Comprehensive Systematic Review of Poly-L-lactic Acid in Facial Clinical Application.

OBJECTIVES: With the increasing global clinical application of regenerative injection materials, there is a growing recognition of the crucial role played by poly-L-lactic acid (PLLA). The aim of this study is to conduct a systematic review on the therapeutic efficacy and safety of PLLA in clinical applications for facial treatments. METHODS: We conducted a search of the PubMed, EMBASE, Web of Science, and Wanfang databases, followed by screening of the retrieved articles based on predefined inclusion and exclusion criteria. We then performed an analysis on the final set of included articles that met our inclusion criteria. Within these included articles, quality assessment for randomized controlled trials (RCTs) was carried out using the Jadad scale, while non-randomized controlled trials (non-RCTs) were evaluated using the MINORS scale. RESULTS: Our search of above database, using the relevant search terms, yielded a total of 1300 PLLA-related articles. After applying the inclusion and exclusion criteria, 1280 articles were excluded. Only 20 articles, 16 in English and 4 in Chinese, were included in our final analysis, among them 16 NRCTs and 4 RCTs. According to the different clinical evaluation standards, the treatment of PLLA has achieved good outcomes. Most PLLA injection-related adverse events are mild and self-limited, without any additional treatment requirement. CONCLUSION: PLLA is a reasonably safe and effective facial injection material that can be applied in different facial injection areas and depth using various reconstitute and injection methods. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

WTAP mediates FOXP3 mRNA stability to promote SMARCE1 expression and augment glycolysis in colon adenocarcinoma.

N6-methyladenosine (m6A) is the most abundant mRNA internal modification and has reportedly been linked to aerobic glycolysis, a hallmark event in tumor development. This work focuses on the role of the m6A methyltransferase WT1-associated protein (WTAP) in metabolic reprogramming and development of colon adenocarcinoma (COAD) and the molecules involved. The WTAP expression in COAD tissues and cells was detected. WTAP was knocked down in two COAD cell lines to figure out its role in the glycolytic activity and malignant phenotype of cancer cells. Cancer cells were further injected into nude mice subcutaneously or via tail vein to evaluate tumor growth and metastasis. The downstream molecules involved were explored using bioinformatics tools, and the molecular interactions were confirmed by immunoprecipitation, luciferase assays, and rescue experiments. WTAP was abundantly expressed in COAD samples. Knockdown of WTAP suppressed glucose consumption, lactate production, and glycolysis, which consequently suppressed cancer cell growth and dissemination in vitro and in vivo. WTAP promoted m6A methylation and stabilized forkhead box P3 (FOXP3) mRNA with the participation of the m6A "reader" YTHDF1. FOXP3 could further bind to SMARCE1 promoter for transcriptional activation. Rescue experiments showed that upregulation of FOXP3 or SMARCE1 restored the glycolytic activity in COAD cells and augmented the growth and mobility of cells both in vitro and in vivo. This study demonstrates that WTAP grants glycolytic activity to COAD and promotes tumor malignant development via the m6A modification of FOXP3 mRNA and the upregulation of SMARCE1.

Microchannelled alkylated chitosan sponge to treat noncompressible hemorrhages and facilitate wound healing.

Developing an anti-infective shape-memory hemostatic sponge able to guide in situ tissue regeneration for noncompressible hemorrhages in civilian and battlefield settings remains a challenge. Here we engineer hemostatic chitosan sponges with highly interconnective microchannels by combining 3D printed microfiber leaching, freeze-drying, and superficial active modification. We demonstrate that the microchannelled alkylated chitosan sponge (MACS) exhibits the capacity for water and blood absorption, as well as rapid shape recovery. We show that compared to clinically used gauze, gelatin sponge, CELOX™, and CELOX™-gauze, the MACS provides higher pro-coagulant and hemostatic capacities in lethally normal and heparinized rat and pig liver perforation wound models. We demonstrate its anti-infective activity against S. aureus and E. coli and its promotion of liver parenchymal cell infiltration, vascularization, and tissue integration in a rat liver defect model. Overall, the MACS demonstrates promising clinical translational potential in treating lethal noncompressible hemorrhage and facilitating wound healing.

Highly interconnected inverse opal extracellular matrix scaffolds enhance stem cell therapy in limb ischemia.

The therapeutic effectiveness of cell transplantation in treatment of diseases and injuries is often limited by low cell retention, survivability, and engraftment. Extracellular matrix (ECM)-derived scaffolds are capable of controlling cell responses, thereby offering potential solutions to current challenges associated with cell therapy. However, it remains a technical challenge to produce ECM scaffolds with highly interconnected porous structure specifically required for cell transplantation. Here, we developed inverse opal porous extracellular matrix (ioECM) scaffolds through subcutaneous implantation of sacrificial templates assembled from polymer microspheres, followed by removal of the microsphere template and cellular content. Such highly interconnected porous ioECM scaffolds supported the anchorage, survival, viability, anti-apoptotic and paracrine activities of rat bone marrow mesenchymal stem cells (BMSCs), which further promoted endothelial cell migration and tube formation and viability. Upon transplantation into nude mouse critical limb ischemic model, ioECM promoted the engraftment of laden BMSCs, facilitated interconnected vascular network formation with accelerated recovery of blood perfusion and inhibited muscle atrophy and fibrosis. Our study demonstrates a unique strategy to engineer highly porous yet well-interconnected ECM scaffolds specifically for cell transplantation with marked improvement of survivability and vascularization, which offers an essential step toward the success of cell therapy and regenerative medicine. STATEMENT OF SIGNIFICANCE: Cell-based therapy has a good developing foreground applied in a variety of tissue regeneration. Extracellular matrix (ECM) scaffolds is an optimal choice for cell delivery duo to its superior biocompatibility and favorable immune responses. However, the current ECM scaffolds lacking of the controllable pore structure restrict the cell delivery efficiency and therapeutic outcome. Here, we fabricated highly interconnected inverse opal extracellular matrix (ioECM) scaffolds, which can enhance the effect of stem cell therapy in limb ischemic model by improving the survival, viability, and paracrine activities of stem cells. Our study provides reference value for the design and fabrication of ECM based biomaterials for cell transplantation.

Sufentanil preconditioning protects against myocardial ischemia/reperfusion injury via miR-125a/DRAM2 axis.

This project aimed to investigate the protective mechanism of sufentanil pretreatment on myocardial ischemia-reperfusion injury (IRI). An in vivo rat model of myocardial IRI and an in vitro cultured cardiomyocyte model of hypoxia-reoxygenation (H/R) were used to confirm the anti-oxidation and anti-autophagy effects of sufentanil. The interaction between miR-125a and damage-regulated autophagy regulator 2 (DRAM2) was verified by luciferase reporter assay. We showed that pretreatment with sufentanil suppressed myocardial damage caused by IRI in rats by inhibiting oxidative stress and mitochondrial autophagy. Furthermore, the cardioprotective mechanism of sufentanil was mediated by miR-125a. MiR-125a targeted DRAM2 to ameliorate cardiomyocyte autophagy and oxidative injury following H/R treatment. In conclusion, our results demonstrated that sufentanil pretreatment produced a protective effect against myocardial IRI via regulating miR-125a/DRAM2 signaling axis.

Measurement of dilation pulses using a pulse-dilation framing camera.

A pulse-dilation framing camera (PFC) and its working principle are introduced. The influence of the dilation pulse on the exposure time is discussed. The measurement of the dilation pulse using the PFC are theoretically analyzed and experimentally verified. The waveform and the entire time history of the potential of the dilation pulse are simulated by the known dilation factors of the PFC in theory, with the potential deviation at the end of the dilation time of pulse being approximately 3.2%. In the experiment, the exposure time and dilation factors of the PFC are measured by using an array of fiber bundles and in taking many measurements, the waveform and the entire time history of the potential of dilation pulse are achieved by the dilation factors, with the potential deviation at the end of the dilation time of pulse being approximately 6.3%. The research results show that the experimental measurement is consistent with theoretical analysis, although there are some deviations, and it is feasible to measure the waveform and the entire time history of the potential of dilation pulse using the PFC. Moreover, the research may provide an idea for new applications of the framing camera.

Subcutaneously engineered autologous extracellular matrix scaffolds with aligned microchannels for enhanced tendon regeneration: Aligned microchannel scaffolds for tendon repair.

Improved strategies for the treatment of tendon defects are required to successfully restore mechanical function and strength to the damaged tissue. This remains a scientific and clinical challenge, given the tendon's limited innate regenerative capacity. Here, we present an engineering solution that stimulates the host cell's remodeling abilities. We combined precision-designed templates with subcutaneous implantation to generate decellularized autologous extracellular matrix (aECM) scaffolds that had highly aligned microchannels after removal of templates and cellular components. The aECM scaffolds promoted rapid cell infiltration, favorable macrophage responses, collagen-rich extracellular matrix (ECM) synthesis, and physiological tissue remodeling in rat Achilles tendon defects. At three months post-surgery, the mechanical strength of tenocyte-populated 'neo-tendons' was comparable to pre-injury state tendons. Overall, we demonstrated an in vivo bioengineering strategy for improved restoration of tendon tissue, which also offers wider implications for the regeneration of other highly organized tissues.

Tellurium/Bovine Serum Albumin Nanocomposites Inducing the Formation of Stress Granules in a Protein Kinase R-Dependent Manner.

The effect of nanoparticles (NPs) on cellular stress responses is important to the understanding of nanotoxicities and developing safe therapies. Although the relationship between NPs and cellular stress responses has been preliminarily investigated, stress responses to NPs remain unclear. Here, tellurium/bovine serum albumin (Te/BSA) nanocomposites were prepared using sodium tellurite, BSA, and glutathione as precursors. The as-prepared Te/BSA nanocomposites, with particle size similar to that of many viruses, are found to induce the formation of stress granules (SGs), a kind of cytoplasmic RNA granule formed under various stresses. The SGs in Te/BSA nanocomposite-treated cells are composed of T-cell internal antigen 1 (TIA1), TIA1-related protein, and eukaryotic initiation factor 3η. Using chemical inhibitors and small interfering RNA-mediated silencing, protein kinase R (PKR) is identified as the α-subunit of eukaryotic initiation factor 2 (eIF2α)-kinase activated upon Te/BSA nanocomposite incubation, which is also the dominant kinase responsible for eIF2α activation under virus infection. Mechanistically, PKR is activated in a heparin-dependent manner. This study reveals a biological effect of Te/BSA nanocomposites on stress responses, providing a preliminary basis for further research on viruslike particles and the application of NPs in biology.

Interaction between fluorescein isothiocyanate and carbon dots: Inner filter effect and fluorescence resonance energy transfer.

Carbon dots (CDs) have been widely used for the preparation of multifunctional probes by conjugation with organic fluorescent dyes. However, the effect of organic fluorescent dyes on CDs still remains poorly understood. Herein, the effect of fluorescein isothiocyanate (FITC) on CDs was explored by spectroscopic techniques at pH5.1, 7.0 and 9.0. The fluorescent intensity of CDs was found to be quenched gradually after mixing directly with different concentrations of FITC, but the fluorescent lifetime of CDs remained unchanged. According to the results of UV-vis absorption spectra and fluorescent lifetime measurements, a pH-dependent inner filter effect (IFE) between CDs and FITC was proposed. However, the fluorescent lifetime of CDs deceased after their conjugation with FITC, implying the fluorescence resonance energy transfer (FRET) between CDs and FITC. This study has revealed two different effects of FITC on CDs with varying pH values and provided useful theoretical guidelines for further research on the interaction between other nanoparticles and fluorophores.

Observation of electron beam moiré fringes in an image conversion tube.

An image conversion tube with a magnetic lens was designed to observe electron beam moiré fringes. Electron beam moiré fringes result from the interference between the photocathode and the anode meshes. The photocathode had a strip line structure with a spatial frequency of 10L/mm. The anode mesh had a fixed spatial frequency of 10L/mm, and could be rotated around the axis of the image tube. The changes to the fringe direction and the spacing as a function of the rotation angle between the photocathode and the anode mesh were examined. The experimental results agreed with the theoretical analysis. Moiré fringes with a modulation of ~20% were obtained using a 3keV electron beam.

Quantitative analysis of tivantinib in rat plasma using ultra performance liquid chromatography with tandem mass spectrometry.

In this work, a simple, sensitive and fast ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitative determination of tivantinib in rat plasma. Plasma samples were processed with a protein precipitation. The separation was achieved by an Acquity UPLC BEH C18 (2.1mm×50mm, 1.7µm) column with a gradient mobile phase consisting of 0.1% formic acid in water and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry via multiple reaction monitoring (MRM). The validated method had an excellent linearity in the range of 1.0-100ng/mL (r(2)>0.9967) with a lower limit of quantification (1.0ng/mL). The extraction recovery was in the range of 79.4-84.2% for tivantinib and 80.3% for carbamazepine (internal standard, IS). The intra- and inter-day precision was below 8.9% and accuracy was from -7.2% to 9.5%. No notable matrix effect and astaticism was observed for tivantinib. The method has been successfully applied to a pharmacokinetic study of tivantinib in rats for the first time, which provides the basis for the further development and application of tivantinib.

Association between microRNA polymorphisms and chronic pancreatitis.

BACKGROUD: MicroRNAs play important roles in the development and progression of many human diseases. mir-146a could significantly suppress the induction of proinflammatory cytokines IL-1ß, IL-6, TNF-α, NF-κB and chemokine MCP-1, which might play important roles in chronic pancreatitis. This study was conducted to evaluate the association between mir-146a rs2910164, a functional polymorphism in the pre-mir-146a, and chronic pancreatitis risk. METHODS: The rs2910164 genotypes were determined in 165 patients with chronic pancreatitis and 200 healthy controls who were frequency matched for age and gender. One single nucleotide polymorphism (rs2910164) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP). RESULTS: The frequency of individuals who carried [G] allele was significantly higher in cases (62.7%) than in controls (53.7%, p = 0.015), which resulted in a statistically significant pathogenic effect associated with this variant allele (OR: 1.448, CI: 1.076-1.950; p = 0.015). The GC and GG genotypes showed strong and significant increased risk for complication of chronic pancreatitis (OR = 3.668, 95%CI = 1.233-10.916, p = 0.019; OR = 5.667, 95%CI = 1.852-17.336, p = 0.002). The individuals carrying G allele confer a lower expression level of mature mir-146a. CONCLUSION: These findings suggest that the mir-146a rs2910164 may contribute to genetic susceptibility to chronic pancreatitis, and that mir-146a might be involved in chronic pancreatitis development.

Addition of all-trans-retinoic acid to omeprazole and sucralfate therapy improves the prognosis of gastric dysplasia.

OBJECTIVE: To investigate the efficacy of all-trans retinoic acid (ATRA) in human gastric dysplasia. METHODS: In this double-blind study, patients with precancerous gastric dysplasia with or without intestinal metaplasia (IM) received either conventional treatment consisting of omeprazole and sucralfate (control group) or conventional treatment plus ATRA. Gastric mucosal biopsies were performed before and after drug treatment and were analysed histologically; expression of retinoblastoma (Rb) protein and HER2 protein in gastric mucosa were measured using immunohistochemistry. RESULTS: A total of 122 patients were included in the study, 63 in the ATRA group and 59 in the control group. In the ATRA group, dysplasia was attenuated in 43 out of 63 patients (68%) compared with 22 out of 59 patients (37%) in the control group; however, IM was not affected by treatment in either group. ATRA treatment was associated with significantly increased Rb expression and decreased HER2 expression in gastric mucosa. CONCLUSIONS: The use of conventional therapy plus ATRA for gastric dysplasia was associated with improved efficacy compared with conventional therapy alone. It was also accompanied by increased Rb expression and decreased HER2 expression in gastric mucosa. The addition of ATRA to conventional therapy for gastritis may improve the prognosis of gastric dysplasia.

Enhanced chemotherapy efficacy by co-delivery of shABCG2 and doxorubicin with a pH-responsive charge-reversible layered graphene oxide nanocomplex.

In this study, we constructed a layered graphene oxide (GO) nanocomplex with pH-responsive charge-reversible chitosan-aconitic anhydride (CS-Aco), biocompatible polyethylene glycol (PEG) and low molecular weight polyethylenimine (PEI). This was employed as a novel delivery system for intracellular pH-triggered DOX and short hairpin RNA (shRNA) controlled release and synergistic therapy. The nanocomplex GO-PEI-PEG/DOX/CS-Aco/PEI/shRNA exhibited high drug and shRNA loading, and good stability at physiological pH. In an acid pH environment, the negatively charged CS-Aco layer hydrolyzed into positively charged chitosan, causing the shielding layers of the nanocomposite to loosen. The disassembled GO-PEI-PEG/DOX and chitosan efficiently ruptured the endosome, significantly facilitating the release of DOX and PEI/shRNA into the cytoplasm, and then the shRNA disassembled rapidly because of its weak electrostatic interactions with the short PEI chains. Consequently, GO-PEI-PEG/DOX/CS-Aco/PEI/shRNA exhibited excellent shABCG2 and DOX co-delivery efficiency in HepG2 cells, which was better than that of GO/DOX and the non-charge-reversible GO-PEI-PEG/DOX/CS-Car/PEI/shRNA nanocomplex. Furthermore, this novel nanocomplex had high efficiency in silencing ABCG2 expression, and exhibited a significant synergistic efficacy in chemotherapy.

Infection and immune response in the nematode Caenorhabditis elegans elicited by the phytopathogen Xanthomonas.

Xanthomonas oryzae pv. oryzae (Xoo) strains are plant pathogenic bacteria that can cause serious blight of rice, and their virulence towards plant host is complex, making it difficult to be elucidated. Caenorhabditis elegans has been used as a powerful model organism to simplify the host and pathogen system. However, whether the C. elegans is feasible for studying plant pathogens such as Xoo has not been explored. In the present work, we report that Xoo strains PXO99 and JXOIII reduce the lifespan of worms not through acute toxicity, but in an infectious manner; pathogens proliferate and persist in the intestinal lumen to cause marked anterior intestine distension. In addition, Xoo triggers (i) the p38 MAPK signal pathway to upregulate its downstream C17H12.8 expression, and (ii) the DAF-2/DAF-16 pathway to upregulate its downstream gene expressions of mtl-1 and sod-3 under the condition of daf-2 mutation. Our findings suggest that C. elegans can be used as a model to evaluate the virulence of Xoo phytopathogens to host.

Realgar bioleaching solution is a less toxic arsenic agent in suppressing the Ras/MAPK pathway in Caenorhabditis elegans.

To explore other arsenic derivatives with anticancer effects and fewer adverse effects, realgar bioleaching solution (RBS) has been found to be a viable approach. Here we used C. elegans as a model organism to its possible efficacy for anti-cancer effect of RBS. Our results indicated that RBS significantly suppressed the multivulva (Muv) phenotype of let-60 ras(gf) mutant that was positive correlated to arsenic concentrations in worms and also inhibited Muv phenotype of lin-15(lf) upstream of Ras/MAPK pathway, but did not affect the Muv phenotype resulting from loss-of-function mutations of lin-l(lf) downstream of Ras/MAPK pathway, which may be mechanism-based. In toxicity tests, RBS did not lead to reduction resulting from arsenic trioxide (ATO) in the number of pharyngeal pumping which was orthologous to vertebrate heart beating in wild type C. elegans. Overall, RBS was likely to be a potential anti-cancer drug candidate with high efficiency and low toxicity.