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Background: In recent years, the ability of neural stem cells (NSCs) transplantation to treat Parkinson's disease (PD) has attracted attention. However, it is still a challenge to promote the migration of NSCs to the lesion site and their directional differentiation into dopaminergic neurons in PD. C‐C motif chemokine ligand 5 (CCL5) and C‐C motif chemokine receptor 5 (CCR5) are expressed in the brain and are important regulators of cell migration. It has been reported that ethyl stearate (PubChem CID: 8122) has a protective effect in 6‐OHDA‐induced PD rats. Methods: Parkinson's disease rats were injected with 6‐hydroxydopamine (6‐OHDA) into the right substantia nigra, and striatum followed by 8 μL of an NSC cell suspension containing 100 μM ethyl stearate and 8 × 105 cells in the right striatum. The effect of transplantation NSCs combined with ethyl stearate was assessed by evaluating apomorphine (APO)‐induced turning behavior and performance in the pole test. Quantitative real‐time reverse transcription–polymerase chain reaction (qRT‐PCR), Western blotting (WB), and immunofluorescence staining were also performed. Results: NSCs transplantation combined with ethyl stearate ameliorated the behavioral deficits of PD rats. PD rats that received transplantation NSCs combined with ethyl stearate exhibited increased expression of tyrosine hydroxylase (TH) and an increased number of green fluorescent protein (GFP)‐positive cells. Furthermore, GFP‐positive cells migrated into the substantia nigra and differentiated into dopaminergic neurons. The expression of CCL5 and CCR5 was significantly increased after transplantation NSCs combined with ethyl stearate. Conclusions: These findings suggest that NSCs transplantation combined with ethyl stearate can improve the motor behavioral performance of PD rats by promoting NSCs migration from the striatum to the substantia nigra via CCL5/CCR5 and promoting the differentiation of NSCs into dopaminergic neurons. [ABSTRACT FROM AUTHOR]

Background: There is a need for clinical markers to aid in the detection of individuals at risk of harboring an ascending thoracic aneurysm (ATAA) or developing one in the future. Objectives: To our knowledge, ATAA remains without a specific biomarker. This study aims to identify potential biomarkers for ATAA using targeted proteomic analysis. Methods: In this study, 52 patients were divided into three groups depending on their ascending aorta diameter: 4.0–4.5 cm (N = 23), 4.6–5.0 cm (N = 20), and >5.0 cm (N = 9). A total of 30 controls were in-house populations ethnically matched to cases without known or visible ATAA-related symptoms and with no ATAA familial history. Before the debut of our study, all patients provided medical history and underwent physical examination. Diagnosis was confirmed by echocardiography and angio-computed tomography (CT) scans. Targeted-proteomic analysis was conducted to identify possible biomarkers for the diagnosis of ATAA. Results: A Kruskal–Wallis test revealed that C-C motif chemokine ligand 5 (CCL5), defensin beta 1 (HBD1), intracellular adhesion molecule-1 (ICAM1), interleukin-8 (IL8), tumor necrosis factor alpha (TNFα) and transforming growth factor-beta 1 (TGFB1) expressions are significantly increased in ATAA patients in comparison to control subjects with physiological aorta diameter (p < 0.0001). The receiver-operating characteristic analysis showed that the area under the curve values for CCL5 (0.84), HBD1 (0.83) and ICAM1 (0.83) were superior to that of the other analyzed proteins. Conclusions: CCL5, HBD1 and ICAM1 are very promising biomarkers with satisfying sensitivity and specificity that could be helpful in stratifying risk for the development of ATAA. These biomarkers may assist in the diagnosis and follow-up of patients at risk of developing ATAA. This retrospective study is very encouraging; however, further in-depth studies may be worthwhile to investigate the role of these biomarkers in the pathogenesis of ATAA. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is associated with a generally poor breast cancer outcome, intensifying the need for novel therapeutic strategies beyond chemotherapy for this challenging subtype of breast cancer. Evidence shows that omega-3 polyunsaturated fatty acids and their derivatives exert antineoplastic effects within the breast tumor microenvironment, highlighting their potential as anticancer agents. Here, we demonstrated that docosahexaenoic acid conjugated with ethanolamine (DHEA) is able to attenuate the malignant phenotype of TNBC cells, reducing cell migration and invasion and affecting their metabolic profile through a shift from an energetic to a quiescent state. In a co-culture system, TNBC cells exposed to DHEA suppressed macrophage recruitment and cell viability along with the expression of genes related to tumor-associated macrophage (TAM) phenotype. Intriguingly, we unraveled that DHEA effects were mediated by CCL5 secretion from TNBC cells, highlighting this molecule as a promising treatment option against TNBC. Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype lacking effective targeted therapies, is considered to feature a unique cellular microenvironment with high infiltration of tumor-associated macrophages (TAM), which contribute to worsening breast cancer patient outcomes. Previous studies have shown the antitumoral actions of the dietary omega-3 docosahexaenoic acid (DHA) in both tumor epithelial and stromal components of the breast cancer microenvironment. Particularly in breast cancer cells, DHA can be converted into its conjugate with ethanolamine, DHEA, leading to a more effective anti-oncogenic activity of the parent compound in estrogen receptor-positive breast cancer cells. Here, we investigated the ability of DHEA to attenuate the malignant phenotype of MDA-MB-231 and MDA-MB-436 TNBC cell lines, which in turn influenced TAM behaviors. Our findings revealed that DHEA reduced the viability of TNBC cells in a concentration-dependent manner and compromised cell migration and invasion. Interestingly, DHEA inhibited oxygen consumption and extracellular acidification rates, reducing respiration and the glycolytic reserve in both cell lines. In a co-culture system, TNBC cells exposed to DHEA suppressed recruitment of human THP-1 cells, reduced their viability, and the expression of genes associated with TAM phenotype. Interestingly, we unraveled that the effects of DHEA in TNCB cells were mediated by reduced C-C motif chemokine ligand 5 (CCL5) expression and secretion affecting macrophage recruitment. Overall, our data, shedding new light on the antitumoral effects of DHA ethanolamine-conjugated, address this compound as a promising option in the treatment of TNBC patients. [ABSTRACT FROM AUTHOR]

Background: Although toll-like receptor 3 (TLR3) signaling is involved in the development of certain chronic kidney diseases, the specific molecular mechanisms underlying inflammatory reactions via activation of TLR3 signaling in human podocytes remain unclear. Interleukin (IL)-6 is a pleiotropic cytokine associated with innate and adaptive immune responses; however, little is known about the implication of IL-6 via the activation of regional TLR3 signaling in the inflammatory reactions in human podocytes. Methods: We treated immortalized human podocytes with polyinosinic-polycytidylic acid (poly IC), an authentic viral double-stranded RNA, and assessed the expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand 5 (CCL5) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. To further elucidate the poly IC-induced signaling pathway, we subjected the cells to RNA interference against IFN-β and IL-6. Results: We found that the activation of TLR3 induced expression of IL-6, MCP-1, CCL5, and IFN-β in human podocytes. RNA interference experiments revealed that IFN-β was involved in the poly IC-induced expression of IL-6, MCP-1, and CCL5. Interestingly, IL-6 knockdown markedly increased the poly IC-induced expression of MCP-1 and CCL5. Further, treatment of cells with IL-6 attenuated the expression of CCL5 and MCP-1 mRNA and proteins. Conclusion: IL-6 induced by TLR3 signaling negatively regulates the expression of representative TLR3 signaling-dependent proinflammatory chemokines in human podocytes.

Background: There is a need for clinical markers to aid in the detection of individuals at risk of harboring an ascending thoracic aneurysm (ATAA) or developing one in the future. Objectives: To our knowledge, ATAA remains without a specific biomarker. This study aims to identify potential biomarkers for ATAA using targeted proteomic analysis. Methods: In this study, 52 patients were divided into three groups depending on their ascending aorta diameter: 4.0–4.5 cm (N = 23), 4.6–5.0 cm (N = 20), and >5.0 cm (N = 9). A total of 30 controls were in-house populations ethnically matched to cases without known or visible ATAA-related symptoms and with no ATAA familial history. Before the debut of our study, all patients provided medical history and underwent physical examination. Diagnosis was confirmed by echocardiography and angio-computed tomography (CT) scans. Targeted-proteomic analysis was conducted to identify possible biomarkers for the diagnosis of ATAA. Results: A Kruskal–Wallis test revealed that C-C motif chemokine ligand 5 (CCL5), defensin beta 1 (HBD1), intracellular adhesion molecule-1 (ICAM1), interleukin-8 (IL8), tumor necrosis factor alpha (TNFα) and transforming growth factor-beta 1 (TGFB1) expressions are significantly increased in ATAA patients in comparison to control subjects with physiological aorta diameter (p < 0.0001). The receiver-operating characteristic analysis showed that the area under the curve values for CCL5 (0.84), HBD1 (0.83) and ICAM1 (0.83) were superior to that of the other analyzed proteins. Conclusions: CCL5, HBD1 and ICAM1 are very promising biomarkers with satisfying sensitivity and specificity that could be helpful in stratifying risk for the development of ATAA. These biomarkers may assist in the diagnosis and follow-up of patients at risk of developing ATAA. This retrospective study is very encouraging; however, further in-depth studies may be worthwhile to investigate the role of these biomarkers in the pathogenesis of ATAA.

Background: Although toll-like receptor 3 (TLR3) signaling is involved in the development of certain chronic kidney diseases, the specific molecular mechanisms underlying inflammatory reactions via activation of TLR3 signaling in human podocytes remain unclear. Interleukin (IL)-6 is a pleiotropic cytokine associated with innate and adaptive immune responses; however, little is known about the implication of IL-6 via the activation of regional TLR3 signaling in the inflammatory reactions in human podocytes. Methods: We treated immortalized human podocytes with polyinosinic-polycytidylic acid (poly IC), an authentic viral double-stranded RNA, and assessed the expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand 5 (CCL5) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. To further elucidate the poly IC-induced signaling pathway, we subjected the cells to RNA interference against IFN-β and IL-6. Results: We found that the activation of TLR3 induced expression of IL-6, MCP-1, CCL5, and IFN-β in human podocytes. RNA interference experiments revealed that IFN-β was involved in the poly IC-induced expression of IL-6, MCP-1, and CCL5. Interestingly, IL-6 knockdown markedly increased the poly IC-induced expression of MCP-1 and CCL5. Further, treatment of cells with IL-6 attenuated the expression of CCL5 and MCP-1 mRNA and proteins. Conclusion: IL-6 induced by TLR3 signaling negatively regulates the expression of representative TLR3 signaling-dependent proinflammatory chemokines in human podocytes. [ABSTRACT FROM AUTHOR]

Bone metastasis occurs in nearly 70% of patients with metastatic prostate cancer (PCa), and represents the leading cause of death in patients with PCa. Emerging evidence has demonstrated the potential activities of icariin in modulating bone metabolism and remodelling the tumor microenvironment (TME). However, whether icariin could inhibit PCa bone metastasis and destruction by modulating the TME as well as the underlying mechanisms remains unclear. This study investigated whether icariin could inhibit PCa bone metastasis and destruction by modulating the bone TME as well as the underlying mechanisms. Osteoclasts were induced from mouse bone marrow-derived macrophages (BMMs) or Raw264.7 cells. PCa cells were cultured in the conditional medium (CM) of macrophages in vitro or co-injected with macrophages in vivo to simulate their coexistence in the TME. Multiple molecular biology experiments and the mouse RM1-Luc PCa bone metastasis model were used to explore the inhibitory activity and mechanism of icariin on PCa metastasis and bone destruction. Icariin treatment significantly suppressed PCa growth, bone metastasis and destruction as well as osteoclastogenesis in vivo. Furthermore, icariin remarkably inhibited osteoclast differentiation, even in the presence of the CM of tumor-associated macrophages (TAMs), while exhibiting no obvious effect on osteoblasts. Moreover, icariin suppressed the M2 phenotype polarization of Raw264.7-derived TAMs and transcriptionally attenuated their C C motif chemokine ligand 5 (CCL5) expression and secretion via inhibiting SPI1. Additionally, CCL5 induced the differentiation and chemotaxis of osteoclast precursor cells by binding with its receptor CCR5. The clinicopathological analysis further verified the positive correlation between the TAM/CCL5/CCR5 axis and osteoclastogenesis within the TME of PCa patients. More importantly, icariin remarkably suppressed PCa metastasis-induced bone destruction in vivo by inhibiting osteoclastogenesis via downregulating the TAM/CCL5 pathway. Altogether, these results not only implicate icariin as a promising candidate immunomodulator for PCa bone metastasis and destruction but also shed novel insight into targeting TAM/CCL5-mediated osteoclastogenesis as a potential treatment strategy for osteolytic bone metastasis. This study helps to advance the understanding of the crosstalk between bone TME and bone homeostasis. [Display omitted] [ABSTRACT FROM AUTHOR]

Aberrant C-C motif chemokine ligand 5 (CCL5) is associated with disease progression, poor prognosis and chemotherapy resistance in human malignancy. The tumor microenvironment (TME) contributes to chemotherapy resistance. However, the role of cancer-associated fibroblasts (CAFs)-derived CCL5 is not well documented. Hence, the present study aimed to investigate the effects of CAFs on chemotherapy resistance in A549 non-small cell lung cancer (NSCLC) cells and the underlying mechanism. Primary CAFs isolated from patients with NSCLC were found to express and secrete elevated levels of CCL5, which attenuated cisplatin (DDP)-induced apoptosis, as indicated by flow cytometry analysis. In addition, CCL5 upregulated the expression levels of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) in the tumor cells, and silencing HOTAIR in tumor cells enhanced the cytotoxic effect of cisplatin, characterized by decreased cell viability and increased apoptotic rate. Mechanistically, HOTAIR was found to inactivate the caspase-3/BCL-2 signaling pathway in A549 NSCLC cells. Collectively, the current study demonstrated that CAFs in the TME may serve a crucial role in the higher expression levels of CCL5 in tumors and that CAF-derived CCL5 may promote cisplatin resistance via upregulating lncRNA HOTAIR expression. [ABSTRACT FROM AUTHOR]

Objective: MicroRNA (miR)-147a acts as an inhibitory miRNA in many cancers. However, its potential roles in non-small-cell lung cancer (NSCLC) remain unclear., Methods: Levels of miR-147a and C-C motif chemokine ligand 5 (CCL5) were measured using a quantitative real-time PCR assay. Cell growth, migration, and invasion of NSCLC cells were assessed by colony formation, wound healing, and Transwell invasion assays, respectively. The role of miR-147a in the growth and metastatic ability of NSCLC in vivo was detected using a xenograft model and experimental lung metastasis model., Results: miR-147a was downregulated in NSCLC cell lines as well as in tissues. Gain-of-function and loss-of-function analyses demonstrated that upregulation of miR-147a decreased the aggressiveness of NSCLC cells in vitro . In addition, CCL5 was identified as a target of miR-147a. We also demonstrated the effect of miR-147a in the progression of NSCLC cells via targeting CCL5. Finally, the in vivo mouse xenograft model showed that miR-147a inhibited progression of NSCLC cells., Conclusions: Overall, expression of miR-147a was downregulated in NSCLC. Importantly, upregulation of miR-147a suppressed the growth and metastasis of NSCLC cells in vivo by targeting CCL5.