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.

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.

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.

Bexarotene Improve Depression-Like Behaviour in Mice by Protecting Against Neuro-inflammation and Synaptic Damage.

The growing number of evidences suggest that neuroinflammation and synaptic damage are closely related to the onset of depression. Bexarotene (Bex), a retinoid X receptor agonist, is an U.S. Food and Drug Administration-approved drug for the treatment of cutaneous T-cell lymphoma that has recently been reported to have anti-inflammatory and neuroprotective effects in several models of neurological disease including Parkinson's disease, Alzheimer's disease, and so forth. However, the effect of Bex on depression remains unclear. In this study, we investigated effect of Bex on depression-like behaviour in mice induced by lipopolysaccharide (LPS) or corticosterone (CORT). Our results showed that treatment with Bex for 15 days significantly improved LPS-induced depression-like behaviour in social interaction test and CORT-induced depression-like behaviour in forced swimming test and tail suspension test in mice. We found that the Bex treatment depressed the increase in the number of activated microglia and astrocytes in the frontal cortex, and the increase in the levels of inflammatory cytokines TNF-α, IL-1ß and IL-6 in LPS-injected mice. Furthermore, Bex treatment also rescued the decrease in the expression of BDNF, and inhibition of CREB/BDNF/ERK pathway, and improved the expression of synaptic related protein in CORT-induced mice. Based on these results, it is possible that Bex reversed depression-like behaviour in mice by reducing neuroinflammation and protecting against synaptic damage induced by LPS or CORT.

(3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one enhanced the therapeutic efficacy of anti-PD1 antibody through inhibiting PI3Kδ/γ.

Purpose: Immunotherapy has demonstrated durable clinical responses in various cancers by disinhibiting the immune system, largely attributed to the success of immune-checkpoint blockade. However, there are still subsets of patients across multiple cancers not showing robust responses to these agents and one significant barrier to their efficacy may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. In this study, we demonstrated that functional inhibition of MDSCs with (3 R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIMO), a potent PI3Kδ/γ inhibitor, enhanced the therapeutic efficacy of anti-PD1 antibody in the tumor model.Materials and methods: A syngeneic ovarian tumor model was established. MDSCs from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. Proliferation and killing effects of T-lymphocytes were measured. IFNγ production was measured by ELISA assay. qPCR and western blot were used to detect the gene and protein expression. Furthermore, the therapeutic effects of TIMO combined with anti-PD1 antibody were assessed by the tumor model.Results: Our data demonstrated that inhibition of granulocytic myeloid-derived suppressor cells (G-MDSCs) function with TIMO could overcome MDSCs-mediated immunosuppression and promote antigen-specific T-lymphocyte responses, resulting in the restoration of cytotoxic T cell-mediated tumor control. We further demonstrated that TIMO and anti-PD1 combination therapy promoted tumor growth control in a syngeneic ovarian tumor model.Conclusions: Our results provided proof of concept for a new combination strategy involving the use of a selective inhibitor of PI3Kδ/γ to inhibit the function of MDSCs to enhance tumor responses to immune checkpoint blocking antibodies.

Comparison of Volatile Oil between the Fruits of Amomum villosum Lour. and Amomum villosum Lour. var. xanthioides T. L. Wu et Senjen Based on GC-MS and Chemometric Techniques.

Fructus Amomi (FA) is usually regarded as the dried ripe fruit of Amomum villosum Lour. (FAL) or Amomum villosum Lour. var. xanthioides T. L. Wu et Senjen (FALX.). However, FAL, which always has a much higher price because of its better quality, is often confused with FALX. in the market. As volatile oil is the main constituent of FA, a strategy combining gas chromatography-mass spectrometry (GC-MS) and chemometric approaches was applied to compare the chemical composition of FAL and FALX. The results showed that the oil yield of FAL was significantly higher than that of FALX. Total ion chromatography (TIC) showed that cis-nerolidol existed only in FALX. Bornyl acetate and camphor can be considered the most important volatile components in FAL and FALX., respectively. Moreover, hierarchical cluster analysis (HCA) and principal component analysis (PCA) successfully distinguished the chemical constituents of the volatile oils in FAL and FALX. Additionally, bornyl acetate, α-cadinol, linalool, ß-myrcene, camphor, d-limonene, terpinolene and borneol were selected as the potential markers for discriminating FAL and FALX. by partial least squares discrimination analysis (PLS-DA). In conclusion, this present study has developed a scientific approach to separate FAL and FALX. based on volatile oils, by GC-MS combined with chemometric techniques.

mTORC2 facilitates endothelial cell senescence by suppressing Nrf2 expression via the Akt/GSK-3ß/C/EBPα signaling pathway.

Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated ß-galactosidase (ß-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3ß/C/EBPα signaling pathway. These results suggest that the mTORC2/Akt/GSK-3ß/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.

Total Oxidant/Antioxidant Status in Sera of Patients with Esophageal Cancer.

BACKGROUND Oxidative stress parameters such as total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) have been studied in breast, thyroid, and simple esophageal cancers (EC). We evaluated these parameters in patients with EC and analyzed their correlations with treatment outcomes. MATERIAL AND METHODS Serum TOS, TAS, and OSI in 92 patients with EC at different clinical stages and in 64 healthy people (controls) were measured. RESULTS Serum TOS, TAS, and OSI were significantly different between patients with EC and healthy controls (all p<0.001); however, there were no significant differences across different clinical stages (all p>0.05). These factors are not correlated with smoking or drinking history (all p>0.05). Patients with EC with higher TOS and OSI and lower TAS had better responses to chemotherapy and/or radiotherapy, but there was no significant correlation with different responses (all p>0.05). In a receiver operating characteristic curve analysis comparing patients with EC with healthy controls, the Youden indices were 0.391, 0.886, and 1, respectively. CONCLUSIONS Serum TOS, TAS, and OSI were significantly different between patients with EC and healthy controls. In patients with EC, these factors were not correlated with smoking or drinking history or with clinical stage. Patients with EC with higher TOS and OSI and lower TAS had a trend towards better outcomes but it did not reach significance. Serum TOS and OSI are potential diagnostic biomarkers that can be used to identify cases of EC.

[Biological assay in quality control of animal medicines].

Animal medicine is a unique part of traditional Chinese medicine. They have strong effects, but their effective compounds are not entirely known. The efficiency and safety of animal medicines can't be effectively controlled by current quality assurance system and evaluation method, which has deeply influenced the development of animal medicines. Biological assay does not focus on efficacy of single component, but directly reflects the pharmacodynamics and safety of animal medicines by biological effect. With the development of biotechnology, many new technologies have emerged, such as biochip and high content analysis. Based on the related targets, pathways and key biochemical factors, the field of biological assay has been expanded. With advantages of pharmacology andoverall controllability, as well as the characteristics of in line with the quality control of Chinese Medicine, biological assay will become one of the important development directionsfor quality standardization of animal medicines.

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.

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 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.

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.

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.

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.

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.

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.