Low concentrations of saracatinib promote definitive endoderm differentiation through inhibition of FAK-YAP signaling axis.

Optimizing the efficiency of definitive endoderm (DE) differentiation is necessary for the generation of diverse organ-like structures. In this study, we used the small molecule inhibitor saracatinib (SAR) to enhance DE differentiation of human embryonic stem cells and induced pluripotent stem cells. SAR significantly improved DE differentiation efficiency at low concentrations. The interaction between SAR and Focal Adhesion Kinase (FAK) was explored through RNA-seq and molecular docking simulations, which further supported the inhibition of DE differentiation by p-FAK overexpression in SAR-treated cells. In addition, we found that SAR inhibited the nuclear translocation of Yes-associated protein (YAP), a downstream effector of FAK, which promoted DE differentiation. Moreover, the addition of SAR enabled a significant reduction in activin A (AA) from 50 to 10 ng/mL without compromising DE differentiation efficiency. For induction of the pancreatic lineage, 10 ng/ml AA combined with SAR at the DE differentiation stage yielded a comparative number of PDX1+/NKX6.1+ pancreatic progenitor cells to those obtained by 50 ng/ml AA treatment. Our study highlights SAR as a potential modulator that facilitates the cost-effective generation of DE cells and provides insight into the orchestration of cell fate determination.

Aligned lovastatin-loaded electrospun nanofibers regulate collagen organization and reduce scar formation.

Excessive scar formation caused by cutaneous injury leads to pruritus, pain, contracture, dyskinesia, and unpleasant appearance. Functional wound dressings are designed to accelerate wound healing and reduce scar formation. In this study, we fabricated aligned or random polycaprolactone/silk fibroin electrospun nanofiber membranes with or without lovastatin loading, and then evaluated their scar-inhibitory effects on wounds under a specific tension direction. The nanofiber membranes exhibited good controlled-release performance, mechanical properties, hydrophilicity, and biocompatibility. Furthermore, nanofibers' perpendicular placement to the tension direction of the wound most effectively reduced scar formation (the scar area decreased by 66.9%) and promoted skin regeneration in vivo. The mechanism was associated with aligned nanofibers regulated collagen organization in the early stage of wound healing. Moreover, lovastatin-loaded nanofibers inhibited myofibroblast differentiation and migration. Both tension direction-perpendicular topographical cues and lovastatin synergistically inhibited mechanical transduction and fibrosis progression, further reducing scar formation. In summary, our study may provide an effective scar prevention strategy in which individualized dressings can be designed according to the local mechanical force direction of patients' wounds, and the addition of lovastatin can further inhibit scar formation. STATEMENT OF SIGNIFICANCE: In vivo, cells and collagen are always arranged parallel to the tension direction. However, the aligned topographic cues themselves promote myofibroblast differentiation and exacerbate scar formation. Electrospun nanofibers' perpendicular placement to the tension direction of the wound most effectively reduces scar formation and promotes skin regeneration in vivo. The mechanism is associated with tension direction-perpendicular nanofibers reregulate collagen organization in the early stage of wound healing. In addition, tension direction-perpendicular topographical cue and lovastatin could inhibit mechanical transduction and fibrosis progression synergistically, further reducing scar formation. This study proves that combining topographical cues of wound dressing and drugs would be a promising therapy for clinical scar management.

Early Application of Quaternized Chitin Derivatives Inhibits Hypertrophic Scar Formation.

Various treatments for hypertrophic scars (HS) are applied after wound re-epithelialization. However, the lack of early intervention within the wound bed leads to poor HS treatment outcomes. In this study, quaternized chitin (QC) derivatives with different degrees of deacetylation (7.4% and 78.9%) are synthesized and their effects on HS formation are evaluated in a rabbit ear scar model. Early application of QC alleviates scar hypertrophy without delayed wound healing. Fibroblast count, collagen content, and α-smooth muscle actin expression are decreased, while matrix metalloproteinase-1 is upregulated on day 35 in the QC treatment group. QC suppresses inflammatory cell infiltration and IL-6 expression. A subsequent reduction in transforming growth factor ß1 expression is also observed. The inhibitory effect of QC on HS formation is eliminated through the administration of exogenous IL-6. Taken together, early application of QC inhibits HS formation by downregulating IL-6 expression, and QC with a low degree of deacetylation tends to be more effective. Considering its potential for accelerating wound healing, inhibiting HS formation, and its antibacterial activity, QC may be used as an effective dressing in clinical wound management.

Efficacy and Safety of Tranexamic Acid in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Tranexamic acid has been shown to reduce rebleeding after aneurysmal subarachnoid hemorrhage; however, whether it can reduce mortality and improve clinical outcomes is controversial. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of the tranexamic acid in aneurysmal subarachnoid hemorrhage. We conducted a comprehensive literature search of PubMed, Embase, Web of Science, and Cochrane Library from inception to March 2021 for randomized controlled trials (RCTs) comparing tranexamic acid and placebo in adults with aneurysmal subarachnoid hemorrhage. The risk of bias was evaluated using the Cochrane Handbook, and the quality of evidence was evaluated using the GRADE approach. This meta-analysis included 13 RCTs, involving 2,888 patients. In patients with aneurysmal subarachnoid hemorrhage tranexamic acid had no significant effect on all-cause mortality (RR = 0.96; 95% CI = 0.84-1.10, p = 0.55, I 2 = 44%) or poor functional outcome (RR = 1.04; 95% CI = 0.95-1.15, p = 0.41) compared with the control group. However, risk of rebleeding was significantly lower (RR = 0.59; 95% CI = 0.43-0.80, p = 0.0007, I 2 = 53%). There were no significant differences in other adverse events between tranexamic acid and control treatments, including cerebral ischemia (RR = 1.17; 95% CI = 0.95-1.46, p = 0.15, I 2 = 53%). At present, routine use of tranexamic acid after subarachnoid hemorrhage cannot be recommended. For a patient with subarachnoid hemorrhage, it is essential to obliterate the aneurysm as early as possible. Additional higher-quality studies are needed to further assess the effect of tranexamic acid on patients with subarachnoid hemorrhage.

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Patients With Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Observational Studies.

The neutrophil-to-lymphocyte ratio (NLR), as an essential systemic inflammation factor, has been widely used as a prognostic indicator in various diseases, such as malignant tumors, cardiovascular disease, and intracranial hemorrhage. An increasing number of studies have believed that NLR is a valuable predictor of prognosis for patients with aneurysmal subarachnoid hemorrhage (aSAH). However, these results remain controversial. In the current study, we planned to carry out a systematic review and meta-analysis to investigate the association between NLR and poor outcome, and the occurrence of delayed cerebral ischemia (DCI). We carried out a comprehensive search for published literatures on PubMed, EMBASE, Cochrane Library, and Web of Science databases from inception to April 1, 2021. We conducted an assessment of all included studies based on the principles proposed in the Newcastle-Ottawa Quality Assessment Scale (NOS). Poor outcome and the occurrence of DCI were considered as the main outcome measure. We calculated the pooled odds ratio (OR) and corresponding 95% confidence interval (CI) to examine the strength of the association of NLR with poor outcome or the occurrence of DCI. We strictly selected a total of 10 studies comprising 4,989 patients. Nine studies reported the association between NLR and poor outcome, and five studies reported the association between NLR and the occurrence of DCI. The pooled results indicated higher NLR was significantly associated with both poorer outcomes (OR = 1.32, 95%CI 1.11-1.57; P = 0.002, I 2 = 87%), and the occurrence of DCI (OR = 1.72, 95%CI 1.22-2.41; P = 0.002, I 2 = 82%) in aSAH patients. The NLR is a valuable indicator of inflammation to independently predict poor outcome and occurrence of DCI after aSAH, where a higher NLR is significantly associated with poor outcomes and occurrence of DCI. These findings suggest that the NLR can help clinicians evaluate the prognosis and identify potentially severe patients early, which may contribute to better management and improve poor prognosis of aSAH patients.

Ultrabroad-spectrum, multidrug resistant bacteria-killing, and biocompatible quaternized chitin derivative for infected wound healing.

Wound infections have consistently been recognized as serious threats to human. The design of antimicrobial and biocompatible wound dressings for infected wounds is an area of constant research. Herein, we homogeneously synthesized an ultrabroad-spectrum antimicrobial and biocompatible quaternized chitin derivative (QC-4) in a high-efficiency and sustainable route using aqueous KOH/urea solution. Particularly, QC-4 displayed powerful multidrug resistant bacteria-killing activities even at a very low antimicrobial concentration range from 500 ng/mL to 5 µg/mL, including clinically prevalent multidrug-resistant Escherichia coli (MDR-E. coli), methicillin resistant Staphylococcus aureus (MRSA), multidrug-resistant Pseudomonas aeruginosa (MRPA), and multidrug-resistant Acinetobacter baumannii (MDR-A. baumannii). With the aim to facilitate clinical translation, we validated the biocompatibility and safety of QC-4 both in vitro and in vivo, and further assessed the effects of QC-4 on infected wound healing in a porcine infectious full-thickness skin wound model. QC-4 demonstrated significant reduction of microbial aggregates and enhanced wound-healing effects by promoted re-epithelialization and collagen deposition, which were quite comparable to that of commercial Alginate-Ag dressing and absolutely superior to commercial Chitoclot Bandage dressing. Additionally, we provided clear evidences that QC-4 had a unique mechanism of action by attracting electrostatically to the negatively charged microbial surface, thus damaging the microbial cell wall and membrane. Findings of this work provided robust preclinical rationale for the future translational applications of QC-4 as a novel ultrabroad-spectrum and multidrug resistant bacteria-killing antimicrobial wound dressing for clinical wound management.