Metabolic dysfunction associated steatotic liver disease in patients with plaque psoriasis: a case-control study and serological comparison.

Background: The relationship between plaque psoriasis and both MASLD and lean MASLD has not been sufficiently explored in the current literature. Method: This retrospective and observational study was carried out from January 2021 to January 2023 at The First Affiliated Hospital of Zhejiang Chinese Medical University. Patients diagnosed with plaque psoriasis and a control group consisting of individuals undergoing routine physical examinations were enrolled. The incidence of MASLD and lean MASLD among these groups was compared. Additionally, patients with plaque psoriasis were divided into those with MASLD, those with lean MASLD, and a control group with only psoriasis for a serological comparative analysis. Results: The incidence of MASLD in the observation group and the control group was 43.67% (69/158) and 22.15% (35/158), respectively (p < 0.01). Furthermore, the incidence of lean MASLD within the observation group and the control group was 10.76% (17/158) and 4.43% (7/158), respectively (p < 0.01). After controlling for potential confounding variables, plaque psoriasis was identified as an independent risk factor for MASLD with an odds ratio of 1.88 (95% cl: 1.10-3.21). In terms of serological comparison, compared to the simple psoriasis group, we observed a significant elevation in the tumor marker CYFRA21-1 levels in both groups compared to the control group with simple psoriasis (p < 0.01). Moreover, the MASLD group exhibited elevated levels of inflammatory markers and psoriasis score, whereas these effects were mitigated in the lean MASLD group. Conclusion: The prevalence of MASLD and lean MASLD is higher among patients with psoriasis. Those suffering from psoriasis along with MASLD show increased psoriasis scores and inflammatory markers compared to those without metabolic disorders. MASLD likely worsens psoriasis conditions, indicating the necessity of targeted health education for affected individuals to reduce the risk of MASLD, this education should include guidelines on exercise and diet. In serological assessments, elevated levels of cytokeratin 19 fragment (CYFRA21-1) were noted in both MASLD and lean MASLD groups, implying a potential synergistic role between psoriasis and MASLD.

Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.

In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 µM) significantly enhanced the anti-tumor efficacy of osimertinib (1 µM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg-1·d-1) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg-1·d-1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.

High-level co-production of 3-hydroxypropionic acid and 1,3-propanediol from glycerol: Metabolic engineering and process optimization.

3-Hydroxypropionic acid (3-HP) and 1,3-propanediol (1,3-PDO) are value-added chemicals with versatile applications in the chemical, pharmaceutical, and food industries. Nevertheless, sustainable production of 3-HP and 1,3-PDO is often limited by the lack of efficient strains and suitable fermentation configurations. Herein, attempts have been made to improve the co-production of both metabolites through metabolic engineering of Escherichia coli and process optimization. First, the 3-HP and 1,3-PDO co-biosynthetic pathways were recruited and optimized in E. coli, followed by coupling the pathways to the transhydrogenase-mediated cofactor regeneration systems that increased cofactor availability and product synthesis. Next, pathway rebalancing and block of by-product formation significantly improved 3-HP and 1,3-PDO net titer. Subsequently, glycerol flux toward 3-HP and 1,3-PDO synthesis was maximized by removing metabolic repression and fine-tuning the glycerol oxidation pathway. Lastly, the combined fermentation process optimization and two-stage pH-controlled fed-batch fermentation co-produced 140.50 g/L 3-HP and 1,3-PDO, with 0.85 mol/mol net yield.

Establishment of an Ex Vivo Tissue Culture Model for Evaluation of Antitumor Efficacy in Clear Cell Renal Cell Carcinoma.

There are many potential immunotherapeutic targets for cancer immunotherapy, which should be assessed for efficacy before they enter clinical trials. Here we established an ex vivo cultured patient-derived tumor tissue model to evaluate antitumor effectiveness of one VISTA inhibitor, given that our previous study showed that VISTA was selectively highly expressed in human clear cell renal cell carcinoma (ccRCC) tumors. We observed that all the tested patients responded to the anti-VISTA monoclonal antibody as manifested by TNF-α production, but only a small fraction were responders to the anti-PD-1 antibody. Co-blockade of VISTA and PD-1 resulted in a synergistic effect in 20% of RCC patients. Taken together, these findings indicate that this ex vivo tumor slice culture model represents a viable tool to evaluate antitumor efficacies for the inhibitors of immune checkpoints and further supports that VISTA could serve as a promising target for immunotherapy in ccRCC.

Research progress in electrical cardioversion of atrial fibrillation during perioperative cardiac surgery / 中国胸心血管外科临床杂志

@#Atrial fibrillation (AF) is one of the most common complications after cardiac surgery. The existing treatment of postoperative AF mainly focuses on preoperative prevention, intraoperative protection and postoperative treatment for factors prone to AF before, during and after surgery, but the postoperative treatment in various areas and hospitals is different. This article combines the latest literature published in Europace about the practice guidance of cardioversion of AF and atrial flutter, and summarizes the treatment of electrical cardioversion, in order to provide clinical guidance for electrical cardioversion of AF after cardiac surgery.

HGF/c-MET pathway contributes to cisplatin-mediated PD-L1 expression in hepatocellular carcinoma.

Cisplatin has been reported to promote the expression of programmed cell death ligand-1 (PD-L1) in some cancer cells. However, the underlying mechanism through which PD-L1 is transcriptionally regulated by cisplatin in hepatocellular carcinoma (HCC) cells remains largely unknown. In the present study, we found that the expression of hepatocyte growth factor (HGF), p-Akt, p-ERK, and PD-L1 was increased in cisplatin-treated SNU-368 and SNU-739 cells. HGF stimulation also increased PD-L1 expression in these cells. Moreover, Inhibition of HGF/c-MET, PI3K/Akt, and MEK/ERK signaling pathways can dramatically block cisplatin or HGF-induced PD-L1 expression in SNU-368 and SNU-739 cells. In vivo, combination PHA665752 with cisplatin significantly reduced tumor weight with increased infiltration of CD8+ T cells in the tumor. Taken together, our study suggested that HGF/c-Met axis-induced the activation of PI3K/Akt and MEK/ERK pathways contributes to cisplatin-mediated PD-L1 expression. These findings may provide an alternative avenue for the treatment of HCC.

Hydrogen Sulfide Inhibits Enzymatic Browning of Fresh-Cut Chinese Water Chestnuts.

This work investigates the role of hydrogen sulfide (H2S) in the browning and regulating the antioxidant defensive system in fresh-cut Chinese water chestnuts. The samples were fumigated with 0, 10, and 15 µl L-1 of H2S and stored at 10°C for 8 days. The results indicated that the H2S treatment significantly inhibited the browning of fresh-cut Chinese water chestnuts, reduced superoxide anion ( O 2 · - ) production rate and H2O2 content accumulation, promoted the increase of total phenol content, and enhanced activities of catalase (CAT), superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR) (P < 0.05). On the other hand, phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), and peroxidase (POD) activities remained at a low level in the H2S treatment (P < 0.05). This result suggested that H2S treatment might be a promising approach to inhibit browning and prolong the shelf life by enhancing oxidation resistance and inhibiting browning enzyme activity of fresh-cut Chinese water chestnuts during storage. Among them, the 15 µl L-1 H2S treatment had the best effect on fresh-cut Chinese water chestnuts.

Transcriptome analysis reveals delaying of the ripening and cell-wall degradation of kiwifruit by hydrogen sulfide.

BACKGROUND: Hydrogen sulfide (H2 S) is a known signaling molecule in plants, which has the ability to delay fruit ripening. Our previous studies have shown that H2 S treatment could delay the maturation of kiwifruits by inhibiting ethylene production, improving protective enzyme activities, and decreasing the accumulation of reactive oxygen species to protect the cell membrane during storage. The mechanism related to the way in which H2 S affected kiwifruit maturation was still unclear. We performed transcriptome sequencing to explore the influences of H2 S on the softening of kiwifruit. RESULTS: The firmness and the soluble solids content (SSC) of the kiwifruit were significantly better maintained with H2 S treatment compared to the control during the storage period (P < 0.05). Transmission electron microscopy (TEM) showed that degradation of the cell wall was inhibited after H2 S treatment. Based on transcriptome data analysis and quantitative real-time polymerase chain reaction (qRT-PCR), expression levels of endo-1,4-ß-glucanase (ß-glu), ß-galactosidase (ß-gal) and pectinesterase (PME) decreased whereas pectinesterase inhibitor (PMEI) significantly increased in response to H2 S. The members of the signal transduction pathway involved in ethylene were also identified. Hydrogen sulfide inhibited the expression of ethylene receptor 2 (ETR2), ERF003, ERF5, and ERF016, and increased the expression of ethylene-responsive transcription factor 4 (ERF4) and ERF113. CONCLUSION: Hydrogen sulfide could delay the ripening and senescence of kiwifruit by regulating the cell-wall degrading enzyme genes and affecting ethylene signal transduction pathway genes. Our results revealed the effect of H2 S treatment on the softening of kiwifruit at the transcription level, laying a foundation for further research. © 2020 Society of Chemical Industry.

Effects of different 2A peptides on transgene expression mediated by tricistronic vectors in transfected CHO cells.

Multicistronic vectors can increase transgene expression and decrease the imbalance of gene expression in the Chinese hamster ovary (CHO) cell expression system. Small, self-cleaving 2A peptides have a high cleavage efficiency and are essential for constructing high-expression multicistronic vectors. In this study, we investigated the effects of two different 2A peptides on transgene expression in CHO cells via their mediating action on tricistronic vectors. The enhanced green fluorescent protein (eGFP) and red fluorescent protein (RFP) genes were linked by the porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A) peptides in a multicistronic vector. We transfected CHO cells with these vectors and screened for the presence of blasticidin-resistant colonies. Flow cytometry and real-time quantitative PCR (qPCR) were used to detect the expression levels of eGFP and RFP and the copy numbers of stably transfected cells. The results showed that P2A could enhance eGFP and RFP expression by 1.48- and 1.47-fold, respectively, compared to T2A. The expression levels of the genes were not proportional to their copy numbers. In conclusion, we found that P2A can effectively drive transgene expression in CHO cells and a potent 2A peptide can be used for recombinant protein production in the CHO cell system.

Polyacrylonitrile-based fiber modified with thiosemicarbazide by microwave irradiation and its adsorption behavior for Cd(II) and Pb(II).

A novel thiosemicarbazide modified adsorbent (PAN(MW)-TSC) based on polyacrylonitrile fiber was successfully synthesized under microwave irradiation, which was applied for the uptake of Cd(II) and Pb(II) from aqueous solution subsequently. Microwave irradiation method is a new approach to achieve the modification and it turns out that just a 30min process is enough for the anchoring of functional groups in the fiber matrix. The surface characterization was performed by fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) elemental analysis (EA) and thermogravimetric analysis (TGA), indicating that the modification was successfully accomplished. Batch adsorption experiments including equilibrium isotherms, kinetics and the effects of pH and temperature on the adsorption of Cd(II) and Pb(II) were systematically studied. Among three kinetic models, the pseudo-second-order kinetic model provides the best correlation for the process. The nonlinear resolution of the Langmuir isotherm equation has been found to show the closest fit to the equilibrium date. Thermodynamic parameters, involving △G, △H and △S were also calculated from graphical interpretation of the experimental data, which suggest that metal ions adsorption onto PAN(MW)-TSC fibers is spontaneous and exothermic. Regeneration of PAN(MW)-TSC fibers loaded with metal ions was efficiently done with 0.5M HNO3, by which the investigated adsorbent could be used reproductively for five times with a small decrease in sorption capacity. The feasible preparation of PAN(MW)-TSC fibers with high adsorption capacities opens a new perspective in the potential application for wastewater treatment.

Comparison of a novel TiO2/diatomite composite and pure TiO2 for the purification of phosvitin phosphopeptides.

A novel TiO2/diatomite composite (TD) was prepared and then characterized by scanning electron microscope (SEM) and Fourier Transform Infrared (FTIR). The results of SEM showed that after modification, the porous surface of diatomite was covered with TiO2. Both diatomite and TD had clear disc-shaped structures with average grain diameters of around 25 µm. Then TD and pure TiO2 were applied in the purification of phosvitin phosphopeptides (PPPs) from the digest of egg yolk protein, and a comparative study of adsorption properties of PPPs on TD and TiO2 was performed. In the study of adsorption kinetics, the adsorption equilibrium of PPPs on TD and TiO2 fitted well with the Langmuir model, and the time needed to reach adsorption equilibrium were both around 10 min. The maximum dynamic adsorption capacity of TD (8.15 mg/g) was higher than that of TiO2 (4.96 mg/g). The results of repeated use showed that TD and TiO2 were very stable after being subjected to ten repeated adsorption-elution cycles, and TD could easily be separated from aqueous solution by filtration. On the other hand, the present synthetic technology of TD was very simple, cost-effective, organic solvent-free and available for large-scale preparation. Thus, this separation method not only brings great advantages in the purification of PPPs from egg yolk protein but also provides a promising purification material for the enrichment of phosphopeptides in proteomic researches.

Activating glucocorticoid receptor-ERK signaling pathway contributes to ginsenoside Rg1 protection against ß-amyloid peptide-induced human endothelial cells apoptosis.

The deposition of ß-amyloid (Aß) in neurons and vascular cells of the brain has been characterized in Alzheimer's disease. Ginsenoside Rg1 (Rg1) is an active components in Panax ginseng, a famous traditional Chinese medicines recorded in Compendium of Materia Medica. Present study attempted to evaluate the potential mechanisms of Aß-mediated insult and the protective effects of Rg1 on human endothelial cells. Rg1 attenuated the Aß25-35-associated mitochondrial apoptotic events, accompanied by inhibiting HIF-1α expression followed by intracellular reactive nitrogen species generation, and protein nitrotyrosination. These protective effects were abolished by glucocorticoid receptor (GR) antagonist RU486 or p-ERK inhibitor U0126 rather than estrogen receptor α antagonist ICI 82,780. Taken together, our results suggested that Rg1 protected against Aß25-35-induced apoptosis at least in part by two complementary GR-dependent ERK phosphorylation pathways: (1) down-regulating HIF-1α initiated protein nitrotyrosination, and (2) inhibiting mitochondrial apoptotic cascades. These data provided a novel insight to the mechanisms of Rg1protective effects on Aß25-35-induced endothelial cells apoptosis, suggesting that GR-ERK signaling pathway might play an important role in it.

Asiatic acid protects primary neurons against C2-ceramide-induced apoptosis.

Ceramides derived from sphingosine contribute to the apoptotic processes of neuronal cells in neurodegenerative disorders including Alzheimer's disease. This study investigates the potential neuroprotective effects of Asiatic acid, a triterpenoid derived from Centella asiatica, against C(2)-ceramides-induced cell death in primary cultured rat cortical neuronal cells. In primary neurons, Asiatic acid (0.01 to 1.0 µmol/l) reduced C(2)-ceramide-induced cell death and mitochondria membrane potential loss in a concentration-dependent manner. Furthermore, Asiatic acid decreased cellular production of reactive oxygen species following C(2)-ceramide treatment. At a maximal concentration of 1.0 µmol/l, Asiatic acid partly counteracted the pro-apoptotic effects of the C(2)-ceramide by reducing the cytosolic release of HtrA2/Omi, the upregulation of Bax and caspase 3, as well as the dephosphorlyation of ERK1/2. Taken together, these data suggest that Asiatic acid protects neurons from C(2)-ceramide-induced cell death by antagonizing mitochondria-dependent apoptosis.

Cysteinyl leukotrienes synthesis is involved in aristolochic acid I-induced apoptosis in renal proximal tubular epithelial cells.

Aristolochic acid I (AAI) is a primary nephrotoxin and carcinogen that is found in some Chinese herbal medicines, and AAI is responsible for the progression of aristolochic acid nephropathy. The membrane associated proteins in the eicosanoid and glutathione metabolism (MAPEG) superfamily are associated with cysteinyl leukotrienes (cysLTs) synthesis. The present study investigated whether cysLTs synthesis was involved in AAI-induced renal proximal tubular epithelial cell injury in LLC-PK1 cells. Based on MAPEG and related molecular events, the potential mechanisms of AAI-induced LLC-PK1 cell injury were explored. AAI triggered the mitochondrial/caspase apoptotic pathway in LLC-PK1 cells, which was indicated by an enhanced Bax/Bcl-2 ratio, loss of mitochondrial membrane potential, cytochrome C release, and caspase 3 activation. In addition, AAI-induced cysLTs release was accompanied by selective upregulation of 5-lipoxygenase activating protein (FLAP) and microsomal glutathione S-transferase 3 (mGST3) in a concentration-dependent manner. The FLAP inhibitor MK866 significantly protected cells from AAI-induced apoptosis. Furthermore, activation of extracellular signal-regulated kinase (ERK) 1/2 and inhibition of phosphorylated p38-MAPK were demonstrated at the early phase of AAI treatment. Notably, the MEK/ERK inhibitor U0126 reversed AAI-induced apoptosis and reduced both FLAP, mGST3 and mitochondrial/caspase protein expression. Taken together, these findings suggest that cysLTs synthesis is involved in AAI-induced apoptosis via an ERK activation way.