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Neuromelanin granules (NMGs) are organelle-like structures present in the human substantia nigra pars compacta. In addition to neuromelanin, NMGs contain proteins, lipids and metals. As NMG-containing dopaminergic neurons are preferentially lost in Parkinson's disease and dementia with Lewy bodies (DLB), it is assumed that NMGs may play a role in neurodegenerative processes. Until now, this role is not completely understood and needs further investigation. We therefore set up an exploratory proteomic study to identify differences in the proteomic profile of NMGs from DLB patients (n = 5) compared to healthy controls (CTRL, n = 5). We applied a laser microdissection and mass-spectrometry-based approach, in which we used targeted mass spectrometric experiments for validation. In NMG-surrounding (SNSurr.) tissue of DLB patients, we found evidence for ongoing oxidative damage and an impairment of protein degradation. As a potentially disease-related mechanism, we found α-synuclein and protein S100A9 to be enriched in NMGs of DLB cases, while the abundance of several ribosomal proteins was significantly decreased. As S100A9 is known to be able to enhance the formation of toxic α-synuclein fibrils, this finding points towards an involvement of NMGs in pathogenesis, however the exact role of NMGs as either neuroprotective or neurotoxic needs to be further investigated. Nevertheless, our study provides evidence for an impairment of protein degradation, ongoing oxidative damage and accumulation of potentially neurotoxic protein aggregates to be central mechanisms of neurodegeneration in DLB. [ABSTRACT FROM AUTHOR]

Protein quantitation in tissue cells or physiological fluids based on liquid chromatography/mass spectrometry is one of the key sources of information on the mechanisms of cell functioning during chemotherapeutic treatment. Information on significant changes in protein expression upon treatment can be obtained by chemical proteomics and requires analysis of the cellular proteomes, as well as development of experimental and bioinformatic methods for identification of the drug targets. Low throughput of whole proteome analysis based on liquid chromatography and tandem mass spectrometry is one of the main factors limiting the scale of these studies. The method of direct mass spectrometric identification of proteins, DirectMS1, is one of the approaches developed in recent years allowing ultrafast proteome-wide analyses employing minute-scale gradients for separation of proteolytic mixtures. Aim of this work was evaluation of both possibilities and limitations of the method for identification of drug targets at the level of whole proteome and for revealing cellular processes activated by the treatment. Particularly, the available literature data on chemical proteomics obtained earlier for a large set of onco-pharmaceuticals using multiplex quantitative proteome profiling were analyzed. The results obtained were further compared with the proteome-wide data acquired by the DirectMS1 method using ultrashort separation gradients to evaluate efficiency of the method in identifying known drug targets. Using ovarian cancer cell line A2780 as an example, a whole-proteome comparison of two cell lysis techniques was performed, including the freeze-thaw lysis commonly employed in chemical proteomics and the one based on ultrasonication for cell disruption, which is the widely accepted as a standard in proteomic studies. Also, the proteome-wide profiling was performed using ultrafast DirectMS1 method for A2780 cell line treated with lonidamine, followed by gene ontology analyses to evaluate capabilities of the method in revealing regulation of proteins in the cellular processes associated with drug treatment. [ABSTRACT FROM AUTHOR]

Aim: The study aimed to identify the underlying differentially expressed genes (DEGs) and mechanism of unstable atherosclerotic plaque using bioinformatics methods. Methods: GSE120521, which includes four unstable samples and four stable atherosclerotic samples, was downloaded from the GEO database. DEGs were identified using LIMMA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using the Database for metascape Visualization online tool. Based on the STRING database, protein–protein interactions (PPIs) network among DEGs were constructed. Regulatory networks were visualized using Cytoscape. We use the xCell to analyze the different immune cell subtypes. Results: A total of 1626 DEGs (1034 up-regulated and 592 down-regulated DEGs) were identified between unstable and stable samples. I pulled 62 transcription factors (34 up-regulated TFs and 28 down-regulated TFs) from the Trust database. The up-regulated TFs were mainly enrichment in positive regulation of myeloid leukocyte differentiation, and the down-regulated TFs were mainly enrichment in connective tissue development. In the PPI network, RB1, CEBPA, PPARG, BATF was the most significantly up-regulated gene in ruptured atherosclerotic samples. The immune cell composition enriched in CD cells and macrophages in the unstable carotid plaque. Conclusions: Upregulated RB1, CEBPA, PPARG, BATF and down-regulated SRF, MYOCD, HEY2, GATA6 might perform critical promotional roles in atherosclerotic plaque rupture, furthermore, number and polarization of macrophages may play an important role in vulnerable plaques. [ABSTRACT FROM AUTHOR]

There is strong evidence that physical activity has a profound protective effect against multiple types of cancer. Here, we show that this effect may be mediated by factors released from skeletal muscle during simulated exercise, in situ, which suppress canonical anabolic signaling in breast cancer. We report attenuated growth of MCF7 breast cancer cells in the presence of a rodent-derived exercise conditioned perfusate, independent of prior exercise training. This reduction was concomitant with increased levels of DEPTOR protein and reduced mTOR activity. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive disorder without a cure. Develop risk prediction models for detecting presymptomatic AD using non-cognitive measures is necessary to enable early interventions.Objective: Examine if non-cognitive metrics alone can be used to construct risk models to identify adults at risk for AD dementia and cognitive impairment.Methods: Clinical data from older adults without dementia from the Memory and Aging Project (MAP, n = 1,179) and Religious Orders Study (ROS, n = 1,103) were analyzed using Cox proportional hazard models to develop risk prediction models for AD dementia and cognitive impairment. Models using only non-cognitive covariates were compared to models that added cognitive covariates. All models were trained in MAP, tested in ROS, and evaluated by the AUC of ROC curve.Results: Models based on non-cognitive covariates alone achieved AUC (0.800,0.785) for predicting AD dementia (3.5) years from baseline. Including additional cognitive covariates improved AUC to (0.916,0.881). A model with a single covariate of composite cognition score achieved AUC (0.905,0.863). Models based on non-cognitive covariates alone achieved AUC (0.717,0.714) for predicting cognitive impairment (3.5) years from baseline. Including additional cognitive covariates improved AUC to (0.783,0.770). A model with a single covariate of composite cognition score achieved AUC (0.754,0.730).Conclusion: Risk models based on non-cognitive metrics predict both AD dementia and cognitive impairment. However, non-cognitive covariates do not provide incremental predictivity for models that include cognitive metrics in predicting AD dementia, but do in models predicting cognitive impairment. Further improved risk prediction models for cognitive impairment are needed. [ABSTRACT FROM AUTHOR]

Copyright of Asian Journals of Ecotoxicology is the property of Gai Kan Bian Wei Hui and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Lafora disease (LD) is a fatal rare neurodegenerative disorder that affects young adolescents and has no treatment yet. The hallmark of LD is the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), in the brain and peripheral tissues. LD is caused by mutations in either EPM2A or EPM2B genes, which, respectively, encode laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase, with identical clinical features. LD knockout mouse models (Epm2a − / − and Epm2b − / −) recapitulate PG body accumulation, as in the human pathology, and display alterations in glutamatergic transmission and neuroinflammatory pathways in the brain. In this work, we show the results of four pre-clinical trials based on the modulation of glutamatergic transmission (riluzole and memantine) and anti-neuroinflammatory interventions (resveratrol and minocycline) as therapeutical strategies in an Epm2b − / − mouse model. Drugs were administered in mice from 3 to 5 months of age, corresponding to early stage of the disease, and we evaluated the beneficial effect of the drugs by in vivo behavioral phenotyping and ex vivo histopathological brain analyses. The behavioral assessment was based on a battery of anxiety, cognitive, and neurodegenerative tests and the histopathological analyses included a panel of markers regarding PG accumulation, astrogliosis, and microgliosis. Overall, the outcome of ameliorating the excessive glutamatergic neurotransmission present in Epm2b − / − mice by memantine displayed therapeutic effectiveness at the behavioral levels. Modulation of neuroinflammation by resveratrol and minocycline also showed beneficial effects at the behavioral level. Therefore, our study suggests that both therapeutical strategies could be beneficial for the treatment of LD patients. A mouse model of Lafora disease (Epm2b-/-) was used to check the putative beneficial effect of different drugs aimed to ameliorate the alterations in glutamatergic transmission and/or neuroinflammation present in the model. Drugs in blue gave a more positive outcome than the rest. [ABSTRACT FROM AUTHOR]

Axenically cultured C. elegans show many characteristic traits of worms subjected to dietary restriction, such as slowed development, reduced fertility, and increased stress resistance. Hence, the term axenic dietary restriction (ADR) is often applied. ADR dramatically extends the worm lifespan compared to other DR regimens such as bacterial dilution. However, the underlying molecular mechanisms still remain unclear. The primary goal of this study is to comprehensively investigate transcriptional alterations that occur when worms are subjected to ADR and to estimate the molecular and physiological changes that may underlie ADR-induced longevity. One of the most enriched clusters of up-regulated genes under ADR conditions is linked to lysosomal activity, while proteasomal genes are significantly down-regulated. The up-regulation of genes specifically involved in amino acid metabolism is likely a response to the high peptide levels found in axenic culture medium. Genes related to the integrity and function of muscles and the extracellular matrix are also up-regulated. Consistent down-regulation of genes involved in DNA replication and repair may reflect the reduced fertility phenotype of ADR worms. Neuropeptide genes are found to be largely up-regulated, suggesting a possible involvement of neuroendocrinal signaling in ADR-induced longevity. In conclusion, axenically cultured worms seem to rely on increased amino acid catabolism, relocate protein breakdown from the cytosol to the lysosomes, and do not invest in DNA maintenance but rather retain muscle integrity and the extracellular matrix. All these changes may be coordinated by peptidergic signaling. [ABSTRACT FROM AUTHOR]

With the completion of Sc2.0 chromosomes, synthetic chromosome rearrangement and modification by loxP-mediated evolution (SCRaMbLE) becomes more critical for in-depth investigation of fundamental biological questions and screening of industrially valuable characteristics. Further applications, however, are hindered due to the lack of facile and tight regulation of the SCRaMbLE process, and limited understanding of key factors that may affect the rearrangement outcomes. Here we propose an approach to precisely regulate SCRaMbLE recombination in a dose-dependent manner using genetic code expansion (GCE) technology with low basal activity. By systematically analyzing 1380 derived strains and six yeast pools subjected to GCE-SCRaMbLE, we find that Cre enzyme abundance, genome ploidy and chromosome conformation play key roles in recombination frequencies and determine the SCRaMbLE outcomes. With these insights, the GCE-SCRaMbLE system will serve as a powerful tool in the future exploitation and optimization of the Sc2.0-related technologies. Applications of the SCRaMbLE process are hindered due to the lack of facile and tight regulation and limited understanding of key factors that may affect the rearrangement outcomes. Here the authors present an approach to precisely regulate SCRaMbLE recombination in a dose-dependent manner using genetic code expansion technology with low basal activity. [ABSTRACT FROM AUTHOR]

The pathogenesis of type 2 diabetes mellitus (T2DM) is closely associated with mitochondrial functions in insulin-responsive tissues. The mitochondrial proteome, compared with the mitochondrial genome, which only contains 37 genes in humans, can provide more comprehensive information for thousands of mitochondrial proteins regarding T2DM-associated mitochondrial functions. However, T2DM-associated protein signatures in insulin-responsive tissues are still unclear. Here, we performed extensive proteome profiling of mitochondria from skeletal muscles in nine T2DM patients and nine nondiabetic controls. A comparison of the mitochondrial proteomes identified 335 differentially expressed proteins (DEPs) between T2DM and nondiabetic samples. Functional and network analyses of the DEPs showed that mitochondrial metabolic processes were downregulated and mitochondria-associated ER membrane (MAM) processes were upregulated. Of the DEPs, we selected two (NDUFS3 and COX2) for downregulated oxidative phosphorylation and three (CALR, SORT, and RAB1A) for upregulated calcium and protein transport as representative mitochondrial and MAM processes, respectively, and then confirmed their differential expression in independent mouse and human samples. Therefore, we propose that these five proteins be used as a potential protein profile that is indicative of the dysregulation of mitochondrial functions in T2DM, representing downregulated oxidative phosphorylation and upregulated MAM functions.

A bifunctional peroxidase enzyme, 4-coumarate 3-hydroxylase (C3H/APX), provides a parallel route to the shikimate shunt pathway for the conversion of 4-coumarate to caffeate in the early steps of lignin biosynthesis. Knockdown of C3H/APX (C3H/APX-KD) expression has been shown to reduce the lignin content in Brachypodium distachyon. However, like many other ligninmodified plants, C3H/APX-KDs show unpredictable pleiotropic phenotypes, including stunted growth, delayed senescence, and reduced seed yield. A system-wide level understanding of altered biological processes in ligninmodified plants can help pinpoint the lignin-modification associated growth defects to benefit future studies aiming to negate the yield penalty. Here, a multi-omic approach was used to characterize molecular changes resulting from C3H/APX-KD associated lignin modification and negative growth phenotype in Brachypodium distachyon. Our findings demonstrate that C3H/APX knockdown in Brachypodium stems substantially alters the abundance of enzymes implicated in the phenylpropanoid biosynthetic pathway and disrupt cellular redox homeostasis. Moreover, it elicits plant defense responses associated with intracellular kinases and phytohormone-based signaling to facilitate growth-defense trade-offs. A deeper understanding along with potential targets to mitigate the pleiotropic phenotypes identified in this study could aid to increase the economic feasibility of lignocellulosic biofuel production. [ABSTRACT FROM AUTHOR]

Vinculin and talin-1, which are cytoskeletal proteins affecting focal adhesions, were reported to be down-expressed in atherosclerotic lesions. Recently, we reported high concentrations of plasma talin-1 in patients with coronary artery disease (CAD). However, blood vinculin concentrations in CAD patients have not been clarified. Plasma vinculin concentrations as well as talin-1 were studied in 327 patients in whom coronary angiography was performed. CAD was proven in 177 patients (1-vessel, n = 79; 2-vessel, n = 57; 3-vessel disease, n = 41). However, vinculin concentrations were not markedly different between the CAD(-) and CAD groups (median 122.5 vs. 119.6 pg/mL, p = 0.325) or among patients with CAD(-), 1-, 2-, and 3-vessel diseases (122.5, 112.8, 107.9, and 137.2 pg/mL, p = 0.202). In contrast, talin-1 concentrations were higher in CAD than the CAD(-) group (0.29 vs. 0.23 ng/mL, p = 0.006) and increased stepwise in the number of stenotic vessels: 0.23 in CAD(-), 0.28 in 1-vessel, 0.29 in 2-vessel, and 0.33 ng/mL in 3-vessel disease (p = 0.043). No correlation was observed between vinculin and talin-1 concentrations. In multivariate analysis, vinculin concentrations were not a factor for CAD. In conclusion, plasma vinculin concentrations in patients with CAD were not high and were not associated with the presence or severity of CAD. [ABSTRACT FROM AUTHOR]

Bone mass reduction due to an imbalance in osteogenesis and osteolysis is characterized by low bone mineral density (LBMD) and is clinically classified as osteopenia (ON) or osteoporosis (OP), which is more severe. Multiple biomarkers for diagnosing OP and its progression have been reported; however, most of these lack specificity. This cohort study aimed to investigate sensitive and specific LBMD-associated protein biomarkers in patients diagnosed with ON and OP. A label-free liquid chromatography-mass spectrometry (LC-MS) proteomics approach was used to analyze serum samples. Patients' proteomics profiles were filtered for potential confounding effects, such as age, sex, chronic diseases, and medication. A distinctive proteomics profile between the control, ON, and OP groups (Q2 = 0.7295, R2 = 0.9180) was identified, and significant dysregulation in a panel of proteins (n = 20) was common among the three groups. A comparison of these proteins showed that the levels of eight proteins were upregulated in ON, compared to those in the control and the OP groups, while the levels of eleven proteins were downregulated in the ON group compared to those in the control group. Interestingly, only one protein, myosin heavy chain 14 (MYH14), showed a linear increase from the control to the ON group, with the highest abundance in the OP group. A significant separation in the proteomics profile between the ON and OP groups (Q2 = 0.8760, R2 = 0.991) was also noted. Furthermore, a total of twenty-six proteins were found to be dysregulated between the ON and the OP groups, with fourteen upregulated and twelve downregulated proteins in the OP, compared to that in the ON group. Most of the identified dysregulated proteins were immunoglobulins, complement proteins, cytoskeletal proteins, coagulation factors, and various enzymes. Of these identified proteins, the highest area under the curve (AUC) in the receiver operating characteristic (ROC) analysis was related to three proteins (immunoglobulin Lambda constant 1 (IGLC1), RNA binding protein (MEX3B), and fibulin 1 (FBLN1)). Multiple reaction monitoring (MRM), LC-MS, was used to validate some of the identified proteins. A network pathway analysis of the differentially abundant proteins demonstrated dysregulation of inflammatory signaling pathways in the LBMD patients, including the tumor necrosis factor (TNF), toll-like receptor (TL4), and interferon-γ (IFNG) signaling pathways. These results reveal the existence of potentially sensitive protein biomarkers that could be used in further investigations of bone health and OP progression. [ABSTRACT FROM AUTHOR]

Several proteins contain signaling domains that can regulate the cell membrane dynamics as well as the underlying cytoskeleton. Among these, Bin‐Amphiphysin‐Rvs (BAR) domain‐containing proteins, with their membrane deforming properties, have emerged as the key players in regulating neuronal morphology and inducing neuronal signaling that can modulate synaptic architecture. While the biochemical and structural basis of membrane deformation by the BAR‐domain proteins has been extensively studied, the in vivo contexts in which these proteins function remain to be elucidated. Despite the discovery of BAR‐domain proteins over 25 years ago, most of the studies have primarily focused on understanding the structural and biochemical properties and cell biological processes regulated by these proteins. Understanding the functional requirements of these proteins at the level of multicellular organisms and the way these proteins regulate biological processes remains a topic of intensive study. In this review, we discuss the functional roles of BAR‐domain proteins in the context of membrane dynamics and cellular signaling. We highlight recent developments describing the functional role of these proteins in neuronal morphogenesis, synaptic function, and disease. [ABSTRACT FROM AUTHOR]

Aging is associated with the increased risk of most age-related diseases in humans. Complanatoside A (CA) is a flavonoid compound isolated from the herbal medicine Semen Astragali Complanati. CA was reported to have potential anti-inflammatory and anti-oxidative activities. In this study, we investigated whether CA could increase the stress resistance capability and life span of Caenorhabditis elegans. Our results showed that CA could extend the longevity of C. elegans in a dosage-dependent manner, while 50 μM of CA has the best effect and increased the life span of C. elegans by about 16.87%. CA also improved the physiological functions in aging worms, such as enhanced locomotor capacity, and reduced the accumulation of the aging pigment. CA could also reduce the accumulation of toxic proteins (α-synuclein and βamyloid) and delay the onset of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, in models of C. elegans. Further investigation has revealed that CA requires DAF-16/FOXO, SKN-1, and HSF-1 to extend the life span of C. elegans. CA could increase the antioxidation and detoxification activities regulated by transcription factor SKN-1 and the heat resistance by activating HSF-1 that mediated the expression of the chaperone heat shock proteins. Our results suggest that CA is a potential antiaging agent worth further research for its pharmacological mechanism and development for pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignant carcinomas. CRC is characterized by asymptomatic onset, and most patients are already in the middle and advanced stages of disease when they are diagnosed. Inflammatory bowel disease (IBD) and the inflammatory-cancer transformation of advanced colorectal adenoma are the main causes of CRC. There is an urgent need for effective prevention and intervention strategies for CRC. In recent years, rapid research progress has increased our understanding of gut microbiota. Meanwhile, with the deepening of research on the pathogenesis of colorectal cancer, gut microbiota has been confirmed to play a direct role in the occurrence and treatment of colorectal cancer. Strategies to regulate the gut microbiota have potential value for application in the prevention and treatment of CRC. Regulation of gut microbiota is one of the important ways for natural products to exert pharmacological effects, especially in the treatment of metabolic diseases and tumours. This review summarizes the role of gut microbiota in colorectal tumorigenesis and the mechanism by which natural products reduce tumorigenesis and improve therapeutic response. We point out that the regulation of gut microbiota by natural products may serve as a potential means of treatment and prevention of CRC. [ABSTRACT FROM AUTHOR]

Objective. Glioblastoma is one of the most common and fatal malignancies in adults. Current treatment is still not optimistic. Glioblastoma (GBM) transports RNA to platelets in the blood system via microvesicles, suggesting that platelet RNA can be a potential diagnostic and therapeutic target. The roles of specific platelet RNAs in treatment of GBM are not well understood. Methods. Platelet RNA profiling of 8 GBM and 12 normal samples were downloaded from the GEO database. Differentially expressed genes (DEGs) were identified between tumors and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to elucidate the functions of up- and downregulated genes. miRNA was predicted by miRTarBase, TargetScan, and miRDB databases. circBase and circBank were used for circRNA prediction. ceRNA (circRNA-mRNA-miRNA) network was constructed to investigate the potential interactions. Results. 22 genes were upregulated and 9 genes were downregulated. There are only two genes (CCR7 and FAM102A) that connect to miRNAs (hsa-let-7a-5p, hsa-miR-1-3p). We assessed the overall survival rates by Kaplan-Meier plotter, and relative expression of GBM and subtypes for overlapped mRNA (CCR7 and FAM102A) were evaluated, and further, we obtained circRNAs (has-circ-0015164, hsa-circ-0003243) by circBank and circBase and bind sites through the CSCD database. Finally, a ceRNA network (circRNA-mRNA-miRNA) was constructed based on 2 miRNAs, 2 mRNAs, and 2 circRNAs by Cytoscape. This study focused on potential mRNA and ceRNA biomarkers to targeted treatment of GBM and provided ideas for clinical treatment through the combination of hematology and oncology. Conclusion. The findings of this study contribute to better understand the relationship between GBM and the blood system (platelets) and might lay a solid foundation for improving GBM molecule and gene diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Background: Applying directed acyclic graph (DAG) models to proteogenomic data has been shown effective for detecting causal biomarkers of complex diseases. However, there remain unsolved challenges in DAG learning to jointly model binary clinical outcome variables and continuous biomarker measurements. Results: In this paper, we propose a new tool, DAGBagM, to learn DAGs with both continuous and binary nodes. By using appropriate models, DAGBagM allows for either continuous or binary nodes to be parent or child nodes. It employs a bootstrap aggregating strategy to reduce false positives in edge inference. At the same time, the aggregation procedure provides a flexible framework to robustly incorporate prior information on edges. Conclusions: Through extensive simulation experiments, we demonstrate that DAGBagM has superior performance compared to alternative strategies for modeling mixed types of nodes. In addition, DAGBagM is computationally more efficient than two competing methods. When applying DAGBagM to proteogenomic datasets from ovarian cancer studies, we identify potential protein biomarkers for platinum refractory/resistant response in ovarian cancer. DAGBagM is made available as a github repository at https://github.com/jie108/dagbagM. [ABSTRACT FROM AUTHOR]

The genetic protective factors for cognitive decline in aging remain unknown. Predicting an individual's rate of cognitive decline—or with better cognitive resilience—using genetics will allow personalized intervention for cognitive enhancement and the optimal selection of target samples in clinical trials. Here, using genome-wide polygenic scores (GPS) of cognitive capacity as the genomic indicators for variations of human intelligence, we analyzed the 18-year records of cognitive and behavioral data of 8511 European-ancestry adults from the Wisconsin Longitudinal Study (WLS), specifically focusing on the cognitive assessments that were repeatedly administered to the participants with their average ages of 64.5 and 71.5. We identified a significant interaction effect between age and cognitive capacity GPS, which indicated that a higher cognitive capacity GPS significantly correlated with a slower cognitive decline in the domain of immediate memory recall (β = 1.86 × 10−1, p-value = 1.79 × 10−3). The additional phenome-wide analyses identified several associations between cognitive capacity GPSs and cognitive/behavioral phenotypes, such as similarities task (β = 1.36, 95% CI = (1.22, 1.51), p-value = 3.59 × 10−74), number series task (β = 0.94, 95% CI = (0.85, 1.04), p-value = 2.55 × 10−78), IQ scores (β = 1.42, 95% CI = (1.32, 1.51), p-value = 7.74 × 10−179), high school classrank (β = 1.86, 95% CI = (1.69, 2.02), p-value = 3.07 × 10−101), Openness from the BIG 5 personality factor (p-value = 2.19 × 10−14, β = 0.57, 95% CI = (0.42, 0.71)), and leisure activity of reading books (β = 0.50, 95% CI = (0.40, 0.60), p-value = 2.03 × 10−21), attending cultural events, such as concerts, plays, or museums (β = 0.60, 95% CI = (0.49, 0.72), p-value = 2.06 × 10−23), and watching TV (β = −0.48, 95% CI = (−0.59, −0.37), p-value = 4.16 × 10−18). As the first phenome-wide analysis of cognitive and behavioral phenotypes, this study presents the novel genetic protective effects of cognitive ability on the decline of memory recall in an aging population. [ABSTRACT FROM AUTHOR]

Background: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown.Objective: Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology.Methods: Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia.Results: Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function.Conclusion: Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective anti-leishmanial through pointing to new drug targets in less time, having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future. [ABSTRACT FROM AUTHOR]

Few studies have examined tick proteomes, how they adapt to their environment, and their roles in the parasite–host interactions that drive tick infestation and pathogen transmission. Here we used a proteomics approach to screen for biologically and immunologically relevant proteins acting at the tick‐host interface during tick feeding and, as proof of principle, measured host antibody responses to some of the discovered candidates. We used a label‐free quantitative proteomic workflow to study salivary proteomes of (i) wild Ixodes ricinus ticks fed on different hosts, (ii) wild or laboratory ticks fed on the same host, and (iii) adult ticks cofed with nymphs. Our results reveal high and stable expression of several protease inhibitors and other tick‐specific proteins under different feeding conditions. Most pathways functionally enriched in sialoproteomes were related to proteolysis, endopeptidase, and amine‐binding activities. The generated catalogue of tick salivary proteins enabled the selection of six candidate secreted immunogenic peptides for rabbit immunizations, three of which induced strong and durable antigen‐specific antibody responses in rabbits. Furthermore, rabbits exposed to ticks mounted immune responses against the candidate peptides/proteins, confirming their expression at the tick‐vertebrate interface. Our approach provides insights into tick adaptation strategies to different feeding conditions and promising candidates for developing antitick vaccines or markers of exposure of vertebrate hosts to tick bites. [ABSTRACT FROM AUTHOR]

Background: The analysis of volatile organic compounds (VOCs) collected in breath samples has the potential to be a rapid, non-invasive test to aid in the clinical diagnosis and tracking of chronic conditions such as Parkinson's disease (PD). Objective: To assess the feasibility and utility of breath sample analysis done, both at point of collection in clinic and when sent away to be analyzed remotely, to diagnose, stratify and monitor disease course in a moderately large cohort of patients with PD. Methods: Breath samples were collected from 177 people with PD and 37 healthy matched control individuals followed over time. Standard clinical data (MDS-UPDRS & cognitive assessments) from the PD patients were collected at the same time as the breath sample was taken, these measures were then correlated with the breath test analysis of exhaled VOCs. Results: The breath test was able to distinguish patients with PD from healthy control participants and correlated with disease stage. The off-line system (remote analysis) gave good results with overall classification accuracies across a range of clinical measures of between 73.6% to 95.6%. The on-line (in clinic) system showed comparable results but with lower levels of correlation, varying between 33.5% to 82.4%. Chemical analysis identified 29 potential molecules that were different and which may relate to pathogenic pathways in PD. Conclusion: Breath analysis shows potential for PD diagnostics and monitoring. Both off-line and on-line sensor systems were easy to do and provided comparable results which will enable this technique to be easily adopted in clinic if larger studies confirm our findings. [ABSTRACT FROM AUTHOR]

In three novel peptidoids based on the tryptophan—histidine—tryptophan (WHW) peptide, the central histidine was replaced by Ala-(triazole), and two derivatives also had one tryptophan replaced with pyrene-alkyls of different lengths and flexibility. Pyrene analogues show strong fluorescence at 480–500 nm, attributed to intramolecular exciplex formation with tryptophan. All three peptidoids bind Cu2+ cation in water with strong affinity, with Trp- Ala-(triazole)-Trp binding comparably to the parent WHW, and the pyrene analogues even stronger, demonstrating that replacement of histidine with triazole in peptides does not hamper Cu2+ coordination. The studied peptidoids strongly bind to ds-DNA and ds-RNA, whereby their complexes with Cu2+ exhibit distinctively different interactions in comparison to metal-free analogues, particularly in the stabilization of ds-DNA against thermal denaturation. The pyrene peptidoids efficiently enter living cells with no apparent cytotoxic effect, whereby their red-shifted emission compared to the parent pyrene allows intracellular confocal microscopy imaging, showing accumulation in cytoplasmic organelles. However, irradiation with 350 nm light resulted in evident antiproliferative effect on cells treated with micromolar concentrations of the pyrene analogues, presumably attributed to pyrene-induced production of singlet oxygen and consecutive cellular damage. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex disease, and numerous cellular events may be involved in etiology. RNAseq-based transcriptome data hold multilayer information content, which could be crucial in unraveling molecular mysteries of AD. It enables quantification of gene expression levels, identification of genomic variants, and elucidation of splicing anomalies such as exon skipping and intron retention. Additional integration of this information into protein-protein interaction networks and genome-scale metabolic models from the literature has potential to decipher functional modules and affected mechanisms for complex scenarios such as AD. In this chapter, we review the application areas of the multilayer content of RNAseq and associated integrative approaches available, with a special focus on AD., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: There is an urgent need for cost-effective, easy-to-measure biomarkers to identify subjects who will develop Alzheimer's disease (AD), especially at the pre-symptomatic stage. This stage can be determined in autosomal dominant AD (ADAD) which offers the opportunity to observe the dynamic biomarker changes during the life-course of AD stages. This study aimed to investigate serum biomarkers during different AD stages and potential novel protein biomarkers of presymptomatic AD. Methods: In the first stage, 32 individuals [20 mutation carriers including 10 with AD, and 10 with mild cognitive impairment (MCI), and 12 healthy controls] from ADAD families were analyzed. All subjects underwent a complete clinical evaluation and a comprehensive neuropsychological battery. Serum samples were collected from all subjects, and antibody arrays were used to analyze 170 proteins in these samples. The most promising biomarkers were identified during this screening and were then measured in serum samples of 12 subjects with pre-MCI and 20 controls. Results: The serum levels of 13 proteins were significantly different in patients with AD or MCI compared to controls. Of the 13 proteins, cathepsin D, immunoglobulin E, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP-9), von Willebrand factor (vWF), haptoglobin, and phosphorylated Tau-181 (p-Tau181) correlated with all cognitive measures (R2 = −0.69–0.76). The areas under the receiver operating characteristic curve of these seven proteins were 0.71–0.93 for the classification of AD and 0.57–0.95 for the classification of MCI. Higher levels of p-Tau181 were found in the serum of pre-MCI subjects than in the serum of controls. The p-Tau181 serum level might detect AD before symptoms occur (area under the curve 0.85, sensitivity 75%, specificity 81.67%). Conclusions: A total of 13 serum proteins showed significant differences between subjects with AD and MCI and healthy controls. The p-Tau181 serum level might be a broadly available and cost-effective biomarker to identify individuals with preclinical AD and assess the severity of AD. [ABSTRACT FROM AUTHOR]

Cortical neuron loss is a pathological hallmark of late-onset Alzheimer's disease (AD). However, it remains unclear which neuronal subtypes beyond broad excitatory and inhibitory classes are most vulnerable. Here, we analyzed cell subtype proportion differences in AD compared to non-AD controls using 1037 post-mortem brain samples from six neocortical regions. We identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β = −0.48, p bonf = 8.98 × 10–9) and intra-telencephalic (IT) excitatory neurons (β = -0.45, p bonf = 4.32 × 10–7). Replication in three AD case-control single-nucleus RNAseq datasets most strongly supported the bulk tissue association of fewer SST neurons in AD. In depth analyses of cell type proportions with specific AD-related neuropathological and cognitive phenotypes revealed fewer SST neurons with greater brain-wide post-mortem tau and beta amyloid, as well as a faster rate of antemortem cognitive decline. In contrast, greater IT neuron proportions were associated with a slower rate of cognitive decline as well as greater residual cognition–a measure of cognitive resilience–but not canonical AD neuropathology. Our findings implicate somatostatin inhibitory and intra-telencephalic excitatory neuron subclasses in the pathogenesis of AD and in cognitive resilience to AD pathology, respectively. [ABSTRACT FROM AUTHOR]

Background. Endocrine disruption is an important factor in the development of endometrial cancer. Expression of miR-149-3p is observed in some cancer types, while its role in uterine corpus endometrial carcinoma (UCEC) is unclear. Methods. The clinical and genomic data and prognostic information on UCEC were obtained for patients from the TCGA database. The Kruskal–Wallis test, Wilcoxon signed-rank test, and logistic regression were used to analyze the relationship between clinical characteristics and miR-149-3p expression. Kaplan–Meier survival curve analysis was used to study the influence of miR-149-3p expression and miR-149-3p target genes on the prognosis of UCEC patients. The TargetScan, PicTar, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to determine the involvement of miR-149-3p target genes in function. Immune infiltration analysis was used to analyze the functional involvement of miR-149-3p. QRT-PCR was used to validate the expression of miR-149-3p in UCEC cell lines. Results. High expression of miR-149-3p in UCEC was significantly associated with age (P < 0.001), histological type (P < 0.001), histological grade (P < 0.001), tumor invasion (P = 0.014), and radiation therapy (P = 0.011). High miR-149-3p expression predicted poorer overall survival (OS) (HR: 2.56; 95% CI: 1.64–4.00; P < 0.001), progression-free interval (PFI) (HR: 1.85; 95% CI: 1.29–2.65; P = 0.001), and disease-specific survival (DSS) (HR: 2.33; 95% CI: 1.37–3.99; P = 0.002). Low expressions of miR-149-3p target genes, including ADCYAP1R1, CGNL1, CHST3, CYGB, DNAH9, ESR1, HHIP, HIC1, HOXD11, IGF1, INMT, LSP1, MTMR10, NFIC, PLCE1, RARA, SNTN, SPRYD3, and ZBTB7A, were associated with poor OS in UCEC. MiR-149-3p may be involved in the occurrence and development of UCEC via pathways including PI3K-Akt signaling pathway, Ras signaling pathway, AGE-RAGE signaling pathway in diabetic complications, focal adhesion, and MAPK signaling pathway. miR-149-3p may inhibit the function of CD8 T cells, cytotoxic cells, eosinophils, iDC, mast cells, neutrophils, NK CD56bright cells, NK CD56dim cells, pDC, T cells, T helper cells, TFH, Th17 cells, and Treg. miR-149-3p was significantly upregulated in UCEC cell lines compared with endometriotic stromal cells. Conclusion. High expression of miR-149-3p was significantly associated with poor survival in UCEC patients. It may be a promising biomarker of prognosis and response to immunotherapy for UCEC patients. [ABSTRACT FROM AUTHOR]

Estrogen and progesterone are the major determinants of the occurrence and development of endometrial cancer (EC), which is one of the most common gynecological cancers worldwide. Our purpose was to develop a novel estrogen/progesterone-related gene signature to better predict the prognosis of EC and help discover effective therapeutic strategies. We downloaded the clinical and RNA-seq data of 397 EC patients from The Cancer Genome Atlas (TCGA) database. The "limma" R package was used to screen for estrogen/progesterone-related differentially expressed genes (DEGs) between EC and normal tissues. Univariate and multivariate Cox proportional hazards regression analyses were applied to identify these DEGs that were associated with prognosis; then, a novel estrogen/progesterone-related prognostic signature comprising CDC25B, GNG3, ITIH3, PRXL2A and SDHB was established. The Kaplan–Meier (KM) survival analysis showed that the low-risk group identified by this signature had significantly longer overall survival (OS) than the high-risk group; the receiver operating characteristic (ROC) and risk distribution curves suggested this signature was an accurate predictor independent of risk factors. A nomogram incorporating the signature risk score and stage was constructed, and the calibration plot suggested it could accurately predict the survival rate. Compared with normal tissues, tumor tissues had increased mRNA levels of GNG3 and PRXL2A and a reduced mRNA level of ITIH3. The knockdown of PRXL2A and GNG3 significantly inhibited the proliferation and colony formation of Ishikawa and AN3CA cells, while the inhibition of PRXL2A expression suppressed xenograft growth. In this study, five estrogen/progesterone-related genes were identified and incorporated into a novel signature, which provided a new classification tool for improved risk assessment and potential molecular targets for EC therapies. [ABSTRACT FROM AUTHOR]

Chromatin structure is a major regulator of DNA-associated processes, such as transcription, DNA repair, and replication. Histone post-translational modifications, or PTMs, play a key role on chromatin dynamics. PTMs are involved in a wide range of biological processes in eukaryotes, including fungal species. Their deposition/removal and their underlying functions have been extensively investigated in yeasts but much less in other fungi. Nonetheless, the major role of histone PTMs in regulating primary and secondary metabolisms of filamentous fungi, including human and plant pathogens, has been pinpointed. In this review, an overview of major identified PTMs and their respective functions in fungi is provided, with a focus on filamentous fungi when knowledge is available. To date, most of these studies investigated histone acetylations and methylations, but the development of new methodologies and technologies increasingly allows the wider exploration of other PTMs, such as phosphorylation, ubiquitylation, sumoylation, and acylation. Considering the increasing number of known PTMs and the full range of their possible interactions, investigations of the subsequent Histone Code, i.e., the biological consequence of the combinatorial language of all histone PTMs, from a functional point of view, are exponentially complex. Better knowledge about histone PTMs would make it possible to efficiently fight plant or human contamination, avoid the production of toxic secondary metabolites, or optimize the industrial biosynthesis of certain beneficial compounds. [ABSTRACT FROM AUTHOR]

In the control strategy for process related impurities in biopharmaceuticals, the enzyme linked immunosorbent assay (ELISA) is the method of choice for the quantification of host cell proteins (HCPs). Besides two dimensional‐western blots (2D‐WB), the coverage of ELISA antibodies is increasingly evaluated by affinity purification‐based liquid chromatography–tandem mass spectrometry (AP‐MS) methods. However, all these methods face the problem of unspecific binding issues between antibodies and the matrix, involving the application of arbitrarily defined thresholds during data evaluation. To solve this, a new approach (optimized AP‐MS) was developed in this study, for which a cleavable linker was conjugated to the ELISA antibodies enabling the subsequent isolation of specifically interacting HCPs. By comparing both approaches in terms of method variability and the number of false positive or negative hits, we could demonstrate that the optimized AP‐MS method is very reproducible and superior in the identification of antibody detection gaps, while previously described strategies suffered from over‐ or underestimating the coverage. As only antibody associated HCPs were identified, we demonstrated that the method is beneficial for hitchhiker analysis. Overall, the method described herein has proven as a powerful tool for reliable coverage determination of ELISA antibodies, without the need to arbitrarily exclude HCPs during the coverage evaluation. [ABSTRACT FROM AUTHOR]

Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single‐cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single‐cell microglia transcriptomes. We discovered microglial co‐expression network modules associated with age, sex, and APOE‐ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single‐cell transcriptomes revealed significant overlap between age‐associated module genes and both pro‐inflammatory and disease‐associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta‐analyses with published bulk and single‐cell microglial datasets further supported our findings. Thus, these data represent a well‐characterized human microglial transcriptome resource and highlight age, sex, and APOE‐related microglial immunometabolism perturbations with potential relevance in neurodegeneration. [ABSTRACT FROM AUTHOR]

Aging is an inevitable process that all individuals experience, of which the extent differs among individuals. It has been recognized as the risk factor of neurodegenerative diseases by affecting gut microbiota compositions, microglia, and cognition abilities. Aging‐induced changes in gut microbiota compositions have a critical role in orchestrating the morphology and functions of microglia through the gut‐brain axis. Gut microbiota communicates with microglia by its secreted metabolites and neurotransmitters. This is highly associated with age‐related cognitive declines. Here, we review the main composition of microbiota in the aged individuals, outline the changes of the brain in age‐related cognitive decline from a neuroinflammation perspective, especially the changes of morphology and functions of microglia, discuss the crosstalk between microbiota and microglia in the aged brain and further highlight the role of microbiota‐microglia connections in neurodegenerative diseases (Alzheimer's disease and Parkinson's disease). [ABSTRACT FROM AUTHOR]

The aim of the study was to explore new markers in serum proteome associated with the response to antiosteoporosis drugs, namely teriparatide and denosumab. We obtained serum samples from 14 patients with osteoporosis, both at baseline and after 6 months of treatment with teriparatide (n = 10) or denosumab (n = 4). Samples were analyzed by nanoliquid chromatography coupled to high-resolution mass spectrometry on a QTOF 5600 (SCIEX) apparatus. The spectrometry data were analyzed with Mascot against the UniProtKB base and then several quality-control filters were applied for the identification of peptides (false discovery rate, FDR q < 0.02) and their quantification (FDR q < 0.05). In the group treated with teriparatide, 28 proteins were identified with significant differences before and after treatment. A pathway analysis by using the Reactome database revealed significant enrichment in the Insulin Like Growth Factor 1 (IGF-I) (FDR q 4 × 10−2) and innate immune system (FDR q 2 × 10−3) pathways. Among patients treated with denosumab, we observed significant differences in the levels of 10 proteins, which were also enriched in the pathways related to the innate immune system (FDR q 3 × 10−2). These results suggest that the innate immune system may be involved in the response to antiosteoporosis drugs. [ABSTRACT FROM AUTHOR]

Purpose. This study was designed to clarify the prognostic value of tumor microenvironment score and abnormal genomic alterations in TME for breast cancer patients. Method. The TCGA-BRCA data were downloaded from TCGA and analyzed with R software. The results from analyses were further validated using the dataset from GSE96058, GSE124647, and GSE25066. Results. After analyzing the TCGA data and verifying it with the GEO data, we developed a TMEscore model based on the TME infiltration pattern and validated it in 3273 breast cancer patients. The results suggested that our TMEscore model has high prognostic value. TME features with the TMEscore model can help to predict breast cancer patients' response to immunotherapy and provide new strategies for breast cancer treatment. Signature 24 was first found in breast cancer. In focal SCNAs, a total of 95 amplified genes and 169 deletion genes in the TMEscore high group were found to be significantly related to the prognosis of breast cancer patients, while 61 amplified genes and 174 deletion genes in the TMEscore low group were identified. LRRC48, CFAP69, and cg25726128 were first discovered and reported to be related to the survival of breast cancer patients. We identified specific mutation signatures that correlate with TMEscore and prognosis. Conclusion. TMEscore model has high predictive value regarding prognosis and patients' response to immunotherapy. Signature 24 was first found in breast cancer. Specific mutation signatures that correlate with TMEscore and prognosis might be used for providing additional indicators for disease evaluation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia and one of the top medical concerns worldwide. Currently, the approved drugs to treat AD are effective only in treating the symptoms, but do not cure or prevent AD. Although the exact causes of AD are not understood, it is recognized that tau aggregation in neurons plays a key role. Chuanxiong Rhizoma (CR) has been widely reported as effective for brain diseases such as dementia. Thus, we explored the protections of CR in AD by a tau pathogenesis–based network pharmacology approach. According to ultra-HPLC with triple quadrupole mass spectrometry data and Lipinski's rule of five, 18 bioactive phytochemicals of CR were screened out. They were shown corresponding to 127 tau pathogenesis–related targets, among which VEGFA, IL1B, CTNNB1, JUN, ESR1, STAT3, APP, BCL2L1, PTGS2, and PPARG were identified as the core ones. We further analyzed the specific actions of CR-active phytochemicals on tau pathogenesis from the aspects of tau aggregation and tau-mediated toxicities. It was shown that neocnidilide, ferulic acid, coniferyl ferulate, levistilide A, Z-ligustilide, butylidenephthalide, and caffeic acid can be effective in reversing tau hyperphosphorylation. Neocnidilide, senkyunolide A, butylphthalide, butylidenephthalide, Z-ligustilide, and L-tryptophan may be effective in promoting lysosome-associated degradation of tau, and levistilide A, neocnidilide, ferulic acid, L-tryptophan, senkyunolide A, Z-ligustilide, and butylidenephthalide may antagonize tau-mediated impairments of intracellular transport, axon and synaptic damages, and neuron death (especially apoptosis). The present study suggests that acting on tau aggregation and tau-mediated toxicities is part of the therapeutic mechanism of CR against AD. [ABSTRACT FROM AUTHOR]

Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease and dementia are among the most significant current healthcare challenges given the rapidly growing elderly population, and the almost total lack of effective therapeutic interventions. Alzheimer's disease pathology has long been considered in terms of accumulation of amyloid beta and hyperphosphorylated tau, but the importance of neuroinflammation in driving disease has taken greater precedence over the last 15–20 years. Inflammatory activation of the primary brain immune cells, the microglia, has been implicated in Alzheimer's pathogenesis through genetic, preclinical, imaging and postmortem human studies, and strategies to regulate microglial activity may hold great promise for disease modification. Neuroinflammation is necessary for defence of the brain against pathogen invasion or damage but is normally self‐limiting due to the engagement of endogenous pro‐resolving circuitry that terminates inflammatory activity, a process that appears to fail in Alzheimer's disease. Here, we discuss the potential for a major regulator and promoter of resolution, the receptor FPR2, to restrain pro‐inflammatory microglial activity, and propose that it may serve as a valuable target for therapeutic investigation in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objective : Amphetamine-type stimulant (ATS) and opioid dependencies are chronic inflammatory diseases with similar symptoms and common genomics. However, their coexpressive genes have not been thoroughly investigated. We aimed to identify and verify the coexpressive hub genes and pathway involved in the pathogenesis of ATS and opioid dependencies. Methods : The microarray of ATS- and opioid-treatment mouse models was obtained from the Gene Expression Omnibus database. GEO2R and Venn diagram were performed to identify differentially expressed genes (DEGs) and coexpressive DEGs (CDEGs). Functional annotation and protein–protein interaction network detected the potential functions. The hub genes were screened using the CytoHubba and MCODE plugin with different algorithms, and further validated by receiver operating characteristic analysis in the GSE15774 database. We also validated the hub genes mRNA levels in BV2 cells using qPCR. Result : Forty-four CDEGs were identified between ATS and opioid databases, which were prominently enriched in the PI3K/Akt signaling pathway. The top 10 hub genes were mainly enriched in apoptotic process (CD44, Dusp1, Sgk1, and Hspa1b), neuron differentiation, migration, and proliferation (Nr4a2 and Ddit4), response to external stimulation (Fos and Cdkn1a), and transcriptional regulation (Nr4a2 and Npas4). Receiver operating characteristic (ROC) analysis found that six hub genes (Fos, Dusp1, Sgk1, Ddit4, Cdkn1a, and Nr4a2) have an area under the curve (AUC) of more than 0.70 in GSE15774. The mRNA levels of Fos, Dusp1, Sgk1, Ddit4, Cdkn1a, PI3K, and Akt in BV2 cells and GSE15774 with METH and heroin treatments were higher than those of controls. However, the Nr4a2 mRNA levels increased in BV2 cells and decreased in the bioinformatic analysis. Conclusions: The identification of hub genes was associated with ATS and opioid dependencies, which were involved in apoptosis, neuron differentiation, migration, and proliferation. The PI3K/Akt signaling pathway might play a critical role in the pathogenesis of substance dependence. [ABSTRACT FROM AUTHOR]