Design, synthesis and biological evaluation of matrine contains benzimidazole derivatives as dual TOPOI and PARP inhibitors for cancer therapy.

TOPOI inhibitors have long been a focal point in the research and development of antitumor drugs. PARP-1 plays a crucial role in repairing DNA damage induced by TOPOI inhibitors. Thus, concurrent inhibition of TOPOI and PARP-1 has the potential to augment drug activity. Matrine, characterized by low toxicity and good water solubility, offers advantageous properties. In this investigation, a series of benzimidazole matrine derivatives were designed and synthesized using matrine as the lead compound with the aim of developing dual inhibitors targeting both TOPOI and PARP-1. Among these derivatives, Compound B6 exhibited potent inhibitory effects on PARP-1 and TOPOI, effectively suppressing cancer cell proliferation and migration. Mechanistic assessments revealed that B6 induced DNA damage in HGC-27 cells, leading to G0/G1 cell cycle arrest and significant apoptosis. Molecular docking experiments demonstrated that B6 can effectively enter the active pocket of target proteins, where it forms stable hydrogen bonds with amino acid residues. In vivo, experiments demonstrated that B6 exhibited antitumor activity comparable to that of the positive control drug. The tumor growth inhibition rates (TGIs) for irinotecan, B6 and matrine were 87.0%, 75.4% and 9.7%, respectively. Importantly, B6 demonstrated lower toxicity than the positive control drug. Our findings suggest that TOPOI and PARP-1 may represent potential targets for matrine and B6 emerges as a promising candidate for cancer therapy.

The diagnostic value of cognitive assessment indicators for mild cognitive impairment (MCI).

OBJECTIVE: This study aims to evaluate and analyze the standard diagnostic methods for mild cognitive impairment (MCI). METHODS: This study used a prospective case-control study to examine baseline data and diagnostic indicators in a population of elderly with MCI. Based on different cognitive abilities, this study divided MCI and healthy control groups. The diagnostic indicators included CDT, MOCA, MMSE, PSQI, MBI, DST, HAMD, AD-related blood markers, and olfactory testing. The diagnostic value of each indicator was done using the ROC curve. RESULTS: This study included 240 adult participants, 135 in the health group and 105 in the MCI group. A comparison of baseline data revealed statistically significant differences between the two groups regarding age, blood glucose, MMSE, CTD, MOCA, ability to perform daily living, AD-related blood indices and olfactory tests (all p < 0.05). Logistic regression analysis statistically showed that age, MOCA, and CDT were independent diagnostic factors for MCI (all p < 0.05). Combining these three indicators has the best diagnostic specificity (92.54%). AD-related blood and olfactory tests indices had only moderate diagnostic values (AUC: 0.7-0.8). CONCLUSION: Age, MOCA, and CDT are good indicators for diagnosing early-stage MCI. AD-related blood indices and olfactory tests can serve as valuable adjuncts in diagnosing MCI.

Treatment outcomes and cognitive function following electroconvulsive therapy in patients with severe depression.

BACKGROUND: Traditional treatments for major depressive disorder (MDD), including medication and therapy, often fail and have undesirable side effects. Electroconvulsive therapy (ECT) uses electrical currents to induce brief seizures in the brain, resulting in rapid and potent antidepressant effects. However, owing to misconceptions and controversies, ECT is not as widely used as it could and often faces stigmatization. AIM: To evaluate the efficacy and safety of ECT compared to those of medication and/or therapy in patients with severe MDD. METHODS: This prospective cohort study included 220 individuals with severe MDD who were divided into the ECT and non-ECT groups. The patients in the ECT group underwent bilateral ECT three times a wk until they either achieved remission or reached a maximum of 12 sessions. The non-ECT group received medication and/or therapy according to clinical guidelines for MDD. The primary outcome was the variation in the hamilton depression rating scale (HDRS) score from treatment/ECT initiation to week 12. In addition, patients' quality of life, cognitive abilities, and biomarkers were measured throughout the study. RESULTS: Although both groups showed significant improvements in their HDRS scores over time, the improvement was more pronounced in the ECT group than in the non-ECT group. Additionally, the ECT group exhibited a more substantial improvement in the quality of life and cognitive function than those of the non-ECT group. Compared with the non-ECT group, the ECT group exhibited evi-dently lower variations in the brain-derived neurotrophic factor (BDNF) and cytokine interleukin-6 (IL-6) levels. The side effects were generally mild and comparable between the two groups. ECT is safer and more potent than medication and/or therapy in mitigating depressive symptoms, enhancing well-being, and bolstering cognitive capabilities in individuals with severe MDD. ECT may also affect the levels of BDNF and IL-6, which are indicators of neuroplasticity and inflammation, respectively. CONCLUSION: ECT has emerged as a potentially advantageous therapeutic approach for patients with MDD who are unresponsive to alternative treatments.

Induction of Apoptosis by Matrine Derivative ZS17 in Human Hepatocellular Carcinoma BEL-7402 and HepG2 Cells through ROS-JNK-P53 Signalling Pathway Activation.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks third among cancer-related deaths worldwide. Using matrine as a lead compound, 12 matrine derivatives were designed and synthesised, and their antiproliferative activities were evaluated in four cancer cell lines. Eight of the twelve compounds showed strong antiproliferative activity, with an IC50 of <10 µM. The compound ZS17 exhibited strong antiproliferative activity in hepatocellular carcinoma cell lines with IC50 values in the range of 3.014−3.388 µM, which was much lower than that of matrine. Furthermore, we explored the role of ZS17 in inducing apoptosis in HCC cells in vitro and in vivo, as well as possible mechanisms involved. ZS17 inhibited the proliferation of BEL-7402 and HepG2 cells in time- and dose-dependent manners. In addition, we found that ZS17 significantly induced apoptosis and ROS (reactive oxygen species) production, promoted JNK phosphorylation, activated p53, and activated the caspase signalling pathway. Furthermore, the antioxidant NAC, JNK inhibitor SP600125, and Si-JNK increased cell viability, re-established cell metastasis, and inhibited ZS17-induced apoptosis. An in vivo antitumour assay demonstrated that ZS17 significantly reduced the number of migrating HepG2 cells in zebrafish embryos and suppressed the growth of HepG2 xenografts in nude mice without any obvious side effects. Our study demonstrated that the ROS-JNK-P53 pathway plays an important role in the destruction of liver tumour cells by ZS17. Thus, ZS17 may represent a promising chemotherapeutic agent for the treatment of HCC patients.

Novel matrinic acid derivatives bearing 2-anilinothiazole structure for non-small cell lung cancer treatment with improved Hsp90 targeting effect.

Involved in mediating the folding and maturation of more than 300 client proteins, many of which are oncoproteins, Hsp90 has emerged as a promising drug target for cancer therapy. In particular, inhibiting Hsp90 plays a vital role in the treatment of non-small cell lung cancer. Owing to undesirable outcomes of Hsp90 inhibitors in clinical trials, a series of matrinic acid compounds bearing 2-anilinothiazole moiety were designed based on the structural features allocation shared among Hsp90 inhibitors within the ATP-binding pocket. Most of the compounds showed potent anticancer activities validated by MTT assay. Among them, the most potent compound C4 (IC50 < 10 µM against four cell lines) was chosen for further mechanism study. Notably, C4 showed a better safety profile than 17AAG with a higher SI value. Thermal shift assay data indicated C4 exhibited a strong binding affinity with Hsp90 (-18.85 ± 0.56°C) comparable to radicicol. Mechanism studies verified that C4 significantly inhibited proliferation and migration activities of A549 cells. Besides, C4 can induce a prolonged G1-phase and cell apoptosis. Western blot analysis results indicated C4 could moderately suppress Hsp90 and upregulate Hsp70 expression. Furthermore, the downregulated trend of the client proteins of Hsp90, such as ß-Catenin and Bcl-2, were consistent with the cellular effect of C4, suggesting that C4 could exert anticancer activity via targeting Hsp90. In the xenograft model in vivo, C4 effectively inhibited lung cancer growth without obvious side effects. Collectively, C4 could be a promising therapeutic agent for lung cancer and the novel scaffold provided new insights into the design of Hsp90 inhibitors.

Effects of shift work on sleep and cognitive function among male miners.

Shift work is associated with circadian rhythm disruption that manifests in several aspects related to sleep disorder, including trouble falling asleep, shortened sleep, and daytime fatigue. The objective of this study was to investigate the effects of shift work on sleep and cognitive function in the middle-aged male miners in Kailuan Mining Group. From May 2013 to May 2015, male miners were recruited and enrolled in prospective study. The results of PSQI demonstrated that there were significant differences in the total score, subjective sleep quality and sleep duration between two groups. For subjects with education level of senior middle school or below, our results showed that the scores of BVMT-R and HVLT-R in the day shift group were significantly higher than that in the night shift group. According to PSQI score, further test was conducted for HVLT-R and BVMT-R. For subjects with PSQI score≤5, there were significant differences in HVLT-R scores between two groups. In terms of PSQI score>5, BVMT-R scores in the night shift group were significantly lower than that in the day shift group. The workers for night shift work in adulthood would tend to impaired working memory. Education can also influence the performance of working memory.

Childhood physical neglect promotes development of mild cognitive impairment in old age - A case-control study.

This study aimed to investigate the role of early traumatic experiences in development of mild cognitive impairment (MCI) in Chinese elderly people. Seventy six patients and 61 controls were selected and assigned into two study groups, MCI and control, respectively. Childhood Trauma Questionnaire-Short Form (CTQ-SF) was used for assessment of early trauma, episodic memory and association learning scales for memory evaluation. In addition, event-related potentials (ERPs) were measured using electroencephalography (EEG) to indicate brain electrical activity of subjects during memory/cognitive tests. MCI patients showed higher scores of physical neglect and lower scores of emotional abuse in childhood than control group. Physical neglect score was negatively correlated with scores of MMSE, MoCA, episodic memory, calculation, and the amplitude of CzP300, FzP300 and PzP300, while a positive correlation was seen between the score of physical neglect and the latency of PzN200, FzN200, CzN200, CzP300, FzP300 and PzP300. The score of emotional abuse was weakly correlated with FzP300 amplitude, but not with any other ERP components. Our results suggested that early childhood exposure to physical neglect may lead to impairment in learning and memory, particularly in the associative learning and episodic memory, in old age.

High prevalence of mild cognitive impairment in the elderly: a community-based study in four cities of the Hebei province, china.

BACKGROUND: Mild cognitive impairment (MCI) has been suggested as a term for a boundary area between normal aging and dementia. This study was designed to determine the prevalence of MCI in the elderly in the Hebei province, China, and explore its related factors. METHODS: Participants included 2,601 community-dwelling people aged 60 years or older who resided in the four major cities of the Hebei province. In stage 1 of the study, the Mini-Mental State Examination and the Montreal Cognitive Assessment were administered for screening purposes. In stage 2, the subjects who screened positive were further examined by neurologists. The diagnosis of MCI was made according to Petersen's criteria. RESULTS: The estimated prevalence of MCI was 21.3%. MCI was more prevalent at age 65-69 (28.3%), and its overall rates among men (24.1%) were higher than those of women (19.9%). The higher prevalence of MCI was associated with very old age (≥80 years old; OR = 2.457, 95% CI = 1.471-4.104), male gender (OR = 1.363, 95% CI = 1.097-1.694), low education level (OR = 2.439, 95% CI = 1.623-3.663), and poor economic status (OR = 2.882, 95% CI = 1.949-4.255). CONCLUSIONS: Our findings show a high prevalence of MCI in the elderly urban population in the Hebei province. Gender, education level, and economic status may have an important role in the etiology of MCI.