Objective To evaluate the palliative effect on pain relief in patients with multiple bone metastases treated with 89SrCl2 together with Sodium Ibandronate,Sodium Ibandronate alone and 89SrCl2 alone. Methods Eighty-four patients with bone pain secondary to bone metastases were divided into three groups. Thirty patients were treated with combined 89SrCl2 and Sodium Ibandronate,26 with 89SrCl2 alone and 28 with Sodium Ibandronate alone. The x2 test was used in data analysis. Results The overall palliative pain relief rate in the combined treatment group was 96.6 % (29/30). For the groups using Sodium Ibandronate or 89SrCl2 only,the palliative rates were 71.4% (20/28) and 73.1% (19/26),respectively. There are statistically significant differences between the combined treatment group and the other 2 groups with single treatment modalities in the overall palliative pain relief rate (x2 = 7.497 ),in terms of improvement in (1) whole body Karnofsky performance status (KPS) score (80.0% (24/30) vs 50.0% (14/28)/53.8% (14/26),x2 =35.476) and (2) focal palliative rate (47.6% (50/105) vs 11.2% (11/98)/22.2% (20/90),x2 =6. 564,all P ＜ 0. 05 ). Conclusions Combined treatment with 89 SrCl2 and Sodium Ibandronate is more effective than single treatment modalities to relieve bone pain seccondary to multiple bone metastases.

Objective To observe the influence of tumor necrosis factor-alpha(TNFα) on skeletal muscle protein catabolism in rats with chronic obstructive pulmonary disease (COPD) and the effects of indomethacin (IND) on it. Methods Duplicated COPD model rats were divided into two groups: the malnutrition group and the normal nutrition group. The malnutrition group were further divided by randomized block design into four groups. Isotonic physiologic saline was administered to group A, the control and the normal nutrition group, and different doses of oral IND were administered to groups B, C, and D weight, concentrations of TNFα, contents of 3-methyl-histidine ( 3- M H ) and tyrosine (Tyr) in the diaphragm and extensor digitorum longus muscle homogenates were measured before and after the intervention. Results Before the intervention, the concentrations of TNFα in the serum of malnutrition groups were all significantly higher than those of normal nutrition group and the control group. After the intervention: (1) The concentrations of TNFα in the serum of the rats of group B, C and D were significantly lower than the group A, especially in group C. The levels of TNFα in serum and body weight of model group rats were negatively correlated ( r = -0. 846, P ＜0. 01 ), as well as the diaphragm and extensor digitorum longus muscle weights ( r = - 0. 778, P ＜ 0. 01; r = - 0. 772, P ＜ 0. 01 ). (2) The levels of 3-methyl-histidine in the diaphragm and extensor digitorum longus muscles of the intervention group C was lower than the COPD normal nutrition group, as well as the intervention groups B and D. The contents of tyrosine in the diaphragm and extensor digitorum longus muscles of the intervention group C was lower than that of the COPD normal nutrition group,as well as the groups B and D. The body weight growth value of the intervention group B were slightly higher than the group A, without significant difference( P ＞ 0. 05 ), while the group C was significantly higher than the group A ( P ＜ 0. 01 ). Conclusions TNFα is involved in the occurrence of COPD malnutrition and skeletal muscle amyotrophy. IND can reduce the TNFα levels in the serum and the catabolic rates of the skeletal muscle proteins in malnutrition rats with COPD, so as to improve partly the skeletal muscle atrophy.

OBJECTIVETo investigate the therapeutic effect of Qingyi Decoction (QYD) and tetrandrine (Tet), used singly or combind, in treating miniature pigs with severe acute pancreatitis (SAP) and its mechanism.

METHODSThirty-two Guizhou miniature pigs were made into SAP model by pancreatic duct retrograde injection of 5% sodium taurocholate. They were randomly divided into 4 groups: the control group, the QYD group, the Tet group and the combined treated group. The serum amylase activity and interleukin-1 and 6 (IL-1, IL-6) contents in serum from vena cava and portal vein were tested by biochemistry and radioimmunoassay (RIA). Serum emodin and plasma Tet levels were measured by high performance liquid chromatography (HPLC) 24, 48 and 72 hrs after treatment. And the pathological changes of pancreas, lung and liver were observed under microscope.

RESULTSThe mortality of SAP pigs was reduced significantly and the inflammatory injury of the organs was ameliorated obviously in all treated groups, and the increased amylase activity and IL-1, IL-6 levels was attenuated. The therapeutic effect was much more obvious, and the plasma Tet level at different time points were much higher in the combined treated group than those in the other two groups treated by single drug (P < 0.01).

CONCLUSIONBoth QYD and Tet could treat effectively SAP through multiple pathways, combination of them reveals an elevation of serum drug concentration and shows a synergistic effect.

Alkaloids ; blood ; pharmacokinetics ; therapeutic use ; Animals ; Benzylisoquinolines ; blood ; pharmacokinetics ; therapeutic use ; Drug Synergism ; Drugs, Chinese Herbal ; pharmacokinetics ; therapeutic use ; Emodin ; blood ; Female ; Interleukin-1 ; blood ; Interleukin-6 ; blood ; Male ; Pancreatitis, Acute Necrotizing ; blood ; drug therapy ; Phytotherapy ; Random Allocation ; Swine, Miniature

Objective: To investigate the effects of tumor necrosis factor-α (TNF-α) monoclonal anti-body on nuclear factor-κB (NF-κB) activation and inducible nitric oxide synthase (iNOS) expression in rats with pulmonary fibrosis induced by silica dust. Methods: A total of 48 male Wistar rats were randomly divided into intervention group, silica dust exposure group, and control group, with 16 rats in each group. The rats in the intervention group were given intratracheal injection of 50 mg silicon dioxide dust once to establish a rat model and then treated with subcutaneously injected TNF-α monoclonal antibody 15 mg/kg for 5 consecutive days at 2-6 days after the establishment of the model. The rats in the silica dust exposure group were treated with the same method to establish the model and then given subcutaneous injection of the same volume of normal saline. The rats in the control group were given intratracheal and subcutaneous injection of normal saline. In both groups, 8 rats each were sacrificed at 7 and 14 days after the establishment of the model. Hematoxylin-eosin staining or Masson staining was used to observe morphological changes in lung tissue, ELISA was used to measure the serum level of TNF-α, IHC was used to measure the expression of NF-κBp65 in lung tissue, Western blot was used to measure the protein expression of I-κB in lung tissue, and RT-qPCR was used to measure the transcriptional level of iNOS mRNA in lung tissue. Results: Compared with the control group, the silica dust exposure group had significant increases in the lung inflammation score (3.375±1.061 and 2.500±0.535) , serum TNF-α level (86.405±20.494 and 77.064±11.829) , absorbance of cells with positive NF-κBp65 in lung tissue (0.297±0.05 and 0.287±0.039) , and mRNA expression of iNOS (12.906±0.590 and 12.600±0.517) at 7 and 14 days after dust exposure, a significant increase in pulmonary fibrosis score at 14 days (3.250±0.707) , and significant reductions in the protein expression of I-κB at 7 and 14 days (0.579±0.141 and 0.748±0.081) (P<0.05) . Compared with the silica dust exposure group, the intervention group had significant reductions in the lung inflammation score at 7 days (2.375±1.061) , pulmonary fibrosis score at 14 days (2.375±1.061) , serum level of TNF-α at 7 and 14 days (66.565±19.850 and 58.734±16.335) , absorbance of cells with positive NF-κBp65 in lung tissue at 7 and 14 days (0.248±0.028 and 0.238±0.027) , and mRNA expression of iNOS at 7 and 14 days (11.656±0.405 and 12.025±0.618) , as well as significant increases in the protein expression of I-κB at 7 and 14 days (0.802±0.165 and 0.888±0.144) (P<0.05) . Conclusion TNF-α monoclonal antibody can inhibit the activation of the NF-κB signaling pathway and down-regulate the expression of iNOS, and thus exerts a certain protective effect on lung tissue in rats with pulmonary fibrosis induced by silica dust.

COVID-19 epidemic continues to spread around the world till these days, and it is urgent to develop more safe and effective new drugs. Due to the limited P3 biosafety laboratories for directly screening inhibitors of virulent viruses with high infectivity, it is necessary to develop rapid and efficient screening methods for viral proteases and other related targets. The main protease (M^pro), which plays a key role in the replication cycle of SARS-CoV-2, is highly conserved and has no homologous proteases in humans, making it an ideal target for drug development. From two different levels, namely, molecular level and cellular level, this paper summarizes the reported screening methods of SARS-CoV-2 M^pro inhibitors through a variety of representative examples, expecting to provide references for further development of SARS-CoV-2 M^pro inhibitors.

As a common protease with high similarity among coronavirus species, the main protease (M^pro) of SARS-CoV-2 is responsible for the catalytic hydrolysis of viral precursor proteins into functional proteins, which is essential for coronavirus replication and is one of the ideal targets for the development of broad-spectrum antiviral drugs. This paper reviews the main protease inhibitors of SARS-CoV-2, including their molecular structures, potencies and drug-like profiles, binding modes and structure-activity relationships, etc.

Uterine leiomyosarcoma is an uncommon malignant neoplasm of smooth muscle origination and is associated with a poor prognosis. We report two cases of uterine leiomyosarcoma that presented with pulmonary metastases. 2-deoxy-2-(¹⁸F)fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) was performed to identify the primary carcinoma and found the focus located in the uterus. The follow-up magnetic resonance imaging (MRI) confirmed the diagnosis was uterine leiomyosarcoma.
Adult ; Female ; Fluorodeoxyglucose F18 ; Humans ; Leiomyosarcoma ; diagnosis ; Magnetic Resonance Imaging ; methods ; Middle Aged ; Positron-Emission Tomography ; methods ; Tomography, X-Ray Computed ; methods ; Uterine Neoplasms ; diagnosis

BACKGROUNDAirway hyperresponsiveness (AHR) is one of the most important characteristics of asthma. This study investigated the parameters, by which assess the airway responsiveness under tidal ventilation.

METHODSFemale BALB/c mice were sensitized and challenged with ovalbumin (OVA) (group A), and part of them were treated with budesonide aerosol (group B). All the mice were anaesthetized and mechanically ventilated. The values of tidal volume (Vt), airway pressure (PA), airway flow (F), expiratory lung resistance (RL) and dynamic compliance of the thorax and lung (CT-L) were recorded by the AniRes2003 animal lung function system. In addition, the expiratory volume in the first 0.1 second after the start of expiration (EV0.1) was obtained according to the flow-volume (F-V) curve. The maximal or minimal values of EV0.1, RL and CT-L were documented after each dose of methacholine (MCH) and compared with values from negative control group (group C).

RESULTS(1) When the dose of MCH reached 100 ng/g or 200 ng/g, the decrease of Vt in group A was much more significant than group C (P = 0.001, < 0.001 respectively), but not so between groups B and group C (P = 0.974, 0.362 respectively). (2) With the dose of 25, 50, 100 or 200 ng/g MCH, the decrease in percentage of EV0.1 in group A was much higher than group C (P = 0.012, 0.025, 0.001, 0.003 respectively), while that in group B showed no significant difference as compared with group C (P = 0.507, 0.896, 0.972, 0.785). (3) RL and CT-L: with the dose of 200 ng/g MCH, there was a statistically significant increase of RL in group A compared to group B or group C (P < 0.001, < 0.001 respectively), but no significant difference between groups B and C (P = 0.266). With doses of 100 ng/g and 200 ng/g MCH, there was a statistically significant decrease of CT-L in group A compared to group B (P = 0.001, = 0.001) and group C (P < 0.001, < 0.001 respectively), but no significant difference between groups B and C (P = 0.775, 0.310). (4) Histopathology: there were eosinophilic predominant peribronchial and perivascular inflammatory influx in murine lungs after OVA sensitizing and challenging, which could be counteracted by inhalation of budesonide in group B.

CONCLUSIONSThe decline in EV0.1 in response to MCH challenge correlated with simultaneous changes in Vt, RL and CT-L, but more sensitively than all the other parameters. The decline in EV0.1 and inflammation in murine lung could be significantly alleviated by inhalation of nebulized budesonide solution, which indicated that EV0.1 to MCH is a valid measure of AHR in mice.

Airway Resistance ; drug effects ; Animals ; Bronchial Hyperreactivity ; drug therapy ; Budesonide ; therapeutic use ; Female ; Lung Compliance ; drug effects ; Methacholine Chloride ; pharmacology ; Mice ; Mice, Inbred BALB C ; Ovalbumin ; immunology

BACKGROUNDNF-kappaB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis in the liver. To understand the mechanism of action of NF-kappaB p65, we investigated the nuclear receptor corepressor in the regulation of PEPCK transcription.

METHODSRat H4IIE cells, human hepatoma HepG2 cells and human embryo kidney (HEK) 293 cells were used in this study. The transcriptional activity of a rat PEPCK gene promoter (-490/+100) was analyzed in HepG2 cells, a HepG2 super suppressor IkBalpha (ssIkBalpha) stable cell line, and HEK 293 cells. The effects of p65 and ssIkBalpha on a rat PEPCK gene promoter were observed using the PEPCK luciferase reporter system. The interaction of the cAMP-response- element-binding (CREB) protein, histone deacetylase 3 (HDAC3) and silencing mediator for retinoic and thyroid hormone receptors (SMRT) with the PEPCK gene promoter were investigated using the chromatin immunoprecipitation (ChIP) assay. p65 cotransfection and RNAi-mediated gene knockdown were used to determine the corepressor involved in the inhibition of PEPCK by NF-kappaB p65 and the transcriptional regulation of CREB by NF-kappaB p65.

RESULTSNF-kappaB p65 inhibited PEPCK expression and the inhibition was blocked by ssIkBalpha. The inhibitory effect of p65 was completely blocked in a HepG2 stable cell line in which ssIkBalpha was expressed. HDAC3 or SMRT knockdown led to a significant up-regulation of PEPCK reporter activity in the presence of p65 cotransfection. In the ChIP assay the interaction of HDAC3 and SMRT with the PEPCK gene promoter was induced by p65 activation, but the CREB signal was reduced. Transcriptional activity of CREB was inhibited by NF-kappaB p65 cotransfection. The inhibitory effect of NF-kappaB p65 was blocked by HDAC3 RNAi or SMRT RNAi.

CONCLUSIONSThe study showed that the inhibition of PEPCK by NF-kappaB p65 was dependent on HDAC3 and SMRT, which form a nuclear corepressor complex for transcriptional inhibition. The transcription factors NF-kappaB p65 and CREB share the same corepressor HDAC3-SMRT, and the corepressor exchange leads to inhibition of PEPCK gene transcription by NF-kappaB p65.

Animals ; Blotting, Western ; Cell Line ; Chromatin Immunoprecipitation ; Cyclic AMP Response Element-Binding Protein ; genetics ; metabolism ; Hep G2 Cells ; Histone Deacetylases ; genetics ; metabolism ; Humans ; NF-kappa B ; genetics ; metabolism ; Nuclear Receptor Co-Repressor 2 ; genetics ; metabolism ; Phosphoenolpyruvate Carboxykinase (ATP) ; genetics ; Promoter Regions, Genetic ; genetics ; Protein Binding ; genetics ; physiology ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor RelA ; genetics ; metabolism

OBJECTIVETo investigate the expression of TGF-beta receptors in CD8+ T cells of oral lichen planus (OLP).

METHODSImmunohistochemical double labeling technique was used to examine the expression of TGF-betaR I and TGF-betaR II in CD8+ T cells of 28 OLP patients and in 10 controls. The results were compared between the two groups.

RESULTSThe double labeled cells were negative in controls. The positive rates of double labeled cells of CD8+/TGF-betaR I and CD8+/TGF-betaR II in OLP were (8.82 +/- 9.98)% and (1.11 +/- 2.94)% respectively.

CONCLUSIONSThe expression level of TGF-betaR II in CD8+ T cells of OLP did not increase compared with the controls, but the expression of TGF-betaR I increased. The results indicate the abnormal TGF-beta signal transduction in CD8+ T cells of OLP, which may contribute to the persistence of the chronic inflammation in OLP.

Adult ; CD8-Positive T-Lymphocytes ; metabolism ; Case-Control Studies ; Female ; Humans ; Lichen Planus, Oral ; metabolism ; pathology ; Male ; Mouth Mucosa ; metabolism ; pathology ; Protein-Serine-Threonine Kinases ; metabolism ; Receptors, Transforming Growth Factor beta ; metabolism ; Signal Transduction