Search

There have been outbreaks of SARS-CoV-2 around the world for over three years, and its variants continue to evolve. This has become a major global health threat. The main protease (Mpro, also called 3CLpro) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified a novel potential inhibitor of Mpro, by applying the virtual screening of hundreds of nilotinib-structure-like compounds that we designed and synthesized. The screened compounds were assessed using SP docking, XP docking, MM-GBSA analysis, IFD docking, MD simulation, ADME/T prediction, and then an enzymatic assay in vitro. We finally identified the compound V291 as a potential SARS-CoV-2 Mpro inhibitor, with a high docking affinity and enzyme inhibitory activity. Moreover, the docking results indicate that His41 is a favorable amino acid for pi-pi interactions, while Glu166 can participate in salt-bridge formation with the protonated primary or secondary amines in the screened molecules. Thus, the compounds reported here are capable of engaging the key amino acids His41 and Glu166 in ligand-receptor interactions. A pharmacophore analysis further validates this assertion. [ABSTRACT FROM AUTHOR]

Heterotopic ossification (HO) is a double‐edged sword. Pathological HO presents as an undesired clinical complication, whereas controlled heterotopic bone formation by synthetic osteoinductive materials shows promising therapeutic potentials for bone regeneration. However, the mechanism of material‐induced heterotopic bone formation remains largely unknown. Early acquired HO being usually accompanied by severe tissue hypoxia prompts the hypothesis that hypoxia caused by the implantation coordinates serial cellular events and ultimately induces heterotopic bone formation in osteoinductive materials. The data presented herein shows a link between hypoxia, macrophage polarization to M2, osteoclastogenesis, and material‐induced bone formation. Hypoxia inducible factor‐1α (HIF‐1α), a crucial mediator of cellular responses to hypoxia, is highly expressed in an osteoinductive calcium phosphate ceramic (CaP) during the early phase of implantation, while pharmacological inhibition of HIF‐1α significantly inhibits M2 macrophage, subsequent osteoclast, and material‐induced bone formation. Similarly, in vitro, hypoxia enhances M2 macrophage and osteoclast formation. Osteoclast‐conditioned medium enhances osteogenic differentiation of mesenchymal stem cells, such enhancement disappears with the presence of HIF‐1α inhibitor. Furthermore, metabolomics analysis reveals that hypoxia enhances osteoclastogenesis via the axis of M2/lipid‐loaded macrophages. The current findings shed new light on the mechanism of HO and favor the design of more potent osteoinductive materials for bone regeneration. [ABSTRACT FROM AUTHOR]

Zinc finger protein 24 (ZNF24) has been demonstrated to regulate proliferation, differentiation and migration as well as invasion in several types of cells. However, the molecular role and clinical effects of ZNF24 in prostate cancer (PCa) remain unclear. The present study revealed that ZNF24 expression is upregulated in PCa, and associated with tumor volume, Gleason score, pathological grade and metastasis. Wound healing and Transwell invasion assays revealed that ectopic ZNF24 expression facilitated cell migration and invasion through the Twist1-induced epithelial-to-mesenchymal transition (EMT) process. In addition, colony formation and Cell Counting Kit-8 assays were used to determine the regulatory effects of ZNF24 on proliferation. The results suggested that ZNF24 also promoted cell proliferation in PCa. ZNF24 acted as an oncogene and promoted migration, invasion and EMT of PCa cells via the regulation of Twist1. [ABSTRACT FROM AUTHOR]

Objective: To explore the effects and underlying biological mechanisms of tetrahedral DNA nanostructures (TDNs) on the proliferation and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Materials and methods: Real‐time cell analysis (RTCA) and CCK8 were used to screen the best concentration of TDN for PDLSCs. Cell proliferation and osteogenic differentiation were assessed after PDLSCs were treated with TDN. Data were analysed using one‐way ANOVA. Results: Tetrahedral DNA nanostructures could play a crucial role in accelerating the proliferation of PDLSCs and had the strongest promotive effect on PDLSCs at a concentration of 250 nmol/L. Simultaneously, the osteogenic differentiation of PDLSCs could be promoted significantly by TDNs and the finding displayed that the Wnt/β‐catenin signalling pathway might be the underlying biological mechanisms of TDNs on promoting the osteogenic differentiation of PDLSCs. Conclusion: Tetrahedral DNA nanostructure treatment facilitated the proliferation of PDLSCs, significantly promoted osteogenic differentiation by regulating the Wnt/β‐catenin signalling pathway. Therefore, TDNs could be a novel nanomaterial with great potential for application to PDLSC‐based bone tissue engineering. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Researches showed that stiffness of the extracellular matrix can affect the differentiation of many stem cells. Dental pulp stem cells (DPSCs) are a promising type of adult stem cell. However, we know little about whether and how the behaviour of DPSCs is influenced by stiffness. Materials and methods: We carried out a study that cultured DPSCs on tunable elasticity polydimethylsiloxane substrates to investigate the influence on morphology, proliferation, osteogenic/odontogenic differentiation and its possible mechanism. Results: Soft substrates changed the cell morphology and inhibited the proliferation of DPSCs. Expression of markers related to osteogenic/odontogenic differentiation was significantly increased as the substrate stiffness increased, including ALP (alkaline phosphatase), OCN (osteocalcin), OPN (osteopontin), RUNX‐2 (runt‐related transcription factor‐2), BMP‐2 (bone morphogenetic protein‐2), DSPP (dentin sialophosphoprotein) and DMP‐1 (dentin matrix protein‐1). Mechanical properties promote the function of DPSCs related to the Wnt signalling pathway. Conclusions: Our results showed that mechanical factors can regulate the proliferation and differentiation of DPSCs via the WNT signalling pathway. This provides theoretical basis to optimize dental or bone tissue regeneration through increasing stiffness of extracelluar matrix. [ABSTRACT FROM AUTHOR]

A series of novel Bcr-AblT315I inhibitors with amino acids as flexible linker were developed and performed biological evaluation in vitro. [Display omitted] Despite the success of imatinib in CML therapy through Bcr-Abl inhibition, acquired drug resistance occurs over time in patients. In particular, the resistance caused by T315I mutation remains a challenge in clinic. Herein, we embarked on a structural optimization campaign aiming at discovery of novel Bcr-Abl inhibitors toward T315I mutant based on previously reported dibenzoylpiperazin derivatives. We proposed that incorporation of flexible linker could achieve potent inhibition of Bcr-AblT315I by avoiding steric clash with bulky sidechain of Ile315. A library of 28 compounds with amino acids as linker has been developed and evaluated. Among them, compound AA2 displayed the most potent activity against Bcr-AblWT and Bcr-AblT315I, as well as toward Bcr-Abl driven K562 and K562R cells. Further investigations indicated that AA2 could induce apoptosis of K562 cells and down regulate phosphorylation of Bcr-Abl. In summary, the compounds with amino acid as novel flexible linker exhibited certain antitumor activities, providing valuable hints for the discovery of novel Bcr-Abl inhibitors to overcome T315I mutant resistance, and AA2 could be considered as a candidate for further optimization. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to understand the effect of substrate stiffness (a mechanical factor of the extracellular matrix) on periodontal ligament stem cells (PDLSCs) and its underlying mechanism. Materials and methods: Elastic substrates were fabricated by mixing 2 components, a base and curing agent in proportions of 10:1, 20:1, 30:1 or 40:1. PDLSC morphology was observed using scanning electron microscopy (SEM). Cell proliferation and differentiation were assessed after PDLSCs was cultured on various elastic substrates. Data were analysed using one‐way ANOVA. Results: SEM revealed variations in the morphology of PDLSCs cultured on elastic substrates. PDLSC proliferation increased with substrate stiffness (P < .05). Osteogenic differentiation of PDLSCs was higher on stiff substrates. Notch pathway markers were up‐regulated in PDLSCs cultured on stiff substrates. Conclusions: Results suggested that the osteogenic differentiation of PDLSCs might be promoted by culturing them in a stiffness‐dependent manner, which regulates the Notch pathway. This might provide a new method of enhancing osteogenesis in PDLSCs. [ABSTRACT FROM AUTHOR]

Bcr-Abl is successfully applied to drug discovery as a CML therapeutic target, but point mutation resistance has become a major challenge in the clinical treatment of CML. Our previous studies have shown that the introduction of amino acids as flexible linkers and heterocyclic structures as HBMs can achieve potent inhibition of Bcr-Abl T315I . In continuation of these studies, we further enriched the linker types by developing a library of compounds with tert -leucine or serine as a linker. Biological results showed that these compounds exhibited enhanced inhibition against Bcr-Abl WT and Bcr-Abl T315I kinases as well as improved antiproliferative activity in leukemia cell assays compared to previously disclosed compounds. In particular, compounds TL8, TL10, BS4, BS10, SR5 and SR11 exhibited potent inhibitory activities against Ba/F3 cells bearing a T315I mutant. Additionally, compounds TL8, BS4 and SR5 effectively induced K562 cell apoptosis, arrested the cell cycle at the S or G2/M phase, and inhibited the phosphorylation of Bcr-Abl and STAT5 in a dose-dependent manner. Docking studies verified the rationality of tert -leucine or serine as a flexible linker and indicated that phenylpyridine with an amide side chain favored the potency of these inhibitors. Moreover, ADME prediction suggested that the tested compounds had a favorable safety profile. Thus, tert -leucine or serine can be used as a promising class of flexible linkers for Bcr-Abl inhibitors with heterocyclic structures as HBMs, and compounds BS4, SR5, and especially TL8, can be used as starting points for further optimization., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: To evaluate bone preservation and esthetic recovery between the socket-shield technique (SST) with different labial bone plate thicknesses and the conventional immediate implant technique (CIIT)., Materials and Methods: Patients who underwent immediate implant placement in the anterior region were divided into three groups: the SST with a thickwall phenotype (> 1 mm; SSTA group), the SST with a thin-wall phenotype (< 1 mm; SSTB group), and the CIIT with a thickwall phenotype (> 1 mm; CIIT group). Radiologic images and clinical photos were collected before surgery, immediately postoperatively, and 6 months postoperatively. The labial bone width, labial bone width change (BWC), labial bone volume change (BVC), pink esthetic score (PES), and complication rate were evaluated among the three groups. Statistical analysis was performed using SPSS software., Results: A total of 60 patients (n = 20/group) were enrolled in this 6-month retrospective study. The BWC in the SSTA group (0.22 to 0.30 mm) and the SSTB group (0.18 to 0.33 mm) was less than that in the CIIT group (0.61 to 0.80 mm; P < .004). The SSTA group and the SSTB group had a lower BVC (24.08 vs 21.14 vs 54.81, respectively; P = .004) and greater PES (11.75 vs 11.65 vs 10.65, respectively; P = .009) than the CIIT group. No complications occurred among these patients., Conclusions: With the limitations of this study, it can be concluded that the SST is a reliable method for preserving bone and achieving satisfactory esthetic outcomes. The labial bone plate phenotype associated with the SST has minimal impact on both clinical and radiologic outcomes.

Macrophages' activation plays a central role during the development and progression of inflammation, while the regulation of metabolic reprogramming of macrophages has been recently identified as a novel strategy for anti-inflammatory therapies. Our previous studies have found that tetrahedral framework nucleic acid (tFNA) plays a mild anti-inflammatory effect by inhibiting macrophage activation, but the specific mechanism remains unclear. Here, by metabolomics and RNA sequencing, choline uptake is identified to be significantly repressed by decreased slc44a1 expression in tFNA-treated activated macrophages. Inspired by this result, combined with the excellent delivery capacities of tFNA, siR-slc44a1 is loaded into the tFNA to develop a new tFNA-based small interfering RNA (siRNA) delivery system named 'nano-windmill,' which exhibits a synergetic role by targeting slc44a1, finally blowing up the anti-inflammatory effects of tFNA to inhibit macrophages activation via reducing choline uptake. By confirming its anti-inflammatory effects in chronic (periodontitis) and acute (sepsis) inflammatory disease, the tFNA-based nanomedicine developed for inflammatory diseases may provide broad prospects for tFNA upgrading and various biological applications such as anti-inflammatory., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components of the innate immune system, and their study has become a research hotspot in recent years. Many biochemical and structural studies that have collectively elucidated the mechanism of activation of the cGAS-STING pathway with atomic resolution have provided insights into the roles of the cGAS-STING pathway in innate immunity and clues to the origin and evolution of the modern cGAS-STING signaling pathway. The cGAS-STING pathway has been identified to protect the host against viral infection. After detecting viral dsDNA, cGAS synthesizes a second messenger to activate STING, eliciting antiviral immune responses by promoting the expression of interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs). Recently, the cGAS-STING pathway has also been found to be involved in response to bacterial infections, including bacterial pneumonia, melioidosis, tuberculosis, and sepsis. However, compared with its functions in viral infection, the cGAS-STING signaling pathway in bacterial infection is more complex and diverse since the protective and detrimental effects of type I IFN (IFN-I) on the host depend on the bacterial species and infection mode. Besides, STING activation can also affect infection prognosis through other mechanisms in different bacterial infections, independent of the IFN-I response. Interestingly, the core protein components of the mammalian cGAS-STING signaling pathway have been found in the bacterial defense system, suggesting that this widespread signaling pathway may have originated in bacteria. Here, we review recent findings related to the structures of major molecules involved in the cGAS-STING pathway and the effects of the cGAS-STING pathway in various bacterial infections and bacterial immunity, which may pave the way for the development of new antibacterial drugs that specifically kill bacteria without harmful effects on the host., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Pang, Zhang and Ji.)

In recent years, tetrahedral Framework Nucleic Acids(tFNAs) have become a hot topic in the field of DNA nanostructures because of their stable structures, nanoscale size, superior mechanical properties and convenient synthesis with high yield. tFNAs are considered promising drug delivery carriers because they can pass through the cellular membrane without any help and they have a good biocompatibility and biodegradability. Besides, they have rich modification sites, they can be modified by kinds of functional groups. The functionalization molecules can be modified on the vertexes, embedded between the double-stranded DNA of the tetrahedron edges, hanged on the edges, or encapsulated in the cage-like structure of the tetrahedron. The structure of tetrahedron can also be intelligently controlled through smart design, such as integrating DNA hairpin loop structure onto the edges. Nowadays, DNA tetrahedron will have a broader development prospect in the application of drug transport carriers and intelligent drug carriers. Therefore, DNA material is a new carrier material with great advantages and has a very broad application prospect in the construction of an intelligent drug transport system., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Eye diseases often lead to impaired vision and seriously affect the daily life of patients. Local administration of ophthalmic drugs is one of the most important approaches for the treatment of ophthalmic diseases. However, due to the special biochemical environment of the ocular tissue and the existence of many barriers, the bioavailability of conventional ophthalmic preparations in the eye is very low. Nanomaterials can be utilized as carriers of drugs, which can improve the absorption, distribution, metabolism and bioavailability of drugs in eyes. Nanomaterials have also the advantages of small size, simple preparation, good degradability, strong targeting, and little stimulation to biological tissues, providing an innovative and practical method for the drug delivery of ophthalmic diseases. In addition, nanomaterials can be used as an auxiliary means for early diagnosis of ophthalmic diseases by improving the specificity and accuracy of detection methods. Nanomaterials help clinicians and researchers delve deeper into the physiology and pathology of the eye at the nanoscale. We summarize the application of nanomaterials in the diagnosis and treatment of ophthalmic diseases in this review., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cancer is the second leading cause of human death after cardiovascular disease, and the most used drugs in clinics are cytotoxic agents. However, these drugs have some inherent disadvantages, such as the risk of toxicity, low selectivity, poor solubility, and so on. To overcome these shortcomings, a variety of drug delivery strategies based on prodrugs have been developed. The application of drug delivery systems can optimize ADME properties of cytotoxic agents and improve their selectivity at the target, thereby greatly enhancing the anticancer effect in clinics. At present, it has become mainstream in drug design. This review systematically summarized the studies of prodrug- based drug delivery systems over the past five to ten years, according to four aspects, solubility, controlled release, in situ concentration, and targeting., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Antisense oligonucleotides are considered to be a promising strategy for cancer therapy because of their high specificity and minimal side effects. They can bind specifically to mRNA silencing the expression of target genes. However, ssDNA cannot enter cells in large quantities, which limits its applications. Tetrahedral framework nucleic acids (tFNA) are considered to be optimal nanoscopic drug carriers because of their editability and biocompatibility. Most importantly, they can be modified with functional molecules. The over-expression of c-Met is associated with a wide variety of tumor occurrences, developments, drug resistance and prognoses. Activation of HGF/c-Met signaling pathways can promote cell migration and invasion in cancer. Therefore, blocking the expression of c-Met is a valid technique for cancer therapy. In this study, we used tFNA as carriers to deliver antisense oligonucleotides, which can bind to c-Met mRNA with high specificity and affinity, into cells resulting in the inhibition of c-Met expression for cancer therapy.