Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Inflammatory bowel disease (IBD) is a chronic and recurrent intestinal disease, and has become a major global health issue. Individuals with IBD face an elevated risk of developing colorectal cancer (CRC), and recent studies have indicated that mitochondrial dysfunction plays a pivotal role in the pathogenesis of both IBD and CRC. This review covers the pathogenesis of IBD and CRC, focusing on mitochondrial dysfunction, and explores pharmacological targets and strategies for addressing both conditions by modulating mitochondrial function. Additionally, recent advancements in the pharmacological modulation of mitochondrial dysfunction for treating IBD and CRC, encompassing mitochondrial damage, release of mitochondrial DNA (mtDNA), and impairment of mitophagy, are thoroughly summarized. The review also provides a systematic overview of natural compounds (such as flavonoids, alkaloids, and diterpenoids), Chinese medicines, and intestinal microbiota, which can alleviate IBD and attenuate the progression of CRC by modulating mitochondrial function. In the future, it will be imperative to develop more practical methodologies for real-time monitoring and accurate detection of mitochondrial function, which will greatly aid scientists in identifying more effective agents for treating IBD and CRC through modulation of mitochondrial function.

Uridine diphosphate glucuronic acid transferase (UDP-glucuronosyltransferases, UGT) is an important Ⅱmetabolic enzymes in the body. It is invovled in the metabolism of exogenous compounds, and also in endogenous substances such as bile acid metabolism and regulation. Parsing uridine diphosphate glucuronic acid transferase mediated bile acid metabolism and its influence factors can help enhance related disease treatment and prevention. Studies have shown that the interaction between UGT and bile acids is influenced by many endogenous and exogenous factors. This paper will focus on the effects of internal and exogenous factors such as nuclear receptors, genetic factors, xenobiotics and liver-related diseases on the action of UGT enzyme, and discuss the potential mechanism of bile acid balance intervention.

Objective: To explore the diagnostic value of single or combined detection of serum tumor markers alpha-fetoprotein (AFP), α-fetoprotein (AFP)-L3 and abnormal clotting (PIVKA-II) in the primary hepatic carcinoma. Methods: Serum AFP, AFP-L3 and PIVKA-II of 56 cases with primary hepatic carcinoma, 46 cases with cirrhosis, 45 cases with other liver disease and 41 healthy persons (control group) were examined by chemiluminescence method, and the differences in the levels of AFP, AFP-L3 and PIVKA-II in each group were compared. Results: Serum level of AFP, AFP-L3 and PIVKA-II in patients with primary liver cancer was significantly higher than that of the cirrhosis, other liver disease and control groups, and the difference was statistically significant (P < 0.05). The receiver operating characteristic curve analysis showed that the areas under the curve for the diagnosis of primary hepatic carcinoma by AFP, AFP-L3 and PIVKA-II were 0.887, 0.846 and 0.885, respectively. The combined use of the three tumor markers for the diagnosis of primary hepatic carcinoma increased the area under the curve to 0.899. Among the single detection, AFP had the highest sensitivity of 91.07% and PIVKA-II had the highest specificity at 88.63%. In the combined detection, AFP/PIVKA-II combination had the highest sensitivity of 94.64 %, while the AFP + AFP-L3 + PIVKA-II combination had the highest specificity at 98.48%. Conclusion Combined detection of AFP, AFP-L3 and PIVKA-II could improve the diagnostic specificity and the sensitivity of primary hepatic carcinoma; thereby make up the deficiency of single detection and improve the early diagnosis rate.

Objective To know the anxiety status of preschool children in rural areas and to explore its influential factors. Methods Subjects of 1363 rural preschool children aged 3-6 years were selected from Anhui Province( Changfeng and Feixi county of Hefei city; Qianshan county of Anqing city; Funan county of Fuyang city) . The primary caregivers of preschool children were investigated by Chinese version of Spence Preschool Anxiety Scale (SPAS),Devereux Early Childhood Assessment for Preschoolers (DECA-P2) ,Neglect Norms for Children Aged 3 to 6 Years in Rural Areas of China,Adaptation Partnership Growth Affection Resolve (APGAR),Self-rating anxiety scale (SAS) and Self-rating depression (SDS). Result-s Among the 1363 preschool children,the positive rate of anxiety was 14. 7％. Physical injury fears score was highest (1. 24±0. 84),followed by social phobia anxiety (0. 86±0. 75) and separation anxiety (0. 85± 0. 74) . Except for obsessive compulsive disorder,the other four types of anxiety and total anxiety scores were negatively correlated with the total protective factors of mental resilience (r=-0. 054- -0. 070,P<0. 05). Besides,all anxiety scores were positively correlated with behavioral problems(r=0. 121-0. 237,P<0. 05)and neglect degree (r=0. 157-0. 269,P<0. 05). The results of multiple linear regression analysis of different anxiety types showed that gender,family type,family income status,parental rearing pattern was consistent or inconsistent,children' s neglect degree,behavior problem and anxiety/depression status of primary caregivers were the main factors affecting the anxiety level of preschool children in rural areas. Conclusions In order to reduce or avoid anxiety of preschool children,it is necessary to establish a good family environment,im-prove parents' upbringing level,and take effective education intervention.

UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug-drug interactions (DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risksUGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The ICvalues of icotinib and erlotinib against UGT1A1-mediated NCHN--glucuronidation in human liver microsomes (HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with thevalues of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risksUGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration-time curve (AUC) of NCHN. These findings are helpful for the medicinal chemists to design and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risksUGT1A1 inhibition.

Purpose To investigate the expression of reactive oxygen species (ROS) and PI3K/AKT signaling pathway associated gene protein p70S6K1, VEGF in prostate cancer and adjacent tissues, and to determine their relationship with micro-vascular density ( MVD) , as well as the relationship between themselves. Methods The expression of ROS was detected by immunofluorescence, and the expression of p70S6K1, VEGF and MVD counting were detected by immunohistochemistry. Results Compared to adjacent tis-sues, the expression of ROS, p70S6K1, VEGF and MVD in PCa were increased considerablely (P<0. 05). In prostate cancer the ex-pression of ROS were positively correlated to the expression of p70S6K1, VEGF protein, and the expression of ROS and p70S6K1, VEGF were positively correlated to the number of MVD. Conclusion (1)The expression level of ROS in prostate cancer tissues was significantly higher than adjacent tissues. (2) The expression of PI3K/AKT pathway associated gene protein p70S6K1, VEGF protein and MVD counting in prostate cancer tissue was higher than the adjacent tissues, suggesting PI3K/AKT signaling pathways may play a role in tumor angiogenesis. (3) The expression of ROS and PI3K/AKT pathway associated gene protein p70S6K1, VEGF and MVD counting in prostate cancer tissues was positively correlated, suggesting that ROS may play a positive regulatory role for the development of prostate cancer by PI3K/AKT signaling pathway.