Combined Metabolite Analysis and Network Pharmacology to Elucidate the Mechanisms of Therapeutic Effect of Melastoma dodecandrum Ellagitannins on Abnormal Uterine Bleeding.

The abnormal uterine bleeding (AUB) is complex and usually leads to severe anemia. Melastomadodecandrum (MD) is clinically used for the treatment of metrorrhagia bleeding. The MD ellagitannins (MD-ETs) had been evidenced being effective at hemorrhage, and exerts biological activities upon their metabolites including ellagic acid and urolithins. In this study, the blood-permeated metabolites from theMD-ETs were analyzed using LC-MS approach, and 19 metabolites including ellagic acid and urolithin A derivatives were identified. Furthermore, a network pharmacology analysis including the target prediction analysis, AUB target analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to reveal the relationships between "metabolites-targets-pathways", which was further verified by molecular docking analysis. The results showed that methyl ellagic acid, urolithin A and isourolithin A produced from MD-ETs can be absorbed into the blood, and might act on the core targets of VEGFA, SRC, MTOR, EGFR and CCND1. And the hemostatic effects were exerted through PI3K-Akt, endocrine resistance and Rap 1 signaling pathways. These results implied the potential effective constituents and action mechanism of MD-ETs in the therapy of AUB, which will promote the application of MD-ETs as natural agent for the treatment of gynecological bleeding diseases.

Molecular networking-assisted systematical profiling and the in vivo neuroprotective effect of ellagitannins from the Melastoma dodecandrum Lour.

BACKGROUND: Ellagitannins (ETs) are a major classification of natural tannins, with relatively large and complex structures. ETs from medicinal plants are focused increasingly due to urolithins, a kind of intestinal metabolite of ETs, which showed promising anti-Alzheimer's disease (AD) effects. Melastoma dodecandrum (MD), a widely used traditional Chinese medicine is rich in ETs, but their chemistry and potential neuroprotective effects have not been investigated. PURPOSE: This study aimed to identify the chemical composition of ETs in the crude extract of MD and to investigate their neuroprotective effects in vivo. METHODS: UPLC-QTOF-MS-based molecular networking (MN) and structural characterization were applied to targeted profiling of the MD-ETs. Animal behavior experiments, including the novel object recognition test (NOR), open field test (OFT), and Morris water maze test (MWM), were conducted to assess the memory improvement effects of MD-ETs in AD model mice. RESULTS: A total of 70 ETs, ranging from monomers to tetramers, were tracked and characterized in the MD extract using MN-guided targeted profiling, with 59 of them reported for the first time in this species. MD-ETs significantly improved memory impairment in AD mice, as indicated by decreased escape latency, increased number of crossings and target quadrant distance in MWM, increased rearing number in OFT, and increased preference index in NOR. CONCLUSION: This study systematically characterized the composition and structural features of ETs in MD using targeted LC-MS profiling, expanding the chemical information of ETs in MD. Furthermore, the results demonstrate that MD-ETs have significant effects on improving impaired memory in AD mice, suggesting their potential as alternative natural medicines for the treatment of neurodegenerative diseases.

[Relationship Between Social Isolation and Health Behaviors and Ulcer Severity in Diabetic Foot Patients].

Objective: To explore the relationship between social isolation and health behaviors and ulcer severity in patients with diabetic foot. Methods: A cross-sectional study was conducted with 160 patients suffering from type 2 diabetes mellitus combined with diabetic foot. The patients received treatment at the Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University between September 2020 and December 2021. Patient information was collected, including the scores for Lubben Social Network Scale and the Wagner classification of foot ulcers. Analysis was conducted to study the characteristics of the patients' health behaviors, including whether they received information and education on diabetic foot, whether there were delays in their attempt to access medical service, the frequency of foot examinations, etc. In addition, patient demographic data were collected, including sex, age, education, and employment status. According to their scores for Lubben Social Network Scale, the patients were divided into a social isolation group ( n=60) and a non-social-isolation group ( n=100). The severity of the foot ulcers and the health behaviors of the two groups were compared to identify differences. Results: The findings suggest that, compared with the non-social-isolation group, the social isolation group had a higher proportion of diabetic foot patients with Wagner grade 3-5 diabetic foot ulcers ( P<0.05). Analysis of the health behaviors showed that the social isolation group had a higher proportion of diabetes foot patients who had never undergone examination of their feet and those who had delayed attempts to access medical service for their condition ( P<0.05). There were no significant differences between the two groups in terms of whether the patients had received information and education concerning diabetic foot, causes of foot injury, self-treatment of wounds, smoking, and drinking. Correlational analysis suggested that the scores of Lubben Social Network Scale were negatively correlated with the delayed attempts to access medical service ( r=-0.353, P=0.001), that is, the higher the degree of social isolation, the longer the delay in patients' attempt to access medical service for their diabetic foot. Conclusions: Social isolation is correlated to health behaviors and ulcer severity in patients with diabetic foot. Giving more attention to the problem of social isolation of diabetic foot patients and increasing their ties with the social environment and the members of their social network may have a positive effect on improving the delays in diabetic foot patients' attempt to access medical service, which is particularly important for follow-up treatment.

Antitumor activity of 7RH, a discoidin domain receptor 1 inhibitor, alone or in combination with dasatinib exhibits antitumor effects in nasopharyngeal carcinoma cells.

Dysregulation of the discoidin domain receptors (DDRs) has been implicated in the development of numerous types of tumors, including head and neck cancer, and nasopharyngeal, breast, ovarian and esophageal carcinomas. Furthermore, agents that inhibit DDR1 activity are hypothesized to be useful for the treatment of nasopharyngeal carcinoma (NPC). The aim of the present study was to evaluate the effect of the DDR1 inhibitory (3-(2-(pyrazolo(1,5-a)pyrimidin-6-yl)-ethynyl)benzamide compound, 7RH, in NPC cells both in vitro and in vivo, and its effect when used in combination with dasatinib, a SRC family kinase (SFK) inhibitor. The effects of 7RH alone or in combination with dasatinib on cell viability were assessed using MTT assays and apoptosis was detected by flow cytometry. In addition, western blotting was performed to analyze the relative protein expression levels of cell cycle-associated genes in human NPC cell lines (CNE1, CNE2, HONE1 and SUNE1). Cell migration was also assessed using cell adhesion assays. Furthermore, tumor xenografts of CNE2 NPC cells were established in nude mice and the growth inhibitory effects of 7RH treatment alone or in combination with dasatinib were evaluated. Finally, knockdown of DDR1 protein expression was achieved by transfection of CNE2 cells with DDR1-specific small interfering RNA. Treatment with 7RH effectively suppressed the proliferation and induced the apoptosis of NPC cells. In addition, the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT3) signaling pathway was downregulated by 7RH, whereas the activities of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways were upregulated in response to 7RH treatment. Furthermore, the expression levels of phosphorylated SRC were increased in NPC cells treated with 7RH; thus indicating that SRC exhibits a vital function in the resistance of NPC cells to 7RH via activation of the PI3K/AKT signaling pathway. The results of the present study indicate that DDR1 and SFK inhibition may present a potential therapeutic strategy for patients with NPC.

[Evaluation of factors associated with variability in retinal nerve fiber layer thickness in myopic juveniles aged 7-18 years].

OBJECTIVE: To evaluate the relationship between retinal nerve fiber layer thickness(RNFLT)measured by optical coherence tomography (OCT) and age, spherical equivalent (SE), axial length, and gender in myopic juveniles. METHODS: Cross-sectional observational study. One hundred and fifty-four juveniles (age range, 7-18 years) underwent ophthalmic examinations. Peripapillary Fast RNFL scans were performed by Stratus OCT with a nominal diameter of 3.46 mm centered on the optic disc on one randomly selected eye of each subject. Axial length was measured by A-ultrasound. The effects of several factors (age, SE, axial length, gender and eye) on RNFLT were investigated in univariate and multivariate stepwise regression analyses. RESULTS: The mean global RNFLT (x(-) ± s) was (114.106 ± 11.473) µm. The RNFLT was thickest superiorly (145.468 ± 19.064) µm and inferiorly (138.091 ± 20.464) µm, thinner temporally (94.396 ± 18.544) µm, and thinnest nasally (78.558 ± 16.981) µm. Both global and superior peripapillary RNFLT had no significant relationship with age (r = 0.129, 0.014; P > 0.05), SE (r = 0.006, 0.123; P > 0.05), axial length (r = -0.067, -0.141; P > 0.05), gender (r = -0.095, 0.025; P > 0.05) and laterality (r = -0.148, 0.095; P > 0.05). In multivariate stepwise regression analyses, there was significant inverse linear correlation between temporal RNFLT and SE (r = -0.465, P < 0.05). There was significant inverse linear correlation between nasal RNFLT and axial length and laterality (r = -0.327, P < 0.05). There was significant inverse linear correlation between inferior RNFLT and axial length (r = -0.276, P < 0.05), and direct linear correlation between inferior RNFLT and age (r = 0.276, P < 0.05). CONCLUSIONS: When we assess the RNFLT in myopic juveniles, we should consider the influence of age, refraction, axial length, spherical equivalent and laterality comprehensively.