Aldo-keto reductases: Role in cancer development and theranostics.

Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized.

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression-A Study on an Obese Rat Model with Impaired Glucose Tolerance.

Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3ß/ß-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3ß/ß-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.

A short-term chick embryo in vivo xenograft model to study retinoblastoma cancer stem cells.

Purpose: Cancer stem cells (CSCs) reported in various tumors play a crucial role in tumorigenesis and metastasis of retinoblastoma (Rb). Following the efforts to reduce, replace, and refine the use of mammalian models, we aimed to establish a short-term xenograft for Rb to evaluate the CSC properties of CD133- Rb Y79 cells, using the well-established chick embryo chorioallantoic membrane (CE-CAM) assay. Methods: Y79 cells were cultured, labeled with two different dyes (CM-Dil Y79 and enhanced green fluorescent protein (eGFP)) and sorted for CD133- and CD133 + subsets. Two million cells from each of the labeled groups were transplanted onto the abraded CAM on embryonic day 7 (E7). On E14, the tumor nodule formation on CAM and spontaneous metastasis to the embryos were evaluated by confocal microscopy, in vivo imaging, and histology. Results: Y79 cells formed pink-white raised perivascular nodules with feeder vessels on the CAM with both the types of labeled CD133- cells. CD133- cells, when compared to CD133 + cells, demonstrated significantly larger tumor volume (40.45 ± 7.744 mm3 vs 3.478 ± 0.69 mm3, P = 0.0014) and higher fluorescence intensity (CM-Dil: AUF = 6.37 × 107 ± 7.7 × 106 vs 1.08 × 107 ± 1.6 × 106; P < 0.0001; eGFP: AUF = 13.94 × 104 ± 2.54 × 104 vs AUF = 1.39 × 104 ± 0.4 × 104; P = 0.0003). The metastatic potential of CD133- cells was also observed to be higher as noted by in vivo imaging and histopathology. Conclusion: This study highlights that CE-CAM is a feasible alternative nonmammalian model for evaluating tumorigenicity and metastatic potential of Y79 CSCs. Increased tumorigenicity and metastatic potential of CD133- subset of tumor cells substantiate their CSC properties.

Inheritance and molecular mapping of powdery mildew (Golovinomyces orontii) resistance gene(s) in sunflower (Helianthus annuus L.).

Sources of resistance to powdery mildew incited by Golovinomyces orontii have been identified in wild sunflowers and few exotic lines. The present investigation has been undertaken to study the inheritance of powdery mildew resistance and to map the quantitative trait loci (QTLs) governing resistance to powdery mildew in a multiple disease resistance line, TX16R (PI 642072). The inheritance was observed as a continuous distribution in a set of 264 F2 population and 93 recombinant inbred lines (RILs) of a cross between a highly susceptible accession PS 2023 and TX16R. Screening of the two population sets was done with 484 sunflower-specific SSR primers of which 175 primers showed polymorphism between the parents. Based on the phenotyping and genotyping data, the linkage map was constructed with 93 RILs. The map spanned 1200 cM and included 64 markers distributed along the 17 sunflower chromosomes in the haploid set. Quantitative trait loci (QTL) analysis identified three genomic regions for resistance to powdery mildew, two of which mapped on chromosome 10 and one on chromosome 5. This is the first report on mapping of powdery mildew resistance in sunflower and paves the way in fine mapping and introgression of resistance for powdery mildew in sunflower through marker-assisted breeding.

Genetically Inherited Obesity and High-Fat Diet-Induced Obesity Differentially Alter Spermatogenesis in Adult Male Rats.

Obesity is a multifactorial disorder with predominantly genetic and/or environmental causes. Our aim was to delineate effects of genetically inherited and high-fat diet-induced obesity on fertility and spermatogenesis using two Wistar rat models: genetically inherited obese (GIO) WNIN/Ob rats and diet-induced obese (DIO) rats, which received a high-fat diet. The terminal body weights were similar in both groups, but there was a significant difference in metabolic and hormone profiles between the groups. Fertility assessment revealed a significant decrease in the litter size due to increased pre- and postimplantation loss in the DIO group, whereas the rats in the GIO group were infertile due to lack of libido. Significantly decreased sperm counts were observed in the GIO group compared with the DIO group. Enumeration of testicular cells on the basis of ploidy and cell type-specific expression markers, to study the effect of obesity on spermatogenesis, demonstrated that the GIO and DIO states affected mitosis: spermatogonia and S-phase population were increased. However, distinctive effects were observed on meiosis and spermiogenesis in both the groups. Differential effects of GIO and DIO on fertility and spermatogenesis could be due to the significant difference in white adipose tissue accumulation between the groups and not due to high body weights. The differential effects of obesity suggest male obesity-induced infertility observed in humans could be a combination of genetic and environmental factors.

An Insight into Powdery Mildew-Infected, Susceptible, Resistant, and Immune Sunflower Genotypes.

Powdery mildew (PM, caused by Golovinomyces orontii) is one of the major diseases on sunflower that causes severe yield losses in the tropics. Sources of resistance to PM are reported in an exotic accession and some wild Helianthus species. The present study aims at quantitative proteomic analysis of susceptible, resistant, and immune genotypes of sunflower in response to PM infection at 3, 7, 10 days post infection. The majority of differentially expressed proteins in the resistant genotype belonged to oxidative stress (catalase, ATP-sulfurylase, and formate dehydrogenase), defense (HSP-70, heat shock transcription factors), and photosynthesis (LHCB3). In case of immune genotype, 50% of proteins are related to photosynthesis, which play a key role in plant immunity, whereas a few similar proteins are also expressed in the susceptible genotype, but in their reduced abundance besides being inadequate in timing of expression probably leading to its susceptibility to PM. KEGG enrichment analysis shows that carbon metabolism (6-phosphogluconate dehydrogenase, pyruvate dehydrogenase, glutamine synthetase), photosynthesis, and plant-pathogen protein pathways are key pathways governing the resistance. The transcriptional expression of eight of nine differentially expressed proteins are in agreement with the expression of proteins at the corresponding time. The present study provides information on the key proteins that are upregulated in resistant and immune genotypes which restrict the disease progression and constitutes the first quantitative proteomic data of sunflower-PM infection process.