Figure - available from: Oxidative Medicine and Cellular Longevity
This content is subject to copyright. Terms and conditions apply.
The association between pO2 levels and tissue size of CRC and/or protein levels of biomarkers in different-size CRC tissues. (a) The correlation between pO2 levels and tissue size of CRC. (b) The correlation between pO2 levels and the protein level of HIF-1 alpha in different-size CRC tissues. (c) The correlation between pO2 levels and the protein level of CK20 in different-size CRC tissues. (d) The correlation between pO2 levels and the protein level of Ki67 in different-size CRC tissues. Small-size CRC tissues (<300 mm³, n=36); middle-size CRC tissues (301–600 mm³, n=60); big-size CRC tissues (601–900 mm³, n=47); super-size CRC tissues (>900 mm³, n=25). Statistical values were measured by using a test for Spearman’s rank correlation. If the values were between −1 and −0.5, there was a strong negative relation. If the values were between 0.5 and 1, there was a strong positive relation.
Source publication
Hypoxia is prognostically important in colorectal cancer (CRC) therapy. Partial oxygen pressure (pO 2 ) is an important parameter of hypoxia. The correlation between pO 2 levels and expression levels of prognostic biomarkers was measured in CRC tissues. Human CRC tissues were collected and pO 2 levels were measured by OxyLite. Three methods for tis...
Citations
... Ki-67 exerted a vital role in the initiation and development of CC and was related to tumor cell invasion and angiogenesis. 28 Our research manifested that the positive expression of Ki-67 in CC cells was attenuated by crocin. Moreover, mitochondrial dysfunction was found in apoptosis induced by many factors, which is considered to be the key to irreversible cell death. ...
Crocin has been reported to have therapeutic effects on multiple cancers including colon cancer, but its specific mechanism is still ambiguous and needs to be further explored. Human colorectal adenocarcinoma cells (HCT-116) and human normal colonic epithelial cells (CCD841) were first treated with increasing concentrations of crocin. Subsequently, with 150 and 200 μM of crocin, the cell vitality was examined by cell counting kit 8. Cell apoptosis and proliferation were tested by TUNEL staining and colony formation assay, respectively. The expression of Ki-67 was assessed by immunofluorescence. Enzyme-linked immunosorbent assay was used to evaluate the level of inflammation- and oxidative-related factors. The reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) were examined by flow cytometer. Janus kinase (JAK), signal transducer and activator of transcription 3 (STAT3), and extracellular regulated protein kinases (ERK) in HCT-116 cells were tested by Western blot. Different concentrations of crocin barely affected the CCD841 cell vitality, while crocin restrained the HCT-116 cells vitality, proliferation and the expression of Ki-67, while inducing apoptosis in a concentration-dependent manner. Moreover, the contents of inflammation- and oxidative-related factors in HCT-116 cells were largely blunted by crocin that enhanced ROS and restrained the MMP and suppressed p-JAK2/JAK2, p-STAT3/STAT3, and p-ERK/ERK expression in HCT-116 cells. Crocin induced apoptosis and restored mitochondrial function in HCT-116 cells via repressing the JAK pathway. If the threptic effect works in patients, it could herald a new, effective treatment for colon cancer, improving the patients’ prognosis and quality of life.
... The copyright holder for this preprint this version posted August 31, 2023. ; https://doi.org/10.1101/2023.08.29.555442 doi: bioRxiv preprint Effect of culture environment on the expression of cancer-related genes CRC tumors are characterized by loss of tissue architecture 21 and heterogeneous oxygen distribution ranging from hypoxia to near anoxia due to poorly developed vasculature 22 . These alterations are associated with changes in the expression of (which was not certified by peer review) is the author/funder. ...
Changes in the abundance of certain bacterial species within the colorectal microbiota correlate with colorectal cancer development. While carcinogenic mechanisms of single pathogenic bacteria have been characterized in vitro, limited tools are available to investigate interactions between pathogenic bacteria and both commensal microbiota and colonocytes in a physiologically relevant tumor microenvironment. To address this, we developed a microfluidic device that can be used to co-culture colonocytes and colorectal microbiota. The device was used to explore the effect of Fusobacterium nucleatum, an opportunistic pathogen associated with colorectal cancer development in humans, on colonocyte gene expression and microbiota composition. F. nucleatum altered the transcription of genes involved in cytokine production, epithelial-to-mesenchymal transition, and proliferation in colonocytes in a contact-independent manner; however, most of these effects were diminished by the presence of fecal microbiota. Interestingly, F. nucleatum significantly altered the abundance of multiple bacterial clades associated with mucosal immune responses and cancer development in the colon. Our results highlight the importance of evaluating the potential carcinogenic activity of pathogens in the context of a commensal microbiota, and the potential to discover novel inter-species microbial interactions in the colorectal cancer microenvironment.
... Additionally, carbon dioxide partial pressure and bicarbonate concentration were also decreased, but not significantly ( Figure 4). Partial oxygen pressure and oxygen saturation are important and sensi-tive parameters of hypoxia, 30 and neurons are the most sensitive to hypoxia among the cells. 31 This analysis of arterial blood gas before and after surgery showed a certain degree of hypoxia in individuals with PFO that could be relieved after PFO closure, which is beneficial for patients with NCDEMs. ...
Patent foramen ovale (PFO) is a congenital defect in the partition between two atria, which may cause right‐to‐left shunt (RLS), leading to neurological chronic diseases with episodic manifestations (NCDEMs), such as migraine and epilepsy. However, whether PFO closure was effective in improving NCDEMs and the mechanism were unclear. Twenty‐eight patients with migraine or epilepsy who underwent PFO closure were recruited. Notably, approximately half of patients received 50% or more reduction in seizure or headache attacks. Meanwhile, the postoperative blood oxygen partial pressure and oxygen saturation were elevated after PFO closure. Multisite (peripheral, right, and left atrial) and multitimepoint (before and after surgery) plasma proteomics from patients showed that the levels of free hemoglobin and cell adhesion molecules (CAMs) were significantly increased after PFO closure, which may be related to the relief of the hypoxic state. Furtherly, the omics data from multiple brain regions of mice revealed that a large number of proteins were differentially expressed in the occipital region in response to PFO, including redox molecules and CAMs, suggesting PFO‐caused hypoxia may have great impacts on occipital region. Collectively, PFO may cause NCDEMs due to RLS‐induced hypoxia, and PFO closure could prevent RLS to improve migraine and epilepsy.
... 43,44 PaO 2 is one of the most sensitive parameters of hypoxia. 45 PWEs with RLS showed lower PaO 2 in our study, which might explain the result that RLS is an independent risk factor for DRE. ...
Objective
A right‐to‐left shunt (RLS) can mediate the hypoxic state, and hypoxemia is relevant for the development of drug‐resistant epilepsy (DRE). The objective of this study was to identify the relationship between RLS and DRE and further investigate the contribution of RLS to the oxygenation state in patients with epilepsy (PWEs).
Methods
We performed a prospective observational clinical study of PWEs who underwent contrast medium transthoracic echocardiography (cTTE) between January 2018 and December 2021 at West China Hospital. The collected data included demographics, clinical features of epilepsy, antiseizure medications (ASMs), RLS identified by cTTE, electroencephalography (EEG), and magnetic resonance imaging (MRI). Arterial blood gas was also assessed in PWEs with or without RLS. The association between DRE and RLS was quantified using multiple logistic regression, and the parameters of oxygen levels were furtherly analyzed in PWEs with or without RLS.
Results
A total of 604 PWEs who completed cTTE were included in the analysis, of which 265 were diagnosed with RLS. The proportion of RLS was 47.2% in the group of DRE, and the proportion of RLS was 40.3% in the group of non‐DRE. Having RLS was associated with DRE in multivariate logistic regression analysis (adjusted OR = 1.53, P = 0.045). In the analysis of blood gas, the partial oxygen pressure in PWEs with RLS was lower than those without RLS (88.74 mmHg versus 91.84 mmHg, P = 0.044).
Significance
Right‐to‐left shunt could be an independent risk factor of DRE, and low oxygenation might be a possible reason.
... These predominantly include the upregulation of HIF-1α (104), nuclear factor-kappa B (NF-κB) (105,106), and reactive oxygen species (ROS); the decreased availability of nitric oxide (107); or complex changes in ion channel activity (108). It has been shown multiple times in both cell culture and in vivo that these processes are very tightly governed by O 2 concentration (109)(110)(111)(112). Namely, HIF-1 expression, which is a central molecule in cellular signaling during hypoxia, increases exponentially as oxygen tension decreases (113). ...
Hypoxia is characterized as insufficient oxygen delivery to tissues and cells in the body and is prevalent in many human physiology processes and diseases. Thus, it is an attractive state to experimentally study to understand its inner mechanisms as well as to develop and test therapies against pathological conditions related to hypoxia. Animal models in vivo fail to recapitulate some of the key hallmarks of human physiology, which leads to human cell cultures; however, they are prone to bias, namely when pericellular oxygen concentration (partial pressure) does not respect oxygen dynamics in vivo. A search of the current literature on the topic revealed this was the case for many original studies pertaining to experimental models of hypoxia in vitro. Therefore, in this review, we present evidence mandating for the close control of oxygen levels in cell culture models of hypoxia. First, we discuss the basic physical laws required for understanding the oxygen dynamics in vitro, most notably the limited diffusion through a liquid medium that hampers the oxygenation of cells in conventional cultures. We then summarize up-to-date knowledge of techniques that help standardize the culture environment in a replicable fashion by increasing oxygen delivery to the cells and measuring pericellular levels. We also discuss how these tools may be applied to model both constant and intermittent hypoxia in a physiologically relevant manner, considering known values of partial pressure of tissue normoxia and hypoxia in vivo, compared to conventional cultures incubated at rigid oxygen pressure. Attention is given to the potential influence of three-dimensional tissue cultures and hypercapnia management on these models. Finally, we discuss the implications of these concepts for cell cultures, which try to emulate tissue normoxia, and conclude that the maintenance of precise oxygen levels is important in any cell culture setting.
... Low Ki-67 expression in Duke B colorectal cancer was associated with poor prognosis [32] . In addition, Ki-67 combined with HIF-1α and CK20 can be used as a prognostic biomarker in colorectal cancer tissue microenvironment [35] . Therefore, the expression of tissue Ki-67 and its clinical prognosis were still uncertain. ...
... An imbalance between cell proliferation and cell death would result in tumor formation and growth [41]. And, hypoxia is a common characteristic in tumor microenvironment and could induce the upregulation of HIF-1 , which induces angiogenesis and also activates many other target genes mediating cell proliferation and apoptosis of cancer [42][43][44]. Cleaved caspase 3 is considered as an apoptosis marker and Ki 67 is considered as a proliferative cell marker in tumor formation [41,45,46]. Ki67 could be highly induced under hypoxia [46]. ...
... Ki67 could be highly induced under hypoxia [46]. Indeed, HIF-1 could enhance cell proliferation and broke the balance between proliferation and apoptosis, and the increased expression of Ki67 and high level of HIF-1 in cancer predicts poor prognosis in many cancers, such as pancreatic cancer, colorectal cancer, breast cancer, and so on [44,[47][48][49]. In this study, the protein expression of Ki67 in the pyloric gastric mucosa of CAG was significantly increased, while the protein expression of cleaved caspase 3 was significantly decreased compared with that of control rats, indicating disturbed cell homeostasis of proliferation and apoptosis existed in pyloric gastric mucosa of CAG rats with precancerous lesions and also indicating the existence of atypical hyperplasia and intestinal metaplasia. ...
Aim:
Chronic atrophic gastritis (CAG), the precancerous lesions of gastric cancer, plays an important role in the stepwise process of gastric cancer. The ancient Chinese medicine believes in that Qi deficiency and blood stasis are involved in the pathogenesis of CAG. Weiqi decoction, a classical formula from Longhua Hospital, could supplement Qi and activate blood circulation of human beings and has been used for treating CAG in clinic over twenty years. The study aims to clarify the effect and underlying molecular mechanism of Weiqi decoction on CAG rats.
Methods:
Forty-eight male Wistar rats were divided randomly into six groups: control group, model group, folic acid group, and WQD-treated groups at doses of 4 g/kg, 2 g/kg, and 1 g/kg, with eight rats in each group. MNNG and saturated NaCl were used to induce CAG rat with precancerous lesion (intestinal metaplasia and dysplasia). After 40 weeks, gastric mucosal blood flow was measured using Laser Doppler Flowmetry. The pathological changes of the gastric mucosa were identified by H&E staining and AB-PAS staining. The protein expression of COX-2, HIF-1α, VEGFR1, VEGFR2, Ki67, and cleaved caspase 3 in the gastric tissues was measured by western blotting approach. Gene expression of COX-2, HIF-1α, VEGF, VEGFR1, VEGFR2, Ang-1, and Ang-2 was detected by using Quantitative PCR method. The PGE2 concentrations in serum were detected by ELISA method. The protein expression of Ki67 in gastric mucosa was also detected by immunohistochemistry.
Results:
Compared with control rats, atrophy and intestinal metaplasia as well as the microcirculation disturbance of gastric mucosa were induced in the stomach of CAG rats identified by the H&E and AB-PAS staining as well as microcirculation measurement, which could be significantly attenuated by WQD treatment. Moreover, compared with the control group, the protein and gene expression of COX-2, HIF-1α, VEGFR1, and VEGFR2 in gastric tissues of pylorus was obviously increased and the serum PGE2 level was significantly deceased in CAG rats, which could be significantly counteracted by WQD administration. However, the gene expression of Ang-1 and Ang-2 was not significant difference between control rats and CAG rats, and WQD also had no significant effect on the gene expression of Ang-1 and Ang-2. Furthermore, the increased cell proliferation marked by upregulated protein expression of Ki67 and decreased cell apoptosis marked by downregulated protein expression of cleaved caspase 3 in stomach of pylorus in CAG rats were obviously reversed by WQD treatment.
Conclusion:
WQD attenuated CAG with precancerous lesion through regulating gastric mucosal blood flow disturbance and HIF-1α signaling pathway.
... Colon cancer tumors are even more hypoxic than breast cancer tumors [49][50][51]. The average oxygen partial pressure of normal mammary tissue is 60 mmHg, whereas the average oxygen partial pressure in colon cancer tumors is 30 mmHg [49]. ...
... The average oxygen partial pressure of normal mammary tissue is 60 mmHg, whereas the average oxygen partial pressure in colon cancer tumors is 30 mmHg [49]. However, in patients with colon cancer, the degree of hypoxia in colon cancer tumor tissue is more obvious, with an average oxygen partial pressure of only approximately 10 mmHg [50,51]. Therefore, to verify the efficacy of the two-stage PFTBA@HSA oxygen delivery system, a more hypoxic CT26 colon cancer model was chosen to study the radio-sensitization effect of PFTBA@HSA. ...
Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two-stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles.
Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used.
Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor-bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O2 as the second-stage of oxygen delivery.
Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia.
... Кроме того, опухолевое микроокружение участвует в формировании опухолевой резистентности [4]. В клетках микроокружения изменяется уровень пролиферации, дифференцировки, экспрессия гипоксия-индуцибельного фактора [5]. Несколько видов стромальных клеток, включая эндотелиальные, клетки иммунной системы и фибробласты, выделяющие факторы роста, способствующих росту и пролиферации злокачественных клеток в микроокружении опухоли, признаны возможными объектами для снижения резистентности к противоопухолевой терапии и рецидива опухоли. ...
Tumor microenvironment is known to be an active participant of tumor development. Tumor microenvironment is functional cell community interacting with cancer cells and promoting proliferation, invasion and metastasis of tumor cells. In the article features of Ki-67 and NFE2L2 expression levels in target organs of melanoma metastasis in premetastatic phase are investigated. Increased Ki-67expression levels in lung tissue, liver and kidneys and decreased NFE2L2 levels in liverandkidneys can be the markers of structural and functional reorganization of melanoma metastasis target organs in premetastatic phase of melanoma development.
... In solid tumors, hypoxia is a common feature that leads to oxidative stress and results in redox imbalance (19). It has been demonstrated that hypoxia is involved in the growth and aggressiveness of many types of cancer (20)(21)(22). In this study, two OSCC cell lines, CAL33 and HSC6, were cultured under hypoxic conditions for 12, 24 and 48 h. ...
The majority of cases of oral squamous cell carcinoma (OSCC) develop from oral potentially malignant disorders, which have been confirmed to be involved in chronic oxidative stimulation. However, no effective treatment approaches have been used to prevent the development of dysplasia into cancerous lesions thus far. In the present study, a well-established OSCC model was used to detect proteomics profiles at different stages during oral malignant transformation. Of the 15 proteins that were found to be upregulated in both the dysplasia and carcinoma stages, the oxidative stress-associated proteins, thioredoxin-1 (Trx-1), glutaredoxin-1 and peroxiredoxin-2 were note as the proteins with significant changes in expression Trx-1 was identified to be the most significantly upregulated protein in the precancerous stage. Validation experiments confirmed that Trx-1 was overexpressed both in dysplasia and cancerous tissue samples, and the inhibition of Trx-1 was able to promote the apoptosis of OSCC cells under hypoxic conditions. Furthermore, the experimental application of a Trx-1-specific inhibitory agent in an animal model led to a lower cancerization rate and a delay in tumor formation. The possible mechanisms were associated with the increased apoptosis via a reactive oxygen species (ROS)-dependent pathway. Taken together, our findings indicate that Trx-1 may be an important target for delaying oral malignant transformation, which provides a novel therapeutic strategy for the prevention and treatment of OSCC.
