G protein-coupled receptors (GPCRs) are significant drug targets, but their potential in cancer therapy remains underexplored. Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment, necessitating new GPCR-targeting strategies for more effective therapies. This study discovers that Yersinia pestis LcrV, a crucial linker protein for plague infection, acts as a biased agonist of a GPCR, the formyl peptide receptor 1 (FPR1). The LcrV protein induces unique conformational changes in FPR1, resulting in G proteins being activated in a distinctive state without subunit dissociation. This leads to a biased signaling profile characterized by cyclic adenosine monophosphate (cAMP) responses and β-arrestin2 recruitment, but not calcium mobilization. In FPR1-expressing triple-negative breast cancer (TNBC) cells, LcrV bi-directionally modulates intracellular signaling pathways, downregulating extracellular signal-regulated kinases (ERK1/2) and Akt pathways while upregulating Jun N-terminal kinase (JNK) and p38 pathways. This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation. In TNBC xenograft mouse models, long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist. Additionally, LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC. Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.

Objective To investigate the efficacy of transcranial direct current stimulation(tDCS)on sleep disorder in patients with Parkinson's disease(PD).Methods From July 2021 to July 2023,patients with PD and sleep disorders in the Department of Neurosurgery of the Second People's Hospital of Guangdong Province were selected.The enrolled patients were divided into sham stimulation group(n=28)and true stimulation group(tDCS)(n=29)according to the inclusion and exclusion criteria.MDS-UPDRS,PDSS and other rating scales were used to evaluate the patients.Before and after tDCS treatment,MS-11 was used for intelligent sleep monitor-ing.The baseline and improvement of sleep disorders in the two groups before and after treatment were analyzed.Results Before tDCS treatment,there was no significant difference in general conditions and scale scores between the two groups(P＞0.05).There was no significant difference in polysomnographic monitoring results between the two groups before treatment(P＞0.05).Compared with pre-treatment,there was no significant difference in sleep monitoring results in the sham stimulation group(P＞0.05),while the sleep duration and sleep efficiency signifi-cantly increased,the nighttime awakening duration,nighttime awakening frequency,MDS-UPDRS-Ⅲ score,and LEDD dose significantly decreased in the true stimulation group,with statistical significance(P＜0.05).Conclusion Pharmacological treatment combined with tDCS treatment is effective for sleep disorders and motor function in patients with PD,which could increase the sleep duration and sleep efficiency of PD patients with sleep disorders to a certain extent,reduce the nighttime awakening duration and frequency,thereby improving the fatigue symp-toms during the daytime,and improving the efficacy of conventional pharmacological treatment for PD.

Humans ; Carcinoma, Hepatocellular/drug therapy* ; Liver Neoplasms/drug therapy* ; Biological Products/therapeutic use* ; B7-H1 Antigen

Cancer stands as one of the predominant causes of mortality globally, necessitating ongoing efforts to develop innovative therapeutics. Historically, natural products have been foundational in the quest for anticancer agents. Bulbocodin D (BD) and Bulbocodin C (BC), two bibenzyls derived from Pleione bulbocodioides (Franch.) Rolfe, have demonstrated notable in vitro anticancer activity. In human lung cancer A549 cells, the IC_50s for BD and BC were 11.63 and 11.71 μmol·L^-1, respectively. BD triggered apoptosis, as evidenced by an upsurge in Annexin V-positive cells and elevated protein expression of cleaved-PARP in cancer cells. Furthermore, BD and BC markedly inhibited the migratory and invasive potentials of A549 cells. The altered genes identified through RNA-sequencing analysis were integrated into the CMap dataset, suggesting BD's role as a potential signal transducer and activator of transcription 3 (STAT3) inhibitor. SwissDock and MOE analyses further revealed that both BD and BC exhibited a commendable binding affinity with STAT3. Additionally, a surface plasmon resonance assay confirmed the direct binding affinity between these compounds and STAT3. Notably, treatment with either BD or BC led to a significant reduction in p-STAT3 (Tyr 705) protein levels, regardless of interleukin-6 stimulation in A549 cells. In addition, the extracellular signal-regulated kinase (ERK) was activated after BD or BC treatment. An enhancement in cancer cell mortality was observed upon combined treatment of BD and U0126, the MEK1/2 inhibitor. In conclusion, BD and BC emerge as promising novel STAT3 inhibitors with potential implications in cancer therapy.
Humans ; Lung Neoplasms/metabolism* ; STAT3 Transcription Factor/metabolism* ; Antineoplastic Agents/chemistry* ; A549 Cells ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation

PURPOSE: Isocryptotanshinone (ICTS) is a natural bioactive product that is isolated from the roots of the widely used medical herb Salvia miltiorrhiza. However, few reports exist on the mechanisms underlying the therapeutic effects of ICTS. Here, we report that ICTS has anticancer activity and describe the mechanism underlying this effect. METHODS: The antiproliferative effect of ICTS was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and clonogenic assays. The effect of ICTS on the cell cycle was measured using flow cytometry. Apoptosis was determined by Hoechst 33342 staining, DNA fragmentation assays, and Western blotting for apoptotic proteins. Finally, the effect of ICTS on mitogen-activated protein kinases (MAPKs) was determined by Western blotting. RESULTS: ICTS significantly inhibited proliferation of MCF-7 and MDA-MB-231 human breast cancer cells, HepG2 human liver cancer cells, and A549 human lung cancer cells in vitro. Among the tested cell lines, MCF-7 cells showed the highest sensitivity to ICTS. ICTS significantly inhibited colony formation by MCF-7 cells. Furthermore, exposure of MCF-7 cells to ICTS induced cell cycle arrest at the G1 phase and decreased mitochondrial membrane potential. Hoechst 33342 staining and Western blot analysis for apoptotic proteins suggested that ICTS induced apoptosis in MCF-7 cells. In addition, ICTS activated MAPK signaling in MCF-7 cells by inducing time- and concentration-dependent phosphorylation of JNK, ERK, and p38 MAPK. CONCLUSION: Our results suggest that ICTS inhibited MCF-7 cell proliferation by inducing apoptosis and activating MAPK signaling pathways.
Apoptosis* ; Blotting, Western ; Breast Neoplasms* ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Line ; DNA Fragmentation ; Flow Cytometry ; G1 Phase ; Hep G2 Cells ; Humans ; Liver Neoplasms ; Lung Neoplasms ; MCF-7 Cells* ; Membrane Potential, Mitochondrial ; Mitogen-Activated Protein Kinases ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Salvia miltiorrhiza

Intensity-modulated radiotherapy (IMRT) is gradually replacing conventional radiation therapy and has become the mainstream radical treatment for patients with nasopharyngeal carcinoma (NPC). IMRT can conform and increase radiation doses to tu-mor-associated regions as well as decrease exposure doses and volumes on normal organs and tissues to avoid damage on critical or-gans. Aside from system and setup errors, other factors, such as the gradual reduction of the primary NPC lesion and the decrease in vol-ume of involved neck lymph nodes as well as body weight loss and changes in the head and neck shape during IMRT, may cause devia-tions in the radiation doses and volume delivered to the NPC targets and the organs at risk. These factors may affect the accuracy of IMRT. Several researchers have attempted to correct such deviations during IMRT for NPC patients by using adaptive radiotherapy (ART). The results indicate that ART is feasible to a certain degree and can correct the deviations, including decrease in tumor volume, body weight loss, and changes in head and neck shape of NPC patients.

Natural product is an important source of new drug research and development (R&D). Traditional Chinese medicine (TCM) innovation is the key step for its modernization and internationalization. However, due to the complexity of TCM, there are many difficulties and confusions in this process. Target-based drug discovery is the mainstream model and method of R&D. TTD, short for therapeutic target database, is developed by National University of Singapore. Besides a large amount of information on drug targets, the database also contains considerable information related to natural products. This paper briefly introduces the TTD, analyzes the natural products derived drugs/compounds recorded in TTD, which we think might provide some inspiration for the innovation of TCM.

Artermisinin compounds are widely used anti-malarial drugs,which also possess anti-cancer activities in various tumor cells and mouse models.It has been shown that artemisinin compounds exert their anti-cancer activity by inducing oxidative stress,cell cycle arrest,apoptosis and anti-angiogenesis activity,etc. Due to the low cytotoxicity and anti-multidrug-resistant activity,artermisinin compounds may be potentially developed for cancer therapy.