The disbalance of LRP1 and SIRPα by psychological stress dampens the clearance of tumor cells by macrophages

The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies; however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stress-evoked tumor susceptibility, and the stress hormone glucocorticoid (GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor (low-density lipoprotein receptor-related protein-1, LRP1) and the "don't eat me" signal receptor (signal regulatory protein alpha, SIRPα). Further analysis revealed that GC led to a direct, glucocorticoid receptor (GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevated gene level of SIRPα by down-regulating miRNA-4695-3p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPα axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPα axis may serve as a potential therapeutic strategy for tumor treatment.

Liuwei Dihuangwan Regulate Brain Microvessels in SAMP8 Mice Through RAGE/LRP1 Receptors / 中国实验方剂学杂志

ObjectiveTo investigate the protective effect of Liuwei Dihuangwan on neurovascular injury in SAMP8 mice. MethodThe Alzheimer's disease （AD） model with insufficiency of kidney essence was induced in 75 SAMP8 mice aging 6 months. The model mice were divided into model group， positive control group （donepezil hydrochloride， 0.747 mg·kg-1·d-1）， and high-， medium-， and low-dose Liuwei Dihuangwan groups （2.700， 1.350， 0.675 g·kg-1·d-1）， with 15 mice in each group. Fifteen SAMR1 mice were assigned to a normal control group. All mice were administered continuously for 2 months. The spatial memory of mice was tested by the Morris water maze. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the hippocampus and cortex of brain tissues. The immunohistochemical method （IHC） was used to detect the deposition of amyloid β-protein （Aβ） and the expression of von Willebrand factor （vWF） and CD34 in the hippocampus and cortex of brain tissues. Electron microscopy was used to observe the ultrastructural changes in cerebral microvessels. Western blot was used to detect the protein expression levels of the receptor of advanced glycation endproduct （RAGE）， low-density lipoprotein receptor-related protein 1 （LRP1）， vascular endothelial growth factor A （VEGF-A）， and P-selection in the hippocampus and cortex of brain tissues. ResultCompared with the normal control group， the model group showed prolonged escape latency and swimming distance （P<0.01）， increased number of glial cells， decreased number of nerve cells， blurred tight junctions or enlarged gap of the brain microvascular endothelial cells， severely injured membrane structure， swollen mitochondria of endothelial cells， ruptured membrane， massive dissolution in cristae， increased protein expression of Aβ and vWF in the hippocampus and cortex （P<0.01）， reduced protein expression of CD34 （P<0.05）， elevated protein expression of RAGE and P-selection in the cortex （P<0.01）， and decreased protein expression level of LRP1 and VEGF-A （P<0.01）. Compared with the model group， the Liuwei Dihuangwan groups showed shortened escape latency and swimming distance （P<0.05）， reduced number of glial cells in the cortex and hippocampus， increased number of microvessels in the cortex， clear double-layer membrane structure in tight junctions between the microvascular endothelial cells， increased number of mitochondria with intact membrane and recovered mitochondrial cristae， decreased protein expression of Aβ， vWF， RAGE， and P-selection in the hippocampus and cortex （P<0.05）， and increased protein expression of CD34， LRP1， and VEGF-A （P<0.05）. ConclusionLiuwei Dihuangwan can regulate Aβ metabolism through the RAGE/LRP1 receptor system and promote cerebral microvascular angiogenesis by inhibiting vWF expression and increasing VEGF-A and CD34， thereby improving cerebral microvascular injury in SAMP8 mice.

Expressão de Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade (LRP1) em Monócito em Correlação com EIMC em Pacientes Mexicanos Hipertensos / Monocyte Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Expression Correlates with cIMT in Mexican Hypertensive Patients

Resumo Fundamento A hipertensão arterial (HTA) representa um grande fator de risco de morbidade e mortalidade cardiovascular. Ainda não se sabe que mecanismos moleculares específicos estão associados ao desenvolvimento de hipertensão essencial. Objetivo Neste trabalho, analisamos a associação entre expressão mRNA de monócito LRP1, expressão de proteína LRP1, e espessura íntima-média de carótida (EIMC) de pacientes com hipertensão essencial. Métodos A expressão mRNA de monócito LRP1 e os níveis de proteína e EIMC foram quantificados em 200 indivíduos mexicanos, sendo 91 normotensos (NT) e 109 hipertensos (HT) A significância estatística foi definida em p < 0,05. Resultados O grupo de pacientes HT tinha EIMC maior altamente significativa em comparação com os pacientes NT (p = 0,002), e isso está relacionado ao aumento na expressão mRNA de LRP1 (6,54 versus. 2,87) (p = 0,002) e expressão de proteína LRP1 (17,83 versus 6,25), respectivamente (p = 0,001). Essas diferenças foram mantidas mesmo quando dividimos nossos grupos de estudo, levando em consideração apenas aqueles que apresentavam dislipidemia na expressão de mRNA (p = 0,041) e de proteínas (p < 0,001). Também se identificou que a indução de LRP1 mediada por LRP1 em monócitos em de maneira dependente de dose e tempo, com diferença significativa em NT versus HT (0,195 ± 0,09 versus 0,226 ± 0,12, p = 0,046). Conclusão Foi encontrado um aumento em EIMC em indivíduos com hipertensão, associada a expressões de proteína LRP1 e mRNA mais altas em monócitos, independente da presença de dislipidemia em pacientes HT. Esses resultados que a upregulation de LRP1 em monócitos de pacientes hipertensos mexicanos poderia estar envolvida na diminuição da EIMC. (Arq Bras Cardiol. 2021; 116(1):56-65)

Abstract Background Arterial hypertension (HTA) represents a major risk factor for cardiovascular morbidity and mortality. It is not yet known which specific molecular mechanisms are associated with the development of essential hypertension. Objective In this study, we analyzed the association between LRP1 monocyte mRNA expression, LRP1 protein expression, and carotid intima media thickness (cIMT) of patients with essential hypertension. Methods The LRP1 monocyte mRNA expression and protein levels and cIMT were quantified in 200 Mexican subjects, 91 normotensive (NT) and 109 hypertensive (HT). Statistical significance was defined as p < 0.05. Results HT patients group had highly significant greater cIMT as compared to NT patients (p=0.002) and this correlated with an increase in the expression of LRP1 mRNA expression (6.54 vs. 2.87) (p = 0.002) and LRP1 protein expression (17.83 vs. 6.25), respectively (p = 0.001). These differences were maintained even when we divided our study groups, taking into account only those who presented dyslipidemia in both, mRNA (p = 0.041) and proteins expression (p < 0.001). It was also found that Ang II mediated LRP1 induction on monocytes in a dose and time dependent manner with significant difference in NT vs. HT (0.195 ± 0.09 vs. 0.226 ± 0.12, p = 0.046). Conclusion An increase in cIMT was found in subjects with hypertension, associated with higher mRNA and LRP1 protein expressions in monocytes, irrespective of the presence of dyslipidemias in HT patients. These results suggest that LRP1 upregulation in monocytes from Mexican hypertensive patients could be involved in the increased cIMT. (Arq Bras Cardiol. 2021; 116(1):56-65)

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.

Effects of Abnormal Phlegmatic Munziq on Ability of Learning and Memory and Protein Expressions of Brain Tissue RAGE and LRP1 of APP/PS1 Transgenic Mice Model of AD / 中国中医药信息杂志

Objective To investigate the effects of Abnormal Phlegmatic Munziq on ability of learning and memory, and protein expressions of brain tissue RAGE and LRP1 of APP/PS1 transgenetic mice model of AD;To discuss its mechanism of action. Methods Three-month-old APP/PS1 transgenic mice were randomly divided into 5 groups: model control group, positive control group, Abnormal Phlegmatic Munziq high-, medium-, and low-dose groups, 18 mice in each group. Another 18 three-month-old C57BL/6J mice were chosen as normal control group. All administration groups received relevant medicine for successive 6 months. Then the changes in ability of learning and memory of mice were detected by Step-down test; protein expressions of LRP1 and RAGE were detected by immunohistochemistry and Western blot. Results Compared with the normal control group, the reaction time of learning grades and the mistake times increased, incubation of memory grades decreased and the mistake times increased in the model control group (P<0.01);Compared with the model control group, the reaction time of learning grades and the mistake times decreased, incubation of memory grades increased and the mistake times decreased in all administration groups (P<0.05, P<0.01). Immunohistochemistry and Western blot results showed that compared with normal control group, the LRP1 expression decreased and RAGE increased in the model control group (P<0.05);Compared with the model control group, the LRP1 expression decreased and RAGE increased in Abnormal Phlegmatic Munziq high-, medium-, and low-dose groups (P<0.05,P<0.01). Conclusion Abnormal Phlegmatic Munziq can improve ability of spatial learning and memory in APP/PS1 mice and regulate the expressions of RAGE and LRP1.

Traditional Chinese Medicine Regulation on Aβ Transporter in Blood-brain Barrier / 世界科学技术-中医药现代化

The main pathological change of Alzheimer’s disease (AD) was the formation of senile plaques (SP) induced by the abnormal accumulation ofβ-amyloid protein (Aβ). Blood-brain barrier (BBB) can regulate the Aβ metabolism in the brain through relevant transporter to complete the across BBB transport. This paper introduced two main transporters, which were the receptor for advanced glycation end products (RAGE) and the low density lipoprotein receptor-related protein-1 (LRP-1) in BBB for the elucidation of neuronal cell toxicity induced by inflammatory factors from Aβ accumulation within the brain. It further explored the regulation on two transport proteins, which were RAGE and LRP-1 in BBB for the reduction of abnormal accumulation of Aβ, relieving of inflammation in the brain, and protection of cerebral neurons by traditional Chinese medicine (TCM).

Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.

Regulation of ? amyloid protein level in the brain / 中国临床药理学与治疗学

? amyloid protein(A?) including A?40 and A?42 are the important bioactive substances in vivo.Their toxic and beneficial attributes in the body depend on its concentration.The brain A? level is maintained by two balances under the physiological condition.The first balance is the generation involved in ?-secretase and ?-secretase and the degradation involved in neprilysin(NEP) and insulin-degrading enzyme(IDE) of A?. The second one is the balance between the receptor for advanced end glycation products(RAGE)-mediated influx and low-density lipoprotein receptor related protein 1(LRP1)-mediated efflux of A? across the blood-brain barrier(BBB).Breakdowning any one of the two balances would result in the aggregation and precipitation of A? in the brain,which is a crucial event in the pathogenesis of Alzheimer's disease(AD).This paper reviews the regulation of brain A? level under the physiological condition and the reducing strategies on the level of brain A? under the pathological condition for developing new drugs in the treatment of AD.