Background and Purpose
Mitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins), ...which inhibit ROS synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear.
Experimental Approach
Rats were treated with angiotensin II (1.5 mg·kg−1·day−1) or co‐administered simvastatin (oral, 10 mg·kg−1) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated, and intracellular ROS and mitochondrial membrane potential (ΔΨm) changes were measured by flow cytometry and JC‐1 staining, respectively. Autophagy and mitophagy‐related and mitochondria‐regulated apoptotic proteins were identified by immunohistochemistry and western blotting.
Key Results
Simvastatin significantly reduced ROS production and attenuated the disruption of ΔΨm. Simvastatin induced the accumulation of lipid droplets to provide energy for maintaining mitochondrial function, promoted autophagy and mitophagy, and inhibited mitochondria‐mediated apoptosis. These findings suggest that mitochondrial protection mediated by simvastatin plays a therapeutic role in heart failure prevention by modulating antioxidant status and promoting energy supplies for autophagy and mitophagy to inhibit mitochondrial damage and cardiomyocyte apoptosis.
Conclusion and Implications
Mitochondria play a key role in mediating heart failure progression. Simvastatin attenuated heart failure, induced by angiotensin II, via mitochondrial protection and might provide a new therapy to prevent heart failure.
The direct acetoxylation of substituted benzylamines has been accomplished through methoxyiminoacyl (MIA)‐mediated Pd‐catalyzed C−H functionalization. A diverse array of phenylalanine substrates is ...amenable to this protocol, providing acetoxylation benzylamine derivatives with good to high efficiency. Computational results revealed that HOAc enhanced the stability of Pd−O bond, which obviously accelerate the reductive elimination step of the acetoxylation process.
A highly efficient MIA‐mediated acetoxylation of substituted benzylamines was reported, which tolerate various substituent groups with good to high yields. DFT‐Studies showed that a weaker electrostatic attraction of HOAc to OAc led to the preferential formation of a five‐membered cyclopalladium intermediate (OAc−Pd−C).
We report here a single-benzene based fluorescent framework, amino-terephthalonitrile, denoted
SB-Fluor
. This scaffold displays versatile emission wavelength tunability
via
structure modification, ...covering the full visible light spectrum, both in the solution and solid state. Moreover, one molecule, SBF3, exhibits polymorphism-dependent reversible mechanochromic luminescence.
We report here a single-benzene based fluorescent framework, amino-terephthalonitrile, denoted
SB-Fluor
.
MicroRNAs (miRs) play critical roles in cancer development, proliferation, epithelial-mesenchymal transition (EMT), invasion, and migration through regulating the expression of oncogenes and tumour ...suppressor genes. Previous studies have indicated that miR-200c acts as a tumour suppressor in various cancers by downregulating high-mobility group box 1 (HMGB1) and thereby suppressing EMT and metastasis. In addition, miR-200c was reported to be downregulated and correlated with poor outcomes in non-small cell lung cancer (NSCLC). However, its functional role in HMGB1 regulation in NSCLC is still unclear. This study aimed to clarify whether miR-200c acts as a tumour suppressor in NSCLC by downregulating HMGB1, which is associated with EMT, invasion, cytoskeleton rearrangement, and migration in vitro and in vivo. In order to demonstrate HMGB1 downregulation by miR-200c, the NSCLC cell line A549 was transfected with miR-200c mimic or inhibitor. The mimic significantly reduced HMGB1 expression and suppressed EMT, invasion, and migration, while the inhibitor generated the opposite effects. Additionally, using xenograft mouse models, we confirmed that HMGB1 overexpression increased tumour EMT. In summary, our results demonstrated that miR-200c could suppress EMT, invasion, and migration of NSCLC cells by downregulating HMGB1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exosomes are implicated in cancer cell development, migration and invasion. Pigment epithelium-derived factor (PEDF) is a secreted anticancer protein that can regulate lung cancer progression; ...however, the role of PEDF in non-small cell lung cancer (NSCLC), including metastasis and cancer cell-derived exosome secretion, is unclear. In this study, we analyzed the effects of PEDF on exosome-mediated migration, invasion, and tumorigenicity of cultured NSCLC cells. The results showed that PEDF overexpression significantly reduced NSCLC invasion and migration, while inducing cell aggregation, whereas PEDF knockdown had the opposite effects. Exosomes from NSCLC cells treated with recombinant PEDF had a significantly reduced ability to promote cancer cell motility, migration, and invasion compared to exosomes from untreated cells. Exosomes from PEDF-treated cells contained thrombospondin 1 (THBS1), which inhibited cytoskeletal remodeling and exosome-induced lung cancer cell motility, migration, and invasion. Furthermore, PEDF-overexpressing NSCLC cells formed smaller xenograft tumors with higher THBS1 expression compared to control tumors. Our findings indicate that PEDF decreases the metastatic potential of NSCLC cells through regulation of THBS1 release in cancer cell-derived exosomes, thus uncovering a new mechanism of lung cancer progression.
•PEDF induces aggregation and reduces invasion and migration of lung cancer cells.•Exosomes from PEDF-treated cancer cells inhibit metastatic behavior of NSCLC cells.•PEDF-expressing NSCLC cells have reduced tumorigenicity in vivo.•PEDF increases thrombospondin 1 content in lung cancer cell-derived exosomes.•Thrombospondin 1 inhibits exosome-induced lung cancer cell migration and invasion.
Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive ...platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Three novel Cd(
ii
)/Zn(
ii
) coordination polymers (CPs), namely Cd(L)(BPDC)
0.5
H
2
O·0.5H
2
O (
1
), Zn
2
(L)
2
(BPDC)·2H
2
O (
2
) and Cd
2
(L)(BTC)H
2
O·3H
2
O (
3
) (L = ...4-(tetrazol-5-yl)phenyl-4,2′:6′,4′′-terpyridine, H
2
BPDC = 4,4′-biphenyldicarboxylic acid, and H
3
BTC = 1,3,5-benzenetricarboxylic acid), have been successfully synthesized and characterized. CP
1
and CP
2
display new two-dimensional double-layered honeycomb frameworks containing uncoordinated nitrogen atoms from pyridine and tetrazole rings, which can easily form hydrogen bonds with various analytes. CP
3
exhibits a 3D framework also with uncoordinated nitrogen atoms from pyridine and tetrazole rings. The fluorescence explorations indicate that CPs
1-3
exhibit strong blue luminescence and excellent chemical stability under a relatively wide range of pH conditions. It is worth noting that CPs
1-3
can quantitatively detect hippuric acid (HA), which is a metabolite of toluene in human urine, with high selectivity, sensitivity, fast response and relatively low detection limits. Moreover, the sensing mechanism of CPs
1-3
for HA can mainly be ascribed to fluorescence resonance energy transfer (FRET). CPs
1-3
could be ideal candidates as HA sensors in human urine samples for practical applications. Notably, to the best of our knowledge, we report for the first time Cd(
ii
)/Zn(
ii
)-based luminescent sensors for detecting HA in simulated urine.
Water stable Cd(
ii
)/Zn(
ii
) coordination polymers exhibit rapid, sensitive, selective and recyclable detection towards hippuric acid in simulated urine for indexing toluene exposure.
Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133(+) cells are the cause of drug ...resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133(+) cells has not been investigated methodically. In this study, we revealed that CD133(+) lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC(20)) was sufficient to enrich CD133(+) cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133(+) cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the γ-secretase inhibitor, N-N-(3,5-difluorophenacetyl)-1-alanyl-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133(+) cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133(+) cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133(+) cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133(+) cell number. Together, our results showed that cisplatin induces the enrichment of CD133(+) cells, leading to multidrug resistance by the activation of Notch signaling.
Fluorescent probes have become an indispensable tool in the detection and imaging of biological and disease‐related analytes due to their sensitivity and technical simplicity. In particular, ...fluorescent probes with far‐red to near‐infrared (FR‐NIR) emissions are very attractive for biomedical applications. However, many available FR‐NIR fluorophores suffer from small Stokes shifts and sometimes low quantum yields, resulting in self‐quenching and low contrast. In this work, we describe the rational design and engineering of FR‐NIR 2,4,6‐triphenylpyrylium‐based fluorophores (TPP‐Fluors) with the help of theoretical calculations. Our strategy is based on the appending of electron‐donating substituents and fusing groups onto 2,4,6‐triphenylpyrylium. In contrast to the parent TPP with short emission wavelength, weak quantum yields, and low chemical stability, the obtained novel TPP‐Fluors display some favorable properties, such as long‐wavelength emission, large Stokes shifts, moderate to high quantum yields, and chemical stability. TPP‐Fluors demonstrate their biological value as mitochondria‐specific labeling reagents due to their inherently positive nature. In addition, TPP‐Fluors can also be applied to develop ratiometric fluorescent probes, as the electron‐donating ability of the 2,6‐phenyl substituents is closely correlated with their emission wavelength. A proof‐of‐concept ratiometric probe has been developed by derivatizing the amino groups of TPP‐Fluor for the detection and imaging of nitroreductase in vitro and in hypoxic cells.
Rigidified and activated probes: Rational modification of the 2,4,6‐triphenylpyrylium salt (TPP) results in fluorophores (TPPF) with far‐red to NIR emissions, large Stokes shifts, and high quantum yields (see figure). In addition, through acylation of the amino groups, TPPF dye can be exploited as a novel platform for designing ratiometric fluorescent probes with highly shifted emission bands.
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