Tabersonine Induces the Apoptosis of Human Hepatocellular Carcinoma In vitro and In vivo.

BACKGROUND: Tabersonine, a natural indole alkaloid derived from Apocynaceae plants, exhibits antiinflammatory and acetylcholinesterase inhibitory activities, among other pharmacological effects. However, its anti-tumor properties and the underlying molecular mechanisms remain underexplored. OBJECTIVE: The present study aims to investigate the anti-tumor effects of tabersonine and its mechanisms in inducing apoptosis in hepatocellular carcinoma. METHODS: The inhibitory effects of tabersonine on the viability and proliferation of liver cancer cells were evaluated using MTT assay and colony formation assay. AO/EB, Hoechst, and Annexin V-FITC/ PI staining techniques were employed to observe cell damage and apoptosis. JC-1 staining was used to detect changes in mitochondrial membrane potential. Western blot analysis was conducted to study the anti-tumor mechanism of tabersonine on liver cancer cells. Additionally, a xenograft model using mice hepatoma HepG2 cells was established to assess the anti-tumor potency of tabersonine in vivo. RESULTS AND DISCUSSION: Our findings revealed that tabersonine significantly inhibited cell viability and proliferation, inducing apoptosis in liver cancer cells. Treatment with tabersonine inhibited Akt phosphorylation, reduced mitochondrial membrane potential, promoted cytochrome c release from mitochondria to the cytoplasm, and increased the ratio of Bax to Bcl-2. These findings suggested that tabersonine induces apoptosis in liver cancer cells through the mitochondrial pathway. Furthermore, tabersonine treatment activated the death receptor pathway of apoptosis. In vivo studies demonstrated that tabersonine significantly inhibited xenograft tumor growth. CONCLUSION: Our study is the first to demonstrate that tabersonine induces apoptosis in HepG2 cells through both mitochondrial and death receptor apoptotic pathways, suggesting its potential as a therapeutic agent candidate for hepatic cancer.

Design, synthesis, and biological evaluation of novel 4,4'-bipyridine derivatives acting as CDK9-Cyclin T1 protein-protein interaction inhibitors against triple-negative breast cancer.

Cyclin-dependent kinase 9 (CDK9) is directly related to tumor development in triple-negative breast cancer (TNBC) patients. Increased CDK9 is significantly associated with poor patient prognosis, while inhibiting CDK9-Cyclin T1 protein-protein interaction has recently been demonstrated as a new approach to TNBC treatment. Herein, we synthesized a novel class of 4,4'-bipyridine derivatives as potential CDK9-Cyclin T1 PPI inhibitors against TNBC. The represented compound B19 was found to be an excellent and selective CDK9-Cyclin T1 PPI inhibitor with good potency against TNBC cell lines while exhibiting lower toxicity in normal human cell lines than the positive compound I-CDK9. Notably, compound B19 showed good pharmacokinetic properties and excellent antitumor activity against TNBC (4T1) allografts in mice with a therapeutic index of more than 42 (TGI4T1(12.5 mg/kg,i.p.) = 63.1% vs. LD50 = 537 mg/kg). Moreover, the administration of B19 in combination with the PARP inhibitor Olaparib results in a significant increase of the antitumor activity in MDA-MB-231 cells relative to that of either single agent. To our knowledge, B19 is the first reported non-metal organic compound that acts as a selective CDK9-Cyclin T1 PPI inhibitor with in vivo antitumor activity, and it may be alone and in combination with PARP inhibitor Olaparib for TNBC therapy.

Orphan Nuclear Receptor Nur77 Mediates the Lethal Endoplasmic Reticulum Stress and Therapeutic Efficacy of Cryptomeridiol in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) commonly possesses chronical elevation of IRE1α-ASK1 signaling. Orphan nuclear receptor Nur77, a promising therapeutic target in various cancer types, is frequently silenced in HCC. In this study, we show that cryptomeridiol (Bkh126), a naturally occurring sesquiterpenoid derivative isolated from traditional Chinese medicine Magnolia officinalis, has therapeutic efficacy in HCC by aggravating the pre-activated UPR and activating the silenced Nur77. Mechanistically, Nur77 is induced to sense IRE1α-ASK1-JNK signaling and translocate to the mitochondria, which leads to the loss of mitochondrial membrane potential (Δψm). The Bkh126-induced aggravation of ER stress and mitochondrial dysfunction result in increased cytotoxic product of reactive oxygen species (ROS). The in vivo anti-HCC activity of Bkh126 is superior to that of sorafenib, currently used to treat advanced HCC. Our study shows that Bkh126 induces Nur77 to connect ER stress to mitochondria-mediated cell killing. The identification of Nur77 as a molecular target of Bhk126 provides a basis for improving the leads for the further development of anti-HCC drugs.

The Ginsenoside Compound K Suppresses Stem-Cell-like Properties and Colorectal Cancer Metastasis by Targeting Hypoxia-Driven Nur77-Akt Feed-Forward Signaling.

Hypoxia reprograms cancer stem cells. Nur77, an orphan nuclear receptor, highly expresses and facilitates colorectal cancer (CRC) stemness and metastasis under a hypoxic microenvironment. However, safe and effective small molecules that target Nur77 for CSC depletion remain unexplored. Here, we report our identification of the ginsenoside compound K (CK) as a new ligand of Nur77. CK strongly inhibits hypoxia-induced CRC sphere formation and CSC phenotypes in a Nur77-dependent manner. Hypoxia induces an intriguing Nur77-Akt feed-forward loop, resulting in reinforced PI3K/Akt signaling that is druggable by targeting Nur77. CK directly binds and modulates Nur77 phosphorylation to block the Nur77-Akt activation loop by disassociating Nur77 from the p63-bound Dicer promoter. The transcription of Dicer that is silenced under a hypoxia microenvironment is thus reactivated by CK. Consequently, the expression and processing capability of microRNA let-7i-5p are significantly increased, which targets PIK3CA mRNA for decay. The in vivo results showed that CK suppresses cancer stemness and metastasis without causing significant adverse effects. Given that the majority of FDA-approved and currently clinically tested PI3K/Akt inhibitors are reversible ATP-competitive kinase antagonists, targeting Nur77 for PI3K/Akt inactivation may provide an alternative strategy to overcoming concerns about drug selectivity and safety. The mechanistic target identification provides a basis for exploring CK as a promising nutraceutical against CRC.

Factors Influencing the Adoption of Online Health Consultation Services: The Role of Subjective Norm, Trust, Perceived Benefit, and Offline Habit.

The cyberspace plays an important role in improving the quality, equity, and efficiency of health services. Studying people's adoption of online health services, such as online health consultation services (OHCS) can benefit both industry and policy in the health service sector. This paper investigates influencing factors and paths of people's intention of adopting OHCS by employing the extended valence framework, with our new contribution of integrating subjective norm and offline habit into the model. Five hundred forty-three university students participated in the survey. Structural equation models and Sobel-Goodman tests were applied to test the models. The results show that subjective norm (ß = 0.077, p = 0.041), trust in providers (ß = 0.194, p = 0.002) and perceived benefit (ß = 0.463, p < 0.001) positively affect the intention to adopt OHCS, while offline habit (ß = -0.111, p = 0.026) has a negative effect. However, the association of perceived risk (ß = -0.062, p = 0.315) and adoption is not supported. Moreover, trust in providers plays a mediating role between subjective norm and the intention of adopting, while perceived benefit mediates the relationship between trust in providers and the intention of adopting. This study highlights the importance of trust, subjective norm, perceived benefit, and persisting habits in promoting the adoption of OHCS.

Corilagin induces the apoptosis of hepatocellular carcinoma cells through the mitochondrial apoptotic and death receptor pathways.

Corilagin, a gallotannin, is one of the major active components of many ethnopharmacological plants and exhibits antitumor, anti-inflammatory and antioxidative properties. In recent years, corilagin has provoked much attention due to its antitumor activity, yet the mechanisms attributed to its anticancer actions are largely unknown. In our previous research, our group reported that corilagin could inhibit the proliferation of hepatocellular carcinoma (HCC) cells by inducing G2/M phase arrest. In the present study, observation of the morphological changes showed that corilagin induced the apoptosis of HCC cells as determined by AO/EB and Hoechst 33258 staining assays. Furthermore, flow cytometric analysis was carried out to calculate the apoptotic rate which was 24.1% following treatment with corilagin (37.5 µM). At the molecular level, mitochondrial membrane potential assay and western blot analysis showed that the mitochondrial transmembrane potential was reduced and the rate of release of cytochrome c was increased, which led to the activation of caspase-9, caspase-3 and cleavage of PARP in the cytoplasm indicating activation of the mitochondrial apoptotic pathway. Moreover, following treatment with corilagin, we noted upregulation of Fas and FasL and activation of caspase-8 which represented activation of the death receptor pathway, and we also observed downregulation of Bcl-2 and survivin which was also attributed to the antitumor effect of corilagin. These results suggest that corilagin significantly induced the apoptosis of HCC cells through both the mitochondrial apoptotic pathway and the death receptor pathway, and corilagin is a potential complementary anticancer herbal drug for HCC therapy.

Evaluating the efficacy and safety of continuous arterial infusion chemotherapy with cisplatin and 5-fluorouracil in treating oral cancer.

OBJECTIVE: To investigate the clinical effects and safety for cisplatin combined with 5-fluorouracil (5-FU) intra-arterial chemotherapy in the treatment of oral cancer. MATERIALS AND METHODS: A total of ninety cases with oral cancer were recruited in this study. Forty-three subjects received the pingyangmycin (PYM) (control group) with PYM 8 mg, intramuscular injection, QD for 21 days per cycle. Moreover, other 47 cases received cisplatin 100 mg/m 2 24 h perfusion chemotherapy, day 1 with 21 days per cycle, and 5-FU 1000 mg/m 2 perfusion chemotherapy 72 h with 21 days per cycle. All the patients received three cycles treatment. After three cycles chemotherapy, the objective response rate (ORR) and chemotherapy-related toxicities were evaluated between the two groups. RESULTS: The ORR were 53.49% and 72.34%, respectively in the control and observation group which indicated observation group significant higher (P < 0.05). The chemotherapy-related toxicities incidence was much higher in control group compared with observation group (36.17% vs. 11.63%, P < 0.05). CONCLUSION: Cisplatin combined with 5-FU intra-arterial chemotherapy was effective in the treatment of oral cancer with less toxicties.

A meta-analysis of contrast-enhanced computer tomography in the diagnosis of colorectal cancer.

OBJECTIVE: To investigate the diagnostic value of contrast-enhanced computer tomography in diagnosis of colorectal cancer. METHODS: All the diagnostic studies about contrast-enhanced computer tomography in diagnosis of colorectal cancer were searched in the PubMed, Medline, EMBASE, CNKI, and Wanfang databases and included in this meta-analysis. The diagnostic sensitivity and specificity were pooled. The data were analyzed by statistic software Meta-DiSc1.4. RESULTS: After searching the databases, eight studies with 4764 cases were finally included in this meta-analysis. The combined results showed the pooled diagnostic sensitivity and specificity were 0.73 (95% confidence interval [CI] of 0.69-0.76) and 0.86 (95% CI of 0.85-0.87). Moreover, the area under the receiver operating characteristic was 0.896. CONCLUSION: Contrast-enhanced computer tomography was a good method for detection colorectal cancer.

Evaluation of Hepatic Tumors Using Intravoxel Incoherent Motion Diffusion-Weighted MRI.

BACKGROUND This study aimed to evaluate the diagnostic value of the D value, D* value, and f magnitude for identifying benign and malignant hepatic tumors using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). MATERIAL AND METHODS Data of 89 cases (123 lesions) with hepatic tumor confirmed by surgical pathology and postoperative follow-up were retrospectively collected. Among these cases, 40 cases were benign hepatic tumors (57 lesions) and 49 cases were malignant hepatic tumors (66 lesions). All subjects underwent conventional MRI with T1WI, T2WI, multi-b-value DWI, and dynamic enhanced LAVA scan. Diffusion-weighted images with 11 b values (0, 10, 20, 30, 50, 80, 100, 200, 400, 800, and 1000 s/mm2) were obtained to calculate true molecular diffusion (D), perfusion-related diffusion coefficient (D*), and perfusion fraction (f). The diagnostic performance in differentiating between malignant and benign hepatic lesions was analyzed. RESULTS Malignant lesions had a significantly lower D value ([1.04±0.34]×10-3 mm2/s) and D* value ([16.5±7.7]×10-3 mm2/s) compared to benign lesions (D value: [1.70±0.55]×10-3 mm2/s, P<0.01; D* value: [21.7±9.9]×10-3 mm2/s, P<0.01). There was no statistically significant difference in f values between malignant (23.3±9.5) and benign lesions (33.5±14.9, P=0.13). In addition, D exhibited a better diagnostic performance than D* in terms of the area under the curve, sensitivity, and specificity when identifying malignancies from benign lesions. CONCLUSIONS D and D* are significant parameters for diagnosing hepatic tumors. Moreover, the D value is a more reliable parameter in distinguishing benign and malignant hepatic tumors.