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.

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.

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.

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

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

To investigate the chemical constituents of the roots of Aconitum taipaicum, silica gel column chromatography was used for the isolation and purification of compounds. A new norditerpenoid alkaloid, isodelelatine (1), along with five known alkaloids, atisine (2), delfissinol (3), liangshanine (4), hypaconitine (5) and delelatine (6) were isolated and identified. The structure of the new compound was elucidated on the basis of spectral data.
Aconitine ; analogs & derivatives ; chemistry ; isolation & purification ; Aconitum ; chemistry ; Alkaloids ; chemistry ; Diterpenes ; chemistry ; Molecular Structure ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry

OBJECTIVETo investigate the effects of repeated injections of L-NMMA on a goat model with osteoarthrotic temporomandibular joint (TMJ) disease.

METHODSEight goats were selected in this study. Bilateral TMJ osteoarthrosis (OA) was induced by injecting 0.5% collagenase. L-NMMA was injected into one side of TMJs at 4 weeks after collagenase injection (one time every three days). Another joint as control was simultaneously injected using 0.9% saline solution. All goats were killed at 12 weeks after collagenase injection. The TMJ specimens were harvested and processed for histological examination. Modified Mankin's grading score system was used for evaluating changes in the TMJ.

RESULTSThe control side of TMJs showed severe osteoarhrotic changes in the condyle whereas the L-NMMA-treated TMJs showed less degenerative alterations. The histologic score was 3.83 in the L-NMMA treated side, and 6.33 in the control. There was a significant difference in osteoarthrotic changes between the L-NMMA-treated and control TMJs (P < 0.01).

CONCLUSIONSRepeated intra-articular injection of L-NMMA into TMJ may play a role in inhibiting TMJOA progression.

Animals ; Enzyme Inhibitors ; administration & dosage ; therapeutic use ; Female ; Goats ; Injections, Intra-Articular ; Male ; Osteoarthritis ; drug therapy ; Temporomandibular Joint Disorders ; drug therapy ; omega-N-Methylarginine ; administration & dosage ; therapeutic use