Coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. Previous studies have shown that complement component 3 (C3) is associated with atherosclerosis and cardiovascular risk factors.

Grape polyphenols contributing to more than half of the global polyphenol market were well studied; however, how melatonin (MLT), a potential plant hormone, and abscisic acid (ABA) affects polyphenols profile is still poorly understood. To explore whether these hormones are involved in polyphenolic biosynthesis, grape (Vitis vinifera cv. Kyoho) was exposed to MLT, ABA, and NDGA (nordihydroguaiaretic acid, an ABA biosynthesis inhibitor) treatments, and 16 polyphenols were identified from grape extracts by high performance liquid chromatography quadrupole time of flight mass spectrometry (HPLC-Q-TOF-MS). Both exogenous MLT and ABA significantly enhanced the biosynthesis of each flavonol and flavanol component, especially catechin, which was almost increased double by 200 µM of MLT treatment. Furthermore, the expression of genes involved in flavonoid biosynthesis, including 4-coumaroyl-CoA synthase, chalcone synthase, flavonoid 3'-hydroxylase, anthocyanin 3'-methyltransferase, flavonol synthase, flavonoid-3-O-glucosyltransferase, and flavonoid 3',5'-methyltransferase were highly up-regulated as well but were down-regulated by NDGA. The present study provided new insights for improving flavonoids accumulation in agricultural production and its underlying mechanism.

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.

The aim of the present research was to study the therapeutic impacts of fluorofenidone (AKF-PD) on pig serum (PS)-induced liver fibrosis in rats and the complex molecular mechanisms of its effects on hepatic stellate cells (HSCs). Wistar rats were randomly divided into normal control, PS and PS/AKF-PD treatment groups. The activated human HSC LX-2 cell line was also treated with AKF-PD. The expression of collagen I and III, and α-smooth muscle actin (α-SMA) was determined by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting and/or RT-qPCR analyses were used to determine the expression of transforming growth factor (TGF)-β1, α-SMA, collagen I, mothers against decapentaplegic homolog (Smad)-3, extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). AKF-PD attenuated the degree of hepatic fibrosis and liver injury in vivo, which was associated with the downregulation of collagen I and III, and α-SMA at the mRNA and protein levels. In vitro, AKF-PD treatment significantly reduced the TGF-β1-induced activation of HSCs, as determined by the reduction in collagen I and α-SMA protein expression. The TGF-β1-induced upregulation of the phosphorylation of Smad 3, ERK1/2, p38 and JNK was attenuated by AKF-PD treatment. These findings suggested that AKF-PD attenuated the progression of hepatic fibrosis by suppressing HSCs activation via the TGF-β1/Smad and MAPK signaling pathways, and therefore that AKF-PD may be suitable for use as a novel therapeutic agent against liver fibrosis.

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.

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.

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.

Sepsis-induced cardiac dysfunction represents a main cause of death in intensive care units. Previous studies have indicated that GSK-3β is involved in the modulation of sepsis. However, the signalling details of GSK-3β regulation in endotoxin lipopolysaccharide (LPS)-induced septic myocardial dysfunction are still unclear. Here, based on the rat septic myocardial injury model, we found that LPS could induce GSK-3β phosphorylation at its active site (Y216) and up-regulate FOXO3A level in primary cardiomyocytes. The FOXO3A expression was significantly reduced by GSK-3β inhibitors and further reversed through β-catenin knock-down. This pharmacological inhibition of GSK-3β attenuated the LPS-induced cell injury via mediating β-catenin signalling, which could be abolished by FOXO3A activation. In vivo, GSK-3β suppression consistently improved cardiac function and relieved heart injury induced by LPS. In addition, the increase in inflammatory cytokines in LPS-induced model was also blocked by inhibition of GSK-3β, which curbed both ERK and NF-κB pathways, and suppressed cardiomyocyte apoptosis via activating the AMP-activated protein kinase (AMPK). Our results demonstrate that GSK-3β inhibition attenuates myocardial injury induced by endotoxin that mediates the activation of FOXO3A, which suggests a potential target for the therapy of septic cardiac dysfunction.

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.

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.

In the past decades, behavioral medicine has attained global recognition. Due to its global reach, a critical need has emerged to consider whether the original definition of behavioral medicine is still valid, comprehensive, and inclusive, and to reconsider the main tasks and goals of the International Society of Behavioral Medicine (ISBM), as the umbrella organization in the field. The purpose of the present study was to (i) update the definition and scope of behavioral medicine and its defining characteristics; and (ii) develop a proposal on ISBM's main tasks and goals.

Ascochyta lentis is a foliar pathogen of Lens species and is of worldwide importance in cultivated lentil production. High levels of resistance were identified in the wild species Lens ervoides. This resistance was explored through histopathology, qPCR estimation of fungal biomass and transcriptome sequencing in a susceptible and a resistant recombinant inbred line (RIL) of L. ervoides infected with an aggressive isolate of A. lentis. Necrotrophic growth was delayed in the resistant RIL compared to accelerated necrotrophy of A. lentis in the susceptible RIL. Analysis of the fungal secretome indicated that the early activation of cell wall-degrading enzymes contributed to increased virulence of A. lentis. On the host side, gene co-expression analysis revealed that the invasion by A. lentis caused mRNA, DNA and protein decay in infected plants regardless of the level of resistance in the host. The resistant RIL exhibited a stronger gene co-expression in lipid localization and sulfur processes, and cellular responses to nutrients and stimuli than the susceptible RIL. In addition, differential gene analysis revealed that the repression of both, gibberellin signaling and cell death associated with the hypersensitive response (HR), were associated with enhanced A. lentis resistance.

Early B cell factor 1 (EBF1) has been identified as an upstream transcription factor of the potential oncogene PNO1 and is involved in the growth of colorectal cancer (CRC) cells. However, its expression, biological function, and underlying mechanism of action in most solid tumors remain largely unknown. We postulated that EBF1 has a role in the pathophysiology of CRC. Analysis of EBF1 mRNA expression in CRC tumor samples from several public databases and directly from banked tissues revealed that EBF1 mRNA expression is lower in CRC tissue compared to non-cancerous colorectal tissue. Survival analysis of multiple datasets revealed that low EBF1 expression was correlated with shorter overall survival, relapse-free survival, and event-free survival in CRC patients. Transduction of lentivirus encoding full length EBF1 followed by in vitro and in vivo assays demonstrated that EBF1 over-expression in CRC cell lines suppresses cell growth by inhibiting cell viability, cell survival, and induces cell cycle arrest and apoptosis. Mechanistic investigation indicated that EBF1 over-expression down-regulates PNO1 mRNA and protein expression, as well as transcriptional activity while up-regulating the expression of p53 and p21 proteins. These findings suggest that EBF1 is a novel potential tumor suppressor in CRC with prognostic value for the identification of patients at high-risk of relapse.

In this study, total lesion glycolysis (TLG) on positron emission tomography images was estimated by a trained and validated CT radiomics model, and its prognostic ability was explored among lung cancer (LC) and esophageal cancer patients (EC).

Xiaoxuming decoction (XXMD) is a traditional Chinese herbal medicine (CHM) that is used for the treatment of stroke in China. Stroke injury damages the cerebral vasculature and disrupts the autoregulation of vasoconstriction and vasodilatation, which is crucial for maintaining constant cerebral blood flow (CBF). It has been reported that XXMD exerts a positive effect on cerebral circulation in animal models of stroke. However, the mechanisms underlying the regulatory effect of XXMD on vascular tone, and the interactions among the multiple components of XXMD, remain unclear. In this study, XXMD was found to induce relaxation of the basilar artery rings of rats precontracted by 5-hydroxytryptamine (5-HT) in vitro, in a dose-dependent manner. The modulation of vascular tone and the process of cerebral ischemia are mediated via the interactions between G protein-coupled receptors (GPCRs) and their ligands, including 5-HT, angiotensin II (Ang II), and urotensin II (UII). Thus, the potential synergistic effects of the different components of XXMD on the regulation of vasoconstriction and vasodilation were further investigated by molecular docking based on network pharmacology. We constructed and analyzed a database comprising 963 compounds of XXMD and studied the interactions between five vascular GPCRs (5-HT1A receptor (5-HT1AR), 5-HT1B receptor (5-HT1BR), Ang II type 1 receptor (AT1R), beta 2-adrenergic receptor (β2-AR), and UII receptor (UTR)) and the various herbal constituents of XXMD using molecular docking. By constructing and analyzing the compound-target networks of XXMD, we found that Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, and Paeoniae Radix Alba were the three major herbs that contained a large number of compounds with high docking scores. We additionally observed that several constituents of XXMD, including gallotannin, liquiritin apioside, nariutin, 1,2,3,4,6-pentagalloylglucose, folic acid, and ginsenoside Rb1, targeted multiple vascular GPCRs. Moreover, the interactions between the components of XXMD and the targets related to vascular tone constituted the comprehensive cerebrovascular regulatory function of XXMD and provided a material basis of the vasoregulatory function of XXMD. The study reports the contributions of various components of XXMD to the regulatory effects on vascular tone and provides scientific evidence for the multicomponent and multitargeting characteristics of XXMD.

Non-coding RNAs (ncRNAs) have been identified as key regulators during the pathogenesis and development of cancers. However, most of ncRNAs have never been explored in acute myeloid leukemia (AML).

The human kinome comprises 538 kinases playing essential functions by catalyzing protein phosphorylation. Annotation of subcellular distribution of the kinome greatly facilitates investigation of normal and disease mechanisms. Here, we present Kinome Atlas (KA), an image-based map of the kinome annotated to 10 cellular compartments. 456 epitope-tagged kinases, representing 85% of the human kinome, were expressed in HeLa cells and imaged by immunofluorescent microscopy under a similar condition. KA revealed kinase family-enriched subcellular localizations and discovered a collection of new kinase localizations at mitochondria, plasma membrane, extracellular space, and other structures. Furthermore, KA demonstrated the role of liquid-liquid phase separation in formation of kinase condensates. Identification of MOK as a mitochondrial kinase revealed its function in cristae dynamics, respiration, and oxidative stress response. Although limited by possible mislocalization due to overexpression or epitope tagging, this subcellular map of the kinome can be used to refine regulatory mechanisms involving protein phosphorylation.

Cardiomyocyte apoptosis is a crucial factor leading to myocardial dysfunction. Adiponectin (APN) has a cardiomyocyte-protective impact. Studies have shown that the connexin43 (Cx43) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathways play an important role in the heart, but whether APN plays a protective role by regulating these pathways is unclear. Our study aimed to confirm whether APN protects against lipopolysaccharide (LPS)-induced cardiomyocyte apoptosis and to explore whether it plays an important role through regulating the Cx43 and PI3K/AKT signaling pathways. In addition, our research aimed to explore the relationship between the Cx43 and PI3K/AKT signaling pathways. In vitro experiments: Before H9c2 cells were treated with LPS for 24 h, they were pre-treated with APN for 2 h. The cytotoxic effect of APN on H9c2 cells was evaluated by a CCK-8 assay. The protein levels of Bax, Bcl2, cleaved caspase-3, cleaved caspase-9, Cx43, PI3K, p-PI3K, AKT and p-AKT were evaluated by Western blot analysis, and the apoptosis rate was evaluated by flow cytometry. APN attenuated the cytotoxicity induced by LPS. LPS upregulated Bax, cleaved caspase-3 and cleaved caspase-9 and downregulated Bcl2 in H9c2 cells; however, these effects were attenuated by APN. In addition, LPS upregulated Cx43 expression, and APN downregulated Cx43 expression and activated the PI3K/AKT signaling pathway. LPS induced apoptosis and inhibited PI3K/AKT signaling pathway in H9c2 cells, and these effects were attenuated by Gap26 (a Cx43 inhibitor). Moreover, the preservation of APN expression was reversed by LY294002 (a PI3K/AKT signaling pathway inhibitor). In vivo experiments: In C57BL/6J mice, a sepsis model was established by intraperitoneal injection of LPS, and APN was injected into enterocoelia. The protein levels of Bax, Bcl2, cleaved caspase-3, and Cx43 were evaluated by Western blot analysis, and immunohistochemistry was used to detect Cx43 expression and localization in myocardial tissue. LPS upregulated Bax and cleaved caspase-3 and downregulated Bcl2 in sepsis; however, these effects were attenuated by APN. In addition, the expression of Cx43 was upregulated in septic myocardial tissue, and APN downregulated Cx43 expression in septic myocardial tissue. In conclusion, both in vitro and in vivo, the data demonstrated that APN can protect against LPS-induced apoptosis during sepsis by modifying the Cx43 and PI3K/AKT signaling pathways.

Cellphone use while driving (CUWD) is a frequent source of distraction for young drivers. These distractions commonly lead to motor vehicle crashes and, in some cases, death. Crash risk differs depending on if the driver is engaging in handheld or hands-free CUWD. This pilot study sought to investigate the differences between handheld versus hands-free CUWD behaviors in younger drivers and the attitudes and social norms that inform them.