The molecular mechanisms of TRß receptor interaction with polychlorinated biphenyls: A multispectral and computational exploration.

The thyroid hormone (TH) system is susceptible to the toxic effects of polychlorinated biphenyls (PCBs). Pollutants may disrupt the TH system by binding to serum TH transport proteins or interacting with thyroid hormone receptors (TRs) in target cells. However, the molecular mechanism of interaction with the Thyroid Hormone Receptor Beta (TRß) is not fully understood. This study employed fluorescence, UV-visible absorption, three-dimensional fluorescence, and Fourier-transform infrared spectroscopy, along with molecular docking and molecular dynamics simulations, to investigate the interaction between TRß and PCBs. Moreover, molecular docking and fluorescence resonance energy transfer (FRET) findings suggest that TRß and PCBs underwent resonance energy transfer consistent with Förster's theory. The root mean square deviation (RMSD) and docking outcomes indicate that the TRß-PCB29 complex exhibited optimal structural stability. Thus, the study concludes that integrating spectroscopic data with molecular docking is essential for a comprehensive analysis. Further analysis of intermolecular interactions using quantum chemistry and reduced density gradient analysis (RDG) analysis revealed that van der Waals forces are the primary drivers of PCBs to TRß.

The nutritional profile of chia seeds and sprouts: tailoring germination practices for enhancing health benefits-a comprehensive review.

Chia seeds have gained significant attention due to their unique composition and potential health benefits, including high dietary fibers, omega-3 fatty acids, proteins, and phenolic compounds. These components contribute to their antioxidant, anti-inflammatory effects, as well as their ability to improve glucose metabolism and dyslipidemia. Germination is recognized as a promising strategy to enhance the nutritional value and bioavailability of chia seeds. Chia seed sprouts have been found to exhibit increased essential amino acid content, elevated levels of dietary fiber and total phenols, and enhanced antioxidant capability. However, there is limited information available concerning the dynamic changes of bioactive compounds during the germination process and the key factors influencing these alterations in biosynthetic pathways. Additionally, the influence of various processing conditions, such as temperature, light exposure, and duration, on the nutritional value of chia seed sprouts requires further investigation. This review aims to provide a comprehensive analysis of the nutritional profile of chia seeds and the dynamic changes that occur during germination. Furthermore, the potential for tailored germination practices to produce chia sprouts with personalized nutrition, targeting specific health needs, is also discussed.

Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer.

BACKGROUND: Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear. METHODS: Conditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression. RESULTS: Gli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis. CONCLUSION: The Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.

Overview of distinct 5-methylcytosine profiles of messenger RNA in normal and knock-down NSUN2 colorectal cancer cells.

Background: Colorectal cancer (CRC) is a harmful cancer with high morbidity and poor prognosis. There is growing evidence that RNA methylation is closely related to the occurrence of cancer and its malignant biological behavior. N6-methyladenosine (m6A) methylation is the most common RNA modification in eukaryotes, and its multiple regulatory mechanisms in CRC have been elucidated from multiple perspectives. At the same time, the role of 5-methylcytosine (m5C), another important and widely distributed methylation modification, in CRC is far from being elucidated. Methods: In this study, we used RNA immunoprecipitation sequencing combined with bioinformatics methods to identify the m5C peaks on messenger RNA (mRNA) in HCT15 cells and sh-NSUN2 HCT15 cells, understand which transcripts are modified by m5C, and characterize the distribution of m5C modifications. In addition, we performed further bioinformatics analysis of the detected data to initially clarify the potential function of these m5C-modified transcripts. Results: We found significant differences in the distribution of m5C between HCT15 cells and sh-NSUN2 HCT15 cells, suggesting that m5C is likely to play a key role in the occurrence and development of CRC. Furthermore, Gene Ontology (GO) enrichment analysis showed that genes altered by m5C were mainly enriched in phylogeny, synaptic membrane, and transcription factor binding. The Kyoto Encyclopedia of Genes and Genomes (KEGG)pathway analysis showed that the genes altered by m5C are enriched in ECM receptor interaction pathway, the circadian pathway, and the cAMP signaling pathway. Conclusion: Here, our study preliminarily revealed the different distribution patterns of m5C between HCT15 cell and sh-NSUN2 HCT15 cell. Our results open a new window to understand the role of m5C RNA methylation of mRNA in the development of CRC.

Naringenin Inhibits Platelet Activation and Arterial Thrombosis Through Inhibition of Phosphoinositide 3-Kinase and Cyclic Nucleotide Signaling.

Citrus flavanoids intake can reduce the risk of cardiovascular diseases. Naringenin, a natural predominant flavonoid abundant in citrus fruits, possesses protective effects against atherothrombotic diseases. As platelet activation plays central roles in atherothrombogenesis, we studied the effects of naringenin on platelet activation, signaling, thrombosis and hemostasis. Naringenin dose-dependently inhibited agonist-induced platelet aggregation in vitro, and exhibited more-potent efficacy on ADP-induced platelet aggregation. It also suppressed platelet aggregation stimulated by ADP ex vivo. Naringenin inhibited ADP-induced platelet α-granule secretion, fibrinogen binding, intracellular calcium mobilization and platelet adhesion on collagen-coated surface. Naringenin also inhibited platelet spreading on fibrinogen and clot retraction, processes mediated by outside-in integrin signaling. Mechanism studies indicated that naringenin suppressed PI3K-mediated signaling and phosphodiesterase activity in platelets, in addition to increasing cGMP levels and VASP phosphorylation at Ser239. Furthermore, naringenin-induced VASP phosphorylation and inhibition of platelet aggregation were reversed by a PKA inhibitor treatment. Interestingly, naringenin inhibited thrombus formation in the (FeCl3)-induced rat carotid arterial thrombus model, but not cause a prolonged bleeding time in mice. This study suggests that naringenin may represent a potential antiplatelet agent targeting PI3K and cyclic nucleotide signaling, with a low bleeding risk.

Prevention of platelet aggregation and arterial thrombosis using a modified Shenzhu Guanxin Formula.

OBJECTIVE: Modified Shenzhu Guanxin Formula (mSGF) has beneficial effects in coronary artery disease. Previously, we found that mSGF inhibited platelet aggregation in rats. In the present study we further investigated the antiplatelet and antithrombotic activities of mSGF in rats. METHODS: Rats were orally administered mSGF (4.2, 8.4, or 16.8 g crude drug/kg), the adenosine 5'-diphosphate (ADP) receptor antagonist clopidogrel (7.875 mg/kg), or saline once a day for 7 days. The effects of mSGF on platelet aggregation were measured. Levels of cyclic adenosine monophosphate (cAMP) and phosphoinositide 3-kinase (PI3K) signaling were analyzed by ELISA and western blotting, respectively. The antithrombotic effect of mSGF was investigated using a FeCl3-induced carotid arterial thrombosis model and effects on bleeding time were assessed in a rat tail transection model. RESULTS: mSGF significantly inhibited ADP-induced platelet aggregation in a dose-dependent manner, elevated cAMP levels and inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and PI3K/protein kinase B (Akt). Moreover, mSGF dose-dependently inhibited thrombosis in a FeCl3-induced carotid arterial thrombus model and had a significantly smaller effect on bleeding time compared with clopidogrel. CONCLUSIONS: mSGF represents a potent and safe antithrombotic agent whose antiplatelet activity is probably mediated through blockade of PI3K/Akt signaling and increased cAMP generation.

Investigating the interaction between three perfluorinated carboxylic acids and the G protein-coupled estrogen receptor: spectroscopic analyses and computational simulations.

In this paper, perfluorinated compounds (PFCs), such as perfluorobutyric acid (PFBA), perfluorooctanoic acid (PFOA) and perfluorododecanoic acid (PFDoA), were selected as typical representatives of perfluorinated carboxylic acids (PFCAs) to study the effects of PFCAs on the G protein-coupled estrogen receptor (GPER). The interaction mechanism of the three types of PFCAs with the GPER was investigated using steady-state fluorescence spectroscopy, ultraviolet-visible spectroscopy, three-dimensional fluorescence spectroscopy, and Fourier transform infrared spectroscopy combined with molecular docking and molecular dynamics simulations. Among these techniques, steady-state fluorescence and ultraviolet-visible spectroscopic analyses showed that PFBA, PFOA and PFDoA quenched the endogenous GPER fluorescence by combined dynamic and static quenching and non-radiative energy transfer. The binding constants (Ka) of PFCAs on the GPER were all larger than 105 L mol-1, indicating that their affinity for the GPER was strong. Fourier transform infrared spectroscopy and three-dimensional fluorescence showed that the secondary structure of the GPER changed after binding to PFCAs. Thermodynamic analysis showed ΔG < 0, which indicated that the interaction between the GPER and PFCAs was spontaneous. For the binding of PFBA and PFOA to the GPER, ΔH > 0 and ΔS > 0, indicating that the interaction was mainly driven by hydrophobic forces; for the binding of PFDoA to the GPER, ΔH < 0 and ΔS < 0, suggesting that van der Waals force and hydrogen bonding were the main interaction forces. Molecular dynamics simulations suggested that the stability of the GPER-PFCA complexes was higher than that of the free GPER, and also that the structure and hydrophobicity of the GPER changed after binding to PFCAs. Molecular docking analysis showed that all three PFCAs could form hydrogen bonds with the GPER, which improved the stability of the complex.

Dynamic Changes of Beclin-1 in the Hippocampus of Male Mice with Vascular Dementia at Different Time Points.

This study tried to investigate the dynamic changes of Beclin-1 in the hippocampus of male mice with vascular dementia (VD) at different time points. The mouse model of VD was established by the four-vessel blocking method. Then, the VD mice were randomly divided into five groups (n = 12) according to the disease duration: the 0.1-day model group, 0.5-day model group, 1-day model group, 3-day model group, 5-day model group and 14-day model group. In addition, all surgical procedures were the same in the sham group as those in the model groups, except the mice in the sham group were not subjected to clipping. The expression of Beclin-1, LC3B, p62, Bcl-2, Bax, BACE1, GFAP, MBP and ET-1 mRNA were determined by RT-PCR; the expression of Beclin-1 was detected by Western blot and immunofluorescence; the pathological characteristics of the hippocampus were observed by haematoxylin-eosin (HE) staining; and the correlation of Beclin-1 with other VD-related proteins was analysed by Pearson's correlation. Compared with that in the sham group, the expression of Beclin-1, LC3B, Bax, BACE1, GFAP, MBP and ET-1 mRNA was increased in the VD mice at different time points (0.1 day, 0.5 day, 1 day, 3 days, 5 days and 14 days) (P < 0.05) and then remained relatively stable in the 0.5-day VD mice, whereas the p62 and Bcl-2 mRNA levels decreased (P < 0.05). Beclin-1 protein expression was significantly increased in the VD mice at different time points (P < 0.05). The hippocampus showed a certain degree of neuronal damage in the VD mice at different time points (P < 0.05). Additionally, certain correlations among LC3B, p62, Bcl-2, Bax, BACE1, GFAP, MBP, ET-1 and Beclin-1 were observed in this study. In conclusion, the results described above demonstrated that neuronal damage and dynamic stability of Beclin-1 expression were established in the VD male mice after 0.5 day by the four-vessel blocking method.

Ginsenoside Rb1 prevents homocysteine-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation.

Hyperhomocystinemia (HHcy) is known as an independent risk factor for cardiovascular disease. Our previous study showed that ginsenoside Rb1, the major active constituent of ginseng, prevents homocysteine (Hcy)-induced endothelial damage. However, the role of ginsenoside Rb1 in Hcy-induced dysfunction in endothelial progenitor cells (EPCs) remains unknown. In the study, we found that ginsenoside Rb1 reversed the Hcy-induced impairment of adhesive and migratory ability in EPCs which were significantly abolished by CXCR4 antagonist AMD3100 and VEGFR2 inhibitor SU5416. Ginsenoside Rb1 significantly reversed Hcy-induced SDF-1 reduction in the supernatant and in the serum. Ginsenoside Rb1 reversed downregulation of SDF-1 and VEGFR2 protein expression, inhibition of p38MAPK phosphorylation induced by Hcy. Re-endothelialization in balloon-injured carotid arteries significantly increased with EPCs transplant, and was even better with Rb1 treatment. This effect was significantly abolished by AMD3100. AMD3100 also decreased the number of CM-DiI labeled EPCs in injured arteries. Here we show for the first time that Rb1 prevents Hcy-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation. These findings demonstrate a novel mechanism of the action of Rb1 that may have value in prevention of HHcy associated cardiovascular disease.

[Application of molecular biotechnology in Pharmacognosy].

Using the methods of informetrics analysis, articles retrieved from the database of CNKI were statistically analyzed on development course and knowledge system, so as to reflect the overall situation of pharmacognostical studies by molecular biotechnology. The result shows that the research on pharmacognosy by molecular biotechnology is an inter-disciplinary research area, the major research fields can be divided into 7 categories, including molecular identification of Chinese medicinal materials, molecular systematics and genetic diversity analysis of Chinese medicinal materials, biosynthesis and bioregulation of secondary metabolites in medicinal plants, molecular mechanism and genetic basis of Dao-di Herbs, and tissue culture and molecular breeding in medicinal plants. The research on pharmacognosy by molecular have achieved remarkable progress in recent 20 years, and have broad development prospects.