Targeting organelles by modulating the redox potential of mitochondria is a promising approach to kill cancer cells that minimizes acquired drug resistance. However, it lacks selectivity because ...mitochondria perform essential functions for (almost) all cells. We show that enzyme-instructed self-assembly (EISA), a bioinspired molecular process, selectively generates the assemblies of redox modulators (e.g., triphenyl phosphinium (TPP)) in the pericellular space of cancer cells for uptake, which allows selectively targeting the mitochondria of cancer cells. The attachment of TPP to a pair of enantiomeric, phosphorylated tetrapeptides produces the precursors (L-1P or D-1P) that form oligomers. Upon dephosphorylation catalyzed by ectophosphatases (e.g., alkaline phosphatase (ALP)) overexpressed on cancer cells (e.g., Saos2), the oligomers self-assemble to form nanoscale assemblies only on the surface of the cancer cells. The cancer cells thus uptake these assemblies of TPP via endocytosis, mainly via a caveolae/raft-dependent pathway. Inside the cells, the assemblies of TPP-peptide conjugates escape from the lysosome, induce dysfunction of mitochondria to release cytochrome c, and result in cell death, while the controls (i.e., omitting TPP motif, inhibiting ALP, or removing phosphate trigger) hardly kill the Saos2 cells. Most importantly, the repeated stimulation of the cancers by the precursors, unexpectedly, sensitizes the cancer cells to the precursors. As the first example of the integration of subcellular targeting with cell targeting, this study validates the spatial control of the assemblies of nonspecific cytotoxic agents by EISA as a promising molecular process for selectively killing cancer cells without inducing acquired drug resistance.
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•The manuscript mainly writes the structure of JAKs and STATs.•The regulation mechanism and negative regulators of JAK/STAT signaling pathway.•Some diseases associated with the ...JAK/STAT pathway and JAKs inhibitors.
The JAK/STAT signaling pathway is an universally expressed intracellular signal transduction pathway and involved in many crucial biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. It provides a direct mechanism for extracellular factors-regulated gene expression. Current researches on this pathway have been focusing on the inflammatory and neoplastic diseases and related drug.
The mechanism of JAK/STAT signaling is relatively simple. However, the biological consequences of the pathway are complicated due to its crosstalk with other signaling pathways. In addition, there is increasing evidence indicates that the persistent activation of JAK/STAT signaling pathway is closely related to many immune and inflammatory diseases, yet the specific mechanism remains unclear. Therefore, it is necessary to study the detailed mechanisms of JAK/STAT signaling in disease formation to provide critical reference for clinical treatments of the diseases.
In this review, we focus on the structure of JAKs and STATs, the JAK/STAT signaling pathway and its negative regulators, the associated diseases, and the JAK inhibitors for the clinical therapy.
Promising vaccine adjuvants of self‐assembling peptide hydrogels for protein ovalbumin (OVA) are introduced in this study. The hydrogels are formed by the enzyme of phosphatase, and the vaccine ...adjuvant potency of both l‐ and d‐peptide hydrogels is evaluated. The results indicate that, compared with the clinically used alum adjuvant, both l‐ and d‐peptide hydrogels can increase the IgG production of OVA for about 1.3 and 3.8 times, respectively. Both gels can enhance antigen uptake and induce dendritic cell maturation, and promote and prolong accumulation of antigen in lymph node, as well as evoke germinal center formation. However, the d‐peptide hydrogel with OVA exhibits a slightly more efficient accumulation of OVA in the lymph nodes and seems preventing tumor growth more significantly than its l‐counterpart. With the good biocompatibility and degradability of peptide hydrogels, the hydrogels described in this study have big potential for the production of protein vaccines for immunotherapy against different diseases.
Short peptides and the protein antigen can coassemble into supramolecular hydrogels capable of raising both humoral and cellular immune responses in mice.
Prostate cancer is a common malignant tumor, which can spread to multiple organs in the body. Metastatic disease is the dominant reason of death for patients with prostate cancer. Prostate cancer ...usually transfers to bone. Bone metastases are related to pathologic fracture, pain, and reduced survival. There are many known targets for prostate cancer treatment, including androgen receptor (AR) axis, but drug resistance and metastasis eventually develop in advanced disease, suggesting the necessity to better understand the resistance mechanisms and consider multi-target medical treatment. Because of the limitations of approved treatments, further research into other potential targets is necessary. Metastasis is an important marker of cancer development, involving numerous factors, such as AKT, EMT, ECM, tumor angiogenesis, the development of inflammatory tumor microenvironment, and defect in programmed cell death. In tumor metastasis, programmed cell death (autophagy, apoptosis, and necroptosis) plays a key role. Malignant cancer cells have to overcome the different forms of cell death to transfer. The article sums up the recent studies on the mechanism of bone metastasis involving key regulatory factors such as macrophages and AKT and further discusses as to how regulating autophagy is crucial in relieving prostate cancer bone metastasis.
In this study, a framework of a bi-level multi-objective linear fractional programming (BMLFP) approach is developed for the optimization of water consumption structure based on water shortage risk. ...It incorporates linear fractional programming (LFP), multi-objective programming (MOP) into bi-level programming (BP). The model considers the water shortage risk measured by interior-outer-set risk assessment method, and integrates it into inexact water resources optimization model. The complicated model not only can enhance the conventional programming method through the interactive influence and mutual restriction between the upper- and lower-level decision processes, and multiple objectives, but also improve the robustness of conventional programming methods by integrating the water shortage risk. Besides, the model could achieve the tradeoff between equality and economic benefit of system and figure out the interaction amid water shortage risk, water allocation and objectives. It is applied to a case study to conduct water resources management among different water users including agricultural, industrial, domestic, and ecological sectors in the middle reaches of Heihe River Basin, northwest China. The water allocation schemes with ten water-shortage risk scenarios is formed to compare the influence of water shortage degree on water allocation and figure out the optimal water allocation schemes. Besides, the performance of the developed model is enhanced by comparing with the two-level linear fractional water management (TLFWM) model and actual condition. The results indicate that the water shortage belongs to general risk area, and the water-shortage risk has obvious effect on agricultural water allocations while has insensitive influence on that of the industrial, domestic and ecological sectors. Compared with the TLFWM model and actual condition, the developed BMLFP model could improve the equality and benefit of system and lessen the water allocation. The decision makers can find better water-allocation decision alternatives obtained from BMLFP model according to their risk attitude to support social harmony and economic development.
•A bi-level multi-objective linear fractional programming model is built.•The water shortage risk is measured through interior-outer set model.•The equality water allocation and economic return are optimized.•The model is applied into a case study in northwest China for water resources management.•The framework can provide tradeoff amid water allocation, risk, equality and benefit.
1 Introduction
The importance of reservoir has been widely recognized in the field of unconventional oil and gas r, esource（Zou Caineng et al., 2012）. The pore structure is the core problem of coal ...reservoir. One side, the pore structure influenced the adsorption ability of the coal pore structure; The other hand, the pore structure determines the coalbed methane output mode（Zou Caineng et al., 2013）. Hou QuanLin（2012） thinked that different deformation mechanisms, such as composition of the pore system and structure of coal are different, mainly in microstructure and pore structure and coal and chemical structure.
The incidence of bladder urothelial carcinoma (UC), a common malignancy of the urinary tract, is approximately three times higher in men than in women. High expression of the mitotic kinase BUB1 is ...associated with the occurrence and development of several cancers, although the relationship between BUB1 and bladder tumorigenesis remains unclear.
Using a microarray approach, we found increased BUB1 expression in human BCa. The association between BUB1 and STAT3 phosphorylation was determined through molecular and cell biological methods. We evaluated the impact of pharmacologic inhibition of BUB1 kinase activity on proliferation and BCa progression in vitro and in vivo.
In this study, we found that BUB1 expression was increased in human bladder cancer (BCa). We further identified through a series of molecular and cell biological approaches that BUB1 interacted directly with STAT3 and mediated the phosphorylation of STAT3 at Ser727. In addition, the findings that pharmacologic inhibition of BUB1 kinase activity significantly suppressed BCa cell proliferation and the progression of bladder cancer in vitro and in vivo were further verified. Finally, we found that the BUB1/STAT3 complex promoted the transcription of STAT3 target genes and that depletion of BUB1 and mutation of the BUB1 kinase domain abrogated this transcriptional activity, further highlighting the critical role of kinase activity in the activation of STAT3 target genes. A pharmacological inhibitor of BUB1 (2OH-BNPP1) was able to significantly inhibit the growth of BCa cell xenografts.
This study showed that the BUB1 kinase drives the progression and proliferation of BCa by regulating the transcriptional activation of STAT3 signaling and may be an attractive candidate for therapeutic targeting in BCa.
This paper combines a risk-based two-stage stochastic robust programming (RTSRP) model into an agricultural-ecological system dynamics (AESD) to conduct agricultural-ecological water resources ...management. It integrates the chance- constrained programming, conditional risk-at-value, two-stage stochastic robust programming with the AESD model. The RTSRP model improves upon the TSRP model by introducing the risk control measurements. The agricultural-ecological dynamic system (AEDS) model can build water connections amid wheat, field corn, seed corn, economic crops, woodland, meadow, and city greening and farmland shelterbelts. Besides, the ecological service value is transformed into the irrigation benefit of ecological sector to guide water allocation amid sub-ecological sectors at a more applicable detailed scale. It can tradeoff relationships between economic benefit and ecological recovery by formulating two enlarging ecological areas scenarios. The combinations of the RTSRP model and the AEDS model can get optimal water allocation schemes, and simulate future sustainable degree (SD) of optimal water allocation schemes and explore relationships amid water allocation, economic benefit, and SD and risk and robustness of model. It is used to the middle reaches of the Heihe River Basin in China to verify its application. The results show that water allocation schemes have different responses on various risk scenarios. Higher water allocation corresponds to bigger water shortage risk and higher robustness of the model. The economic benefit positive with water allocation is contradictory with SD. Enlarging ecological areas contributes to improvements of economic benefit and ecological recovery, but not the SD under the condition of enough water resources.
A common stage of advanced prostate cancer is castration-resistant prostate cancer (CRPC), greater understanding of which is required in order to address and solve the clinically difficult challenge. ...Cathepsin K (CTSK) is a cysteine protease that usually has a strong activity of degrading extracellular matrix and is related to osteoclast-mediated bone destruction. However, the mechanism of CTSK-regulation in CRPC is still unclear to us. The current study aimed to analyze the expression of differentially expressed genes (DEGs) in patient samples (from localized PC and CRPC). Interestingly, we found that CTSK to be significantly up-regulated in CRPC. Through further signal pathway enrichment analysis, we found that the IL-17 signaling pathway to be highly correlated with CTSK. The oncogenic functions of CTSK and IL-17 in CRPC were proven by a series of in vivo and in vitro experiments. Possible downstream molecules of CTSK were investigated, which could serve as control elements to regulate the expression of EMT, thereby facilitating the metastasis and excessive proliferation of PC cells. Expression of CTSK was related to high concentration of M2 tumor-associated macrophages (TAMs) M2 in CRPC. A CTSK-mediated feedback circuit between TAMs and CRPC tissues was indicated in the process of transfer, proving the possibility of CTSK could be use as an available therapeutic target for CRPC.
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