Compound 13, an α1-selective small molecule activator of AMPK, potently inhibits melanoma cell proliferation.

It is vital to develop new therapeutic agents for the treatment of melanoma. In the current study, we studied the potential effect of Compound 13 (C13), a novel α1-selective AMP-activated protein kinase (AMPK) activator, in melanoma cells. We showed that C13 exerted mainly cytostatic, but not cytotoxic activities in melanoma cells. C13 potently inhibited proliferation in melanoma cell lines (A375, OCM-1 and B16), but not in B10BR melanocytes. Meanwhile, the AMPK activator inhibited melanoma cell cycle progression by inducing G1-S arrest. Significantly, we failed to detect significant melanoma cell death or apoptosis after the C13 treatment. For the mechanism study, we showed that C13 activated AMPK and inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling in melanoma cells through interaction with the α1 subunit. Short hairpin RNA (shRNA)-mediated knockdown of AMPKα1 not only blocked C13-mediated AMPK activation but also abolished its antiproliferative activity against melanoma cells. Together, these results show that C13 inhibits melanoma cell proliferation through activating AMPK signaling. Our data suggest that C13 along with other small molecular AMPK activators may be beneficial for patients with melanoma.

Lgr5 expression is a valuable prognostic factor for colorectal cancer: evidence from a meta-analysis.

BACKGROUND: Lgr5 has recently been identified as a reliable biomarker of cancer stem cells (CSCs) in colorectal cancer (CRC); however, its prognostic value is still controversial. METHODS: We searched PubMed, Web of Science, and Wanfang databases with identical strategies to retrieve articles. We evaluated the impact of Lgr5 expression on survival of CRC patients through meta-analysis. RESULTS: A total of 12 studies comprising 2600 patients revealed that Lgr5 overexpression was negatively associated with overall survival (OS) (HR = 1.73, 95% CI: 1.28-2.33; P = 0.00) and disease free survival (DFS) (HR = 2.89, 95% CI: 1.89-4.44; P = 0.000) in CRC patients. Subgroup analysis suggested that Lgr5 overexpression was significantly associated with worse OS in subgroups with IHC as the method of Lgr5 assessment (HR = 2.01, 95% CI: 1.39-2.89; P = 0.001), patients from Asia (HR = 1.81, 95% CI: 1.27-2.58; P = 0.000), and NOS scores greater than 6 (HR = 2.12, 95% CI: 1.41-3.19; P = 0.000). Furthermore, sensitivity analysis showed that the estimated HR ranged from 1.6 to 1.86 upon excluding one study sequentially from each analysis. In addition, Lgr5 overexpression was significantly associated with deep invasion of CRC (OR = 0.39, 95% CI: 0.17-0.87; P = 0.002), lymphnode metastasis (OR = 0.45, 95% CI: 0.26-0.76; P = 0.003), distant metastasis (OR = 0.37, 95% CI: 0.22-0.62; P = 0.000), and AJCC stage (OR = 0.35, 95% CI: 0.15-0.78; P = 0.01). However, Lgr5 overexpression was not correlated with tumor grade (OR = 0.75 95% CI: 0.37-1.54; P = 0.433). CONCLUSIONS: This study shows that Lgr5 can be a valuable and reliable prognostic factor of colorectal cancer progression.

Lgr5 expression is a valuable prognostic factor for colorectal cancer: evidence from a meta-analysis.

BACKGROUND: Lgr5 has recently been identified as a reliable biomarker of cancer stem cells (CSCs) in colorectal cancer (CRC); however, its prognostic value is still controversial. METHODS: We searched PubMed, Web of Science, and Wanfang databases with identical strategies to retrieve articles. We evaluated the impact of Lgr5 expression on survival of CRC patients through meta-analysis. RESULTS: A total of 12 studies comprising 2600 patients revealed that Lgr5 overexpression was negatively associated with overall survival (OS) (HR=1.73, 95% CI: 1.28-2.33; P=0.00) and disease free survival (DFS) (HR=2.89, 95% CI: 1.89-4.44; P=0.000) in CRC patients. Subgroup analysis suggested that Lgr5 overexpression was significantly associated with worse OS in subgroups with IHC as the method of Lgr5 assessment (HR=2.01, 95% CI: 1.39-2.89; P=0.001), patients from Asia (HR=1.81, 95% CI: 1.27-2.58; P=0.000), and NOS scores greater than 6 (HR=2.12, 95% CI: 1.41-3.19; P=0.000). Furthermore, sensitivity analysis showed that the estimated HR ranged from 1.6 to 1.86 upon excluding one study sequentially from each analysis. In addition, Lgr5 overexpression was significantly associated with deep invasion of CRC (OR=0.39, 95% CI: 0.17-0.87; P=0.002), lymphnode metastasis (OR=0.45, 95% CI: 0.26-0.76; P=0.003), distant metastasis (OR=0.37, 95% CI: 0.22-0.62; P=0.000), and AJCC stage (OR=0.35, 95% CI: 0.15-0.78; P=0.01). However, Lgr5 overexpression was not correlated with tumor grade (OR=0.75 95% CI: 0.37-1.54; P=0.433). CONCLUSIONS: This study shows that Lgr5 can be a valuable and reliable prognostic factor of colorectal cancer progression.

Use of a tourniquet in total knee arthroplasty: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: A tourniquet is commonly used in total knee arthroplasty (TKA). However, the effectiveness and safety of tourniquets are debated. We performed this study to investigate whether patients benefit from the use of tourniquets in TKA. METHODS: The literature search was conducted using PubMed, Cochrane Library, MEDLINE, Embase, and other medical databases. After a literature search, 26 randomized controlled trials involving 1,450 knees were analyzed. RESULTS: Tourniquet use significantly decreased intraoperative blood loss, transfusion rate, and operation time but not postoperative blood loss, measurable total blood loss, calculated total blood loss, transfusion volume, incidence of pulmonary embolism, or duration of hospital stay. It also slowed down joint functional recovery in the short term and increased the incidence of deep vein thrombosis and other minor wound complications. CONCLUSIONS: Data from this meta-analysis indicate that patients may benefit from the use of a tourniquet in TKA; however, it use is accompanied by disadvantages and complications. Because of the very low-evidence quality and lower grading of recommendations, assessment, development, and evaluation recommendation strength, no guidelines can be developed based on current evidence.

17ß-estradiol protects human eyelid-derived adipose stem cells against cytotoxicity and increases transplanted cell survival in spinal cord injury.

Stem cell transplantation represents a promising strategy for the repair of spinal cord injury (SCI). However, the low survival rate of the grafted cells is a major obstacle hindering clinical success because of ongoing secondary injury processes, which includes excitotoxicity, inflammation and oxidative stress. Previous studies have shown that 17b-estradiol (E2) protects several cell types against cytotoxicity. Thus, we examined the effects of E2 on the viability of human eyelid adipose-derived stem cells (hEASCs) in vitro with hydrogen peroxide (H2O2)-induced cell model and in vivo within a rat SCI model. Our results showed that E2 protected hEASCs against H2O2-induced cell death in vitro, and enhanced the survival of grafted hEASCs in vivo by reducing apoptosis. Additionally, E2 also enhanced the secretion of growth factors by hEASCs, thereby making the local microenvironment more conducive for tissue regeneration. Overall, E2 administration enhanced the therapeutic efficacy of hEASCs transplantation and facilitated motor function recovery after SCI. Hence, E2 administration may be an intervention of choice for enhancing survival of transplanted hEASCs after SCI.

Liposomal C6 Ceramide Activates Protein Phosphatase 1 to Inhibit Melanoma Cells.

Melanoma is one common skin cancer. In the present study, the potential anti-melanoma activity by a liposomal C6 ceramide was tested in vitro. We showed that the liposomal C6 (ceramide) was cytotoxic and anti-proliferative against a panel of human melanoma cell lines (SK-Mel2, WM-266.4 and A-375 and WM-115). In addition, liposomal C6 induced caspase-dependent apoptotic death in the melanoma cells. Reversely, its cytotoxicity was attenuated by several caspase inhibitors. Intriguingly, liposomal C6 was non-cytotoxic to B10BR mouse melanocytes and primary human melanocytes. Molecularly, liposomal C6 activated protein phosphatase 1 (PP1) to inactivate Akt-mammalian target of rapamycin (mTOR) signaling in melanoma cells. On the other hand, PP1 shRNA knockdown or exogenous expression of constitutively activate Akt1 (CA-Akt1) restored Akt-mTOR activation and significantly attenuated liposomal C6-mediated cytotoxicity and apoptosis in melanoma cells. Our results suggest that liposomal C6 activates PP1 to inhibit melanoma cells.

VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth In Vitro and In Vivo.

Melanomas cause over 76% of skin cancer deaths annually. Phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway is important for melanoma initiation and progression. In the current study, we evaluated the potential anti-melanoma effect of VS-5584, a novel and highly potent PI3K-mTOR dual inhibitor. We demonstrated that VS-5584 potently inhibited survival and proliferation of established (A375, A-2058 and SK-MEL-3 lines) and primary human melanoma cells, but was non-cytotoxic to non-cancerous human skin keratinocytes and B10BR murine melanocytes. At the meantime, VS-5584 induced caspase-dependent apoptotic death in melanoma cells, and its cytotoxicity was alleviated by the caspase inhibitors. At the molecular level, VS-5584 blocked AKT-mTOR activation and downregulated cyclin D1 expression in melanoma cells, while the expressions of Bcl-xL and Bcl-2 were not affected by VS-5584 treatment. On the other hand, a BH-3 mimetic Bcl-xL/Bcl-2 inhibitor ABT-737, as well as siRNA-mediated knockdown of Bcl-xL or Bcl-2, enhanced the activity of VS-5584 in melanoma cells. In vivo, oral administration of VS-5584 suppressed A375 melanoma xenograft growth in nude mice, and its activity was further enhanced by co-administration of ABT-737. These results provide the rationale for the clinical assessment of VS-5584 in melanoma patients and development of ABT-737 and other Bcl-xL/Bcl-2 inhibitors as the possible adjuvants.

Aging and age-related diseases--from endocrine therapy to target therapy.

Aging represents an important health issue not only for the individual, but also for society in general. Burdens associated with aging are expanding as longevity increases. This has led to an enhanced focus on issues related to aging and age-related diseases. Until recently, anti-aging endocrine-therapy has been largely limited to hormone-replacement therapy (HRT) that is associated with multiple side effects, including an increased risk of cancer. This has greatly limited the application of HRT in anti-aging therapy. Recently, the focus of anti-aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks. In this regard, the GHRH-GH-IGF-1/Insulin, TOR-S6K1,NAD(+)-Sirtuin, P53, Klotho and APOE pathways have been linked to processes associated with age-related diseases, including cancer, cardiovascular disease, diabetes, osteoporosis, and neurodegenerative diseases, all of which directly influence health in aging, and represent key targets in anti-aging therapy.

The alteration of 5-HT(2A) and 5-HT(2C) receptors is involved in neuronal apoptosis of goldfish cerebellum following traumatic experience.

5-HT receptor changes remain controversial in posttraumatic stress disorder (PTSD) models. This study looks at the relationship between traumatic injuries and the alterations in 5-HT(2A) and 5-HT(2C) receptors in the goldfish brain. The effect of treatment with doxepin and fluoxetine, known to be selective serotonin reuptake inhibitor (SSRI) antidepressants, on 5-HT receptor expression in goldfish with fin ablation was also investigated. We demonstrated that fin ablation induced anxiety-like behavioural alterations and significant up-regulation of c-fos expression in goldfish cerebellum. The behavioural alterations correlated well with an increased expression of 5-HT(2A) receptors in the cerebellum of the fish with traumatic injury. An increase in the number of apoptotic cells and a higher caspase-8 protein level was present in the brains of goldfish with fin ablation compared to the control. Our findings suggest that neuronal apoptosis occured in the cerebellum as a result of fin ablation and may be related to the alterations of 5-HT(2A) and 5-HT(2C) levels and that the beneficial clinical effects of doxepin/fluoxetine treatment are due to the down-regulation of 5-HT(2A) and up-regulation of 5-HT(2C) receptors in the brain.