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Background and AimEurope faces an elevated risk of nonalcoholic fatty liver disease (NAFLD) among people living with HIV (PLWH), contributing to the region’s highest global burden of NAFLD. However, the prevalence of NAFLD across various European countries and regions remains unclear. This study aims to investigate the prevalence and risk factors associated with NAFLD among PLWH across European countries.MethodsA systematic search was conducted across four databases: PubMed, Embase, Web of Science, and Cochrane Library. Data on the prevalence of NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis, as well as the associated risk factors, were collected among PLWH in Europe.ResultsThirty-six studies from 13 European nations were included. The prevalence of NAFLD, NASH, and fibrosis were 42% (95%CI 37–48), 35% (95%CI 21–50) and 13% (95%CI 10–15), respectively. Male gender, BMI, waist circumference, Diabetes, hypertension, metabolic syndrome, dyslipidemia, triglycerides, HDL, LDL, ALT, AST, and years on antiretroviral therapy (ART) were found to be risk factors for NAFLD. High BMI and triglycerides were associated with NASH. Patients with high BMI and triglycerides are at increased risk of significant liver fibrosis.ConclusionThe high prevalence of NAFLD, NASH, and fibrosis among PLWH in Europe highlights the need for early screening, intervention, and increased research focus on adolescents living with HIV. Furthermore, the significant variations observed between countries and regions underscore the influence of related risk factors.

Objective: This study aimed to assess the efficacy of currently used anti-diabetic medications in the treatment of non-alcoholic fatty liver disease (NAFLD) without diabetes. DESIGN: The efficacy of various anti-diabetic medicines on non-alcoholic fatty liver disease in the absence of diabetes was evaluated by searching Pubmed, Embase, Cochrane Library, and Web of Science for randomized controlled trials (RCT) only. The methodological quality was evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2), and the data were analyzed using Stata software (version 15.1). Results: All papers published between the time of the pooling and September 2022 were searched. There were a total of 18 randomized controlled studies with a total sample size of 1141 cases. The outcomes of interest included variations in alanine transaminase (ALT) and aspartate transaminase (AST). Rosiglitazone (SUCRA: 100%) and vildagliptin (SUCRA: 99.9%) were the best anti-diabetic medicines to improve ALT and AST, respectively, in patients with NAFLD without diabetes, according to the findings of this network meta-analysis. Conclusion: In accordance with the Network Ranking plot, Rosiglitazone was the best anti-diabetic medicine for improving ALT, and vildagliptin was the best for improving AST in patients with non-diabetic NAFLD.

Objective: To evaluate the efficacy of the Chinese herbal compound GAPT for the treatment of Alzheimer’s disease (AD) and to provide current evidence for potential treatment mechanisms. Methods: A comprehensive search of PubMed, Embase, Web of Science, SinoMed, China Network Knowledge Infrastructure, Wanfang Data, and Chinese Scientific Journals Database was performed to identify GAPT mouse/rat studies published from inception to July 2019. The outcomes extracted were Morris water maze results and molecular biological quantifications. Results: A total of 19 studies were included in this analysis. The analysis indicated that GAPT was able to significantly improve learning and memory abilities compared with model mice/rats, as assessed by Morris water maze, and showed similar efficacy as donepezil. Subgroup analyses showed that low, medium, and high doses resulted in no obvious dose-dependent effects. Additionally, the GAPT group had significantly reduced expression levels of amyloid-beta peptide, presenilin 1, phosphorylated tau, acetylcholinesterase, and glycogen synthase kinase-3β, but increased expression levels of Shank1, and protein phosphatase-2A, and improved synapses structures compared with the model group, and subgroup analyses showed the medium dose of GAPT was superior to the low and high doses. Conclusions: Based on the pooled analysis, GAPT improved the learning and memory abilities and regulated the expression levels of related proteins during the progression of AD in mouse/rat studies. Notably, the medium dose of GAPT exhibited better performance than the other two doses, providing experimental evidence for further applications of GAPT during clinical practice. Keywords: Chinese herbal compound, Alzheimer’s disease, Mouse, Systematic review, Meta-analysis

The sustained increase in atmospheric [CO2] over the past two centuries has brought a series of global challenges in plant-environment interactions. However, genetic mechanisms in botanical adaption and feedback to environmental alteration remain elusive. Here we collected and analysed transcriptome sequencing data from leaf tissues of maize Zea mays conditioned under high [CO2] stress for 0, 7 or 14 d. A total of 1390 genes, either up- or down-regulated, differed significantly in these conditions. Gene Ontology (GO) enrichment terms and KEGG metabolism pathways included protein phosphorylation, protein ubiquitination, oxidation-reduction, plant organ development, cellular response to endogenous response and MAPK signaling. We also identified three densely connected gene clusters: TCP/PYE, WRKYs and MYC/JAZ from significant DEGs. In conclusion, we provided a genetic database for biologists in botany, agronomy and ecology to further investigate the molecular machinery by which C4-plants respond to elevated atmospheric [CO2] and accompanying global climate change.

Adipose tissue and more specifically micro-fragmented adipose tissue (MFAT) obtained from liposuction has recently been shown to possess interesting medicinal properties whereby its application supports pain reduction and may enhance tissue regeneration particularly in osteoarthritis. Here we have characterised samples of MFAT produced using the Lipogems® International Spa system from eight volunteer individuals in order to understand the critical biological mechanisms through which they act. A variation was found in the MFAT cluster size between individual samples and this translated into a similar variation in the ability of purified mesenchymal stem cells (MSCs) to form colony-forming units. Almost all of the isolated cells were CD105/CD90/CD45+ indicating stemness. An analysis of the secretions of cytokines from MFAT samples in a culture using targeted arrays and an enzyme-linked immunosorbent assay (ELISA) showed a long-term specific and significant expression of proteins associated with anti-inflammation (e.g., interleukin-1 receptor alpha (Il-1Rα) antagonist), pro-regeneration (e.g., hepatocyte growth factor), anti-scarring and pro-angiogenesis (e.g., transforming growth factor beta 1 and 2 (TGFβ1/2) and anti-bacterial (e.g., chemokine C-X-C motif ligand-9 (CXCL-9). Angiogenesis and angiogenic signalling were notably increased in primary bovine aortic endothelial cells (BAEC) to a different extent in each individual sample of the conditioned medium whilst a direct capacity of the conditioned medium to block inflammation induced by lipopolysaccharides was shown. This work characterises the biological mechanisms through which a strong, long-lasting, and potentially beneficial effect can be observed regarding pain reduction, protection and regeneration in osteoarthritic joints treated with MFAT.

Background: We previously identified increased tissue localization of monomeric C-reactive protein (mCRP) in the infarcted cortical brain tissue of patients following ischaemic stroke. Here, we investigated the relationship of mCRP expression in haemorrhagic stroke, and additionally examined the capacity of mCRP to travel to or appear at other locations within the brain that might account for later chronic neuroinflammatory or neurodegenerative effects. Methods: Immunohistochemistry was performed on Formalin-fixed, paraffin-embedded archived brain tissue blocks obtained at autopsy from stroke patients and age-matched controls. We modelled mCRP migration into the brain after haemorrhagic stroke by infusing mCRP (3.5 µg) into the hippocampus of mice and localized mCRP with histological and immunohistochemistry methods. Results: On human tissue in the early stages of haemorrhage, there was no staining of mCRP. However, with increasing post-stroke survival time, mCRP immunostaining was associated with some parenchymal brain cells, some stroke-affected neurons in the surrounding areas and the lumen of large blood vessels as well as brain capillaries. Further from the peri-haematoma region, however, mCRP was detected in the lumen of micro-vessels expressing aquaporin 4 (AQP4). In the hypothalamus, we detected clusters of neurons loaded with mCRP along with scattered lipofuscin-like deposits. In the peri-haematoma region of patients, mCRP was abundantly seen adjacent to AQP4 immunoreactivity. When we stereotactically injected mCRP into the hippocampus of mice, we also observed strong expression in distant neurones of the hypothalamus as well as cortical capillaries. Conclusions: mCRP is abundantly expressed in the brain after haemorrhagic stroke, directly impacting the pathophysiological development of the haematoma. In addition, it may have indirect effects, where the microcirculatory system appears to be able to carry it throughout the cortex as far as the hypothalamus, allowing for long-distance effects and damage through its capacity to induce inflammation and degenerate neuronal perivascular compartments.

Objectives: In this study, we examined the possibility of using targeted antibodies and the potential of small molecular therapeutics (acetylcholine, nicotine and tacrine) to block the pro-inflammatory and adhesion-related properties of monomeric C-reactive protein (mCRP).Methods: We used three established models (platelet aggregation assay, endothelial leucocyte binding assay and monocyte inflammation via ELISA and Western blotting) to assess the potential of these therapeutics.Results: The results of this study showed that monocyte induced inflammation (raised tumor necrosis factor-alpha-TNF-α) induced by mCRP was significantly blocked in the presence of acetylcholine and nicotine, whilst tacrine and targeted antibodies (clones 8C10 and 3H12) had less of or no significant effects. Western blotting confirmed the ability of acetylcholine to inhibit mCRP-induced cell signaling phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), p38 and nuclear factor-kappa B (NF-κB). There was no evidence of direct binding between small molecules and mCRP. mCRP also induced endothelial cell-monocyte adhesion in a dose dependent fashion, however, both acetylcholine and nicotine as well as targeting antibodies notably inhibited adhesion. Finally, we investigated their effects on mCRP-induced platelet aggregation. All three small molecules significantly attenuated platelet aggregation as did the antibody 8C10, although 3H12 had a weaker effect.Discussion: Acetylcholine and to a lesser extent nicotine show potential for therapeutic inhibition of mCRP-induced inflammation and cell and platelet adhesion. These results highlight the potential of targeted antibodies and small molecule therapeutics to inhibit the binding of mCRP by prevention of membrane interaction and subsequent activation of cellular cascade systems, which produce the pro-inflammatory effects associated with mCRP.

Circulating C-reactive protein (CRP) is a key acute-phase protein and one of the main clinical biomarkers for inflammation and infection. CRP is an important upstream mediator of inflammation and is associated with the onset of a number of important disease states including cardiovascular disease and neurodegenerative disorders such as Alzheimer’s disease. This pentraxin exerts pro-inflammatory properties via dissociation of the pentamer (pCRP) to a monomeric form (mCRP). This dissociation is induced by binding of pCRP to cell surface phosphocholine residues exposed by the action of phospholipase A2 (PLA2). Given the association of CRP with the onset of a range of serious disease states this CRP dissociation process is a tempting drug target for the development of novel small-molecule therapeutics. This review will discuss potential targets for chemotherapeutic intervention elucidated during studies of CRP-mediated inflammation and provide an up-to-date summary of the development of small molecules, not only targeted directly at inhibiting conversion of pCRP to mCRP, but also those developed for activity against PLA2, given the key role of this enzyme in the activation of CRP.

Protein SUMOylation represents an important regulatory event that changes the activities of numerous proteins. Recent evidence demonstrates that polySUMO chains can act as a trigger to direct the ubiquitin ligase RNF4 to substrates to cause their turnover through the ubiquitin pathway. RNF4 uses multiple SUMO interaction motifs (SIMs) to bind to these chains. However, in addition to polySUMO chains, a multimeric binding surface created by the simultaneous SUMOylation of multiple residues on a protein or complex could also provide a platform for the recruitment of multi-SIM proteins like RNF4. Here we demonstrate that multiSUMOylated ETV4 can bind to RNF4 and that a unique combination of SIMs is required for RNF4 to interact with this multiSUMOylated platform. Thus RNF4 can bind to proteins that are either polySUMOylated through a single site or multiSUMOylated on several sites and raises the possibility that such multiSIM-multiSUMO interactions might be more widespread.

Circulating C-reactive protein (CRP) is a key acute-phase protein and one of the main clinical biomarkers for inflammation and infection. CRP is an important upstream mediator of inflammation and is associated with the onset of a number of important disease states including cardiovascular disease and neurodegenerative disorders such as Alzheimer's disease. This pentraxin exerts pro-inflammatory properties via dissociation of the pentamer (pCRP) to a monomeric form (mCRP). This dissociation is induced by binding of pCRP to cell surface phosphocholine residues exposed by the action of phospholipase A2 (PLA2). Given the association of CRP with the onset of a range of serious disease states this CRP dissociation process is a tempting drug target for the development of novel small-molecule therapeutics. This review will discuss potential targets for chemotherapeutic intervention elucidated during studies of CRP-mediated inflammation and provide an up-to-date summary of the development of small molecules, not only targeted directly at inhibiting conversion of pCRP to mCRP, but also those developed for activity against PLA2, given the key role of this enzyme in the activation of CRP. [ABSTRACT FROM AUTHOR]

Background: Many members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is particularly relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers. Results: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal adenocarcinomas and determined their role in oesophageal adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal adenocarcinomas. Conclusions: This study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal adenocarcinomas. [ABSTRACT FROM AUTHOR]

PEA3 is a member of a subfamily of ETS domain transcription factors which is regulated by a number of signaling cascades, including the mitogen-activated protein (MAP) kinase pathways. PEA3 activates gene expression and is thought to play an important role in promoting tumor metastasis and also in neuronal development. Here, we have identified the LIM domain protein LPP as a novel coregulatory binding partner for PEA3. LPP has intrinsic transactivation capacity, forms a complex with PEA3, and is found associated with PEA3-regulated promoters. By manipulating LPP levels, we show that it acts to upregulate the transactivation capacity of PEA3. LPP can also functionally interact in a similar manner with the related family member ER81. Thus, we have uncovered a novel nuclear function for the LIM domain protein LPP as a transcriptional coactivator. As LPP continually shuttles between the cell periphery and the nucleus, it represents a potential novel link between cell surface events and changes in gene expression. [ABSTRACT FROM AUTHOR]

Specificity protein 1 (Sp1) is an important transcription factor implicated in numerous cellular processes. However, whether Sp1 is involved in the regulation of RNA polymerase III (Pol III)- directed gene transcription in human cells remains unknown. Here, we first show that filamin A (FLNA) represses Sp1 expression as well as expression of TFIIB-related factor 1 (BRF1) and general transcription factor III C subunit 2 (GTF3C2) in HeLa, 293T, and SaOS2 cell lines stably expressing FLNA-silencing shRNAs. Both BRF1 promoter 4 (BRF1P4) and GTF3C2 promoter 2 (GTF3C2P2) contain putative Sp1-binding sites, suggesting that Sp1 affects Pol III gene transcription by regulating BRF1 and GTF3C2 expression. We demonstrate that Sp1 knockdown inhibits Pol III gene transcription, BRF1 and GTF3C2 expression, and the proliferation of 293T and HeLa cells, whereas Sp1 overexpression enhances these activities. We obtained a comparable result in a cell line in which both FLNA and Sp1 were depleted. These results indicate that Sp1 is involved in the regulation of Pol III gene transcription independently of FLNA expression. Reporter gene assays showed that alteration of Sp1 expression affects BRF1P4 and GTF3C2P2 activation, suggesting that Sp1 modulates Pol III-mediated gene transcription by controlling BRF1 and GTF3C2 gene expression. Further analysis revealed that Sp1 interacts with and thereby promotes the occupancies of TATA box-binding protein, TFIIAα, and p300 at both BRF1P4 and GTF3C2P2. These findings indicate that Sp1 controls Pol III-directed transcription and shed light on how Sp1 regulates cancer cell proliferation. [ABSTRACT FROM AUTHOR]