Lysophosphatidylcholine acyltransferase 3 (LPCAT3) is an important enzyme in phospholipid remodeling, a process that influences the biophysical properties of cell membranes and thus cell function. Multiple lines of evidence suggest that LPCAT3 is involved in several diseases, including atherosclerosis, non-alcoholic steatohepatitis, and carcinoma. Thus, LPCAT3 may have potential as a therapeutic target for these diseases. In the present study, we devised an assay based on reversed-phase HPLC to measure LPCAT3 activity, which may facilitate the identification of LPCAT3 inhibitors and activators. We found that optimal pH and temperature of recombinant human LPCAT3 are 6.0 and 30 °C, respectively. The enzyme Km values for substrates NBD-labelled lysophosphatidylcholine and arachidonoyl CoA were 266.84 ± 3.65 and 11.03 ± 0.51 μmol·L-1 , respectively, and the Vmax was 39.76 ± 1.86 pmol·min-1 ·U-1 . Moreover, we used our new method to determine the IC50 of a known LPCAT inhibitor, TSI-10. In conclusion, this novel assay can be used to measure the effects of compounds on LPCAT3 activity.

Ezrin is a member of the ezrin-radixin-moesin (ERM) protein family and has been shown to be associated with poor prognosis in patients with a variety of solid tumors. However, the clinical prognostic significance of ezrin in patients with bone and soft tissue sarcomas remains unclear. Here, we performed a systematic meta-analysis by searching PubMed, the Cochrane Library Database, EMBASE, the Web of Science, and the CBM, WanFang Med Online and CNKI databases. In total, 19 studies with a total of 1316 bone and soft tissue sarcoma patients were included. Pooled analyses showed that ezrin overexpression was correlated with a higher rate of tumor metastasis (OR 6.59, 95% CI: 2.84-15.33, P < 0.01, PFDR  < 0.01) and recurrence (OR 3.18, 95% CI: 1.88-5.37, P < 0.01, PFDR  < 0.01) and a more advanced tumor grade (OR 3.252, 95% CI: 1.371-7.715, P = 0.01, PFDR  = 0.03). Moreover, elevated ezrin expression could predict poor OS (HR 3.02, 95% CI: 2.35-3.89, P < 0.01, PFDR  < 0.01), MFS (HR 5.22, 95% CI: 2.08-13.08, P < 0.01, PFDR  < 0.01), and EFS (HR 1.07, 95% CI: 1.03-1.11, P < 0.01, PFDR  < 0.01). Subgroup analyses revealed the underlying sources of heterogeneity. Publication bias was observed in the analysis of metastasis. Sensitivity analysis revealed that the results were robust. Our findings indicated that ezrin overexpression was significantly correlated with poor survival and more advanced tumor progression in bone and soft tissue sarcomas, which suggests that ezrin might be a valuable prognostic biomarker and a potential therapeutic target.

The use of deep learning (DL) for the analysis and diagnosis of biomedical and health care problems has received unprecedented attention in the last decade. The technique has recorded a number of achievements for unearthing meaningful features and accomplishing tasks that were hitherto difficult to solve by other methods and human experts. Currently, biological and medical devices, treatment, and applications are capable of generating large volumes of data in the form of images, sounds, text, graphs, and signals creating the concept of big data. The innovation of DL is a developing trend in the wake of big data for data representation and analysis. DL is a type of machine learning algorithm that has deeper (or more) hidden layers of similar function cascaded into the network and has the capability to make meaning from medical big data. Current transformation drivers to achieve personalized health care delivery will be possible with the use of mobile health (mHealth). DL can provide the analysis for the deluge of data generated from mHealth apps. This paper reviews the fundamentals of DL methods and presents a general view of the trends in DL by capturing literature from PubMed and the Institute of Electrical and Electronics Engineers database publications that implement different variants of DL. We highlight the implementation of DL in health care, which we categorize into biological system, electronic health record, medical image, and physiological signals. In addition, we discuss some inherent challenges of DL affecting biomedical and health domain, as well as prospective research directions that focus on improving health management by promoting the application of physiological signals and modern internet technology.

Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin-eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ2 (2) = 20.61, P < 0.001) and T-allele (χ2 (1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A-allele (χ2 (1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.

Yes-associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin-producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy-resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2-induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2-to-YAP pathway that drives GC growth, progression and therapy-resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy-resistant GC.

Severe early-onset fetal growth restriction is an obstetric condition with significant risks of perinatal mortality, major and minor neonatal morbidity, and long-term health sequelae. The prognosis of a fetus is influenced by the extent of prematurity and fetal weight. Clinical care is individually adjusted. In literature, survival rates vary and studies often only include live-born neonates with missing rates of antenatal death. This systematic review aims to summarize the literature on mortality and morbidity.

Tumor necrosis factor-alpha (TNF-α), checkpoint inhibitors, and interleukin-17 (IL-17) are critical targets in inflammation and autoimmune diseases. Monoclonal antibodies (mAbs) have a successful portfolio in the treatment of chronic diseases. With the current progress in stem cells and gene therapy technologies, there is the promise of replacing costly mAbs production in bioreactors with a more direct and cost-effective production method inside the patient's cells. In this paper we examine the results of an investigational assessment of secukinumab gene therapy.

BACKGROUND The purpose of this study was to investigate the role and mechanism of steroid receptor coactivator-interacting protein (SIP) in an astrocyte model of 1-methyl-4-phenylpyridinium (MPP⁺)-induced Parkinson's disease. MATERIAL AND METHODS To perform our study, a Parkinson's disease cell model was established by treating the rat glioblastoma cell line C6 with MPP⁺. SIP was overexpressed in C6 cells using SIP-plasmid. Cell viability and apoptosis were analyzed using MTT assay and flow cytometer respectively. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1ß levels were detected using enzyme linked immunosorbent assay and quantitative reverse transcription PCR. Besides, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production, and superoxide dismutase (SOD) enzyme activity were determined in the present study. For protein and mRNA detection, western blot assay, and qRT-PCR were performed respectively. RESULTS SIP was decreased in MPP⁺-induced C6 cells. SIP overexpression relieved MPP⁺-induced cytotoxicity of C6 cells, displayed as increased cell viability and reduced cell apoptosis and reduced LDH release. Besides, SIP inhibited MPP⁺-induced inflammatory response and oxidative stress, evidenced by decreased levels of inflammatory factors (TNF-alpha and IL-1ß), reduced ROS generation and enhanced SOD activity. Moreover, MPP⁺-induced nuclear factor-kappaB activation was inhibited by SIP overexpression. CONCLUSIONS SIP was downregulated in Parkinson's disease and it played a protective role in the development Parkinson's disease, thus may be a promising target for Parkinson's disease treatment.

The atmospheric concentration of the potent greenhouse gases methane and nitrous oxide (N2O) has increased drastically during the last century. Methylomirabilis bacteria can play an important role in controlling the emission of these two gases from natural ecosystems, by oxidizing methane to CO2 and reducing nitrite to N2 without producing N2O. These bacteria have an anaerobic metabolism, but are proposed to possess an oxygen-dependent pathway for methane activation. Methylomirabilis bacteria reduce nitrite to NO, and are proposed to dismutate NO into O2 and N2 by a putative NO dismutase (NO-D). The O2 produced in the cell can then be used to activate methane by a particulate methane monooxygenase. So far, the metabolic model of Methylomirabilis bacteria was based mainly on (meta)genomics and physiological experiments. Here we applied a complexome profiling approach to determine which of the proposed enzymes are actually expressed in Methylomirabilis lanthanidiphila. To validate the proposed metabolic model, we focused on enzymes involved in respiration, as well as nitrogen and carbon transformation. All complexes suggested to be involved in nitrite-dependent methane oxidation, were identified in M. lanthanidiphila, including the putative NO-D. Furthermore, several complexes involved in nitrate reduction/nitrite oxidation and NO reduction were detected, which likely play a role in detoxification and redox homeostasis. In conclusion, complexome profiling validated the expression and composition of enzymes hypothesized to be involved in the energy, methane and nitrogen metabolism of M. lanthanidiphila, thereby further corroborating their unique metabolism involved in the environmentally relevant process of nitrite-dependent methane oxidation.

PDZ and LIM domain protein 4 (PDLIM4) is frequently repressed in cancer tissues. However, the expression and role of PDLIM4 in ovarian cancer has not been addressed.

Neuropathic pain is chronic pain that follows nerve injury, mediated in the brain by elevated levels of the inflammatory protein tumor necrosis factor-alpha (TNF). We have shown that peripheral nerve injury increases TNF in the hippocampus/pain perception region, which regulates neuropathic pain symptoms. In this study we assessed pain sensation and perception subsequent to specific targeting of brain-TNF (via TNF antibody) administered through a novel subcutaneous perispinal route. Neuropathic pain was induced in Sprague-Dawley rats via chronic constriction injury (CCI), and thermal hyperalgesia was monitored for 10 days post-surgery. On day 8 following CCI and sensory pain behavior testing, rats were randomized to receive perispinal injection of TNF antibody or control IgG isotype antibody. Pain perception was assessed using conditioned place preference (CPP) to the analgesic, amitriptyline. CCI-rats receiving the perispinal injection of TNF antibody had significantly decreased CCI-induced thermal hyperalgesia the following day, and did not form an amitriptyline-induced CPP, whereas CCI-rats receiving perispinal IgG antibody experienced pain alleviation only in conjunction with i.p. amitriptyline and did form an amitriptyline-induced CPP. The specific targeting of brain TNF via perispinal delivery alleviates thermal hyperalgesia and positively influences the affective component of pain. PERSPECTIVE: This study presents a novel route of drug administration to target central TNF for treatment of neuropathic pain. Targeting central TNF through perispinal drug delivery could potentially be a more efficient and sustained method to treat patients with neuropathic pain.

Chronic excessive drinking leads to a wide spectrum of neurological disorders, including cognitive deficits, such as learning and memory impairment. However, the neurobiological mechanisms underlying these deleterious changes are still poorly understood. We conducted a comprehensive study to investigate the role and mechanism of autophagy in alcohol-induced memory impairment. To establish an ethanol-induced memory impairment mouse model, we allowed C57BL/6J mice intermittent access to 20% ethanol (four-bottle choice) to escalate ethanol drinking levels. Memory impairment was confirmed by a Morris water maze test. We found that mice exposed to EtOH (ethanol) and EtOH combined with the autophagy inhibitor 3-methyladenine (3-MA) showed high alcohol intake and blood alcohol concentration. We confirmed that the EtOH group exhibited notable memory impairment. Inhibition of autophagy by 3-MA worsened ethanol-induced memory impairment. Ethanol induced autophagy in the hippocampus of mice as indicated by western blotting, electron microscopy, RT-qPCR, and fluorescence confocal microscopy. We determined that the mTOR/BECN1 (S14) pathway is involved in ethanol-induced autophagy in vivo. Further, ethanol-induced autophagy suppressed the NLRP3 inflammatory and apoptosis pathways in the hippocampus in mice and in vitro. These findings suggest that autophagy activation in hippocampal cells alleviates ethanol-induced memory impairment in association with anti-apoptotic and anti-inflammatory pathways.

A chronic neuroinflammatory response has been considered as a critical pathogenesis promoting neurodegenerative progression in Alzheimer's disease (AD). During neuroinflammatory process, microglia are excessively activated and simultaneously release numerous pro-inflammatory mediators that cause synaptic dysfunction in the forebrain prior to neuronal degeneration and memory deficits in AD. Thus, prevention of neuroinflammation-mediated synaptic dysfunction may be a potential therapeutic approach against neurodegenerative disorders. Trans-cinnamaldehyde (TCA) is a primary bioactive component derived from the stem bark of Cinnamomum cassia, and it possesses potent anti-inflammatory and neuroprotective activities in in vivo and in vitro experiments. However, the in-depth molecular mechanisms of TCA underlying anti-neuroinflammatory and neuroprotective effects on memory deficits in AD are still unclear. The presenilin 1 and 2 conditional double knockout (PS cDKO) mice exhibit AD-like phenotypes including obvious neuroinflammatory responses and synaptic dysfunction and memory deficits. Here, PS cDKO were used to evaluate the potential neuroprotective effects of TCA against neuroinflammation-mediated dementia by performing behavioral tests, electrophysiological recordings and molecular biology analyses. We observed that TCA treatment reversed abnormal expression of synaptic proteins and tau hyperphosphorylation in the hippocampus and prefrontal cortex of PS cDKO mice. TCA treatment also ameliorated NMDA receptor (NMDAR) dysfunction including impaired NMDAR-mediated responses and long-term potentiation (LTP) induction in the hippocampus of PS cDKO mice. Moreover, TCA possesses an ability to suppress neuroinflammatory responses by diminishing microglial activation and levels of pro-inflammatory mediators in the hippocampus and prefrontal cortex of PS cDKO mice. Importantly, improving NMDAR dysfunction and memory deficits of PS cDKO mice was due to the inhibition of neuroinflammatory responses through TCA's interruptive effect on the nuclear factor kappa B (NF-κB) signaling pathway. Therefore, TCA may be a potential anti-neuroinflammatory agent for deterring neurodegenerative progression of AD.

To investigate the expression patterns of LIM Homeobox 6 (Lhx6) in the adult and developing mouse retina.

Oryeong-san (ORS) is a traditional formula that has long been used for the treatment of dysfunctions of body fluids and electrolyte homeostasis in Korea, China and Japan. Recent reports have shown that ORS may suppress hypertension by controlling the renin-angiotensin-aldosterone system (RAAS) in the kidney, but its action mechanism has not been well defined.

Osteoarthritis (OA) is a highly prevalent skeletal disease. Mesenchymal stem cell-derived cartilage tissue engineering is a clinical method used for OA treatment. Investigations on the molecular regulatory mechanisms of the chondrogenic differentiation of synovium-derived mesenchymal stem cells(SMSCs) will help promote its clinical applications. In this study, bioinformatics analysis from three different databases indicated that the long non-coding RNA (lncRNA) MEG3 may regulate the chondrogenic differentiation of SMSCs by targeting TRIB2. We then performed assays and found that both knockdown of MEG3 or overexpression of TRIB2 can stimulate the chondrogenic differentiation of SMSCs and increase Col2A1 and aggrecan expression. Knockdown of MEG3 can induce the expression of TRIB2; conversely, overexpression of MEG3 can inhibit the expression of TRIB2. Futhermore, knockdown of the TRIB2 can rescue the MEG3 silencing-mediated promotion of chondrogenic differentiation. Moreover, RNA immunoprecipitation(RIP) and RNA pull-down assays demonstrated that MEG3 can interact with EZH2, thus recruiting it to induce H3K27me3, which promotes the methylation of TRIB2 by binding with the promoter of TRIB2 in SMSCs. Additionally, EZH2 silencing significantly rescued the MEG3 overexpression-mediated inhibition of TRIB2 expression and chondrogenic differentiation of SMSCs. Taken together, these data indicated that MEG3 regulates chondrogenic differentiation by inhibiting TRIB2 expression through EZH2-mediated H3K27me3.

A previous study observed bell-shaped concentration-response isotherms for activation of Gαi3 G-protein subunits by high efficacy 5-HT1A receptor agonists in a Chinese hamster ovary (CHO) cell line expressing high levels of these receptors. This suggested that a signaling switch took place in that cell line (from Gαi3 to activation of other G-proteins) but it was unclear if such effects are observed for 5-HT1A receptors in other cellular environments. Here, using an antibody capture-based [35S]GTPγS binding assay for Gαi3 activation, we investigated whether efficacious 5-HT1A receptor agonists (5-HT, F13714, befiradol, NLX-101), prototypical agonists ((+) and (-)8-OH-DPAT), and partial agonist, antagonists, inverse agonists (pindolol, WAY100635, spiperone) produced similar effects on 5 cell lines expressing different levels of human 5-HT1A receptors. In membranes from cell lines (HeLa, C6-glia and CHO-low) expressing moderate receptor levels (between 1 and 4 pmol/mg of protein), 5-HT, F13714, befiradol and NLX-101 elicited classical sigmoid concentration-response isotherms. In contrast, in cell lines (CHO-high, HEK-293F) expressing high receptor levels (>9 pmol/mg) these agonists elicited bell-shaped concentration-response isotherms that peaked at nanomolar-range concentrations and then returned to baseline or below. Spiperone elicited inverse agonist inhibitory sigmoid isotherms in all membrane preparations while WAY100635 was mostly 'silent' for Gαi3 activation. The other compounds elicited diverse responses in the different cell lines suggesting that other factors, in addition to receptor expression levels, could be influencing Gαi3 activation. These data indicate that Gαi3 G-protein activation by 5-HT1A receptor ligands is highly dependent on receptor expression levels and on cellular background. Moreover, the induction of bell-shape concentration-response isotherms by 5-HT and other high-efficacy agonists is consistent with a switch in signaling to other G-protein-mediated signaling cascades, possibly elicited by receptor conformational changes.

Cellular senescence is an irreversible cell cycle arrest process associated with aging and senescence-related diseases. DNA damage is an extensive feature of cellular senescence and aging. Different levels of DNA damage could lead to cellular senescence or transient cell-cycle arrest, but the genetic regulatory mechanisms determining cell fate are still not clear. In this work, high-resolution time course analysis of gene expression in DNA damage-induced cellular senescence and transient cell-cycle arrest was used to explore the transcriptomic differences between different cell fates after DNA damage response and to investigate the key regulatory factors affecting senescent cell fates. Pathways such as the cell cycle, DNA repair and cholesterol metabolism showed characteristic differential response. A number of key transcription factors were predicted to regulating cell cycle and DNA repair. Our study provides genome-wide insights into the molecular-level mechanisms of senescent cell fate decisions after DNA damage response.

Deltamethrin (DM) is widely used in a variety of pest control, resulting in serious drug resistance. Keap1-Nrf2-ARE is the antioxidant stress pathway. We identified 268 genes differentially expressed (DEGs) in Drosophila Kc cells treated with DM, including up-regulated 180 genes and down-regulated 88 genes compared with the control group (fold-change≥2, qValue≤0.001) by RNA-seq, they are mainly linked to metabolic process, stimulation response, immune system process. When the cells are treated with DM in the case of overexpression of the Keap1 gene, the cytochrome P450 family genes were significantly down-regulated, and some diseases-related genes and non-coding genes also changed. Our data shown that Keap1-Nrf2-ARE pathway may play an important role in DM stress, which will provide a new direction for studying the mechanism of insect resistance.

Nine new and unique xanthone derivatives, including one novel hybrid monoterpene-tetrahydroxanthone (1), three dihydro-xanthone derivatives (2-4), and five skeleton-rearranged xanthone derivatives (5-9), were obtained from a 95% EtOH extract of Garcinia oligantha leaves by a LC-MS-guided fractionation procedure. The structures of the new compounds were elucidated by analysis of their 1D and 2D NMR and MS data. The relative configurations of 2 and 8 were determined via X-ray crystallographic data analysis, while the absolute configurations of 1-2, 5-9 were assigned based on a comparison of calculated and experimental ECD and/or OR data. In SRB, PI-exclusion and Hoechst staining assays, 6 showed strong cytotoxic activities which could dose-dependently induce Taxol-insensitive quiescent LNCaP cell death. Additionally, a preliminary mechanism investigation using immunoblotting and Caspase-3 activity assay, indicated that 6 induced quiescent LNCaP cell death potentially through caspase-dependent mitochondrial apoptosis pathway.