Apolipoprotein C1 (APOC1) has been found to play an essential part in proliferation and metastasis of numerous cancers, but related mechanism has not been elucidated, especially its function and role ...in tumor immunity. Through systematic pan-cancer analysis, we identified that APOC1 was closely associated with the infiltration of various immune cells in multiple cancers. Besides, APOC1 was significantly co-expressed with the immune checkpoints, major histocompatibility complex (MHC) molecules, chemokines and other immune-related genes. Furthermore, single-cell sequencing analysis suggested that the vast majority of APOC1 was expressed in macrophages or tumor-associated macrophages (TAMs). Additionally, the expression of APOC1 was significantly related to the prognosis of different cancers. Since APOC1 was most significantly abnormally expressed in renal cell cancer (RCC), subsequent experiments were carried out in RCC to explore the role of APOC1 in tumor immunity. The expression of APOC1 was significantly elevated in the tumor and serum of RCC patients. Besides, APOC1 was mainly expressed in the macrophage and it was closely related to the immune cell infiltration of RCC. Co-culture with RCC cells could induce the generation of TAMs with M2 phenotype which be blocked by silencing APOC1. The expression of APOC1 was elevated in the M2 or TAMs and APOC1 promoted M2 polarization of macrophages through interacting with CD163 and CD206. Furthermore, macrophages overexpressing APOC1 promoted the metastasis of RCC cells via secreting CCL5. Together, these data indicate that APOC1 is an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.
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Glioblastoma multiforme (GBM) in the central nervous system is the most lethal advanced glioma and currently there is no effective treatment for it. Studies of sinomenine, an alkaloid from the ...Chinese medicinal plant, Sinomenium acutum, showed that it had inhibitory effects on several kinds of cancer. Here, we synthesized a sinomenine derivative, sino-wcj-33 (SW33), tested it for antitumor activity on GBM and explored the underlying mechanism. SW33 significantly inhibited proliferation and colony formation of GBM and reduced migration and invasion of U87 and U251 cells. It also arrested the cell cycle at G2/M phase and induced mitochondria-dependent apoptosis. Differential gene enrichment analysis and pathway validation showed that SW33 exerted anti-GBM effects by regulating PI3K/AKT and AMPK signaling pathways and significantly suppressed tumorigenicity with no obvious adverse effects on the body. SW33 also induced autophagy through the PI3K/AKT/mTOR and AMPK/mTOR pathways. Thus, SW33 appears to be a promising drug for treating GBM effectively and safely.
Sinomenine ester derivative SW33 significantly inhibited glioblastoma multiforme (GBM) by arresting cell cycle at G2/M phase, promoting apoptosis in mitochondria-dependent manner and inducing autophagy via PI3K/AKT/mTOR and AMPK/mTOR pathways with a good safety profile in vivo and in vitro. Display omitted
Numerous studies have shown that genistein has a good therapeutic effect on pulmonary hypertension (PH). However, there has been no systematic research performed yet to elucidate its exact mechanism ...of action in relation to PH. In this study, a systemic pharmacology approach was employed to analyze the anti-PH effect of genistein. Firstly, the preliminary predicted targets of genistein against PH were obtained through database mining, and then the correlation of these targets with PH was analyzed. After that, the protein-protein interaction network was constructed, and the functional annotation and cluster analysis were performed to obtain the core targets and key pathways involved in exerting the anti-PH effect of genistein. Finally, the mechanism was further analyzed via molecular docking of genistein with peroxisome proliferator-activated receptor γ (PPARγ). The results showed that the anti-PH effect of genistein may be closely related to PPARγ, apoptotic signaling pathway, and the nitric oxide synthesis process. This study not only provides new insights into the mechanism of genistein against PH, but also provides novel ideas for network approaches for PH-related research.
have been frequently used for clinical application in China, and the herb residues of
turn out to be a waste of resources. To escape from this, the medicine value of
herb residues is mined in this ...article. We isolated hemicellulose polysaccharide AX-I-3b from
herb residues by fractional extraction. Monosaccharide-composition analysis revealed that AX-I-3b consisted of arabinose, xylose, and glucose with a molar ratio of 10.4:79.3:1.1. Methylation, NMR and FT-IR analyses showed that AX-I-3b monosaccharide residue was linked as follows: →2,3,4)-β-d-Xylp-(1→, →4)-β-d-Arap-(1→, →4)-β-d-Glcp-(1→. Then, we found that AX-I-3b exhibited antitumor activity against lung cancer in vitro and vivo through MTT assay and xenograft tumor model. Mechanistically, AX-I-3b induced apoptosis in lung cancer cells and xenograft tumors, which is evidenced by the up-regulation of p53, Bax and cleaved caspase-3, and the down-regulation of Bcl-2. Moreover, AX-I-3b synergistically improved the therapeutic ability of cisplatin in xenograft tumors model. Furthermore, AX-I-3b treatment effectively improved the immune organ index, the percentage of spleen lymphocyte subsets and serum cytokine levels in lung cancer mice, supporting that AX-I-3b showed immunomodulatory activity. In conclusion, our results identified AX-I-3b as an antitumor and immunomodulatory agent, providing a new insight into the reutilization of
herb residue.
Inflammation is a defensive response of living tissues to damaging agents, which exists in two forms, acute inflammation and chronic inflammation, and chronic inflammation is closely related to ...arthritis. Currently, the commonly prescribed anti-inflammatory medications are greatly limited by high incidence of gastrointestinal erosions in the clinical applications. Rhein, a bioactive constituent of anthraquinone, exhibits excellent anti-inflammatory activities and therapeutic effects on arthritis with less gastrointestinal damages. Although there are numbers of studies on anti-inflammatory effects and mechanisms of rhein in the last few decades, to the best of our knowledge, only a few review articles pay attention to the interactive relationships of rhein on multiple inflammatory signaling pathways and cellular processes from a comprehensive perspective. Herein, we summarized anti-inflammatory effects and mechanisms of rhein and its practical applications in the treatment of arthritis, thereby providing a reference for its basic researches and clinical applications.
Abstract
Background
Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic ...drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate.
Methods
By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism.
Results
Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way.
Conclusions
CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.
► Theaflavin extract and its three derivatives displayed anti-influenza viral activity. ► Their action mechanisms are through inhibition of neuraminidase and haemagglutinin. ► They also decreased the ...expression level of IL-6 during viral infection. ► Theaflavins are potential natural compounds for influenza prevention and treatment. ► These findings will be important for the development of anti-influenza drug.
The theaflavins fraction (TF80%, with a purity of 80%) and three theaflavin (TF) derivatives from black tea have been found to exhibit potent inhibitory effects against influenza virus in vitro. They were evaluated with a neuraminidase (NA) activity assay, a hemagglutination (HA) inhibition assay, a real-time quantitative PCR (qPCR) assay for gene expression of hemagglutinin (HA) and a cytopathic effect (CPE) reduction assay. The experimental results showed that they all exerted significant inhibitory effects on the NA of three different subtypes of influenza virus strains A/PR/8/34(H1N1), A/Sydney/5/97(H3N2) and B/Jiangsu/10/2003 with 50% inhibitory concentration (IC50) values ranging from 9.27 to 36.55μg/mL, and they also displayed an inhibitory effect on HA; these inhibitory effects might constitute two major mechanisms of their antiviral activity. Time-of-addition studies demonstrated that TF derivatives might have a direct effect on viral particle infectivity, which was consistent with the inhibitory effect on HA. Subsequently, the inhibitory effect of TF derivatives on the replication of the viral HA gene as assayed by qPCR and on the nuclear localization of the influenza virus vRNP further demonstrated that they may primarily act during the early stage of infection. Interestingly, besides the activity against functional viral proteins, TF derivatives also decreased the expression level of the inflammatory cytokine IL-6 during viral infection, expression of which may result in serious tissue injury and apoptosis. Our results indicated that TF derivatives are potential compounds with anti-influenza viral replication and anti-inflammatory properties. These findings will provide important information for new drug design and development for the treatment of influenza virus infection.
The root of Scutellaria baicalensis Georgi has been used extensively in traditional Chinese medicine for the treatment of inflammation, fever, cough, dysentery, and hypertension. Baicalein is a ...flavonoid isolated from the root of Scutellaria baicalensis Georgi and is a novel neuroprotective agent under development for the treatment of Parkinson׳s disease. We aimed to investigate the pharmacokinetic (PK) properties of baicalein and its main metabolite, bacalin, after single-dose administration in healthy Chinese subjects. The safety and tolerability of baicalein were also assessed.
This was a Phase I, randomized, double-blind, single-dose trial of baicalein (100–2800mg) in 72 healthy adults. Samples of blood, urine and feces were collected at regular intervals up to 48h after administration of the study drug. Baicalein and baicalin were then analyzed using liquid chromatography-tandem mass spectrometry (LC/MS/MS). The maximum concentration that the drug achieved after dosing (Cmax), time to Cmax (Tmax), terminal half-life (t1/2), area under the curve from time zero to time of last quantifiable concentration (AUC(0, t)), area under the curve from time zero to infinity (AUC(0, ∞)), apparent total plasma clearance (CL/F), and apparent total volume of distribution (V/F) were determined using non-compartmental models. Dose proportion was tested using a method combining the equivalence criterion and power model. Physical examinations, vital signs, ECG findings, hematology, and urinalysis were monitored before and at regular intervals after administration of the study drug.
The PK profile of baicelein and baicelin was characterized by a median Tmax of 0.75–3.5h and 0.5–3h, respectively, followed by a multiphasic profile with a t1/2 of 1.90–15.01h and 4.22–10.80h, respectively. The estimates of the proportionality coefficient (90% CI) for Cmax, AUC0–t and AUC0–∞ were 0.83 (0.70–0.96), 0.91 (0.81–1.00) and 0.92 (0.82–1.02), respectively. All values overlapped within the pre-specified range of (0.89–1.11), (0.93–1.07), and (0.93–1.07), respectively. Dose proportionality was inconclusive for a baicalein dose range of 100–2800mg. The total urinary clearance of baicalein and baicalin was <1%. Approximately 27% of baicalein was eliminated as unchanged drug in feces. Baicalein was well tolerated. Eleven treatment-related adverse events were observed, and all were rated as “mild” and resolved without further treatment. No serious adverse events occurred.
Single oral doses of 100–2800mg of baicalein were safe and well tolerated by healthy subjects. Clinical laboratory assessments showed no signs of toxicity in the liver or kidney. The favorable safety profile and PK properties warrant further clinical studies for baicalein.
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The aim of this study was to investigate the effects of pinocembrin on brain ischemia/reperfusion (I/R) injury and the potential involvement of autophagy activity changes in the penumbra area in the ...mechanisms of pinocembrin activity. Focal cerebral I/R model was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 24 h reperfusion. Pinocembrin was administered intravenously at different doses (1, 3, and 10 mg/kg, respectively) at the onset of reperfusion. Neurological function, brain infarction and brain swelling ratio were evaluated. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and immunohistochemical analysis (Caspase-3) were used to evaluate apoptosis in the penumbra cortex. Two key proteins of autophagy, LC3B and Beclin1, were detected by western blot. The results showed that pinocembrin-treatment could significantly reduce neurological deficit scores, infarct volume, cerebral edema and improve pathological lesion in the I/R rats. Pinocembrin-treatment could also reduce the number of TUNEL-positive and Caspase-3-positive neurons, and upregulate the expression of LC3B and Beclin1 in penumbra area. These results suggested that pinocembrin could protect the brain against I/R injury, and the possible mechanisms might be attributed to inhibition of apoptosis and reversed autophagy activity in penumbra area.
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