Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown impressive effects in reducing major vascular events in several randomized controlled trials (RCTs). The purpose of this study ...was to perform a meta-analysis to evaluate the effect of SGLT2 inhibitors on the risk of stroke and its subtypes. All data from prospective RCTs up to 20 October 2020 involving SGLT2 inhibitors that reported stroke events as the primary endpoint or safety in subjects with type 2 diabetes were subjected to meta-analysis. Five eligible RCTs (EMPA-REG, CANVAS, DECLARE-TIMI 58, CREDENCE and VERTIS CV) involving 46,969 participants were included. Pooled analysis of the RCTs showed no significant effect of SGLT2 inhibitors on total stroke risk ratio (RR) = 0.95; 95% confidence interval (CI) 0.79–1.13, P = 0.585. Subgroup analysis indicated that SGLT2 inhibitors had no significant effect against fatal stroke, non-fatal stroke, ischemic stroke or transient ischemic attack. When only hemorrhagic stroke was included, SGLT2 inhibitors were associated with a significant 50% reduction compared with placebo (RR = 0.49, 95% CI 0.30–0.82, P = 0.007). This meta-analysis shows that SGLT2 inhibitors have a neutral effect on the risk of stroke and its subtypes but a potential protective effect against hemorrhagic stroke.
An insufficient oxygen supply within the intratumoral environment, also known as hypoxia, induces glioblastoma multiforme (GBM) invasion, stemness, and temozolomide (TMZ) drug resistance. Long ...noncoding (lnc)RNAs have been reported to be involved in hypoxia and GBM progression. However, their roles in hypoxic GBM malignancy are still unclear. We investigated the mechanisms of hypoxia‐mediated lncRNAs in regulating GBM processes. Using The Cancer Genome Atlas (TCGA) and data mining, hypoxia‐correlated lncRNAs were identified. A hypoxia‐upregulated lncRNA, MIR210HG, locating in nuclear regions, predicted poor prognoses of patients and modulated hypoxia‐promoted glioma stemness, TMZ resistance, and invasion. Depletion of hypoxic MIR210HG suppressed GBM and patient‐derived cell growth and increased TMZ sensitivity in vitro and vivo. Using RNA sequencing and gene set enrichment analysis (GSEA), MIR210HG‐upregulated genes significantly belonged to the targets of octamer transcription factor 1 (OCT1) transcription factor. The direct interaction between OCT1 and MIR210HG was also validated. Two well‐established worse prognostic factors of GBM, insulin‐like growth factor–binding protein 2 (IGFBP2) and fibroblast growth factor receptor 1 (FGFR1), were identified as downstream targets of OCT1 through MIR210HG mediation in hypoxia. Consequently, the lncRNA MIR210HG is upregulated by hypoxia and interacts with OCT1 for modulating hypoxic GBM, leading to poor prognoses. These findings might provide a better understanding in functions of hypoxia/MIR210HG signaling for regulating GBM malignancy.
Hypoxia‐inducible lncRNA MIR210HG predicts a poor prognosis in hypoxic glioblastoma multiforme (GBM) malignancy. MIR210HG directly interacts with OCT1 in hypoxic GBM malignancy. MIR210HG upregulates IGFBP2 and FGFR1 through OCT1 in hypoxic GBM malignancy.
Oral squamous cell carcinoma (OSCC) can arise anywhere in the oral cavity. OSCC's molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic ...mutations and altered levels of transcripts, proteins, and metabolites. Platinum-based drugs are the first-line treatment for OSCC; however, severe side-effects and resistance are challenging issues. Thus, there is an urgent clinical need to develop novel and/or combinatory therapeutics. In this study, we investigated the cytotoxic effects of pharmacological concentrations of ascorbate on two human oral cell lines, the oral epidermoid carcinoma meng-1 (OECM-1) cell and the Smulow-Glickman (SG) human normal gingival epithelial cell. Our study examined the potential functional impact of pharmacological concentrations of ascorbates on the cell-cycle profiles, mitochondrial-membrane potential, oxidative response, the synergistic effect of cisplatin, and the differential responsiveness between OECM-1 and SG cells. Two forms of ascorbate, free and sodium forms, were applied to examine the cytotoxic effect and it was found that both forms had a similar higher sensitivity to OECM-1 cells than to SG cells. In addition, our study data suggest that the determinant factor of cell density is important for ascorbate-induced cytotoxicity in OECM-1 and SG cells. Our findings further revealed that the cytotoxic effect might be mediated through the induction of mitochondrial reactive oxygen species (ROS) generation and the reduction in cytosolic ROS generation. The combination index supported the agonistic effect between sodium ascorbate and cisplatin in OECM-1 cells, but not in SG cells. In summary, our current findings provide supporting evidence for ascorbate to serve as a sensitizer for platinum-based treatment of OSCC. Hence, our work provides not only repurposing of the drug, ascorbate, but also an opportunity to decrease the side-effects of, and risk of resistance to, platinum-based treatment for OSCC.
Disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor, is being used in anticancer therapy, as its effects in humans are known and less adverse than conventional chemotherapy. We ...explored the potential mechanism behind the cytotoxicity of DSF-Cu
/Cu
complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl
or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu
/Cu
induced cell death in OECM-1 cells, but not SG cells. DSF-Cu
/Cu
also increased the subG1 population and decreased the G1, S, and G2/M populations in OECM-1 cells, but not SG cells, and suppressed cell proliferation in both OECM-1 and SG cells. ALDH enzyme activity was inhibited by CuCl and DSF-Cu
/Cu
in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu
/Cu
-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu
/Cu
induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl
increased but DSF- Cu
impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl
stabilized HIF-1α expression under normoxia in OECM-1 cells, and complex with DSF enhanced that effect. Levels of c-Myc protein and its phosphorylation at Tyr58 and Ser62 were increased, while levels of the N-terminal truncated form (Myc-nick) were decreased in DSF-Cu
/Cu
-treated OECM-1 cells. These effects were all suppressed by pretreatment with the ROS scavenger NAC. Overexpression of c-Myc failed to induce HIF-1α expression. These findings provide novel insight into the potential application of DSF-CuCl
complex as a repurposed agent for OSCC cancer therapy.
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which ...currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Hydroxyapatite (HA), especially in the form of HA nanoparticles (HANPs), has excellent bioactivity, biodegradability, and osteoconductivity and therefore has been widely used as a template or ...additives for drug delivery in clinical applications, such as dentistry and orthopedic repair. Due to the atomically anisotropic distribution on the preferred growth of HA crystals, especially the nanoscale rod-/whisker-like morphology, HA can generally be a good candidate for carrying a variety of substances. HA is biocompatible and suitable for medical applications, but most drugs carried by HANPs have an initial burst release. In the adsorption mechanism of HA as a carrier, specific surface area, pore size, and porosity are important factors that mainly affect the adsorption and release amounts. At present, many studies have developed HA as a drug carrier with targeted effect, porous structure, and high porosity. This review mainly discusses the influence of HA structures as a carrier on the adsorption and release of active molecules. It then focuses on the benefits and effects of different types of polymer-HA composites to re-examine the proteins/drugs carry and release behavior and related potential clinical applications. This literature survey can be divided into three main parts: 1. interaction and adsorption mechanism of HA and drugs; 2. advantages and application fields of HA/organic composites; 3. loading and drug release behavior of multifunctional HA composites in different environments. This work also presents the latest development and future prospects of HA as a drug carrier.
With the rapid growth of solar energy, recycling and reuse of end-of-life solar modules have become a critical issue. In light of this, a simple, yet environmentally friendly, ball milling process ...was used to transform the recycled Si of waste solar cells into a lithium ion battery anode material. The ball-milled recycled Si was further combined with a carbon fiber paper (CP) substrate to fabricate a composite electrode. The milling time and rotation speed were optimized to form a Si/SiOx/Al2O3 active material with a moderate primary particle size, agglomeration extent, and oxidation states of Si and Al. These features allow the recycled Si to exhibit promising cycling and rate performances. Additionally, introducing a hydrothermally treated CP substrate can further improve the electrochemical performance of the composite electrode, delivering a high discharge capacity of 1603 mA h g−1 after 100 cycles (capacity retention of approximately 91% (200 mA g−1)) and 813 mA h g−1 at 2000 mA g−1, due to the presence of nitrogen-containing groups, particularly the pyridinic-N group. This is evidenced by the reduced solid electrolyte interface and charge transfer resistances and the increased ion diffusion coefficient of the Si/SiOx/Al2O3-based cell.
Breast cancer accounts for almost one quarter of all female cancers worldwide, and more than 90% of those who are diagnosed with breast cancer undergo mastectomy or breast conservation surgery. Local ...anesthetics effectively inhibit the invasion of cancer cells at concentrations that are used in surgical procedures. The limited treatment options for triple-negative breast cancer (TNBC) demonstrate unmet clinical needs. In this study, four local anesthetics, lidocaine, levobupivacaine, bupivacaine, and ropivacaine, were applied to two breast tumor cell types, TNBC MDA-MB-231 cells and triple-positive breast cancer BT-474 cells. In addition to the induction of apoptosis and the suppression of the cellular proliferation rate, the four local anesthetics decreased the levels of reactive oxygen species and increased the autophagy elongation indicator in both cell types. Our combination index analysis with doxorubicin showed that ropivacaine had a synergistic effect on the two cell types, and lidocaine had a synergistic effect only in MDA-MB-231 cells; the others had no synergistic effects on doxorubicin. Lidocaine contributed significantly to the formation of autophagolysosomes in a dose-dependent manner in MDA-MB-231 cells but not in BT-474 cells. Our study demonstrated that the four local anesthetics can reduce tumor growth and proliferation and promote apoptosis and autophagy.
In this study, we suppressed the parasitic emission caused by electron overflow found in typical ultraviolet B (UVB) and ultraviolet C (UVC) light-emitting diodes (LEDs). The modulation of the ...p-layer structure and aluminum composition as well as a trade-off in the structure to ensure strain compensation allowed us to increase the p-AlGaN doping efficiency and hole numbers in the p-neutral region. This approach led to greater matching of the electron and hole numbers in the UVB and UVC emission quantum wells. Our UVB LED (sample A) exhibited clear exciton emission, with its peak near 306 nm, and a band-to-band emission at 303 nm. The relative intensity of the exciton emission of sample A decreased as a result of the thermal energy effect of the temperature increase. Nevertheless, sample A displayed its exciton emission at temperatures of up to 368 K. In contrast, our corresponding UVC LED (sample B) only exhibited a Gaussian peak emission at a wavelength of approximately 272 nm.
PDF
