Construction of the coexpression network involved in the pathogenesis of thyroid eye disease via bioinformatics analysis.

BACKGROUND: Thyroid eye disease (TED) is the most common orbital pathology that occurs in up to 50% of patients with Graves' disease. Herein, we aimed at discovering the possible hub genes and pathways involved in TED based on bioinformatical approaches. RESULTS: The GSE105149 and GSE58331 datasets were downloaded from the Gene Expression Omnibus (GEO) database and merged for identifying TED-associated modules by weighted gene coexpression network analysis (WGCNA) and local maximal quasi-clique merger (lmQCM) analysis. EdgeR was run to screen differentially expressed genes (DEGs). Transcription factor (TF), microRNA (miR) and drug prediction analyses were performed using ToppGene suite. Function enrichment analysis was used to investigate the biological function of genes. Protein-protein interaction (PPI) analysis was performed based on the intersection between the list of genes obtained by WGCNA, lmQCM and DEGs, and hub genes were identified using the MCODE plugin. Based on the overlap of 497 genes retrieved from the different approaches, a robust TED coexpression network was constructed and 11 genes (ATP6V1A, PTGES3, PSMD12, PSMA4, METAP2, DNAJA1, PSMA1, UBQLN1, CCT2, VBP1 and NAA50) were identified as hub genes. Key TFs regulating genes in the TED-associated coexpression network, including NFRKB, ZNF711, ZNF407 and MORC2, and miRs including hsa-miR-144, hsa-miR-3662, hsa-miR-12136 and hsa-miR-3646, were identified. Genes in the coexpression network were enriched in the biological processes including proteasomal protein catabolic process and proteasome-mediated ubiquitin-dependent protein catabolic process and the pathways of endocytosis and ubiquitin-mediated proteolysis. Drugs perturbing genes in the coexpression network were also predicted and included enzyme inhibitors, chlorodiphenyl and finasteride. CONCLUSIONS: For the first time, TED-associated coexpression network was constructed and key genes and their functions, as well as TFs, miRs and drugs, were predicted. The results of the present work may be relevant in the treatment and diagnosis of TED and may boost molecular studies regarding TED.

High prevalence of vitamin D deficiency in Asia: A systematic review and meta-analysis.

Vitamin D deficiency is a worldwide health problem. However, the prevalence of vitamin D deficiency in Asian populations is unclear. The aims of our study were to investigate the prevalence of vitamin D deficiency and its association with different health outcomes in Asia. Searches for studies published from January 2009 to January 2021 were performed in the MEDLINE (via PubMed), EMBASE, and Web of Science databases. This study was registered in the PROSPERO database (CRD42021229841). In total, 472 studies with 746,564 subjects were included in the meta-analysis. The mean serum 25-hydroxyvitamin D (25[OH]D) concentration was 49.39 nmol/L; 20.93% of the participants had 25(OH)D levels <25 nmol/L, 22.82% had levels <30 nmol/L, 57.69% had levels <50 nmol/L, and 76.85% had levels <75 nmol/L. This review found that the prevalence of vitamin D deficiency in Asia is high. The factors significantly related to vitamin D deficiency were gender, age, altitude, region, and specific diseases (diabetes, cancer, fracture, systemic lupus erythematosus [SLE], fatty liver disease, osteopenia, thyroiditis, anemia, hepatitis, metabolic diseases, and dermatitis). These findings may serve as the foundation for more detailed public health strategies and policies on this issue.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1990850.

Recent research advances in ATX inhibitors: An overview of primary literature.

The autoglobulin gene is the main enzyme for circulating LPA production and has lysophosphatidylcholine D activity, which catalyzes the production of lysophosphatidic acid and choline with lysophosphatidylcholine as substrate. A growing body of experimental evidence suggests that autoglobulin is involved in the pathogenesis of a variety of diseases. This review summarizes the different structural ATX inhibitors classified according to their binding mode to the ATX triple orientation site, and summarizes the conformational relationships and molecular docking of each type with ATX structure, hoping to contribute to the development of novel ATX inhibitors.

Loss of α7nAChR enhances endothelial-to-mesenchymal transition after myocardial infarction via NF-κB activation.

The myocardial fibrosis in response to myocardial infarction (MI) is closely related to the dysbalance of endothelial-to-mesenchymal transition (EndMT). Although numerous reports indicate that α7 nicotinic acetylcholine receptor (α7nAChR) activates the cholinergic anti-inflammatory pathway (CAP) to regulate the magnitude of inflammatory responses, the role of α7nAChR in myocardial fibrosis, as well as the underlying mechanisms, have not been elucidated. In this study, we evaluated cardiac function, fibrosis, and EndMT signaling using a mouse model of MI and interleukin (IL)-1ß-induced human cardiac microvascular endothelial cells (HCMECs). In vivo, α7nAChR deletion increased cardiac dysfunction, exacerbated the cardiac inflammatory response, and NF-κB activation, and enhanced EndMT, as shown by higher expression levels of fibroblast markers (FSP-1, α-SMA, collagen I, Snail) and decreased levels of the FGFR1, glucocorticoid receptor (GR) and endothelial marker (CD31) compared to wild-type mice. In vitro, the pharmacological activation of α7nAChR with PNU282987 significantly inhibited IL-1ß-induced EndMT, as shown by a reduced transition to the fibroblast-like phenotype and the expression of fibrotic markers. Moreover, the IL-1ß-mediated activation of NF-κB pathway was suppressed by PNU282987. This anti-EndMT effect of α7nAChR was associated with regulation of Snail. Furthermore, Western blot analysis further revealed that the GR antagonist RU38486 could partially counteract the effect of PNU282987 on NF-κB expression. In conclusion, our results show that α7nAChR is involved in cardiac fibrosis by inhibiting EndMT, providing a novel approach to the treatment of MI.

Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFRL858R/T790M inhibitors.

EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC50 value of 13 nM for kinase inhibitory activity against EGFRL858R/T790M and more than 76-fold selectivity for EGFRWT. Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC50 value of 0.087 µΜ. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFRL858R/T790M by cell migration assay and apoptosis assay.

Systematic review and meta-analysis: association between obesity/overweight and surgical complications in IBD.

PURPOSE: While the prevalence of obesity in inflammatory bowel disease (IBD) patients is rapidly increasing, it is unclear whether obesity affects surgical outcomes in this population. This meta-analysis aims to assess the impact of obesity/overweight on patients undergoing surgery for IBD. METHODS: Databases (PubMed, Web of Science, Cochrane Library, and Springer) were searched through September 2021. The meta-analysis included patients with surgically treated IBD to investigate the impact of obesity/overweight on this population. Primary outcomes included overall complications, infectious complications, noninfectious complications, and conversion to laparotomy. RESULTS: Fifteen studies totaling 12,622 IBD patients were enrolled. Compared with nonobese (including overweight) patients, obese IBD patients have increased the risk in terms of overall complications (OR = 1.45, p < 0.001), infectious complications (OR = 1.48, p = 0.003) (especially wound complications), as well as conversion to laparotomy (OR = 1.90, p < 0.001). Among the noninfectious complications, only the incidence of visceral injury (OR = 2.36, p = 0.05) had significantly increased. Compared with non-overweight patients, the risk of developing wound complications (OR = 1.65, p = 0.01) and sepsis (OR = 1.73, p = 0.007) were increased in overweight patients, but the rates of overall complications (OR = 1.04, p = 0.81), infectious complications (OR = 1.31, p = 0.07), and conversion to laparotomy (OR = 1.33, p = 0.08) associated with body mass index (BMI) were not significantly different. CONCLUSION: Obesity is a risk factor for surgical complications in IBD patients, mainly reflected in infectious complications. Moreover, obese patients seem to have a more common chance of developing surgical complications than overweight patients.

Color-Dense Illumination Adjustment Network for Removing Haze and Smoke from Fire Scenario Images.

The atmospheric particles and aerosols from burning usually cause visual artifacts in single images captured from fire scenarios. Most existing haze removal methods exploit the atmospheric scattering model (ASM) for visual enhancement, which inevitably leads to inaccurate estimation of the atmosphere light and transmission matrix of the smoky and hazy inputs. To solve these problems, we present a novel color-dense illumination adjustment network (CIANet) for joint recovery of transmission matrix, illumination intensity, and the dominant color of aerosols from a single image. Meanwhile, to improve the visual effects of the recovered images, the proposed CIANet jointly optimizes the transmission map, atmospheric optical value, the color of aerosol, and a preliminary recovered scene. Furthermore, we designed a reformulated ASM, called the aerosol scattering model (ESM), to smooth out the enhancement results while keeping the visual effects and the semantic information of different objects. Experimental results on both the proposed RFSIE and NTIRE'20 demonstrate our superior performance favorably against state-of-the-art dehazing methods regarding PSNR, SSIM and subjective visual quality. Furthermore, when concatenating CIANet with Faster R-CNN, we witness an improvement of the objection performance with a large margin.

Metformin Attenuates Hypoxia-induced Endothelial Cell Injury by Activating the AMP-Activated Protein Kinase Pathway.

ABSTRACT: Metformin reduces the incidence of cardiovascular diseases, and potential underlying mechanisms of action have been suggested. Here, we investigated the role of metformin in endothelial cell injury and endothelial-mesenchymal transition (EndMT) induced by hypoxia. All experiments were performed in human cardiac microvascular endothelial cells (HCMECs). HCMECs were exposed to hypoxic conditions for 24, 48, 72, and 96 hours, and we assessed the cell viability by cell counting kit 8; metformin (2, 5, 10, and 20 mmol/L) was added to the cells after exposure to the hypoxic conditions for 48 hours. The cells were randomly divided into the control group, hypoxia group, hypoxia + metformin group, hypoxia + control small interfering RNA group, hypoxia + small interfering Prkaa1 (siPrkaa1) group, and hypoxia + siPrkaa1 + metformin group. Flow cytometry and cell counting kit 8 were used to monitor apoptosis and assess cell viability. Immunofluorescence staining was used to identify the CD31+/alpha smooth muscle actin+ double-positive cells. Quantitative real-time-PCR and Western blot were used for mRNA and protein expression analyses, respectively. Hypoxia contributed to endothelial injuries and EndMT of HCMECs in a time-dependent manner, which was mainly manifested as decreases in cell viability, increases in apoptotic rate, and changes in expression of apoptosis-related and EndMT-related mRNAs and proteins. Furthermore, metformin could attenuate the injuries and EndMT caused by hypoxia. After metformin treatment, phosphorylated-AMPK (pAMPK) and p-endothelial nitric oxide synthase expression increased, whereas p-mammalian target of rapamycin expression decreased. However, results obtained after transfection with siPrkaa1 were in contrast to the results of metformin treatment. In conclusion, metformin can attenuate endothelial injuries and suppress EndMT of HCMECs under hypoxic conditions because of its ability to activate the AMPK pathway, increase p-AMPK/AMP-activated protein kinase, and inhibit mammalian target of rapamycin.

Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold.

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.

Biodegradation and chemotaxis of polychlorinated biphenyls, biphenyls, and their metabolites by Rhodococcus spp.

Two biphenyl-degrading bacterial strains, SS1 and SS2, were isolated from polychlorinated biphenyl (PCB)-contaminated soil. They were identified as Rhodococcus ruber and Rhodococcus pyridinivorans based on the 16S rRNA gene sequence, as well as morphological, physiological and biochemical characteristics. SS1 and SS2 exhibited tolerance to 2000 and 3000 mg/L of biphenyl. And they could degrade 83.2 and 71.5% of 1300 mg/L biphenyl within 84 h, respectively. In the case of low-chlorinated PCB congeners, benzoate and 3-chlorobenzoate, the degradation activities of SS1 and SS2 were also significant. In addition, these two strains exhibited chemotactic response toward TCA-cycle intermediates, benzoate, biphenyl and 2-chlorobenzoate. This study indicated that, like the flagellated bacteria, non-flagellated Rhodococcus spp. might actively seek substrates through the process of chemotaxis once the substrates are depleted in their surroundings. Together, these data provide supporting evidence that SS1 and SS2 might be good candidates for restoring biphenyl/PCB-polluted environments.

Extracellular Adenosine Diphosphate Ribose Mobilizes Intracellular Ca2+ via Purinergic-Dependent Ca2+ Pathways in Rat Pulmonary Artery Smooth Muscle Cells.

BACKGROUND/AIMS: Adenosine diphosphate ribose (ADPR), a product of ß-NAD+ metabolism generated by the multifunctional enzyme CD38, is recognized as a novel signaling molecule. The catalytic site of CD38 orients extracellularly or intracellularly, capable of generating ADPR outside and inside the cells. CD38-dependent pathways have been characterized in pulmonary artery smooth muscle cells (PASMCs); however the physiological function of extracellular ADPR is unclear. METHODS: Ca2+ mobilizing and proliferative effects of extracellular ADPR were characterized and compared with the ATP-induced responses in rat PASMCs; and the expression of purinergic receptor (P2X and P2Y) subtypes were examined in pulmonary arteries. RESULTS: ADPR elicited concentration-dependent increase in [Ca2+]i with a fast transient and a sustained phase in PASMCs. The sustained phase was abolished by Ca2+ removal and inhibited by the non-selective cation channel blocker SKF-96365, but was unaffected by TRPM2 antagonists or nifedipine. The purinergic receptor (P2X) antagonist pyridoxal-phosphate-6-azophenyl-2', 4'-disulfonate inhibited partially the transient and the sustained Ca2+ response, while the P2(XY) inhibitor suramin and the phospholipase C inhibitor U73122 abolished the sustained Ca2+ influx. The P2Y1 antagonist MRS2179 had no effect on the response. By contrast, ATP and ADP activated Ca2+ response exhibited a high and a low affinity component, and the pharmacological profile of ATP-induced Ca2+ response was distinctive from that of ADPR. BrdU incorporation assay showed that ADPR caused significant inhibition whereas ATP caused slight stimulation of PASMC proliferation. RT-PCR analysis found that almost all P2X and P2Y subtypes are expressed in PAs. CONCLUSION: ADPR and ATP activate Ca2+ responses through different combinations of multiple purinergic receptor subtypes; and extracellular ADPR may exert an autocrine/paracrine action via purinergic receptors on PASMCs.

Chronic Hypoxia Increases Intracellular Ca(2+) Concentration via Enhanced Ca(2+) Entry Through Receptor-Operated Ca(2+) Channels in Pulmonary Venous Smooth Muscle Cells.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is characterized by pulmonary vascular remodeling. Intracellular Ca(2+)concentration ([Ca(2+)]i) is an essential signal for myocyte proliferation. Whether chronic hypoxia (CH) affects the basal [Ca(2+)]I and Ca(2+)entry through store- and/or receptor-operated calcium channels (SOCC, ROCC), and whether canonical transient receptor potential (TRPC) proteins are involved in CH-induced Ca(2+)influx and proliferation in pulmonary venous smooth muscle cells (PVSMCs) is examined. METHODS AND RESULTS: Rats were exposed to CH. PVSMCs were isolated from distal pulmonary veins. In freshly isolated PVSMCs, CH increased the basal [Ca(2+)]i; removal of Ca(2+)or application of SKF-96365 reversed the elevated [Ca(2+)]i, whereas nifedipine had no effect. Receptor-operated Ca(2+)entry (ROCE) was expressed in PVSMCs. In freshly isolated PVSMCs from CH rats, ROCE was enhanced, whereas store-operated Ca(2+)entry had no alteration. Furthermore, real-time polymerase chain reaction and western blotting showed that mRNA and protein expression level of TRPC6, but neither TRPC1 nor TRPC3, in pulmonary venous smooth muscle (PV) from CH rats and PVSMCs exposed to CH was greater than in normal PV and PVSMCs. The knockdown of TRPC6 in hypoxic PVSMCs with siRNA inhibited the enhanced ROCE and attenuated CH-induced PVSMCs proliferation. CONCLUSIONS: The enhanced Ca(2+)entry through ROCC, due to upregulated TRPC6, is a novel pathogenic mechanism contributing to the increased basal [Ca(2+)]iin PVSMCs and excessive PVSMC proliferation during the development of HPH.

Enhanced degradation of biphenyl from PCB-contaminated sediments: the impact of extracellular organic matter from Micrococcus luteus.

Recent advances in the bioremediation of polychlorinated biphenyl (PCB)-contaminated environments have focused on the development of approaches to stimulate the activities of indigenous bacterial communities. In this study, extracellular organic matter (EOM) from Micrococcus luteus was used to enhance the biphenyl-degrading capability of potentially functional microorganisms. The obtained results suggest that EOM significantly enhanced the biphenyl (BP)-degradation capability. Under a concentration of 3,500 mg/L BP, BP-degradation efficiency reached 60.8 % at a dosage of 10 % EOM (v/v), whereas the degradation efficiencies of control group (with inactivated EOM addition) and blank group (with lactate minimal medium) were only 21.5 and 6.2 %, respectively. Denaturing gradient gel electrophoresis (DGGE) profiles demonstrated that EOM played a key role in shifts in the composition and diversity of bacterial community. The Illumina high-throughput sequencing analysis indicated that the genera of Rhodococcus and Pseudomonas closely related to BP/PCB-degradation were greatly abundant after EOM addition. Together with polymerase chain reaction (PCR)-DGGE analysis, the link between the enhanced BP-degrading capability and the stimulation and resuscitation function of EOM in uncultured bacteria belonging to phylum Actinobacteria was tentatively established. These results suggest that EOM from M. luteus as an additive holds great potential for the efficient and cost-effective bioremediation of PCB-contaminated environment.

Rhodococcus biphenylivorans sp. nov., a polychlorinated biphenyl-degrading bacterium.

A Gram-positive, aerobic, non-motile and rod-coccus shaped novel actinobacterial strain, designated as TG9(T), was isolated from a polychlorinated biphenyl (PCB)-contaminated sediment in Taizhou city, Zhejiang province, eastern China. The isolate was observed to grow at 10-45 °C (optimum 28-32 °C), pH 5.0-11.0 (optimum pH 7.0-8.0) and with 0-9.0 % (w/v) NaCl (optimum 0-3.0 %). Comparison of the 16S rRNA gene sequences of strain TG9(T) and other members of the genus Rhodococcus showed that strain TG9(T) shared highest similarities with Rhodococcus pyridinivorans DSM 44555(T) (99.4 %), R. rhodochrous DSM 43241(T) (99.2 %), R. gordoniae DSM 44689(T) (99.2 %) and R. artemisiae DSM 45380(T) (98.2 %). However, low levels of DNA-DNA relatedness (15-48 %), which are below the 70 % limit for prokaryotic species identification, were obtained by DNA-DNA hybridization. Strain TG9(T) was found to contain meso-diaminopimelic acid as the diagnostic diamino acid and arabinose and galactose in the whole-cell hydrolysate. Mycolic acids were found to be present. The major fatty acids were identified as C16:0, C16:1 ω7c and/or iso-C15:0 2-OH, 10-methyl C18:0 and C18:1 ω9c. The only menaquinone detected was MK-8 (H2). The major polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, glycolipid and traces of some unknown lipids. The genomic DNA G+C content of strain TG9(T) was determined to be 62.8 %. The combined phenotypic and genotypic data show that the strain represents a novel species of the genus Rhodococcus for which the name Rhodococcus biphenylivorans sp. nov. is proposed, with the type strain TG9(T) (=CGMCC 1.12975(T) = KCTC 29673(T) = MCCC 1K00286(T)).

Hormetic effects of noncoplanar PCB exposed to human lung fibroblast cells (HELF) and possible role of oxidative stress.

Hormesis, a biphasic dose-response phenomenon, which is characterized by stimulation of an end point at a low-dose and inhibition at a high-dose. In the present study we used human lungs fibroblast (HELF) cells as a test model to evaluate the role of oxidative stress (OS) in hormetic effects of non coplanar PCB 101. Results from 3-(4,5-dime-thylthiazol-2-yl)-2,5-diphenyltetrazo-lium bromide (MTT) assay indicated that PCB101 at lower concentrations (10(-5) to 10(-1) µg mL(-1) ) stimulated HELF cell proliferation and inhibited at high concentrations (1, 5, 10, and 20 µg mL(-1) ) in a dose- and time-dependent manner. Reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) (except 48 h) showed a significant increase at higher concentrations of PCB 101 than those at the lower concentrations with the passage of time. Antioxidant enzymes such as glutathione peroxidase (GSH-Px) exhibited decreasing trends in dose and time dependent manner. Lipid peroxidation assay resulted in a significant increase (P < 0.05) of MDA level in PCB 101-treated HELF cells compared with controls, suggesting that OS plays a key role in PCB 101-induced toxicity. Comet assay indicated a significant increase in genotoxicity at higher concentrations of PCB 101 exposure compared to lower concentrations. Overall, we found that HELF cell proliferation was higher at low ROS level and vice versa, which revealed activation of cell signaling-mediated hormetic mechanisms. The results suggested that PCB 101 has hormetic effects to HELF cells and these were associated with oxidative stress.

Thermodynamics-based models of transcriptional regulation with gene sequence.

Quantitative models of gene regulatory activity have the potential to improve our mechanistic understanding of transcriptional regulation. However, the few models available today have been based on simplistic assumptions about the sequences being modeled or heuristic approximations of the underlying regulatory mechanisms. In this work, we have developed a thermodynamics-based model to predict gene expression driven by any DNA sequence. The proposed model relies on a continuous time, differential equation description of transcriptional dynamics. The sequence features of the promoter are exploited to derive the binding affinity which is derived based on statistical molecular thermodynamics. Experimental results show that the proposed model can effectively identify the activity levels of transcription factors and the regulatory parameters. Comparing with the previous models, the proposed model can reveal more biological sense.

Design, synthesis and biological evaluation of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors.

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50=1.63nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055µM, 0.071µM, 0.13µM, and 0.43µM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.

Retinol binding protein 4 and type 2 diabetes: from insulin resistance to pancreatic ß-cell function.

BACKGROUND AND AIM: Retinol binding protein 4 (RBP4) is an adipokine that has been explored as a key biomarker of type 2 diabetes mellitus (T2DM) in recent years. Researchers have conducted a series of experiments to understand the interplay between RBP4 and T2DM, including its role in insulin resistance and pancreatic ß-cell function. The results of these studies indicate that RBP4 has a significant influence on T2DM and is considered a potential biomarker of T2DM. However, there have also been some controversies about the relationship between RBP4 levels and T2DM. In this review, we update and summarize recent studies focused on the relationship between RBP4 and T2DM and its role in insulin resistance and pancreatic ß-cell function to clarify the existing controversy and provide evidence for future studies. We also assessed the potential therapeutic applications of RBP4 in treating T2DM. METHODS: A narrative review. RESULTS: Overall, there were significant associations between RBP4 levels, insulin resistance, pancreatic ß-cell function, and T2DM. CONCLUSIONS: More mechanistic studies are needed to determine the role of RBP4 in the onset of T2DM, especially in terms of pancreatic ß-cell function. In addition, further studies are required to evaluate the effects of drug intervention, lifestyle intervention, and bariatric surgery on RBP4 levels to control T2DM and the role of reducing RBP4 levels in improving insulin sensitivity and pancreatic ß-cell function.

Recent advances in developing modified C14 side chain pleuromutilins as novel antibacterial agents.

Owing to the increasing resistance to most existing antimicrobial drugs, research has shifted towards developing novel antimicrobial agents with mechanisms of action distinct from those of current clinical options. Pleuromutilins are antibiotics known for their distinct mechanism of action, inhibiting bacterial protein synthesis by binding to the peptidyl transferase center of the ribosome. Recent studies have revealed that pleuromutilin derivatives can disrupt bacterial cell membranes, thereby enhancing antibacterial efficacy. Both marketed pleuromutilin derivatives and those in clinical trials have been developed by structurally modifying the pleuromutilin C14 side chain to improve their antimicrobial activity. Therefore, this review aims to review advancement in the chemical structural characteristics, antibacterial activities, and structure-activity relationship studies of pleuromutilins, specifically focusing on modifications made to the C14 side chain in recent years. These findings provide a valuable reference for future research and development of pleuromutilins.

A prediction model for prognosis of nephrotic syndrome with tuberculosis in intensive care unit patients: a nomogram based on the MIMIC-IV v2.2 database.

Background: Currently, a scarcity of prognostic research exists that concentrates on patients with nephrotic syndrome (NS) who also have tuberculosis. The purpose of this study was to assess the in-hospital mortality status of NS patients with tuberculosis, identify crucial risk factors, and create a sturdy prognostic prediction model that can improve disease evaluation and guide clinical decision-making. Methods: We utilized the Medical Information Mart for Intensive Care IV version 2.2 (MIMIC-IV v2.2) database to include 1,063 patients with NS complicated by TB infection. Confounding factors included demographics, vital signs, laboratory indicators, and comorbidities. The Least Absolute Shrinkage and Selection Operator (LASSO) regression and the diagnostic experiment the receiver operating characteristic (ROC) curve analyses were used to select determinant variables. A nomogram was established by using a logistic regression model. The performance of the nomogram was tested and validated using the concordance index (C-index) of the ROC curve, calibration curves, internal cross-validation, and clinical decision curve analysis. Results: The cumulative in-hospital mortality rate for patients with NS and TB was 18.7%. A nomogram was created to predict in-hospital mortality, utilizing Alb, Bun, INR, HR, Abp, Resp., Glu, CVD, Sepsis-3, and AKI stage 7 days. The area under the curve of the receiver operating characteristic evaluation was 0.847 (0.812-0.881), with a calibration curve slope of 1.00 (0.83-1.17) and a mean absolute error of 0.013. The cross-validated C-index was 0.860. The decision curves indicated that the patients benefited from this model when the risk threshold was 0.1 and 0.81. Conclusion: Our clinical prediction model nomogram demonstrated a good predictive ability for in-hospital mortality among patients with NS combined with TB. Therefore, it can aid clinicians in assessing the condition, judging prognosis, and making clinical decisions for such patients.