BackgroundZuotai, a famous Tibetan medicinal mixture containing metacinnabar, is traditionally used for the purpose of tranquilizing minds and soothing nerves. However, it still lacks substantial experimental data for it to be approved for use.AimThis study was designed to assess the effects of Zuotai on depressive-like symptoms in a chronic unpredictable mild stress (CUMS) mouse model, and to explore its potential mechanism, particularly the hypothalamic–pituitary–adrenal (HPA) axis pathway.Materials and methodsFirst, Kunming mice were exposed to the CUMS procedure and simultaneously administered Zuotai or imipramine (positive control) by gavage continuously for 6 weeks. Then, depressive-like behaviors of mice in each group were tested with the sucrose preference test, forced swimming test, tail suspension test, and open field test. Meanwhile, the three key neuroendocrine hormones (corticotropin releasing hormone, adrenocorticotropic hormone and corticosterone) in HPA axis pathway, and the level of the emotion-related monoamine neurotransmitters (5-hydroxytryptamine and norepinephrine) were measured using enzyme-linked immunosorbent assay. Furthermore, total mercury in the hypothalamus and hippocampus were determined using an automatic, direct mercury analyzer.ResultsZuotai or imipramine significantly increased the body weight and the sucrose preference ratio in sucrose preference test, and dramatically improved motor activity in forced swimming test, tail suspension test, and open field test in CUMS mice. Zuotai or imipramine remarkably decreased levels of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone in the HPA axis, and increased levels of 5-hydroxytryptamine and norepinephrine in the serum in CUMS mice. However, a small amount of mercury was deposited in the hypothalamus and hippocampus in Zuotai-treated mice, which may pose a potential risk to the central nervous system.ConclusionZuotai has a strong ability to ameliorate depressive-like behaviors in CUMS-treated mice through inhibition of the HPA axis and upregulation of monoamine neurotransmitters. These findings provide new insight into the pharmacological effect of Zuotai on depression.

The increased drug resistance and metastasis of melanoma resulted in poor prognosis of patients. Here, we designed and synthesized a novel hemicyanine-based fluorescent probe ZWZ-3, and investigated its application for melanoma imaging and treatment both in vitro and in vivo. ZWZ-3 preferentially accumulated in melanoma cells via a process that depended on the organic anion-transporting polypeptide (OATP), which targeted mitochondria on the hemicyanine cationic nitrogen. In addition, we investigated the effect and molecular mechanism of ZWZ-3 in melanoma. In vitro studies showed that ZWZ-3 promoted the generation of reactive oxygen species and induced mitochondrial-mediated cell apoptosis by upregulating Bax and activating caspase-3, caspase-9, and PARP. Importantly, ZWZ-3 also induced autophagy by upregulating LC-3II and Atg5 and downregulating P62. It significantly suppressed tumor growth of A375 xenograft tumor in mice without notable side effects. Histological and immunohistochemical analyses revealed that ZWZ-3 induced apoptosis and inhibited tumor cell proliferation. Thus, ZWZ-3 represents a novel theranostic agent that can be used to effectively targeting, detecting, and treating melanoma. It could also help monitoring disease progression and response to treatment.

Malignant melanoma is the most fatal form of skin cancer worldwide, and earlier diagnosis and more effective therapies are required to improve prognosis. As a possible solution, near-infrared fluorescent heptamethine cyanine dyes have been shown to be useful for tumor diagnosis and treatment. Here, we synthesized a novel theranostic agent, IR-817, a multifunctional bioactive small-molecule that has near-infrared emission, targets mitochondria in cancer cells, and has selective anti-cancer effects. In in vitro experiments, IR-817 preferentially accumulated in melanoma cells through organic anion transporting polypeptide transporters but also selectively inhibited the growth of tumor cells by inducing mitochondrial-dependent intrinsic apoptosis. Mechanistically, IR-817 caused G0/G1 cell cycle arrest by targeting the E2F/Cyclin/CDK pathway. Finally, IR-817 significantly suppressed the growth of xenograft tumors in zebrafish and mice. Immunohistochemical staining and hematoxylin and eosin staining revealed that IR-817 induced apoptosis and inhibited tumor cell proliferation without notable side effects. Therefore, mitochondrial-targeting theranostic agent IR-817 may be promising for accurate tumor diagnosis, real-time monitoring, and safe anti-cancer treatments.

Melanoma is the most aggressive skin cancer with high mortality. It is vital to develop novel low toxicity drugs with anti-proliferation activity and metastasis suppressive activity in melanoma. Here, we reported a novel anti-tumor drug SCZ0148, and then investigated its inhibition effect on melanoma. The anticancer efficacy of SCZ0148 was confirmed by using cytotoxicity test, colony formation assay, wound-healing assay, cell apoptosis detection, mitochondrial potential assay, reactive oxygen species (ROS) production and western-blot analysis. The cytotoxicity test showed that SCZ0148 inhibited melanoma cell lines proliferation in a dose- and time-dependent manner without obvious toxicity and side effects on normal cells. The results of the colony formation assay were in agreement with the cytotoxicity test. In addition, SCZ0148 induced melanoma cell apoptosis and promoted cell destructive autophagy through the ROS-mediated mitochondrial apoptosis pathway. Notably, SCZ0148 significantly inhibited the migration of melanoma cells through the matrix metalloprotein 9 (MMP-9) mediated pathway. In conclusion, these findings suggest that SCZ0148 may be a potential therapeutic drug to inhibit the proliferation and metastasis of melanoma.

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