Molecular medicine reports最新文献

Acute ischemic stroke (AIS) is a common acute cerebrovascular disease. Circular RNAs (circRNAs) have been demonstrated to have critical functions in a wide range of physiological processes and disorders in humans. However, their precise function in ischemic stroke (IS) remains largely unknown. The present study explored the function and potential mechanisms of circ_0000018 in AIS in vivo and in vitro. The cerebral ischemia/reperfusion injury model was established in vivo and in vitro using the oxygen‑glucose deprivation (OGD/R) and transient middle cerebral artery occlusion (tMCAO) methods. Subsequently, the impact of circ_0000018 on cerebral ischemia/reperfusion injury was assessed using various techniques, including TTC staining, quantitative PCR, western blotting, cell counting kit‑8 assay, Annexin V‑FITC Apoptosis Detection Kit, luciferase reporter gene assays, and others. The levels of circ_0000018 were markedly increased in the OGD/R‑treated neuronal cells and in a mouse model of tMCAO. The blocking of microRNA (miR)‑871 by circ_0000018 promoted Bcl‑2‑like protein 11 (BCL2L11) expression to increase neuronal cell damage. Furthermore, circ_0000018 knockdown significantly improved neuronal cell viability and attenuated OGD/R‑treated neuronal cell death. Meanwhile, circ_0000018 knockdown improved brain infarct volume and neuronal apoptosis in tMCAO mice. The present study found that circ_0000018 knockdown relieved cerebral ischemia‑reperfusion injury progression in vitro and in vivo. Mechanistically, circ_0000018 regulated the levels of BCL2L11 by sponging miR‑871.

Vascular endothelial growth factor B (VEGFB) plays a crucial role in glucolipid metabolism and is highly associated with type 2 diabetes mellitus (T2DM). The role of VEGFB in the insulin secretion of β cells remains unverified. Thus, the present study aimed to discuss the effect of VEGFB on regulating insulin secretion in T2DM development, and its underlying mechanism. A high‑fat diet and streptozocin (STZ) were used for inducing T2DM in mice model, and VEGFB gene in islet cells of T2DM mice was knocked out by CRISPR Cas9 and overexpressed by adeno‑Associated Virus (AAV) injection. The effect of VEGFB and its underlying mechanism was assessed by light microscopy, electron microscopy and fluorescence confocal microscopy, enzyme‑linked immunosorbent assay, mass spectrometer and western blot analysis. The decrement of insulin secretion in islet β cell of T2DM mice were aggravated and blood glucose remained at a high level after VEGFB knockout (KO). However, glucose tolerance and insulin sensitivity of T2DM mice were improved after the AAV‑VEGFB¹⁸⁶ injection. VEGFB KO or overexpression can inhibit or activate PLCγ/IP3R in a VEGFR1‑dependent manner. Then, the change of PLCγ/IP3R caused by VEGFB/VEGFR1 will alter the expression of key factors on the Ca2⁺/CaMK2 signaling pathway such as PPP3CA. Moreover, VEGFB can cause altered insulin secretion by changing the calcium concentration in β cells of T2DM mice. These findings indicated that VEGFB activated the Ca2⁺/CaMK2 pathway via VEGFR1‑PLCγ and IP3R pathway to regulate insulin secretion, which provides new insight into the regulatory mechanism of abnormal insulin secretion in T2DM.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that the Transwell assay data shown in Fig. 4D on p. 1634 contained overlapping sections, such that these data, which were intended to show the results from differently performed experiments, were likely to have been derived from the same original source. After having examined their original data, the authors have realized that this figure was inadvertently assembled incorrectly. The corrected version of Fig. 4, now showing data in Fig. 4D from one of the repeated experiments, is shown on the next page. Note that this error did not significantly affect the results or the conclusions reported in this paper, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for granting them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 1628-1636, 2018; DOI: 10.3892/mmr.2018.9099].

In recent years, inhibiting tumor cell activity by triggering cell ferroptosis has become a research hotspot. The development of generic targeted nanotherapeutics might bring new ideas for non‑invasive applications. Currently, the potential mechanism underlying the universal application of paclitaxel (PTX)‑loaded iron oxide nanoparticles (IONP@PTX) to different types of tumors is unclear. The present study aimed to prepare IONP@PTX for targeted cancer therapy and further explore the potential mechanisms underlying the inhibitory effects of this material on the NCI‑H446 human small cell lung cancer and brain M059K malignant glioblastoma cell lines. First, a CCK‑8 assay was performed to determine cell viability, and then the combination index for evaluating drug combination interaction effect was evaluated. Intracellular reactive oxygen species (ROS) and lipid peroxidation levels were monitored using a DCFH‑DA fluorescent probe and a C11‑BODIPY™ fluorescent probe, respectively. Furthermore, western blotting assay was performed to determine the expression of autophagy‑ and iron death‑related proteins. The experimental results showed that, compared with either IONP monotherapy, PTX monotherapy, or IONP + PTX, IONP@PTX exerted a synergistic effect on the viability of both cell types, with significantly increased total iron ion concentration, ROS levels and lipid peroxidation levels. IONP@PTX significantly increased the expression of autophagy‑related proteins Beclin 1 and histone deacetylase 6 (HDAC6) in both cell lines (P<0.05), increased the expression of light chain 3 (LC3)‑II/I in NCI‑H446 cells (P<0.05) and decreased that of sequestosome1 (p62) in M059K cells (P<0.05). Moreover, the addition of rapamycin enhanced the IONP@PTX‑induced the upregulation of Beclin 1, LC3‑II/I and HDAC6 and the downregulation of mTORC1 protein in both cell lines (P<0.05). Moreover, rapamycin enhanced the IONP@PTX‑induced downregulation of p62 protein in NCI‑H446 cells (P<0.05), suggesting that IONP@PTX induces ferroptosis, most likely through autophagy. Collectively, the present findings show that IONP works synergistically with PTX to induce ferroptosis via the autophagic pathway.

Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E2, an arachidonic acid metabolite, has been shown to promote the formation of new blood and lymphatic vessels. However, the role of another arachidonic acid metabolite, thromboxane A₂ (TXA₂) in angiogenesis and lymphangiogenesis during endometriosis remains largely unexplored. Using a murine model of ectopic endometrial transplantation, fragments from the endometrium of WT donor mice were transplanted into the peritoneal walls of recipient WT mice (WT→WT), resulting in an increase in both the area and density of blood and lymphatic vessels. Upon transplantation of endometrial tissue from thromboxane prostanoid (TP) receptor (TXA₂ receptor)‑deficient (TP^‑/‑) mice into TP^‑/‑ mice (TP^‑/‑→TP^‑/‑), an increase in implant growth, angiogenesis, and lymphangiogenesis were observed along with upregulation of pro‑angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs). Similar results were obtained using a thromboxane synthase (TXS) inhibitor in WT→WT mice. Furthermore, TP^‑/‑→TP^‑/‑ mice had a higher number of F4/80⁺ cells than that of WT→WT mice, with increased expression of genes related to the anti‑inflammatory macrophage phenotype in endometrial lesions. In cultured bone marrow (BM)‑derived macrophages, the levels of VEGF‑A, VEGF‑C, and VEGF‑D decreased in a TP‑dependent manner. Furthermore, TP signaling affected the polarization of cultured BM‑derived macrophages to the anti‑inflammatory phenotype. These findings imply that inhibition of TP signaling promotes endometrial implant growth and neovascularization.

Drug‑resistance in hepatitis B virus (HBV), especially due to prolonged treatment with nucleoside analogs, such as lamivudine (LAM), remains a clinical challenge. Alternatively, several plant products and isolated phytochemicals have been used as promising anti‑HBV therapeutics with no sign of resistance. Among all known Rhus species, R. coriaria, R. succedanea and R. tripartite have been widely studied for their anti‑HBV efficacy, however, the effects of R. retinorrhoea have not been previously investigated. The current study reported the isolation of two flavonoids, namely sakuranetin (SEK) and velutin (VEL), from the dichloromethane fraction of R. retinorrhoea aerial parts using chromatography and spectral analyses. The two flavonoids (6.25‑50 µg/ml) were pre‑tested for non‑hepatocytotoxicity using an MTT assay and their dose‑ and time‑dependent inhibitory activities against HBV [hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg)] in cultured HepG2.2.15 cells were assessed by ELISA. SEK and VEL at the selected doses (12.5 µg/ml) significantly inhibited HBsAg by ~58.8 and ~56.4%, respectively, and HBeAg by ~55.5 and ~52.4%, respectively, on day 5. The reference drugs LAM and quercetin (anti‑HBV flavonoids), suppressed the production of HBsAg/HBeAg by ~86.4/~64 and ~84.5/~62%, respectively. Furthermore, molecular docking of the flavonoids with HBV polymerase and capsid proteins revealed the formation of stable complexes with good docking energies, thus supporting their structure‑based antiviral mechanism. In conclusion, the present study was the first to demonstrate the anti‑HBV therapeutic activities of SEK and VEL isolated from R. retinorrhoea.

Exosomes isolated from potato (Solanum tuberosum) exhibit the biophysical characteristics of exosomes observed in mammalian cells and microorganisms, as determined by dynamic light scattering analysis and transmission electron microscopy. In the present study, it was shown that potato exosomes (ExoPs) can penetrate keratinocyte HaCaT cells, as determined by confocal microscopy and flow cytometry. In addition, ExoPs can suppress the expression of the collagen‑destroying enzymes MMP1, 2 and 9, and the inflammatory cytokines IL6 and TNF‑α, while inducing the expression of glutathione S‑transferase α 4, a cellular detoxifying enzyme, as revealed by reverse transcription‑quantitative PCR. Furthermore, ExoPs promote HaCaT cell proliferation, exhibit in vitro antioxidant activity against the free radical 2,2‑diphenyl‑β‑picrylhydrazyl, and protect cells from hydrogen peroxide‑induced cytotoxicity. ExoPs can also minimize the induction of photodamage initiated by ultraviolet B (UVB) irradiation, and have the tendency to cure the photodamage already incurred on cells by UVB irradiation. ExoPs also prevent collagen degradation as observed in the culture media of UVB‑irradiated HaCaT cells. Collectively, ExoPs may protect and ameliorate photodamage in keratinocyte HaCaT cells.

Chronic kidney disease (CKD)‑associated cardiac injury is a common complication in patients with CKD. Indole‑3 acetic acid (IAA) is a uremic toxin that injures the cardiovascular system. Saikosaponin A (SSA) protects against pressure overload‑induced cardiac fibrosis. However, the role and molecular mechanisms of IAA and SSA in CKD‑associated cardiac injury remain unclear. The present study investigated the effects of IAA and SSA on CKD‑associated cardiac injury in neonatal mouse cardiomyocytes and a mouse model of CKD. The expression of tripartite motif‑containing protein 16 (Trim16), receptor interacting protein kinase 2 (RIP2) and phosphorylated‑p38 were assessed using western blotting. The ubiquitination of RIP2 was measured by coimmunoprecipitation, and mouse cardiac structure and function were evaluated using hematoxylin and eosin staining and echocardiography. The results demonstrated that, SSA inhibited IAA‑induced cardiomyocyte hypertrophy, upregulated Trim16 expression, downregulated RIP2 expression and decreased p38 phosphorylation. Furthermore, Trim16 mediated SSA‑induced degradation of RIP2 by ubiquitination. In a mouse model of IAA‑induced CKD‑associated cardiac injury, SSA upregulated the protein expression levels of Trim16 and downregulated those of RIP2. Moreover, SSA alleviated heart hypertrophy and diastolic dysfunction in IAA‑treated mice. Taken together, these results suggest that SSA is a protective agent against IAA‑induced CKD‑associated cardiac injury and that Trim16‑mediated ubiquitination‑related degradation of RIP2 and p38 phosphorylation may contribute to the development of CKD‑associated cardiac injury.

Diabetic liver injury (DLI) can result in several diseases of the liver, including steatohepatitis, liver fibrosis, cirrhosis, and liver cancer. Low‑dose ionizing radiation (LDIR) has hormetic effects in normal/disease conditions. However, whether LDIR has a beneficial effect on DLI has not been assessed previously. MicroRNA (miR)‑155 and its target gene suppressor of cytokine signaling 1 (SOCS1) play critical roles in modulating hepatic proliferation, apoptosis, and immunity. However, whether a miR‑155‑SOCS1 axis is involved in high glucose (HG) induced hepatic damage remains to be determined. In the present study, mouse hepatocyte AML12 cells were treated with 30 mM glucose (HG), 75 mGy X‑ray (LDIR), or HG plus LDIR. The expression levels of miR‑155 and SOCS1 were determined by reverse transcription‑quantitative PCR and western blotting. Additionally, apoptosis was measured using flow cytometry. The release of inflammatory factors, including TNF‑α, IL‑1β, IL‑6, IL‑10, and IFN‑γ, after HG and/or LDIR treatment was detected by ELISA. The results showed that HG may induce hepatic apoptosis by upregulating the levels of miR‑155 and downregulating the levels of SOCS1. HG also stimulated the secretion of TNF‑α, IL‑1β, IL‑6, and IL‑10. However, LDIR blocked the HG‑induced activation of a miR‑155‑SOCS1 axis and suppressed the release of inflammatory factors. These results indicated that a miR‑155‑SOCS1 axis plays a role in HG‑induced liver injury, and LDIR may exert a hepatoprotective effect by regulating the miR‑155‑SOCS1 axis.

Erectile dysfunction (ED) is a prevalent disease that causes sexual dysfunction in males. Inflammation‑induced endothelial dysfunction is a fundamental pathophysiological symptom of ED, which is impacted by cell death. Pyroptosis is a type of programmed cell death mediated by the inflammasome that was discovered in inflammatory disorders. The activation of nucleotide‑binding oligomerization domain‑like receptors, particularly downstream inflammatory factors, such as IL‑1β and IL‑18, is indicative of caspase‑dependent pyroptosis. Although the underlying mechanisms of pyroptosis have been investigated in several disorders, the role of pyroptosis in ED remains to be fully elucidated. At present, studies on pyroptosis have focused on improving the understanding of ED pathogenesis and promoting the development of novel therapeutic options. The present review article aimed to discuss the literature surrounding the mechanisms underlying pyroptosis, and summarize the role of pyroptosis in the development and progression of inflammation‑mediated ED.