Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.

Objective: To investigate the efficacy and safety of Liqingtong (LQT) granules in patients with dampness-heat hyperuricemia. Methods: A randomized, double-blind, placebo-controlled pilot trial was conducted at the 983rd Hospital of the Joint Logistic Support Force of the People's Liberation Army from March 15, 2023, to August 10, 2023. In total, 119 participants were enrolled in this trial, and participants were given either LQT granules or placebo for 60 days based on a health education. The primary outcome was serum uric acid (SUA) level, and the secondary outcome was the traditional Chinese medicine (TCM) symptom score, measured on days 0, 30, and 60. Safety indicators, including liver function, kidney function, blood routine, glucose, blood lipid, blood pressure, and heart rate were tested on days 0 and 60 of the trial. The data were analyzed using Prism 9 software, and the significance level was set at P < .05. Results: Among 119 participants, six in the LQT granule group and seven in the placebo group dropped out, and 106 participants completed clinical observation. Baseline information, including SUA levels, TCM symptom scores, and other clinical characteristics, did not differ between the groups. At the end of the trial, compared with baseline values, the SUA levels in the LQT granule group decreased (P < .001), and no significant change was observed in the placebo group (P = .422); compared with the placebo group, the SUA levels decreased in the LQT granule group (P = .001). Compared with baseline values, the total TCM symptom scores in the LQT granule group decreased (P < .001), with no change in the placebo group (P = .136). Safety indicators did not differ significantly between the two groups. Conclusion The pilot trial demonstrated the potential of LQT granules to lower SUA levels and improve symptoms of dampness and heat.

Objective In this study,we analyzed the transcriptome sequences of Kupffer cells exposed to simulated microgravity for 3 d and conducted biological experiments to determine how microgravity initiates apoptosis in Kupffer cells. Methods Rotary cell culture system was used to construct a simulated microgravity model.GO and KEGG analyses were conducted using the DAVID database.GSEA was performed using the R language.The STRING database was used to conduct PPI analysis.qPCR was used to measure the IL1B,TNFA,CASP3,CASP9,and BCL2L11 mRNA expressions.Western Blotting was performed to detect the level of proteins CASP3 and CASP 9.Flow cytometry was used to detect apoptosis and mitochondrial membrane cells.Transmission electron microscopy was used to detect changes in the ultrastructure of Kupffer cells. Results Transcriptome Sequencing indicated that simulated microgravity affected apoptosis and the inflammatory state of Kupffer cells.Simulated microgravity improved the CASP3,CASP9,and BCL2L11 expressions in Kupffer cells.Annexin-V/PI and JC-1 assays showed that simulated microgravity promoted apoptosis in Kupffer cells.Simulated microgravity causes M1 polarization in Kupffer cells. Conclusion Our study found that simulated microgravity facilitated the apoptosis of Kupffer cells through the mitochondrial pathway and activated Kupffer cells into M1 polarization,which can secrete TNFA to promote apoptosis.

Objective:To identify the influencing factors of postoperative nausea and vomiting (PONV) in the patients undergoing egg retrieval with general anesthesia for in vitro fertilization-embryo transfer (IVF-ET).Methods:This was a case-control study. Medical records from IVF-ET patients undergoing egg retrieval with general anesthesia in the Center for Reproductive Medicine in our hospital from November to December 2020 were retrospectively collected, 52 patients with PONV were identified (group PONV), and 252 patients without PONV were selected as control group (group C). Univariate analysis was performed on the suspicious influencing factors, and the factors with statistically significant differences were included in the logistic regression analysis model to identify the influencing factors of PONV.Results:Compared with group C, statistically significant differences were found in the number of eggs, anesthesia time, and the proportion of PONV history and/or motion sickness history in group PONV ( P<0.05). The results of multivariate logistic regression analysis showed that a large number of eggs, long anesthesia time, and a high proportion of PONV history and/or motion sickness history were independent risk factors for PONV. Conclusions:A large number of eggs, long anesthesia time, and a high proportion of PONV history and/or motion sickness history are independent risk factors for PONV in IVF-ET patients undergoing egg retrieval with general anesthesia.

Abstract: Objective To investigate the function and molecular mechanism of LRH-1 in regulating the sensitivity of hepatocellular carcinoma (HCC) cells to oxaliplatin, providing new ideas for the treatment of liver cancer. Methods Knockdown and overexpression of LRH-1 in HCC cell lines were constructed, and the effect of LRH-1 on oxaliplatin resistance of HCC cells was explored by detecting IC50, cell proliferation, and plate colony formation assay. The transcriptional regulation of the MDR-1 gene by LRH-1 was detected through quantitative PCR. The transcriptional activation ability of LRH-1 on the MDR1 gene was evaluated by luciferase reporter assay. Results In HuH7 cells overexpressing LRH-1, the IC50 significantly increased to 18.012 μmol/L under oxaliplatin treatment, significantly higher than the 2.042 μmol/L in the HuH-7 control group, showing statistically significant differences (P<0.05). After overexpression of LRH-1 in HuH-7 cells, the cell proliferation ability was significantly increased, with a noticeable increase in MDR1 mRNA level. In HepG2 cells with knockdown LRH-1 expression, the IC50 significantly dropped to 1.012 μmol/L, significantly lower than the 6.294 μmol/L in the HepG2 control group, with statistically significant differences (P<0.05). After knockdown of LRH-1 in HepG2 cells, the cell proliferation and plate colony formation ability were significantly inhibited, with a notable decrease in MDR1 mRNA expression level. Luciferase reporter assay confirmed that LRH-1 can activate the transcriptional activity of the MDR1 promoter in a dosedependent manner, and its specific inhibitor ML-180 can significantly reduce LRH-1′s transcription activation ability on the MDR1 promoter. Conclusions LRH-1 may promote oxaliplatin resistance in hepatocellular carcinoma cells by regulating the transcriptional activity of MDR1 gene. Since its specific small molecule inhibitor has been successfully synthesized, LRH-1 can potentially become a target for the treatment of drug resistance in hepatocellular carcinoma.

OBJECTIVE To analyze the research status and hotspots of wine processing of Chinese medicine， and to provide reference for its related research. METHODS Related literature about wine processing research in Chinese medicine was retrieved from CNKI and Web of Science （WOS）. VOSviewer 1.6.18 and CiteSpace 6.1.1R2 software were used to visualize the core authors， research institutions， keywords， and other contents. RESULTS A total of 962 Chinese literature and 57 English literature were included in the study. In total， the trend in the amount of Chinese and English literature was on the rise during 2000-2022. The analysis of the authors showed that ZHANG Xuelan and CAI Baochang had the most publications in Chinese and English literature. Research institutions were mainly Chinese medicine universities， and Chengdu University of Chinese Medicine and Nanjing University of Chinese Medicine were the research institutions with the largest number of Chinese and English literature published. The analysis of keywords in Chinese and English literature showed that the wine-processing research of Chinese medicine mainly focused on wine-processed varieties， chemical constituents， wine-processed process， and quality standards. Response surface method， chroma value， metabolomics， and action mechanism had become current research hotspots. CONCLUSIONS The related research of wine processing for Chinese medicine is still in the development period. In the future， the response surface method to optimize the wine-processed process and the combination of metabolomics with related technologies of other omics to reveal the pharmacodynamic mechanism of wine processing for Chinese medicine is still the future development trend. In the future， cooperation between institutions should be further strengthened， and research on the use of excipients and alcohol should be strengthened. Modern analytical methods should be utilized to enhance the efficiency of wine processing for Chinese medicine， thereby promoting the modernization and internationalization of wine processing for Chinese medicine.

ObjectiveBy exploring the volatile components， polysaccharide composition and changes in the contents of five carbohydrate components of Polygonatum cyrtonema rhizoma before and after processing， and then the effect of yellow rice wine on the odour formation of P. cyrtonema rhizoma was investigated. MethodThe volatile components of P. cyrtonema rhizoma before and after processing were detected by headspace gas chromatography-mass spectrometry（HS-GC-MS）， and sample data were subjected to principal component analysis（PCA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） using SIMCA 14.1， then the differences between these components of P. cyrtonema rhizoma before and after processing were screened according to the principle of variable importance in the projection（VIP） value>1. Crude carbohydrate components in raw and wine-processed P. cyrtonema rhizoma were subjected to oxime and silylation， the carbohydrate components were analyzed by gas chromatography-mass spectrometry（GC-MS/MS）， and the relative contents of various components were calculated by peak area normalization， then quantitative analysis of four carbohydrate components was also carried out. ResultA total of 23 volatile components were identified from the raw products and the wine-processed products， including 15 components in raw products and 20 components in wine-processed products. Among them， 2-methylbutyraldehyde and isovaleraldehyde had a sweet odor and their contents increased after processing， but the contents of hexanal and caproic acid decreased， new components such as 2-acetylfuran and 5-methylfuranal were produced after processing. PCA and OPLS-DA results showed that there were significant differences between raw products and the wine-processed products， a total of 13 differential compounds were screened out， of which 7 showed an upward trend in relative content and 6 showed a downward trend. A total of 7 carbohydrate components， including 5 monosaccharides and 2 disaccharides， were identified in raw products and the wine-processed products. The results of determination showed that the contents of fructose， glucose， mannose and sucrose in P. cyrtonema rhizoma increased after wine-processing， and their increases were 4.54， 1.51， 2.93， 3.66 times， respectively. ConclusionAfter processing， the increase of aromatic flavor of P. cyrtonema rhizoma may be related to the increase of the contents of aldehydes such as 2-methylbutyraldehyde and isovaleraldehyde， while the decrease of raw flavor may be related to the decrease of the contents of volatile components such as hexanal and hexanoic acid， the increase of sweet flavor may be related to the increase of the contents of monosaccharides and oligosaccharides such as fructose and sucrose.

According to understanding of the pathogenesis of acne, scholars have established animal models of acne inflammation, animal models of grafting human skin acne, and natural acne animal models. The acne inflammation model is mainly induced by bacterial infection, chemical drug application, and foreign matter injection. Natural acne animal models include animals that some are sensitivity to hormones and some have clinical symptoms of acne. It is necessary to select appropriate model animals and replicate model methods for the development of acne intervention products with different degrees and mechanisms. At present, there are only human evaluation standards of acne health functions in China, but no animal evaluation standards, which has affected the in-depth study of the pathogenesis of acne as well as the research and development progress of acne products. This article summarizes the conditions for the occurrence of acne, the characteristics of human skin, the bidirectional effect of Cutibacterium acnes on human skin, acne animal models, and commonly used observation and evaluation indicators, providing the reference for studying the pathogenesis of acne, promoting acne treatment and health care, and developing treatment products.

OBJECTIVE To investigate the mechanism of Mayuan tongbian zhitong decoction on improving slow-transmission constipation（STC）in rats by regulating AMP activated protein kinase （AMPK）/endothelial nitric oxide synthase （eNOS）signaling pathway. METHODS The rats were randomly divided into blank group ，model group ，Mayuan tongbian zhitong decoction low-dose，medium-dose and high-dose groups （6，12，18 mg/kg），with 10 rats in each group. Except for blank group ，other groups were given Compound diphenoxylate suspension to induce STC model. After modeling ，blank group and model group were given normal saline intragastrically ，and Mayuan tongbian zhitong decoction groups were given relevant medicine intragastrically ， once a day ，for consecutive 2 weeks. The number of feces and water content of feces in each group were observed before and after treatment；the carbon powder propulsion rate of rats in each group was calculated ；the pathological structure of colon in each group was observed ；the levels of nitric oxide （NO）and nitric oxide synthase （NOS）in colon tissues of rats in each group were detected；the expressions of AMPK ，eNOS，mammalian target of rapamycin （mTOR），tuberous sclerosis complex 1（Tsc-1）， Tsc-2 and eukaryotic promoter 4E binding protein （4ebp）were also detected. The active ingredients of Cannabis sativa ，Citrus aurantium and Rehmannia glutinosa were screened from Mayuan tongbian zhitong decoction. The active ingredients with high Degree value were docked with AMPK and eNOS ，to verify the interaction. RESULTS Compared with before treatment ，the number and water content of feces were increased significantly in Mayuan tongbian zhitong decoction groups （P＜0.05）. Compared with blank group ，carbon powder propulsion rate of model group was decreased significantly （P＜0.05）； colonic structure was disordered ，and a large number of inflammatory cells were seen in submucosa ；the levels of NO and NOS in colon tissue as well as the protein expressions of AMPK ，eNOS，mTOR，Tsc-1，Tsc-2 and 4ebp were increased significantly （P＜0.05）. Compared with model group ，above indexes of Mayuan tongbian zhitong decoction groups （except for NOS in low-dose group ）were reserved significantly （P＜0.05）. In the molecular docking experiment ，the active components with the highest Degree values in C. sativa ，C. aurantium and R. glutinosa were（Z）-3-（4-hydroxy-3-methoxy-phenyl）-N-[2-（4-hydroxyphenyl）ethyl] acrylamide，nobiletin and stigmasterol. The binding energies of AMPK with these three components were －5.15，－4.61 and －4.83 kJ/mol，the binding energies of eNOS with these three components were －6.11，－5.40 and －5.91 kJ/mol. The conformations of these three compounds with AMPK and eNOS were stable and their binding activities were high. CONCLUSIONS Mayuan tongbian zhitong decoction can improve the constipation symptoms and intestinal function in STC model rats ，and its specific mechanism may be related to the inhibition of AMPK/eNOS signaling pathway.

The 4-hydroxyphenylacetate 3-hydroxylase (4HPA3H), originated from Escherichia coli, converts p-coumaric acid to caffeic acid. In order to improve the efficiency of caffeic acid biosynthesis, we engineered E. coli for overexpression of 4HPA3H. The high-density fermentation of the engineered E. coli was conducted in a 5 L bioreactor. Subsequently, the conditions for whole-cell biocatalysis were optimized. The dry cell weight of the 4HPA3H-expressed strain reached 34.80 g/L. After incubated in the bioreactor for 6 h, 18.74 g/L (0.85 g/(L·OD₆₀₀)) of caffeic acid was obtained, with a conversion rate of 78.81% achieved. To the best of our knowledge, the titer of caffeic acid is the highest reported to date. The high-density fermentation of E. coli for overexpression of 4HPA3H and the efficient biosynthesis of caffeic acid may facilitate future large-scale production of caffeic acid.
Caffeic Acids ; Escherichia coli/metabolism* ; Fermentation ; Metabolic Engineering ; Mixed Function Oxygenases/metabolism* ; Phenylacetates