Construction of a Necroptosis-Related lncRNA Signature for Predicting Prognosis and Immune Response in Kidney Renal Clear Cell Carcinoma.

Necroptosis is a new type of programmed cell death and involves the occurrence and development of various cancers. Moreover, the aberrantly expressed lncRNA can also affect tumorigenesis, migration, and invasion. However, there are few types of research on the necroptosis-related lncRNA (NRL), especially in kidney renal clear cell carcinoma (KIRC). In this study, we analyzed the sequencing data obtained from the TGCA-KIRC dataset, then applied the LASSO and COX analysis to identify 6 NRLs (AC124854.1, AL117336.1, DLGAP1-AS2, EPB41L4A-DT, HOXA-AS2, and LINC02100) to construct a risk model. Patients suffering from KIRC were divided into high- and low-risk groups according to the risk score, and the patients in the low-risk group had a longer OS. This signature can be used as an indicator to predict the prognosis of KIRC independent of other clinicopathological features. In addition, the gene set enrichment analysis showed that some tumor and immune-associated pathways were more enriched in a high-risk group. We also found significant differences between the high and low-risk groups in the infiltrating immune cells, immune functions, and expression of immune checkpoint molecules. Finally, we use the "pRRophetic" package to complete the drug sensitivity prediction, and the risk score could reflect patients' response to 8 small molecule compounds. In general, NRLs divided KIRC into two subtypes with different risk scores. Furthermore, this signature based on the 6 NRLs could provide a promising method to predict the prognosis and immune response of KIRC patients. To some extent, our findings helped give a reference for further research between NRLs and KIRC and find more effective therapeutic drugs for KIRC.

SRY-related high-mobility-group box 4: Crucial regulators of the EMT in cancer.

The epithelial-mesenchymal transition (EMT) is a process of cell transformation under certain physiological and pathological states in which epithelial cells are transformed into mesenchymal cells with fibroblast-like properties, which confers upon them the increased invasion and migration capabilities of cancer cells. Previous studies have demonstrated that SRY-related high-mobility-group box 4 (Sox4) protein coordinates EMT-related pathways and EMT-related transcription factors, thereby regulating the EMT process. The focus of this review is to evaluate recent advances regarding the role of Sox4 protein in the cancer EMT. First, we provide an overview of the general background of Sox4 (structure and function) and the EMT in cancer. Next, we introduce the interactions between Sox4 protein and various factors during cancer EMT. Finally, we suggest directions for future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information on the subject matter and contribute to the design of other research and future efforts to develop therapeutic strategies that target the Sox4 protein.

Mechanisms explaining the efficacy of psoralidin in cancer and osteoporosis, a review.

Psoralidin (PSO) is a natural phenolic coumarin that is extracted from the seeds of Psoralea corylifolia L. PSO possesses a variety of pharmacological activities, including anti-oxidative, antibacterial, anti-inflammatory, anti-depressive and estrogenic-like effects. Other studies have indicated that PSO plays a beneficial role in multiple disease, especially cancer and osteoporosis. In this review, we first outline the basic background of PSO. Then we introduced the molecular mechanisms and signaling pathways of PSO in multiple cancers to elucidate its anticancer potential via inducing oxidative stress and apoptosis, inhibiting proliferation, promoting autophagy-dependent cell death, and activating the estrogen receptors (ER)-signaling pathway. Finally, we recommend the direction of future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information to help design PSO in other research and future efforts.

Bakuchiol: A newly discovered warrior against organ damage.

Bakuchiol (BAK), [(1E,3S)-3-ethenyl-3,7-dimethyl-1,6-octadien-1-yl]phenol is a prenylated phenolic monoterpene extracted from the fruit of Psoralea corylifolia L., which belongs to the Leguminosae plant family. Previous research has shown that BAK exerts a variety of pharmacological effects, including antioxidant, antibacterial, anti-inflammatory, antiaging and estrogen-like effects. In addition, recent studies have indicated that BAK exerts protective effects in the heart, liver, skin and other organs. BAK treatment protects the heart against ischemia-reperfusion injury through modulating cardioprotective pathways. BAK also inhibits liver fibrosis via promoting myofibroblast apoptosis and relieves the hepatotoxicity of multiple toxicants by suppressing oxidative stress and inflammatory changes. BAK inhibits the proliferation of various cancer cells, including stomach, breast and skin cancer cells, thereby exerting anticancer effects. Further, BAK effectively slows skin aging by preserving skin collagen. BAK treatment can protect against bone loss and delay osteoporosis by exerting estrogen-like effects. In addition, BAK remarkably reduces blood glucose and triglycerides and might be a potential pharmacological agent that can be used to protect against pancreatic beta-cell damage and diabetes progression. In this review, the pharmacological mechanisms and protective effects of BAK in human diseases are discussed, with a focus on the protective effects of BAK in the heart, liver and other important organs.

Melatonin: Another avenue for treating osteoporosis?

Melatonin is a signal molecule that modulates the biological circadian rhythms of vertebrates. Melatonin deficiency is thought to be associated with several disorders, including insomnia, cancer, and cardiovascular and neurodegenerative diseases. Accumulating evidence has also indicated that melatonin may be involved in the homeostasis of bone metabolism. Age-related reductions in melatonin are considered to be critical factors in bone loss and osteoporosis with aging. Thus, serum melatonin levels might serve as a biomarker for the early detection and prevention of osteoporosis. Compared to conventional antiosteoporosis medicines, which primarily inhibit bone loss, melatonin both suppresses bone loss and promotes new bone formation. Mechanistically, by activating melatonin receptor 2 (MT2), melatonin upregulates the gene expression of alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), BMP6, osteocalcin, and osteoprotegerin to promote osteogenesis while inhibiting the receptor activator of NF-kB ligand (RANKL) pathway to suppress osteolysis. In view of the distinct actions of melatonin on bone metabolism, we hypothesize that melatonin may be a novel remedy for the prevention and clinical treatment of osteoporosis.

SIRT1 activation by butein attenuates sepsis-induced brain injury in mice subjected to cecal ligation and puncture via alleviating inflammatory and oxidative stress.

Sepsis-induced brain injury is frequently encountered in critically ill patients with severe systemic infection. Butein (3,4,2',4'-tetrahydroxychalcone) has been demonstrated as the neuro-protective agent via reducing inflammation and oxidative stress on neurons. Moreover, activation of silent information regulator 1 (SIRT1) inhibits apoptosis, oxidation and inflammation thus alleviating sepsis-induced multiorgan injuries. In present study, we show that butein administrated intraperitoneally (10 mg/kg) saved mice from sepsis-induced lethality by increasing 7-day survival rate after cecal ligation and puncture (CLP) surgery. Additionally, butein treatment enhanced SIRT1 signaling thus decreasing the Ac-NF-κB, Ac-FOXO1 and Ac-p53 levels, thus attenuating the brain injury of mice after CLP surgery by decreasing cerebral edema, maintaining the blood-brain barrier integrity, inhibiting neuronal apoptosis, and decreasing pro-inflammatory cytokines production (IL-6, TNF-α and IL-1ß) and oxidative stress (downregulation of MDA, and upregulation of SOD and CAT) in both serum and cerebral cortex tissues. Moreover, butein treatment attenuated LPS induced neurological function loss. However, all above mentioned neuro-protective actions of butein were partially inhibited by EX527 co-treatment, one standard SIRT1 inhibitor. Collectively, butein attenuates sepsis-induced brain injury through alleviation of cerebral inflammation, oxidative stress and apoptosis by SIRT1 signaling activation.

Forkhead box O proteins: Crucial regulators of cancer EMT.

The epithelial-mesenchymal transition (EMT) is an acknowledged cellular transition process in which epithelial cells acquire mesenchymal-like properties that endow cancer cells with increased migratory and invasive behavior. Forkhead box O (FOXO) proteins have been shown to orchestrate multiple EMT-associated pathways and EMT-related transcription factors (EMT-TFs), thereby modulating the EMT process. The focus of the current review is to evaluate the latest research progress regarding the roles of FOXO proteins in cancer EMT. First, a brief overview of the EMT process in cancer and a general background on the FOXO family are provided. Next, we present the interactions between FOXO proteins and multiple EMT-associated pathways during malignancy development. Finally, we propose several novel potential directions for future research. Collectively, the information compiled herein should serve as a comprehensive repository of information on this topic and should aid in the design of additional studies and the future development of FOXO proteins as therapeutic targets.

FOXO1/3: Potential suppressors of fibrosis.

Fibrosis is a universally age-related disease that involves nearly all organs. It is typically initiated by organic injury and eventually results in organ failure. There are still few effective therapeutic strategy targets for fibrogenesis. Forkhead box proteins O1 and O3 (FOXO1/3) have been shown to have favorable inhibitory effects on fibroblast activation and subsequent extracellular matrix production and can ameliorate fibrosis levels in numerous organs, including the heart, liver, lung, and kidney; they are therefore promising targets for anti-fibrosis therapy. Moreover, we can develop appropriate strategies to make the best use of FOXO1/3's anti-fibrosis properties. The information reviewed here should be significant for understanding the roles of FOXO1/3 in fibrosis and should contribute to the design of further studies related to FOXO1/3 and the fibrotic response and shed light on a potential treatment for fibrosis.

FOXOs in the impaired heart: New therapeutic targets for cardiac diseases.

Cardiac diseases have a high morbidity and mortality and affect the global population. Based on recent accumulating evidence, Forkhead box O (FOXOs) play important roles in cardiac diseases. Therefore, a summary of the current literature on the molecular mechanisms and roles of FOXOs in the heart will provide valuable information. In this review, we first briefly introduce the molecular features of FOXOs. Then, we discuss the regulation and cardiac actions of the FOXO pathways. Based on this background, we expand our discussion to the roles of FOXOs in several major cardiac diseases, such as ischemic cardiac diseases, diabetic cardiomyopathy and myocardial hypertrophy. Then, we describe some methodological problems associated with the FOXO gene-modified animal models. Finally, we discuss potential future directions. The information reviewed here may be significant for the design of future studies and may increase the potential of FOXOs as therapeutic targets.

Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent for esophageal squamous cell carcinoma (ESCC). Forced expression of CHOP, one of the key downstream transcription factors during endoplasmic reticulum (ER) stress, upregulates the death receptor 5 (DR5) levels and promotes oxidative stress and cell death. In this study, we show that ER stress mediated by thapsigargin promoted CHOP and DR5 synthesis thus sensitizing TRAIL treatment, which induced ESCC cells apoptosis. These effects were reversed by DR5 siRNA in vitro and CHOP siRNA both in vitro and in vivo. Besides, chemically inhibition of AMPK by Compound C and AMPK siRNA weakened the anti-cancer effect of thapsigargin and TRAIL co-treatment. Therefore, our findings suggest ER stress effectively sensitizes human ESCC to TRAIL-mediated apoptosis via the TRAIL-DR5-AMPK signaling pathway, and that activation of ER stress may be beneficial for improving the efficacy of TRAIL-based anti-cancer therapy.

Pterostilbene Inhibits the Growth of Human Esophageal Cancer Cells by Regulating Endoplasmic Reticulum Stress.

BACKGROUND/AIMS: Pterostilbene (PTE), a natural dimethylated resveratrol analog from blueberries, is known to have diverse pharmacological activities, including anticancer properties. In this study, we investigated the anticancer activity of PTE against human esophageal cancer cells both in vitro and in vivo and explored the role of endoplasmic reticulum (ER) stress (ERS) signaling in this process. METHODS: Cell viability, the apoptotic index, Caspase 3 activity, adhesion, migration, reactive oxygen species (ROS) levels, and glutathione (GSH) levels were detected to explore the effect of PTE on human EC109 esophageal cancer cells. Furthermore, siRNA transfection and a chemical inhibitor were employed to confirm the role of ERS. RESULTS: PTE treatment dose- and time-dependently decreased the viability of human esophageal cancer EC109 cells. PTE also decreased tumor cell adhesion, migration and intracellular GSH levels while increasing the apoptotic index, Caspase 3 activity and ROS levels, which suggest the strong anticancer activity of PTE. Furthermore, PTE treatment increased the expression of ERS-related molecules (GRP78, ATF6, p-PERK, p-eIF2α and CHOP), upregulated the pro-apoptosis-related protein PUMA and downregulated the anti-apoptosis-related protein Bcl-2 while promoting the translocation of cytochrome c from mitochondria to cytosol and the activation of Caspase 9 and Caspase 12. The downregulation of ERS signaling by CHOP siRNA desensitized esophageal cancer cells to PTE treatment, whereas upregulation of ERS signaling by thapsigargin (THA) had the opposite effect. N-Acetylcysteine (NAC), a ROS scavenger, also desensitized esophageal cancer cells to PTE treatment. CONCLUSIONS: Overall, the results indicate that PTE is a potent anti-cancer pharmaceutical against human esophageal cancer, and the possible mechanism involves the activation of ERS signaling pathways.

Icariin displays anticancer activity against human esophageal cancer cells via regulating endoplasmic reticulum stress-mediated apoptotic signaling.

In this study, we investigated the antitumor activity of icariin (ICA) in human esophageal squamous cell carcinoma (ESCC) in vitro and in vivo and explored the role of endoplasmic reticulum stress (ERS) signaling in this activity. ICA treatment resulted in a dose- and time-dependent decrease in the viability of human EC109 and TE1 ESCCs. Additionally, ICA exhibited strong antitumor activity, as evidenced by reductions in cell migration, adhesion, and intracellular glutathione (GSH) levels and by increases in the EC109 and TE1 cell apoptotic index, Caspase 9 activity, reactive oxygen species (ROS) level, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Furthermore, ICA treatments upregulated the levels of ERS-related molecules (p-PERK, GRP78, ATF4, p-eIF2α, and CHOP) and a pro-apoptotic protein (PUMA) and simultaneously downregulated an anti-apoptotic protein (Bcl2) in the two ESCC cell lines. The downregulation of ERS signaling using eIF2α siRNA desensitized EC109 and TE1 cells to ICA treatment, and the upregulation of ERS signaling using thapsigargin sensitized EC109 and TE1 cells to ICA treatment. In summary, ERS activation may represent a mechanism of action for the anticancer activity of ICA in ESCCs, and the activation of ERS signaling may represent a novel therapeutic intervention for human esophageal cancer.

Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling.

Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation associated with the upregulation of apoptotic signaling pathway has been implicated in various inflammatory diseases including hemorrhagic insults. Melatonin is reported to possess substantial anti-inflammatory properties, which is beneficial for early brain injury (EBI) after SAH. However, the molecular mechanisms have not been clearly identified. This study was designed to investigate the protective effects of melatonin against EBI induced by SAH and to elucidate the potential mechanisms. The adult mice were subjected to SAH. Melatonin or vehicle was injected intraperitoneally 2 hr after SAH. Melatonin was neuroprotective, as shown by increased survival rate, as well as elevated neurological score, greater survival of neurons, preserved brain glutathione levels, and reduced brain edema, malondialdehyde concentrations, apoptotic ratio, and blood-brain barrier (BBB) disruption. Melatonin also attenuated the expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, interleukin-1ß (IL-1ß), and interleukin-6 (IL-6); these changes were also associated with an increase in the anti-apoptotic factor (Bcl2) and reduction in the pro-apoptotic factor (Bim). In summary, our results demonstrate that melatonin treatment attenuates the EBI following SAH by inhibiting NLRP3 inflammasome-associated apoptosis.

Activation of endoplasmic reticulum stress is involved in the activity of icariin against human lung adenocarcinoma cells.

In this study, we investigated the anticancer activity of icariin (ICA) against human lung adenocarcinoma cells in vitro and in vivo and explored the role of endoplasmic reticulum (ER) stress (ERS) signaling in this process. ICA treatment resulted in a dose- and time-dependent decrease in the viability of human lung adenocarcinoma A549 cells. Additionally, ICA exhibited potent anticancer activity, as evidenced by reductions in A549 cell adhesion, migration and intracellular glutathione (GSH) levels and increases in the apoptotic index, Caspase 3 activity, and reactive oxygen species. Furthermore, ICA treatment increased the expression of ERS-related molecules (p-PERK, ATF6, GRP78, p-eIF2α, and CHOP), up-regulated the apoptosis-related protein PUMA and down-regulated the anti-apoptosis-related protein Bcl2. The down-regulation of ERS signaling using PERK siRNA desensitized lung adenocarcinoma cells to ICA treatment, whereas the up-regulation of ERS signaling using thapsigargin (THA) sensitized lung adenocarcinoma cells to ICA treatment. Additionally, ICA inhibited the growth of human lung adenocarcinoma A549 cell xenografts by increasing the expression of ERS-related molecules (p-PERK and CHOP), up-regulating PUMA, and down-regulating Bcl2. These data indicate that ICA is a potential inhibitor of lung adenocarcinoma cell growth by targeting ERS signaling and suggest that the activation of ERS signaling may represent a novel therapeutic intervention for lung adenocarcinoma.

Melatonin as a treatment for gastrointestinal cancer: a review.

Gastrointestinal cancer is a disease that affects the population worldwide with high morbidity and mortality. Melatonin, an endogenously produced molecule, may provide a defense against a variety of cancer types. In particular, the ability of melatonin to inhibit gastrointestinal cancer is substantial. In this review, we first clarify the relationship between the disruption of the melatonin rhythm and gastrointestinal cancer (based on epidemiologic surveys and animal and human studies) and summarize the preventive effect of melatonin on carcinogenesis. Thereafter, the mechanisms through which melatonin exerts its anti-gastrointestinal cancer actions are explained, including inhibition of proliferation, invasion, metastasis, and angiogenesis, and promotion of apoptosis and cancer immunity. Moreover, we discuss the drug synergy effects and the role of melatonin receptors involved in the growth-inhibitory effects on gastrointestinal cancer. Taken together, the information compiled here serves as a comprehensive reference for the anti-gastrointestinal cancer actions of melatonin that have been identified to date and will hopefully aid in the design of further experimental and clinical studies and increase the awareness of melatonin as a therapeutic agent in cancers of the gastrointestinal tract.