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Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor‐promoting effect of senescence is mainly elicited by a senescence‐associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A "one‐two‐punch" therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field. [ABSTRACT FROM AUTHOR]

Background & Aims: Insulin resistance is strongly associated with non‐alcoholic fatty liver disease, a chronic, obesity–related liver disease. Increased endoplasmic reticulum (ER) stress plays an important role in the development of insulin resistance. In this study, we investigated the roles of miRNAs in regulating ER stress in the liver of rats with obesity. Methods: We used miRNA microarray to determine the miRNA expression profiles in the liver of rats fed with a high fat diet (HFD). We used prediction algorithms and luciferase reporter assay to identify the target gene of miRNAs. To overexpress the miRNA miR‐30b or inhibit miR‐30b rats were injected with lentivirus particles containing PGLV3‐miR‐30b or PGLV3‐miR‐30b antimiR through tail vein. Hepatic steatosis was measured using transient elastography in human subjects. Results: Our data showed that miR‐30b was markedly up‐regulated in the liver of HFD–treated rats. Bioinformatic and in vitro and in vivo studies led us to identify sarco(endo)plasmic reticulum Ca2+‐ATPase 2b (SERCA2b), as a novel target of miR‐30b. Overexpression of miR‐30b induced ER stress and insulin resistance in rats fed with normal diet, whereas inhibition of miR‐30b by miR‐30b antimiR suppressed ER stress and insulin resistance in HFD–treated rats. Finally, our data demonstrated that there was a positive correlation between serum miR‐30b levels and hepatic steatosis or homoeostasis model assessment of insulin resistance (HOMA‐IR) in human subjects. Conclusions: Our findings suggest that miR‐30b represents not only a potential target for the treatment of insulin resistance, but also a non‐invasive disease biomarker of NAFLD. [ABSTRACT FROM AUTHOR]

Nematode-trapping fungi live mainly as saprobes in soil environments. When encountering nematodes, these fungi become 'carnivorous' and develop specialized trapping devices to attack their hosts for extracting nutrients, especially nitrogen source. Thus, nematode-trapping fungi are model organisms for understanding the molecular mechanism of the switch between saprobic and parasitic phases of pathogen life cycles. Arthrobotrys oligospora, one of the best-studied nematode-trapping fungi, mainly lives as a saprobe. In the presence of nematodes, A. oligospora enters the parasitic stage by forming adhesive reticulate traps to capture nematodes. In filamentous fungi, autophagy has been shown to be involved in morphogenesis and morphology. In this study, we demonstrate that autophagy is induced by nematodes during the early stage of trap formation in A. oligospora. Disruption of atg8 gene not only abolishes the nematode-induced autophagy, but also suppresses trap formation and reduces pathogenicity for nematodes. During the early stage of trap formation, the expression of genes involved in amino acid biosynthesis is upregulated and the transcriptional activity of GCN4 is induced in A. oligospora, suggesting that nematodes induce autophagy probably by triggering intracellular amino acid starvation. Autophagy is thus crucial for trap formation in A. oligospora during infection of nematodes. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia (HHcy) has been shown to induce endothelial dysfunction, an early event in the progression of atherosclerosis. However, the underlying mechanism of endothelial cell injury in HHcy has not been clearly elucidated. In this study, we examined the effect of homocysteine on tribbles-related protein 3 (TRB3)-mediated cell-cycle arrest in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with homocysteine (0-250 µmol/L) resulted in inhibition of cell proliferation assessed by [3H]-thymidine incorporation into DNA. Homocysteine induced cell-cycle arrest in the G1 phase by up-regulating the protein levels of p27kip1. Under these conditions, homocysteine did not induce endoplasmic reticulum stress. However, homocysteine up-regulated the expression of TRB3, thus leading to the dephosphorylation of Akt (Thr308). Knock-down of endogenous TRB3 using siRNA significantly suppressed the inhibitory effect of homocysteine on the proliferation of HUVECs. Homocysteine-induced TRB3 expression was mediated by the cAMP/cAMP response element-binding protein (CREB) pathway. These results demonstrate that TRB3 is a critical molecule in the homocysteine-mediated cell-cycle arrest in endothelial cells. J. Cell. Physiol. 226: 2782-2789, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Nematophagous fungi have been used as biological control agents against nematodes parasitic to plants and animals. These fungi can secret subtilisin-like extracellular serine proteases during the infection of nematodes. The expression of these subtilisin-like serine proteases is regulated by nitrogen sources, including nematode cuticle. However, the mechanisms underlying the nitrogen sources-induced expression of these serine proteases is not well understood. In this study, we investigated the effect of nitrogen sources on the expression of a subtilisin-like extracellular protease, prC, in the nematophagous fungus Clonostachys rosea. Disruption of prC attenuated infection of the fungus to nematodes, indicating that this gene functions as a virulence factor. The inhibition of basal expression of prC by the preferred nitrogen sources (glutamine, ammonia) occurred at the transcriptional level. In contrast, nematode cuticle induced the expression of prC at the post-transcriptional level. The inducible expression of prC by nematode cuticle was significantly suppressed by glutamine, ammonia and phenylmethylsulfonyl fluoride (an inhibitor of serine protease). Thus, the existence of active PrC, albeit at a low level in the medium, is probably essential for further induction of this gene by nematode cuticle. Moreover, the low molecule weight (< 3 kD) degradation products of nematode cuticle could significantly induce the expression of prC. Ammonia suppresses the virulence of C. rosea against nematodes, probably by inhibiting prC expression. Thus, the nematophagous fungi probably could not function well as biocontrol agents in fields fertilized with a large amount of ammonium salt. [ABSTRACT FROM AUTHOR]