RESUMO
We conducted a meta-analysis to evaluate the clinical efficacy of berberine (BBR) in treating acute ischemic stroke (AIS), explore its anti-inflammatory effects, and assess its potential applications for AIS patients. We comprehensively searched nine databases from inception until July 1, 2022, to identify clinical trials investigating the use of BBR in treating AIS. We performed statistical analyses using RevMan5.4 software and focused on primary outcomes such as inflammatory markers as well as secondary outcomes including immune system indicators, relevant biomarkers, carotid artery atherosclerosis, and adverse reactions. Our analysis included data from 17 clinical trials involving 1670 patients with AIS. Our results revealed that BBR in combination with conventional treatment significantly reduced levels of high-sensitivity C-reactive protein (hs-CRP), macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6), complement C3, hypoxic inducible factor-1 α (HIF-1α), cysteine protease-3 (Caspase-3), the national institutes of health stroke scale (NIHSS), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), carotid intima-media thickness (IMT), the number of unstable plaques, and carotid crouse score on ultrasound when compared with conventional treatment alone. Furthermore, combining BBR with conventional treatment may improve the overall effective rate. Therefore, our findings suggest that BBR can be used as an adjuvant therapy for AIS due to its ability to reduce inflammatory cytokine levels, providing a novel therapeutic option for AIS. However, larger randomized controlled trials are necessary to confirm these results.
Assuntos
Aterosclerose , Berberina , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/tratamento farmacológico , Berberina/uso terapêutico , Espessura Intima-Media Carotídea , Triglicerídeos , Aterosclerose/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy. However, its mechanism of action remains elusive. Here, we performed chemoproteomics-aided target deconvolution of lipoic acid and its active close analog lipoamide. We find that histone deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are molecular targets of the reduced form of lipoic acid and lipoamide. Importantly, only the naturally occurring (R)-enantiomer inhibits HDACs at physiologically relevant concentrations and leads to hyperacetylation of HDAC substrates. The inhibition of HDACs by (R)-lipoic acid and lipoamide explain why both compounds prevent stress granule formation in cells and may also provide a molecular rationale for many other phenotypic effects elicited by lipoic acid.
Assuntos
Inibidores de Histona Desacetilases , Ácido Tióctico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Ácido Tióctico/farmacologia , Histona Desacetilases/metabolismo , Antioxidantes/farmacologiaRESUMO
Anti-angiogenesis is an important and promising strategy in cancer therapy. However, the current methods using anti-vascular endothelial growth factor A (VEGFA) antibodies or inhibitors targeting VEGFA receptors are not as efficient as expected partly due to their low efficiencies in blocking VEGFA signaling in vivo. Until now, there is still no method to effectively block VEGFA production in cancer cells from the very beginning, i.e., from the transcriptional level. Here, we aimed to find bioactive small molecules to block VEGFA transcription. Methods: We screened our natural compound pool containing 330 small molecules derived from Chinese traditional herbs for small molecules activating the expression of seryl-tRNA synthetase (SerRS), which is a newly identified potent transcriptional repressor of VEGFA, by a cell-based screening system in MDA-MB-231 cell line. The activities of the candidate molecules on regulating SerRS and VEGFA expression were first tested in breast cancer cells. We next investigated the antiangiogenic activity in vivo by testing the effects of candidate drugs on the vascular development in zebrafish and by matrigel plug angiogenesis assay in mice. We further examined the antitumor activities of candidate drugs in two triple-negative breast cancer (TNBC)-bearing mouse models. Furthermore, streptavidin-biotin affinity pull-down assay, coimmunoprecipitation assays, docking analysis and chromatin immunoprecipitation were performed to identify the direct targets of candidate drugs. Results: We identified emodin that could greatly increase SerRS expression in TNBC cells, consequently reducing VEGFA transcription. Emodin potently inhibited vascular development of zebrafish and blocked tumor angiogenesis in TNBC-bearing mice, greatly improving the survival. We also identified nuclear receptor corepressor 2 (NCOR2) to be the direct target of emodin. Once bound by emodin, NCOR2 got released from SerRS promoter, resulting in the activation of SerRS expression and eventually the suppression of VEGFA transcription. Conclusion: We discovered a herb-sourced small molecule emodin with the potential for the therapy of TNBC by targeting transcriptional regulators NCOR2 and SerRS to suppress VEGFA transcription and tumor angiogenesis.