DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics.

BACKGROUND: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. METHODS: We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. RESULTS: We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. CONCLUSIONS: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

F3, a novel active fraction of Valeriana jatamansi Jones induces cell death via DNA damage in human breast cancer cells.

BACKGROUND: F3 is a novel fraction, for the first time isolated from Valeriana jatamansi Jones, which is a traditional Chinese folk medicine. Its anti-cancer potential and the underlying molecular mechanisms have not been well elucidated. PURPOSE: This study aims to investigate the anti-cancer effects of F3 on human breast cancer cell lines and its underlying mechanisms. METHODS: MTT assay was first performed to detect the effect of F3 on cell viability in human breast cancer cell lines and human mammary epithelial MCF-10A cells. Cell apoptosis, mitochondrial membrane potential and ROS level were detected by flow cytometry. Comet and immunofluorescence assays were utilized to assess DNA damage and expression of γ-H2AX. Autophagy were observed by AO staining and fluorescence microscopy. The expression of relative proteins was detected by western blotting. The xenograft model in nude mice was used to elucidate the effect of F3 on tumor growth and DNA damage in vivo. RESULTS: F3 could significantly inhibit the growth of breast cancer cells in concentration-dependent manner by inducing apoptosis and has no obvious inhibitory effect of the growth on MCF-10A cells. Mechanistic studies demonstrated that F3-induced apoptosis was mediated by DNA damage as presented by DNA strand breaks and γ-H2AX activation that might be attacked by ROS accumulation. This triggered several key molecular events involving activation of MAPKs pathway. Further study showed that F3 induced autophagy with the autophagosome formation and increased LC3-II levels. Finally, in vivo study, F3 exhibited a potential antitumor effect and induced DNA damage in MDA-MB-231 xenografts. CONCLUSION: The antitumorigenic activity of F3 was found in vitro and in vivo. These data suggest that F3 may be a potential natural active fraction for the treatment of human breast cancer.

Multi-level ecotoxicological effects of imidacloprid on earthworm (Eisenia fetida).

As a neurotoxic insecticide, imidacloprid (IMI) has been widely used for crop protection. However, continuous application of such pesticide in the environment may damage the non-target organisms in soil. In the present study, we aimed to investigate the effects of IMI on earthworms in terms of survival, avoidance behavior, reproduction, detoxification enzyme activity and gene expression using a systematic experimental approach. The results showed that the 14-day LC50 value of IMI was 2.26 (2.09-2.43) mg a.i. kg-1, and the 2-day AC50 value (concentration inducing an avoidance rate of 50%) of IMI was 1.34 (1.02-1.91) mg a.i. kg-1 to E. fetida. For reproduction, the 56-day EC50 value of IMI was 0.87 (0.66-1.33) mg a.i. kg-1 to E. fetida, and there was a positive correlation between the growth rate of earthworms and the number of juveniles in IMI treatments. Activities of carboxylesterase (CarE) and glutathione-S-transferases (GST) in earthworms were disturbed by IMI exposure. Moreover, effects of IMI on the CarE activity in earthworms were more severe and sensitive compared with the GST activity. The expressions of annetocin (ann) and calreticulin (crt) at the transcriptional level were decreased upon IMI exposure, reaching the lowest levels of 0.09 fold and 0.16 fold on day 7 and day 14, respectively. Transcriptionally controlled tumor protein (tctp), heat shock protein 70 (hsp70) and gst exhibited relatively obvious variations (up-regulation or down-regulation) when the exposure duration was extended. Taken together, these results comprehensively contributed to further understandings of the impacts of IMI on earthworms.

Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice.

BACKGROUND: Hydrogen selectively reduces levels of hydroxyl radicals and alleviates acute oxidative stress in many models. Hydrogen-rich saline provides a high concentration of hydrogen that can be easily and safely applied. AIMS: In this study, we investigated the effects of hydrogen-rich saline on the prevention of liver injury induced by obstructive jaundice in rats. METHODS: Male Sprague-Dawley rats (n=56) were divided randomly into four experimental groups: sham operated, bile duct ligation (BDL) plus saline treatment [5 ml/kg, intraperitoneal (i.p.)], BDL plus low-dose hydrogen-rich saline treatment (5 ml/kg, i.p.) and BDL plus high-dose hydrogen-rich saline treatment (10 ml/kg, i.p.). RESULTS: The liver damage was evaluated microscopically 10 days after BDL. Serum alanine aminotransferase and aspartate aminotransferase levels, tissue malondialdehyde content, myeloperoxidase activity, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and high-mobility group box 1 levels were all increased significantly by BDL. Hydrogen-rich saline reduced levels of these markers and relieved morphological liver injury. Additionally, hydrogen-rich saline markedly increased the activities of anti-oxidant enzymes superoxide dismutase and catalase and downregulated extracellular signal-regulated protein kinase (ERK)1/2 activation. CONCLUSIONS: Hydrogen-rich saline attenuates BDL-induced liver damage, possibly by the reduction of inflammation and oxidative stress and the inhibition of the ERK1/2 pathway.

Development of the trauma emergency care system based on the three links theory.

The three links theory applied in trauma emergency care system refers to an integrated system with the three important components of trauma emergency care system, viz. prehospital trauma services, hospital trauma services and critical care services. The development of the trauma emergency care system should be guided by the three links theory so as to set up a practical and highly efficient system: a prompt operating and monitoring transportation system, a smooth and real-time information system, a rational and sustainable system of regulations and contingency plans, and a system for cultivating all-round trauma physicians.