NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression.

Nonalcoholic fatty liver disease (NAFLD) is mainly characterized by excessive fat accumulation in the liver, and it is associated with liver-related complications and adverse systemic diseases. NAFLD has become the most prevalent liver disease; however, effective therapeutic agents for NAFLD are still lacking. We combined clinical data with proteomics and metabolomics data, and found that the mitochondrial nucleoside diphosphate kinase NME4 plays a central role in mitochondrial lipid metabolism. Nme4 is markedly upregulated in mice fed with high-fat diet, and its expression is positively correlated with the level of steatosis. Hepatic deletion of Nme4 suppresses the progression of hepatic steatosis. Further studies demonstrated that NME4 interacts with several key enzymes in coenzyme A (CoA) metabolism and increases the level of acetyl-CoA and malonyl-CoA, which are the major lipid components of the liver in NAFLD. Increased level of acetyl-CoA and malonyl-CoA  lead to increased triglyceride levels and lipid accumulation in the liver. Taken together, these findings reveal that NME4 is a critical regulator of NAFLD progression and a potential therapeutic target for NAFLD.

Effects of Moringa Oleifera Leaf Extract Plus Rosiglitazone on Serum Leptin and Glucose and Lipid Metabolism in Type 2 Diabetic Rats.

Objective: To investigate the effects of Moringa Oleifera Leaf Extract (MOLE) plus rosiglitazone (RSG) on glucose and lipid metabolism, serum leptin, and the Akt/GSK3ß/ß-Catenin signaling pathway in type 2 diabetic (T2D) rats. Methods: Sixty male Sprague-Dawley (SD) rats were randomly divided into six groups: the normal group, the model group, the RSG group, the low- and high-dose MOLE group, and the MOLE+RSG group. The normal group was fed a standard rat diet, while the other groups were given a single intraperitoneal injection of low-dose streptozomycin (STZ) (35 mg/kg) and fed a high-sugar and high-fat diet. After 8 weeks, the treatment outcomes were evaluated by measuring key parameters of blood glucose and lipid metabolism and the protein kinase B (AKT) / Glycogen synthase kinase 3beta (GSK3ß) /ß-Catenin signaling pathway in the T2D rats. Results: Compared with the normal group, the model group showed significantly increased levels of blood glucose, blood lipids, serum leptin, free fatty acid (FFA), and tumor necrosis factor-α (TNF-α). Compared with the model group, the RSG, low-dose MOLE, and high-dose MOLE groups displayed effective control of blood glucose, blood lipids, serum leptin, FFA, and TNF-α. The MOLE+RSG group surpassed the RSG group in regulating glucose, lipid metabolism, and serum leptin levels in T2D rats. In addition, the MOLE+RSG group also had superiority over the RSG group in activating the AKT/GSK3ß/ß-Catenin pathway. Conclusion: MOLE plus RSG can effectively reduce blood glucose and blood lipids in T2DM rats.

Influence of Gegenqinlian decoction on pharmacokinetics and pharmacodynamics of saxagliptin in type 2 diabetes mellitus rats.

Gegenqinlian decoction (GQD) is a classic prescription of traditional Chinese medicine (TCM), which originated from Shanghanlun. The combination of GQD and hypoglycemic drugs (saxagliptin, Sax, metformin) is often used to treat Type 2 diabetes mellitus (T2DM) in TCM clinics. However, the herb-drug interactions (HDIs) between GQD and hypoglycemic drugs are still unclear. In order to determine the safety of the combination, we assessed the influences of GQD on the pharmacokinetics and pharmacodynamics of Sax in T2DM rats. The plasma concentration of Sax (5 mg/kg) pretreated with GQD (freeze-dried powder, 1.35 g/kg) or not was determined by high-performance liquid chromatography (HPLC), and pharmacokinetics parameters were calculated. The influence of GQD on the pharmacodynamics of Sax was investigated by detecting the levels of weight, (see abbreviations list) OGTT, TC, TG, LDL-C, HDL-C, FBG, FINS, HOMA-IR, QUICKI, AST, ALT, and the liver coefficient. The Cmax , AUC0-t ,and AUC0-∞ of Sax increased significantly in the combination group whether in normal or T2DM rats. The results of pharmacodynamics showed that the weight of rats in each treatment group increased. FBG, TC, TG, LDL-C, and HOMA-IR decreased, HDL-C, FINS, and QUICKI increased significantly (p < 0.05) compared with the model control group. The result showed that the combination of GQD and Sax could not only improve the hypoglycemic effect but also increase the plasma exposure of Sax. The potential HDIs between GQD and Sax should be taken into consideration in clinics. Moreover, for the complexity of the human compared with experimental animals, as well as genetic differences, the in-depth study should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.

Comparison of three sedation models for same-day painless bidirectional endoscopy: A multicenter randomized controlled trial.

BACKGROUND AND AIM: We investigated the most beneficial propofol sedation model for same-day painless bidirectional endoscopy (BDE). METHODS: Asymptomatic participants scheduled for same-day painless BDE examination from October 2020 to September 2021 were randomized to three groups: sedated esophagogastroduodenoscopy followed by unsedated colonoscopy (Group A); sedated esophagogastroduodenoscopy followed by sedated colonoscopy (Group B); and sedated esophagogastroduodenoscopy followed by sedated insertion colonoscopy (Group C). Patient discomfort, colonoscopy performance, doses of propofol, cardiovascular stress, anesthesia resuscitation, and sedation-related adverse events were evaluated. RESULTS: A total of 3200 participants were analyzed. Baseline demographics, patient discomfort, cecal intubation rate, adenoma detection rate and sedation-related adverse events were similar in the three groups. Propofol dose was the lowest in Group A (137.65 ± 36.865 mg) compared with Group B (177.71 ± 40.112 mg, P < 0.05) and Group C (161.63 ± 31.789 mg, P < 0.05). Decline in vital signs was most obvious in Group B during the procedure (P < 0.05). Recovery time was the shortest in Group A (5.01 ± 1.404 min) compared with Group B (9.51 ± 2.870 min, P < 0.05) and Group C (5.83 ± 2.594 min, P < 0.05); discharge time was the shortest in Group A (3.53 ± 1.685 min) compared with Group B (11.29 ± 5.172 min, P < 0.05) and Group C (6.47 ± 2.338 min, P < 0.05). Adenomas per positive patient of Group A (2.29 ± 1.055) and Group C (2.28 ± 0.931) were more than that in Group B (2.11 ± 0.946, P < 0.05). CONCLUSIONS: Sedated esophagogastroduodenoscopy followed by unsedated colonoscopy is the superior model for same-day painless BDE with the benefits of satisfactory patient comfort, reduced sedation dose, less cardiovascular stress, faster recovery, shorter discharge time and high colonoscopy quality.

Fucoxanthin@Polyvinylpyrrolidone Nanoparticles Promoted Oxidative Stress-Induced Cell Death in Caco-2 Human Colon Cancer Cells.

Fucoxanthin (FX), a natural carotenoid found in seaweed with multiple functional activities, is unstable with a poor water solubility that limits its utilization. This study aimed to improve FX's stability and bioavailability via the nano-encapsulation of FX in polyvinylpyrrolidone (PVP)-coated FX@PVP nanoparticles (NPs). The FX@PVP NPs were evaluated in terms of their morphology, stability, encapsulation efficiency (EE), loading capacity (LC), and in vitro release to optimize the encapsulation parameters, and a 1:8 FX:PVP ratio was found to perform the best with the highest EE (85.50 ± 0.19%) and LC (10.68 ± 0.15%) and improved FX stability. In addition, the FX@PVP NPs were shown to effectively deliver FX into Caco-2 cancer cells, and the accumulation of FX in these cancer cells showed pro-oxidative activities to ameliorate H2O2-induced damage and cell death. The FX@PVP NPs could potentially become a new therapeutical approach for targeted cancer treatment.

Stepwise frontal affinity chromatography model for drug and protein interaction.

Frontal affinity chromatography is an efficient technique that combines affinity interaction and high-performance liquid chromatography, and frontal analysis has been used in studying the interaction between drugs and proteins. Based on frontal analysis, stepwise frontal analysis has been established. The present study aimed to use the Lineweaver-Burk plot in stepwise frontal analysis by taking the weighted average of time data. Commercial human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP) columns were used as an affinity column. Warfarin and digitoxin were chosen as model drugs for the HSA column, whereas verapamil and tamsulosin were selected as model drugs for the AGP column. The time data obtained by frontal analysis and stepwise frontal analysis were compared, and the results revealed good correlation (r2 = 0.9946-0.9998). Frontal analysis and stepwise frontal analysis were also used to analyze the equilibrium dissociation constants (Kd) of model drugs on the HSA and AGP columns. The Kd values were compared with literature values, which revealed the same order of magnitude. These results illustrate that conversion of the time data is reasonable and feasible. The Lineweaver-Burk plot can be used in the stepwise frontal analysis model to study the characteristics of the interaction between drugs and proteins. Graphical abstract ᅟ.

Functional identification of AeHMGR gene involved in regulation of saponin biosynthesis in Aralia elata.

Aralia elata (Miq.) Seem, a significant tree species in the Araliaceae family, has medicinal and edible properties. Saponins are the primary active components of A. elata. The 3-hydroxy-3-methylglutaryl- CoA reductase (HMGR) is the initial rate-limiting enzyme of the major metabolic pathway of saponins in A. elata. In this study, the AeHMGR gene was identified through screening of transcriptome data. Through the qRT-PCR analysis, it was determined that the expression level of AeHMGR gene is highest in the somatic embryo and stem of A. elata. Heterologous transformation in tobacco revealed that ectopic expression of the AeHMGR gene leads to a significant reduction in the expression levels of the NtSS, NtFPS, and NtSE genes in transgenic tobacco lines, with a minimum expression level of 0.24 times that of the wild type. In the overexpressed callus lines of A. elata, the expression levels of the AeFPS, AeSE, AeSS, and Aeß-AS genes were also significantly lower compared to the wild type, with a minimum expression level of approximately 0.3 times that of the wild type. Interestingly, the overexpression of the AeHMGR gene in A. elata somatic embryos led to a substantial decrease in the expression levels of AeFPS and AeSS, while the expression levels of AeSE and Aeß-AS increased. Among the transgenic somatic embryo strain lines, line 7 exhibited the highest expression levels of AeSE and Aeß-AS, with fold increases of 11.51 and 9.38, respectively, compared with that of the wild-type. Additionally, a high-performance liquid chromatography method was established to detect five individual saponins in transgenic A. elata. The total saponin content in line 7 somatic embryos was 1.14 times higher than that of wild-type materials, but only 0.30 times that of wild-type cultivated leaves. Moreover, the content of oleanolic acid saponin in line 7 was 1.35 times higher than that of wild-type cultivated leaves. These indicate that HMGR can affect triterpene biosynthesis.

Cryoprotective isoliquiritigenin-zein phosphatidylcholine nanoparticles inhibits breast cancer-bone metastasis by targeting JAK-STAT signaling pathways.

Breast cancer (BC) is the most common cancer in women and is known for its tendency to spread to the bones, causing significant health issues and mortality. In this study, we aimed to investigate whether cryoprotective isoliquiritigenin-zein phosphatidylcholine nanoparticles (ISL@ZLH NPs) could inhibit BC-induced bone destruction and tumor metastasis in both in vitro and animal models. To evaluate the potential of ISL@ZLH NPs, we conducted various experiments. First, we assessed cell viability, colony formation, transwell migration, and wound healing assays to determine the impact of ISL@ZLH NPs on BC cell behavior. Western blotting, TRAP staining and ALP activity were performed to examine the effects of ISL@ZLH NPs on osteoclast formation induced by MDA-MB-231 cell-conditioned medium and RANKL treated RAW 264.7 cells. Furthermore, we assessed the therapeutic impact of ISL@ZLH NPs on tumor-induced bone destruction using a mouse model of BC bone metastasis. Treatment with ISL@ZLH NPs effectively suppressed BC cell proliferation, colony formation, and motility, reducing their ability to metastasize. ISL@ZLH NPs significantly inhibited osteoclast formation and the expression of factors associated with bone destruction in BC cells. Additionally, ISL@ZLH NPs suppressed JAK-STAT signaling in RAW264.7 cells. In the BCBM mouse model, ISL@ZLH NPs led to a significant reduction in osteolytic bone lesions compared to the control group. Histological analysis and TRAP staining confirmed that ISL@ZLH NPs preserved the integrity of bone structure, preventing invasive metastasis by confining tumor growth to the bone marrow cavity. Furthermore, ISL@ZLH NPs effectively suppressed tumor-induced osteoclastogenesis, a key process in BC-related bone destruction. Our findings demonstrate that ISL@ZLH NPs have the potential to inhibit BC-induced bone destruction and tumor metastasis by targeting JAK-STAT signaling pathways and suppressing tumor-induced osteoclastogenesis. These results underscore the therapeutic promise of ISL@ZLH NPs in managing BC metastasis to the bones.

Analysis of endoscopic and pathological features of 6961 cases of gastric cancer.

Gastric cancer (GC) stage and tissue differentiation affect treatment efficacy and prognosis, highlighting the importance of understanding the risk factors that affect these parameters. Therefore, this study analyzed risk factors affecting the GC stage and differentiation and the relationships between the cancer site and the sex and age of the patient. We collected clinical data from 6961 patients with GC, including sex, age, endoscopic lesion location, and pathological differentiation. Patients were grouped based on GC stage (early or advanced), differentiation (well or poorly differentiated), and lesion site (upper stomach [cardia and fundus], middle stomach [gastric body], and lower stomach [gastric antrum]). Differences in sex, age, location, stage, and degree of differentiation were assessed based on these groupings. Univariate analysis revealed that the disease location and differentiation significantly differed based on the GC stage (P < 0.05), whereas sex, age, site, and stage significantly differed based on GC differentiation (P < 0.05). A multivariate analysis confirmed these factors as independent risk factors affecting GC. Moreover, lesion sites significantly differed between sexes (P < 0.05) and among age groups (P < 0.05). Although the effects of family history, lifestyle, and Helicobacter pylori infection status of the patients were not considered, this single-center retrospective study established independent risk factors for GC.Trial registration ChiCTR2200061989.

Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway.

The spreading of cancer cells from the primary tumor site to other parts of the body, known as metastasis, is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer (TNBC). Overexpression of epidermal growth factor receptor (EGFR) is observed in approximately 70% of TNBC patients. EGFR is crucial for promoting tumor metastasis and associated with poor prognosis. Therefore, it is vital to identify effective therapeutic strategies targeting EGFR inhibition. Ononin, an isoflavonoid found in various plants, such as clover and soybeans, has been shown to have anticancer properties in several cancers. In the present study, we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular pathways. We used various assays, including cell viability, colony formation, Transwell, wound healing, ELISA, Western blotting, and staining techniques, to achieve this objective. The results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis, as evidenced by the cell viability assay, colony formation assay, and expression of apoptosis markers, and reduced the metastatic capabilities of TNBC cells. These effects were achieved through the direct suppression of cell adhesion, invasiveness and motility. Furthermore, in TNBC xenograft lung metastatic models, ononin treatment significantly reduced tumor growth and lung metastasis. Additionally, ononin reversed the epithelial-mesenchymal transition (EMT) by downregulating the expression of EMT markers and matrix metalloproteinases, as confirmed by Western blot analysis. Furthermore, ononin treatment reduced EGFR phosphorylation and suppressed the PI3K, Akt, and mTOR signaling pathways, which was further confirmed using EGFR agonists or inhibitors. Importantly, ononin treatment did not exert any toxic effects on liver or kidney function. In conclusion, our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFR-mediated PI3K/Akt/mTOR pathway. Further studies are warranted to validate its efficacy and explore its potential clinical applications.

Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21.

Non-alcoholic fatty liver disease (NAFLD) has been shown to influence breast cancer progression, but the underlying mechanisms remain unclear. In this study, we investigated the impact of NAFLD on breast cancer tumor growth and cell viability through the potential mediator, hepatic fibroblast growth factor 21 (FGF21). Both peritumoral and systemic administration of FGF21 promoted breast cancer tumor growth, while FGF21 knockout attenuated the tumor-promoting effects of the high-fat diet. Mechanistically, exogenous FGF21 treatment enhanced the anti-apoptotic ability of breast cancer cells through STAT3 and Akt/FoXO1 signaling pathways, and mitigated doxorubicin-induced cell death. Furthermore, we observed overexpression of FGF21 in tumor tissues from breast cancer patients, which was associated with poor prognosis. These findings suggest a novel role for FGF21 as an upregulated mediator in the context of NAFLD, promoting breast cancer development and highlighting its potential as a therapeutic target for cancer treatment.

Analyzing the impact of industrial growth and agricultural development on environmental degradation in South and East Asia.

This study aims to examine the impact of industrial growth, agricultural value added, economic growth, and renewable energy consumption on environmental pollution in South and East Asian countries using panel ARDL approach over the period 1970-2020. Furthermore, the impact of institutional quality in this relationship is uniquely explored. Baseline model suggests that environmental damage is exacerbated by agricultural value added and industrial growth in the long run, but not in the short run. The relationship between economic growth and carbon emissions is an obvious inverted U-shaped link in the long run, but it is a U-shaped association in the short run. Renewable energy consumption has significant adverse effects on environmental pollution both in the short and long term. In the long run, institutional quality plays a stronger moderating role in the association between baseline regressors and environmental pollution. Also, institutional quality helps to expand the ability of industry and agriculture to improve environmental quality. Lastly, the threshold results reflect that the impact of regressors on environmental degradation is penetrating into the level of institutional quality. The strong progressive effects of agricultural and industrial growth on environmental degradation are more similar to the existing literature in the long term, but not in the short term. In addition, the long-term condensation effect of renewable energy on CO2 emissions and the enhancing effect of economic growth on CO2 emissions are relatively similar to existing literature. In contrast to weak institutional quality, strong institutions can improve the ability of agriculture and industry to reduce environmental damage.

Prognostic significance of high NPC2 expression in gastric cancer.

Gastric cancer is one of the most common malignancies worldwide, and the third leading cause of cancer-related death. The identification of novel biomarkers and therapeutic targets is critical to improve the prognosis. A total of 380 patients with primary gastric cancer from the TCGA database were analyzed. The receiver operating characteristic curves were plotted. We further evaluated the independent prognostic ability of NPC2 expression for overall survival (OS) and relapse-free survival (RFS) through the Kaplan-Meier curve and Cox analysis. The NPC2 expression was significantly higher (P < 0.001) in gastric cancer. High NPC2 expression was significantly (P < 0.0001) associated with poor OS and poor RFS. The age, stage, radiation therapy, residual tumor, and NPC2 expression showed independent prognostic value for OS. The gender and NPC2 expression showed independent prognostic value for RFS. The higher NPC2 expression was observed in gastric cancer, compared with adjacent normal tissue (P < 0.001), confirmed by the IHC staining. The CCK-8 assay showed that NPC2 knockdown inhibits cell proliferation while NPC2 overexpression promotes cell proliferation (P < 0.05). NPC2 expression may serve as a promising prognostic biomarker for patients with gastric cancer.

Unraveling the Role of Hepatic PGC1α in Breast Cancer Invasion: A New Target for Therapeutic Intervention?

Breast cancer (BC) is the most common cancer among women worldwide and the main cause of cancer deaths in women. Metabolic components are key risk factors for the development of non-alcoholic fatty liver disease (NAFLD), which may promote BC. Studies have reported that increasing PGC1α levels increases mitochondrial biogenesis, thereby increasing cell proliferation and metastasis. Moreover, the PGC1α/ERRα axis is a crucial regulator of cellular metabolism in various tissues, including BC. However, it remains unclear whether NAFLD is closely associated with the risk of BC. Therefore, the present study aimed to determine whether hepatic PGC1α promotes BC cell invasion via ERRα. Various assays, including ELISA, western blotting, and immunoprecipitation, have been employed to explore these mechanisms. According to the KM plot and TCGA data, elevated PGC1α expression was highly associated with a shorter overall survival time in patients with BC. High concentrations of palmitic acid (PA) promoted PGC1α expression, lipogenesis, and inflammatory processes in hepatocytes. Conditioned medium obtained from PA-treated hepatocytes significantly increased BC cell proliferation. Similarly, recombinant PGC1α in E0771 and MCF7 cells promoted cell proliferation, migration, and invasion in vitro. However, silencing PGC1α in both BC cell lines resulted in a decrease in this trend. As determined by immunoprecipitation assay, PCG1a interacted with ERRα, thereby facilitating the proliferation of BC cells. This outcome recognizes the importance of further investigations in exploring the full potential of hepatic PGC1α as a prognostic marker for BC development.

Predicting reflux symptom recurrence: The impact of gastroesophageal junction indicators and body mass index among outpatients.

The present study aimed to evaluate the efficacy of the prediction model in predicting reflux symptom recurrence among outpatients with reflux esophagitis (RE). A total of 261 outpatients diagnosed with RE complicated by anatomical alterations at the gastroesophageal junction and reflux symptoms were included in the study. Through follow-up, patients were divided into a General group (149 cases) and a Recurrent group (112 cases). Receiver operating characteristic curves of the related factors and prediction model were analyzed to compare the efficacy of each element in predicting reflux recurrence. A prediction model was constructed for predicting reflux recurrence using the axial length of the hiatal hernia (HH), the diameter of the esophageal hiatus, Hill classification, and body mass index (BMI) as risk factors. The cutoff values of the aforementioned factors for predicting reflux recurrence were: an axial length of HH >2 cm, esophageal hiatus diameter ≥3 cm, Hill grade >III, and BMI >25.1 kg/m2. The multivariate prediction model constructed using the aforementioned four indicators together with chronic atrophic gastritis and Helicobacter pylori infection had the area under the curve of 0.801 (95% confidence interval: 0.748-0.854), and the cutoff value of 46.8 had a sensitivity and specificity of 71.4% and 75.8%, respectively. The predictive model in the present study can be used for the primary assessment of reflux recurrence in patients with RE.

Augmenting mesenchymal stem cell therapy for osteoarthritis via inflammatory priming: a comparative study on mesenchymal stem cells derived from various perinatal tissue sources.

Background: Osteoarthritis (OA), a degenerative disease prevalent among the elderly, poses significant challenges due to its high incidence and disability rates. Regrettably, there exists a lack of effective regenerative therapies for the irreversible degradation of cartilage in OA. Mesenchymal stem cells (MSCs), known for their robust differentiation and immune regulatory capabilities, have emerged as promising candidates for OA treatment. MSCs sourced from perinatal tissues offer the dual advantage of convenience in extraction and ethical non-controversy. However, the heterogeneous nature of MSCs derived from different perinatal tissue sources gives rise to varying therapeutic indications. Moreover, the immune response of MSCs may be modulated under the influence of inflammatory factors. Methods: In this study, we isolated mesenchymal stem cells from distinct parts of human perinatal tissue: umbilical cord-derived MSCs (UC-MSCs), fetal placenta-derived MSCs (FP-MSCs), and umbilical cord placental junction-derived MSCs (CPJ-MSCs). These cells were cultured in vitro and subjected to a 24-hour treatment with the inflammatory mediator Interleukin-1ß (IL-1ß). Subsequently, the MSCs were evaluated for changes in proliferation, migration, and regulatory capabilities. To assess the comparative anti-injury potential of MSCs from different sources, primary articular chondrocytes (ACs) were exposed to H2O2-induced injury and co-cultured with IL-1ß-primed MSCs. Changes in the proliferation, migration, and regulatory abilities of ACs resembling those observed in OA were examined. Results: Following IL-1ß treatment, all three types of MSCs displayed decreased rates of proliferation and migration. Notably, their chondrogenic differentiation capacities exhibited an enhancement. Additionally, diverse MSCs exhibited a degree of efficacy in restoring damaged ACs in vitro. Among these, CPJ-MSCs demonstrated superior potential in promoting cartilage cell proliferation, while FP-MSCs displayed notable anti-inflammatory effects. Conclusion: Our findings underscore the substantial capacity of primed FP-MSCs and CPJ-MSCs to alleviate the injury in OA-like ACs. Consequently, this study advocates for the prospective use of preconditioning strategies involving FP-MSCs and CPJ-MSCs in forthcoming OA therapies.

Anti-migratory Properties of Cryoprotective Isoliquiritigenin-zein Phosphatidylcholine Nanoparticles Prevent Triple-negative Breast Cancer through PI3K-mTOR and MMP2/9 Pathways.

INTRODUCTION: Triple-negative breast cancer (TNBC), an aggressive type of breast cancer, remains difficult to treat. Isoliquiritigenin (ISL) is a bioactive compound that is insoluble in water and exhibits significant anti-TNBC activity. METHOD: We previously prepared oral aqueous ISL@ZLH NPs; however, they were less stable in a freezing environment. Hence, the present study aimed to improve the stability of ISL@ZLH NPs using cryoprotectants that can withstand long storage times and are effective in TNBC treatment by creating an efficient oral drug delivery system. Freeze-dried ISL@ZLH NP powder was prepared by solvent evaporation, followed by the addition of trehalose and sucrose. The freeze-dried ISL@ZLH NP pow was optimized and characterized. The anti-TNBC efficacy and pharmacokinetics of the ISL@ZLH NP-pow were examined in plasma and organs, compared with those of aqueous ISL@ZLH NPs. RESULT: The ideal particle size of the ISL@ZLH NP pow was 118 nm, which was not filtered out by the glomerulus and allowed the drug to be delivered to the lesions more effectively. Cellular uptake and biodistribution of the ISL@ZLH NP-pow in vivo and in vitro showed prolonged storage in the organs. In addition, cryopreserved ISL@ZLH NP-treated tumors showed significant anti-proliferative and anti-migratory effects through the downregulation of the PI3K-Akt-mToR and MMP2/9 signaling pathways. CONCLUSION: These results suggest that oral ingestion of cryopreserved ISL@ZLH NP has the potential for longterm storage and can be employed as a clinical therapeutic approach to treat TNBC.

Comparison of missed adenomas in deep-sedated and unsedated colonoscopy: A multicenter retrospective study.

BACKGROUND: Deep-sedated colonoscopy with propofol is widely used in China. However, its impact on quality metrics remains controversial. We aimed to investigate the effects of deep-sedated colonoscopy on missed adenomas, specifically in each colorectal segment. METHODS: Data of 3710 individuals from seven hospitals in China who underwent an initial colonoscopy with or without propofol sedation and a second colonoscopy without sedation within six months for surveillance or polypectomy by endoscopist of the same level between October 2020 and September 2021 were retrospectively analyzed. RESULTS: A total of 1113 missed adenomas in 3710 patients were evaluated. The adenoma miss rate (AMR) was significantly higher in deep-sedated colonoscopy than in unsedated colonoscop [19.14% (578/3020) vs. 16.15% (535/3313), P < 0.05]. The risk of missing adenomas in deep-sedated colonoscopy was 1.229 times higher than in unsedated colonoscopy (OR, 1.229; 95% CI: 1.080-1.399). AMRs of the splenic flexure (26.02% [96/369] vs. 16.04% [47/293], P < 0.05) and descending colon (20.86% [102/489] vs. 13.37% [54/404], P < 0.05) were significantly higher in deep-sedated colonoscopy than in unsedated colonoscopy when performed by middle-level endoscopists rather than high-level endoscopists (P < 0.05). CONCLUSIONS: AMR was higher in deep-sedated colonoscopy than in unsedated colonoscopy. Furthermore, adenomas in the splenic flexure and descending colon were more frequently missed in deep-sedated colonoscopy than in unsedated colonoscopy, particularly when performed by less experienced endoscopists.

Hepatic FGF21: Its Emerging Role in Inter-Organ Crosstalk and Cancers.

Fibroblast growth factor (FGF) 21 is one of the FGF members with special endocrine properties. In the last twenty years, it has attracted intense research and development for its physiological functions that respond to dietary manipulation, pharmacological benefits of improving the macronutrient metabolism, and clinical values as a biomarker of various human diseases. Generally, FGF21 can be produced by major metabolic organs, but only the subgroup from the liver shows canonical endocrine properties, which emphasizes the special value of delineating the unique secretory and functional characteristics of hepatic FGF21. There has been a growth in literature to address the extra-hepatic activities of FGF21, and many striking findings have therefore been published. Yet, they are fragmented and scattered, and controversies are raised from divergent findings. For this reason, there is a need for a systematic and critical evaluation of current research in this aspect. In this review, we focus on the current knowledge about the molecular biology of endocrine FGF21, especially present details on the regulation of circulating levels of FGF21. We also emphasize its emerging roles in inter-organ crosstalk and cancer development.

Influence of Gegenqinlian Decoction on Pharmacokinetics and Pharmacodynamics of Atorvastatin Calcium in Hyperlipidemic Rats.

BACKGROUND AND OBJECTIVES: Gegenqinlian decoction (GQD), a classic traditional Chinese medicine (TCM), was described in Shanghan Lun. GQD is often combined with antihyperlipidemic drugs (mainly atrovastatin calcium) in TCM clinics. However, the herb-drug interaction between GQD and atrovastatin calcium (AC) is still unknown. To determine whether the combination is safe, we evaluated the effects of GQD on the activities of cytochrome P450 (CYP) 3A2 enzyme and investigated the impact of GQD on the pharmacokinetics and pharmacodynamics of AC in rats. METHODS: The pharmacokinetics of AC (10 mg/kg) with or without pretreatment with GQD (freeze-dried powder, 1.35 g/kg) were investigated using HPLC. The influence of GQD on pharmacodynamics of AC were determined by detecting the levels of serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Moreover, the probe drug method was used to explore the effect of GQD on CYP3A2 activity. RESULTS: The pharmacokinetic parameters of AC combined with GQD were significantly affected (P < 0.05) in hyperlipidemic rats. The serum TC, TG and LDL-C levels of the combination were significantly reduced (P < 0.05), and the serum HDL-C level was significantly increased (P < 0.05) compared with AC/GQD alone. AST and ALT activities treated with both GQD and AC+GQD group were significantly reduced (P < 0.05) compared with AC group. There was a significant difference in the pharmacokinetic parameters of midazolam between control and GQD groups (P < 0.05). Maximum concentration (Cmax), area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) increased significantly in GQD group. CONCLUSIONS: The result suggested that GQD combined with AC can improve the lipid-lowering effect of AC and reduce the damage of AC to the liver simultaneously. However, GQD can inhibit the activity of CYP3A2 in hyperlipidemic rats and increase the blood concentration of AC. Therefore, the clinical dose of AC should be adjusted when they are combined. Since the study was conducted in rats,  further research should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.