Herein, a hetero(S,N)‐quintuple 9helicene (SNQ9H) molecule with an azacorannulene core was synthesized, currently representing the highest hetero‐helicene reported in the field of multiple ...nhelicenes. X‐ray crystallography indicated that SNQ9H includes not only a propeller‐shaped conformer SNQ9H‐1, but also an unforeseen quasi‐propeller‐shaped conformer SNQ9H‐2. Different conformers were observed for the first time in multiple n≥9helicenes, likely owing to the doping of heteroatomic sulfurs in the helical skeletons. Remarkably, the ratio of SNQ9H‐1 to SNQ9H‐2 can be regulated in situ by the reaction temperature. Experimental studies on the photophysical and redox properties of SNQ9H and theoretical calculations clearly demonstrated that the electronic structures of SNQ9H depend on their molecular conformations. The strategy of introducing heteroatomic sulfurs into the helical skeleton may be useful in constructing various conformers of higher multiple nhelicenes in the future.
Two conformers of a novel quintuple 9helicene with an azabuckybowl as the core were obtained by the deliberate introduction of sulfur heteroatoms into the helical skeleton. The structure–property relationship of different conformers was investigated through detailed experiment and theoretical calculations. The success of the sulfur‐doped strategy implies the potential of realizing higher multiple nhelicenes with various conformers.
Diallyl trisulfide （DATS）, a garlic organosulfide, has shown excellent chemopreventive potential. Cisplatin （DDP） is widely used to treat solid malignant tumors, but causing serious side effects. In ...the current study, we attempted to elucidate the chemopreventive mechanisms of DATS in human gastric cancer BGC-823 cells in vitro, and to investigate whether DATS could enhance the anti-tumor efficacy of DDP and improve quality of life in BGC-823 xenograft mice in vivo. Treatment with DATS （25-400 pmol/L） dose-dependently inhibited the viability of BGC-823 cells in vitro with an IC5o of 115.2＋4.3 pmol/L after 24 h drug exposure. DATS （50-200 pmol/L） induced cell cycle arrest at G2/M phase in BGC-823 cells, which correlated with significant accumulation of cyclin A2 and B1. DATS also induced BGC-823 cell apoptosis, which was accompanied by the modulation of Bcl-2 family members and caspase cascade activation. In BGC-823 xenograft mice, administration of DATS （20-40 mg.kg-1.d-1, ip） dose-dependently inhibited tumor growth and markedly reduced the number of Ki-67 positive cells in tumors. Interestingly, combined administration of DATS （30 mg.kg-1.d-1, ip） with DDP （5 mg/kg, every 5 d, ip） exhibited enhanced anti-tumor activity with fewer side effects. We showed that treatment of BGC-823 cells with DATS in vitro and in vivo significantly activated kinases such as p38 and JNK/MAPK and attenuated the Nrf2/Akt pathway. This study provides evidence that DATS exerts anticancer effects and enhances the antitumor efficacy of DDP, making it a novel candidate for adjuvant therapy for gastric cancer.
Mutations in PTEN-induced kinase 1 (PINK1) gene cause recessive familial type 6 of Parkinson's disease (PARK6). PINK1 is believed to exert neuroprotective effect on SN dopaminergic cells by acting as ...a mitochondrial Ser/Thr protein kinase. Autosomal recessive inheritance indicates the involvement of loss of PINK1 function in PARK6 pathogenesis. In the present study, confocal imaging of cultured SN dopaminergic neurons prepared from PINK1 knockout mice was performed to investigate physiological importance of PINK1 in maintaining mitochondrial membrane potential (Δ
Ψ
m) and mitochondrial morphology and test the hypothesis that PARK6 mutations cause the loss of PINK1 function. PINK1-deficient SN dopaminergic neurons exhibited a depolarized Δ
Ψ
m. In contrast to long thread-like mitochondria of wild-type neurons, fragmented mitochondria were observed from PINK1-null SN dopaminergic cells. Basal level of mitochondrial superoxide and oxidative stressor H
2O
2-induced ROS generation were significantly increased in PINK1-deficient dopaminergic neurons. Overexpression of wild-type PINK1 restored hyperpolarized Δ
Ψ
m and thread-like mitochondrial morphology and inhibited ROS formation in PINK1-null dopaminergic cells. PARK6 mutant (G309D), (E417G) or (CΔ145) PINK1 failed to rescue mitochondrial dysfunction and inhibit oxidative stress in PINK1-deficient dopaminergic neurons. Mitochondrial toxin rotenone-induced cell death of dopaminergic neurons was augmented in PINK1-null SN neuronal culture. These results indicate that PINK1 is required for maintaining normal Δ
Ψ
m and mitochondrial morphology of cultured SN dopaminergic neurons and exerts its neuroprotective effect by inhibiting ROS formation. Our study also provides the evidence that PARK6 mutant (G309D), (E417G) or (CΔ145) PINK1 is defective in regulating mitochondrial functions and attenuating ROS production of SN dopaminergic cells.
► PINK1-null SN dopaminergic neurons exhibited depolarized mitochondrial potential. ► PINK1-deficient SN dopaminergic neurons displayed mitochondrial fragmentation. ► Overexpression of wild-type PINK1 restored mitochondrial potential and morphology. ► PARK6 PINK1 mutants failed to restore mitochondrial function and morphology.
•The anti-depressive mechanisms of Millettia speciosa Champ (MSC) were studied.•Urine metabolomics based on UPLC-Q-TOF/MS was established to elucidate the pathogenesis of depression .•Nine ...metabolites were considered as potential biomarkers related to CUMS-induced depression.•Pentose and glucuronate interconversions, and tyrosine metabolism contributed to MSC efficacy.•L-isoleucine, sebacic acid, and allantoin were potential pharmacodynamic biomarkers associated with the efficacy of MSC.
As a traditional Chinese medicine (TCM), Millettia speciosa Champ (MSC), exerts a wide range of pharmacological activities. Our research group previously found that MSC has antidepressant effects, but the specific antidepressant mechanisms remain unclear. Therefore, in this study, urine metabolomics based on ultra-performance liquid chromatography/quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) combined with pharmacodynamics was used to explore the pathogenesis of depression and the antidepressant effects of MSC. The results showed that MSC treatment could significantly improve chronic unpredictable mild stress (CUMS)-induced depression. Urine metabolic showed that the profiles of the CUMS model group were significantly separated from the control group, while the drug-treated groups were closer to the control group, especially the MSC group treated with a 14 g/kg dose of MSC. Furthermore, 9 metabolites, including glutaric acid, L-isoleucine, L-Dopa, sebacic acid, 3-methylhistidine, allantoin, caprylic acid, tryptophol, and 2-phenylethanol glucuronide, were identified as potential biomarkers of depression. Metabolic pathway analysis showed that these potential biomarkers were mainly involved in valine, leucine, and isoleucine biosynthesis, aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine degradation, tyrosine metabolism, histidine metabolism, fatty acid biosynthesis, and pentose and glucuronate interconversions. Through Receiver operating characteristic (ROC) analysis and Pearson correlation analysis, the combination of L-isoleucine, sebacic acid, and allantoin, were further screened out as potential pharmacodynamic biomarkers associated with the efficacy of MSC. This study suggests that the integration of metabolomics with pharmacodynamics helps to further understand the pathogenesis of depression and provides novel insight into the efficacy of TCM.
This study reported two cases of intracranial thrombotic events of aplastic anemia (AA) under therapy with cyclosporine-A (CsA) and reviewed both drug-induced cerebral venous thrombosis (CVT) and ...CsA-related thrombotic events systematically. We searched PubMed Central (PMC) and EMBASE up to Sep 2019 for publications on drug-induced CVT and Cs-A-induced thrombotic events. Medical subject headings and Emtree headings were used with the following keywords: "cyclosporine-A" and "cerebral venous thrombosis OR cerebral vein thrombosis" and "stroke OR Brain Ischemia OR Brain Infarction OR cerebral infarction OR intracerebral hemorrhage OR intracranial hemorrhage." We found that CsA might be a significant risk factor in inducing not only CVT but also cerebral arterial thrombosis in patients with AA.
Cerebral cortical vein thrombosis (CCVT) is often misdiagnosed because of its non-specific diagnostic symptoms. Here, we analyzed a cohort of patients with CCVT in hopes of improving understandings ...and treatments of the disease. A total of 23 patients with CCVT (confirmed with high-resolution imaging), who had been diagnosed between 2017 and 2019, were enrolled in this cohort study. Baseline demographics, clinical manifestations, laboratory data, radiological findings, treatment, and outcomes were collected and analyzed. Fourteen females and nine males were enrolled (mean age: 32.7 ± 11.9 years), presenting in the acute (within 7 days,
n
= 9), subacute (8–30 days,
n
= 7), and chronic (over 1 month,
n
= 7) stages. Headaches (65.2%) and seizures (39.1%) were the most common symptoms. Abnormally elevated plasma D-dimers were observed in the majority of acute stage patients (87.5%). The diagnostic accuracy of contrast-enhanced magnetic resonance venography (CE-MRV) and high-resolution magnetic resonance black-blood thrombus imaging (HR-MRBTI) in detecting CCVT were 57.1 and 100.0%, respectively. All patients had good functional outcomes after 6-month of standard anticoagulation (mRS 0–1) treatment. However, four CCVT patients that had cases involving multiple veins showed symptom relief after batroxobin therapy (
p
= 0.030). HR-MRBTI may be a fast and accurate tool for non-invasive CCVT diagnosis. HR-MRBTI combined with D-dimer can also precisely identify the pathological stage of CCVT. Batroxobin may safely accelerate cortical venous recanalization in combination with anticoagulation. Follow-up studies with larger sample sizes are suggested to evaluate the safety and efficacy of batroxobin for treating CCVT.
The regulatory effect of luteolin on the progression of Alzheimer’s disease (AD) remains unclear from the perspective of apoptosis. The present study aimed to investigate the protective effects of ...luteolin against Aβ25-35-induced cell apoptosis in pheochromocytoma (PC-12) cells. Aβ25-35 was used to induce an in vitro model of AD. Estradiol was used as a positive control. The PC-12 cells were incubated with luteolin alone or in combination with fulvestrant or U0126. The results showed that luteolin treatment significantly prevents Aβ25-35-induced decrease in cell viability and inhibits Aβ25-35-induced cell apoptosis. After the addition of fulvestrant and U0126, the apoptosis rate of PC-12 cells increased significantly. In addition, luteolin treatment significantly upregulated the expression of Bcl-2 and downregulated the expression of Bax and caspase-3, whereas fulvestrant and U0126 partially reversed the effects of luteolin. Moreover, luteolin treatment upregulated the expression of ERβ and p-ERK1/2, whereas fulvestrant blocked the expression of p-ERK1/2. The study showed that luteolin could activate the ER/ERK/MAPK signalling pathway to protect PC-12 cells against Aβ25-35-induced cell apoptosis via selectively acting on ERβ. Thus, luteolin may be considered as a potential novel therapeutic strategy for AD.
Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor ...suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology.
In this review, we mainly review the effects of epigenetic modifications on chromosomal structure, thereby affecting gene expression and their functional realization. Combining cutting-edge epigenetic methods, we summarize in detail how DNA methylation, histone modification, and chromatin 3D structure affect the tumor microenvironment through immune cells to regulate tumorigenesis and tumor metastasis. At the same time, we summarize the effects of genomic topology on immune cells and tumors. This review provides detailed and in-depth methods and insights in epigenetics and tumor immunity, providing doctors and cancer patients with new ideas. Display omitted
•This paper mainly studies the effect of Epigenetics regulation on tumor immune cell function.•The key abnormal Epigenetics processes include DNA methylation, histone modification and their influence in Chromatin structure to modulate tumor immune cells.•Summarized the research methods of these epigenetic modifications for the antitumor immunity.•The value of epigenetic modulators and small molecule inhibitors in enhancing anti-tumor immune response was emphasized.•The challenges of developing a combination of epigenetic and immunotherapy regimens were discussed.
The pathologic consequences of inflammatory responses in chronic cerebrospinal venous insufficiency (CCSVI) remains poorly understood. Hence, this study was aimed to evaluate the peripheral ...inflammatory biomarkers in patients with intracranial and extracranial CCSVI pathology. In addition, the relationship between inflammatory cytokine profile and CCSVI prognosis was also evaluated.
Patients diagnosed with CCSVI between July 2017 and July 2019 were included and subsequently divided into 3 groups based on the location of stenosis. The inflammatory biomarker assay included neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs), red blood cell distribution widths (RDW), C-reactive protein (CRP) levels, interleukin-6 (IL-6) levels, and neuron-specific enolase levels. Clinical outcomes were assessed using the modified Rankin Scale and Patient Global Impression of Change score. Univariate and multivariate regression analyses were performed to identify significant prognostic factors for poorer outcomes. Finally, we established a nomogram based on the multivariate regression analysis.
We enrolled 248 patients in total, including 102 males and 146 females, with an average age of 57.85±12.28 years. Compared with patients with internal jugular vein stenosis, cerebral venous sinus stenosis (CVSS) patients were mostly younger and had been suffering from headaches and severe papilledema. Higher levels of NLR, RDW, and CRP were also observed in the CVSS group. Multivariate analysis indicated that NLR, PLR, and IL-6 were the independent prognostic factors for poor CCSVI outcomes.
The clinical presentations and increases in NLR, PLR, IL-6, and CRP levels could be distinctly marked in patients with CVSS-related CCSVI than that in internal jugular vein stenosis-related CCSVI, indicating poor prognostic outcomes in these patients. A proinflammatory state might be associated with CCSVI pathology.
A phenomenological model for the prediction of the forming limit curve (FLC) based on basic mechanical properties through a uniaxial tensile test can tremendously shorten the design time of the ...forming process and reduce the measuring costs. In this paper, a novel phenomenological model named the IMR-Baosteel model (abbreviated as the IB model) is proposed for efficient and accurate FLC prediction of hot-rolled steel sheets featuring distinct variations in thickness and mechanical properties. With a systematic test of the plane strain forming limit (FLC0), it was found that a higher regression correlation exists between the FLC0 and the total elongation under different sheet thicknesses. For accurate assessment of the FLC0 from tensile properties, compared using experiments, the error of FLC0 calculated with the proposed model is within 10%. In the IB model, the left side of FLC can be calculated using a line with a slope of −1 while the right side of the FLC is obtained via a modified Keeler model with the exponent (p) determined as 0.45 for hot-rolled steels. Complete experimental FLCs of hot-rolled steels from measurements and the literature were used to validate the reliability of the proposed model. Resultantly, the prediction of FLCs with the proposed IB model is greatly improved, and agrees much better with the experimental FLCs than the predictions of the well-known Keeler model, Arcelor model and Tata Steel model.
![Sulfur‐Doped Quintuple [9]H...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1433-7851/small "Sulfur‐Doped Quintuple [9]Helicene with Azacorannulene as Core")
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