Search

In the process of cancer EMT, some subgroups of cancer cells simultaneously exhibit both mesenchymal and epithelial characteristics, a phenomenon termed partial EMT (pEMT). pEMT is a plastic state in which cells coexpress epithelial and mesenchymal markers. In squamous cell carcinoma (SCC), pEMT is regulated, and the phenotype is maintained via the HIPPO pathway, NOTCH pathway and TGF-β pathways and by microRNAs, lncRNAs and the cancer microenvironment (CME); thus, SCC exhibits aggressive tumorigenic properties and high stemness, which leads collective migration and therapy resistance. Few studies have reported therapeutic interventions to address cells that have undergone pEMT, and this approach may be an effective way to inhibit the plasticity, drug resistance and metastatic potential of SCC.

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC50 value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.

In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the superior derivative 13ac. Compound 13ac showed excellent potency on JAK2 kinase, SET-2, and Ba/F3V617F cells (high expression of JAK2V617F mutation) with IC50 values of 3, 11.7, and 41 nM, respectively. Further mechanistic studies demonstrated that compound 13ac could downregulate the phosphorylation of downstream proteins of JAK2 kinase in cells. Compound 13ac also showed good selectivity in kinase scanning and potent in vivo antitumor efficacy with 82.3% tumor growth inhibition in the SET-2 xenograft model. Moreover, 13ac significantly ameliorated the disease symptoms in a Ba/F3-JAK2V617F allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.

Herein, we describe the design, synthesis, and structure-activity relationships of a series of unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases. These screening cascades revealed that 18e was a preferred compound, with IC50 values of 0.7 and 4 nM for JAK2 and FLT3, respectively. Moreover, 18e was a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, respectively, and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays, 18e exhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of 18e could significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, respectively. Additionally, 18e showed an excellent bioavailability (F = 58%), a suitable half-life time (T1/2 = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that 18e might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia.

A series of pyrrolo[2,3- d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in the G0/G1 stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability ( F = 59.5%) and suitable eliminated half-life time ( T1/2 = 2.06 h), suggesting that 9u may be a potent candidate for treating acute myelogenous leukemia.

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1

The development of biomimetic bone graft materials for periodontal tissue engineering is a field of topical interest. In this study, we designed a dual-functionalized apatite nanocomposite, which could integrate multiple molecular cues for manipulating the fate of periodontal ligament stem cells (PDLSCs). Briefly, inspired by mussels, a biomimetic nanohydroxyapatite was fabricated using a polydopamine structure as a template (named as tHA) and then surface-modified with bone-forming peptide-1 (BFP-1) and vascular endothelial growth factor-mimicking peptide (QK) via a single step of catechol chemistry. Our study showed that the biofunctions of tethered peptides were not compromised on the surface of apatite nanoparticles. Because of the synergistic effect of BFP-1 and QK peptides, the dual-functionalized apatite nanocomposite showed improved cytocompatibility compared to controls. Moreover, it can boost the proliferation and osteogenic differentiation of PDLSCs, indicating excellent bioactivity of tHA-BFP/QK nanoparticles on cell fate decision. More importantly, animal experiments showed that dual-functionalized apatite nanocomposites could dramatically promote the regeneration of periodontal bone. It is concluded that our work provides an instructive insight into the design of biomimetic apatite nanocomposites, which holds a great potential for applications in periodontal bone repair.

Janus tyrosine kinase 3 (JAK3) is expressed in lymphoid cells and is involved in the signalling of T cell functions. The development of a selective JAK3 inhibitor has been shown to have a potential benefit in the treatment of autoimmune disorders. In this article, we developed the 4-aminopiperidine-based compound RB1, which was highly selective for JAK3 inhibition, with an IC50 of value of 40 nM, but did not inhibit JAK1, JAK2 or tyrosine kinase 2 (TYK2) at concentrations up to 5 µM. Furthermore, RB1 also exhibited favourable selectivity against a panel of representative kinases. In a battery of cytokine-stimulated cell-based assays, this potent inhibitor of JAK3 activity with good selectivity against other kinases could potently inhibit JAK3 activity over the activity of JAK1 or JAK2 (over at least 100-fold). A combination of liquid chromatography-mass spectrometry (LC-MS) experiments validated that RB1 covalently modified the unique cysteine 909 residue in JAK3. In vivo, RB1 exerted significantly improved pathology in the joints of a collagen-induced arthritis mouse model. The reasonable pharmacokinetics properties (F = 72.52%, T1/2 = 14.6 h) and favourable results of toxicology experiments (LD50 > 2 g/kg) suggest that RB1 has the potential to be an efficacious treatment for RA.

Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16. B16 preferentially inhibited Btk (IC50 = 21.70 ± 0.82 nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto-phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1 cell lines with IC50 values over 30 μM. Moreover, B16 showed very weak potential to block the hERG channel (IC50 = 11.10 μM) in comparison to ibrutinib (IC50 = 0.97 μM). Owing to its favorable physicochemical properties (ClogP = 2.53, aqueous solubility ≈ 0.1 mg/mL), pharmacokinetic profiles (F = 49.15%, t1/2 = 7.02 h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis.

Rationale: Colorectal cancer (CRC) is the third most commonly diagnosed cancer around the world. Over the past several years, immunotherapy has demonstrated considerable clinical benefit in CRC therapy, and the number of immunologic therapies for cancer treatment continues to climb each year. Interleukin-15 (IL15), a potent pro-inflammatory cytokine, has emerged as a candidate immunomodulator for the treatment of CRC. Methods: In this study, we developed a novel gene delivery system with a self-assembly method using DOTAP and MPEG-PLA (DMA) to carry pIL15, denoted as DMA-pIL15 which was used to treat tumor-bearing mice. Results: Supernatant from lymphocytes treated with supernatant derived from CT26 cells transfected with DMA-pIL15 inhibited the growth of CT26 cells and induced cell apoptosis in vitro. Treatment of tumor-bearing mice with DMA-pIL15 complex significantly inhibited tumor growth in both subcutaneous and peritoneal models in vivo by inhibiting angiogenesis, promoting apoptosis, and reducing proliferation through activation of the host immune system. Conclusion: The IL-15 plasmid and DMA complex showed promise for treating CRC clinically as an experimental new drug.

Secondhand smoke (SHS) has adverse effects on health, particularly for children. Our purpose was to analyze the correlation between SHS exposure and heavy metal concentrations in children. The investigation was conducted in Xinxiang County, Henan Province, China, from August 2015 to December 2015. In total, 821 students (433 boys and 388 girls) were recruited, and the contents of heavy metals in their hair-including chromium, manganese, nickel, arsenic, lead, and cadmium-were detected by ICP-MS. The children's parents were informed, and a questionnaire was conducted, which included questions about smoking habits and demographic characteristics. Our results indicate that all parent smokers are fathers, 48.9% of fathers who are smokers, but 25.2% of fathers smoke in front of their children. The levels of chromium (median girls vs boys, μg/g) (2.36 vs 2.06, p 0.001), nickel (1.28 vs 0.97, p 0.001), arsenic (0.55 vs 0.49, p 0.001), and lead (2.73 vs 2.16, p 0.001) in girls were significantly higher than in boys. The levels of cadmium (median, SHS group vs control: 0.43 vs 0.29 (μg/g), p 0.001) and lead (median, SHS group vs control: 2.71 vs 2.27 (μg/g), p = 0.007) in the SHS group were significantly higher than in the control. Multi-linear regression analysis indicated that SHS exposure in children is very likely to be correlated with increasing levels of lead (β (95% CI): 0.53 (0.99-5.14), p = 0.023) and cadmium (β (95% CI): 0.43 (0.14-0.73), p = 0.003) in their hair. In conclusion, children exposed to SHS have increased lead and cadmium accumulations in the body.In our study, 821 students (433 boys and 388 girls) were recruited, and the contents of heavy metals in their hair-including chromium, manganese, nickel, arsenic, lead, and cadmium-were detected by ICP-MS. And the secondhand smoking (SHS) exposure was inquired by face-to-face investigation of their parents. We illustrated that children exposed to SHS have increased lead and cadmium accumulations in the body. What is Known: • Secondhand smoke (SHS) has adverse effects on health, particularly for children. • There might be correlation between SHS exposure and heavy metal concentrations in children. What is New: • The levels of chromium, nickel, arsenic, and lead in girls were significantly higher than in boys. • SHS exposure in children was correlated with increasing levels of lead and cadmium in their hair because of exposure to SHS.

The purpose of the study was to evaluate the treatment effects of functional appliances (FAs) on upper airway dimensions in growing Class II patients with mandibular retrognathism.Five databases and the references of identified articles were electronically searched for relevant studies that met our eligibility criteria. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. The effects of FAs on airway dimensions were combined by meta-analysis using the RevMan and STATA software.Seven studies (177 treated patients with mean age: 11.48 years and 153 untreated controls with mean age: 11.20 years) were included in this review. Compared to the control group, the oropharyngeal dimensions in the treatment group subjects were significantly increased at the superior pharyngeal space (MD = 1.73 mm/year, 95% CI, 1.13-2.32 mm, P 0.00001), middle pharyngeal space (MD = 1.68 mm/year, 95% CI, 1.13-2.23 mm, P 0.00001) and inferior pharyngeal space (MD = 1.21 mm/year, 95% CI, 0.48-1.95 mm, P = 0.001). No significant differences were found in nasopharyngeal and hypopharyngeal dimensions and the position of hyoid bone (P 0.05). Soft palate length and soft palate inclination were improved significantly in the treatment group (P 0.05).The results showed that FAs can enlarge the upper airway dimensions, specifically in the oropharyngeal region, in growing subjects with skeletal Class II malocclusion. The early intervention for mandibular retrognathism with FAs may help enlarge the airway dimensions and decrease potential risk of obstructive sleep apnea syndrome for growing patients in the future.

Periodontitis is a chronic infectious disease involving periodontal tissues. Periodontal ligament cells (PDLCs) play an important role in the regeneration of periodontal tissue. However, senescent PDLCs have an impeded regenerative potential. Metformin has been reported to prevent senescence at both the cellular and individual levels. The objectives of the present study were to evaluate the effects of metformin on cellular senescence in human PDLCs (hPDLCs) under oxidative stress. hPDLCs were pretreated with metformin, followed by H2O2 exposure. The cell viability, oxidative damage, cellular senescence and osteogenic potential were detected. To inhibit autophagy, hPDLCs were treated with 3-methyladenine before metformin treatment. The present study revealed that H2O2 exposure inhibits proliferation, increased lysosomal β-galactosidase activity, augments reactive oxidative species (ROS) accumulation, elevates the oxidative damage, stimulates the expression of senescence-related genes and impedes the activity of the osteogenic differentiation of hPDLCs. Metformin pretreatment could partly reverse the detrimental influences of H2O2 on hPDLCs. Moreover, metformin could stimulate autophagy, whereas the inhibition of autophagy with 3-methyladenine reversed the anti-senescence effects of metformin on hPDLCs under oxidative stress. The present study manifested that metformin could alleviate oxidative stress-induced senescence via stimulating autophagy and could partially recover the osteogenic potential of hPDLCs, possibly providing a reference for the discovery of periodontal treatment from the perspective of antisenescence.

Polydopamine-templated hydroxyapatite (tHA) is a type of nano-biomaterial that can promote osteogenesis in bone tissue engineering. However, high concentrations of tHA stimulate production of reactive oxygen species (ROS), resulting in cell injury and apoptosis. Metformin has been demonstrated to activate the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, which induces autophagy and decreases ROS production to prevent apoptosis. The present study was performed to investigate the potential application of tHA in combination with metformin in periodontal bone tissue engineering. Human periodontal ligament stem cells (hPDLSCs) were exposed to tHA in the presence or absence of metformin, and cytocompatibility and osteogenesis were detected by related assays. Additionally, the autophagy signaling pathway was analyzed by western blotting. Polydopamine-templated hydroxyapatite, in combination with metformin, substantially reduced ROS production and apoptosis, and enhanced proliferation and osteogenic differentiation of hPDLSCs. Enhanced levels of microtubule-associated protein 1 light chain 3 II and Beclin-1 were observed after exposure to tHA plus metformin. Expression of phosphorylated AMPK was increased and that of phosphorylated mammalian target of rapamycin (mTOR) was decreased after exposure to tHA plus metformin. Taken together, our results demonstrate that tHA, combined with metformin, increases the viability of hPDLSCs via the AMPK/mTOR signaling pathway by regulating autophagy and further improving the osteogenic effect.

α-Mangostin (αM), a traditional natural product with promising application of treating a series of diseases, was limited use in clinical due to its hydrophobicity. Herein, MPEG-PCL nanomicelles were used to embed the αM for resolving hydrophobicity and improving the anti-melanoma effect of the αM. The anti-melanoma activity and potential mechanisms of biodegradable αM/MPEG-PCL nanomicelles were investigated. The αM/MPEG-PCL nanomicelles possessed a stronger effect on anti-melanoma compared to the free αM both in vitro and in vivo with a low cytotoxicity in non-tumor cell lines. In the research of mechanisms, the αM/MPEG-PCL nanomicelles inhibited the proliferation of melanoma cell, induced apoptosis via both apoptosis pathways of intrinsic and exogenous in vitro, as well as suppressed tumor growth and restrained angiogenesis in vivo, which implied that the αM/MPEG-PCL nanomicelles have potential application as a novel chemotherapeutic agent in melanoma therapy.

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized as reversible BTK inhibitors, and evaluated their kinase selectivity, anti-proliferation against the B-cell lymphoma cell lines (Ramos, Jeko-1) and cell line BTK enhanced (Daudi) in vitro. Among them, compound 28a exhibited the most excellent potency (IC50 = 3.0 nM against BTK enzyme, 8.52 μM, 11.10 μM and 7.04 μM against Ramos, Jeko-1, Daudi cells, respectively), good kinase selectivity and inhibited BTK Y223 auto-phosphorylation and PLCγ2 Tyr1217 phosphorylation. Importantly, 28a showed efficacy anti-arthritic effect on collagen-induced arthritis (CIA) model in vivo. 28a 60 mg/kg dose level once a day group displayed markedly reduced joint damage and cellular infiltration without any bone and cartilage morphology change.

Currently, there is a lack of adequate standards for evaluating the integrity inspection cycle of polyethylene (PE) gas pipelines. In this study, a series of photo-oxidation accelerated-aging experimental tests for PE80 gas pipe samples were performed. The attenuation laws of several critical performance parameters, such as micro-morphology, tensile strength, and thermal stability tests, were established. These parameters were determined at different aging times. A novel comprehensive performance evaluation method for pipeline integrity was developed using the analytic hierarchy process, and a reasonable inspection period for pipeline integrity was identified. The results showed that the samples experienced two stages of aging: rapid aging stage and aging platform stage. During the rapid aging stage, the comprehensive evaluation index for the aging performance decreased rapidly. However, the comprehensive evaluation index for the aging performance remained almost unchanged during the aging platform stage.

Nano silver material has been regarded as a kind of promising candidate for biomedical application due to its low cytotoxicity and striking antibacterial activity. In this study, an injectable silver-gelatin-cellulose ternary hydrogel dressing was prepared by the introduction of gelatin and aminated silver nanoparticles into the carboxylated cellulose nanofibers for efficient wound therapy in infant nursing. The produced silver nanoparticles and composite hydrogel were characterized by using transmission electron microscopy (TEM), scanning electron microscopy (SEM), Thermogravimetric analysis (TGA), and X-ray diffraction (XRD) techniques. The as-synthesized silver-cellulose-gelatin ternary hydrogel demonstrated high porosity and satisfactory antibacterial activity. In vitro cytocompatibility measurement revealed the very low toxic nature of such composite hydrogel dressing. Additionally, the in vivo assessment in mice confirmed that the silver-cellulose-gelatin ternary dressing possessed improved wound healing ability. Hence, this study strongly supports the possibility of using this novel silver-gelatin-cellulose ternary dressing for efficient cutaneous wound healing in nursing care of infants.

In this study, surfactant modified zeolite-clinoptilolite (SMZ) by CPB (cetylpyridinium bromide) was used for simultaneous removal of ammonium, nitrate and phosphate in synthetic wastewater, and the sorption properties of SMZ were determined and compared with natural zeolite. Results showed that natural clinoptilolite had good affinity for ammonium (8.940 mg/g), but not for nitrate (0.427 mg/g) and phosphate (0.801 mg/g). With the increase of surfactant loading from 5 g/L to 40 g/L, the sorption capacity for nitrate increased from 0.462 mg/g to 4.661 mg/g. when the surfactant loading is 40 g/L, the SMZ has a phosphate adsorption capacity of 2.119 mg/g. The SMZ had a significant enhancement on nitrate and phosphate sorption, could simultaneously remove ammonium, nitrate and phosphate at specific conditions, with removal efficiency up to 85.2%, 83.1% and 56.7%, respectively. Orthogonal experiments showed that ammonium concentration was the most important factor for ammonium sorption on SMZ. Surfactant loading was the major factor for nitrate and phosphate sorption. With the increase of surfactant loading from 5 g/L to 40 g/L, the sorption capacity for nitrate increased from 0.462 mg/g to 4.661 mg/g. When the surfactant loading is 40 g/L, the SMZ has the best phosphate adsorption capacity 2.119 mg/g. Samples were characterized by X-ray diffraction (XRD) and Brunauer–Emmett–Teller (BET). Semi-empirical quantum mechanics molecular simulation indicated that electrostatic attraction existed between CPB and dihydrogen phosphate ion. Results indicate that SMZs might have great potential of removing cations and anions simultaneously in the aquatic environment, which is good for eutrophication control and nutrients removal.

In this study, surfactant (hexadecyltrimethylammonium, HDTMA) modified zeolite (clinoptilolite) (SMZ) was used for simultaneous removal of ammonium and nitrate in wastewater, and the sorption properties of SMZ were determined. Results showed that natural clinoptilolite had good affinity for ammonium, but low sorption ability for nitrate, and the ammonium sorption process was well described by the pseudo-second order kinetic model. The SMZ had a significant enhancement on nitrate sorption and could simultaneously remove ammonium and nitrate at specific conditions, with removal efficiency up to 93.6% and 81.8%, respectively. The sorption process fitted well with the Langmuir isotherm. Orthogonal experiments showed that ammonium concentration was the most important factor for ammonium sorption on SMZ. However, surfactant loading was the major factor for nitrate sorption. Meanwhile, phosphate did not interfere with nitrate removal. Semi-empirical quantum mechanics molecular simulation indicated that electrostatic attraction existed between HDTMA and nitrate. Results of this study demonstrated that SMZs may have great potential for removing cations and anions simultaneously in the aquatic environment.

In our previous work, 3I inhibited the LPS-induced iNOS activity and NO production in RAW 264.7 cells and improved joint inflammation and cartilage destruction in inflammatory model. In this study, we synthesized 59 derivatives and bioisosteres on the basis of 3I by Knoevenagel condensation and biologically evaluated for the study of structure-activity relationship (SAR). We found that 7–44 suppressed the iNOS activity (IC50 25.2 μM) and LPS-induced NO production (IC50 45.6 μM) in RAW 264.7 cells. As for the SAR study, the dimethoxylphenyl group of 7–44 was potential for a further modification. At a dose of 10 mg/kg, oral administration of 7–44 possessed protective properties in both carrageenan-induced paw edema of male ICR mice and adjuvant-induced arthritis of Lewis female rats. Although the activity of 7–44 was slightly inferior, the PK profiles of 7–44 were superior to those of 3I.

Colorectal peritoneal carcinomatosis (CRPC) is a common form of systemic metastasis of intra-abdominal cancers, occurring in as many as 50% of colon cancer patients, and is associated with a poor prognosis. For the treatment of CRPC, cytoreductive surgery alone is inadequate at the microscopic level, and systemic chemotherapy has a limited effect due to the peritoneal-plasma barrier. Intraperitoneal chemotherapy is logically proposed early after surgery to treat the residual small and microscopic tumors. Traditional chemotherapy is typically infused intravenously. However, intraperitoneal chemotherapy allows direct contact of anti-cancer agents with tumor cells, which could improve tumor regression efficacy and minimize systemic toxicity. Furthermore, injectable and thermosensitive polymer hydrogels have shown promising applications as controlled drug delivery systems for in situ chemotherapy. In this study, a biodegradable thermogelling block copolymer poly(L-lactide acid)–Pluronic L35–poly(L-lactide acid) (PLLA–L35–PLLA) was synthesized to fabricate a novel local drug delivery system (DOC-M/OXA-H) composed of docetaxel loaded micelles (DOC-M) and an oxaliplatin loaded hydrogel (OXA-H). DOC, a widely used anticancer drug with extremely high hydrophobicity, was loaded into the biodegradable copolymer micelles by the membrane dialysis method without using any surfactants or excipients. And DOC-M was encapsulated in OXA-H to achieve the aim of synergistic combination therapy with significantly high efficacy and good patient compliance. As a result, DOC-M/OXA-H was an injectable flowing sol at ambient temperature and became a solid-like gel at physiological temperature without any crosslinking agent. Meanwhile, DOC-M/OXA-H demonstrated a slow and sustained drug release profile and the combination therapy of DOC and OXA exhibited quite potent cytotoxicity in vitro. Furthermore, an in vivo antitumor test with CRPC-bearing mice suggested that DOC-M/OXA-H was more competent for suppressing tumor growth and prolonging survival time by inhibiting tumor cell proliferation and angiogenesis and increasing apoptosis of tumor cells. Overall, our data suggested that DOC-M/OXA-H may be potentially useful in the treatment of CRPC.

Binary polymer blends of hydrophobic poly(vinylidene fluoride) (PVDF) and hydrophilic poly(vinylpyrrolidone) (PVP) were prepared by melt blending. The crystallization behavior, mechanical properties and hydrophilicity of the binary blends were investigated using Fourier transform infrared spectroscopy (FTIR), wide-angle X-ray diffractometry (WAXD), differential scanning calorimeter (DSC) scanning, non-isothermal crystallization kinetics, successive self-nucleation and annealing (SSA) fractionation, tensile tests and contact angle tests. The analysis of FTIR, WAXD, DSC scanning, non-isothermal crystallization kinetics and SSA fractionation showed that the addition of PVP greatly influenced the crystallization behavior of the sample. As the PVP content increased, the crystallization temperature, crystallization rate, degree of crystallinity, and the amount of thick lamellaes decreased gradually. Meanwhile, PVP favored the formation of β-phase of PVDF. The results of tensile test revealed that the addition of PVP increased the elongation at break of the sample, and lowered the yield stress. Besides, the result of contact angle test indicated that the hydrophilicity of PVDF was remarkably improved in the presence PVP. The relationship between crystallization behavior and the tensile behavior, hydrophilicity were discussed.

To discuss the expression of T helper cell 17 (Th17) cells and CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in peripheral blood (PB) of patients with acute leukemia (AL), and to explore the relationship between them and disease prognosis. 40 patients diagnosed with acute leukemia in The First Affiliated Hospital of Zhengzhou University from July 2012 to August 2014 were selected as the observation group. Meanwhile, 40 healthy people were taken as the control group. Flow Cytometry Method (FCM) was used to detect the level of Th17 cells and CD4

In this paper, barbigerone (1a) and its twenty-seven related structural analogues were synthesized via complementary synthetic routes and their anti-inflammatory effects on the expression of TNF-α in LPS-stimulated splenocytes were evaluated. Among these compounds, 1a, 1d, 1f and 1g were found to remarkably inhibit TNF-α production. Furthermore, 1g showed the most potent and dose-dependent manner inhibitory effect on TNF-α release, with better IC50 value (3.58 μM) than barbigerone (8.46 μM). Oral administration of 1g at 20 mg/kg/day for two weeks obviously demonstrated protective effect in adjuvant-induced arthritis models as evaluated by clinical score of paws, and histological examination of joint tissues from rats. Mechanism studies on mRNA and protein level suggested that 1g inhibited the TNF-α production via depressing TNF-α converting enzyme (TACE) mRNA expression. In conclusion, these data show 1g with potential therapeutic effects as an anti-inflammatory agent.

PIM-1 kinase is an important therapeutic target in the treatment of cancer. Discovery and identification of PIM-1 Inhibitors with novel scaffolds are an effective way for developing potent therapeutic agents for the treatment of cancers. Here we proposed a hybrid screening approach which combines an optimal structure-based drug design strategy and a simple pharmacophore model to discover PIM-1 kinase inhibitors. With the proposed hybrid screening approach, the SPECS database containing 204,580 molecules was screened. In total, 89 hits were obtained. Forty three of them were purchased and tested in bioassays. Finally, 5 lead compounds with novel scaffolds were identified to exhibit promising antitumor activities against human leukemia cell line MV4-11, K-562 and human prostate cancer cell line PC-3 and DU145. Their IC(50) values range from 4.40 to 37.96 μM. Three hits with 3 different scaffolds were selected from these five hits for binding mode analysis. It was demonstrated that the subtle differences in the interactions of the representatives with PIM-1 kinase contribute to the different inhibitory activities. It was also demonstrated that the suggested hybrid screening approach is an effective method to discover PIM-1 inhibitors possessing different scaffolds. These leads have a strong likelihood to act as further starting points for us in the optimization and development of potent PIM-1 inhibitors.

A series of novel tubulin polymerization inhibitors (9a-9p) have been synthesized and evaluated for their in vitro and in vivo biological activities. Among these compounds, 9e displayed strong antiproliferative activity against several tumor cell lines (IC50=0.15-0.62μM). Compound 9e was also shown to arrest cells in the G2/M phase of the cell cycle and inhibit the polymerization of tubulin. Molecular docking studies suggested that 9e binds into the colchicine binding site of tubulin. In xenograft experiments, 9e exerted more potent anticancer effect than anticancer drug taxol against the H460 Human lung carcinoma in BALB/c nude mice. In summary, these findings suggest that 9e is a promising new antimitotic compound for the potential treatment of cancer.

In our previous study, a series of 6-aryl-3-amino-thieno[2,3- b ]pyridine derivatives exhibited potent antiproliferative activities and an unique hepatocellular carcinoma (HCC)-specific anticancer activity was also observed. In further anti-inflammatory research, thienopyridine derivative 1a showed potent inhibition of nitric oxide (NO) production. So a series of thienopyridine analogues of 1a were synthesized and evaluated for anti-inflammatory activities. The structure–activity relationships (SARs) revealed that the most potent analogues 1f and 1o were identified as potent inhibitors of NO production with IC 50 values of 3.30 and 3.24 μM, respectively. These results suggest that these 6-aryl-3-amino-thieno[2,3- b ]pyridine derivatives might potentially constitute a novel class of anti-inflammatory agents, which require further studies.

Twenty-five novel pyranochalcone derivatives were synthesized and evaluated for their in vitro and in vivo antiproliferative activities. Among them, compound 10i exhibited superior potent activity against 21 tumor cell lines including multidrug resistant phenotype with the IC50 values ranged from 0.09 to 1.30 μM. In addition, 10i significantly induced cell cycle arrest in G2/M phase, promoted tubulin polymerization into microtubules and caused microtubule stabilization. Further studies confirmed that 10i significantly suppressed the growth of tumor volume in HepG2 xenograft tumor model. Our study demonstrated that 10i could have beneficial antitumor activity as a novel microtubule stabilizing agent.

A series of spirooxindolo-pyrrolidines, pyrrolizidines, and pyrrolothiazoles hybrid compounds were prepared in good yields by regioselective, three-component, 1,3-dipolar cycloaddition reactions between $$\alpha , \beta $$ -unsaturated ketones with furanyl substituents and unstable azomethine ylides, which were generated in situ from isatin and various types of amino acids. The synthesized compounds were screened for their antibacterial activities against a spectrum of pathogens. Preliminary studies identified compound 5c as a potent antimicrobial agent against drug-resistant bacteria. In addition, molecular docking studies indicated that compound 5c showed strong interactions with the active sites of lanosterol demethylase, dihydrofolate reductase, and topoisomerase II. This study provides an effective entry to the rapidly construction of a chemical library of heterocycles and compound 5c is one potent antibacterial lead for subsequent optimization.

Dehydrosqualene synthase (CrtM) is a key enzyme in the synthesis of presqualene diphosphate in Staphylococcus aureus. In the current study, a combination of structure-based pharmacophore and 3D-QSAR methods are used to clarify the essential quantitative structure–activity relationship (QSAR) of known CrtM inhibitors; the multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of CrtM based on twenty crystal structures of CrtM inhibitor complex. Performances of the MCBP-based virtual screening approach were applied to screen specs chemical databases (202, 408 compounds). Thirty-eight compounds were selected from the final hits and should be shifted to experimental studies. The MCBP model has been successfully used to identify the bioactive conformation and align 24 structurally diverse CrtM inhibitors. The QSAR analyses have been performed on these CrtM inhibitors based on MCBP guided alignment. These results may provide important information for further design and discovery of novel CrtM inhibitors.

To analyze the complications and nursing countermeasures of PICC (Peripherally Inserted Central Catheter) catheters using children PICC catheter technique 40 cases, complications were observed, and analyze the original causes, in order to propose a solution. There were 10 cases of catheter blockage, 5 cases of catheter infection, 6 cases of phlebitis, 5 cases of puncture difficulties, 2 cases of poor feeding tube, 2 cases of bleeding puncture site with the continuous exploration and research of nursing intervention, the production of clinical complications from PICC has been used in children were greatly reduced.

Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin-resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. HE stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice.