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Fengjiao Bu,1,2,* Yong-Soon Cho,3,4,* Qingfeng He,1 Xiaowen Wang,1 Saurav Howlader,3,4 Dong-Hyun Kim,3,4 Mingshe Zhu,5 Jae Gook Shin,3,4 Xiaoqiang Xiang1,6 1Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2Department of Pharmacy, Eye and ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; 4Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Republic of Korea; 5Department of DMPK, MassDefect Technologies, Princeton, NJ, USA; 6Department of Preclinical Evaluation, Quzhou Fudan Institute, Quzhou, Zhejiang Province, 324002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jae Gook Shin; Xiaoqiang Xiang, Email phshinjg@gmail.com; xiangxq@fudan.edu.cnBackground: Anlotinib was approved as a third line therapy for advanced non-small cell lung cancer in China. However, the impact of concurrent administration of various clinical drugs on the drug–drug interaction (DDI) potential of anlotinib remains undetermined. As such, this study aims to evaluate the DDI of anlotinib as a victim by establishing a physiologically based pharmacokinetic (PBPK) model.Methods: The PBPK model of anlotinib as a victim drug was constructed and validated in the Simcyp® incorporating parameters derived from in vitro studies, pre-clinical investigations, and clinical research encompassing patients with cancer. Subsequently, plasma exposure of anlotinib in cancer patients was predicted for single- and multi-dose co-administration with typical perpetrators mentioned in Food and Drug Administration (FDA) industrial guidance.Results: Based on predictions, the CYP3A potent inhibitor ketoconazole demonstrated the most significant DDI with anlotinib, regardless of whether anlotinib is administered as a single dose or multiple doses. Ketoconazole increased the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of single-dose anlotinib to 1.41-fold and 1.08-fold, respectively. In contrast, rifampicin, a potent inducer of CYP3A enzymes, exhibited a relatively higher level of DDI, with AUCR and CmaxR values of 0.44 and 0.79, respectively.Conclusion: Based on the PBPK modeling, there is a low risk of DDI between anlotinib and potent CYP3A/1A2 inhibitors, but caution and enhanced monitoring for adverse reactions are advised. To mitigate the risk of anti-tumor treatment failure, it is recommended to avoid concurrent use of strong CYP3A inducers. In conclusion, our study enhances understanding of anlotinib’s interaction with medications, aiding scientists, prescribers, and drug labels in gauging the expected impact of CYP3A/1A2 modulators on anlotinib’s pharmacokinetics. Keywords: anlotinib, DDIs, CYP3A, CYP1A2, PBPK

Rong Wang,1,* Tuo Chen,2,* Qiong Wang,3 Xiao-Min Yuan,1 Zheng-Lan Duan,1 Ze-Yu Feng,1 Yang Ding,1 Fan Bu,1 Guo-Ping Shi,4 Yu-Gen Chen1 1Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 2Department of General Surgery, Affiliated hospital of Yangzhou university, Yangzhou, Jiangsu, 225000, People’s Republic of China; 3Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 4Collaborative Innovation Center for Cancer Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Gen Chen; Guo-Ping Shi Email chenyg666@126.com; 457569423@qq.comPurpose: Total flavone of Abelmoschus manihot (TFA), the effective constituents extracted from Flos Abelmoschus Manihot, has been reported to inhibit inflammation. However, the effect of TFA on ulcerative colitis (UC) progression in patients with depression is unknown. The purpose of our research was to explore the anti-UC effects of TFA in the context of depression in mice with UC by regulating the gut microbiota to drive the intestinal barrier.Methods: In this study, chronic stress (CS) and dextran sodium sulfate (DSS) were used to induce depression and UC, respectively, in C57BL/6J mice. Fecal microbiota transplantation (FMT) was used to evaluate how treating mice modeling UC and depression with TFA effected their gut microbiota.Results: Our results showed that TFA effectively improved UC aggravated by CS. In addition, TFA treatment improved the depression-like phenotype, the disturbed gut microbiota, and the intestinal barrier function in CS mice. It is worth noting that FMT from the CS mice to the receptor group further aggravated the damage of the intestinal barrier and the disturbance of the gut microbiota in the recipient DSS mice, thus further aggravating UC, however, treatment of the intervention of TFA in the CS fecal microbiota transplant with TFA also played its therapeutic outcome.Conclusion: Taken together, our results show that CS disrupts the gut microbiota, triggers intestinal barrier injury and aggravates DSS colitis, while TFA is a promising drug for the treatment of UC in patients with depression.Keywords: total flavone of Abelmoschus manihot, ulcerative colitis, depression, gut microbiota, intestinal barrier

Fanqin Bu,1,2,* Xiaojian Zhu,3,* Jinfeng Zhu,1,2,* Zitao Liu,1,2 Ting Wu,4 Chen Luo,1,2 Kang Lin,1,2 Jun Huang1 1Department of Gastrointestinal Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, People’s Republic of China; 2Jiangxi Medical College of Nanchang University, Nanchang, People’s Republic of China; 3Research Center of The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, People’s Republic of China; 4Department of Infectious Diseases of Guixi Traditional Chinese Medicine Hospital, Yingtan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Huang Email huangjun0727@163.comBackground: Colorectal cancer (CRC) is one of the most lethal malignancies and the incidence of CRC has been on the rise. Herein, we aimed to identify effective biomarkers for early diagnosis and treatment of colorectal cancer via bioinformatic tools.Methods: To identify differentially expressed genes (DEGs) in CRC, we downloaded CRC gene expression data from GSE24514 and GSE110223 datasets in Gene Expression Omnibus (GEO) and employed R to analyze the data. We further performed functional enrichment analysis of the DEGs on the DAVID gene ontology analysis tool. STRING database and Cytoscape visualization tool were employed to construct a PPI (protein–protein interaction) network and establish intensive intervals in the network. Immunohistochemistry, qRT-PCR and Western blotting were performed to identify the expression level of GINS1 in CRC. In vitro and in vivo experiments were performed to assess the impact of GINS1 in the pathogenesis of CRC in terms of proliferation, migration and metastasis.Results: Among the two datasets, 389 DEGs were identified and used to construct a PPI network. These genes were mainly involved in cell proliferation and cell cycle. Among them, 15 genes including GINS1 were found to be strongly associated with the PPI network. We further performed immunohistochemistry, qRT-PCR and Western blotting to identify that GINS1 expression was higher in CRC than in paired normal tissues. Moreover, in vitro and in vivo experiments demonstrated GINS1 could promote the proliferation, invasion and migration of colorectal cancer cells.Conclusions: GINS1 could be considered as a potential biomarker for CRC patients.Keywords: GINS1, colorectal cancer, bioinformatics screening

Simona Hapca,1 Bruce Guthrie,1 Vera Cvoro,2 Feifei Bu,3 Alasdair C Rutherford,3 Emma Reynish,3 Peter T Donnan1 1Population Health and Genomics, School of Medicine, University of Dundee, Dundee DD2 4BF, UK; 2NHS Fife, Kirkcaldy, Fife KY2 5AH, UK; 3Dementia and Ageing Research Group, Faculty of Social Science, University of Stirling, Stirling, FK9 4LA, UK Purpose: Cognitive impairment is common in older people admitted to hospital, but the outcomes are generally poorly understood, and previous research has shown inconsistent associations with mortality depending on the type of cognitive impairment examined and duration of follow-up. This study examines mortality in older people with any cognitive impairment during acute hospital admission.Patients and methods: Prospective cohort of 6,724 people aged ≥65 years with a structured cognitive assessment on acute admission were included in this study. Cognitive spectrum disorder (CSD) was defined as delirium alone, known dementia alone, delirium superimposed on known dementia, or unspecified cognitive impairment. Mortality associated with different types of CSD was examined using a non-proportional hazards model with 2-year follow-up.Results: On admission, 35.4% of patients had CSD, of which 52.6% died within 2 years. After adjustment for demographics and comorbidity, delirium alone was associated with increased mortality in the 6 months post-admission (HR =1.45, 95% CI 1.28–1.65) and again after 1 year (HR =1.44, 95% CI 1.17–1.77). Patients with known dementia (alone or with superimposed delirium) had increased mortality only after 3 months from admission (HR =1.85, 95% CI 1.56–2.18 and HR =1.80, 95% CI 1.52–2.14) compared with patients with unspecified cognitive impairment after 6 months (HR =1.55, 95% CI 1.21–1.99). Similar but partially attenuated associations were seen after adjustment for functional ability.Conclusion: Mortality post-admission is high in older people with CSD. Immediate risk is highest in those with delirium, while dementia or unspecified cognitive impairment is associated with medium- to long-term risk. These findings suggest that individuals without dementia who develop delirium are more seriously ill (have required a larger acute insult in order to precipitate delirium) than those with pre-existing brain pathology (dementia). Further research to explain the mortality patterns observed is required in order to translate the findings into clinical care. Keywords: acute admission, elderly, cognition, function, non-proportional hazards