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The toxicity of doxorubicin (DOX) limits its clinical application. Nevertheless, at present, there is no effective drug to prevent DOX-induced cardiac injury. miR-204 is a newly discovered miRNA with many protective effects on cardiovascular diseases. However, little research has been done on the effects of miR-204 on DOX-induced cardiac injury. Our study is aimed at investigating the effect of miR-204 on DOX-induced myocardial injury. An adenoassociated virus system was used to achieve cardiac-specific overexpression of miR-204. Two weeks later, the mice were intraperitoneally injected with DOX (15 mg/kg) to induce cardiac injury. H9c2 myocardial cells were used to validate the role of miR-204 in vitro. Our study showed that miR-204 expression was decreased in DOX-treated hearts. miR-204 overexpression improved cardiac function and alleviated cardiac inflammation, apoptosis, and autophagy induced by DOX. In addition, our results showed that miR-204 prevented DOX-induced injury in cardiomyocytes by directly decreasing HMGB1 expression. Moreover, the overexpression of HMGB1 could offset the protective effects of miR-204 against DOX-induced cardiac injury. In summary, our study showed that miR-204 protected against DOX-induced cardiac injury via the inhibition of HMGB1, and increasing miR-204 expression may be a new treatment option for patients with DOX-induced cardiac injury., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Youyou Du et al.)

Fracture healing is regulated by proinflammatory mediators such as tumor necrosis factor-α (TNF-α), which poses influence on the balance between bone formation and remodeling. And the diabetes is thought to contribute to the delayed diabetic fracture healing. In the present study, we examined the promotion to proinflammatory cytokines and chemokines in type 2 diabetes mellitus (T2DM) patients with bone fractures, and then evaluated the promotion to TNF-α by the high glucose treatment in human osteoblast-like MG-63 cells and the regulatory role of the promoted TNF-α on the MG-63 cell apoptosis. It was demonstrated that there were significantly-upregulated high-sensitivity C-reactive protein (hsCRP) TNF-α, IL-1β, IL-6, IFN-γ-inducible protein 10 (IP-10) and RANTES in T2DM patients with bone fracture. And the promotion to TNF-α and IL-1β was confirmed in vitro in both mRNA and protein levels in high glucose-treated MG-63 cells. And either TNF-α or high glucose reduced the viability of MG-63 cells, promoted apoptosis and upregulated apoptosis-associated markers, such as released cytochrome c, cleaved caspase 3 and lyzed PARP. Moreover, there was a synergistic effect between TNF-α and high glucose. The viability reduction and the apoptosis induction of MG-63 cells were significantly higher in the group with both TNF-α and high glucose treatments, than in the group with singular TNF-α treatment. In conclusion, our study demonstrated that proinflammatory cytokines and chemokines were promoted in T2DM patients with bone fracture or in osteoblasts by the high glucose stimulation. TNF-α and high glucose synergistically reduced the viability and induced the apoptosis in the osteoblast-like MG-63 cells in vitro. It implies the significant regulatory role of TNF-α in the delayed fracture healing in T2DM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Recently studies indicated that valsartan could prevent the progression of heart failure caused by diabetic cardiomyopathy (DCM), while the mechanisms were still poorly understood. The present study was designed to investigate whether valsartan could reduce the endoplasmic reticulum (ER) stress and DCM-induced cardiac remodeling. Our data has shown that valsartan can ameliorate ER stress-induced cardiac remodeling and myocardial apoptosis in DCM rats. By using of immunofluorescence and RT-PCR, valsartan has been found to play a protective role via down-regulating the expression of transcriptional induction of C/EBP homologous protein (CHOP) and p53 upregulated modulator of apoptosis (Puma), two crucial factors known to be implicated in the ER stress-induced myocardial apoptosis. And the expression level of Puma was closely related to CHOP. Thus, our experiment strongly suggests that the administration of valsartan can ameliorate the ER stress through blocking the activation of CHOP/Puma signaling pathway, which provides a new insight into the potential molecular mechanism of cardiomyocyte apoptosis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Endoplasmic reticulum stress has been suggested to play a crucial role in the pathogenesis of diabetic complications. However, whether it is involved in the renal injury of diabetic nephropathy is still not known. We investigated the involvement of ER-associated apoptosis in kidney disease of streptozocin (STZ)-induced diabetic rats. We used albuminuria examination, hematoxylin & eosin (H&E) staining and TUNEL analysis to identify the existence of diabetic nephropathy and enhanced apoptosis. We performed immunohistochemistry, Western blot, and real-time PCR to analyze indicators of ER molecule chaperone and ER-associated apoptosis. GRP78, the ER chaperone, was up-regulated significantly in diabetic kidney compared to control. Furthermore, three hallmarks of ER-associated apoptosis, C/EBP homologous protein (CHOP), c-JUN NH2-terminal kinase (JNK) and caspase-12, were found to have activated in the diabetic kidney. Taken together, those results suggested that apoptosis induced by ER stress occurred in diabetic kidney, which may contribute to the development of diabetic nephropathy.

Apoptosis plays a critical role in the diabetic cardiomyopathy, and endoplasmic reticulum stress (ERS) is one of the intrinsic apoptosis pathways. Previous studies have shown that the endoplasmic reticulum becomes swollen and dilated in diabetic myocardium, and ERS is involved in heart failure and diabetic kidney. This study is aimed to demonstrate whether ERS is induced in myocardium of streptozotocin (STZ)-induced diabetic rats. We established a type 1 diabetic rat model, used echocardiographic evaluation, hematoxylin-eosin staining, and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of diabetic cardiomyopathy and enhanced apoptosis in the diabetic heart. We performed immunohistochemistry, western blot, and real-time PCR to analyze the hallmarks of ERS that include glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase12. We found these hallmarks to have enhanced expression in protein and mRNA levels in diabetic myocardium. Also, another pathway that can lead to cell death of ERS, c-Jun NH(2)-terminal kinase-dependent pathway, was also activated in diabetic heart. Those results suggested that ERS was induced in STZ-induced diabetic rats' myocardium, and ERS-associated apoptosis occurred in the pathophysiology of diabetic cardiomyopathy.

Geraniol, a natural compound found in the essential oils of various aromatic plants, has attracted attention for its probable anticancer effects. The molecular mechanisms of the cell proliferation suppression and apoptosis induction via geraniol in gastric cancer cells (AGS), however, remain unclear. Gastric cancer cells were treated with geraniol, and it was found that the IC50 values were 25 μM/ml, as determined by the 3‐(4,5‐dimethylthiazol‐2‐yl)−2,5‐diphenyltetrazolium bromide assay. Results showed that 20 and 25 μM geraniol‐induced reactive oxygen species (ROS) production (2ʹ‐7ʹdichlorofluorescin diacetate staining) and decreased mitochondrial membrane potential (rhodamine 123 staining) in AGS cells. Then, it effectively inhibited cell growth and induced apoptosis, confirmed through acridine orange/ethidium bromide, 4′,6‐diamidino‐2‐phenylindole, and propidium iodide staining and molecular marker analysis in AGS cells. Also, geraniol potently diminished caspase‐9, Bax, Bcl‐2, and caspase‐3 expression in AGS cells. We also evaluated the essential mechanism of the cytotoxic effect of geraniol. Moreover, the present study depicted that geraniol‐induced cell death through mitochondrial ROS production and inhibited the phosphorylation form of mitogen‐activated protein kinase (p38, MAPK, JNK, and ERK1/2) signaling pathway. Taken together, these results concluded that geraniol has a novel therapeutic property against human stomach cancer. [ABSTRACT FROM AUTHOR]

Hyperthermia is one of the most widely employed adjuvant treatments for cancer, especially for hyperthermic intraperitoneal chemotherapy, and has few side effects. Gastric cancer has various hyperthermia sensitivities, but the exact molecular mechanisms remain to be elucidated. In the present study, western blotting was performed to detect differential expression of proteins that have been reported to be upregulated in gastric cancer. Following knockdown of these proteins, apoptosis was measured by Annexin V-FITC/propidium iodide (PI) double staining and hyperthermia treatment was applied. To evaluate the effect of cyclin-dependent kinase 6 (CDK6) on hyperthermia-induced apoptosis, CDK6 was knocked down or inhibited by the addition of a specific inhibitor and subsequent PI staining and cell proliferation, migration and invasion assays were performed. Hyperthermia-induced protein kinase B (AKT) expression and phosphorylation inhibition were detected. As demonstrated in the present study, the hyperthermia-induced proteins kinesin family member 11 (KIF11), cyclin-dependent kinase 6 (CDK6), stromal antigen 2, NIMA-related kinase 2 and karyopherin subunit α 4 were highly expressed in gastric cancer cells, including SH-10-TC and HGC-27 cells. Knockdown of KIF11 significantly increased apoptosis without hyperthermia treatment and CDK6 significantly increased hyperthermia-induced apoptosis, prompting the present study to focus on CDK6. It was further confirmed that CDK6 activity was critical for decreasing hyperthermia-induced apoptosis and for cell proliferation. Hyperthermia-induced AKT expression and phosphorylation inhibition is potentially the main cause of CDK6 transcriptional upregulation. Taken together, these findings demonstrated that CDK6 is upregulated via hyperthermia-induced AKT inhibition and subsequently protected gastric cancer cells from hyperthermia-induced apoptosis, indicating that it is a potential therapeutic target to sensitize gastric cancer cells to hyperthermia-based therapy. [ABSTRACT FROM AUTHOR]

• Linc00936/miR-425-3p/ZC3H12A axis mediated immune escape of GC cells. • Overexpressed miR-425-3p, declined linc00936 and ZC3H12A existed in GC. • Up-regulated linc00936 or inhibited miR-425-3p restrained the immune escape of GC. • Linc00936 could competitively bind with miR-425-3p. • ZC3H12A was a direct target of miR-425-3p. Gastric cancer (GC) is a malignant tumor originated from gastric mucosa. Without effective therapy, this study was to investigate the mechanism of long intergenic noncoding RNA 00936 (linc00936)/microRNA-425-3p (miR-425-3p)/monocyte chemotactic protein-induced protein 1 (ZC3H12A) axis mediating immune escape of GC cells. Peripheral blood samples, GC tissues and adjacent tissues were collected. The levels of CD3+, CD4+, and CD8+ in peripheral blood were detected. The expression levels of linc00936, miR-425-3p and ZC3H12A in GC tissues and cells were detected. The correlation between the expression of linc00936 in the tissues and the levels of CD3+, CD4+ and CD8+ in the peripheral blood of GC patients was analyzed. Cytokine-induced killer (CIK) cells were induced, and co-incubated with GC cells. BGC-823 and MKN-45 cells were screened and transfected with linc00936- or miR-425-3p-related oligonucleotides to figure out their roles in immune escape, migration, apoptosis and the cytotoxicity of CIK cells in GC cells. Elevated miR-425-3p and reduced linc00936, and ZC3H12A expression levels were found in GC tissues and cells. Linc00936 expression was positively correlated with CD3+ and CD4+, and negatively correlated with CD8+ in peripheral blood of patients with GC. Up-regulating linc00936 or down-regulating miR-425-3p inhibited immune escape, migration, promoted apoptosis of GC cells, as well induced CIK cell cytotoxicity to GC cells. Down-regulated linc00936 or elevated miR-425-3p facilitated immune escape, migration, depressed apoptosis of GC cells, and reduced the cytotoxicity of CIK cells to GC cells. The study concludes that up-regulated linc00936 or silenced miR-425-3p inhibits immune escape of GC cells via elevation of ZC3H12A. [ABSTRACT FROM AUTHOR]