Our previous work has shown that tanshinone IIA (Tan IIA) is a DNA minor groove binder instead of an intercalator as previously thought. In this study, we have further demonstrated that the molecular ...antitumor pharmacology of Tan IIA is dependent on its groove-binding capability. First, we investigated the structure damage to duplex DNA upon Tan IIA binding using circular dichroism spectra. Subsequently, we performed western blot, flow cytometry analysis, chromatin immunoprecipitation, and quantitative real-time PCR to illustrate the RNAPII degradation, phosphorylation, and distribution along the transcribed gene in H22 cells exposed to Tan IIA. In addition, p53 activation and apoptosis induction in both cultured H22 cells and in mice bearing the ascitic-type H22 were measured following Tan IIA treatment. It was revealed that Tan IIA decreases the level of RNAPII by altering DNA structure. At the low dose range (0.2–4
μM) of Tan IIA exposure, the DNA structure damage results in the inhibition of RNAPII binding to DNA and the initiation of RNAPII phosphorylation, while higher concentrations of Tan IIA (4–20
μM) cause complete phosphorylation and degradation of RNAPII followed by p53 activation and apoptosis. A similar apoptosis induction by RNAPII was observed in animals. Apoptosis of tumor cells from ascitic fluid was not detected until RNAPII levels were downregulated by Tan IIA, which requires 40
mg/kg body weight of Tan IIA. It was concluded that DNA-conformational-damage-dependent RNAPII response upon groove binding is the molecular basis of the antitumor property of Tan IIA,
in vivo and
in vitro.
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•Baicalein administered in the subacute phase ameliorated I/R induced brain injury.•Baicalein regulated M1/M2 transformation of microglia/macrophages in I/R injury.•Baicalein blocked ...the nuclear translocation of NF-κB/p65 in I/R injury.
Ischemic stroke is a cerebrovascular disease with high morbidity, high mortality, and high disability, representing a serious threat to human life and health. Clinically, the extensive injury caused by ischemic stroke results from ischemia-reperfusion (I/R) injury thrombolytic treatment. However, there are few reports on the use of medications in the subacute stage of cerebral I/R. Baicalein (5,6,7-trihydroxyflavone) is a biologically active ingredient extracted from the root of Scutellaria baicalensis Georgi. In the present study, we investigated the therapeutic effect of baicalein administered in the subacute phase of cerebral I/R injury in a rat model of ischemia induced by occlusion of the middle cerebral artery (MCA). Rats were treated daily with baicalein (200 mg/kg, i.g.) in the subacute phase (24 h after reperfusion) for 7 days. The results showed that baicalein significantly reduced neurobehavioral deficits and decreased brain infarct volume from 18.99% to 7.41%. Immunofluorescence analysis of the ischemic penumbra showed that baicalein significantly reduced expression of the M1 marker, cluster of differentiation (CD) 16 and CD86, and increased expression of the M2 marker, CD 163 and CD206, indicating that baicalein inhibited M1 transformation and promoted M2 transformation of microglia/macrophage to inhibit neuroinflammation. Moreover, baicalein suppressed NF-κB signaling by reducing IκBα phosphorylation and nuclear translocation of NF-κB/p65, which decreased the release of the pro-inflammatory factors IL-6, IL-18, and TNF-α. In addition, baicalein reduced phosphorylation of JNK, ERK and p38, which are involved modulation of microglia/macrophage M1/M2 polarization. Western blot analysis of apoptosis- and autophagy-related proteins showed that baicalein increased the Bcl-2/Bax ratio and reduced caspase-3 expression to decrease neuronal apoptosis and ameliorate neuronal loss. Baicalein also decreased the LC3-II/LC3-I ratio and promoted phosphorylation of the PI3K/Akt/mTOR signaling pathway which implied inhibition of autophagy. These observations suggest that baicalein exerts neuroprotective effects by reducing neuroinflammation, apoptosis and autophagy, and protects against cerebral I/R injury in the subacute phase in vivo.
Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids ...for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial–mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.
This review summarizes the biology, function, and applications of exosomes in cancers. Exosomes can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Exosomes also act as natural drug delivery vehicles for cancer therapy. Display omitted
Xiaoyaosan (XYS), a classic description, has a history of thousands of years for treating depression through invigorating the liver and strengthening the spleen, which have been verified both ...clinically and experimentally. However, explanation of its underlying mechanisms remains a great challenge.
The mechanisms of XYS in treating depression were investigated, with emphasis on the important biomarkers, targets and pathways.
In this study, taking the targeted organ of depression, hippocampus, as the object, a combination of GC-MS based metabolomics and network pharmacology was established to illustrate the abnormality of metabolic characteristics of hippocampus of depression rats and to demonstrate the antidepressant mechanisms of XYS. Hippocampal metabolomics demonstrated potential metabolites involving in the antidepressant effects of XYS, as well as the corresponding metabolic pathways. Network pharmacology screened the potential ingredients and the targets of XYS against depression.
Metabolomics revealed that XYS significantly regulated the abnormal levels of lactic acid, glycerol, glutamine, glutamic acid, hypoxanthine, myo-inositol and cholesterol, which involved in the D-glutamine and D-glutamate metabolism, arginine biosynthesis and alanine, aspartate and glutamate metabolism. Network pharmacology showed that XYS exhibited anti-depression effects through paeoniflorin, quercetin, licochalcone a, naringenin, β-sitosterol, formononetin and kaempferol acting on interleukin-6 (IL6), mitogen-activated protein kinase 1 (MAPK1), signal transducer and activator of transcription 3 (STAT3) and transcription factor AP-1 (JUN).
Based on hippocampal metabolomics and network pharmacology, this study proved that the actions of XYS in treating depression depend on multi-components, multi-targets and multi-pathways, the unique characteristics of TCMs.
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•The combination of hippocampal metabolomics and network pharmacology were applied.•7 hippocampal biomarkers were associated with the antidepressant mechanisms of XYS.•7 antidepressant ingredients and 4 key targets of XYS were identified.•Integrating metabolomics and network pharmacology is valuable for TCMs.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. In addition to motor symptoms, a variety of non-motor symptoms seriously affect the life quality of PD ...patients. Baicalein, a flavonoid extracted from the herb Scutellaria baicalensis Georgi, exhibits anti-PD activity through alleviation of its motor symptoms. However, its effects on non-motor symptoms were barely reported. This study aimed to investigate the therapeutic effects of baicalein on PD-related depression.
After a 2-week injection of rotenone, mice with PD-related depression behavior were selected, divided into three groups, and administrated saline, baicalein, or madopar orally for four weeks. Behavior, neuroinflammation, neurotransmitters, and synaptic plasticity were evaluated.
Our results showed that 4-week baicalein treatment significantly alleviated the depression-like behavior in the rotenone-induced mice model. Repeated baicalein treatment reduced α-synuclein aggregation, inhibited neuroinflammation, and maintained neurotransmitters homeostasis. Moreover, we found that baicalein treatment could remarkably protect the synaptic plasticity and activate the BDNF/TrkB/CREB pathway in the PD-related depression mice model. As traditional dopamine replacement therapy unleashed few effects on depression-like symptom amelioration and synaptic function protection, baicalein might be a more appropriate choice for PD-related depression.
The current results suggested that baicalein could act as a treatment for PD-related depression.
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•The rotenone-induced PD-related depression mice is valuable for drug discovery.•Baicalein attenuated depression-like symptom in rotenone-induced PD mice model.•Baicalein reduced α-synuclein toxicity and neuroinflammation damage.•Baicalein maintained the homeostasis of monoamine neurotransmitters.•Baicalein protected synaptic plasticity through BDNF/TrkB/CREB pathway.
Objective
Withaferin A (WA) is a bioactive compound with a remarkable anti‐cancer effect derived from Withania somnifera, commonly known as ashwagandha. However, the anti‐cancer mechanisms of WA in ...glioblastoma multiforme (GBM) are still unclear.
Materials and Methods
Cell viability assays and xenografted nude mice were used to evaluate the effects of WA, along with flow cytometry to detect apoptosis and cell cycle of GBM. RNA‐seq analysis, Western blotting, immunofluorescence staining, qRT‐PCR and siRNA gene silencing were carried out to determine the signalling pathways affected by WA.
Results
Withaferin A significantly inhibited the growth of GBM in vitro and in vivo and triggered the intrinsic apoptosis of GBM cells by up‐regulating expression of Bim and Bad. WA arrested GBM cells at the G2/M phase of the cell cycle through dephosphorylating Thr161 of CDK1 by activating p53‐independent p21 up‐regulation. Knockdown of p21 restored cell cycle progression and cell viability by down‐regulating the expression of Bad rather than Bim. We demonstrated that endoplasmic reticulum (ER) stress induced by WA through the ATF4‐ATF3‐CHOP axis, initiated apoptosis and G2/M arrest in GBM cells.
Conclusion
We revealed a novel pathway that elucidated WA activation of apoptosis and G2/M arrest in GBM cells through the ATF4‐ATF3‐CHOP axis. This discovery is important for optimization of WA‐based regimens for prevention and/or treatment of GBM.
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Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this ...paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 μM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form β of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum. In conclusion, oral administration of crystal form β of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.
HuangQi (HQ) is a major medicinal herb commonly used as an ingredient of traditional Chinese medicine (TCM) formulas. It has been proved to be effective against heart failure (HF). However, its ...holistic therapeutic mechanism is not yet well explored.
The present study was designed to investigate the inhibitory effects and action mechanism of HQ in adriamycin (ADR)-induced HF rats.
An integrative approach combining comprehensive echocardiography index (CEI) and metabonomics was conducted to assess the integral efficacy of HQ against HF. CEI was constructed to comprehensively evaluate the protection of HQ through principal component analysis of eight echocardiography parameters. Meanwhile, NMR-based untargeted metabolomic studies were performed to investigate the regulative effects of HQ coupled with correlation analysis.
HQ showed significant regulatory effects on four echocardiography parameters (left ventricular diastolic diameter, left ventricular systolic wall thickness, ejection fraction and fractional shortening). The effect on comprehensive CEI also demonstrated the efficacy of HQ against HF, especially on the first principal component (PC1). HQ could exert marked metabolic regulations on five key metabolites related to HF (NAG, 3-hydroxybutyrate, glutamine, succinate and acetoacetate), which were mainly involved into alterations of energy metabolism, oxidative stress, hypertrophy, as well as inflammatory. Their correlation analysis revealed the relationship between the metabolic profiles and cardiac function, which further authenticated the systemic regulation of HQ against HF.
Current evidences revealed that HQ was effective in control of HF from cardiac dysfunction and metabolic alterations. This study provided a useful approach for evaluating the efficacy of TCMs against HF.
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Apolipoproteins and cancer Ren, Liwen; Yi, Jie; Li, Wan ...
Cancer medicine (Malden, MA),
November 2019, Letnik:
8, Številka:
16
Journal Article
Recenzirano
Odprti dostop
The role of apolipoproteins in cardiovascular disease has been well investigated, but their participation in cancer has only been explored in a few published studies which showed a close link with ...certain kinds of cancer. In this review, we focused on the function of different kinds of apolipoproteins in cancers, autophagy, oxidative stress, and drug resistance. The potential application of apolipoproteins as biomarkers for cancer diagnosis and prognosis was highlighted, together with an investigation of their potential as drug targets for cancer treatment. Many important roles of apolipoproteins and their mechanisms in cancers were reviewed in detail and future perspectives of apolipoprotein research were discussed.
We focused on roles of different kind apolipoproteins in cancers, autophagy, oxidative stress, resistance of drugs and hypolipidemic agents and cancers. In addition, apolipoproteins as drug targets of cancer treatment and biomarkers for cancer diagnosis and prognosis were discussed. Future perspectives of apolipoproteins research were described in the end.
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