Inhaled Macrophage Apoptotic Bodies-Engineered Microparticle Enabling Construction of Pro-Regenerative Microenvironment to Fight Hypoxic Lung Injury in Mice.

Oxygen therapy cannot rescue local lung hypoxia in patients with severe respiratory failure. Here, an inhalable platform is reported for overcoming the aberrant hypoxia-induced immune changes and alveolar damage using camouflaged poly(lactic-co-glycolic) acid (PLGA) microparticles with macrophage apoptotic body membrane (cMAB). cMABs are preloaded with mitochondria-targeting superoxide dismutase/catalase nanocomplexes (NCs) and modified with pathology-responsive macrophage growth factor colony-stimulating factor (CSF) chains, which form a core-shell platform called C-cMAB/NC with efficient deposition in deeper alveoli and high affinity to alveolar epithelial cells (AECs) after CSF chains are cleaved by matrix metalloproteinase 9. Therefore, NCs can be effectively transported into mitochondria to inhibit inflammasome-mediated AECs damage in mouse models of hypoxic acute lung injury. Additionally, the at-site CSF release is sufficient to rescue circulating monocytes and macrophages and alter their phenotypes, maximizing synergetic effects of NCs on creating a pro-regenerative microenvironment that enables resolution of lung injury and inflammation. This inhalable platform may have applications to numerous inflammatory lung diseases.

Xiasangju alleviate metabolic syndrome by enhancing noradrenaline biosynthesis and activating brown adipose tissue.

Metabolic syndrome (MetS) is a clinical condition associated with multiple metabolic risk factors leading to type 2 diabetes mellitus and other metabolic diseases. Recent evidence suggests that modulating adipose tissue to adaptive thermogenesis may offer therapeutic potential for MetS. Xiasangju (XSJ) is a marketed drug and dietary supplement used for the treatment of metabolic disease with anti-inflammatory activity. This study investigated the therapeutic effects of XSJ and the underlying mechanisms affecting the activation of brown adipose tissue (BAT) in MetS. The results revealed that XSJ ameliorated MetS by enhancing glucose and lipid metabolism, leading to reduced body weight and abdominal circumference, decreased adipose tissue and liver index, and improved blood glucose tolerance. XSJ administration stimulated catecholamine biosynthesis, increasing noradrenaline (NA) levels and activating NA-mediated proteins in BAT. Thus, BAT enhanced thermogenesis and oxidative phosphorylation (OXPHOS). Moreover, XSJ induced changes in gut microbiota composition, with an increase in Oscillibacter abundance and a decrease in Bilophila, Candidatus Stoquefichus, Holdemania, Parasutterella and Rothia. XSJ upregulated the proteins associated with intestinal tight junctions corresponding with lower serum lipopolysaccharide (LPS), tumor necrosis factor α (TNF-α) monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) levels to maintain NA signaling transport. In summary, XSJ may alleviate MetS by promoting thermogenesis in BAT to ultimately boost energy metabolism through increasing NA biosynthesis, strengthening intestinal barrier integrity and reducing low-grade inflammation. These findings suggest XSJ has potential as a natural therapeutic agent for the treatment of MetS.

Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke.

Background: Ischemic stroke (IS) causes tragic death and disability worldwide. However, effective therapeutic interventions are finite. After IS, blood-brain barrier (BBB) integrity is disrupted, resulting in deteriorating neurological function. As a novel therapeutic, extracellular vesicles (EVs) have shown ideal restorative effects on BBB integrity post-stroke; however, the definite mechanisms remain ambiguous. In the present study, we investigated the curative effects and the mechanisms of EVs derived from bone marrow mesenchymal stem cells and brain endothelial cells (BMSC-EVs and BEC-EVs) on BBB integrity after acute IS. Methods: EVs were isolated from BMSCs and BECs, and we investigated the therapeutic effect in vitro oxygen-glucose deprivation (OGD) insulted BECs model and in vivo rat middle cerebral artery occlusion (MCAo) model. The cell monolayer leakage, tight junction expression, and metalloproteinase (MMP) activity were evaluated, and rat brain infarct volume and neurological function were also analyzed. Results: The administration of two kinds of EVs not only enhanced ZO-1 and Occludin expressions but also reduced the permeability and the activity of MMP-2/9 in OGD-insulted BECs. The amelioration of the cerebral infarction, BBB leakage, neurological function deficits, and the increasing ZO-1 and Occludin levels, as well as MMP activity inhibition was observed in MCAo rats. Additionally, the increased levels of Caveolin-1, CD147, vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor A (VEGFA) in isolated brain microvessels were downregulated after EVs treatment. In vitro, the employment of Caveolin-1 and CD147 siRNA partly suppressed the expressions of VEGFR2, VEGFA and MMP-2/9 activity and reduced the leakage of OGD insulted BECs and enhanced ZO-1 and Occludin expressions. Conclusion: Our study firstly demonstrates that BEC and BMSC-EVs administrations maintain BBB integrity via the suppression of Caveolin-1/CD147/VEGFR2/MMP pathway after IS, and the efficacy of BMSC-EVs is superior to that of BEC-EVs.

Spatio-temporal characteristics and driving mechanism of land degradation sensitivity in Northwest China.

Northwest China has been experiencing severe land degradation for a long time due to various natural and social elements. Evaluating and analyzing the process of occurrence and driving mechanism of land degradation sensitivity in this area is crucial for enhancing the local ecological environment. In this study, 18 social and environmental elements were used to construct a land degradation sensitivity index (LDSI) evaluation system in the area from vegetation, climate, management, soil, and geomorphology five factors. The spatio-temporal characteristics of LDSI in Northwest China from 2000 to 2020 were evaluated on the basis of analyzing the developmental changes of each factor. Correlation analysis and multiscale geographical weighting regression (MGWR) were used to reveal the driving mechanism of land degradation sensitivity. The results indicated a high level of land degradation sensitivity in Northwest China, with >66 % of the area (190.96 × 104 km2) in the critical sensitive class from 2000 to 2020. But the land degradation sensitivity decreased in 18.52 % of the area (53.58 × 104 km2) from 2000 to 2020, the overall trend was weakening. The spatial distribution mainly showed stronger sensitivity in the northwest and weaker sensitivity in the southeast. By exploring the driving mechanism of land degradation sensitivity, it was found that vegetation and climate showed a strong correlation, with a correlation coefficient >0.8. Drought resistance played a strong role in the dynamic process of land degradation. The basic dynamic elements showed some spatial variability in land degradation in different regions. This study is of significance for land degradation prevention and sustainable development in Northwest China.

Total flavonoids of Astragalus protects glomerular filtration barrier in diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is a prevalent complication of diabetes and the leading cause of end-stage renal disease. Recent evidence suggests that total flavonoids of Astragalus (TFA) has promising effects on diabetes; however, its influence on DKD and the underlying mechanism remains unclear. METHODS: In this study, we induced the DKD model using streptozotocin (STZ) in male C57BL/6J mice and utilized glomerular endothelial cell (GEC) lines for in vitro investigations. We constructed a network pharmacology analysis to understand the mechanism of TFA in DKD. The mechanism of TFA action on DKD was investigated through Western blot analysis and multi-immunological methods. RESULTS: Our findings revealed that TFA significantly reduced levels of urinary albumin (ALB). Network pharmacology and intracellular pathway experiments indicated the crucial involvement of the PI3K/AKT signaling pathway in mediating these effects. In vitro experiments showed that TFA can preserve the integrity of the glomerular filtration barrier by inhibiting the expression of inflammatory factors TNF-alpha and IL-8, reducing oxidative stress. CONCLUSION: Our findings demonstrated that TFA can ameliorates the progression of DKD by ameliorating renal fibrosis and preserving the integrity of the kidney filtration barrier. These results provide pharmacological evidence supporting the use of TFA in the treatment of kidney diseases.

The effects of Chinese proprietary medicine and vaccination on patients with COVID-19: a retrospective study in Macao.

BACKGROUND: COVID-19 is continuing to ravage globally and has resulted in a huge health and financial burden. Chinese proprietary medicines, such as Lianhua Qingwen (LHQW) and Huoxiang Zhengqi (HXZQ) capsules, have been recommended for non-high-risk patients with COVID-19 in China. Based on this, we described the baseline information, using status of LHQW and HXZQ capsules and inoculation history of quarantined patients in the second half of 2022 in Macao. Additionally, we analyzed the underlying association among medicines administration, vaccination and COVID-19 indices, in order to explore novel clues for the regular control and prevention of local epidemic situation in the future. METHODS: A total of 976 patients in Macao quarantine hotels from June to August 2022 were included in the present study, of which, 857 subjects were followed-up for prognosis evaluation. During quarantine, the baseline demographic information, including sex, age, BMI, occupation and personal habits were collected. Additionally, the inoculation history, medicine employment status and cycle threshold (Ct) values were also reported. We interviewed the patients for collection of their symptoms at the beginning and end of quarantine, as well as prognostic ones. Basic statistical description of baseline information, vaccination history and medication were displayed. Chi-squared test or with continuous correction test was employed for comparison of dichotomous data between two or multiple groups. Binary logistic regression was applied to reveal the correlation between potential risk factors and Ct values or prognosis symptoms. We also used Cox regression model to identify the effect of different types of vaccine products on Ct value altering rate. RESULTS: Patients who were female (52.0%), engaged in service industry (31.8%), from Macao native (65.8%), never took physical exercises (33.6%) and preferred irritated diet (59.5%) enjoyed more dominant proportions. Over 80% of participants were inoculated and 74.6% of them chose inactivated COVID-19 vaccine produced by China National Biotech Group (CNBG). Participants used LHQW capsules accounted for 92.1% and the duration of medicating lasted for one to two weeks. All of the reported symptoms were significantly ameliorated after quarantine and the duration of quarantine was concentrated on 21 days. People with different age, sex, occupation and region had different choices of HXZQ administration and vaccination. Additionally, middle dose (4-5 boxes) of LHQW capsules exhibited evidently negative association with positive Ct values (adjusted, - 0.037 ± 0.19, p = 0.04). Two doses of CNBG and one dose of mRNA vaccine had obvious protective effect on reducing Ct positive rate (p = 0.041). Meanwhile, symptoms after quarantine were significantly positive correlated with those in prognosis (adjusted, 1.38 ± 0.18, p < 0.0001). CONCLUSION: Our study found that the administration of LHQW capsules was beneficial for Ct value turning negative, meanwhile, certain mixed inoculation may be the promoting factor to reduce the positive rate of Ct value. These findings provide data basis for the Chinese proprietary medicine treatment and mixed vaccination applying for prevention and control of local COVID-19 epidemic in the future.

The fusion of multi-omics profile and multimodal EEG data contributes to the personalized diagnostic strategy for neurocognitive disorders.

BACKGROUND: The increasing prevalence of neurocognitive disorders (NCDs) in the aging population worldwide has become a significant concern due to subjectivity of evaluations and the lack of precise diagnostic methods and specific indicators. Developing personalized diagnostic strategies for NCDs has therefore become a priority. RESULTS: Multimodal electroencephalography (EEG) data of a matched cohort of normal aging (NA) and NCDs seniors were recorded, and their faecal samples and urine exosomes were collected to identify multi-omics signatures and metabolic pathways in NCDs by integrating metagenomics, proteomics, and metabolomics analysis. Additionally, experimental verification of multi-omics signatures was carried out in aged mice using faecal microbiota transplantation (FMT). We found that NCDs seniors had low EEG power spectral density and identified specific microbiota, including Ruminococcus gnavus, Enterocloster bolteae, Lachnoclostridium sp. YL 32, and metabolites, including L-tryptophan, L-glutamic acid, gamma-aminobutyric acid (GABA), and fatty acid esters of hydroxy fatty acids (FAHFAs), as well as disturbed biosynthesis of aromatic amino acids and TCA cycle dysfunction, validated in aged mice. Finally, we employed a support vector machine (SVM) algorithm to construct a machine learning model to classify NA and NCDs groups based on the fusion of EEG data and multi-omics profiles and the model demonstrated 92.69% accuracy in classifying NA and NCDs groups. CONCLUSIONS: Our study highlights the potential of multi-omics profiling and EEG data fusion in personalized diagnosis of NCDs, with the potential to improve diagnostic precision and provide insights into the underlying mechanisms of NCDs. Video Abstract.

Animal Models of Type 2 Diabetes Complications: A Review.

Diabetes mellitus is a multifactorial metabolic disease, of which type 2 diabetes (T2D) is one of the most common. The complications of diabetes are far more harmful than diabetes itself. Type 2 diabetes complications include diabetic nephropathy (DN), diabetic heart disease, diabetic foot ulcers (DFU), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (DR) et al. Many animal models have been developed to study the pathogenesis of T2D and discover an effective strategy to treat its consequences. In this sense, it is crucial to choose the right animal model for the corresponding diabetic complication. This paper summarizes and classifies the animal modeling approaches to T2D complications and provides a comprehensive review of their advantages and disadvantages. It is hopeful that this paper will provide theoretical support for animal trials of diabetic complications.

Probabilistic Risk Assessment of Heavy Metals in Mining Soils Based on Fractions: A Case Study in Southern Shaanxi, China.

With rapid economic development, soil heavy metal (HM) pollution has emerged as a global environmental concern. Because the toxicity of HMs differs dramatically among various fractions, risk assessments based on these fractions are of great significance for environmental management. This study employed a modified Hakanson index approach to evaluate the possible ecological impacts of soil HMs in a gold mine tailings pond in Shaanxi Province, China. A modified Hakanson-Monte Carlo model was built to perform a probabilistic risk assessment. The results showed that: (1) the exceedance rates of chromium (Cr) and zinc (Zn) were 68.75% and 93.75%, respectively. Moreover, the overall concentrations of nickel (Ni), copper (Cu), arsenic (As), and lead (Pb) were higher than the background soil environmental values in China. (2) HMs with the lowest oxidizable fraction were mostly present in the residual fraction. The oxidizable portions of Cr, Cu, and Pb and the reducible and residual fractions of As were notably distinct. (3) The risk degrees of Cr, Ni, Cu, and Zn were low; those of As and Pb were very high and moderate; and the comprehensive ecological hazard index was very high. This study offers a solid scientific foundation for ecological risk notification and environmental management.

Characteristics of Soil Arsenic Contamination and the Potential of Pioneer Plants for Arsenic Remediation in Gold Mine Tailings.

Arsenic (As) contamination of gold mine tailings poses major threats to the natural environment and human health, necessitating adequate management measures. To investigate the soil As contamination level and the potential of pioneer plants for As remediation, the soil and plants of an abandoned gold mine tailings in the Qinling Mountains were analyzed. The level of As contamination was assessed using the single-factor pollution index and potential ecological risk index, and its bioeffectiveness was analyzed. The enrichment capability of plants was investigated using the bioaccumulation factor and translocation factor. Redundancy analysis and partial least squares regression were employed to investigate factors affecting the distribution of As in soil and plants. The results show that As in soil mainly existed in the difficult-available state, with serious contamination and extremely high ecological risk. Lythrum salicaria L. and Equisetum ramosissimum Desf. are the preferred plants for remediation of As contamination through screening pioneer plants. Soil total nitrogen (STN) and available phosphorus (SAP) are the main factors influencing the characteristics of As distribution in the soil. Soil available potassium (SAK), water content (SWC), and SAP promote the accumulation of As by plants. This study provides plant materials and new ideas for mine ecological remediation.

Effects of cadmium and pyrene on earthworm-associated bacterial communities: Unveiling new perspectives for soil pollution management.

Earthworms are considered to be excellent bioindicators of soil pollution. In recent years, there has been increasing interest in examining the effects of soil pollution on earthworm-associated microbiomes, with a particular focus on the gut microbiomes. However, relatively little effort has been invested in comprehensively investigating other microbiomes associated with earthworms and their responses to soil pollution. To fill this gap, we systematically studied the effects of Cd, pyrene, and combined pollution on the bacterial community in different vermicompartments, i.e., burrow wall, gut, and cast, in both epigeic Eisenia fetida and anecic Metaphire guillelmi, using a 2D-terraria incubator and high-throughput sequencing techniques. The results showed that bacterial alpha diversity followed the order of burrow wall > cast > gut, and this did not vary with soil pollution or earthworm ecotypes. Moreover, the dominant phyla in the vermicompartments were similar across different pollution treatments. Principal coordinate analysis (PCoA) revealed that the bacterial communities in different vermicompartments and ecotypes of earthworm were separated from each other, whereas they were grouped together in polluted treatments and unpolluted conditions. These results imply that even in polluted soil, vermicompartment and earthworm ecotypes remain the most significant factors affecting earthworm-associated microbiomes. However, the impacts of soil pollution on the bacterial composition in each vermicompartment were still evident. A comprehensive analysis revealed that the gut bacterial communities are more sensitive to soil contamination than casts and burrow wall in different ecotypes. Additionally, linear discriminant analysis of effect size (LefSe) identified several bacteria in Gemmatimonadota, the Firmicutes phylum in the burrow walls, and Patescibacteria (phyla) in the gut as potential biomarkers for pyrene contamination in soil. This research provides a comprehensive understanding of the effects of soil pollution on earthworm-associated microbiomes, thereby enhancing our understanding of earthworm ecotoxicology and soil pollution management.

A mini review on recent progress of steam reforming of ethanol.

H2 is one of the promising renewable energy sources, but its production and transportation remain challenging. Distributed H2 production using liquid H2 carriers is one of the ideal ways of H2 utilization. Among common H2 carriers, ethanol is promising as it has high H2 content and can be derived from renewable bio-energy sources such as sucrose, starch compounds, and cellulosic biomass. To generate H2 from ethanol, steam reforming of ethanol (SRE) is the most common way, while appropriate catalysts, usually supported metal catalysts, are indispensable. However, the SRE process is quite complicated and always accompanied by various undesirable by-products, causing low H2 yield. Moreover, the catalysts for SRE are easy to deactivate due to sintering and carbon deposition under high reaction temperatures. In recent years, lots of efforts have been made to reveal SRE mechanisms and synthesize catalysts with high H2 yield and excellent stability. Both active metals and supports play an important role in the reaction. This mini-review summarizes the recent progress of SRE catalysts from the view of the impacts of active metals and supports and draws an outlook for future research directions.

Adaptive response of flavonoids in Robinia pseudoacacia L. affected by the contamination of cadmium and elevated CO2 to arbuscular mycorrhizal symbiosis.

As a key component in non-enzyme resistance system, flavonoids play a crucial role in the plant growth and defenses, which are significantly affected by biotic and abiotic factors such as fungi, bacteria, viruses, heavy metals, and atmospheric CO2. Arbuscular mycorrhizal fungi (AMF) play an important role in enhancing plant tolerance to adverse environments, which can significantly affect the synthesis of flavonoids by forming mycorrhizal symbionts with plant roots. However, few studies explored the combined effects of AMF, elevated CO2, and heavy metals on flavonoids in plants. Here, we investigated the adaptive response of flavonoids accumulation in Robinia pseudoacacia L. seedlings affected by the contamination of cadmium (Cd) and elevated CO2 to arbuscular mycorrhizal symbiosis. The results showed that G. mosseae decreased (p < 0.05) Cd content in leaves by 62.2% under elevated CO2. Moreover, G. mosseae colonization led to significant decreases in robinin, quercetin, kaempferol and acacetin by 17.4%, 11.1%, 15.5% and 23.1% under elevated CO2 + Cd, respectively. Additionally, G. mosseae down-regulated (p < 0.05) expression levels of phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS) genes under elevated CO2 + Cd, and CHS and uridine diphosphate flavonoid glucosyltransferase (UFGT) activities decreased (p < 0.05). Quercetin, kaempferol and acacetin showed positive (p < 0.05) correlation with PAL and CHS genes expression and PAL, CHS, and UFGT activities. Cadmium, C/N ratio, carotenoids, leaf biomass, total chlorophyll, P, and starch in leaves and G. mosseae colonization rate in roots influenced (p < 0.05) flavonoids content. Overall, G. mosseae reduced flavonoids synthesis by down-regulating gene expression levels and activities of key enzymes under elevated CO2 + Cd. The results improved our understanding of the regulation of AMF on non-enzymatic resistance of plants grown in heavy metal-contaminated soils under increasing atmospheric CO2 scenarios.

20(S)- Protopanaxadiol saponins isolated from Panax notoginseng target the binding of HMGB1 to TLR4 against inflammation in experimental ulcerative colitis.

Ulcerative colitis (UC) has emerged as a global healthcare issue due to high prevalence and unsatisfying therapeutic measures. 20(S)- Protopanaxadiol saponins (PDS) from Panax notoginseng with anti-inflammatory properties is a potential anti-colitis agent. Herein, we explored the effects and mechanisms of PDS administration on experimental murine UC. Dextran sulfate sodium-induced murine UC model was employed to investigate anti-colitis effects of PDS, and associated mechanisms were further verified in HMGB1-exposed THP-1 macrophages. Results indicated that PDS administration exerted ameliorative effects against experimental UC. Moreover, PDS administration remarkably downregulated mRNA expressions and productions of related pro-inflammatory mediators, and reversed elevated expressions of proteins related to NLRP3 inflammasome after colitis induction. Furthermore, administration with PDS also suppressed the expression and translocation of HMGB1, interrupting the downstream TLR4/NF-κB pathway. In vitro, ginsenoside CK and 20(S)-protopanaxadiol, the metabolites of PDS, exhibited greater potential in anti-inflammation, and intervened with the TLR4-binding domain of HMGB1 predictably. Expectedly, ginsenoside CK and 20(S)-protopanaxadiol administrations inhibited the activation of TLR4/NF-κB/NLRP3 inflammasome pathway in HMGB1-exposed THP-1 macrophages. Summarily, PDS administration attenuated inflammatory injury in experimental colitis by blocking the binding of HMGB1 to TLR4, majorly attributed to the antagonistic efficacies of ginsenoside CK and 20(S)-protopanaxadiol.

NPLC0393 from Gynostemma pentaphyllum ameliorates Alzheimer's disease-like pathology in mice by targeting protein phosphatase magnesium-dependent 1A phosphatase.

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment and memory loss. Gynostemma pentaphyllum ameliorates cognitive impairment, but the mechanisms remain obscure. Here, we determine the effect of triterpene saponin NPLC0393 from G. pentaphyllum on AD-like pathology in 3×Tg-AD mice and elucidate the underlying mechanisms. NPLC0393 was administered daily in vivo by intraperitoneal injection for 3 months and its amelioration on the cognitive impairment in 3×Tg-AD mice was assessed by new object recognition (NOR), Y-maze, Morris water maze (MWM), and elevated plus-maze (EPM) tests. The mechanisms were investigated by RT-PCR, western blot, and immunohistochemistry techniques, while verified by the 3×Tg-AD mice with protein phosphatase magnesium-dependent 1A (PPM1A) knockdown (KD) through brain-specific injection of adeno-associated virus (AAV)-ePHP-KD-PPM1A. NPLC0393 ameliorated AD-like pathology targeting PPM1A. It repressed microglial NLRP3 inflammasome activation by reducing NLRP3 transcription during priming and promoting PPM1A binding to NLRP3 to disrupt NLRP3 assembly with apoptosis-associated speck-like protein containing a CARD and pro-caspase-1. Moreover, NPLC0393 suppressed tauopathy by inhibiting tau hyperphosphorylation through PPM1A/NLRP3/tau axis and promoting microglial phagocytosis of tau oligomers through PPM1A/nuclear factor-κB/CX3CR1 pathway. PPM1A mediates microglia/neurons crosstalk in AD pathology, whose activation by NPLC0393 represents a promising therapeutic strategy for AD.

Platelet-mimicking supramolecular nanomedicine with precisely integrated prodrugs for cascade amplification of synergistic chemotherapy.

Camptothecin (CPT) and cisplatin (Pt) have shown synergistic effects on a variety of cancers during preclinical and clinical studies. However, the ratio of the two drugs often could not be precisely regulated in different delivery systems, which hinders the desired synergistic effect. In addition, the low delivery efficiency of the two drugs to the tumor further impedes the ideal therapeutic outcomes. Herein, we report that a platelet-mimicking supramolecular nanomedicine (SN) could precisely control of the ratio of CPT and Pt with a high tumor accumulation rate for cascade amplification of synergistic chemotherapy. The SN was fabricated via the host-guest interaction between cucurbit[7]uril conjugated hyaluronic acid (HA-CB[7]) and adamantane (ADA) respectively functionalized CPT- and Pt-based prodrugs. The ratio of CPT and Pt in the SN could be facilely regulated by simply controlling the loading ratio, based on the strong binding affinity between CB[7] and ADA, and SN60 with 60% CPT and 40% Pt showed the highest synergistic effects on 4T1 cells. To improve the tumor accumulation efficiency of SN, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a tumor vasculature-disruptive agent) was loaded into the optimized SN and then coated with platelet membrane to yield platelet-mimicking supramolecular nanomedicine (D@SN-P). D@SN-P could first passively accumulate in tumors owing to the enhanced permeability and retention (EPR) effect after intravenous administration. The initially release of DMXAA from D@SN-P could induce tumor vascular disruption, and the resultant epithelial collagen exposure around the disrupted tumor vasculature provided a target for further recruitment of platelet-mimicking SN, leading to cascade amplification of tumor accumulation with synergistic chemotherapy. Hence, this platelet-mimicking supramolecular nanomedicine presents a universal supramolecular strategy to finely regulate the ratio of loaded pro-drugs, and improve the accumulation efficiency to amplify chemotherapy via platelet-mimics.

Variations and driving mechanisms of desertification in the southeast section of the China-Mongolia-Russia Economic Zone.

Desertification seriously restricts sustainable development in the arid-semiarid areas of the eastern section of the China-Mongolia-Russia Economic Zone, especially in China and Mongolia. In this study, the potential range of desertification was bounded. Spatio-temporal dynamics from 2000 to 2020 were analyzed using best-performing indices (fvc, albedo and LST). Further analysis focused on the driving factors resulting in desertification. The research showed that the potential range of desertification accounted for 50.99 % of the entire region, mainly distributed in central and western parts of Inner Mongolia, and central and southern parts of Mongolia. From 2000 to 2020, desertification in the entire study area improved, with a 2.23 % decrease in the area of severe and extremely severe desertification. Among the studied countries, the grades of desertification in China decreased over the years of study; the area of desertification in Mongolia expanded. The study also indicated that the restoration regions were affected mainly by climatic factor sand human activities, and the degradation area was driven primarily by human activities. Therefore, it is essential to formulate a reasonable land policy for desertification control.

Individual-specific functional connectivity improves prediction of Alzheimer's disease's symptoms in elderly people regardless of APOE ε4 genotype.

To date, reliable biomarkers remain unclear that could link functional connectivity to patients' symptoms for detecting and predicting the process from normal aging to Alzheimer's disease (AD) in elderly people with specific genotypes. To address this, individual-specific functional connectivity is constructed for elderly participants with/without APOE ε4 allele. Then, we utilize recursive feature selection-based machine learning to reveal individual brain-behavior relationships and to predict the symptom transition in different genotypes. Our findings reveal that compared with conventional atlas-based functional connectivity, individual-specific functional connectivity exhibits higher classification and prediction performance from normal aging to AD in both APOE ε4 groups, while no significant performance is detected when the data of two genotyping groups are combined. Furthermore, individual-specific between-network connectivity constitutes a major contributor to assessing cognitive symptoms. This study highlights the essential role of individual variation in cortical functional anatomy and the integration of brain and behavior in predicting individualized symptoms.

Spatial and temporal dynamics of large natural lake areas and shoreline morphology in the Yellow River Basin.

Given their important roles in the regulation and storage functions for river flow and in the regional ecological environment and ecosystem services, natural lakes are essential for the ecological protection and high-quality development of the Yellow River Basin. We used the Landsat TM/OLI remote sensing data to analyze the area changes of Dongping Lake, Gyaring Lake, and Ngoring Lake, three representative large natural lakes in the Yellow River Basin from 1990 to 2020. We used the landscape ecology approach to study the morphological characteristics of lake shoreline and shoreland changes and the relationship between the landscape indices. The results showed that the main areas of Gyaring Lake and Ngoring Lake were mainly in the trend of expansion, while the main area of Dongping Lake significantly reduced during 1990-2000 and 2010-2020. The changes in the area of lake all occurred mainly near the lake inlet of the river. The shoreline morphology of Dongping Lake was more complex, with the fragmentation and aggregation of shoreland landscape significantly changed. The circularity ratio of Gyaring Lake gradually decreased with the expansion of the lake area, and the number of patches in its shoreland changed significantly. The fractal dimension index-mean of the shoreland of Ngoring Lake was relatively high, the complexity of its shoreline landscape was stronger, and the number of patches had increased significantly from 2000 to 2010. Meanwhile, there was a significant correlation between certain lake shoreline (shoreland) landscape indices. The changes in circularity ratio and shoreline development coefficient caused changes in the patch density of shoreland.

Comparative study of extracellular vesicles derived from mesenchymal stem cells and brain endothelial cells attenuating blood-brain barrier permeability via regulating Caveolin-1-dependent ZO-1 and Claudin-5 endocytosis in acute ischemic stroke.

BACKGROUND: Blood-brain barrier (BBB) disruption is a major adverse event after ischemic stroke (IS). Caveolin-1 (Cav-1), a scaffolding protein, played multiple roles in BBB permeability after IS, while the pros and cons of Cav-1 on BBB permeability remain controversial. Numerous studies revealed that extracellular vesicles (EVs), especially stem cells derived EVs, exerted therapeutic efficacy on IS; however, the mechanisms of BBB permeability needed to be clearly illustrated. Herein, we compared the protective efficacy on BBB integrity between bone marrow mesenchymal stem cells derived extracellular vesicles (BMSC-EVs) and EVs from brain endothelial cells (BEC-EVs) after acute IS and investigated whether the mechanism was associated with EVs antagonizing Cav-1-dependent tight junction proteins endocytosis. METHODS: BMSC-EVs and BEC-EVs were isolated and characterized by nanoparticle tracking analysis, western blotting, and transmission electron microscope. Oxygen and glucose deprivation (OGD) treated b. End3 cells were utilized to evaluate brain endothelial cell leakage. CCK-8 and TRITC-dextran leakage assays were used to measure cell viability and transwell monolayer permeability. Permanent middle cerebral artery occlusion (pMCAo) model was established, and EVs were intravenously administered in rats. Animal neurological function tests were applied, and microvessels were isolated from the ischemic cortex. BBB leakage and tight junction proteins were analyzed by Evans Blue (EB) staining and western blotting, respectively. Co-IP assay and Cav-1 siRNA/pcDNA 3.1 vector transfection were employed to verify the endocytosis efficacy of Cav-1 on tight junction proteins. RESULTS: Both kinds of EVs exerted similar efficacies in reducing the cerebral infarction volume and BBB leakage and enhancing the expressions of ZO-1 and Claudin-5 after 24 h pMCAo in rats. At the same time, BMSC-EVs were outstanding in ameliorating neurological function. Simultaneously, both EVs treatments suppressed the highly expressed Cav-1 in OGD-exposed b. End3 cells and ischemic cerebral microvessels, and this efficacy was more prominent after BMSC-EVs administration. Cav-1 knockdown reduced OGD-treated b. End3 cells monolayer permeability and recovered ZO-1 and Claudin-5 expressions, whereas Cav-1 overexpression aggravated permeability and enhanced the colocalization of Cav-1 with ZO-1 and Claudin-5. Furthermore, Cav-1 overexpression partly reversed the lower cell leakage by BMSC-EVs and BEC-EVs administrations in OGD-treated b. End3 cells. CONCLUSIONS: Our results demonstrated that Cav-1 aggravated BBB permeability in acute ischemic stroke, and BMSC-EVs exerted similar antagonistic efficacy to BEC-EVs on Cav-1-dependent ZO-1 and Claudin-5 endocytosis. BMSC-EVs treatment was superior in Cav-1 suppression and neurological function amelioration.