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Obesity is positively linked to multiple metabolic complications including renal diseases. Several studies have demonstrated Kruppel-like factor 4 (KLF4) participated in renal dysfunction and structural disorders in acute kidney injuries, but whether it affected the process of chronic kidney diseases was unknown. Therefore, present study was to disclose the role of renal KLF4 in dietary-induced renal injuries and underlying mechanisms in obesity. Through utilizing high-fat diet-fed mice and human renal biopsies, we provided the physiological roles of KLF4 in protecting against obesity-related nephropathy. Decreased levels of renal KLF4 were positively correlated with dietary-induced renal dysfunction, including increased levels of creatinine and blood urea nitrogen. Overexpression of renal KLF4 suppressed inflammatory response in palmitic acid-treated mouse endothelial cells. Furthermore, overexpressed KLF4 also attenuated dietary-induced renal functional disorders, abnormal structural remodelling and inflammation. Mechanistically, KLF4 maintained renal mitochondrial biogenesis and activities to combat obesity-induced mitochondrial dysfunction. In clinical renal biopsies and plasma, the renal Klf4 level was negatively associated with circulating levels of creatinine but positively associated with renal creatinine clearance. In conclusions, the present findings firstly supported that renal KLF4 played an important role in combating obesity-related nephropathy, and KLF4/mitochondrial function partially determined the energy homeostasis in chronic kidney diseases., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: The dosage of ovalbumin (OVA) during the sensitization stage is considered a crucial factor in the development of airway hyperresponsiveness (AHR). However, the inconsistent dosages of sensitizing OVA used in current studies and the lack of research on their impact on AHR are notable limitations. Methods: We examined the impact of increasing sensitizing doses of OVA in a murine asthma model, which entailed initial sensitization with OVA followed by repeated exposure to OVA aerosols. BALB/c mice were primed with doses of OVA (0, 10, 20, 50, and 100 μg) plus 1 mg Alum on Days 0 and 7, and were challenged with OVA aerosols (10 mg/mL for 30 min) between Days 14 and 17. Antigen‐induced AHR to methacholine (MCh), as well as histological changes, eosinophilic infiltration, and epithelial injury were assessed. Results: The result indicated that there are striking OVA dose‐related differences in antigen‐induced AHR to MCh. The most intense antigen‐induced AHR to MCh was observed with sensitization at 50 μg, while weaker responses were seen at 10, 20, and 100 μg. Meanwhile, there was a significant increase in eosinophil count with sensitization at 50 μg. The changes of AHR were correlated with total cells count, lymphocytes count, eosinophils count, and basophils count in bronchoalveolar lavage fluid; however, it did not correlate with histological changes such as cellular infiltration into bronchovascular bundles and goblet cell hyperplasia of the bronchial epithelium. Conclusion: Overall, this study demonstrated that sensitization with 50 μg of OVA resulted in the most significant AHR compared to other dosages. These findings may offer valuable insights for future research on mouse asthma modeling protocols. [ABSTRACT FROM AUTHOR]

Aimed to clarify the effect of quercetin and its derivatives on wound healing in animal experiments. PubMed, Embase, Science Direct, Web of Science, SinoMed, Vip Journal Integration Platform, China National Knowledge Infrastructure and WanFang databases were searched for animal experiments investigating the effect of quercetin and its derivatives on wound healing to April 2023. The Review Manager 5.4 software was used to conduct meta‐analysis. Eighteen studies were enrolled in this article. According to the SYRCLE's RoB tool assessment, these studies exposed relatively low methodological quality. It was shown that animals with cutaneous wound receiving quercetin had faster wound healing in wound closure (%) than the control group. Moreover, the difference in efficacy gradually emerged after third day (WMD = 7.13 [5.52, 8.74]), with a peak reached on the tenth day after wounding (WMD = 19.78 [17.82, 21.74]). Subgroup analysis revealed that quercetin for wound closure (%) was independent of the types of rats and mice, wound area and with or without diabetes. Clear conclusion was also shown regarding the external application of quercetin for wound healing (WMD = 17.77 [11.11, 24.43]). A significant reduction in the distribution of inflammatory cells occurred in the quercetin group. Quercetin could increase blood vessel density (WMD = 1.85 [0.68, −3.02]), fibroblast distribution and collagen fraction. Biochemical indicators, including IL‐1β, IL‐10, TNF‐α, TGF‐β, vascular endothelial growth factor (VEGF), hydroxyproline and alpha‐smooth muscle actin (α‐SMA), had the consistent results. Quercetin and its derivatives could promote the recovery of cutaneous wound in animals, through inhibiting inflammatory response and accelerating angiogenesis, proliferation of fibroblast and collagen deposition. [ABSTRACT FROM AUTHOR]

Background: Diterpene ginkgolides meglumine injection (DGMI) is a platelet‐activating factor receptor (PAFR) antagonist that can be used to treat acute ischemic stroke (AIS). This study evaluated the efficacy and safety of an intensive antiplatelet strategy based on PAFR antagonists and explored the underlying mechanisms of PAFR antagonists in AIS treatment. Methods: This is a retrospective study applying propensity score methods to match AIS patients treated with DGMI to nontreated patients. The primary outcome was functional independence (modified Rankin Scale [mRS] 0–2) at 90 days. The safety outcome was bleeding risk. We used McNemar test to compare the efficacy outcome. Subsequently, the network pharmacology analysis was performed. Results: 161 AIS patients treated with DGMI in the study were matched with 161 untreated patients. Compared with untreated patients, DGMI‐treated patients had a significantly higher rate of mRS ranking 0–2 at 90 days (82.0% vs. 75.8%, p < 0.001), without increased risk of bleeding. The gene enrichment analysis showed that the overlap genes of DGMI targeted and AIS‐related enriched in thrombosis and inflammatory‐related signaling pathways. Conclusions: An intensive antiplatelet strategy of DGMI plus traditional antiplatelet agents is effective in treating AIS and may work by mediating post‐stroke inflammation and thrombosis. [ABSTRACT FROM AUTHOR]

The objective of the present study was to explore the function and mechanism of long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) in pulmonary fibrosis (PF) progression. HPAEpic cells and A549 cells were exposed to hypoxic conditions to establish an in vitro model. Cell apoptosis was detected by TUNEL assay, and inflammatory cytokine levels were detected by ELISA. Gene and protein expression levels were identified by qRT–PCR and Western blot assays, respectively. The interaction among NEAT1, miR‐29a, and NFATc3 was identified by dual‐luciferase reporter and RNA pull‐down assays. In hypoxia‐treated cells, hypoxia markers (HIF‐1α and HIF‐2α), cytokines (TNF‐α, IL‐1β, and IL‐6) and fibrotic markers (α‐SMA, collagen I and collagen III) were significantly enhanced. Consistently, the expression levels of NEAT1 and NFATc3 were increased, but miR‐29a was decreased in hypoxia‐stimulated cells. Knockdown of NEAT1 significantly decreased cell apoptosis and the releases of TNF‐α, IL‐1β, and IL‐6 as well as reduced the levels of α‐SMA, collagen I, and collagen III. Moreover, NEAT1 positively regulated NFATc3 expression by directly targeting miR‐29a. Functional experiments showed that the anti‐apoptotic, anti‐inflammatory, and anti‐fibrotic effects mediated by NETA1 silencing were impeded by miR‐29a inhibition or NFATc3 overexpression in hypoxia‐stimulated HPAEpic and A549 cells. Collectively, these data demonstrated that NEAT1 knockdown inhibited hypoxia‐induced cell apoptosis, inflammation, and fibrosis by targeting the miR‐29a/NFATc3 axis in PF, suggesting that NEAT1 might be a potential therapeutic target for relieving PF progression. [ABSTRACT FROM AUTHOR]

Aims This study explored sFasL expression in neurons and the potential role of neuronal sFasL in modulating the microglial phenotypes. Methods In vivo, middle cerebral artery occlusion ( MCAO) was induced in both FasL-mutant ( gld) and wild-type (wt) mice. In vitro, primary cortical neuron or microglia or coculture from wt/ gld mice was subjected to oxygen glucose deprivation ( OGD). sFasL level in the supernatant was evaluated by ELISA. Neuronal-conditioned medium (NCM) or exogenous sFasL was applied to primary microglia with or without FasL neutralizing antibody. Protein expression of JAK2/ STAT3 and NF-κB pathways were determined by Western blot. The effect of microglia phenotype from wt/ gld mice on the fate of ischemic neurons was further elucidated. Results In vivo, compared with wild-type mice, M1 markers ( CD16, CD32 and iNOS) were attenuated in gld mice after MCAO. In vitro, post- OGD neuron released more sFasL. Both post- OGD NCM and exogenous sFasL could trigger M1-microglial polarization. However, this M1 phenotype shift was partially blocked by utilization of FasL neutralizing antibody or gld NCM. Consistently, JAK2/ STAT3 and NF-κB signal pathways were both activated in microglia after exogenous sFasL treatment. Compared with wild-type mice, M1-conditioned medium prepared from gld mice protected neuron against OGD injury. Conclusions Ischemic neurons release sFasL, which contributes to M1-microglial polarization. The underlying mechanisms may involve the activation of JAK2/ STAT3 and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]