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Objective To investigate the effect of ginkgolide B on hepatic ischemia-reperfusion injury in mice with fatty liver disease and its mechanism. Methods A total of 25 male C57BL/6J mice were fed with 60% high-fat diet for 16 weeks, and then they were divided into sham-operation group (laparotomy and suture), model group (occlusion of blood flow in the middle and left lobes of the liver for 1 h, followed by reperfusion for 6 h), ginkgolide B group (intraperitoneal injection of 25 mg/kg ginkgolide B twice, followed by the treatment in the model group), GW9662 group (intraperitoneal injection of 1 mg/kg GW9662 twice, followed by the treatment in the model group), and GW9662+ginkgolide B group (intraperitoneal injection of 25 mg/kg ginkgolide B+1 mg/kg GW9662 twice, followed by the treatment in the model group). At 6 h after administration and surgery, the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured for each group; Western blotting was used to measure the protein expression levels of Bax, Bcl-2, and PPARγ in liver tissue; oil red O staining was used to measure the degree of fatty changes in the liver, and HE staining was used to measure the degree of necrosis in liver tissue. Results Oil red O staining showed that the degree of fatty changes in the liver had reached the level of fatty liver disease in each group. The se-rum enzymatic analysis showed that the ginkgolide B group and the GW9662+ginkgolide B group had significantly lower serum le-vels of ALT and AST than the model group (P

Objective To investigate the effect of indoxyl sulfate (IS) on myocardial remodeling in a mouse model of myocardial infarction (MI). Methods A total of 50 adult male C57BL/6J mice were randomly divided into sham-operation group (Sham group) with 10 mice, sham operation+indoxyl sulfate group (Sham+IS group) with 10 mice, myocardial infarction group (MI group) with 15 mice, and myocardial infarction+indoxyl sulfate group (MI+IS group) with 15 mice. Left anterior descending coronary artery ligation was performed to establish a mouse model of MI, and at 24 hours after surgery, the mice in the Sham+IS group and the MI+IS group were given intraperitoneal injection of IS (100 mg/kg), while those in the Sham group and the MI group were given intraperitoneal injection of an equal volume of PBS, once a day for 28 consecutive days. The survival status of the mice in each group was recorded during this period of time. On day 30 of the experiment, echocardiography was performed to evaluate the cardiac function of mice in each group. Ultra-performance liquid chromatography was used to measure the serum concentration of IS. Masson staining was used to assess the degree of myocardial fibrosis in the infarct zone. RT-qPCR was used to measure the mRNA expression levels of α-sma and Collagen Ⅰ in myocardial tissue. Western blot was used to measure the protein expression levels of the TGF-β signaling pathway marker proteins TGF-β, p-Smad2, and p-Smad3 in myocardial tissue. Results On day 30 of the experiment, the MI+IS group had a significant reduction in the survival rate of mice compared with the MI group (χ2=5.02,P0.05). Compared with the MI group, the MI+IS group had significant increases in LVIDd and LVIDs (t=3.96,4.31,P

Objective To investigate the neuroprotective effect of curcumin on mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) and its mechanism. Methods A total of 72 male C57BL/6J mice were randomly divided into control group (group A), MPTP group (group B), and MPTP+curcumin group (group C). For the 5 d before the experiment, the mice in groups B and C were given intraperitoneal injection of MPTP every day, and those in group A were given intraperitoneal injection of an equal volume of normal saline; since day 6, the mice in group C were given intraperitoneal injection of curcumin dissolved in DMSO at a dose of 50 mg/kg, and those in groups A and B were given intraperitoneal injection of an equal volume of DMSO, every day for 7 consecutive days. After the end of administration, behavioral experiments were used to evaluate the motor, learning, and memory functions of mice in each group. On day 15 of the experiment, the samples of substantia nigra were collected from the mice in each group, and ELISA was used to measure the content of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6); Western blotting was used to measure the relative content of CD86 and NF-κB; immunohistochemical staining was used to measure the number of TH-positive neurons. Results Compared with group B, groups A and C had a significant reduction in descending time, significant increases in drop latency and percentage of alternation (F=17.29-19.28,P

Objective To investigate the effect of bone window closure on moderate to severe traumatic brain injury (TBI) in mice by controlled cortical impact (CCI). Methods A total of 200 healthy male mice were divided into 2 groups for moderate and severe TBI. Fifty were randomly selected from each group for bone window closed, and the remaining 50 were not closed. The intracranial pressure (ICP) was monitored, the water content of brain tissue and the volume of cerebral edema were measured, the degree of neurological impairment was assessed by modified Neurological Severity Score (mNSS), and the spatial learning ability and memory were evaluated by Morris water maze test. Nissl staining assessed the degree of neuronal damage in the cerebral cortex and CA1 region of the hippocampus. Results For ICP, there were differences in ICP between the bone window closed group and the unclosed group in both the moderate and severe TBI (P = 0.007, 0.000). There were also significant differences in ICP at different observation time points after modeling (P = 0.000, 0.000). The ICP on 1 d of the moderate bone window closed group was higher than that in the moderate bone window unclosed group (P = 0.009), 1 d (P = 0.000) and 3 d (P = 0.038) of the severe bone window closed group was higher than that of the severe bone window unclosed group. On 7 d, the ICP in the moderate bone window closed group (P = 0.000, 0.000) and the severe bone window closed group (P = 0.000, 0.008) was lower than that on 1 and 3 d, and the ICP on 3 d was also lower than that on 1 d (P = 0.000, 0.000). The ICP in the moderate bone window unclosed group on 7 d was lower than that on 1 d (P = 0.031). The water content of brain tissue was lower on 1 d (P = 0.028), 3 d (P = 0.023) and 7 d (P = 0.023) in severe bone window closed group than that of severe bone window unclosed group. The volume of brain edema in the bone window closed group was smaller than that in the bone window unclosed group (P = 0.021, 0.037). In the evaluation of the degree of neurological impairment, there were differences in mNSS scores at different observation time points between the bone window closed group and the bone window unclosed group (P = 0.000, 0.001). On 7 d, the mNSS scores of the moderate bone window closed group (P = 0.002), the moderate bone window unclosed group (P = 0.013) and the severe bone window closed group (P = 0.009) were all lower than those on 1 d. The mNSS scores of the severe bone window closed group (P = 0.006) and the severe bone window unclosed group (P = 0.002) were all lower than those of 3 d. Morris water maze test showed that the platform latency of mice in the severe bone window closed group was longer than that in the severe bone window unclosed group (P = 0.045), and the target quadrant residence time was shorter than that in the severe bone window unclosed group (P = 0.025). Nissl staining showed compared with the moderate bone window unclosed group, the density of Nissl bodies in cerebral cortex neurons was decreased, the staining was lighter, and the density of Nissl bodies in cerebral cortex neurons of CA1 region of hippocampus was decreased, the Nissl staining was lighter and the shape was blurred in the moderate bone window closed group. In severe TBI model mice, compared with the bone window unclosed group, the density of Nissl bodies in cerebral cortex and hippocampal CA1 region of the bone window closed group was decreased, the staining was blurred, and more metachromic particles appeared, hippocampal CA1 region body edema, the Nissl staining blurred. Conclusions In moderate TBI model mice, bone window closure increases ICP in the acute stage, but has no significant effect on the degree of cerebral edema, neurological function and cognitive function. In severe TBI model mice, bone window closure can lead to increased ICP and decreased spatial learning ability and memory, but it can reduce the degree of brain edema and improve neurological function. It is suggested that bone window closure should be selected according to the purpose of the study.

Abstract Eosinophilic oesophagitis (EoE) is an allergen/immune‐mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction. Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2‐type immune response, the exact pathogenesis is complex, and the efficacy of existing treatments is unsatisfactory. Therefore, the study of the pathophysiological process of EOE has received increasing attention. Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents. To maximize the use of existing animal models of EOE, it is important to understand the advantages or limitations of each modeling approach. This paper systematically describes the selection of experimental animals, types of allergens, and methods of sensitization and excitation during the preparation of animal models of EoE. It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.

Objective To establish a nude mouse model of type 2 diabetes mellitus (T2DM) and pancreatic cancer that allows dynamic observation of tumor formation process and facilitates in vivo research. Methods At first, human pancreatic cancer PANC-1 cells were transfected with lentiviral vector GV260 to construct the pancreatic cancer cell line PANC-1-Luc with stable expression of firefly luciferase. Then, 36 specific pathogen-free nude mice were randomly divided into control group with 12 mice and model group with 24 mice (nude mice with T2DM and pancreatic cancer). The mice in the control group were fed with breeding diet and were then given ectopic subcutaneous implantation of PANC-1-Luc cells, and those in the model group were first given high-fat diet and intraperitoneal injection of 1% STZ, followed by ectopic subcutaneous implantation of PANC-1-Luc cells. The fluorescence in vivo imaging system and the manual measurement method were used for simultaneous and dynamic monitoring of the growth of pancreatic cancer in nude mice in the two groups, and the tumor growth curve was plotted to investigate the correlation between fluorescence value and tumor volume. Subcutaneous tumors and pancreatic islets were observed under a microscope to verify whether the model was successfully established, and immunohistochemistry was used to measure the expression of Ki-67 in tumor tissue to investigate the influence of hyperglycemia on the growth of pancreatic cancer in nude mice. The independent-samples t test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. Results The optimal virus titer was determined as 5×107 TU/mL for the stable transfection of lentiviral vector in PANC-1 cells, and the optimal concentration selected with puromycin was 20 µg/mL, with an optimal selection time of 9 days. The fluorescence value of PANC-1-Luc cells was linearly and positively correlated with the number of cells, with the linear equation of y=42.56x－42 504(r=0.977, P=0.004). The blood glucose value of T2DM nude mice was 23.05(19.25 — 26.40) mmol/L, with a blood glucose level of >11.1 mmol/L in each nude mouse, and there was a significant difference in blood glucose value between the T2DM nude mice and the control nude [6.15 (5.20 — 7.30) mmol/L] (Z=−8.45, P<0.001). Compared with the control group, the model group had reductions in the number and volume of pancreatic islets, with irregular shapes and unclear boundaries, and pathological examination confirmed that the xenograft tumor was pancreatic cancer tissue, which showed that the model was established successfully. In the model group, there was a linear positive correlation between subcutaneous tumor size and fluorescence values, with the linear equation of y=232 348 691x－ 8 258 608(r=0.911, P=0.031). The model group had a significantly higher positive rate of Ki-67 than the control group (50.333%± 7.808% vs 15.917%±4.055%, t=13.55, P<0.001), suggesting rapid tumor proliferation in the model group. Conclusion The T2DM nude mouse model of pancreatic cancer established in this study can simulate the pathological process of the development and progression of pancreatic cancer in the context of T2DM and dynamically observe the influence of hyperglycemia on the growth of pancreatic cancer cells in vivo, thereby providing a new experimental vector for the in vivo study of the development and progression of pancreatic cancer in the context of T2DM. [ABSTRACT FROM AUTHOR]

Background/Aims Upper gastrointestinal bleeding (UGIB) is a life-threatening condition that necessitates early identification and intervention and is associated with substantial morbidity, mortality, and socioeconomic burden. However, several diagnostic challenges remain regarding risk stratification and the optimal timing of endoscopy. The PillSense System is a noninvasive device developed to detect blood in patients with UGIB in real time. This study aimed to assess the safety and performance characteristics of PillSense using a simulated bleeding model. Methods A preclinical study was performed using an in vivo porcine model (14 animals). Fourteen PillSense capsules were endoscopically placed in the stomach and blood was injected into the stomach to simulate bleeding. The safety and sensitivity of blood detection and pill excretion were also investigated. Results All the sensors successfully detected the presence or absence of blood. The minimum threshold was 9% blood concentration, with additional detection of increasing concentrations of up to 22.5% blood. All the sensors passed naturally through the gastrointestinal tract. Conclusions This study demonstrated the ability of the PillSense System sensor to detect UGIB across a wide range of blood concentrations. This ingestible device detects UGIB in real time and has the potential to be an effective tool to supplement the current standard of care. These favorable results will be further investigated in future clinical studies.

Portal vein thrombosis （PVT） refers to thromboembolism that occurs in the extrahepatic main portal vein and/or intrahepatic portal vein branches. PVT is the result of the combined effect of multiple factors， but its pathogenesis remains unclear. Animal models are an important method for exploring the pathophysiological mechanism of PVT. Based on the different species of animals， this article reviews the existing animal models of PVT in terms of modeling methods， principles， advantages and disadvantages， and application. [ABSTRACT FROM AUTHOR]

In China, the incidence of tumors is increasing year by year, with the number of patients with new tumors ranking first in the world. Currently, tumors are usually treated with surgery combined with radiotherapy, chemotherapy, targeted therapy, or immunotherapy. However, individuals with tumors vary substantially in response to chemotherapeutic drugs. Therefore, selecting the drugs that patients are most sensitive to through the in vitro drug sensitivity screening technology is of great importance to guide personalized drug treatment of patients with tumors. Currently, there are various techniques for personalized anti-tumor drug screening, each with its own advantages and disadvantages. This article reviews the application progress on several commonly used techniques, with the aim to provide a reference for the selection of personalized anti-tumor drug screening techno-logy.

Objective To investigate the effect of probucol on the progression of atherosclerosis in ApoE-/- mice by inhibiting macrophage M1 polarization and its mechanism. Methods A total of 20 ApoE-/- mice were randomly divided into control group and probucol group. Both groups were given high-fat diet, and the mice in the probucol group were given probucol by gavage once every other day, while those in the control group were given an equal volume of normal saline by gavage. After 12 weeks of intervention, blood samples were collected from the apex of the heart after anesthesia, and the mice were sacrificed by cervical dislocation to collect the aorta vessels. A biochemical analyzer was used to measure blood lipids and liver and renal functions, and ELISA was used to measure the serum levels of inflammatory factors (IL-1β, IL-6, and TNF-α). Oil red O staining was performed for the aorta to measure the plaque area of atherosclerosis; the aortic root was collected to prepare frozen sections, and then oil red O staining was used to measure plaque area and lipid deposition; Masson staining was used to measure plaque stability. Immunof-luorescence assay was used to observe macrophages, smooth muscle cells, collagen fibers, and macrophage M1 polarization in plaques, and quantitative real-time PCR was used to measure the mRNA expression levels of inflammatory factors in aortic plaques. Primary peritoneal macrophages were collected from C57BL/6J mice and divided into control group and probucol group. The macrophages in the control group were treated with lipopolysaccharide (LPS) combined with interferon-γ (IFN-γ), and those in the probucol group were treated with probucol in addition to the treatment in the control group. ELISA and RT-qPCR were used to measure the mRNA expression levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and macrophage M1 polarization mar-kers (iNOS and CD86). Results Compared with the control group, the probucol group had significant improvements in the se-rum levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol (t=2.445-4.024,P

Objective To explore the mechanism of FGFR3⁃TACC3 (F3⁃T3) fusion gene mediating DNA damage repair through promoting pyruvate kinase M2 (PKM2)'s nuclear translocation in glioblastoma. Methods The lentiviral transfection technology was used to constructed stable transitional cell lines U87MG cells and U251MG cells that stably expressing F3 ⁃ T3 and empty vector. In vivo glioblastoma model was constructed by intracranial in situ tumor implantation in athymic mice, and the tumorigenic ability of F3⁃T3 transfected cells in athymic mice of each treatment group was observed by small⁃animal in vivo imaging system. Bioinformatics analysis was performed to analyze gene microarray data exploring the possible biological functions of F3 ⁃ T3 mediating chemoresistance and identify the relationship between survival expectations and PKM2 expression levels in glioblastoma patients from The Cancer Genome Atlas (TCGA) database. Transient transfection of small interference RNA (siRNA) was used to knock down the expression of PKM2 in the F3 ⁃ T3 transfected cells. Proliferative activity of U87MG and U251MG cells treated with different concentrations of temozolomide (TMZ), transfected with siRNA, and TMZ in combination with Compound 3k, a PKM2 inhibitor, was observed in CCK ⁃ 8 cell proliferation assays. Nuclear and cytoplasmic proteins were extracted separately and PKM2 protein expression was observed in whole cell extract, cytoplasmic extract and cytosolic extract after TMZ treatment. Relative expression of PKM2, relative expression of cytosolic phosphorylated histone H2AX (p⁃H2AX) and relative expression of siRNA knockdown PKM2 gene in U87MG and U251MG cells stably expressing the F3 ⁃ T3 fusion gene, detected by Western blotting. Results 1) CCK⁃8 cell proliferation assay showed that the survival rate of U87MG cells in the F3 ⁃ T3 transfected group was higher than that in the empty vector transfected group after treatment with TMZ 640, 320, 160, 80, 40 μmol/L (P = 0.000, 0.000, 0.000, 0.000, 0.004, 0.010), and the survival rate of U251MG cells in the F3 ⁃ T3 transfected group was also higher than that in the empty vector transfected group after TMZ 640, 320, 160, 80, 40, 20, 5 μmol/L (P = 0.000, 0.000, 0.000, 0.002, 0.001, 0.002); the survial rate of U87MG cells in the si⁃PKM2⁃1009 transfected group was lower than that of F3 ⁃ T3 transfected group after TMZ 640, 320, 160, 80, 40, 20, 10, 5, 2.50 μmol/L, the survival rate of U251MG cells in the si⁃PKM2⁃1377 transfected group was also lower than that in F3⁃T3 transfected group after TMZ 640, 320, 160, 80, 40, 20, 5 μmol/L (P = 0.000, 0.000, 0.002, 0.000, 0.002, 0.048, 0.042); and the survival rate of U87MG cells in TMZ + Compound 3k group was lower than TMZ group after TMZ 640, 320, 160, 80, 40, 20 μmol/L (P = 0.000, 0.000, 0.000, 0.000, 0.001, 0.002), and the survival rate of U251MG cells in TMZ + Compound 3k group after treatment with high concentrations of TMZ (640, 320, 160, 80 and 40 μmol/L) was also lower than TMZ group (P = 0.000, 0.000, 0.000, 0.000, 0.003), while the survival rate of U251MG cells in TMZ + Compound 3k group after treatment with low concentrations of TMZ (10, 5 and 2.50 μmol/L) was higher than that of TMZ group (P = 0.000, 0.000, 0.006). 2) An animal model of glioblastoma showed the presence of TMZ resistance in homozygous mice. 3) Bioinformatic analysis showed that the biological function of F3⁃T3 was significantly enriched in the DNA repair pathway (P = 0.000). Survival and overall survival of glioblastoma patients in the TCGA database were lower in the PKM2 high expression group than in the low expression group (P < 0.05). 4) Western blotting showed that the relative expression of p⁃H2AX in U87MG (P = 0.000, 0.000, 0.004) and U251MG (P = 0.000, 0.007, 0.005) cells in the F3 ⁃ T3 transfected group were lower than those in the empty vector transfected group after TMZ treatment for 48 h and then medium change for 24, 36 and 48 h. PKM2 protein incorporation into the nucleus was observed in both U87MG and U251MG cells in the F3⁃T3 transfected group after TMZ treatment, whereas it was not observed in cells in the empty vector transfected group; si⁃PKM2⁃1009 and si⁃ PKM2⁃1377 knocked down the relative expression of p⁃H2AX in U87MG (P = 0.000, 0.001, 0.006) and U251MG (P = 0.000, 0.000, 0.000) cells, respectively. Conclusions In the presence of TMZ, F3 ⁃ T3 promotes PKM2's nuclear translocation and activates DNA damage repair pathways, which in the eventually results resistance of glioblastoma cell to TMZ. PKM2 inhibitors can compromise the resistance glioblastoma cells stably expressing F3⁃T3 fusion gene to TMZ.

Objective To investigate the analgesic effect of transcranial direct current stimulation (tDCS) on chronic pain in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA) and its mechanism. Methods Healthy male Sprague-Dawley rats were randomly divided into sham-operation group, MIA group, tDCS group, and sham-tDCS group, with 9 rats in each group. The rats in the sham-operation group were given intra-articular injection of normal saline into the left knee joint, and those in the MIA group, the tDCS group, and the sham-tDCS group were given MIA injection at the same site to establish a model of chronic pain in OA. On day 21 after MIA injection, the rats in the tDCS group and the sham-tDCS group were treated with real or sham tDCS, respectively, for 8 d. The pain behavioral test was performed for the rats in each group on day 1, 2, and 7 after treatment; the periaqueductal gray (PAG) of rats were collected on day 2 after treatment and Western blot was used to measure the expression of brain-derived neurotrophic factor (BDNF). Results The pain behavioral test showed that compared with the sham-tDCS group, the tDCS group had a significantly longer thermal paw withdrawal latency at each time point after treatment (F=11.25-21.48,P

Objective To investigate the protective effect of sodium butyrate on intestinal barrier in mice with hyperuricemia. Methods Male C57BL/6 mice were randomly divided into control group, model group, and sodium butyrate group. Mice in the model group were intraperitoneally injected with potassium oxonate (250 mg/kg) every day, and fed with high yeast diet freely. Mice in the sodium butyrate group were given 200 mg/kg sodium butyrate by gavage every day on the basis of the treatment in the model group. Mice in the control group were intraperitoneally injected and intragastrically administered with the same dose of normal saline every day. The intervention lasted for 21 d. The expression levels of ZO-1 and Occludin protein and mRNA in small intestine tissues of mice in each group were measured by Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemical staining. The pathological morphology of small intestine tissues in each group was observed by hematoxylin-eosin (HE) staining. The content of inflammatory factors in small intestine tissues was measured by enzyme-linked immunosorbent assay (ELISA). Results There was a significant difference in body mass among the three groups (F=4.70,P

Objective To investigate the differentially expressed genes (DEGs) in the substantia nigra of mice with Parkinson’s disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) based on bioinformatics, as well as their role in the pathological and progression of PD. Methods GEO database was used to obtain the gene expression microarray data in the substantia nigra of mice in the normal group and the PD model group, and the bioinformatics method was used to screen for DEGs in the substantia nigra between the normal group and the PD model. Metascape tool was used to perform GO functional enrichment analysis and KEGG pathway enrichment analysis. Quantitative real-time PCR was used to measure the mRNA expression levels of key functional genes regulating neuronal apoptosis and prion transmission. Results There were 174 upregulated DEGs and 173 downregulated DEGs in the substantia nigra of mice with MPTP-induced PD (P0.26). The upregulated genes were significantly enriched in the pathways regulating prion transmission, neuronal development, iron homeostasis, and export across the plasma membrane, while the downregulated genes were significantly enriched in the pathways regulating synaptic vesicle release, transsynaptic complex transmission, neuronal apoptosis, and actin in cytoskeleton. Compared with the normal group, the PD model group had significant reductions in the expressions of Bdnf and Fbxw7 in the substantia nigra of mice (t=2.25,2.39,P0.05). Conclusion There are significant changes in the key functional genes Bdnf and Fbxw7 that regulate neuronal apoptosis in PD model, which lays a foundation for further clarifying their role in the pathological progression of PD.

Objective To investigate the effect of berberine on skin damage and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor-κB (NF-κB) signaling pathway in rats with chronic eczema. Methods Sixty SD rats were divided into the control group, the chronic eczema group, the berberine (low, medium and high dose) groups and the prednisone group (n=10 for each group). Except for the control group, the other groups of rats were treated with 2, 4- dinitrochlorobenzene (DNCB) on back to establish chronic eczema model. Eczema area and severity index (EASI) scores were measured in groups. Serum levels of histamine, gastrin-releasing peptide (GRP), immunoglobulin E (IgE), interleukin (IL)-4, IL-6, tumor necrosis factor α (TNF-α) and γ interferon (IFN- γ) were detected by enzyme-linked immunosorbent assay (ELISA). Histopathological changes of skin lesions were observed by hematoxylin-eosin (HE) staining. Expression levels of PI3K/AKT/NF- κB signaling pathway-related proteins in skin lesions were detected by Western blot assay. Results Compared with the control group, skin lesions were seriously damaged in the chronic eczema group. Serum levels of histamine, GRP, IgE, IL-4, IL-6 and TNF-α, and protein expression levels of IL-4, IL-6 and TNF-α and p-PI3K/PI3K, pAKT/AKT, p-NF-κB p65/NF-κB p65 and p-NF-κB inhibitor protein α (IκBα)/IκBα ratio in skin lesions were increased, serum and skin lesion IFN-γ decreased (P＜0.05). Compared with the chronic eczema group, the pathological damage of skin lesions of rats was improved in the berberine groups and the prednisone group. EASI score, serum levels of histamine, GRP, IgE, IL-4, IL-6 and TNF-α levels, and protein expression levels of IL-4, IL-6 and TNF-α and p-PI3K/PI3K, pAKT/AKT, p-NF-κB p65/NF-κB p65, p-IκBα/ IκBα ratio in skin lesions decreased, serum and skin lesion tissue IFN-γ increased (P＜0.05). Serum IgE and IL-4 in skin lesions of rats decreased in the berberine groups (medium and high dose groups) and the prednisone group (P＜0.05). The effect was better in the high dose berberine group. There were no significant differences in the above indexes between the high dose berberine group and the prednisone group (P＞0.05). Conclusion Berberine, especially high dose berberine, can inhibit the activation of PI3K/AKT/NF-κB signaling pathway, reduce immune imbalance and inflammatory response, and improve skin damage in rats with chronic eczema. [ABSTRACT FROM AUTHOR]

Cholestatic liver diseases (CLD) are a series of diseases due to impaired bile flow and accumulation of bile acid in the liver and/or systemic circulation caused by immune, genetic, and environmental factors. The pathogenesis of CLD remains unclear and CLD is difficult to treat. As a substitute for human diseases, animal models can provide a platform for exploring the etiology and pathogenesis of the disease and finding appropriate therapeutic targets. This article reviews the current research advances in the animal models of CLD. [ABSTRACT FROM AUTHOR]

Objective To explore the effect of Shengyang Yiwei Decoction on the immune function of lung cancer rats and its possible mechanism. Methods Twelve of 72 SPF Wistar rats were randomly divided as the control group, and the remaining 60 rats were infused with carcinogenic iodized oil solution into trachea to establish lung cancer models. After modeling, model rats were divided into the model group, the cisplatin group (5 mg/kg), the Shengyang Yiwei Decoction group (14 g/kg), the phosphoinositide 3-kinase (PI3K) activator 740 Y-P group (10 mg/kg) and the Shengyang Yiwei Decoction + 740 Y-P group (Shengyang Yiwei Decoction 14 g/kg + 740 Y-P 10 mg/kg), with 12 animals in per group. After corresponding drug intervention, the proportions of peripheral blood T lymphocyte subsets CD3+, CD4+ and CD8+were detected by flow cytometry, and CD4+ /CD8+ ratio was calculated. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the serum inflammatory factors interleukin-6 (IL-6), tumor necrosis factor α (TNF- α) and immunoglobulin (IgG, IgA, IgM) levels. Samples of lung, spleen and thymus were taken and weighed to calculate the indexes of lung, spleen and thymus. HE staining was performed to observe the pathological changes of lung tissue. Real-time fluorescent quantitative PCR (RT-qPCR) was performed to measure the expression of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) mRNA in lung tissue. Western blot assay was performed to measure PI3K/ protein kinase B (Akt)/nuclear factor-κB (NF-κB) pathway related protein expression in lung tissue. Results Compared with the control group, CD3+, CD4+ proportions, CD4+ /CD8+ ratio, spleen index and thymus index, IgG, IgA and IgM levels were decreased in the model group, and CD8+ proportion, lung index, IL-6 and TNF-α levels, lung tissue ICAM-1 mRNA and MMP-9 mRNA levels, p-PI3K/PI3K, p-Akt/Akt ratios and nuclear NF-κB p65 protein level increased (P＜0.05). The left lobe of lung tissue was hyperplasia, squamous epithelial metaplasia and a large number of tumor cells were arranged disorderly in sheets or strips, accompanied by more inflammatory cell infiltration. Compared with the model group, the Shengyang Yiwei Decoction group showed increased CD3+ and CD4+ proportions, CD4+ /CD8+ ratio, spleen index and thymus index, IgG, IgA, and IgM levels, and decreased CD8+ proportion, lung index, IL-6 and TNF-α levels, lung tissue ICAM-1 mRNA and MMP-9 mRNA levels, p-PI3K/PI3K, p-Akt/Akt ratios and nuclear NF-κB p65 protein level (P＜0.05). Lung tissue lesions were reduced, lung tissue swelling was not obvious, and the structure of alveolar sacs and epithelial cells were basically clear. On the basis of 740 Y-P, Shengyang Yiwei Decoction could inhibit PI3K/Akt/NF-κB signal pathway and enhance the immunity of lung cancer rats. Conclusion Shengyang Yiwei Decoction may enhance the immune function of T lymphocytes in lung cancer rats by inhibiting PI3K/Akt/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Background/Aim. Staphylococcus aureus (S. aureus) is a gram-positive pathogen that causes various human diseases. S. aureus causes pneumonia, which is characterized by localized tissue necrosis. The aim of the study was to explore the expression of mouse β-defensin 3 (mBD-3) induced by S. aureus in mouse lungs and the effect of mBD-3 expression on the mitogen-activated protein kinase (MAPK) pathway. Methods. An experimental model of S. aureus pneumonia in mice was developed, and the expression of mBD-3 and activation of the MAPK pathway were investigated using the methods of immunofluorescence and western blot. Results. The experimental model was created successfully. The number of white blood cells was elevated 48 and 72 hrs after the introduction of bacteria through mouse airways, and bronchiolar mucosal hyperemia was observed, along with a large number of white blood cells and mucus in the bronchioles. The mBD-3 expression levels 48 and 72 hrs after the induction of infection were greater than the levels in the control group and 24 hrs after the induction. The amount of phosphorylated extracellular signal-regulated kinase (ERK1/2) was increased 48 and 72 hrs after infection induction, compared with the levels in the control group and 24 hrs after induction. The expression of mBD-3 was lower when ERK1/2 phosphorylation was inhibited by the U0126 inhibitor. Conclusion. S. aureus in experimental pneumonia mouse model accelerates mBD-3 expression in the mouse lung mainly through an ERK1/2-dependent signaling pathway.

Objective To investigate the influence of Morin on neuronal apoptosis in cerebral ischemia-reperfusion rats by regulating TXNIP/NLRP3/Caspase-1 signaling pathway. Methods Sixty rats were randomly grouped into the sham operation group, the model group, the Morin low-dose group (Morin-L, 10 mg/kg), the Morin high-dose group (Morin-H, 40 mg/kg), the Morin-H+pLVX-NC group (40 mg/kg Morin+pLVX-NC) and Morin-H+pLVX-TXNIPgroup (pLVX-TXNIP, 40 mg/kg Morin+pLVX-TXNIP). The rat middle cerebral artery embolism model was established by the suture method (except for the sham group), and then perfused after 1 h of administration. After 72 hours of perfusion, neurological deficits were scored. The whole brain was removed for brain edema determination. Hematoxylin-Eosin (HE) staining was performed to observe the pathological damage in the penumbra area of brain tissue. TTC was performed to detect the infarct size of brain tissue. ELISA was performed to detect serum contents of IL-1β and IL-18. Western blot assay was used to detect expression levels of TXNIP/NLRP3/Caspase-1 signaling pathway-related proteins in brain tissue. Results Compared with the sham operation group, the neurological deficit score, contents of IL-1β and IL-18, brain water content, infarct size, expression levels of TXNIP, NLRP3 and Caspase-1 proteins were increased in the model group (P＜0.05). Compared with the model group, the neurological deficit score, contents of IL-1β and IL-18, brain water content, infarct size, expression levels of TXNIP, NLRP3 and Caspase-1 proteins were decreased in the Morin-L group and the Morin-H group (P＜0.05). Compared with Morin-H+pLVX-NC group, the neurological deficit score, contents of IL-1β and IL-18, brain water content, infarct size, expression levels of TXNIP, NLRP3 and Caspase-1 proteins were increased in the Morin-H+pLVX-TXNIP group (P＜ 0.05). Conclusion Morin can reduce brain injury and inhibit neuronal apoptosis in rats with cerebral ischemiareperfusion, which may be related to the inhibition of TXNIP/NLRP3/Caspase-1 signaling pathway. [ABSTRACT FROM AUTHOR]

positive pathogen that causes various human diseases. S. aureus causes pneumonia, which is characterized by localized tissue necrosis. The aim of the study was to explore the expression of mouse β-defensin 3 (mBD-3) induced by S. aureus in mouse lungs and the effect of mBD-3 expression on the mitogenactivated protein kinase (MAPK) pathway. Methods. An experimental model of S. aureus pneumonia in mice was developed, and the expression of mBD-3 and activation of the MAPK pathway were investigated using the methods of immunofluorescence and western blot. Results. The experimental model was created successfully. The number of white blood cells was elevated 48 and 72 hrs after the introduction of bacteria through mouse airways, and bronchiolar mucosal hyperemia was observed, along with a large number of white blood cells and mucus in the bronchioles. The mBD-3 expression levels 48 and 72 hrs after the induction of infection were greater than the levels in the control group and 24 hrs after the induction. The amount of phosphorylated extracellular signalregulated kinase (ERK1/2) was increased 48 and 72 hrs after infection induction, compared with the levels in the control group and 24 hrs after induction. The expression of mBD-3 was lower when ERK1/2 phosphorylation was inhibited by the U0126 inhibitor. Conclusion. S. aureus in experimental pneumonia mouse model accelerates mBD-3 expression in the mouse lung mainly through an ERK1/2-dependent signaling pathway. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect and mechanism of let-7e-5p on allergic rhinitis in mice. Methods Eighteen BALB/c mice were randomly divided into the control group, the allergic rhinitis (AR) group, the let-7e-5p agonist negative control (AR+agomir-NC) group, the let-7e-5p agonist (AR+agomir) group, the let-7e-5p inhibitor negative control (AR+antagomir-NC) group and the let-7e-5p inhibitor (AR+antagomir) group. Except the control group, the other groups were sensitized with ovalbumin (OVA) to establish AR model. The AR+agomir group and the AR+antagomir group were treated with let-7e-5p agomir or let-7e-5p antagomir at the same time for intervention. After the last sensitization, the allergic rhinitis of mice were scored. HE staining was used to observe nasal mucosa. The number of eosinophils was counted. Real-time PCR was used to detect mRNA expression levels of let-7e-5p, Fas and FasL, and Western blot assay was used to detect protein expression levels of Fas and FasL. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of immunoglobulin E (IgE), specific immunoglobulin E (sIgE), interferon gamma (IFN-γ), interleukin (IL)-12, IL-4 and IL-13. The targeting relationship between let-7e-5p and Fas and FasL were analyzed by dual luciferase assay. Results Compared with the control group, the allergic rhinitis score was increased in the AR group, nasal mucosa hyperplasia was obvious and the number of eosinophils was increased. The expression levels of let-7e-5p and IFN-γ and IL-12 were decreased, while the expression of Fas and FasL and levels of IgE, sIgE, IL-4 and IL-13 were increased (all P＜0.05). Compared with the AR+agomir-NC group, the allergic rhinitis score was decreased in the AR+agomir group, the nasal mucosa structure was clear and the number of eosinophils was reduced. The expression of let-7e-5p and levels of IFN-γ and IL-12 were increased, while the expression of Fas and FasL and levels of IgE, sIgE, IL-4 and IL-13 were decreased (all P＜ 0.05). Compared with the AR+antagomir-NC group, the allergic rhinitis score was increased in the AR+antagomir group, the nasal mucosa was significantly thickened, and the number of eosinophils was increased. The expression of let-7e-5p was decreased, and the expression of Fas, FasL and levels of IgE, sIgE, IL-4 and IL-13 were increased (all P＜0.05). There were no significant differences in IL-12 and IFN- γ between the AR+antagomir-NC group and the AR+antagomir group (P＞ 0.05). Compared with the NC+3'UTR-WT group, luciferase activity was decreased in the let-7e-5p agomir+3'UTR-WT group (P＜0.05). Conclusion Let-7e-5p may affect the balance of T helper type 1 (Th1)/ T helper type 2 (Th2) cells by targeting Fas/FasL, and thus participate in the progression of AR in mice. [ABSTRACT FROM AUTHOR]

Objective: This study verified the replication efficiency of the Rocio virus in a primary culture of mouse neural cells. Methods: Mixed primary cultures (neurons/glia) obtained from the brains of newborn isogenic BALB/c mice were inoculated with Rocio virus on the 7th day of culture, and the development of cytopathogenic effects was monitored. The infection was confirmed via immunocytochemistry (anti-ROCV), while viral replication was quantified in infected primary cultures. The titration method used depended on the infection period. Results: Rocio virus efficiently infected primary cultured neural cells, with the highest viral titer causing cytopathic changes was observed at 2 days post infection. The virus-infected primary culture survived for up to 7 days post infection, and viral load quantitation showed viral replication kinetics compatible with the cell death kinetics of cultures. Conclusion: The findings of this study suggest that mouse neural cell primary cultures support Rocio virus replication and could be used as an alternative system for studying Flavivirus infection in the central nervous system. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective This study verified the replication efficiency of the Rocio virus in a primary culture of mouse neural cells. Methods Mixed primary cultures (neurons/glia) obtained from the brains of newborn isogenic BALB/c mice were inoculated with Rocio virus on the 7 th day of culture, and the development of cytopathogenic effects was monitored. The infection was confirmed via immunocytochemistry (anti-ROCV), while viral replication was quantified in infected primary cultures. The titration method used depended on the infection period. Results Rocio virus efficiently infected primary cultured neural cells, with the highest viral titer causing cytopathic changes was observed at 2 days post infection. The virus-infected primary culture survived for up to 7 days post infection, and viral load quantitation showed viral replication kinetics compatible with the cell death kinetics of cultures. Conclusion The findings of this study suggest that mouse neural cell primary cultures support Rocio virus replication and could be used as an alternative system for studying Flavivirus infection in the central nervous system.

Pancreatic cancer (PC) has the characteristics of insidious onset, rapid progression, and poor prognosis. Up to now, there are no standard clinical regimens for the treatment of PC, and the benefit rate of new targeted therapy remains at a relatively low level, which results in the high mortality rate of PC. Therefore, an understanding of the development and progression mechanisms for PC has become a difficult issue to be solved, and establishment of reliable animal models for PC is the basis for exploring the development, progression, invasion, and metastasis of PC and the optimization of effective therapeutic targets. At present, a large number of studies have established various animal models for PC, and this article compares the commonly used animal models to provide a reference for the selection of animal models in PC research. [ABSTRACT FROM AUTHOR]

Objective To observe the effect of drug-containing serum of Xijiao Dihuang combined prescription (XJDHCP) on the proliferation and differentiation of dendritic cell (DC)-activated T cells and its mechanism on immune thrombocytopenia (ITP). Methods Ten male SD rats were randomly divided into the drug-containing serum group and the blank serum group, with 5 rats in each group. Rats were gavaged with XJDHCF and distilled water for 3 days. Bloodextraction from the abdominal aorta was prepared for drug-containing serum and blank serum. Fifteen healthy volunteers and 8 ITP patients with CD4+ T cells were selected, and the DCs loaded with platelet antigens were co-cultured with CD4+ T cells and randomly divided into the normal control group, the model group and the low, medium and high (5%, 10% and 20%) dose groups of XJDHCF. The normal control group consisted of platelet antigen-loaded DCs and CD4+ T cells from healthy volunteers, and the model group and the low, medium and high dose groups of XJDHCF were platelet antigen-loaded DCs and CD4+ T cells from ITP patients, in which the normal control group and the model group were added with rat blank serum, and the low, medium and high dose groups of XJDHCF were added with 5%, 10% and 20% drug-containing serum. The proliferation of CD4+ T cells, the ratio of regulatory T cells (Treg), effector T cells (Teff) and the expression of programmed death receptor-1 (PD-1) on the surface of CD4+ T were detected by flow cytometry (FCM). Enzyme-linked immunosorbent assay was used to detect the expression levels of pro-inflammatory factors IL-2, IFN- γ, IL-17 and anti-inflammatory factors TGF-β and IL-10 in the supernatant of each group. Results Compared with the control group, the percentage of CD4+ T cell proliferation, the proportion of Teff cells and amounts of pro-inflammatory factors IL-2, IFN-γ and IL-17 were significantly higher in the model group (P＜0.05), and the proportion of Treg cells, the amount of PD-1 expression on the surface of CD4+ T cells and amounts of anti-inflammatory factors TGF-β and IL-10 were greatly lower in the model group (P＜0.05). Compared with the model group, the percentage of CD4+ T cell proliferation and the proportion of Teff cells decreased successively in the low, medium and high dose groups of XJDHCF (P＜0.05), and the amount of PD-1 expression on the surface of CD4+ T cells and the amounts of TGF-β, an inflammatory factor were increased (P＜0.05). The amount of IFN-γ was significantly lower in the high dose group of XJDHCF (P＜0.05). Compared with the model group, the amounts of IFN- γ and IL-17 were significantly lower in the middle and high dose groups of XJDHCF (P＜0.05). Conclusion XJDHCF can regulate the excessive proliferation and differentiation of CD4+ T cells and the secretion of cytokines in ITP patients in vitro, which may be one of the mechanisms of XJDHCF in the treatment of ITP. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of the conserved long non-coding RNA myocardial infarction associate transcript (lncRNA MIAT) targeting and regulating miR-128-3p on ventricular remodeling and myocardial fibrosis in atrial fibrillation (AF) in rats. Methods The calcium chloride-acetylcholine mixture was injected into the sublingual vein to induce AF rat models. The rat models were divided into five groups by random number table method: the model group, the lncRNA MIAT siRNA plasmid group (MIAT group), the miR-128-3p siRNA plasmid group (miR-128-3p group), the lncRNA MIAT siRNA plasmid + miR-128-3p siRNA plasmid group (MIAT+miR-128-3p group) and the empty plasmid group, with 12 rats in each group. Another 12 rats were given with the same dose of normal saline through sublingual vein and were used as the control group. After intervention, the atrial myocardial electrophysiological level of rats was detected, and the effective refractory period (ERP) and 90% action potential duration (APD90) were compared between groups. The left ventricular mass index was also measured in five groups of rats. Sirius red staining was used to detect the degree of myocardial tissue fibrosis in rats. The myocardial collagen volume fraction (CVF) was compared between groups. Serum levels of interleukin (IL) -18, IL-6 and transforming growth factor- β1 (TGF- β1) were detected by kit. Real-time quantitative PCR (qRT-PCR) was used to detect the expression of miR-128-3p in myocardial tissues in each group. Dual luciferase reporter gene assay was used to detect the targeted regulation effect of lncRNA MIAT on miR-128-3p. Results Compared with the control group, the ERP, APD90, and myocardial tissue miR-128-3p expression were significantly reduced in the model group (P＜0.05), and the left ventricular mass index, CVF, serum IL-18, IL-6 and TGF-β1 levels were significantly increased (P＜0.05). Compared with the model group and the lncRNA MIAT siRNA plasmid+miR-128- 3p siRNA plasmid group, the ERP, APD90, and myocardial tissue miR-128-3p expression were significantly increased in the lncRNA MIAT siRNA plasmid group (P＜0.05), and the left ventricular mass index, CVF, serum IL-18, IL-6 and TGF)β1 levels were significantly reduced (P＜0.05). The ERP, APD90 and myocardial tissue miR-128-3p expression were significantly decreased in the miR-128-3p siRNA plasmid group (P＜0.05), and the left ventricular mass index, CVF, serum IL-18, IL-6 and TGF- β1 levels were significantly increased (P＜0.05). There were no significant differences in the indicators between the empty plasmid groups (P＞0.05). LncRNA MIAT could down-regulate the expression of miR-128-3p by targeting. Conclusion LncRNA MIAT can participate in the pathogenesis of AF by targeting down-regulation of miR)128-3p expression. The down-regulation of lncRNA MIAT can inhibit inflammation by promoting miR-128-3p expression, reduce myocardial fibrosis in AF rats, improve the atrial myocardial electrophysiological level and delay the process of ventricular remodeling in rats. [ABSTRACT FROM AUTHOR]

Asthma is the most prevalent chronic inflammatory disease of the airways in children. The most prevalent phenotype of asthma is eosinophilic asthma, which is driven by a Th2 immune response and can be effectively managed by inhaled corticosteroid therapy. However, there are phenotypes of asthma with Th17 immune response that are insensitive to corticosteroid therapy and manifest a more severe phenotype. The treatment of this corticosteroid-insensitive asthma is currently immature and requires further attention. The objective of this study is to elucidate the regulation of the Hedgehog signaling pathway in Th17 cell differentiation in asthma. The study demonstrated that both Smo and Gli3, key components of the Hedgehog signaling pathway, were upregulated in Th17 polarization in vitro and in a Th17-dominant asthma model in vivo. Inhibiting Smo with a small molecule inhibitor or genetically knocking down Gli3 was found to suppress Th17 polarization. Smo was found to increase in Th1, Th2, Th17 and Treg polarization, while Gli3 specifically increased in Th17 polarization. ChIP-qPCR analyses indicated that Gli3 can directly interact with IL-6 in T cells, inducing STAT3 phosphorylation and promoting Th17 cell differentiation. Furthermore, the study demonstrated a correlation between elevated Gli3 expression and IL-17A and IL-6 expression in children with asthma. In conclusion, the study demonstrated that the Hedgehog signaling pathway plays an important role in the pathogenesis of asthma, as it regulates the differentiation of Th17 cells through the IL-6/STAT3 signaling. This may provide a potential therapeutic target for corticosteroid-insensitive asthma driven by Th17 cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Lung ischemia reperfusion injury (IRI) is the principal cause of primary graft dysfunction (PGD) after lung transplantation, affecting short-term and long-term mortality post-transplantation. PANoptosis, a newly identified form of regulated cell death involving apoptosis, necroptosis, and pyroptosis, is now considered a possible cause of organ damage and IRI. However, the specific role of PANoptosis to the development of lung IRI following lung transplantation is still not fully understood., Methods: In this study, we identified differentially expressed genes (DEGs) by analyzing the gene expression data from the GEO database related to lung IRI following lung transplantation. PANoptosis-IRI DEGs were determined based on the intersection of PANoptosis-related genes and screened DEGs. Hub genes associated with lung IRI were further screened using Lasso regression and the SVM-RFE algorithm. Additionally, the Cibersort algorithm was employed to assess immune cell infiltration and investigate the interaction between immune cells and hub genes. The upstream miRNAs that may regulate hub genes and compounds that may interact with hub genes were also analyzed. Moreover, an external dataset was utilized to validate the differential expression analysis of hub genes. Finally, the expressions of hub genes were ultimately confirmed using quantitative real-time PCR, western blotting, and immunohistochemistry in both animal models of lung IRI and lung transplant patients., Results: PANoptosis-related genes, specifically interferon regulatory factor 1 (IRF1) and interleukin 1 alpha (IL1A), have been identified as potential biomarkers for lung IRI following lung transplantation. In mouse models of lung IRI, both the mRNA and protein expression levels of IRF1 and IL1A were significantly elevated in lung tissues of the IRI group compared to the control group. Moreover, lung transplant recipients exhibited significantly higher protein levels of IRF1 and IL1A in PBMCs when compared to healthy controls. Patients who experienced PGD showed elevated levels of IRF1 and IL1A proteins in their blood samples. Furthermore, in patients undergoing lung transplantation, the protein levels of IRF1 and IL1A were notably increased in peripheral blood mononuclear cells (PBMCs) compared to healthy controls. In addition, patients who developed primary graft dysfunction (PGD) exhibited even higher protein levels of IRF1 and IL1A than those without PGD. Furthermore, PANoptosis was observed in the lung tissues of mouse models of lung IRI and in the PBMCs of patients who underwent lung transplantation., Conclusions: Our research identified IRF1 and IL1A as biomarkers associated with PANoptosis in lung IRI, suggesting their potential utility as targets for diagnosing and therapeutically intervening in lung IRI and PGD following lung transplantation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nobiletin (NOB), a polymethoxylated flavone isolated from citrus peels, is a promising dietary treatment for lung diseases, such as pulmonary fiborsis. In this work, the underlying mechanisms of NOB's preventative effect on pulmonary fibrosis were explored using bleomycin-exposed mice and IL-4-induced M2 polarization of the macrophages. Results showed that NOB treatment could significantly ameliorate lung fibrosis by suppressing pathological damages, collagen deposition, and fibroblat activation. Moreover, NOB obviously reduced the M2 macrophage-related proteins, including CD206, Arg1, and pro-fibrotic mediators such as TGF-β and CTGF, which might contribute to the antifibrosis effect of NOB. Network analysis of the differentially expressed genes in NOB-treated M2 macrophages showed that autophagy, mTOR signaling pathway, and AMPK signaling pathway might be involved in the effects of NOB. Further exploration illustrated that autophagy was enhanced in NOB-treated lung and M2 macrophages.The addition of 3MA, an autophagy inhibitor, could significantly weaken the effect of NOB on lung fibrosis and macrophage M2 polarization. Additionally, NOB also markedly decreased the expression of p-AMPK, p-mTOR, and p-P70S6K in the M2 macrophages and lung tissues of BLM-exposed mice. Compound C, an AMPK agonist, significantly suppressed NOB-induced activation of AMPK and mTOR signals, as well as its inhibitory effect on autophagy, M2 macrophages and lung fibrosis both in vitro and in vivo, supporting the requirement of AMPK-mTOR-mediated autophagy for the NOB's antifibrosis activity. Taken together, this study suggests that NOB ameliorates pulmonary fibrosis likely involving the inhibition of M2 macrophage via activating AMPK-mTOR-mediated autophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Silybum marianum, known as milk thistle (MT), is traditionally used to manage liver diseases. This study aimed to investigate the role of MT extract topical application as a potential treatment for imiquimod (IMQ)-induced psoriatic lesions in mice with particular emphasis on phosphoinositol-3 Kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) and Kelch-like ECH-associated protein 1 (KEAP1)/ nuclear factor erythroid-2-related factor (NRF2)/ nuclear factor-kappa B (NF-κB) molecular cascades involvement. To address this aim, forty male Swiss albino mice were subdivided into four groups (n = 10 mice/group): control, IMQ model, standard group where mice were treated topically with IMQ, then the anti-psoriatic mometasone cream, and MT extract-treated group where mice were treated topically with IMQ followed by MT extract. In most measured parameters, MT extract, rich in silymarin, exhibited potent anti-psoriatic activity comparable to the standard cortisone treatment. MT extract mitigated dorsal skin erythema, scaling, and epidermal thickening, reflected by lowering the Psoriasis Area Severity Index (PASI) score. Moreover, it alleviated IMQ-induced splenomegaly. Mechanistically, the PI3K/AKT/mTOR pathway was the main functional pathway behind such improvements, where it was significantly inhibited by MT extract application. This led to NRF2 activation via KEAP1 downregulation with subsequent anti-inflammatory effect proven by reducing NF-κB, interleukin (IL)-23, and IL-17A and antioxidant ability proven by boosting the antioxidant glutathione and heme oxygenase-1. Such improvements were confirmed by alleviating the histopathological alteration. Thus, MT extract could be a promising therapeutic agent for psoriasis treatment by inhibiting PI3K/AKT/mTOR cascade, along with NRF2 signaling activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by unknown etiology. This study employs robust ranking aggregation to identify consistent differential genes across multiple datasets, aiming to enhance prognostic evaluation and facilitate the development of more effective immunotherapy strategies for IPF. Using the GSE10667, GSE110147, and GSE24206 datasets, the analysis identifies 92 robust differentially expressed genes (DEGs), including SPP1, IGF1, ASPN, and KLHL13, highlighted as potential biomarkers through machine learning and experimental validation. Additionally, significant differences in immune cell types between IPF samples and controls, such as Plasma cells, Macrophages M0, Mast cells resting, T cells CD8, and NK cells resting, inform the construction of diagnostic and survival prediction models, demonstrating good applicability. These findings provide insights into IPF pathophysiology and suggest potential therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim of the Study: Cholestasis induces severe liver injury and subsequent liver fibrosis. However, a comprehensive understanding of the relationships between liver fibrosis and cholestasis-induced changes in metabolites in the gut and fibrotic liver tissue and in the gut microbiota is insufficient., Methods: Common bile duct ligation (BDL) was employed to establish a cholestatic liver fibrosis model in mice for 26 days. Fibrotic liver tissue and the gut contents were collected. Untargeted metabolomics was conducted for the determination of metabolites in the gut contents and liver tissues. Metagenomics was adopted to explore the gut microbiota., Results: The metabolites in the gut contents and liver tissues between normal and cholestatic liver fibrosis mice were highly distinct. Beta-alanine metabolism and glutathione metabolism were downregulated in the gut of the BDL group. Galactose metabolism, biosynthesis of unsaturated fatty acids, and ABC transporters were upregulated in the gut and downregulated in the liver of the BDL group. Arginine biosynthesis, taurine and hypotaurine metabolism, arginine and proline metabolism, and primary bile acid biosynthesis were downregulated in the gut and upregulated in the liver of the BDL group. Metagenomic analysis revealed that the alpha diversity of the microbiota in the BDL group decreased. The altered structure of the gut microbiota in the BDL group led to the hypofunction of important metabolic pathways (such as folate biosynthesis, histidine metabolism, thiamine metabolism, biotin metabolism, and phenylalanine, tyrosine and tryptophan biosynthesis) and enzymes (such as NADH, DNA helicase, and DNA-directed DNA polymerase). Correlation analyses indicated that certain gut microbes were associated with gut and liver metabolites., Conclusions: Untargeted metabolomics and metagenomics provided comprehensive information on gut and liver metabolism and gut microbiota in mice with cholestatic liver fibrosis. Therefore, significantly altered bacteria and metabolites may help provide some targets against cholestatic liver fibrosis in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Sepsis is a syndrome that occurs following an infection and marked by severe inflammatory responses, and if not treated in time, it can lead to multi-organ failure syndrome and death. This study examines the effects of a novel combination therapy using azithromycin and mesenchymal stem cell-derived extracellular vesicles (EVs) on a cecal ligation and puncture (CLP) model of sepsis., Methods: Human Wharton's jelly-mesenchymal stem cells were cultured, characterized, and used to extract EVs. The CLP sepsis model was induced in mice, followed by treatments: saline, AZM, EVs, and combination therapy (A+E). Clinical sepsis scores were recorded 24 h post-treatment. Serum, peritoneal fluid, and organ tissues (kidney, liver, lung) were collected and analyzed for biochemical parameters (AST ALT, and creatinine), inflammatory markers, bacterial load, and histopathological changes., Results: The A+E combined treatment improved the clinical scores of septic mice. The administration of A+E reduced bacterial loads in the peritoneum of septic mice, contributing to effective control of infection. Inflammatory markers of neutrophils-to-lymphocytes ratio (NLR) and TNF-α serum levels were significantly lower in the combinational therapy group, indicating significant anti-inflammatory effect of this combination. Additionally, combination of AZM and EVs alleviated organ damage mainly within liver, kidneys and lungs. Based on histopathological assessments and biochemical parameters, there was diminished tissue damage as well as reduced inflammation, which is correlated with improved functions of these vital organs., Conclusion: The combined use of azithromycin and EVs offers a promising therapeutic approach for sepsis by effectively controlling infection and modulating the inflammatory response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Anti-factor VIII (FVIII) antibody development poses a significant challenge in hemophilia A (HA) patients receiving FVIII protein replacement therapy. There is an urgent need for novel therapeutic strategies to inhibit the production of anti-FVIII inhibitory antibodies (inhibitors) in HA. This study aimed to investigate a combination monoclonal antibody (mAb) therapy targeting CXCL13 and CD20 on the development of anti-FVIII antibodies in a HA murine model, along with the underlying mechanisms involved. Specifically, mAbs targeting mouse CD20 (18B12) with an IgG2a backbone and mouse CXCL13 (2C4) with an IgG1 backbone were synthesized. HA mice with FVIII inhibitors were established, and the results revealed that the combination therapy of anti-mCD20 with α-mCXCL13 significantly suppressed anti-FVIII antibody development and induced FVIII tolerance. Furthermore, this combination therapy led to a marked reduction of peripheral and splenic follicular helper T cells and an enhancement of regulatory T cell induction, along with sustained depletion of bone marrow and splenic plasma cells in HA mice with preexisting FVIII immunity. Thus, the concurrence of blockage of CD20 and neutralization of CXCL13 hold promise as a therapeutic strategy for HA patients with inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sepsis is a severe immune response to an infection. It is associated with multiple organ dysfunction syndrome (MODs) along with systemic and neuronal inflammatory response. This study focused on the acute neurologic dysfunction associated with sepsis by exploring the role of PPARγ/SIRT1 pathway against sepsis. We studied the role of this axis in ameliorating sepsis-associated encephalopathy (SAE) and its linked neurobehavioral disorders by using pioglitazone (PIO). This PPARγ agonist showed neuroprotective actions in neuroinflammatory disorders. Sepsis was induced in mice by LPS (10 mg/kg). Survival rate and MODs were assessed. Furthermore, behavioral deficits, cerebral oxidative, inflammatory, and apoptotic markers, and the cerebral expression level of SIRT1 were determined. In this study, we observed that PIO attenuated sepsis-induced cerebral injury. PIO significantly enhanced survival rate, attenuated MODs, and systemic inflammatory response in septic mice. PIO also promoted cerebral SIRT1 expression and reduced cerebral activation of microglia, oxidative stress, HMGB, iNOS, NLRP3 and caspase-3 along with an obvious improvement in behavioral deficits and cerebral pathological damage induced by LPS. Most of the neuroprotective effects of PIO were abolished by EX-527, a SIRT1 inhibitor. These results highlight that the neuroprotective effect of PIO in SAE is mainly SIRT1-dependent., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Repetitive traumatic brain injury (RTBI) is acknowledged as a silent overlooked public health crisis, with an incomplete understanding of its pathomechanistic signaling pathways. Mounting evidence suggests the involvement of thrombin and its receptor, the protease-activated receptor (PAR)1, in the development of secondary injury in TBI; however, the consequences of PAR1 modulation and its impact on ferroptosis-redox signaling, and NLRP3 inflammasome activation in RTBI, remain unclear. Further, the utilitarian function of PAR1 as a therapeutic target in RTBI has not been elucidated. To study this crosstalk, RTBI was induced in Wistar rats by daily weight drops on the right frontal region for five days. Three groups were included: normal control, untreated RTBI, and RTBI+SCH79797 (a PAR1 inhibitor administered post-trauma at 25 μg/kg/day). The concomitant treatment of PAR1 antagonism improved altered behavior function, cortical histoarchitecture, and neuronal cell survival. Moreover, the receptor blockade downregulated mRNA expression of PAR1 but upregulatedthat of the neuroprotective receptor PPAR-γ. The anti-inflammatory impact of SCH79797 was signified by the low immune expression/levels of NF-κB p65,TNF-α, IL-1β, and IL-18. Consequently, the PAR1 blocker hindered the formation of inflammasome components NLRP3, ASC, and activated caspase-1. Ultimately, SCH79797 treatment abated ferroptosis-dependent iron redox signaling through the activation of the antioxidant Nrf2/HO-1 axis and its subsequent antioxidant machinery (GPX4, SOD) to limit lipid peroxidation, iron accumulation, and transferrin serum increment. Collectively, SCH79797 offered putative preventive mechanisms against secondary RTBI consequences in rats by impeding ferroptosis and NLRP3 inflammasome through activating the PPAR-γ/Nrf2 antioxidant cue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fibrosis is a pathological change mainly characterized by an increase of fibrous connective tissue and decrease of parenchymal cells. Its continuous progress may lead to the destruction of organ structure and function decline. An excess of alternatively activated M2 macrophages have been considered crucial candidates in the progression of fibrosis. Bone morphogenetic proteins (BMPs), a group of multifunctional growth factors, are essential for organ development and pathophysiological process, however, the roles that BMPs play in innate immune homeostasis in the development of fibrosis and the downstream signals have not been fully explored. In the current study, we firstly found that the expression of BMP4 was significantly down-regulated in human and mouse fibrosis samples. Then we investigated the effects of BMP4 on macrophage polarization in IL-4 environment and related molecular mechanisms, and found that BMP4 caused a decrease in polarized response towards M2, reflected in the expression of the markers Fizz1, Ym1 and Arg1, together with an inhibition in Stat6 phosphorylation. This relied on the Smad1/5/8 signaling, which had a crosstalk with Stat6. Moreover, the in vivo study showed that BMP4 treatment can reduce collagen deposition and delay the development of experimental pulmonary fibrosis in mice by inhibiting M2 macrophages through adoptive transfer experiment. These findings revealed a novel role of BMP4 in regulating macrophages, offering potential strategies for treating pulmonary fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Sepsis-associated encephalopathy (SAE) can lead to severe cerebral dysfunction as well as cognitive dysfunction, resulting in a significant disease burden. 3-Methyladenine (3-MA) has been confirmed to have anti-inflammatory effects on diseases characterized by enhanced autophagy. However, its role in SAE has not been clarified., Methods: An SAE mouse model was generated by intraperitoneal injection of lipopolysaccharide (LPS). Mice were given 5, 20, or 80 mg/kg 3-MA to determine the therapeutic dose. The mice in the different groups were given 20 mg/kg 3-MA or saline, and survival, body temperature, body weight and neurobehavioral scores were measured at different time points. The expression of autophagy-related proteins and inflammatory factors was detected by Western blotting, enzyme linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR) 12 h after LPS induction. Glial activation and neuronal injury in the hippocampus were detected by immunofluorescence staining and HE staining. The open Field test, novel object recognition (NOR) test, Y-maze test, and Morris water maze (MWM) test were performed to assess cognitive function., Results: Treatment with 20 or 80 mg/kg 3-MA reduced the increase in hippocampal TNF-α, IL-6, and IL-1β expression in SAE model mice, with 20 mg/kg 3-MA having the greatest therapeutic effect. Treatment with 20 mg/kg 3-MA effectively reduced the expression of hippocampal autophagy-related proteins and mortality, ameliorated hypothermia, decreased body weight and electroencephalography (EEG) performance, and attenuated the activation of neuroglia and neuronal damage. Moreover, it alleviated the cognitive dysfunction 2 weeks after LPS induction., Conclusions: 3-MA reduced neuroglial activation and neuronal damage, attenuated neuroinflammation, and improved cognitive deficits during recovery period by inhibiting autophagy in SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The eradication of tuberculosis remains a global challenge. Despite being the only licensed vaccine, Bacillus Calmette-Guérin (BCG) confers limited protective efficacy in adults and individuals with latent tuberculosis infections (LTBI). There is an urgent need to develop novel vaccines that can enhance the protective effect of BCG. Protein subunit vaccines have garnered significant research interest due to their safety and plasticity. Based on previous studies, we selected three antigens associated with LTBI (Rv2028c, Rv2029c, Rv3126c) and fused them with an immunodominant antigen Ag85A, resulting in the construction of a multistage protein subunit vaccine named A986. We evaluated the protective effect of recombinant protein A986 adjuvanted with MPL/QS21 as a booster vaccine for BCG against Mycobacterium tuberculosis (Mtb) infection in mice. The A986 + MPL/QS21 induced the secretion of antigen-specific Th1 (IL-2 + , IFN-γ + and TNF-α + ) and Th17 (IL-17A + ) cytokines in CD4 + and CD8 + T cells within the lung and spleen of mice, while also increased the frequency of central memory and effector memory T cells. Additionally, it also induced the enhanced production of IgG antibodies. Compared to BCG alone, A986 + MPL/QS21 boosting significantly augmented the proliferation of antigen-specific multifunctional T cells and effectively reduced bacterial load in infected mice. Taken together, A986 + MPL/QS21 formulation induced robust antigen-specific immune responses and provided enhanced protection against Mtb infection as a booster of BCG vaccine., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Ischemic stroke is one of the leading causes of chronic disability worldwide, and stroke-induced heart damage can lead to death. According to research, patients with a variety of brain disease have good clinical results after vagus nerve stimulation (VNS). After ischemic stroke, mast cells (MCs) degranulate and release a large number of mediators, which may cause systemic inflammation. Chymase secreted by MCs can increase the levels of pathological angiotensin II (AngⅡ), which plays a crucial role in the deterioration of heart disease. Our goal was to develop a minimally invasive, targeted, and convenient VNS approach to assess the impact of VNS and to clarify the relationship between VNS and MCs in the prognosis of patients with myocardial atrophy after acute ischemic stroke., Methods: In this study, we verified the role of VNS in the treatment of myocardial atrophy after stroke and its molecular mechanism using a rat model of middle cerebral artery occlusion (MCAO/r). Behavioral studies were assessed using neurobehavioral deficit scores. Enzyme-linked immunosorbent assays, immunofluorescence staining, Western blotting and qRT-PCR were used to analyze the expression levels of myocardial atrophy, MC and inflammatory markers in rat hearts., Results: VNS improved myocardial atrophy in MCAO/r rats, inhibited MC activation, reduced the expression of chymase and AngⅡ, and inhibited the expression of proinflammatory factors. The chymase activator C48/80 reversed these effects of VNS. Chymase activation inhibited the effect of VNS on myocardial atrophy in MCAO/r rats, increased AngⅡ expression and aggravated inflammation and autophagy. The myocardial atrophy of MCAO/r rats was improved after chymase inhibition, and AngⅡ expression, inflammation and autophagy were reduced. Our results suggest that VNS may reduce the expression of chymase and AngⅡ by inhibiting MC activation, thereby improving myocardial atrophy and reducing inflammation and autophagy in MCAO/r rats. Inhibition of MC activation may be an effective strategy for treating myocardial atrophy after stroke., Conclusions: VNS inhibits MC activation and reduces the expression of chymase and AngII, thereby alleviating myocardial atrophy, inflammation and autophagy after stroke., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate esketamine's impact on inflammation and oxidative stress in ventilated chronic obstructive pulmonary disease (COPD) rats, examining its regulatory mechanisms., Methods: Rats were divided into four groups: control group (Con), COPD model group (M), COPD model with saline treatment group (M+S), and COPD model with esketamine treatment group (M+K), with 12 rats in each group. After two months, all rats underwent anesthesia and mechanical ventilation. Group M+K received 5 mg/kg esketamine intravenously, while Group M+S received the same volume of saline. Lung tissues were collected for analysis two hours later, including airway peak pressure, wet-to-dry(W/D) ratio, lung permeability index(LPI), hematoxylin and eosin(H&E) staining, and transmission electron microscopy(TEM). Tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), interleukin-8(IL-8), and interleukin-10(IL-10) levels were determined by enzyme-linked immunosorbent assay(ELISA); phosphorylated Nuclear Factor Kappa B(p-NF-κB), mitogen-activated protein kinase 14(p38), phosphorylated p38 (p-p38), c-Jun N-terminal kinase(JNK), and phosphorylated JNK (p-JNK) expressions by Western blotting and immunohistochemistry; and malondialdehyde(MDA), myeloperoxidase(MPO), and superoxide dismutase(SOD) levels were also measured by corresponding biochemical assays., Results: Lung specimens from groups M, M+S, and M+K manifested hallmark histopathological features of COPD. Compared with group Con, group M displayed increased peak airway pressure, W/D ratio, and LPI. In group M+K, compared with group M, esketamine significantly reduced the W/D ratio, LPI, and concentrations of pro-inflammatory cytokines TNF-α, IL-6, and IL-8 while concurrently elevating IL-10 levels. Furthermore, the treatment attenuated the activation of the NF-κB and MAPK pathways, indicated by decreased levels of p-NF-κB, p-p38, and p-JNK.Additionally, compared to group M, group M+K showed decreased MDA and MPO levels and increased SOD levels in lung tissue., Conclusion: Esketamine attenuates mechanical ventilation-induced lung injury in COPD rat models by inhibiting the MAPK/NF-κB signaling pathway and reducing oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Acute kidney injury (AKI) manifests as a clinical syndrome characterised by the rapid accumulation of metabolic wastes, such as blood creatinine and urea nitrogen, leading to a sudden decline in renal function. Currently, there is a lack of specific therapeutic drugs for AKI. Previously, we identified gastrin-releasing peptide receptor (GRPR) as a pathogenic factor in AKI. In this study, we investigated the therapeutic potential of a novel Chinese medicine monomer, aurantiamide (AA), which exhibits structural similarities to our previously reported GRPR antagonist, RH-1402. We compared the therapeutic efficacy of AA with RH-1402 both in vitro and in vivo using various AKI models. Our results demonstrated that, in vitro, AA attenuated injury, necroptosis, and inflammatory responses in human renal tubular epithelial cells subjected to repeated hypoxia/reoxygenation and lipopolysaccharide stimulation. In vivo, AA ameliorated renal tubular injury and inflammation in mouse models of ischemia/reperfusion and cecum ligation puncture-induced AKI, surpassing the efficacy of RH-1402. Furthermore, molecular docking and cellular thermal shift assay confirmed GRPR as a direct target of AA, which was further validated in primary cells. Notably, in GRPR-silenced HK-2 cells and GRPR systemic knockout mice, AA failed to mitigate renal inflammation and injury, underscoring the importance of GRPR in AA's mechanism of action. In conclusion, our study has demonstrated that AA serve as a novel antagonist of GRPR and a promising clinical candidate for AKI treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Acute-on-chronic liver failure (ACLF) is a syndrome characterized by a high short-term mortality rate, and effective interventions are still lacking. This study aims to investigate whether the small molecule baicalein can mitigate ACLF and elucidate the molecular mechanisms., Methods: The ACLF mouse model was induced through chronic liver injury using carbon tetrachloride, followed by acute inflammation induction with lipopolysaccharide (LPS). Baicalein was administered through intraperitoneal injection to explore its therapeutic effects. In vitro experiments utilized the iBMDM macrophage cell line to investigate the underlying mechanisms. Peripheral blood was collected from clinical ACLF patients for validation., Results: In the LPS-induced ACLF mouse model, baicalein demonstrated a significant reduction in acute inflammation and liver damage, as evidenced by histopathological evaluation, liver function analysis, and inflammatory marker measurements. Transcriptomic analysis, coupled with molecular biology experiments, uncovered that baicalein exerts its effects in ACLF by activating the TrKB-CREB1 signaling axis to upregulate the surface expression of the TREM2 receptor on macrophages. This promotes M2 macrophage polarization and activates efferocytosis, thereby inhibiting inflammation and alleviating liver damage. Furthermore, we observed a substantial negative correlation between postoperative peripheral blood plasma soluble TREM2 (sTREM2) levels and inflammation, as well as adverse outcomes in clinical ACLF patients., Conclusion: Baicalein plays a protective role in ACLF by enhancing the surface expression of the TREM2 receptor on macrophages, leading to the suppression of inflammation, mitigation of liver damage, and a reduction in mortality. Additionally, plasma sTREM2 emerges as a critical indicator for predicting adverse outcomes in ACLF patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Psoriasis is an inflammatory immune-mediated skin disease that affects nearly 2-3 % of the global population. The current study aimed to develop safe and efficient anti-psoriatic nanoformulations from Artemisia monosperma essential oil (EO). EO was extracted using hydrodistillation (HD), microwave-assisted hydrodistillation (MAHD), and head-space solid-phase microextraction (HS-SPME), as well as GC/ MS was used for its analysis. EO nanoemulsion (NE) was prepared using the phase inversion method, while the biodegradable polymeric film (BF) was prepared using the solvent casting technique. A.monosperma EO contains a high percentage of non-oxygenated compounds, being 90.45 (HD), 82.62 (MADH), and 95.17 (HS-SPME). Acenaphthene represents the major aromatic hydrocarbon in HD (39.14 %) and MADH (48.60 %), while sabinene as monoterpene hydrocarbon (44.2 %) is the primary compound in the case of HS-SPME. The anti-psoriatic Effect of NE and BF on the successful delivery of A.monosperma EO was studied using the imiquimod (IMQ)-induced psoriatic model in mice. Five groups (n = 6 mice) were classified into control group, IMQ group, IMQ+standard group, IMQ+NE group, and IMQ+BF group. NE and BF significantly alleviated the psoriatic skin lesions and decreased the psoriasis area severity index, Baker's score, and spleen index. Also, they reduced the expression of Ki67 and attenuated the levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 17. Additionally, NE and NF were able to downregulate the NF-κB and GSK-3β signaling pathways. Despite the healing properties of BF, NE showed a more prominent effect on treating the psoriatic model, which could be referred to as its high skin penetration ability and absorption. These results potentially contribute to documenting experimental and theoretical evidence for the clinical uses of A.monosperma EO nanoformulations for treating psoriasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Prolonged exposure to interleukin-17A (IL-17A) can induce autoimmune myocarditis, and MLN4924, an inhibitor of NEDD8 activating enzyme (NAE), has been reported to effectively suppress various inflammatory reactions. However, the effects of MLN4924 in IL-17A-mediated inflammation associated with autoimmune myocarditis remain uncertain., Methods: An experimental autoimmune myocarditis (EAM) model was established and treated with MLN4924. The inflammation degree of heart tissues was assessed histopathologically. The expression levels of inflammatory cytokines and chemokines were measured using ELISA and RT-qPCR, respectively. Additionally, the interaction of biomacromolecules was detected through co-immunoprecipitation (Co-IP) and RNA immunoprecipitation (RIP)., Results: MLN4924 could attenuate IL-17A-induced inflammation. In the in vivo studies, MLN4924 treatment improved inflammatory responses, diminished immune cell infiltration and tissue fibrosis, and reduced the secretion of various inflammatory cytokines in serum, including IL-1β, IL-6, TNF-α, and MCP-1. In vitro experiments further corroborated these findings, showing that MLN4924 treatment reduced the secretion and transcription of pro-inflammatory factors, particularly MCP-1. Mechanistically, we confirmed that MLN4924 promoted Act1 ubiquitination degradation and disrupted Act1's interaction with IL-17R, thereby impeding the formation of the IL-17R/Act1/TRAF6 complex and subsequent activation of TAK1, c-Jun, and p65. Moreover, MLN4924 interfered with Act1's binding to mRNA, resulting in mRNA instability., Conclusions: In conclusion, MLN4924 effectively alleviated inflammatory symptoms in EAM by disrupting the interaction between IL and 17R and Act1, thereby reducing Act1-mediated mRNA stability and resulting in decreased expression of pro-inflammatory factors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Sarcopenia manifests as a chronic, low-level inflammation along with multiple inflammatory cells infiltration. Interleukin (IL)-25 can regulate the function of macrophages. However, the specific role and mechanisms through which IL-25 functions in sarcopenia are still not fully understood and require further investigation., Methods: Aged mice were utilized as sarcopenia models and examined the expression of inflammatory factors. To investigate the effects of IL-25 on sarcopenia, the model mice received IL-25 treatment and underwent in vivo adoptive transfer of IL-25-induced macrophages. Meanwhile, RAW264.7 cells, bone marrow-derived macrophages, satellite cells and C2C12 cells were used in vitro. Shh insufficiency was induced through intramuscular administration of SHH-shRNA adenoviruses. Then, various assays including scratch wound, cell counting kit-8 and Transwell assays, as well as histological staining and molecular biological methods, were conducted., Results: Aged mice exhibited an accelerated decline in muscle strength and mass, along with an increased muscle lipid droplets and macrophage infiltration, and decreased IL-25 levels compared to the young group. IL-25 therapy and the transfer of IL-25-preconditioned macrophages could improve these conditions by promoting M2 macrophage polarization in vivo as well as in vitro. M2 macrophage conditioned medium enhanced satellite cell proliferation and migration, as well as the vitality, migration, and differentiation of C2C12 cells in vitro. Furthermore, IL-25 enhanced Shh expression in macrophages in vitro, and activated the Shh signaling pathway in muscle tissue of aged mice, which could be suppressed by either the inhibitor cyclopamine or Shh knockdown. Mechanistic studies showed that Shh insufficiency suppressed the activation of Akt/mTOR signaling pathway in muscle tissue of aged mice., Conclusion: IL-25 promotes the secretion of Shh by M2 macrophages and activates the Shh/Akt/mTOR signaling pathway, which improves symptoms and function in sarcopenia mice. This suggests that IL-25 has potential as a therapeutic agent for treating sarcopenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Autophagy in alveolar macrophages (AMs) is an important mechanism for maintaining immune homeostasis and normal lung tissue function, and insufficient autophagy in AMs may mediate the development of sepsis-induced acute lung injury (SALI). Insufficient autophagy in AMs and the activation of the NLRP3 inflammasome were observed in a mouse model with SALI induced by cecal ligation and puncture (CLP), resulting in the release of a substantial quantity of proinflammatory factors and the formation of SALI. However, after andrographolide (AG) intervention, autophagy in AMs was significantly promoted, the activation of the NLRP3 inflammasome was inhibited, the release of proinflammatory factors and pyroptosis were suppressed, and SALI was then ameliorated. In the MH-S cell model stimulated with LPS, insufficient autophagy was discovered to promote the overactivation of the NLRP3 inflammasome. AG was found to significantly promote autophagy, inhibit the activation of the NLRP3 inflammasome, and attenuate the release of proinflammatory factors. The primary mechanism of AG promoting autophagy was to inhibit the activation of the PI3K/AKT/mTOR pathway by binding RAGE to the membrane. In addition, it inhibited the activation of the NLRP3 inflammasome to ameliorate SALI. Our findings suggest that AG promotes autophagy in AMs through the RAGE/PI3K/AKT/mTOR pathway to inhibit the activation of the NLRP3 inflammasome, remodel the functional homeostasis of AMs in SALI, and exert anti-inflammatory and lung-protective effects. It has also been the first to suggest that RAGE is likely a direct target through which AG regulates autophagy, providing theoretical support for a novel therapeutic strategy in sepsis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Citalopram and escitalopram are structurally close-related antidepressants and both forms are widely used in the world. We aimed to comparatively evaluate the anti-neuroinflammatory and neuroprotective effects of escitalopram and citalopram in Parkinson's disease (PD) mouse model. Mice were randomly divided into six groups and received 6-hydroxydopamine (6-OHDA) or vehicle administration. The mice were then treated with escitalopram, citalopram or saline for consecutive 7 days. Behaviors, neuroinflammation, neurotransmitters, and neurotoxicity were assessed. Results showed that citalopram but not escitalopram worsened body weight loss and increased freezing time in the PD mice. Both drugs had no impact on the anxiety-like behaviors but ameliorated the depressive-like behaviors as in elevated plus maze and sucrose splash tests. Escitalopram but not citalopram ameliorated motor discoordination in the PD mice as in rotarod test. In accordance, escitalopram but not citalopram attenuated the 6-OHDA-induced nigrostriatal dopaminergic loss. Further mechanistic investigations showed that both drugs mitigated activations of microglia and astrocytes and/or levels of pro-inflammatory cytokines in the PD mice, but escitalopram showed appreciably better effects in the substantia nigra. Neurotransmitter examination in the prefrontal cortex suggested that the two drugs had comparable effects on the disturbed neurotransmitters in the PD mice, but citalopram was prone to disrupt certain normal homeostasis. In conclusion, escitalopram is moderately superior than citalopram to suppress neuroinflammation and to protect against dopaminergic neuronal death and motor discoordination in the 6-OHDA-induced PD mice. Our findings imply that escitalopram shall be prescribed with priority over citalopram to treat PD patients with depression as escitalopram may meanwhile provide greater additional benefits to the patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Emu oil is the oil extracted from the body fat of the Australian bird emu. Although previous studies have reported that emu oil has anti-inflammatory effects, the effect and mechanism of emu oil on the treatment of atopic dermatitis have not been reported. Here, 2, 4-dinitrofluorobenzene was used to induce atopic dermatitis-like appearance on the back skin of C57BL/6 mice. And then, the effect of emu oil in the atopic dermatitis treatment was evaluated. We found that emu oil reduced the transdermal water loss in the atopic dermatitis model. Additionally, the epidermal thickness treated with emu oil was significantly thinner. The number of mast cells and inflammatory cells were significantly decreased. The thymic stromal lymphopoietin (TSLP), which is secreted by keratinocyte, was decreased significantly after treatment. Moreover, the serum levels of cytokines TSLP, interleukin-4, interleukin-13, and immunoglobulin (Ig) E were decreased after emu oil treatment. Surprisingly, we found that the high level of Cdc42 expression in the atopic dermatitis, which was decreased after emu oil treatment. To detect the role of Cdc42 in atopic dermatitis, we constructed atopic dermatitis model in mice with sustained activation of Cdc42 signaling. Furthermore, we have confirmed that emu oil demonstrates anti-inflammatory effects in atopic dermatitis by inhibiting the expression of Cdc42 signaling in keratinocytes. In conclusion, we discovered a new role of Cdc42 in the development of atopic dermatitis, which mediated the therapeutic effect of emu oil on atopic dermatitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The field of cancer immunotherapy has experienced significant progress, resulting in the emergence of numerous biological drug candidates requiring in vivo efficacy testing and a better understanding of their mechanism of action (MOA). Humanized immune system (HIS) models are valuable tools in this regard. However, there is a lack of systematic guidance on HIS modeling. To address this issue, the present study aimed to establish and optimize a variety of HIS models for immune-oncology (IO) study, including genetically engineered mouse models and HIS models with human immune components reconstituted in severely immunocompromised mice. The efficacy and utility of these models were tested with several marketed or investigational IO drugs according to their MOA, followed by immunophenotypic analysis and efficacy evaluation. The results of the present study demonstrated that the HIS models responded to various IO drugs as expected and that each model had unique niches, utilities and limitations. Researchers should carefully choose the appropriate models based on the MOA and the targeted immune cell populations of the investigational drug. The present study provides valuable methodologies and actionable technical guidance on designing, generating or utilizing appropriate HIS models to address specific questions in translational IO., (Copyright © 2024 Elsevier B.V. All rights reserved.)