Intestinal excretion (IE), one of the under-investigated mechanisms of drug elimination, has been identified as the loci of drug-drug interactions (DDIs) within the intestinal tract. Here, we employed a modified rat in situ intestinal perfusion model to examine of the drug clearance of apixaban, talinolol, and irinotecan in the short time drug recovery study. The influence of specific efflux transporter inhibitors, including P-glycoprotein (P-gp) inhibitor elacridar, multidrug resistance-associated protein 2 (Mrp2) inhibitor MK571, and breast cancer resistance protein (Bcrp) inhibitor KO143, on IE, systemic exposure and metabolite ratio were accessed using a 2.5-h constant-rate intravenous infusion. IE plays a major role in the elimination of apixaban (36 ± 14

Background:The US Food and Drug Administration (FDA) issued a drug safety communication warning of dental-related adverse events (DAE) reported in patients using buprenorphine films or tablets in January 2022. This study utilized more recent data with a broader dental outcome definition beyond what has been previously reported to provide comprehensive evidence of this risk. Objective:Assess the association between buprenorphine use and the risk of DAE among opioid use disorder (OUD) patients. Design:A retrospective cohort study. Methods:Using the Veradigm-MarketScan® linked dataset, adults aged ⩾18 years with an OUD diagnosis between June 30, 2018, and July 1, 2023, and who met our selection criteria were included. Patients were grouped as: (1) BUP users and (2) non-BUP users (control group). We used Prescription Time Distribution Matching (PTDM) and Inverse Probability Treatment Weighting (IPTW) methods to balance potential confounders between the 2 groups. The primary outcome was dental-related adverse events (DAE). Cox proportional hazards models estimated adjusted hazard ratios (HRs). Results:A total of 14 495 OUD adult patients were included. Of these patients, 4199 (28.97%) initiated oral buprenorphine. Among the overall population, most were males, 8742 (60.3%), with an average age of 44.9 years. The absolute risk of DAE was slightly higher among buprenorphine users (2.17%) compared to controls (1.66%). We found an increased risk of DAE in buprenorphine users compared to the control group (adjusted HR, 1.36; 95%CI, 1.04-1.78). Conclusions:There is an increased risk of DAE among buprenorphine users compared to non-users after 6 months of follow-up. Although this risk is modest, this finding suggests the need for increased awareness and preventive interventions among these users.

Breast cancer is the most frequently diagnosed malignancy in women and a primary contributor to cancer-related mortality worldwide. Despite significant advances in treatment, a substantial number of patients with metastatic breast cancer remain unresponsive to treatment. Accordingly, we prepared multiple chrysin-based triazine compounds to assess their anti-proliferative activity against human malignancies, particularly targeting breast cancer cell apoptosis and the related molecular pathways. RQ-6 demonstrated potent inhibition of breast cancer cell proliferation, colony formation, migration, adhesion, and invasion, and induced apoptosis. Additionally, RQ-6 modulated the levels of apoptosis-related proteins and transcriptomically suggested the activation of pathways such as caspase-3, p53, and TNF. In conclusion, RQ-6 demonstrates notable in vitro antineoplastic efficacy in breast cancer cell lines and shows promise as a candidate for further investigation as a therapeutic intervention in breast cancer. Future studies are warranted to confirm the selectivity and in vivo potential of this compound.

Dehydroepiandrosterone sulfate (DHEAS) is an important hormone precursor, and changes in its levels are associated with various health conditions. DHEAS levels are also influenced by dietary supplementation of DHEA and its enterohepatic recirculation (EHR). Surprisingly, biliary exposure to DHEAS has not been determined since most ELISA methods do not work with bile samples. Therefore, we developed and validated a simple, sensitive, and specific LC-MS/MS method for quantifying DHEAS in various rat biological matrices using small sample volumes and charcoal-stripped bile. We then extended the method to liver homogenates and blood. An API 7500 Qtrap mass spectrometer equipped with a chromatographic system (UPLC) was used, and separation was achieved using an HSS-T3 column. We validated the assay according to the U.S. Food and Drug Administration (FDA) guideline for bioanalysis (M10, 2022). Using a simple precipitation method, we achieved good recovery across all matrices (bile, liver and blood), with linearity in the nanogram per mL range, and acceptable intra- and inter-day precision (%CV) and accuracy (%bias) of ±15%. The lower limit of quantification for DHEAS in all matrices was 0.08 ng/mL. Varied storage conditions did not affect DHEAS quantification in these matrices. Using this validated method to analyze basal DHEAS levels in bile, we found significantly higher biliary DHEAS concentrations in female rats than in male rats, indicating sex as a significant biological variable in the pattern of DHEAS biliary excretion.

The oral microbiome may capture system-specific information about host metabolic health, yet large-scale, multi-system evidence remains scarce. We analyzed 9,431 participants in the Human Phenotype Project (HPP), integrating buccal-swab oral whole metagenome profiles with 44 metabolic measures spanning liver ultrasound, continuous glucose monitoring (CGM), and dual energy X ray absorptiometry (DXA). Here we show that using a microbiome-wide association study (MWAS) framework, we constructed a multilayer map across strains, gene families and pathways, revealing widespread associations: 213 strains, 124,603 gene families and 299 pathways were significantly associated with metabolic measures. Prioritizing the strongest and cross-phenotype signals, we identified multiple oral features with most significant associations to metabolic health. For example, acyl carrier protein (ACP) was associated with lower liver inflammation and reduced adiposity, whereas polyamine biosynthesis and ceramide α oxidation tracked higher glucose variability and adverse liver and adiposity phenotypes. Leveraging these MWAS-derived signals, we trained disease classification models using phenotype-selected oral features, which outperformed full-feature oral models across six metabolic diseases. These association signals were also robust in oral-health sensitivity analyses in HPP, and key BMI and waist-circumference associations directionally replicated at the genus level in an independent cohort (n = 20, 293). Together, these findings provide a population-scale oral-metabolic association map and highlight the potential of oral microbial markers as non-invasive tools for metabolic risk stratification.

Abstract PURPOSE: The Pirc rat (F344/NTac-Apcam1137) model has played a critical role in advancing our understanding of colorectal cancer (CRC) pathogenesis and in evaluating preventive/therapeutic strategies. The objective of this study was to establish an inflammation-driven accelerated model of colon polyp growth in Pirc rats. This model replicates chronic epithelial barrier disruption and low-grade gut inflammation, thereby reflecting real-world scenarios of lifestyle and environmental factors combined with genetic predisposition towards CRC development. METHODS: Dextran sodium sulfate/DSS (in drinking water) and/or high-fat diet/HFD (60 kcal% as fat) treatment was given to Pirc rats, whereas control rats received a regular rodent diet with no DSS. Two cycles (5 days ON, 9 days OFF, and 3 days ON) of DSS treatment (1-2% w/v) were administered starting at 6.5 weeks of age to accelerate colon polyp development without causing colitis. The effects of HFD treatment alone (6.5-16.5 weeks) and in combination with 2%DSS treatment were established. 2%DSS+HFD-treated rats received Celecoxib (70 mg/Kg/day, p.o. from 10.5-16.5 weeks) to confirm the response of the model to the anti-inflammatory agent. The colon polyp burden was determined after euthanizing rats at Week 16.5. RESULTS: No colitis was observed in animals during 1% or 2%DSS treatment, whereas consumption of HFD caused constipation. Minor body weight loss (<5%) was observed during DSS treatment. Administration of 2%DSS but not 1%DSS or HFD alone increased the polyp burden (n=2/group). However, the addition of HFD to 2%DSS treatment dramatically increased colon polyp number (9.7-fold, p<0.001) and volume (12.7-fold, p<0.01) in treated female rats (n=10) as compared to control rats (n=10), with larger size (>6 mm in diameter) polyps observed in the treated group only. In male rats, 2% DSS alone (n=4) or in combination with HFD (n=7) led to higher polyp numbers (2.6-2.8-fold), volumes (1.8-3.5-fold), and larger size compared to control (n=7). Celecoxib treatment reduced the polyp growth in male and female rats treated with 2%DSS+HFD (n=7), though statistical significance was not achieved. CONCLUSION: We successfully established an accelerated polyp development Pirc rat model, providing a better platform for high-throughput screening of pharmacological and dietary interventions for CRC chemoprevention in FAP and other high-risk populations, with greater translational potential. A single anti-inflammatory agent was ineffective at preventing aggressive polyp growth in this model, suggesting that combination therapies targeting multiple targets may be required. The mechanism of action underlying CRC development in this model is being investigated to identify new pharmacological targets and combinations. ACKNOWLEDGEMENTS: This research was funded by CPRIT RP240401. Rashim Singh is supported by the NCATS under award number K12TR004522. Citation Format: Rashim Singh, Vesna Tumbas Saponjac, Trang Le Nu Huyen, Jie Yang, Jie Chen, Taijun Yin, Songpol Srinual, Ming Hu. Accelerated Pirc rat model for animal efficacy trials for prevention and treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 964.

Abstract Background: Familial adenomatous polyposis (FAP) is a rare disease affecting ∼1 in 10,000 individuals and accounts for <1% of colorectal cancer cases. Untreated FAP carries a nearly 100% lifetime risk of colorectal cancer, typically manifesting by age 40 and is treated by colon resection between 15-25 of age. The Pirc (polyposis in rat colon) model of FAP harbors an Apc gene mutation analogous to that in humans. This model develops multiple polyps in the colon and duodenum with age and is widely used to test preventive interventions and in mechanistic studies. Longitudinal monitoring of polyp number, size, and grade is essential for preclinical testing of efficacy of preventive interventions and can be achieved through colonoscopy. In this study, we compared rigid endoscope-enabled colonoscopy with postmortem analysis of polyps in Pirc rats. Methods: Colons of 16-week-old male and female Pirc rats (n=8) were examined using a rigid endoscope (Small Coloview scope, 10 cm, Karl Storz, Tuttingen, Germany). Before colonoscopy, rats were anesthetized with isoflurane, colons were flushed with warm water to remove fecal matter. In the video review, polyps were graded based on the degree of lumen obstruction: G1: barely detectable; G2: ≥ barely detectable to <1/8th of lumen; G3: ≥1/8 to <1/4 of lumen; G4: ≥1/4 to <1/2 of lumen; and G5: ≥1/2 of lumen to complete blockade. Animals were then euthanized, and colons were excised to determine polyp number and diameter measured with digital caliper (General® Ultratech, CA, USA). Total and detectable polyp counts were compared between the two methods using Wilcoxon matched-pairs signed rank test. Mean ± standard deviation (SD) of polyp diameter for each polyp grade was reported. Statistical analyses were performed using GraphPad Prism v.10. Results: The median total polyps count was 2 (range: 0-5) using the endoscope and 3 (range: 1-12) postmortem, with no statistically significant difference (p= 0.09). Because the rigid endoscope visualizes only the distal 10 cm of rat colon, detectable polyps were compared. The median detectable polyps count was 2.5 (range: 0-7) postmortem and was not significantly different from colonoscopy (p= 0.5). The mean ± SD of the polyp diameter was as follows: G2: 2.9±0.7 mm, G3: 3.4±0.5 mm, G4: 3.6±0.6 mm, and G5: 3.6±0.7. Limitations of colonoscopy included incomplete visualization of the entire colon, difficulty distinguishing adjacent polyps, and challenges in detecting rectal polyps. Conclusion: Polyp detection using a rigid endoscope is feasible and comparable to postmortem evaluation, supporting its use for longitudinal monitoring in preclinical prevention studies. Flexible and extendable endoscopes may enhance polyp detection and monitoring. Acknowledgements: This research was funded by CPRIT RP240401. Dr. Rashim Singh is supported by the NCATS/NIH under award number K12TR004522. Citation Format: Ishan T. Narkar, Vesna Tumbas Saponjac, Ming Hu, Rashim Singh. Comparison of colonoscopy using a multipurpose rigid endoscope with postmortem detection of polyp in Pirc rat model of familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 934.

With annual overdose deaths in the United States over 1 million, medication-assisted treatment with buprenorphine (BUP) remains the first-line, gold-standard therapy for opioid use disorder (OUD). Because OUD is a chronic, relapsing condition that requires long-term pharmacotherapy, long acting injectables (LAI) and implantable formulations offer important advantages over daily formulations for maintenance treatment. By comparing transmucosal BUP and LAI formulations' systemic exposure profiles and μ-opioid receptor (MOR) occupancy, converging data demonstrate that higher and more sustained BUP exposure with low variability is required to fully suppress withdrawal, cravings, and illicit opioid use. These findings indicated that currently marketed formulations may not adequately address the clinical challenges associated in the fentanyl/polysubstance era. Accordingly, this rationale-based review proposes a mechanistic framework supporting the development of next-generation BUP-PLGA solid biodegradable implants to maintain a conservative therapeutic benchmark (e.g. Css ≥ 5 ng/mL) for extended durations (e.g. 3-6 months) with low variability (e.g. no large burst release, major lag phase or phase inversion). However, progress in implant development has been hindered by limited mechanistic understanding of drug release. In PLGA-BUP systems, poor IVIVC is largely driven by the low and pH-dependent solubility of BUP, which can make dissolution rate-limiting in vivo and interact with the evolving PLGA acidic microenvironment (acidification, porosity formation, and autocatalytic degradation). Future research should be prioritized to determine directly whether polymer erosion coincides with drug release in PLGA depots, or whether residual, poorly soluble BUP persists locally and releases under dissolution-limited kinetics. Clarifying these mechanisms is not only essential to fulfill the regulatory and translational expectations of the FDA and NIDA, but also to deepen mechanistic understanding and accelerate the rational development of LAI formulations for poorly soluble drug.

Molecular cages with an adjustable cavity have great potential in selective separation, adsorption, drug releasing etc. But to construct resizable cages is highly challenging. Here, retractable cages with a continually change of cavity size are found for the first time. The as-prepared 2 + 3 cages are highly compressed with only 2.83 & Aring; height of cavity. However, the cage is prolonged to 12.88 angstrom by crystalizing from CHCl3/CH3OH and encapsulating six methanol molecules while it is transferred into half-expanded state with 7.50 & Aring; cavity if it is immersed in methanol and includes three methanol molecules. Interestingly, using CHCl3/CH3CN mixed solvent, compressed cages with both 2.83 and 5.29 & Aring; cavity are obtained by rapid crystallization, whereas expanded cage with 12.12 & Aring; height of cavity is got by slow crystallization. Furthermore, with acid treatment, the compressed cage is expanded to 12.29 & Aring; height. Consequently, the cage's cavity could be continually and precisely adjusted between 12.88, 12.29, 12.12, 7.50, 5.29, and 2.83 & Aring;. This cage change could be easily monitored by 1H NMR, CPL, and visual color change etc. Due to adaptive adsorption, the scalable cage exhibits very high iodine uptake capacity of up to 6.02 g/g in iodine vapor and 3.70 g/g in water. Exceptionally, by reducing the rigid imine cage into the flexible amine cage, iodine uptake is enhanced by 37% in vapor and 91% in solution, giving an unprecedented example of organic adsorbents with high capacity from flexible cavity.

Ten previously undescribed labdane diterpenoids, hypochins A-J (1-10), were isolated from the aerial parts of Hypoestes phyllostachya with white spots. Their structures and absolute configurations were elucidated through comprehensive spectroscopic characterization, including IR, HRMS, NMR, electronic circular dichroism analysis, single-crystal X-ray diffraction, and biosynthetic considerations. Notably, compound 10 represents a rare labdane diterpenoid incorporating 16,15;19,6-dilactone units. Compound 1 exhibited potent inhibition of sphere formation in pancreatic cancer stem cells (PCSCs), which are known to drive tumor growth and contribute to resistance against cancer therapies. The suppression of PCSCs by 1 was confirmed by the down-regulation of cancer stem cell markers CD44, CD133, Oct-4, Sox-2, ALDH1A1, Musashi1, CXCR4, and PON1. Further investigations demonstrated that 1 suppressed the self-renewal of PANC-1 cells and inhibited their migration and invasion by suppressing epithelial-mesenchymal transition. Moreover, the selectivity of 1 against PCSCs and pancreatic cancer cells was evaluated through apoptosis analysis. Compared to paclitaxel, which is effective against cancer cells but inactive on PCSCs, compound 1 induced marked apoptosis in PCSCs, demonstrating its selectivity as a PCSC-targeted inhibitor. These results address the critical need for therapies that specifically target PCSCs, which play a crucial role in pancreatic cancer progression.

Chiral molecular cages have exhibited potential in chiral recognition, chiroptical materials, etc. They are generally obtained by introduction of chiral groups into linkers. Chiral cages derived from chiral lids are very rare. Here, enantiomerically pure hindered tetraphenylethene (hTPE) was used as a lid to synthesize chiral TPE cages. While the same helical-handed hTPE units are exploited as lids to give homochiral cages, heterochiral cages with two lids having inverse helical directions are obtained when one hTPE unit and one simple TPE unit are used as lids. Due to the homochirality of the two lids, the homochiral cages display 3-fold stronger circularly polarized luminescence (CPL) than the heterochiral cages. However, the heterochiral cages can adaptively include aromatic guest molecules whereas the homochiral cages fail to do so, thanks to the greater flexibility of TPE compared to the hTPE unit. Very exceptionally, one enantiomer of the chiral guest induces opposite helical chirality between the TPE lid and hTPE lid, turning off the CPL whereas the other enantiomer induces the same helical chirality of the two lids, maintaining or enhancing the CPL signal and furnishing a novel CPL switch. This discrimination between two enantiomers can be carried out using fluorescence spectra, and can even be applied to enantiomer excess (ee%) determination of chiral diacids. Furthermore, through adaptive inclusion, chiral energy transfer between the heterochiral cages and achiral dyes such as Eosin Y occurs, leading to CPL multi-color emission from the achiral dyes.

Hindered tetraphenylethylene (hTPE) helicates are resolved into two left-handed (M) and right-handed (P) isomers by linkage and removal of chiral auxiliary (1R,2S,5R)-menthol, furnishing gram-scale hTPE enantiomers via flash silica column chromatography. hTPE helicate enantiomers bearing electron-accepting cyano and electron-donating triphenylamine groups can emit deep-blue CPL signals with a fluorescence quantum yield surpassing 50%. Full-color and white-light emission were achieved by blending them with dyes in a poly(methyl methacrylate) (PMMA) film.

Vancomycin is one of the most commonly used parenteral antibiotics for treating drug-resistant bacterial infections, however, it is hindered by nephrotoxicity. We previously demonstrated that zileuton could delay the onset of vancomycin-associated nephrotoxicity in rats. Here, we sought to understand the mechanism(s) of zileuton renal protection. Sprague-Dawley rats were administered vancomycin (200 mg/kg) and zileuton (1 and 4 mg/kg) daily for 10 days. After 3 days, kidneys were collected from select animals for histopathological analysis of renal injury. Single-dose vancomycin serum pharmacokinetics and renal tissue spatial distribution with adjuvant zileuton were evaluated. In vitro, proximal tubular cells were exposed to vancomycin and zileuton; cell viability, vancomycin accumulation, ROS levels, and p62/KEAP1 and ferroptosis-related protein levels were measured. Vancomycin was associated with increased serum creatinine and proximal tubule injury in rats including tubular cell necrosis, cytoplasmic vacuolization, interstitial edema, and mononuclear inflammatory cell infiltration. Adjuvant zileuton reduced renal injury and serum creatinine elevation without altering vancomycin serum pharmacokinetics or renal tissue distribution. In vitro, vancomycin exposure resulted in cellular injury, increased ROS, and significantly decreased HO-1 levels. Concomitant zileuton reduced cellular injury, decreased ROS, and rescued HO-1 levels. These preliminary findings indicate that zileuton may be protective against vancomycin-associated renal injury potentially by rescuing HO-1 levels and reducing oxidative stress in proximal tubular cells. Attenuation of nephrotoxicity would allow the optimal clinical use of vancomycin to treat drug-resistant bacterial infections, which could reduce patient harm and hospitalization costs.