Aim To investigate the mechanism of Guanxinning injection regulating cardiac immune mi-croenvironment to improve myocardial infarction in mice.Methods In this study,MI model was estab-lished by permanent ligation of left anterior descending coronary artery in mice.The mice were divided into five groups:sham operation group,model group,Guanxinning injection low dose group,Guanxinning in-jection high dose group and positive drug captopril group.Hearts were weighed,heart tissues were collect-ed,and Masson staining was used for pathological anal-ysis of heart tissues;immunofluorescence staining was used to detect apoptosis and CCL21 expression in the infarct border zone;flow cytometry was used to detect the proportion of immune cells in myocardial ischemia tissues and lymph nodes;PCR was used to detect CCL21 expression in heart and in vitro human lymphat-ic endothelial cells(HLEC).Results Compared with the model group,the low and high dose groups of Guanxinning injection significantly improved cardiac hypertrophy.Apoptosis in the border zone of myocardi-al infarction was reduced in the low and high dose groups of Guanxinning injection and captopril group.Compared with the model group,the proportion of leu-kocytes in the infarct border zone was dreduced and the proportion of CD4+T cells,Treg cells,and CD8+T cells in the mediastinal lymph nodes and infarct border zone of the heart was regulated in the low and high dose groups of Guanxinning injection;CCL21 secretion by the heart and lymphatic vessels increased.Conclu-sions Guanxinning injection can significantly improve cardiac hypertrophy and fibrosis in MI mice,reduce ap-optosis in the infarct border zone,and play a role in an-ti-myocardial ischemia injury by promoting CCL21 ex-pression in lymphatic vessels to regulate the proportion of mediastinal lymph nodes and cardiac T cells after myocardial infarction.

Aim To investigate the mechanism of Guanxinning injection regulating cardiac immune mi-croenvironment to improve myocardial infarction in mice.Methods In this study,MI model was estab-lished by permanent ligation of left anterior descending coronary artery in mice.The mice were divided into five groups:sham operation group,model group,Guanxinning injection low dose group,Guanxinning in-jection high dose group and positive drug captopril group.Hearts were weighed,heart tissues were collect-ed,and Masson staining was used for pathological anal-ysis of heart tissues;immunofluorescence staining was used to detect apoptosis and CCL21 expression in the infarct border zone;flow cytometry was used to detect the proportion of immune cells in myocardial ischemia tissues and lymph nodes;PCR was used to detect CCL21 expression in heart and in vitro human lymphat-ic endothelial cells(HLEC).Results Compared with the model group,the low and high dose groups of Guanxinning injection significantly improved cardiac hypertrophy.Apoptosis in the border zone of myocardi-al infarction was reduced in the low and high dose groups of Guanxinning injection and captopril group.Compared with the model group,the proportion of leu-kocytes in the infarct border zone was dreduced and the proportion of CD4+T cells,Treg cells,and CD8+T cells in the mediastinal lymph nodes and infarct border zone of the heart was regulated in the low and high dose groups of Guanxinning injection;CCL21 secretion by the heart and lymphatic vessels increased.Conclu-sions Guanxinning injection can significantly improve cardiac hypertrophy and fibrosis in MI mice,reduce ap-optosis in the infarct border zone,and play a role in an-ti-myocardial ischemia injury by promoting CCL21 ex-pression in lymphatic vessels to regulate the proportion of mediastinal lymph nodes and cardiac T cells after myocardial infarction.

Objective To evaluate the bioequivalency of single administration of metformin hydrochloride sustained-release tablets(Ⅲ)and double administration of metformin hydrochloride tablet by self-cross test in healthy subjects.Methods A two-cycle,open,self-controlled cross-control trial was conducted in which 10 cases healthy subjects first received test prepatration metformin hydrochloride sustained-release tablet(Ⅲ)2.0 g and then received reference preparation(metformin hydrochloride tablet)1.0 g twice daily after a 7-day washout period.The plasma concentrations of metformin at different time points after administration were measured by liquid chromatography tandem mass spectrometry(LC-MS/MS).The pharmacokinetic parameters were calculated by Analyst 1.6.3,and the bioequivalency of the two drugs was evaluated.A double unilateral t-test and 90％confidence interval were used to assess the equivalence.A non-parametric test statistical analysis was used to evaluate the equivalence of the secondary parameter tmax.Results The pharmacokinetic parameters of test prepatration and reference preparation were AUC0-24h were(16.43±4.46)and(18.69±4.68)μg·h·mL-1,AUCINF-obs were(17.60±4.56)and(20.09±5.78)μg·h·mL-1,Cmax were(1 893.97±585.88)and(1 437.35±281.21)ng·mL-1,tmax were(7.60±1.58)and(4.70±2.41)h;t1/2 were(10.95±2.58)and(3.33±0.62)h.Conclusion The peak time and half-life of metformin hydrochloride sustained-release tablet(Ⅲ)after single administration in Chinese healthy subjects are longer than that of metformin hydrochloride tablet,and the bioequivalency is comparable to that of metformin hydrochloride tablet after two administration.

The study is designed to observe the mechanism of Tongfu Xiefei Guanchang Solution(TFXF) in the treatment of acute lung injury(ALI) in rats by improving intestinal barrier and intestinal flora structure via p38 mitogen-activated protein kinase(p38 MAPK)/myosin light chain kinase(MLCK) signaling pathway. Sixty SPF-grade Wistar rats were randomly divided into the control(CON) group, lipopolysaccharide(LPS) group(7.5 mg·kg~(-1)), LPS + dexamethasone(DEX) group(3.5 mg·kg~(-1)), LPS + high-dose(HD)-TFXF group(14.74 g·kg~(-1)), LPS + middle-dose(MD)-TFXF group(7.37 g·kg~(-1)), and LPS + low-dose(LD)-TFXF group(3.69 g·kg~(-1)). ALI model of the rat was established by intraperitoneal injection of LPS. The lactate dehydrogenase(LDH) activity and total protein concentration in the bronchoalveolar lavage fluid(BALF) were measured; tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) levels in lung and colon tissue of rats were detected by enzyme linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE) staining was used to observe the pathological expression in the lung and colon tissue of rats. The mRNA expression of p38 MAPK, TNF-α, and IL-1β in rat lung tissue was determined by real-time fluorescence quantitative polymerase chain reaction(real-time PCR). Western blot was used to detect the protein expression related to the p38 MAPK/MLCK signaling pathway in the colon tissue of rats. 16S rRNA sequencing was used to detect changes in the composition and content of intestinal flora in rats, and correlation analyses were performed to explore the regulatory role of intestinal flora in improving ALI in rats. The results showed that compared with those in the LPS group, the histopathological scores of lung and colon tissue, LDH activity, and total protein concentration in BALF were significantly reduced in rats in all groups after drug administration. Except for the LPS + LD-TFXF group, the remaining groups significantly reduced the levels of TNF-α and IL-1β in the lung and colon tissue of rats. The protein expressions of phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK)/p38, phosphorylated myosin light chain(p-MLC)/myosin light chain 2(MLC2), and MLCK in colon tissue of rats in each drug administration group were significantly decreased. The mRNA expression levels of p38 MAPK, TNF-α, and IL-1β were significantly reduced in the LPS + HD-TFXF group. 16S rRNA sequencing results showed that the abundance of intestinal flora was significantly higher in the LPS + HD-TFXF group, and intestinal floras including Sobs, Shannon, and Npshannon were significantly higher. The β-diversity distribution of intestinal flora tends toward the CON group, and the abundance of Firmicutes was significantly higher. The abundance of Proteobacteria was significantly reduced; the abundance of Bacteroides was significantly reduced, and the abundance of Ruminococcus was significantly higher. The main species differences were Blautia, Roseburia＿sp＿499, and Butyricicoccus. TNF-α and IL-1β of lung tissue were negatively correlated with Muribaculaceae, unclassified norank＿f＿Eubacterium＿coprostanoligenes, and Ruminococcus and positively correlated with Bacteroides. Meanwhile, TNF-α and IL-1β of colon tissue were negatively correlated with unclassified norank＿f＿Eubacterium＿coprostanoligenes and Ruminococcus and positively correlated with Bacteroides. The predicted biological function of the flora was related to the biosynthesis of secondary metabolites, amino acid biosynthesis, sugar metabolism, and oxidative phosphorylation. The above studies show that TFXF can repair lung and colon tissue structure and regulate inflammatory factor levels by modulating the abundance and diversity of intestinal flora species in ALI rats. Its mechanism of action in ameliorating ALI in rats may be related to the inhibition of inflammation, improvement of intestinal mucosal permeability, and maintenance of intestinal flora homeostasis and barrier through the p38 MAPK/MLCK signaling pathway.
Animals ; Acute Lung Injury/genetics* ; Rats ; p38 Mitogen-Activated Protein Kinases/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Myosin-Light-Chain Kinase/genetics* ; Male ; Gastrointestinal Microbiome/drug effects* ; Rats, Wistar ; Signal Transduction/drug effects* ; Interleukin-1beta/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Lung/metabolism* ; Intestinal Mucosa/metabolism* ; Humans

Mycobacterium intracellular CHPC 1.5701 strain was isolated from the sputum specimen of the patient.This study attempted to establish a guinea pig infection model to evaluate its virulence,so as to provide basic scientific basis for the prevention and treatment of Mycobacterium intracellular infection.Mycobacterium intracellular CHPC 1.5701 was cultured in 7H10 medium.The morphology of the colony changed from colorless to light yellow smooth colony,and the acid-fast staining was positive.Mycobacterium intracellular suspension was diluted with 0.9％sodium chloride solution to 1 × 1010 CFU/mL,1×109 CFU/mL,1 × 108 CFU/mL,1 × 107 CFU/mL and 1 × 106 CFU/mL,respectively.Healthy Hartly guinea pigs with negative skin test of pure protein derivatives of tuberculin were selected and randomly divided into 6 groups with 10 guinea pigs in each group,half male and half female.Guinea pigs in the ex-perimental group were divided into 5 groups,which were intra-peritoneally injected with 5 different concentrations of 1.0 mL suspension/guinea pig,and those in the control group were in-traperitoneally injected with 0.9％sodium chloride solution 1.0 mL suspension/guinea pig.The guinea pigs was then observed,weighed every week,dissected 5 weeks later,lung,spleen and liver tissues were taken,and the tissue lesions were analyzed by hematoxylin-eosin(HE)staining,and the bacteria load was detected by tissue homogenate culture in 7H10 medium.The results showed that Mycobacterium intracellular challenge test had no significant effect on body weight of male guinea pigs(P＞0.05),but could reduce body weight of female guinea pigs(P＜0.01).No pathological changes of organ tissues were ob-served in guinea pigs in the control group,while HE staining of lung,spleen and liver tissues of guinea pigs in challenge experi-mental groups showed alveolar wall alveolar epithelial hyperplasia,monocyte infiltration in liver and spleen,granulomatous in-flammation and other pathological changes,and the degree of pathological changes was related to the injection dose of Mycobac-terium intracellular.Mycobacteria intracellular could be isolated from tissue culture of some organs,among which the spleen had a large amount of bacteria.Intrabitoneal injection of Mycobacteria intracellular CHPC 1.5701 can affect the body weight of female guinea pigs and cause lung,liver and spleen infection of guinea pigs,but no caseous necrosis of guinea pigs was ob-served.Compared with the reported data of Mycobacterium tuberculosis virulence test,it is concluded that Mycobacterium in-tracellular has certain virulence to guinea pigs and belongs to low virulence and low pathogenicity bacteria...

Objective To evaluate the bioequivalency of single administration of metformin hydrochloride sustained-release tablets(Ⅲ)and double administration of metformin hydrochloride tablet by self-cross test in healthy subjects.Methods A two-cycle,open,self-controlled cross-control trial was conducted in which 10 cases healthy subjects first received test prepatration metformin hydrochloride sustained-release tablet(Ⅲ)2.0 g and then received reference preparation(metformin hydrochloride tablet)1.0 g twice daily after a 7-day washout period.The plasma concentrations of metformin at different time points after administration were measured by liquid chromatography tandem mass spectrometry(LC-MS/MS).The pharmacokinetic parameters were calculated by Analyst 1.6.3,and the bioequivalency of the two drugs was evaluated.A double unilateral t-test and 90％confidence interval were used to assess the equivalence.A non-parametric test statistical analysis was used to evaluate the equivalence of the secondary parameter tmax.Results The pharmacokinetic parameters of test prepatration and reference preparation were AUC0-24h were(16.43±4.46)and(18.69±4.68)μg·h·mL-1,AUCINF-obs were(17.60±4.56)and(20.09±5.78)μg·h·mL-1,Cmax were(1 893.97±585.88)and(1 437.35±281.21)ng·mL-1,tmax were(7.60±1.58)and(4.70±2.41)h;t1/2 were(10.95±2.58)and(3.33±0.62)h.Conclusion The peak time and half-life of metformin hydrochloride sustained-release tablet(Ⅲ)after single administration in Chinese healthy subjects are longer than that of metformin hydrochloride tablet,and the bioequivalency is comparable to that of metformin hydrochloride tablet after two administration.

Mycobacterium intracellular CHPC 1.5701 strain was isolated from the sputum specimen of the patient.This study attempted to establish a guinea pig infection model to evaluate its virulence,so as to provide basic scientific basis for the prevention and treatment of Mycobacterium intracellular infection.Mycobacterium intracellular CHPC 1.5701 was cultured in 7H10 medium.The morphology of the colony changed from colorless to light yellow smooth colony,and the acid-fast staining was positive.Mycobacterium intracellular suspension was diluted with 0.9％sodium chloride solution to 1 × 1010 CFU/mL,1×109 CFU/mL,1 × 108 CFU/mL,1 × 107 CFU/mL and 1 × 106 CFU/mL,respectively.Healthy Hartly guinea pigs with negative skin test of pure protein derivatives of tuberculin were selected and randomly divided into 6 groups with 10 guinea pigs in each group,half male and half female.Guinea pigs in the ex-perimental group were divided into 5 groups,which were intra-peritoneally injected with 5 different concentrations of 1.0 mL suspension/guinea pig,and those in the control group were in-traperitoneally injected with 0.9％sodium chloride solution 1.0 mL suspension/guinea pig.The guinea pigs was then observed,weighed every week,dissected 5 weeks later,lung,spleen and liver tissues were taken,and the tissue lesions were analyzed by hematoxylin-eosin(HE)staining,and the bacteria load was detected by tissue homogenate culture in 7H10 medium.The results showed that Mycobacterium intracellular challenge test had no significant effect on body weight of male guinea pigs(P＞0.05),but could reduce body weight of female guinea pigs(P＜0.01).No pathological changes of organ tissues were ob-served in guinea pigs in the control group,while HE staining of lung,spleen and liver tissues of guinea pigs in challenge experi-mental groups showed alveolar wall alveolar epithelial hyperplasia,monocyte infiltration in liver and spleen,granulomatous in-flammation and other pathological changes,and the degree of pathological changes was related to the injection dose of Mycobac-terium intracellular.Mycobacteria intracellular could be isolated from tissue culture of some organs,among which the spleen had a large amount of bacteria.Intrabitoneal injection of Mycobacteria intracellular CHPC 1.5701 can affect the body weight of female guinea pigs and cause lung,liver and spleen infection of guinea pigs,but no caseous necrosis of guinea pigs was ob-served.Compared with the reported data of Mycobacterium tuberculosis virulence test,it is concluded that Mycobacterium in-tracellular has certain virulence to guinea pigs and belongs to low virulence and low pathogenicity bacteria...

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

Objective: To observe the characteristics of the evolution of liver indexes in patients with relapsed/refractory multiple myeloma (RRMM) treated with CAR-T-cells based on BCMA. Methods: Retrospective analysis was performed of patients with RRMM who received an infusion of anti-BCMA CAR-T-cells and anti-BCMA combined with anti-CD19 CAR-T-cells at our center between June 1, 2019, and February 28, 2023. Clinical data were collected to observe the characteristics of changes in liver indexes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL) in patients, and its relationship with cytokine-release syndrome (CRS) . Results: Ninety-two patients were included in the analysis, including 41 patients (44.6%) in the group receiving a single infusion of anti-BCMA CAR-T-cells, and 51 patients (55.4%) in the group receiving an infusion of anti-BCMA combined with anti-CD19 CAR-T-cells. After infusing CAR-T-cells, 31 patients (33.7%) experienced changes in liver indexes at or above grade 2, which included 20 patients (21.7%) with changes in one index, five patients (5.4%) with changes in two indexes, and six patients (6.5%) with changes in three or more indexes. The median time of peak values of ALT and AST were d17 and d14, respectively, and the median duration of exceeding grade 2 was 5.0 and 3.5 days, respectively. The median time of peak values of TBIL and DBIL was on d19 and d21, respectively, and the median duration of exceeding grade 2 was 4.0 days, respectively. The median time of onset of CRS was d8, and the peak time of fever was d9. The ALT, AST, and TBIL of patients with CRS were higher than those of patients without CRS (P=0.011, 0.002, and 0.015, respectively). CRS is an independent factor that affects ALT and TBIL levels (OR=19.668, 95% CI 18.959-20.173, P=0.001). The evolution of liver indexes can be reversed through anti-CRS and liver-protection treatments, and no patient died of liver injury. Conclusions: In BCMA-based CAR-T-cell therapy for RRMM, CRS is an important factor causing the evolution of liver indexes. The evolution of liver indexes after CAR-T-cell infusion is transient and reversible after treatment.
Humans ; Antigens, CD19 ; B-Cell Maturation Antigen/therapeutic use* ; Bilirubin ; Immunotherapy, Adoptive ; Liver ; Multiple Myeloma/drug therapy* ; Retrospective Studies ; T-Lymphocytes

Humans ; Communicable Diseases ; Research