Effect of Different Insertion Methods on LMA Protector-Related Complications: A Prospective Randomized Double-Blind Clinical Trail.

OBJECTIVE: The authors compared the effect of 2 insertion methods, namely the conventional laryngeal mask airway (LMA) insertion and the index finger-assisted LMA insertion, on the incidence of complications associated with LMA Protector insertion. METHODS: The authors enrolled 300 patients, who underwent painless bronchoscopy. The patients ranged in age between 18 and 75 and were classified as American Society of Anesthesiologists grade I to III. They were randomly divided into 2 groups: a control group of 150 patients and an assisted group comprising 150 patients. LMA was inserted using the conventional and index finger-assisted insertion methods in both groups, respectively. The primary outcome was postoperative complications, such as oral mucosal injury and pharyngeal pain. Secondary outcomes included the success rate of first-time insertion, the incidence rate of inverse folding of LMA tips, oropharyngeal leak pressure (OLP), and other postoperative complications. RESULTS: Compared with the conventional LMA insertion method, index finger-assisted LMA insertion can significantly reduce the incidence rate of oral mucosal injury and pharyngeal pain, with fewer insertion failures. There was a statistically significant difference between the 2 groups in the visual field grading before adjustment for LMA alignment (P<0.0001). The conventional insertion method increased the likelihood of inverse folding of LMA tips. When the conventional insertion method was utilized, there was a significant difference in airway pressure and tidal volume before and after alignment under a fiberoptic bronchoscope (P<0.0001), but no significant difference in visual field grading and respiratory mechanics-related indicators. CONCLUSIONS: Index finger-assisted insertion can significantly reduce the incidence rate of LMA Protector-related complications and inverse folding of LMA tips.

Targeted metabolomics study of fatty-acid metabolism in lean metabolic-associated fatty liver disease patients.

BACKGROUND: The annual incidence of metabolic-associated fatty liver disease (MAFLD) in China has been increasing and is often overlooked owing to its insidious characteristics. Approximately 50% of the patients have a normal weight or are not obese. They are said to have lean-type MAFLD, and few studies of such patients are available. Because MAFLD is associated with abnormal lipid metabolism, lipid-targeted metabolomics was used in this study to provide experimental evidence for early diagnosis and pathogenesis. AIM: To investigate the serum fatty-acid metabolic characteristics in lean-type MAFLD patients using targeted serum metabolomic technology. METHODS: Between January and June 2022, serum samples were collected from MAFLD patients and healthy individuals who were treated at Shanghai Putuo District Central Hospital for serum metabolomics analysis. Principal component analysis and orthogonal partial least squares-discriminant analysis models were developed, and univariate analysis was used to screen for biomarkers of lean-type MAFLD and analyze metabolic pathways. UPLC-Q-Orbitrap/MS content determination was used to determine serum palmitic acid (PA), oleic acid (OA), linoleic acid (LA), and arachidonic acid (AA) levels in lean-type MAFLD patients. RESULTS: Urea nitrogen and uric acid levels were higher in lean-type MAFLD patients than in healthy individuals (P < 0.05). Alanine transaminase and cholinesterase levels were higher in lean-type MAFLD patients than in healthy individuals (P < 0.01). The expression of high-density lipoprotein and apolipoprotein A-1 were lower in lean-type MAFLD patients than in healthy individuals (P < 0.05) and the expression of triglycerides and fasting blood glucose were increased (P < 0.01). A total of 65 biomarkers that affected the synthesis and metabolism of fatty acids were found with P < 0.05 and variable importance in projection > 1". The levels of PA, OA, LA, and AA were significantly increased compared with healthy individuals. CONCLUSION: The metabolic profiles of lean-type MAFLD patients and healthy participants differed significantly, yielding 65 identified biomarkers. PA, OA, LA, and AA exhibited the most significant changes, offering valuable clinical guidance for prevention and treatment of lean-type MAFLD.

Physiologically based pharmacokinetic modeling in obesity: applications and challenges.

INTRODUCTION: Rising global obesity rates pose a threat to people's health. Obesity causes a series of pathophysiologic changes, making the response of patients with obesity to drugs different from that of nonobese, thus affecting the treatment efficacy and even leading to adverse events. Therefore, understanding obesity's effects on pharmacokinetics is essential for the rational use of drugs in patients with obesity. AREAS COVERED: Articles related to physiologically based pharmacokinetic (PBPK) modeling in patients with obesity from inception to October 2023 were searched in PubMed, Embase, Web of Science and the Cochrane Library. This review outlines PBPK modeling applications in exploring factors influencing obesity's effects on pharmacokinetics, guiding clinical drug development and evaluating and optimizing clinical use of drugs in patients with obesity. EXPERT OPINION: Obesity-induced pathophysiologic alterations impact drug pharmacokinetics and drug-drug interactions (DDIs), altering drug exposure. However, there is a lack of universal body size indices or quantitative pharmacology models to predict the optimal for the patients with obesity. Therefore, dosage regimens for patients with obesity must consider individual physiological and biochemical information, and clinically individualize therapeutic drug monitoring for highly variable drugs to ensure effective drug dosing and avoid adverse effects.

Evaluating local plant species for effective fall armyworm management strategies in Taiwan.

BACKGROUND: The emergence of Spodoptera frugiperda (fall armyworm; FAW) in the world has raised concerns regarding its impact on crop production, particularly on corn and sorghum. While chemical control and Bt crops have been effective in managing FAW damage, the development of pesticide-resistant and Bt-resistant strains necessitates alternative control methods. The push-pull farming system has gained attention, but direct utilization of African plant species in Taiwan faces challenges due to invasive potential and climatic disparities. Therefore, identifying and evaluating suitable local plant species, such as Napier grass (Pennisetum purpureum), Desmodium species, and signal grass (Brachiaria brizantha), is crucial for implementing effective FAW management strategies in Taiwan. RESULTS: In screening fifty Napier grass germplasms, all demonstrated an antibiotic effect, reducing leaf consumption compared to corn. Notably, thirty-five germplasms exhibited robust antibiotic traits, decreasing FAW consumption and increasing mortality rates. Three Napier grass germplasms also attracted more female moths for oviposition. Further evaluation of selected Napier grass germplasms and signal grass demonstrated efficacy in reducing FAW larval weight and survival duration. Additionally, Desmodium species, particularly D. uncinatum, showed promising toxicity against FAW larvae. CONCLUSION: Our findings support the effectiveness of selected Napier grass germplasms and signal grass as pull plants, and highlight the potential of D. uncinatum as a push plant in FAW management strategies in Taiwan.

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 ).

Establishing Virtual Bioequivalence and Clinically Relevant Specifications for Omeprazole Enteric-Coated Capsules by Incorporating Dissolution Data in PBPK Modeling.

Currently, Biopharmaceutics Classification System (BCS) classes I and III are the only biological exemptions of immediate-release solid oral dosage forms eligible for regulatory approval. However, through virtual bioequivalence (VBE) studies, BCS class II drugs may qualify for biological exemptions if reliable and validated modeling is used. Here, we sought to establish physiologically based pharmacokinetic (PBPK) models, in vitro-in vivo relationship (IVIVR), and VBE models for enteric-coated omeprazole capsules, to establish a clinically-relevant dissolution specification (CRDS) for screening BE and non-BE batches, and to ultimately develop evaluation criteria for generic omeprazole enteric-coated capsules. To establish omeprazole's IVIVR based on the PBPK model, we explored its in vitro dissolution conditions and then combined in vitro dissolution profile studies with in vivo clinical trials. The predicted omeprazole pharmacokinetics (PK) profiles and parameters closely matched the observed PK data. Based on the VBE results, the bioequivalence study of omeprazole enteric-coated capsules required at least 48 healthy Chinese subjects. Based on the CRDS, the capsules' in vitro dissolution should not be < 28%-54%, < 52%, or < 80% after two, three, and six hours, respectively. Failure to meet these dissolution criteria may result in non-bioequivalence. Here, PBPK modeling and IVIVR methods were used to bridge the in vitro dissolution of the drug with in vivo PK to establish the BE safety space of omeprazole enteric-coated capsules. The strategy used in this study can be applied in BE studies of other BCS II generics to obtain biological exemptions and accelerate drug development.

Anti-coronavirus and anti-pulmonary inflammation effects of iridoids, the common component from Chinese herbal medicines for the treatment of COVID-19.

The practice of Chinese herbal medicines for the treatment of COVID-19 in China played an essential role for the control of mortality rate and reduction of recovery time. The iridoids is one of the main constituents of many heat-clearing and detoxifying Chinese medicines that were largely planted and frequently used in clinical practice. Twenty-three representative high content iridoids from several staple Chinese medicines were obtained and tested by a SARS-CoV-2 pseudo-virus entry-inhibition assay on HEK-293 T/ACE2 cells, a live HCoV-OC43 virus infection assay on HRT-18 cells, and a SARS-CoV-2 3CL protease inhibitory FRET assay followed by molecular docking simulation. The anti-pulmonary inflammation activities were further evaluated on a TNF-α induced inflammation model in A549 cells and preliminary SARs were concluded. The results showed that specnuezhenide (7), cornuside (12), neonuezhenide (15), and picroside III (21) exhibited promising antiviral activities, and neonuezhenide (15) could inhibit 3CL protease with an IC50 of 14.3 µM. Docking computation showed that compound 15 could bind to 3CL protease through a variety of hydrogen bonding and hydrophobic interactions. In the anti-pulmonary inflammation test, cornuside (12), aucubin (16), monotropein (17), and shanzhiside methyl ester (18) could strongly decrease the content of IL-1ß and IL-8 at 10 µM. Compound 17 could also upregulate the expression of the anti-inflammatory cytokine IL-10 significantly. The iridoids exhibited both anti-coronavirus and anti-pulmonary inflammation activities for their significance of existence in Chinese herbal medicines, which also provided a theoretical basis for their potential utilization in the pharmaceutical and food industries.

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.

Synaptotagmins family affect glucose transport in retinal pigment epithelial cells through their ubiquitination-mediated degradation and glucose transporter-1 regulation.

BACKGROUND: Synaptotagmins (SYTs) are a family of 17 membrane transporters that function as calcium ion sensors during the release of Ca2+-dependent neurotransmitters and hormones. However, few studies have reported whether members of the SYT family play a role in glucose uptake in diabetic retinopathy (DR) through Ca2+/glucose transporter-1 (GLUT1) and the possible regulatory mechanism of SYTs. AIM: To elucidate the role of the SYT family in the regulation of glucose transport in retinal pigment epithelial cells and explore its potential as a therapeutic target for the clinical management of DR. METHODS: DR was induced by streptozotocin in C57BL/6J mice and by high glucose medium in human retinal pigment epithelial cells (ARPE-19). Bioinformatics analysis, reverse transcriptase-polymerase chain reaction, Western blot, flow cytometry, ELISA, HE staining, and TUNEL staining were used for analysis. RESULTS: Six differentially expressed proteins (SYT2, SYT3, SYT4, SYT7, SYT11, and SYT13) were found between the DR and control groups, and SYT4 was highly expressed. Hyperglycemia induces SYT4 overexpression, manipulates Ca2+ influx to induce GLUT1 fusion with the plasma membrane, promotes abnormal expression of the glucose transporter GLUT1 and excessive glucose uptake, induces ARPE-19 cell apoptosis, and promotes DR progression. Parkin deficiency inhibits the proteasomal degradation of SYT4 in DR, resulting in SYT4 accumulation and enhanced GLUT1 fusion with the plasma membrane, and these effects were blocked by oe-Parkin treatment. Moreover, dysregulation of the myelin transcription factor 1 (Myt1)-induced transcription of SYT4 in DR further activated the SYT4-mediated stimulus-secretion coupling process, and this process was inhibited in the oe-MYT1-treated group. CONCLUSION: Our study reveals the key role of SYT4 in regulating glucose transport in retinal pigment epithelial cells during the pathogenesis of DR and the underlying mechanism and suggests potential therapeutic targets for clinical DR.

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.

Human UDP-glucuronosyltransferase 1As catalyze aristolochic acid D O-glucuronidation to form a lesser nephrotoxic glucuronide.

ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochic acids (AAs) are naturally occurring nitro phenanthrene carboxylic acids primarily found in plants of the Aristolochiaceae family. Aristolochic acid D (AAD) is a major constituent in the roots and rhizomes of the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), which is a key material for preparing a suite of marketed Chinese medicines. Structurally, AAD is nearly identical to the nephrotoxic aristolochic acid I (AAI), with an additional phenolic group at the C-6 site. Although the nephrotoxicity and metabolic pathways of AAI have been well-investigated, the metabolic pathway(s) of AAD in humans and the influence of AAD metabolism on its nephrotoxicity has not been investigated yet. AIM OF THE STUDY: To identify the major metabolites of AAD in human tissues and to characterize AAD O-glucuronidation kinetics in different enzyme sources, as well as to explore the influence of AAD O-glucuronidation on its nephrotoxicity. MATERIALS AND METHODS: The O-glucuronide of AAD was biosynthesized and its chemical structure was fully characterized by both 1H-NMR and 13C-NMR. Reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses were conducted to assess the crucial enzymes involved in AAD O-glucuronidation in humans. Docking simulations were performed to mimic the catalytic conformations of AAD in human UDP-glucuronosyltransferases (UGTs), while the predicted binding energies and distances between the deprotonated C-6 phenolic group of AAD and the glucuronyl moiety of UDPGA in each tested human UGT isoenzyme were measured. The mitochondrial membrane potentials (MMP) and reactive oxygen species (ROS) levels in HK-2 cells treated with either AAI, or AAD, or AAD O-glucuronide were tested, to elucidate the impact of O-glucuronidation on the nephrotoxicity of AAD. RESULTS: AAD could be rapidly metabolized in human liver and intestinal microsomes (HLM and HIM, respectively) to form a mono-glucuronide, which was purified and fully characterized as AAD-6-O-ß-D-glucuronide (AADG) by NMR. UGT1A1 was the predominant enzyme responsible for AAD-6-O-glucuronidation, while UGT1A9 contributed to a lesser extent. AAD-6-O-glucuronidation in HLM, HIM, UGT1A1 and UGT1A9 followed Michaelis-Menten kinetics, with the Km values of 4.27 µM, 9.05 µM, 3.87 µM, and 7.00 µM, respectively. Docking simulations suggested that AAD was accessible to the catalytic cavity of UGT1A1 or UGT1A9 and formed catalytic conformations. Further investigations showed that both AAI and AAD could trigger the elevated intracellular ROS levels and induce mitochondrial dysfunction and in HK-2 cells, but AADG was hardly to trigger ROS accumulation and mitochondrial dysfunction. CONCLUSION: Collectively, UGT1A-catalyzed AAD 6-O-glucuronidation represents a crucial detoxification pathway of this naturally occurring AAI analogs in humans, which is very different from that of AAI.

CPhaMAS: An online platform for pharmacokinetic data analysis based on optimized parameter fitting algorithm.

BACKGROUND AND OBJECTIVE: Clinical pharmacological modeling and statistical analysis software is an essential basic tool for drug development and personalized drug therapy. The learning curve of current basic tools is steep and unfriendly to beginners. The curve is even more challenging in cases of significant individual differences or measurement errors in data, resulting in difficulties in accurately estimating pharmacokinetic parameters by existing fitting algorithms. Hence, this study aims to explore a new optimized parameter fitting algorithm that reduces the sensitivity of the model to initial values and integrate it into the CPhaMAS platform, a user-friendly online application for pharmacokinetic data analysis. METHODS: In this study, we proposed an optimized Nelder-Mead method that reinitializes simplex vertices when trapped in local solutions and integrated it into the CPhaMAS platform. The CPhaMAS, an online platform for pharmacokinetic data analysis, includes three modules: compartment model analysis, non-compartment analysis (NCA) and bioequivalence/bioavailability (BE/BA) analysis. Our proposed CPhaMAS platform was evaluated and compared with existing WinNonlin. RESULTS: The platform was easy to learn and did not require code programming. The accuracy investigation found that the optimized Nelder-Mead method of the CPhaMAS platform showed better accuracy (smaller mean relative error and higher R2) in two-compartment and extravascular administration models when the initial value was set to true and abnormal values (10 times larger or smaller than the true value) compared with the WinNonlin. The mean relative error of the NCA calculation parameters of CPhaMAS and WinNonlin was <0.0001 %. When calculating BE for conventional, high-variability and narrow-therapeutic drugs. The main statistical parameters of the parameters Cmax, AUCt, and AUCinf in CPhaMAS have a mean relative error of <0.01% compared to WinNonLin. CONCLUSIONS: In summary, CPhaMAS is a user-friendly platform with relatively accurate algorithms. It is a powerful tool for analysing pharmacokinetic data for new drug development and precision medicine.

[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.

Pyramiding BPH genes in rice maintains resistance against the brown planthopper under climate change.

BACKGROUND: Nilaparvata lugens (brown planthopper; BPH) is a significant rice pest in Asia, causing substantial yield losses. Pyramiding BPH resistance genes with diverse resistance traits into rice cultivars is an effective strategy for pest management. However, the response of pyramiding combinations to environmental changes remains unclear. To address this knowledge gap, we investigated three pyramiding rice lines (BPH2 + 32, BPH9 + 32, and BPH18 + 32) in the context of varying climate change conditions, ensuring sufficient N. lugens-rice interactions. Thus, we set three environmental conditions [30/25 °C (day/night) with 500 ppm CO2 concentration, 32/27 °C (day/night) with 600 ppm CO2 concentration, and 35/30 °C (day/night) with 1000 ppm CO2 concentration]. RESULTS: All three pyramiding rice lines maintained the insect resistant ability under the three environmental settings. In particular, the BPH18 + 32 rice line exhibited stronger antibiotic and antixenosis effects against N. lugens. In addition, BPH18 + 32 rice line had better shoot resilience under N. lugens infestation, whereas the performance of the other two selected pyramiding rice lines varied. Thus, although BPH2, BPH9, and BPH18 represent three alleles at the same locus, their resistance levels against N. lugens may vary under distinct climate change scenarios, as evidenced by the performance of N. lugens on the three pyramiding rice lines. CONCLUSION: Our findings indicate that all three tested pyramiding rice lines maintained their insect resistance in the face of diverse climate change scenarios. However, these lines exhibited varied repellent responses and resilience capacities in response to climate change. Thus, the combination of pyramiding genes needs to be considered for future breeding programs. © 2023 Society of Chemical Industry.

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.

Evaluation of the microbiological efficacy of cleaning agents for tracheostomy inner cannulas.

PURPOSE: Biofilms are a significant cause of morbidity in patients with indwelling medical devices. Biofilms pose a potential risk with reusable inner cannulas by increasing the risk of infections. Effective decontamination is thus vital in decreasing bioburden. The current guidelines for cleaning inner cannulas are varied, with multiple techniques being recommended, which are not supported by strong evidence. This randomized, controlled, cross-over study attempted to enumerate the bacterial count of inner cannulas used in tracheostomy patients (n = 60) pre-and post-decontamination with detergent (A) or sterile water (B). MATERIALS AND METHODS: The patients were randomly allocated to sequence A > B or B > A in 1:1 fashion. The saline flushing of the inner cannulas was plated on trypticase soy agar with 5 % sheep blood to enumerate the bacterial count. RESULTS: The mean ratio [Log (CFU)post/Log (CFU)pre]A/[Log (CFU)post/Log (CFU)pre]B based on 53 samples was 0.918 ± 0.470, two-sided 90 % confidence interval (CI) 0.812, 1.024. The equivalence criterion was met as the mean ratio after cleaning fell within the equivalence region of 0.8 and 1.25. CONCLUSION: This study demonstrated the microbiological efficacy of both detergent and sterile water in the decontamination of inner cannulas, and that sterile water was not less effective than detergent in reducing the bacterial load for safe re-use of inner cannulas. This has the potential to promote cost savings for patients with tracheostomy, both in the hospital and the community. The study findings may also be relevant in formulating tracheostomy care policies.

Cellular and molecular overview of gestational diabetes mellitus: Is it predictable and preventable?

BACKGROUND: In contrast to overt diabetes mellitus (DM), gestational DM (GDM) is defined as impaired glucose tolerance induced by pregnancy, which may arise from exaggerated physiologic changes in glucose metabolism. GDM prevalence is reported to be as high as 20% among pregnancies depending on the screening method, gestational age, and the population studied. Maternal and fetal effects of uncontrolled GDM include stillbirth, macrosomia, neonatal diabetes, birth trauma, and subsequent postpartum hemorrhage. Therefore, it is essential to find the potential target population and associated predictive and preventive measures for future intensive peripartum care. AIM: To review studies that explored the cellular and molecular mechanisms of GDM as well as predictive measures and prevention strategies. METHODS: The search was performed in the Medline and PubMed databases using the terms "gestational diabetes mellitus," "overt diabetes mellitus," and "insulin resistance." In the literature, only full-text articles were considered for inclusion (237 articles). Furthermore, articles published before 1997 and duplicate articles were excluded. After a final review by two experts, all studies (1997-2023) included in the review met the search terms and search strategy (identification from the database, screening of the studies, selection of potential articles, and final inclusion). RESULTS: Finally, a total of 79 articles were collected for review. Reported risk factors for GDM included maternal obesity or overweight, pre-existing DM, and polycystic ovary syndrome. The pathophysiology of GDM involves genetic variants responsible for insulin secretion and glycemic control, pancreatic ß cell depletion or dysfunction, aggravated insulin resistance due to failure in the plasma membrane translocation of glucose transporter 4, and the effects of chronic, low-grade inflammation. Currently, many antepartum measurements including adipokines (leptin), body mass ratio (waist circumference and waist-to-hip ratio], and biomarkers (microRNA in extracellular vesicles) have been studied and confirmed to be useful markers for predicting GDM. For preventing GDM, physical activity and dietary approaches are effective interventions to control body weight, improve glycemic control, and reduce insulin resistance. CONCLUSION: This review explored the possible factors that influence GDM and the underlying molecular and cellular mechanisms of GDM and provided predictive measures and prevention strategies based on results of clinical studies.

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.