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The protein encoded by the ephrin type-A receptor 2 (EphA2) gene is a member of the ephrin receptor subfamily of the receptor tyrosine kinase family (RTKs). Eph receptors play a significant role in various biological processes, particularly cancer progression, development, and pathogenesis. They have been observed to regulate cancer cell growth, migration, invasion, tumor development, invasiveness, angiogenesis, and metastasis. To target EphA2 activity, various molecular, genetic, biochemical, and pharmacological strategies have been extensively tested in laboratory cultures and animal models. Notably, drugs, such as dasatinib, initially designed to target the kinase family, have demonstrated an additional capability to target EphA2 activity. Additionally, a novel monoclonal antibody named EA5 has emerged as a promising option to counteract the effects of EphA2 overexpression and restore tamoxifen sensitivity in EphA2-transfected MCF-7 cells during in vitro experiments. This antibody mimicked the binding of Ephrin A to EphA2. These methods offer potential avenues for inhibiting EphA2 activity, which could significantly decelerate breast cancer progression and restore sensitivity to certain drugs. This review article comprehensively covers EphA2’s involvement in multiple malignancies, including ovarian, colorectal, breast, lung, glioma, and melanoma. Furthermore, we discuss the structure of EphA2, the Eph-Ephrin signaling pathway, various EphA2 inhibitors, and the mechanisms of EphA2 degradation. This article provides an extensive overview of EphA2’s vital role in different types of cancers and outlines potential therapeutic approaches to target EphA2, shedding light on the underlying molecular mechanisms that make it an attractive target for cancer treatment.

It has been demonstrated that the duplicated carbonic anhydrase is induced by salt in the Dunaliella salina (D. salina) and duplicated carbonic anhydrase 1 (DCA1) is a member of carbonic anhydrase family. The purpose of this study was to identify whether both the DCA1 gene and its promoter from D. salina are salt-inducible. In this study, the results of real time RT–PCR showed that the transcripts of DCA1 were induced by gradient concentration of sodium chloride. Subsequently, a structurally novel promoter containing highly repeated GT/AC sequences of the DCA1 gene was isolated, which was able to drive a stable expression of the foreign bar gene in transformed cells of D. salina, and the gradient concentrations of sodium chloride in media paralleled regulations in the levels of both proteins and mRNA of the bar gene driven by the DCA1 promoter. Furthermore, analysis of GUS activities revealed that the salt-inducible expression of the external gus gene was regulated by the promoter fragments containing highly repeated GT sequences, but not by the promoter fragments deleting highly repeated GT sequences. The findings above-mentioned suggest that the highly repeated GT sequence in the DCA1 promoter is involved in the salt-inducible regulation in D. salina and may be a novel salt-inducible element.

Prostate cancer antigen 3 (PCA3) is the most promising diagnostic biomarker for the differential diagnosis of prostate cancer identified to date. As a dominant-negative oncogene, PCA3 negatively regulates the expression of tumor suppressor PRUNE2 (a human homolog of the Drosophila prune gene) gene. Although interaction between PCA3-PRUNE2 was clearly reported, the precise mechanism how PCA3 is upregulated in prostate cancer remained highly elusive. Accordingly, here we aimed demonstrate the role of microRNAs in PCA3 upregulation and interplay between these miRNAs and PCA3-PRUNE2 axis. We evaluated expression of PCA3, PRUNE2 and miRNAs by quantitative reverse transcription polymerase chain reaction. Overexpression and silencing of miRNAs were achieved by synthetic miRNA mimics and inhibitors, respectively. Colony formation, migration, apoptosis, and cell cycle assays were performed to reveal the effects of miRNA modulation. We identified that PCA3 expression was significantly downregulated in both prostate cancer tissues and cells and inversely correlated with the expressions of miR-19a and miR-421. Restoring the functions of miR-19a and miR-421 by miRNA mimics significantly downregulated the expression of PCA3 and promoted apoptosis and cell cycle blockade and interfered with the proliferation and migration in prostate cancer cells. Conversely, silencing the expressions of these miRNAs yielded the opposite effect. Collectively, our results uncover a previously unrecognized novel mechanism on PCA3 upregulation in prostate cancer and proved that miR-19a and miR-421 might be responsible for the increased expression of PCA3, indicating that both miRNAs might be novel candidates for prostate cancer diagnosis and therapy.

MicroRNAs (microRNAs) have been implicated to play crucial roles in various liver diseases. Hepatic microRNAs are released in to the circulation in a systematic fashion, and are, therefore, being extensively explored for their role as prognostic or diagnostic markers or therapeutic targets for numerous hepatic diseases. Advantages such as disease- or tissue-specific expression, and ease of detection have implicated circulating microRNAs (c-microRNAs) as the most desirable candidate for biomarker studies. Although several studies have explored c-microRNAs in serum or plasma, consistency of detection of microRNAs remains demanding because of many biological and methodological challenges. Lack of methodological consensus has limited the universal use of c-microRNAs as potential prognostic or diagnostic disease-specific biomarkers. In this review, we have discussed pre-analytical and analytical factors that might affect c-miRNA expression and selection of appropriate data normalization strategy by incorporating endogenous reference microRNAs. This review will aid designing of better approaches and protocols for future diagnostic research on hepatic c-microRNAs.

κ-Casein is one of the major proteins in the milk of mammals. It plays an important role in determining the size and specific function of milk micelles. We have previously identified and characterized a genetic variant of yak κ-casein by evaluating genomic DNA. Here, we isolate and characterize a yak κ-casein cDNA harboring the full-length open reading frame (ORF) from lactating mammary gland. Total RNA was extracted from mammary tissue of lactating female yak, and the κ-casein cDNA were synthesized by RT-PCR technique, then cloned and sequenced. The obtained cDNA of 660-bp contained an ORF sufficient to encode the entire amino acid sequence of κ-casein precursor protein consisting of 190 amino acids with a signal peptide of 21 amino acids. Yak κ-casein has a predicted molecular mass of 19,006.588 Da with a calculated isoelectric point of 7.245. Compared with the corresponding sequences in GenBank of cattle, buffalo, sheep, goat, Arabian camel, horse, and rabbit, yak κ-casein sequence had identity of 64.76–98.78% in cDNA, and identity of 44.79–98.42% and similarity of 53.65–98.42% in deduced amino acids, revealing a high homology with the other livestock species. Based on κ-casein cDNA sequences, the phylogenetic analysis indicated that yak κ-casein had a close relationship with that of cattle. This work might be useful in the genetic engineering researches for yak κ-casein.

Pollution with heavy metals (HMs) is time- and concentration-dependent. Lead and zinc pollute the aquatic environment, causing severe health issues in aquatic animals. Nile tilapia, the predominant cultured fish in Egypt, were experimentally exposed to 10% of LC50 of lead nitrate (PbNO3) and zinc sulfate (ZnSO4). Samples were collected in three different periods, 4, 6, and 8 weeks, in addition to a trial to treat the experimental fish infected with Aeromonas hydrophila, with an antibiotic (florfenicol). Liver enzymes were linearly upsurged in a time-dependent manner in response to HMs exposure. ALT was 92.1 IU/l and AST was 82.53 IU/l after eight weeks. In the eighth week of the HMs exposure, in the hepatic tissue, the levels of glutathione peroxidase (GPx), catalase (CAT), and metallothionein (MT) were increased to 117.8 U/mg prot, 72.2 U/mg prot, and 154.5 U/mg prot, respectively. On exposure to HMs, gene expressions of some cytokines were linearly downregulated in a time-dependent manner compared to the control. After four weeks of exposure to the HMs, the oxidative burst activity (OBA) of immune cells was decreased compared to the control 9.33 and 10.3 cells, respectively. Meanwhile, the serum bactericidal activity (SBA) significantly declined to 18.5% compared to the control 32.6% after eight weeks of exposure. Clinical signs of A. hydrophila infection were exaggerated in polluted fish, with a mortality rate (MR) of 100%. The re-isolation rate of A. hydrophila was decreased in fish treated with florfenicol regardless of the pollution impacts after eight weeks of HMs exposure. It could be concluded that the immune suppression and oxidative stress resulting from exposure to HMs are time-dependent. Clinical signs and post-mortem lesions in polluted fish infected with A. hydrophila were prominent. Infected-Nile tilapia had weak responses to florfenicol treatment due to HMs exposure.

Concerning the different clinical behavior of epidermal growth factor receptor (EGFR) subtypes in advanced-stage lung cancer patients, the current study aimed to evaluate the clinical, pathological, and prognostic significance of EGFR mutation subtypes, and treatment response in patients with advanced-stage lung cancer. A retrospective study enrolled a total of 346 patients with advanced-stage lung cancer tested for EGFR mutation. EGFR mutation was analyzed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Statistical analysis was performed using SPSS version 20.0. EGFR mutation was evident in 38% of patients with the highest prevalence of exon 19 deletions. A higher incidence of 19-deletions and 20-insertions were observed in young patients, while a higher incidence of L858R was noted in old age patients. Patients with de-novo T790M failed to improve their OS by any of the treatment modalities. Patients with de-novo T790M mutation have a higher risk of developing lung, liver, and multiple site metastases while patients with L858R mutation have a higher risk of developing brain metastasis. Additionally, patients with 19 deletion mutation did not improve their OS after receiving conventional chemotherapy hence, they demonstrate better survival only after EGFR-TKIs. Multivariate survival analysis predicted chemotherapy as an independent predictor of OS. Besides clinicopathological and prognostic consequences of EGFR mutation and mutation subtypes, patients harboring TKI sensitive, or insensitive mutations reveal different secondary disease development and hence should be treated accordingly for better survival. Current findings may provide the basis for a better treatment strategy.

Common polymorphisms within the apolipoprotein E (APOE) gene are suggested to be associated with the development of type 2 diabetes mellitus (T2DM), but the potential association with T2DM complications (nephropathy, neuropathy and retinopathy) remains unclear. We perform the case–control study to analyse the association between the APOE polymorphism and risk of T2DM and to analysed the potential relationship between the APOE and T2DM complications. APOE variants (rs429358 and rs7412) were genotyped by TaqMan assay in T2DM patients (N = 1274; N = 829 with complications including retinopathy, neuropathy and nephropathy status) and with PCR–RFLP in healthy nondiabetic controls (N = 2055). The comparison of subjects with genotypes associated with low plasma cholesterol (APOE2/E2 and APOE2/E3 carriers vs. others) did not show an association with T2DM (OR [95% CI] = 0.88 [0.71–1.08). The differences remained insignificant after adjusting for diabetes duration, sex and BMI. Carriers of at least one APOE4 allele (rs429358) are protected against T2DM related retinopathy (OR [95% CI] = 0.65 [0.42–0.99]. Protection against retinopathy is driven mostly by females (OR [95% CI] = 0.50 [0.25–0.99]); and remains significant (P = 0.044) after adjustment for diabetes duration and BMI. Common APOE polymorphism was not associated with T2DM in the Czech population. Yet, APOE4 allele revealed an association with retinopathy. In particular, female T2DM patients with at least one APOE4 allele exhibit lower prevalence of retinopathy in our study subjects.