Synthesis, preclinical, and initial clinical evaluation of integrin αVß3 and gastrin-releasing peptide receptor (GRPR) dual-targeting radiotracer [68Ga]Ga-RGD-RM26-03.

Integrin receptor αvß3 and gastrin-releasing peptide receptor (GRPR) expression of tumors could be detected using PET imaging with radiolabeled Arg-Gly-Asp (RGD) and the antagonistic bombesin analog RM26, respectively. The purpose of this study was to investigate the dual receptor-targeting property of the heterodimer RGD-RM26-03 (denoted as LNC1015), demonstrate the tumor diagnostic value of [68Ga]Ga-LNC1015 in preclinical experiments, and evaluate its preliminary clinical feasibility. METHODS: LNC1015 was designed and synthesized by linking cyclic RGD and the RM26 peptide. Preclinical pharmacokinetics were detected in a PC3 xenograft model using microPET and biodistribution studies. The clinical feasibility of [68Ga]Ga-LNC1015 PET/CT was performed in patients with breast cancer, and the results were compared with those of 18F-fluorodeoxyglucose (FDG). RESULTS: [68Ga]Ga-LNC1015 had good stability in saline for at least 2 h, and favorable binding affinity and specificity were demonstrated in vitro and in vivo. The tumor uptake and retention of [68Ga]Ga-LNC1015 during PET imaging were improved compared with its monomeric counterparts [68Ga]Ga-RGD and [68Ga]Ga-RM26 at all the time points examined. In our initial clinical studies, the tumor uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in [68Ga]Ga-LNC1015 PET/CT were significantly higher than those in [18F]FDG PET/CT, resulting in high lesion detection rate and tumor delineation. CONCLUSION: The dual targeting radiotracer [68Ga]Ga-LNC1015 showed significantly improved tumor uptake and retention, as well as lower liver uptake than [68Ga]Ga-RGD and [68Ga]Ga-RM26 monomer. The first-in-human study showed high TBRs in patients, suggesting favorable pharmacokinetics and high clinical feasibility for PET/CT imaging of cancer.

Design and synthesis of matrine derivatives for anti myocardial ischemia-reperfusion injury by promoting angiogenesis.

Myocardial ischemia/reperfusion (MI/R) is a common cardiovascular disease that seriously affects the quality of life and prognosis of patients. In recent years, matrine has attracted widespread attention in the treatment of cardiovascular diseases. This study designed, synthesized, and characterized 20 new matrine derivatives and studied their protective effects on ischemia-reperfusion injury through in vivo and in vitro experiments. Based on cellular assays, most newly synthesized derivatives have a certain protective effect on Hypoxia/Reoxygenation (H/R) induced H9C2 cell damage, with compound 22 having the best activity and effectively reducing cell apoptosis and necrosis. In vitro experimental data shows that compound 22 can significantly reduce the infarct size of rat myocardium and improve cardiac function after MI/R injury. In summary, compound 22 is a new potential cardioprotective agent that can promote angiogenesis and enhance antioxidant activity by activating ADCY5, CREB3l4, and VEGFA, thereby protecting myocardial cell apoptosis and necrosis induced by MI/R.

Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aß burden and restores memory functions in 5xFAD mice.

Glial cell-mediated neuroinflammation and neuronal attrition are highly correlated with cognitive impairment in Alzheimer's disease. YKL-40 is a secreted astrocytic glycoprotein that serves as a diagnostic biomarker of Alzheimer's disease. High levels of YKL-40 are associated with either advanced Alzheimer's disease or the normal aging process. However, the functional role of YKL-40 in Alzheimer's disease development has not been firmly established. In a 5xFAD mouse model of Alzheimer's disease, we observed increased YKL-40 expression in the cerebrospinal fluid of 7-month-old mice and was correlated with activated astrocytes. In primary astrocytes, Aß1-42 upregulated YKL-40 in a dose-dependent manner and was correlated with PI3-K signaling pathway activation. Furthermore, primary neurons treated with YKL-40 and/or Aß1-42 resulted in significant synaptic degeneration, reduced dendritic complexity, and impaired electrical parameters. More importantly, astrocyte-specific knockout of YKL-40 over a period of 7 days in symptomatic 5xFAD mice could effectively reduce amyloid plaque deposition in multiple brain regions. This was also associated with attenuated glial activation, reduced neuronal attrition, and restored memory function. These biological phenotypes could be explained by enhanced uptake of Aß1-42 peptides, increased rate of Aß1-42 degradation and acidification of lysosomal compartment in YKL-40 knockout astrocytes. Our results provide new insights into the role of YKL-40 in Alzheimer's disease pathogenesis and demonstrate the potential of targeting this soluble biomarker to alleviate cognitive defects in symptomatic Alzheimer's disease patients.

Effect of different adhesive systems on dental defects and sensitivity to teeth in composite resin restoration: a systematic review and meta-analysis.

OBJECTIVES: This meta-analysis aimed to elucidate the effects of various acid etching patterns on the sensitivity of teeth and their clinical effectiveness following composite resin repair. MATERIALS AND METHODS: PubMed, Cochrane Library, Web of Science, and Embase databases were searched for relevant studies on the postoperative sensitivity (POS) of composite resin restorations after using different bonding systems. The retrieval was from the inception of the databases to August 13, 2022, with no filter of written language. Literature screening was conducted by two independent researchers. The Cochrane risk-of-bias assessment tool was adopted for quality evaluation, and Stata 15.0 for analysis. RESULTS: Twenty-five randomized controlled trials were included in the present study. Following resin composite restoration, 1309 restorations were bonded by self-etching (SE) adhesives, whereas 1271 restorations were bonded by total-etching (TE) adhesives. The meta-analyses showed that there is no evidence to prove the SE and TE will affect POS at present when measured using the modified United States Public Health Service (USPHS) criteria [RR = 1.00 (95% CI: 0.96, 1.04)], the World Dental Federation (FDI) [RR = 1.06 (95% CI: 0.98, 1.15)], or the visual analog scale (VAS) [SMD = 0.02 (95% CI: -0.15, 0.20)] scales. At a certain follow-up time, TE adhesives provide better outcomes in terms of color match, marginal staining, and marginal adaptation. In other words, TE adhesives have better esthetic results. CONCLUSIONS: The type of bonding technique (ER and SE) does not affect the risk and degree of POS in class I/II and class V restorations. Further research is required to verify whether these findings apply to different forms of composite resin restorations. CLINICAL RELEVANCE: Besides the fact that TE barely increase postoperative sensitivity, it also yields superior cosmetic results.

C-Terminal Domains of Spider Silk Proteins Having Divergent Structures but Conserved Functional Roles.

Spider silk is self-assembled from silk proteins or spidroins. C-terminal domains (CTDs) of various types of spidroins are relatively conserved in amino acid sequences and are suggested to adopt similar structures and perform similar functional roles in spidroin storage and silk formation. Here, we solved the structure of the CTD from a capture-spiral silk protein (CTDFl) and characterized its stability and fibril formation in the presence and absence of a reducing agent at different pH values. CTDFl adopts a dimeric structure with 8 helices, but the CTDs of other types of spidroins exist in a domain-swapped dimeric structure with 10 helices. Despite the structural differences, CTDFl is pH-responsive in stability and fibril formation, similar to the CTDs from minor and major ampullate spidroins. Thus, the functional role of CTDs in silk fiber formation seems conserved. Comparing wild-type CTDFl and its mutants, we found that the pH-responsive behavior results from the protonation of H76, which is conserved from different spider species. In addition, the fibril formation rate of CTDFl correlates with its instability, suggesting that structural changes are involved in fibril formation.

Evaluation of iodine nutritional status during pregnancy by estimated 24-h urinary iodine excretion: population variation range and individual accuracy.

OBJECTIVE: To explore the accuracy of estimated 24-h urinary iodine excretion (24-h UIEest) in assessing iodine nutritional status. DESIGN: Fasting venous blood, 24-h and spot urine samples were collected during the day. The urinary iodine concentration (UIC) and urinary creatinine concentration (UCrC) were measured, and the urinary iodine-to-creatinine ratio (UI/Cr), 24-h UIEest, and 24-h urinary iodine excretion (24-h UIE) were calculated. At the population level, correlation and consistency between UIC, UI/Cr, 24-h UIEest and 24-h UIE were assessed using correlation analysis and Bland-Altman plots. At the individual level, receiver operating characteristic (ROC) curves were used to analyse the accuracy of the above indicators for evaluating insufficient and excessive iodine intake. The reference interval of 24-h UIEest was established based on percentile values. SETTING: Indicator can accurately evaluate individual iodine nutrition during pregnancy remains controversial. PARTICIPANTS: Pregnant women (n 788). RESULTS: Using 24-h UIE as standard, the correlation coefficients of 24-h UIEest from different periods of the day ranged from 0·409 to 0·531, and the relative average differences ranged from 4·4 % to 10·9 %. For diagnosis of insufficient iodine intake, the area under the ROC curve of 24-h UIEest was 0·754, sensitivity and specificity were 79·6 % and 65·4 %, respectively. For diagnosis of excessive iodine intake, the area of 24-h UIEest was 0·771, sensitivity and specificity were 66·7 % and 82·0 %, respectively. The reference interval of 24-h UIEest was 58·43-597·65 µg. CONCLUSIONS: Twenty-four-hour UIEest can better indicate iodine nutritional status at a relatively large sample size in a given population of pregnant women. It can be used for early screening at the individual level to obtain more lead time for pregnant women.

Soft Particles Enable Fast and Selective Water Transport through Graphene Oxide Membranes.

The intercalation strategy is successfully applied in tuning the interlayer distance of 2D membranes for efficient desalination and ion sieving. However, it is difficult to pursue a intercalant that is few nanometers in size and suitable for further chemical modification . Here, for the first time, we report the intercalation of soft particles-polyacrylonitrile gel particles (PAN GPs) inside the graphene oxide (GO) membranes, which allows for a tunable interlayer distance via the deformation of soft particles. Furthermore, the base-induced hydrophobic/hydrophilic structure of PAN GPs facilitates the water diffusion through the GO membrane. A fast and selective water permeation was observed through separation Cu-EDTA2-from water, with the permeance of 4-13 times higher than the reported 2D membranes. Intercalation of soft particles represents a promising strategy to fabricate high-performance 2D membranes.

Enhancing the Fenton-like Catalytic Activity of nFe2O3 by MIL-53(Cu) Support: A Mechanistic Investigation.

A novel Fenton-like catalyst was synthesized by immobilizing nano-Fe2O3 (nFe2O3) on MIL-53(Cu). The pseudo-first-order rate constant of bisphenol A degradation in the nFe2O3/MIL-53(Cu)/H2O2 system reached 0.0123 min-1, while the values in MIL-53(Cu)/H2O2 and nFe2O3/H2O2 systems were only 0.0026 and 0.0040 min-1, respectively. The characterization of nFe2O3/MIL-53(Cu) reveals that the supreme catalytic activity of this material could be ascribed to iron-copper synergy, smaller size, and better dispersion of nFe2O3 particles. Moreover, a method of trapping Cu(I) by neocuproine was developed, which could shield Cu(I) from interacting with iron and H2O2, and thus allow quantitative differentiation of the contribution to the enhanced catalytic activity by each of the factors. Using this method, 19% of the enhancement was determined to be contributed by synergistic effect, while 24% of the enhancement was due to the smaller size and better dispersion of the nFe2O3 particles on MIL-53(Cu) support. In addition, the performance of nFe2O3/MIL-53(Cu) only dropped 10.7% after five treatment cycles in real wastewater, showing good potential in practical application. We believe this study sheds light on the tailored design of Fenton-like catalysts and elucidates the catalytic mechanisms of supported bimetallic catalysts.

WBP2 shares a common location in mouse spermatozoa with WBP2NL/PAWP and like its descendent is a candidate mouse oocyte-activating factor.

The sperm-borne oocyte-activating factor (SOAF) resides in the sperm perinuclear theca (PT). A consensus has been reached that SOAF most likely resides in the postacrosomal sheath (PAS), which is the first region of the PT to solubilize upon sperm-oocyte fusion. There are two SOAF candidates under consideration: PLCZ1 and WBP2NL. A mouse gene germline ablation of the latter showed that mice remain fertile with no observable phenotype despite the fact that a competitive inhibitor of WBP2NL, derived from its PPXY motif, blocks oocyte activation when coinjected with WBP2NL or spermatozoa. This suggested that the ortholog of WBP2NL, WBP2, containing the same domain and motifs associated with WBP2NL function, might compensate for its deficiency in oocyte activation. Our objectives were to examine whether WBP2 meets the developmental criteria established for SOAF and whether it has oocyte-activating potential. Immunoblotting detected WBP2 in mice testis and sperm and immunofluorescence localized WBP2 to the PAS and perforatorium of the PT. Immunohistochemistry of the testes revealed that WBP2 reactivity was highest in round spermatids and immunofluorescence detected WBP2 in the cytoplasmic lobe of elongating spermatids and colocalized it with the microtubular manchette during PT assembly. Microinjection of the recombinant forms of WBP2 and WBP2NL into metaphase II mouse oocytes resulted in comparable rates of oocyte activation. This study shows that WBP2 shares a similar testicular developmental pattern and location with WBP2NL and a shared ability to activate the oocyte, supporting its consideration as a mouse SOAF component that can compensate for a WBP2NL.

Optimized Ammonia-Sensing Electrode with CeO2/rGO Nano-Composite Coating Synthesized by Focused Laser Ablation in Liquid.

This study investigated the synthesis of cerium oxide (CeO2) nanoparticles (NPs) and composites with reduced graphene oxide (rGO) for the enhanced electrochemical sensing of ammonia. CeO2 NPs were prepared by the focused laser ablation in liquid (LAL) method, which enabled the production of high-purity, spherical nanoparticles with a uniform dispersion and sizes under 50 nm in a short time. The effects of varying irradiation fluence and time on the nanoparticle size, production yield, and dispersion were systematically studied. The synthesized CeO2 NPs were doped with rGO to form CeO2/rGO composites, which were drop casted to modify the glassy carbon electrodes (GCE). The CeO2/rGO-GCE electrodes exhibited superior electrochemical properties compared with single-component electrodes, which demonstrated the significant potential for ammonia detection, especially at a 4 J/cm2 fluence. The CeO2/rGO composites showed uniformly dispersed CeO2 NPs between the rGO sheets, which enhanced the conductivity, as confirmed by SEM, EDS mapping, and XRD analysis. Cyclic voltammetry data demonstrated superior electrochemical activity of the CeO2/rGO composite electrodes, with the 2rGO/1CeO2 ratio showing the highest current response and sensitivity. The CV response to varying ammonia concentrations exhibited a linear relationship, indicating the electrode's capability for accurate quantification. These findings highlight the effectiveness of focused laser ablation in enhancing nanoparticle synthesis and the promising synergistic effects of CeO2 and rGO in developing high-performance electrochemical sensors.

Quercetin Attenuates Acute Kidney Injury Caused by Cisplatin by Inhibiting Ferroptosis and Cuproptosis.

Ferroptosis, an iron- and ROS-dependent form of regulated cell death. Cuproptosis is a novel form of cellular demise mode. Quercetin, a natural flavonoid, has demonstrated a range of pharmacological activities, including anti-cancer, anti-inflammatory, and antioxidant properties. In this research, we investigated the quercetin effect on cisplatin-induced acute kidney and its mechanism associated ferroptosis and cuproptosis. The HK-2 cells were used in this research. Cell viability was evaluated using the CCK-8 assay. Acute kidney injury (AKI) models were established to perform in vivo experiments. Renal tissue homogenate was used to determine ROS, LPO, MDA, PA, etc., to assess ferroptosis and cuproptosis. To perform bioinformatic analysis, microarray data from the GEO database was utilized. Real-time PCR analysis and ELISA was explored the mechanism of ferroptosis and cuproptosis. We found that ferroptosis and cuproptosis in AKI were abnormally activated caused by cisplatin, and that quercetin attenuated AKI by inhibiting ferroptosis and cuproptosis. QCT suppressed ferroptosis by reducing malondialdehyde (MDA) and ROS levels and increasing glutathione (GSH) levels and alleviated cuproptosis by reducing copper ion, pyruvate (PA) and HSP70 levels. Moreover, bioinformatic analysis revealed that the ferroptosis-related gene SLC7A11 and the cuproptosis-related genes ATP7B and GLS were the differential expression genes. And QCT significantly increased the expression or activity of SLC7A11, GPX4, ATP7B, and GLS in Cis-AKI mice. Our findings highlight the clinical importance of quercetin, which guards against cisplatin-induced acute kidney injury by suppressing ferroptosis and cuproptosis.

Tumor microenvironment characteristics of lipid metabolism reprogramming related to ferroptosis and EndMT influencing prognosis in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a refractory malignant tumor with high tumor heterogeneity, a low rate of early diagnosis, and poor patient prognosis. Lipid metabolism reprogramming plays a critical role in tumorigenesis and progression, but its prognostic role and regulatory mechanism in GC are rarely studied. Thus, the identification of signatures related to lipid metabolism is necessary and may present a new avenue for improving the overall prognosis of GC. METHODS: Lipid metabolism-associated genes (LMAGs) with differential expression in tumor and tumor-adjacent tissue were acquired to identify lipid metabolism-associated subtypes. The differentially expressed genes (DEGs) between the two clusters were then utilized for prognostic analysis and signature construction. Additionally, pathway enrichment analysis and immune cell infiltration analysis were employed to identify the characteristics of the prognostic model. Further analyses were conducted at the single-cell level to better understand the model's prognostic mechanism. Finally, the prediction of immunotherapy response was used to suggest potential treatments. RESULTS: Two lipid metabolism-associated subtypes were identified and 9 prognosis-related genes from the DEGs between the two clusters were collected for the construction of the prognostic model named lipid metabolism-associated signature (LMAS). Then we found the low LMAS patients with favorable prognoses were more sensitive to ferroptosis in the Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD). Meanwhile, the tumor cells exhibiting high levels of lipid peroxidation and accumulation of reactive oxygen species (ROS) in single-cell levels were primarily enriched in the low LMAS group, which was more likely to induce ferroptosis. In addition, endothelial cells and cancer-associated fibroblasts (CAFs) facilitated tumor angiogenesis, proliferation, invasion, and metastasis through endothelial-mesenchymal transition (EndMT), affecting the prognosis of the patients with high LMAS scores. Moreover, CD1C- CD141- dendritic cells (DCs) also secreted pro-tumorigenic cytokines to regulate the function of endothelial cells and CAFs. Finally, the patients with low LMAS scores might have better efficacy in immunotherapy. CONCLUSIONS: A LMAS was constructed to guide GC prognosis and therapy. Meanwhile, a novel anti-tumor effect was found in lipid metabolism reprogramming of GC which improved patients' prognosis by regulating the sensitivity of tumor cells to ferroptosis. Moreover, EndMT may have a negative impact on GC prognosis.

Comparative studies on the chemical composition and pharmacological effects of vinegar-processed antler glue modified from Lei Gong Pao Zhi Lun and traditional water-processed antler glue.

ETHNOPHARMACOLOGICAL RELEVANCE: Antler glue is a classic medicinal to enhance sexual function in traditional Chinese medicine (TCM), which was first recorded in Shen Nong Ben Cao Jing (Shennong's Classic of the Materia Medica). Vinegar-processing is a classic method of processing traditional Chinese medicine. The method of preparing antler glue by boiling antlers in vinegar and then concentrating them is recorded in Lei Gong Pao Zhi Lun (Master Lei's Discourse on Medicinal Processing). In modern times, the typical processing method of antler glue is water extraction and concentration. However, it is not clear whether there is a difference in the effect of these two processing methods on the chemical composition and pharmacological activity of antler glue. AIM OF THE STUDY: The Chinese Pharmacopoeia (2020) records that the processing method of antler glue is water extraction and concentration. But Lei Gong Pao Zhi Lun differs in Chinese Pharmacopoeia (2020), which records the processing method of vinegar extraction and concentration. The effect of the two processing methods on antler glue's chemical composition and pharmacological activity is unknown. So this study aimed to elucidate the difference between different processing methods on the chemical composition and the treatment effect on oligoasthenospermia of antler glue. MATERIALS AND METHODS: So the automatic amino acid analyzer is used to determine the amino acid content of two different processing methods of antler glue. Proteomics was performed to detect the protein components of two different processing methods of antler glue and analyze them. Cyclophosphamide-induced mice models of oligoasthenospermia were used to study the different pharmacological effects of antler glue in two different processing methods. An automatic sperm analyzer observed the quantity and quality of sperm in mice epididymis. Serum sex hormone testosterone (T), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in mice were tested using the enzyme-linked immunosorbent assay (ELISA) kits. Hematoxylin-eosin (H&E) staining was used to analyze pathological alterations in mouse testicular tissue. The transcriptome has been used to reveal the potential mechanism of antler glue in treating oligoasthenospermia. Mitochondrial complex activity assay kits were used to assay the activity of mitochondrial respiratory chain complex I-V in mouse testicular tissue. Western blot was used to determine the expression of related proteins in mouse testicular tissue. RESULTS: Vinegar-processing can increase the alanine, proline, and glycine content in antler glue, reduce the length of protein peptides in antler glue, and produce a variety of unique proteins. Vinegar-processed antler glue (VAG) increased sperm density, sperm survival, sperm viability, and serum sex hormone levels in oligozoospermic mice. It reversed testicular damage caused by cyclophosphamide, and the effects were differently superior to those of water-processed antler glue (WAG). In addition, transcriptomics and related experiments have shown that VAG can increase the expression of Ndufa2, Uqcr11, Cox6b1, and Atp5i genes and proteins in mouse testis, thus promoting adenosine diphosphate (ATP) synthesis by increasing the activity of mitochondrial respiratory chain complexes I, III, IV and V. By promoting the oxidative phosphorylation process to produce more ATP, VAG can achieve the therapeutic effect of oligoasthenospermia. CONCLUSION: Vinegar-processing method can increase the content of active ingredients in antler glue. VAG increases ATP levels in the testes by promoting the process of oxidative phosphorylation to treat oligozoospermia.

Mechanism of action of vinegared Cornu Cervi Degelatinatum in suppressing spleen kidney yang deficient ulcerative colitis through NCK2-JNK pathway.

As a traditional Chinese herbal medicine, Cornu Cervi Degelatinatum (CCD) has the effect of warming the kidney to support yang, astringing, and stopping bleeding, and is used for spleen kidney yang deficient (SKYD). This experiment was to investigate the therapeutic effects of different processes of CCD on SKYD type ulcerative colitis (UC) rats and to explore its impact on the intestinal flora of rats. METHODS: ELISA was used to study the anti-inflammatory activity of Cornu Cervi Degelatinatum processed with water (WCCD) and Cornu Cervi Degelatinatum processed with vinegar (VCCD). 16SrRNA and transcriptome sequencing were used to detect the composition of rat intestinal flora and gene expression; RT-PCR and Western blot were used to verify the role of WCCD and VCCD in treating UC. RESULTS: WCCD and VCCD have therapeutic effects on UC, could reduce tissue damage. VCCD performed better in improving Bacteroidetes/Firmicutes ratios and species evenness and abundance; performed better in increasing the quantity of lactobacillus. VCCD simultaneously inhibit the intestinal inflammatory response through NCK2, PAK4, and JNK signaling pathways. CONCLUSIONS: WCCD and VCCD play a therapeutic role in UC by regulating the proportion of different flora in the intestinal flora. VCCD regulates the intestinal flora and inflammatory response by interfering with the NCK2, PAK4 and JNK signaling pathways.

Improved efficacy of cisplatin delivery by peanut agglutinin­modified liposomes in non­small cell lung cancer.

Globally, non­small cell lung cancer (NSCLC) is a significant threat to human health, and constitutes >80% of lung cancer cases. Cisplatin (CDDP), a commonly used drug in clinical treatment, has been the focus of research aiming to mitigate its potent toxicity through encapsulation within liposomes. However, challenges, such as a reduced drug loading efficiency and nonspecific release, have emerged as obstacles. The present study aimed to improve the encapsulation efficiency of CDDP within liposomes by pre­preparation of CDDP and modifying the liposome surface through the incorporation of peanut agglutinin (PNA) as a ligand [CDDP­loaded PNA­modified liposomes (CDDP­PNA­Lip)]. This strategy was designed to enhance the delivery of CDDP to tumour tissues, thereby reducing associated side effects. The effect of CDDP­PNA­Lip on the proliferation and migration of NSCLC cell lines with high MUC1 expression was elucidated through in vitro studies. Additionally, the capacity of PNA modification to augment the targeted anti­tumour efficacy of liposomes was assessed through xenograft tumour experiments. The results indicated that in an in vitro uptake assay Rhodamine B (RhB)­loaded PNA­modified liposomes were taken up by cells with ~50% higher efficiency compared with free RhB. In addition, CDDP­PNA­Lip resulted in a 2.65­fold enhancement of tumour suppression in vivo compared with free CDDP. These findings suggested that the encapsulation of CDDP within ligand­modified liposomes may significantly improve its tumour­targeting capabilities, providing valuable insights for clinical drug development.

Construction and application of Optimized Comprehensive Drought Index based on lag time: A case study in the middle reaches of Yellow River Basin, China.

Drought is a complex and dynamic natural phenomenon. A single drought index can hardly reflect the multi-type characteristics of drought, and comprehensive drought indices that incorporate data from multiple sources have been proposed recently. In this study, an Optimized Comprehensive Drought Index (OCDI) was constructed by taking into account the lag time of meteorological drought, agricultural drought and hydrological drought. The Standardized Precipitation Evapotranspiration Index (SPEI), Vegetation Condition Index (VCI), and Water Storage Deficit Index (WSDI) represented the three types of droughts, respectively. Specifically, we used the Solar-induced Chlorophyll Fluorescence (SIF) to characterize the vegetation condition instead of the Normalized Difference Vegetation Index (NDVI). The application results of the proposed drought index in the middle reaches of Yellow River basin (MRYRB) showed that the lag time of different types of drought indices had seasonal differences, with a shorter lag time in summer (0-4 months) and a longer lag time in winter and spring (> 4 months). For typical drought events, the drought intensity and duration identified by OCDI were compatible with the drought evolution characteristics and consistent with the historical records, therefore, OCDI is more suitable for drought monitoring in the study area. Based on the monitoring results of the OCDI, the average number of droughts in the MRYRB was 16 times, with a duration of 2.8 months and an average drought intensity of 0.28 (at moderate drought grade). Drought times and intensity were higher in the northwestern part of the study area, and spring was a high-frequency period for drought occurrences.

Effects of climate change and human activities on gross primary productivity in the Heihe River Basin, China.

As the primary source of carbon dioxide fixation, vegetation is critical to the carbon sink process. In this paper, the Net Primary Productivity (NPP) and the Gross Primary Productivity (GPP) were simulated using the Carnegie-Ames-Stanford Approach (CASA) model and the Vegetation Photosynthesis Model (VPM), respectively, and then the Potential Gross Primary Productivity (PGPP) and the GPP affected by human activities (AGPP) were simulated by combining Potential Net Primary Productivity (PNPP), and then the impact of climate change and human activities on GPP was assessed in the Heihe River Basin (HRB). The results showed that the GPP of grassland and Bare or Sparse Vegetation (BSV) exhibited a fluctuation rise, with increases of 0.709 gCm-2 a-1 and 0.115 gCm-2 a-1, respectively, whereas the GPP of cropland showed a fluctuation reduction, with a decline rate of -0.465 gCm-2 a-1. Climate change and human activity are both positive for vegetation growth, and human activity being the primary factor influencing GPP change. Human-dominated vegetation restoration accounted for 56.1% of the overall restoration area, with grassland GPP being the most visible response to human activities. The GPP changes in crop and grassland had a positive correlation with precipitation but a negative correlation with temperature among climate change factors, whereas the GPP changes in BSV had a negative correlation with both precipitation and temperature. Quantitative analyses of climate change and human activities' dynamic contributions to vegetation can give scientific and theoretical insight for dealing with global climate change.

Investigation of the Underlying Mechanism of Huangqi-Dangshen for Myasthenia Gravis Treatment via Molecular Docking and Network Pharmacology.

The herbal pairing of Huangqi and Dangshen (HD) is traditional Chinese herbal medicine and has been widely used in China, especially to treat myasthenia gravis (MG). However, the mechanism of HD on MG is unclear. Aim of the Study. This study aims to investigate HD's possible role in MG treatment. Materials and Methods. The TCMSP database was used to identify the active chemicals and their targets. The GeneCards, DisGeNET, and OMIM databases were used to search for MG-related targets. The STRING database was employed in order to identify the common PPI network targets. We next utilised Cytoscape 3.8.2 for target identification and the DAVID database for gene ontology (GO) function analysis as well as Encyclopaedia of Genomes (KEGG) pathway enrichment analysis on the selected targets. The AutoDock Vina software was used to test the affinity of essential components with the hub gene before concluding that the primary targets were corrected through molecular docking. Results. 41 active compounds were screened from HD, and the number of putative-identified target genes screened from HD was 112. There were 21 target genes that overlapped with the targets of MG, which were postulated to be potential treatment targets. Through further analysis, the results showed that the active compounds from HD (such as 7-methoxy-2-methylisoflavone, quercetin, luteolin, Kaempferol, and isorhamnetin) may achieve the purpose of treating MG by acting on some core targets and related pathways (such as EGFR, FOS, ESR2, MYC, ESR1, CASP3, and IL-6). Molecular docking findings demonstrated that these active molecules have a near-perfect ability to attach to the primary targets. Conclusion. Through network pharmacology, the findings in this study provide light on the coordinated action of several HD formula components, targets, and pathways. It provided a theoretical basis for further study of HD pharmacological action.

Ginsenoside compound K protects against cerebral ischemia/reperfusion injury via Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy.

Background: Ginsenoside compound K (CK), the main active metabolite in Panax ginseng, has shown good safety and bioavailability in clinical trials and exerts neuroprotective effects in cerebral ischemic stroke. However, its potential role in the prevention of cerebral ischemia/reperfusion (I/R) injury remains unclear. Our study aimed to investigate the molecular mechanism of ginsenoside CK against cerebral I/R injury. Methods: We used a combination of in vitro and in vivo models, including oxygen and glucose deprivation/reperfusion induced PC12 cell model and middle cerebral artery occlusion/reperfusion induced rat model, to mimic I/R injury. Intracellular oxygen consumption and extracellular acidification rate were analyzed by Seahorse multifunctional energy metabolism system; ATP production was detected by luciferase method. The number and size of mitochondria were analyzed by transmission electron microscopy and MitoTracker probe combined with confocal laser microscopy. The potential mechanisms of ginsenoside CK on mitochondrial dynamics and bioenergy were evaluated by RNA interference, pharmacological antagonism combined with co-immunoprecipitation analysis and phenotypic analysis. Results: Ginsenoside CK pretreatment could attenuate mitochondrial translocation of DRP1, mitophagy, mitochondrial apoptosis, and neuronal bioenergy imbalance against cerebral I/R injury in both in vitro and in vivo models. Our data also confirmed that ginsenoside CK administration could reduce the binding affinity of Mul1 and Mfn2 to inhibit the ubiquitination and degradation of Mfn2, thereby elevating the protein level of Mfn2 in cerebral I/R injury. Conclusion: These data provide evidence that ginsenoside CK may be a promising therapeutic agent against cerebral I/R injury via Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy.

Assessing Vegetation Ecosystem Resistance to Drought in the Middle Reaches of the Yellow River Basin, China.

The frequency and intensity of droughts are increasing in many parts of the world as a result of global climate change and human activity, posing a serious threat to regional ecological security. The climate in the middle reaches of the Yellow River Basin (MRYRB) has been warm and dry in recent years, with frequent droughts. In order to investigate the temporal trend of drought, and reveal the resistance of vegetation to drought in the MRYRB, this study used remotely-sensed vegetation index products (MODIS-NDVI and SPOT-NDVI) and the standardized precipitation evapotranspiration index (SPEI). The results indicated that: (1) drought intensity showed a weak upward trend in the study area from 2000 to 2018, with linear growth rates of SPEI at temporal scales of 1, 3, 6, 9 and 12 months of -0.002, 0.0034, 0.0198, 0.0234, and 0.0249, respectively; (2) drought was positively correlated with vegetation in most areas (97.6%), and vegetation was most affected by drought on long-term time scales (9 and 12 months); (3) with the extension of drought, vegetation resistance index decreased, then gradually recovered after the end of the drought. Forest had the longest resistance duration of 260 days, while grassland and cultivated land had resistance durations of only 170 days. This study adds to the understanding of vegetation's ability to withstand drought, and these findings provide evidence to support drought response in the MRYRB.