Context-dependent activation of p53 target genes and induction of apoptosis by actinomycin D in aerodigestive tract cancers

Actinomycin D (ActD) was the first anticancer antibiotic approved for the management of human cancers. However, the notorious toxicity profile limits its widespread application in cancers, including cancers of the aerodigestive tract. Recent studies show that combining low-dose ActD with existing chemotherapies could potentially protect normal cells from the toxicity of chemotherapy drugs through p53 activation (cyclotherapy). An understanding of ActD’s effect on p53 signaling is critical for the meaningful application of ActD in cyclotherapy-based combinations. This study evaluated the anti-tumor efficacy and mechanism of action of ActD in aerodigestive tract cancers. We found that ActD strongly inhibited the growth of a panel of aerodigestive tract cancer cell lines and induced efficient apoptosis, although the sensitivity varies among cell lines. The IC₅₀ values of ActD spanned between 0.021 and 2.96?nM. Mechanistic studies revealed that ActD increased the expression of total and phosphorylated p53 (ser15) in a time- and dose-dependent manner. Moreover, ActD-induced apoptosis is dependent on p53 in cells expressing wild-type p53 and that ActD induced context-dependent differential expression of downstream targets p21 and PUMA without significant effects on p27. In the final analysis, this study revealed that p53-p21 is the predominant pathway activated by low-dose ActD, supporting further development of ActD in cyclotherapy.

     

Heavy metal phytoremediation of aqueous solution by Typha domingensis

Aquatic Ecology - More has yet to be indicated on the ability of microphyte plants for the removal of heavy metals from contaminated environments. In the present research, the ability of the...     

HER2+ mCRC patients with exon 20 R784G substitution mutation do not respond to the cetuximab therapy

The human epidermal growth factor 2 (HER2) gene undergoes various mutations that could alter its activity or respond to the antibody therapies. Cetuximab, a known anti-EGFR monoclonal antibody (mAB), is widely administered in metastatic colorectal cancer (mCRC) cases. Here we identified mCRC patients who did not respond to cetuximab (500 mg/m², q2w) after fluoropyrimidine/oxaliplatin regimen failure. Tumor samples were examined with immunohistochemistry for protein distribution, polymerase chain reaction (PCR) sequencing for mutation detection and real-time PCR for mRNA expression pattern analysis between cetuximab sensitive and resistance patients. The conformational differences of normal and mutated protein structures were predicted by bioinformatics analysis. The 5-year survival rates of target groups were estimated using the Kaplan–Meier method. Immunohistochemistry showed that all cases had high level of HER2 protein. No K-Ras or B-Raf mutation was observed among the study population; however, cetuximab resistance patients harbored a somatic mutation R784G at the exon 20 region of HER2 coding sequence. According to bioinformatics analysis, this mutation caused a notable misfold in protein conformation. Meanwhile, survival analysis showed R784G mutated mCRC patients had shortened survival rate compared with the mCRC cases with wild-type HER2. Collectively, these data report a new mechanism of resistance to cetuximab and might be applicable in modifying new therapeutic strategies for HER2 involved cancers.     

The role of nitric oxide signaling in renoprotective effects of hydrogen sulfide against chronic kidney disease in rats: Involvement of oxidative stress,autophagy and apoptosis

The interplay between H₂S and nitric oxide (NO) is thought to contribute to renal functions. The current study was designed to assess the role of NO in mediating the renoprotective effects of hydrogen sulfide in the 5/6 nephrectomy (5/6 Nx) animal model. Forty rats were randomly assigned to 5 experimental groups: (a) Sham; (b) 5/6 Nx; (c) 5/6Nx+sodium hydrosulfide-a donor of H ₂S, (5/6Nx+sodium hydrosulfide [NaHS]); (d) 5/6Nx+NaHS+ L -NAME (a nonspecific nitric oxide synthase [NOS] inhibitor); (e) 5/6Nx+NaHS+aminoguanidine (a selective inhibitor of inducible NOS [iNOS]). Twelve weeks after 5/6 Nx, we assessed the expressions of iNOS and endothelial NOS (eNOS), oxidative/antioxidant status, renal fibrosis, urine N-acetyl-b-glucosaminidase (NAG) activity as the markers of kidney injury and various markers of apoptosis, inflammation, remodeling, and autophagy. NaHS treatment protected the animals against chronic kidney injury as depicted by improved oxidative/antioxidant status, reduced apoptosis, and autophagy and attenuated messenger RNA (mRNA) expression of genes associated with inflammation, remodeling, and NAG activity. Eight weeks Nω-nitro-l-arginine methyl ester ( L -NAME) administration reduced the protective effects of hydrogen sulfide. In contrast, aminoguanidine augmented the beneficial effects of hydrogen sulfide. Our finding revealed some fascinating interactions between NO and H ₂S in the kidney. Moreover, the study suggests that NO, in an isoform-dependent manner, can exert renoprotective effects in 5/6 Nx model of CKD.     

Effects of temperature on sperm motility of burbot Lota lota: spontaneous activation and calcium dependency

Several factors regulating activation of spermatozoon motility in Eurasian burbot, Lota lota, including osmolality, calcium (Ca²⁺) ions, and temperature were investigated. Spermatozoon motility in Eurasian burbot, Lota lota was assessed at 4 and 30°C in seminal fluid, isotonic media (with and without Ca²⁺) and hypotonic media (with and without Ca²⁺). Spermatozoa were spontaneously activated in seminal fluid at 20°C and the maximum motility was recorded at 30°C, which is out of the spawning temperature range, indicating that no risk of activation occurs during routine semen handling in artificial insemination. Initiation of spermatozoon motility in L. lota is mediated by Ca²⁺ and sensitivity to Ca²⁺ is dependent on temperature.     

Effect of single nucleotide polymorphisms in SEPS1 and SEPP1 on expression in the protein level in metabolic syndrome in subjects with cardiovascular disease

Molecular Biology Reports - Metabolic syndrome (MetS) results from the interaction between environmental and genetic factors. Several previous studies considered the role of selenium in developing...     

Insecticidal effect of plant extracts on common pistachio psylla,Agonoscena pistaciae Burckhardt and Lauterer (Hemiptera: Aphalaridae)

The common pistachio psylla, Agonoscena pistaciae (Hemiptera: Aphalaridae) is one of the most detrimental pests to pistachio trees. Nowadays various pesticides are used to control the common pistachio psylla, but extensive pesticide spraying against this pest over a period of several years has overpowered its natural enemies. The plant’s byproducts come as an alternative ecologically more compatible in substitution to the synthetic insecticides. This work aims to evaluate the insecticidal potential of herbal extracts of fruit peels of Citrus sinensis and Citrus reticulata, seeds of C. sinensis and Rubia tinctorum, and leaves of Lawsonia inermis against common pistachio psylla. Five concentration 40, 47, 56, 67 and 80 µl/ml, of these plant extracts were sprayed on the fifth instar nymphs of common pistachio psylla by Potter Spray Tower under laboratory conditions (26?±?2?°C, 60–70% RH and a photoperiod of 16L: 8D h). Results showed significant differences among the treatments of the plant extracts and between the concentrations. The LC₅₀ values of C. sinensis peels, C. reticulata peels, C. sinensis seeds, R. tinctorum seeds and L. inermis leaves were 62.04, 38.84, 43.60, 59.01 and 33.99 µl/ml, respectively. Also, all extracts showed the greatest mortality effect in 80 µl/ml concentration. According to these results, these plant extracts may use as herbal pesticides chemical control programme of common pistachio psylla.     

Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project

The Alzheimer's Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed “consensus calling,” to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.     

Resveratrol potentially increased the tumoricidal effect of doxorubicin on SKOV3 cancer stem cells in vitro

Ovarian cancer is associated with a high percentage of recurrence of tumor and resistance to chemotherapy. Cancer stem cells (CSCs) form a rare population with a significant capacity to begin and expand malignant diseases. Eliminating the drug resistance of CSCs by factors that have fewer side effects to the patient is vital. To investigate the effect of resveratrol (RES) and doxorubicin (DOX) on drug resistance and apoptosis of CSCs; at the first, isolation of CSCs from SKOV3 ovarian carcinoma cells and their dosage adjustment (IC₅₀) with RES and DOX was performed. Then, isolated CSCs were treated with RES and DOX IC ₅₀ of 55 and 250 nM, respectively. Subsequently, their effects on drug resistance and cell death were evaluated using real-time polymerase chain reaction, rhodamine 123 uptakes. The results of the present study demonstrated that treatment of SKOV3 with 55 μM of RES and 250 nM of DOX simultaneously increased cell viability in CSCs to DOX after 24 and 48 hours by increasing the expression of Bcl-2-associated X protein (BAX) and caspase-3 genes, and decreased the expression and function of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) genes indicated by intracellular the rhodamine 123 content. Treatment of RES could increase the activity of DOX cell viability in CSCs originated from SKOV3 ovarian carcinoma and decrease drug resistance capacity to DOX.