Cadherin-responsive hydrogel combined with dental pulp stem cells and fibroblast growth factor 21 promotes diabetic scald repair via regulating epithelial-mesenchymal transition and necroptosis.

Diabetes causes a loss of sensation in the skin, so diabetics are prone to burns when using heating devices. Diabetic scalded skin is often difficult to heal due to the microenvironment of high glucose, high oxidation, and low blood perfusion. The treatment of diabetic scald mainly focuses on three aspects: 1) promote the formation of the epithelium; 2) promote angiogenesis; and 3) maintain intracellular homeostasis. In response to these three major repair factors, we developed a cadherin-responsive hydrogel combined with FGF21 and dental pulp stem cells (DPSCs) to accelerate epithelial formation by recruiting cadherin to the epidermis and promoting the transformation of N cadherin to E cadherin; promoting angiogenesis to increase wound blood perfusion; regulating the stability of lysosomal and activating autophagy to maintain intracellular homeostasis in order to comprehensively advance the recovery of diabetic scald.

Kinetics of ester-105 degradation by La/TiO2 photocatalysis.

Lanthanum-doped titanium (La/TiO2) nano-photocatalysts were prepared using the sol-gel method and characterized by X-ray diffraction (XRD), zeta potential, and low-temperature nitrogen adsorption analyses. Ester-105, a flotation collector from beneficiation wastewater, was chosen as the target pollutant. The influence of the initial ester-105 concentration, pH, and photocatalyst dosage on the photocatalytic degradation of ester-105 was investigated. To examine the kinetics of the adsorption and photocatalytic degradation of ester-105, a Langmuir adsorption model and Langmuir-Hinshelwood kinetic models were established and discussed. The synthesized photocatalyst comprised anatase-phase TiO2, with an isoelectric point of pH = 6.5, specific surface area of 56.1626 m2·g-1, and average pore size of 7.78 nm. The maximum adsorption and the adsorption equilibrium constant of La/TiO2 for ester-105 were determined as 0.338 mg·g-1 and 1.008 L·mg-1, respectively. The first-order kinetic reaction rate constant (k) exhibited a linear relationship with the initial ester-105 concentration. The optimal pH for ester degradation was theoretically determined to be 6.95, and the optimum photocatalyst dosage was found to be 0.2739 g·L-1. Experiments confirmed that the photocatalytic degradation of ester-105 using La/TiO2 followed the Langmuir-Hinshelwood kinetics model, thereby providing a theoretical foundation for the photocatalytic degradation of ester-105 for industrial application.

The therapeutic effect and mechanism of parthenolide in skeletal disease, cancers, and cytokine storm.

Parthenolide (PTL or PAR) was first isolated from Magnolia grandiflora and identified as a small molecule cancer inhibitor. PTL has the chemical structure of C15H20O3 with characteristics of sesquiterpene lactones and exhibits the biological property of inhibiting DNA biosynthesis of cancer cells. In this review, we summarise the recent research progress of medicinal PTL, including the therapeutic effects on skeletal diseases, cancers, and inflammation-induced cytokine storm. Mechanistic investigations reveal that PTL predominantly inhibits NF-κB activation and other signalling pathways, such as reactive oxygen species. As an inhibitor of NF-κB, PTL appears to inhibit several cytokines, including RANKL, TNF-α, IL-1ß, together with LPS induced activation of NF-κB and NF-κB -mediated specific gene expression such as IL-1ß, TNF-α, COX-2, iNOS, IL-8, MCP-1, RANTES, ICAM-1, VCAM-1. It is also proposed that PTL could inhibit cytokine storms or hypercytokinemia triggered by COVID-19 via blocking the activation of NF-κB signalling. Understanding the pharmacologic properties of PTL will assist us in developing its therapeutic application for medical conditions, including arthritis, osteolysis, periodontal disease, cancers, and COVID-19-related disease.

ADR3, a next generation i-body to human RANKL, inhibits osteoclast formation and bone resorption.

Osteoporosis is a chronic skeletal condition characterized by low bone mass and deteriorated microarchitecture of bone tissue and puts tens of millions of people at high risk of fractures. New therapeutic agents like i-bodies, a class of next-generation single-domain antibodies, are needed to overcome some limitations of conventional treatments. An i-body is a human immunoglobulin scaffold with two long binding loops that mimic the shape and position of those found in shark antibodies, the variable new antigen receptors of sharks. Its small size (∼12 kDa) and long binding loops provide access to drug targets, which are considered undruggable by traditional monoclonal antibodies. Here, we have successfully identified a human receptor activator of nuclear factor-κB ligand (RANKL) i-body, ADR3, which demonstrates a high binding affinity to human RANKL (hRANKL) with no adverse effect on the survival or proliferation of bone marrow-derived macrophages. Differential scanning fluorimetry suggested that ADR3 is stable and able to tolerate a wide range of physical environments (including both temperature and pH). In addition, in vitro studies showed a dose-dependent inhibitory effect of ADR3 on osteoclast differentiation, podosome belt formation, and bone resorption activity. Further investigation on the mechanism of action of ADR3 revealed that it can inhibit hRANKL-mediated signaling pathways, supporting the in vitro functional observations. These clues collectively indicate that hRANKL antagonist ADR3 attenuates osteoclast differentiation and bone resorption, with the potential to serve as a novel therapeutic to protect against bone loss.

A shear-thinning, ROS-scavenging hydrogel combined with dental pulp stem cells promotes spinal cord repair by inhibiting ferroptosis.

Spinal cord injury (SCI) is a serious clinical disease. Due to the deformability and fragility of the spinal cord, overly rigid hydrogels cannot be used to treat SCI. Hence, we used TPA and Laponite to develop a hydrogel with shear-thinning ability. This hydrogel exhibits good deformation, allowing it to match the physical properties of the spinal cord; additionally, this hydrogel scavenges ROS well, allowing it to inhibit the lipid peroxidation caused by ferroptosis. According to the in vivo studies, the TPA@Laponite hydrogel could synergistically inhibit ferroptosis by improving vascular function and regulating iron metabolism. In addition, dental pulp stem cells (DPSCs) were introduced into the TPA@Laponite hydrogel to regulate the ratios of excitatory and inhibitory synapses. It was shown that this combination biomaterial effectively reduced muscle spasms and promoted recovery from SCI.

Galanin family peptides: Molecular structure, expression and roles in the neuroendocrine axis and in the spinal cord.

Galanin is a neurohormone as well as a neurotransmitter and plays versatile physiological roles for the neuroendocrine axis, such as regulating food intake, insulin level and somatostatin release. It is expressed in the central nervous system, including hypothalamus, pituitary, and the spinal cord, and colocalises with other neuronal peptides within neurons. Structural analyses reveal that the human galanin precursor is 104 amino acid (aa) residues in length, consisting of a mature galanin peptide (aa 33-62), and galanin message-associated peptide (GMAP; aa 63-104) at the C-terminus. GMAP appears to exhibit distinctive biological effects on anti-fungal activity and the spinal flexor reflex. Galanin-like peptide (GALP) has a similar structure to galanin and acts as a hypothalamic neuropeptide to mediate metabolism and reproduction, food intake, and body weight. Alarin, a differentially spliced variant of GALP, is specifically involved in vasoactive effect in the skin and ganglionic differentiation in neuroblastic tumors. Dysregulation of galanin, GALP and alarin has been implicated in various neuroendocrine conditions such as nociception, Alzheimer's disease, seizures, eating disorders, alcoholism, diabetes, and spinal cord conditions. Further delineation of the common and distinctive effects and mechanisms of various types of galanin family proteins could facilitate the design of therapeutic approaches for neuroendocrine diseases and spinal cord injury.

The versatile roles of odontogenic ameloblast-associated protein in odontogenesis, junctional epithelium regeneration and periodontal disease.

Junctional epithelium (JE) is a vital epithelial component which forms an attachment to the tooth surface at the gingival sulcus by the adhesion of protein complexes from its basal layer. Disruption of the JE is associated with the development of gingivitis, periodontal disease, and alveolar bone loss. Odontogenic ameloblast-associated (ODAM) is comprised of a signal peptide and an ODAM protein with 12 putative glycosylation sites. It is expressed during odontogenesis by maturation stage ameloblasts and is incorporated into the enamel matrix during the formation of outer and surface layer enamel. ODAM, as a secreted protein which is accumulated at the interface between basal lamina and enamel, mediates the adhesion of the JE to the tooth surface; and is involved with extracellular signalling of WNT and ARHGEF5-RhoA, as well as intracellular signalling of BMP-2-BMPR-IB-ODAM. ODAM is also found to be highly expressed in salivary glands and appears to have implications for the regulation of formation, repair, and regeneration of the JE. Bioinformatics and research data have identified the anti-cancer properties of ODAM, indicating its potential both as a prognostic biomarker and therapeutic target. Understanding the biology of ODAM will help to design therapeutic strategies for periodontal and dental disorders.

Corrigendum: Hypoxia response element-directed expression of aFGF in neural stem cells promotes the recovery of spinal cord injury and attenuates SCI-induced apoptosis.

[This corrects the article DOI: 10.3389/fcell.2021.693694.].

Molecular Structure, Expression and Role of TAFA4 and its Receptor FPR1 in the Spinal Cord.

TAFA chemokine like family member 4 (TAFA4, also named FAM19A4) is a member of the TAFA chemokine like ligand or FAM19A family, which includes TAFA1, TAFA2, TAFA3, TAFA4, and TAFA5 (or FAM19A1, FAM19A2, FAM19A3, FAM19A4, and FAM19A5). They are also referred to as neurokines and are involved in the regulation of a diverse range of cellular processes, including chemotaxis of macrophages, phagocytosis, and release of reactive oxygen species (ROS). TAFA4 is a marker of C-low-threshold mechanoreceptors and is expressed predominantly in nociceptors, such as dorsal root ganglia (DRG). TAFA4 has been implicated in the sensory perception of pain in the spinal cord. Mice with deficiency of TAFA4 demonstrate altered excitability in lamina IIi neurons in DRG in addition to increased mechanical and chemical nociception following inflammation or injury. As a secreted protein, TAFA4 binds to cell surface receptor formyl peptide receptor 1 (FPR1), a G protein-coupled receptor to mediate the chemoattraction of macrophages, phagocytosis, and the inflammatory profile of macrophages. It also interacts with cell surface neurexin to mediate signalling across the synapse. Further understanding the mechanisms by which this conserved protein family regulates diverse biological processes such as in neuronal functions, inflammation, and tissue fibrosis will help to design therapeutic targets for the treatment of TAFA related diseases such as spinal cord injury and neuro-inflammatory disorders.

Facile Synthesis with TiO2 Xerogel and Urea Enhanced Aniline Aerofloat Degradation Performance of Direct Z-Scheme Heterojunction TiO2/g-C3N4 Composite.

Different TiO2/g-C3N4 (TCN) composites were synthesized by a simple pyrolysis method with TiO2 xerogel and urea. The structure and physicochemical properties of TCN were characterized by X-ray diffraction, scanning electron microscope, transmission electron microscope, ultraviolet-visible diffuse reflectance spectrum, X-ray photoelectron spectroscopy, N2-adsorption isotherms and electrochemical impedance spectroscopy. Aniline Aerofloat was chosen as a typical degradation-resistant contaminant to investigate the photodegradation activity of TCN under UV irradiation. The results indicated that TCN had higher light absorption intensity, larger specific surface area and smaller particle size compared to pure TiO2. Furthermore, TCN had great recycling photocatalytic stability for the photodegradation of Aniline Aerofloat. The photocatalytic activity depends on the synergistic reaction between holes (h+) and hydroxyl radicals (·OH). Meanwhile, the direct Z-scheme heterojunction structure of TiO2 and g-C3N4 postpones the recombination of h+ and electrons to enhance UV-light photocatalytic activity.

The Molecular Structure and Role of Humanin in Neural and Skeletal Diseases, and in Tissue Regeneration.

Humanin (HN) belongs to a member of mitochondrial-derived peptides (MDPs) which are encoded by mitochondrial genes. HN shares sequence homology with thirteen HN-like proteins, named MTRNR2L1 to MTRNR2L13, which encompass 24-28 amino acid residues in length. HN mediates mitochondrial status and cell survival by acting via an intracellular mechanism, or as a secreted factor via extracellular signals. Intracellularly, it binds Bcl2-associated X protein (BAX), Bim and tBid, and IGFBP3 to inhibit caspase activity and cell apoptosis. When released from cells as a secreted peptide, HN interacts with G protein-coupled formyl peptide receptor-like 1 (FPRL1/2) to mediate apoptosis signal-regulating kinase (ASK) and c-Jun N-terminal kinase (JNK) signalling pathways. Additionally, it interacts with CNTFR-α/gp130/WSX-1 trimeric receptors to induce JAK2/STA3 signalling cascades. HN also binds soluble extracellular proteins such as VSTM2L and IGFBP3 to modulate cytoprotection. It is reported that HN plays a role in neuronal disorders such as Alzheimer's disease, as well as in diabetes mellitus, infertility, and cardiac diseases. Its roles in the skeletal system are emerging, where it appears to be involved with the regulation of osteoclasts, osteoblasts, and chondrocytes. Understanding the molecular structure and role of HN in neural and skeletal diseases is vital to the application of HN in tissue regeneration.

Versatile subtypes of pericytes and their roles in spinal cord injury repair, bone development and repair.

Vascular regeneration is a challenging topic in tissue repair. As one of the important components of the neurovascular unit (NVU), pericytes play an essential role in the maintenance of the vascular network of the spinal cord. To date, subtypes of pericytes have been identified by various markers, namely the PDGFR-ß, Desmin, CD146, and NG2, each of which is involved with spinal cord injury (SCI) repair. In addition, pericytes may act as a stem cell source that is important for bone development and regeneration, whilst specific subtypes of pericyte could facilitate bone fracture and defect repair. One of the major challenges of pericyte biology is to determine the specific markers that would clearly distinguish the different subtypes of pericytes, and to develop efficient approaches to isolate and propagate pericytes. In this review, we discuss the biology and roles of pericytes, their markers for identification, and cell differentiation capacity with a focus on the potential application in the treatment of SCI and bone diseases in orthopedics.

The molecular structure and role of LECT2 or CHM-II in arthritis, cancer, and other diseases.

Leukocyte cell-derived chemotaxin-2 (LECT2 or LECT-2), also called chondromodulin II (ChM-II or CHM2) plays a versatile role in various tissues. It was first identified as a chemotactic factor to promote the migration of neutrophils. It was also reported as a hepatokine to regulate glucose metabolism, obesity, and nonalcoholic fatty liver disease. As a secreted factor, LECT2 binds to several cell surface receptors CD209a, Tie1, and Met to regulate inflammatory reaction, fibrogenesis, vascular invasion, and tumor metastasis in various cell types. As an intracellular molecule, it is associated with LECT2-mediated amyloidosis, in which LECT2 misfolding results in insoluble fibrils in multiple tissues such as the kidney, liver, and lung. Recently, LECT2 was found to be associated with the development of rheumatoid arthritis and osteoarthritis, involving the dysregulation of osteoclasts, mesenchymal stem cells, osteoblasts, chondrocytes, and endothelial cells in the bone microenvironment. LECT2 is implicated in the development of cancers, such as hepatocellular carcinoma via MET-mediated PTP1B/Raf1/ERK signaling pathways and is proposed as a biomarker. The mechanisms by which LECT2 regulates diverse pathogenic conditions in various tissues remain to be fully elucidated. Further research to understand the role of LECT2 in a tissue tropism-dependent manner would facilitate the development of LECT2 as a biomarker for diagnosis and therapeutic target.

Notoginseng Triterpenes Inhibited Autophagy in Random Flaps via the Beclin-1/VPS34/LC3 Signaling Pathway to Improve Tissue Survival.

Random flaps are widely used in tissue reconstruction, attributed to the lack of vascular axial limitation. Nevertheless, the distal end of the flap is prone to necrosis due to the lack of blood supply. Notoginseng triterpenes (NTs) are the active components extracted from Panax notoginseng, reducing oxygen consumption and improving the body's tolerance to hypoxia. However, their role in random flap survival has not been elucidated. In this study, we used a mouse random skin flap model to verify that NT can promote cell proliferation and migration and that increasing blood perfusion can effectively improve the survival area of a skin flap. Our study also showed that the autophagy of random flaps after NT treatment was activated through the Beclin-1/VPS34/LC3 signaling pathway, and the therapeutic effect of NT significantly decreased after VPS34 IN inhibited autophagy. In conclusion, we have demonstrated that NT can significantly improve the survival rate of random flaps through the Beclin-1/VPS34/LC3 signaling pathway, suggesting that it might be a promising clinical treatment option.

Nerve growth factor (NGF) with hypoxia response elements loaded by adeno-associated virus (AAV) combined with neural stem cells improve the spinal cord injury recovery.

The ischemia and hypoxia microenvironment after spinal cord injury (SCI) makes SCI repair a challenging problem. With various stimulus, chances for neural stem cells (NSCs) to differentiate into neurons, astrocytes, oligodendrocytes are great and is considered as a potential source of the stem cell therapy to SCI. Our research used adeno-associated virus (AAV) to carry the target gene to transfect neural stem cells. Transfected NSCs can express nerve growth factor (NGF) navigated by five hypoxia-responsive elements (5HRE). Therefore, the 5HRE-NGF-NSCs could express NGF specifically in hypoxia sites to promote the tissue repair and function recovery. Based on the regeneration of neurocytes and promotion of the recovery found in SCI models, via locomotor assessment, histochemical staining and molecular examinations, our results demonstrated that 5HRE-NGF-NSCs could improve the motor function, neurons survival and molecules expression of SCI rats. Meanwhile, the downregulated expression of autophagy-related proteins indicated the inhibitive effect of 5HRE-NGF-NSCs on autophagy. Our research showed that 5HRE-NGF-NSCs contribute to SCI repair which might via inhibiting autophagy and improving the survival rate of neuronal cells. The new therapy also hampered the hyperplasia of neural glial scars and induced axon regeneration. These positive functions of 5HRE-NGF-NSCs all indicate a promising SCI treatment.

Hypoxia Response Element-Directed Expression of aFGF in Neural Stem Cells Promotes the Recovery of Spinal Cord Injury and Attenuates SCI-Induced Apoptosis.

Reducing neuronal death after spinal cord injury (SCI) is considered to be an important strategy for the renovation of SCI. Studies have shown that, as an important regulator of the development and maintenance of neural structure, acidic fibroblast growth factor (aFGF) has the role of tissue protection and is considered to be an effective drug for the treatment of SCI. Neural stem cells (NSCs) are rendered with the remarkable characteristics to self-replace and differentiate into a variety of cells, so it is promising to be used in cell transplantation therapy. Based on the facts above, our main aim of this research is to explore the role of NSCs expressing aFGF meditated by five hypoxia-responsive elements (5HRE) in the treatment of SCI by constructing AAV-5HRE-aFGF-NSCs and transplanting it into the area of SCI. Our research results showed that AAV-5HRE-aFGF-NSCs can effectively restore the motor function of rats with SCI. This was accomplished by inhibiting the expression of caspase 12/caspase 3 pathway, EIF2α-CHOP pathway, and GRP78 protein to inhibit apoptosis.

Feasibility analysis of the use of anterior screw fixation in the treatment of pediatric odontoid fracture.

BACKGROUND: This study aimed to determine the feasibility of using anterior percutaneous screw fixation to treat odontoid fractures in children of different ages based on computed tomography (CT) measurements. METHODS: A total of 176 children were enrolled and divided into 3 groups: group A (<6 years of age; 18 males and 22 females), group B (6 to 12 years old; 40 males and 35 females), and group C (12 to 18 years old; 34 males and 27 females). Using 2-dimensional CT reconstruction technology, we measured the children's odontoid parameters, including the coronal external diameter of the base of the odontoid process, the sagittal external diameter of the base of the odontoid process, the length of the odontoid process, the height of the axis vertebral body, and the angle between the axial line of the odontoid process and the vertical line of the anterosuperior border of the C3 vertebral body. RESULTS: The mean coronal external diameter of the odontoid process base in children under 6 years old was 4.21±1.62 mm, which was not sufficient to accommodate a single screw. Among children aged 6 to 12 years old, this parameter varied widely, and the mean diameter was 5.50±2.80 mm. In the 12- to 18-year-old group, the diameter was 8.64±1.68 mm, which is similar to that of adults. The values of the total height of the axis, and the angle between the axial line of the and the vertical line of the anterosuperior C3 vertebral body border were lower than those for adults. CONCLUSIONS: The percutaneous odontoid screw fixation technique is not recommended for children under 6 years old. For children aged 6 to 18 years old, this technique is feasible, but individual differences must be considered preoperatively. Selecting the appropriate screw diameter, length, and angle according to the actual CT measurement result is critical.