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Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi–target–directed ligands (MTDLs), we synthesized a series of (R)–N–(benzo[d]thiazol–2–yl)–2–(1–phenyl–3,4–dihydroisoquinolin–2(1H)–yl) acetamides with substituted benzothiazoles and (S)–1–phenyl–1,2,3,4–tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory potency against monoamine oxidase B (MAO–B) and butyrylcholinesterase (BuChE). Among them, six compounds (4b–4d, 4f, 4g and 4i) displayed excellent activity. The classical antidepressant forced swim test (FST) was used to verify the in vitro results, revealing that six compounds reduced the immobility time significantly, especially compound 4g. The cytotoxicity of the compounds was assessed by the MTT method and Acridine Orange (AO) staining, with cell viability found to be above 90% at effective compound concentrations, and not toxic to L929 cells reversibility, kinetics and molecular docking studies were also performed using compound 4g, which showed the highest MAO–B and BuChE inhibitory activities. The results of these studies showed that compound 4g binds to the primary interaction sites of both enzymes and has good blood–brain barrier (BBB) penetration. This study provides new strategies for future research on neurodegenerative diseases complicated by depression. [ABSTRACT FROM AUTHOR]

Over the past decade, advancements in high-throughput sequencing technologies have led to a qualitative leap in our understanding of the role of the microbiota in human diseases, particularly in oncology. Despite the low biomass of the intratumoral microbiota, it remains a crucial component of the tumor immune microenvironment, displaying significant heterogeneity across different tumor tissues and individual patients. Although immunotherapy has emerged a major strategy for treating tumors, patient responses to these treatments vary widely. Increasing evidence suggests that interactions between the intratumoral microbiota and the immune system can modulate host tumor immune responses, thereby influencing the effectiveness of immunotherapy. Therefore, it is critical to gain a deep understanding of how the intratumoral microbiota shapes and regulates the tumor immune microenvironment. Here, we summarize the latest advancements on the role of the intratumoral microbiota in cancer immunity, exploring the potential mechanisms through which immune functions are influenced by intratumoral microbiota within and outside the gut barrier. We also discuss the impact of the intratumoral microbiota on the response to cancer immunotherapy and its clinical applications, highlighting future research directions and challenges in this field. We anticipate that the valuable insights into the interactions between cancer immunity and the intratumoral microbiota provided in this review will foster the development of microbiota-based tumor therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Li, Wu, Guo, Xu, Jin and Zhao.)

Most human papillomavirus (HPV) types, including HPV16 and HPV18, are closely related to the occurrence of cervical cancer, predominantly through the action of viral oncoproteins E6 and E7. Curcumin, the active ingredient of the turmeric plant, has been gaining attention over the past two decades as an antioxidant, anti-inflammatory, and anticancer agent. In the present study, the HPV-positive cervical cancer cells HeLa and CaSki were treated with curcumin, and the results showed that curcumin has a dose-dependent and time-dependent inhibitory effect on cell viability. In addition, apoptosis induction was further quantitatively confirmed through flow cytometric analysis. Furthermore, the influence of different concentrations of curcumin on the mitochondrial membrane potential was evaluated through JC-1 staining and found to dramatically decrease the membrane potential in treated HeLa and CaSki cells, suggesting the critical role of the mitochondrial pathway in their apoptosis-inducing effect. This study also demonstrated the wound-healing potential of curcumin, and the results of transwell assays showed that curcumin treatment inhibited HeLa and CaSki cell invasion and migration in a dose-dependent manner compared with the control treatment. Curcumin also downregulated the expression of Bcl-2, N-cadherin, and Vimentin and upregulated the expression of Bax, C-caspase-3, and E-cadherin in both cell lines. Further research showed that curcumin also selectively inhibited the expression of the viral oncoproteins E6 and E7, as demonstrated by western blot analysis; moreover, the downregulation of E6 was more significant than that of E7. Our research also showed that coculture with cells infected with siE6 lentivirus (siE6 cells) can inhibit the proliferation, invasion, and metastasis of HPV-positive cells. While the siE6 cells were also treated with curcumin, the effect of curcumin monotherapy was offset. In summary, our research shows that curcumin regulates the apoptosis, migration, and invasion of cervical cancer cells, and the mechanism may be related to its ability to downregulate E6. This study provides a foundation for future research on the prevention and treatment of cervical cancer., (© 2023 John Wiley & Sons Ltd.)

The aim of this study was to investigate the effects of soy isoflavones on the injury of human umbilical vein endothelial cells induced by H2O2. EVC‑304 cells were preincubated with soy isoflavones for 12 h, and then exposed to 100 µM H2O2 for 1 h. Cell viability was evaluated by a 3‑(4,5‑di‑methylthiazol‑2‑yl) 2,5‑diphenyltetrazolium bromide assay. The apoptosis of EVC‑304 cells was detected by Hoechst 33258 and Annexin‑V/propidium iodide staining. The oxidative stress‑related biochemical parameters were detected and the expression of apoptosis‑related proteins was examined by western blot analysis. The results showed that incubation with soy isoflavones caused a significant increase in the viability of EVC‑304 cells and a decrease in cell apoptosis induced by H2O2. Soy isoflavones also markedly enhanced the activities of superoxide dismutase and glutathione peroxidase, and reduced the level of malondialdehyde. Western blot analysis results show that soy isoflavones can modulate the activation of nuclear factor‑κB and the mitochondria‑mediated apoptosis signaling pathway. The results of this study indicated the potential biological relevance of soy isoflavones in the therapy of cardiovascular diseases.

Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant property. Herein, we investigated the protective effects of salidroside against hydrogen peroxide (H2O2)-induced oxidative damage in human endothelial cells (EVC-304). EVC-304 cells were incubated in the presence or absence of low steady states of H2O2 (3-4 µM) generated by glucose oxidase (GOX) with or without salidroside. 3(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) assays were performed, together with Hoechst 33258 staining and flow cytometric analysis using Annexin-V and propidium iodide (PI) label. The results indicated that salidroside pretreatment attenuated endogenous H2O2 induced apoptotic cell death in EVC-304 cells in a dose-dependent pattern. Furthermore, Western blot data revealed that salidroside inhibited activation of caspase-3, 9 and cleavage of poly(ADP-ribose) polymerase (PARP) induced by endogenous H2O2. It also decreased the expression of Bax and rescued the balance of pro- and anti-apoptotic proteins. All these results demonstrated that salidroside may present a potential therapy for oxidative stress in cardiovascular and cerebrovascular diseases.