ß-hydroxybutyrate restrains colitis-associated tumorigenesis by inhibiting HIF-1α-mediated angiogenesis.

Decreased levels of ß-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.

Wogonin mitigates acetaminophen-induced liver injury in mice through inhibition of the PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary bioactive components of SBG. Acetaminophen (APAP)-induced liver injury (AILI) represents a prevalent form of drug-induced liver damage and is primarily driven by inflammatory responses and oxidative stress. AIM OF STUDY: To investigate the therapeutic effects of Wogonin on AILI and the underlying mechanisms. MATERIALS AND METHODS: C57BL/6 J mice were pre-treated with Wogonin (1, 2.5, and 5 mg/kg bodyweight) for 3 days, followed by treatment with APAP (300 mg/kg bodyweight). The serum and liver tissue samples were collected at 24 h post-APAP treatment. Bone marrow-derived macrophages and RAW264.7 cells were cultured and pre-treated with Wogonin (5, 10, and 20 µM) for 30 min, followed by stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 3 h. To examine the role of the PI3K/AKT signaling pathway in the therapeutic effect of Wogonin on AILI, mice and cells were treated with LY294002 (a PI3K inhibitor) and MK2206 (an AKT inhibitor). RESULTS: Wogonin pre-treatment dose-dependently alleviated AILI in mice. Additionally, Wogonin suppressed oxidative stress and inflammatory responses. Liver transcriptome analysis indicated that Wogonin primarily regulates immune function and cytokines in AILI. Wogonin suppressed inflammatory responses of macrophages by inhibiting the PI3K/AKT signaling pathway. Consistently, Wogonin exerted therapeutic effects on AILI in mice through the PI3K/AKT signaling pathway. CONCLUSIONS: Wogonin alleviated AILI and APAP-induced hepatotoxicity in mice through the PI3K/AKT signaling pathway.

Anthraquinone/activated carbon electrochemical sensor and its application in acetaminophen analysis.

Acetaminophen (AC) can inhibit the synthesis of prostaglandins in the body, and has antipyretic and analgesic effects. In this paper, a two-step microwave impregnation method was used to prepare anthraquinone (AQ)-doped carbon composite, which were applied to the surface modification of glassy carbon electrodes (GCE) for the determination of acetaminophen (AC) using differential pulse voltammetry (DPV). The composites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), Raman and Fourier infrared spectroscopy (FT-IR). The results showed that anthraquinone was successfully modified on the surface of activated carbon. The peak current of AC increased with its concentration in the range of 0.1 µM to 700 µM (R2 = 0.998) and a detection limit of 0.05 µM was obtained with 20%AQ doped carbon electrochemical sensor (20%AQ-C/GCE). Electrochemical Impedance Spectroscopy (EIS) test results indicated that the charge transfer resistance (Rct) of 20%AQ-C/GCE is only the one-fourth of that of bare GCE. The proposed 20%AQ-C/GCE sensor has good stability, reproducibility and selectivity for the detection of AC. The sensor is also suitable for the detection of real samples, indicating its good practicality.

A bioinformatics analysis of potential cellular communication networks in non-alcoholic steatohepatitis and colorectal adenoma using scRNA-seq and bulk-seq.

Background: Non-alcoholic fatty liver disease (NAFLD) is the global most common chronic liver disease. Non-alcoholic steatohepatitis (NASH), an inflammatory subtype of NAFLD, has been shown to significantly increase the risk of colorectal adenoma (CRA). Therefore, from the perspective of bioinformatics analysis, the potential mechanisms of NASH/NAFLD-CRA can be explored. Methods: In this study, we screened the differentially expressed genes (DEGs) and core effect pathways between NASH and CRA by analyzing the single-cell data of CRA patients and the high-throughput sequencing data (GSE37364 and GSE89632) in the online database. We screened therapeutic targets and biomarkers through gene function classification, pathway enrichment analysis, and protein-protein interaction network analysis. In terms of single cell data, we screened the core effect pathway and specific signal pathway of cell communication through cell annotation and cell communication analyses. The purpose of the study was to find potential biomarkers, therapeutic targets, and related effect pathways of NASH-CRA. Results: NASH-CRA comorbidities were concentrated in inflammatory regulation-related pathways, and the core genes of disease progression included IL1B, FOSL1, EGR1, MYC, PTGS2, and FOS. The results suggested the key pathway of NASH-CRA might be the WNT pathway. The main cell signal communication pathways included WNT2B - (FZD6 + LRP5) and WNT2B - (FZD6 + LRP6). The send-receive process occurred in embryonic stem cells. Conclusions: The core genes of NASH-CRA (FOS, EGR1, MYC, PTGS2, FOSL1, and IL1B) may participate in inflammation and immune responses through up-regulation in the process of disease occurrence, interfering with the pathophysiological process of CRA and NASH. NASH-CRA produces cell signal communication in the WNT pathway sent by WNT2B and received by FZD6, LRP5, and LRP6 in embryonic stem cells. These findings may help formulate early diagnosis and treatment strategies for CRA in NAFLD/NASH patients, and further explore corresponding prognostic markers and potential approaches. The significance of scRNA-seq in exploring tumor heterogeneity lies in promoting our understanding of the expression program of tumor related genes in tumor development patterns. However, the biggest challenge is that this analysis may miss out on some biologically significant gene expression programs.

Nanoemulsions of Hydroxysafflor Yellow A for Enhancing Physicochemical and In Vivo Performance.

Stroke was always a disease that threatened human life and health worldwide. We reported the synthesis of a new type of hyaluronic acid-modified multi-walled carbon nanotube. Then, we produced hydroxysafflor yellow A-hydroxypropyl-ß-cyclodextrin phospholipid complex water-in-oil nanoemulsion with hyaluronic acid-modified multi-walled carbon nanotubes and chitosan (HC@HMC) for oral treatment of an ischemic stroke. We measured the intestinal absorption and pharmacokinetics of HC@HMC in rats. We found that the intestinal absorption and the pharmacokinetic behavior of HC@HMC was superior to that of HYA. We measured intracerebral concentrations after oral administration of HC@HMC and found that more HYA crossed the blood-brain barrier (BBB) in mice. Finally, we evaluated the efficacy of HC@HMC in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice. In MCAO/R mice, oral administration of HC@HMC demonstrated significant protection against cerebral ischemia-reperfusion injury (CIRI). Furthermore, we found HC@HMC may exert a protective effect on cerebral ischemia-reperfusion injury through the COX2/PGD2/DPs pathway. These results suggest that oral administration of HC@HMC may be a potential therapeutic strategy for the treatment of stroke.

[Application of acupuncture in inhibiting intestinal peristalsis in colonoscopy].

Acupuncture regulating gastrointestinal motility has the characteristics of bidirectional benign regulation, acupoint specificity and immediacy. And its regulation is mainly achieved through the "neuro-endocrine-immune" network system. Acupuncture at Neiguan (PC 6) and Hegu (LI 4) to inhibit intestinal peristalsis may have good application value in colonoscopy.

Suppression effect and safety of acupuncture on colonic spasm during colonoscopy: a randomized controlled trial.

Background: Intestinal spasm and peristalsis during colonoscopy are common but undesirable phenomena, which can easily lead to a missed diagnosis of colorectal polyps and other diseases, and antispasmodic drugs can have adverse side effects. Previous studies find that acupuncture can regulate abnormal gastrointestinal motility. But evidence quality is low and limited at present, and high-quality studies are required. So this study sought to explore the efficacy and safety of acupuncture in inhibiting colonic spasm during endoscopy. Methods: In this prospective, single-blinded, randomized controlled trial, 54 patients experiencing intestinal spasms during colonoscopy were randomly assigned to receive either acupuncture of the bilateral Hegu (LI 4) and Neiguan (PC 6) points (n=27) or sham acupuncture (n=27). The sham points were located 1 cm above the proximal end of the true points and had no known function. The primary outcome was the latency time to colonic spasm suppression, and the secondary outcomes were the duration of colonic spasm suppression, the proportion of patients with rebound spasms within 5 minutes, and adverse events related to acupuncture-related side effects. Results: A total of 54 patients were eligible, and 27 in each group. There was no significant difference in the background characteristics of the patients in the 2 groups. The latency time to spasm suppression of the treatment group was significantly shorter than that of the sham control group (acupuncture: 32.00 s vs. sham: 82.00 s; P<0.001). However, the duration of colonic spasm suppression was similar (acupuncture: 300 s vs. sham: 268 s; P=0.142). No rebound spasms were observed in the treatment group but rebound spasms were observed in 3 patients in the sham control group (acupuncture: 0% vs. sham: 11.1%; P=0.236). No adverse events were observed in either group. Conclusions: Acupuncture of the bilateral Hegu (LI 4) and Neiguan (PC 6) points can shorten the latency time to spasm suppression, and may be used to suppress colonic spasm during colonoscopy. Trial registration: Chinese Clinical Trial Registry ChiCTR2000037796.

Better Bioactivity, Cerebral Metabolism and Pharmacokinetics of Natural Medicine and Its Advanced Version.

Currently, many people are afflicted by cerebral diseases that cause dysfunction in the brain and perturb normal daily life of people. Cerebral diseases are greatly affected by cerebral metabolism, including the anabolism and catabolism of neurotransmitters, hormones, neurotrophic molecules and other brain-specific chemicals. Natural medicines (NMs) have the advantages of low cost and low toxicity. NMs are potential treatments for cerebral diseases due to their ability to regulate cerebral metabolism. However, most NMs have low bioavailability due to their low solubility/permeability. The study is to summarize the better bioactivity, cerebral metabolism and pharmacokinetics of NMs and its advanced version. This study sums up research articles on the NMs to treat brain diseases. NMs affect cerebral metabolism and the related mechanisms are revealed. Nanotechnologies are applied to deliver NMs. Appropriate delivery systems (exosomes, nanoparticles, liposomes, lipid polymer hybrid nanoparticles, nanoemulsions, protein conjugation and nanosuspensions, etc.) provide better pharmacological and pharmacokinetic characteristics of NMs. The structure-based metabolic reactions and enzyme-modulated catalytic reactions related to advanced versions of NMs alter the pharmacological activities of NMs.

The early predictive effect of low expression of the ITGA4 in colorectal cancer.

Background: The early diagnosis of colorectal cancer (CRC) is very important for the prognosis of patients. It has been suggested that the cytosine-phosphate-guanine (CpG) island of itga4 is highly methylated in colorectal adenoma cell lines AA/C1, Vaco 235 and so on. So the purpose of our study is to explore the diagnostic accuracy and related mechanism of integrin alpha 4 (ITGA4) in early CRC. Methods: The Cancer Genome Atlas (TCGA) database was used to analyze the relationship between the expression of ITGA4 and the clinicopathological features and the overall survival rate of the disease. Then, the interaction protein and function enrichment region of ITGA4 were analyzed. Finally, the infiltration of related immune cells was analyzed. Results: Compared with normal tissues, the expression of ITGA4 in colon adenocarcinoma and rectum adenocarcinoma (COAD-READ) tumor tissues was lower (P<0.05). The overall survival rate of COAD-READ patients with low ITGA4 level was lower than that of patients with high ITGA4 expression (P<0.05), and expression of ITGA4 had a more significant predictive effect in the early stage of tumor development. The results of protein network and enrichment analysis suggested that ITGA4 was closely related to ITGB2 and might be involved in the inflammatory reaction and inflammatory tumor transformation process in the carcinogenesis of inflammatory bowel disease (IBD), which was verified by another independent sequence. In terms of immune infiltration, the expression level of ITGA4 was positively correlated with the infiltration level of intestinal macrophages (Th17), immature dendritic cells (IDC), dendritic cells (DC), mast cells, and eosinophils in COAD-READ, and significantly negatively correlated with CD56bright natural killer (NK) cells. Conclusions: The low expression of ITGA4 was related to the poor prognosis of COAD-READ. Findings showed that ITGA4 might participate in the inflammatory reaction and inflammatory tumor transformation process in the carcinogenesis of IBD, and that ITGA4 was related to the infiltration of immune cells, macrophages, syndactyls, and CD56bright NK cells. The expression of ITGA4 could be used as an early predictor of CRC. However, the mechanism of ITGA4 promoting tumor progression in CRC still needs further research.

Prognostic value of nicotinamide adenine dinucleotide (NAD+) metabolic genes in patients with stomach adenocarcinoma based on bioinformatics analysis.

Background: Because stomach adenocarcinoma (STAD) has a poor prognosis, it is necessary to explore new prognostic genes to stratify patients to guide existing individualized treatments. Methods: Survival and clinical information, RNA-seq data and mutation data of STAD were acquired from The Cancer Genome Atlas (TCGA) database. Fifty-one nicotinamide adenine dinucleotide (NAD+) metabolism-related genes (NMRGs) were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Differentially expressed NMRGs (DE-NMRGs) between STAD and normal samples were screened, and consistent clustering analysis of STAD patients was performed based on the DE-NMRGs. Survival analysis, Gene Set Enrichment Analysis (GSEA), mutation frequency analysis, immune microenvironment analysis and drug prediction were performed among different clusters. Additionally, the differentially expressed genes (DEGs) among different clusters were selected, and the intersections of DEGs and DE-NMRGs were selected as the prognostic genes. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was performed on a human gastric mucosa epithelial cell line and cancer cell line to verify the expression of the prognostic genes. Results: A total of 27 DE-NMRGs and two clusters were selected. There was a difference in survival between clusters 1 and 2. Furthermore, 18 DE-NMRGs were significantly different between clusters 1 and 2. The different Gene Ontology (GO) biological processes and KEGG pathways between clusters 1 and 2 were mainly enriched in cyclic nucleotide mediated signaling, synaptic signaling and hedgehog signaling pathway, etc. The somatic mutation frequencies were different between the two clusters, and TTN was the highest mutated gene in the patients of the clusters 1 and 2. Additionally, eight immune cells, immune score, stromal score, and estimate score were different between clusters 1 and 2. The patients in cluster 2 were sensitive to CTLA4 inhibitor treatment. Furthermore, the top five drugs (AP.24534, BX.795, Midostaurin, WO2009093927 and CCT007093) were significantly higher in cluster 1 than in cluster 2. Finally, three genes (AOX1, NNMT and PTGIS) were acquired as prognostic, and their expressions were consistent with the results of bioinformatics analysis. Conclusions: Three prognostic genes related to NAD+ metabolism in STAD were screened out, which provides a theoretical basis and reference value for future treatment and prognosis of STAD.

Evaluating the role of Ubiquitin D gene expression in types of leukemia.

Using animal models to develop new treatments is essential, especially in diseases like cancer. In this study, we induced leukemia by intravenous injection of cancer cells (BCL1 cell line) and the examination of cell markers in the animal's blood to study the changes in the expression of the UBD gene as a biomarker for diagnosing and examining the progress of the disease. For this purpose, five million BCL-1 cells were injected into the tail vein of BALBIe mice of the same breed. Fifty mice were killed after four weeks, and we examined peripheral blood cells and histological changes. Then RNA of the samples was extracted, and cDNA synthesis was done with the help of MMuLV enzyme, Oligo dT, and Random hexamer primers. Specific primers for UBD were designed using Primer Express software, and the expression level of the UBD gene was measured by the method. The results showed that in the CML group, the lowest expression level was 1.70 times, and in the ALL group, the highest expression level was 7.97 times compared to the control group. The average increase in UBD gene expression was 3.21 times in the CLL group and 4.94 times in the AML group. The UBD gene can be further investigated so that it may be used as a proposed biomarker for the diagnosis of leukemia. Therefore, the evaluation of the expression level of this gene can be used to diagnose leukemia. However, more studies than the currently applied methods are needed in cancer diagnosis, which has many errors compared to the technique used in this study, and to prove its accuracy and sensitivity.

A retrospective study of the antibiotic-resistant phenotypes and genotypes of Helicobacter pylori strains in China.

Helicobacter pylori antibiotic resistance is a serious concern in China, where it severely influences treatment for H. pylori infection. To overcome this, it is essential to apply personalized therapies based on local or individual data on antibiotic-resistant phenotypes or genotypes. We conducted a large-scale multi-center study with a retrospective cross-sectional observational design to investigate the antibiotic-resistant phenotypes and genotypes of H. pylori in China. Strains were isolated from the gastric biopsy samples of H. pylori-infected patients from five different regions in China. The strains were tested for antibiotic-resistant phenotypes and genotypes, and the agreement between the two was assessed. In total, 4242 H. pylori strains were isolated and cultured, with an 84.43% success rate. The primary and secondary antibiotic resistance rates of H. pylori were 37.00% and 76.93% for clarithromycin, 34.21% and 61.58% for levofloxacin, 2.20% and 6.12% for amoxicillin, 1.61% and 3.11% for furazolidone, 1.18% and 3.31% for tetracycline, and 87.87% and 93.48% for metronidazole, respectively. The dual-resistance patterns for metronidazole/clarithromycin, metronidazole/levofloxacin, and clarithromycin/levofloxacin were 43.6%, 38.4%, and 26.1%, respectively. Clarithromycin- and levofloxacin-resistant H. pylori phenotypes and genotypes showed satisfactory agreement. Based on these findings, clarithromycin- and levofloxacin-resistant genotype testing could partially replace traditional antibiotic susceptibility testing in China. Continuous monitoring and personalized treatments based on individual and local H. pylori antibiotic-resistance data remain necessary.

Ternary supramolecular nanocomplexes for superior anticancer efficacy of natural medicines.

The discovery of effective anticancer drug delivery systems and elucidation of the mechanism are enormous challenges. Using two drug administration-approved biomaterials, we constructed a natural medicine (NM)-loaded ternary supramolecular nanocomplex (TSN) suitable for large-scale production. The TSN has a better effect against cancer cells/stem cells than NM with differentially upregulated (27 versus 59) and downregulated (165 versus 66) proteins, respectively. Treatment with the TSN induced apoptosis and G2/M arrest, inhibited cell proliferation, metastasis and invasion, reduced colony/sphere formation, and decreased the frequency of side population cells and CD133+CD44+ABCG2+ cells. These results were revealed by multiple analyses (proteomic analysis, transwell migration and colony/sphere formation assays, biomarker profiling, etc.). We first reported the proteomic analysis of small lung cancer cells responding to a drug or its nanovesicles. We first conducted a proteomic evaluation of tumor cells responding to a drug supramolecular nanosystem. The supramolecular conformation of the TSN and the interactions of the TSN with albumin were verified by molecular docking experiments. The dominant binding forces in the TSN complexation process were electrostatic interactions, van der Waalsinteractions and bond stretching. The TSN binds to albumin more readily than NM does. The TSN has good in situ absorptive and in vitro/vivo kinetic properties. The relative bioavailability of the TSN to EA was 458.39%. The NM-loaded TSN is a supramolecular vesicle that can be produced at an industrial scale for efficient cancer therapy.

Patterns of Immune Infiltration in Endometriosis and Their Relationship to r-AFS Stages.

Background: Endometriosis (EMS) is an estrogen-dependent disease in which endometrial glands and stroma arise outside the uterus. Current studies have suggested that the number and function of immune cells are abnormal in the abdominal fluid and ectopic lesion tissues of patients with EMS. The developed CIBERSORT method allows immune cell profiling by the deconvolution of gene expression microarray data. Methods: By applying CIBERSORT, we assessed the relative proportions of immune cells in 68 normal endometrial tissues (NO), 112 eutopic endometrial tissues (EU) and 24 ectopic endometrial tissues (EC). The obtained immune cell profiles provided enumeration and activation status of 22 immune cell subtypes. We obtained associations between the immune cell environment and EMS r-AFS stages. Macrophages were evaluated by immunohistochemistry (IHC) in 60 patients with ovarian endometriomas. Results: Total natural killer (NK) cells were significantly decreased in EC, while plasma cells and resting CD4 memory T cells were increased in EC. Total macrophages in EC were significantly increased compared to those of EU and NO, and M2 macrophages were the primary macrophages in EC. Compared to those of EC from patients with r-AFS stage I ~ II, M2 macrophages in EC from patients with stage III ~ IV were significantly increased. IHC experiments showed that total macrophages were increased in EC, with M2 macrophages being the primary subtype. Conclusions: Our data demonstrate that deconvolution of gene expression data by CIBERSORT provides valuable information about immune cell composition in EMS.

Antiviral Drug Delivery System for Enhanced Bioactivity, Better Metabolism and Pharmacokinetic Characteristics.

Antiviral drugs (AvDs) are the primary resource in the global battle against viruses, including the recent fight against corona virus disease 2019 (COVID-19). Most AvDs require multiple medications, and their use frequently leads to drug resistance, since they have poor oral bioavailability and low efficacy due to their low solubility/low permeability. Characterizing the in vivo metabolism and pharmacokinetic characteristics of AvDs may help to solve the problems associated with AvDs and enhance their efficacy. In this review of AvDs, we systematically investigated their structure-based metabolic reactions and related enzymes, their cellular pharmacology, and the effects of metabolism on AvD pharmacodynamics and pharmacokinetics. We further assessed how delivery systems achieve better metabolism and pharmacology of AvDs. This review suggests that suitable nanosystems may help to achieve better pharmacological activity and pharmacokinetic behavior of AvDs by altering drug metabolism through the utilization of advanced nanotechnology and appropriate administration routes. Notably, such AvDs as ribavirin, remdesivir, favipiravir, chloroquine, lopinavir and ritonavir have been confirmed to bind to the severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) receptor and thus may represent anti-COVID-19 treatments. Elucidating the metabolic and pharmacokinetic characteristics of AvDs may help pharmacologists to identify new formulations with high bioavailability and efficacy and help physicians to better treat virus-related diseases, including COVID-19.

[Preparation, Characterization and Pharmacokinetic Study of Arginine Deiminase Lipid Nanoparticles].

OBJECTIVE: To prepare and characterize D-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) modified arginine deiminase (ADI) sulfobutyl-ß-Cyclodextrin liposome nanoparticles (ATCL), and to investigate the pharmacokinetic characteristics of ATCL in animals. METHODS: The reverse evaporation method was used to prepare ATCL, and the particle size and Zeta potential of ATCL were measured. Thiosemicarbazone-diacetylmonooxime colorimetric method was used to measure the activity of ADI. After intravenous administration, blood was drawn at set intervals of time and the enzyme activity in the plasma was measured. Enzyme activity-time curve was drawn subsequently and Debris Assessment Software (DAS) 2.1.1 was used to analyze the pharmacokinetic characteristics. RESULTS: The particle size and the potential of ATCL were (216.1±13.6) nm and (-19.4±2.1) mV, respectively. The optimal temperature and optimal pH for the catalytic reaction of ADI and ATCL were the same, both being 37 ℃ and pH6.5. Results of the analysis showed that the AUC (0-168 h), MRT (0-168 h), C max, T max, and t 1/2 of ATCL were 3.99, 2.56, 1.58, 3.2, and 9.88 times those of free ADI, respectively. Compared with ADI, the bioavailability of ATCL increased by 298.54%. CONCLUSION: ATCL prepared in the study can effectively improve the enzyme activity and bioavailability of ADI in Sprague-Dawley rats.

A novel evodiamine amino derivative as a PI3K/AKT signaling pathway modulator that induces apoptosis in small cell lung cancer cells.

Evodiamine (EVO) was derivatized to a C10-amino derivative (EVA) using a two-step method suitable for industrializing production. This method has advantages such as a short reaction time, high yield, few byproducts and simple purification. The AUC and Cmax values of EVA were 7.02- and 4.62-fold, while the Tmax and Cl values were one-half and one-eighth that of EVO, respectively. EVA markedly improved the bioavailability, which might be ascribed to the serum albumin deposit effect. EVA was bound to albumin in the same hydrophobic pocket as EVO, but one more hydrogen bond was formed between Asp323 and the amino group at the C10 position. The amino derivative of natural alkaloids showed a substantial increase in antitumor activity on small cell lung cancer (SCLC) cells. The role of the PI3K/AKT signaling pathway in alkaloid/derivative-induced apoptosis in tumor cells was thoroughly described. p-AKT, its downstream effectors Bcl-2, Bax, caspase-3 and its upstream regulator PTEN were regulated by EVA. The interaction between EVO/EVA and the upstream protein PI3K p110 was first investigated with molecular docking. The apoptosis induced by EVA was abrogated after the PI3K/AKT signaling pathway was reactivated by IGF-1. The interaction between EVO/EVA and P-gp was also first studied using docking method. Their binding forces were weak. But EVA might reduce much expression of P-gp than EVO, and ultimately led to reduction of EVA efflux. Our study provides novel insights into a feasible and productive amino derivative of natural alkaloids for SCLC therapy.

Smart Stimuli-Responsive and Mitochondria Targeting Delivery in Cancer Therapy.

Dysfunction in the mitochondria (Mc) contributes to tumor progression. It is a major challenge to deliver therapeutic agents specifically to the Mc for precise treatment. Smart drug delivery systems are based on stimuli-responsiveness and active targeting. Here, we give a whole list of documented pathways to achieve smart stimuli-responsive (St-) and Mc-targeted DDSs (St-Mc-DDSs) by combining St and Mc targeting strategies. We present the formulations, targeting characteristics of St-Mc-DDSs and clarify their anti-cancer mechanisms as well as improvement in efficacy and safety. St-Mc-DDSs usually not only have Mc-targeting groups, molecules (lipophilic cations, peptides, and aptamers) or materials but also sense the surrounding environment and correspondingly respond to internal biostimulators such as pH, redox changes, enzyme and glucose, and/or externally applied triggers such as light, magnet, temperature and ultrasound. St-Mc-DDSs exquisitely control the action site, increase therapeutic efficacy and decrease side effects of the drug. We summarize the clinical research progress and propose suggestions for follow-up research. St-Mc-DDSs may be an innovative and sensitive precision medicine for cancer treatment.

Photoresponsive porous ZnO-based broad-spectrum venom first-aid treatment.

A venomous snakebite is an emergency. However, antivenoms are rare and very similar, difficult to produce and preserve, and almost impossible to be used for emergency treatment. Therefore, it would be of great significance to develop convenient, efficient and broad-spectrum snake venom neutralizing nano-materials. In this study, inspired by boiled eggs, a new concept based on a ZnO complex (ZC) for the treatment of snake venoms is proposed. In vitro and in vivo experiments proved that ZC could widely adsorb biological (including snake) venoms and effectively reduce the concentration of toxic protein in the blood. More importantly, ZC could realize photothermal conversion under the stimulation of near-infrared (NIR) irradiation, resulting in protein hydrolyzation of venoms, thereby fundamentally prolonging survival time. In addition, ZC not only showed good biocompatibility, but also could inhibit bacterial reproduction, alleviate inflammation, and contribute to the healing of open wounds caused by biological venoms.

Tiaochang Xiaoliu Decoction Granules prevent the recurrence of colorectal adenoma: a study protocol for a randomized controlled trial.

BACKGROUND: With the changes in lifestyle and diet, the incidence and mortality of colorectal cancer (CRC) is increasing in China. CRC mainly develops from colorectal adenomas (CRAs). There is a lack of chemopreventative drugs with definite efficacy for CRAs. Tiaochang Xiaoliu Decoction (TXD) was developed by Professor Yunjian Luo and has been used clinically over the last ten years for the prevention of CRA recurrence. To facilitate its clinical use, TXD was further standardized and produced as "Tiaochang Xiaoliu Decoction Granules (TXDG)". A study was designed to investigate the preventive effects of TXDG on the recurrence of CRA. METHODS: A randomized, double-blinded, controlled, and multi-center experiment is proposed to assess the effectiveness and safety of TXDG. Patients with CRAs (after complete polypectomy under colonoscopy) will be randomly divided into two groups, one will be treated with TXDG (the TXDG group) and the other will be treated with a TXDG mimetic agent (the TXDG mimetic group). The patients will be treated for 6 months and followed up for 3 years. Follow-up colonoscopy is expected to be carried out within 1 to 3 years after the baseline examinations. The primary outcome measure is adenoma detection rate within 1 to 3 years. The secondary outcome measures are the number, location, and pathology of the adenomas, and the polyp detection rate. DISCUSSION: Reliable objective evidence will be provided to evaluate the efficacy and safety of TXDG as an accessorial therapy for CRA occurrence in post-polypectomy patients. TRIAL REGISTRATION: ChiCTR2000035257.