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Phosphatases are known to play important roles in the regulation of various cellular processes in eukaryotes. However, systematic characterization of the phosphatome has not been reported in phytopathogenic fungi. The wheat scab fungus Fusarium graminearum contains 82 putative phosphatases. The biological functions of each phosphatase were investigated in this study. Although 11 phosphatase genes appeared to be essential, deletion mutants of the other 71 phosphatase genes were obtained and characterized for changes in 15 phenotypes, including vegetative growth, nutrient response and virulence. Overall, the deletion of 63 phosphatase genes resulted in changes in at least one of the phenotypes assayed. Interestingly, the deletion of four genes (Fg06297, Fg03333, Fg03826 and Fg07932) did not dramatically affect hyphal growth, but led to strongly reduced virulence. Western blot analyses showed that three phosphatases (Fg10516, Fg03333 and Fg12867) functioned as negative regulators of the mitogen-activated protein kinase signaling pathways. In addition, we found, for the first time, that FgCdc14 is dispensable for growth, but plays an important role in ribosome biogenesis. Overall, in this first functional characterization of the fungal phosphatome, phosphatases important for various aspects of hyphal growth, development, plant infection and secondary metabolism were identified in the phytopathogenic fungus F. graminearum.

Gold nanoparticles (AuNPs) have been extensively studied for applications in biomedical sciences. AuNPs have exceptional advantages in cells studies include good biocompatibility and very low cytotoxicity. The eco-friendly synthesis of AuNPs with various physical characteristics is simple, and led to the fabrication of nanomaterials showing different biological functions routing cellular physiology. A growing number of recent studies focused on the promoting effect of AuNPs on stem cells osteogenic differentiation. This includes the ability of the AuNP to activate Wnt/β-catenin pathway, ERK/MAPK pathway and p38 MAPK pathway, resulting in the activation of the transcription factors for the osteogenic differentiation. This technology represents a promising therapeutic strategy to heal patients with bone injury, by regenerating bone cells using stem cells therapy. In this review, recent applications of AuNPs in stem cells osteogenic differentiation, along with the related inducing mechanism are discussed. We also provide recent updates on the AuNP synthesis methods.

Background Ultraviolet (UV) exposure‐stimulated reactive oxygen species (ROS) formation in keratinocytes is a crucial factor in skin aging. Phytochemicals have become widely popular for protecting the skin from UV‐induced cell injury. Sesamin (SSM) has been shown to play a role in extensive pharmacological activity and exhibit photoprotective effects. Aim To assess the protective effect of SSM on UVA‐irradiated keratinocytes and determine its potential antiphotoaging effect. Methods HaCaT keratinocytes pretreated with SSM were exposed to UVA radiation at 8 J/cm2 for 10 min. Cell viability and oxidative stress indicators were evaluated using a cell counting kit‐8 and lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) assay kits. Apoptosis and intracellular ROS levels were analyzed using annexin V‐fluorescein isothiocyanate/propyridine iodide and dichlorodihydrofluorescein diacetate staining, respectively. Protein levels of matrix metalloprotein‐1 (MMP‐1), MMP‐9, Bax/Bcl‐2, and mitogen‐activated protein kinase (MAPK) pathway proteins, phospho‐apoptosis signal‐regulating kinase‐1 (p‐ASK‐1)/ASK‐1, phospho‐c‐Jun N‐terminal protein kinase (p‐JNK)/JNK, and p‐p38/p38 were determined using western blotting. Results Sesamin showed no cytotoxicity until 160 μmol/L on human keratinocytes. Sesamin pretreatment (20 and 40 μM) reversed the suppressed cell viability, increased LDH release and MDA content, decreased cellular antioxidants GSH and SOD, and elevated intracellular ROS levels, which were induced by UVA irradiation. Additionally, SSM inhibited the expression of Bax, MMP‐1, and MMP‐9 and stimulated Bcl‐2 expression. In terms of the regulatory mechanisms, we demonstrated that SSM inhibits the phosphorylation of ASK‐1, JNK, and p38. Conclusion The results suggest that SSM attenuates UVA‐induced keratinocyte injury by inhibiting the ASK‐1‐JNK/p38 MAPK pathways.

The protein tyrosine phosphatase interacting protein 51 (PTPIP51) regulates and interconnects signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway and an abundance of different others, e.g., Akt signaling, NF-κB signaling, and the communication between different cell organelles. PTPIP51 acts as a scaffold protein for signaling proteins, e.g., Raf-1, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), as well as for other scaffold proteins, e.g., 14-3-3 proteins. These interactions are governed by the phosphorylation of serine and tyrosine residues of PTPIP51. The phosphorylation status is finely tuned by receptor tyrosine kinases (EGFR, Her2), non-receptor tyrosine kinases (c-Src) and the phosphatase protein tyrosine phosphatase 1B (PTP1B). This review addresses various diseases which display at least one alteration in these enzymes regulating PTPIP51-interactions. The objective of this review is to summarize the knowledge of the MAPK-related interactome of PTPIP51 for several tumor entities and metabolic disorders.

The tumor suppressor gene neurofibromin 1 (NF1) is a major regulator of the RAS‐MAPK pathway. NF1 mutations occur in lung cancer but were not extensively explored. We hypothesized that NF1‐mutated tumors could define a specific population with a distinct clinical and molecular profile. We performed NF1 sequencing using next generation sequencing (NGS) in 154 lung adenocarcinoma surgical specimens with known KRAS, EGFR, TP53, BRAF, HER2, and PIK3CA status, to evaluate the molecular and clinical specificities of NF1‐mutated lung cancers. Clinical data were retrospectively collected, and their associations with molecular profiles assessed. In this series, 24 tumors were NF1 mutated (17.5%) and 11 were NF1 deleted (8%). There was no mutation hotspot. NF1 mutations were rarely associated with other RAS‐MAPK pathway mutations. Most of patients with NF1 alterations were males (74.3%) and smokers (74.3%). Overall survival and disease‐free survival were statistically better in patients with NF1 alterations (N = 34) than in patients with KRAS mutations (N = 30) in univariate analysis. Our results confirm that NF1 is frequently mutated and represents a distinct molecular and clinical subtype of lung adenocarcinoma. Although NF1 gene is a regulator of RAS‐MAPK pathway, only few studies describe NF1 mutations in lung adenocarcinoma. In this study, we found that 17.5% were NF1 mutations and 8% were NF1 deletions: these NF1 alterations define a distinct clinical and molecular entity of lung adenocarcinoma.

Combination chemotherapy is a rational strategy to increase patient response and tolerability and to decrease adverse effects and drug resistance. Recently, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to be associated with reduction in occurrence of a variety of cancers including lung cancer. On the other hand, growing evidences suggest that deuterium-enriched water (DEW, D2O) and deuterium-depleted water (DDW) play a role both in treatment and prevention of cancers. In the present study, we examined the effects of DEW and DDW in combination with two NSAIDs, celecoxib and indomethacin, on A549 human non-small lung cancer cell to identify novel treatment options. The cytotoxicity of celecoxib or indomethacin, alone and in combination with DDW and DEW was determined. The COX-2, MAPK pathway proteins, the anti-apoptotic Bcl2 and pro-apoptotic Bax proteins and caspase-3 activity were studied for cytotoxic combinations. Co-administration of selective and non-selective COX-2 inhibitors with DEW led to a remarkable increase in cytotoxicity and apoptosis of A549 cells. These events were associated with activation of p38 and JNK MAPKs and decreasing pro-survival proteins Bcl-2, COX-2 and ERK1/2. Furthermore, the combination therapy activated caspase-3, and the apoptosis mediator, and disabled poly ADP-ribose polymerase (PARP), the key DNA repair enzyme, by cleaving it. The combination of DEW with NSAIDs might be effective against lung cancer cells by influence on principal cell signalling pathways, and this has a potential to become a candidate for chemotherapy.

Coixol, a plant polyphenol extracted from coix (Coix lachryma-jobi L.var.ma-yuen Stapf), has not been investigated for its anti-inflammatory effect. In this study, using a lipopolysaccharide (LPS)-induced macrophage cell model, we observed that coixol can effectively reduce the expression of interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor (TNF)-α, nitric oxide (NO), inducible nitric oxide synthases (iNOS), and cyclooxygenase (COX)-2, but had no effect on the expression of the anti-inflammatory mediator IL-10. Furthermore, we found that coixol inhibits mitogen-activated protein kinases (MAPKs), nuclear transcription factor κ B (NF-κB) pathways, and NOD-like receptor protein (NLRP) 3 inflammasome activation. In conclusion, the present study demonstrates that coixol exerts certain anti-inflammatory effects by inhibiting the expression of pro-inflammatory mediators in vitro. The mechanism of this effect was in part related to its ability to inhibit the activation of NF-κB, MAPKs pathways, and NLRP3 inflammasome.

The mitogen‐activated protein kinase (MAPK) signaling pathways have been characterized in Fusarium graminearum. Currently, the upstream sensors of these pathways are unknown. Biological functions of a transmembrane protein FgSho1 were investigated using a target gene deletion strategy. The relationship between FgSho1 and the MAPK cassette FgSte50‐Ste11‐Ste7 was analyzed in depth. The transmembrane protein FgSho1 is required for conidiation, full virulence, and deoxynivalenol (DON) biosynthesis in F. graminearum. Furthermore, FgSho1 and FgSln1 have an additive effect on virulence of F. graminearum. The yeast two‐hybrid, coimmunoprecipitation, colocalization and affinity capture‐mass spectrometry analyses strongly indicated that FgSho1 physically interacts with the MAPK module FgSte50‐Ste11‐Ste7. Similar to the FgSho1 mutant, the mutants of FgSte50, FgSte11, and FgSte7 were defective in conidiation, pathogenicity, and DON biosynthesis. In addition, FgSho1 plays a minor role in the response to osmotic stress but it is involved in the cell wall integrity pathway, which is independent of the module FgSte50‐Ste11‐Ste7 in F. graminearum. Collectively, results of this study strongly indicate that FgSho1 regulates fungal development and pathogenicity via the MAPK module FgSte50‐Ste11‐Ste7 in F. graminearum, which is different from what is known in the budding yeast Saccharomyces cerevisiae.

Background The dipeptidyl peptidase-4 inhibitor sitagliptin, a new anti-diabetic medicine, is effective in treating type 2 diabetes mellitus by increasing the activation and duration of action of glucagon-like peptide-1. Since atherosclerosis is the main pathological feature of diabetic cardiovascular complications, it is important to investigate the anti-atherosclerotic effect of sitagliptin and explore the relevant mechanisms. Methods Male apolipoprotein-E-knockout mice were randomly divided into two groups and fed either high-fat diet (HFD) or HFD plus sitagliptin at a concentration of 0.3% for 16 weeks. Body weight, food intake, blood glucose, serum lipids and adhesion molecules were measured. The atherosclerotic plaque area and its histological composition were analyzed using Sudan staining and immunohistochemistry. The expression of inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6) and the activation of AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) in the aortas were determined using quantitative polymerase chain reaction and western blot, respectively. Results Mice treated with sitagliptin developed fewer atherosclerotic plaques than the control group (7.64 ± 1.98% vs 12.91 ± 1.15%, p < 0.001), particularly in the aortic arch and abdominal aorta, where plaques were decreased 1.92- and 2.74-fold, respectively (p < 0.05 and p < 0.01). Sitagliptin significantly reduced the content of collagen fiber in plaques 1.2-fold (p < 0.05). Moreover, sitagliptin significantly reduced the expression of monocyte chemoattractant protein-1 and interleukin-6 in the aorta (p < 0.01 and p < 0.05), as well as the serum levels of soluble vascular cell adhesion molecule-1 and P-selectin (both p < 0.05). In addition, Sitagliptin induced phosphorylation of AMPK and Akt (p < 0.05 and p < 0.01), while suppressed phosphorylation of p38 and extracellular signal-regulated kinase (Erk) 1/2 (p < 0.05 and p < 0.01) in aortas. Conclusions Our present study indicates that sitagliptin can reduce the area of the atherosclerotic lesion, possibly by regulating the AMPK and MAPK pathways and then reducing leukocyte –endothelial cell interaction and inflammation reactions. These actions are independent of weight loss and glucose-reducing effects.

Background Childhood and adult-onset craniopharyngioma is a rare embryogenic tumor of the sellar, suprasellar, and parasellar region. Survival rates are high; however, tumor location and treatment sequalae including endocrine deficits, visual impairment, metabolic complications, cognitive and psychosocial deficits can significantly impair patient's quality of life. There is considerable controversy regarding the optimal management of craniopharyngiomas. Subtotal resection of the tumor followed by targeted irradiation to avoid further hypothalamic damage is currently indicated. Novel insights in the tumor's molecular pathology present the possibility for targeted therapy possibly decreasing the rate and severity of treatment-associated morbidity. Conclusions Craniopharyngioma should be seen as a chronic disease. To achieve optimal outcomes a multidisciplinary team of specialized neurosurgeons, neuro-radiologists, neuro-oncologists, pathologists and endocrinologists should be involved in the diagnosis, planning of the surgery, irradiation and long-term follow-up.