Osteoporosis can be induced by various factors including prolonged glucocorticoid usage, diminished estrogen levels, secondary hyperparathyroidism, and alterations in the microenvironment of bone tissue. The bone metabolism imbalance(osteogenic-lipogenic imbalance) plays a crucial role in the development of osteoporosis. This imbalance is primarily driven by an increase in the differentiation of bone marrow mesenchymal stem cells into adipocytes and a decrease in their differentiation into osteoblasts, thus forming the core of the osteogenic-lipogenic imbalance observed in osteoporosis. The bone morphogenesis protein(BMP) plays a crucial role in the regulation of the osteogenic-lipid balance in osteoporosis. This regulatory function is accomplished through both the Smad-dependent and Smad-independent pathways. This review centers on the Smad-dependent and Smad-independent pathways facilitated by BMP, offering a comprehensive overview of the potential mechanisms through which BMP-2, 4, 6, 7, and 9 contribute to the regulation of osteogenesis and lipid metabolism in osteoporosis via these pathways. In order to present novel insights for the identification of efficacious targets for clinical anti-osteoporosis medications.

Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identified.Thus,it is extremely warranted to explore more effective and better-tolerated β2-AR blocker.Currently,we demonstrated that baicalin(BA),a major bioactive component of Scutellaria bai-calensis Georgi,could significantly attenuate stress hormones especially epinephrine(Epi)-induced breast cancer cell migration and invasion in vitro.Mechanistically,we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability(DARTS)combined with mass spectrum assay,and BA photoaffinity probe with pull-down assay,which was further confirmed by a couple of bio-physical and biochemical assays.Furthermore,we demonstrated that BA could directly bind to the Phe-193 and Phe-289 of β2-AR,subsequently inhibit cyclic adenosine monophosphate-protein kinase A-focal adhesion kinase(cAMP-PKA-FAK)pathway,and thus impede epithelial-mesenchymal transition(EMT),thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model.These findings firstly identify BA as a potential β2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.

Objective:To explore the value of amide proton transfer-weighted (APTw) imaging and intravoxel incoherent motion (IVIM) imaging for diagnosing and evaluating the pathological differentiation of cervix squamous cell carcinoma (CSCC).Methods:This study was a diagnostic trial. Totally 56 patients pathologically diagnosed with CSCC at the First Hospital of Lanzhou University from October 2021 to October 2022 were retrospectively collected, as the CSCC group. And 36 female healthy volunteers who underwent physical examinations at the First Hospital of Lanzhou University from October 2021 to October 2023 were recruited as the control group. CSCC patients were divided into well-moderately differentiated ( n=34) and poorly differentiated groups ( n=22). The region of interest was placed in the lesions of CSCC group and normal cervical stroma of control group, and the quantitative parameters for asymmetric magnetization transfer ratio (MTR asym) of APTw imaging and pure diffusion coefficient (D), false diffusion coefficient (D *) and perfusion fraction (f) for IVIM were obtained. The independent sample t test was used to compare the differences in quantitative parameters between the two groups, the logistic regression model was used to establish combined parameters for the quantitative parameters with statistical significance between the two groups. The receiver operator characteristic curve was used to evaluate the diagnostic efficacy of single quantitative parameters and combined parameters to distinguish the CSCC group from the control group, and the well-moderately differentiated group from the poorly differentiated group in CSCC patients. The area under the curve (AUC) was compared using the DeLong test. Results:There were significant differences in MTR asym, D and f between CSCC group and control group ( t=-9.79, 10.09, 11.35, P<0.001). Also, significant differences were found for MTR asym and D between the well-moderately differentiated and poorly differentiated group ( t=4.11, -3.76, P<0.001). There was no significant difference in other quantitative parameters ( P>0.05). When comparing the CSCC group and control group, the AUC (95% CI) of MTR asym, D, f and combined parameter (MTR asym+D+f) were 0.887 (0.804-0.944), 0.940 (0.871-0.979), 0.968 (0.909-0.993), 0.995 (0.950-1.000). The AUC of the combined parameter was higher than those of MTR asym and D, with statistical significance ( Z=3.07, 2.06, P=0.002, 0.040). When comparing the well-moderately differentiated and poorly differentiated group, the AUC (95% CI) of MTR asym, D, and combined parameter (MTR asym+D) were 0.789 (0.660-0.887), 0.775 (0.644-0.876), 0.852 (0.731-0.932). There was no significant difference between each two AUCs ( P>0.05). Conclusion:The quantitative parameters of APTw and IVIM imaging can be used to diagnose and preliminarily evaluate the pathological differentiation of CSCC. Joint parameters can improve the diagnostic efficiency of CSCC.

Objective:To observe the effects of four prostaglandin E2 (PGE2) receptors (EP 1-4R) on the activation of inflammasomes and cell damage in human retinal microvascular endothelial cells (hRMEC) in a high glucose environment. Methods:The hRMEC were divided into normal group and high glucose group, and they were cultured in Dulbecco modified Eagle medium containing 5.5 and 30.0 mmol/L glucose, respectively. Flow cytometry was used to observe the apoptosis rate of the high glucose group and the normal group; enzyme chain immunosorbent assay (ELISA) was used to detect the level of PGE2 in the culture supernatant of hRMEC cells. Western blot was used to detect the protein expression of cyclooxyganese (COX2) and EP 1-4R in hRMEC. Real-time fluorescent quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of EP 1-4R mRNA in hRMEC. After 72 h of culture, the cells in the high glucose group were divided into control group, PGE2 group, EP 1-4R agonist group, PGE2+EP 1-4R inhibitor group, and dimethylsulfoxide group. According to the group, each group was given the corresponding agonist or inhibitor to continue the culture for 24 h. QRT-PCR was used to detect the expression of nucleotide-binding oligomerization structure-like receptor protein (NLRP3) and pro-interleukin (IL)-1β mRNA in each group of cells. ELISA was used to detect the content of IL-1β and lactic dehydrogenase (LDH) in the cell culture supernatant. Western blot was used to detect the expression of cleaved Caspase-1 in each group of cells. At the same time, hRMEC in a high glucose environment was given IL-1β stimulation for 24 h, and the activity of LDH in the supernatant of the cell culture medium was detected. Results:The apoptotic rate, COX2 protein expression, and PGE2 protein content in hRMEC in the high glucose group were significantly higher than those in the normal group, and they were time-dependent. Compared with the normal group, the expression levels of EP 1R, EP 2R, EP 4R protein and mRNA in hRMEC in the high glucose group were higher than those in the normal group ( P<0.05). Compared with the control group, PGE2 group ( t=4.627, P<0.01), EP 1-4R agonist group ( t=3.889, 3.583, 2.445, 3.216; P<0.05) hRMEC NLRP3 mRNA expression level was significantly increased; the expression level of pro-IL-1β mRNA increased, however the difference was not statistically significant (PGE2 group: t=1.807, P>0.05; EP 1-4R agonist group: t=1.807, 1.477, 0.302, 1.926, P>0.05). Compared with the PGE2 group, the expression of NLRP3 mRNA in hRMEC in the PGE2+EP 2R inhibitor group was significantly reduced ( t=2.812, P<0.05); the expression of pro-IL-1β mRNA in hRMEC in the PGE2+EP 3R inhibitor group was significantly increased ( t=4.113, P<0.01). The protein content of IL-1β in the cell culture supernatant of the PGE2 group, EP 1R agonist group and EP 2R agonist group was significantly higher than that of the control group ( t=5.155, 4.136, 4.817; P<0.01). Compared with PGE2 group, the protein content of IL-1β in the cell culture supernatant of the PGE2+EP 2R inhibitor group and the PGE2+EP 4R inhibitor group were significantly lower than that of the PGE2 group ( t=1.964, 4.765; P<0.05). The expression of cleaved Caspase-1 in hRMEC in the PGE2 group and EP 2R agonist group was significantly higher than that in the control group ( t=5.332, 4.889; P<0.05). The expression of cleaved Caspase-1 in hRMEC in the PGE2+EP 2R inhibitor group was significantly lower than that of the PGE2 group ( t=6.699, P<0.01). The LDH activity in the cell culture supernatant of the PGE2 group and the EP 2R agonist group was significantly higher than that of the control group ( t=4.908, 4.225; P<0.05). The activity of LDH in the cell culture supernatant of the PGE2+EP 2R inhibitor group was significantly lower than that of the PGE2 group ( t=5.301, P<0.01). Compared with the control group, the LDH activity in the culture supernatant of hRMEC cells in the high glucose environment was significantly increased ( t=3.499, P<0.05). Conclusions:The four receptors of PGE2 can activate NLRP3 and its effector molecules to varying degrees. EP 2R mainly mediates hRMEC damage under high glucose environment.

Objective To compare the effects of dobutamine with those milrinone on myocardial strain in patients undergoing valve replacement surgery.Methods Fifty-five patients udergoing valve replacement surgery, 27 males and 28 females, aged 40-75 years, falling into ASA physical statusⅡ orⅢ, New York Heart Association (NYHA) ⅡorⅢ, were included in this study.They were divided into 3 groups by using a random number table:intravenous infusion dobutamine group (group D, n=18), intravenous infusion milrinone group (group M, n=20) and intravenous infusion saline group (group C, n=17).All patients were used general anesthesia.In groups D, the patients received intravenous infusion dobutamine (4μg·kg-1·min-1) for an hour starting from 15 min after termination of CPB.In group M, the patients did intravenous infusion milrinone (0.4μg·kg-1·min-1) in the same way.In group C, the patients got intravenous infusion saline also.After induction of anesthesia, these patients were recorded for hemodynamic measurement at three points after induction of anesthesia and before splitting of sternum (T0), starting from 15 min after termination of CPB (T1), intravenous infusion medicine for 30 min (T2), intravenous infusion medicine for one hour (T3):HR, CVP, cardiac output (CO), left ventricular ejection fraction (LVEF), right ventricular fractional area change (RVFAC), cardiac index (CI) and systemic vascular resistance index (SVRI) and strained indicator:global longitudinal strain of left ventricle (S-LVL), global circumferential strain of the left ventricle (S-LVM), global longitudinal strain of right ventricle (S-RV).Results Compared with group M, HR in group D at T2 and T3 was higher (P<0.05).Compared with group C, HR in group D at T3 was higher (P<0.05).And CI in group D at T2 was higher than that in groups C and M (P<0.05).Compared with groups C, S-LVMin groups D and M at T2 and T3 were stronger, S-LVL, S-RV in group D and S-RV in group M at T3 were stronger (P<0.05).Conclusion Intravenous infusion dobutamine can improve S-LVM, S-LVLand S-RV;Intravenous infusion milrinone can improve S-LVMand S-RV.

Objective To observe the changes of short-chain acyl-CoA dehydrogenase (SCAD) expression on human umbilical vein endothelial cell (HUVEC) apoptosis and investigate its relationship with apoptosis. Methods The HUVEC was cultured normally for 2-3 days. The apoptotic model of HUVEC was established by tert-butyl hydrogen peroxide (tBHP). The HUVEC was treated by different concentrations of tBHP (0, 10, 20, 30, 40, 50 μmol/L) for 12 hours and different time (0, 3, 6, 9, 12 hours) with 50 μmol/L tBHP to establish the apoptotic model of HUVEC. The cell viability was detected by methyl thiazolyl tetrazolium (MTT), the mRNA expression of SCAD was determined by real-time polymerase chain reaction (PCR), the protein expression of SCAD was achieved by Western Blot. The best concentrate and time were determined to interfere the HUVEC to achieve the apoptotic model of HUVEC. The SCAD gene of HUVEC was knocked down by RNA interference sequence (siRNA274, siRNA414, siRNA679). The mRNA expression of SCAD, the protein expression of SCAD and the activity of SCAD enzyme were detected to achieve the best RNA interference sequence. The HUVEC was intervened by the best RNA interference sequence and tBHP. The cell activity and apoptosis rate, the enzyme activity of SCAD, the mRNA and protein expression of SCAD, the contents of reactive oxygen species (ROS), aderosine triphosphate (ATP) and free fatty acid (FFA) were detected to observe the effect of SCAD on apoptosis of HUVEC. Results ① The cell viability, the mRNA expression and the protein expression of SCAD were decreased gradually in a concentration and time dependent manner with the increase of tBHP concentration and the prolongation of intervention time. The decline was most significant in the group of the 50 μmol/L tBHP to interfere HUVEC for 12 hours. ② The siRNA679 transfection was the most significant in reducing SCAD mRNA and protein expressions among the three interference sequences (siRNA274, siRNA414, siRNA679). ③ Compare with blank control group, the cell viability was significantly decreased in the siRNA679 group (A value: 0.48±0.09 vs. 1.00±0.09, P < 0.01), the apoptotic rate of HUVEC was significantly increased [(29.96±2.09)% vs. (2.90±1.90)%, P < 0.01], the expression of SCAD mRNA and SCAD protein, the activity of SCAD enzyme and the content of ATP were significantly decreased [SCAD mRNA (2-ΔΔCt): 0.50±0.16 vs. 1.34±0.12, SCAD/α-Tubulin: 0.67±0.11 vs. 1.00±0.06, the activity of SCAD enzyme (kU/g): 0.38±0.04 vs. 0.53±0.04, the content of ATP (μmol/g): 0.14±0.02 vs. 0.19±0.01, all P < 0.05], the contents of FFA and ROS were significantly increased [FFA (nmol/g): 0.84±0.07 vs. 0.47±0.04, ROS (average fluorescence intensity): 647.5±23.7 vs. 434.2±46.5, both P < 0.01]. Meanwhile, SCAD siRNA treatment triggered the same apoptosis as HUVEC treated with tBHP. Conclusions Down-regulation of SCAD may play an important role in HUVEC apoptosis. Increase in the expression of SCAD may become an important part in intervening HUVEC apoptosis.

The purpose of the present work is to establish an ultra-minimal invasive percutaneous puncture inoculation method for a VX2 orthotopic lung cancer rabbit model with fewer technical difficulties, lower mortality of rabbits, a higher success rate and a shorter operation time, to evaluate the growth, metastasis and apoptosis of tumor by CT scans, necropsy, histological examination, flow cytometry and immunohistochemistry. The average inoculation time was 10–15 min per rabbit. The tumor-bearing rate was 100%. More than 90% of the tumor-bearing rabbits showed local solitary tumor with 2–10 mm diameters after two weeks post-inoculation, and the rate of chest seeding was only 8.3% (2/24). The tumors diameters increased to 4–16 mm, and irregularly short thorns were observed 3 weeks after inoculation. Five weeks post-inoculation, the liquefaction necrosis and a cavity developed, and the size of tumor grew further. Before natural death, the CT images showed that the tumors spread to the chest. The flow cytometry and immunohistochemistry indicated that there was less apoptosis in VX2 orthotopic lung cancer rabbit model compared to chemotherapy drug treatment group. Minimal invasive percutaneous puncture inoculation is an easy, fast and accurate method to establish the VX2 orthotopic lung cancer rabbit model, an ideal in situ tumor model similar to human malignant tumor growth.
Apoptosis ; Drug Therapy ; Flow Cytometry ; Humans ; Immunohistochemistry ; Lung Neoplasms* ; Lung* ; Methods* ; Mortality ; Necrosis ; Neoplasm Metastasis ; Punctures* ; Rabbits ; Thorax ; Tomography, X-Ray Computed

Objective To investigate the effects of intravenous infusion of methoxamine and phenylephrine on blood pressure and coronary artery blood flow in elderly patients with post volume treatment hypotension after cardiopulmonary bypass (CPB ) undergoing coronary artery bypass grafting (CABG).Methods Forty patients,physical status ASA Ⅱ or Ⅲ,>65 years old,undergo-ing CABG,following CPB,with a mean arterial pressure (MAP)<70% of baseline,despite adequate volume replacement (based on achieving a normal CVP),were randomly assigned to me-thoxamine group (group M,n=20)or phenylephrine group (group P,n=20).The initial infusion rate was 3 μg·kg-1·min-1in group M and 0.24 μg·kg-1·min-1in group P,respectively.The rate was increased or decreased by one third of initial dose in order to maintain the MAP at the target level (±20% of baseline MAP).Coronary sinus (CS),systolic blood flow velocity time integral (SV-TI),diastolic velocity time integral (DVTI),CS blood flow (CSBF)were recorded before adminis-tration,at 3,5,10,15,30 min after administration.Results Compared with pre-administration,SV-TI,DVTI,CSBF were increased at each point in the two groups (P<0.05 or P<0.01).SVI was in-creased at 15 min and 30 min in group M (P<0.05).Compared with group P,DVTI and CSBF at 10,15 min and 30 min was higher in group M (P<0.05 or P<0.01).There were 2 cases of atrial fibrillation and 1 case of frequent ventricular premature beat after operation in group M;1 case of bradycardia and 1 case of frequent ventricular premature beats after operation in group P.Conclusion Intravenous infusion of methox-amine and phenylephrine both can correct post volume treatment hypotension after CPB in elderly patients undergoing CABG,but methoxamine increases coronary blood flow more significantly and may be more ben-eficial to patients with coronary heart disease.

Objective To evaluate the effect of dobutamine or milrinone on intraventricular syn-chronization in the patients undergoing cardiac valve replacement with cardiopulmonary bypass ( CPB). Methods Sixty American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients of both sexes, aged 40-75 yr, of New York Heart AssociationⅡorⅢ, scheduled for elective cardiac valve replacement with CPB, were divided into 3 groups (n＝20 each) using a random number table: control group ( group C), dobutamine group ( group D) and milrinone group ( group M). Dobutamine 4 μg·kg-1·min-1was intravenously infused for 60 min starting from 15 min after termination of CPB in group D. Milrinone 0. 4 μg·kg-1·min-1was intravenously infused for 60 min starting from 15 min after termination of CPB in group M. The equal volume of normal saline was given instead in group C. The parameters of heart function were monitored using transesophageal echocardiography. After induction of anesthesia and before splitting the sternum (T0), at 15 min after termination of CPB (T1), and at 30 and 60 min of dobutamine, milri-none or normal saline infusion (T2, average value at two time points), the parameters of intraventricular synchronization were calculated with QLAB software (9. 1 version): standard deviation of time to peak sys-tolic velocity of the left ventricular longitudinal strain 7 segments (LVSDt-L), standard deviation of time to peak systolic velocity of the right ventricular longitudinal strain 7 segments (RVSDt), standard deviation of time to peak systolic velocity of the left ventricular circumferential strain 6 segments (LVSDt-C). Results Compared with group C, LVSDt-C, LVSDt-L and RVSDt were significantly decreased at T2in group D (P＜0. 05), and no significant change was found in the indices mentioned above at each time point in group M (P＞0. 05). RVSDt was significantly higher at T2in group M than in group D ( P＜0. 05). Compared with the baseline at T0, LVSDt-L was significantly increased at T2in group C, and RVSDt was significantly in-creased at T2in group M ( P＜0. 05). Conclusion Intravenously infusing dobutamine after CPB can im-prove the ventricular synchronization, however, intravenously infusing milrinone may increase the right ventricular asynchronization in the patients undergoing cardiac valve replacement.

The elaboration of the mechanism and pharmacodynamic substance are the main obstacles to the modernization of Chinese medicine.The rich ingredient of Chinese medicine is almost attention,with a research strategy of forward pharmacology.This strategy often neglects the study of trace components of Chinese medicine.Synthetic lethality,a extremely complex gene interactions,is to magnify the effects of the co-regulation of biological effects (＞ 1 000 times).The theory of synthetic lethality has achieved good results in the development of anti-tumor drugs,including the discovery of PARP inhibitors,the clinical use of chemotherapy drug addition and attenuation combination.In view of this,this research model may be used to elucidate trace effective substance.Based on the reverse thinking of "targetcomponent-effect"and clear synergistic targets,the mechanism of traces and weak-potency substance of traditional Chinese medicine was studied,and the synergistic combination of potential was found.