Diverse Landscape of Genetically Engineered Mouse Models: Genomic and Molecular Insights into Prostate Cancer.

Prostate cancer (PCa) is a significant health concern for men worldwide and is particularly prevalent in the United States. It is a complex disease presenting different molecular subtypes and varying degrees of aggressiveness. Transgenic/genetically engineered mouse models (GEMMs) greatly enhanced our understanding of the intricate molecular processes that underlie PCa progression and advancement and have offered valuable insights into potential therapeutic targets for this disease. The integration of whole-exome and whole-genome sequencing, along with expression profiling, has played a pivotal role in advancing GEMMs by facilitating the identification of genetic alterations driving PCa development. This review focuses on genetically modified mice classified into the first and second generations of PCa models. We summarize whether models created by manipulating the function of specific genes replicate the consequences of genomic alterations observed in human PCa, including early and later disease stages. We discuss cases where GEMMs did not fully exhibit the expected human PCa phenotypes and possible causes of the failure. Here, we summarize the comprehensive understanding, recent advances, and the strengths and limitations of the GEMMs in advancing our insights into PCa, offering genetic and molecular perspectives for developing novel GEMM models.

DNASCANNER v2: A Web-Based Tool to Analyze the Characteristic Properties of Nucleotide Sequences.

Throughout the process of evolution, DNA undergoes the accumulation of distinct mutations, which can often result in highly organized patterns that serve various essential biological functions. These patterns encompass various genomic elements and provide valuable insights into the regulatory and functional aspects of DNA. The physicochemical, mechanical, thermodynamic, and structural properties of DNA sequences play a crucial role in the formation of specific patterns. These properties contribute to the three-dimensional structure of DNA and influence their interactions with proteins, regulatory elements, and other molecules. In this study, we introduce DNASCANNER v2, an advanced version of our previously published algorithm DNASCANNER for analyzing DNA properties. The current tool is built using the FLASK framework in Python language. Featuring a user-friendly interface tailored for nonspecialized researchers, it offers an extensive analysis of 158 DNA properties, including mono/di/trinucleotide frequencies, structural, physicochemical, thermodynamics, and mechanical properties of DNA sequences. The tool provides downloadable results and offers interactive plots for easy interpretation and comparison between different features. We also demonstrate the utility of DNASCANNER v2 in analyzing splice-site junctions, casposon insertion sequences, and transposon insertion sites (TIS) within the bacterial and human genomes, respectively. We also developed a deep learning module for the prediction of potential TIS in a given nucleotide sequence. In the future, we aim to optimize the performance of this prediction model through extensive training on larger data sets.

Hydroxychloroquine interaction with phosphoinositide 3-kinase modulates prostate cancer growth in bone microenvironment: In vitro and molecular dynamics based approach.

Patients with advanced prostate cancer (PCa) are more likely to develop bone metastases. Tumor cells thrive in the bone microenvironment, interacting with osteoblasts and osteoclasts. Given the PI3K/AKT pathway's metastatic potential and signal integration's ability to modulate cell fates in PCa development, drugs targeting this system have great therapeutic promise. Hydroxychloroquine (HCQ) is an anti-malarial medication commonly used to treat clinical conditions such as rheumatology and infectious disorders. We explored the anti-neoplastic effect of HCQ on PC3 and C4-2B cell lines in the bone microenvironment. Interestingly, HCQ treatment substantially decreases the viability, proliferation, and migration potential of PCa cells in the bone microenvironment. HCQ induces apoptosis and cell cycle arrest, even in the presence of osteoblast-secreted factors. Mechanistically, HCQ inhibited the activity of the PI3K/AKT signaling pathway, which ultimately regulates the proliferation and migration of PCa cells in the bone. The binding energy for docking HCQ with PI3K was -6.7 kcal/mol, and the complex was stabilized by hydrogen bonds, hydrophobic forces, and van der Waals forces. Molecular simulations further validated the structural integrity of the HCQ-PI3K complex without altering PI3K's secondary structure. Our findings underscore the efficacy of HCQ as a potential therapeutic agent in treating PCa.

Copper metabolism and cuproptosis in human malignancies: Unraveling the complex interplay for therapeutic insights.

Copper, a vital trace element, orchestrates diverse cellular processes ranging from energy production to antioxidant defense and angiogenesis. Copper metabolism and cuproptosis are closely linked in the context of human diseases, with a particular focus on cancer. Cuproptosis refers to a specific type of copper-mediated cell death or copper toxicity triggered by disruptions in copper metabolism within the cells. This phenomenon encompasses a spectrum of mechanisms, such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and perturbations in metal ion equilibrium. Mechanistically, cuproptosis is driven by copper binding to the lipoylated enzymes within the tricarboxylic acid (TCA) cycle. This interaction participates in protein aggregation and proteotoxic stress, ultimately culminating in cell death. Targeting copper metabolism and its associated pathways in cancer cells hold therapeutic potential by selectively targeting and eliminating cancerous cells. Strategies to modulate copper levels, enhance copper excretion, or interfere with cuproptotic pathways are being explored to identify novel therapeutic targets for cancer therapy and improve patient outcomes. Understanding the relationship between cuproptosis and copper metabolism in human malignancies remains an active area of research. This review provides a comprehensive overview of the association among copper metabolism, copper homeostasis, and carcinogenesis, explicitly emphasizing the cuproptosis mechanism and its implications for cancer pathogenesis. Additionally, we emphasize the therapeutic aspects of targeting copper and cuproptosis for cancer treatment.

From orphan to oncogene: The role of GPR35 in cancer and immune modulation.

G protein-coupled receptors (GPCRs) are well-studied and the most traceable cell surface receptors for drug discovery. One of the intriguing members of this family is G protein-coupled receptors 35 (GPR35), which belongs to the class A rhodopsin-like family of GPCRs identified over two decades ago. GPR35 presents interesting features such as ubiquitous expression and distinct isoforms. Moreover, functional and genome-wide association studies on its widespread expression have linked GPR35 with pathophysiological disease progression. Various pieces of evidence have been accumulated regarding the independent or endogenous ligand-dependent role of GPR35 in cancer progression and metastasis. In the current scenario, the relationship of this versatile receptor and its putative endogenous ligands for the activation of oncogenic signal transduction pathways at the cellular level is an active area of research. These intriguing features offered by GPR35 make it an oncological target, justifying its uniqueness at the physiological and pathophysiological levels concerning other GPCRs. For pharmacologically targeting receptor-induced signaling, few potential competitive antagonists have been discovered that offer high selectivity at a human level. In addition to its fascinating features, targeting GPR35 at rodent and human orthologue levels is distinct, thus contributing to the sub-species selectivity. Strategies to modulate these issues will help us understand and truly target GPR35 at the therapeutic level. In this article, we have provided prospects on each topic mentioned above and suggestions to overcome the challenges. This review discusses the molecular mechanism and signal transduction pathways activated by endogenous ligands or spontaneous auto-activation of GPR35 that contributes towards disease progression. Furthermore, we have highlighted the GPR35 structure, ubiquitous expression, its role in immunomodulation, and at the pathophysiological level, especially in cancer, indicating its status as a versatile receptor. Subsequently, we discussed the various proposed ligands and their mechanism of interaction with GPR35. Additionally, we have summarized the GPR35 antagonist that provides insights into the opportunities for therapeutically targeting this receptor.

α-lipoic acid modulates prostate cancer cell growth and bone cell differentiation.

Prostate cancer (PCa) progression leads to bone modulation in approximately 70% of affected men. A nutraceutical, namely, α-lipoic acid (α-LA), is known for its potent anti-cancer properties towards various cancers and has been implicated in treating and promoting bone health. Our study aimed to explore the molecular mechanism behind the role of α-LA as therapeutics in preventing PCa and its associated bone modulation. Notably, α-LA treatment significantly reduced the cell viability, migration, and invasion of PCa cell lines in a dose-dependent manner. In addition, α-LA supplementation dramatically increased reactive oxygen species (ROS) levels and HIF-1α expression, which started the downstream molecular cascade and activated JNK/caspase-3 signaling pathway. Flow cytometry data revealed the arrest of the cell cycle in the S-phase, which has led to apoptosis of PCa cells. Furthermore, the results of ALP (Alkaline phosphatase) and TRAP (tartrate-resistant acid phosphatase) staining signifies that α-LA supplementation diminished the PCa-mediated differentiation of osteoblasts and osteoclasts, respectively, in the MC3T3-E1 and bone marrow macrophages (BMMs) cells. In summary, α-LA supplementation enhanced cellular apoptosis via increased ROS levels, HIF-1α expression, and JNK/caspase-3 signaling pathway in advanced human PCa cell lines. Also, the treatment of α-LA improved bone health by reducing PCa-mediated bone cell modulation.

An Integrative Approach to Study Bacterial Enzymatic Degradation of Toxic Dyes.

Synthetic dyes pose a large threat to the environment and consequently to human health. Various dyes are used in textile, cosmetics, and pharmaceutical industries, and are released into the environment without any treatment, thus adversely affecting both the environment and neighboring human populations. Several existing physical and chemical methods for dye degradation are effective but have many drawbacks. Biological methods over the years have gained importance in the decolorization and degradation of dye and have also overcome the disadvantages of physiochemical methods. Furthermore, biological methods are eco-friendly and lead to complete decolorization. The mechanism of decolorization and degradation by several bacterial enzymes are discussed in detail. For the identification of ecologically sustainable strains and their application at the field level, we have focused on bioaugmentation aspects. Furthermore, in silico studies such as molecular docking of bacterial enzymes with dyes can give a new insight into biological studies and provide an easy way to understand the interaction at the molecular level. This review mainly focuses on an integrative approach and its importance for the effective treatment and decolorization of dyes.