Protective Effect and Related Mechanism of Modified Danggui Buxue Decoction on Retinal Oxidative Damage in Mice based on Network Pharmacology.

INTRODUCTION: Age-related macular degeneration (AMD) is one of the common diseases that cause vision loss in the elderly, and oxidative stress has been considered a major pathogenic factor for AMD. Modified Danggui Buxue Decoction (RRP) has a good therapeutic effect on non-proliferatic diabetic retinopathy and can improve the clinical symptoms of patients. AIM: This study aimed to predict and verify the protective effect and mechanism of RRP on retinal oxidative damage in mice based on network pharmacology and animal experiments. METHODS: A total of 15 key active components included in RRP interacted with 57 core targets related to retinal oxidative damage (such as AKT1, NFE2L2, HMOX1), mainly involved in the AGE-RAGE signaling pathway in diabetic complications, PI3K-AKT signaling pathway and so on. Further studies in vivo found that RRP improved the retinal oxidative damage, increased the content of SOD and GSH, decreased the content of MDA in mouse serum, promoted the expression of p-PI3K, p-AKT, Nrf2, HO-1 and NQO1 proteins in the mouse retina, and inhibited the expression of Nrf2 in the cytoplasm. RESULTS: This study revealed that RRP had a protective effect on oxidative damage of the retina in mice, and might exert anti-oxidative effect by activating the PI3K/Akt/Nrf2 signal pathway. CONCLUSION: This study provided scientific data for the further development of hospital preparations of RRP, and a good theoretical basis for the clinical application of RRP.

Real-world application of nirmatrelvir/ritonavir in hospitalized COVID-19 patients with onset of symptoms beyond 5 days: a comparative study.

PURPOSE: Physicians may administer Nirmatrelvir-ritonavir to patients who have been symptomatic for more than 5 days. There is currently no clear evidence to support this approach. METHODS: A real-world study was conducted to investigate the potential relationship between the administration of Nirmatrelvir-ritonavir and the rates of intubation or in-hospital mortality among COVID-19 patients who experienced symptoms for more than 5 days. The end point was a composite event of intubation or in-hospital mortality. The outcomes between those patients who received Nirmatrelvir-ritonavir and those who did not were compared. RESULTS: A total of 847 patients were included in the analysis. Among them, 312 patients (36.84%) received Nirmatrelvir-ritonavir. Within the entire population, 86 patients (10.15%) experienced intubation or in-hospital mortality. The main analysis indicated that there was a significant association between the application of Nirmatrelvir-ritonavir and intubation or in-hospital mortality, with an odds ratio of 0.50 (95% confidence interval, 0.28 to 0.87; P = 0.0153) using inverse probability of treatment weighting. The finding was consistent with multiple sensitivity analyses. CONCLUSIONS: The application of Nirmatrelvir-ritonavir was associated with a significantly reduced risk of intubation or death in hospitalized COVID-19 patients who experienced symptoms for more than 5 days as compared to those who did not receive the treatment.

Role of uranium toxicity and uranium-induced oxidative stress in advancing kidney injury and endothelial inflammation in rats.

OBJECTIVE: Uranium exposure may cause serious pathological injury to the body, which is attributed to oxidative stress and inflammation. However, the pathogenesis of uranium toxicity has not been clarified. Here, we evaluated the level of oxidative stress to determine the relationship between uranium exposure, nephrotoxic oxidative stress, and endothelial inflammation. METHODS: Forty male Sprague-Dawley rats were divided into three experimental groups (U-24h, U-48h, and U-72h) and one control group. The three experimental groups were intraperitoneally injected with 2.0 mg/kg uranyl acetate, and tissue and serum samples were collected after 24, 48, and 72 h, respectively, whereas the control group was intraperitoneally injected with 1.0 ml/kg normal saline and samples were collected after 24 h. Then, we observed changes in the uranium levels and oxidative stress parameters, including the total oxidative state (TOS), total antioxidant state (TAS), and oxidative stress index (OSI) in kidney tissue and serum. We also detected the markers of kidney injury, namely urea (Ure), creatine (Cre), cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL). The endothelial inflammatory markers, namely C-reactive protein (CRP), lipoprotein phospholipase A2 (Lp-PLA2), and homocysteine (Hcy), were also quantified. Finally, we analyzed the relationship among these parameters. RESULTS: TOS (z = 3.949; P < 0.001), OSI (z = 5.576; P < 0.001), Ure (z = 3.559; P < 0.001), Cre (z = 3.476; P < 0.001), CysC (z = 4.052; P < 0.001), NGAL (z = 3.661; P < 0.001), and CRP (z = 5.286; P < 0.001) gradually increased after uranium exposure, whereas TAS (z = -3.823; P < 0.001), tissue U (z = -2.736; P = 0.001), Hcy (z = -2.794; P = 0.005), and Lp-PLA2 (z = -4.515; P < 0.001) gradually decreased. The serum U level showed a V-shape change (z = -1.655; P = 0.094). The uranium levels in the kidney tissue and serum were positively correlated with TOS (r = 0.440 and 0.424; P = 0.005 and 0.007) and OSI (r = 0.389 and 0.449; P = 0.013 and 0.004); however, serum U levels were negatively correlated with TAS (r = -0.349; P = 0.027). Partial correlation analysis revealed that NGAL was closely correlated to tissue U (rpartial = 0.455; P = 0.003), CysC was closely correlated to serum U (rpartial = 0.501; P = 0.001), and Lp-PLA2 was closely correlated to TOS (rpartial = 0.391; P = 0.014), TAS (rpartial = 0.569; P < 0.001), and OSI (rpartial = -0.494; P = 0.001). Pearson correlation analysis indicated that the Hcy levels were negatively correlated with tissue U (r = -0.344; P = 0.030) and positively correlated with TAS (r = 0.396; P = 0.011). CONCLUSION: The uranium-induced oxidative injury may be mainly reflected in enhanced endothelial inflammation, and the direct chemical toxicity of uranium plays an important role in the process of kidney injury, especially in renal tubular injury. In addition, CysC may be a sensitive marker reflecting the nephrotoxicity of uranium; however, Hcy is not suitable for evaluating short-term endothelial inflammation involving oxidative stress.

Study on effects and relevant mechanisms of Mudan granules on renal fibrosis in streptozotocin-induced diabetes rats.

AIMS: The effects and relevant mechanisms of Mudan granules in the renal fibrosis of diabetic rats were explored through in vivo experiments, which provided a scientific basis for expanding their clinical indications. METHODS: Male SD rats were given a single intraperitoneal injection of STZ (65 mg/kg) to induce diabetes rat models. After treatment with Mudan granules, the general condition of rats was recorded. Blood glucose, blood lipids, and renal function-related indicators were detected, renal tissue morphological changes and fibrosis-related indicators were observed, and the expression of pathway-related proteins were examined. RESULTS: The general condition of diabetes rats was improved after the treatment of Mudan granules, the 24-h urinary protein and urinary albumin to creatinine ratio were reduced, and the renal function and lipid results were modified. The tissue damage to the rat kidney has been repaired. Expression of TGF-ß1/Smad-related pathway proteins was suppressed in kidney tissues, and the fibrosis factor CO-IV, FN, and LN were reduced in serum. CONCLUSION: Mudan granules may inhibit of TGF-ß1/Smad pathway, inhibit the production of ECM, reduce the levels of fibrosis factors CO-IV, FN, and LN, to have a protective effect on kidney in diabetes rats.

Assessment of Purity, Stability, and Pharmacokinetics of NGP-1, a Novel Prodrug of GS441254 with Potential Anti-SARS-CoV-2 Activity, Using Liquid Chromatography.

SARS-CoV-2 is a highly contagious and pathogenic virus that first appeared in late December 2019 and caused a global pandemic in a short period. The virus is a single-stranded RNA virus belonging to the Coronaviridae family. Numerous treatments have been developed and tested in response to the pandemic, particularly antiviral drugs. Among them, GS441524 (GS441), a nucleoside antiviral drug, has demonstrated promising results in inhibiting SARS-CoV-2. Nevertheless, the limited oral bioavailability of GS441 restricts its application to patients with the virus. In this study, a novel prodrug of GS441 (NGP-1) with an isobutyl ester and cyclic carbonate structure was designed and synthesized. Its purity and the stability in different artificial digestive juices of NGP-1 was determined with HPLC-DAD methods. The pharmacokinetics of NGP-1 and GS441 were studied in rats via gavage administration. A new LC-MS/MS method was developed to quantitatively analyze GS441 in plasma samples. The results showed that the ka, Cmax, and MRT of converted GS441 from NGP-1 were 5.9, 3, and 2.5 times greater than those of GS441 alone. The Frel of NGP-1 was approximately four-fold that of GS441, with an AUC0-∞ of 9716.3 h·ng mL-1. As a prodrug of GS441, NGP-1 increased its lipophilicity, absorption, and bioavailability, indicating that it holds promise in improving the clinical efficacy of anti-SARS-CoV-2 medications.

Study on the therapeutic effect and mechanism of Tangningtongluo Tablet on diabetic mice.

AIMS: To investigate the therapeutic effects of Tangningtongluo Tablet on diabetic mice and its mechanism. This study was established the scientific basis for the clinical application of Tangningtongluo Tablet in the treatment of diabetes mellitus and provided data supporting the transformation of Tangningtongluo Tablet from an in-hospital preparation to a new Chinese medicine. METHODS: In this study, a diabetic mouse model was established by high-glucose and high-fat diet feeding in combination with STZ injection for 4 weeks. Glucose metabolism, lipid metabolism, liver histomorphological changes and liver function related indexes were detected, pancreatic histomorphological changes and insulin resistance related indexes were observed, and the expression of pathway related proteins and inflammatory factors were examined. RESULTS: Glycemia and glycated hemoglobin were reduced in diabetic mice after the treatment of Tangningtongluo Tablet, and glucose tolerance and lipid results were modified. The insulin resistance status of the mice was diminished and tissue damage to the pancreas and liver was repaired. Expression of ERS/NF-κB related pathway proteins was reduced in liver tissues, and inflammatory factors such as TNF-α, IL-6 and IL-1ß were reduced in serum. CONCLUSIONS: Tangningtongluo Tablet could reduce blood glucose in diabetic mice, regulate the disorder of lipid metabolism, enhance insulin sensitivity, improve insulin resistance, repair pancreatic tissue damage and protect mouse liver in diabetic mice. The mechanism of action might be related to the regulation of ERS/NF-κB signaling pathway and the reduction of TNF-α, IL-6 and IL-1ß production.

Study on potential markers for diagnosis of renal cell carcinoma by serum untargeted metabolomics based on UPLC-MS/MS.

Objective: Renal cell carcinoma (RCC) is the most common malignancy of the kidney. However, there is no reliable biomarker with high sensitivity and specificity for diagnosis and differential diagnosis. This study aims to analyze serum metabolite profile of patients with RCC and screen for potential diagnostic biomarkers. Methods: Forty-five healthy controls (HC), 40 patients with benign kidney tumor (BKT) and 46 patients with RCC were enrolled in this study. Serum metabolites were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and then subjected to multivariate statistical analysis, metabolic pathway analysis and diagnostic performance evaluation. Results: The changes of glycerophospholipid metabolism, phosphatidylinositol signaling system, glycerolipid metabolism, d-glutamine and d-glutamate metabolism, galactose metabolism, and folate biosynthesis were observed in RCC group. Two hundred and forty differential metabolites were screened between RCC and HC groups, and 64 differential metabolites were screened between RCC and BKT groups. Among them, 4 differential metabolites, including 3-ß-D-Galactosyl-sn-glycerol, 7,8-Dihydroneopterin, lysophosphatidylcholine (LPC) 19:2, and γ-Aminobutyryl-lysine (an amino acid metabolite), were of high clinical value not only in the diagnosis of RCC (RCC group vs. HC group; AUC = 0.990, 0.916, 0.909, and 0.962; Sensitivity = 97.73%, 97.73%, 93.18%, and 86.36%; Specificity = 100.00%, 73.33%, 80.00%, and 95.56%), but also in the differential diagnosis of benign and malignant kidney tumors (RCC group vs. BKT group; AUC = 0.989, 0.941, 0.845 and 0.981; Sensitivity = 93.33%, 93.33%, 77.27% and 93.33%; Specificity = 100.00%, 84.21%, 78.38% and 92.11%). Conclusion: The occurrence of RCC may involve changes in multiple metabolic pathways. The 3-ß-D-Galactosyl-sn-glycerol, 7,8-Dihydroneopterin, LPC 19:2 and γ-Aminobutyryl-lysine may be potential biomarkers for the diagnosis or differential diagnosis of RCC.

A Review of Traditional Chinese Medicine on Treatment of Diabetic Nephropathy and the Involved Mechanisms.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM), which can lead to renal failure in diabetic patients. At present, the first-line drugs for DN are mainly the renin-angiotensin system (RAS) inhibitors or angiotensin receptor blockers, and the latest approved aldosterone receptor antagonist finerenone, which delay the progression of DN to end-stage renal disease (ESRD), but the therapeutic effect is still not ideal. With a history of thousands of years, traditional Chinese medicine (TCM) has rich experience in the treatment of DN. Based on the theory of TCM, the clinical treatment of DN mainly focuses on generating fluid and nourishing blood, nourishing Qi and Yin, detoxifying and detumescent. In recently years, the therapeutic effects and mechanisms of TCM prescription, Chinese herbal medicine, and its active components on DN have received extensive attention in new drug development. This paper reviews the research progress of the mechanism of TCM on DN.

Epigallocatechin Gallate Protects Diabetes Mellitus Rats Complicated with Cardiomyopathy through TGF-ß1/JNK Signaling Pathway.

BACKGROUND: Epigallocatechin gallate (EGCG) is the main component of rhubarb tannin, with antioxidant, anti-angiogenic, anti-cancer and antiviral activities. Diabetes mellitus (DM) is a high blood sugar and protein metabolism disorder syndrome, which is caused by absolute or relative factors, such as deficiency of insulin and oxidative stress. Diabetes cardiomyopathy (DCM) is one of the most frequent complications of DM. OBJECTIVE: This study aims to explore whether EGCG can improve diabetic complication, myocardial fibrosis, in diabetic rats with an intraperitoneal injection of streptozotocin (STZ) through the transforming growth factor ß1 (TGF-ß1)/C-Jun N -terminal kinase (JNK) signaling pathway. METHODS: 50 male SD rats were randomly divided into five groups, including the control group, model group, and EGCG drug groups (10 mg/kg, 20 mg/kg, 40 mg/kg), with 10 rats in each group. Rats, except for the control group, were intraperitoneally injected with STZ (65 mg/kg) to induce the diabetic rats model. EGCG drug groups were given distilled water according to the dose, while the control group and model group were given the same volume of distilled water for 12 weeks. The levels of glucose (GLU), triglyceride (TG), cholesterol (CHO), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in serum were detected by ELISA of all rats. Myocardial function was observed by HE, Masson staining and Sirius red staining in DCM rats. Immunohistochemistry was used to detect the expression of Collagen I (COL-I) and Collagen III (COL-III), and detect the degree of myocardial fibrosis of DM rats. Western blot was used to detect the expression of matrix metalloproteinases (MMPs), tissue inhibitor of matrix metalloproteinase (TIMPs), TGF-ß1, JNK and p-JNK in the myocardium. RESULTS: Compared to the model group, the levels of GLU, TG, CHO, and LDL in serum were decreased while the level of HDL in serum was increased in EGCG groups rats; cardiac index and left ventricular mass index were decreased while heart function was improved in EGCG groups rats; the expressions of the COL-I and COL-III were decreased in EGCG groups, and the high dose group was the best; the expressions of TGF-ß1, JNK, p-JNK, and TIMP-1 were down-regulated, and the expression of MMP-9 was up-regulated in EGCG groups. CONCLUSION: The results demonstrated that EGCG could improve STZ-induced diabetic complication, i.e., myocardial fibrosis, in diabetic rats, and protect their heart through TGF-ß1/JNK signaling pathway.

Circ_000829 Plays an Anticancer Role in Renal Cell Carcinoma by Suppressing SRSF1-Mediated Alternative Splicing of SLC39A14.

Background: Covalently closed circular RNAs (circRNAs) play critical oncogenic or anticancer roles in various cancers including renal cell carcinoma (RCC), pointing to their regulation as a promising strategy against development of RCC. We, thus, studied the tumor-suppressive role of circ_000829 in RCC through in vitro and in vivo experiments. Methods: The expression of circ_000829 was validated in clinical RCC tissues and RCC cell lines. Based on ectopic expression and knockdown experiments, we examined the interactions among circ_000829, serine and arginine rich splicing factor 1 (SRSF1), and solute carrier family 39 member 14 (SLC39A14, zinc transporter). Then, the effects of circ_000829, SRSF1, and SLC39A14 on cell cycle distribution and proliferation in vitro and on tumor growth in vivo were evaluated in RCC cells. Results: Circ_000829 was poorly expressed in RCC tissues and cells, while SRSF1 was highly expressed. Restoration of circ_000829 reduced the levels of SRSF1 and SLC39A14B, thereby repressing the RCC cell proliferation in vitro and tumor growth in vivo. Meanwhile, overexpression of SRSF1 and SLC39A14B promoted the proliferation and cell cycle entry of RCC cells. Mechanistically, circ_000829 directly bound to SRSF1, and SRSF1 enhanced the expression of SLC39A14B by mediating the alternative splicing of SLC39A14. SLC39A14B upregulation negated the effect of SLC39A14 knockdown on RCC cell proliferation. Conclusion: Hence, this study suggests the antiproliferative role of circ_000829 in RCC growth and further elucidates the underlying mechanism involving the inhibited SRSF1-mediated alternative splicing of SLC39A14 mRNA.

Study on the Anti-Inflammatory Effect and Mechanism of Yuxuebi Tablet Based on Network Pharmacology.

Yuxuebi tablet (YXB) is a Chinese patent medicine with the effect of activating blood circulation and dissipating blood stasis and has been used to treat "Bi" syndrome in China. The aim of this study was to reveal its anti-inflammatory efficacy and mechanism. A carrageenan-induced inflammation mouse model was established to demonstrate the anti-inflammatory efficacy of YXB by detecting the paw swelling degree and inflammatory cell infiltration in paws. The active chemical ingredients and anti-inflammatory targets of YXB were obtained through network pharmacology analysis. Finally, the core anti-inflammatory targets of YXB were determined by the ELISA method and western blot. YXB significantly reduced the paw swelling degree and inflammatory cell infiltration in paws. A total of 120 key active components included in YXB interacted with 56 core inflammatory targets (such as TNF, IL1B, IL6, PTGS2, RELA, MAPK1, MAPK8, and MAPK14), mainly involving in the TNF signaling pathway, Toll-like receptor signaling pathway, NF-kappaB signaling pathway, and NOD-like receptor signaling pathway. Further studies in vivo found that YXB reduced the levels of TNF-α, IL-1ß, and IL-6 in serum and inhibited the expression of COX-2 and the phosphorylation levels of NF-κB p65, JNK, and p38 protein in paws. Taken together, YXB had a good anti-inflammatory effect, which might be related to inhibiting the phosphorylation of NF-κB, JUN, and p38 and the decrease of COX-2 expression and the levels of inflammatory factors.

Retraction: Efficient in vivo wound healing using noble metal nanoclusters.

Retraction of 'Efficient in vivo wound healing using noble metal nanoclusters' by Kuo Li et al. Nanoscale, 2021, 13, 6531-6537. DOI: 10.1039/D0NR07176E.

Protective Effect of Panax Notoginseng Saponins on Apolipoprotein-E-deficient Atherosclerosis-prone Mice.

BACKGROUND: It is widely recognized that atherosclerosis (AS) is related to vascular inflammation. Panax notoginseng saponins (PNS) extracted from the roots of Panax notoginseng have been shown to possess anti-inflammatory activity. It is widely used in the clinical treatment of cardiovascular and cerebrovascular diseases, but the protective effect of PNS on atherosclerosis is not fully understood. This study was designed to test the effects of PNS administration in apolipoprotein (apo)-E-deficient (ApoE-/-) mice on the activation of NF-κB p65, IL-1ß, IL-6, TNF-α and Calpain1 proteins. METHODS: 24 ApoE-/- mice fed with high-fat diet for 8 weeks to create the AS model. PNS, dissolved in three distilled water, was administered orally to two treatment groups at dosages of 60 mg/kg/d/mice and 180 mg/kg/d/mice. After 8 weeks, peripheral blood was collected for assessing the levels of TG, TC, LDL-C and HDL-C in serum by Biochemical Analyzer. HE staining was used to observe pathomorphological changes in the aortic root. Oil Red O staining was used to observe the lipid deposition in the aortic root. ELISA kits were used to assess the levels of IL-1ß and TNF-α in serum. The expression levels of NF-κB p65, IL-1ß, IL-6, TNF-α, and Calpain1 proteins in the aortic root were identified by Western blot. RESULTS: After PNS administration for 8 weeks, the levels of TG, TC, LDL-C, IL-1ß and TNF-α were decreased, the level of HDL-C was increased in apoE-/- mice. The arrangement of the tissue of aortic root tended to be normal, the cell morphology was restored, and the lipid depositions were reduced in apoE-/- mice treated with PNS. Moreover, PNS inhibited the expression levels of NF-κB p65, IL-6, IL-1ß, TNF-α and Calpain1 proteins of aortic root tissues in apoE-/- mice. CONCLUSION: PNS may inhibit the progression of atherosclerotic lesions via their anti-inflammatory biological property. PNS suppress the NF-κB signaling pathway and inhibits the expression of pro-inflammatory factors such as NF-κB p65, IL-6, IL-1ß, TNF-α and Calpain1 proteins in aortic root tissues of apoE-/- mice.

Associations between air pollutants and risk of respiratory infection: patient-based bacterial culture in sputum.

Air pollution is a crucial risk factor for respiratory infection. However, the relationships between air pollution and respiratory infection based on pathogen detection are scarcely explored in the available literature. We detected respiratory infections through patient-based bacterial culture in sputum, obtained hourly data of all six pollutants (PM2.5, PM10, SO2, NO, CO, and O3) from four air quality monitoring stations, and assessed the relationships of air pollutants and respiratory bacterial infection and multi-drug-resistant bacteria. Air pollution remains a challenge for Mianyang, China, especially PM2.5 and PM10, and there are seasonal differences; pollution is the heaviest in winter and the lowest in summer. A total of 4237 pathogenic bacteria were detected, and the positive rate of multi-drug-resistant bacteria was 0.38%. Similar seasonal differences were found with respect to respiratory infection. In a single-pollutant model, all pollutants were significantly associated with respiratory bacterial infection, but only O3 was significantly associated with multi-drug-resistant bacteria. In multi-pollutant models (adjusted for one pollutant), the relationships of air pollutants with respiratory bacterial infection remained significant, while PM2.5, PM10, and O3 were significantly associated with the risk of infection with multi-drug-resistant bacteria. When adjusted for other five pollutants, only O3 was significantly associated with respiratory bacterial infection and the risk of infection with multi-drug-resistant bacteria, showing that O3 is an independent risk factor for respiratory bacterial infection and infection with multi-drug-resistant bacteria. In summary, this study highlights the adverse effects of air pollution on respiratory infection and the risk of infection with multi-drug-resistant bacteria, which may provide a basis for the formulation of environmental policy to prevent respiratory infections.

Evodiamine Inhibits Gastric Cancer Cell Proliferation via PTEN-Mediated EGF/PI3K Signaling Pathway.

AIMS: In this study, the pharmacological effects and potential molecular mechanisms of evodiamine in treating gastric cancer (GC) were investigated. METHODS: GC cells lines of AGS and BGC-823 were treated with evodiamine at various concentrations for different times (24, 48, and 72 h). Inhibition of the proliferation of AGS and BGC-823 cells was assessed using a CCK-8 assay. The morphology of gastric cancer cells was detected by high-content screening (HCS). The apoptosis-inducing effect of evodiamine on AGS and BGC-823 cells was detected by flow cytometric analysis. Cell migration and invasion were detected by Transwell assay. The relative mRNA and protein expression levels of PTEN-mediated EGF/PI3K signaling pathways were investigated via RT-qPCR or western blotting, respectively. RESULTS: Evodiamine substantially inhibited AGS and BGC-823 cells proliferation in a dose- and time-dependent manner. Flow cytometric analysis revealed that evodiamine could induce apoptosis of AGS and BGC-823 cells in a dose-dependent manner. In addition, evodiamine inhibited AGS and BGC-823 cell migration and invasion. Mechanistically, the results demonstrated that evodiamine promoted the relative mRNA and protein expression of PTEN and decreased expression of EGF, EGFR, PI3K, AKT, p-AKT, and mTOR. Most importantly, evodiamine could effectively increase the mRNA and protein expression of PTEN and decrease the protein expression of EGF/PI3K pathway, indicating that evodiamine downregulated EGF/PI3K through the activation of PTEN pathway. CONCLUSION: Evodiamine inhibited the directional migration and invasion of GC cells by inhibiting PTEN-mediated EGF/PI3K signaling pathway. These findings revealed that evodiamine might serve as a potential candidate for the treatment or prevention of GC.

The Relationship between Serum Trace Elements and Oxidative Stress of Patients with Different Types of Cancer.

OBJECTIVE: Many studies have identified causal and promotive roles of oxidative stress (OxS) and oxidative damage caused by OxS in the occurrence and progression of cancer. Many biomarkers in the blood circulation of patients may change correspondingly with the development of tumors. This study is aimed at investigating the correlation between OxS and serum trace element (TE) levels of patients with different types of cancer. METHODS: 1143 different types of cancer patients and 178 healthy controls from Mar. 2018 to Aug. 2020 in Mianyang Central Hospital were involved in this study. Their levels of OxS parameters (including total oxidant status (TOS), total antioxidant status (TAS), and oxidant stress index (OSI)) and the concentrations of serum TEs (including Cu, Zn, Fe, and Se) were determined. RESULTS: Compared with healthy controls, all types of cancer patients had higher TOS level (all P adj < 0.001) and OSI level (z = 6.228 ~ 9.909, all P adj < 0.001) and lower TAS level (all P adj < 0.001). Compared with healthy controls, the changes of four TE levels in serum were different in different types of cancer patients, among which Cu increased in all groups, but there was no statistical difference in gastric and brain cancer; Se decreased in all groups, but there was no statistical difference in gastric, colorectal, esophageal, and other cancer; Zn was significantly decreased in breast cancer patients (P adj < 0.001); there was no statistical difference in the change of Fe in liver, kidney, and other cancer. Spearman correlation showed that the change of Cu concentration was most closely related to the three OxS parameters and was strongly correlated in the observed several types of tumors (r s > 0.6). Multinomial logistic regression showed that the risks of different tumors are related to the level change of multiple TEs and OxS parameters (ORTOS = 1.19 ~ 2.82, OROSI = 2.56 ~ 4.70, ORTAS = 0.20 ~ 0.46, ORCu = 0.73 ~ 1.44, ORZn = 0.81 ~ 0.91, ORFe = 0.68 ~ 1.18, and ORSe = 0.22 ~ 0.45, all P < 0.006). CONCLUSIONS: The OxS exists in the occurrence and development of cancer, which may be related to the changes of certain trace elements. In order to evaluate OxS correctly, it is necessary to detect TAS and TOS and at the same time, their ratio OSI should be detected. Assessment of markers representing the overall level of OxS and TEs may guarantee improved the monitoring of disease occurrence and development risk in cancer patients.

Integrated bioinformatics analysis reveals CDK1 and PLK1 as potential therapeutic targets of lung adenocarcinoma.

ABSTRACT: This study is to identify potential biomarkers and therapeutic targets for lung adenocarcinoma (LUAD).GSE6044 and GSE118370 raw data from the Gene Expression Omnibus database were normalized with Robust Multichip Average. After merging these two datasets, the combat function of sva packages was used to eliminate batch effects. Then, limma packages were used to filtrate differentially expressed genes. We constructed protein-protein interaction relationships using STRING database and hub genes were identified based on connectivity degrees. The cBioportal database was used to explore the alterations of the hub genes. The promoter methylation of cyclin dependent kinase 1 (CDK1) and polo-like Kinase 1 (PLK1) and their association with tumor immune infiltration in patients with LUAD were investigated using DiseaseMeth version 2.0 and TIMER databases. The Cancer Genome Atlas-LUAD dataset was used to perform gene set enrichment analysis.We identified 10 hub genes, which were upregulated in LUAD, among which 8 were successfully verified in the Cancer Genome Atlas and Oncomine databases. Kaplan-Meier analysis indicated that the expressions of CDK1 and PLK1 in LUAD patients were associated with overall survival and disease-free survival. The methylation levels in the promoter regions of these 2 genes in LUAD patients were lower than those in normal lung tissues. Their expressions in LUAD were associated with tumor stages and relative abundance of tumor infiltrating immune cells, such as B cells, CD4+ T cells, and macrophages. Moreover, cell cycle, DNA replication, homologous recombination, mismatch repair, P53 signaling pathway, and small cell lung cancer signaling were significantly enriched in CDK1 and PLK1 high expression phenotype.CDK1 and PLK1 may be used as potential biomarkers and therapeutic targets for LUAD.

HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity.

Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.

Efficient in vivo wound healing using noble metal nanoclusters.

The wound healing process involves multiple steps including hemostasis, inflammation, proliferation, and tissue remodeling. Nanomaterials have been employed externally for healing wounds. However, their use as systemic therapeutics has not been extensively explored. We report the use of ultra-small noble metal nanoclusters (NCs) for the treatment of skin wounds. Both in vitro and in vivo studies indicate NCs have comprehensive therapeutic effects for wound healing, promoting cell proliferation and migration while decreasing inflammation.

Particulate air pollution and respiratory Haemophilus influenzae infection in Mianyang, southwest China.

Particulate air pollution is correlated with many respiratory diseases. However, few studies have focused on the relationship between air particulate exposure and respiratory Heamophilus influenzae infection. Therefore, we detected respiratory Heamophilus influenzae infection by bacterial culture of sputum of patients, and we collected particulate air pollution data (including PM2.5 and PM10) from a national real-time urban air quality platform to analyze the relationship between particulate air pollution and respiratory Heamophilus influenzae infection. The mean concentrations of PM2.5 and PM10 were 37.58 µg/m3 and 58.44 µg/m3, respectively, showing particulate air pollution remains a severe issue in Mianyang. A total of 828 strains of Heamophilus influenzae were detected in sputum by bacterial culture. Multiple correspondence analysis suggested the heaviest particulate air pollution and the highest Heamophilus influenzae infection rates were all in winter, while the lowest particulate air pollution and the lowest Heamophilus influenzae infection rates were all in summer. In a single-pollutant model, each elevation of 10 µg/m3 of PM2.5, PM10, and PM2.5/10 (combined exposure level) increased the risk of respiratory Heamophilus influenzae infection by 34%, 23%, and 29%, respectively. Additionally, in the multiple-pollutant model, only PM2.5 was significantly associated with respiratory Heamophilus influenzae infection (B, 0.46; 95% confidence interval, 0.05-0.87), showing PM2.5 is an independent risk factor for respiratory Heamophilus influenzae infection. In summary, this study highlights air particulate exposure could increase the risk of respiratory Heamophilus influenzae infection, implying that stronger measures need to be taken to protect against respiratory infection induced by particulate air pollution.