As the crucial powerhouse for cell metabolism and tissue survival, the mitochondrion frequently undergoes morphological or positional changes when responding to various stresses and energy demands. ...In addition to intracellular changes, mitochondria can also be transferred intercellularly. Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction, the intercellular mitochondrial transfer also occurs under physiological conditions. In this review, the phenomenon of mitochondrial transfer is described according to its function under both physiological and pathological conditions, including tissue homeostasis, damaged tissue repair, tumor progression, and immunoregulation. Then, the mechanisms that contribute to this process are summarized, such as the trigger factors and transfer routes. Furthermore, various perspectives are explored to better understand the mysteries of cell-cell mitochondrial trafficking. In addition, potential therapeutic strategies for mitochondria-targeted application to rescue tissue damage and degeneration, as well as the inhibition of tumor progression, are discussed.
Highlights
2D Nb
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C MXene-integrated 3D-printing scaffolds against osteosarcoma were constructed with theragenerative functionality.
Nb
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C MXene in 3D scaffolds enabled photothermal ablation of ...osteosarcoma at NIR-II biowindow.
Nb
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C MXene in 3D scaffolds promoted osteogenesis, osteoconduction and osteoinduction, and drove vascularization for bone regeneration.
Early surgical resection and chemotherapy of bone cancer are commonly used in the treatment of bone tumor, but it is still highly challenging to prevent recurrence and fill the bone defect caused by the resection site. In this work, we report a rational integration of photonic-responsive two-dimensional (2D) ultrathin niobium carbide (Nb
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C) MXene nanosheets (NSs) into the 3D-printed bone-mimetic scaffolds (NBGS) for osteosarcoma treatment. The integrated 2D Nb
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C-MXene NSs feature specific photonic response in the second near-infrared (NIR-II) biowindow with high tissue-penetrating depth, making it highly efficient in killing bone cancer cells. Importantly, Nb-based species released by the biodegradation of Nb
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C MXene can obviously promote the neogenesis and migration of blood vessels in the defect site, which can transport more oxygen, vitamins and energy around the bone defect for the reparative process, and gather more immune cells around the defect site to accelerate the degradation of NBGS. The degradation of NBGS provides sufficient space for the bone remodeling. Besides, calcium and phosphate released during the degradation of the scaffold can promote the mineralization of new bone tissue. The intrinsic multifunctionality of killing bone tumor cell and promoting angiogenesis and bone regeneration makes the engineered Nb
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C MXene-integrated composite scaffolds a distinctive implanting biomaterial on the efficient treatment of bone tumor.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The skeletal system contains a series of sophisticated cellular lineages arising from the mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) that determine the homeostasis of bone and ...bone marrow. Here, we reasoned that osteocyte may exert a function in regulation of these lineage cell specifications and tissue homeostasis. Using a mouse model of conditional deletion of osteocytes by the expression of diphtheria toxin subunit α in dentin matrix protein 1 (DMP1)-positive osteocytes, we demonstrated that partial ablation of DMP1-positive osteocytes caused severe sarcopenia, osteoporosis, and degenerative kyphosis, leading to shorter lifespan in these animals. Osteocytes reduction altered mesenchymal lineage commitment, resulting in impairment of osteogenesis and induction of osteoclastogensis. Single-cell RNA sequencing further revealed that hematopoietic lineage was mobilized toward myeloid lineage differentiation with expanded myeloid progenitors, neutrophils, and monocytes, while the lymphopoiesis was impaired with reduced B cells in the osteocyte ablation mice. The acquisition of a senescence-associated secretory phenotype (SASP) in both osteogenic and myeloid lineage cells was the underlying cause. Together, we showed that osteocytes play critical roles in regulation of lineage cell specifications in bone and bone marrow through mediation of senescence.
A hallmark of aging is the weakening of our muscles and bones, which become more fragile as we get older. These gradual changes can result in a humpback and muscle shrinking among other conditions. At the same time little is known about what role osteocytes – the most abundant type of bone cell – play in the process of bone and muscle aging.
One way to investigate the role of osteocytes in aging is to remove them and observe what happens to nearby cells as they age. To achieve this Ding, Gao, Gao et al. genetically altered mice so that they would carry and activate a gene called DTA in their osteocytes. DTA is a gene derived from the bacterium that causes diphtheria, and when it is activated, it produces a toxin that accumulates in cells, eventually killing them. In the mice line developed by Ding, Gao, Gao et al. DTA slowly killed osteocytes, leading to adult mice lacking most of their osteocyte population that have a normal embryonic development. This is important because the fact that the mice develop normally before birth allowed the team to rule out embryonic defects when looking at their results.
Ding, Gao, Gao et al. found that, without enough osteocytes, the nearby bone and bone marrow cells aged faster than expected. Indeed, the skeleton and muscles of adult mice was severely affected by the loss of osteocytes, leading to fragile bones with lower mass and muscle shrinking. These mice looked old in their young age and died earlier.
At the cellular level, the removal of osteocytes impaired the formation of osteoblasts, the cells that are responsible for making bones. It also led to an increase in the numbers of osteoclasts – the cells that destroy bone tissue to repair it and maintain it – and fat tissue cells. Furthermore, cells in the bone marrow, which go on to make white blood cells, were also affected. The mechanisms through which osteocytes affect the growth of these other cells is yet to be fully understood. However, Ding, Gao, Gao et al. did observe that these cells acquired traits characteristic of aging cells, implying that osteocytes have a role in regulating cellular aging or senescence. Among these senescence traits is the increased production and secretion of molecules that interact with the immune system, a feature known as the ‘senescence-associated secretory phenotype’.
Overall, the results of Ding, Gao, Gao et al. suggest that reducing the number of osteocytes in mice leads to faster bone aging and affects the balance of the different cell types required for healthy bone and bone marrow growth. Future research could focus on finding drugs that allow osteocytes to keep performing their role during aging, and thus help maintain bone health. The findings of Ding, Gao, Gao et al. also suggest that osteocytes may be playing a previously underappreciated role in age-related diseases, which warrants further investigation.
Osteoarthritis (OA) is the most common joint disease and is the leading cause of chronic disability among older people. Chondrocyte death and extracellular matrix (ECM) degradation was involved in OA ...pathogenesis. Ferroptosis was an iron-dependent cell death associated with peroxidation of lipids. Here, we proved that ferroptosis exists in OA and identified glutathione peroxidase 4 (GPX4) as an important regulator of OA.
Ferroptosis-related alterations were analyzed in human OA and undamaged cartilage. Expression of GPX4 was examined in 55 paired human OA samples. Ferrostatin-1 (Fer-1) and Deferoxamine (DFO) were used to treat OA, in vitro and in vivo. Alterations of GPX4-mediated signaling pathway were identified by RNA-seq analysis. AAV-Gpx4-shRNA were used to downregulate GPX4 expression in vivo.
Transcriptomic, biochemical, and microscopical analyses indicated that ferroptosis was closely associated with OA. Expression of GPX4 in the OA cartilage from 55 OA patients were significantly lower than undamaged cartilage. Fer-1 and DFO could protect OA in a necroptosis-independent manner, suggesting that ferroptosis exists in OA prog. Importantly, GPX4 downregulation could increase the sensitivity of chondrocytes to oxidative stress and aggravate ECM degradation through the MAPK/NFκB pathway. Furthermore, downregulation of GPX4 expression by AAV-Gpx4 shRNA aggravated OA in vivo.
Ferroptosis contributes to OA pathogenesis and GPX4 was the intersection of two mechanisms in regulating OA progression: ferroptosis and ECM degradation.
This work was supported by the Projects of International Cooperation and Exchanges of National Natural Science Funding of China (Grant no. 81820108020), the National Key Research and Development Project of China (Grant no. 2018YFC1106300) and the Basic Science Program of Shanghai Jiao Tong University Affiliated Sixth People's Hospital (Grant no. ynms202102).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•We revealed lncRNA NR_033515 as a novel biomarker for Diabetic nephropathy patient.•We indicated the role of lncRNA NR_033515 in Diabetic nephropathy.•LncRNA NR_033515 directly ...interacted with miR-743b-5p in Diabetic nephropathy.
Diabetic nephropathy (DN) is a crucial microvascular complication of diabetes. Long non-coding RNAs (lncRNAs) participate in the occurrence and development of various diseases, but the function and regular mechanism of lncRNA-NR_033515 in DN is still unclear. In the present study, we demonstrated that the expression of NR_033515 was significantly increased in the serum of DN patients and was related to the different stages of DN. NR_033515 was also positively associated with diagnostic markers of DN (KIM-1 and NGAL). Overexpression of NR_033515 promoted proliferation, and inhibited apoptosis of MMC cells and increased the expression levels of proliferation-related genes. NR_033515 also accelerated the expression levels of fibrogenesis-related genes. TGF-β1 enhanced NR_033515-induced Epithelial-mesenchymal transition (EMT), while NR_033515 over-expression accelerated TGF-β1-induced EMT. Furthermore, we found that NR_033515 promoted cell proliferation and regulated P38, ASK1, Fibronectin, α-SMA, E-cadherin, and Vimentin expressions by miR-743b-5p. Therefore, our data indicated the potential role of NR_033515 in the proliferation, fibrogenesis and EMT in DN. NR_033515 could be a pivotal potential diagnostic and therapeutic target for the treatment of DN.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Denosumab is a monoclonal antibody against RANK ligand for treatment of giant cell tumor of bone (GCTB). Clinical trials and case series have demonstrated that denosumab is relevant to beneficial ...tumor response and surgical down-staging in patients of GCTB. However, these trials or case series have limitations with a short follow-up. Recent increasing studies revealed that denosumab probably increased the local recurrence risk in patients treated with curettage. This may be caused by the thicken bone margin of tumor that trapped tumor cells from curettage. The direct bone formation by tumor cells in the margin after denosumab treatment also contributed to the local recurrence.
in vitro
studies showed denosumab resulted in a cytostatic instead of a true cytotoxic response on neoplastic stromal cells. More importantly, denosumab-treated GCTB exhibited morphologic overlap with malignancy, and a growing number of patients of malignant transformation of GCTB during denosumab treatment have been reported. The optimal duration, long term safety, maintenance dose, and optimum indications remain to be elucidated. With these concerns in mind, this review warns that the denosumab therapy of GCTB should be applied with caution.
Under the public utilities franchise system, the executive branch may transfer the task of providing public utilities services for the common good to a private party. It should undertake to regulate ...and prevent the private party from pursuing its own interests to the detriment of public interest while discharging its duty under the public utilities franchise. Since any public interest must be enjoyed by all individuals, we can say that the obligations owed under administrative regulations aim at the ultimate goal of increasing individual welfare. In the public utilities franchise system, regulations of this kind can be divided into six different categories: maintaining and promoting necessary market competition, ensuring the continuity of public utilities services, ensuring non-discriminatory provision of public utilities services, ensuring the quality of public utilities services, ensuring reasonable charges for public utilities services, and ensuring the conservation of energy and protection of the environment while providing public utilities services. The absence of governmental regulation of the provision of public utilities and of reforms in such services in China has harmed both public interest and the rights and interests of consumers. Some of the problems caused include chaotic market access for public utilities, no guarantee of the sustainability of public utilities, the failure of the universality of public utilities, declining quality of public utilities, sharp rise in the prices of public utilities, insufficient regulations on the conservation of energy and environmental protection, and so on. In order to achieve the effective implementation of the administrative regulations and obligations therein with respect to public utilities and the maximization of public interest, the Chinese government should enhance its consciousness of regulating public utilities, improve the legal system to regulate public utilities, perfect the regulatory system for public utilities, and establish a system of liability to compensate for failures in regulation.
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CEKLJ, NUK, ODKLJ, PRFLJ, UM
Fbxo45, a conserved F-box protein, comprises of an atypical SKP1, CUL1, F-box protein (SCF) ubiquitin ligase complex that promotes tumorigenesis and development. However, the biological function and ...molecular mechanisms of Fbxo45 involved in pancreatic carcinogenesis are ambiguous. We conducted several approaches, including transfection, coIP, real-time polymerase chain reaction (RT-PCR), Western blotting, ubiquitin assays, and animal studies, to explore the role of Fbxo45 in pancreatic cancer. Here, we report that USP49 stability is governed by Fbxo45-mediated ubiquitination and is enhanced by the absence of Fbxo45. Moreover, Fbxo45 binds to a short consensus sequence of USP49 through its SPRY domain. Furthermore, Fbxo45-mediated USP49 ubiquitination and degradation are enhanced by NEK6 kinase. Functionally, Fbxo45 increases cell viability and motility capacity by targeting USP49 in pancreatic cancer cells. Xenograft mouse experiments demonstrated that ectopic expression of Fbxo45 enhanced tumor growth in mice and that USP49 overexpression inhibited tumor growth in vivo. Notably, Fbxo45 expression was negatively associated with USP49 expression in pancreatic cancer tissues. Fbxo45 serves as an oncoprotein to facilitate pancreatic oncogenesis by regulating the stability of the tumor suppressor USP49 in pancreatic cancer.
In this paper, a dynamic automatic obstacle avoidance trajectory planning and tracking control framework is proposed for tractor-trailer system. Tractor-trailer is a special class of multibody and ...nonholonomic system, whose backward and forward operations have difference kinetic mechanisms. Because the obstacle avoidance behaviors are concerned with the two motion modes, the kinematic models including backward and forward movements are firstly derived. Secondly, a time-based quintic polynomial function is developed to plan two kinds of dynamic obstacle avoidance trajectories based on dynamics constraints and the information from on board sensors, so as to minimize the collision risk. Thirdly, a model predictive control (MPC)-based posture controller is designed, by which better tracking performance can be achieved for both forward and backward obstacle avoidance maneuvers. Lastly, the simulation results validate the effectiveness of the proposed dynamic obstacle avoidance framework and the designed methods.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells. Recent studies have revealed a close relationship between exosomes and ...bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.
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