Trp53 Deletion Promotes Exacerbated Colitis, Facilitates Lgr5+ Cancer Stem Cell Expansion, and Fuels Tumorigenesis in AOM/DSS-Induced Colorectal Cancer.

Colorectal cancer CRC remains one of the leading causes of cancer-related deaths worldwide, with chronic intestinal inflammation identified as a major risk factor. Notably, the tumor suppressor undergoes mutation at higher rates and earlier stages during human inflammation-driven colon tumorigenesis than in sporadic cases. We investigated whether deleting affects inflammation-induced tumor growth and the expression of Lgr5+ cancer stem cells in mice.

p53 Signaling on Microenvironment and Its Contribution to Tissue Chemoresistance.

Chemoresistance persists as a significant, unresolved clinical challenge in many cancer types. The tumor microenvironment, in which cancer cells reside and interact with non-cancer cells and tissue structures, has a known role in promoting every aspect of tumor progression, including chemoresistance. However, the molecular determinants of microenvironment-driven chemoresistance are mainly unknown.

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%.

Inhibition of SARS-CoV-2 infection in human iPSC-derived cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoarchitecture and beating.

SARS-CoV-2 infects cardiac cells and causes heart dysfunction. Conditions such as myocarditis and arrhythmia have been reported in COVID-19 patients. The Sigma-1 receptor (S1R) is a ubiquitously expressed chaperone that plays a central role in cardiomyocyte function.

WIN 55,212-2 shows anti-inflammatory and survival properties in human iPSC-derived cardiomyocytes infected with SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can infect several organs, especially impacting respiratory capacity. Among the extrapulmonary manifestations of COVID-19 is myocardial injury, which is associated with a high risk of mortality. Myocardial injury, caused directly or indirectly by SARS-CoV-2 infection, can be triggered by inflammatory processes that lead to damage to the heart tissue.

3-D Endoluminal Ultrasound Biomicroscopic Imaging and Volumetry of Mouse Colon Tumors.

Currently, colonoscopy is considered the gold standard procedure for diagnosis of colorectal cancer (CRC), the third most common cancer in the United States. However, this technique fails to detect flat adenomas, serrated polyps and advanced adenomas, with miss rates of 34%, 27% and 14%, respectively. These miss rates, more frequent than previously supposed, suggest the need for new CRC screening tools.

Non-permissive SARS-CoV-2 infection in human neurospheres.

Coronavirus disease 2019 (COVID-19) was initially described as a viral infection of the respiratory tract. It is now known, however, that several other organs are affected, including the brain. Neurological manifestations such as stroke, encephalitis, and psychiatric conditions have been reported in COVID-19 patients, but the neurotropic potential of the virus is still debated.

Non-permissive SARS-CoV-2 infection in human neurospheres.

Coronavirus disease 2019 (COVID-19) was initially described as a viral infection of the respiratory tract. It is now known, however, that several other organs are affected, including the brain. Neurological manifestations such as stroke, encephalitis, and psychiatric conditions have been reported in COVID-19 patients, but the neurotropic potential of the virus is still debated.

Detection of Mice Colorectal Tumors by Endoluminal Ultrasound Biomicroscopic Images and Quantification of Image Augmented Gray Values Following Injection of VEGFR-2 Targeted Contrast Agent.

Rationale And Objectives: Ultrasound biomicroscopy (UBM) is a noninvasive imaging technique that can be applied in detecting colonic tumors and, once associated with an ultrasound contrast agent (UCA), can identify the molecular expression of cancer-related biomarkers, such as the vascular endothelial growth factor receptor 2 (VEGFR-2). The present work aimed to detect colonic tumors and quantify augmented gray values of endoluminal UBM (eUBM) images from colonic tumors following the injection of VEGFR-2 targeted UCA (VEGFR2-UCA) into a mouse model of colorectal cancer.

Material And Methods: A 40 MHz miniprobe catheter inserted through the biopsy channel of a pediatric flexible bronchofiberscope was used to obtain colonoscopic and B-mode eUBM images simultaneously.

Zika virus infection leads to mitochondrial failure, oxidative stress and DNA damage in human iPSC-derived astrocytes.

Zika virus (ZIKV) has been extensively studied since it was linked to congenital malformations, and recent research has revealed that astrocytes are targets of ZIKV. However, the consequences of ZIKV infection, especially to this cell type, remain largely unknown, particularly considering integrative studies aiming to understand the crosstalk among key cellular mechanisms and fates involved in the neurotoxicity of the virus. Here, the consequences of ZIKV infection in iPSC-derived astrocytes are presented.

The Chalcone Lonchocarpin Inhibits Wnt/β-Catenin Signaling and Suppresses Colorectal Cancer Proliferation.

The deregulation of the Wnt/β-catenin signaling pathway is a central event in colorectal cancer progression, thus a promising target for drug development. Many natural compounds, such as flavonoids, have been described as Wnt/β-catenin inhibitors and consequently modulate important biological processes like inflammation, redox balance, cancer promotion and progress, as well as cancer cell death. In this context, we identified the chalcone lonchocarpin isolated from as a Wnt/β-catenin pathway inhibitor, both in vitro and in vivo.

Highlights in Resistance Mechanism Pathways for Combination Therapy.

Combination chemotherapy has been a mainstay in cancer treatment for the last 60 years. Although the mechanisms of action and signaling pathways affected by most treatments with single antineoplastic agents might be relatively well understood, most combinations remain poorly understood. This review presents the most common alterations of signaling pathways in response to cytotoxic and targeted anticancer drug treatments, with a discussion of how the knowledge of signaling pathways might support and orient the development of innovative strategies for anticancer combination therapy.

Specific Cytostatic and Cytotoxic Effect of Dihydrochelerythrine in Glioblastoma Cells: Role of NF-κB/β-catenin and STAT3/IL-6 Pathways.

Background: A glioblastoma is a primary CNS tumor that is more aggressive and lethal than other brain tumors. Its location, rapid proliferation, invasive growth, angiogenesis and immunosuppression are the main factors that limit its treatment, making it a major challenge to neuro-oncology.

Objective: This study investigated the in vitro effects of the alkaloid dihydrochelerythrine (DHC), which is extracted from Zanthoxylum stelligerum, on the viability, proliferation, cell death and β-catenin, NFκB, STAT3/pSTAT3 and interleukins roles.

Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells.

Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Current chemotherapy regimens include a combination of 5-fluorouracil (5-FU) and cisplatin, but more efficient therapy strategies are needed to increase 5-year survival. Alterations in the signaling pathway of the tumor suppressor gene Rb-1, which encodes a phosphoprotein (pRB) that negatively regulates the G1/S transition of the cell cycle, are present in 70% of all tumors, but its role in esophageal cancer is still unclear.

The Complex Link between Apoptosis and Autophagy: a Promising New Role for RB.

Physiological processes, as autophagy, proliferation and apoptosis are affected during carcinogenesis. Restoring cellular sensitivity to apoptotic stimuli, such as the antineoplastic cocktails, has been explored as a strategy to eliminate cancer cells. Autophagy, a physiological process of recycling organelles and macromolecules can be deviated from homeostasis to support cancer cells survival, proliferation, escape from apoptosis, and therapy resistance.

Isoquercitrin suppresses colon cancer cell growth in vitro by targeting the Wnt/β-catenin signaling pathway.

Flavonoids are plant-derived polyphenolic molecules that have potential biological effects including anti-oxidative, anti-inflammatory, anti-viral, and anti-tumoral effects. These effects are related to the ability of flavonoids to modulate signaling pathways, such as the canonical Wnt signaling pathway. This pathway controls many aspects of embryonic development and tissue maintenance and has been found to be deregulated in a range of human cancers.

Simultaneous follow-up of mouse colon lesions by colonoscopy and endoluminal ultrasound biomicroscopy.

Aim: To evaluate the potential use of colonoscopy and endoluminal ultrasonic biomicroscopy (eUBM) to track the progression of mouse colonic lesions.

Methods: Ten mice were treated with a single azoxymethane intraperitoneal injection (week 1) followed by seven days of a dextran sulfate sodium treatment in their drinking water (week 2) to induce inflammation-associated colon tumors. eUBM was performed simultaneously with colonoscopy at weeks 13, 17-20 and 21.

Immunohistochemical analysis of retinoblastoma and β-catenin as an assistant tool in the differential diagnosis between Crohn's disease and ulcerative colitis.

In about 10-15% of patients with inflammatory bowel diseases (IBD) there is no clear definitive differential diagnosis between Crohn's disease (CD) and ulcerative colitis (UC) and the disease is classified as indeterminate colitis. Since pharmacological and surgical treatments differ in CD and UC, establishing a correct diagnosis is critical. The aim of this work was to access the expression profile of proteins involved in colonic inflammation and cancer in samples from CD and UC.

Nuclear expression of β-catenin promotes RB stability and resistance to TNF-induced apoptosis in colon cancer cells.

Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF-induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of β-catenin in tumors of wild-type, but not mutant, mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma (RB) protein, despite similar frequencies of β-catenin exon-3 mutations in these two genetic backgrounds.

Implications of aneuploidy for stem cell biology and brain therapeutics.

Understanding the cellular basis of neurological disorders have advanced at a slow pace, especially due to the extreme invasiveness of brain biopsying and limitations of cell lines and animal models that have been used. Since the derivation of pluripotent stem cells (PSCs), a novel source of cells for regenerative medicine and disease modeling has become available, holding great potential for the neurology field. However, safety for therapy and accurateness for modeling have been a matter of intense debate, considering that genomic instability, including the gain and loss of chromosomes (aneuploidy), has been repeatedly observed in those cells.

In vivo endoluminal ultrasound biomicroscopic imaging in a mouse model of colorectal cancer.

Rationale And Objectives: The gold-standard tool for colorectal cancer detection is colonoscopy, but it provides only mucosal surface visualization. Ultrasound biomicroscopy allows a clear delineation of the epithelium and adjacent colonic layers. The aim of this study was to design a system to generate endoluminal ultrasound biomicroscopic images of the mouse colon, in vivo, in an animal model of inflammation-associated colon cancer.

Features of in vitro ultrasound biomicroscopic imaging and colonoscopy for detection of colon tumor in mice.

The present work tested the capability of ultrasound biomicroscopy (UBM), at 45 MHz, to provide cross-sectional images with appropriate resolution and contrast to detect tumors and determine their penetration depths on the colon of mice, Mus musculus (Linnaeus 1758), treated with carcinogen for colon tumor induction. B-mode images were obtained, in vitro, from each animal (13 treated and 4 untreated) colon opened longitudinally and immersed in saline solution at room temperature. Prior to UBM inspection, all animals were also examined by colonoscopy.

Agathisflavone enhances retinoic acid-induced neurogenesis and its receptors α and β in pluripotent stem cells.

Flavonoids have key functions in the regulation of multiple cellular processes; however, their effects have been poorly examined in pluripotent stem cells. Here, we tested the hypothesis that neurogenesis induced by all-trans retinoic acid (RA) is enhanced by agathisflavone (FAB, Caesalpinia pyramidalis Tull). Mouse embryonic stem (mES) cells and induced pluripotent stem (miPS) cells growing as embryoid bodies (EBs) for 4 days were treated with FAB (60 μM) and/or RA (2 μM) for additional 4 days.

Inhibition of MAPK/ERK, PKC and CaMKII signaling blocks cytolysin-induced human glioma cell death.

Background: Cytolysins are pore-forming toxins that show anticancer activity by a mechanism hitherto poorly investigated.

Materials And Methods: To investigate how cytolysins are cytotoxic to resistant cancer cells, proliferation and cell death were evaluated on U87 glioblastoma cells treated with toxin Bc2 or equinatoxin-II (EqTx-II).

Results: Toxins Bc2 and EqTx-II decreased cell viability and increased lactate dehydrogenase (LDH) release in a concentration-dependent manner.