Human dental pulp stem cells have comparable abilities to umbilical cord mesenchymal stem/stromal cells in regulating inflammation and ameliorating hepatic fibrosis.

Hepatic fibrosis, also called cirrhosis, have wide prevalence worldwide for long yeas. Recently, many treatments for liver cirrhosis made marked progress, especially the umbilical cord-derived mesenchymal stromal cells (UCMSC) therapy. However, limited recourses and potential immune-related issues become the obstacles on UCMSC popularization in clinic. Therefore, we took dental pulp stem cells (DPSCs) into the consideration, since autologous DPSCs can be easily obtained without any ethnic or immune-related issues that heterogenous UCMSCs could encounter. We systematically compared the effects of both cell types and found that DPSCs had similar results to UCMSCs in regulating inflammation and reversing hepatic fibrosis. In our study, co-culturing T cells and PBMSCs showed that DPSCs have the ability to inhibit the proliferation of inflammatory cells and downregulate relevant inflammatory factors. In vitro and in vivo sterility tests confirmed the bio-safety of DPSCs. Moreover, the 1 year-aged mouse model demonstrated that DPSCs successfully reversed hepatic fibrosis. Overall, DPSCs demonstrated comparable effectiveness to UCMSCs in regulating inflammation and reversing hepatic fibrosis, particularly in the aged mouse model that represents middle-aged and elderly humans. Since autologous DPSCs avoid potential immune-related issues that heterogenous UCMSCs could encounter, they may be a better choice for stem cell-related therapies.

Synergistic antibacterial attributes of copper-doped polydopamine nanoparticles: an insight into photothermal enhanced antibacterial efficacy.

Antibiotic-resistant bacteria and associated infectious diseases pose a grave threat to human health. The antibacterial activity of metal nanoparticles has been extensively utilized in several biomedical applications, showing that they can effectively inhibit the growth of various bacteria. In this research, copper-doped polydopamine nanoparticles (Cu@PDA NPs) were synthesized through an economical process employing deionized water and ethanol as a solvent. By harnessing the high photothermal conversion efficiency of polydopamine nanoparticles (PDA NPs) and the inherent antibacterial attributes of copper ions, we engineered nanoparticles with enhanced antibacterial characteristics. Cu@PDA NPs exhibited a rougher surface and a higher zeta potential in comparison to PDA NPs, and both demonstrated remarkable photothermal conversion efficiency. Comprehensive antibacterial evaluations substantiated the superior efficacy of Cu@PDA NPs attributable to their copper content. These readily prepared nano-antibacterial materials exhibit substantial potential in infection prevention and treatment, owing to their synergistic combination of photothermal and spectral antibacterial features.

Kartogenin delivery systems for biomedical therapeutics and regenerative medicine.

Kartogenin, a small and heterocyclic molecule, has emerged as a promising therapeutic agent for incorporation into biomaterials, owing to its unique physicochemical and biological properties. It holds potential for the regeneration of cartilage-related tissues in various common conditions and injuries. Achieving sustained release of kartogenin through appropriate formulation and efficient delivery systems is crucial for modulating cell behavior and tissue function. This review provides an overview of cutting-edge kartogenin-functionalized biomaterials, with a primarily focus on their design, structure, functions, and applications in regenerative medicine. Initially, we discuss the physicochemical properties and biological functions of kartogenin, summarizing the underlying molecular mechanisms. Subsequently, we delve into recent advancements in nanoscale and macroscopic materials for the carriage and delivery of kartogenin. Lastly, we address the opportunities and challenges presented by current biomaterial developments and explore the prospects for their application in tissue regeneration. We aim to enhance the generation of insightful ideas for the development of kartogenin delivery materials in the field of biomedical therapeutics and regenerative medicine by providing a comprehensive understanding of common preparation methods.

Burden of esophageal cancer and its attributable risk factors in 204 countries and territories from 1990 to 2019.

Background: Esophageal cancer is a global health concern. Regularly updated data about the burden of esophageal cancer are essential for formulating specific public policies. We aimed to estimate the global, regional, and national burden and trends of esophageal cancer and its attributable risk factors from 1990 to 2019, by age, sex and socio-demographic index (SDI). Methods: Data about the incidence, death, disability-adjusted life-years (DALYs), and age-standardized rates were collected from Global Burden of Disease study 2019. Estimated annual percentage changes were used to quantify the temporal trends of age-standardized rates. Moreover, the risk factors attributable to esophageal cancer deaths were also presented. Results: There were 534,563 incident cases and 498,067 deaths in 2019, contributing to 11,666,017 DALYs. The absolute numbers of incidence, death, and DALYs had increased from 1990 to 2019, contrasting with declined changes in their corresponding age-standardized rates. The burden of esophageal cancer varied across different regions and countries, and the age-standardized rates were negative with SDI. Almost half of the esophageal cancer was concentrated in China. Males accounted for most of the burden of esophageal cancer, and the onset age tended to be older. The death of esophageal cancer was primarily attributable to smoking, followed by alcohol use, high body mass index, diet low in fruits and diet low in vegetables. Conclusion: The burden of esophageal cancer was heterogeneous across regions and countries by sex, age, and SDI, providing information for governments that may help to formulate more targeted policies.

MSC-derived immunomodulatory extracellular matrix functionalized electrospun fibers for mitigating foreign-body reaction and tendon adhesion.

Adhesion formation during tendon healing remains a severe problem in clinical practice. Multiple factors contribute to postoperative adhesion formation, and macrophage-driven inflammation is thought to be greatly involved in this process. We hypothesize that reducing macrophage-mediated inflammation in the injured tendon by regulating M1 to M2 macrophage polarization may effectively inhibit adhesion formation. Here, we developed an acellular immunomodulatory biomaterial consisting of an electrospun polycaprolactone/silk fibroin (PCL/SF) composite fibrous scaffold functionalized with mesenchymal stem cell (MSC)-derived extracellular matrix (ECM). To enhance the immunoregulatory potential of MSCs, we performed inflammatory licensing with IFN-γ to obtain immunomodulatory ECM (iECM). Proteomic analyses of MSCs and their secreted ECM components from different culture conditions revealed the MSC-ECM molecular signatures and the potential mechanism of ECM immunoregulation. Then, the immunoregulatory potential of the iECM-modified scaffold was evaluated in vitro and in vivo. Relative to the PCL/SF fibrous scaffold, the iECM-functionalized scaffold facilitated M2 macrophage polarization and inhibited the expression of multiple cytokines (IL-1ß, IL-6, CXCL11, IL-10, IL-1R2, and TGF-ß1) in vitro, strongly suggesting the immunosuppressive ability of iECM derived from inflammatory licensed MSCs. Consistent with the in vitro findings, the results of rat subcutaneous implantation indicated that a markedly lower foreign-body reaction (FBR) was obtained in the PCL/SF-iECM group than in the other groups, as evidenced by thinner fibrotic capsule formation, less type I collagen production and more M2-type macrophage polarization. In the rat Achilles tendon injury model, the PCL/SF-iECM scaffold greatly mitigated tendon adhesion with clear sheath space formation between the tendon and the scaffold. These data highlight the immunomodulatory potential of iECM-functionalized fibrous scaffolds to attenuate FBR by modulating M2 macrophage polarization, thereby preventing tendon adhesion. STATEMENT OF SIGNIFICANCE: Electrospun PCL/SF fibrous scaffolds functionalized with ECM secreted by MSCs stimulated by inflammatory factor IFN-γ was developed that combined physical barrier and immunomodulatory functions to prevent tendon adhesion formation. PCL/SF micro-nanoscale bimodal fibrous scaffolds prepared by emulsion electrospinning possess high porosity and a large pore size beneficial for nutrient transport to promote intrinsic healing; moreover, surface modification with immunomodulatory ECM (iECM) mitigates the FBR of fibrous scaffolds to prevent tendon adhesion. The iECM-functionalized electrospun scaffolds exhibit powerful immunomodulatory potency in vitro and in vivo. Moreover, the iECM-modified scaffolds, as an anti-adhesion physical barrier with immunomodulatory ability, have an excellent performance in a rat Achilles tendon adhesion model. MSC secretome-based therapeutics, as an acellular regenerative medicine strategy, are expected to be applied to other inflammatory diseases due to its strong immunoregulatory potential.

Gradient Biomineralized Silk Fibroin Nanofibrous Scaffold with Osteochondral Inductivity for Integration of Tendon to Bone.

Enthesis injury repair remains a huge challenge because of the unique biomolecular composition, microstructure, and mechanics in the interfacial region. Surgical reconstruction often creates new bone-scaffold interfaces with mismatched properties, resulting in poor osseointegration. To mimic the natural interface tissue structures and properties, we fabricated a nanofibrous scaffold with gradient mineral coating based on 10 × simulated body fluid (SBF) and silk fibroin (SF). We then characterized the physicochemical properties of the scaffold and evaluated its biological functions both in vitro and in vivo. The results showed that different areas of SF nanofibrous scaffold had varying levels of mineralization with disparate mechanical properties and had different effects on bone marrow mesenchymal stem cell growth and differentiation. Furthermore, the gradient scaffolds exhibited an enhancement of integration in the tendon-to-bone interface with a higher ultimate load and more fibrocartilage-like tissue formation. These findings demonstrate that the silk-based nanofibrous scaffold with gradient mineral coating can regulate the formation of interfacial tissue and has the potential to be applied in interface tissue engineering.

Synthesis and evaluation of bisulfate/mesylate-conjugated chlortetracycline with high solubility and bioavailability.

The aim of this work is to improve the solubility and bioavailability of chlortetracycline and the function of the immune response. Chlortetracycline bisulfate and chlortetracycline mesylate were successfully synthesized and characterized with several techniques, including spectroscopy, chromatography and mass spectrometry, which demonstrated that the C4-dimethylamino group of chlortetracycline can accept a proton from sulfuric acid and methanesulfonic acid to form the corresponding salts. In addition, chlortetracycline bisulfate and chlortetracycline mesylate were more soluble in water than chlortetracycline hydrochloride, but the antibacterial activity was not enhanced. The influences of chlortetracycline hydrochloride, chlortetracycline bisulfate and chlortetracycline mesylate on chlortetracycline and immunoglobulin concentrations in mouse serum were also investigated. These results suggested that the chlortetracycline bisulfate and chlortetracycline mesylate have good bioavailability and strong immune response and have potential applications in animal breeding and formulation technologies.

Mechanical injury and IL-1ß regulated LOXs and MMP-1, 2, 3 expression in ACL fibroblasts co-cultured with synoviocytes.

OBJECTIVE: Interleukin (IL)-1ß in the joint cavity increases to promote healing after anterior cruciate ligament (ACL) injury. Synovial tissue is a major joint microenvironmental regulator after ACL injury. The purpose of this study was to investigate the effects of synovial cells (SCs) on lysyl oxidase (LOX) and matrix metalloproteinase (MMP) production by ACL fibroblasts (ACLfs) in the presence of IL-1ß. RESULTS: This study sheds light on the regulation of LOX and MMP-1, -2, -3 expression by ACLfs co-cultured with SCs and treated with IL-1ß. LOX and MMP-1, 2, 3 gene/protein expression in IL-1ß/stretch-stimulated ACLfs co-cultured with SCs were measured by real-time quantitative PCR and Western blot. Meanwhile, MMP-2 activity was analyzed by zymogram. The results showed that co-culture with SCs increased LOX and MMP-1, -2, -3 gene and protein expression in the presence of IL-1ß. Next, ACLfs were subjected to 12% mechanical stretch to simulate pathological injury. Under these conditions, SCs inhibited IL-1ß-mediated upregulation of LOXs. However, IL-1ß enhanced the expression of MMP-1, -2, -3 in injured ACLfs. CONCLUSIONS: SCs can either inhibit or increase LOX production in the presence of IL-1ß, while promoting the accumulation of MMP in injured ACLfs. These results may provide crucial insights into the mechanisms underlying ACL poor healing capacity after injury.

Surface modification of nanofibrous matrices via layer-by-layer functionalized silk assembly for mitigating the foreign body reaction.

The inherent hydrophobicity and large surface area of electrospun synthetic polymeric scaffolds often cause non-specific protein adsorption, thereby influencing macrophage functions and eventually leading to fibrosis at the tissue-scaffold interface. This work reports fabrication of silk fibroin (SF)-functionalized electrospun polycaprolactone (PCL) fibers by single-component layer-by-layer assembly and decorate the SF with heparin disaccharide (HD), resulting in the non-covalent binding of interleukin-4 (IL-4) with the capacity to modulate macrophage polarization. A modified SF derivative was obtained by diazonium coupling and then covalently bonded with HD via click chemistry to eventually bind IL-4 efficiently and maintain its bioactivity. In vitro studies showed that IL-4 surface-functionalized nanofibrous scaffolds promoted polarization to M2 macrophages in the short-term. Importantly, in a murine subcutaneous implantation model, we found that promoting transient shifts in macrophage polarization at early stage can significantly inhibit the extent of the late foreign body reactions. Furthermore, the results of a transcriptomic profiling showed that MARK, PI3K, JNK and NF-κB signaling pathways played an important role in regulating the macrophage phenotypes in the SF/HD/IL-4-functionalized fibers. Our results suggest that such a strategy offers a new approach for utilizing biological agent surface functionalization to modulate the foreign body reaction to nanofibrous scaffolds.

Effect of substrate stiffness on hepatocyte migration and cellular Young's modulus.

Hepatic fibrosis progress accompanied by an unbalanced extracellular matrix (ECM) degradation and deposition leads to an increased tissue stiffness. Hepatocytes interplay with all intrahepatic cell populations inside the liver. However, how hepatocytes migration and cellular Young's modulus influenced by the substrate stiffness are not well understood. Here, we established a stiffness-controllable in vitro cell culture model by using a polyvinyl alcohol (PVA) hydrogel that mimicked the same physical stiffness as a fibrotic liver. Three levels of stiffness were used in our experiment that corresponded to the stiffness levels found in normal liver tissue (4.5 kPa), the early (19 kPa) and late stages (37 kPa) of fibrotic liver tissues. Cytoskeleton of hepatocyte was influenced by substrate stiffness. Soft substrate promoted the cellular migration and directionality. The cellular Young's modulus firstly increased and then decreased with increasing substrate stiffness. Integrin-ß1 and ß-catenin expression on cytomembrane were up-regulated and down-regulated with the increase of substrate stiffness, respectively. Our data not only suggested that hepatocytes were sensitive to substrate stiffness, but also suggested that there may be a potential relationship among substrate stiffness, cellular Young's modulus and the dynamic balance of integrin-ß1 and ß-catenin pathways. These results may provide us a new insight in mechanism investigation of mechano-dependent diseases, especially like fibrosis related diseases.

Construction of three-dimensional net-like polyelectrolyte multilayered nanostructures onto titanium substrates for combined antibacterial and antioxidant applications.

Bacterial biofilm formation and oxidative stress induced by the production of reactive oxygen species (ROS) are major causes of implant failure. An emerging approach to overcome these issues is to combine chitosan-polycaprolactone (PCL) nanofibers and polyelectrolyte multilayers composed of tannic acid (TA) and gentamicin sulfate (GS) for the localized co-delivery of antioxidants and antibiotics from the titanium surface. The integration of nanofibers (NFs) and layer-by-layer (LBL) technology could provide a larger surface area and thus increase the number of cationic sites of Ti substrates. The coating of NF substrates with TA/GS resulted in higher (p < 0.05 or p < 0.01) cellular activities than those of Ti substrates, including enhanced proliferation and gene expression. Furthermore, in vitro investigation demonstrated that TA/GS-incorporated Ti-polydopamine (PDA)/NF implants exhibited excellent stability, and antibacterial and antioxidant properties. The results showed that Ti-PDA/NF/LBL substrates have a biodegradable character in vivo. All the results indicated that the combination of NFs and the bacteria-triggered antibiotic-releasing coating could be used for the tailored co-delivery of antibacterial and antioxidant agents from various metallic implantable devices to effectively improve early bone healing even under ROS stress and decrease the risk of biofilm-associated infections in patients.

The use of mechano growth factor to prevent cartilage degeneration in knee osteoarthritis.

Previous studies have attached more importance to growth factors in treating cartilage degeneration and osteoarthritis (OA). Here, the capability of mechano growth factor-C24E (MGF) to prevent osteoarthritic cartilage degeneration was evaluated in vitro and in vivo. Using in vitro cultured human OA chondrocytes treated with 10-60-ng/ml MGF for 12 hr, we detected the cell proliferation, migration, and anabolism of OA chondrocytes. The unfolded protein response and the protein characteristic of OA pathology, such as transforming growth factor ß, SMAD family member 3, and hypoxia-inducible factor 2α of OA chondrocytes, were also detected by western blotting. Furthermore, protein kinase RNA-like endoplasmic reticulum kinase was knocked down via small interfering RNA to illuminate the potential mechanism of MGF's treatment of OA. In a rabbit knee joint OA model, cartilage degeneration was inhibited after 2 weeks of treatment with 0.1-10-µg/ml MGF. This study demonstrated that MGF treatment can inhibit the pathological apoptosis of OA chondrocytes and promote the proliferation, migration, and matrix synthesis of the chondrocytes. The results also demonstrate that the degeneration of OA cartilage can be delayed by MGF treatment partially via unfolded protein response regulated by protein kinase RNA-like endoplasmic reticulum kinase and suggest a potential therapeutic application of MGF for OA treatment.

Gsdma3 regulates hair follicle differentiation via Wnt5a-mediated non-canonical Wnt signaling pathway.

Hair follicle is a mini-organ that consists of complex but well-organized structures, which are differentiated from hair follicle progenitor or stem cells. How non-canonical Wnt signaling pathway is involved in regulating hair follicle differentiation remains elusive. Here we showed that Wnt5a regulates hair follicle differentiation through an epithelial-mesenchymal interaction mechanism in mice. We first observed that Wnt5a is expressed in the epithelial and dermal papilla cells during hair follicle development and growth. For the upstream of Wnt5a, RT-PCR and immunohistochemistry staining showed that Wnt5a expression is significantly decreased in the Gsdma3-mutant mice in vivo. Overexpression of Gsdma3 results in a significantly increased expression of Wnt5a in the cultured epidermal cells in vitro. We also checked the downstream factors of Wnt5a by adenovirus-mediated overexpression of Wnt5a to the dermal papilla cells isolated from the mouse whisker. We found that overexpression of Wnt5a suppresses canonical Wnt signaling pathway effectors such as ß-catenin and Lef1. In addition, genes involved in maintaining cell quiescent state are also significantly decreased in their expression to the DP cells which were treated by Wnt5a. Our study indicates that Wnt5a mediates epithelia-expressed Gsdma3 to influence DP cell behaviors, which in turn regulate hair follicle epithelia differentiation in mice.

Isolable Boron Persulfide: Activation of Elemental Sulfur with a 2-Chloro-Azaborolyl Anion.

The novel boron persulfide 2 LB(η(2) -S2 ) (L=[ArNC(R)CHC(R)](-) ; Ar=2,6-Me2 C6 H3 , R=tBu) was obtained by the reaction of the 2-chloro-azaborolyl anion 1 (LBCl)K(THF) with 0.25 equiv of elemental sulfur (S8 ). Persulfide 2 is labile in solution and could be converted to the cyclic tetrasulfide LBS4 (3) and hexasulfide LBS6 (4) in the presence of sulfur at room temperature and 50 °C, respectively. Desulfination of 2 with triphenylphosphine resulted in the formation of the thioxoborane LB=S (5). Alternatively, 3 and 4 could be obtained by the reaction of 1 with an excess of sulfur. Structural analysis of 2 disclosed the relatively long S-S bond of 2.1004(8) Šdue to the lone-pair repulsions of the two sulfur atoms, as disclosed by DFT calculations.

Synthesis of N-alkyl isatins via oxidative cyclization of N-alkyl 2-bromo(chloro)acetanilides.

A highly efficient method for the synthesis of N-alkyl isatins starting from N-alkyl 2-bromo or 2-chloro acetanilides is described. The starting materials are easy to prepare and the yields of isatins are generally high. Operationally the reaction is very simple to run. Even though best results were obtained with a catalytic amount of CuI, the reactions of N-alkyl 2-bromo acetanilides actually performed well even in the absence of any metal catalyst.