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Acute lung injury (ALI) is a prevalent and critical condition in clinical practice. Although certain pharmacological interventions have demonstrated benefits in preclinical studies, none have been proven entirely effective thus far. Therefore, the development of more efficient treatment strategies for ALI is imperative. In this study, we prepared nanostructured lipid carriers (NLCs) conjugated with anti-VCAM-1 antibodies to encapsulate melatonin (MLT), resulting in VCAM/MLT NLCs. This approach aimed to enhance the distribution of melatonin in lung vascular endothelial cells. The VCAM/MLT NLCs had an average diameter of 364 nm, high drug loading content, and a sustained drug release profile. Notably, the NLCs conjugated with anti-VCAM-1 antibodies demonstrated more specific cellular delivery mediated by the VCAM-1 receptors, increased cellular internalization, and enhanced accumulation in lung tissues. Treatment with VCAM/MLT NLCs effectively alleviated pulmonary inflammation by activating NLRP3 inflammasome-dependent pyroptosis through up-regulation of Sirtuin 1. Our findings suggest that VCAM/MLT NLCs demonstrate remarkable therapeutic effects on ALI in both in vitro and in vivo settings, making them a promising and efficient treatment strategy for ALI. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is one of the most severe complications of diabetes mellitus, diabetes belongs to the category of "emaciation-thirst disease" in traditional Chinese medicine (TCM). Bushen Huoxue Prescription (BHP) is composed of traditional Chinese materia medica, which has therapeutic effects on DR and early diabetic retinal edema (EDRE). However, the therapeutic mechanism is unclear. Exploring the mechanism of BHP against EDRE. Feeding Sprague Dawley (SD) rats a high-fat, high-sugar diet as well as providing intraperitoneal injections of streptozotocin (STZ) to promote inner blood-retinal barrier (iBRB) damage that can trigger EDRE, evaluating the therapeutic effect of BHP by the level of expressiveness of TJ proteins (ZO-1,Occludin) of the iBRB and the leakage of rhodamine B isothiocyanate (RITC) in the retina. The combination of network pharmacology and metabolomics was employed to study the mechanism of BHP in preventing of EDRE, then four proteins which were closely to the damage of iBRB were chosen for the validation by employing Western Blot (WB). Research of network pharmacology had shown that BHP had efficacy against EDRE by regulating targets such as AKT1, ALB, TNF, PPARG, etc, its potential pathways mainly involving signaling pathways such as HIF-1. In untargeted metabolomics analysis of serum, 15 differential metabolites were identified, with the metabolic pathways focusing on ketone body metabolism and synthesis, sphingolipid metabolism and phenylalanine metabolism. The conclusions of metabolomics and network pharmacology revealed that BHP can treat EDRE by alleviating hypoxia and oxidative stress and exerting protection of the iBRB. Finally, BHP's protection behavior of the iBRB was validated by WB experiments. Through integrating pharmacodynamics, network pharmacology and metabolomics, BHP was discovered to have a crucial function in EDRE therapy by preserving the integrity of iBRB. This comprehensive strategy also provided a reasonable way to reveal the multi-components, multi-targets, multi-pathways mechanism of TCM. [Display omitted] • Presentation of "early diabetic retinal edema" as a crucial therapeutic point. • Dyslipidemia is believed to play a significant influence in the progression of EDRE. • The mechanism of BHP anti-EDRE was studied. [ABSTRACT FROM AUTHOR]

• Electro-acupuncture at Shuigou (GV 26) can promote the multiplication of hemal endothelial cells, induce angiogenesis, treatment of cerebral infarction. • Shh induces the downstream factors to promote angiogenesis via the Gli2 pathway. • Electro-acupuncture at Shuigou (GV 26) can upregulate the expression of the Shh signaling pathway factors Shh, Ptch, Smo, and Gli2 mRNA and proteins. To study the factors of the Sonic Hedgehog (Shh) signaling pathway after permanent cerebral ischemic and the effects by acupuncture. Male Wistar rats were divided into Electro-acupuncture (EA) group, Model Control (MC) group, and blank control (Control) group. EA and MC were divided into 9 phases, namely 1 h, 3 h, 6 h, 9 h, 12 h, 24 h, 3 d, 7 d, and 12 d after the operation. The neurological deficits and permanent cerebral ischemic volume were observed. The immunofluorescence method was used to examine the angiogenesis. (Polymerase Chain Reaction) PCR and (Immunohistochemistry) IHC were used to test the changes in Shh, Ptch, Smo, and Gli2 mRNA and proteins. The neurological severity scores (NSS) of the Control was 0, the score of the EA group was less than that of the MC. The cerebral permanent ischemic volume of the Control was 0 %, and the EA group's was smaller than that of the MC. The expression of copositive cells in the EA group was higher than the MC's from 12 h to 12 d, and the EA group had more peripheral blood vessels. The rat brain expressions of Shh, Ptch, Smo and Gli2 mRNA and proteins in the MC was higher than that of the Control, the rat brain expression of the EA group was higher than that of the MC. EA can upregulate the expression of the Shh signaling pathway factors, thereby promoting angiogenesis. [ABSTRACT FROM AUTHOR]

Acute-on-chronic liver failure (ACLF) progresses rapidly with a high short-term death rate. Although JianPi LiShi YangGan formula (YGF) has been used to treat ACLF by managing inflammatory responses and reducing endotoxemia, hepatocyte injury, and mortality, the underlying mechanisms remain unclear. This study aims to investigate the potential mechanisms underlying the efficacy and protective benefits of YGF in mice with ACLF. YGF composition was determined using high-performance liquid chromatography coupled with mass spectrometry. We constructed a mouse model of ACLF using carbon tetrachloride, lipopolysaccharide (LPS), and D-galactosamine (D-Gal), as well as an in vitro model of D-Gal/LPS-induced hepatocyte injury. The therapeutic effects of YGF in ACLF mice were verified using hematoxylin-eosin, Sirius red, and Masson staining, and by measuring serum alanine transaminase (ALT), aspartate transaminase (AST), and inflammatory cytokine levels. Mitochondrial damage in hepatocytes was evaluated using electron microscopy, while superoxide anion levels in liver tissue were investigated using dihydroethidium. Transcriptome analysis, immunohistochemistry, western blotting, and immunofluorescence assays were performed to explore the mechanisms underlying the ameliorative effects of YGF against ACLF. In mice with ACLF, YGF therapy partially decreased serum inflammatory cytokine levels, as well as hepatocyte injury and liver fibrosis. The livers of ACLF mice treated with YGF exhibited decreased mitochondrial damage and reactive oxygen species generation, as well as a decreased number of M1 macrophages and increased number of M2 macrophages. Transcriptome analysis revealed that YGF may regulate biological processes such as autophagy, mitophagy, and PI3K/AKT signaling. In ACLF mice, YGF promoted mitophagy and inhibited PI3K/AKT/mTOR pathway activation in hepatocytes. Meanwhile, the autophagy inhibitor 3M-A reduced the capacity of YGF to induce autophagy and protect against hepatocyte injury in vitro. In contrast, the PI3K agonist 740 Y–P suppressed the ability of YGF to control PI3K/AKT/mTOR pathway activation and induce autophagy. Together, our findings suggest that YGF mediates autophagy, tight junctions, cytokine generation, and other biological processes. In addition, YGF inhibits hepatic inflammatory responses and ameliorates hepatocyte injury in mice with ACLF. Mechanistically, YGF can promote mitophagy to ameliorate acute-on-chronic liver failure by inhibiting the PI3K/AKT/mTOR pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

The association between PM 2.5 (particulate matter ≤ 2.5 µm) short-term exposure and its health effect is non-linear from the epidemiological studies. And this nonlinearity is suggested to be related with the PM 2.5 heterogeneity, however, the underlying biological mechanism is still unclear. Here, a total of 38 PM 2.5 filters were collected continuously for three weeks in winter Beijing, with the ambient PM 2.5 varying between 10 and 270 µg/m3. Human monocytes-derived macrophages (THP-1) were treated with PM 2.5 water-soluble elutes at 10 µg/mL to investigate the PM 2.5 short-term exposure effect from a proinflammatory perspective. The proinflammatory cytokine tumor necrosis factor (TNF) induced by the PM 2.5 elutes at equal concentrations were unequal, showing the heterogeneity of PM 2.5 proinflammatory potentials. Of the various chemical and biological components, lipopolysaccharide (LPS) showed a strong positive association with the TNF heterogeneity. However, some outliers were observed among the TNF-LPS association. Specifically, for PM 2.5 from relatively clean air episodes, the higher LPS amount corresponded to relatively low TNF levels. And this phenomenon was also observed in the promotion tests by treating macrophages with PM 2.5 elutes dosed with additional trace LPS. Gene expression analysis indicated the involvement of oxidative-stress related genes in the LPS signaling pathway. Therefore, a potential oxidative-stress-mediated suppression on the PM 2.5 -borne LPS proinflammatory effect was proposed to be accounted for the outliers. Overall, the results showed the differential role of LPS in the heterogeneity of PM 2.5 proinflammatory effects from a component-based perspective. Future experimental studies are needed to elucidate the signaling pathway of LPS attached on PM 2.5 from different air quality episodes. [Display omitted] [ABSTRACT FROM AUTHOR]

• MGL significantly ameliorated CD-like colitis. • MGL protected the intestinal barrier through inhibiting IEC apoptosis. • The effect of MGL might be partly mediated via suppressing PI3K/AKT signalling pathway in IECs. Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved. Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis. The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro. MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD. [ABSTRACT FROM AUTHOR]

Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway. [Display omitted] • XLP combined with 5-FU could alleviate the diarrhea and reduce the inflammation of gastrointestinal mucosa in GC mice model. • XLP combined with 5-FU could inhibit the growth of xenogaft and promote tumor cell apoptosis in GC mice model. • Those effects were related to the regulation of p38MAPK/NF-κB signaling pathway by XLP. [ABSTRACT FROM AUTHOR]

• IL-11 directly protects neuronal cells from oxidative damage caused by H 2 O 2 and reduces neuronal apoptosis. • Transcriptome analysis suggests that the JAK/STAT pathway may be involved in the antioxidant activity of IL-11. • Rescue experiments and animal models demonstrated that IL-11 prevented neuronal apoptosis caused by oxidative imbalance through activation of the JAK/STAT signaling pathway and promoted the recovery of motor function in SCI rats. Excess reactive oxygen species (ROS) generated by oxidative stress is a crucial factor affecting neuronal dysfunction after spinal cord injury (SCI). IL-11 has been reported to have antioxidative stress capacity. In the present study, we investigated the protective effect and mechanism of IL-11 against neuronal cell damage caused by oxidative imbalance. We established a H 2 O 2 -induced oxidative stress injury model in PC12 cells and observed the effects of IL-11 on cellular activity, morphology, oxidase and antioxidant enzymes, and ROS release. Furthermore, the effect of IL-11 on apoptosis of PC12 cells was assessed by flow cytometry, a TUNEL assay and Western blotting. Transcriptome analysis and rescue experiments revealed the mechanism by which IL-11 protects neurons from oxidative stress damage. For the in vivo investigation, an adenovirus-mediated IL-11 overexpression SCI rat model was constructed to validate the beneficial effect of IL-11 against SCI. IL-11 significantly improved the viability and enhanced the antioxidant activity of H 2 O 2 -treated PC12 cells while reducing ROS release. In addition, IL-11 reduced H 2 O 2 -induced PC12 cell apoptosis. Transcriptome analysis revealed that the JAK/STAT pathway may be related to the antioxidant activity of IL-11. Treatment with a JAK/STAT inhibitor (Stattic) exacerbated the oxidative damage induced by H 2 O 2 and attenuated the protective effects of IL-11. The results of in vivo studies showed that IL-11 prevented neuronal apoptosis due to oxidative imbalance and promoted the restoration of motor function in SCI rats by activating the JAK/STAT signaling pathway. IL-11 inhibited oxidative stress-induced neuronal apoptosis at least in part by activating the JAK/STAT signaling pathway and further promoted the recovery of motor function. These findings suggest that IL-11 may be an effective target for the treatment for SCI. [ABSTRACT FROM AUTHOR]

Fuzheng Kang-Ai (FZKA) decoction is mainly composed of 12 components with different types of herbs. In the last decade, FZKA has been used as an adjuvant treatment for lung cancer in clinical practice. Our previous studies have confirmed that FZKA shows a strong anti-cancer activity, significantly increases the clinical efficacy of gefitinib and reverses gefitinib resistance in non-small cell lung cancer (NSCLC). However, the molecular mechanism still needs to be further elucidated. The aim of this study was to investigate the role and mechanism by which FZKA inhibited the cell growth, proliferation and invasion of lung adenocarcinoma(LUAD) and reversed the acquired resistance of gefitinib for the therapy in LUAD. Cell viability assay and EDU assay were used for detecting of cell viability and cell proliferation. Transwell assay was performed to measure cell invasion. Western Blot and qRT-PCR were used for protein and gene expression test. The gene promoter activity was determined by dul-luciferase reporter assay. The in situ expression of protein was measured by cell immunofluorescence. Stabilized cell lines were established for stable overexpression of EZH2. Transient transfection assay was used for gene silence and overexpression. Xenograft tumors and bioluminescent imaging were used for in vivo experiments. FZKA significantly inhibited the cell viability, proliferation and cell invasion of LUAD, the combination of FZKA and gefitinib had a great synergy on the above processes. Moreover, FZKA significantly decreased EZH2 mRNA and protein expression, FZKA reversed the resistance of gefitinib by down-regulation of EZH2 protein. ERK1/2 kinase mediated the down-regulation of EZH2 reduced by FZKA. In addition, FZKA decreased the expression of Snail and EGFR by decreasing EZH2. Overexpression of Snail and EGFR significantly reversed the effect of FZKA-inhibited cell invasion and cell proliferation. More important, the combination of FZKA and gefitinib enhanced the inhibitory effect on EZH2, Snail and EGFR proteins. Furthermore, the growth inhibition and reversal of gefitinib resistance induced by FZKA were further validated in vivo. Finally, the expression and clinical correlation of EZH2,EGFR and Snail in cancer patients were further validated using bioinformatics analysis. FZKA significantly suppressed tumor progression and reversed gefitinib resistance by regulating the p-ERK1/2-EZH2-Snail/EGFR signaling pathway in LUAD. [Display omitted] • FZKA significantly inhibited the cell growth, proliferation and invasion of LUAD and reversed the resistance of gefitinib. • The pERK1/2-EZH2-Snail/EGFR pathway is the underlying mechanism by which FZKA reversed gefitinib resistance in LUAD. • Bioinformatics analysis further confirmed the clinical correlation of EZH2, EGFR and Snail in patients with human cancer. [ABSTRACT FROM AUTHOR]