L-carnitine ameliorated fatty liver in high-calorie diet/STZ-induced type 2 diabetic mice by improving mitochondrial function

<p>Abstract</p> <p>Background</p> <p>There are an increasing number of patients suffering from fatty liver caused by type 2 diabetes. We intended to study the preventive and therapeutic effect of L-carnitine (LC) on nonalcoholic fatty liver disease (NAFLD) in streptozotocin (STZ)-induced type 2 diabetic mice and to explore its possible mechanism.</p> <p>Methods</p> <p>Thirty male Kungming mice were randomly divided into five groups: control group, diabetic group, pre-treatment group (125 mg/kg BW), low-dose (125 mg/kg BW) therapeutic group and high-dose (250 mg/kg BW) therapeutic group. The morphology of hepatocytes was observed by light and electron microscopy. LC and ALC (acetyl L-carnitine) concentrations in the liver were determined by high-performance liquid chromatography (HPLC). Moreover, liver weight, insulin levels and free fatty acid (FFA) and triglyceride (TG) levels in the liver and plasma were measured.</p> <p>Results</p> <p>Average liver LC and ALC levels were 33.7% and 20% lower, respectively, in diabetic mice compared to control mice (P < 0.05). After preventive and therapeutic treatment with LC, less hepatocyte steatosis, clearer crista and fewer glycogen granules in the mitochondria were observed. Decreased liver weight, TG levels, and FFA concentrations (P < 0.05) in the liver were also observed after treatment with LC in diabetic mice. Moreover, liver LC and ALC levels increased upon treatment with LC, whereas the ratio of LC and ALC decreased significantly (P < 0.01).</p> <p>Conclusion</p> <p>LC supplements ameliorated fatty liver in type 2 diabetic mice by increasing fatty acid oxidation and decreasing the LC/ALC ratio in the liver. Therefore, oral administration of LC protected mitochondrial function in liver.</p

Substance P Inhibits Hyperosmotic Stress-Induced Apoptosis in Corneal Epithelial Cells through the Mechanism of Akt Activation and Reactive Oxygen Species Scavenging via the Neurokinin-1 Receptor.

Hyperosmolarity has been recognized as an important pathological factor in dry eye leading to ocular discomfort and damage. As one of the major neuropeptides of corneal innervation, substance P (SP) has been shown to possess anti-apoptotic effects in various cells. The aim of this study was to determine the capacity and mechanism of SP against hyperosmotic stress-induced apoptosis in cultured corneal epithelial cells. The cells were exposed to hyperosmotic stress by the addition of high glucose in the presence or absence of SP. The results showed that SP inhibited hyperosmotic stress-induced apoptosis of mouse corneal epithelial cells. Moreover, SP promoted the recovery of phosphorylated Akt level, mitochondrial membrane potential, Ca2+ contents, intracellular reactive oxygen species (ROS) and glutathione levels that impaired by hyperosmotic stress. However, the antiapoptotic capacity of SP was partially suppressed by Akt inhibitor or glutathione depleting agent, while the neurokinin-1 (NK-1) receptor antagonist impaired Akt activation and ROS scavenging that promoted by SP addition. In conclusion, SP protects corneal epithelial cells from hyperosmotic stress-induced apoptosis through the mechanism of Akt activation and ROS scavenging via the NK-1 receptor

Phase I trial of human umbilical cord-derived mesenchymal stem cells for treatment of severe bronchopulmonary dysplasia

Severe bronchopulmonary dysplasia (BPD) is a chronic lung disorder that primarily affects premature babies with extremely low birth weight and involves in multiple organ system; no effective pharmacotherapy for this disease exists, and mortality remains high. Based on the evidence from previous preclinical studies and phase I clinical trials, this study aims to test the safety of intravenous application of a single dose of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in patients with severe BPD. The Mesenchymal Stem cells for Bronchopulmonary Dysplasia Treatment (MSBDT) trial is a single center, open-label, dose-escalation phase I clinical trial. Severe BPD patients were enrolled in Children Hospital of Chongqing Medical University, Chongqing, China. The first six patients were treated with low-dose hUC-MSCs (1 × 106 cells/kg) and the next seven patients were treated with high-dose hUC-MSCs (5 × 106 cells/kg). This study is registered with ClinicalTrials.gov, number NCT03558334. No prespecified infusion-associated adverse events, immediate complication, respiratory or cardiovascular compromise were observed during infusion and 24 h after infusion. No significant changes in safety laboratory values were observed. One death event occurred in the low-dose group on study day 10, and one death event occurred in the high-dose group on study day 24, while, after review in detail, the two cases are not believed to be infusion-associated events. In conclusion, intravenous application of a single dose of hUC-MSCs was tolerated in thirteen patients with severe BPD

Additional file 1 of Serum lipidomic study of long-chain fatty acids in psoriasis patients prior to and after anti-IL-17A monoclonal antibody treatment by quantitative GC‒MS analysis with in situ extraction

Additional file 1: Table S1. Qualitative and quantitative ions of 14 LCFAs in SIM mode. Table S2. Concentrations (μM) of LCFAs in serum samples of healthy individuals and psoriasis patients receiving pretherapy and posttreatment with anti-IL-17A mAb. Table S3. Concentrations (μM) of LCFAs in serum samples of IMQ-treat WT and Tcrd-/- mice. Fig. S1. LCFAs derivatization method optimization. To achieve optimal efficiency, 30 μL LCFAs should be heated in the 500 μL 15% BF3-CH3OH solution (a-c) at 40°C for 30 minutes (d, e). Dichloromethane was also recommended as a superior extraction solvent (f). *P <0.05, **P <0.01, ***P <0.001, ****P <0.0001. Fig. S2. Correlation analysis of serum ω-6 (a) and ω-3 (b) PUFAs with PASI scores in psoriasis patients. Fig. S3. LCFAs were conducted on ROC curve analysis. AUC values of 10 LCFAs in the PSV/HC (a) and W8/PSV (b) comparisons

SP reactivates the phosphorylation of Akt and recovers the redox balance of corneal epithelial cells impaired by hyperosmotic stress.

<p>Mouse corneal epithelial cells were treated with 550 mOsm hyperosmotic stress by addition of glucose with or without 1 μM SP for 24 h. The phosphorylation of Akt was evaluated by Immunofluorescence staining or Western blot (A). The intracellular ROS and glutathione (GSH) levels were detected by staining with the fluorescence probes (B) and measured by the fluorescence intensity (C). The cellular total antioxidant capacity (TAC) was measured by the ABTS assay (C).</p

SP protects from hyperosmotic stress-induced apoptosis of corneal epithelial cells.

<p>Mouse corneal epithelial cells were treated with 550 mOsm hyperosmotic stress by addition of glucose with or without 0.1, 1 or 10 μM SP for 24 h. Cell morphology was observed under inverted contrast microscopy (A). The apoptosis was evaluated by FACS analysis followed by FITC-Annexin V/PI staining (B), caspase activity measurement (C), and the detection of Bcl-2-associated death promoter (Bad), BCL2-associated X protein (Bax), apoptosis inducing factor (AIF), Ca²⁺ and mitochondrial membrane potential (JC-1 staining) (D).</p

Role of Akt reactivation in the anti-apoptotic effects of SP.

<p>Mouse corneal epithelial cells were treated with 40 μM Akt inhibitor V and 1 μM SP 2 h before the addition of glucose for 24 h. The phosphorylation of Akt was evaluated by Immunofluorescence staining or Western blot (A). The apoptosis was evaluated by FACS analysis followed by FITC-Annexin V/PI staining (B), and the detection of Bad, Bax, AIF, Ca²⁺ and mitochondrial membrane potential (C). The intracellular ROS and glutathione (GSH) were detected by staining with the fluorescence probes (D) and measured by the fluorescence intensity (E). The cellular total antioxidant capacity (TAC) was measured by the ABTS assay (E).</p

Hyperosmotic stress induces a dose- and time-dependent apoptosis in mouse corneal epithelial cells.

<p>Mouse corneal epithelial cells were treated with varying osmolarities (450, 550 or 650 mOsm) by addition of glucose for 24 h. The apoptotic cells were observed under inverted contrast microscopy (A) and detected by staining with FITC-Annexin V/PI and FACS analysis (B). Mouse corneal epithelial cells were treated with 550 mOsm hyperosmotic stress by addition of glucose for 12, 24 or 48h, and the apoptotic cells were investigated by staining with FITC-Annexin V/PI and FACS analysis (C). Hyperosmotic stress treatment induced the apoptosis of mouse corneal epithelial cells in a dose and time-dependent manner (B, C).</p

Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells

<p>Tumors are comprised of malignant cancer cells and stromal cells which constitute the tumor microenvironment (TME). Previous studies have shown that cancer associated fibroblast (CAF) in TME is an important promoter of tumor initiation and progression. However, the underlying molecular mechanisms by which CAFs influence the growth of colorectal cancer cells (CRCs) have not been clearly elucidated. In this study, by using a non-contact co-culture system between human colorectal fibroblasts (CCD-18-co) and CRCs (LoVo, SW480, and SW620), we found that fibroblasts existing in tumor microenvironment positively influenced the metabolism of colorectal cancer cells, through its autophagy and oxidative stress pathway which were initially induced by neighboring tumor cells. Therefore, our data provided a novel possibility to develop fibroblasts as a potential target to treat CRC.</p