Thrombosis is a common complication of chronic kidney disease (CKD), but the causes and mechanisms of CKD-associated thrombosis are not well clarified. Here, we show that platelet activity is ...remarkably enhanced in CKD mice, with increase of serum indoxyl sulfate (IS), a typical uremic toxin, which cannot be effectively cleared by routine dialysis. Ex vivo and in vitro experiments reveal that IS displays a distinct ability to enhance platelet activities, including elevated response to collagen and thrombin, increases in platelet-derived microparticles, and platelet-monocyte aggregates. The flow chamber assay and carotid artery thrombosis model demonstrate that IS-induced platelet hyperactivity contributes to thrombus formation. Further investigations disclose that reactive oxygen species (ROS)-mediated p38MAPK signaling plays a key role in IS-induced platelet hyperactivity. Moreover, we show that Klotho, which is expressed dominantly in the kidneys, has the capacity to counteract IS-induced platelet hyperactivity by inhibiting ROS/p38MAPK signaling, whereas Klotho reduction may aggravate the effect of IS on platelet activation in CKD and klotho+/− mice. Finally, we demonstrate that Klotho protein treatment can protect against IS-induced thrombosis and atherosclerosis in apoE−/− mice. Our findings uncover the mechanism of platelet hyperactivity induced by IS and provide new insights into the pathogenesis and treatment of CKD-associated thrombosis.
•Uremic solute IS increases platelet activity via activation of ROS/p38MAPK signaling.•Klotho counteracts IS-induced thrombosis by restraining platelet hyperactivity.
Fatigue and diarrhea are the most frequent adverse effects of pelvic radiotherapy, while their etiologies are largely unknown. The aim of this study is to investigate the correlations between ...fatigue, diarrhea, and alterations in gut microbiota induced by pelvic radiotherapy. During the 5-week treatment of pelvic radiotherapy in 11 cancer patients, the general fatigue score significantly increased and was more prominent in the patients with diarrhea. The fatigue score was closely correlated with the decrease of serum citrulline (an indicator of the functional enterocyte mass) and the increases of systemic inflammatory proteins, including haptoglobin, orosomuoid, α1-antitrypsin and TNF-α. Serum level of lipopolysaccharide (LPS) was also elevated, especially in the patients with diarrhea indicating epithelial barrier breach and endotoxemia. Pyrosequencing analysis of 16S rRNA gene revealed that microbial diversity, richness, and the Firmicutes/Bacteroidetes ratio were significantly altered prior to radiotherapy in patients who later developed diarrhea. Pelvic radiotherapy induced further changes in fecal microbial ecology, some of which were specific to the patients with or without diarrhea. Our results indicate that gut microbial dysbiosis prior to radiation therapy may be exploited to predict development of diarrhea and to guide preventive treatment options. Radiation-induced dysbiosis may contribute to pelvic radiation disease, including mucositis, diarrhea, systemic inflammatory response, and pelvic radiotherapy-associated fatigue in cancer patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Quiescence maintenance is an important property of hematopoietic stem cells (HSCs), whereas the regulatory factors and underlying mechanisms involved in HSC quiescence maintenance are not fully ...uncovered. Here, we show that steroid receptor coactivator 3 (SRC-3) is highly expressed in HSCs, and SRC-3–deficient HSCs are less quiescent and more proliferative, resulting in increased sensitivity to chemotherapy and irradiation. Moreover, the long-term reconstituting ability of HSCs is markedly impaired in the absence of SRC-3, and SRC-3 knockout (SRC-3−/−) mice exhibit a significant disruption of hematopoietic stem and progenitor cell homeostasis. Further investigations show that SRC-3 deficiency leads to enhanced mitochondrial metabolism, accompanied by overproduction of reactive oxygen species (ROS) in HSCs. Notably, the downstream target genes of peroxisome proliferator–activated receptor-coactivators 1α (PGC-1α) involved in the regulation of mitochondrial metabolism are significantly upregulated in SRC-3–deficient HSCs. Meanwhile, a significant decrease in the expression of histone acetyltransferase GCN5 accompanied by downregulation of PGC-1α acetylation is observed in SRC-3–null HSCs. Conversely, overexpression of GCN5 can inhibit SRC-3 deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in SRC-3−/− mice. Collectively, our findings demonstrate that SRC-3 plays an important role in HSC quiescence maintenance by regulating mitochondrial metabolism.
•SRC-3 deficiency causes reduced quiescence and functional impairment of HSCs.•SRC-3 participates in HSC quiescence maintenance by regulating mitochondrial metabolism.
Display omitted
With the clarification of the important roles of microRNAs (miRNAs) in diverse physiologic and pathologic processes, the effects of miRNAs in wound healing have attracted more attention recently. ...However, the global pattern of miRNA expression in wound tissue is still unknown. In the present study, we depicted the miRNA profile and identified at least 54 miRNAs, including miR-21, changed for more than twofold at the stage of granulation formation during wound healing. These miRNAs were closely related to the major events of wound healing, including cell migration and proliferation, angiogenesis, and matrix remolding. Furthermore, we found that miR-21 was up-regulated after skin injury, mainly in activated and migrating epithelial cells of epidermis and mesenchymal cells of dermis. Locally antagonizing miR-21 by directly injecting antagomir to wound edge caused significant delay of wound closure with impaired collagen deposition. Unexpectedly, we found wounds treated with miR-21 antagomir had an obvious defect in wound contraction at an early stage of wound healing. The significant role of miR-21 in wound contraction was further confirmed by in vivo gain-of-function and in vitro loss-of-function experiments. In conclusion, the present study has for the first time depicted miRNA profiling of wound healing and demonstrated the involvement of miR-21 in regulating the wound contraction and collagen deposition. These results suggest that miR-21 may be a new medical target in skin wound manipulation.
Hematopoietic stem cell (HSC) fate is tightly controlled by various regulators, whereas the underlying mechanism has not been fully uncovered due to the high heterogeneity of these populations. In ...this study, we identify tetraspanin CD63 as a novel functional marker of HSCs in mice. We show that CD63 is unevenly expressed on the cell surface in HSC populations. Importantly, HSCs with high CD63 expression (CD63
) are more quiescent and have more robust self-renewal and myeloid differentiation abilities than those with negative/low CD63 expression (CD63
). On the other hand, using CD63 knockout mice, we find that loss of CD63 leads to reduced HSC numbers in the bone marrow. In addition, CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity, accompanied by increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations demonstrate that CD63 is required to sustain TGFβ signaling activity through its interaction with TGFβ receptors I and II, thereby playing an important role in regulating the quiescence of HSCs. Collectively, our data not only reveal a previously unrecognized role of CD63 but also provide us with new insights into HSC heterogeneity.
The development of multifunctional agents that could be used for simultaneous tumor targeting, imaging and treatment is a major goal in cancer research and is expected to contribute significantly to ...the realization of personalized oncology. Mitochondria are involved in diverse physiological activities and confer vital roles in cancer development and progression. Increasing efforts are being made to develop cancer treatment strategies based on various mitochondrial targets and novel mitochondrial drug delivery systems. Multifunctional nanostructures or multifunctional chemical compounds further broaden the current concept of tumor targeting and provide alternative solutions for mitochondrially targeted cancer therapy.
Long-term hematopoietic output is dependent on hematopoietic stem cell (HSC) homeostasis which is maintained by a complex molecular network. Among these, microRNAs play crucial roles, while the ...underlying molecular basis has not been fully elucidated. Here, we show that miR-21 is enriched in murine HSCs, and mice with conditional knockout of miR-21 exhibit an obvious perturbation in normal hematopoiesis. Moreover, significant loss of HSC quiescence and long-term reconstituting ability are observed in the absence of miR-21. Further studies reveal that miR-21 deficiency markedly decreases the NF-κB pathway, accompanied by increased expression of PDCD4, a direct target of miR-21, in HSCs. Interestingly, overexpression of PDCD4 in wild-type HSCs generates similar phenotypes as those of miR-21-deficient HSCs. More importantly, knockdown of PDCD4 can significantly rescue the attenuation of NF-κB activity, thereby improving the defects in miR-21-null HSCs. On the other hand, we find that miR-21 is capable of preventing HSCs from ionizing radiation-induced DNA damage via activation of the NF-κB pathway. Collectively, our data demonstrate that miR-21 is involved in maintaining HSC homeostasis and function, at least in part, by regulating the PDCD4-mediated NF-κB pathway and provide a new insight into the radioprotection of HSCs.
The roles played by cholesterol in cancer development and progression represent a popular field in the cancer community. High cholesterol levels are positively correlated with the risk of various ...types of cancer. APOA-I binding protein (AIBP) promotes the reverse cholesterol transport pathway (RCT) in cooperation with Apolipoprotein A-I (APOA-I) or high-density lipoprotein cholesterol. However, the combined effect of AIBP and APOA-I on intestinal tumor cells is still unclear.
Immunohistochemistry, western blot and qPCR were performed to investigate the expression of AIBP and APOA-I in intestinal tumor tissues and cell lines. The anti-tumor activity of AIBP and APOA-I was evaluated by overexpression or recombinant protein treatment. Cholesterol efflux and localization of lipid raft-related proteins were analyzed by a cholesterol efflux assay and lipid raft fraction assay, respectively.
Here, we reported that both AIBP expression and APOA-I expression were associated with the degree of malignancy in intestinal tumors. Co-overexpression of AIBP and APOA-I more potently inhibited colon cancer cell-mediated tumor growth and metastasis compared to overexpression of each protein individually. Additionally, the recombinant fusion proteins of AIBP and APOA-I exhibited a significant therapeutic effect on tumor growth in Apc
mice as an inherited intestinal tumor model. The synergistic effect of the two proteins inhibited colon cancer cell migration, invasion and tumor-induced angiogenesis by promoting cholesterol efflux, reducing the membrane raft content, and eventually disrupting the proper localization of migration- and invasion-related proteins on the membrane raft. Moreover, cyclosporine A, a cholesterol efflux inhibitor, rescued the inhibitory effect induced by the combination of AIBP and APOA-I.
These results indicate that the combination of APOA-I and AIBP has an obvious anticancer effect on colorectal cancer by promoting cholesterol efflux.
Cell-based transplantation, tissue engineering and gene therapy are important therapeutic strategies for present and future regenerative medicine. One challenge is to present the target cells in a ...suitable matrix to allow the cells to survive the wound contraction, tissue repair, and remodeling in certain tissues. Recently, functional biomaterial research has been directed towards the development of improved scaffolds and new drug delivery systems for regenerative medicine.
A literature survey was performed in basic and clinic publications relevant to the therapeutic potential of chitosan and its derivatives in regenerative medicine. In this review the functional properties and potential applications of chitosan and its derivatives in regenerative medicine are presented and discussed.
Chitosan can be obtained by alkaline deacetylation of chitin and is found to be a natural-based nontoxic, biocompatible, and biodegradable polymer with anti-microbial activity. Chitosan and its derivatives could accelerate wound healing by enhancing the functions of inflammatory cells and repairing cells. Recent studies further indicated that chitosan and its derivatives also are novel scaffold materials for tissue engineering and are-promising non-viral vectors for gene delivery.
Regenerative medicine has entered a new era with the development of modern science and technology. The novel properties of chitosan make it a versatile biomaterial for cell therapy, tissue engineering and gene therapy. It is hoped that these diverse approaches for regenerative medicine will translate from "bench to bedside" in the future.
The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not ...fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19
HSCs exhibit similar phenotypes to those of cells treated with SenexinB. Interestingly, the p53 signaling pathway is significantly activated in HSCs lacking CDK19 expression. Further investigations show that CDK19 can interact with p53 to inhibit p53-mediated transcription of p21 in HSCs and treatment with a specific p53 inhibitor (PFTβ) partially rescues the defects of CDK19-null HSCs. Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.
PDF
