Global trends and partial forecast of adverse effects of medical treatment from 1990 to 2019: an epidemiological analysis based on the global burden of disease study 2019.

BACKGROUND: The possibility of adverse effects of medical treatment (AEMT) is increasing worldwide, but little is known about AEMT in China. This study analyzed the health burden of AEMT in China in recent years through the Global Burden of Disease Study (GBD) 2019 and compared it with the worldwide average level and those in different sociodemographic index (SDI) regions. METHODS: We calculated the age-standardized rate (ASR) of deaths, disability-adjusted life years (DALYs), years of life lost (YLLs), years lived with disability (YLDs), incidence and prevalence attributed to AEMT in China, worldwide and countries with different sociodemographic indices during 1990-2019 using the latest data and methods from the GBD 2019. RESULTS: From 1990 to 2019, the global age-standardized death rate (ASDR), DALYs, and YLLs for AEMT showed a significant downward trend and were negatively associated with the SDI. By 2040, the ASDR is expected to reach approximately 1.58 (95% UI: 1.33-1.80). From 1990 to 2019, there was no significant change in the global incidence of AEMT. The occurrence of AEMT was related to sex, and the incidence of AEMT was greater among females. In addition, the incidence of AEMT-related injuries and burdens, such as ASR of DALYs, ASR of YLLs and ASR of YLDs, was greater among women than among men. Very old and very young people were more likely to be exposed to AEMT. CONCLUSIONS: From 1990 to 2019, progress was made worldwide in reducing the harm caused by AEMT. However, the incidence and prevalence of AEMT did not change significantly overall during this period. Therefore, the health sector should pay more attention to AEMT and take effective measures to reduce AEMT.

Success stories of natural product-derived compounds from plants as multidrug resistance modulators in microorganisms.

Microorganisms evolve resistance to antibiotics as a function of evolution. Antibiotics have accelerated bacterial resistance through mutations and acquired resistance through a combination of factors. In some cases, multiple antibiotic-resistant determinants are encoded in these genes, immediately making the recipient organism a "superbug". Current antimicrobials are no longer effective against infections caused by pathogens that have developed antimicrobial resistance (AMR), and the problem has become a crisis. Microorganisms that acquire resistance to chemotherapy (multidrug resistance) are a major obstacle for successful treatments. Pharmaceutical industries should be highly interested in natural product-derived compounds, as they offer new sources of chemical entities for the development of new drugs. Phytochemical research and recent experimental advances are discussed in this review in relation to the antimicrobial efficacy of selected natural product-derived compounds as well as details of synergistic mechanisms and structures. The present review recognizesand amplifies the importance of compounds with natural origins, which can be used to create safer and more effective antimicrobial drugs by combating microorganisms that are resistant to multiple types of drugs.

Acanthopanax trifoliatus (L.) Merr polysaccharides ameliorates hyperglycemia by regulating hepatic glycogen metabolism in type 2 diabetic mice.

Introduction: Drug monotherapy was inadequate in controlling blood glucose levels and other comorbidities. An agent that selectively tunes multiple targets was regarded as a new therapeutic strategy for type 2 diabetes. Acanthopanax trifoliatus (L.) Merr polysaccharide (ATMP) is a bio-macromolecule isolated from Acanthopanax trifoliatus (L.) Merr and has therapeutic potential for diabetes management due to its anti-hyperglycemia activity. Methods: Type 2 diabetes mellitus was induced in mice using streptozotocin, and 40 and 80 mg/kg ATMP was administered daily via the intragastric route for 8 weeks. Food intake, water intake, and body weight were recorded. The fasting blood glucose (FBG), fasting insulin (FINS) and an oral glucose tolerance test (OGTT) were performed. Histological changes in the liver and pancreas were analyzed by H&E staining. The mRNA and the protein levels of key factors involved in glycogen synthesis, glycogenolysis, and gluconeogenesis were measured by quantitative real time PCR and Western blotting. Results: In this study, we found that ATMP could effectively improve glucose tolerance and alleviate insulin resistance by promoting insulin secretion and inhibiting glucagon secretion. In addition, ATMP decreases glycogen synthesis by inhibiting PI3K/Akt/GSK3ß signaling, reduces glycogenolysis via suppressing cAMP/PKA signaling, and suppresses liver gluconeogenesis by activating AMPK signaling. Conclusion: Together, ATMP has the potential to be developed as a new multitargets therapeutics for type 2 diabetes.

[Clinical Study of San Wei Sheng Huo Decoction in the Treatment of Refractory Chemotherapy-Induced Thrombocytopenia].

Objective: To investigate the efficacy and safety of treating refractory chemotherapy-induced thrombocytopenia (RCIT) with San Wei Sheng Huo Decoction (SWSHD) as the main formula. Methods: A retrospective study was conducted and the data of RCIT patients treated with SWSHD as the main formula were collected. Changes in peripheral blood platelet (PLT) levels at different time points of treatment were examined and the significant effective rate (SER) and effective rate (ER) were analyzed. We measured the increase in peripheral blood PLT count before and after treatment, analyzed the differences in PLT count increase for different degrees of RCIT treatment, and evaluated the safety of the treatment. Results: A total of 35 cases of RCIT were included in the study. With SWSHD as the main treatment formula, the 2-week ER and SER were 74.29% and 14.29%, respectively, the 2-month ER and SER were 84.38% and 60.50, respectively, and the 1-year ER and SER were 92.31% and 80.77%, respectively. PLT count increased at all time points after treatment compared with that before treatment ( P<0.01). Subgroup analysis showed that, 2 months after treatment started, peripheral blood PLT counts increased by as much as 51.02×10 9L －1 in the severe RCIT group, higher than that of the moderate RCIT group at 36.58×10 9L －1 ( P<0.05), and the difference persisted until 1 year after the treatment. No obvious traditional Chinese medicine-related adverse reaction was observed during the treatment. Conclusion: SWSHD takes effect rapidly and its effect is long-lasting and stable. Furthermore, SWSHD has a more significant effect on severe RCIT.

A mitophagy-related gene signature associated with prognosis and immune microenvironment in colorectal cancer.

Colorectal cancer (CRC) is a heterogeneous disease and one of the most prevalent malignancies worldwide. Previous research has demonstrated that mitophagy is crucial to developing colorectal cancer. This study aims to examine the association between mitophagy-related genes and the prognosis of CRC patients. Gene expression profiles and clinical information of CRC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) regression analysis were applied to establish a prognostic signature using mitophagy related genes. Kaplan-Meier and receiver operating characteristic (ROC) curves were used to analyze patient survival and predictive accuracy. Meanwhile, we also used the Genomics of Drug Sensitivity in Cancer (GDSC) database and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to estimate the sensitivity of chemotherapy, targeted therapy and immunotherapy. ATG14 overexpression plasmid was used to regulate the ATG14 expression level in HCT116 and SW480 cell lines, and cell counting kit-8, colony formation and transwell migration assay were performed to validate the function of ATG14 in CRC cells. A total of 22 mitophagy-driven genes connected with CRC survival were identified, and then a novel prognostic signature was established based on 10 of them (AMBRA1, ATG14, MAP1LC3A, MAP1LC3B, OPTN, VDAC1, ATG5, CSNK2A2, MFN1, TOMM22). Patients were divided into high-risk and low-risk groups based on the median risk score, and the survival of patients in the high-risk group was significantly shorter in both the training cohort and two independent cohorts. ROC curve showed that the area under the curves (AUC) of 1-, 3- and 5-year survival were 0.66, 0.66 and 0.64, respectively. Multivariate Cox regression analysis confirmed the independent prognostic value of the signature. Then we constructed a Nomogram combining the risk score, age and M stage, which had a concordance index of survival prediction of 0.77 (95% CI 0.71-0.83) and more robust predictive accuracy. Results showed that CD8+ T cells, regulatory T cells and activated NK cells were significantly more enriched in the high-risk group. Furthermore, patients in the high-risk group are more sensitive to targeted therapy or chemotherapy, including bosutinib, elesclomol, lenalidomide, midostaurin, pazopanib and sunitinib, while the low-risk group is more likely to benefit from immunotherapy. Finally, in vitro study confirmed the oncogenic significance of ATG14 in both HCT116 and SW480 cells, whose overexpression increased CRC cell proliferation, colony formation, and migration. In conclusion, we developed a novel mitophagy-related gene signature that can be utilized not only as an independent predictive biomarker but also as a tool for tailoring personalizing treatment for CRC patients, and we confirmed ATG14 as a novel oncogene in CRC.

Research Progress on the Positive and Negative Regulatory Effects of Rhein on the Kidney: A Review of Its Molecular Targets.

Currently, both acute kidney injury (AKI) and chronic kidney disease (CKD) are considered to be the leading public health problems with gradually increasing incidence rates around the world. Rhein is a monomeric component of anthraquinone isolated from rhubarb, a traditional Chinese medicine. It has anti-inflammation, anti-oxidation, anti-apoptosis, anti-bacterial and other pharmacological activities, as well as a renal protective effects. Rhein exerts its nephroprotective effects mainly through decreasing hypoglycemic and hypolipidemic, playing anti-inflammatory, antioxidant and anti-fibrotic effects and regulating drug-transporters. However, the latest studies show that rhein also has potential kidney toxicity in case of large dosages and long use times. The present review highlights rhein's molecular targets and its different effects on the kidney based on the available literature and clarifies that rhein regulates the function of the kidney in a positive and negative way. It will be helpful to conduct further studies on how to make full use of rhein in the kidney and to avoid kidney damage so as to make it an effective kidney protection drug.

Distinct characteristics of correlation analysis at the single-cell and the population level.

Correlation analysis is widely used in biological studies to infer molecular relationships within biological networks. Recently, single-cell analysis has drawn tremendous interests, for its ability to obtain high-resolution molecular phenotypes. It turns out that there is little overlap of co-expressed genes identified in single-cell level investigations with that of population level investigations. However, the nature of the relationship of correlations between single-cell and population levels remains unclear. In this manuscript, we aimed to unveil the origin of the differences between the correlation coefficients at the single-cell level and that at the population level, and bridge the gap between them. Through developing formulations to link correlations at the single-cell and the population level, we illustrated that aggregated correlations could be stronger, weaker or equal to the corresponding individual correlations, depending on the variations and the correlations within the population. When the correlation within the population is weaker than the individual correlation, the aggregated correlation is stronger than the corresponding individual correlation. Besides, our data indicated that aggregated correlation is more likely to be stronger than the corresponding individual correlation, and it was rare to find gene-pairs exclusively strongly correlated at the single-cell level. Through a bottom-up approach to model interactions between molecules in a signaling cascade or a multi-regulator-controlled gene expression, we surprisingly found that the existence of interaction between two components could not be excluded simply based on their low correlation coefficients, suggesting a reconsideration of connectivity within biological networks which was derived solely from correlation analysis. We also investigated the impact of technical random measurement errors on the correlation coefficients for the single-cell level and the population level. The results indicate that the aggregated correlation is relatively robust and less affected. Because of the heterogeneity among single cells, correlation coefficients calculated based on data of the single-cell level might be different from that of the population level. Depending on the specific question we are asking, proper sampling and normalization procedure should be done before we draw any conclusions.

TGF-ß induced reprogramming and drug resistance in triple-negative breast cells.

BACKGROUND: The development of drug resistance remains to be a major cause of therapeutic failure in breast cancer patients. How drug-sensitive cells first evade drug inhibition to proliferate remains to be fully investigated. METHODS: Here we characterized the early transcriptional evolution in response to TGF-ß in the human triple-negative breast cells through bioinformatical analysis using a published RNA-seq dataset, for which MCF10A cells were treated with 5 ng/ml TGF-ß1 for 0 h, 24 h, 48 h and 72 h, and the RNA-seq were performed in biological duplicates. The protein-protein interaction networks of the differentially expressed genes were constructed. KEGG enrichment analysis, cis-regulatory sequence analysis and Kaplan-Meier analysis were also performed to analyze the cellular reprograming induced by TGF-ß and its contribution to the survival probability decline of breast cancer patients. RESULT: Transcriptomic analysis revealed that cell growth was severely suppressed by TGF-ß in the first 24 h but this anti-proliferate impact attenuated between 48 h and 72 h. The oncogenic actions of TGF-ß happened within the same time frame with its anti-proliferative effects. In addition, sustained high expression of several drug resistance markers was observed after TGF-ß treatment. We also identified 17 TGF-ß induced genes that were highly correlated with the survival probability decline of breast cancer patients. CONCLUSION: Together, TGF-ß plays an important role in tumorigenesis and the development of drug resistance, which implies potential therapeutic strategies targeting the early-stage TGF-ß signaling activities.

Enhanced phosphate removal with fine activated alumina synthesized from a sodium aluminate solution: performance and mechanism.

Fine activated alumina (FAA) acting as an adsorbent for phosphate was synthesized from an industrial sodium aluminate solution based on phase evolution from Al(OH)3 and NH4Al(OH)2CO3. This material was obtained in the form of γ-Al2O3 with an open mesoporous structure and a specific surface area of 648.02 m2 g-1. The phosphate adsorption capacity of the FAA gradually increased with increases in phosphate concentration or contact time. The maximum adsorption capacity was 261.66 mg g-1 when phosphate was present as H2PO4 - at a pH of 5.0. A removal efficiency of over 96% was achieved in a 50 mg L-1 phosphate solution. The adsorption of phosphate anions could be explained using non-linear Langmuir or Freundlich isotherm models and a pseudo-second-order kinetic model. Tetra-coordinate AlO4 sites acting as Lewis acids resulted in some chemisorption, while (O) n Al(OH)2 + (n = 4, 5, 6) Brønsted acid groups generated by the protonation of AlO4 or AlO6 sites in the FAA led to physisorption. Analyses of aluminum-oxygen coordination units using Fourier transform infrared and X-ray photoelectron spectroscopy demonstrated that physisorption was predominant. Minimal chemisorption was also verified by the significant desorption rate observed in dilute NaOH solutions and the high performance of the regenerated FAA. The high specific surface area, many open mesopores and numerous highly active tetra-coordinate AlO4 sites on the FAA all synergistically contributed to its exceptional adsorption capacity.

A mathematical model for cell cycle control: graded response or quantized response.

Cell cycle is an important and complex biological system. A lot of efforts have been put in understanding cell cycle arrest for its vital role in clinical therapies. The cell-cycle-arrest outcomes upon stimulation are complicated. The response could be stringent or relaxed, and graded or quantized. A model fully addressing various cell-cycle-arrest outcomes is to be developed. Here, we developed a mathematical model of cell cycle control incorporating distinct characteristics of various cell-cycle-arrest outcomes. The model can simulate two typical properties of cell cycle arrest, quantized and graded. We also characterized the inheritable quiescence and refractory state, which were crucial in long-term response of the population. Then, we monitored cells respond to multiple stimulations, and the results indicated that cells responded to stimulations with small interval did not induce significantly sustained cell cycle arrest as the existence of refractory state. Our work will benefit fundamental research and make efforts to predicting outcomes of clinical therapeutics.

New chemical constituents from the fruits of Tetradium ruticarpum.

Two new γ-lactone derivatives, evodinoids A (1) and B (2), along with a new essential oil (3) were isolated from the nearly ripe fruits of Tetradium ruticarpum. The structures of these isolations were determined by 1D and 2D NMR, HR-ESI-MS and ECD data analysis. In addition, the cytotoxic effect of compounds 1-3 was evaluated against human cancer cells A498, A549, HepG-2, MCF-7 and SHSY-5Y, which displayed no significant cytotoxicity (IC50 > 100 µM).

Can Aspirin Use Be Associated With the Risk or Prognosis of Bladder Cancer? A Case-Control Study and Meta-analytic Assessment.

Aspirin, widely used to prevent cardiovascular disease, had been linked to the incidence of bladder cancer (BCa). Existing studies focusing on Chinese populations are relatively rare, especially for Northeast China. Meanwhile, relevant studies on the effects of aspirin on the occurrence or prognosis of BCa are inconsistent or even controversial. First, in the case control study, logistic regression analysis was used to investigate the association between aspirin intake and risk of BCa including 1121 patients with BCa and the 2242 controls. Subsequently, Kaplan-Meier curve and Cox regression analyses were applied to explore the association between aspirin intake and clinicopathological factors which may predict overall survival (OS) and recurrence-free survival (RFS) of BCa patients. Finally, we quantificationally combined the results with those from the published literature evaluating aspirin intake and its effects on the occurrence, outcome of surgery and prognosis of BCa by meta-analysis up to May 1, 2021.Our case-control study demonstrated that the regular use of aspirin was not associated with a reduced incidence of BCa (P=0.175). Stratified analyses of sex showed that aspirin intake did not lead to a lower risk of BCa in female patients (P=0.063). However, the male population who regularly took aspirin had a lower incidence of BCa (OR=0.748, 95% CI= 0.584-0.958, P=0.021). Subgroup analyses stratified by smoking found a significant reduction in the risk of BCa in current smokers with aspirin intake (OR=0.522, 95% CI=0.342-0.797, P=0.002). In terms of prognosis of BCa, patients with a history of aspirin intake did not had a markedly longer OS or RFS than those with no history of aspirin intake by Kaplan-Meier curves. Stratified analysis by sex showed no correlation between aspirin intake and the recurrence or survival of BCa for either male or female patients. However, in people younger than 68, aspirin intake seemed to have prolonged effects for overall survival (HR=3.876; 95% CI=1.326-11.325, P=0.019). Then, we performed a meta-analysis and the combined results from 19 articles and our study involving more than 39524 BCa cases indicated that aspirin intake was not associated with the occurrence of BCa (P=0.671). Subgroup analysis by whether regular use of aspirin, by the mean duration of use of aspirin, by sex, by smoking exposure, by research region and by study type also supported the above results. In terms of the impact of aspirin intake on the prognosis of patients with BCa, 11 articles and our study involving 8825 BCa cases were eligible. The combined results showed that patients with aspirin intake did not have significantly influence on survival, recurrence, progression and metastasis than those without aspirin intake. On the whole, both our retrospective study and literature meta-analysis suggested a lack of a strong relevant association between the use of aspirin and the incidence or prognosis of BCa. Thus, additional long-term follow-up prospective research is warranted to clarify the association of aspirin with BCa incidence and prognosis.

Chinese Medicine Combined With EGFR-TKIs Prolongs Progression-Free Survival and Overall Survival of Non-small Cell Lung Cancer (NSCLC) Patients Harboring EGFR Mutations, Compared With the Use of TKIs Alone.

Objective: To explore the efficacy comparison between epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) combined with traditional Chinese medicine (TCM) and single EGFR-TKIs for advanced non-small cell lung cancer (NSCLC). Methods: A total of 91 NSCLC patients with EGFR mutation were divided into an experimental group and a control group (in a ratio of 2:1) to receive TCM and EGFR-TKIs (61 cases) or single EGFR-TKIs (30 cases). Patients in the control group took EGFR-TKIs and those in the experimental group took EGFR-TKIs plus TCM. We analyzed the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and treatment-related adverse events of two groups. Results: The mPFS of the experimental group and the control group was 12.3 and 8.9 months (P = 0.02), respectively, and the mOS of the experimental group and the control group was 28.2 and 24.2 months (P = 0.02), respectively. Subgroup analysis showed that for the patients with exon 19 deletion mutation (19DEL), mPFS between experimental group and control group was 12.7 and 10.1 months, respectively (P = 0.12). For exon 21 deletion mutation (L858R), the PFS of two groups was 10.8 vs. 8.2 months, respectively (P = 0.03). The subgroup analysis also showed that, for the patients with exon 19 deletion mutation, mOS between the experimental group and the control group was 30.3 and 28.7 months, respectively (P = 0.19). For exon 21 deletion mutation, the mOS of two groups was 25.5 vs. 21.3 months, respectively (P = 0.01). The DCR of the experimental group and the control group was 93.3% and 80.1%, respectively (P = 0.77). Grade 3-4 treatment-related adverse events were less common with the experimental group (11.48%) than the control group (26.67%). Conclusion: For NSCLC patients with EGFR mutation, EGFR-TKIs combined with TCM had a certain effect to prolong mPFS and mOS, compared with the use of EGFR-TKIs alone, especially for the patients with L858R. This conclusion has a significant effect on improving the survival of NSCLC patients after EGFR-TKIs resistance. It deserves further study.

Efficacy and Safety of Banxia XieXin Decoction, a Blended Traditional Chinese Medicine, as Monotherapy for Patients With Advanced Hepatocellular Carcinoma.

PURPOSE: To explore a new therapeutic option for patients with hepatocellular carcinoma (HCC), the efficacy and safety of a group of traditional Chinese medicines (Banxia XieXin recipe) as monotherapy for patients with advanced HCC was studied. MATERIALS AND METHODS: The study included 68 patients with advanced HCC from August 16,2016 to August 15,2019 for analysis. These eligible patients received treatment with Banxia XieXin recipe for at least 1 month. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary efficacy endpoints included objective response rate (ORR) and disease control rate (DCR). In addition, safety was also assessed. RESULTS: The median treatment duration of these 68 patients was 10.3 months (range = 1.6-33.5 months), and follow-up is still ongoing. The median PFS was 6.07 months (95% confidence interval [CI] = 3.748-8.392 months), and the median OS was 12.60 months (95% CI = 8.019-17.181 months). The ORR was 10.3% and the DCR was 41.2%. In the subgroup analysis, the median OS in the transcatheter arterial chemoembolization (TACE) group was not reached, and the median OS in the NO TACE group was 11.30 months (95% CI = 3.219-19.381 months). In addition, no drug-related serious adverse events were observed during the study. CONCLUSION: This is the first clinical analysis of traditional Chinese medicine as a single treatment for advanced HCC. The obtained results are encouraging as they suggest that this panel of Chinese herbs is safe and it may be effective for patients with advanced HCC in a real-world clinical setting.

eDetect: A Fast Error Detection and Correction Tool for Live Cell Imaging Data Analysis.

Live cell imaging has been widely used to generate data for quantitative understanding of cellular dynamics. Various applications have been developed to perform automated imaging data analysis, which often requires tedious manual correction. It remains a challenge to develop an efficient curation method that can analyze massive imaging datasets with high accuracy. Here, we present eDetect, a fast error detection and correction tool that provides a powerful and convenient solution for the curation of live cell imaging analysis results. In eDetect, we propose a gating strategy to distinguish correct and incorrect image analysis results by visualizing image features based on principal component analysis. We demonstrate that this approach can substantially accelerate the data correction process and improve the accuracy of imaging data analysis. eDetect is well documented and designed to be user friendly for non-expert users. It is freely available at https://sites.google.com/view/edetect/ and https://github.com/Zi-Lab/eDetect.

A green approach of preparation of fine active alumina with high specific surface area from sodium aluminate solution.

Fine active alumina (FAA) with a high specific surface area (SSA) is used in catalysis, adsorbents and other applications. This study presents a novel method of preparing high surface area FAA via a phase evolution from gibbsite through ammonium aluminum carbonate hydroxide (AACH) to FAA. Thermodynamic calculations showed that increasing the pH and (NH4)2CO3 concentration both promoted the transformation of gibbsite to AACH. Fine gibbsite precipitated from a sodium aluminate solution could thus be efficiently changed to AACH and subsequently to FAA. Minimal particle aggregation was achieved from gibbsite to AACH to FAA owing to the filling of capillaries by NH3 and CO2, the formation of boehmite and interfacial hydrophobicity. Furthermore, capillary pressures of 1.25-46.56 MPa during the AACH roasting process prevented the collapse of mesopores. The high capillary pressure, numerous open mesopores, and inhibition of aggregation produced FAA with an extremely high SSA. The SSA of FAA was as high as 1088.72 m2 g-1 following the roasting of AACH at 300 °C for 180 min. This FAA was demonstrated to remove phosphate from wastewater with an adsorption capacity of 300.28 mg g-1.

N-acetylaminogalactosyl-decorated biodegradable PLGA-TPGS copolymer nanoparticles containing emodin for the active targeting therapy of liver cancer.

Primary liver cancer (PLC) is one of the most common malignant tumours and has the third highest mortality rate worldwide. An active liver-targeting drug delivery system via the asialoglycoprotein receptors expressed in the hepatic parenchyma cells of mammals has become a research focus for the treatment of PLC. N-acetylaminogalactosyl-poly(lactide-co-glycolide)-succinyl-D-α-tocopherol polyethylene glycol 1000 succinate (GalNAc-PLGA-sTPGS) was synthesized to achieve active liver-targeting properties. Emodin (EMO)-loaded GalNAc-PLGA-sTPGS nanoparticles (EGPTN) were prepared with EMO which was selected for its potential antitumour efficacy. The in vitro cellular uptake, mechanism, cytotoxicity, and apoptosis of HepG2 cells were analyzed. The in vivo therapeutic effects of EGPTN were assessed in a PLC mouse model. The results showed that GalNAc-PLGA-sTPGS was successfully synthesized. The cellular uptake assay demonstrated that coumarin 6-loaded GalNAc-PLGA-sTPGS nanoparticles had superior active liver-targeting properties. The results of the cytotoxity and apoptosis studies indicated that EGPTN achieved the highest levels of cytotoxicity and cell apoptotic rate among the nanoparticles examined. Furthermore, EGPTN showed better in vivo therapeutic effects and anticancer efficacy in the PLC mice than did the other groups. Therefore, EGPTN enhanced the anticancer effect of EMO both in vitro and in vivo, making it a potential option for the treatment of PLC.

Spatiotemporal Control of TGF-ß Signaling with Light.

Cells employ signaling pathways to make decisions in response to changes in their immediate environment. Transforming growth factor beta (TGF-ß) is an important growth factor that regulates many cellular functions in development and disease. Although the molecular mechanisms of TGF-ß signaling have been well studied, our understanding of this pathway is limited by the lack of tools that allow the control of TGF-ß signaling with high spatiotemporal resolution. Here, we developed an optogenetic system (optoTGFBRs) that enables the precise control of TGF-ß signaling in time and space. Using the optoTGFBRs system, we show that TGF-ß signaling can be selectively and sequentially activated in single cells through the modulation of the pattern of light stimulations. By simultaneously monitoring the subcellular localization of TGF-ß receptor and Smad2 proteins, we characterized the dynamics of TGF-ß signaling in response to different patterns of blue light stimulations. The spatial and temporal precision of light control will make the optoTGFBRs system as a powerful tool for quantitative analyses of TGF-ß signaling at the single cell level.

Evodiamine activates AMPK and promotes adiponectin multimerization in 3T3-L1 adipocytes.

Adiponectin, an adipokine with insulin-sensitizing effect, is secreted from adipocytes into circulation as high, medium, and low molecular weight (HMW, MMW, and LMW) forms. The HMW adiponectin is more metabolically active and the ratio of HMW adiponectin to total adiponectin directly correlates with insulin sensitivity. Evodiamine is an indole alkaloid found in the traditional Chinese medicinal plant Evodia rutaecarpa. In this study, evodiamine was found to activate AMP-activated protein kinase (AMPK) in both 3T3-L1 adipocytes and 293T cells. Activation of AMPK by evodiamine promoted the assembly of HMW adiponectin and increased the HMW/total ratio of adiponectin in 3T3-L1 adipocytes. The Ca(2+)-dependent PI3K/Akt/CaMKII-signaling pathway was demonstrated to be involved in evodiamine-induced AMPK activation. This study revealed a novel role of this Ca(2+)-mediated signaling pathway in promoting the multimerization of adiponectin.