NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD⁺), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD⁺ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.
Humans ; NAD/metabolism* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Nicotinamide Phosphoribosyltransferase/metabolism* ; Cytokines/metabolism* ; Quinones ; Oxidoreductases

Urine nontargeted metabolomics technology was developed for investigating the effect and mechanism of improving learning and memory ability in APP/PS1 mice of Psoralea corylifolia. All animal experiments were approved by the Animal Ethics Committee of Heilongjiang University of Chinese Medicine (Approval No.: 2020092502). Sixteen APP/PS1 mice were randomly divided into the model group and Psoralea corylifolia group (0.5 g·kg^-1), and eight male C57BL/6J mice of the same background were selected as control group, step-through test and novel object recognition were used as evaluation indexes. Changes in urine endogenous metabolites of mice from eachgroup were determined by ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS), and differential metabolites were screened, and metabolic pathway enrichment analysis was performed. The results of pharmacodynamic investigation showed that Psoralea corylifolia can reduce the dark incubation period and number of errors in APP/PS1 mice (P < 0.01) and improve the new object recognition index of APP/PS1 mice (P < 0.01). Metabolomics analysis identified 15 differential metabolites, and 9 differential metabolites were significantly call back by Psoralea corylifolia. Metabolic pathway analysis showed that histidine metabolism, citric acid cycle, taurine and hypotaurine metabolism and glucose metabolism were the main metabolic pathways of Psoralea corylifolia in improving learning and memory ability. These studies suggest that Psoralea corylifolia improves the learning and memory ability of APP/PS1 mice, and its mechanism may be related to improving mitochondrial dysfunction, reducing peripheral histamine level, regulating energy metabolism disorders and antioxidant levels.

Aim To explore the effect of CXCL7/CX-CR2 axis on obesity-related cognitive dysfunction at both animal and cellular levels.Methods The novel object recognition test was performed to assess the cog-nition.After the preparation of the frozen sections,the activation of microglia and astrocytes in hippocampi and the level of PSD95 were determined by immunoflu-orescence staining.The content of CXCL7 in hipp-ocampi was determined by enzymelinked immunosor-bent assay.The dendritic spine density of hippocampal neurons was observed by Golgi staining.Furthermore,HT22 cells were treated with the recombinant mouse CXCL7 and/or si-RNA targeting CXCR2.After the treatment,the levels of CXCL7 and PSD95 were ob-served by immunocytochemistry staining.Results Compared with animals in the control group,there was significantly decreased discrimination index,increased activation of microglia and astrocytes,decreased con-tent of PSD95,decreased density of dendritic spine,and increased content of CXCL7 in hippocampi in the DIO group.Compared with animals in the DIO group,there were significantly increased discrimination index in the AWL group.In HT22 cells,the level of PSD95 significantly decreased in the Ctrl+CXCL7 group com-pared with the control group.This decrease was attenu-ated in the si-CXCR2+CXCL7 group compared with the Ctrl+CXCL7 group.Conclusion Chronic high-fat diet induces neuroinflammation and subsequently induces cognitive dysfunction,which may be related to the synaptic plasticity mediated by the CXCL7/CXCR2 axis.

OBJECTIVE: To explore the genotyping characteristics of human fecal Escherichia coli( E. coli) and the relationships between antibiotic resistance genes (ARGs) and multidrug resistance (MDR) of E. coli in Miyun District, Beijing, an area with high incidence of infectious diarrheal cases but no related data. METHODS: Over a period of 3 years, 94 E. coli strains were isolated from fecal samples collected from Miyun District Hospital, a surveillance hospital of the National Pathogen Identification Network. The antibiotic susceptibility of the isolates was determined by the broth microdilution method. ARGs, multilocus sequence typing (MLST), and polymorphism trees were analyzed using whole-genome sequencing data (WGS). RESULTS: This study revealed that 68.09% of the isolates had MDR, prevalent and distributed in different clades, with a relatively high rate and low pathogenicity. There was no difference in MDR between the diarrheal (49/70) and healthy groups (15/24). CONCLUSION We developed a random forest (RF) prediction model of TEM.1 + baeR + mphA + mphB + QnrS1 + AAC.3-IId to identify MDR status, highlighting its potential for early resistance identification. The causes of MDR are likely mobile units transmitting the ARGs. In the future, we will continue to strengthen the monitoring of ARGs and MDR, and increase the number of strains to further verify the accuracy of the MDR markers.
Humans ; Escherichia coli/genetics* ; Escherichia coli Infections/epidemiology* ; Multilocus Sequence Typing ; Genotype ; Beijing ; Drug Resistance, Multiple, Bacterial/genetics* ; Anti-Bacterial Agents/pharmacology* ; Diarrhea ; Microbial Sensitivity Tests

Objective: To investigate whether pre-lingual deafness adult caused by inadequate auditory compensation in childhood can benefit from cochlear implants and the related influencing factors. Methods: A total of 26 prelingual deafness as experimental group [11 males and 15 females, the age of operation was (24.5±5.7) years] and 13 postlingual deafness as control group [5 males and 8 females, the age at the time of operation was (42.2±11.4) years] were recruited. Objective assessment included hearing threshold and speech recognition rate tests while wearing cochlear implants. Subjective assessment used Nijmegen Cochlear Implant Questionnaire to assess hearing-related quality of life of subjects. The changes of hearing ability in the prelingual deafness group before and after operation and the differences with the postlingual deafness group were compared, and the correlation between speech recognition ability and the age diagnosed as severe or profound deafness, the age of hearing aid invalid, and duration of wearing cochlear implant were analyzed as factor indicators. All statistical results were analyzed by SAS 9.4 software. Results: In terms of objective indicators, the speech recognition rate of pre-lingual deafness was significantly lower than that of post-lingual deafness [(35.4±28.0)% vs (80.9±8.0)%,t=7.67, P<0.001], while there was no statistical difference in hearing threshold between the two groups [(34.8±4.0) dB HL vs (33.1±3.7) dB HL, t=1.30, P>0.05]. The indicators in the subjective questionnaire showed that the prelingual deafness group was only weaker in advanced sound perception, confidence and total mean score than the post-lingual deafness group (P<0.05), and there was no significant difference in other aspects(P>0.05), meanwhile, all indicators of the prelingual deafness group were significantly improved compared with the preoperative level (P<0.001). There was a moderate positive correlation between the hearing quality and the speech recognition rate in the prelingual deafness group(r=0.51, P=0.008). The regression analysis showed that the invalid age of hearing aid was the exact influencing factor of speech recognition rate. Conclusions: Certain prelingual deaf adults can adapt to cochlear implants and obtain different degrees of auditory assistance. Compared with the improvement of objective auditory ability assessment, the patient who received cochlear implantation gain more improvement in auditory related quality of life subjectively. The ineffective age of preoperative hearing aid is an important factor, which needs to be aroused sufficient preoperative attention.
Adolescent ; Adult ; Cochlear Implantation/methods* ; Cochlear Implants ; Deafness/rehabilitation* ; Female ; Humans ; Male ; Quality of Life ; Speech Perception ; Young Adult

Chronic kidney disease (CKD) is a serious chronic disease with high incidence, poor prognosis, and a variety of complications. Indoxyl-sulfate (IS) and p-cresol sulfate (PCS) are two typical gut-derived uremic toxins, which are produced by the co-metabolism of intestinal microbes and the host. With the progression of CKD, gut-derived uremic toxins such as IS and PCS accumulate in patients with CKD and thereafter accelerate the progression of CKD. Gut microbiota is closely related with CKD, and targeting gut microbiota to regulate gut-derived uremic toxins synthesis and metabolic pathways may be a promising strategy to delay the progression of CKD. In this paper, the relationship between gut microbiota, gut-derived uremic toxins, and CKD was analyzed, and the strategy to delay the progression of CKD by targeting gut microbiota and uremic toxins metabolism pathway was proposed.

Insulin resistance refers to the impaired ability of insulin to regulate glucose metabolism in peripheral organs, which is considered to be the etiology of type 2 diabetes. This study aims to explore the mechanism of improving insulin resistance by compatibility of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos (DH). Insulin resistance was conducted on C56BL/6J mice by treatment of high fat diet. The energy intake and body weight, plasma levels of triglycerides, total cholesterol, insulin and glucose, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT), as well as gene transcription and protein expression levels of insulin signaling pathway in liver, heart, kidney, and skeletal muscle of insulin resistance mice were evaluated. Animal experiments and welfare were performed in compliance with the guidelines of Animal Ethics Committee of Nanjing University of Chinese Medicine. The results showed that DH treatment significantly alleviated the excessive food intake and weight gain, and significantly decreased the levels of plasma triglycerides and total cholesterol, and constantly mitigated the hyperinsulinemia in insulin resistance mice. The results of OGTT and ITT suggested that DH treatment dramatically improved the response of insulin resistance mice to insulin stimulated glucose metabolism. Furthermore, the imbalance of metabolic arm and mitogenic arm of insulin signaling pathway in insulin resistance mice was normalized after DH treatment. DH treatment regulated insulin signaling pathway and improved the ability of glucose metabolism of insulin resistance mice.

Huang-Kui-Si-Wu Formula (HKSWF) can reduce the accumulation of uremic toxin p-cresyl sulfate (PCS) and its precursor p-cresol (PC) in a rat model of chronic kidney disease (CKD) and delay the progression of CKD. However, the mechanism by which HKSWF decreases PC accumulation is not clear. This study investigated the effect of HKSWF on PC production in intestinal microbes as well as its mechanism of action. After CKD model rats were given HKSWF by intragastric administration, feces were collected to analyze the gut bacterial composition by 16S rDNA sequencing technology. All procedures were approved by the Institutional Animal Care and Use Committee of the Nanjing University of Chinese Medicine. The results showed that HKSWF inhibited PC production without decreasing the abundance of harmful bacteria. HPLC-UV-FLD was used to detect p-cresol. An in vitro anaerobic culture system was used to study the effect and mechanism of action of HKSWF on PC production in gut bacteria. The results show that food-derived tyrosine (Tyr) could significantly promote PC production in intestinal bacteria, and HKSWF (4000, 400, 40 μg·mL^-1) could dose-dependently inhibit PC production in gut bacteria in vitro. HKSWF inhibited bacterial PC synthesis by two pathways: it decreased the oxidation pathway from 82.83% to 38.87%, and increased the reductive pathway from 17.17% to 61.13%. This result suggests that HKSWF could inhibit PC production by switching tyrosine metabolism from an oxidative pathway to a reductive pathway. Secondly, HKSWF could directly inhibit the oxidative pathway of tyrosine and decrease the decomposition of PHA, thereby inhibiting PC production. These results suggest that HKSWF could inhibit the formation of harmful uremic toxins by modulating the metabolic pathway of PC in gut microbiota and thereby delaying CKD progression.

Objective To document the impact of conversion to mycophenolate mofetil (MMF)at different time points after transplantation on the renal function of renal function.Methods A longterm,multicenter,non-interventional and observational study was done.Two cohorts were included:One was Switch cohort (340 cases) including renal allograft recipients who switched to MMF at least 6 months after renal transplantation and followed up for 4 years after switch; The other was Stay cohort (123 cases),including renal allograft recipients who received MMF treatment after transplantation and followed up for 4 years after enrollment.Results GFR values of patients in Switch cohort was significantly increased after switch,and the change in GFR slope was 3.1 mL· min-1 · year-1 (P＜0.01).GFR values of patients in Stay cohort kept steady before and after enrollment,and the change in GFR slope was 0.44 mL·min-1 ·year-1 (P＞0.05).Statistically significant difference in the onset time of GFR decline (defined as 20％ decline from the baseline) was observed among subgroups within Switch cohort (P＜0.01),but there was no significant difference among subgroups within Stay cohort (P＞0.05).Stay cohort was 12％ higher than in Switch cohort every year.Conclusion Conversion to MMF ＞6 months or even many years after transplantation can obviously improve the renal function of recipients.The earlier conversion can benefit improvement of the renal function.