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Hepatocellular carcinoma (HCC) is one of the most common malignancies and accounts for ~6% of all types of human cancer worldwide, particularly in Asia. The incidence and mortality rates in the USA have also rapidly increased. Saikosaponin‑d (SSD), a saponin derivative extracted from several species of Bupleurum (Umbelliferae), possesses unique biological activities, including anti‑inflammatory, antihepatitic and immunomodulatory effects. Our previous studies have demonstrated that SSD inhibits the proliferation and induces the apoptosis of HCC SMMC‑7721 cells by downregulating the expression of cyclooxygenase (COX)‑2 and decreasing the production of prostaglandin E2. However, the specific mechanism underlying how SSD controls the expression of COX‑2 remains to be elucidated. In the present study, it was demonstrated that hypoxia inducible factor‑1α (HIF‑1α) was responsible for the expression of COX‑2 under hypoxic conditions in HCC cells, and the activation of signal transducer and activator of transcription 3 (STAT3) was required for the expression of HIF‑1α. SSD treatment inhibited STAT3 activation [phosphorylation of STAT3 (p‑STAT3)], reduced the protein level of HIF‑1α and decreased the expression of COX‑2. These results suggested that SSD may target HCC cells by suppressing the expression of COX‑2 through the p‑STAT3/HIF‑1α pathway.

Saikosaponin-d (SSd) is an active extract from Radix Bupleuri , the dried root from the plant Bupleurum falcatum used in China for thousands of years to treat liver diseases. The SSd extract possesses valuable pharmacological activities including anti-cancer and anti-inflammatory effects; however, the mechanism underlying the anti-cancer activity of SSd is largely unknown. Here, we explored the mechanism of action of SSd as an anti-cancer agent for liver cancer in two human hepatocellular carcinoma cell lines. Using MTT and annexin-V-FITC/PI assays, Western blots, immunohistochemistry, qRT-PCR, luciferase reporter assay, and a JAK2-specific inhibitor (AG490), we demonstrated that the anti-tumorigenic effects of SSd act through the intermediatory p-STAT3/C/EBPβ signaling pathway to suppress cyclooxygenase (COX)-2. SSd effectively inhibited cell proliferation in a dose-dependent manner. Apoptosis was significantly increased in cells treated with SSd (2.5–15 µg/ml) with concurrent increase and decrease in pro- and anti-apoptosis proteins, respectively. COX-2, C/EBPβ, and p-STAT3 were significantly decreased, at both the translational and transcriptional levels, by SSd treatment. AG490 produced similar inhibitory effects on STAT3, p-STAT3, C/EBPβ, and COX-2. In conclusion, our data suggest that SSd controls liver cancer proliferation through suppression of the p-STAT3/C/EBPβ signaling pathway inhibiting COX2 expression. These findings further our understanding of the pharmacological action of SSd, providing new information on SSd mechanism of action and showing potential for SSd as a novel therapy for liver cancer.

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Background and Aims: Diagonal earlobe crease (ELC) has been considered a potential cutaneous marker of atherosclerosis. However, the potential mechanism by which ELC and atherosclerosis are linked has not been adequately defined. Roles of adropin and irisin, novel biomarkers of endothelial function, in ELC have not been well-studied. This study aimed to test whether individuals with ELC are deficient in adropin and irisin, a characteristic that would likely promote endothelial dysfunction and provide a plausible common pathological basis for atherosclerosis and ELC.Methods: Patients diagnosed with coronary artery disease (CAD) with (n = 45) and without (n = 45) ELC were consecutively enrolled in the study. The ages of the patients enrolled ranged from 40–70 years. Other patients (n = 45) without ELC or CAD were recruited as the control group. All patients underwent coronary angiography. Serum adropin and irisin concentrations were assessed via enzyme-linked immunosorbent assay.Results: Circulating levels of irisin in the ELC group were significantly lower than those in the non-ELC group, and were highest in the control group. Serum adropin levels of the ELC group were significantly lower than those of the non-ELC group (P < 0.001). Interestingly, although the serum adropin level of the control group was greater than that of the non-ELC group, the difference failed to achieve statistical significance. In subgroup analysis of CAD and ELC, both serum adropin and irisin levels of the CAD and ELC groups were lower than those of the control group (P < 0.001). Receiver-operating characteristic curve analysis revealed that adropin and irisin have similar prognostic power for CAD and ELC.Conclusions: Low adropin and irisin were significantly associated with CAD and ELC. The deficiencies in adropin and irisin may be a common cause of both atherosclerosis and ELC, which explains why patients with ELC are prone to CAD.