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1.
Int Immunopharmacol ; 96: 107607, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33831809

RESUMO

Colorectal cancer (CRC) is one of the most common malignant tumours of the digestive system, and most patients are already in an advanced stage at the time of diagnosis. Moreover, current single-use immune checkpoint inhibitors (ICIs), such as programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, are only effective for some advanced CRC patients with microsatellite instability-high (MSI-H), and most patients may be unable to benefit from it due to a lack of CD8+ T cells in the tumour microenvironment. Additionally, the subtype of CRC has emerged as a factor affecting treatment responses, with immunogenic subtypes carrying a better prognosis. In this review, we discuss bottlenecks encountered with the single use of PD-1/PD-L1 inhibitors and summarize the research status and mechanisms of PD-1/PD-L1 inhibitor-based immunotherapeutic amplification strategies, including chemotherapy, radiotherapy, photomediated therapy and other immunotherapies used for colorectal cancer.

2.
Chemosphere ; 278: 130397, 2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33823355

RESUMO

Aluminum (Al), a neurotoxin agent, is universal in the earth crust, but its bioavailability and toxicity are manifested under acidic conditions. Up to 60% of the acid soils are distributed in tropical and subtropical regions, where crops simultaneously experience heat-shock stress. Here, we investigated the effects of heat shock-priming on Al tolerance in two different wheat genotypes. Conditioning of wheat seedlings with short period high temperature significantly alleviated Al-induced root growth inhibition, but did not significantly affect Al accumulation. However, we observed that heat shock-primed roots maintained lower levels of lipid peroxidation and higher cell viability. These priming-triggered effects were associated with reactive oxygen species (ROS) homeostasis. Furthermore, conditioning of plants with high temperature increased the contents of reduced ascorbate and glutathione, and ratios of reduced to oxidized forms of these molecules in wheat roots. However, ascorbate or glutathione biosynthesis inhibitors markedly prevented heat shock priming-induced ROS reduction accompanied by aggravated root elongation. Moreover, heat shock-priming enhanced the metabolic intensity of ascorbate-glutathione cycle, as activities of the cycle-allied enzymes were significantly increased. These results suggest that heat-shock induces cross adaptation to Al toxicity through sustaining efficient ascorbate-glutathione cycle operation in wheat plants.

3.
Neuroreport ; 32(7): 596-602, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33850085

RESUMO

Changes in the hippocampus are closely associated with learning and memory in Alzheimer's disease; however, it is not clear which morphological and cellular and subcellular changes are essential for learning and memory. Here, we accurately quantitatively studied the hippocampal microstructure changes in Alzheimer's disease model mice and analyzed the relationship between the hippocampal microstructure changes and learning and memory. Ten-month-old male APP/PS1 transgenic mice and age-matched nontransgenic littermate mice were randomly selected. The spatial learning and memory abilities were assessed using the Morris water maze. The volumes of each layer and numbers of neurons, dendritic spines and oligodendrocytes in the hippocampal subregions were investigated using unbiased stereological techniques. The APP/PS1 transgenic mice showed a decline in hippocampus-dependent spatial learning and memory abilities, smaller volumes of each layer (other than stratum radiatum) and fewer numbers of neurons, dendritic spine synapses and mature oligodendrocytes in the hippocampal subregions than nontransgenic mice. In particular, the decline of spatial learning ability was significantly correlated with the atrophy of lacunosum moleculare layer (LMol) and the decrease of hippocampal neurons and mature oligodendrocytes rather than dendritic spines. The CA1-3 fields (including LMol) atrophy was significantly correlated with the decrease both of neurons, dendritic spines and mature oligodendrocytes. However, the dentate gyrus atrophy was significantly correlated with the decrease of neurons and mature oligodendrocytes rather than dendritic spines. The loss of neurons, dendritic spines synapses and mature oligodendrocytes together caused the LMol atrophy and then led to a decline in hippocampus-dependent spatial learning ability in mice with Alzheimer's disease.

4.
Cell Oncol (Dordr) ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33788151

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor. Compared with previous treatment modalities, such as amputation, more recent comprehensive treatment modalities based on neoadjuvant chemotherapy combined with limb salvage surgery have improved the survival rates of patients. Osteosarcoma treatment has, however, not further improved in recent years. Therefore, attention has shifted to the tumor microenvironment (TME) in which osteosarcoma cells are embedded. Therapeutic targets in the TME may be key to improving osteosarcoma treatment. Tumor-associated macrophages (TAMs) are the most common immune cells within the TME. TAMs in osteosarcoma may account for over 50% of the immune cells, and may play important roles in tumorigenesis, angiogenesis, immunosuppression, drug resistance and metastasis. Knowledge on the role of TAMs in the development, progression and treatment of osteosarcoma is gradually improving, although different or even opposing opinions still remain. CONCLUSIONS: TAMs may participate in the malignant progression of osteosarcoma through self-polarization, the promotion of blood vessel and lymphatic vessel formation, immunosuppression, and drug resistance. Besides, various immune checkpoint proteins expressed on the surface of TAMs, such as PD-1 and CD47, provide the possibility of the application of immune checkpoint inhibitors. Several clinical trials have been carried out and/or are in progress. Mifamotide and the immune checkpoint inhibitor Camrelizumab were both found to be effective in prolonging progression-free survival. Thus, TAMs may serve as attractive therapeutic targets. Targeting TAMs as a complementary therapy is expected to improve the prognosis of osteosarcoma. Further efforts may be made to identify potential beneficiaries of TAM-targeted therapies.

5.
Oncol Rep ; 45(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33786627

RESUMO

Ovarian cancer displays the highest mortality rate among all types of gynecological cancer worldwide. The survival of patients with ovarian cancer remains poor due to poor responses to anticancer treatments. The present study aimed to investigate the therapeutic effects and potential mechanism underlying matrine in ovarian cancer tissues, ovarian cancer cells and a CAOV­3­derived tumor­bearing mouse model. MTT, migration, invasion, flow cytometry, immunofluorescence and immunohistochemistry assays were performed to assess the inhibitory effects of matrine on ovarian cancer. A xenograft ovarian cancer mouse model was established and treated with matrine or PBS. The results demonstrated that compared with the control group, matrine significantly induced ovarian cancer cell apoptosis by upregulating caspase­8 and Fas cell surface death receptor (Fas) expression levels, and downregulating Bcl­2 and Bcl­xl expression levels. Moreover, compared with the control group, matrine significantly inhibited ovarian cancer cell viability, migration and invasion by downregulating metastasis associated protein­1, fibronectin, angiotensin II type 2 receptor-interacting protein 3a and H high mobility group AT­hook 2 expression levels. Compared with the control group, matrine significantly increased p38MAPK, phosphorylated (p)ERK/ERK and pJNK/JNK expression levels in ovarian cancer cells. p38MAPK knockdown significantly downregulated p38MAPK, pERK/ERK and pJNK/JNK expression levels compared with the control group, which significantly promoted ovarian cancer cell viability, migration and invasion. In vivo experiments demonstrated that compared with the control group, matrine significantly suppressed tumor growth by markedly upregulating p38MAPK, ERK and JNK expression levels. The immunohistochemistry results demonstrated that caspase­8 and Fas expression levels were notably increased, whereas Bcl­2 and Bcl­xl expression levels were obviously decreased in matrine­treated tumors compared with PBS­treated tumors. In conclusion, the present study demonstrated that matrine inhibited ovarian cancer cell viability, migration and invasion, but induced cell apoptosis, suggesting that matrine may serve as a promising anticancer agent for the treatment of ovarian cancer.

6.
Arch Insect Biochem Physiol ; 106(4): e21783, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33719082

RESUMO

Vitamin C (VC) is an essential nutrient for many animals. However, whether insects, including Bombyx mori, can synthesize VC remains unclear. In this article, the optimized HPLC method was used to determine the content of l-ascorbic acid (AsA) in silkworm eggs, larvae and pupae, and the activity of l-gulono-1,4-lactone oxidase (GULO), a key enzyme in VC synthesis. The RNA interference method was used to determine the effect of the BmGulo-like gene on embryonic development and GULO activity in the pupal fat body. The AsA content increased significantly during E144 h-E168 h in the late embryonic stage and P48 h-P144 h in the middle-late pupal stage, in which exogenous VC was not ingested. Furthermore, the body AsA content in larvae fed VC-free feed also increased with larval stage. The GULO enzymatic activity was present in eggs and the fat bodies of larvae and pupae, even when the larvae were reared with fresh mulberry leaves. Moreover, the activity was higher in the later embryonic stages (E144 h-E168 h) and the early pupal stage (before P24 h). The GULO activity in the pupal fat body dramatically decreased when the screened BmGulo-like gene (BGIBMGA005735) was knocked down with small interfering RNA; in addition, the survival rate and hatching rate of eggs significantly decreased 21% and 44%, respectively, and embryonic development was delayed. Thus, Bombyx mori can synthesize AsA through the l-gulose pathway, albeit with low activity, and this synthesis ability varies with developmental stages.


Assuntos
Ácido Ascórbico/metabolismo , Bombyx/metabolismo , Animais , Bombyx/crescimento & desenvolvimento , Hexoses/metabolismo , Larva/crescimento & desenvolvimento , Larva/metabolismo , Pupa/crescimento & desenvolvimento , Pupa/metabolismo , Açúcares Ácidos/metabolismo
7.
J Food Biochem ; : e13703, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33742464

RESUMO

Aberrant activation of the nuclear factor-kappa B (NF-κB) signaling pathway is closely implicated in colorectal cancer (CRC) growth, metastasis, and immune escape. In the present study, we reported natural derived compound of baicalin (BA), an efficient inhibitor of NF-κB, with good anti-tumor effect on CRC. CCK8 and colony formation assays showed that Baicalin significantly inhibit viability and proliferation in HCT-116 and CT26 cells. Additionally, Baicalin dramatically triggers mitochondria-mediated apoptosis in both HCT-116 and CT-26 cells, which is evidenced by loss of mitochondrial membrane potential and elevated cellular reactive oxygen species level. Treatment with Baicalin suppresses migration and invasion of CT26 cells by impairing TLR4/NF-κB signaling pathway. What's more, administration of Baicalin significantly retarded tumor growth rate in a subcutaneous xenograft tumor mouse model of CT26 cells. Treatment with Baicalin could ameliorate tumor immunosuppressive environment by downregulation of PD-L1 expression and proportion of myeloid-derived suppressor cells (MDSCs) and upregulation of percent of CD4+ and CD8+ T cells in CT26 tumors, thus improving anti-tumor immunity. In conclusion, our study demonstrated that baicalin triggers apoptosis, inhibits migration, and enhances anti-tumor immunity in colorectal cancer via TLR4/NF-κB signaling pathway, suggesting it might serve as a potential candidate drug for the treatment of CRC. PRACTICAL APPLICATIONS: In the present study, we reported natural derived compound of baicalin (BA), an efficient inhibitor of NF-κB, with good anti-tumor effect on CRC. We demonstrated that baicalin triggers mitochondria-mediated apoptosis, inhibits migration, and improves anti-tumor immunity in colorectal cancer via TLR4/NF-κB signaling pathway.

8.
Toxicol Appl Pharmacol ; 418: 115484, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33716044

RESUMO

The clinical use of cisplatin are limited due to its drug resistance. Thus, it is urgent to find effective combination therapy that sensitizes tumor cells to this drug. The combined chemo-photodynamic therapy could increase anti-tumor efficacy while also reduce the side effects of cisplatin. Berberine is an isoquinoline alkaloid, which has been reported to show high photosensitizing activity. In this study, we have examined the effect of a combination of cisplatin and berberine-PDT in cisplatin-resistant melanoma cells. The cytotoxic effects of berberine-PDT alone or in combination with cisplatin were tested by MTT assays. We then examined the subcellular localization of berberine with confocal fluorescence microscopy. The percentage of apoptotic cells, the mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) generation assessed using flow cytometry analysis. Western blotting used in this study to determine the expression levels of MAPK signaling pathways and apoptosis-related proteins. Experimental data revealed that the mode of cell death is the caspase-dependent mitochondrial apoptotic pathways. Excessive accumulation of ROS played a key role in this process, which is confirmed by alleviation of cytotoxicity upon pretreatment with NAC. Furthermore, we found that the combined treatment activated MAPK signaling pathway. The inhibition of p38 MAPK by pretreating with SB203580 block the combined treatment-induced apoptotic cell death. In conclusion, berberine-PDT could be used as a chemo-sensitizer by promoting cell death through activation of a ROS/p38/caspase cascade.

9.
Biochem Biophys Res Commun ; 552: 183-190, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33751936

RESUMO

Malignant melanoma is a critical and aggressive skin tumor with a steeply rising incidence and a less favorable prognosis due to the lack of efficient treatment. Photodynamic therapy (PDT) is a new promising treatment for this tumor through photosensitizers-mediated oxidative cytotoxicity. In this study, we explored the role of berberine-mediated PDT (BBR-PDT) in the anti-proliferative effect on human malignant melanoma cells (MMCs). We found that there were significant differences between MMCs with BBR-PDT and MMCs with BBR or PDT only. Further research showed that BBR-PDT induced apoptosis via up-regulating the expression of cleaved caspase-3 protein. We also observed that LC3-related autophagy level was upregulated in MMCs with BBR-PDT. Besides, it was also found that BBR-PDT activated endoplasmic reticulum (ER) stress, involving a dramatic increase in reactive oxygen species (ROS). Interestingly, the knockdown of CHOP protein expression inhibited apoptosis, autophagy and ER stress levels caused by BBR-PDT, suggesting that CHOP protein may be related to apoptosis, autophagy and ER stress in MMCs with BBR-PDT. Collectively, our results indicated that BBR-PDT had an essential impact on MMCs' growth inhibition, and therefore may reveal the possibility of developing BBR-PDT into human malignant melanoma.

10.
Cancer Cell Int ; 21(1): 184, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771156

RESUMO

Cancer dormancy is defined that the residual cancer cells could enter into a state of quiescence and patients remain asymptomatic for years or even decades after anti-tumor therapies. Fibroblasts, which represent a predominant cell type in tumor microenvironment, play a pivotal role in determining the ultimate fate of tumor cells. This review recapitulates the pleiotropic roles of fibroblasts which are divided into normal, senescent, cancer-associated fibroblasts (CAFs) and circulation CAFs in tumor dormancy, relapse, metastasis and resistance to therapy to help the treatment of cancer metastasis.

11.
Eur J Pharmacol ; 898: 173994, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33675784

RESUMO

Disintegrin and metalloproteinase 28 (ADAM28) is a member of the disintegrin and metalloprotease domain (ADAM) family. It is associated with the growth and metastasis of various malignancies in vivo, but its role in gastric cancer remains unclear. The purpose of this study was to investigate the effect of ADAM28 derived from gastric cancer and endothelium on gastric cancer cells and its related mechanisms. In this study, Western blot analysis and q-PCR results showed that ADAM28 was up-regulated in gastric cancer cell lines. The TCGA database showed that patients with high ADAM28 expression had significantly shorter overall survival than those with low ADAM28 expression. By MTT analysis, wound healing assay, and flow cytometry, we found that overexpression/knockdown of ADAM28 expression in gastric cancer cells can regulate cell proliferation, apoptosis and migration in vitro. In addition, overexpression/knockdown of ADAM28 in human umbilical vein endothelial cells (HUVECs) in the upper ventricle can regulate the apoptosis of lower ventricular gastric cancer cells in the co-culture system. Furthermore, ELISA demonstrated that knockdown of ADAM28 from endothelial cells increased the expression of von Willebrand Factor (vWF) in the supernatant. We found that ADAM28 both from gastric cancer cells and HUVECs eliminated vWF-induced apoptosis of gastric cancer cells by cleaving vWF, and the addition of the vWF knockdown plasmid eliminated the increase of integrin ß3, p-TP53 and c-Casp3 caused by ADAM28 knockdown. In conclusion, ADAM28 from endothelium and gastric cancer may cleave vWF to eliminate vWF-induced apoptosis of gastric cancer cells and play an pro-metastasis effect.

12.
ACS Appl Mater Interfaces ; 13(11): 12899-12911, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33720701

RESUMO

Ultrasonography (US) contrast imaging using US contrast agents has been widely applied for the diagnosis and differential diagnosis of tumors. Commercial US contrast agents have limited applications because of their large size and shorter imaging time. At the same time, the desired therapeutic purpose cannot be achieved by applying only conventional US contrast agents. The development of nanoscale US agents with US imaging and therapeutic functions has attracted increasing attention. In this study, we successfully developed DOX-loaded poly-1,6-hexanedithiol-sodium bicarbonate nanoparticles (DOX@HADT-SS-NaHCO3 NPs) with pH-responsive NaHCO3 and GSH-responsive disulfide linkages. DOX@HADT-SS-NaHCO3 NPs underwent acid-triggered decomposition of NaHCO3 to generate CO2 bubbles and a reduction of disulfide linkages to further promote the release of CO2 and DOX. The potential of DOX@HADT-SS-NaHCO3 NPs for contrast-enhanced US imaging and therapy of prostate cancer was thoroughly evaluated using in vitro agarose gel phantoms and a C4-2 tumor-bearing nude mice model. These polymeric NPs displayed significantly enhanced US contrast at acidic pH and antitumor efficacy. Therefore, the NaHCO3 and DOX-encapsulated polymeric NPs hold tremendous potential for effective US imaging and therapy of prostate cancer.

13.
Zhongguo Zhong Yao Za Zhi ; 46(4): 830-836, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33645087

RESUMO

To verify the appropriate preparation process of extracts for the solid substance benchmark of Linggui Zhugan Decoction. The extracts were prepared by different preparation processes, namely the traditional process(process 1), the extract combined with volatile oil separated from traditional process extract liquid(process 2), the modern secondary reflux extraction process(process 3) and the process that volatile oil was extracted first, then prepared according to the traditional process, and combined with extract(process 4); based on the characteristic spectrum, index components of cinnamaldehyde, glycyrrhizin, ammonium glycyrrhizinate, cinnamic acid, and the dry extract rate of process 1, the differences and similarities of four extracts were compared. The results showed that the similarity of the characteristic spectrum of process 2, process 4 and process 1 were all greater than 0.97, while there was no significant difference for the content of 4 quality control components and dry extract rate; the similarity of the characteristic spectrum of process 3 and process 1 was 0.91, the absolute peak area of 13 out of 21 peaks and the relative peak area of 7 peaks increased significantly, and the content of 3 out of 4 quality control components and dry extract rate also significantly increased. In conclusion, the material standards of extracts by the process 2 and 4 are consistent with that of the traditional process, so the two processes are suitable.


Assuntos
Medicamentos de Ervas Chinesas , Óleos Voláteis , Cromatografia Líquida de Alta Pressão , Ácido Glicirrízico , Controle de Qualidade , Padrões de Referência
14.
Biomed Res Int ; 2021: 6653793, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681364

RESUMO

Background: Cancer of unknown primary (CUP) is a type of malignant tumor, which is histologically diagnosed as a metastatic carcinoma while the tissue-of-origin cannot be identified. CUP accounts for roughly 5% of all cancers. Traditional treatment for CUP is primarily broad-spectrum chemotherapy; however, the prognosis is relatively poor. Thus, it is of clinical importance to accurately infer the tissue-of-origin of CUP. Methods: We developed a gradient boosting framework to trace tissue-of-origin of 20 types of solid tumors. Specifically, we downloaded the expression profiles of 20,501 genes for 7713 samples from The Cancer Genome Atlas (TCGA), which were used as the training data set. The RNA-seq data of 79 tumor samples from 6 cancer types with known origins were also downloaded from the Gene Expression Omnibus (GEO) for an independent data set. Results: 400 genes were selected to train a gradient boosting model for identification of the primary site of the tumor. The overall 10-fold cross-validation accuracy of our method was 96.1% across 20 types of cancer, while the accuracy for the independent data set reached 83.5%. Conclusion: Our gradient boosting framework was proven to be accurate in identifying tumor tissue-of-origin on both training data and independent testing data, which might be of practical usage.

15.
J Pharm Pharmacol ; 73(5): 641-652, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33772289

RESUMO

OBJECTIVES: The current study was focused on preparing curcumin (CUR) supersaturated self-nano-emulsion (PI-CUR-SNEDDS) using hydrophilic polymer and to study the influence of polymer precipitation inhibitor on the physicochemical and biopharmaceutical properties of the PI-CUR-SNEDDS. METHODS: PI-CUR-SNEDDS were prepared using hydrophilic polymer in order to maintain the supersaturation of CUR in nano-emulsion solution, artificial gastrointestinal fluid (AGF), and the precipitates formed, and characterised by in vitro dispersion tests, in vitro intestinal absorption and in vivo pharmacokinetic and compared with CUR-SNEDDS. KEY FINDINGS: PI-CUR-SNEDDS prepared with 2% hydroxypropyl methylcellulose 55-60 (HPMC55-60) as precipitation inhibitor (PI) significantly improved the viscosity, physical stability and CUR's equilibrium solubility of nanoemulsion. HPMC55-60 and CUR interact in AGF through intermolecular interactions, form hydrogen bonds, and produce amorphous precipitates. Compared with CUR-SNEDDS, the proportion of CUR in the hydrophilic phase increased by about 3-fold, and apparent permeability coefficient (Papp) in duodenum, jejunum, ileum, and colon increased by 2.30, 3.65, 1.54 and 2.08-fold, respectively, and the area under the plasma concentration-time curve0-12h of PI-CUR-SNEDDS also increased by 3.50-fold. CONCLUSIONS: Our results suggested that HPMC55-60 maintained the CUR supersaturation state by forming hydrogen bonds with CUR, increasing the solution's viscosity and drug solubilisation, thus improving the absorption and bioavailability of CUR.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33535524

RESUMO

Climate change driven increases in the frequency of extreme heat events (EHE) and extreme precipitation events (EPE) are contributing to both infectious and non-infectious disease burden, particularly in urban city centers. While the share of urban populations continues to grow, a comprehensive assessment of populations impacted by these threats is lacking. Using data from weather stations, climate models, and urban population growth during 1980-2017, here, we show that the concurrent rise in the frequency of EHE, EPE, and urban populations has resulted in over 500% increases in individuals exposed to EHE and EPE in the 150 most populated cities of the world. Since most of the population increases over the next several decades are projected to take place in city centers within low- and middle-income countries, skillful early warnings and community specific response strategies are urgently needed to minimize public health impacts and associated costs to the global economy.


Assuntos
Doenças Transmissíveis , Calor Extremo , Cidades , Mudança Climática , Humanos , Saúde Pública
18.
Transl Psychiatry ; 11(1): 83, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526783

RESUMO

Running exercise has been shown to alleviate depressive symptoms, but the mechanism of its antidepressant effect is still unclear. Astrocytes are the predominant cell type in the brain and perform key functions vital to central nervous system (CNS) physiology. Mounting evidence suggests that changes in astrocyte number in the hippocampus are closely associated with depression. However, the effects of running exercise on astrocytes in the hippocampus of depression have not been investigated. Here, adult male rats were subjected to chronic unpredictable stress (CUS) for 5 weeks followed by treadmill running for 6 weeks. The sucrose preference test (SPT) was used to assess anhedonia of rats. Then, immunohistochemistry and modern stereological methods were used to precisely quantify the total number of glial fibrillary acidic protein (GFAP)+ astrocytes in each hippocampal subregion, and immunofluorescence was used to quantify the density of bromodeoxyuridine (BrdU)+ and GFAP+ cells in each hippocampal subregion. We found that running exercise alleviated CUS-induced deficit in sucrose preference and hippocampal volume decline, and that CUS intervention significantly reduced the number of GFAP+ cells and the density of BrdU+/GFAP+ cells in the hippocampal CA1 region and dentate gyrus (DG), while 6 weeks of running exercise reversed these decreases. These results further confirmed that running exercise alleviates depressive symptoms and protects hippocampal astrocytes in depressed rats. These findings suggested that the positive effects of running exercise on astrocytes and the generation of new astrocytes in the hippocampus might be important structural bases for the antidepressant effects of running exercise.

19.
Anticancer Drugs ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33587352

RESUMO

OBJECTIVE: Translocation of full-length Her2 receptor into nucleus was reported by some studies. Here, we tested whether nuclear Her2 contributes to paclitaxel resistance in Her2-overexpressing breast cancer cells. EXPERIMENTAL DESIGN: Breast cancer cell was transfected with plasmids containing cDNA of wild-type Her2 or mutant-type Her2 lacking the nuclear localization signal (NLS) sequence which is required for Her2 nuclear transport. Cell resistance to paclitaxel was analyzed. Paclitaxel-resistant breast cancer cell was also developed and nuclear Her2 expression was tested. Then, correlation between nuclear Her2 and resistance to paclitaxel were analyzed. Expression of importin ß1 was decreased to downregulate nuclear Her2 level and cell resistance to paclitaxel was tested. RESULTS: We found that Her2 overexpression increases Her2 nuclear expression and cells resistance to paclitaxel in MCF-7 cells. In the paclitaxel resistant cell (SK-BR-3/R), nuclear Her2 expression is upregulated compared with parental SK-BR-3 cells. Increased expression of nuclear Her2 after short-time (48 h) treatment of paclitaxel was also observed in SK-BR-3 cells. Further downregulation of Her2 nuclear expression through blocking expression of importin ß1 sensitizes the cells to paclitaxel. The analysis showed that the Her2 nuclear expression increases the survivin expression which leads to resistance to paclitaxel. Her2 nuclear expression decreases paclitaxel-induced apoptosis. However, co-immunoprecipitation was applied, and the physical interaction of nuclear Her2 and survivin was not detected. CONCLUSION: We show for the first time that nuclear Her2 contributes to paclitaxel resistance in breast cancer cells which suggests that nuclear Her2 as a potential target to sensitize breast cancers to paclitaxel treatment.

20.
J Cell Biol ; 220(4)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33533934

RESUMO

The centrosome is the main microtubule-organizing center in animal cells. It comprises of two centrioles and the surrounding pericentriolar material. Protein organization at the outer layer of the centriole and outward has been studied extensively; however, an overall picture of the protein architecture at the centriole core has been missing. Here we report a direct view of Drosophila centriolar proteins at ∼50-nm resolution. This reveals a Sas6 ring at the C-terminus, where it overlaps with the C-terminus of Cep135. The ninefold symmetrical pattern of Cep135 is further conveyed through Ana1-Asterless axes that extend past the microtubule wall from between the blades. Ana3 and Rcd4, whose termini are close to Cep135, are arranged in ninefold symmetry that does not match the above axes. During centriole biogenesis, Ana3 and Rcd4 are sequentially loaded on the newly formed centriole and are required for centriole-to-centrosome conversion through recruiting the Cep135-Ana1-Asterless complex. Together, our results provide a spatiotemporal map of the centriole core and implications of how the structure might be built.

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