A specific super-enhancer actuated by berberine regulates EGFR-mediated RAS-RAF1-MEK1/2-ERK1/2 pathway to induce nasopharyngeal carcinoma autophagy.

Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality rates caused by the distant metastasis and disease recurrence remain unsolved clinical problems. In clinic, the berberine (BBR) compound has widely been in NPC therapy to decrease metastasis and disease recurrence, and BBR was documented as a main component with multiple anti-NPC effects. However, the mechanism by which BBR inhibits the growth and metastasis of nasopharyngeal carcinoma remains elusive. Herein, we show that BBR effectively inhibits the growth, metastasis, and invasion of NPC via inducing a specific super enhancer (SE). From a mechanistic perspective, the RNA sequencing (RNA-seq) results suggest that the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway, activated by the epidermal growth factor receptor (EGFR), plays a significant role in BBR-induced autophagy in NPC. Blockading of autophagy markedly attenuated the effect of BBR-mediated NPC cell growth and metastasis inhibition. Notably, BBR increased the expression of EGFR by transcription, and knockout of EGFR significantly inhibited BBR-induced microtubule associated protein 1 light chain 3 (LC3)-II increase and p62 inhibition, proposing that EGFR plays a pivotal role in BBR-induced autophagy in NPC. Chromatin immunoprecipitation sequencing (ChIP-seq) results found that a specific SE existed only in NPC cells treated with BBR. This SE knockdown markedly repressed the expression of EGFR and phosphorylated EGFR (EGFR-p) and reversed the inhibition of BBR on NPC proliferation, metastasis, and invasion. Furthermore, BBR-specific SE may trigger autophagy by enhancing EGFR gene transcription, thereby upregulating the RAS-RAF1-MEK1/2-ERK1/2 signaling pathway. In addition, in vivo BBR effectively inhibited NPC cells growth and metastasis, following an increase LC3 and EGFR and a decrease p62. Collectively, this study identifies a novel BBR-special SE and established a new epigenetic paradigm, by which BBR regulates autophagy, inhibits proliferation, metastasis, and invasion. It provides a rationale for BBR application as the treatment regime in NPC therapy in future.

Selective Solid-Liquid Extraction of Lithium Cation Using Tripodal Sulfate-Binding Receptors Driven by Electrostatic Interactions.

Owing to the important role of and increasing demand for lithium resources, lithium extraction is crucial. The use of molecular extractants is a promising strategy for selective lithium recovery, in which the interaction between lithium and the designed extractant can be manipulated at the molecular level. Herein, we demonstrate that anion receptors of tripodal hexaureas can selectively extract Li2SO4 solids into water containing DMSO (0.8% water) compared to other alkali metal sulfates. The hexaurea receptor with terminal hexyl chains displays the best Li+ extraction selectivity at 2-fold over Na+ and 12.5-fold over K+. The driving force underpinning selective lithium extraction is due to the combined interactions of Li+-SO42- electrostatics and the ion-dipole interaction of the lithium-receptor (carbonyl groups and N atoms); the latter was found to be cation size dependent, as supported by computational calculations. This work indicates that anion binding receptors could drive selective cation extraction, thus providing new insights into the design of receptors for ion recognition and separation.

Integrated 3D Open Network of Interconnected Bismuthene Arrays for Energy-Efficient and Electrosynthesis-Assisted Electrocatalytic CO2 Reduction.

Electrocatalytic CO2 reduction reaction (CO2 RR) toward formate production can be operated under mild conditions with high energy conversion efficiency while migrating the greenhouse effect. Herein, an integrated 3D open network of interconnected bismuthene arrays (3D Bi-ene-A/CM) is fabricated via in situ electrochemically topotactic transformation from BiOCOOH nanosheet arrays supported on the copper mesh. The resulted 3D Bi-ene-A/CM consists of 2D atomically thin metallic bismuthene (Bi-ene) in the form of an integrated array superstructure with a 3D interconnected and open network, which harvests the multiple structural advantages of both metallenes and self-supported electrodes for electrocatalysis. Such distinctive superstructure affords the maximized quantity and availability of the active sites with high intrinsic activity and superior charge and mass transfer capability, endowing the catalyst with good CO2 RR performance for stable formate production with high Faradaic efficiency (≈90%) and current density (>300 mA cm-2 ). Theoretical calculation verifies the superior intermediate stabilization of the dominant Bi plane during CO2 RR. Moreover, by further coupling anodic methanol oxidation reaction, an exotic electrolytic system enables highly energy-efficient and value-added pair-electrosynthesis for concurrent formate production at both electrodes, achieving substantially improved electrochemical and economic efficiency and revealing the feasibility for practical implementation.

Sinomenine exerts a neuroprotective effect on PD mouse model through inhibiting PI3K/AKT/mTOR pathway to enhance autophagy.

BACKGROUND: Parkinson's disease (PD), as a chronic and progressive neurodegenerative disease, is associated with autophagy. This study focused on the regulation of sinomenine (SN) on autophagy in PD and its related mechanism. METHODS: The PD mouse model was constructed by MPTP inducement, and the mouse motor function after modeling and SN treatment was examined by rotarod, grip strength, and foot printing tests. Tyrosine hydroxylase (TH)/LC3B-positive neurons in the substantia nigra pars compacta of mouse brains were detected by immunofluorescence. The expressions of proteins related to autophagy (Beclin1, p62, LC3-I and LC3-II) and phosphorylated phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin kinase (mTOR) signaling pathway were measured by western blot. Rescue experiments were performed to determine the effects of MHY1485 (mTOR activator) on SN-treated PD mice. RESULTS: SN potentiated the motor ability in PD mice, promoted the survival of dopaminergic neurons, increased the protein expression level of Beclin1, LC3-II/LC3-I ratio and LC3B-positive neurons, lowered the protein expression level of p62 and inactivated PI3K/AKT/mTOR pathway in the substantia nigra tissue of mouse brains. Moreover, MHY1485 reversed the above effects of SN on PD mice via reactivating PI3K/AKT/mTOR pathway. CONCLUSION: SN augments the autophagy of dopaminergic neurons via inhibiting the PI3K/AKT/mTOR pathway and exerts a neuroprotective effect on PD mice.

A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health.

Curcumin is the most important active component in turmeric extracts. Curcumin, a natural monomer from plants has received a considerable attention as a dietary supplement, exhibiting evident activity in a wide range of human pathological conditions. In general, curcumin is beneficial to human health, demonstrating pharmacological activities of anti-inflammation and antioxidation, as well as antitumor and immune regulation activities. Curcumin also presents therapeutic potential in neurodegenerative, cardiovascular and cerebrovascular diseases. In this review article, we summarize the advancements made in recent years with respect to curcumin as a biologically active agent in malignant tumors, Alzheimer's disease (AD), hematological diseases and viral infectious diseases. We also focus on problems associated with curcumin from basic research to clinical translation, such as its low solubility, leading to poor bioavailability, as well as the controversy surrounding the association between curcumin purity and effect. Through a review and summary of the clinical research on curcumin and case reports of adverse effects, we found that the clinical transformation of curcumin is not successful, and excessive intake of curcumin may have adverse effects on the kidneys, heart, liver, blood and immune system, which leads us to warn that curcumin has a long way to go from basic research to application transformation.

PRMT5 promotes inflammation of cigarette smoke extract-induced bronchial epithelial cells by up-regulation of CXCL10.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is related to inflammation and obstruction of the lungs and airways. Protein arginine methyltransferase 5 (PRMT5) that promotes arginine methylation of histones is associated with inflammation of endothelial cell and is implicated in lung branching morphogenesis and progression of lung cancer. The mechanism of PRMT5 in inflammatory response of COPD was explored in this study. METHODS: Human bronchial epithelial cells, 16HBE, were treated with cigarette smoke extract for 24 h to establish cell model of COPD. Cell viability was examined by MTT assay. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to explore expression of PRMT5. Expression of Interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and IL-1ß were investigated by enzyme-linked-ithe mmunosorbent serologic assay. RESULTS: Cigarette smoke extract treatment induced cytotoxity of 16HBE with reduced cell viability. PRMT5 was enhanced in cigarette smoke extract-induced 16HBE. Knockdown of PRMT5 increased cell viability of cigarette smoke extract-induced 16HBE, and attenuated cigarette smoke extract-induced increase of IL-6, IL-8, TNF-α, and IL-1ß. Up-regulation of C-X-C Motif Chemokine 10 (CXCL10) in cigarette smoke extract-induced 16HBE was restored by knockdown of PRMT5. Over-expression of CXCL10 counteracted with the suppressive effect of PRMT5 silence on expression of IL-6, IL-8, TNF-α, and IL-1ß. Moreover, PRMT5 silence-induced increase of cell viability in cigarette smoke extract-induced 16HBE was reversed by over-expression of CXCL10. CONCLUSION: Knockdown of PRMT5 promoted cell viability of cigarette smoke extract-induced 16HBE, and reduced inflammation through down-regulation of CXCL10.

Characteristics of electrophysiological changes in the process of astrocytes pyroptosis after hyperoxia exposure. / 高氧损伤性星形胶质细胞焦亡过程的电生理变化特征.

OBJECTIVES: To observe the electrophysiological changes of astrocytes in the process of hyperoxia induced apoptosis and analyze the relationship between electrophysiological characteristics and morphological changes. METHODS: Astrocytes were exposed to 90% hyperoxia for 12-72 h. The electrophysiological characteristics of astrocytes in each group were detected by patch clamp technique, and the morphological characteristics of astrocytes were observed at the same time. Then the same batch of astrocytes were collected, and the expression levels of caspase-1, caspase-3, gasdermin D (GSDMD) and gasdermin E (GSDME) were detected by Western blotting. RESULTS: From 12 h to 72 h after hyperoxia exposure, the inward current was significantly lower than that of the control group (P<0.05), while the outward current was significantly decreased at 12 h and increased at 48 h (P<0.05). There was no significant difference between 24 h or 72 h after hyperoxia exposure and the control group (P>0.05). At each time point, the morphology of cells changed correspondingly. Western blotting showed that the expression of caspase-1 was increased significantly at 24 h and decreased significantly at 72 h after hyperoxia exposure (P<0.05); the expression of GSDMD was increased at 12 h and decreased gradually from 24 h to 72 h after hyperoxia exposure (P<0.05); the expression of caspase-3 did not change significantly at 12 h and 24 h after hyperoxia exposure (P>0.05), but began to decrease at 48 h (P<0.05); GSDME increased gradually at 24 h after hyperoxia exposure (P<0.05). CONCLUSIONS: Under hyperoxia exposure, the ion channels of astrocytes are damaged, which can maintain the dysfunction of ion homeostasis, activate GSDME, induce the damaged cells to break away from the apoptotic pathway, and mediate the pyroptosis.

Efficacy of triptans for the treatment of acute migraines: a quantitative comparison based on the dose-effect and time-course characteristics.

OBJECTIVES: This study aimed to establish a pharmacodynamic model to quantitatively compare the efficacy characteristics of seven kinds of triptans and their different dosage forms in the treatment of acute migraines. METHODS: Clinical studies of triptans in the treatment of acute migraines were comprehensively searched in the public databases. Pharmacodynamic models were established to describe the dose-effect and time-course of each kind of triptan for the proportion of patients who became pain free or had pain relief. RESULTS: A total of 92 articles involving 47,376 subjects were included in the analysis. After eliminating the placebo effect, oral eletriptan (40 mg) had the highest efficacy among all oral drugs at the maximum approved dose, and the proportion of patients who became pain free and had pain relief were 30.9% and 37.9% at 2 h, respectively. However, oral naratriptan (2.5 mg) had the lowest efficacy, and the proportion of patients who became pain free and had pain relief was 10.3% and 21.6% at 2 h, respectively. The efficacy of subcutaneous administration was significantly higher than that of oral administration, and the efficacy of nasal spray administration was comparable to that of oral administration. Regarding the dose-effect, the efficacy of the sumatriptan nasal spray significantly increased within the FDA (Food and Drug Administration)-approved dose range. When the dose was increased from 5 to 20 mg of sumatriptan nasal spray, the proportion of patients who became pain free and had pain relief increased by 16.8% and 18.3% at 2 h, respectively. Regarding the time-course, the time of onset of subcutaneous sumatriptan (6 mg) was the fastest, and the fraction of patients who were pain free at 2 h accounted for 90.6% of that at 4 h. CONCLUSIONS: This study evaluated the efficacy characteristics of seven kinds of triptans and their different dosage forms. The present findings provide necessary quantitative information for migraine medication guidelines.

Curcumin Nicotinate Selectively Induces Cancer Cell Apoptosis and Cycle Arrest through a P53-Mediated Mechanism.

Curcumin is an anticancer agent, but adverse effects and low bioavailability are its main drawbacks, which drives efforts in chemical modifications of curcumin. This study evaluated antiproliferative activity and cancer cell selectivity of a curcumin derivative, curcumin nicotinate (CN), in which two niacin molecules were introduced. Our data showed that CN effectively inhibited proliferation and clonogenic growth of colon (HCT116), breast (MCF-7) and nasopharyngeal (CNE2, 5-8F and 6-10B) cancer cells with IC50 at 27.7 µM, 73.4 µM, 64.7 µM, 46.3 µM, and 31.2 µM, respectively. In cancer cells, CN induced apoptosis and cell cycle arrest at G2/M phase through a p53-mediated mechanism, where p53 was activated, p21 and pro-apoptotic proteins Bid and Bak were upregulated, and PARP was cleaved. In non-transformed human mammary epithelial cells MCF10A, CN at 50 µM had no cytotoxicity and p53 was not activated, but curcumin at 12.5 µM activated p53 and p21 and inhibited MCF10A cell growth. These data suggest that CN inhibits cell growth and proliferation through p53-mediated apoptosis and cell cycle arrest with cancer cell selectivity.

[Inhibition of Yiqi Jiedu formula on proliferation of nasopharyngeal carcinoma cells by MAPK/ERK signaling pathway].

To study the effect of aqueous extracts of Yiqi Jiedu formula (YQ) on the proliferation of CNE2 cells in human nasopharyngeal carcinoma, and investigate its mechanism to provide a new theoretical basis for the clinical application of YQ. CNE2 cells were treated with different concentrations (0.125, 0.25, 0.5, 0.25 g·L⁻¹) of YQ, positive control medicine (cisplatin 4.0 mg·L⁻¹), inhibitor PD98059 (50 µmol·L⁻¹), activator isoproterenol hydrochloride (20 µmol·L⁻¹), activator isoproterenol hydrochloride (ISO)+YQ 0.5 g·L⁻¹. Then cell labeling by using real-time analyzer (RTCA) and CCK 8 method were used to detect cell proliferation activity, and the half inhibitory concentration (IC50) was calculated. The cell cycle distribution was detected by fluorescence double dye flow cytometry PI staining, and Western blot method was used to detect the expression levels of related protein and MAPK/ERK signaling pathway. The results of RTCA and CCK-8 test showed that as compared with the control group, YQ group could effectively inhibit the proliferation of CNE2 cells (P<0.01), with a dose and time dependence, and 48 h IC50 value was 0.5 g·L⁻¹. The results of cell cycle showed that after 48 h of water extract treatment, the cell cycle was significantly changed, the proportion of G0/G1 was reduced, the ratio of G2/M increased, and the cell cycle was in G2/M period (P<0.01). Western blot results showed that after 48 h treatment with different concentrations of aqueous extract, cell cycle-related proteins cyclinD1, cyclinD3 and CDK2 expression levels were down-regulated; MAPK/ERK signaling pathway related protein p-c-Raf, p-MEK, p-ERK1/2 expression level significantly lower as compared with the control group (P<0.05). After adding activator and inhibitor in MAPK/ERK signaling pathway on this basis, the results showed that after adding activator ISO, cell proliferation was significantly higher than that in the Control group; the cycle related proteins cyclinD1, cyclinD3, and CDK2 expression levels were increased; at the same time, key protein p-c-Raf, p-MEK, p-ERK1/2 expression levels in the signal pathways were relatively increased. While after the addition of inhibitor PD98059, the cell proliferation was significantly lower than that in the Control group, and the expression level of corresponding protein was decreased, which was significantly different from the Control group (P<0.05). So YQ could block cell cycle and inhibit the proliferation of CNE2 cells mainly by reducing the expression of MAPK/ERK signaling pathway key protein p-c-Raf, p-MEK and p-ERK1/2.

Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers.

Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (ΔQTc), or ΔQTc adjusted with time-matched placebo corrections (ΔΔQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/ΔQTc/ΔΔQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 µg/mL) and a mean slope ranging from 2.33 to 2.96 ms per µg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation.

A phosphomimetic mutant of RelA/p65 at Ser536 induces apoptosis and senescence: An implication for tumor-suppressive role of Ser536 phosphorylation.

Hundreds of NF-κB inhibitors have been developed for cancer therapy, but their clinical efficacy is unsatisfactory. Here we show that the phosphorylation activation at Ser536 of RelA/p65 protein, a main subunit in the NF-κB family, may play a tumor-suppressive role. In normal colon mucosa, RelA/p65 phosphorylation at Ser536 was increasingly increased with the maturation and apoptotic shedding of epithelial cells, but the phosphorylation at Ser536 was decreased in colon cancer. In colon (HCT116 p53 wt and p53 -/-), breast (MCF7), and prostate (LNCaP and DU145) cancer cells, a phosphomimetic mutation of RelA/p65 at Ser536 (named p65/S536D) triggered dramatic apoptosis through affecting expression of a wide range of cell death/survival genes, such as Bim, Puma, Noxa, Bcl-2 and survivin. In HCT116 cells, p65/S536D mutant upregulated Fas, insulted mitochondrial membrane potential, and triggered cleavage and activation of caspase-3, 7, 8 and 9. A FasL neutralizing antibody (NOK1) prevented cell death induced by the p65/S536D. A pan inhibitor of caspases, Z-VAD-FMK (20 µM), blocked caspase-mediated mitochondrial membrane depolarization. This p65/S536D also triggered senescence in HCT116 cells through a p16-dependent pathway, but not in MFC7 due to lack of p16. Intratumoral delivery of the p65/S536D effectively suppressed tumor growth in nude mice. Together our data suggest that the phosphorylation of RelA/p65 at Ser536 may confer it a tumor-suppressive role by inducing apoptosis and senescence, highlighting the importance of discriminating the function and active status of individual active sites in RelA/p65 when NF-κB inhibitors are considered for targeted therapy of cancer.

Advantage of population pharmacokinetic method for evaluating the bioequivalence and accuracy of parameter estimation of pidotimod.

OBJECTIVE: This study was aimed at exploring the accuracy of population pharmacokinetic method in evaluating the bioequivalence of pidotimod with sparse data profiles and whether this method is suitable for bioequivalence evaluation in special populations such as children with fewer samplings. Methods In this single-dose, two-period crossover study, 20 healthy male Chinese volunteers were randomized 1 : 1 to receive either the test or reference formulation, with a 1-week washout before receiving the alternative formulation. Noncompartmental and population compartmental pharmacokinetic analyses were conducted. Simulated data were analyzed to graphically evaluate the model and the pharmacokinetic characteristics of the two pidotimod formulations. Various sparse sampling scenarios were generated from the real bioequivalence clinical trial data and evaluated by population pharmacokinetic method. RESULTS: The 90% confidence intervals (CIs) for AUC0-12h, AUC0-∞, and Cmax were 97.3 - 118.7%, 96.9 - 118.7%, and 95.1 - 109.8%, respectively, within the 80 - 125% range for bioequivalence using noncompartmental analysis. The population compartmental pharmacokinetics of pidotimod were described using a one-compartment model with first-order absorption and lag time. In the comparison of estimations in different dataset, the estimation of random three- and< fixed four-point sampling strategies can provide results similar to those obtained through rich sampling. The nonlinear mixed-effects model requires fewer data points. Moreover, compared with the noncompartmental analysis method, the pharmacokinetic parameters can be more accurately estimated using nonlinear mixed-effects model. CONCLUSIONS: The population pharmacokinetic modeling method was used to assess the bioequivalence of two pidotimod formulations with relatively few sampling points and further validated the bioequivalence of the two formulations. This method may provide useful information for regulating bioequivalence evaluation in special populations.

[Exploration of visual check approaches in clinical data management].

Due to a great amount of data in clinical trials, the data cleansing needs to adopt a variety of measures, including the latest developed visual check approach. According to the different types of clinical data and the different stages in the course of clinical data management, this study reviews 8 types of visual graphics that show the relevance and trend among the data. The series of graphics can rapidly detect abnormal data, monitor clinical research in real-time, make the data management process much easier and improve the clinical trial efficiency and data quality.

[Comparison of paper and electronic data management in clinical trials].

Electronic case report forms (eCRFs) instead of the traditional paper case report forms (pCRFs) are increasingly used by investigators and sponsors of clinical research. We include a total of 14 phase III studies (8 pCRF, 6 eCRF) to compare paper and electronic data documentation both quantitatively and qualitatively in clinical studies. The result suggests that adaptions of electronic data capture (EDC) in clinical trials have the advantages in optimization of data capture process, improvement of data quality and earlier clinical decision compared to paper-based methods. Furthermore, the successful implementation of EDC requires accouplements with corresponding data management processes and reallocation of resources.

[Quality control of clinical data management based on EDC].

With the wide application of electronic data management (EDC), the data management is shifting to a new mode. In order to recognize the advantages of EDC, we choose 20 representative registered clinical trials, which involve 5 404 subjects and 321 sites. We found that EDC has many beneficial impacts on the course of clinical trial data management, including the process of data collection, data cleaning, data quality control and clinical trial decision-making. The result also provides a reference for the adoption of EDC in clinical trials.

Heat shock protein 90-α mediates aldo-keto reductase 1B10 (AKR1B10) protein secretion through secretory lysosomes.

Aldo-keto reductase 1B10 (AKR1B10) protein is a new tumor biomarker in humans. Our previous studies have shown that AKR1B10 is secreted through a lysosome-mediated nonclassical pathway, leading to an increase in the serum of breast cancer patients. This study illuminates the regulatory mechanism of AKR1B10 secretion. The cytosolic AKR1B10 associates with and is translocated to lysosomes by heat shock protein 90α (HSP90α), a chaperone molecule. Ectopic expression of HSP90α significantly increased the secretion of endogenous AKR1B10 and exogenous GFP-AKR1B10 fusion protein when cotransfected. Geldanamycin, a HSP90α inhibitor, dissociated AKR1B10-HSP90α complexes and significantly reduced AKR1B10 secretion in a dose-dependent manner. We characterized the functional domain in AKR1B10 and found that helix 10 (amino acids 233-240), located at the C terminus, regulates AKR1B10 secretion. Targeted point mutations recognized that amino acids Lys-233, Glu-236, and Lys-240 in helix 10 mediate the interaction of AKR1B10 with HSP90α. Together, our data suggest that HSP90α mediates AKR1B10 secretion through binding to its helix 10 domain. This finding is significant in exploiting the use of AKR1B10 in cancer clinics.

Population pharmacokinetics of adefovir dipivoxil tablets in healthy Chinese volunteers.

AIM: To develop a population pharmacokinetic model of adefovir dipivoxil in healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of adefovir dipivoxil. METHODS: Plasma concentration data collected from 32 healthy Chinese subjects in a Phase I clinical study was pooled. Subjects received a single oral dose of 10 mg, 20 mg, or 30 mg adefovir dipivoxil, or multiple doses of 10 mg once a day for 9 days. Plasma concentrations of adefovir dipivoxil were measured using a validated liquid chromatography-mass spectrometric method. A nonlinear mixed-effect model was used to analyze the plasma concentration data of adefovir dipivoxil in healthy volunteers and to calculate the relevant parameters as well as inter- and intra-individual variability. RESULTS: The time course of adefovir dipivoxil concentration is best described by a first-order absorption and first-order elimination two-compartment model with lag time. The final estimate of total body clearance (CL) is 56.9 L/h and 78.7 L/h for single and multiple dosing regimen, respectively; the volume distribution of the central compartment (V2) is 106 L; inter-compartmental clearance (Q) is 220 L/h; volume distribution of the peripheral compartment (V3) is 498 L and 800 L for single and multiple dosing regimen, respectively; absorption rate is 0.509 h-1; and lag time is 0.315 hours. The inter-individual variabilities of CL and V2 were 22.4% and 58.9%, respectively. The proportional error of residual variability is 14.1% and the additive error is 0.30 ng/L. The final pharmacokinetic model was evaluated using a bootstrap method. CONCLUSIONS: A nonlinear mixed effect model for oral adefovir dipivoxil formulations was developed in healthy Chinese subjects. A multiple dosing regimen may significantly increase the body clearance and volume distribution of the peripheral compartment compared to a single dosing regimen. *These authors contribute equally to this work.

Apoptotic death of cancer stem cells for cancer therapy.

Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with a focus on major signaling pathways and effectors that regulate CSC apoptosis. Selective CSC apoptotic inducers are introduced and their therapeutic potentials are discussed. These include synthetic and natural compounds, antibodies and recombinant proteins, and oligonucleotides.

The Role of PTEN in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck tumor that is influenced by a variety of molecular factors during its pathogenesis. Among these, the phosphatase and tensin homolog (PTEN) plays a crucial role in regulatory networks. This article systematically reviews the multifaceted functions of PTEN in NPC, including its roles in inhibiting cell proliferation, regulating migration and invasion, promoting autophagy and apoptosis, and influencing resistance to radiotherapy. Molecular factors such as long non-coding RNA, microRNA (miRNA), and circular RNA can modulate PTEN through various pathways, thereby impacting the biological behavior of NPC. In addition, PTEN is involved in regulating the tumor microenvironment of NPC, and its interaction with the Epstein-Barr virus has also recently become a focus of research. A comprehensive understanding of the PTEN regulatory network provides a foundation for future personalized and targeted therapeutic strategies. This study expands our understanding of the pathogenesis of NPC and suggests new directions in the field of tumor biology and NPC treatment.