Redox-responsive glycosylated combretastatin A-4 derivative as novel tubulin polymerization inhibitor for glioma and drug delivery.

Combretastatin A-4 (CA4), a tubulin inhibitor, binds to the colchicine site of tubulin, inhibits tubulin polymerization, and leads to the apoptosis of tumor cells. However, the poor hydrophilicity and blood-brain barrier (BBB) penetration ability of CA4 hampers its application in the treatment of glioma. In this study, a novel combretastatin A-4 derivative (CA4D) was designed and developed, which was further conjugated with glucose via disulfide-bond-bridged (CA4D-SS-Glu) to enhance the BBB penetration capacity. The obtained CA4D-SS-Glu conjugate displayed a suitable water partition coefficient and the superior ability across BBB in vitro and in vivo. In addition, the CA4D-SS-Glu exhibited rapid redox-responsive drug release in the presence of glutathione, enhanced in vitro cytotoxicity, and cell apoptosis. Our data further confirmed that CA4D-SS-Glu inhibited proliferation, and restrained migration via affecting microtubule stabilization. Additionally, the conjugate also showed the highest antiproliferative and antitumor action on glioma in vivo as compared to CA4D and CA4. Taken together, the novel CA4D-SS-Glu conjugate possess improved physicochemical property and BBB penetration ability, reduction triggered release of CA4D, and efficient antiproliferative activity. These results provided a novel and effective entry to the treatment of glioma.

Accelerating thermokarst lake changes on the Qinghai-Tibetan Plateau.

As significant evidence of ice-rich permafrost degradation due to climate warming, thermokarst lake was developing and undergoing substantial changes. Thermokarst lake was an essential ecosystem component, which significantly impacted the global carbon cycle, hydrology process and the stability of the Qinghai-Tibet Engineering Corridor. In this paper, based on Sentinel-2 (2021) and Landsat (1988-2020) images, thermokarst lakes within a 5000 m range along both sides of Qinghai-Tibet Highway were extracted to analyse the spatio-temporal variations. The results showed that the number and area of thermokarst lake in 2021 were 3965 and 4038.6 ha (1 ha = 10,000 m[Formula: see text]), with an average size of 1.0186 ha. Small thermokarst lakes ([Formula: see text]1 ha) accounted for 85.65% of the entire lake count, and large thermokarst lakes ([Formula: see text]10 ha) occupied for 44.92% of the whole lake area. In all sub-regions, the number of small lake far exceeds 75% of the total lake number in each sub-region. R1 sub-region (around Wudaoliang region) had the maximum number density of thermokarst lakes with 0.0071, and R6 sub-region (around Anduo region) had the minimum number density with 0.0032. Thermokarst lakes were mainly distributed within elevation range of 4300 m-5000 m a.s.l. (94.27% and 97.13% of the total number and size), on flat terrain with slopes less than 3[Formula: see text] (99.17% and 98.47% of the total number and surface) and in the north, south, and southeast aspects (51.98% and 50.00% of the total number and area). Thermokarst lakes were significantly developed in warm permafrost region with mean annual ground temperature (MAGT) > - 1.5 [Formula: see text]C, accounting for 47.39% and 54.38% of the total count and coverage, respectively. From 1988 to 2020, in spite of shrinkage or even drain of small portion of thermokarst lake, there was a general expansion trend of thermokarst lake with increase in number of 195 (8.58%) and area of 1160.19 ha (41.36%), which decreased during 1988-1995 (- 702 each year and - 706.27 ha/yr) and then increased during 1995-2020 (184.96-702 each year and 360.82 ha/yr). This significant expansion was attributed to ground ice melting as rising air temperature at a rate of 0.03-0.04 [Formula: see text]C/yr. Followed by the increasing precipitation (1.76-3.07 mm/yr) that accelerated the injection of water into lake.

New permafrost is forming on the exposed bottom of Zonag Lake on the Qinghai-Tibet Plateau.

Most lakes on the Qinghai-Tibet Plateau have expanded in recent years. Zonag Lake, a critical habitat for Tibetan antelopes in the continuous permafrost zone, burst and overflowed after several years of expansion, resulting in a reduction of approximately 100 km2 in the lake area. Observations have revealed new permafrost is forming on the exposed bottom, accompanied by various periglacial landscapes. The permafrost aggradation on the exposed bottom is rapid, and the permafrost base reached 4.9 m, 5.4 m, and 5.7 m in the first three years, respectively. In this study, the future changes and influencing factors of recently formed permafrost are simulated using a one-dimensional finite element model of heat flow. The simulated results indicate that the permafrost on the exposed bottom is likely to continue to develop, appearing first quick back slow trend. Besides the surface temperature, the annual amplitude is also an important factor in affecting the aggradation of permafrost. The unidirectional permafrost aggradation in the study area is different from the bidirectional permafrost aggradation on the closed taliks around the Arctic. Additionally, snow cover and vegetation are two important factors influencing the future development of permafrost on the exposed lake bottom.

Permafrost degradation is accelerating beneath the bottom of Yanhu Lake in the Hoh Xil, Qinghai-Tibet Plateau.

Lakes on the Qinghai-Tibet Plateau (QTP) have notably expanded over the past 20 years. Due to lake water level rise and lake area expansion, the permafrost surrounding these lakes is increasingly becoming submerged by lake water. However, the change process of submerged permafrost remains unclear, which is not conducive to further analyzing the environmental effects of permafrost change. Yanhu Lake, a tectonic lake on the QTP, has experienced significant expansion and water level rise. Field measurement results indicate that the water level of Yanhu Lake increased by 2.87 m per year on average from 2016 to 2019. Cold permafrost, developed in the lake basin, was partially submerged by lake water at the end of 2017. Based on the water level change and permafrost thermal regime, a numerical heat conduction permafrost model was employed to predict future changes in permafrost beneath the lake bottom. The simulated results indicate that the submerged permafrost would continuously degrade because of the significant thermal impact of lake water. By 2100, the maximum talik thicknesses could reach approximately 7, 12, 16, and 19 m under lake-bottom temperatures of +2.0, +4.0, +6.0, and +8.0 °C, respectively. Approximately 291 years would be required to completely melt 47 m of submerged permafrost under the lake-bottom temperature of +4 °C. Note that the permafrost table begins to melt earlier than does the permafrost base, and the decline in the permafrost table occurs relatively fast at first, but then the process is attenuated, after which the permafrost table again rapidly declines. Compared to climate warming, the degradation of the submerged permafrost beneath the lake bottom occurred more rapidly and notably.

Domino effect of a natural cascade alpine lake system on the Third Pole.

Third Pole natural cascade alpine lakes (NCALs) are exceptionally sensitive to climate change, yet the underlying cryosphere-hydrological processes and associated societal impacts are largely unknown. Here, with a state-of-the-art cryosphere-hydrology-lake-dam model, we quantified the notable high-mountain Hoh-Xil NCALs basin (including Lakes Zonag, Kusai, Hedin Noel, and Yanhu, from upstream to downstream) formed by the Lake Zonag outburst in September 2011. We demonstrate that long-term increased precipitation and accelerated ice and snow melting as well as short-term heavy precipitation and earthquake events were responsible for the Lake Zonag outburst; while the permafrost degradation only had a marginal impact on the lake inflows but was crucial to lakeshore stability. The quadrupling of the Lake Yanhu area since 2012 was due to the tripling of inflows (from 0.25 to 0.76 km3/year for 1999 to 2010 and 2012 to 2018, respectively). Prediction of the NCALs changes suggests a high risk of the downstream Qinghai-Tibet Railway, necessitating timely adaptions/mitigations.

Design, synthesis and evaluation of liposomes modified with dendritic aspartic acid for bone-specific targeting.

Bone diseases are notoriously difficult diseases to treat due to the comparatively low blood flows in bone tissue. Therefore, targeting delivery of drugs to bone may not only enhance the treatment efficacy, but also reduce the quantity of drug administered. In order to increase the distribution of paclitaxel (PTX) in bone, in this study, a series of novel dendritic aspartic acid derivatives were designed and synthesized as liposome ligands to deliver PTX to bone effectively. The liposomes were prepared by thin film hydration method and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis were also characterized. All the aspartic acid-coated liposomes showed more than 60% binding rates to hydroxyapatite (HAP), especially the PTX-Asp8-Lip exhibited dramatic binding rates (> 97%) after 24 h. Moreover, the bone-targeting study in vivo indicated that all liposomes could improve the accumulation of PTX in bone, among which, the PTX-Asp8-Lip showed the best affinity due to the increase of aspartic acid residues exposed on the liposome surface. These results provided a novel and effective entry to the development of bone-targeting drugs.

Dual-targeting liposome modified by glutamic hexapeptide and folic acid for bone metastatic breast cancer.

Bone is the most common organ affected by metastatic breast cancer. Targeting delivery of drugs to bone may not only enhance the treatment efficacy, but also reduce the quantity of drug administered. In order to increase the distribution of paclitaxel (PTX) in bone, herein, a novel bone metastasis-targeted glutamic hexapeptide-folic acid (Glu6-FA) derivative was designed and synthesized as liposome ligand to deliver PTX to bone metastasis effectively. The liposomes were prepared by thin film hydration method and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis were also characterized. What's more, the anti-tumor effects of PTX-Glu6-FA-Lip were confirmed by the detection of cell cycle, migration, and further measurement of microtubule stabilization. In addition, the PTX-Glu6-FA-Lip showed superior targeting ability in vitro and in vivo evaluation as compared to naked PTX, non-coated, singly-modified and co-modified by physical blending liposomes. All the results suggested that Glu6-FA-modified liposome showed excellent targeting activity to metastatic bone cancer. These findings suggested that Glu6-FA-Lip was a promising bone metastasis-targeting carrier for the delivery of PTX. This study may therefore be conducive to the field of bone-targeting drugs delivery.

Spatial distribution and changes of permafrost on the Qinghai-Tibet Plateau revealed by statistical models during the period of 1980 to 2010.

The Qinghai-Tibet Plateau (QTP), where is underlain by the highest and most extensive mid-altitude permafrost, is undergoing more dramatic climatic warming than its surrounding regions. Mapping the distribution of permafrost is of great importance to assess the impacts of permafrost changes on the regional climate system. In this study, we applied logistic regression model (LRM) and multi-criteria analysis (MCA) methods to map the decadal permafrost distribution on the QTP and to assess permafrost dynamics from the 1980s to 2000s. The occurrence of permafrost and its impacting factors (i.e., climatic and topographic elements) were constructed from in-situ field investigation-derived permafrost distribution patterns in 4 selected study regions. The validation results indicate that both LRM and MCA could efficiently map the permafrost distribution on the QTP. The areas of permafrost simulated by LRM and MCA are 1.23 × 106 km2 and 1.20 × 106 km2, respectively, between 2008 and 2012. The LRM and MCA modeling results revealed that permafrost area has significantly decreased at a rate of 0.066 × 106 km2 decade-1 over the past 30 years, and the decrease of permafrost area is accelerating. The sensitivity test results indicated that LRM did well in identifying the spatial distribution of permafrost and seasonally frozen ground, and MCA did well in reflecting permafrost dynamics. More parameters such as vegetation, soil property, and soil moisture are suggested to be integrated into the models to enhance the performance of both models.

Dual-active targeting liposomes drug delivery system for bone metastatic breast cancer: Synthesis and biological evaluation.

Bone is the most common organ affected by metastatic breast cancer. Targeting cancers within the bone remains a great challenge due to the inefficient delivery of therapeutic to bone. In order to increase the distribution of paclitaxel (PTX) in bone metastases, in this study, a novel bone-targeted glutamic oligopeptides-RGD peptide (Glu6-RGD) derivative was designed and synthesized as liposome ligand for preparing liposome to effectively deliver PTX to bone metastases. The liposome was prepared and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis and cytotoxicity were also characterized. What's more, the Glu6-RGD-Lip showed superior targeting ability in vitro and in vivo evaluation as compared to naked PTX, non-coated, singly-modified and co-modified by physical blending liposomes. All the results suggested that Glu6-RGD-modified liposome showed excellent targeting activity to metastatic bone cancer. This study may be conducive to the field of bone-targeting drugs delivery.

Spatial variations and controlling factors of ground ice isotopes in permafrost areas of the central Qinghai-Tibet Plateau.

Ground ice is a distinctive feature of permafrost, and its thawing under climate change can alter the regional hydrological and biogeochemical cycles. Spatial variations and determinants of ground ice isotopes are critical to understand subsurface water cycling during freeze-thaw process in the context of climate change, while they are not well known in permafrost region due to lack of field investigation. We examined spatial distributions and controlling factors of ground ice isotopes using data of 8 soil profiles surveyed in permafrost areas of the Qinghai-Tibet Plateau (QTP). The stable isotope values (δ2H and δ18O) of subsurface water on the QTP were higher than those in Arctic tundra ecosystem and East Siberian permafrost region. Isotopic values of water components differed each other, and varied significantly among the sampling sites. The spatial distribution of isotopes was complex. Isotopes generally decreased with depth within the soil profile, implying a general isotope depth gradient across different permafrost-affected areas. Water source, evaporative and freeze-out fractionation, and cryoturbation affect soil water isotopes. Correlation analyses showed that δ2H and δ18O in soil water positively related to air temperature and soil temperature, while negatively related to soil moisture, depth, active layer thickness, vegetation coverage, elevation, and precipitation. Elevation and soil depth mainly controlled spatial distributions of ground ice isotopes. The results could provide a new insight into soil moisture movement and cycling during freeze-thaw process in the permafrost region of the QTP, which is helpful to understand subsurface water cycle mechanism in the context of permafrost degradation.

Exploring the contribution of precipitation to water within the active layer during the thawing period in the permafrost regions of central Qinghai-Tibet Plateau by stable isotopic tracing.

Stable isotopic tracing has proven to be a useful tool for assessing surface water source dynamics and hydrological connectivity in permafrost regions. This study has investigated the contribution of precipitation to water within the active layer at three long-term observation sites, including Fenghuoshan (FHS), Hoh Xil (KKXL) and Wudaoliang (WDL), by using isotopic tracer technique and two-component mixing model. The results showed that precipitation was the predominant source for water within the active layer, permafrost and ground ice near permafrost table at the three sites. Precipitation in August was the predominant source for water within the active layer at FHS, and precipitation in September was the main source at KKXL and WDL. The variation of isotopic values at different levels indicated that the water sources within the active layer could vary as the depth increases. The evaporation fractionation of water within the active layer at WDL was noticeable at depths of 0-50 cm, and the evaporation intensity decrease gradually from late June to late September. The relationship of isotopic tracing values between precipitation and water within the active layer at depths of 0-50 cm becomes more significant as the amount of the recently-occurring precipitation increases. Moreover, the relatively higher d-excess in precipitation indicates that local recycled moisture has greater contribution to precipitation. The differences of d-excess in most water within the active layer, permafrost and ground ice near permafrost table revealed that there were isotopic fractionation when precipitation supplying to above-mentioned three water bodies. The precipitation event amounted to 8.1 mm at KKXL can exert 49% ±â€¯7.1% and 30.8% ±â€¯3.6% contribution to water within the active layer at depths of 0-10 cm and 10-20 cm, respectively. While the long-period contribution cannot be identified because of the impact of evaporation. The results would provide new insights into the contribution of precipitation to water within the active layer on the QTP, which is also helpful to improve process-based hydrological models in the permafrost regions.

Hydrochemical characteristics of ground ice in permafrost regions of the Qinghai-Tibet Plateau.

Ground ice is a distinctive feature of permafrost terrain. The vertical distribution and factors controlling the hydrochemistry of ground ice are important for studying soil moisture and salt migration during the freeze-thaw process in soil. These factors are also important components of hydrological cycles in cold regions. The hydrochemical characteristics of ground ice on the Qinghai-Tibetan Plateau (QTP) are not well known. We examined the characteristics of ground ice hydrochemistry using data from 9 soil profiles in permafrost regions of the central QTP. The isotopes and anion concentrations of subsurface water on the QTP were higher than those in Arctic polygonal ground regions. The spatial distribution of anions was complex. Well-developed hydrochemical depth gradients occurred within the soil profile. Isotopes decreased and anions increased with depth, suggesting general vertical patterns of soil hydrochemistry across different permafrost regions. Cl- and SO42- concentrations in soil water increased with depth, while NO3- concentration did not change with depth. Freeze-out fractionation, self-purification, and desalination greatly impact soil hydrochemistry. The major factors controlling variation of soil water chemistry were soil moisture, air temperature, and active layer thickness. The results could provide a framework for understanding ground ice origins and the moisture and salt migration pathways in the context of permafrost changes. This information could be useful in developing process-based permafrost hydrologic models.

Eco-environmental degradation in the source region of the Yellow River, Northeast Qinghai-Xizang Plateau.

The Yellow River is the second longest river in China and the cradle of the Chinese civilization. The source region of the Yellow River is the most important water holding area for the Yellow River, about 49.2% of the whole runoff comes from this region. However, for the special location, it is a region with most fragile eco-environment in China as well. Eco-environmental degradation in the source region of the Yellow River has been a very serious ecological and socially economic problem. According to census data, historical documents and climatic information, during the last half century, especially the last 30 years, great changes have taken place in the eco-environment of this region. Such changes are mainly manifested in the temporal-spatial changes of water environment, deglaciation, permafrost reduction, vegetation degeneracy and desertification extent, which led to land capacity decreasing and river disconnecting. At present, desertification of the region is showing an accelerating tendency. This paper analyzes the present status of eco-environment degradation in this region supported by GIS and RS, as well as field investigation and indoor analysis, based on knowledge, multi-source data is gathered and the classification is worked out, deals with their natural and anthropogenic causes, and points out that in the last half century the desertification and environmental degradation of this region are mainly attributed to human activities under the background of regional climate changes. To halt further degradation of the environment of this region, great efforts should be made to use land resources rationally, develop advantages animal agriculture and protect the natural grassland.