Oscillatory Dynamics and Regulatory Mechanisms of the p53-Per2 Network in DNA-Damaged Cells.

Circadian rhythm disruptions are linked to increased cancer risk and unfavorable prognosis in patients with cancer, highlighting the critical role of the interplay between the circadian rhythm factor Per2 and the tumor suppressor p53. This brief presents, for the first time, a mathematical model to capture the dynamics of the p53-Per2 network in DNA-damaged cells. The model accurately describes the different stages of the process from unstressed cells to cellular repair and finally to apoptosis as the degree of DNA damage increases. Furthermore, it is found that increasing the inhibition of Per2 by p53 leads to the phase advance of Per2 oscillations, whereas by modulating the inhibition of Mdm2 by Per2, an independent amplitude modulation of active p53 can be achieved, with the range of modulation increasing with the strength of the inhibition. Moreover, the effects of time delays inherent in the transcription, translation, and nuclear translocation of Per2 on the circadian rhythm of DNA-damaged cells are quantitatively investigated by theoretical analyses. It is found that time delays can induce stable oscillations through a supercritical Hopf bifurcation, thereby maintaining the circadian function of DNA-damaged cells and enhancing their DNA-damage repair capacity. This study proposes new insights into cancer prevention and treatment strategies.

Treatment strategies for clear cell renal cell carcinoma: Past, present and future.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent histological subtype of kidney cancer, which is prone to metastasis, recurrence, and resistance to radiotherapy and chemotherapy. The burden it places on human health due to its refractory nature and rising incidence rate is substantial. Researchers have recently determined the ccRCC risk factors and optimized the clinical therapy based on the disease's underlying molecular mechanisms. In this paper, we review the established clinical therapies and novel potential therapeutic approaches for ccRCC, and we support the importance of investigating novel therapeutic options in the context of combining established therapies as a research hotspot, with the goal of providing diversified therapeutic options that promise to address the issue of drug resistance, with a view to the early realization of precision medicine and individualized treatment.

Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage.

BACKGROUND: Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. METHODS: The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), ß-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. RESULTS: The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. CONCLUSION: Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

MoS2-based nanocomposites for cancer diagnosis and therapy.

Molybdenum is a trace dietary element necessary for the survival of humans. Some molybdenum-bearing enzymes are involved in key metabolic activities in the human body (such as xanthine oxidase, aldehyde oxidase and sulfite oxidase). Many molybdenum-based compounds have been widely used in biomedical research. Especially, MoS2-nanomaterials have attracted more attention in cancer diagnosis and treatment recently because of their unique physical and chemical properties. MoS2 can adsorb various biomolecules and drug molecules via covalent or non-covalent interactions because it is easy to modify and possess a high specific surface area, improving its tumor targeting and colloidal stability, as well as accuracy and sensitivity for detecting specific biomarkers. At the same time, in the near-infrared (NIR) window, MoS2 has excellent optical absorption and prominent photothermal conversion efficiency, which can achieve NIR-based phototherapy and NIR-responsive controlled drug-release. Significantly, the modified MoS2-nanocomposite can specifically respond to the tumor microenvironment, leading to drug accumulation in the tumor site increased, reducing its side effects on non-cancerous tissues, and improved therapeutic effect. In this review, we introduced the latest developments of MoS2-nanocomposites in cancer diagnosis and therapy, mainly focusing on biosensors, bioimaging, chemotherapy, phototherapy, microwave hyperthermia, and combination therapy. Furthermore, we also discuss the current challenges and prospects of MoS2-nanocomposites in cancer treatment.

Cytotoxic triterpenoid glycosides from leaves of Cyclocarya paliurus.

Three previously undescribed dammarane triterpenoid glycosides (1-3) along with five known analogues (4-8) were isolated from the leaves of Cyclocarya paliurus. Their structures and configurations were determined on the basis of comprehensive spectroscopic analyses, chemical hydrolysis and DFT GIAO 13C NMR calculation. All the isolates were evaluated cytotoxic activities against seven human cancer cell lines (MCF-7, PC-3, Du145, NCI-H1975, PC-9, SKVO3 and HepG2). Moreover, compound 4 showed a wide spectrum of cytotoxicity against human cancer cells with IC50 values ranging from 11.31 to 29.51 µM.

SOX10 - A Novel Marker for the Differential Diagnosis of Breast Metaplastic Squamous Cell Carcinoma.

INTRODUCTION: Differential diagnosis of metaplastic squamous cell carcinoma of breast (MSCCB) is difficult. In particular, in terms of metastatic MSCCB, because of the low speciality of traditional markers such as mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15) and GATA binding protein 3 (GATA3), the most common problem is differentiating the spread of MSCCB to the lung from a primary lung squamous cell carcinoma. It is urgently required to explore a novel marker to aid in differential diagnosis. AIM: The aim of this study is to explore a novel marker to aid in the differential diagnosis of MSCCB from other squamous cell carcinomas (SCC) in other organs. METHODS: We tested the expression of SOX10 in 375 human SCC specimens with immunohistochemistry (IHC). RESULTS: In a series of 20 MSCCB, 9 (45%) were positive for SOX10. All of them were triple-negative MSCCB. Conversely, SOX10 was totally negative in another 205 SCC originating from lung, skin, cervix, oral mucosa, and esophagus. In a series of 150 triple-negative breast cancer and their metastatic foci, SOX10 labeling in the primary tumor and metastasis was 78% and 79.3%, respectively, and the agreement rate was 97.3% (P>0.05). CONCLUSION: Our findings demonstrate that SOX10 was recommended for differentiating MSCCB from non-mammary metastasis to the breast, as well as for distinguishing primary SCC from metastatic MSCCB, and SOX10 may be valuable in the pathological diagnosis of breast-derived metaplastic squamous cell carcinoma.

Silibinin restores the sensitivity of cisplatin and taxol in A2780-resistant cell and reduces drug-induced hepatotoxicity.

PURPOSE: Ovarian cancer is the most lethal cancer among all gynaecological malignancies. The combination theraputics of cisplatin and taxol is widely used in clinicals for ovarian cancer treatment. However, long-term use of cisplatin and taxol induces strong tolerance and hepatotoxicity. Since silibinin is a commonly used anti-hepatotoxic drug in Europe and Asia, the aim of this study was to determine whether silibinin could restore the sensitivity of combination use of cisplatin and taxol in drug-resistant human ovarian cancer cells and reduce drug-induced hepatotoxicity. PATIENTS AND METHODS: Normal hepatocyte LO2 cells and A2780/DDP cells were treated with silibinin, cisplatin, taxol, cisplatin and taxol plus silibinin for 48 h. Cell viability was determined by MTT and long-term proliferation assay, while apoptosis and cell cycle progression were assessed by flow cytometric analysis. DNA damage was evluated by immunofluorescence assays. The metastatic activity of A2780/DDP was determined by cell adhesion assay. RESULTS: The addition of silibinin on cisplatin and/or toxal could sensitize the antitumor activity of cisplatin and toxal on A2780/DDP cells, supress cell-matrix adhesion of A2780/DDP, inhibit the cell proliferation, result in A2780/DDP cells apoptosis. In addition, silibinin could effectively reduce cisplatin and/or toxal-induced hepatotoxicity by protecting DNA from damage and restoring the potential of cell proliferation in cisplatin and/or toxal-treated LO2 cells. CONCLUSION: Our results suggest that silibinin could restore the sensitivity of cisplatin and taxol in drug-resistant human ovarian cancer cells and reduce durg-induced hepatotoxicity in cell level.

CTRP3 deficiency reduces liver size and alters IL-6 and TGFß levels in obese mice.

C1q/TNF-related protein 3 (CTRP3) is a secreted metabolic regulator whose circulating levels are reduced in human and rodent models of obesity and diabetes. Previously, we showed that CTRP3 infusion lowers blood glucose by suppressing gluconeogenesis and that transgenic overexpression of CTRP3 protects mice against diet-induced hepatic steatosis. Here, we used a genetic loss-of-function mouse model to further address whether CTRP3 is indeed required for metabolic homeostasis under normal and obese states. Both male and female mice lacking CTRP3 had similar weight gain when fed a control low-fat (LFD) or high-fat diet (HFD). Regardless of diet, no differences were observed in adiposity, food intake, metabolic rate, energy expenditure, or physical activity levels between wild-type (WT) and Ctrp3-knockout (KO) animals of either sex. Contrary to expectations, loss of CTRP3 in LFD- or HFD-fed male and female mice also had minimal or no impact on whole body glucose metabolism, insulin sensitivity, and fasting-induced hepatic gluconeogenesis. Unexpectedly, the liver sizes of HFD-fed Ctrp3-KO male mice were markedly reduced despite a modest increase in triglyceride content. Furthermore, liver expression of fat oxidation genes was upregulated in the Ctrp3-KO mice. Whereas the liver and adipose expression of profibrotic TGFß1, as well as its serum levels, was suppressed in HFD-fed KO mice, circulating proinflammatory IL-6 levels were markedly increased; these changes, however, were insufficient to affect systemic metabolic outcome. We conclude that, although it is dispensable for physiological control of energy balance, CTRP3 plays a previously unsuspected role in modulating liver size and circulating cytokine levels in response to obesity.

Beneficial effects of capsiate on ethanol-induced mucosal injury in rats are related to stimulation of calcitonin gene-related Peptide release.

Capsiate is a non-pungent analogue of capsaicin from CH-19 Sweet peppers. Capsaicin is reported to trigger calcitonin gene-related peptide (CGRP) release through activation of transient receptor potential vanilloid subfamily member 1 (TRPV1) and produces beneficial effects on gastric mucosa. This study aimed to investigate whether capsiate is able to produce beneficial effects on gastric mucosa and whether the protective effects of capsipate occur through a mechanism involving the activation of TRPV1 and CGRP release. A rat model of gastric mucosal injury was established by the oral administration of acidified ethanol. Gastric tissues were collected for analysis of the gastric ulcer index, cellular apoptosis, activities of caspase-3, catalase and superoxide dismutase (SOD), and levels of CGRP, TNF-α, and malondialdehyde (MDA). Our results show that the acute administration of ethanol significantly increased the gastric ulcer index concomitantly with an increase in cellular apoptosis, caspase-3 activity, and TNF-α and MDA levels, as well as a decrease in the activities of catalase and SOD. Pretreatment with 1 mg/kg capsiate attenuated ethanol-induced gastric mucosal injury and cellular apoptosis accompanied by an increase in CGRP level, catalase, and SOD activities, and a decrease in caspase-3 activity, and TNF-α and MDA levels. The effects of capsiate were inhibited by capsazepine, an antagonist of TRPV1. These results suggest that capsiate is able to produce beneficial effects on ethanol-induced gastric mucosal injury. These effects are related to the stimulation of CGRP release through the activation of TRPV1.

Vanillyl nonanoate protects rat gastric mucosa from ethanol-induced injury through a mechanism involving calcitonin gene-related peptide.

Previous studies have demonstrated that capsaicin-sensitive sensory nerves are involved in the protection of gastric mucosa against damage by various stimuli and calcitoin gene-related peptide (CGRP) is a potential mediator in this process. This study was performed to explore the effect of vanillyl nonanoate, a capsaicin analog, on ethanol-induced gastric mucosal injury and the possible underlying mechanisms. A rat model of gastric mucosal injury was induced by oral administration of acidified ethanol and gastric tissues were collected for analysis of gastric ulcer index, cellular apoptosis, the activities of caspase-3, catalase and superoxide dismutase (SOD), levels of CGRP, TNF-α and malondialdehyde (MDA). The results showed that acute administration of ethanol significantly increased gastric ulcer index concomitantly with increased cellular apoptosis, caspase-3 activity, TNF-α and MDA levels as well as decreased activities of catalase and SOD. Pretreatment with 1mg/kg vanillyl nonanoate significantly attenuated ethanol-induced gastric mucosal injury and cellular apoptosis accompanied by increase of CGRP expression, and SOD activity and decrease of caspase-3 activity, TNF-α and MDA levels. The effects of vanillyl nonanoate were inhibited by capsazepine, an antagonist of capsaicin receptor. Our results suggested that vanillyl nonanoate was able to protect the gastric mucosa against ethanol-induced gastric mucosal injury. The underlying mechanism is related to stimulation of CGRP release and subsequent suppression of ethanol-induced inflammatory reaction, cellular apoptosis and oxidative stress.

Asymmetric dimethylarginine impairs glucose utilization via ROS/TLR4 pathway in adipocytes: an effect prevented by vitamin E.

BACKGROUND: Asymmetric dimethylarginine (ADMA), the inhibitor of nitric oxide synthase (NOS), has been reported to be associated with glucose metabolism, but its mechanisms remain unknown. METHODS: In 3T3-L1 adipocytes, we measured the effects of ADMA on glucose transport process under basal or insulin-induced condition, and examined the production of nitric oxide (NO), reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-alpha), and the expression of toll-like receptor 4 (TLR4). RESULTS: ADMA significantly impaired basal or insulin-stimulated 2-deoxy- [3H] glucose uptake, and decreased the expression of insulin receptor substrate-1 (IRS-1) and glucose transporter-4 (GLUT4). Phosphorylated protein of IRS-1 and translocation of GLUT4 with insulin-stimulation were also inhibited by ADMA. NO decreased, while production of ROS and TNF-alpha, and expression of TLR4 increased after ADMA treatment. Vitamin E reduced the effects of ADMA on glucose transport system, and on NO, ROS and TLR4. Moreover, vitamin E decreased ADMA contents by up-regulating dimethylarginine dimethylaminohydrolase (DDAH) activity in adipocytes. Though L-arginine also increased NO level, but failed to reduce the effects of ADMA. CONCLUSION: ADMA significantly impairs both basal and insulin-stimulated glucose transport in adipocytes, which may relate to activation of the ROS/TLR4 pathway.

Detrimental effects of nicotine on the acute gastric mucosal injury induced by ethanol: role of asymmetric dimethylarginine.

The aim of this study was to determine whether asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is responsible for the detrimental effects of nicotine on ethanol-induced gastric mucosal injury and its underlying mechanisms. Gastric mucosal injury was induced by an injection of ethanol in the stomach in rats. Animals were pretreated with nicotine for 28 days before ethanol injection. The gastric mucosal ulcer index (UI) and the levels of ADMA and NO in gastric juice were determined. In vitro, the cultured mucosal epithelial cells were treated with nicotine in the presence or absence of ethanol. The concentration of ADMA in the culture medium and the ratio of cell apoptosis were measured, and the effect of nicotine or ADMA alone on cell apoptosis was also examined. In rats treated with ethanol, the UI and ADMA levels were increased and the NO level was decreased, and these effects of ethanol were augmented by pretreatment with nicotine. Administration of nicotine alone did not show significant impact on UI, ADMA level, or NO level. In vitro, incubation of human epithelial cells with ethanol induced cell injury accompanied by increased ADMA levels in the culture medium, an effect which was amplified in the presence of nicotine. Similarly, ethanol was able to induce epithelial cell apoptosis that was exacerbated by nicotine. Incubation of epithelial cells with nicotine alone did not induce cell apoptosis, but administration of ADMA alone did induce cell apoptosis. The results suggest that the gastric mucosal injury induced by ethanol is augmented by nicotine, which is related to the increased ADMA level.