Oxidative stress has long been known as a pathogenic factor of ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC), but the effects of secondary carbonyl lesions receive less ...emphasis. In inflammatory conditions, reactive oxygen species (ROS), such as superoxide anion free radical ( O 2 ∙ - ), hydrogen peroxide (H2O2), and hydroxyl radical ( H O ∙ ), are produced at high levels and accumulated to cause oxidative stress (OS). In oxidative status, accumulated ROS can cause protein dysfunction and DNA damage, leading to gene mutations and cell death. Accumulated ROS could also act as chemical messengers to activate signaling pathways, such as NF-κB and p38 MAPK, to affect cell proliferation, differentiation, and apoptosis. More importantly, electrophilic carbonyl compounds produced by lipid peroxidation may function as secondary pathogenic factors, causing further protein and membrane lesions. This may in turn exaggerate oxidative stress, forming a vicious cycle. Electrophilic carbonyls could also cause DNA mutations and breaks, driving malignant progression of UC. The secondary lesions caused by carbonyl compounds may be exceptionally important in the case of host carbonyl defensive system deficit, such as aldo-keto reductase 1B10 deficiency. This review article updates the current understanding of oxidative stress and carbonyl lesions in the development and progression of UC and CAC.
Aldo‐keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, ...we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time‐resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha‐fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early‐stage HCC and AFP‐negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion: AKR1B10 is a potent serum marker for detection of HCC and early‐stage HCC, with better diagnostic performance than AFP.
Exosomes have been considered as novel and potent vehicles of intercellular communication, instead of "cell dust". Exosomes are consistent with anucleate cells, and organelles with lipid bilayer ...consisting of the proteins and abundant lipid, enhancing their "rigidity" and "flexibility". Neighboring cells or distant cells are capable of exchanging genetic or metabolic information via exosomes binding to recipient cell and releasing bioactive molecules, such as lipids, proteins, and nucleic acids. Of note, exosomes exert the remarkable effects on lipid metabolism, including the synthesis, transportation and degradation of the lipid. The disorder of lipid metabolism mediated by exosomes leads to the occurrence and progression of diseases, such as atherosclerosis, cancer, non-alcoholic fatty liver disease (NAFLD), obesity and Alzheimer's diseases and so on. More importantly, lipid metabolism can also affect the production and secretion of exosomes, as well as interactions with the recipient cells. Therefore, exosomes may be applied as effective targets for diagnosis and treatment of diseases. Video abstract.
Curcumin is an anticancer agent, but adverse effects and low bioavailability are its main drawbacks, which drives efforts in chemical modifications of curcumin. This study evaluated antiproliferative ...activity and cancer cell selectivity of a curcumin derivative, curcumin nicotinate (CN), in which two niacin molecules were introduced. Our data showed that CN effectively inhibited proliferation and clonogenic growth of colon (HCT116), breast (MCF-7) and nasopharyngeal (CNE2, 5-8F and 6-10B) cancer cells with IC
at 27.7 μM, 73.4 μM, 64.7 μM, 46.3 μM, and 31.2 μM, respectively. In cancer cells, CN induced apoptosis and cell cycle arrest at G2/M phase through a p53-mediated mechanism, where p53 was activated, p21 and pro-apoptotic proteins Bid and Bak were upregulated, and PARP was cleaved. In non-transformed human mammary epithelial cells MCF10A, CN at 50 µM had no cytotoxicity and p53 was not activated, but curcumin at 12.5 µM activated p53 and p21 and inhibited MCF10A cell growth. These data suggest that CN inhibits cell growth and proliferation through p53-mediated apoptosis and cell cycle arrest with cancer cell selectivity.
The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been ...discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents.
Strategies in the designing of multi-targeted agents. Display omitted
•Multi-targeted agents contain privileged substructures and pharmacophores that are relevant to multiple targets.•More and more of all marketed medicines can be classified as multi-targeted agents.•The commonness of multi-targeted agents is multi-pharmacophore mode.
Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The senescence and death of ECs are ...not only adverse outcomes, but also causal contributors to endothelial dysfunction, an early risk marker of atherosclerosis. The pathophysiological process of EC senescence involves both structural and functional changes and has been linked to various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, and aberrant metabolite sensing and signaling. Multiple forms of EC death have been documented in atherosclerosis, including autophagic cell death, apoptosis, pyroptosis, NETosis, necroptosis, and ferroptosis. Despite this, the molecular mechanisms underlying EC senescence or death in atherogenesis are not fully understood. To provide a comprehensive update on the subject, this review examines the historic and latest findings on the molecular mechanisms and functional alterations associated with EC senescence and death in different stages of atherosclerosis.
Aspirin and curcumin have been reported to be beneficial to anti-aging in a variety of biological models. Here, we synthesized a novel compound, curcumin acetylsalicylate (CA), by combining aspirin ...and curcumin. We characterized how CA affects the lifespan of
(
) worms. Our results demonstrated that CA extended the lifespan of worms in a dose-dependent manner and reached its highest anti-aging effect at the concentration of 20 μM. In addition, CA reduced the deposition of lipofuscin or "age pigment" without affecting the reproductivity of worms. CA also caused a rightward shift of
lifespan curves in the presence of paraquat-induced (5 mM) oxidative stress or 37 °C acute heat shock. Additionally, CA treatment decreased the reactive oxygen species (ROS) level in
and increased the expression of downstream genes superoxide dismutase
, glutathione S-transferase
, heat shock protein
and catalase-1
. Notably, CA treatment resulted in nuclear translocation of the DAF-16 transcription factor, which is known to stimulate the expression of SOD-3, GST-4, HSP-16, and CTL-1. CA did not produce a longevity effect in
mutants. In sum, our data indicate that CA delayed the aging of
without affecting reproductivity, and this effect may be mediated by its activation of DAF-16 and subsequent expression of antioxidative genes, such as
and
. Our study suggests that novel anti-aging drugs may be developed by combining two individual drugs.
Epidemiological studies have shown that plasma HDL‐C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol ...regulation, high‐density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti‐inflammation, antioxidation, immune‐modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor‐associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.
The tumor microenvironment (TME) compose of tumor cells, nontumor cells, and extracellular matrix (ECM). HDL may play roles in cancer development by acting with both tumor and nontumor cells. In the submitted paper, we summarized clinical observations and carefully dissected possible mechanisms based on experimental data obtained in levels from cellular, organ, and genetically engineered animal models. A moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.
Aldo‐keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the molecular mechanisms of action. Herein we report that ...AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF‐7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT‐20 and colon cancer cells HCT‐8 led to decrease of these lipid messengers. Qualitative analyses by liquid chromatography‐mass spectrum (LC‐MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCµ (Ser744/748), and PKCα/βII (Thr638/641) and activity of the PKC‐mediated c‐Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho‐p90RSK, phospho‐MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho‐p90RSK, phospho‐MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two‐dimension (2D) and three‐dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG‐mediated PKC/ERK signaling pathway.
Obesity is well‐known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, ...colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity‐related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity‐related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy.
1.
Adipose tissue accumulation is not a necessarily carcinogenic factor but may act as a protective factor for multiple malignancies. Whether it is a foe or a friend depends on the functional status of adipose tissue and/or cells. Definitely, the aberrant phenotype and function alteration of adipose tissue induced by cancer is a key factor leading to cancer progression.
2.
The underlying mechanisms linking dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity‐related microenvironment, adipokine secretion disorder and browning of adipose tissue. Thus, the increased morbidity and mortality of obesity‐related cancers are mostly attributed to dysfunctional adipose tissue.
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