ABSTRACT
ObjectiveThis study aims to investigate the effect of modified Baitouwengtang （MBTWD） on tumor growth and the number of tumor-associated macrophages （TAMs） in tumor tissue of MC38 cell tumor-bearing mice with colorectal cancer and explores whether MBTWD mediates the remodeling of TAM phenotype to play an immunologically antitumor effect. MethodFirstly， The C57BL/6 mouse tumor model grafted subcutaneously was established， and then model mice were classified into a model group， positive control group（3 mg·kg-1）， and MBTWD groups with high and low dosages（23.43、46.86 g·kg-1）， with 10 mice in each group. In addition， 10 healthy mice were set as the blank group， and the changes in body weight， tumor volume， and survival status of mice in each group were observed. Tumor tissue， spleen， and peripheral blood were collected to calculate the tumor volume change， tumor inhibition rate， and spleen mass. Hematoxylin-eosin （HE） staining was used to observe the morphological changes of tumor tissue， and an immunofluorescence assay was used to detect the expression levels of CD4， CD8， and CD206 in tumor tissues of tumor-bearing mice. The secretion levels of transforming growth factor （TGF）-β， interleukin （IL）-6， and chemokine （C-C Motif） ligand 2 （CCL2） in peripheral serum were measured by using enzyme-linked immunosorbent assay （ELISA）. Secondly， a co-culture model induced by IL-4 in vitro of MC38 cells and murine monocytic macrophage RAW264.7 cells was established. Cell proliferation and activity assay （CCK-8） was used to detect the inhibitory effect of MBTWD containing serum on cell proliferation. A transwell experiment was used to detect the effect of IL-4-induced M2 macrophages on the invasion of MC38 cells. Flow cytometry was used to detect the expression of CD86 on the membrane of M2 macrophages induced by IL-4 with MBTWD containing serum. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the effect of MBTWD containing serum on the mRNA expression levels of M1 macrophage-related polarization factors CD86， nitric oxide synthase （iNOS）， and IL-12， as well as M2 macrophage-related polarization factors CD206， CD163， and IL-10 after co-cultivation. Finally， the protein expression levels of colony-stimulating factor 1 receptor （CSF1R）， stimulator of interferon genes （STING）， and TANK binding kinase 1 （TBK1） in tumor tissues of tumor-bearing mice were detected by Western blot. ResultIn vivo experimental results show that compared with the model group， the MBTWD can significantly inhibit the tumor growth of tumor-bearing mice. Immunofluorescence experiments show that the MBTWD can increase the number of CD8+ T cell infiltration in tumor tissue of tumor-bearing mice， reduce the number of CD206+ TAMs infiltration， and down-regulate the secretion levels of cytokines IL-6， TGF-β， and CCL2 in peripheral blood of tumor-bearing mice. The results of in vitro experiments show that the MBTWD containing serum has no obvious inhibitory effect on cell proliferation， but the cell supernatant after co-cultivation with RAW264.7 cells can inhibit the proliferation activity of MC38 cells， and the invasion ability of MC38 cells is enhanced by IL-4-induced M2 macrophages. However， this effect can be inhibited in a concentration-dependent manner by the MBTWD containing serum. At the same time， the results of Real-time PCR show that the MBTWD containing serum can up-regulate the mRNA expression levels of M1 macrophage-related polarization factors CD86， iNOS， and IL-12 and down-regulate those of M2 macrophage-related polarization factors CD206， CD163， and IL-10. Flow cytometry results also confirm that the MBTWD containing serum can increase the number of repolarized CD86+ M1 macrophages， indicating that MBTWD can induce M2 macrophages to repolarized M1 macrophages to play an anti-tumor growth role. Finally， Western blot results show that MBTWD can down-regulate the expression of CSF1R protein and up-regulate that of STING and TBK1 proteins in tumor tissue of tumor-bearing mice. ConclusionMBTWD can down-regulate the infiltration number of CD206+ TAMs and increase the infiltration of CD8+ T cells， thereby playing an immunologically antitumor effect on the growth inhibition of colorectal cancer， which may be related to regulating CSF1R signaling and then activating STING/TBK1 signaling pathway to induce phenotypic remodeling of TAMs.
ABSTRACT
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal-dominant progressive leukodystrophy, caused by mutations of colony stimulating factor-1 receptor (CSF1R) gene. Age of onset is usually between 40 and 50 years old and the clinical presentations include dementia, apraxia, behavioral changes, pyramidal and extrapyramidal signs. Varying clinical manifestations have led to misdiagnoses. Magnetic resonance imaging (MRI) typically reveals white matter changes with T2-Flair/DWI hyperintensity and atrophy especially for thinning of the corpus callosum. Here, we report a young woman experiencing hypomnesia for 2 years with lower extremities weakness and rigidity for 1 month. Considering the evidence of clinical manifestations, imaging and genetic test, this patient was diagnosed with ALSP.
ABSTRACT
Objective To explore the clinical and neuroimaging features in a Chinese family with hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) caused by mutation of the colony stimulating factor 1 receptor gene (CSF1R). Methods The proband and another patient from a HDLS pedigree were assessed respectively through standardized clinical evaluation (medical history inquiry, physical examination),neuropsychology assessment,MRI,genetic sequencing, as well as brain PET imaging with carbon11-labelled Pittsburgh compound-B(11C-PIB). Results A HDLS pedigree with three patients was recruited to this study. Apathy, memory decline, slow behavior were the first symptoms for two of the patients. Being bedridden, urinary incontinence and epilepsy were developed at the later stage. A missense mutation c. 2381T>C(p. I794T) in exon 18 of the CSF1R gene of chromosome 5 was identified in the proband. The brain DWI illustrated multiple patchy high signal in periventricular white matter and centrum semiovale which was characterized by persistence, and the corpus callosum was affected in the early stage. Conclusion The multiple patchy high signal with persistence in periventricular white matter and centrum semiovale of DWI is helpful for the early diagnosis of HDLS.
ABSTRACT
Early motor symptoms of neurodegenerative diseases often appear in combination with psychiatric symptoms, such as depression or personality changes, and are in danger of being misdiagnosed as psychogenic in young patients. We present the case of a 32-year-old woman who presented with rapid-onset depression, followed by a hypokinetic movement disorder and cognitive decline during pregnancy. Genetic testing revealed a mutation in the colony-stimulating factor 1 receptor gene, which led to the diagnosis of hereditary diffuse leukoencephalopathy with spheroids. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is probably an under-recognized disease. HDLS should be considered in patients with rapidly progressing parkinsonian symptoms and dementia accompanied by white matter lesions.
Subject(s)
Adult , Female , Humans , Pregnancy , Dementia , Depression , Diagnosis , Genetic Testing , Leukoencephalopathies , Macrophage Colony-Stimulating Factor , Movement Disorders , Neurodegenerative Diseases , Parkinsonian Disorders , White MatterABSTRACT
The expression of cancer gene products of insuline-like growth factor Ⅱ (IGF-Ⅱ),IGF-Ⅱ receptors (IGF-Ⅱ-R),and colony-stimulating factor 1 receptors (CSF-1-R) /c-fms in 17 cases of human primary hepatic cancer,the non-cancerous liver tissue adjacent to the cancer,and normal liver tissue was studied with immunocytochemistry (ABC),Western blot and Northern blot techniques.It was found that the expression of IGF-Ⅱ,IGF-Ⅱ-R and CSF-1-R was significantly higher in the cancers than in normal liver tissues,and the expression of IGF-Ⅱ and IGF-Ⅱ-R was higher in the non-cancerous liver tissues than in the cancers.It was noteworthy that the expression of IGF-Ⅱ in both the cancerous and non-cancerous hepatic tissues was characterized by its fetal type.However the expression of CSF-1-R was distinctly higher in the cancers than in the non-cancerous hepatic tissue.These findings,the authors believe,imply that the aberrant overexpression of IGF-Ⅱ,IGF-Ⅱ-R and CSF-l-R might be related to the mechanism of auto-crine-stimulated growtth of the cells of human primary hepatic cancer.