Coagulation Function and Type 2 Diabetic Kidney Disease: A Real-World Observational Study.

Objectives: Type 2 diabetic kidney disease (DKD), a chronic microvascular complication of diabetes, may exhibit a complex interrelation with coagulation function. This study is aimed at elucidating the association between coagulation function and DKD. Methods: This was a real-world observational study conducted in Beijing, involving 2,703 participants. All patients with diabetes were classified into two groups, viz., DKD and non-DKD groups. Effect magnitudes are denoted as odds ratios (OR) with a 95% confidence interval (CI). To mitigate potential bias in group comparisons, we employed propensity score matching (PSM). Results: After adjusting for variables such as age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), triglyceride (TG), c-reactive protein (CRP), platelet (PLT), and serum albumin (sALB), it was discerned that fibrinogen (FIB) (OR, 95% CI, P: 1.565, 1.289-1.901, <0.001) and fibrinogen degradation products (FDP) (1.203, 1.077-1.344, 0.001) were significantly correlated with an increased risk of DKD. To facilitate clinical applications, a nomogram prediction model was established, demonstrating commendable accuracy for DKD prediction. Conclusions: Our findings suggest that elevated levels of FIB and FDP serve as potential risk indicators for DKD, and coagulation function may play an important role in the occurrence and development of DKD.

Association between serum complements and kidney function in patients with diabetic kidney disease.

Objective: We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients. Methods: This is a retrospective study involving 2,441 participants. DKD was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Participants were classified as stages G1-G5 by KDIGO glomerular filtration rate (GFR) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). Results: After balancing age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1C), serum triglyceride (TG), and urinary albumin-to-creatinine ratio (UACR) between the G2-G5 and control groups, per 0.1 g/L increment in serum complement C3 was significantly associated with a 27.8% reduced risk of DKD at G5 stage (OR, 95% CI, P: 0.722, 0.616-0.847, <0.001) relative to the G1 stage. Conversely, per 0.1 g/L increment in serum complement C4 was associated with an 83.0-177.6% increased risk of G2-G5 stage (P<0.001). Serum complement C1q was not statistically significant compared to controls at all stages prior to or after propensity score matching. Conclusions: Our results indicate that high concentrations of serum C4 were associated with the significantly elevated risk of kidney function deterioration across all stages, and reduced serum C3 levels with an increased risk of DKD stage G5.

Association between thyroid hormones and diabetic kidney disease in Chinese adults.

OBJECTIVE: We aimed to explore the association between thyroid hormones and different stages of diabetic kidney disease (DKD) in Chinese adults. METHODS: This is a retrospective study involving 2,832 participants. DKD was diagnosed and classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: After propensity score matching (PSM) on age, gender, hypertension, hemoglobin A1c(HbA1c), total cholesterol (TC), serum triglyceride (TG) and duration of diabetes, per 0.2 pg/mL increment in serum free triiodothyronine (FT3) was significantly associated with 13%, 22% and 37% reduced risk of moderate-risk (OR, 95% CI, P: 0.87, 0.70-0.87, < 0.001), high-risk (0.78, 0.70-0.87, < 0.001) and very-high-risk (0.63, 0.55-0.72, < 0.001) DKD stages relative to the low-risk DKD stage, respectively. After PSM analyses, serum FT4 and TSH showed no statistical significance in risk estimates for all DKD stages. To facilitate clinical application, a nomogram prediction model was established for the moderate-risk, high-risk and very-high-risk DKD stages, with decent accuracy. CONCLUSION: Our results indicate that high concentrations of serum FT3 were associated with the significantly reduced risk of having moderate-risk to very-high-risk DKD stages.

BaoShenTongLuo formula protects against podocyte injury by regulating AMPK-mediated mitochondrial biogenesis in diabetic kidney disease.

BACKGROUND: Mitochondrial dysfunction is considered to be an important contributor in podocyte injury under diabetic conditions. The BaoShenTongLuo (BSTL) formula has been shown to reduce podocyte damage and postpone the progression of diabetic kidney disease (DKD). The potential mechanisms underlying the effects of BSTL, however, have yet to be elucidated. In this study, we aimed to investigate whether the effects of BSTL are related to the regulation of mitochondrial biogenesis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS: High-Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer (HPLC-ESI-MS) analysis was performed to investigate the characteristics of pure compounds in BSTL. db/db mice and mouse podocyte clone-5 (MPC5) cells were exposed to high glucose (HG) to induce DKD and podocyte damage. Body weight, random blood glucose, urinary albumin/creatinine ratio (UACR), indicators of renal function and renal histological lesions were measured. Markers of podocyte injury, mitochondrial morphology, mitochondrial deoxyribonucleic acid (mtDNA) content, mitochondrial respiratory chain complexes activities, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) levels were assessed. Protein expressions of AMPK, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), transcription factor A (TFAM), mitochondrial fusion protein 2 (MFN2) and dynamin-related protein 1 (DRP1) were also detected. MPC5 cells were transfected with AMPKα small interfering RNA (AMPKα siRNA) to determine the underlying mechanisms of BSTL improvement of mitochondrial function under diabetic conditions. RESULTS: In vivo, treatment with BSTL reduced the UACR levels, reversed the histopathological changes in renal tissues, and alleviated the podocyte injury observed in db/db mice. After BSTL treatment, the decreased mtDNA content and mitochondrial respiratory chain complex I, III, and IV activities were significantly improved, and these effects were accompanied by maintenance of the protein expression of p-AMPKαT172, PGC-1α, TFAM and MFN2. The in vitro experiments also showed that BSTL reduced podocyte apoptosis, suppressed excessive cellular ROS production, and reversed the decreased in MMP that were observed under HG conditions. More importantly, the effects of BSTL in enhancing mitochondrial biogenesis and reducing podocyte apoptosis were inhibited in AMPKα siRNA-treated podocytes. CONCLUSION: BSTL plays a crucial role in protecting against podocyte injury by regulating the AMPK-mediated mitochondrial biogenesis in DKD.

Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus. However, the pathological mechanisms contributing to DKD are multifactorial and poorly understood. Diabetes is characterized by metabolic disorders that can bring about a series of changes in energy metabolism. As the most energy-consuming organs secondary only to the heart, the kidneys must maintain energy homeostasis. Aberrations in energy metabolism can lead to cellular dysfunction or even death. Metabolic reprogramming, a shift from mitochondrial oxidative phosphorylation to glycolysis and its side branches, is thought to play a critical role in the development and progression of DKD. This review focuses on the current knowledge about metabolic reprogramming and the role it plays in DKD development. The underlying etiologies, pathological damages in the involved cells, and potential molecular regulators of metabolic alterations are also discussed. Understanding the role of metabolic reprogramming in DKD may provide novel therapeutic approaches to delay its progression to end-stage renal disease.

Efficacy and safety of artesunate for patients with IgA nephropathy: a study protocol for a multicenter, double-blind, randomized, placebo-controlled trial.

BACKGROUND: IgA nephropathy is the most common glomerular disease and is a common cause of progression to end-stage renal disease in patients with kidney diseases. Proteinuria levels are critical for the prognosis of patients with IgA nephropathy, but many patients are still unable to effectively control their proteinuria levels after receiving RAAS blockers. Antimalarial drugs have shown good efficacy in the treatment of kidney disease in previous studies; however, there have been no strictly designed randomized controlled trials to confirm the clinical efficacy of artesunate for treating IgA nephropathy patients. Therefore, we designed this clinical trial to compare the effect of artesunate versus placebo in patients with IgA nephropathy. METHODS: This study is a randomized, double-blind, three-group-parallel, placebo-controlled clinical trial. One hundred and twenty eligible IgA nephropathy patients at risk of progression will be randomly divided into the artesunate 100-mg group, artesunate 50-mg group, and placebo group. Changes in proteinuria and renal function will be measured 6 months after the intervention. The levels of Gd-IgA1 and anti-Gd-IgA1 in the patient's blood will also be tested to explore the possible immune mechanisms. DISCUSSION: Clinical evidence supporting artesunate treatment of IgA nephropathy is currently lacking, and we expect that the results of this trial will provide high-quality clinical evidence for artesunate as a treatment option for IgA nephropathy in the future. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000038104 . Registered on 10 September 2020.

Effect of Tang-Shen-Ning decoction on podocyte epithelial-esenchymal transformation via inhibiting Wnt/ß-catenin pathway in diabetic mice.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). Podocyte epithelial-esenchymal transformation (EMT) induced by the activated Wnt/ß-catenin pathway plays a key role in DN. Tang-Shen-Ning (TSN), a Chinese herbal formula, has been shown to decrease proteinuria and protect the renal function in DN. However, the effect of TSN on the Wnt/ß-catenin pathway and podocyte EMT is unclear. METHODS: TSN was orally administrated in KK-Ay mice for 4 weeks, at a daily dose of 20 g/kg body weight in our in vivo study. Rat serum containing TSN was added in podocyte cultured in high glucose for 24 h. The levels of 24 h urine protein, serum creatinine and blood urea nitrogen were detected by ELISA. Nephrin, Synaptopodin, P-cadherin, desmin, FSP-1, and collagen I protein and mRNA expressions were detected by western blot, immunohistochemistry, immunofluorescence, and RT-PCR. Snail, ß-catenin, and TCF/LEF were detected by Western blot, RT-PCR and luciferase. RESULTS: TSN significantly decreased 24-h urine protein, serum creatinine, and blood urea nitrogen in DN mice. Further, TSN also significantly increased the expression of nephrin, synaptopodin, and P-cadherin, while the expression of desmin, fibroblast-specific protein 1 (FSP-1), and collagen I of podocytes was significantly decreased. Moreover, TSN significantly inhibited the activation of the Wnt/ß-catenin pathway in podocytes cultured under high glucose (HG). Notably, the effect of TSN on podocyte EMT was reversed by activation of the Wnt/ß-catenin pathway. CONCLUSIONS: TSN could protect podocytes from injury in DN, partly via inhibiting the activation of the Wnt/ß-catenin pathway and ameliorating podocyte EMT.

Effects of BSF on Podocyte Apoptosis via Regulating the ROS-Mediated PI3K/AKT Pathway in DN.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The ROS-mediated PI3K/AKT pathway plays a key role in podocyte apoptosis and DN progression. Our previous study demonstrated that Baoshenfang (BSF) can decrease proteinuria and attenuate podocyte injury. However, the effects of BSF on podocyte apoptosis induced by the ROS-mediated PI3K/AKT pathway remain unclear. Herein, in vivo and in vitro studies have been performed. In our in vivo study, BSF significantly decreased 24-h urinary protein, serum creatinine, and blood urea nitrogen levels in DN mice. Meanwhile, BSF significantly inhibited oxidative stress and podocyte apoptosis in our in vivo and in vitro studies. Moreover, BSF significantly decreased the inhibition of the PI3K/AKT pathway induced by HG in DN. More importantly, the effects of BSF on podocyte apoptosis were reversed by PI3K siRNA transfection. In conclusion, BSF can decrease proteinuria and podocyte apoptosis in DN, in part through regulating the ROS-mediated PI3K/AKT pathway.

Effect of Baoshenfang Formula on Podocyte Injury via Inhibiting the NOX-4/ROS/p38 Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious kidney-related complication of type 1 and type 2 diabetes. The Chinese herbal formula Baoshenfang (BSF) shows therapeutic potential in attenuating oxidative stress and apoptosis in podocytes in DN. This study evaluated the effects of BSF on podocyte injury in vivo and in vitro and explored the possible involvement of the nicotinamide adenine dinucleotide phosphate-oxidase-4/reactive oxygen species- (NOX-4/ROS-) activated p38 pathway. In the identified compounds by mass spectrometry, some active constituents of BSF were reported to show antioxidative activity. In addition, we found that BSF significantly decreased 24-hour urinary protein, serum creatinine, and blood urea nitrogen in DN patients. BSF treatment increased the nephrin expression, alleviated oxidative cellular damage, and inhibited Bcl-2 family-associated podocyte apoptosis in high-glucose cultured podocytes and/or in diabetic rats. More importantly, BSF also decreased phospho-p38, while high glucose-mediated apoptosis was blocked by p38 mitogen-activated protein kinase inhibitor in cultured podocytes, indicating that the antiapoptotic effect of BSF is p38 pathway-dependent. High glucose-induced upexpression of NOX-4 was normalized by BSF, and NOX-4 siRNAs inhibited the phosphorylation of p38, suggesting that the activated p38 pathway is at least partially mediated by NOX-4. In conclusion, BSF can decrease proteinuria and protect podocytes from injury in DN, in part through inhibiting the NOX-4/ROS/p38 pathway.

Hypertension as a predictive biomarker in patients with advanced non-small-cell lung cancer treated with apatinib.

BACKGROUND: Hypertension (HTN) is a common adverse event of the vascular endothelial growth factor pathway inhibitor apatinib. This study was conducted to evaluate the association of apatinib-induced HTN with clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: We retrospectively analyzed 110 consecutive patients with advanced NSCLC who were treated with apatinib from August 2014 to January 2018. All patients were classified as normotensive or hypertensive based on blood pressure measurements after initiating therapy. Therapeutic response, progression-free survival (PFS), and overall survival (OS) were evaluated. Univariate and multivariate analyses were performed using the Cox proportional hazards method. RESULTS: A total of 46 patients (42%) were diagnosed with HTN. The median PFS for the hypertensive and normotensive groups were 5.6 months and 4.2 months, respectively (P=0.0027). The median OS times for the hypertensive and normotensive groups were 9.9 months and 7.8 months, respectively (P=0.005). Thirty percent of patients who experienced HTN showed partial response to apatinib as compared with 6.3% of non-hypertensive patients (P=0.002). HTN was independently associated with improved PFS and OS on both univariate and multivariate analyses. CONCLUSION: Apatinib-induced HTN may be an inexpensive, valid, and easily measurable biomarker for apatinib antitumor efficacy in patients with advanced NSCLC.

Apatinib as post second-line therapy in EGFR wild-type and ALK-negative advanced lung adenocarcinoma.

In the absence of a driver mutation, chemotherapy is the standard treatment option as first- and second-line therapy for advanced non-small-cell lung cancer (NSCLC). Though a large number of patients are suitable for post second-line therapies, the quality and quantity of the available drugs in this setting is poor. Apatinib, a small molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, is a first-generation oral antiangiogenesis drug approved in the People's Republic of China for use as a subsequent line of treatment for advanced gastric cancer. Herein, we report three cases of advanced NSCLC with epidermal growth factor receptor wild-type and anaplastic lymphoma kinase-negative status, wherein the patients showed partial response to apatinib. Moreover, the three patients have achieved a progression-free survival of 2.8, 5.8, and 6 months, respectively. The main toxicities were hypertension, proteinuria, and hand-foot syndrome. Apatinib may provide an additional option for the treatment of advanced NSCLC, especially for advanced lung adenocarcinoma without a driver mutation.

[Effect of respiratory syncytial virus-related pulmonary infection on endogenous metabolites in large intestinal mucosa in mice].

OBJECTIVE: To investigate the effect of respiratory syncytial virus (RSV)-related pulmonary infection on endogenous metabolites in large intestinal mucosa in BALB/c mice using metabolomics technology based on gas chromatography-mass spectrometry (GC-MS). METHODS: Mice were randomly divided into a control group and a RSV pneumonia model group (n=16 each). The mouse model of RSV pneumonia was established using intranasal RSV infection (100×TCID50, 50 µL/mouse, once a day). After 7 days of intranasal RSV infection, the mice were sacrificed and GC-MS was used to identify endogenous metabolites and measure the changes in their relative content in colon tissue. SMCA-P12.0 software was used to perform principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) for endogenous metabolites in colon tissue. The differentially expressed metabolites in colon tissue were imported into the metabolic pathway platform Metaboanalyst to analyze related metabolic pathways. RESULTS: PCA and OPLS-DA showed significant differences between the control and RSV pneumonia model groups. A total of 32 metabolites were identified in the colon tissue of the mice with RSV pneumonia. The RSV pneumonia model group had significant increases in the content of leucine, isoleucine, glycine, alanine, arachidonic acid, and lactic acid, which were related to the valine, leucine, isoleucine, arachidonic acid, and pyruvic acid metabolic pathways. CONCLUSIONS: RSV pneumonia might cause metabolic disorders in the large intestinal tissue in mice.

Application of Traditional Chinese Medical Herbs in Prevention and Treatment of Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is a common viral pathogen of the lower respiratory tract, which, in the absence of effective management, causes millions of cases of severe illness per year. Many of these infections develop into fatal pneumonia. In a review of English and Chinese medical literature, recent traditional Chinese medical herb- (TCMH-) based progress in the area of prevention and treatment was identified, and the potential anti-RSV compounds, herbs, and formulas were explored. Traditional Chinese medical herbs have a positive effect on inhibiting viral attachment, inhibiting viral internalization, syncytial formation, alleviation of airway inflammation, and stimulation of interferon secretion and immune system; however, the anti-RSV mechanisms of TCMHs are complicated, which should be further investigated.

[Metabolomics analysis of Tripterygium wilfordii formulation based on theory of detoxicity compatibility].

Tripterygium wilfordii Hook. f. induced-hepatotoxicity was the main limitation for its usage in clinic. Qingluo Tongbi formulation showed obvious attenuation for hepatotoxicity in clinic and fundamental research in vivo. To explore the potential mechanism of the attenuation, we conducted a study on the plasma metabolomic profiles of T. wilfordii and Qingluo Tongbi formulation in rats by a sensitive gas chromatography-mass spectrometry (GC-MS/MS) method. In plasma samples, a total of 72 compounds were analyzed by EI source MS, and were successfully identified by matching NIST database. The semi-quantification results were then calculated by OPLS-DA model with SIMCA-P 13.0 software. The three groups were clearly distinguished in OPLS-DA score plot. In addition, the observation values of Qingluo Tongbi formulation showed the obvious trend towards the control levels, suggesting the detoxicity effect of the formulation. Variation metabolites were further analyzed by VIP and One Way ANOVAs, and the results showed a significant increase in compounds of glycogenic amino acids, such as alanine, proline, serine and glutamine after the administration of T. wilfordii, indicated that the tissue proteins were decomposed and amino acids were leakage into blood. Qingluo Tongbi formulation could reverse the amino acids into normal level. On the contrary, the levels of glucose, lactic acid and hydroxy butyrate decrease, and the formulation can relieve the disorder in the levels of lactic acid, suggesting the regulation of the energy metabolism. Additionally, the level of branched chain amino acid was decreased, suggested the toxicity was induced, but the formulation cannot increase it into the normal levels. Nevertheless, all the above results suggested that the classical Qingluo Tongbi formulation displayed the liver protection effect by adjusting the amino acid levels and regulating the energy metabolism. Qingluo Tongbi formulation was developed based on traditional Chinese medicine theory "detoxicity compatibility", and contained Panax notoginseng (Burk.) F. H. Chen to nourish blood and absorb clots. Modern pharmacology suggested that its liver protection effect was correlated with the promotion of protein synthesis. Another important herb is Rehmannia glutinosa Libosch., which can regulate the energy metabolism. Both were consistent with the metabolomic results in this study, which explained the potential mechanism of "detoxicity compatibility" theory. Therefore, the currently developed metabolomic approach and the obtained results would be highly useful for the comprehensive toxicity studies for other herbal medicines and various complex deoxicity formulations.

Efficacy of Whole-Lung Lavage in Treatment of Pulmonary Alveolar Proteinosis.

The aim of the study was to investigate the therapeutic effect of whole-lung lavage (WLL) for pulmonary alveolar proteinosis (PAP). The cohort studies that investigated the therapeutic effect of WLL for PAP were selected strictly on the basis of the inclusion and exclusion criteria. The statistical analysis was performed using STATA statistical software (version 12.0; Stata Corporation, College Station, TX). Twelve studies were included in this meta-analysis. Totally, 206 PAP patients who received WLL were recruited in the 12 studies. We compared the differences in blood gas analysis and lung function before and after the treatment in this meta-analysis. The results indicated that there were statistical differences in the levels of diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen after the treatment of WLL for patients with PAP, whereas there were no evident differences in the levels of arterial partial pressure of carbon dioxide and arterial oxygen saturation. In conclusion, WLL can evidently improve the diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen of patients with PAP, thus WLL may be an important treatment of PAP.

MMP-9 1562C>T Gene Polymorphism and Efficacy of Glucocorticoid Therapy in Idiopathic Pulmonary Fibrosis Patients.

OBJECTIVE: To investigate the relationship between matrix metalloproteinase 9 (MMP-9) gene polymorphism and the efficacy of glucocorticoid therapy in idiopathic pulmonary fibrosis (IPF) patients. METHODS: We conducted a case-control study. Between January 2013 and September 2014, 115 patients at the Nine Department of Respiratory Medicine, Nanjing Chest Hospital, diagnosed with IPF were enrolled to be the IPF group and 100 healthy subjects were enrolled to be the control group. Prednisone was used to treat IPF patients. Polymerase chain reaction-restriction fragment length polymorphism was used to identify MMP-9 1562C> T polymorphism. The Sandwich enzyme-linked immunosorbent assay was used to measure the serum level of MMP-9 and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the IPF patients before and after the glucocorticoid treatment. RESULTS: The frequencies of the TT genotype and the T allele of MMP-9 1562C> T gene were found significantly higher in the IPF group compared with the control group (both p < 0.05). Serum levels of MMP-9 and TIMP-1 in IPF patients in each of the three genotype groups before glucocorticoid treatment were significantly higher than those in the control group (all p < 0.05). After the glucocorticoid treatment, MMP-9 and TIMP-1 levels decreased significantly compared with the levels before the glucocorticoid treatment in the IPF patients in each genotype group (all p < 0.05), but were still higher than those in the control group (all p < 0.05). The proportion of "remarkable effect" in the IPF patients of the CC genotype group was significantly higher than that in the other two genotype groups, while the rate of adverse reactions of the CC group was significantly lower than the other two groups (all p < 0.05). CONCLUSION: MMP-9 gene 1562C> T polymorphism may affect the efficacy of the glucocorticoid therapy for IPF and may be a predictor of IPF treatment outcome.

Effects of Gancao on pharmacokinetic profiles of platycodin D and deapio-platycodin D in Jiegeng.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiegeng (Radix Platycodi), the dried root of Platycodon grandiflorum A. DC (Campanulaceae), has been used to treat cough, sore throat, bronchitis, and bronchial asthma for thousands of years. It is commonly prescribed with Gancao (Radix et Rhizoma Glycyrrhizae) as a herbal combination in traditional Chinese medicine (TCM) to produce synergistic effects. AIM OF THE STUDY: To elucidate the herbaceous compatibility of Jiegeng and Gancao, we investigated the comparative pharmacokinetics, intestinal absorption, and microbial metabolism of platycodin D (PD) and deapio-platycodin D (DPD), the platycodins contained in Jiegeng. MATERIALS AND METHODS: In the comparative pharmacokinetic study, the concentrations of PD and DPD in Jiegeng extract (JE) and the Jiegeng-Gancao herb pair (JGHP) were determined in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, the main pharmacokinetic parameters were calculated using data analysis software (DAS). Furthermore, in vitro studies using Caco-2 cells and fecal lysates were performed to contradistinguish the intestinal absorption and microbial metabolism of PD and DPD in JE from those in JGHP. RESULTS: The peak concentration (Cmax) and area under the plasma concentration curve (AUC) of PD in rats orally administrated JGHP significantly increased compared to that in rats treated with JE. In addition, the time to reach peak concentration (Tmax) and half-life (t1/2) of PD and DPD in combination with JGHP were all prolonged compared with those of JE. There was no significant difference in the absorption of PD between JE and JGHP in Caco-2 cells. However, the hydrolysis of both PD and DPD in JGHP were weaker than that in JE after a 2-h incubation in fecal lysate which might be responsible for the different pharmacokinetic profiles of the platycodins in JE and JGHP. CONCLUSION: In this study, we discovered that Gancao might influence the pharmacokinetic profiles of PD and DPD in Jiegeng. Furthermore, the difference in profiles may be attributable to the inequable microbial metabolism rather than intestinal absorption of the platycodins in JE and JGHP. The results of this study elucidated the pharmacokinetic compatibility and rationale for the use of JGHP.

Effect of Endostar combined with angiopoietin-2 inhibitor on malignant pleural effusion in mice.

The present study was designed to investigate the synergetic effect of Endostar combined with an angiopoietin-2 specific inhibitor L1-10 on malignant pleural effusion (MPE) mouse model. A MPE mouse model was established by injecting Lewis lung carcinoma (LLC) cells into pleural cavity of C57BL/6 mice. The mice were randomly divided into four treatment groups: saline, Endostar, L1-10, and Endostar + L1-10. In the present study, we reported for the first time that Endostar combined with L1-10 had significant synergistic effects on the formation of MPE and tumor growth. Moreover, Endostar combined with L1-10 had additive effect on the attenuation of pleural inflammation, inhibition of tumor angiogenesis and pleural vascular hyperpermeability, which are central to the inhibition of MPE. Finally, these studies also found that Endostar combined with L1-10 could have complementary actions by reducing VEGF and IL-6 local release and downregulating VEGF expression in pleural tumors, which involved in the pathogenesis of MPE. Therefore, combined therapy with Endostar and L1-10 may be an encouraging strategy for the treatment of MPE.

Influence of curcumin on HOTAIR-mediated migration of human renal cell carcinoma cells.

BACKGROUND: This study investigated the influence of curcumin on HOX transcript antisense RNA (HOTAIR)- mediated migration of cultured renal cell carcinoma (RCC) cells. MATERIALS AND METHODS: Five RCC cell lines (769-P, 769-P-vector, 769-P-HOTAIR, 786-0, and Kert-3 ) were maintained in vitro. The expression of HOTAIR mRNA was determined by quantitative real-time PCR and cell migration was measured by transwell migration assay. The effects of different concentrations of curcumin (0 to 80 µmol/L) on cell proliferation was determined by the CCK-8 assay and influence of non-toxic levels (0 to 10 µM) on the migration of RCC cells was also determined. RESULTS: Comparison of the 5 cell lines indicated a correlation between HOTAIR mRNA expression and cell migration. In particular, the migration of 769-P-HOTAIR cells was significantly higher than that of 769-P-vector cells. Curcumin at 2.5-10 µM had no evident toxicity against RCC cells, but inhibited cell migration in a concentration-dependent manner. CONCLUSIONS: HOTAIR expression is correlated with the migration of RCC cells, and HOTAIR may be involved in the curcumin-induced inhibition of RCC metastasis.

PKM2 regulates hepatocellular carcinoma cell epithelial-mesenchymal transition and migration upon EGFR activation.

Pyruvate kinase isozyme type M2(PKM2) was first found in hepatocellular carcinoma(HCC), and its expression has been thought to correlate with prognosis. A large number of studies have demonstrated that epithelial-mesenchymal transition (EMT) is a crucial event in hepatocellular carcinoma (HCC) and associated metastasis, resulting in enhanced malignancy of HCC. However, the roles of PKM2 in HCC EMT and metastasis remain largely unknown. The present study aimed to determine the effects of PKM2 in EGF-induced HCC EMT and elucidate the molecular mechanisms in vitro. Our results showed that EGF promoted EMT in HCC cell lines as evidenced by altered morphology, expression of EMT-associated markers, and enhanced invasion capacity. Furthermore, the present study also revealed that nuclear translocation of PKM2, which is regulated by ERK pathway, regulated ß-catenin-TCF/LEF-1 transcriptional activity and associated EMT in HCC cell lines. These discoveries provide evidence of novel roles of PKM2 in the progression of HCC and potential therapeutic target for advanced cases.