichrysum and Pseudognaphalium. Two and four main clades of Anaphalis were identified in cp genome and nrDNA trees, respectively. Compared with nrDNA trees, the cp genome trees were more effective for phylogenetic resolution. After comprehensively analyzing morphological and phylogenetic evidence, it was concluded that the achene surface ornamentation and leaf base showed less homoplasy and supported the two Anaphalis lineages that were inferred from cp genome. Our biogeographical analyses based on cp genome indicated that HAP clade underwent rapid diversification from late Miocene to Pliocene. The two Anaphalis lineages appeared to have originated in Africa, then spread to Western and Southern Asia, and subsequently moved into Southwestern China forming a diversity center. The dispersal patterns of the two Anaphalis lineages were different. One dispersed around the world, except in Africa and South America. The other one dispersed to Eastern and Southeastern Asia from the ancestral origin region.

Phylogeny of Leontopodium (Asteraceae) in China-with a reference to plastid genome and nuclear ribosomal DNA.

The infrageneric taxonomy system, species delimitation, and interspecies systematic relationships of Leontopodium remain controversial and complex. However, only a few studies have focused on the molecular phylogeny of this genus. In this study, the characteristics of 43 chloroplast genomes of Leontopodium and its closely related genera were analyzed. Phylogenetic relationships were inferred based on chloroplast genomes and nuclear ribosomal DNA (nrDNA). Finally, together with the morphological characteristics, the relationships within Leontopodium were identified and discussed. The results showed that the chloroplast genomes of Filago, Gamochaeta, and Leontopodium were well-conserved in terms of gene number, gene order, and GC content. The most remarkable differences among the three genera were the length of the complete chloroplast genome, large single-copy region, small single-copy region, and inverted repeat region. In addition, the chloroplast genome structure of Leontopodium exhibited high consistency and was obviously different from that of Filago and Gamochaeta in some regions, such as matk, trnK (UUU)-rps16, petN-psbM, and trnE (UUC)-rpoB. All the phylogenetic trees indicated that Leontopodium was monophyletic. Except for the subgeneric level, our molecular phylogenetic results were inconsistent with the previous taxonomic system, which was based on morphological characteristics. Nevertheless, we found that the characteristics of the leaf base, stem types, and carpopodium base were phylogenetically correlated and may have potential value in the taxonomic study of Leontopodium. In the phylogenetic trees inferred using complete chloroplast genomes, the subgen. Leontopodium was divided into two clades (Clades 1 and 2), with most species in Clade 1 having herbaceous stems, amplexicaul, or sheathed leaves, and constricted carpopodium; most species in Clade 2 had woody stems, not amplexicaul and sheathed leaves, and not constricted carpopodium.

Phylogeny of Trigonotis in China-with a special reference to its nutlet morphology and plastid genome.

The genus Trigonotis comprises nearly 60 species mainly distributed in East and Southeast Asia. China has the largest number of Trigonotis species in the world, with a total of 44 species, of which 38 are endemic. Nutlet morphology is useful for the taxonomic delimitation of Trigonotis. However, there are still controversial circumscriptions of nutlet shape in some species. In previous studies, interspecies phylogenetic relationships were inferred using few DNA markers and very few taxa, which possibly led to erroneous or incomplete conclusions. In this study, the nutlet morphology of 39 Trigonotis taxa and the characteristics of 34 complete chloroplast genomes (29 taxa) were investigated and analyzed. Then, the phylogenetic relationships were discussed within this genus based on complete chloroplast genomes. To the best of our knowledge, this study is the first comprehensive analysis of nutlet morphology and complete chloroplast genome of Trigonotis. Based on nutlet morphology, Trigonotis can be divided into two groups: Group 1, hemispherical or oblique tetrahedron with carpopodiums, and Group 2, inverted tetrahedron without carpopodiums. The chloroplast genome of Trigonotis exhibited a typical quadripartite structure, including 84-86 protein-coding, 37 transfer RNA, and 8 ribosomal RNA genes, with a total length of 147,247-148,986 bp. Genes in the junctions were well conserved in Trigonotis, similar to those in other Boraginaceae s.str. species. Furthermore, Trigonotis chloroplast genomes showed relatively high diversity, with more conserved genic regions than intergenic regions; in addition, we detected 14 hot spots (Pi > 0.005) in non-coding regions. Phylogenetic analyses based on chloroplast genome data identified highly resolved relationships between Trigonotis species. Specifically, Trigonotis was divided into two clades with strong support: one clade included species with hemispherical or oblique tetrahedron nutlets with carpopodiums and bracts, whereas the other clade included species with inverted tetrahedron nutlets without carpopodiums or bracts. Our results may inform future taxonomic, phylogenetic, and evolutionary studies on Boraginaceae.

Microbial communities associated with thermogenic gas hydrate-bearing marine sediments in Qiongdongnan Basin, South China Sea.

Biogenic and thermogenic gas are two major contributors to gas hydrate formation. Methane hydrates from both origins may have critical impacts on the ecological properties of marine sediments. However, research on microbial diversity in thermogenic hydrate-containing sediments is limited. This study examined the prokaryotic diversity and distributions along a sediment core with a vertical distribution of thermogenic gas hydrates with different occurrences obtained from the Qiongdongnan Basin by Illumina sequencing of 16S rRNA genes as well as molecular and geochemical techniques. Here, we show that gas hydrate occurrence has substantial impacts on both microbial diversity and community composition. Compared to the hydrate-free zone, distinct microbiomes with significantly higher abundance and lower diversity were observed within the gas hydrate-containing layers. Gammaproteobacteria and Actinobacterota dominated the bacterial taxa in all collected samples, while archaeal communities shifted sharply along the vertical profile of sediment layers. A notable stratified distribution of anaerobic methanotrophs shaped by both geophysical and geochemical parameters was also determined. In addition, the hydrate-free zone hosted a large number of rare taxa that might perform a fermentative breakdown of proteins in the deep biosphere and probably respond to the hydrate formation.

Plastome-based phylogeny and biogeography of Lactuca L. (Asteraceae) support revised lettuce gene pool categories.

This study generated and analyzed complete plastome and internal transcribed spacer (ITS) data of 46 Lactuca species, 13 African endemic (AE) Lactuca species, and 15 species from eight related genera in Lactucinae. The new plastome and nuclear ITS sequences were then used to reconstruct the phylogenetic relationships of Lactuca species. The whole-plastome data were used to estimate divergence time and ancestral area reconstruction of the identified major Lactuca lineages. The results showed that Lactuca species are generally similar in plastome size, Guanine and Cytosine (GC) content, gene structure, and categories, although crop lettuce (Lactuca sativa L.) and its gene pool relatives were found to have one unique pseudogene (ψ ndhF), and accD, atpF, cemA, clpP, and rpl22 showed signs of positive selection. Our phylogenomic analysis demonstrated that Lactuca is monophyletic after excluding Lactuca alatipes Collett and Hemsl and AE Lactuca species. AE Lactuca species are morphologically distinct from core Lactuca lineage and need to be excluded from Lactua. The core Lactuca species most likely originated from Asia-Temperate W ~6.82 Mya and then dispersed globally and formed nine clades. Finally, the lettuce gene pool concept was amended according to the phylogenetic and historical biogeographic analyses. This study revised the circumscription of Lactuca, revealed robust phylogenetic relationships within the genus, and provided insights into Lactucinae phylogeny. The lettuce gene pool species could be used as potential genetic resources for lettuce breeding.

Geochemical Characteristics and Significance of Organic Matter in Hydrate-Bearing Sediments from Shenhu Area, South China Sea.

Rock-Eval pyrolysis and the biomarker composition of organic matter were systematically studied in hydrate-bearing sediments from the Shenhu area, South China Sea. The n-alkane distribution patterns revealed that the organic matter in the sediments appeared to originate from mixed sources of marine autochthonous input, terrestrial higher plants, and ancient reworked organic matter. The low total organic carbon contents (average < 0.5%) and the low hydrogen index (HI, <80 mg HC/g TOC) suggested the poor hydrocarbon-generation potential of the deposited organic matter at a surrounding temperature of <20 °C in unconsolidated sediments. The abnormally high production index and the fossil-originated unresolved complex mixture (UCM) accompanied by sterane and hopane of high maturity indicated the contribution of deep hydrocarbon reservoirs. Preliminary oil-to-source correlation for the extracts implied that the allochthonous hydrocarbons in the W01B and W02B sediments might have originated from the terrestrial source rocks of mature Enping and Wenchang formations, while those of W03B seem to be derived from more reduced and immature marine source rocks such as the Zhuhai formation. The results of the organic extracts supported the previous identification of source rocks based on the isotopic composition of C2+ hydrate-bound gases. The biomarker of methanogens, squalane, was recognized in the sediments of this study, possibly suggesting the generation of secondary microbial gases which are coupled with the biodegradation of the deep allochthonous hydrocarbons.

Bak interacts with AKT and is involved in TNFα/CHX-induced apoptosis.

Bak is important for TNFα/CHX-induced neuronal death, but the precise molecular mechanism remains unclear. At the same time, TNFα/CHX concomitantly activates the phosphorylation of the MAPK and PI3K/AKT kinases. This study for the first time clarified the association between the MAPK and AKT under the TNFα/CHX stimulation upon addition of different kinase inhibitors to show whether Bak is associated with the kinase activation. The bioinformatics software HDOCK predicted the interaction between Bak and AKT. The addition of TNFα/CHX was proposed to destroy the complex, such that the dissociated Bak would exert a proapoptosis effect AKT can influence the inhibition of cell apoptosis. There was no cell death upon inducing TNFα/CHX for 3 h. AKT was less obvious with apoptosis but in the Bak knockout cells, the anti-apoptotic effect of AKT was very obvious. This study, therefore, provides the theoretical basis for the molecular mechanism of apoptosis induced by TNFα/CHX, providing a new target and direction for studying drug resistance.

Fe3O4@polydopamine nanoparticle-loaded human umbilical cord mesenchymal stem cells improve the cognitive function in Alzheimer's disease mice by promoting hippocampal neurogenesis.

One of the most promising treatments for neurodegenerative diseases is the stem cell therapy; however, there are still some limitations in the treatment of Alzheimer's disease. In this study, superparamagnetic nanoparticles composed of magnetic Fe3O4 and polydopamine shells were used to label human umbilical cord mesenchymal stem cells (hUC-MSCs) in order to increase the targeting of hUC-MSCs. Our data suggested that Fe3O4@PDA labeling increase the efficiency of hUC-MSCs entering the brain. Moreover, the water maze test showed that compared with hUC-MSCs only, Fe3O4@PDA-labeled hUC-MSCs improved the cognitive ability of APP/PS1 transgenic mice more significantly. Other experimental data showed that the expression of essential proteins in the hippocampus, such as Aß, synaptophysin, brain-derived neurotrophic factor, are affected by Fe3O4@PDA coated-hUC-MSCs. The regulation of Fe3O4@PDA coated-hUC-MSCs could improve the memory and cognitive ability of AD mice by excessive generation of neuroprotective factors, which might be considered a viable therapy to treat AD.

OGDHL ameliorates cognitive impairment and Alzheimer's disease-like pathology via activating Wnt/ß-catenin signaling in Alzheimer's disease mice.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases related to several types of pathophysiological signs, including ß-amyloid (Aß) plaque accumulation, neuroinflammation, and neurofibrillary tangles. Similar to one of the three subunits of α-ketoglutarate dehydrogenase complex (KGDHC), oxoglutarate dehydrogenase-like (OGDHL) appears to be downregulated in triple-transgenic Alzheimer's (3 × Tg-AD) mice. KGDHC activity is specifically reduced in the brains of people with AD. However, the underlying mechanism of OGDHL in the cause of AD is still unknown. Herein, we confirmed the low expression of OGDHL in the brain of 3 × Tg-AD based on real-time quantitative PCR, Western blot, and immunohistochemistry. We also found that the upregulation of OGDHL can reduce the memory deficits of 3 × Tg-AD mice, thereby reminding its nervous system neuroprotective effect in AD. Next, we confirmed that the increase in OGDHL could reduce neuroinflammation, amyloid plaque load, and tau phosphorylation in 3 × Tg-AD mice. Additionally, we showed that the overexpression of OGDHL could activate Wnt/ß-catenin signaling based on the expression of Wnt7B in vitro. Taken together, the results show that the rise of OGDHL reasonably improves the cognitive functions according to the activation of the Wnt/ß-catenin signaling pathway. Therefore, this enzyme may be a potential strategy for AD treatment.

The complete chloroplast genome of Onosma fuyunensis Y. He & Q.R. Liu and its phylogenetic analysis.

The chloroplast genome sequences of Chinese Boraginaceae species, Onosma fuyunensis Y. He & Q.R. Liu, were reported in this study. We sequenced O. fuyunensis using the Illumina HiSeq X Ten platform. The total length of O. fuyunensis chloroplast genome is 150,612 bp, including a large single-copy region of length 82,853 bp, a small single-copy region of length 17,281 bp, and a pair of 25,239-bp inverted repeat regions. The chloroplast genome of O. fuyunensis has 133 genes, including 84 protein-coding, eight ribosomal RNA, and 37 transfer RNA genes. The overall GC content of the whole genome was 43.3%. The phylogenetic analysis revealed that O. fuyunensis is closely related to Borago officinalis and Plagiobothrys nothofulvus.

LPA1-mediated PKD2 activation promotes LPA-induced tissue factor expression via the p38α and JNK2 MAPK pathways in smooth muscle cells.

Tissue factor (TF) is the principal initiator of blood coagulation and is necessary for thrombosis. We previously reported that lysophosphatidic acid (LPA), a potent bioactive lipid, highly induces TF expression at the transcriptional level in vascular smooth muscle cells. To date, however, the specific role of the LPA receptor is unknown, and the intracellular signaling pathways that lead to LPA induction of TF have been largely undetermined. In the current study, we found that LPA markedly induced protein kinase D (PKD) activation in mouse aortic smooth muscle cells (MASMCs). Small-interfering RNA-mediated knockdown of PKD2 blocked LPA-induced TF expression and activity, indicating that PKD2 is the key intracellular mediator of LPA signaling leading to the expression and cell surface activity of TF. Furthermore, our data reveal a novel finding that PKD2 mediates LPA-induced TF expression via the p38α and JNK2 MAPK signaling pathways, which are accompanied by the PKD-independent MEK1/2-ERK-JNK pathway. To identify the LPA receptor(s) responsible for LPA-induced TF expression, we isolated MASMCs from LPA receptor-knockout mice. Our results demonstrated that SMCs isolated from LPA receptor 1 (LPA1)-deficient mice completely lost responsiveness to LPA stimulation, which mediates induction of TF expression and activation of PKD and p38/JNK MAPK, indicating that LPA1 is responsible for PKD2-mediated activation of JNK2 and p38α. Taken together, our data reveal a new signaling mechanism in which the LPA1-PKD2 axis mediates LPA-induced TF expression via the p38α and JNK2 pathways. This finding provides new insights into LPA signaling, the PKD2 pathway, and the mechanisms of coagulation/atherothrombosis.

Factors Controlling the Lower Radioactivity and Its Relation with Higher Organic Matter Content for Middle Jurassic Oil Shale in Yuqia Depression, Northern Qaidam Basin, China: Evidence from Organic and Inorganic Geochemistry.

Organic-rich oil shale with unusual lower radioactivity (expressed by GR) was found in Member 7 of Dameigou Formation, middle Jurassic (J2d7) in Yuqia depression of northern Qaidam Basin, China. In order to systematically and contrastively investigate the factors controlling the lower GR and its relation with higher organic matter (OM) content (expressed by total organic carbon, abbr. TOC), organic and inorganic geochemical analyses were performed on samples consisting of oil shale and the underlying conformable contact dark shale from Well YQ-1Y. Our study shows that GR of J2d7 oil shale is mainly derived from uranium and thorium. Compared with dark shale, oil shale is characterized by higher OY and TOC, lower GR, and clay mineral content. During oil shale deposition, the paleoclimate was relatively arid, indicated by a decreased C value and siderite content as well as an increased carbonate content and Classopollis. Under such paleoclimate conditions, sedimentary water became more anoxic, suggested by higher V/(V + Ni), pyrite content and lower pristane/phytane (Pr/Ph). From oil shale to dark shale deposition, according to analyses of Al2O3/TiO2, TiO2 versus Zr, La/Sc versus Th/Co, La/Th versus Hf, and La-Th-Sc, the felsic igneous rock could always be deduced as the parent rock of provenance; however, the increasing arid paleoclimate resulted in weakened chemical weathering of provenance, inferred by relatively low chemical index of alteration, chemical index of weathering, and plagioclase index of alteration corresponding to the input degree of radioactive materials and other terrigenous detrital materials (TDMs), evidenced by Ti and Al contents and terrigenous (%). Meanwhile, the relatively high P/Ti and Ba/Al both indicated increased primary paleoproductivity. Together with the maximum flooding stage of oil shale deposition, the relatively low radioactivity tends to be associated with the inhibited input of clay minerals and radioactive materials, largely caused by increasing arid paleoclimate. The accompanying decreased TDM benefited primary paleoproductivity and anoxic conditions; their combined influence could induce sapropelic OM accumulation.

A new combination in Pseudolappula (Boraginaceae, Rochelieae) based on morphological, molecular and palynological evidence.

Lappulasinaica was recently transferred to the monotypic genus Pseudolappula based on phylogenetic studies, while the related species, L.occultata, has remained in the genus Lappula. In this study, morphological, molecular, and palynological evidence supports that L.occultata should be transferred to the genus Pseudolappula. Both L.occultata and P.sinaica share a combination of nutlets features that distinguish them from Lappula: a longer adaxial keel and a linear attachment scar. Phylogenetic analysis based on ITS and trnL-F strongly supports L.occultata as the sister taxon of P.sinaica. In addition, pollen grains of these two species are 3-syncolporate with 3 alternating pseudocolpi, which is significantly different from the grains of Lappula taxa. Based on the above evidence, the new combination Pseudolappulaoccultata is proposed.

Onosma fuyunensis (Boraginaceae), a new species from Xinjiang, China.

Onosma fuyunensis, a new species of Boraginaceae from northern Xinjiang, China, is described and illustrated here. Onosma fuyunensis is similar to O. simplicissima and O. gmelinii; it differs in having a particularly bristly indumentum, unbranched stems, white and yellow corollas, anthers united only at base, and nutlets with a stipitate cicatrix. An updated key to the species of Onosma from Xinjiang and Altai Mountains is also provided.

Proapoptotic Mitochondrial Carrier Homolog Protein PSAP Mediates Death Receptor 6 Induced Apoptosis.

Presenilin-associated protein (PSAP) was originally identified as a mitochondrial proapoptotic protein. To further explore the apoptotic pathway that involves PSAP, our yeast two-hybrid screen revealed that PSAP interacts with a death receptor, DR6. DR6 is a relatively less common member of the death receptor family and has been shown to mediate the neurotoxicity of amyloid-ß, mutant SOD1, and prion proteins and has also been implicated in the regulation of immune cell proliferation and differentiation. Our previous study showed that DR6 induces apoptosis via a unique mitochondria-dependent pathway different from the conventional death receptor-mediated extrinsic apoptotic pathways. Thus, the interaction of DR6 with PSAP established a direct molecular link between DR6 and mitochondrial apoptotic pathway. We investigated the possible role of PSAP in DR6-induced apoptosis. Interestingly, it was discovered that knockdown of PSAP strongly inhibited DR6-induced apoptosis. To further elucidate the mechanism by which PSAP mediates DR6-induced mitochondria-dependent apoptosis, our data demonstrated that knockdown of PSAP blocked DR6-induced Bax translocation and cytochrome c release from the mitochondria. Moreover, it was found that both PSAP and DR6 form complexes with Bax, but at different subcellular locations. The DR6-Bax complex was detected in the cytosolic fraction while the PSAP-Bax complex was detected in the mitochondrial fraction. The observation that knockdown of DR6 significantly reduced the amount of PSAP-Bax complex detected in mitochondria suggests a possibility that DR6-bound Bax is transferred to PSAP upon interaction with PSAP at the mitochondria, leading to cytochrome c release and eventually apoptosis.

Chromium-Containing Traditional Chinese Medicine, Tianmai Xiaoke Tablet, for Newly Diagnosed Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review of Randomized Clinical Trials.

OBJECTIVE: Chromium-containing traditional Chinese medicine Tianmai Xiaoke tablet (TMXKT) is approved for treating newly diagnosed type 2 diabetes mellitus (T2DM) in China. This review aimed to compile the evidence from randomized clinical trials (RCTs) and quantify the effects of TMXKT on newly diagnosed T2DM. METHODS: Seven online databases were investigated up to March 20, 2017. The meta-analysis included RCTs investigating the treatment of newly diagnosed T2DM, in which TMXKT combined with conventional therapy was compared with placebo or conventional therapy. The risk of bias was evaluated using the Cochrane Collaboration tool. The estimated mean difference (MD) and the standardized mean difference were within 95% confidence intervals (CI) with respect to the interstudy heterogeneity. The outcomes were measured using fasting blood glucose (FBG), 2-h postprandial blood glucose (2hPG), glycosylated hemoglobin A1c (HbA1c), and body mass index (BMI) levels. RESULTS: TMXKT combined with conventional therapy lowered FBG level (MD = -0.68, 95% CI -0.90 to -0.45, P < 0.00001), 2hPG (MD = -1.33, 95% CI -1.86 to -0.79, P < 0.00001), HbA1c (MD = -0.46, 95% CI -0.57 to -0.36, P < 0.00001), and BMI (MD = -0.77, 95% CI -1.12 to -0.41, P < 0.00001). CONCLUSIONS: TMXKT combined with conventional therapy is beneficial for patients with newly diagnosed T2DM. However, the effectiveness and safety of TMXKT are uncertain because of the limited number of trials and low methodological quality. Therefore, practitioners should be cautious when applying TMXKT in daily practice. Also, well-designed clinical trials are needed in the future.

CD14 is a key mediator of both lysophosphatidic acid and lipopolysaccharide induction of foam cell formation.

Macrophage uptake of oxidized low-density lipoprotein (oxLDL) plays an important role in foam cell formation and the pathogenesis of atherosclerosis. We report here that lysophosphatidic acid (LPA) enhances lipopolysaccharide (LPS)-induced oxLDL uptake in macrophages. Our data revealed that both LPA and LPS highly induce the CD14 expression at messenger RNA and protein levels in macrophages. The role of CD14, one component of the LPS receptor cluster, in LPA-induced biological functions has been unknown. We took several steps to examine the role of CD14 in LPA signaling pathways. Knockdown of CD14 expression nearly completely blocked LPA/LPS-induced oxLDL uptake in macrophages, demonstrating for the first time that CD14 is a key mediator responsible for both LPA- and LPS-induced oxLDL uptake/foam cell formation. To determine the molecular mechanism mediating CD14 function, we demonstrated that both LPA and LPS significantly induce the expression of scavenger receptor class A type I (SR-AI), which has been implicated in lipid uptake process, and depletion of CD14 levels blocked LPA/LPS-induced SR-AI expression. We further showed that the SR-AI-specific antibody, which quenches SR-AI function, blocked LPA- and LPS-induced foam cell formation. Thus, SR-AI is the downstream mediator of CD14 in regulating LPA-, LPS-, and LPA/LPS-induced foam cell formation. Taken together, our results provide the first experimental evidence that CD14 is a novel connecting molecule linking both LPA and LPS pathways and is a key mediator responsible for LPA/LPS-induced foam cell formation. The LPA/LPS-CD14-SR-AI nexus might be the new convergent pathway, contributing to the worsening of atherosclerosis.

Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21.

Lysophosphatidic acid (LPA), a naturally occurring bioactive phospholipid, activates G protein-coupled receptors (GPCRs), leading to regulation of diverse cellular events including cell survival and apoptosis. Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival, the mechanisms underlying the apoptotic effect of LPA remain largely unclear. In this study, we investigated this issue in HeLa cells. Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 (tumor necrosis factor receptor superfamily member 21), also known as death receptor number 6 (DR6) involved in inflammation. Moreover, treatment of cells with LPA receptor (LPAR) antagonist abolished the DR6 upregulation by LPA. LPA-induced DR6 expression was also abrogated by pertussis toxin (PTX), an inhibitor of GPCRs, and by inhibitors of PI3K, PKC, MEK, and ERK. Intriguingly, LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKCδ (PKCδ-DN). LPA-induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB. These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression. More interestingly, knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis. In conclusion, our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression.