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We previously found that the disorder of soluble epoxide hydrolase (sEH)/cyclooxygenase-2 (COX-2)-mediated arachidonic acid (ARA) metabolism contributes to the pathogenesis of the non-alcoholic fatty liver disease (NAFLD) in mice. However, the exact mechanism has not been elucidated. Accumulating evidence points to the essential role of cellular senescence in NAFLD. Herein, we investigated whether restoring the balance of sEH/COX-2-mediated ARA metabolism attenuated NAFLD via hepatocyte senescence. A promised dual inhibitor of sEH and COX-2, PTUPB, was used in our study to restore the balance of sEH/COX-2-mediated ARA metabolism. In vivo, NAFLD was induced by a high-fat diet (HFD) using C57BL/6J mice. In vitro, mouse hepatocytes (AML12) and mouse hepatic astrocytes (JS1) were used to investigate the effects of PTUPB on palmitic acid (PA)-induced hepatocyte senescence and its mechanism. PTUPB alleviated liver injury, decreased collagen and lipid accumulation, restored glucose tolerance, and reduced hepatic triglyceride levels in HFD-induced NAFLD mice. Importantly, PTUPB significantly reduced the expression of liver senescence-related molecules p16, p53, and p21 in HFD mice. In vitro, the protein levels of γH2AX, p53, p21, COX-2, and sEH were increased in AML12 hepatocytes treated with PA, while Ki67 and PCNA were significantly decreased. PTUPB decreased the lipid content, the number of β-gal positive cells, and the expression of p53, p21, and γH2AX proteins in AML12 cells. Meanwhile, PTUPB reduced the activation of hepatic astrocytes JS1 by slowing the senescence of AML12 cells in a co-culture system. It was further observed that PTUPB enhanced the ratio of autophagy-related protein LC3II/I in AML12 cells, up-regulated the expression of Fundc1 protein, reduced p62 protein, and suppressed hepatocyte senescence. In addition, PTUPB enhanced hepatocyte autophagy by inhibiting the PI3K/AKT/mTOR pathway through Sirt1, contributing to the suppression of senescence. PTUPB inhibits the PI3K/AKT/mTOR pathway through Sirt1, improves autophagy, slows down the senescence of hepatocytes, and alleviates NAFLD.

Ischaemia‐reperfusion injury (I/RI) is a common cause of acute kidney injury (AKI). The molecular basis underlying I/RI‐induced renal pathogenesis and measures to prevent or reverse this pathologic process remains to be resolved. Basic fibroblast growth factor (FGF2) is reported to have protective roles of myocardial infarction as well as in several other I/R related disorders. Herein we present evidence that FGF2 exhibits robust protective effect against renal histological and functional damages in a rat I/RI model. FGF2 treatment greatly alleviated I/R‐induced acute renal dysfunction and largely blunted I/R‐induced elevation in serum creatinine and blood urea nitrogen, and also the number of TUNEL‐positive tubular cells in the kidney. Mechanistically, FGF2 substantially ameliorated renal I/RI by mitigating several mitochondria damaging parameters including pro‐apoptotic alteration of Bcl2/Bax expression, caspase‐3 activation, loss of mitochondrial membrane potential and KATP channel integrity. Of note, the protective effect of FGF2 was significantly compromised by the KATP channel blocker 5‐HD. Interestingly, I/RI alone resulted in mild activation of FGFR, whereas FGF2 treatment led to more robust receptor activation. More significantly, post‐I/RI administration of FGF2 also exhibited robust protection against I/RI by reducing cell apoptosis, inhibiting the release of damage‐associated molecular pattern molecule HMBG1 and activation of its downstream inflammatory cytokines such as IL‐1α, IL‐6 and TNF α. Taken together, our data suggest that FGF2 offers effective protection against I/RI and improves animal survival by attenuating mitochondrial damage and HMGB1‐mediated inflammatory response. Therefore, FGF2 has the potential to be used for the prevention and treatment of I/RI‐induced AKI.

Background The epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBECs) is essential for airway remodeling during asthma. Wnt5a has been implicated in various lung diseases, while its role in the EMT of HBECs during asthma is yet to be determined. This study sought to define whether Wnt5a initiated EMT, leading to airway remodeling through the induction of autophagy in HBECs. Methods Microarray analysis was used to investigate the expression change of WNT5A in asthma patients. In parallel, EMT models were induced using 16HBE cells by exposing them to house dust mites (HDM) or interleukin-4 (IL-4), and then the expression of Wnt5a was observed. Using in vitro gain- and loss-of-function approaches via Wnt5a mimic peptide FOXY5 and Wnt5a inhibitor BOX5, the alterations in the expression of the epithelial marker E-cadherin and the mesenchymal marker protein were observed. Mechanistically, the Ca 2+ /CaMKII signaling pathway and autophagy were evaluated. An autophagy inhibitor 3-MA was used to examine Wnt5a in the regulation of autophagy during EMT. Furthermore, we used a CaMKII inhibitor KN-93 to determine whether Wnt5a induced autophagy overactivation and EMT via the Ca 2+ /CaMKII signaling pathway. Results Asthma patients exhibited a significant increase in the gene expression of WNT5A compared to the healthy control. Upon HDM and IL-4 treatments, we observed that Wnt5a gene and protein expression levels were significantly increased in 16HBE cells. Interestingly, Wnt5a mimic peptide FOXY5 significantly inhibited E-cadherin and upregulated α-SMA, Collagen I, and autophagy marker proteins (Beclin1 and LC3-II). Rhodamine-phalloidin staining showed that FOXY5 resulted in a rearrangement of the cytoskeleton and an increase in the quantity of stress fibers in 16HBE cells. Importantly, blocking Wnt5a with BOX5 significantly inhibited autophagy and EMT induced by IL-4 in 16HBE cells. Mechanistically, autophagy inhibitor 3-MA and CaMKII inhibitor KN-93 reduced the EMT of 16HBE cells caused by FOXY5, as well as the increase in stress fibers, cell adhesion, and autophagy. Conclusion This study illustrates a new link in the Wnt5a-Ca 2+ /CaMKII-autophagy axis to triggering airway remodeling. Our findings may provide novel strategies for the treatment of EMT-related diseases.

Performing stress‐sensitivity evaluation on a high‐temperature and high‐pressure gas reservoir is essential for correctly understanding the characteristics of physical property changes and reasonably designing the development scheme of a reservoir under stratum conditions. By focusing on six core samples with different physical properties in a gas field in the Yingqiong Basin, stress‐sensitivity experiments have been conducted along with mercury intrusion porosimetry and X‐ray diffraction measurements to study the relationship among porosity, permeability, and effective stress at a temperature of 140°C and effective stress ranging from 2 MPa to 70 MPa. Our results showed that the stress‐sensitivity curve characterized by three‐stage segmentation is primarily affected by average pore radius and mineral composition but has no direct relation with porosity and permeability. Meanwhile, the stress sensitivity of permeability is mainly related to the average pore throat radius and mineral composition of core specimen. The smaller the pore throat radius and the higher the clay content, the stronger the stress sensitivity of permeability. Under high‐temperature and high‐pressure conditions, the stress sensitivities of permeability and porosity can be characterized by power functions although the stress sensitivity of permeability is about 2–11 times higher than that of porosity. The stress sensitivity of core has no concern with its porosity and permeability value, but with its mineral composition and microstructure. The stress sensitivity of porosity is primarily affected by the average pore radius and the mineral composition. The permeability is mainly subject to the average pore throat radius and the mineral composition.

When a spherical droplet moves parallel to the direction of motion of its surrounding gas medium, it will deform into an ellipsoidal droplet. In this paper, an exposition of a novel model for predicting the minimum flow rate for the continuous removal of liquids from gas wells based on two theories is presented. First, droplet breakup principle is utilized to microscopically obtain the maximum size parameters of ellipsoidal droplets, and second, droplet force equilibrium is adopted to macroscopically calculate the critical droplet entrainment rate. Moreover, effect of variations in the windward area (attributed to droplet deformation) on the drag coefficient is determined. Impacts of variations in pressure, temperature, and pipe diameter on the gas‐liquid two‐phase friction resistance and gas‐liquid surface tension are also considered. For model verification and comparison with other droplet entrainment models, field data from 3436 gas wells are utilized. The field data well validates the results with a 92% accuracy, indicating that the new model has a better comprehensive performance in determining whether or not a gas well is loaded. Besides, parameter sensitivity analyses including the effects of drag coefficient, surface tension, and friction coefficient on the minimum flow rate of gas are performed. Finally, the relationship curve of critical droplet entrainment rates corresponding to different pressures and pipe diameters is established. An optimization method for designing the manifold to obtain the uniform flow for each branch is proposed. The proposed model is validated under the turbulence condition. The effect of the static pressure change coefficient, local loss, and frictional loss on the accuracy of the model is studied.

To characterize the clinical features, risk factors, and outcomes of juvenile idiopathic arthritis-associated uveitis (JIA-U), aiming to improve early detection and management strategies. This study conducted a retrospective cohort analysis of JIA patients diagnosed and treated at the Department of Rheumatology at Beijing Children's Hospital (2016-2023), with subgroup evaluation of JIA-U cases. Among 1494 JIA patients, 72 (4.82%) developed uveitis. The oligoarticular subtype (OJIA, 47.2%) and enthesitis-related arthritis (ERA, 27.8%) predominated. Uveitis onset occurred at a median of 10 months post-arthritis diagnosis (range: 0-86 months), with 93% manifesting within 4 years. Chronic anterior uveitis was the most frequent phenotype. ANA positivity and HLA-B27 were significantly associated uveitis. First-line acute management involved topical corticosteroids, with methotrexate escalation for severe cases and TNF-α inhibitors (adalimumab preferred) for refractory disease. Ocular complications arose in 25.9% during follow-up. Uveitis, often bilateral and insidious, is a common extra-articular manifestation of JIA. Absent arthritis signs may delay diagnosis, highlighting the need for regular screening and close rheumatology-ophthalmology collaboration to optimize outcomes.

This paper presents a study of characteristic value method of well test analysis for horizontal gas well. Owing to the complicated seepage flow mechanism in horizontal gas well and the difficulty in the analysis of transient pressure test data, this paper establishes the mathematical models of well test analysis for horizontal gas well with different inner and outer boundary conditions. On the basis of obtaining the solutions of the mathematical models, several type curves are plotted with Stehfest inversion algorithm. For gas reservoir with closed outer boundary in vertical direction and infinite outer boundary in horizontal direction, while considering the effect of wellbore storage and skin effect, the pseudopressure behavior of the horizontal gas well can manifest four characteristic periods: pure wellbore storage period, early vertical radial flow period, early linear flow period, and late horizontal pseudoradial flow period. For gas reservoir with closed outer boundary both in vertical and horizontal directions, the pseudopressure behavior of the horizontal gas well adds the pseudosteady state flow period which appears after the boundary response. For gas reservoir with closed outer boundary in vertical direction and constant pressure outer boundary in horizontal direction, the pseudopressure behavior of the horizontal gas well adds the steady state flow period which appears after the boundary response. According to the characteristic lines which are manifested by pseudopressure derivative curve of each flow period, formulas are developed to obtain horizontal permeability, vertical permeability, skin factor, reservoir pressure, and pore volume of the gas reservoir, and thus the characteristic value method of well test analysis for horizontal gas well is established. Finally, the example study verifies that the new method is reliable. Characteristic value method of well test analysis for horizontal gas well makes the well test analysis process more simple and the results more accurate.

During the development of water drive gas reservoirs, the phenomena of gas escaping from water and water separating out from gas will change the seepage characteristics of formation fluid. Therefore, the traditional gas-water two-phase inflow performance relationship (IPR) models are not suitable for calculating the water producing gas well inflow performance relationship in water drive gas reservoirs. Based on the basic theory of fluid mechanics in porous medium, using the principle of mass conservation, and considering the process of dissolution and volatilization of gas and water formation, this paper establishes a new mathematical model of gas-water two-phase flow. Multiobjective optimization method is used to automatically match the sample well production data in water drive gas reservoirs and then we can achieve the sample well’s productivity equation, relative permeability curve, water influx intensity, and single well controlled reserves. In addition, the influence of different production gas water ratios (GWR) and gas-soluble water coefficients on absolute open flow rate (qAOF) is discussed. This method remedied the limitation of well testing on site and was considered to be a new way to analyze the production behaviors in water producing gas well.

A dual fractal reservoir transient flow model was created by embedding a fracture system simulated by a tree-shaped fractal network into a matrix system simulated by fractal porous media. The dimensionless bottom hole pressure model was created using the Laplace transform and Stehfest numerical inversion methods. According to the model's solution, the bilogarithmic type curves of the dual fractal reservoirs are illustrated, and the influence of different fractal factors on pressure transient responses is discussed. This semianalytical model provides a practical and reliable method for empirical applications.

Aim: Oncolytic adenovirus, also called conditionally replicating adenovirus (CRAD), can selectively propagate in tumor cells and cause cell lysis. The released viral progeny can infect neighboring cancer cells, initiating a cascade that can lead to the ultimate destruction of the tumor. Suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) offers a potential treatment strategy for cancer and is undergoing preclinical trials for a variety of tumors. We hypothesized that HSV-TK gene therapy combined with oncolytic adenoviral therapy would have an enhanced effect compared with the individual effects of the therapies and is a potential novel therapeutic strategy to treat liver cancer. Methods: To address our hypothesis, a novel CRAD was created, which consisted of a telomerase-dependent oncolytic adenovirus engineered to express E1A and HSV-TK genes (Ad-ETK). The combined effect of Ad-ETK and GCV was assessed both in vitro and in vivo in nude mice bearing HepG2 cell-derived tumors. Expression of the therapeutic genes by the transduced tumor cells was analyzed by RT-PCR and Western blotting. Results: We confirmed that Ad-ETK had antitumorigenic effects on human hepatocellular carcinoma (HCC) both in vitro and in vivo , and the TK/GCV system enhanced oncolytic adenoviral therapy. We confirmed that both E1A and HSV-TK genes were expressed in vivo . Conclusion: The Ad-ETK construct should provide a relatively safe and selective approach to killing cancer cells and should be investigated as an adjuvant therapy for hepatocellular carcinoma.