The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and ...C1s (C1qr
2
s
2
), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.
Nuclear factor kappa B (NF‐κB) signaling pathway is activated in many colorectal cancer (CRC) cells and in the tumor microenvironment, which plays a critical role in cancer initiation, development, ...and response to therapies. In the present study, we found that the widely used antimalarial drug mefloquine was a NF‐κB inhibitor that blocked the activation of IκBα kinase, leading to reduction of IκBα degradation, decrease of p65 phosphorylation, and suppressed expression of NF‐κB target genes in CRC cells. We also found that mefloquine induced growth arrest and apoptosis of CRC cells harboring phosphorylated p65 in culture and in mice. Furthermore, expression of constitutive active IKKβ kinase significantly attenuated the cytotoxic effect of the compound. These results showed that mefloquine could exert antitumor action through inhibiting the NF‐κB signaling pathway, and indicated that the antimalarial drug might be repurposed for anti‐CRC therapy in the clinic as a single agent or in combination with other anticancer drugs.
Antimalarial drug mefloquine can be repurposed for anticolorectal cancer therapy as a novel NF‐κB inhibitor.
Sequence-defined polymers prepared from vinyl monomers attract tremendous research interests in mimicking the precise primary sequence and remarkable biological functions of natural biopolymers. ...Sequential single unit monomer insertion (SUMI) via the reversible addition–fragmentation chain-transfer (RAFT) mechanism shows the ability to assemble vinyl monomers in defined orders efficiently with high yields. However, the approach of RAFT SUMI to produce both degradable and biocompatible sequence-defined oligomers has not been reported yet. In this research, we report the radical ring-opening SUMI of a cyclic ketene acetal monomer, 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), with the alternating insertion of N-substituted maleimides to afford sequence-defined oligomers. The oligomers can be degraded into shorter fragments due to the ester bonds incorporated in the backbone. Moreover, one prepared trimer demonstrates the biocompatibility to the investigated human normal cells while showing the cytotoxic effect against the studied human cancer cells. The properties of the produced oligomers endowed by BMDO hold promise for decoding information stored in sequence-defined polymers and the potential in biomedical applications.
The ubiquitin‐proteasome system plays a critical role in controlling the level, activity and location of various cellular proteins. Significant progress has been made in investigating the molecular ...mechanisms of ubiquitination, particularly in understanding the structure of the ubiquitination machinery and identifying ubiquitin protein ligases, the primary specificity‐determining enzymes. Therefore, it is now possible to target specific molecules involved in ubiquitination and proteasomal degradation to regulate many cellular processes such as signal transduction, proliferation and apoptosis. In particular, alterations in ubiquitination are observed in most, if not all, cancer cells. This is manifested by destabilization of tumor suppressors, such as p53, and overexpression of oncogenes such as c‐Myc and c‐Jun. In addition to the development and clinical validation of proteasome inhibitor, bortezomib, in myeloma therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination enzymes. With the help of structural studies, rational design and chemical synthesis, it is conceivable that we will be able to use ‘druggable’ inhibitors of the ubiquitin system to evaluate their effects in animal tumor models in the not‐so‐distant future. (Cancer Sci 2009; 100: 24–28)
Previous literatures reported insulin‐like growth factor‐2 messenger RNA‐binding protein 3 (IGF2BP3) is a poor prognostic marker for colorectal cancer (CRC) patients. However, basic research on the ...effect and biological role of IGF2BP3 in CRC was still scare. Real‐time quantitative polymerase chain reaction and western blot analysis were used to examine IGF2BP3 expression level in tumors and paired normal tissues from CRC patients. Tissue microarrays with 192 CRC patients were subjected to immunohistochemical staining to analyze the prognostic value of IGF2BP3. Proliferation assays, migration assays, and xenograft tumor formation in nude mice were performed to assess the biological role of IGF2BP3 in CRC cells. IGF2BP3 expression was significantly upregulated in tumor tissues compared with the matched normal tissues both in messenger RNA and protein level and was associated with worse prognosis. IGF2BP3 knockdown made cell cycle arrest to impair the proliferation ability of CRC cells and further inhibited the xenograft tumor growth in nude mice, also inhibited the migration ability of CRC cells via inducing epithelial–mesenchymal transition. Therefore, the research demonstrated that increased IGF2BP3 expression promoted the aggressive phenotypes of CRC cells. Targeted IGF2BP3 could be a novel and effective gene therapy for CRC patients to make a better prognosis.
Insulin‐like growth factor‐2 messenger RNA‐binding protein 3 (IGF2BP3) expression was significantly increased in tumor tissues of colorectal cancer (CRC) patients and were related with the worse disease‐free survival and overall survival compared with those with low IGF2BP3 expression. Increased IGF2BP3 expression promoted the aggressive phenotypes of CRC cells. Targeted IGF2BP3 could be a novel and effective gene therapy for CRC patients to make a better prognosis.
ObjectivesTo delineate hospital service areas (HSAs) using the Dartmouth approach in China and identify the hypothesised demand-side, supply-side and region-specific factors of health expenditure ...within HSAs.DesignPopulation-based descriptive study.SettingWe selected the metropolis of Chengdu, one of the three most populous cities in China as a case for the analysis, where approximately 16.33 million residents living.ParticipantsIndividual-level in-patient discharge records (n=904 298) during the fourth quarter of 2018 (from 1 September to 31 December) were extracted from Sichuan Health Commission. Cases of non-residents of Chengdu were excluded from the datasets.MethodsWe conducted three sets of analyses: (1) apply Dartmouth approach to delineate HSAs; (2) use Geographic Information System (GIS)-based method to demonstrate health expenditure variations across delineated HSAs and (3) employ a three-level multilevel linear model to examine the association between health expenditure and demand-side, supply-side and region-specific factors.ResultsA total of 113 HSAs with a median population of 60 472 (ranging from 7022 to 827 750) was delineated. Total in-patient expenditure per admission varied more than threefold across HSAs after adjusting for age and gender. Apart from a list of demand-side factors, an increased number of physicians, healthcare facilities at higher levels and for-profit healthcare facilities were significantly associated with increased total in-patient expenditures. At the HSA level, the proportion of private healthcare facilities located in a single HSA was associated with increased total in-patient expenditure generated by that HSA, while the increased number of healthcare facilities in a HSA was negatively associated with the total in-patient expenditures.ConclusionHSAs were delineated to help establish an accountable healthcare delivery system, which serves as local hospital markets to provide in-patient healthcare via connecting demanders with suppliers inside particular HSAs. Policy-makers should adopt HSAs to identify variations of total in-patient expenditures among different areas and the potential associated factors. Findings from the HSA-based analysis could inform the formulation of relevant health policies and the optimisation of healthcare resource allocations.
The acute-phase protein orosomucoid (ORM) exhibits a variety of activities in vitro and in vivo, notably modulation of immunity and transportation of drugs. We found in this study that mice lacking ...ORM1 displayed aberrant energy homeostasis characterized by increased body weight and fat mass. Further investigation found that ORM, predominantly ORM1, is significantly elevated in sera, liver, and adipose tissues from the mice with high-fat diet (HFD)-induced obesity and db/db mice that develop obesity spontaneously due to mutation in the leptin receptor (LepR). Intravenous or intraperitoneal administration of exogenous ORM decreased food intake in C57BL/6, HFD, and leptin-deficient ob/ob mice, which was absent in db/db mice and was significantly reduced in mice with arcuate nucleus (ARC) LepR knockdown, whereas enforced expression of ORM1 in ARC significantly decreased food intake, body weight, and serum insulin level. Furthermore, we found that ORM is able to bind directly to LepR and activate the receptor-mediated JAK2-STAT3 signaling in hypothalamus tissue and GT1-7 cells, which was derived from hypothalamic tumor. These data indicated that ORM could function through LepR to regulate food intake and energy homeostasis in response to nutrition status. Modulating the expression of ORM is a novel strategy for the management of obesity and related metabolic disorders.
We and others have previously shown that the STAT3 signaling pathway is activated in some esophageal squamous cell carcinoma (ESCC) cells and is required for the survival and growth of these primary ...ESCC-derived xenografts. It has also been shown that the natural polyphenol curcumin is an effective anti-tumor agent.
Luciferase assay and immunoblotting were performed to examine whether curcumin suppressed STAT3 signaling. CCK-8 assay and xenografts were utilized for analyzing ESCC cell growth in culture and mice. Soft agar assay was carried out to determine the colony formation ability of ESCC cells in the presence or absence of curcumin. Cell death and cell cycle were assessed by In CELL Analyzer 2000. Immunohistochemistry and TUNEL assay were used for detecting apoptosis in ESCC tisuses. Molecular docking was performed to evaluate the interaction of curcumin with JAK2. JAK2 activity was assessed using an in vitro cell-free system. HE staining was used to evaluate the ESCC tissues.
The natural polyphenol curcumin inhibited STAT3 phosphorylation rapidly and blocked STAT3-mediated signaling in ESCC cells. It also induced growth arrest and apoptosis in cultured ESCC cells, which were attenuated by enforced expression of STAT3. Furthermore, curcumin preferentially blocked the growth of primary ESCC-derived xenografts that harbored activated STAT3.
Curcumin is able to exert anti-tumor action through inhibiting the STAT3 signaling pathway. Giving its wide use in traditional medicines with low toxicity and few adverse reactions, it is conceivable that curcumin might be further explored as a unique STAT3 inhibitor for anti-cancer therapies.
The ubiquitin–proteasome system regulates a variety of cellular processes including growth, differentiation and apoptosis. While E1, E2, and E3 are responsible for the conjugation of ubiquitin to ...substrates, deubiquitinating enzymes (DUBs) reverse the process to remove ubiquitin and edit ubiquitin chains, which have profound effects on substrates’ degradation, localization, and activities. In the present study, we found that the deubiquitinating enzyme USP47 was markedly decreased in primary colorectal cancers (CRC). Its reduced expression was associated with shorter disease-free survival of CRC patients. In cultured CRC cells, knockdown of USP47 increased pyroptosis and apoptosis induced by chemotherapeutic doxorubicin. We found that USP47 was able to bind with transcription elongation factor a3 (TCEA3) and regulated its deubiquitination and intracellular level. While ectopic expression of USP47 increased cellular TCEA3 and resistance to doxorubicin, the effect was markedly attenuated by TCEA3 knockdown. Further analysis showed that the level of pro-apoptotic Bax was regulated by TCEA3. These results indicated that the USP47-TCEA3 axis modulates cell pyroptosis and apoptosis and may serve as a target for therapeutic intervention in CRC.
Comprehensive investigation on understanding geographical inequalities of healthcare resources and their influencing factors in China remains scarce. This study aimed to explore both spatial and ...temporal heterogeneous impacts of various socioeconomic and environmental factors on healthcare resource inequalities at a fine-scale administrative county level. We collected data on county-level hospital beds per ten thousand people to represent healthcare resources, as well as data on 32 candidate socioeconomic and environmental covariates in southwest China from 2002 to 2011. We innovatively employed a cutting-edge local spatiotemporal regression, namely, a Bayesian spatiotemporally varying coefficients (STVC) model, to simultaneously detect spatial and temporal autocorrelated nonstationarity in healthcare-covariate relationships via estimating posterior space-coefficients (SC) within each county, as well as time-coefficients (TC) over ten years. Our findings reported that in addition to socioeconomic factors, environmental factors also had significant impacts on healthcare resources inequalities at both global and local space-time scales. Globally, the personal economy was identified as the most significant explanatory factor. However, the temporal impacts of personal economy demonstrated a gradual decline, while the impacts of the regional economy and government investment showed a constant growth from 2002 to 2011. Spatially, geographical clustered regions for both hospital bed distributions and various hospital bed-covariates relationships were detected. Finally, the first spatiotemporal series of complete county-level hospital bed inequality maps in southwest China was produced. This work is expected to provide evidence-based implications for future policy making procedures to improve healthcare equalities from a spatiotemporal perspective. The employed Bayesian STVC model provides frontier insights into investigating spatiotemporal heterogeneous variables relationships embedded in broader areas such as public health, environment, and earth sciences.
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