Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.

AIMS/HYPOTHESIS: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD. METHODS: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c). RESULTS: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing. CONCLUSIONS/INTERPRETATION: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD. DATA AVAILABILITY: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 ).

Prolactin receptor potentiates chemotherapy through miRNAs-induced G6PD/TKT inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR-4763-3p and miR-3663-5p. Notably, miR-4763-3p and miR-3663-5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, and PDX1-cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR-miRNAs-PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.

Effectiveness of non-pharmacological interventions in improving sleep quality after cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Sleep disturbance is highly prevalent among post-operative cardiac patients, with negative impacts on surgical recovery and rehabilitation. Post-operative pain and anxiety commonly seen in cardiac surgery patients are associated with poor sleep. Sleep medications commonly used are not ideal with prolonged usage, and non-pharmacological interventions can be good alternatives or complements. AIM: To examine effectiveness of non-pharmacological interventions in post-operative cardiac settings on sleep quality, pain intensity and anxiety. DESIGN: Systematic review and meta-analysis. METHODS: PubMed, CENTRAL, Embase, CINAHL, Scopus, CNKI and ProQuest Dissertations and Theses were searched on 12 October 2022. Randomised controlled trials of non-pharmacological interventions examining sleep quality for adult post-operative cardiac patients were included. Included studies were appraised using Cochrane Risk of Bias tool version 1. Meta-analysis was conducted using RevMan version 5.4.1, and heterogeneity was assessed using I2 statistics and Cochran Q's test. RESULTS: Eighteen studies involving 1701 participants were identified. Coronary artery bypass graft was most common. Non-pharmacological interventions varied in types and duration. All intervention groups were compared to usual care, placebo, no interventions or active comparators. Statistically significant improvement in sleep quality (SMD = -.91, 95% CI = -1.17 to -.65) was found among intervention groups that explored cognitive behavioural therapy, relaxation techniques, exercise, massage, acupressure, aromatherapy, music, eye mask and earplugs. Pain intensity was reduced (SMD = -.63, 95% CI = -1.05 to -.20) with cognitive behavioural therapy, relaxation techniques, massage, music and eye mask. Anxiety was improved (SMD = -.21, 95% CI = -.38 to -.04) with exercise and music. CONCLUSION: The overall use of non-pharmacological interventions can optimise sleep after cardiac surgery. Further research with greater methodological rigour is needed to investigate different intervention-related characteristics while considering potential confounders. RELEVANCE TO CLINICAL PRACTICE: Post-operative cardiac settings can consider incorporating non-pharmacological interventions. Patients and healthcare providers can be better informed about the use of such interventions to improve sleep. REGISTRATION: PROSPERO CRD42022384991.

[A new benzopyran glycoside from Gentiana macrophylla].

Thirteen compounds were isolated and identified from 70% ethanol extract of the roots of Gentiana macrophylla by multi-chromatographic methods, including microporous resin, silica gel, and C_(18) reversed-phase column chromatography, as well as HPLC as follows: macrophylloside G(1), macrophylloside D(2), 5-formyl-2,3-dihydroisocoumarin(3),(+)-medicarpin(4),(+)-syringaresinol(5), liquiritigenin(6),(3R)-sativanone(7),(3R)-3'-O-methylviolanone(8), 4,2',4'-trihydroxychalcone(9), latifolin(10), gentioxepine(11), 6α-hydroxycyclonerolidol(12), and ethyl linoleate(13). Compound 1 was a new benzopyran glycoside. Compounds 4, 6-10, 12, and 13 were isolated for the first time from Gentiana plants. Compounds 1 and 2 showed promising hepatoprotective activity against D-GalN-induced AML12 cell damage at the concentration of 10 µmol·L~(-1), and compound 2 exhibited more significant activity than silybin at the same concentration.

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Tracing the Change and Contribution of Subcutaneous Adipose to Skin Expansion Using a Luciferase-Transgenic Fat Transplantation Model.

BACKGROUND: During skin expansion, subcutaneous adipose tissue undergoes the greatest change. The adipose layer appears to gradually thin or even disappear in long-term expansion. The response and contribution of adipose tissue to skin expansion remain to be elucidated. METHODS: The authors established a novel expansion model by transplanting luciferase-transgenic adipose tissue into the rat dorsum, followed by integrated expansion, to trace the dynamic changes in subcutaneous adipose tissue during expansion and the migration of adipose tissue-derived cells. In vivo luminescent imaging was performed to continuously track the adipose tissue changes. Histologic analysis and immunohistochemical staining evaluated the regeneration and vascularization of the expanded skin. Growth factor expression in expanded skin with or without adipose tissue was determined to evaluate the paracrine effect of adipose tissue. Adipose tissue-derived cells were traced in vitro by anti-luciferase staining, and their fate was determined by costaining for PDGFRα, DLK1, and CD31. RESULTS: In vivo bioimaging showed that cells in adipose tissue were alive during expansion. After expansion, the adipose tissue exhibited fibrotic-like structures, with more DLK1 + preadipocytes. Skin expanded with adipose tissue was significantly thicker than that without adipose tissue, with more blood vessels and cell proliferation. Vascular endothelial growth factor, epidermal growth factor, and basic fibroblast growth factor expression was higher in adipose tissue than in skin, indicating paracrine support from adipose tissue. Luciferase-positive adipose tissue-derived cells were observed in expanded skin, indicating direct participation in skin regeneration. CONCLUSION: Adipose tissue transplantation can effectively promote long-term skin expansion by contributing to vascularization and cell proliferation by means of various mechanisms. CLINICAL RELEVANCE STATEMENT: The authors' findings suggest that it would be better if the expander pocket is dissected over the superficial fascia to preserve a layer of adipose tissue with skin. In addition, their findings support the treatment of fat grafting when expanded skin presents with thinning.

Lignan glucosides from Gentiana macrophylla with potential anti-arthritis and hepatoprotective activities.

Ten lignans, including six previously undescribed phenolic ester glycosyl lignans (1-6), were isolated from a well-known traditional Chinese medicine, Qin-Jiao, which is the dry root of Gentiana macrophylla Pall. (Gentianaceae). Their structures were determined by spectroscopic and chemical methods, especially 2D NMR techniques. Quantum chemical calculations of theoretical ECD spectra allowed the determination of their absolute configurations. Refer to its traditional applications for the treatment of rheumatic arthralgia and hepatopathy, these compounds were evaluated on a TNF-α induced MH7A human synoviocyte inflammation model and a D-GalN induced AML12 hepatocyte injury model. Compounds 1, 2, 5, and 6 significantly reduced the release of proinflammatory cytokine IL-1ß in MH7A cells at 15 µM and they also could strongly protect AML12 cells against D-GalN injury at 30 µM. Flow cytometry and Western blot analysis showed that compound 5 ameliorated D-GalN induced AML12 cell apoptosis by upregulating the expression of anti-apoptotic Bcl-2 protein and down-regulating the expression of pro-apoptotic Bax protein.

Value of ultrasound and magnetic resonance imaging combined with tumor markers in the diagnosis of ovarian tumors.

BACKGROUND: Compare the diagnostic performance of ultrasound (US), magnetic resonance imaging (MRI), and serum tumor markers alone or in combination for detecting ovarian tumors. AIM: To investigate the diagnostic value of US, MRI combined with tumor markers in ovarian tumors. METHODS: The data of 110 patients with ovarian tumors, confirmed by surgery and pathology, were collected in our hospital from February 2018 to May 2023. The dataset included 60 cases of benign tumors and 50 cases of malignant tumors. Prior to surgery, all patients underwent preoperative US and MRI examinations, as well as serum tumor marker tests [carbohydrate antigen 125 (CA125), human epididymis protein 4 (HE4)]. The aim of the study was to compare the diagnostic performance of these three methods individually and in combination for ovarian tumors. RESULTS: This study found statistically significant differences in the ultrasonic imaging characteristics between benign and malignant tumors. These differences include echo characteristics, presence or absence of a capsule, blood flow resistance index, clear tumor shape, and blood flow signal display rate (P < 0.05). The apparent diffusion coefficient values of the solid and cystic parts in benign tumors were found to be higher compared to malignant tumors (P < 0.05). Additionally, the time-intensity curve image features of benign and malignant tumors showed significant statistical differences (P < 0.05). The levels of serum CA125 and HE4 in benign tumors were lower than those in malignant tumors (P < 0.05). The combined use of US, MRI, and tumor markers in the diagnosis of ovarian tumors demonstrates higher accuracy, sensitivity, and specificity compared to using each method individually (P < 0.05). CONCLUSION: US, MRI, and tumor markers each have their own advantages and disadvantages when it comes to diagnosing ovarian tumors. However, by combining these three methods, we can significantly enhance the accuracy of ovarian tumor diagnosis, enabling early detection and identification of the tumor's nature, and providing valuable guidance for clinical treatment.

Synergistic Effect of Hyperactive Antifreeze Protein on Inhibition of Gas-Hydrate Growth by Hydrophobic and Hydrophilic Groups.

Antifreeze proteins (AFPs) are biodegradable inhibitors that effectively prevent the formation of natural gas hydrates that block pipelines. In this study, molecular dynamics simulations were employed to establish a kinetic model of the hyperactive insect antifreeze protein (Tenebrio molitor, TmAFP) and its mutants to inhibit the growth of sI natural methane hydrate. Simulations revealed that the hydrophobic and hydrophilic groups of threonine (Thr) residues at hydrate-binding sites played a synergistic role in binding hydrates. The hydrophobic groups anchored TmAFP to the hydrate surface through residues Thr39-Thr65 by migrating pendant hydrophobic methyl groups to the hydrate semicages. The hydrophilic groups stabilized TmAFP by hydrogen bonding with water molecules and integrating them into a quasi-hydrate structure, which more effectively inhibited hydrate growth. The results suggest that the hydrate growth inhibition is attributed to both the shape complementarity and the flexibility of binding residues. The synergy between hydrophobic and hydrophilic groups provides guidance for the design of more effective hydrate inhibitors.

Terpenoid Glucosides from Gentiana macrophylla That Attenuate TNF-α Induced Pulmonary Inflammation in A549 Cells.

Four previously undescribed terpenoid glucosides, including one sesquiterpenoid di-glucoside (1), two new iridoid glucosides (2, 3), and a new triterpenoid tri-glucoside (4), were isolated from a 70% ethanol extract of the root of Gentiana macrophylla (Gentianaceae), along with eight known terpenoids. Their structures were determined by spectroscopic techniques, including 1D, 2D NMR, and HRMS (ESI), as well as chemical methods. The absolute configuration of compound 1 was determined by quantum chemical calculation of its theoretical electronic circular dichroism (ECD) spectrum. The sugar moieties of all the new compounds were confirmed to be D-glucose by GC analysis after acid hydrolysis and acetylation. Anti-pulmonary inflammation activity of the iridoids were evaluated on a TNF-α induced inflammation model in A549 cells. Compound 2 could significantly alleviate the release of proinflammatory cytokines IL-1ß and IL-8 and increase the expression of anti-inflammatory cytokine IL-10.

Pharmacokinetics, safety, and efficacy of GM1 ganglioside in healthy subjects and patients with multiple myeloma: Two dose-escalation studies.

PURPOSE: This study aimed to assess the pharmacokinetics, safety, and efficacy of GM1 in healthy Chinese subjects and patients with multiple myeloma. METHODS: The data used in this study was derived from two dose-escalation trials: GM1-101, involving 70 healthy subjects, and GM1-201, which included 160 multiple myeloma patients. Population pharmacokinetics (PopPK) analysis was conducted on a subset of 90 participants using a nonlinear mixed-effects approach, and potential covariates were explored quantitatively. Observations of any abnormalities in vital signs, physical examinations, laboratory tests, and electrocardiograms during the study period, along with any spontaneously reported and directly observed adverse events, were documented for safety evaluation. Furthermore, neurotoxicity scales were used to assess the efficacy of GM1 as a prophylaxis for chemotherapy-induced peripheral neuropathy and to perform exposure-response analyses in conjunction with pharmacokinetic parameters. RESULTS: A one-compartment model with first-order elimination best characterized the pharmacokinetics of GM1. The clearance and volume of distribution, as estimated by the final model, were 0.0942 L/h and 3.27 L for GM1-A, and 0.0714 L/h and 2.82 L for GM1-B, respectively. Covariates such as sex, body weight, and albumin significantly influenced pharmacokinetic parameters, yet the variation in steady-state exposure between subjects and reference subjects was less than 45% within their 90% confidence interval. Adverse reactions related to GM1 occurred in 20 (28.6%) and 57 (35.6%) subjects in the GM1-101 and GM1-201 cohorts, respectively. The changes in TNSc and FACT-Ntx scores from baseline at the end of periods 4 and 6 were lower in each GM1 dose group compared to the blank control group. The 400 mg dose group of GM1 displayed greater effectiveness than other dose groups. However, exposure-response analysis revealed no significant modification in efficacy with increasing GM1 exposure. CONCLUSIONS: This study provides the first population pharmacokinetic analysis of GM1. GM1 exhibits a favorable safety profile among healthy subjects and patients with multiple myeloma. GM1 proved effective in mitigating chemotherapy-induced peripheral neuropathy, but this study observed no significant correlation between its efficacy and exposure. TRIAL REGISTRATION NUMBERS: ChiCTR2000041283 and ChiCTR2000041283.

Network pharmacology and bioinformatics analysis identifies potential therapeutic targets of Naringenin against COVID-19/LUSC.

Background: Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease that has posed a serious threat to people's daily lives and caused an unprecedented challenge to public health and people's health worldwide. Lung squamous cell carcinoma (LUSC) is a common type of lung malignancy with a highly aggressive nature and poor prognosis. Patients with LUSC could be at risk for COVID-19, We conducted this study to examine the potential for naringenin to develop into an ideal medicine and investigate the underlying action mechanisms of naringenin in COVID-19 and LUSC due to the anti-viral, anti-tumor, and anti-inflammatory activities of naringenin. Methods: LUSC related genes were obtained from TCGA, PharmGKB, TTD,GeneCards and NCBI, and then the transcriptome data for COVID-19 was downloaded from GEO, DisGeNET, CTD, DrugBank, PubChem, TTD, NCBI Gene, OMIM. The drug targets of Naringenin were revealed through CTD, BATMAN, TCMIP, SymMap, Chemical Association Networks, SwissTargetPrediction, PharmMapper, ECTM, and DGIdb. The genes related to susceptibility to COVID-19 in LUSC patients were obtained through differential analysis. The interaction of COVID-19/LUSC related genes was evaluated and demonstrated using STRING to develop a a COX risk regression model to screen and evaluate the association of genes with clinical characteristics. To investigate the related functional and pathway analysis of the common targets of COVID-19/LUSC and Naringenin, KEGG and GO enrichment analysis were employed to perform the functional analysis of the target genes. Finally, The Hub Gene was screened and visualized using Cytoscape, and molecular docking between the drug and the target was performed using Autodock. Results: We discovered numerous COVID-19/LUSC target genes and examined their prognostic value in LUSC patients utilizing a variety of bioinformatics and network pharmacology methods. Furthermore, a risk score model with strong predictive performance was developed based on these target genes to assess the prognosis of LUSC patients with COVID-19. We intersected the therapeutic target genes of naringenin with the LUSC, COVID-19-related targets, and identified 354 common targets, which could be used as potential target genes for naringenin to treat COVID-19/LUSC. The treatment of COVID-19/LUSC with naringenin may involve oxidative stress, anti-inflammatory, antiviral, antiviral, apoptosis, immunological, and multiple pathways containing PI3K-Akt, HIF-1, and VEGF, according to the results of the GO and KEGG enrichment analysis of these 354 common targets. By constructing a PPI network, we ascertained AKT1, TP53, SRC, MAPK1, MAPK3, and HSP90AA1 as possible hub targets of naringenin for the treatment of COVID-19/LUSC. Last but not least, molecular docking investigations showed that naringenin has strong binding activity in COVID-19/LUSC. Conclusion: We revealed for the first time the pharmacological targets and potential molecular processes of naringenin for the treatment of COVID-19/LUSC. However, these results need to be confirmed by additional research and validation in real LUSC patients with COVID-19.

The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells.

PURPOSE: Gastric cancer (GC) is a malignant tumour with high mortality, and liver metastasis is one of the main causes of poor prognosis. SLIT- and NTRK-like family member 4 (SLITRK4) plays an important role in the nervous system, such as synapse formation. Our study aimed to explore the functional role of SLITRK4 in GC and liver metastasis. METHODS: The mRNA level of SLITRK4 was evaluated using publicly available transcriptome GEO datasets and Renji cohort. The protein level of SLITRK4 in the tissue microarray of GC was observed using immunohistochemistry. Cell Counting Kit-8, colony formation, transwell migration assays in vitro and mouse model of liver metastasis in vivo was performed to investigate the functional roles of SLITRK4 in GC. Bioinformatics predictions and Co-IP experiments were applied to screen and identify SLITRK4-binding proteins. Western blot was performed to detect Tyrosine Kinase receptor B (TrkB)-related signaling molecules. RESULTS: By comparing primary and liver metastases from GC, SLITRK4 was found to be upregulated in tissues of GC with liver metastasis and to be closely related to poor clinical prognosis. SLITRK4 knockdown significantly abrogated the growth, invasion, and metastasis of GC in vitro and in vivo. Further study revealed that SLITRK4 could interact with Canopy FGF Signalling Regulator 3 (CNPY3), thus enhancing TrkB- related signaling by promoting the endocytosis and recycling of the TrkB receptor. CONCLUSION: In conclusion, the CNPY3-SLITRK4 axis contributes to liver metastasis of GC according to the TrkB-related signaling pathway. which may be a therapeutic target for the treatment of GC with liver metastasis.

Autologous Concentrated Growth Factor Increases Skin Thickness and Area during Tissue Expansion: A Randomized Clinical Trial.

BACKGROUND: Mechanical stretching of the skin (ie, tissue expansion) could generate additional skin, but it is limited by the intrinsic growth capacity. The authors conducted a study of autologous concentrated growth factor (CGF) to promote skin regeneration by increasing skin thickness and area during tissue expansion. METHODS: A single-center randomized controlled trial was conducted from 2016 to 2019. Participants undergoing skin expansion received either CGF or saline by means of intradermal injection on the expanded skin (0.02 mL/cm 2 ), for a total of three treatments at 4-week intervals. The primary endpoint was the expanded skin thickness at 12 weeks, which was measured by ultrasound. The secondary endpoints included skin thickness at 4 and 8 weeks and surface area, expansion index, and skin texture score of the expanded skin at 12 weeks. Safety assessments, for infection symptoms and nodule formation, were assessed at 24 weeks. RESULTS: In total, 26 patients were enrolled and assigned to the CGF or control group. Compared with the control group, the CGF group had significantly increased skin thickness at 8 (control, 1.1 ± 0.1 mm; CGF, 1.4 ± 0.1 mm; -0.6 to 0.0 mm; P = 0.047) and 12 weeks (control, 1.0 ± 0.1 mm; CGF, 1.3 ± 0.1 mm; -0.6 to 0.0 mm; P = 0.047). Compared with the baseline thickness (control, 1.6 ± 0.1 mm; CGF, 1.5 ± 0.1 mm; -0.3 to 0.5 mm; P = 0.987), skin thickness was sustained in the CGF group at 8 weeks after treatment (-0.1 to 0.3 mm; P = 0.711) but decreased in the control group (0.3 to 0.7 mm; P < 0.001). At 12 weeks, the CGF group showed greater increases in surface area (control, 77.7 ± 18.5 cm 2 ; CGF, 135.0 ± 15.7 cm 2 ; 7.2 cm 2 to 107.4 cm 2 ; P = 0.027) and expansion index (control, 0.9 ± 0.1; CGF, 1.4 ± 0.2; 0.0 to 0.8; P = 0.030) than the control group. In addition, CGF-treated skin showed an improvement in texture [CGF: grade 3, n = 2 (15.8%), grade 2, n = 4 (30.7%); control: grade 3, n = 0 (0.0%), grade 2, n = 3 (23.0%)]. No severe adverse events occurred. CONCLUSION: CGF treatment increases skin thickness and area during tissue expansion, and represents a safe and effective strategy for managing skin expansion. CLINICAL RELEVANCE STATEMENT: The findings of this study indicate that it is practically feasible to improve skin regeneration by applying autologous platelet concentrate therapy for skin expansion management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma.

To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.

Effect of Laparoscopic Sleeve Gastrectomy on the Pharmacokinetics of Oral Omeprazole Using a Population Approach.

Omeprazole is commonly prescribed to obese patients and patients after laparoscopic sleeve gastrectomy (LSG). The pharmacokinetics of oral omeprazole after LSG are still unknown. Therefore, the aim of this study was to investigate the pharmacokinetics of oral omeprazole in obese patients before and after LSG. A total of 331 blood samples were collected from 62 obese patients preoperatively (visit 1) followed by 41 patients 7 days post-LSG (visit 2) and 20 patients 1 month post-LSG (visit 3). Population pharmacokinetic analysis was performed using NONMEM to characterize the effect of LSG on omeprazole absorption and disposition. A one-compartment model with 12 transit absorption compartments and linear elimination successfully described the data. Compared with pre-surgery, the oral omeprazole time to maximum plasma concentration (Tmax) was reduced and maximum plasma concentration (Cmax) was higher, but the apparent clearance (CL/F) and area under the plasma concentration-time curve (AUC) were unchanged 7 days and 1 month after surgery. In addition, the CYP2C19 genotype and liver function exhibited a significant influence on omeprazole CL/F. LSG increased the rate of omeprazole absorption but did not affect omeprazole exposure. A dose of 20 mg omeprazole once daily may be adequate for relieving gastrointestinal tract discomfort at short-term follow-up post-LSG.

Asprosin in the Paraventricular Nucleus Induces Sympathetic Activation and Pressor Responses via cAMP-Dependent ROS Production.

Asprosin is a newly discovered adipokine that is involved in regulating metabolism. Sympathetic overactivity contributes to the pathogenesis of several cardiovascular diseases. The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in the regulation of sympathetic outflow and blood pressure. This study was designed to determine the roles and underlying mechanisms of asprosin in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male adult SD rats under anesthesia. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded, and PVN microinjections were performed bilaterally. Asprosin mRNA and protein expressions were high in the PVN. The high asprosin expression in the PVN was involved in both the parvocellular and magnocellular regions according to immunohistochemical analysis. Microinjection of asprosin into the PVN produced dose-related increases in RSNA, MAP, and HR, which were abolished by superoxide scavenger tempol, antioxidant N-acetylcysteine (NAC), and NADPH oxidase inhibitor apocynin. The asprosin promoted superoxide production and increased NADPH oxidase activity in the PVN. Furthermore, it increased the cAMP level, adenylyl cyclase (AC) activity, and protein kinase A (PKA) activity in the PVN. The roles of asprosin in increasing RSNA, MAP, and HR were prevented by pretreatment with AC inhibitor SQ22536 or PKA inhibitor H89 in the PVN. Microinjection of cAMP analog db-cAMP into the PVN played similar roles with asprosin in increasing the RSNA, MAP, and HR, but failed to further augment the effects of asprosin. Pretreatment with PVN microinjection of SQ22536 or H89 abolished the roles of asprosin in increasing superoxide production and NADPH oxidase activity in the PVN. These results indicated that asprosin in the PVN increased the sympathetic outflow, blood pressure, and heart rate via cAMP-PKA signaling-mediated NADPH oxidase activation and the subsequent superoxide production.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers.

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III-IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal-plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation.

Biosimilarity of HS-20090 to Denosumab in healthy Chinese subjects: a randomized, double-blinded, pharmacokinetics/pharmacodynamics study.

OBJECTIVE: HS-20090 is a proposed biosimilar candidate of Denosumab (Xgeva®). The study aimed to evaluate the similarity of pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity between HS-20090 and Xgeva® in healthy Chinese subjects. METHODS: A single-center, randomized, double-blinded, active-controlled study was conducted in healthy Chinese adult male subjects. A total of 154 subjects were planned to be randomly assigned (1:1) to receive 120 mg of either HS-20090 or Xgeva® in a single subcutaneous injection, with a follow-up period of 155 days. The primary objective was to evaluate the bioequivalence of PK. The primary endpoints were Cmax and AUC0-∞. The secondary objectives were to evaluate the similarity of PD, safety, and immunogenicity. RESULTS: All 154 subjects were included in the PK, PD, and safety analyses. The 90% CIs of GMRs of HS-20090/Xgeva® for Cmax, AUC0-t, and AUC0-∞ were 90.49 ~ 100.23%, 94.45 ~ 104.61%, and 94.08 ~ 105.23%, respectively, achieving the bioequivalence criteria of 80 ~ 125%. The PD parameters and incidence of adverse events between HS-20090 and denosumab were also similar, with no detection of ADA in both the groups. CONCLUSION: HS-20090 was highly similar to Xgeva®, with regard to PK, PD, safety profiles, and immunogenicity in healthy Chinese subjects. These data support subsequently comparative clinical study for bone metastases in solid tumors. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT04494373.

Population pharmacokinetics of intravenous colistin sulfate and dosage optimization in critically ill patients.

Aims: To explore the population pharmacokinetics of colistin sulfate and to optimize the dosing strategy for critically ill patients. Methods: The study enrolled critically ill adult patients who received colistin sulfate intravenously for more than 72 h with at least one measurement of plasma concentration. Colistin concentrations in plasma or urine samples were measured by ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS). The population pharmacokinetics (PPK) model for colistin sulfate was developed using the Phoenix NLME program. Monte Carlo simulation was conducted to evaluate the probability of target attainment (PTA) for optimizing dosing regimens. Results: A total of 98 plasma concentrations from 20 patients were recorded for PPK modeling. The data were adequately described by a two-compartment model with linear elimination. During modeling, creatinine clearance (CrCL) and alanine aminotransferase (ALT) were identified as covariates of the clearance (CL) and volume of peripheral compartment distribution (V2), respectively. In addition, colistin sulfate was predominantly cleared by the nonrenal pathway with a median urinary recovery of 10.05% with large inter-individual variability. Monte Carlo simulations revealed a greater creatinine clearance associated with a higher risk of sub-therapeutic exposure to colistin sulfate. The target PTA (≥90%) of dosage regimens recommended by the label sheet was achievable only in patients infected by pathogens with MIC ≤0.5 mg/L or with renal impairments. Conclusion: Our study showed that the dose of intravenous colistin sulfate was best adjusted by CrCL and ALT. Importantly, the recommended dosing regimen of 1.0-1.5 million units daily was insufficient for patients with normal renal functions (CrCL ≥80 ml/min) or those infected by pathogens with MIC ≥1.0 mg/L. The dosage of colistin sulfate should be adjusted according to renal function and drug exposure.