Safety, tolerability, pharmacokinetics and effects of diet on AD16, a novel neuroinflammatory inhibitor for Alzheimer's disease: a randomized phase 1 study.

BACKGROUND: AD16 is a Class 1.1 new drug candidate for Alzheimer's disease (AD), which has demonstrated potential benefits in AD by reducing neuroinflammation in preclinical studies. Herein, the pharmacokinetics (PK), safety, and tolerability of single and multiple-dose AD16 and the effect of food were assessed in healthy Chinese adults. METHODS: Single-center, randomized, placebo-controlled, double-blind studies were conducted for single and multiple ascending doses. A total of 62 subjects were enrolled in single-dose groups; 10 each in 5, 10, 20, 30, and 40 mg groups, and 6 each in 60 and 80 mg dose groups. Twenty subjects were divided equally into 30 and 40 mg groups for the multiple-dose study. To determine the effect of a high-fat diet on AD16, 16 subjects were administered a single 20 mg dose of AD16 under the fasted and fed condition in a single-center, randomized, open-label, two-cycle, two-crossover study. Moreover, safety and PK parameters were also assessed. RESULTS: Plasma exposure to a single oral dose of AD16 increased at an approximate dose-increasing rate. The pharmacodynamic dose of the AD16 can be maintained through the accumulation effect of the drug within the safety window. Compared to fasting, ingesting a high-fat meal decelerated the rate of AD16 absorption, albeit without effect on its overall absorption. No dose-related toxicities were seen in any of the studies, all treatment-emergent adverse events were grade I/II, and no serious adverse event occurred. CONCLUSIONS: The present study exhibited favorable safety, tolerability, and PK profile of AD16, supporting its further research as a potential drug treatment for AD. TRIAL REGISTRATION: ClinicalTrials.gov; NCT05787028, NCT05787041, NCT05806177. The SAD and FE studies were retrospectively registered on 28 March 2023. The MAD study was retrospectively registered on 10 April 2023.

Effect of a strong CYP3A4 inhibitor and inducer on the pharmacokinetics of senaparib (IMP4297) in healthy volunteers: A drug-drug interaction study.

AIMS: A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inhibitor (itraconazole) and inducer (rifampicin) on the pharmacokinetic profile of a single oral dose of senaparib, a novel, highly potent poly-(ADP-ribose) polymerase 1/2 inhibitor and CYP3A4 substrate, in Chinese healthy male volunteers (HMV). METHODS: Adult HMV were enrolled to the itraconazole or rifampicin group (n = 16 each). In Period 1, all participants received a single oral dose of senaparib 40 mg (itraconazole group) or 100 mg (rifampicin group). In Period 2, the same dose was coadministered with itraconazole (200 mg) and rifampicin (600 mg), respectively. The primary endpoints were senaparib exposure parameters. RESULTS: Coadministration with itraconazole significantly increased exposure of senaparib and decreased that of its major metabolites M9 and M14. Maximum plasma senaparib concentration (Cmax ) was increased by ~79% and area under the concentration-time curve (AUC) increased by ~2.8-fold. Coadministration with rifampicin significantly reduced the Cmax and AUC of senaparib by ~59 and 83%, respectively. The Cmax for both M9 and M14 was slightly increased, although AUC was decreased. All treatment-emergent adverse events were grade ≤2, regardless of the treatment administered. CONCLUSION: In Chinese HMV, the exposure of senaparib was significantly increased when coadministered with itraconazole and significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of senaparib and strong inhibitors or inducers of CYP3A4.

Development and Validation of a UHPLC-MS/MS Method for the Quantification of a Novel PYGB Inhibitor in Plasma: Application to Pharmacokinetic Studies.

In previous studies, we reported compound 1 (5-chloro-N-(4-oxo-2,2-dipropyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-1H-indole-2-carboxamide) as a novel PYGB inhibitor, and found that it had better anti-ischemic brain injury activity. In this study, we established and validated a novel UHPLC-MS/MS method for the quantitative determination of compound 1 in plasma, then applied the method to study the pharmacokinetic parameters and brain tissue distribution of compound 1 in SD (Sprague-Dawley) rats after intravenous administration. The experimental results showed that the method met the validation requirements set by the US FDA in terms of linearity, accuracy, precision, and stability. The validated method was then used for pharmacokinetic studies in rat plasma, and it was found that compound 1 exhibited linear pharmacokinetic characteristics when administered in the dose range of 0.8-3.2 mg/kg. Finally, we also conducted a brief preliminary investigation of the brain tissue distribution of compound 1 in rats after injection and found that the brain tissue concentrations at 0.25 h and 2 h of administration were 440 ± 19.1 ng/kg and 111 ± 23.9 ng/kg, respectively. Additionally, the CBrain/CPlasma ratio was 0.112 ± 0.0185 and 0.112 ± 0.0292, respectively. These results indicated that compound 1 was able to cross the blood-brain barrier. This study provides important support for the application of compound 1 in ischemic brain injury diseases.

Method development and validation of sildenafil, N-desmethylsildenafil and N1,N4-desmethylsildenafil by LC-MS/MS and its application.

This study aimed to develop an LC-MS/MS method for determining sildenafil and its metabolites N-desmethylsildenafil and N1,N4-desmethylsildenafil in human plasma and applying it to a pharmacokinetic study of sildenafil in healthy volunteers. Sildenafil-d8 was used as the internal standard. Plasma samples were pretreated via protein precipitation with acetonitrile. The extractives were then separated on an ACQUITY UPLC BEH C18 (50-mm × 2.1-mm, 1.7-µm) column using gradient elution. The aqueous and organic mobile phases were ammonium formate 2 mM supplemented with 0.1% formic acid in water and acetonitrile, respectively, and the flow rate was 0.3 mL/min. An electrospray ionization source was applied, and multiple reaction monitoring was operated in the positive mode with selective channels at m/z 475.30 â†’ 100.10, 461.20 â†’ 283.30, 483.30 â†’ 108.10, and 449.00 â†’ 283.00 for sildenafil, sildenafil-d8, N-desmethylsildenafil, and N1,N4-desmethylsildenafil, respectively. The linear calibration curves of sildenafil and its metabolites spanned 1.0-1000 ng/mL. The lower limit of quantification was 1.0 ng/mL. The extractive recovery of analytes from the biological matrix was more than 90% and the matrix effect complied with relevant provisions. The intra- and inter-day precisions of sildenafil and its metabolite were <10%. The intra- and inter-day accuracy of sildenafil, N-desmethylsildenafil, and N1,N4-desmethylsildenafil was more than 99%. The method is highly sensitive and selective, and it was successfully applied to the bioequivalence studies of 100-mg sildenafil citrate tablets in 40 healthy Chinese volunteers.

Identification of a prognostic gene signature of colon cancer using integrated bioinformatics analysis.

BACKGROUND: Colon cancer is a worldwide leading cause of cancer-related mortality, and the prognosis of colon cancer is still needed to be improved. This study aimed to construct a prognostic model for predicting the prognosis of colon cancer. METHODS: The gene expression profile data of colon cancer were obtained from the TCGA, GSE44861, and GSE44076 datasets. The WGCNA module genes and common differentially expressed genes (DEGs) were used to screen out the prognosis-associated DEGs, which were used to construct a prognostic model. The performance of the prognostic model was assessed and validated in the TCGA training and microarray validation sets (GSE38832 and GSE17538). At last, the model and prognosis-associated clinical factors were used for the construction of the nomogram. RESULTS: Five colon cancer-related WGCNA modules (including 1160 genes) and 1153 DEGs between tumor and normal tissues were identified, inclusive of 556 overlapping DEGs. Stepwise Cox regression analyses identified there were 14 prognosis-associated DEGs, of which 12 DEGs were included in the optimized prognostic gene signature. This prognostic model presented a high forecast ability for the prognosis of colon cancer both in the TCGA training dataset and the validation datasets (GSE38832 and GSE17538; AUC > 0.8). In addition, patients' age, T classification, recurrence status, and prognostic risk score were associated with the prognosis of TCGA patients with colon cancer. The nomogram was constructed using the above factors, and the predictive 3- and 5-year survival probabilities had high compliance with the actual survival proportions. CONCLUSIONS: The 12-gene signature prognostic model had a high predictive ability for the prognosis of colon cancer.

Validation of the ADVIA Centaur® XP system for the determination of insulin and its application.

In this study, a direct chemiluminescent immunoassay for the determination of human serum insulin levels using the ADVIA Centaur® XP system was validated. Dilution recovery, linearity, precision, sensitivity, between analyzer variation, reference interval and stability were analyzed. The linear range of the insulin assay was from 0.64 to 277.27 mU/L. Intra- and inter-assay coefficients of variation were 3.67-7.96% and 4.66-8.69%, respectively. The lower and upper limits of quantification were 0.61 mU/L and 8872.64 mU/L, respectively. In terms of between analyzer variation, our study showed comparable results with a good correlation of r2 = 0.9934. The human serum insulin reference interval was in the range of 3.0-25.0 mU/L. Serum insulin can be kept for 7 days between 2-8 °C and 18-26 °C, and the corresponding results for -20 °C and -70 °C were 1 month and 6 months are reported. We proved that this insulin assay was robust and the analytical performance met the requirements. We successfully applied this insulin assay to a bioequivalence study of miglitol in 48 healthy Chinese subjects. The miglitol bioequivalence study was evaluated based on pharmacokinetic and pharmacodynamic parameter endpoints. The results demonstrated that the test formulation and the reference formulation were bioequivalent.

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of atorvastatin in Chinese subjects
.

OBJECTIVE: The purpose of this study was to evaluate the bioequivalence of two formulations of atorvastatin using the reference-scaled average bioequivalence (RSABE) method and to study the pharmacokinetics of atorvastatin in healthy Chinese subjects under fed conditions. MATERIALS AND METHODS: A single-dose, randomized, open-label, four-way crossover study was conducted in healthy Chinese subjects after informed consent was obtained. Healthy subjects were randomly assigned to receive 20 mg of either the test or reference formulation, following a 7-day washout period. The formulations were considered bioequivalent if 90% confidence intervals (CIs) for the ln-transformed ratios and ratio of geometric means (GMR) of AUC and Cmax of atorvastatin were within the bioequivalence range (80 - 125%). Plasma atorvastatin, ortho-hydroxy atorvastatin and para-hydroxy atorvastatin concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Tolerability was assessed during the entire study period. RESULTS: ANOVA indicated that the period, sequence, and formulation had no significant effect on the pharmacokinetic parameters (p < 0.05). The test formulation was bioequivalent to the marketed formulation as the 90% CIs for natural log-transformed ratios of atorvastatin of Cmax (88.45 - 103.57%), AUC0-t (98.08 - 104.89%) and AUC0-∞ (98.15 - 104.87%) were within equivalence limits (80 - 125%). No serious adverse events were found among the subjects. CONCLUSION: The RSABE approach was successful in evaluating the bioequivalence of these two formulations. This study confirmed that test and reference atorvastatin calcium tablets were bioequivalent under fed condition.

Randomized, two-way crossover bioequivalence study of levamlodipine besylate tablets in healthy Chinese subjects
.

OBJECTIVE: The present bioequivalence study was designed to compare the newly-developed levamlodipine besylate 2.5-mg tablet (test) with that of its 2.5-mg marketed counterpart (reference) in healthy Chinese adult male volunteers. METHODS: A single-dose, randomized, open-label, two-period, and two-treatment self-crossover study was conducted in healthy Chinese volunteers after informed consent was obtained. In each part of the study, the subjects were randomly assigned to receive the test or reference product (5 mg levamlodipine) in a 1 : 1 ratio, and then received the alternative product, following a 14-day washout period. Plasma levamlodipine concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters (noncompartmental model) were assessed with WinNonlin software. Analysis of variance (ANOVA) and FDA (USA) bioequivalence statistical criterion of 90% CI for 80 - 125% range (set at p ≤ 0.05) of geometric means ratios of test : reference product for Cmax, AUC0-t, and AUC0-∞ were determined. Tolerability was assessed during the entire study period. RESULTS: ANOVA indicated that the period, sequence, and formulation had no significant effect on the PK parameters (p ≥ 0.05), although there was a statistically-significant difference between formulations in AUC0-t (p ≤ 0.05). The test formulation was bioequivalent to the marketed formulation as the 90% CI for the ratio of geometric means of Cmax (84.52 - 103.00%), AUC0-t (87.49 - 98.23%), and AUC0-∞ (84.30 - 103.25%) were within equivalence limits (80 - 125%) under fasting condition. No serious adverse events were found among the subjects. CONCLUSION: This study confirmed that test and reference levamlodipine besylate tablets were bioequivalent under fasting condition.
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A single dose, randomized, open-label, cross-over bioequivalence study of sildenafil citrate tablets in healthy Chinese volunteers
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OBJECTIVE: The present study was designed to evaluate the bioequivalence of a newly developed sildenafil citrate tablet 50 mg (Jinge®, Test) and a marketed counterpart (Viagra®, 100 mg, Reference) in healthy adult male Chinese volunteers. METHODS: This single-dose, randomized, open-label, four-period, and two-treatment self-crossover study included two parts: fasting and postprandial studies. In each part of the study, the subjects were randomly assigned to receive test or reference products (100 mg sildenafil) in a 1 : 1 ratio, and then received the alternative products, following a 1-week washout period. Plasma sildenafil concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Tolerability was assessed during the entire study period. RESULTS: 32 healthy volunteers (aged 19 - 30) were enrolled in the study; 31 volunteers completed the fasting study, while 32 volunteers completed the postprandial study. The test formulation was bioequivalent to the marketed formulation as the 90% CIs for the ratio of geometric means of Cmax (fasting: 98.79 - 119.61%; fed: 94.47 - 119.65%), AUClast (fasting: 98.70 - 109.71%; fed: 96.39 - 112.89%), and AUC∞ (fasting: 98.45 - 108.87%; fed: 96.36 - 112.74%) were within equivalence limits (80 - 125%) under both fasting and postprandial conditions. When sildenafil was given with high-fat meals, mean Cmax was reduced by 23%, and median tmax ranged from 0.75 to 1.50 hours (p ≤ 0.05). However, both AUClast and AUC∞ were comparable between fasting and postprandial conditions. No serious adverse events were found among the subjects. CONCLUSIONS: This study confirmed that test and reference sildenafil citrate tablets were bioequivalent under fasting and postprandial conditions.
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Nonalcoholic or metabolic-associated fatty liver disease and colorectal polyps: evidence from meta-analysis and two-sample Mendelian randomization.

Introduction: Nonalcoholic or metabolism-associated fatty liver disease (NAFLD or MAFLD) and colorectal polyps are chronic conditions strongly linked to lifestyle factors. However, the precise causal link between NAFLD or MAFLD and the development of colorectal polyps is not yet fully understood. This study aimed to evaluate the association between NAFLD or MAFLD and the risk of colorectal polyps based on a meta-analysis and two-sample Mendelian randomization (MR) analyses. Methods: PubMed, Embase, Cochrane Library databases were searched for eligible studies to be included in the meta-analysis. We conducted a thorough search of the PubMed, Embase, and Cochrane Library databases to identify eligible studies prior to 22 March 2024. Subgroup analyses were performed based on sex, age, and geographical region. Causality between NAFLD/MAFLD and colorectal polyps was explored by using two-sample Mendelian randomization (MR) analyses. Results: Based on an analysis of 17 studies encompassed within this meta-analysis, a significant correlation was identified between the presence of NAFLD/MAFLD and elevated incidence of colorectal polyps (NAFLD: OR = 1.57, 95% CI: 1.43-1.73, I2 = 38%, p = 0.06; MAFLD: OR = 1.67, 95% CI: 1.40-2.00, I2 = 77%, p = 0.002). However, current evidence does not support a causal relationship between NAFLD/MAFLD and the prevalence of colorectal polyps (OR = 0.9998315, 95% CI: 0.9987566-1.000907, P = 0.7587638). Conclusion: NAFLD/MAFLD demonstrated a significant positive correlation with an elevated risk of developing colorectal polyps. However, the MR analysis suggested that no causal relationship existed between NAFLD/MAFLD and colorectal polyps. Therefore, further research is required to identify the underlying mechanism of causal link between these diseases.

Unveiling the therapeutic potential of airpotato yam rhizome against colorectal cancer: a network pharmacology approach.

Objective: The objective of this investigation was to elucidate the key active compounds and molecular mechanisms underlying the therapeutic potential of airpotato yam rhizome (AYR) in colorectal cancer (CRC) treatment. Methods: By utilizing network pharmacology and molecular docking, key targets and signaling pathways of AYR against CRC were predicted and subsequently validated in cellular and mouse xenograft models. Results: This study initially predicted that quercetin was the primary compound in AYR that might have potential efficacy against CRC and that EGFR and AKT1 could be the main targets of AYR, with the EGF/EGFR-induced PI3K/AKT signaling pathway potentially playing a crucial role in the anti-CRC effects of AYR. Molecular docking analysis further indicated a strong binding affinity between quercetin and EGFR, primarily through hydrogen bonds. Additionally, the AYR-derived drug-containing serum was found to inhibit the PI3K/AKT signaling pathway, as demonstrated by decreased levels of p-PI3K, p-AKT, and BCL2, which ultimately led to enhanced apoptosis of HCT116 and HT29 cells. The potential antitumor effects of AYR were investigated in nude mouse xenograft models of human HCT116 and HT29 cells, in which AYR was found to induce tumor cell apoptosis and inhibit tumor formation. Conclusion: AYR may promote CRC cell apoptosis by suppressing the PI3K/AKT signaling pathway, which provides a basis for further research on the safe and effective use of AYR for the treatment of CRC.

Electrostatic Smart Textiles for Braille-To-Speech Translation.

A wearable Braille-to-speech translation system is of great importance for providing auditory feedback in assisting blind people and people with speech impairment. However, previous reported Braille-to-speech translation systems still need to be improved in terms of comfortability or integration. Here, a Braille-to-speech translation system that uses dual-functional electrostatic transducers which are made of fabric-based materials and can be integrated into textiles is reported. Based on electrostatic induction, the electrostatic transducer can either serve as a tactile sensor or a loudspeaker with the same design. The proposed electrostatic transducers have excellent output performances, mechanical robustness, and working stability. By combining the devices with machine learning algorithms, it is possible to translate the Braille alphabet and 40 commonly used words (extensible) into speech with an accuracy of 99.09% and 97.08%, respectively. This work demonstrates a new approach for further developments of advanced assistive technology toward improving the lives of disabled people.

Pure total flavonoids from citrus alleviate oxidative stress and inflammation in nonalcoholic fatty liver disease by regulating the miR-137-3p/NOXA2/NOX2 pathway.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become a global health issue owing to its large disease population and high morbidity. We previously reported that the improvement in oxidative stress (OS) using pure total flavonoids from citrus (PTFC), flavonoids isolated from the peel of Citrus changshan-huyou Y.B. Chan, is a crucial strategy for NAFLD treatment. However, OS-associated intervention pathways in NAFLD remain unclear. METHODS: In this study, we used microRNA (miR)- and mRNA-sequencing to identify the pathway by which PTFC improve OS in NAFLD. Clinical data, mimic/inhibitor assays, and a dual-luciferase reporter assay were selected to verify the regulatory relationships of this pathway. Moreover, in vivo and in vitro experiments were used to confime the regulatory effect of PTFC on this pathway. RESULTS: miR-seq, mRNA-seq, and bioinformatics analyses revealed that the miR-137-3p/neutrophil cytosolic factor 2 (NCF2, also known as NOXA2)/cytochrome b-245 beta chain (CYBB, also known as NOX2) pathway may be a target pathway for PTFC to improve OS and NAFLD. Additionally, bivariate logistic regression analysis combining the serum and clinical data of patients revealed NOX2 and NOXA2 as risk factors and total antioxidant capacity (indicator of OS level) as a protective factor for NAFLD. miR-137-3p mimic/inhibitor assays revealed that the upregulation of miR-137-3p is vital for improving cellular steatosis, OS, and inflammation. Dual-luciferase reporter assay confirmed that NOXA2 acts as an miR-137-3p sponge. These results co-determined that miR-137-3p/NOXA2/NOX2 is an essential pathway involved in NAFLD pathogenesis, including lipid accumulation, OS, and inflammation. In vivo and in vitro experiments further confirmed that the miR-137-3p/NOXA2/NOX2 pathway is regulated by PTFC. CONCLUSION: PTFC alleviates OS and inflammation in NAFLD by regulating the miR-137-3p/NOXA2/NOX2 pathway.

GRN is a prognostic biomarker and correlated with immune infiltration in glioma: A study based on TCGA data.

Background: Among primary brain tumors, gliomas are associated with a poor prognosis and a median survival that varies depending on the tumor grade and subtype. As the most malignant form of glioma, glioblastoma (GBM) constitutes a significant health concern. Alteration in granulin(GRN) has been proved to be accountable for several diseases. However, the relationship between GRN and GBM remains unclear. We evaluated the role of GRN in GBM through The Cancer Genome Atlas (TCGA) database. Methods: First, we assessed the relationship between GRN and GBM through the GEPIA database. Next, the relationship between GRN and GBM prognosis was analyzed by logistic regression and multivariate cox methods. Using CIBERSORT and the GEPIA correlation module, we also investigated the link between GRN and immune infiltrates in cancer. Using the TCGA data, a gene set enrichment analysis (GSEA) was performed. We also employed Tumor Immune Estimation Resource (TIMER) to examine the data set of GRN expression and immune infiltration level in GBM and investigate the cumulative survival in GBM. We also validated tissues from GBM patients by Western blotting, RT-qPCR, and immunohistochemistry. Results: Increased GRN expression was shown to have a significant relationship to tumor grade in a univariate study utilizing logistic regression. Furthermore, multivariate analysis disclosed that GRN expression down-regulation is an independent predictive factor for a favorable outcome. GRN expression level positively correlates with the number of CD4+ T cells, neutrophils, macrophages, and dendritic cells (DCs) that infiltrate a GBM. The GSEA also found that the high GRN expression phenotype pathway was enriched for genes involved in immune response molecular mediator production, lymphocyte-mediated immunity, cytokine-mediated signaling pathway, leukocyte proliferation, cell chemotaxis, and CD4+ alpha beta T cell activation. Differentially enriched pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) include lysosome, apoptosis, primary immunodeficiency, chemokine signaling pathway, natural killer cell-mediated cytotoxicity, and B cell receptor signaling pathway. Validated result showed that GRN was upregulated in GBM tissues. These results suggested that GRN was a potential indicator for the status of GBM. Conclusion: GRN is a prognostic biomarker and correlated with immune infiltrates in GBM.

Pharmacokinetics of Nifedipine-Sustained Release Tablets in Healthy Subjects After a Single Oral Administration: Bioequivalence Analysis and Food Effects.

We compared newly developed delayed-release oral tablets (test) of 30-mg nifedipine (NFP) with its marketed counterpart (30 mg; reference) in healthy adult Chinese volunteers to assess the former's bioequivalence. This was a randomized, open-label, four-period, crossover trial study including fasting and fed trials. The participants were randomly administered test or reference formulations (1:1 ratio) throughout each period, with a 7-day washout period. In the next session, they were administered the alternate products. Liquid chromatography-tandem mass spectrometry and WinNonlin software were used to evaluate the bioequivalence of the maximum plasma concentration (Cmax ) of NFP and the area under the concentration-time curve (AUC). In total, 46 and 48 people participated in the fasting and postprandial trials. In both groups, the 90% confidence intervals of geometric mean ratios of Cmax , AUC from time zero to time t, and AUC from time zero to infinity were in the equivalence range (80%-125%). When NFP was administered concomitantly with a high-fat meal, time to maximum concentration was approximately twofold earlier, absorption was approximately 4.8% less, and Cmax exhibited a slight change relative to those under fasting conditions. Moreover, no serious adverse events were recorded in the participants. The present findings confirm the bioequivalence of test and reference formulations of NFP tablets under fasting and postprandial conditions.

HOXD9 is a potential prognostic biomarker involved in immune microenvironment of glioma.

BACKGROUND: Glioma is the prevailing malignant tumor affecting the brain and central nervous system, constituting over 80% of all malignant brain tumors. HOXD9 has been implicated in the development of glioma, but the specific mechanism of its influence on glioma pathogenesis remains incompletely understood. The purpose of this study was to investigate the role of HOXD9 in glioma and examine the changes in HOXD9 expression during the progression of glioma, thus contributing new insights into the pathogenesis of glioma. METHODS: Glioma samples from the Cancer Gene Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets were included in this study. Variations in HOXD9 expression in gliomas between different subgroups of multiple clinical characteristics were explored, and the expression was validated in glioma samples using qRT-PCR and western blotting. Next, the impact of HOXD9 on the prognosis of gliomas was explored by survival analysis, receiver operating characteristic curve, and nomogram plots. Subsequently, the association between HOXD9 and the tumor immune microenvironment was explored using the ssGSEA algorithm and the ESTIMATE algorithm. Then, immune-related pathways associated with HOXD9 were determined by differential express analysis and GSEA. Finally, HOXD9-related genomic alterations were identified. RESULTS: HOXD9 expression is upregulated and correlated with malignant properties in glioma. Similarly, our validation results showed significantly upregulated protein and mRNA levels of HOXD9 in glioma brain tissues. In addition, high HOXD9 expression was indicative of a poor prognosis for glioma patients. Additionally, elevated HOXD9 levels were associated with reduced tumor purity and higher levels of immune invasion. Finally, HOXD9 was significantly associated with genomic alterations. CONCLUSION: Overall, this study has unveiled a significant association between HOXD9 and the prognosis and survival of glioma patients. Our findings highlight the potential of HOXD9 as a prognostic biomarker, implicating its role in influencing the glioma immune microenvironment.

Safety, tolerability, and pharmacokinetics of TG-1000, a new molecular entity against influenza virus: first-in-human study.

Background: The cap-snatching mechanism of influenza virus mRNA transcription is strongly suppressed by TG-1000, a prodrug rapidly metabolized into TG-0527, is a potent cap-dependent nucleic acid endonuclease inhibitor. Herein, we aimed to assess the safety, tolerability, and pharmacokinetics of TG-1000 in healthy participants and the effect of food on the pharmacokinetics and safety of TG-1000. Method: The study was divided into 2 parts: Part A [Single Ascending-Dose (SAD) study, 10-160 mg] and Part B [Food-Effect (FE) study, 40 mg] were launched sequentially. The study included 66 participants for both investigations. We administered different TG-1000 capsules or placebo doses per the study protocol and collected blood samples for pharmacokinetic assessments at specific times. In plasma, TG-1000 and its active metabolite TG-0527 were assayed, and PK parameters were determined. Results: In SAD, the increase in AUC was less than the proportional increase in dose over the 20-160 mg dose range, while the increase in Cmax was proportional to the increase in dose. In the 10-160 mg dose range, T1/2, λz and Tmax of TG-0527 were dose-independent; and T1/2 and Tmax were within 33.8-39.4 h and 3.02-6 h, respectively. In FE, the AUC0-inf, AUC0-last, and Cmax of TG-0527 decreased by approximately 17.52%, 18.76%, and 41.35%, respectively, and the Tmax delay was around 1.50 h. No serious adverse events occurred during the studies. Conclusion: Overall, TG-1000 was well tolerated and exhibited an acceptable safety and PK profile, supporting further clinical investigation of TG-1000 for the treatment of influenza.

A Flexible Self-Powered Noncontact Sensor with an Ultrawide Sensing Range for Human-Machine Interactions in Harsh Environments.

Noncontact human-machine interactions (HMIs) provide a hygienic and intelligent approach to communicate between humans and machines. However, current noncontact HMIs are generally hampered by the interaction distance, and they lack the adaptability to environmental interference such as high humidity conditions. Here, we explore a self-powered electret-based noncontact sensor (ENS) with moisture-resisting ability and ultrawide sensing range exceeding 2.5 m. A megascopic air-bubble structure is designed to enhance charge-storage stability and charge-recovery ability of the ENS based on the heterocharge-synergy effect in electrets. Besides, multilayer electret films are introduced to strengthen the electric field by utilizing the electrostatic field superposition effect. Thanks to the above improved performances of the ENS, we demonstrate various noncontact HMI applications in harsh environments, including noncontact appliances, a moving trajectory and accidental fall tracking system, and a real-time machine learning-assisted gesture recognition system with accuracy as high as 99.21%. This research expands the way for noncontact sensor design and may further broaden applications in noncontact HMIs.

Multiple Mechanisms of Shenqi Pill in Treating Nonalcoholic Fatty Liver Disease Based on Network Pharmacology and Molecular Docking.

Background: Shenqi pill (SQP), a traditional Chinese prescription, has proven to be effective in treating nonalcoholic fatty liver disease (NAFLD). However, its bioactive ingredients and underlying mechanisms remain elusive. Aim: We aimed to predict the active compounds, potential targets, and molecular mechanisms of SQP anti-NAFLD by applying network pharmacology and molecular docking methods. Methods: Active ingredients and related targets of SQP were obtained from the TCMSP database. Potential targets of NAFLD were acquired from OMIM and GeneCards databases. The STRING database and Cytoscape software analyzed the protein-protein interaction (PPI) network and core targets of overlapping genes between SQP and NAFLD. GO enrichment analysis and KEGG enrichment analysis were performed in the DAVID database. Finally, molecular docking was employed to find possible binding conformations of macromolecular targets. Results: 15 anti-NAFLD bioactive ingredients and 99 anti-NAFLD potential targets of SQP were determined using Network pharmacology. Quercetin, kaempferol, stigmasterol, diosgenin, and tetrahydroalstonine were the major active ingredients and AKT1, TNF, MAPK8, IL-6, and VEGFA were the key target proteins against NAFLD. The KEGG analysis suggested that the main pathways included PI3K/Akt signaling pathway, HIF-1 signaling pathway, MAPK signaling pathway, and TNF signaling pathway. Molecular docking predicted that quercetin, kaempferol, stigmasterol, diosgenin, and tetrahydroalstonine could bind with AKT1, TNF, and MAPK8. Conclusion: This study successfully predicts the active compounds, potential targets, and signaling pathways of SQP against NAFLD. Moreover, this study contributed to the application and development of SQP.

Pharmacokinetics of Amoxicillin and Clavulanate Potassium for Suspension (200 mg/28.5 mg) in Healthy Subjects: Sample Add Stabilizer Study and Food Effects.

The present study compares the pharmacokinetics of amoxicillin and clavulanate potassium suspension (200 mg/28.5 mg) during fasting and postprandial conditions, and the sample adds a stabilizer study. Two randomized, crossover trials were conducted in an open-label, single-center study (a fasting trial and a postprandial trial). In each part of the study, the subjects were randomly assigned to receive either test or reference products (200 mg/28.5 mg) in a 1:1:1 ratio, followed by the alternative products after a 7-day washout period. Plasma amoxicillin and clavulanic acid concentrations were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin software was used to evaluate the pharmacokinetic parameters (noncompartmental model). The formulations were considered bioequivalent if the geometric means of area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of amoxicillin and clavulanic acid were within the predetermined bioequivalence range established by average bioequivalence (ABE) or reference-scaled ABE. Tolerability was assessed throughout the study. The postprandial trial and the fasting study each had 12 volunteers. Under fasting and postprandial conditions, the 90%CI for the ratio of geometric means of amoxicillin of Cmax , AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity were within the ABE acceptance limits (80%-125%); the geometric means of clavulanic acid of Cmax (critbound, -0.03; point estimate, 1.07) were within the reference-scaled ABE acceptance limits, and the AUC from time 0 to the last measurable concentration and AUC from time 0 to infinity were within the ABE acceptance limits (80%-125%). Time to maximum concentration of amoxicillin was delayed 1.0 hour with high-fat meals compared to fasting conditions. Meantime, high-fat meals decreased the exposure of clavulanic acid by nearly 40%. No serious adverse events were found among the subjects. The bioequivalence of test and reference amoxicillin and clavulanate potassium for suspension was validated in this study under fasting and postprandial conditions.