Enhanced osteogenic and antibacterial properties of titanium implant surface modified with Zn-incorporated nanowires: Preclinical in vitro and in vivo investigations.

OBJECTIVE: This study aimed to synthesize zinc-incorporated nanowires structure modified titanium implant surface (Zn-NW-Ti) and explore its superior osteogenic and antibacterial properties in vitro and in vivo. MATERIALS AND METHODS: Zn-NW-Ti was synthesized via displacement reactions between zinc sulfate solutions and the titanium (Ti) surface, which was pretreated by hydrofluoric acid etching and hyperthermal alkalinization. The physicochemical properties of the Zn-NW-Ti surface were examined. Moreover, the biological effects of Zn-NW-Ti on MC3T3-E1 cells and its antibacterial property against oral pathogenic bacteria (Staphylococcus aureus, Porphyromonas gingivalis, and Actinobacillus actinomycetemcomitans) compared with sandblasted and acid-etched Ti (SLA-Ti) and nanowires modified Ti (NW-Ti) surface were assessed. Zn-NW-Ti and SLA-Ti modified implants were inserted into the anterior extraction socket of the rabbit mandible with or without exposure to the mixed bacterial solution (S. aureus, P. gingivalis, and A. actinomycetemcomitans) to investigate the osteointegration and antibacterial performance via radiographic and histomorphometric analysis. RESULTS: The Zn-NW-Ti surface was successfully prepared. The resultant titanium surface appeared as a nanowires structure with hydrophilicity, from which zinc ions were released in an effective concentration range. The Zn-NW-Ti surface performed better in facilitating the adhesion, proliferation, and differentiation of MC3T3-E1 cells while inhibiting the colonization of bacteria compared with SLA-Ti and NW-Ti surface. The Zn-NW-Ti implant exhibited enhanced osseointegration in vivo, which was attributed to increased osteogenic activity and reduced bacterial-induced inflammation compared with the SLA-Ti implant. CONCLUSIONS: The Zn-incorporated nanowires structure modified titanium implant surface exhibited improvements in osteogenic and antibacterial properties, which optimized osteointegration in comparison with SLA titanium implant surface.

Modulation of SEMA4D-modified titanium surface on M2 macrophage polarization via activation of Rho/ROCK-mediated lactate release of endothelial cells: In vitro and in vivo.

SEMA4D-modified titanium surfaces can indirectly regulate macrophages through endothelial cells to achieve an anti-inflammatory effect, which is beneficial for healing soft tissues around the gingival abutment. However, the mechanism of surface-induced cellular phenotypic changes in SEMA4D-modified titanium has not yet been elucidated. SEMA4D activates the RhoA signaling pathway in endothelial cells, which coordinates metabolism and cytoskeletal remodeling. This study hypothesized that endothelial cells inoculated on SEMA4D-modified titanium surfaces can direct M2 polarization of macrophages via metabolites. An indirect co-culture model of endothelial cells and macrophages was constructed in vitro, and specific inhibitors were employed. Subsequently, endothelial cell adhesion and migration, metabolic changes, Rho/ROCK1 expression, and inflammatory expression of macrophages were assessed via immunofluorescence microscopy, specific kits, qRT-PCR, and Western blotting. Moreover, an in vivo rat bilateral maxillary implant model was constructed to evaluate the soft tissue healing effect. The in vitro experiments showed that the SEMA4D group had stronger endothelial cell adhesion and migration, increased Rho/ROCK1 expression, and enhanced release of lactate. Additionally, decreased macrophage inflammatory expression was observed. In contrast, the inhibitor group partially suppressed lactate metabolism and motility, whereas increased inflammatory expression. The in vivo analyses indicated that the SEMA4D group had faster and better angiogenic and anti-inflammatory effects, especially in the early stage. In conclusion, via the Rho/ROCK1 signaling pathway, the SEMA4D-modified titanium surface promotes endothelial cell adhesion and migration and lactic acid release, then the paracrine lactic acid promotes the polarization of macrophages to M2, thus obtaining the dual effects of angiogenesis and anti-inflammation.

Multi-omics analysis of multiple myeloma patients with differential response to first-line treatment.

The genome backgrounds of multiple myeloma (MM) would affect the efficacy of specific treatment. However, the mutational and transcriptional landscapes in MM patients with differential response to first-line treatment remains unclear. We collected paired whole-exome sequencing (WES) and transcriptomic data of over 200 MM cases from MMRF-COMPASS project. R package, maftools was applied to analyze the somatic mutations and mutational signatures across MM samples. Differential expressed genes (DEG) was calculated using R package, DESeq2. The feature selection of the predictive model was determined by LASSO regression. In silico analysis revealed newly discovered recurrent mutated genes such as TTN, MUC16. TP53 mutation was observed more frequent in nonCR (complete remission) group with poor prognosis. DNA repair-associated mutational signatures were enriched in CR patients. Transcriptomic profiling showed that the activity of NF-kappa B and TGF-ß pathways was suppressed in CR patients. A transcriptome-based response predictive model was constructed and showed promising predictive accuracy in MM patients receiving first-line treatment. Our study delineated distinctive mutational and transcriptional landscapes in MM patients with differential response to first-line treatment. Furthermore, we constructed a 20-gene predictive model which showed promising accuracy in predicting treatment response in newly diagnosed MM patients.

Prediction of cardiovascular adverse events in newly diagnosed multiple myeloma: Development and validation of a risk score prognostic model.

Background: Multiple myeloma (MM) is the second most common hematological malignancy, and the treatments markedly elevate the survival rate of the patients in recent years. However, the prevalence of cardiovascular adverse events (CVAEs) in MM had been increasing recently. CVAEs in MM patients are an important problem that we should focus on. Clinical tools for prognostication and risk-stratification are needed. Patients and methods: This is a retrospective study that included patients who were newly diagnosed with multiple myeloma (NDMM) in Shanghai Changzheng Hospital and Affiliated Jinhua Hospital, Zhejiang University School of Medicine from June 2018 to July 2020. A total of 253 patients from two medical centers were divided into training cohort and validation cohort randomly. Univariable analysis of the baseline factors was performed using CVAEs endpoints. Multivariable analysis identified three factors for a prognostic model that was validated in internal validation cohorts. Results: Factors independently associated with CVAEs in NDMM were as follows: age>61 years old, high level of baseline office blood pressure, and left ventricular hypertrophy (LVH). Age contributed 2 points, and the other two factors contributed 1 point to a prognostic model. The model distinguished the patients into three groups: 3-4 points, high risk; 2 points, intermediate risk; 0-1 point, low risk. These groups had significant difference in CVAEs during follow-up days in both training cohort (p<0.0001) and validation cohort (p=0.0018). In addition, the model had good calibration. The C-indexes for the prediction of overall survival of CVAEs in the training and validation cohorts were 0.73 (95% CI, 0.67-0.79) and 0.66 (95% CI, 0.51-0.81), respectively. The areas under the receiver operating characteristic curve (AUROCs) of the 1-year CVAEs probability in the training and validation cohorts were 0.738 and 0.673, respectively. The AUROCs of the 2-year CVAE probability in the training and validation cohorts were 0.722 and 0.742, respectively. The decision-curve analysis indicated that the prediction model provided greater net benefit than the default strategies of providing assessment or not providing assessment for all patients. Conclusion: A prognostic risk prediction model for predicting CVAEs risk of NDMM patients was developed and internally validated. Patients at increased risk of CVAEs can be identified at treatment initiation and be more focused on cardiovascular protection in the treatment plan.

Osteogenic and anti-inflammatory effects of SLA titanium substrates doped with chitosan-stabilized selenium nanoparticles via a covalent coupling strategy.

Osseointegration is a prerequisite for the function of dental implants, and macrophage-dominated immune responses triggered by implantation determine the outcome of ultimate bone healing mediated by osteogenic cells. The present study aimed to develop a modified titanium (Ti) surface by covalently immobilizing chitosan-stabilized selenium nanoparticles (CS-SeNPs) to sandblasted, large grit, and acid-etched (SLA) Ti substrates and further explore its surface characteristics as well as osteogenic and anti-inflammatory activities in vitro. CS-SeNPs were successfully prepared by chemical synthesis and characterized their morphology, elemental composition, particle size, and Zeta potential. Subsequently, three different concentrations of CS-SeNPs were loaded to SLA Ti substrates (Ti-Se1, Ti-Se5, and Ti-Se10) using a covalent coupling strategy, and the SLA Ti surface (Ti-SLA) was used as a control. Scanning electron microscopy images revealed different amounts of CS-SeNPs, and the roughness and wettability of Ti surfaces were less susceptible to Ti substrate pretreatment and CS-SeNP immobilization. Besides, X-ray photoelectron spectroscopy analysis showed that CS-SeNPs were successfully anchored to Ti surfaces. The results of in vitro study showed that the four as-prepared Ti surfaces exhibited good biocompatibility, with Ti-Se1 and Ti-Se5 groups showing enhanced adhesion and differentiation of MC3T3-E1 cells compared with the Ti-SLA group. In addition, Ti-Se1, Ti-Se5, and Ti-Se10 surfaces modulated the secretion of pro-/anti-inflammatory cytokines by inhibiting the nuclear factor kappa B pathway in Raw 264.7 cells. In conclusion, doping SLA Ti substrates with a modest amount of CS-SeNPs (1-5 mM) may be a promising strategy to improve the osteogenic and anti-inflammatory activities of Ti implants.

Sustained ameliorating effects and autonomic mechanisms of transcutaneous electrical acustimulation at ST36 in patients with chronic constipation.

Background and aims: The treatment of chronic constipation is still a great challenge in clinical practice. This study aimed to determine the efficacy and sustained effects of transcutaneous electrical acustimulation (TEA) at acupoint ST36 on the treatment of chronic constipation and explore possible underlying mechanisms. Methods: Forty-four patients with chronic constipation were recruited and randomly assigned to a TEA group or sham-TEA group. A bowel diary was recorded by the patients. The Patient Assessment of Constipation Symptom (PAC-SYM) and the Patient Assessment of Constipation Quality of Life (PAC-QoL) questionnaires were administered during each visit. Anal and rectal functions were evaluated with anorectal manometry. Autonomic functions were assessed by the special analysis of heart rate variability derived from the ECG recording. Results: Compared with sham-TEA, 2-week TEA treatment significantly increased the number of spontaneous bowel movements (SBMs) (5.64 ± 0.54 vs. 2.82 ± 0.36, P < 0.001) and lowered the total scores of PAC-SYM (0.90 ± 0.14 vs. 1.35 ± 0.13, P < 0.001) and PAC-QoL (0.89 ± 0.13 vs. 1.32 ± 0.14, P < 0.05). TEA improved symptoms, as reflected by a reduction in the straining (P < 0.001), the incomplete defecation (P < 0.05), the frequency of emergency drug use (P < 0.05), the days of abdominal distension (P < 0.01) and an increase in intestinal satisfaction (P < 0.01). Interestingly, the effects of TEA on the improvement of weekly SBMs sustained four weeks after the cessation of treatment (P < 0.001). Anorectal manometry indicated that 2-week treatment of TEA lowered the threshold of first sensation (P < 0.05), desire of defecation (P < 0.01) and maximum tolerable volume (P < 0.001) compared with sham-TEA group. TEA also significantly enhanced vagal activity, reflected by high-frequency band of heart rate variability, compared with sham-TEA (57.86 ± 1.83 vs. 48.51 ± 2.04, P < 0.01). Conclusion: TEA ameliorates constipation with sustained effects, which may be mediated via improvement of rectal sensitivity and enhancement of vagal activity. Clinical trial registration: [https://clinicaltrials.gov/], identifier [ChiCTR210004267].

Transcutaneous Electrical Acustimulation Ameliorates Motion Sickness Induced by Rotary Chair in Healthy Subjects: A Prospective Randomized Crossover Study.

OBJECTIVES: Motion sickness (MS) is a common physiological response to real or virtual motion. The purpose of this study was to investigate the effects of transcutaneous electrical acustimulation (TEA) on MS and the underlying mechanisms in healthy subjects. MATERIALS AND METHODS: A total of 50 healthy participants were recruited and randomly assigned into two groups to complete two separate sessions in a crossover study. A Coriolis rotary chair was used as a model to provoke severe MS. The total tolerable rotation time and Graybiel scoring scale were recorded. Gastric slow waves were detected by electrogastrogram. The autonomic nervous function, including the vagal activity, was evaluated by the analysis of heart rate variability derived from the electrocardiogram recording. The serum levels of arginine vasopressin (AVP) and norepinephrine (NE) were examined. RESULTS: Of note, 22 participants in TEA and only 11 participants in the sham-TEA session completed the entire five-rotation MS stimuli (p = 0.019). TEA significantly prolonged the total tolerable rotation time of MS stimuli (220.4 ± 11.59 vs 173.6 ± 12.3 seconds, p < 0.001) and lowered MS symptom scores (12.56 ± 2.03 vs 22.06 ± 3.0, p < 0.001). TEA improved the percentage of normal gastric slow waves, compared with sham-TEA (56.0 ± 2.1% vs 51.6 ± 2.0%, p = 0.033). TEA also significantly enhanced vagal activity compared with sham-TEA (0.41 ± 0.02 vs 0.31 ± 0.02, p < 0.001). In addition, the increased serum levels of AVP and NE on MS stimulation were markedly suppressed by TEA treatment, compared with sham-TEA (AVP, 56.791 ± 4.057 vs 79.312 ± 10.036 ng/mL, p = 0.033; NE, 0.388 ± 0.037 vs 0.501 ± 0.055 ng/mL, p = 0.021). CONCLUSIONS: Needleless TEA is a potent therapeutic approach for severe MS, as it increases participants' tolerance and ameliorates MS symptoms, which may be attributed to the integrative effects of TEA on autonomic functions and neuroendocrine balance.

Cobalt-Based Metal-Organic Cages for Visible-Light-Driven Water Oxidation.

Water oxidation to molecular oxygen is indispensable but a challenge for splitting H2O. In this work, a series of Co-based metal-organic cages (MOCs) for photoinduced water oxidation were prepared. MOC-1 with both bis(µ-oxo) bridged dicobalt and Co-O (O from H2O) displays catalytic activity with an initial oxygen evolution rate of 80.4 mmol/g/h and a TOF of 7.49 × 10-3 s-1 in 10 min. In contrast, MOC-2 containing only Co-O (O from H2O) in the structure results in a lower oxygen evolution rate (40.8 mmol/g/h, 4.78 × 10-3 s-1), while the amount of oxygen evolved from the solution of MOC-4 without both active sites is undetectable. Isotope experiments with or without H218O as the reactant successfully demonstrate that the molecular oxygen was produced from water oxidation. Photophysical and electrochemical studies reveal that photoinduced water oxidation initializes via electron transfer from the excited [Ru(bpy)3]2+* to Na2S2O8, and then, the cobalt active sites further donate electrons to the oxidized [Ru(bpy)3]3+ to drive water oxidation. This proof-of-concept study indicates that MOCs can work as potential efficient catalysts for photoinduced water oxidation.

Iron(II) Metal-Organic Framework with unh Topology and Tetrazole-Padded Helical Channels.

A unique metal-organic framework (MOF) with tetrazole-padded helical channels has been successfully synthesized in one pot from iron(II) trifluoromethanesulfonate, 4-formylimidazole, hydrazine, and sodium azide under solvothermal conditions and features a rare unh topology and porous structure for gas adsorption. Transformations of condensation, cycloaddition, and coordination occurred during the synthetic process, in which a 1,5-disubstituted tetrazole ligand was formed in situ.

Isolation, characterization and inoculation of Cd tolerant rice endophytes and their impacts on rice under Cd contaminated environment.

Cadmium (Cd) contamination in paddy soil becomes increasingly prominent in recent years, which endangers the safe production of food crops. Cd-tolerant endophytes are ideal mediators for decreasing Cd content in rice plants, but their effects on the rice endophytic microbial community and gene expression profile have not yet been well elucidated. In this study, 58 endophytic bacteria from rice seeds were isolated and characterized. Five strains of them were selected based on their potential growth-promoting traits and strong Cd tolerance that could grow well under 4 mM Cd2+. By 16S ribosomal RNA (rRNA) identification, these five strains were designated as Enterobacter tabaci R2-7, Pantoea agglomerans R3-3, Stenotrophomonas maltophilia R5-5, Sphingomonas sanguinis R7-3 and Enterobacter tabaci R3-2. Pot experiments in relieving Cd stress in rice plants showed that the S. maltophilia R5-5 performed the strongest potential for reducing the Cd content in root and blade by 81.33% and 77.78%, respectively. The endophytic microbial community diversity, richness and composition were significantly altered in S. maltophilia R5-5 inoculated rice plants. Reverse-transcription qPCR (RT-qPCR) showed that the expression of Cd transporters, OsNramp5 and OsHMA2, were down-regulated in S. maltophilia R5-5-innoculated rice roots. The results indicate that the inoculation of endophytic bacteria S. maltophilia R5-5 provides a reference for alleviating the heavy metal contamination in paddy fields and can be a better alternative for guaranteeing the safe production of crops. Changes in the relative abundance of Cd-resistant microorganisms and the expression of Cd transporters might be the intrinsic factors affecting cadmium content in rice.

Bioremediation of cadmium-contaminated paddy soil using an autotrophic and heterotrophic mixture.

Cadmium (Cd) pollution poses a serious risk to human health and ecological security. Bioremediation can be a promising and effective remediation technology for treating Cd contaminated soils. In this study, seven heterotrophic strains were isolated from Cd contaminated soil and 7 autotrophic strains were isolated from acid mine drainage. Cd removal efficiencies were compared after leaching with autotrophic bacteria (Att-sys), heterotrophic isolates (Htt-sys) and cooperative leaching systems (Co-sys) in laboratory agitating reactors. The results indicated that Cd removal efficiency of Co-sys (32.09%) was significantly higher than that of Att-sys (23.24%) and Htt-sys (0.74%). By analyzing the soil microbial community in different bioleaching systems, we found that the addition of heterotrophic isolates significantly promoted the growth of some heavy metal resistant inhabitants (Massilia, Alicyclobacillus, Micromonospora, etc.), and Co-sys had a minor effect on the growth of soil indigenous microbes. In Co-sys, the content of the four Cd fractions all decreased compared with other leaching systems. The analysis of soil physicochemical parameters during the leaching process showed that pH and ORP (oxidation reduction potential) were not the only determinants for Cd removal efficiency in Co-sys, synergistic metabolic activities of autotrophic and heterotrophic strains may be other determinants. This study demonstrated that cooperative bioremediation may prove to be a safe and efficient technique for field application in heavy metal soil pollution.

Hydroxo Iron(III) Sites in a Metal-Organic Framework: Proton-Coupled Electron Transfer and Catalytic Oxidation of Alcohol with Molecular Oxygen.

Metalloenzymes are powerful biocatalysts that can catalyze particular chemical reactions with high activity, selectivity, and specificity under mild conditions. Metal-organic frameworks (MOFs) composed of metal ions or metal clusters and organic ligands with defined cavities have the potential to impart enzyme-like catalytic activity and mimic metalloenzymes. Here, a new metal-organic framework implanted with hydroxo iron(III) sites with the structural and reactivity characteristics of iron-containing lipoxygenases is reported. Similar to lipoxygenases, the hydrogen atoms and electrons of the substrate can transfer to the hydroxo iron(III) sites, showing typical proton-coupled electron transfer behavior. In the reactivity mimicking biology system, similar to alcohol oxidase, the material also catalyses the oxidation of alcohol into aldehyde by using O2 with a high yield and 100% selectivity under mild conditions, without the use of a radical cocatalyst or photoexcitation. These results provide strong evidence for the high structural fidelity of enzymatically active sites in MOF materials, verifying that MOFs provide an ideal platform for designing biomimetic heterogeneous catalysts with high conversion efficiency and product selectivity.

A direct "touch" approach for gold nanoflowers decoration on graphene/ionic liquid composite modified electrode with good properties for sensing bisphenol A.

In the present work, a direct "touch" method was developed for attaching AuNPs with clean surface on the graphene-ionic liquid modified glassy carbon electrode (G-IL GCE). The morphology and composition of the thus-prepared AuNPs on G-IL GCE were characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy. The results showed that AuNPs with interesting flower-like shapes are well dispersed on the G-IL film. Significantly, as it is a surfactant-free synthesis, the AuNPs are very clean and can be directly modified on a G-IL GCE without any pre-treatments. Comparing with the bare or even various AuNPs-G-IL mixtures modified GCEs, the proposed sensor exhibit better electrochemical activity with a higher peak current and a lower overpotential towards bisphenol A (BPA) oxidation. After optimization, a good linear relationship between current response and the concentration of BPA in the range of 0.01-1 and 1-60 µM were obtained, and the detection limit was as low as 4.8 nM. To testify the reliability, the thus-prepared AuNPs/G-IL GCE was used for determining the concentration of BPA in disposable paper cups, plastic bottles and noodles cups.

Assessment of hepatoprotective potential of Radix Fici Hirtae on alcohol-induced liver injury in Kunming mice.

OBJECTIVE: The objective of the present study was to investigate the hepatoprotective role of Radix Fici Hirtae on acute alcohol-induced liver injury in mice. METHODS: The component of Radix Fici Hirtae was extracted using petroleum ether, chloroform, ethyl acetate and n-butanol and divided into three dose groups of high, medium and low according to the clinical man's normal dose of the 50 g crude drug/d (0.83 g/kg body weight). Saline in concentration of 10 mg/mL, 5 mg/mL and 2.5 mg/mL and a dose of mouse lavage (0.2 mL/10 g mouse body weight) were added to the solution. Histopathlogical analysis of liver was performed. Finally, liver protection was validated by examining the effect of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AKP), and lactate dehydrogenase (LDH) on the hepatic function of mice in alcohol-induced liver injury model. RESULTS: Except for group with saturated n-butyl alcohol, for the rest of the groups, pathological changes of hepatic lipid and inflammatory cells infiltration were alleviated and liver sinus was normal. As compared to model group, the concentrations of AST, ALT, AKP and LDH in chloroform groups and ethyl acetate groups were significantly decreased. CONCLUSIONS: Extracts of Radix Fici Hirtae are effective for the prevention of alcohol-induced hepatic damage in mice. The results revealed that extracts of Radix Fici Hirtae could be used as hepatoprotective agent.