Smad2/3/4 complex could undergo liquid liquid phase separation and induce apoptosis through TAT in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most significant causes of mortality due to cancer-related deaths. It has been previously reported that the TGF-ß signaling pathway may be associated with tumor progression. However, the relationship between TGF-ß signaling pathway and HCC remains to be further elucidated. The objective of our research was to investigate the impact of TGF-ß signaling pathway on HCC progression as well as the potential regulatory mechanism involved. METHODS: We conducted a series of bioinformatics analyses to screen and filter the most relevant hub genes associated with HCC. E. coli was utilized to express recombinant protein, and the Ni-NTA column was employed for purification of the target protein. Liquid liquid phase separation (LLPS) of protein in vitro, and fluorescent recovery after photobleaching (FRAP) were utilized to verify whether the target proteins had the ability to drive force LLPS. Western blot and quantitative real-time polymerase chain reaction (qPCR) were utilized to assess gene expression levels. Transcription factor binding sites of DNA were identified by chromatin immunoprecipitation (CHIP) qPCR. Flow cytometry was employed to examine cell apoptosis. Knockdown of target genes was achieved through shRNA. Cell Counting Kit-8 (CCK-8), colony formation assays, and nude mice tumor transplantation were utilized to test cell proliferation ability in vitro and in vivo. RESULTS: We found that Smad2/3/4 complex could regulate tyrosine aminotransferase (TAT) expression, and this regulation could relate to LLPS. CHIP qPCR results showed that the key targeted DNA binding site of Smad2/3/4 complex in TAT promoter region is -1032 to -1182. In addition. CCK-8, colony formation, and nude mice tumor transplantation assays showed that Smad2/3/4 complex could repress cell proliferation through TAT. Flow cytometry assay results showed that Smad2/3/4 complex could increase the apoptosis of hepatoma cells. Western blot results showed that Smad2/3/4 complex would active caspase-9 through TAT, which uncovered the mechanism of Smad2/3/4 complex inducing hepatoma cell apoptosis. CONCLUSION: This study proved that Smad2/3/4 complex could undergo LLPS to active TAT transcription, then active caspase-9 to induce hepatoma cell apoptosis in inhibiting HCC progress. The research further elucidate the relationship between TGF-ß signaling pathway and HCC, which contributes to discover the mechanism of HCC development.

Advances in Metabolism and Metabolic Toxicology of Quinoxaline 1,4-Di-N-oxides.

Quinoxaline 1,4-di-N-Oxides (QdNOs) have been used as synthetic antimicrobial agents in animal husbandry and aquaculture. The metabolism and potential toxicity have been also concerns in recently years. The metabolism investigations showed that there were 8 metabolites of Carbadox (CBX), 34 metabolites of Cyadox (CYA), 33 metabolites of Mequindox (MEQ), 35 metabolites of Olaquindox (OLA), and 56 metabolites of Quinocetone (QCT) in different animals. Among them, Cb3 and Cb8, M6, and O9 are metabolic residual markers of CBX, MEQ and OLA, which are associated with N → O reduction. Toxicity studies revealed that QdNOs exhibited severe tumorigenicity, cytotoxicity, and adrenal toxicity. Metabolic toxicology showed that toxicity of QdNOs metabolites might be related to the N → O group reduction, and some metabolites exhibited higher toxic effects than the precursor, which could provide guidance for further research on the metabolic toxicology of QdNOs and provide a wealth of information for food safety evaluation.

Deficiency of interleukin-6 receptor ameliorates PM2.5 exposure-induced pulmonary dysfunction and inflammation but not abnormalities in glucose homeostasis.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure increases local and systemic interleukin-6 (IL-6). However, the pathogenic role of IL-6 signalling following PM2.5 exposure, particularly in the development of pulmonary dysfunction and abnormal glucose homeostasis, has hardly been investigated. RESULTS: In the study, IL-6 receptor (IL-6R)-deficient (IL-6R-/-) and wildtype littermate (IL-6R+/+) mice were exposed to concentrated ambient PM2.5 (CAP) or filtered air (FA), and their pulmonary and metabolic responses to these exposures were analyzed. Our results demonstrated that IL-6R deficiency markedly alleviated PM2.5 exposure-induced increases in lung inflammatory markers including the inflammation score of histological analysis, the number of macrophages in bronchoalveolar lavage fluid (BALF), and mRNA expressions of TNFα, IL-1ß and IL-6 and abnormalities in lung function test. However, IL-6R deficiency did not reduce the hepatic insulin resistance nor systemic glucose intolerance and insulin resistance induced by PM2.5 exposure. CONCLUSION: Our findings support the crucial role of IL-6 signalling in the development of pulmonary inflammation and dysfunction due to PM2.5 exposure but question the putative central role of pulmonary inflammation for the extra-pulmonary dysfunctions following PM2.5 exposure, providing a deep mechanistic insight into the pathogenesis caused by PM2.5 exposure.

Exposure to different fractions of diesel exhaust PM2.5 induces different levels of pulmonary inflammation and acute phase response.

AIM: Ambient fine particulate matter (PM2.5) consists of various components, and their respective contributions to the toxicity of PM2.5 remains to be determined. To provide specific recommendations for preventing adverse effects due to PM2.5 pollution, we determined whether the induction of pulmonary inflammation, the putative pathogenesis for the morbidity and mortality due to PM2.5 exposure, was fractioned through solubility-dependent fractioning. METHODS: In the present study, the water and heptane solubilities-dependent serial fractioning of diesel exhaust particulate matter (DEP), a prominent source of urban PM2.5 pollution, was performed. The pro-inflammatory actions of these resultant fractions were then determined using both an intratracheal instillation mouse model and cultured BEAS-2B cells, a human bronchial epithelial cell line. RESULTS: Instillation of the water-insoluble, but not -soluble fraction elicited significant pulmonary inflammatory and acute phase responses, comparable to those induced by instillation of DEP. The water-insoluble fraction was further fractioned using heptane, a polar organic solvent, and instillation of heptane-insoluble, but not -soluble fraction elicited significant pulmonary inflammation and acute phase responses. Furthermore, we showed that DEP and water-insoluble DEP, but not water-soluble DEP, activated pro-inflammatory signaling in cultured BEAS-2B cells, ruling out the possibility that the solubility impacts the in vivo distribution and thus the pulmonary inflammatory response.

Hypothalamic-pituitary-adrenal axis mediates ambient PM2.5 exposure-induced pulmonary inflammation.

Ambient fine particulate matter (PM2.5) exposure correlates with adverse cardiometabolic effects. The underlying mechanisms have not yet been fully understood. Hypothalamic-pituitary-adrenal (HPA) axis, as the central stress response system, regulates cardiometabolic homeostasis and is implicated in the progression of various adverse health effects caused by inhalational airborne pollutant exposure. In this study, we investigated whether ambient PM2.5 exposure activates HPA axis and its effect mediating PM2.5-induced pulmonary inflammation. C57Bl/6 J mice were intratracheally instilled with different concentrations of diesel exhaust PM2.5 (DEP), and plasma was harvested at different times. Assessments of plasma stress hormones revealed that DEP instillation dose- and time-dependently increased mouse circulating corticosterone and adrenocorticotropic hormone (ACTH) levels, strongly supporting that DEP instillation activates HPA axis. To determine which components of DEP activate HPA axis, C57Bl/6J mice were intratracheally instilled with water-soluble and -insoluble fractions of DEP. Plasma analyses showed that water-insoluble but not -soluble fraction of DEP increased circulating corticosterone and ACTH levels. Consistently, concentrated ambient PM2.5 (CAP) exposure significantly increased mouse urine and hair corticosterone levels, corroborating the activation of HPA axis by ambient PM2.5. Furthermore, deletion of stress hormones by total bilateral adrenalectomy alleviated PM2.5-induced pulmonary inflammation, providing insights into the contribution of central neurohormonal mechanisms in modulating adverse health effects caused by exposure to PM2.5.

[Preparation and in vitro release of ginkgolide B nanosuspension].

To prepare ginkgolide B nanosuspension(GB-NS), and investigate its dissolution behaviors in vitro. The miniaturized media milling method was used to prepare nanosuspensions, with average particle size and polydispersity index as the evaluation indexes. The formulation and process of GB-NS were optimized by single factor experiment and Box-Behnken design-response surface method. The morphology was observed by scanning electron microscope(SEM), and thecrystallinity of GB-NS was investigated by X-rays diffraction(XRD). The paddle method was used to study the dissolution of GB-NS in vitro. The mean particle size of optimized GB-NS was(180±7) nm, with a polydispersity index of 0.196±0.036. SEM showed that GB-NS was rod-like or irregular granular. XRD showed that the crystallinity of GB-NS was significantly reduced compared with GB raw material. The cumulative dissolution rate of GB-NS reached 90% in 30 min, which was higher than that of GB raw material. The findings suggested that the miniaturized media milling method was simple, efficient and feasible to prepare GB-NS. And the dissolution rate of GB was significantly improved by nanosuspension technology.

High YBX1 expression indicates poor prognosis and promotes cell migration and invasion in nasopharyngeal carcinoma.

Y-box binding protein-1 (YBX1) is a multifunctional protein and often acts as an indicator of poor prognosis in cancers. Increasing evidence has shown that the levels of YBX1 protein were closely associated with multidrug resistance, relapse, metastasis and poor prognosis in cancers. However, its role in nasopharyngeal carcinoma (NPC) metastasis remains unknown. In our study, we discovered that the expression of YBX1 was increased in nasopharyngeal carcinoma tissues. YBX1 protein levels positively correlated with T stage and metastasis of NPC patients. Moreover, expression of YBX1 was negatively correlated with membrane E-cadherin levels and positively correlated with Vimentin expression. In vitro, the expression of YBX1 was closely related to the invasive and migratory ability of nasopharyngeal carcinoma cells. Knockdown of YBX1 inhibited migration and invasion in 5-8F cells, and over-expression of YBX1 promoted CNE1 cells migration and invasion. Transforming growth factor-ß1 (TGF-ß1) treatment led to epithelial-to-mesenchymal transition (EMT) in CNE1 cells accompanied by elevated YBX1 expression. On the contrary, knockdown of YBX1 partially inhibited the TGF-ß1-induced CNE1 cell migration, together with changes of EMT-associated markers. Our study revealed that TGF-ß1/YBX1 signaling might be one of novel mechanisms mediating EMT in NPC, providing a new target for the treatment of nasopharyngeal carcinoma.

Cost-effectiveness of sotorasib as a second-line treatment for non-small cell lung cancer with KRASG12C mutation in China and the United States.

Purpose: To evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRASG12C mutation from the China and United States'social perspective. Materials and Methods: A Markov model that included three states (progression-free survival, post-progression survival, and death) was developed. Incremental cost-effectiveness ratio (ICER), quality-adjusted life-year (QALY), and incremental QALY were calculated for the two treatment strategies. One-way sensitivity analysis was used to investigate the factors that had a greater impact on the model results, and tornado diagrams were used to present the results. Probabilistic sensitivity analysis was performed with 1,000 Monte Carlo simulations. Assume distributions based on parameter types and randomly sample all parameter distributions each time., The results were presented as cost-effectiveness acceptable curves. Results: This economic evaluation of data from the CodeBreak 200 randomized clinical trial. In China, sotorasib generated 0.44 QAYL with a total cost of $84372.59. Compared with docetaxel, the ICER value of sotorasib was $102701.84/QALY, which was higher than willingness to pay (WTP), so sotorasib had no economic advantage. In the US, sotorasib obtained 0.35 QALY more than docetaxel, ICER was $15,976.50/QALY, which was more than 1 WTP but less than 3 WTP, indicating that the increased cost of sotorasib was acceptable. One-way sensitivity analysis showed that the probability of sotorasib having economic benefits gradually increased when the cost of follow-up examination was reduced in China. And there was no influence on the conclusions within the range of changes in China. When the willingness to pay (WTP) exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%. Conclusion: Sotorasib had a cost effect from the perspective in the United States. However, sotorasib had no cost effect from the perspective in China, and only when the WTP exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.

Risk prediction models of mortality after hip fracture surgery in older individuals: a systematic review.

OBJECTIVE: This study aimed to critically assess existing risk prediction models for postoperative mortality in older individuals with hip fractures, with the objective of offering substantive insights for their clinical application. DESIGN: A comprehensive search was conducted across prominent databases, including PubMed, Embase, Cochrane Library, SinoMed, CNKI, VIP, and Wanfang, spanning original articles in both Chinese and English up until 1 December 2023. Two researchers independently extracted pertinent research characteristics, such as predictors, model performance metrics, and modeling methodologies. Additionally, the bias risk and applicability of the incorporated risk prediction models were systematically evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST). RESULTS: Within the purview of this investigation, a total of 21 studies were identified, constituting 21 original risk prediction models. The discriminatory capacity of the included risk prediction models, as denoted by the minimum and maximum areas under the subject operating characteristic curve, ranged from 0.710 to 0.964. Noteworthy predictors, recurrent across various models, included age, sex, comorbidities, and nutritional status. However, among the models assessed through the PROBAST framework, only one was deemed to exhibit a low risk of bias. Beyond this assessment, the principal limitations observed in risk prediction models pertain to deficiencies in data analysis, encompassing insufficient sample size and suboptimal handling of missing data. CONCLUSION: Subsequent research endeavors should adopt more stringent experimental designs and employ advanced statistical methodologies in the construction of risk prediction models. Moreover, large-scale external validation studies are warranted to rigorously assess the generalizability and clinical utility of existing models, thereby enhancing their relevance as valuable clinical references.

Dynamic Changes in the Global Transcriptome of Postnatal Skeletal Muscle in Different Sheep.

Sheep growth performance, mainly skeletal muscle growth, provides direct economic benefits to the animal husbandry industry. However, the underlying genetic mechanisms of different breeds remain unclear. We found that the cross-sectional area (CSA) of skeletal muscle in Dorper (D) and binary cross-breeding (HD) was higher than that in Hu sheep (H) from 3 months to 12 months after birth. The transcriptomic analysis of 42 quadriceps femoris samples showed that a total of 5053 differential expression genes (DEGs) were identified. The differences in the global gene expression patterns, the dynamic transcriptome of skeletal muscle development, and the transcriptome of the transformation of fast and slow muscles were explored using weighted correlation network analysis (WGCNA) and allele-specific expression analysis. Moreover, the gene expression patterns of HD were more similar to D rather than H from 3 months to 12 months, which might be the reason for the difference in muscle growth in the three breeds. Additionally, several genes (GNB2L1, RPL15, DVL1, FBXO31, etc.) were identified as candidates related to skeletal muscle growth. These results should serve as an important resource revealing the molecular basis of muscle growth and development in sheep.

Association between preoperative diagnosis of sarcopenia and postoperative pneumonia in resectable esophageal squamous cell carcinoma patients: a retrospective cohort study.

Background: Postoperative outcomes for patients suffering from resectable esophageal squamous cell carcinoma (ESCC) are related to sarcopenia. In patients with resectable ESCC, this study investigated the link between sarcopenia and postoperative pneumonia. Methods: The McKewon procedure was the only one used to treat resectable ESCC patients from January 2018 to December 2021 in this retrospective analysis. Sarcopenia was assessed using skeletal muscles at L3 and planning CT scans. It was defined when PMI was below 6.36 cm2/m2 and 3.92 cm2/m2 for men and women, separately. Analyses of multivariate and univariate logistic regression were applied for identifying the risk factors for postoperative pneumonia. Results: The study included 773 patients with resectable ESCC in total. Sarcopenia was an independent risk factor for postoperative pneumonia in individuals with resectable ESCC based on univariate and multivariate analysis (P < 0.05). The stratified analysis indicated that neither of the clinical outcomes in the logistic regression model were affected by gender, age, BMI, smoking, or pre-albumin (P for interaction > 0.006). Conclusion: Following the McKewon procedure, patients with resectable ESCC who were sarcopenic had a higher postoperative pneumonia rate. To prevent the development of postoperative pneumonia during the perioperative period, it may be important to control the incidence of sarcopenia.

A mid-infrared spectroscopy-random forest system for the origin tracing of Chinese geographical indication Aconiti Lateralis Radix Praeparata.

Reliable origin certification methods are essential for the protection of high-value genuine medicinal material with designated origins and geographical indication (GI) products. Aconiti Lateralis Radix Praeparata (Fuzi), one well-known traditional Chinese medicine and geographical indication products have remarkable efficacy and wide clinical application, with high demand in domestic and international markets. The efficacy and price of Fuzi from different origins vary, and it is difficult for the general public to accurately identify them through traditional experience. The mass spectrometry detection technology based on the plant metabolomics is tedious and lengthy in test sample preparation, complicated in operation, long in detection time, and low in reproducibility. As a sophisticated, green, fast, and low-loss detection technique, infrared spectroscopy is integrated by machine learning to bring new ways for quality regulation and control of traditional Chinese medicines. An analytical method based on mid-infrared spectroscopy combined with a random forest algorithm was developed to verify the geographical origin of authentic herbs and/or GI products. The method successfully predicted and classified three varieties of Chinese GI Fuzi and four varieties of non-GI Fuzi. In this study, an environment-friendly traceability strategy with fast analysis, low sample loss and high precision was used to provide a new strategy for identifying the origin of Fuzi.

CTSL, a prognostic marker of breast cancer, that promotes proliferation, migration, and invasion in cells in triple-negative breast cancer.

Introduction: In the world, the incidence of breast cancer has surpassed that of lung cancer, and it has become the first malignant tumor among women. Triple-negative breast cancer (TNBC) shows an extremely heterogeneous malignancy toward high recurrence, metastasis, and mortality, but there is a lack of effective targeted therapy. It is urgent to develop novel molecular targets in the occurrence and therapeutics for TNBC, and novel therapeutic strategies to block the recurrence and metastasis of TNBC. Methods: In this study, CTSL (cathepsin L) expression in tissues and adjacent tissues of TNBC patients was monitored by immunohistochemistry and western blots. The correlations between CTSL expressions and clinicopathological characteristics in the patient tissues for TNBC were analyzed. Cell proliferation, migration, and invasion assay were also performed when over-expressed or knocked-down CTSL. Results: We found that the level of CTSL in TNBC is significantly higher than that in the matched adjacent tissues, and associated with differentiated degree, TNM Stage, tumor size, and lymph node metastatic status in TNBC patients. The high level of CTSL was correlated with a short RFS (p<0.001), OS (p<0.001), DMFS (p<0.001), PPS (p= 0.0025) in breast cancer from online databases; while in breast cancer with lymph node-positive, high level of CTSL was correlated with a short DMFS (p<0.001) and RFS (p<0.001). Moreover, in vitro experiments showed that CTSL overexpression promotes the abilities for proliferation, migration, and invasion in MCF-7 and MDA-MB-231 cell lines, while knocking-down CTSL decreases its characteristics in MDA-MB-231 cell lines. Conclusion: CTSL might involve into the regulation of the proliferation, invasion, and metastasis of TNBC. Thus, CTSL would be a novel, potential therapeutic, and prognostic target of TNBC.

Temperature-dependent mycotoxins production investigation in Alternaria infected cherry by ultra-high performance liquid chromatography and Orbitrap high resolution mass spectrometry.

For temperature-dependent Alternaria mycotoxins production analysis, cherry samples were inoculated with Alternaria sp. and incubated at two different temperatures (4 °C and 25 °C). Six Alternaria mycotoxins, including altenuene (ALT), alternariol monomethyl ether (AME), alternariol (AOH), altertoxin-I (ATX-I), tenuazonic acid (TeA), and tentoxin (TEN), in cherries were detected with integrated visible data-processing tools. Maximum concentration of these mycotoxins reached 71,862.2 µg/kg at 25 °C. Notably, considerable amount of TeA (290.4 µg/kg) was detected at 4 °C, which indicated that low temperature is not a safe storage condition for fruits. A total of 102 compounds were detected with a neutral loss of 162.0528 Da, and TeA-glucose was identified in this work. Based on MS/MS cosine similarity, products were verified and annotated with feature based molecular networking (FBMN) in global natural products social networking (GNPS). The results showed Alternaria mycotoxins in cherry samples were mainly demethylation, hydrogenation, and dehydration. This work revealed the production of Alternaria mycotoxins in cherries under different storage temperature, which will provide theoretical basis for the control of mycotoxin contamination in food commodities.

How about trust in physician-patient relationship? A concept analysis of physicians' perspectives.

OBJECTIVE: Trust is an essential part of the physician-patient relationship. Yet physicians' perspectives in physician-patient trust has always been ignored, and the concept has not yet been clearly defined and analyzed. This study explores the conceptual understanding of physicians' trust in patients in the context of healthcare and clinical practice and provides a theoretical frameworks foundation for practitioners and researchers. METHODS: Seven databases were systematically searched for relevant studies, including Pubmed, CINAHL, ScienceDirect, Web of Science, CNKI, Wanfang and Weipu. Walker and Avant's approach to concept analysis was performed to extract the concept attributes, antecedents, consequences, and define empirical referents. RESULTS: Of the 8028 articles identified, 43 met the inclusion criteria. Five core attributes were identified: (a) Interaction and support; (b) Confidence and expectation in building trust; (c) Motivation for medical treatment; (d) Socially and medically epistemic competence of patients; (e) Self-reported accuracy. Antecedents were divided into a physician-patient relationship and the social context of medicine. Consequences included treatment outcomes, patient outcomes, and treatment efficiency for physicians and patients. CONCLUSIONS: Our findings offer insights into refining the concept of trust. By collaborating across healthcare trusts, we can contribute to the development of theoretical models and empirical research. This concept analysis serves as a foundation to develop instruments to measure the concept and highlight the need to design a qualitative study and enhancement strategy for physician trust in patients. PRACTICE IMPLICATIONS: Trust in Physicians' perspectives is an essential part of the physician-patient relationship. Establishing and strengthening physicians' trust in patients is significant to healthcare and clinical practice. Concept analysis of physicians' trust in patients will give policymakers a more evident concept and understanding of the importance of the trust improvement strategy and guide healthcare managers to improve theoretical development.

Alternaria Mycotoxins Analysis and Exposure Investigation in Ruminant Feeds.

Alternaria mycotoxins are a class of important, agriculture-related hazardous materials, and their contamination in ruminant feeds and products might bring severe toxic effects to animals and even human beings. To control these hazardous compounds, a reliable and sensitive LC-MS/MS (liquid chromatography-tandem mass spectrometry) method was established for simultaneous determination of six target Alternaria mycotoxins in ruminant feeds, including ALT (Altenuene), AME (Alternariol Monomethyl Ether), AOH (Alternariol), ATX-Ι (Altertoxins I), TeA (Tenuazonic Acid), and TEN (Tentoxin). This developed analytical method was used for the determination of the presence of these substances in cattle and sheep feeds in Xinjiang Province, China. The results revealed that Alternaria mycotoxins are ubiquitously detected in feed samples. Especially, AME, AOH, TeA, and TEN are the most frequently found mycotoxins with a positive rate over 40% and a concentration range of 4~551 µg/kg. The proposed method could be applied for exposure investigation of Alternaria mycotoxins in ruminant feeds and for the reduction in the health risk to animals and even consumers.

Genome-wide epigenetic dynamics during postnatal skeletal muscle growth in Hu sheep.

Hypertrophy and fiber transformation are two prominent features of postnatal skeletal muscle development. However, the role of epigenetic modifications is less understood. ATAC-seq, whole genome bisulfite sequencing, and RNA-seq were applied to investigate the epigenetic dynamics of muscle in Hu sheep at 3 days, 3 months, 6 months, and 12 months after birth. All 6865 differentially expressed genes were assigned into three distinct tendencies, highlighting the balanced protein synthesis, accumulated immune activities, and restrained cell division in postnatal development. We identified 3742 differentially accessible regions and 11799 differentially methylated regions that were associated with muscle-development-related pathways in certain stages, like D3-M6. Transcription factor network analysis, based on genomic loci with high chromatin accessibility and low methylation, showed that ARID5B, MYOG, and ENO1 were associated with muscle hypertrophy, while NR1D1, FADS1, ZFP36L2, and SLC25A1 were associated with muscle fiber transformation. Taken together, these results suggest that DNA methylation and chromatin accessibility contributed toward regulating the growth and fiber transformation of postnatal skeletal muscle in Hu sheep.

Hyaluronic acid-based M1 macrophage targeting and environmental responsive drug releasing nanoparticle for enhanced treatment of rheumatoid arthritis.

Herein, hyaluronic acid (HA) and ß-cyclodextrin (ß-CD) is used to form targeted drug delivery platform HCPC/DEX NPs with previously prepared carbon dots (CDs) as cross-linker, dexamethasone (DEX) is loaded for rheumatoid arthritis (RA) treatment. The drug loading capacity of ß-CD and M1 macrophage targeting of HA were utilized for efficient delivery of DEX to the inflammatory joints. Because of the environmental responsive degradation of HA, DEX can be released in 24 h and inhibit the inflammatory response in M1 macrophages. The drug loading of NPs is 4.79 %. Cellular uptake evaluation confirmed that NPs can specifically target to M1 macrophages via HA ligands, the uptake of M1 macrophages is 3.7 times that of normal macrophages. In vivo experiments revealed that NPs can accumulate in RA joints to alleviate inflammation and accelerate cartilage healing, the accumulation can be observed in 24 h. The cartilage thickness increased to 0.45 mm after HCPC/DEX NPs treatment, indicating its good RA therapeutic effect. Importantly, this study was the first to utilize the potential acid and reactive oxygen species responsiveness of HA to release drug and prepare M1 macrophage targeting nanodrug for RA treatment, which provides a safe and effective RA therapeutic strategy.

[Risk control system construction of Shenfu injection].

OBJECTIVE: To ensure the stable quality of Shenfu injection, control potential risk and reduce risk damage. METHOD: To screen and evaluate the risk in the production, GAP, research and development, circulation, clinical application, intellectual property, emergency treatment,control and prevente the potential risks. RESULT: The risk-control system of Shenfu injection has been constructed initially. CONCLUSION: It has a great significance for the establishment of traditional Chinese medicive injections' risk-control system. The keys of the risk-control in future are to make strategy, perfect the organization structure and collaborating among various departments.

Mitigations pathways towards sustainable development: assessing the influence of higher education on environmental quality in BRICS economies.

Education plays a significant role in the development of economies. This study empirically contributes to the literature by examining the impacts of higher education on CO2 emissions of BRICS economies over the period 1998-2020. For empirical analysis, we used the ARDL bound testing approach. The findings of the study show that higher education significantly and negatively contributed to the CO2 emissions of China and confirm the education-CO2-led hypothesis in the long run. The results of the study also reveal that higher education in Russia, India, and South Africa exerts a positive impact on CO2 emissions in the long run and rejects the education-CO2-led hypothesis. Moreover, financial inclusion has a negative impact on CO2 emissions in China, Russia, and South Africa, while financial inclusion positively affects CO2 emissions in only India in the long run. Based on findings, authorities should extend financial and social support for higher academic activities aimed at the mitigation of environmental pollution. Policymakers should also consider the synergy influence of financial inclusion in designing carbon mitigation policies.