Long non‐coding RNA highly up‐regulated in liver cancer promotes epithelial‐to‐mesenchymal transition process in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is an oral and maxillofacial malignancy that exhibits high incidence worldwide. In diverse human cancers, the long non‐coding RNA (lncRNA) highly up‐regulated in liver cancer (HULC) is aberrantly expressed, but how HULC affects OSCC development and progression has remained mostly unknown. We report that HULC was abnormally up‐regulated in oral cancer tissues and OSCC cell lines, and that suppression of HULC expression in OSCC cells not only inhibited the proliferation, drug tolerance, migration and invasion of the cancer cells, but also increased their apoptosis rate. Notably, in a mouse xenograft model, HULC depletion reduced tumorigenicity and inhibited the epithelial‐to‐mesenchymal transition process. Collectively, our findings reveal a crucial role of the lncRNA HULC in regulating oral cancer carcinogenesis and tumour progression, and thus suggest that HULC could serve as a novel therapeutic target for OSCC.     

Sodium (±)‐5‐bromo‐2‐(α‐hydroxypentyl) benzoate ameliorates pressure overload‐induced cardiac hypertrophy and dysfunction through inhibiting autophagy

Sodium (±)‐5‐bromo‐2‐(a‐hydroxypentyl) benzoate (generic name: brozopine, BZP) has been reported to protect against stroke‐induced brain injury and was approved for Phase II clinical trials for treatment of stroke‐related brain damage by the China Food and Drug Administration (CFDA). However, the role of BZP in cardiac diseases, especially in pressure overload‐induced cardiac hypertrophy and heart failure, remains to be investigated. In the present study, angiotensin II stimulation and transverse aortic constriction were employed to induce cardiomyocyte hypertrophy in vitro and in vivo, respectively, prior to the assessment of myocardial cell autophagy. We observed that BZP administration ameliorated cardiomyocyte hypertrophy and excessive autophagic activity. Further results indicated that AMP‐activated protein kinase (AMPK)‐mediated activation of the mammalian target of rapamycin (mTOR) pathway likely played a role in regulation of autophagy by BZP after Ang II stimulation. The activation of AMPK with metformin reversed the BZP‐induced suppression of autophagy. Finally, for the first time, we demonstrated that BZP could protect the heart from pressure overload‐induced hypertrophy and dysfunction, and this effect is associated with its inhibition of maladaptive cardiomyocyte autophagy through the AMPK‐mTOR signalling pathway. These findings indicated that BZP may serve as a promising compound for treatment of pressure overload‐induced cardiac remodelling and heart failure.     

Deletion of pancreatic β‐cell adenosine kinase improves glucose homeostasis in young mice and ameliorates streptozotocin‐induced hyperglycaemia

Severe reduction in the β‐cell number (collectively known as the β‐cell mass) contributes to the development of both type 1 and type 2 diabetes. Recent pharmacological studies have suggested that increased pancreatic β‐cell proliferation could be due to specific inhibition of adenosine kinase (ADK). However, genetic evidence for the function of pancreatic β‐cell ADK under physiological conditions or in a pathological context is still lacking. In this study, we crossed mice carrying LoxP‐flanked Adk gene with Ins2‐Cre mice to acquire pancreatic β ‐cell ADK deficiency (Ins2‐Cre^±Adk^fl/fl) mice. Our results revealed that Ins2‐Cre^+/‐Adk^fl/fl mice showed improved glucose metabolism and β‐cell mass in younger mice, but showed normal activity in adult mice. Moreover, Ins2‐Cre^±Adk^fl/fl mice were more resistant to streptozotocin (STZ) induced hyperglycaemia and pancreatic β‐cell damage in adult mice. In conclusion, we found that ADK negatively regulates β‐cell replication in young mice as well as under pathological conditions, such as STZ induced pancreatic β‐cell damage. Our study provided genetic evidence that specific inhibition of pancreatic β‐cell ADK has potential for anti‐diabetic therapy.     

Association of interleukin‐27 gene polymorphisms with susceptibility to HIV infection and disease progression

Interleukin‐27 (IL‐27) gene polymorphisms are linked to infectious disease susceptibility and IL‐27 plasma level is associated with HIV infection. Therefore, we aimed to investigate the association between IL‐27 polymorphisms and susceptibility to HIV infection and disease progression. A total of 300 patients with HIV infection (48 long‐term nonprogressors and 252 typical progressors) and 300 healthy controls were genotyped for three IL‐27 polymorphisms, rs17855750, rs181206, rs40837 which were performed by using multiple single nucleotide primer extension technique. Significant association was found between IL‐27 rs40837 polymorphisms with susceptibility to HIV infection (AG vs AA: adjusted OR = 1.60, 95% CI, 1.11‐2.30, P = 0.012; AG+GG vs AA: adjusted OR = 1.44, 95% CI, 1.02‐2.03, P = 0.038) and disease progression (LTNP: AG vs AA: adjusted OR = 2.33, 95% CI, 1.13‐4.80, P = 0.021; TP: AG vs AA: adjusted OR = 1.50, 95% CI, 1.04‐2.24, P = 0.030). Serum IL‐27 levels were significantly lower in cases compared to controls (P < 0.001). There were lower serum IL‐27 levels in TPs than in LTNPs (P < 0.001). We further found that LTNPs with rs40837 AG or GG genotype had lower serum IL‐27 levels than with AA genotype (P < 0.05). The CD4⁺T counts in cases were significantly lower than controls (P < 0.001). In contrast, individuals with rs40837 AG genotype had lower CD4⁺T counts than with AA genotype in cases (P < 0.05). In addition, CD4⁺T counts in TPs were significantly lower than LTNPs (P < 0.001). IL‐27 rs40837 polymorphism might influence the susceptibility to HIV infection and disease progression probably by regulating the level of serum IL‐27 or the quantity of CD4⁺T.     

Berberine attenuates XRCC1‐mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs

Berberine (BBR) is a natural isoquinoline alkaloid, which is used in traditional medicine for its anti‐microbial, anti‐protozoal, anti‐diarrhoeal activities. Berberine interacts with DNA and displays anti‐cancer activities, yet its effects on cellular DNA repair and on synthetic treatments with chemotherapeutic drugs remain unclear. In this study, we investigated the effects of BBR on DNA repair and on sensitization of breast cancer cells to different types of DNA damage anti‐tumoural drugs. We found BBR arrested cells in the cell cycle S phase and induced DNA breaks. Cell growth analysis showed BBR sensitized MDA‐MB‐231 cells to cisplatin, camptothecin and methyl methanesulfonate; however, BBR had no synergistic effects with hydroxurea and olaparib. These results suggest BBR only affects specific DNA repair pathways. Western blot showed BBR down‐regulated XRCC1 expressions, and the rescued XRCC1 recovered the resistance of cancer cells to BBR. Therefore, we conclude that BBR interferes with XRCC1‐mediated base excision repair to sensitize cancer cells to chemotherapeutic drugs. These finding can contribute to understanding the effects of BBR on cellular DNA repair and the clinical employment of BBR in treatment of breast cancer.     

MiR‐103 inhibiting cardiac hypertrophy through inactivation of myocardial cell autophagy via targeting TRPV3 channel in rat hearts

Cardiac hypertrophy is a common pathological change frequently accompanied by chronic hypertension and myocardial infarction. Nevertheless, the pathophysiological mechanisms of cardiac hypertrophy have never been elucidated. Recent studies indicated that miR‐103 expression was significantly decreased in heart failure patients. However, less is known about the role of miR‐103 in cardiac hypertrophy. The present study was designed to investigate the relationship between miR‐103 and the mechanism of pressure overload‐induced cardiac hypertrophy. TRPV3 protein, cardiac hypertrophy marker proteins (BNP and β‐MHC) and autophagy associated proteins (Beclin‐1 and LC3‐II) were up‐regulated, as well as, miR‐103 expression and autophagy associated proteins (p62) were down‐regulated in cardiac hypertrophy models in vivo and in vitro respectively. Further results indicated that silencing TRPV3 or forcing overexpression of miR‐103 could dramatically inhibit cell surface area, relative fluorescence intensity of Ca²⁺ signal and the expressions of BNP, β‐MHC, Beclin‐1 and LC3‐II, but promote p62 expression. Moreover, TRPV3 protein was decreased in neonatal rat ventricular myocyte transfected with miR‐103, but increased by AMO‐103. Co‐transfection of the miR‐103 with the luciferase reporter vector into HEK293 cells caused a sharp decrease in luciferase activity compared with transfection of the luciferase vector alone. The miR‐103‐induced depression of luciferase activity was rescued by an AMO‐103. These findings suggested that TRPV3 was a direct target of miR‐103. In conclusion, miR‐103 could attenuate cardiomyocyte hypertrophy partly by reducing cardiac autophagy activity through the targeted inhibition of TRPV3 signalling in the pressure‐overloaded rat hearts.     

BAG3‐positive pancreatic stellate cells promote migration and invasion of pancreatic ductal adenocarcinoma

BAG3 is constitutively expressed in multiple types of cancer cells and its high expression is associated with tumour progression and poor prognosis of PDAC . However, little is known about the role of BAG3 in the regulation of stromal microenvironment of PDAC. The current study demonstrated that beside PDAC tumour cells, BAG3 was also expressed in some activated stroma cells in PDAC tissue, as well as in activated PSCs. In addition, the current study demonstrated that BAG3 expression in PSCs was involved in maintenance of PSCs activation and promotion of PDACs invasion via releasing multiple cytokines. The current study demonstrated that BAG3‐positive PSCs promoted invasion of PDACs via IL‐8, MCP1, TGF‐β2 and IGFBP2 in a paracrine manner. Furthermore, BAG3 sustained PSCs activation through IL‐6, TGF‐β2 and IGFBP2 in an autocrine manner. Thereby, the current study provides a new insight into the involvement of BAG3 in remodelling of stromal microenvironment favourable for malignant progression of PDAC, indicating that BAG3 might serve as a potential target for anti‐fibrosis of PDAC.     

A functional variant in SLC1A3 influences ADHD risk by disrupting a hsa‐miR‐3171 binding site: A two‐stage association study

Attention‐deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and adolescents with high heritability. Evidence is accumulating that SLC1A3 may play a role in ADHD etiology. Therefore, a two‐stage case‐control study was conducted on 752 cases and 774 controls to explore the role of SLC1A3 in ADHD. Bioinformatic annotations and functional experiments were applied to reveal the potential biological mechanisms. Finally, SLC1A3 rs1049522 showed significant association with ADHD risk in two stages with CA genotype vs AA genotype, odds ratio (OR) = 0.694 (95% confidence interval, CI = 0.570‐0.844) and dominant model, OR = 0.749 (95% CI = 0.621‐0.904) in the combined stage. Besides, rs1049522 was found to be related to ADHD hyperactive/impulsive symptom, and rs1049522‐C showed increased SLC1A3 mRNA expression in the cerebellar cortex. Dual‐luciferase reporter assay further indicated that rs1049522‐C allele enhanced SLC1A3 expression by disrupting the hsa‐miR‐3171 binding site. In conclusion, SLC1A3 variant rs1049522 was implicated in ADHD susceptibility in a Chinese Han population probably by enhancing the SLC1A3 expression in a miRNA‐mediated manner.     

Pristimerin Induces Autophagy‐Mediated Cell Death in K562 Cells through the ROS/JNK Signaling Pathway

Chronic myeloid leukemia (CML) is a lethal malignancy, and the progress toward long‐term survival has stagnated in recent decades. Pristimerin, a quinone methide triterpenoid isolated from the Celastraceae and Hippocrateaceae families, is well‐known to exert potential anticancer activities. In this study, we investigated the effects and the mechanisms of action on CML. We found that pristimerin inhibited cell proliferation of K562 CML cells by causing G1 phase arrest. Furthermore, we demonstrated that pristimerin triggered autophagy and apoptosis. Intriguingly, pristimerin‐induced cell death was restored by an autophagy inhibitor, suggesting that autophagy is cross‐linked with pristimerin‐induced apoptosis. Further studies revealed that pristimerin could produce excessive reactive oxygen species (ROS), which then induce JNK activation. These findings provide clear evidence that pristimerin might be clinical benefit to patients with CML.