The objective was to analyze the effects of aerobic exercise on aging striatum stress resistance, and the adaptive mechanisms related to neurodegenerative diseases, and the occurrence, and development of neural degeneration. The 10-weeks of regular moderate-intensity aerobic exercise intervention were carried out in the aerobic exercise runner Sprague-Dawley rats. Apoptotic nuclei appeared in the striatum of aged rats, showing a tendency to relate to aging. The apoptotic index of the striatum in young, middle-aged, and old-aged rats of the aerobic exercise groups increased by 205.56%, 57%, and 68.24%. Autophagy markers Beclin l and LC 3-II expression, AMPKα1 and pAMPKα1 expression increased significantly in all age-exercise groups. The ratio of AMPKα1/pAMPKα1 increased after exercise, and the tendency of exercise to alter autophagy and cell apoptosis increased with aging. Then SirT2 mRNA was significantly upregulated in the aerobic exercise runner groups. In conclusion, we showed that the balance of autophagy and apoptosis were closely regulated by regular aerobic exercise, which affected the development of aging, and via regulation of the AMPK/SirT2 signaling pathway.

Hypoxic preconditioning (HPC) is neuroprotective against ischaemic brain injury; however, the roles of potential anti‑apoptotic signals in this process have not been assessed. To elucidate the molecular mechanisms involved in HPC‑induced neuroprotection, the effects of HPC on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element‑binding protein (CREB) signalling pathway and apoptosis in Sprague‑Dawley pups (postnatal day 7) treated with propofol were investigated. Western blot and histological analyses demonstrated that HPC exerts multiple effects on the hippocampus, including the upregulation of cAMP and phosphorylation of CREB. These effects were partially blocked by intracerebroventricular injection of the protein kinase antagonist H89 (5 µmol/5 µl). Notably, the level of cleaved caspase‑3 was significantly downregulated by treatment with the cAMP agonist Sp‑cAMP (20 nmol/5 µl). The results indicate that propofol increased the level of cleaved caspase‑3 and Bax by suppressing the activity of cAMP‑dependent proteins and Bcl‑2; thus, HPC prevents propofol from triggering apoptosis via the cAMP/PKA/CREB signalling pathway.

Response patterns with immune checkpoint inhibitors may be different from those with chemotherapy. Therefore, assessment of response to immunotherapy with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, could result in premature treatment termination. The randomized, open-label, phase 3 CheckMate 141 trial (NCT02105636), which evaluated nivolumab in recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, allowed treatment beyond first RECIST-defined progression (TBP) according to protocol-specified criteria.

Salinity stress from soil or irrigation water can significantly limit the growth and development of plants. Emerging evidence suggests that hydrogen sulfide (H2S), as a versatile signal molecule, can ameliorate salt stress-induced adverse effects. However, the possible physiological mechanism underlying H2S-alleviated salt stress in cucumber remains unclear. Here, a pot experiment was conducted with an aim to examine the possible mechanism of H2S in enhancement of cucumber salt stress tolerance. The results showed that H2S ameliorated salt-induced growth inhibition and alleviated the reduction in photosynthetic attributes, chlorophyll fluorescence and stomatal parameters. Meanwhile H2S increased the endogenous H2S level concomitant with increased activities of D/L-cysteine desulfhydrase and β-cyanoalanine synthase and decreased activities of O-acetyl-L-serine(thiol)lyase under excess NaCl. Notably, H2S maintained Na+ and K+ homeostasis via regulation of the expression of PM H+-ATPase, SOS1 and SKOR at the transcriptional level under excess NaCl. Moreover, H2S alleviated salt-induced oxidative stress as indicated by lowered lipid peroxidation and reactive oxygen species accumulation through an enhanced antioxidant system. Altogether, these results demonstrated that application of H2S could protect cucumber seedlings against salinity stress, likely by keeping the Na+/K+ balance, controlling the endogenous H2S level by regulating the H2S synthetic and decomposition enzymes, and preventing oxidative stress by enhancing the antioxidant system under salinity stress.

Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19D89N knockin leads to skin hyperpigmentation and promotes NRASQ61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.

Lycopene, a kind of carotenoid, has been reported to have an inhibitory function on tumor cell migration. However, the potential role of lycopene in the treatment of cutaneous squamous cell carcinoma (cSCC) remains unclear. Therefore, we assessed the biological effects of lycopene in the human cSCC cell line COLO-16, human epidermal keratinocytes (HEKs) and the immortalized human keratinocyte cell line HaCaT. We found that lycopene inhibited the cell proliferation and migration of COLO-16 cells but not normal keratinocytes. In addition, lycopene upregulated the protein levels of ZO-1 in COLO-16 and HaCaT cells but not in HEKs. In contrast, lycopene upregulated the protein level of claudin-1 in HEKs but downregulated claudin-1 in COLO-16 cells. Lycopene led to a decrease in autophagic flux in COLO-16 cells in a mechanistic target of rapamycin complex 1 (MTORC1)-dependent manner. Importantly, autophagy inhibition contributed to the lycopene-induced regulation on ZO-1 and claudin-1 in COLO-16 cells. Moreover, JNK inhibitor (SP600125) and MEK inhibitor (U0126) treatment abolished the increase in phosphorylated MTOR and ribosomal protein S6 as well as the increase in ZO-1 and the decrease in claudin-1 in lycopene-treated COLO-16 cells. Gene silencing of JNK and ERK also prohibited ZO-1 upregulation and claudin-1 downregulation. In conclusion, lycopene upregulates ZO-1 expression and downregulates claudin-1 expression through the activation of ERK, JNK and MTORC1 as well as the inhibition of autophagy in human cSCC cells. Our findings demonstrate that autophagy plays a key role in lycopene-mediated pharmacological effects. This study indicates that lycopene might be a useful chemopreventive agent against cSCC.

This study aims to detect serum levels of monocyte chemoattractant protein-1 (MPC-1) and transforming growth factor-β1 (TGF-β1) in polymyositis/dermatomyositis (PM/DM) patients complicated with interstitial lung disease (ILD), to reveal the significance of the changes in these levels in the pathogenesis of PM/DM complicated with ILD.

This study was to validate changes in the levels of folate receptor-α (FOLR1), dihydrofolate reductase (DHFR), and methionine synthase reductase (MTRR) in the tissue of OC patients. The expression of FOLR1, DHFR, and MTRR was evaluated in 80 cases of primary OC, 50 cases of benign ovarian tumors, and 30 normal ovarian tissues. Associations between protein expression and clinicopathological characters were assessed, and diagnostic and prognostic evaluation of FOLR1, DHFR, and MTRR was performed. Results showed that upregulated FOLR1 and MTRR and downregulated DHFR were detected in OC. Patients with abnormality of FOLR1, DHFR, and MTRR tend to have a higher percentage of platinum resistance. Moreover, the areas under receiver operating characteristic curves (AUCs-ROC) for FOLR1, DHFR, and MTRR were 0.723, 0.717, and 0.714, respectively. The combination of FOLR1, DHFR, and MTRR could produce an area of 0.864 under the receiver-operating characteristic curve in distinguishing platinum-resistant patients from platinum-sensitive patients (P < 0.0001). Correlations were present between the expression of FOLR1, DHFR, and MTRR. Furthermore, Kaplan-Meier curves indicated that the patients with overexpressed MTRR had a poorer overall survival time compared to those with low expression (P < 0.05). Thus, folate metabolic enzymes could provide a potential promising biomarker for diagnosis platinum-resistant in OC.

Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.

The role of chemotherapy has evolved greatly in advanced nasopharyngeal carcinoma (NPC). We undertook this network meta-analysis to establish the optimal chemotherapy strategy in advanced NPC.

Despite many guidelines for the management of gestational diabetes available internationally, little work has been done to summarize and assess the content of existing guidelines. A paucity of analysis guidelines within in a unified system may be one explanatory factor. So this study aims to analyze and evaluate the contents of all available guidelines for the management of gestational diabetes.

Enhancers activate transcription in a distance-, orientation-, and position-independent manner, which makes them difficult to be identified. Self-transcribing active regulatory region sequencing (STARR-seq) measures the enhancer activity of millions of DNA fragments in parallel. Here we used STARR-seq to generate a quantitative global map of rice enhancers. Most enhancers were mapped within genes, especially at the 5' untranslated regions (5'UTR) and in coding sequences. Enhancers were also frequently mapped proximal to silent and lowly-expressed genes in transposable element (TE)-rich regions. Analysis of the epigenetic features of enhancers at their endogenous loci revealed that most enhancers do not co-localize with DNase I hypersensitive sites (DHSs) and lack the enhancer mark of histone modification H3K4me1. Clustering analysis of enhancers according to their epigenetic marks revealed that about 40% of identified enhancers carried one or more epigenetic marks. Repressive H3K27me3 was frequently enriched with positive marks, H3K4me3 and/or H3K27ac, which together label enhancers. Intergenic enhancers were also predicted based on the location of DHS regions relative to genes, which overlap poorly with STARR-seq enhancers. In summary, we quantitatively identified enhancers by functional analysis in the genome of rice, an important model plant. This work provides a valuable resource for further mechanistic studies in different biological contexts.

BACKGROUND Long noncoding RNAs (lncRNA) NF-kappaß-interacting long noncoding RNA (NKILA) is downregulated in various types of cancers, while its involvement in other diseases is unknown. In the present study we found that plasma lncRNA NKILA was expressed at higher levels in active ankylosing spondylitis patients than in healthy controls. MATERIAL AND METHODS According to Youden's index, active disease patients were divided into high and low lncRNA NKILA groups. RESULTS Patients in the high lncRNA NKILA level group had significantly longer length of treatment and higher re-hospitalization rate at 3 years after discharge. Plasma levels of TGF-ß1 were also higher in active ankylosing spondylitis patients than in healthy controls. Levels of plasma lncRNA NKILA and TGF-ß1 were significantly and positively correlated in ankylosing spondylitis patients but not in healthy controls. CONCLUSIONS Overexpression of lncRNA NKILA in ankylosing spondylitis is correlated with active disease and predicts length of treatment. LncRNA NKILA may participate in ankylosing spondylitis through the interaction with TGF-ß1, which is a key player in this disease.

Local or distant relapse is the key event for the overall survival of early-stage breast cancer after initial surgery. A small subset of breast cancer cells, which share similar properties with normal stem cells, has been proven to resist to clinical therapy contributing to recurrence.

Radiation encephalopathy (RE) is deemed to be a disease induced only by radiotherapy (RT), with the effects of chemotherapeutic agents on the brains of nasopharyngeal carcinoma (NPC) patients being largely overlooked. In this study, we investigated structural and functional brain alterations in NPC patients following RT with or without chemotherapy. Fifty-six pre-RT, 37 post-RT, and 108 post-CCRT (concomitant chemo-radiotherapy) NPC patients were enrolled in this study. A surface-based local gyrification index (LGI) was obtained from high resolution MRI and was used to evaluate between-group differences in cortical folding. Seed-based functional connectivity (FC) analysis of resting-state fMRI data was also conducted to investigate the functional significance of the cortical folding alterations. Compared with the Pre-RT group, patients in the Post-CCRT group showed LGI reductions in widespread brain regions including the bilateral temporal lobes, insula, frontal lobes, and parietal lobes. Compared with the Post-RT group, patients in the Post-CCRT group showed LGI reductions in the right insula, which extended to the adjacent frontal lobe. Seed-based FC analysis showed that patients in the Post-CCRT group had lower FC between the insula and the left middle frontal gyrus than patients in the Pre-RT group. The follow-up results showed that patients in the Post-CCRT group had a much higher RE incidence rate (20.4%) than patients in the Post-RT group (2.7%; P = 0.01). These findings indicate that chemotherapy potentially facilitated the occurrence of RE in NPC patients who underwent radiotherapy.

The enhancer of zeste homolog 2 (EZH2), known as a member of the polycomb group (PcG) proteins, is an oncogene overexpressed in a variety of human cancers. Here, we found that EZH2 correlated with poor survival of oral squamous cell carcinoma (OSCC) patients using immunohistochemistry staining. EZH2 overexpression led to a significant induction in tumour glycolysis, Epithelial-mesenchymal transition (EMT), migration and invasion of OSCC cells. Conversely, silencing of EZH2 inhibited tumour glycolysis, EMT, migration and invasion in OSCC cells. Ectopic overexpression of EZH2 increased phosphorylation of STAT3 at pY705 and decreased FoxO1 expression, and FoxO1 expression was enhanced when inhibiting STAT3. In addition, EZH2 overexpression led to a significant decrease in FoxO1 mRNA levels in nude mice xenograft. These results indicated that regulation of EZH2 might have the potential to be targeted for OSCC treatment.

To evaluate the association of GRIK2 and NLGN1 with autism spectrum disorder in a Chinese population.

Gastric adenocarcinoma (GAC), also known as stomach adenocarcinoma (STAD), is one of the most lethal malignancies in the world. It is vital to classify and detect the hub genes and key pathways participated in the initiation and progression of GAC. In this study, we collected and sequenced 15 pairs of GAC tumor tissues and the adjacent normal tissues. Differentially expressed genes (DEGs) were analyzed and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis were used to annotate the unique biological significance and important pathways of enriched DEGs. Moreover, we constructed the protein-protein interaction (PPI) network by Cytoscape and conducted KEGG enrichment analysis of the prime module. We further applied the TCGA database to start the survival analysis of these hub genes by Kaplan-Meier estimates. Finally, we obtained total 233 DEGs consisted of 64 up-regulated genes and 169 down-regulated genes. GO enrichment analysis found that DEGs most significantly enriched in single organism process, extracellular region, and extracellular region part. KEGG pathway enrichment analysis suggested that DEGs most significantly enriched in Protein digestion and absorption, Gastric acid secretion, and ECM-receptor interaction. Furthermore, the PPI network showed that the top 10 hub genes in GAC were IL8, COL1A1, MMP9, SST, COL1A2, TIMP1, FN1, SPARC, ALDH1A1, and SERPINE1 respectively. The prime gene interaction module in PPI network was enriched in protein digestion and absorption, ECM receptor interaction, the PI3K-Akt signaling pathway, and pathway in cancer. Survival analysis based on the TCGA database found that the expression of the FN1, SERPINE1, and SPARC significantly predicted poor prognosis of GAC. Collectively, we identified several hub genes and key pathways associated with GAC initiation and progression by analyzing the microarray data on DEGs, which provided a detailed molecular mechanism underlying GAC occurrence and progression.

Purpose: Esophageal cancer is a common malignant tumor that develops rapidly and has a poor prognosis clinically. Astaxanthin (AST) is a carotenoid pigment with strong antioxidant, anti-inflammation, and antitumor activities. However, little is known about the effects of astaxanthin in esophageal cancer. The present study aimed to investigate the protective effects and related mechanisms of natural astaxanthin against N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer in rats. Methods: F344 rats were induced subcutaneously with NMBA dissolved in dimethyl sulfoxide (0.35 mg/kg body weight three times per week for 5 weeks). Rats were fed normal diets with or without 25 mg/kg/day AST at different stages. At different time points, levels of oxidative stress factors in serum and esophagus tissue were analyzed. Western blotting was performed to observe the expression of NFκB and COX2 in esophagus tissue. Results: AST clearly reduced the incidence of visible tumors in esophageal cancer during the early-stage intervention group. Furthermore, when compared with the simple exposed group, AST significantly increased levels of GPx and SOD activity, decreased the activity level of malondialdehyde (all P<0.05). Early-stage and whole-stage intervention groups effectively attenuated expression levels of NFκB and COX2 proteins compared with the simple exposed group (all P<0.05). Conclusion: Natural AST significantly suppressed the occurrence of esophageal cancer by increasing antioxidant capacity and anti-inflammation capacity by inhibiting expression levels of NFκB and COX2 proteins.

Trichinellosis caused by parasitic nematodes of the genus Trichinella may result in human morbidity and mortality worldwide. Deciphering processes that drive species diversity and adaptation are key to understanding parasitism and developing effective control strategies. Our goal was to identify genes that are under positive selection and possible mechanisms of adaptive evolution of Trichinella spiralis genes using a comparative genomic analysis with the genomes of Brugia malayi, Trichuris suis, Ancylostoma ceylanicum, and Caenorhabditis elegans. The CODEML program derived from the PAML package was used to deduce the most probable dN/dS ratio, a measurement to detect genes/proteins undergoing adaptation. For each pair of sequences, those with a dN/dS ratio > 1 were considered positively selected genes (PSGs). Altogether, 986 genes were positively selected (p-value < 0.01). Genes involved in metabolic pathways, signaling pathways, and cytosolic DNA-sensing pathways were significantly enriched among the PSGs. Several PSGs are associated with exploitation of the host: modification of the host's metabolism, creation of new parasite-specific morphological structures between T. spiralis and the host interface, xenobiotic metabolism to combat low oxygen concentrations and host toxicity, muscle cell transformation, cell cycle arrest, DNA repair processes during nurse cell formation, antiapoptotic factors, immunomodulation, and regulation of epigenetic processes. Some of the T. spiralis PSGs have C. elegans orthologs that confer severe or lethal RNAi phenotypes. Fifty-seven PSGs in T. spiralis were analyzed to encode differentially expressed proteins. The present study utilized an overall comparative genomic analysis to discover PSGs within T. spiralis and their relationships with biological function and organism fitness. This analysis adds to our understanding of the possible mechanism that contributes to T. spiralis parasitism and biological adaptation within the host, and thus these identified genes may be potential targets for drug and vaccine development.