A Chironomid Record of Early-Middle Holocene Environmental Evolution in the Darhad Basin, Northern Mongolia.

Under the influence of various circulation systems, the Holocene humidity conditions on the Mongolian Plateau are spatially heterogeneous and the underlying mechanism is still ambiguous. The complexity of climate change may affect the accuracy of assessing lake ecosystem evolution. In this study, based on the precise chronology, a chironomid assemblage sequence from the Darhad Basin in northern Mongolia is analyzed to elucidate the hydroclimate variation during the early-middle Holocene. The results show that the chironomid communities changed suddenly from littoral taxa to sublittoral/profundal taxa at about 9 cal kyr BP, reflecting an environmental transition from a river or shallow lake condition to a deep lake environment. Thereafter, most parts of the paleolake remained at a relatively high level until 4.5 cal kyr BP. This hydrological pattern resembles the typical humidity variations in the Westerlies affected regions, except that the onset of wetter conditions occurred one thousand years earlier as reflected in our results. The melting of glaciers and permafrost in the basin resulting from the early increased summer solar insolation could be a feasible explanation for these time advances.

The oldest Homo erectus buried lithic horizon from the Eastern Saharan Africa. EDAR 7 - an Acheulean assemblage with Kombewa method from the Eastern Desert, Sudan.

Although essential for reconstructing hominin behaviour during the Early Palaeolithic, only a handful of Acheulean sites have been dated in the Eastern Sahara region. This is due to the scarcity of sites for this time period and the lack of datable material. However, recent excavations in the Atbara region (Sudan) have provided unique opportunities to analyse and date Acheulean stone tools. We report here on EDAR 7, part of a cluster of Acheulean and Middle Stone Age (MSA) sites that were recently discovered in the Eastern Desert Atbara River (EDAR) region, located in the Eastern Desert (Sudan) far from the Nile valley. At EDAR 7, a 3.5 metre sedimentary sequence was excavated, allowing an Acheulean assemblage to be investigated using a combination of sedimentology, stone tool studies and optically stimulated luminescence dating (OSL). The site has delivered a complete Acheulean knapping chaine opératoire, providing new information about the Saharan Acheulean. The EDAR 7 site is interpreted as a remnant of a campsite based on the co-occurrence of two reduction modes: one geared towards the production of Large Cutting Tools (LCTs), and the other based on the flaking of small debitage and production of flake tools. Particularly notable in the EDAR 7 assemblage is the abundance of cleavers, most of which display evidence of flake production. Implementation of giant Kombewa flakes was also observed. A geometric morphometric analysis of hand-axes was conducted to verify a possible Late Acheulean assemblage standardisation in the Nubian Sahara. In addition, the analysis of micro-traces and wear on the artefacts has provided information on the use history of the Acheulean stone tools. Sediment analyses and OSL dating show that the EDAR 7 sequence contains the oldest Acheulean encampment remains in the Eastern Sahara, dated to the MIS 11 or earlier. This confirms that Homo erectus occupied the EDAR region during Middle Pleistocene humid periods, and demonstrates that habitable corridors existed between the Ethiopian Highlands, the Nile and the Red Sea coast, allowing population dispersals across the continent and out of it.

Saharan green corridors and Middle Pleistocene hominin dispersals across the Eastern Desert, Sudan.

The Sahara Desert episodically became a space available for hominins in the Pleistocene. Mostly, desert conditions prevailed during the interpluvial periods, which were only periodically interrupted by enhanced precipitation during pluvial or interglacial periods. Responding to Quaternary climatic changes, hominin dispersal was channeled through vegetated corridors. This manuscript introduces a recently discovered group of Acheulean and Middle Stone Age sites far from the Nile Valley in the Eastern Desert (Sudan), referred to as Eastern Desert Atbara River (EDAR). The ∼5 m stratigraphy of the area is divided into three units (Units I-III) bounded by erosion surfaces. Each contains archaeological horizons. The EDAR area has rich surface sites with Acheulean horizons under the surface, singular finds of hand-axes within stratigraphic context in exposures, and large Acheulean sites partly exposed and destroyed by the gold mining activity. Optically stimulated luminescence (OSL) dating of Acheulean and MSA horizons from the EDAR 135 site indicates that the sedimentary deposits with stone artifacts were formed during the Middle Pleistocene between Marine Isotope Stages (MIS) 7 (pluvial) and 6 (interpluvial). Based on the OSL dating from the top of Unit IB, Acheulean artifact-bearing sedimentary deposits from overlying Unit IIA are younger than ca. 231 ka. Unit IA is the oldest Acheulean horizon in the EDAR area, not yet dated but definitively older than ca. 231 ka. An MSA horizon found in fluvial sediment was dated to be between 156 and 181 ka by OSL. The EDAR Pleistocene archaeological sites provide evidence for the presence of additional corridor(s) across Nubia, which connects the early hominin dispersals from the Nile and Atbara River systems to the Red Sea coast.

The 8.2 ka cooling event in coastal East Asia: High-resolution pollen evidence from southwestern Korea.

In this study, we present a high-resolution multi-proxy record (pollen, magnetic susceptibility, and mean grain size) from Bigeum Island, South Korea, which mainly showed early Holocene paleoenvironmental change. Bigeum pollen records indicated that early Holocene climate variations in coastal East Asia were principally controlled by the Atlantic meridional overturning circulation. Most importantly, the 8.2 ka cooling event was clearly recognized for the first time in coastal East Asia, where few high-resolution proxy data, such as ice core and stalagmite δ18O records, are available. The insular vegetation in the study site was extremely susceptible to even short-term climate changes, such as the 8.2 ka cooling event, which allowed a detailed climate reconstruction from pollen data. Early Holocene climate teleconnections between coastal East Asia and other regions were identified through regional comparisons of Greenland, China, Brazil, Spain, Madagascar, and Korea. Coastal East Asia is one of world's most populated regions and will be particularly vulnerable to future climate change. Accurate and detailed paleoclimate proxy data, such as the Bigeum pollen record, will therefore be increasingly important in this region.

Novel dabigatran etexilate hemisuccinate-loaded polycap: Physicochemical characterisation and in vivo evaluation in beagle dogs.

The purpose of this study was to develop a novel dabigatran etexilate hemisuccinate (DEH) salt-loaded polycap with bioequivalence to the dabigatran etexilate mesylate (DEM)-loaded commercial product. DEH prepared with dabigatran etexilate base (DE) and succinic acid was less hygroscopic but less soluble than DEM. Numerous micronized DEHs and DEH-loaded solid dispersions were prepared employing the spiral jet-milling and spray-drying techniques, respectively. Among the formulations prepared, a micronized DEH prepared with the injection air at 1.5bar and the grinding air at 2bar, and a DEH-loaded solid dispersion prepared with 6g HPMC most improved the drug solubility, respectively. Moreover, the micronized DEH provided more increased drug solubility and dissolution compared with the solid dispersion, even though its drug solubility was still lower than that of DEM. Unlike the situation in other studies, the enhanced solubility and dissolution of DEH was more due to particle size reduction than to a change to the amorphous form. The micronized DEH prepared with Myrj 52S had greater drug solubility than preparations with other surfactants. Among the organic acids investigated, only fumaric acid (128.8mg) showed a similar pattern in pH changes to the DEM-loaded commercial product. Furthermore, in order to make the environment acidic while preventing the direct contact of the drug with fumaric acid, the polycap was composed of a tablet containing the micronized DEH, Myrj 52S and other ingredients, and separate fumaric acid. This micronized DEH-loaded polycap was dissolution- and bio-equivalent to the DEM-loaded commercial product in beagle dogs. Thus, the novel micronized DEH-loaded polycap would be a promising alternative to the DEM-loaded commercial product.

Development of novel prasugrel base microsphere-loaded tablet with enhanced stability: Physicochemical characterization and in vivo evaluation in beagle dogs.

The objective of this study was to develop a novel prasugrel base microsphere-loaded tablet (PBMST) with enhanced stability as a bioequivalent to the commercial prasugrel hydrochloride-loaded tablet. Numerous prasugrel base-loaded microspheres were prepared with hydroxypropylmethyl cellulose (HPMC), colloidal silica and various acidifying agents using a spray-drying process, and the physicochemical properties, solubility and stability were investigated. The PBMSTs were prepared and their dissolution, pharmacokinetics in beagle dogs and stability were evaluated compared to commercial prasugrel hydrochloride-loaded tablets. Among the acidifying agents tested, phosphoric acid provided the greatest increase in drug solubility, by as much as 110-fold. The prasugrel base-loaded microspheres composed of prasugrel base, HPMC, colloidal silica and phosphoric acid at a weight ratio of 10/10/5/2.5 provided an amorphous drug and reduced particle size of about 11.3µm. Moreover, it exhibited excellent solubility and improved stability compared to prasugrel base and hydrochloride. Moreover, PBMST drug dissolution was improved in comparison to the prasugrel base-loaded tablet (PBT), with similar dissolution to the commercial prasugrel hydrochloride-loaded tablet at pH 1.2 and 4.0. PBMST provided significantly higher plasma concentrations of AUC and Cmax in beagle dogs compared to PBT. In particular, the AUC of PBMST was approximately four times greater than PBT, leading to improved oral bioavailability. There were no significant differences observed for all pharmacokinetic parameters between PBMST and the commercial prasugrel hydrochloride-loaded tablet, suggesting their bioequivalence in beagle dogs. Furthermore, the prepared PBMSTs were stable for at least six months. Therefore, this novel prasugrel base microsphere-loaded tablet could be a potential alternative for enhancing the stability and bioavailability of prasugrel.

Effect of HM30181 mesylate salt-loaded microcapsules on the oral absorption of paclitaxel as a novel P-glycoprotein inhibitor.

The purpose of this study was to develop HM30181 mesylate salt (HM30181M)-loaded microcapsules as a novel P-glycoprotein inhibitor for enhancing the oral absorption of paclitaxel. The effect of various carriers including hydrophilic polymers and solvents on the solubility of HM30181M were evaluated. Among the hydrophilic polymers and solvents tested, HPMC and methylene chloride (and ethanol) provided the highest HM30181M solubility. Numerous HM30181M-loaded microcapsules were prepared with HPMC, silicon dioxide and acidifying agents using a spray-drying technique, and their solubility, dissolution and physicochemical properties were evaluated. Furthermore, a pharmacokinetic study was performed after oral administration of paclitaxel alone, simultaneously with HM30181M powder or HM30181M-loaded microcapsules to rats. Among the acidifying agents investigated, phosphoric acid provided the best improvement in the solubility and dissolution of HM30181M. Moreover, the microcapsule composed of HM30181M, HPMC, silicon dioxide and phosphoric acid at a weight ratio of 3:6:3:2 remarkably enhanced the solubility and dissolution of HM30181M compared with the HM30181M powder alone. The microcapsules were spherical in shape, had a reduced particle size of about 7µm, and contained HM30181M in an amorphous state. Furthermore, this microcapsule significantly enhanced HM30181M absorption, making it about 1.7-fold faster and 1.6-fold greater after simultaneous administration, leading to about 70- and 2-fold improved oral bioavailability of paclitaxel compared with paclitaxel alone and the simultaneous administration with HM30181M powder, respectively. Thus, this novel microcapsule could be a potential candidate for effective P-glycoprotein inhibition during oral administration of paclitaxel.

Saucerneol D, a naturally occurring sesquilignan, inhibits LPS-induced iNOS expression in RAW264.7 cells by blocking NF-kappaB and MAPK activation.

We evaluated the ability of saucerneol D (SD), a tetrahydrofuran-type sesquilignan isolated from Saururus chinensis, to regulate the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 cells. SD consistently inhibited nitric oxide (NO) production in a dose-dependent manner, with an IC(50) of 2.62 microM, and also blocked LPS-induced iNOS expression. SD potently suppressed both the reporter gene expression and DNA-binding activity of nuclear factor-kappaB (NF-kappaB). In addition, SD inhibited IkappaB-alpha degradation in a concentration- and time-dependent manner. SD also inhibited LPS-induced activation of various mitogen-activated protein kinases, including extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). These findings suggest that SD may inhibit LPS-induced iNOS expression by blocking NF-kappaB and MAPK activation.

Meso-dihydroguaiaretic acid isolated from Saururus chinensis inhibits cyclooxygenase-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells.

Meso-dihydroguaiaretic acid (MDGA) is a medicinal herbal product isolated from the aerial parts of Saururus chinensis that inhibits the cyclooxygenase-2 (COX-2)-dependent phase of prostaglandin D(2) (PGD(2)) generation in bone marrow-derived mast cells (BMMC) (IC(50) 9.8 microM). However, this compound did not inhibit COX-2 protein expression in BMMC at concentrations up to 30 microM, indicating that MDGA directly inhibits COX-2 activity. In addition, this compound consistently inhibited the production of leukotriene C(4) (IC(50) 1.3 microM). These results demonstrate that MDGA inhibits both COX-2 and 5-lipoxygenase. Furthermore, this compound strongly inhibited the degranulation reaction in BMMC (IC(50) 11.4 microM). Therefore, this compound might provide a basis for novel anti-inflammatory drug development.

Chemical constituents of the root of Dystaenia takeshimana and their anti-inflammatory activity.

In our ongoing search for bioactive compounds originating from the endemic species in Korea, we found that the hexane and EtOAc fractions of the MeOH extract from the root of Dystaenia takeshimana (Nakai) Kitagawa (Umbelliferae) showed cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) dual inhibitory activity by assessing their effects on the production of prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) in mouse bone marrow-derived mast cells. By activity-guided fractionation, five coumarins, viz. psoralen (2), xanthotoxin (3), scopoletin (4), umbelliferone (5), and (+)-marmesin (6), together with beta-sitosterol (1), were isolated from the hexane fraction, and two phenethyl alcohol derivatives, viz. 2-methoxy-2-(4'-hydroxyphenyl)ethanol (7) and 2-hydroxy-2-(4'-hydroxyphenyl)ethanol (8), three flavonoids, viz. apigenin (9), luteolin (10), and cynaroside (11), as well as daucosterol (12) were isolated from the EtOAc fraction using silica gel column chromatography. In addition, D-mannitol (13) was isolated from the BuOH fraction by recrystallization. Two of the coumarins, scopoletin (4) and (+)-marmesin (6), the two phenethyl alcohol derivatives (7, 8) and the three flavonoids (9-11) were isolated for the first time from this plant. Among the compounds isolated from this plant, the five coumarins as well as the three flavonoids showed COX-2/5-LOX dual inhibitory activity. These results suggest that the anti-inflammatory activity of D. takeshimana might in part occur via the inhibition of the generation of eicosanoids.