Liquid–liquid phase separation of amyloid-β oligomers modulates amyloid fibrils formation

Soluble amyloid-β oligomers (AβOs) are proposed to instigate and mediate the pathology of Alzheimer’s disease, but the mechanisms involved are not clear. In this study, we reported that AβOs can undergo liquid–liquid phase separation (LLPS) to form liquid-like droplets in vitro. We determined that AβOs exhibited an α-helix conformation in a membrane-mimicking environment of SDS. Importantly, SDS is capable of reconfiguring the assembly of different AβOs to induce their LLPS. Moreover, we found that the droplet formation of AβOs was promoted by strong hydrated anions and weak hydrated cations, suggesting that hydrophobic interactions play a key role in mediating phase separation of AβOs. Finally, we observed that LLPS of AβOs can further promote Aβ to form amyloid fibrils, which can be modulated by (−)-epigallocatechin gallate. Our study highlights amyloid oligomers as an important entity involved in protein liquid-to-solid phase transition and reveals the regulatory role of LLPS underlying amyloid protein aggregation, which may be relevant to the pathological process of Alzheimer’s disease.     

Nitrate increases cisplatin chemosensitivity of oral squamous cell carcinoma via REDD1/AKT signaling pathway

Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma (OSCC) treatment,it exerts multiple side effects and poo...     

DLK1在干细胞和肿瘤中的作用

DLK1是EGF家族成员之一,是一个父源表达母源沉默的印记基因产物,其表达受等位基因差异性甲基化区(DMR)的调控。Dlk1是细胞分化的重要调节基因,可抑制脂肪前体细胞向脂肪细胞分化。DLK1通过和Notch1相互作用,在Notch通路中起负调控作用。DLK1在肝干细胞中表达,提示可以作为肝干细胞分离的标记物。此外,DLK1在多种分泌性肿瘤细胞中高表达,提示DLK1可能与这些肿瘤的形成密切相关。     

Natural born killers: NK cells in cancer therapy

Chimeric antigen receptor-modified T (CAR-T) cells have brought a major breakthrough in tumor immunotherapy. As research continues to develop, CAR-T therapies have shown certain limitations, such as graft-versus-host reaction and the long time required to generate CAR-T cells. Natural killer (NK) cells, as the first line of defense against pathogens and cancer cells, belong to the innate immune system and have the advantage of being able to replace T cells, and can be used to prepare engineered chimeric antigen receptor-modified NK (CAR-NK) cells. The biological characteristics of CAR-NK cells, their sources, and the latest research progress and prospects for tumor treatment in China and worldwide are presented in this review.     

Participation of lipopolysaccharide in hyperplasic adipose expansion: Involvement of NADPH oxidase/ROS/p42/p44 MAPK‐dependent Cyclooxygenase‐2

Obesity is a world‐wide problem, especially the child obesity, with the complication of various metabolic diseases. Child obesity can be developed as early as the age between 2 and 6. The expansion of fat mass in child age includes both hyperplasia and hypertrophy of adipose tissue, suggesting the importance of proliferation and adipogenesis of preadipocytes. The changed composition of gut microbiota is associated with obesity, revealing the roles of lipopolysaccharide (LPS) on manipulating adipose tissue development. Studies suggest that LPS enters the circulation and acts as a pro‐inflammatory regulator to facilitate pathologies. Nevertheless, the underlying mechanisms behind LPS‐modulated obesity are yet clearly elucidated. This study showed that LPS enhanced the expression of cyclooxygenase‐2 (COX‐2), an inflammatory regulator of obesity, in preadipocytes. Pretreating preadipocytes with the scavenger of reactive oxygen species (ROS) or the inhibitors of NADPH oxidase or p42/p44 MAPK markedly decreased LPS‐stimulated gene expression of COX‐2 together with the phosphorylation of p47^phox and p42/p44 MAPK, separately. LPS activated p42/p44 MAPK via NADPH oxidase‐dependent ROS accumulation in preadipocytes. Reduction of intracellular ROS or attenuation of p42/p44 MAPK activation both reduced LPS‐mediated COX‐2 expression and preadipocyte proliferation. Moreover, LPS‐induced preadipocyte proliferation and adipogenesis were abolished by the inhibition of COX‐2 or PEG₂ receptors. Taken together, our results suggested that LPS enhanced the proliferation and adipogenesis of preadipocytes via NADPH oxidase/ROS/p42/p44 MAPK‐dependent COX‐2 expression.     

Distribution of Small Integrin-binding Ligand, N-linked Glycoproteins (SIBLING) in the Articular Cartilage of the Rat Femoral Head

The small integrin-binding ligand, N-linked glycoprotein (SIBLING) family is closely related to osteogenesis. Until recently, little was known about their existence in articular cartilage. In this study, we systematically evaluated the presence and distribution of four SIBLING family members in rat femoral head cartilage: dentin matrix protein 1 (DMP1), bone sialoprotein (BSP), osteopontin (OPN), and dentin sialophosphoprotein (DSPP). First, non-collagenous proteins were extracted and then separated by ion-exchange chromatography. Next, the protein extracts eluted by chromatography were analyzed by Stains-all staining and Western immunoblotting. IHC was used to assess the distribution of these four SIBLING family members in the femoral head cartilage. Both approaches showed that all the four SIBLING family members are expressed in the femoral head cartilage. IHC showed that SIBLING members are distributed in various locations throughout the articular cartilage. The NH₂-terminal fragments of DMP1, BSP, and OPN are present in the cells and in the extracellular matrix, whereas the COOH-terminal fragment of DMP1 and the NH₂-terminal fragment of DSPP are primarily intracellularly localized in the chondrocytes. The presence of the SIBLING family members in the rat femoral head cartilage suggests that they may play important roles in chondrogenesis. (J Histochem Cytochem 58:1033–1043, 2010)     

The p47 GTPase Lrg-47 (Irgm1) links host defense and hematopoietic stem cell proliferation

Hematopoietic stem cells (HSCs) are self-renewing bone marrow cells that give rise to all blood lineages and retain a remarkable capacity to proliferate in response to insult. Although some controls on HSC activation are known, little is understood about how this process is linked to natural signals. We report that the interferon-inducible GTPase Lrg-47 (Irgm1), previously shown to play a critical role in host defense, inhibits baseline HSC proliferation and is required for a normal HSC response to chemical and infectious stimuli. Overproliferating Lrg-47(-/-) HSCs are severely impaired in functional repopulation assays, and when challenged with hematopoietic ablation by 5-fluorouracil or infection with Mycobacterium avium, Lrg-47(-/-) mice fail to achieve the expected expansion response in stem and progenitor cell populations. Our results establish a link between the response to infection and HSC activation and demonstrate a novel function for a member of the p47 GTPase family.