Multihydrogen Bond Modulated Polyzwitterionic Removable Adhesive Hydrogel with Antibacterial and Hemostatic Function for Wound Healing.

Wound management is a major challenge worldwide, placing a huge financial burden on the government of every nation. Wound dressings that can protect wounds, accelerate healing, prevent infection, and avoid secondary damage continue to be a major focus of research in the health care and clinical communities. Herein, a novel zwitterionic polymer (LST) hydrogel incorporated with [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (SBMA), mussel-inspired N-[tris(hydroxymethyl)methyl] acrylamide (THMA), and lithium magnesium salt was prepared for functional wound dressings. The incorporation of the THMA monomer containing three hydroxyl groups gives the hydrogel suitable adhesion properties (∼6.0 KPa). This allows the LST zwitterionic hydrogels to bind well to the skin, which not only protects the wound and ensures its therapeutic efficacy but also allows for painless removal and reduced patient pain. Zwitterionic sulfobetaine units of SBMA provide antimicrobial and mechanical properties. The chemical structure and microscopic morphology of LST zwitterionic hydrogels were systematically studied, along with their swelling ratio, adhesion, and mechanical properties. The results showed that the LST zwitterionic hydrogels had a uniform and compact porous structure with the highest swelling and mechanical strain of 1607% and 1068.74%, respectively. The antibacterial rate of LST zwitterionic hydrogels was as high as 99.49%, and the hemostatic effect was about 1.5 times that of the commercial gelatin hemostatic sponges group. In further studies, a full-thickness mouse skin model was selected to evaluate the wound healing performance. Wounds covered by LST zwitterionic hydrogels had a complete epithelial reformation and new connective tissue, and its vascular regenerative capacity was increased to about 2.4 times that of the commercial group, and the wound could completely heal within 12-13 days. This study provides significant advances in the design and construction of multifunctional zwitterionic hydrogel adhesives and wound dressings.

Nature-Inspired Gelatin-Based Adhesive Hydrogel: A Rapid and User-Friendly Solution for Hemostatic Applications.

Conventional hemostatic agents face challenges in achieving rapid hemostasis and effective tissue repair due to limited hemostatic scenarios, suboptimal efficacy, and inadequate adhesion to wet tissues. Drawing inspiration from nature-sourced materials, a gelatin-based adhesive hydrogel (AOT)  is designed, easily prepared and quick to form, driven by Schiff base and multiple hydrogen bonds for applications in arterial and liver bleeding models. AOT exhibits exceptional adhesion to wet tissues (48.67 ± 0.16 kPa) and displays superior hemostatic properties with reduced blood loss and hemostatic time compared to other hydrogels and conventional hemostatic materials. Moreover, AOT exhibits good biocompatibility and biodegradability. In summary, this easily prepared adhesive hydrogel has the potential to supplant traditional hemostatic agents, offering a novel approach to achieve swift sealing of hemostasis and facilitate wound healing and repair in broader application scenarios, owing to its unique advantages.

CEBPB upregulates P4HA2 to promote the malignant biological behavior in IDH1 wildtype glioma.

Temozolomide (TMZ), the primary drug for glioma treatment, has limited treatment efficacy. Additionally, considerable evidence shows that isocitrate dehydrogenase 1 mutation-type (IDH1 mut) gliomas have a better response to TMZ than isocitrate dehydrogenase 1 wildtype (IDH1 wt) gliomas. Here, we aimed to identify potential mechanisms underlying this phenotype. Herein, the Cancer Genome Atlas bioinformatic data and 30 clinical samples from patients were analyzed to reveal the expression level of cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT) Enhancer Binding Protein Beta (CEBPB) and prolyl 4-hydroxylase subunit alpha 2 (P4HA2) in gliomas. Next, cellular and animal experiments, including cell proliferation, colony formation, transwell, CCK-8, and xenograft assays, were performed to explore the tumor-promoting effects of P4HA2 and CEBPB. Then, chromatin immunoprecipitation (ChIP) assays were used to confirm the regulatory relationships between them. Finally, a co-immunoprecipitation (Co-IP) assay was performed to confirm the effect of IDH1-132H to CEBPB proteins. We found that CEBPB and P4HA2 expression was significantly upregulated in IDH1 wt gliomas and associated with poor prognosis. CEBPB knockdown inhibited the proliferation, migration, invasion, and temozolomide resistance of glioma cells and hindered the growth of glioma xenograft tumors. CEBPE, as a transcription factor, exerted its function by transcriptionally upregulating P4HA2 expression in glioma cells. Importantly, CEBPB is prone to ubiquitin-proteasomal degradation in IDH1 R132H glioma cells. We also demonstrated that both genes are related to collagen synthesis, as confirmed by in vivo experiments. Thus, CEBPE promotes proliferation and TMZ resistance by inducing P4HA2 expression in glioma cells and offers a potential therapeutic target for glioma treatment.

Ginsenoside Rh2 inhibits CBP/p300-mediated FOXO3a acetylation and epilepsy-induced oxidative damage via the FOXO3a-KEAP1-NRF2 pathway.

Epilepsy is a chronic disease that affects a wide range of people. Furthermore, a third of patients suffering from epileptic seizures do not respond to antiepileptic drugs. In recent years, increasing attention has focused on the role of oxidative stress in acquired epilepsy, and adjuvant antiepileptic drugs to reduce oxidative stress may be a new therapeutic strategy. In this study ginsenoside Rh2 was resistant to oxidative stress induced by epileptic activity in vivo and in vitro. Using online databases, we identified forkhead box O3a (FOXO3a) overexpression in epilepsy tissue and validated this in vitro, in vivo, and in clinical tissues of patients with epilepsy. An in vitro epilepsy model revealed that the overexpression of FOXO3a led to more severe oxidative stress, while the knockdown of FOXO3a had a protective effect on SH-SY5Y cells. Moreover, our results showed that the positive effect of FOXO3a on oxidative stress was caused by the transcriptional activation of Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of nuclear factor erythroid 2-related factor 2 (NRF2). We also found that ginsenoside Rh2 can directly inhibit the activation of FOXO3a by selectively blocking CREB-binding protein (CBP)/p300-mediated FOXO3a acetylation and play a role in regulating the KEAP1-NRF2 pathway to resist oxidative stress.

Treatment of Congenital Radioulnar Synostosis Using a Free Vascularized Fascia Lata Graft.

OBJECTIVE: To describe the modified mobilization surgery technique that uses a free vascularized fascia lata graft as the interposition graft, and to evaluate the outcome of this procedure in treating congenital radioulnar synostosis (CRUS). METHODS: Eleven patients (eight boys and three girls with an average age of 6.0 years) were treated using this procedure between 2012 and 2017 in our institution. Five bilateral cases (four left forearms and one right forearm were treated), and six unilateral cases (three left forearms and three right forearms) were included. All 11 cases were treated with mobilization procedure with free vascularized fascia lata as the interposition graft, and were followed-up for an average of 2.2 years (range, 2-4 years). The parental satisfaction, postoperative ankylosis at proximal radioulnar joint, and active range of forearm rotation motion (measured by physical examination) were evaluated at the last follow-up. RESULTS: The average preoperative fixed pronation angle was 67.3° (range, 20°-90°). Ipsilateral thumb hypoplasia was noted in one case, and cleft palate and bilateral thumb hypoplasia were noted in one case; none of the patients had a family history of congenital radioulnar synostosis. Pronation and supination splints were used 3 days after the operation and were worn every night for 4-6 months postoperatively. Active and passive rehabilitation for elbow flexion and forearm rotation was initiated 4 weeks postoperatively. All patients were followed up for at least 2 years (average, 26 months; range, 24-48 months). The average forearm pronation range was 39° (range, 20°-60°), and the average forearm supination range was 33.2° (range, 10°-60°) at the latest follow-up. Re-ankylosis occurred in one case. An osseous bridge developed between the radius and ulna at the osteotomy site in one case. Radial nerve paralysis developed in two cases and spontaneously resolved 2 months later. Plate breakage was noted in one case 9 weeks postoperatively; however, union was achieved 7 months later. CONCLUSION: Mobilization of proximal radioulnar synostosis using a free vascularized fascia lata graft as the interposition graft may prevent re-ankylosis and restore the forearm rotation function, making it a good option for the surgical treatment of CRUS.

Clinical Characteristics of 90 Macrodactyly Cases.

PURPOSE: Macrodactyly is a rare, nonhereditary congenital deformity. Digital enlargement in macrodactyly involves all tissue types and presents alone or as part of a congenital deformity syndromes. Macrodactyly treatment largely depends on surgeons' experience and knowledge. Because there is a paucity of large cohort studies of macrodactyly in the literature, our goal was to retrospectively analyze macrodactyly cases in order to define a better system for diagnosis, classification, and prognosis. METHODS: Medical records of 90 Chinese macrodactyly patients, including demographic characteristics, clinical presentations, anatomical distributions, x-rays, pathological findings, and treatments, were reviewed. Genetic analyses of 12 patients were also reviewed. RESULTS: Disease incidence was similar across sex and geographical regions. Multiple-digit involvement was 2.6 times more frequent than single-digit involvement. The index finger, middle finger, and thumb were most commonly involved. Two digits were affected more often than 3, with the affected digits adjacent in most cases. The affected digit was in the median nerve innervation distribution in 79% of cases and was accompanied by enlargement and fat infiltration of the median nerve. Seven cases had syndactyly. Ten of the 12 cases subjected to PIK3CA mutation analysis were positive. CONCLUSIONS: Macrodactyly represents a heterogeneous group of conditions, without significant sex or geographical predilection, which is usually present at birth. A high PIK3CA mutation-positive rate in affected tissues suggests a similar cellular mechanism for overgrowth in patients with various clinical presentations. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

In situ forming gelatin/hyaluronic acid hydrogel for tissue sealing and hemostasis.

Fibrin glue has been widely used as a surgical sealing and hemostatic agent. Its application is restricted due to poor tissue adhesion and low mechanical strength. To develop better tissue sealant and hemostatic agent, this study prepared the injectable hydrogels by chemically cross-linking gelatin (G) with or without hyaluronic acid (HA) in situ at a mild condition. The rheological analysis, Fourier transform infrared spectroscopy, swelling, proteolytic degradation, biocompatibility, tissue sealing, and hemostatic ability of the hydrogels were investigated. It was found that the chemical cross-linking rapidly formed in both self-crosslinking gelatin (sc-G) and gelatin/hyaluronate acid (G/HA) hydrogels. The hydrogels could be degraded by trypsin and had a desirable biocompatibility. The tissue sealing ability of the hydrogels was superior to fibrin glue. Furthermore, the G/HA hydrogel had similar hemostatic performance as fibrin glue, and was better than that of gelatin hydrogel. The results in the study indicated that the G/HA hydrogel could be used in clinic as a tissue sealant or surgical hemostat.

In situ injectable hyaluronic acid/gelatin hydrogel for hemorrhage control.

Tissue sealants are used for hemorrhage control which is imperative in many surgical procedures. It is a highly challenging task to obtain the ideal tissue sealant. Only a few commercially tissue sealants are available to be used for internal tissue or organ hemorrhage control. This study introduced two in situ injectable hydrogels for hemorrhage control: self-crosslinking gelatin (sc-G) hydrogel and hyaluronic acid/gelatin (HA/G) hydrogel. They were prepared on the tissue surface in situ and characterized by rheological analysis, stability, cytotoxicity, and bursting strength test. The hemostatic ability of the hydrogels was evaluated in a liver-bleeding rat model. The sc-G and HA/G hydrogels gelled around 90 s and 50 s, respectively. They were preferable for cell attachment and proliferation. The bursting strengths of both hydrogels exceeded that of fibrin glue. The hemostatic ability of HA/G hydrogel was better than that of sc-G hydrogel, and was same as that of fibrin glue. The HA/G hydrogel could be used as a tissue sealant for hemorrhage control in clinic.

An investigation of PIK3CA mutations in isolated macrodactyly.

Somatic PIK3CA mutations may relate to pathogenesis of isolated macrodactyly. We set up to test the association between PIK3CA mutations with isolated macrodactyly in order to establish a more accurate and molecular mechanism-based diagnosis and classification. DNA extracted from affected tissues in 12 individuals with isolated macrodactyly was tested for PIK3CA mutation using targeted Sanger DNA sequencing. Ten patients had macrodactyly in the foot and two in the hand. Nine of the 12 patients were found to carry a low-level, mosaic PIK3CA mutation. The mutations identified, p.His1047Arg, p.His1047Leu, p.Glu545Lys, and p.Glu542Lys, are codons frequently mutated in cancers. Among all tissues tested, adipose had the highest mutation detection rate, followed by nerve and skin. Our results indicate that a high proportion of isolated macrodactyly patients carry a pathogenic PIK3CA mutation. Affected adipose, nerve and skin tissues are ideal for PIK3CA mutation analysis.

Internal force corrections with machine learning for quantum mechanics/molecular mechanics simulations.

Ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulation is a useful tool to calculate thermodynamic properties such as potential of mean force for chemical reactions but intensely time consuming. In this paper, we developed a new method using the internal force correction for low-level semiempirical QM/MM molecular dynamics samplings with a predefined reaction coordinate. As a correction term, the internal force was predicted with a machine learning scheme, which provides a sophisticated force field, and added to the atomic forces on the reaction coordinate related atoms at each integration step. We applied this method to two reactions in aqueous solution and reproduced potentials of mean force at the ab initio QM/MM level. The saving in computational cost is about 2 orders of magnitude. The present work reveals great potentials for machine learning in QM/MM simulations to study complex chemical processes.

Rational design of NIR-emitting iridium(iii) complexes for multimodal phosphorescence imaging of mitochondria under two-photon excitation.

A series of NIR-emitting iridium(iii) complexes were developed for multimodal phosphorescence imaging (NIR imaging, phosphorescence lifetime imaging and time-gated imaging) of mitochondria in living cells, 3D multicellular spheroids (MTCCs) and hippocampus slice under two-photon excitation.

Human Ferrochelatase: Insights for the Mechanism of Ferrous Iron Approaching Protoporphyrin IX by QM/MM and QTCP Free Energy Studies.

Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX, the terminal step in heme biosynthesis. Some disputes in its mechanism remain unsolved, especially for human ferrochelatase. In this paper, high-level quantum mechanical/molecular mechanics (QM/MM) and free-energy studies were performed to address these controversial issues including the iron-binding site, the optimal reaction path, the substrate porphyrin distortion, and the presence of the sitting-atop (SAT) complex. Our results reveal that the ferrous iron is probably at the binding site coordinating with Met76, and His263 plays the role of proton acceptor. The rate-determining step is either the first proton removed by His263 or the proton transition within the porphyrin with an energy barrier of 14.99 or 14.87 kcal/mol by the quantum mechanical thermodynamic cycle perturbation (QTCP) calculations, respectively. The fast deprotonation step with the conservative residues rather than porphyrin deformation found in solution provides the driving force for biochelation. The SAT complex is not a necessity for the catalysis though it induces a modest distortion on the porphyrin ring.

Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks.

Molecular dynamics simulation with multiscale quantum mechanics/molecular mechanics (QM/MM) methods is a very powerful tool for understanding the mechanism of chemical and biological processes in solution or enzymes. However, its computational cost can be too high for many biochemical systems because of the large number of ab initio QM calculations. Semiempirical QM/MM simulations have much higher efficiency. Its accuracy can be improved with a correction to reach the ab initio QM/MM level. The computational cost on the ab initio calculation for the correction determines the efficiency. In this paper we developed a neural network method for QM/MM calculation as an extension of the neural-network representation reported by Behler and Parrinello. With this approach, the potential energy of any configuration along the reaction path for a given QM/MM system can be predicted at the ab initio QM/MM level based on the semiempirical QM/MM simulations. We further applied this method to three reactions in water to calculate the free energy changes. The free-energy profile obtained from the semiempirical QM/MM simulation is corrected to the ab initio QM/MM level with the potential energies predicted with the constructed neural network. The results are in excellent accordance with the reference data that are obtained from the ab initio QM/MM molecular dynamics simulation or corrected with direct ab initio QM/MM potential energies. Compared with the correction using direct ab initio QM/MM potential energies, our method shows a speed-up of 1 or 2 orders of magnitude. It demonstrates that the neural network method combined with the semiempirical QM/MM calculation can be an efficient and reliable strategy for chemical reaction simulations.

Topoisomerase IIα poisoning and DNA double-strand breaking by chiral ruthenium(ii) complexes containing 2-furanyl-imidazo[4,5-f][1,10]phenanthroline derivatives.

Four chiral Ru(ii) complexes bearing furan ligands, Δ/Λ-[Ru(bpy)2(pocl)](2+) () and Δ/Λ-[Ru(bpy)2(poi)](2+) () (bpy = 2,2'-bipyridine, pocl = 2-(5-chlorofuran-2-yl)imidazo[4,5-f][1,10]phenanthroline, poi = 2-(5-5-iodofuran-2-yl)imidazo[4,5-f][1,10]phenanthroline), were synthesized and characterized. These Ru(ii) complexes showed antitumor activities against HeLa, A549, HepG2, HL-60 and K562 tumor cell lines, especially the HL-60 tumor cell line. Moreover, was more active than other complexes accounting for the different cellular uptakes. In addition, could accumulate in the nucleus of HL-60 cells, suggesting that nucleic acids were the cellular target of . Topoisomerase inhibition tests in vitro and in living cells confirmed that the four complexes acted as efficient topoisomerase IIα poisons, DNA double-strand breaks had also been observed from neutral single cell gel electrophoresis (comet assay). inhibited the growth of HL-60 cells through the induction of apoptotic cell death, as evidenced by the Alexa Fluor® 488 annexin V staining assays. The results demonstrated that acted as a topoisomerase IIα poison and caused DNA double-strand damage that could lead to apoptosis.

Direct imaging of biological sulfur dioxide derivatives in vivo using a two-photon phosphorescent probe.

Sulfur dioxide (SO2) and its derivatives sulfite and bisulfite play important roles in biological systems. However, in vivo detection of sulfite/bisulfite remains challenging. In this study, we developed a dinuclear Ir(III) complex (Ir4) as a two-photon phosphorescent probe for sulfite and bisulfite. Ir4 selectively and rapidly responded, with high sensitivity, to sulfite/bisulfite over other bio-related ions and molecules. One-photon and two-photon microscopy images revealed that Ir4 preferentially targeted mitochondria and was capable of imaging biological sulfite/bisulfite levels in vitro and in vivo. In situ sulfite generation in Caenorhabditis elegans was visualized by two-photon excitation real-time imaging. Finally, Ir4 was employed to monitor sulfite distribution in rat brain and other tissues. This study is the first report of the direct visualization of SO2 derivatives in vivo. These results provide new insights into the biological importance of SO2.

Biomechanical evaluation of flexor tendon graft with different repair techniques and graft surface modification.

The purpose of this study was to investigate the biomechanical properties of modified repair techniques for flexor tendon reconstruction and the effects of surface modification using carbodiimide-derivatized synovial fluid plus gelatin (cd-SF-G), compared to the traditional repair techniques. The second and fifth digits from 16 canine forepaws were randomly divided into 4 groups: (1) traditional graft repairs (TGR group) including distal Bunnell repair and proximal Pulvertaft weave repair; (2) modified graft repairs (MGR group) including distal graft bony attachment repair and proximal step-cut repair; (3) group TGR coated with cd-SF-G (TGR-C group); and (4) group MGR coated with cd-SF-G (MGR-C group). Digit normalized work of flexion (nWOF), ultimate failure strength, and stiffness were measured. The nWOF in MGR group was significantly less than TGR group (p < 0.05). The nWOF in groups treated with cd-SF-G was significantly less than their untreated counterparts (p < 0.05). Ultimate load to failure of the MGR-C group was significantly greater than the TGR-C group (p < 0.05), but no significant difference in stiffness was found between these two groups. The modified techniques cannot only improve tendon gliding abilities but can also improve breaking strength. Additionally, surface modification with cd-SF-G significantly decreased the work of flexion.

Dinuclear ruthenium(II) complexes that induce and stabilise G-quadruplex DNA.

A series of dinuclear ruthenium(II) complexes were synthesised, and the complexes were determined to be new highly selective compounds for binding to telomeric G-quadruplex DNA. The interactions of these complexes with telomeric G-quadruplex DNA were studied by using circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assays, isothermal titration calorimetry (ITC) and molecular modelling. The results showed that the complexes 1, 2 and 4 induced and stabilised the formation of antiparallel G-quadruplexes of telomeric DNA in the absence of salt or in the presence of 100 mM K(+)-containing buffer. Furthermore, complexes 1 and 2 strongly bind to and effectively stabilise the telomeric G-quadruplex structure and have significant selectivity for G-quadruplex over duplex DNA. In comparison, complex 3 had a much lesser effect on the G-quadruplex, suggesting that possession of a suitably sized plane for good π-π stacking with the G-quadruplets is essential for the interaction of the dinuclear ruthenium(II) complexes with the G-quadruplex. Moreover, telomerase inhibition by the four complexes and their cellular effects were studied, and complex 1 was determined to be the most promising inhibitor of both telomerase and HeLa cell proliferation.

Ruthenium(II) polypyridyl complexes as dual inhibitors of telomerase and topoisomerase.

One novel ruthenium polypyridyl complex, [Ru(bpy)2(icip)](2+) (1), and two previously reported ruthenium polypyridyl complexes, [Ru(bpy)2(pdppz)](2+) ()2 and [Ru(bpy)2(tactp)](2+) (3) (bpy = 2,2'-bipyridine, icip = 2-(indeno[2,1-b]chromen-6-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, pdppz = phenanthro[4,5-abc]dipyrido[3,2-h:2',3'-j]phenazine, tactp = 4,5,9,18-tetraazachryseno[9,10-b]-triphenylene), have been synthesised. As expected, these complexes show inhibition towards telomerase by inducing and stabilising the G-quadruplex structure, and behave as topoisomerase I/II poisons at the same time. Additionally, the acute and chronic cytotoxicities of the complexes are considered. Furthermore, cell apoptosis experiments are used to briefly study the mechanism. Because studies involving multi-target inhibition towards topoisomerase and telomerase of Ru(II) complexes have not been reported previously, the present research may help to develop innovative chemical strategies and therapies.

Novel ruthenium(II) polypyridyl complexes as G-quadruplex stabilisers and telomerase inhibitors.

Two novel ruthenium polypyridyl complexes, Ru[(bpy)2(pedppz)](2+) (1) and Ru[(bpy)2(pemitatp)](2+) (2) (bpy = 2'2-bipyridine, pdeppz = 10-(2-(piperidin-1-yl)ethoxy)dipyrido[3,2-a:2',3'-c]phenazine, pemitatp = 5-methoxy-1-(2-(piperidin-1-yl)ethyl)-isatino[1,2-b]-1,4,8,9-tetraazatriphenylene), bearing large planar π-delocalized aromatic systems with flexible chains have been synthesised and characterised. As expected, these complexes show inhibition towards telomerase by inducing and stabilising the G-quadruplex structure.