Exposure of environmental trace elements in prostate cancer patients: A multiple metal analysis.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men. To elucidate the connection between trace elements (arsenic: As, cadmium: Cd, lead: Pb, chromium: Cr, and nickel: Ni) and the risk of PCa, we analyzed trace element levels in the serum, urine, and tissues of PCa patients, while also examining their smoking status. We correlated these levels with their smoking habits. Notably, levels of Cd (P ≤ 0.05) and As (P ≤ 0.01) were significantly higher in the tumor tissue than in adjacent tissues. No significant differences were observed in the levels of Pb, Cr and Ni. Additionally, urinary Cd levels in 70% and arsenic levels in 2.3% of the PCa cohort were markedly higher than the CDC-reported cutoff (Cd ≤ 0.185 µg/L & As ≤100 µg/L). None displayed elevated levels of urinary Pb, Cr, and Ni. Conversely, in serum samples, the concentration of arsenic exceeded the CDC-determined limit (As ≤1.0 µg/L) in 31.69% of PCa patients. However, only 7.04% of patients had higher serum Cd levels than the CDC standard values (Cd ≤ 0.315 µg/L), while all PCa patients exceeded the Cr CDC limit (Cr ≤ 0.16 µg/L) and the Ni CDC limit (Ni ≤ 0.2 µg/L). On the contrary, no significant differences were observed in serum Pb (Pb ≤ 35.0 µg/L). Our findings establish a positive link between Cd and arsenic tissue concentrations and the risk of PCa. Subsequent studies are essential to determine whether elevated trace element levels pose a risk for the development of prostate carcinogenesis. Interestingly, among the PCa cohort comprising smokers, notably higher Cd levels were observed only in tumor tissues (P ≤ 0.01) and urine (P ≤ 0.05) compared to other elements or in other specimens.

Cranial Vault Suture Obliteration in Relation to Age: An Autopsy-Based Observational Study.

BACKGROUND: Age is one of the most critical identifiers for both living and dead. Forensic professionals in medical and legal matters are often presented with dismembered, disfigured, putrefied, or skeletal remains for analysis. In such situations, it is essential to identify individuals and estimate their ages. The skull is typically the well-preserved part of the body in such situations. If an aged person needs their age officially established for employment, superannuation, pension settlements, senior citizen benefits, etc., they may turn to medical professionals for help in making that determination. It has always been controversial to use cranial suture obliteration as a reference for age. Different geographical locations have been shown to have vastly different patterns of cranial suture closure. Therefore, this study was conceptualized to assess cranial vault suture obliteration in relation to age in the Meo population. This study was conducted to determine whether obliteration of cranial sutures can be taken into account for the estimation of age in elderly in this region and its reliability along with the influence of other factors such as sex and right and left side differences. MATERIALS AND METHODS: A total of 100 cases of more than 20 years of age brought for medicolegal autopsy were analyzed. The coronal, sagittal, and lambdoid sutures were studied ectocranially and endocranially. The degree of obliteration of sutures was scored ectocranially as well as endocranially. Data were analyzed using IBM SPSS Statistics for Windows, Version 21 (Released 2012; IBM Corp., Armonk, New York, United States). Descriptive statistics were evaluated for continuous data in terms of mean and standard deviation, and categorical data were presented by frequency and percentages. An independent t-test was applied to find out the mean difference between the right and left sides of suture closure for ectocranial and endocranial surfaces. The Spearman rank correlation test was carried out to find out the relationship between the age and score of suture closure both ectocranially and endocranially. RESULT: Ectocranially and endocranially, the overall sagittal suture obliterates early followed by coronal sutures and then lambdoid sutures. On comparing the mean ectocranial and mean endocranial scores of 100 subjects by applying an independent t-test, a highly significant difference was observed in all three sutures. On correlating ectocranial sutures and endocranial sutures and age at death in all the cases through sagittal, right and left coronal, and lambdoid by applying the Spearman rank correlation coefficient, a highly significant correlation was found in all the subjects combined (p-value 0.000). However, no significant correlation (p-value >0.05) was found in ectocranial and endocranial sagittal sutures in individual age groups. CONCLUSION: We concluded that obliteration on the endocranial surface is more reliable than on the ectocranial surface. No statistically significant difference exists on the obliteration of sutures on the right and left sides of coronal and lambdoid sutures. The lapsed union was evident in all three sutures ectocranially. Endocranial suture obliteration can be used as a corroborative tool for age estimation.

Analysis of Changes in Electrolytes Level in Serum After Death and Its Correlation With Postmortem Interval.

Background Apropos estimation of postmortem interval is an important and difficult task for forensic pathologists. In routine practice, postmortem interval is deduced by conventional or physical methods such as early and late postmortem changes, which are subjective methods and prone to errors. Estimating time since death by thanatochemistry is a more objective method as compared to routine conventional or physical methods. The present study is an attempt to analyze the changes in electrolytes level in serum after death and its correlation with postmortem interval. Materials and methods Blood samples were taken from the deceased who were brought for a medicolegal autopsy. The concentration of electrolytes, mainly sodium, potassium, calcium, and phosphate, was evaluated in the serum. The deceased were grouped on the basis of time since death. Log-transferred regression analysis was done to establish the correlation of the concentration of electrolytes with time since death and regression formulas were derived for each parameter. Results Sodium concentration in serum showed a negative correlation with time since death. Potassium, calcium, and phosphate showed a positive correlation with time since death. No statistically significant difference exists in the concentration of electrolytes between males and females. No significant difference was observed in the electrolytes concentration between the age groups. Conclusion Considering the findings of this study, we infer that the concentration of electrolytes, primarily sodium, potassium, and phosphates, in the blood can be used to approximate the amount of time that has passed since death. Nonetheless, until 48 hours after death, electrolyte levels in the blood can be considered for the calculation of the postmortem interval.

Corrigendum: A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth.

[This corrects the article DOI: 10.3389/fphar.2023.1150774.].

A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth.

Although breast cancer stem cells (BCSCs) are well characterized, molecularly targeting and eradicating this sub-population remains a challenge in the clinic. Recent studies have explored several signaling pathways that govern stem cell activation: We and others established that the Notch1 signaling plays a significant role in the proliferation, survival, and differentiation of BCSCs. Earlier, we reported that a newly developed small molecule, ASR490, binds to the negative regulatory region (NRR: The activation switch of the Notch receptor) of Notch1. In vitro results demonstrated that ASR490 significantly inhibited BCSCs (ALDH+ and CD44+/CD24-) and breast cancer (BC) growth at nM concentrations, and subsequently inhibited the colony- and mammosphere-forming abilities of BCSCs and BCs. ASR490 downregulated the expressions of Notch1 intracellular domain (NICD: The active form of Notch1) and its downstream effectors Hey1 and HES1. Inhibition of Notch1-NICD facilitated autophagy-mediated growth inhibition by triggering the fusion of autophagosome and autolysosome in BCSCs. ASR490 was found to be non-toxic to healthy cells as compared to existing Notch1 inhibitors. Moreover, oral administration of ASR490 abrogated BCSC and BC tumor growth in the in vivo xenograft models. Together our results indicate that ASR490 is a potential therapeutic agent that inhibits BC tumor growth by targeting and abolishing Notch1 signaling in BCSCs and BC cells.

Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7.

We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR- CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.

Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC).

BACKGROUND: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). METHODS: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. RESULTS: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR+ CRPC cells but not AR- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR+ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. CONCLUSION: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.

Molecular interplay between NOX1 and autophagy in cadmium-induced prostate carcinogenesis.

Chronic exposure to cadmium (Cd), a class I carcinogen, leads to malignant transformation of normal prostate epithelial cells (RWPE-1). The constant generation of Cd-induced ROS and resulting ER stress induces cellular responses that are needed for cell survival, and autophagy has an important role in this process. However, the mechanisms that regulate Cd-induced ROS and how these differ in terms of acute and chronic cadmium exposure remain unexplained. Here, we show that acute or chronic Cd exposure facilitates NOX1 assembly by activating its cytosolic regulators p47phox and p67phox in RWPE-1 cells. Upregulation of NOX1 complex proteins and generation of ROS activates unfolded protein response (UPR) via phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2α), and selective translation of activating transcription factor 4 (ATF4). Chronic Cd exposure constantly activates NOX1 complex and generates consistent ROS and ER stress that led to defective autophagy, wherein ATG5 expression is downregulated in contrast to acute Cd exposure. As a result, selective/defective autophagy creates depletion of autophagosome-lysosome fusion that gives a survival advantage to transforming cells, which is not available to RWPE-1 cells acutely exposed to Cd. Knockdown of key molecules in a lockstep manner directly affects the most downstream autophagy pathways in transforming cells. Overall, this study demonstrates that assembly of NOX1 complex proteins is indispensable for Cd-induced persistent ROS and controls ER stress-induced defective autophagy in mice and humans.

Machine learning model for classification of predominantly allergic and non-allergic asthma among preschool children with asthma hospitalization.

OBJECTIVE: Asthma is the most frequent chronic airway illness in preschool children and is difficult to diagnose due to the disease's heterogeneity. This study aimed to investigate different machine learning models and suggested the most effective one to classify two forms of asthma in preschool children (predominantly allergic asthma and non-allergic asthma) using a minimum number of features. METHODS: After pre-processing, 127 patients (70 with non-allergic asthma and 57 with predominantly allergic asthma) were chosen for final analysis from the Frankfurt dataset, which had asthma-related information on 205 patients. The Random Forest algorithm and Chi-square were used to select the key features from a total of 63 features. Six machine learning models: random forest, extreme gradient boosting, support vector machines, adaptive boosting, extra tree classifier, and logistic regression were then trained and tested using 10-fold stratified cross-validation. RESULTS: Among all features, age, weight, C-reactive protein, eosinophilic granulocytes, oxygen saturation, pre-medication inhaled corticosteroid + long-acting beta2-agonist (PM-ICS + LABA), PM-other (other pre-medication), H-Pulmicort/celestamine (Pulmicort/celestamine during hospitalization), and H-azithromycin (azithromycin during hospitalization) were found to be highly important. The support vector machine approach with a linear kernel was able to diffrentiate between predominantly allergic asthma and non-allergic asthma with higher accuracy (77.8%), precision (0.81), with a true positive rate of 0.73 and a true negative rate of 0.81, a F1 score of 0.81, and a ROC-AUC score of 0.79. Logistic regression was found to be the second-best classifier with an overall accuracy of 76.2%. CONCLUSION: Predominantly allergic and non-allergic asthma can be classified using machine learning approaches based on nine features.Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Information Seeking Practices and Availability of Smart Devices Among Healthcare Professionals in a Lower-Middle-Income Country: An Analysis From Pakistan.

Introduction Evidence-based medicine (EBM) is a principle that integrates clinical experience with relevant information available to provide adequate healthcare. It requires access to current medical literature. This paper analyzes the information requirements of a lower-middle-income country (LMIC) and the resources available and preferred by medical professionals. Methods A survey-based cross-sectional study was carried out among 160 participants, ranging in expertise from students to attending physicians in Karachi, Pakistan. The survey comprised questions to assess the clinical background, technology access, need for health-related information, and the preference for resources to obtain that information in different scenarios. They were also asked if they use PubMed and their recommended methods to improve information access. Statistical Package for the Social Sciences (SPSS; IBM, NY, USA) software was used for all analyses. Results A basic mobile phone (with limited internet connectivity) was the most common device used at home (n=159; 99.4%) and work (n=141; 88.1%). No smart devices were available to 28 (17.5%) participants at work. Internet connectivity was available for 155 (96.9%) participants at home but only for 118 (73.7%) participants at work. About one-third (n=49; 30.6%) experienced questions arising in practice two to four times a day, and half of the participants (n=80; 50%) were very likely to look up a reference. The most common resource for the majority of given clinical scenarios was a senior colleague. At the same time, medical websites (Medscape, Up-to-Date, WebMD) were the first choice for a non-specific general medical query. About 68.75% (n=110) of participants claimed to use PubMed in daily practice. The most common reason for not using PubMed was the ease of using other search engines (like Google). Conclusions Improved access to the internet and well-reputed journals can enhance the practice of EBM in Pakistan. Limitations of technological access must be considered while designing information resources in lower-middle-income countries.

A Comprehensive Transcriptomic Analysis of Arsenic-Induced Bladder Carcinogenesis.

Arsenic (sodium arsenite: NaAsO2) is a potent carcinogen and a known risk factor for the onset of bladder carcinogenesis. The molecular mechanisms that govern arsenic-induced bladder carcinogenesis remain unclear. We used a physiological concentration of NaAsO2 (250 nM: 33 µg/L) for the malignant transformation of normal bladder epithelial cells (TRT-HU1), exposed for over 12 months. The increased proliferation and colony-forming abilities of arsenic-exposed cells were seen after arsenic exposure from 4 months onwards. Differential gene expression (DEG) analysis revealed that a total of 1558 and 1943 (padj < 0.05) genes were deregulated in 6-month and 12-month arsenic-exposed TRT-HU1 cells. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that cell proliferation and survival pathways, such as the MAPK, PI3K/AKT, and Hippo signaling pathways, were significantly altered. Pathway analysis revealed that the enrichment of stem cell activators such as ALDH1A1, HNF1b, MAL, NR1H4, and CDH1 (p < 0.001) was significantly induced during the transformation compared to respective vehicle controls. Further, these results were validated by qPCR analysis, which corroborated the transcriptomic analysis. Overall, the results suggested that stem cell activators may play a significant role in facilitating the arsenic-exposed cells to gain a survival advantage, enabling the healthy epithelial cells to reprogram into a cancer stem cell phenotype, leading to malignant transformation.

Mechanisms of autophagy and mitophagy in skeletal development, diseases and therapeutics.

Autophagy is a highly evolutionarily conserved process in the eukaryotic cellular system by which dysfunctional organelles are selectively degraded through a series of processes of lysosomal activity and then returned to the cytoplasm for reuse. All cells require this process to maintain cellular homeostasis and promote cell survival during stress responses such as deprivation and hypoxia. Osteoblasts and osteoclasts are two cellular phenotypes in the bone that mediate bone homeostasis. However, an imbalance between osteoblastic bone formation and osteoclastic bone resorption contributes to the onset of bone diseases. Recent studies suggest that autophagy, mitophagy, and selective mitochondrial autophagy may play an essential role in regulating osteoblast differentiation and osteoclast maturation. Autophagic activity dysregulation alters the equilibrium between osteoblastic bone creation and osteoclastic bone resorption, allowing bone disorders like osteoporosis to develop more easily. The current review emphasizes the role of autophagy and mitophagy and their related molecular mechanisms in bone metabolic disorders. In the current review, we emphasize the role of autophagy and mitophagy as well as their related molecular mechanism in bone metabolic disorders. Furthermore, we will discuss autophagy as a target for the treatment of metabolic bone disease and future application in therapeutic translational research.

Prognosis of sexual dimorphism with unfused hyoid bone: Artificial intelligence informed decision making with discriminant analysis.

Depending on the metric and non-metric skeletal features of various bones, forensic experts proposed diverse sex identification methods. The main focus of the present study is to calculate sexual dimorphism in human unfused or disarticulated hyoid bone and compared it with studies conducted by different researchers. For this study, 293 unfused hyoid bones were accumulated and investigated from 173 male and 120 female cadavers of the northwest Indian population from the age of 15 to 80 years. Initially, discriminant analysis was performed on the dataset to predict sex and to get an idea for the crucial variables for sexual dimorphism. Later, significant variables predicted by the discriminant analysis were used for machine learning approaches to improve accuracy for sex determination. The standard scaler method is used for pre-processing of the data before machine learning analysis and to prevent overfitting and underfitting, 70 % of the whole dataset was utilized in the training of the model and the remaining data were used for testing the model. According to the discriminant analysis, body length (BL) and body height (BH) were found to be highly significant for the sex determination and predicted sex with 75.1 % accuracy. However, implementation of machine learning approaches such as the XG Boost classifier increased the accuracy to 83 % with sensitivity, and specificity scores of 0.81 and 0.84, respectively. Moreover, the ROC-AUC score achieved by the XG Boost classifier is 0.89; indicating machine learning investigation can improve the sex determination accuracy up to the appropriate standard.

The role of autophagy in metal-induced urogenital carcinogenesis.

Environmental and/or occupational exposure to metals such as Arsenic (As), Cadmium (Cd), and Chromium (Cr) have been shown to induce carcinogenesis in various organs, including the urogenital system. However, the mechanisms responsible for metal-induced carcinogenesis remain elusive. We and others have shown that metals are potent inducers of autophagy, which has been suggested to be an adaptive stress response to allow metal-exposed cells to survive in hostile environments. Albeit few, recent experimental studies have shown that As and Cd promote tumorigenesis via autophagy and that inhibition of autophagic signaling suppressed metal-induced carcinogenesis. In light of the newly emerging role of autophagic involvement in metal-induced carcinogenesis, the present review focuses explicitly on the mechanistic role of autophagy and potential signaling pathways involved in As-, Cd-, and Cr-induced urogenital carcinogenesis.

Orientation and Alignment dynamics of polar molecule driven by shaped laser pulses.

We review the theoretical status of intense laser induced orientation and alignment-a field of study which lies at the interface of intense laser physics and chemical dynamics and having potential applications such as high harmonic generation, nano-scale processing and control of chemical reactions. The evolution of the rotational wave packet and its dynamics leading to orientation and alignment is the topic of the present discussion. The major part of this article primarily presents an overview of recent theoretical progress in controlling the orientation and alignment dynamics of a molecule by means of shaped laser pulses. The various theoretical approaches that lead to orientation and alignment such as static electrostatic field in combination with laser field(s), combination of orienting and aligning field, combination of aligning fields, combination of orienting fields, application of train of pulses etc. are discussed. It is observed that the train of pulses is quite an efficient tool for increasing the orientation or alignment of a molecule without causing the molecule to ionize. The orientation and alignment both can occur in adiabatic and non-adiabatic conditions with the rotational period of the molecule taken under consideration. The discussion is mostly limited to non-adiabatic rotational excitation (NAREX) i.e. cases in which the pulse duration is shorter than the rotational period of the molecule. We have emphasised on the so called half-cycle pulse (HCP) and square pulse (SQP). The effect of ramped pulses and of collision on the various laser parameters is also studied. We summarize the current discussion by presenting a consistent theoretical approach for describing the action of such pulses on movement of molecules. The impact of a particular pulse shape on the post-pulse dynamics is also calculated and analysed. In addition to this, the roles played by various laser parameters including the laser frequency, the pulse duration and the system temperature etc. are illustrated and discussed. The concept of alignment is extended from one-dimensional alignment to three-dimensional alignment with the proper choice of molecule and the polarised light. We conclude the article by discussing the potential applications of intense laser orientation and alignment.

Discovery of new AKT1 inhibitors by combination of in silico structure based virtual screening approaches and biological evaluations.

Communicated by Ramaswamy H. Sarma.

Diagnostic molecular markers predicting aggressive potential in low-grade prostate cancer.

Currently, clinicians rely on clinical nomograms to stratify progression risk at the time of diagnosis in patients with prostate cancer (CaP). However, these tools may not accurately distinguish aggressive potential in low-grade CaP. The current study determined the diagnostic potential of 3 molecular markers (ROCK1, RUNX3, and miR-301a) in terms of their ability to identify which low-grade tumors are likely to progress. Real-time PCR and immunohistochemical analysis were used to assess ROCK1, RUNX3, and miR-301a expression profiles in 118 serum and needle biopsy specimens. Expressions of ROCK1 and miR-301a were found to be significantly higher in Gleason 6 and 7 CaP as compared to BPH, while an inverse trend was observed with RUNX3. Further, incorporation of all 3 molecular markers significantly improved clinical nomograms' diagnostic accuracy and correlated with disease progression. Hence, in conclusion, the inclusion of these 3 molecular markers identified aggressive phenotype and predicted disease progression in low-grade CaP tumors at the time of diagnosis.

ASR490, a Small Molecule, Overrides Aberrant Expression of Notch1 in Colorectal Cancer.

Notch1 activation triggers significant oncogenic signaling that manifests as enhanced metastatic potential and tumorigenesis in colorectal cancer. Novel small-molecule inhibitors, mainly plant-derived analogs, have low toxicity profiles and higher bioavailability. In this study, we have developed a small molecule, ASR490, by modifying structure of naturally occurring compound Withaferin A. ASR490 showed a growth-inhibitory potential by downregulating Notch1 signaling in HCT116 and SW620 cell lines. Docking studies and thermal shift assays confirmed that ASR490 binds to Notch1, whereas no changes in Notch2 and Notch3 expression were seen in colorectal cancer cells. Notch1 governs epithelial-to-mesenchymal transition signaling and is responsible for metastasis, which was abolished by ASR490 treatment. To further confirm the therapeutic potential of ASR490, we stably overexpressed Notch1 in HCT-116 cells and determined its inhibitory potential in transfected colorectal cancer (Notch1/HCT116) cells. ASR490 effectively prevented cell growth in both the vector (P = 0.005) and Notch1 (P = 0.05) transfectants. The downregulation of Notch1 signaling was evident, which corresponded with downregulation of mesenchymal markers, including N-cadherin and ß-catenin and induction of E-cadherin in HCT-116 transfectants. Intraperitoneal administration of a 1% MTD dose of ASR490 (5 mg/kg) effectively suppressed the tumor growth in control (pCMV/HCT116) and Notch1/HCT116 in xenotransplanted mice. In addition, downregulation of Notch1 and survival signaling in ASR-treated tumors confirmed the in vitro results. In conclusion, ASR490 appears to be a potent agent that can inhibit Notch1 signaling in colorectal cancer.

A Review on Notch Signaling and Colorectal Cancer.

Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according to the difference in their structures; in particular, aberrant activation of Notch1 has been attributed to the severity of CRC. Notch1 activation in CRC is inhibited by small molecule inhibitors that target γ-secretase, an enzyme responsible for the third and last cleavage step of Notch receptors. γ-Secretase also produces the intracellular domain that finally carries out cellular functions by activating downstream effectors. However, most inhibitors block γ-secretase non-selectively and cause severe toxicity. Plant-source-derived small molecules, monoclonal antibodies, biological molecules (such as SiRNAs), and compounds targeting the Notch1 receptor itself or the downstream molecules such as HES1 are some of the options that are in advanced stages of clinical trials. The Negative Regulatory Region (NRR), which plays a central role in the transduction of Notch1 signaling in the event of ligand-dependent and ligand-independent Notch1 processing is also being targeted specifically by monoclonal antibodies (mAbs) to prevent aberrant Notch1 activation. In this review, we discuss the role of Notch1 in CRC, particularly its metastatic phenotype, and how mutations in Notch1, specifically in its NRR region, contribute to the aberrant activation of Notch1 signaling, which, in turn, contributes to CRC pathogenesis. We also discuss prevailing and emerging therapies that target the Notch1 receptor and the NRR region, and we highlight the potential of these therapies in abrogating Notch signaling and, thus, CRC development and progression.