Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and multiple TAM-secreted cytokines have been identified associating with poor clinical outcomes. However, the therapeutic targets existing in the loop between TAMs and cancer cells are still required for further investigation. Here in, cytokine array validated that C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant chemokine secreted by TAMs, and CXCL1 can promote breast cancer migration and invasion ability, as well as epithelial-mesenchymal transition in both mouse and human breast cancer cells. QPCR screening further validated SOX4 as the highest responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 binds to SOX4 promoter and activates its transcription via NF-κB pathway. In vivo breast cancer xenografts demonstrated that CXCL1 silencing in TAMs results in a significant reduction in breast cancer growth and metastatic burden. Bioinformatic analysis and clinical investigation finally suggested that high CXCL1 expression is significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Taken together, our results indicated that TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/SOX4 activation, and CXCL1-based therapy might become a novel strategy for breast cancer metastasis prevention.
Withanolides from six parts (flower, leaf, stem, root, seed, and peel) of Datura metel L. (D metel L.) obtained from ten production areas in China were identified and quantified by UPLC-MS/MS. A total of 85 withanolides were characterized for the first time using the UPLC-Q-TOF-MS/MS system. Additionally, a simultaneous, rapid and accurate measurement method was developed for the determination of 22 bioactive withanolides from ten production areas with the UPLC-Q-TRAP-MS/MS system. The results show the total withanolide content is highest in the leaves (155640.0 ng/g) and lowest in the roots (14839.8 ng/g). Compared with other production areas, the total content of plants from Dujiangyan was the highest at 82013.9 ng/g (value range of ten areas: 82013.9–42278.5 ng/g). The results also show significant differences in the distribution of withanolides in the different plant parts, as well as across different production areas. This is a breakthrough report providing a simultaneous qualitative and quantitative analysis of 22 withanolides in D. metel L. It could be the basis for the more rational use of various parts of D. metel L., and the expansion of medicinal resources. This work also lays a solid foundation for research on the quality control of D. metel L.
Aim: β-asarone, an active component of Acori graminei rhizome, has been reported to have neuroprotective effects in Alzheimer's disease. As the underlying mechanism is not known, we investigated the neuroprotective effects of β-asarone in an APP/PS1 double transgenic mouse model and in NG108 cells. Materials and methods: APPswe/PS1dE9 double transgenic male mice were randomly assigned to a model group, β-asarone treatment groups (21.2, 42.4, or 84.8 mg/kg/d), or donepezil treatment group (2 mg/kg/d). Donepezil treatment was a positive control, and background- and age-matched wild-type B6 mice were an external control group. β-asarone (95.6% purity) was dissolved in 0.8% Tween 80 and administered by gavage once daily for 2.5 months. Control and model animals received an equal volume of vehicle. After 2.5 months of treatment, behavior of all animals was evaluated in a Morris water maze. Expression of synaptophysin (SYP) and glutamatergic receptor 1 (G1uR1) in the hippocampus and cortex of the double transgenic mice was assayed by Western blotting. The antagonistic effects of β-asarone against amyloid-β peptide (Aβ) were investigated in vitro in the NG108-15 cell line. After 24 hours of incubation, cells were treated with 10 µm Aβ with or without β-asarone at different concentrations (6.25, 12.5, or 25 µM) for an additional 36 hours. The cytotoxicity of β-asarone was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay of cell viability, and cell morphology was evaluated by bright-field microscopy after 24 hours of treatment. The expression of SYP and GluR1 in cells was detected by Western blot assay in the hippocampus and brain cortex tissues of mice. Results: β-asarone at a high dose reduced escape latency and upregulated SYP and GluR1 expression at both medium and high doses. Cell morphology evaluation showed that β-asarone treatment did not result in obvious cell surface spots and cytoplasmic granularity. β-asarone had a dose-dependent effect on cell proliferation. Conclusion: β-asarone antagonized the Aβ neurotoxicity in vivo, improved the learning and memory ability of APP/PS1 mice, and increased the expression of SYP and GluR1 both in vivo and in vitro. Thus, β-asarone may be a potential drug for the treatment of Alzheimer's disease. Keywords: neuroprotective effect, β-asarone, synaptic plasticity, synaptophysin, glutamatergic receptor 1
AMA Wang Q, Cai Z, Sheng Y, et al. Evaluation of the association between glutathione S-transferase polymorphisms and susceptibility to cutaneous melanoma: a systematic review and meta-analysis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2024;41(1):20-31. doi:10.5114/ada.2023.135619. APA Wang, Q., Cai, Z., Sheng, Y., Jiang, Z., Cui, W., & Chen, Z. et al. (2024). Evaluation of the association between glutathione S-transferase polymorphisms and susceptibility to cutaneous melanoma: a systematic review and meta-analysis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 41(1), 20-31. https://doi.org/10.5114/ada.2023.135619 Chicago Wang, Qi, Zhen Cai, Yang Sheng, Zhiyuan Jiang, Wei Cui, Zaihong Chen, and Xiaobo You. 2024. "Evaluation of the association between glutathione S-transferase polymorphisms and susceptibility to cutaneous melanoma: a systematic review and meta-analysis". Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii 41 (1): 20-31. doi:10.5114/ada.2023.135619. Harvard Wang, Q., Cai, Z., Sheng, Y., Jiang, Z., Cui, W., Chen, Z., and You, X. (2024). Evaluation of the association between glutathione S-transferase polymorphisms and susceptibility to cutaneous melanoma: a systematic review and meta-analysis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 41(1), pp.20-31. https://doi.org/10.5114/ada.2023.135619 MLA Wang, Qi et al. "Evaluation of the association between glutathione S-transferase polymorphisms and susceptibility to cutaneous melanoma: a systematic review and meta-analysis." Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, vol. 41, no. 1, 2024, pp. 20-31. doi:10.5114/ada.2023.135619. Vancouver Wang Q, Cai Z, Sheng Y, Jiang Z, Cui W, Chen Z et al. Evaluation of the association between glutathione S-transferase polymorphisms and susceptibility to cutaneous melanoma: a systematic review and meta-analysis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2024;41(1):20-31. doi:10.5114/ada.2023.135619.
Most advanced colorectal cancer patients with proficient DNA mismatch repair or microsatellite stability (MSS) are insensitive to immune checkpoint inhibitor therapy. This report describes a heavily pretreated refractory colon adenocarcinoma patient with MSS. After experiencing four lines of treatment, the patient received the fifth-line therapy with the combined sintilimab, bevacizumab and chemotherapy. She achieved a long-term clinical outcome. The patient's progression-free survival after the fifth-line therapy was approximately 9.3 months, and her overall survival was approximately 57 months. To the best of our knowledge, this case represents the first report of durable clinical benefit from combination of an immune checkpoint inhibitor, bevacizumab and chemotherapy in a heavily pretreated patient with refractory metastatic colon adenocarcinoma with MSS.To date, little information is available on the efficacy of combination of immunotherapy, antiangiogenic therapy and chemotherapy in heavily pretreated refractory colon cancer patients with microsatellite stability (MSS). Here, we describe a heavily pretreated refractory colon adenocarcinoma patient with MSS. After experiencing four lines of prior treatment, the patient received the fifth-line therapy with the combined immunotherapy, an antiangiogenetic inhibitor and chemotherapy. She achieved a durable clinical outcome. To our knowledge, this case is the first report of successful treatment of a heavily pretreated refractory metastatic colon adenocarcinoma patient with MSS receiving the combined immunotherapy, antiangiogenic therapy and chemotherapy.
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Genetic studies of Chinese individuals have been performed, but mostly with short read sequencing, limiting the types of variants that can be identified. Here, the authors perform long read sequencing of 945 han Chinese individuals, finding structural variants under natural selection and those associated with human traits and evolutionary history.
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