Tannic acid (TA) is a naturally occurring polyphenol compound commonly found in tea, wine, and fruits. Because of the excellent structural and functional properties afforded by TA, materials based on ...the structure of polyhydroxyphenols have great value, particularly for orthopedic transplantation. This compound, for example, can form a strong interaction with metals and can form a stable coating on their surfaces, thus, improving the physical and chemical properties of bone–implant surfaces and boosting implantation success rates. TA can also inhibit the activity of osteoclasts, thus, playing a potential role in the treatment of osteoporosis. Furthermore, if the body becomes polluted with heavy metals, TA can chelate the ions to protect bone morphology and structure. It also has a significant antibacterial effect and can reduce infections caused by surgical implantation and inhibit a variety of tumor cells, thereby promoting its potential application in spinal metastasis surgery. Furthermore, it can also slow the corrosion caused by magnesium alloys, thereby greatly improving the development of degradable orthopedic metal fixatives. Importantly, TA is cheap and easy to obtain, making it extremely valuable for use in orthopedics. This review focuses on the research status and practical applications of TA, and prospects for its future application for orthopedics (
Figure 1
).
Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising ...route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.
Based on a pharmacophore hypothesis substituted tetramic and tetronic acid 3-carboxamides as well as dihydropyridin-2-one-3-carboxamides were investigated as inhibitors of undecaprenyl pyrophosphate ...synthase (UPPS) for use as novel antimicrobial agents. Synthesis and structure–activity relationship patterns for this class of compounds are discussed. Selectivity data and antibacterial activities for selected compounds are provided.
To discover the bottleneck of business caused by the changing of market, especially in collaborative tasks, an approach is proposed to detect concept drift in the usage of resource services in ...business processes. Firstly, influence degree, described as features, is measured in a Resource-Service Sequence (RSS). Secondly, by mining business dataset, the influence relationship between resource services is resolved according to different time window. Then, the influence degrees are clustered as different clusters, called concept drift. Finally, RSSs with concept drift are derived from the feature sequence. The simulation results show the validity of the proposed approach.
N6-methyladenosine (m6A) is the most common posttranscriptional RNA modification and plays significant roles in physiological and pathological progression. Here, we probed the functions and mechanism ...of the m6A reader YTH domain containing 2 (YTHDC2) in Lung Adenocarcinoma (LUAD) tumorigenesis. Levels of genes and proteins of YTHDC2 and Mitochondrial ribosomal protein L7/L12 (MRPL12) were assayed by quantitative real-time polymerase chain reaction, western blotting and Immunohistochemistry (IHC) analyses. In vitro analysis was conducted using 5-ethynyl-2′-deoxyuridine (EdU), colony formation, flow cytometry, and transwell assays, respectively. In vivo assay was performed by using the mouse lung adenocarcinoma model. The methylated RNA immunoprecipitation (MeRIP) assay was used to detect the m6A modification profile of MRPL12 mRNA. YTHDC2 was lowly expressed in lung adenocarcinoma tissues and cells. Overexpression of YTHDC2 suppressed the proliferation, invasion and migration of lung adenocarcinoma cells, but induced cell apoptosis. As expected, forced expression of YTHDC2 hindered lung adenocarcinoma tumor growth in vivo. Mechanistically, YTHDC2 preferentially bound to m6A-modified MRPL12 mRNA and destabilized its expression. MRPL12 was highly expressed in lung adenocarcinoma tissues and cells, and MRPL12 silencing repressed the growth and mobility of lung adenocarcinoma cells. Moreover, MRPL12 upregulation attenuated the anticancer activity of YTHDC2 in lung adenocarcinoma cells. In vivo assay also showed YTHDC2 suppressed tumor growth in the lung adenocarcinoma mouse model via downregulating MRPL12. The m6A reader YTHDC2 repressed lung adenocarcinoma tumorigenesis by destabilizing MRPL12 in an m6A-dependent manner.
Ortho-biphenyl carboxamides, originally prepared as inhibitors of microsomal triglyceride transfer protein (MTP) have been identified as novel inhibitors of the Hedgehog signaling pathway. ...Structure–activity relationship studies for this class of compounds reduced MTP inhibitory activity and led to low nanomolar Hedgehog inhibitors. Binding assays revealed that the compounds act as antagonists of Smoothened and show cross-reactivity for both the human and mouse receptor.
A series of novel, potent quinolinyl-derived imidazo1,5-
apyrazine IGF-IR (IGF-1R) inhibitors—most notably,
cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo1,5-
...apyrazin-8-ylamine (AQIP)—is described. Synthetic details, structure–activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels.
Medical adhesives have emerged as potential materials for sealing, hemostasis and wound repairing in modern clinical surgery. However, most of existing medical adhesives are still far away from the ...clinical requirements for simultaneously meeting desirable tissue adhesion, safety, biodegradability, anti-swelling property, and convenient operability. Here, we present an entirely new kind of peptide-based underwater adhesives, which are constructed via cross-linked supramolecular copolymerization between cationic short peptides and glycyrrhizic acid (GA) in an aqueous solution. We revealed the unique molecular mechanism of the peptide/GA supramolecular polymers and underlined the importance of arginine residues in the enhancement of the bulk cohesion of the peptide/GA adhesive. We thus concluded a design guideline that the peptide sequence has to be encoded with multiple arginine termini and hydrophobic residues. The resulting adhesives exhibited effective tissue adhesion, robust cohesion, low cell cytotoxicity, acceptable hemocompatibility, inappreciable inflammation response, appropriate biodegradability, and excellent anti-swelling property. More attractively, the dried peptide/GA powder was able to rapidly self-gel into adhesives by absorbing water, suggesting conveniently clinical operability. Animal experiments showed that the peptide/GA supramolecular polymers could be utilized as reliable medical adhesives for dural sealing and repairing.
The fusion of protein science and peptide science opens up new frontiers in creating innovative biomaterials. Herein, a new kind of adhesive soft materials based on a natural occurring plant protein ...and short peptides via a simple co‐assembly route are explored. The hydrophobic zein is supercharged by sodium dodecyl sulfate to form a stable protein colloid, which is intended to interact with charge‐complementary short peptides via multivalent ionic and hydrogen bonds, forming adhesive materials at macroscopic level. The adhesion performance of the resulting soft materials can be fine‐manipulated by customizing the peptide sequences. The adhesive materials can resist over 78 cmH2O of bursting pressure, which is high enough to meet the sealing requirements of dural defect. Dural sealing and repairing capability of the protein‐peptide biomaterials are further identified in rat and rabbit models. In vitro and in vivo assays demonstrate that the protein‐peptide adhesive shows excellent anti‐swelling property, low cell cytotoxicity, hemocompatibility, and inflammation response. In particular, the protein‐peptide supramolecular biomaterials can in vivo dissociate and degrade within two weeks, which can well match with the time‐window of the dural repairing. This work underscores the versatility and availability of the supramolecular toolbox in the easy‐to‐implement fabrication of protein‐peptide biomaterials.
Multivalent ionic bonds between cationic peptides and supercharged plant protein result in the formation of protein/peptide adhesive materials with reliable tissue adhesion, strong cohesion, swelling resistance, hemocompatibility, low cell cytotoxicity, and inappreciable inflammation. This simple and green strategy enables to create novel surgical sealants for sealing and repairing the dural defect as demonstrated by the rat and rabbit models.
In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα ...positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
PDF
