The cellular composition of the tumor microenvironment is an important marker for predicting therapeutic efficacy in breast cancer.

At present, the incidence rate of breast cancer ranks first among new-onset malignant tumors in women. The tumor microenvironment is a hot topic in tumor research. There are abundant cells in the tumor microenvironment that play a protumor or antitumor role in breast cancer. During the treatment of breast cancer, different cells have different influences on the therapeutic response. And after treatment, the cellular composition in the tumor microenvironment will change too. In this review, we summarize the interactions between different cell compositions (such as immune cells, fibroblasts, endothelial cells, and adipocytes) in the tumor microenvironment and the treatment mechanism of breast cancer. We believe that detecting the cellular composition of the tumor microenvironment is able to predict the therapeutic efficacy of treatments for breast cancer and benefit to combination administration of breast cancer.

Synergistic anti-inflammatory effects of peimine, peiminine, and forsythoside a combination on LPS-induced acute lung injury by inhibition of the IL-17-NF-κB/MAPK pathway activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythia suspensa (Thunb.) Vahl and Fritillaria thunbergii Miq are traditional Chinese medicines that exhibit the ability to clear heat and toxic material effects. In China, the combination of these two medicines is widely used to treat mucopurulent sputum and bloody phlegm, arising due to phlegm-heat obstruction in respiratory diseases. However, very limited information is available regarding the combined anti-inflammatory effect of important effective components of Forsythia suspensa (Thunb.) Vahl and Fritillaria thunbergii Miq, namely peimine, peiminine, and forsythoside A. AIM OF THIS STUDY: To investigate synergistic anti-inflammatory effects of combined administration of peimine, peiminine, and forsythoside A on LPS-induced acute lung injury compared to combined administration of two compounds or individual administration, and unravel the underlying mechanism. MATERIAL AND METHODS: In the present study, male BALB/c mice received an oral dosage of sodium carboxymethylcellulose (CMC-Na) (0.5%, 1 mL/100 g), peimine, peiminine, forsythoside A, peimine + forsythoside A, peiminine + forsythoside A, and peimine + peiminine + forsythoside A (suspended in CMC-Na; 0.5%), once daily for 7 days. Subsequently, intratracheal instillation of LPS was applied to establish acute lung injury model. After 6 h of administration, the mice were sacrificed, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. These samples were further used to determine lung W/D (wet/dry) weight ratio, total protein (TP) levels, inflammatory cytokines (IL-6, TNF-α, IL-1ß, and IL-17), and expression of proteins involved in TLR4/MAPK/NF-κB pathway and IL-17 pathway. Further, tissue sections were subjected to H&E staining to assess the pathological alterations induced by LPS. The expression of IL-6 and TNF-α proteins in lung tissues was also analyzed using immunohistochemical staining. RESULTS: A synergistic anti-inflammatory effect of peimine, peiminine, and forsythoside A was observed when administered in combination to LPS-induced acute lung injury. The combined administration of peimine, peiminine, and forsythoside A had a strongly inhibitory effects on the W/D weight ratio, total protein (TP) level and the inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-17) level in acute lung injury mice, compared to combined administration of two compounds or individual administration. The infiltration of inflammatory cells and thickened bronchoalveolar walls induced by LPS were also ameliorated through the combined administration of peimine, peiminine, and forsythoside A. More importantly, the upregulation of protein related to TLR4/MAPK/NF-κB signaling pathway and the activation of IL-17 were significantly suppressed by pretreatment with each of the three compounds alone, while the effects of individual compounds were synergistically augmented by the combined pretreatment of these three compounds. CONCLUSION: The combined administration of peimine, peiminine, and forsythoside A ameliorated inflammatory response in acute lung injury mice induced by LPS in a synergistic manner, the mechanism may be related to the dampening of the TLR4/MAPK/NF-κB signaling pathway and IL-17 activation.

Breast Cancer Resistance to Cyclin-Dependent Kinases 4/6 Inhibitors: Intricacy of the Molecular Mechanisms.

Breast cancer is a common malignant tumor in women, with a highest incidence and mortality among all of the female malignant tumors. Notably, targeted therapy has achieved impressive success in the treatment of breast cancer. As one class of the anti-tumor targeted therapeutics, Cyclin-Dependent Kinases 4/6CDK4/6inhibitors have shown good clinical activity in treating breast cancer. Nevertheless, despite the promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the benefits of this novel target therapy. In the present review, we provide an overview of the currently known molecular mechanisms of resistance to CDK4/6 inhibitors, and discuss the potential strategies to overcoming drug resistance improving the outcomes for breast cancer patients treated with CDK4/6 inhibitors.

[Pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia].

To study the pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia. In this study, the hyperlipidemia model was established by intravenous injection of protocatechuic aldehyde (20 mg•kg⁻¹) and hydroxysafflor yellow A (12 mg•kg⁻¹). The HPLC-DAD method was applied to determine the plasma concentration of protocatechuic aldehyde and hydroxysafflor yellow A at different time points and draw the drug effect-time curve. Meanwhile, the platelet activating factors (PAF) and plasma a granule membrane protein (GMP-140) contents were determined at different time points to draw the time-effect curve. Then DAS 3.2.6 software was used to process the data, analyze their correlation, and compare the difference of pharmacokinetics and pharmacodynamics of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combined application, so as to evaluate the effect of protocatechuic aldehyde and hydroxysafflor yellow A on hyperlipidemia rats. According to the result, the pharmacokinetics and pharmacodynamics process of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combination were consistent to the three-compartment model. In model group, the plasma PAF and GMP-140 were significantly increased, and the PAF and GMP-140 in vivo contents were decreased in a certain time after treatment. The effects of protocatechuic aldehyde and hydroxysafflor yellow A against the pharmacodynamic action may be related with their level in vivo, and their plasma concentration was positively related to the PAF and GMP-140 contents. The pharmacodynamic indexes were better after the combined use of protocatechuic aldehyde and hydroxysafflor yellow A, with certain influence on each other in hyperlipidemia rats; at the same time, it also reflected the rationality of protocatechuic aldehyde and hydroxysafflor yellow A combined application.

[Anti-prostate cancer effect of roemerine: An experimental study].

OBJECTIVE: To investigate the anti-prostate cancer (PCa) effect of roemerine in vitro and in vivo in the mouse model of PCa. METHODS: We detected the effects of roemerine on the proliferation, apoptosis and migration of PCa cells DU145, LNCaP, PC-3 and 22RV1, screened out the sensitive cell line and constructed a tumor-bearing model in mice for verification of the antitumor efficacy of roemerine in vivo. RESULTS: Roemerine inhibited the proliferation and migration of the DU145, LNCaP, PC-3 and 22RV1 cells and induced their apoptosis in different degrees, particularly those of the LNCaP cells. The average tumor weight was less in the roemerine intervention group (ï¼»1.99±0.95ï¼½ g) than in the control (ï¼»2.95±1.04ï¼½ g), the least in the high-dose roemerine (30 mg/kg) plus paclitaxel intervention group (ï¼»0.90±0.16ï¼½ g). The mean heart, liver, and kidney indexes were markedly lower in the roemerine (0.58±0.06, 6.20±0.42 and 1.49±0.33) than in the paclitaxel group (0.66±0.04, 6.99±0.72 and 1.95±0.34), while the mean spleen and thymus indexes were remarkably higher in the former (0.54±0.11 and 0.06±0.01) than in the latter (0.41±0.09 and 0.05±0.01). Pathological staining showed a lower degree of malignancy and metastasis in both the roemerine and the roemerine + paclitaxel intervention group than in the control, as well as a lower degree of visceral injury in the roemerine and roemerine + paclitaxel groups than in the paclitaxel group. CONCLUSIONS: Roemerine has some anti-PCa effect and alleviates adverse reactions in paclitaxel combination administration.

Anti-prostate cancer effect of roemerine: An experimental study / 中华男科学杂志

Objective@#To investigate the anti-prostate cancer (PCa) effect of roemerine in vitro and in vivo in the mouse model of PCa.@*METHODS@#We detected the effects of roemerine on the proliferation, apoptosis and migration of PCa cells DU145, LNCaP, PC-3 and 22RV1, screened out the sensitive cell line and constructed a tumor-bearing model in mice for verification of the antitumor efficacy of roemerine in vivo.@*RESULTS@#Roemerine inhibited the proliferation and migration of the DU145, LNCaP, PC-3 and 22RV1 cells and induced their apoptosis in different degrees, particularly those of the LNCaP cells. The average tumor weight was less in the roemerine intervention group (［1.99±0.95］ g) than in the control (［2.95±1.04］ g), the least in the high-dose roemerine (30 mg/kg) plus paclitaxel intervention group (［0.90±0.16］ g). The mean heart, liver, and kidney indexes were markedly lower in the roemerine (0.58±0.06, 6.20±0.42 and 1.49±0.33) than in the paclitaxel group (0.66±0.04, 6.99±0.72 and 1.95±0.34), while the mean spleen and thymus indexes were remarkably higher in the former (0.54±0.11 and 0.06±0.01) than in the latter (0.41±0.09 and 0.05±0.01). Pathological staining showed a lower degree of malignancy and metastasis in both the roemerine and the roemerine + paclitaxel intervention group than in the control, as well as a lower degree of visceral injury in the roemerine and roemerine + paclitaxel groups than in the paclitaxel group.@*CONCLUSIONS@#Roemerine has some anti-PCa effect and alleviates adverse reactions in paclitaxel combination administration.

Pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia / 中国中药杂志

To study the pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia. In this study, the hyperlipidemia model was established by intravenous injection of protocatechuic aldehyde (20 mg•kg⁻¹) and hydroxysafflor yellow A (12 mg•kg⁻¹). The HPLC-DAD method was applied to determine the plasma concentration of protocatechuic aldehyde and hydroxysafflor yellow A at different time points and draw the drug effect-time curve. Meanwhile, the platelet activating factors (PAF) and plasma a granule membrane protein (GMP-140) contents were determined at different time points to draw the time-effect curve. Then DAS 3.2.6 software was used to process the data, analyze their correlation, and compare the difference of pharmacokinetics and pharmacodynamics of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combined application, so as to evaluate the effect of protocatechuic aldehyde and hydroxysafflor yellow A on hyperlipidemia rats. According to the result, the pharmacokinetics and pharmacodynamics process of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combination were consistent to the three-compartment model. In model group, the plasma PAF and GMP-140 were significantly increased, and the PAF and GMP-140 in vivo contents were decreased in a certain time after treatment. The effects of protocatechuic aldehyde and hydroxysafflor yellow A against the pharmacodynamic action may be related with their level in vivo, and their plasma concentration was positively related to the PAF and GMP-140 contents. The pharmacodynamic indexes were better after the combined use of protocatechuic aldehyde and hydroxysafflor yellow A, with certain influence on each other in hyperlipidemia rats; at the same time, it also reflected the rationality of protocatechuic aldehyde and hydroxysafflor yellow A combined application.

Radioprotective effects of Sipunculus nudus L. polysaccharide combined with WR-2721, rhIL-11 and rhG-CSF on radiation-injured mice.

This study investigated the radioprotective effect of Sipunculus nudus L. polysaccharide (SNP) in combination with WR-2721, rhIL-11 and rhG-CSF on irradiated mice. A total of 70 Imprinting Control Region (ICR) mice were divided into seven groups: the control group, the model group and five administration groups. All groups, except the control group, were exposed to a 5 Gy (60)Co γ-ray beam. Blood parameters [including white blood cell (WBC), red blood cell (RBC) and platelet counts and hemoglobin level] were assessed three days before irradiation, and the on the 3rd, 7th and 14th days after irradiation. Spleen, thymus and testicular indices, DNA contents of bone marrow cells, bone marrow nucleated cells, sperm counts, superoxide dismutase (SOD), malondialdehyde (MDA), testosterone and estradiol levels in the serum were assessed on the 14th day after irradiation. The combined administration of SNP, WR-2721, rhIL-11 and rhG-CSF exerted synergistic recovery effects on peripheral blood WBC, RBC and platelet counts and hemoglobin levels in irradiated mice, and synergistic promotion effects on spleen, thymus, testicle, bone marrow nucleated cells and sperm counts in irradiated mice. The synergistic administration increased the serum SOD activities and serum testosterone content of irradiated mice, but synergy decreased the content of serum MDA and estradiol in irradiated mice. These results suggest that the combined administration of SNP, WR-2721, rhIL-11 and rhG-CSF should increase the efficacy of these drugs for acute radiation sickness, protect immunity, hematopoiesis and the reproductive organs of irradiated-damaged mice, and improve oxidation resistance in the body.

Pharmacokinetic study on puerarin and ferulic acid alone or their combination used in rats with focal cerebral ischemia / 中草药

Objective: To study the pharmacokinetic changes of puerarin and ferulic acid alone or their combination used in rats with focal cerebral ischemia and to analyze their mutual influence. Methods: Twenty-four SD rats were randomly divided into three groups such as puerarin (50 mg/kg) group, ferulic acid (50 mg/kg) group, and combination (50 mg/kg + 50 mg/kg) group. The middle cerebral artery occlusion (MCAO) model was established. The model rats were iv injected with puerarin and ferulic alone, and then the blood was collected at different time points. The HPLC-DAD method was applied to determining the plasma concentration of puerarin and ferulic acid at different time points and the drug-time curve was drawn. The DAS 3.2.6 and SPSS 19.0 softwares were used to analyze the data. Results: The pharmacokinetic parameters: AUC, t1/2, Cmax, and AUMC had no significant difference (P > 0.05), while the clearance of puerarin group had the significant difference with that of the combination group and mean residence time (MRT) of combination group was more extended than that of ferulic acid group. Conclusion: In rats with focal cerebral ischemia, the combination of puerarin and ferulic acid could significantly extend the MRT in rats, which reflects the slow-release effect between drug-drug interaction.

Single tumor imaging with multiple antibodies targeting different antigens.

Antibodies are important drugs for treating cancer and there is strong rationale for using multiple antibodies to improve outcomes. We labeled two breast cancer binding antibodies, anti-ErbB2 and anti-EpCAM, with infrared fluorescence dyes of different wavelengths and determined their in vivo distribution in a breast cancer xenograft model using a near-infrared (NIR) fluorescence imaging system. Our data show that these two antibodies can be readily assessed simultaneously in mouse xenograft model. This will help guide design of dosing strategies for multiple antibodies and identify potential interaction that could affect pharmacokinetics and possible side effects.