OBJECTIVE

This review article aims to determine the properties, uses, toxicity, and other side effects of crosslinking agents in tissue scaffolds when applied in vitro and in vivo.

A literature search was performed using the PubMed-NCBI (MEDLINE) database (https://pubmed.ncbi.nlm. nih.gov/) with keywords: crosslinking reagent, collagen, hydroxyapatite, and bone regeneration. GRADE criteria were used to assess the quality of evidence.

A total of six articles were included in the study. Improved mechanical properties of collagen-hydroxyapatite scaffolds with high porosity can be achieved by employing crosslinking methods, including physical dehydrothermal (DHT) treatment, chemical treatment with glutaraldehyde (GA), Microbial Transglutaminase (mTGase), 1‐ethyl‐3‐(3‐ dimethylaminopropyl) carbodiimide (EDAC), or a combination of both DHT and EDAC. Furthermore, the crosslinking of EDAC and DHT can lead to forming ester bonds between activated carboxyl groups and hydroxyl groups.

The combination of DHT and EDAC crosslinking can increase mechanical strength, make the pore size appropriate, make the scaffold more stable, and support cell adhesion so that new cells can grow, and the process of osteogenesis can run more optimally.

The superficial zone (SFZ) of articular cartilage is an important interface that isolates deeper zones from the microenvironment of the articular cavity and is directly exposed to various biological and mechanical stimuli. The SFZ is not only a crucial structure for maintaining the normal physiological function of articular cartilage but also the earliest site of osteoarthritis (OA) cartilage degeneration and a major site of cartilage progenitor cells, suggesting that the SFZ might represent a key target for the early diagnosis and treatment of OA. However, to date, SFZ research has not received sufficient attention, accounting for only about 0.58% of cartilage tissue research. The structure, biological composition, function, and related mechanisms of the SFZ in the physiological and pathological processes of articular cartilage remain unclear. This article reviews the key role of the SFZ in articular cartilage physiology and pathology and focuses on the characteristics of SFZ in articular cartilage degeneration and regeneration in OA, aiming to provide researchers with a systematic understanding of the current research status of the SFZ of articular cartilage, hoping that scholars will give more attention to the SFZ of articular cartilage in the future.
Cartilage, Articular/pathology* ; Humans ; Regeneration/physiology* ; Animals ; Osteoarthritis/physiopathology*

Neuronal reprogramming is an innovative technique for converting non-neuronal somatic cells into neurons that can be used to replace lost or damaged neurons, providing a potential effective therapeutic strategy for central nervous system (CNS) injuries or diseases. Transcription factors have been used to induce neuronal reprogramming, while their reprogramming efficiency is relatively low, and the introduction of exogenous genes may result in host gene instability or induce gene mutation. Therefore, their future clinical application may be hindered by these safety concerns. Compared with transcription factors, small-molecule compounds have unique advantages in the field of neuronal reprogramming, which can overcome many limitations of traditional transcription factor-induced neuronal reprogramming. Here, we review the recent progress in the research of small-molecule compound-mediated neuronal reprogramming and its application in CNS regeneration and repair.
Humans ; Cellular Reprogramming/drug effects* ; Neurons/cytology* ; Animals ; Transcription Factors ; Small Molecule Libraries/pharmacology* ; Nerve Regeneration

The neurophysiological mechanisms by which exercise improves cognitive function have not been fully elucidated. A comprehensive and systematic review of current domestic and international neurophysiological evidence on exercise improving cognitive function was conducted from multiple perspectives. At the molecular level, exercise promotes nerve cell regeneration and synaptogenesis and maintains cellular development and homeostasis through the modulation of a variety of neurotrophic factors, receptor activity, neuropeptides, and monoamine neurotransmitters, and by decreasing the levels of inflammatory factors and other modulators of neuroplasticity. At the cellular level, exercise enhances neural activation and control and improves brain structure through nerve regeneration, synaptogenesis, improved glial cell function and angiogenesis. At the structural level of the brain, exercise promotes cognitive function by affecting white and gray matter volumes, neural activation and brain region connectivity, as well as increasing cerebral blood flow. This review elucidates how exercise improves the internal environment at the molecular level, promotes cell regeneration and functional differentiation, and enhances the brain structure and neural efficiency. It provides a comprehensive, multi-dimensional explanation of the neurophysiological mechanisms through which exercise promotes cognitive function.
Animals ; Humans ; Brain/physiology* ; Cognition/physiology* ; Exercise/physiology* ; Nerve Regeneration/physiology* ; Neuronal Plasticity/physiology*

The timely and efficient repair of the plasma membrane in skeletal muscle cells following injury is critical for maintaining cellular function and tissue integrity. Extracellular vesicles (EVs) play a pivotal role in this process through multi-level mechanisms. This review systematically summarizes the generation, secretion, and multifunctional roles of EVs in the repair of skeletal muscle plasma membrane damage: (1) removing damaged membrane fragments and cellular debris via endocytosis and exocytosis to maintain plasma membrane stability; (2) fusing with the injured plasma membrane to supply essential components for membrane repair and restore membrane integrity; and (3) serving as a vital mediator of intercellular communication, transmitting repair signals, promoting intercellular interactions, and orchestrating multi-level responses to facilitate tissue regeneration and functional recovery. Additionally, this article explores the potential applications of EVs in the treatment of exercise-induced injuries and muscular diseases, aiming to provide theoretical insights and novel strategies for future research and EV-based therapeutic approaches.
Extracellular Vesicles/physiology* ; Humans ; Muscle, Skeletal/physiology* ; Cell Membrane/physiology* ; Animals ; Regeneration/physiology* ; Exocytosis/physiology* ; Endocytosis/physiology* ; Cell Communication/physiology*

OBJECTIVE: Treating peripheral nerve injury (PNI) presents a clinical challenge due to limited axon regeneration. Strychni Semen, a traditional Chinese medicine, is clinically used for numbness and hemiplegia. However, its role in promoting functional recovery after PNI and the related mechanisms have not yet been systematically studied. METHODS: A mouse model of sciatic nerve crush (SNC) injury was established and the mice received drug treatment via intragastric gavage, followed by behavioral assessments (adhesive removal test, hot-plate test and Von Frey test). Transcriptomic analyses were performed to examine gene expression in the dorsal root ganglia (DRGs) from the third to the sixth lumbar vertebrae, so as to identify the significantly differentially expressed genes. Immunofluorescence staining was used to assess the expression levels of superior cervical ganglia neural-specific 10 protein (SCG10). The ultra-trace protein detection technique was used to evaluate changes in gene expression levels. RESULTS: Strychni Semen and its active compounds (brucine and strychnine) improved functional recovery in mice following SNC injury. Transcriptomic data indicated that Strychni Semen and its active compounds initiated transcriptional reprogramming that impacted cellular morphology and extracellular matrix remodeling in DRGs after SNC, suggesting potential roles in promoting axon regeneration. Imaging data further confirmed that Strychni Semen and its active compounds facilitated axon regrowth in SNC-injured mice. By integrating protein-protein interaction predictions, ultra-trace protein detection, and molecular docking analysis, we identified myeloperoxidase as a potentially critical factor in the axon regenerative effects conferred by Strychni Semen and its active compounds. CONCLUSION Strychni Semen and its active compounds enhance sensory function by promoting axonal regeneration after PNI. These findings establish a foundation for the future applications of Strychni Semen and highlight novel therapeutic strategies and drug targets for axon regeneration. Please cite this article as: Zhang Y, Zhao XY, Liu MT, Zhou ZC, Cheng HB, Jiang XH, Zheng YR, Chen Z. Strychni Semen and its active compounds promote axon regeneration following peripheral nerve injury by suppressing myeloperoxidase in the dorsal root ganglia. J Integr Med. 2025; 23(2): 169-181.
Animals ; Nerve Regeneration/drug effects* ; Mice ; Peripheral Nerve Injuries/physiopathology* ; Male ; Ganglia, Spinal/enzymology* ; Axons/physiology* ; Peroxidase/antagonists & inhibitors* ; Mice, Inbred C57BL ; Drugs, Chinese Herbal/pharmacology* ; Disease Models, Animal ; Strychnine/pharmacology*

OBJECTIVE: Diabetes-induced gastrointestinal (GI) motility disorders are increasingly prevalent. Damage to the enteric nervous system (ENS), composed primarily of enteric neurons and glial cells, is an essential mechanism involved in these disorders. Although electroacupuncture (EA) has shown the potential to mitigate enteric neuronal loss, its mechanism is not fully understood. Additionally, the effects of EA on enteric glial cells have not been investigated. Enteric neural precursor cells (ENPCs) contribute to the structural and functional integrity of the ENS, yet whether EA enhances their differentiation into enteric neurons and glial cells remains unexplored. This study investigates whether EA promotes ENS repair through enhancing ENPC-derived neurogenesis and gliogenesis and elucidates the potential molecular mechanisms involved. METHODS: Transgenic mice were used to trace Nestin⁺/nerve growth factor receptor (Ngfr)⁺ ENPCs labeled with green fluorescent protein (GFP) in vivo. Mice were randomly divided into four groups: control, diabetes mellitus (DM), DM + sham EA, and DM + EA. The effects of EA on diabetic mice were evaluated by GI motility, ENS structure, and ENPC differentiation. Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling was detected to clarify the underlying molecular mechanisms. RESULTS: EA alleviated diabetes-induced GI motility disorders, as indicated by reduced whole gut transit time, shortened colonic bead expulsion time, and enhanced smooth muscle contractility. Furthermore, EA attenuated diabetes-induced losses of enteric neurons and glial cells, thereby restoring ENS integrity. Notably, EA reversed the diabetes-induced decrease in ENPCs and significantly increased the absolute number and the proportion of ENPC-derived enteric neurons. However, immunofluorescence analyses revealed no colocalization between EA-induced glial fibrillary acidic protein⁺ glial cells and GFP-labeled ENPCs. Mechanistically, GDNF/Ret signaling was elevated in intestinal tissues and upregulated in ENPCs in EA-treated diabetic mice. CONCLUSION EA facilitates ENS repair by promoting Nestin⁺/Ngfr⁺ ENPC differentiation into enteric neurons via upregulation of GDNF/Ret signaling, and driving enteric gliogenesis from non-Nestin⁺/Ngfr⁺ ENPCs. These findings highlight EA's role in ameliorating diabetes-induced GI dysmotility through ENPC-derived ENS restoration. Please cite this article as: Guo JL, Liu S, Ding SJ, Yang X, Du F. Electroacupuncture at ST36 improves gastrointestinal motility disorders by promoting enteric nervous system regeneration through GDNF/Ret signaling in diabetic mice. J Integr Med. 2025; 23(5):548-559.
Animals ; Electroacupuncture ; Enteric Nervous System/physiology* ; Gastrointestinal Motility/physiology* ; Glial Cell Line-Derived Neurotrophic Factor/metabolism* ; Diabetes Mellitus, Experimental/therapy* ; Signal Transduction ; Mice ; Gastrointestinal Diseases/physiopathology* ; Proto-Oncogene Proteins c-ret/metabolism* ; Mice, Transgenic ; Male ; Nerve Regeneration ; Neural Stem Cells ; Mice, Inbred C57BL ; Acupuncture Points

In this study, araucarene diterpenes, characterized by a pimarene skeleton with a variably oxidized side chain at C-13, were investigated. A total of 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara, including 11 previously unreported compounds: dammaradione (1), dammarones D-G (2, 5, 14, 15), dammaric acids B-F (8-12), and dammarol (16). The structures of these new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and one-dimensional/two-dimensional (1D/2D) nuclear magnetic resonance (NMR), while their absolute configurations were determined through the electronic circular dichroism (ECD) exciton chirality method and Snatzke's method. The hypoglycemic activity of all isolated compounds was evaluated using a transgenic zebrafish model, and a structure-activity relationship (SAR) analysis was conducted. Araucarone (3) and dammaric acid C (9), serving as representative compounds, demonstrated significant hypoglycemic effects on zebrafish. The primary mechanism involves the promotion of pancreatic β cell regeneration and glucose uptake. Specifically, these compounds enhance the differentiation of pancreatic endocrine precursor cells (PEP cells) into β cells in zebrafish.
Zebrafish ; Animals ; Diterpenes/isolation & purification* ; Insulin-Secreting Cells/cytology* ; Glucose/metabolism* ; Hypoglycemic Agents/isolation & purification* ; Molecular Structure ; Structure-Activity Relationship ; Plant Extracts/pharmacology* ; Regeneration/drug effects*

OBJECTIVES: To study the clinical effect of the L-shape technique combined with concentrated growth factor on the horizontal bone defects of maxillary anterior teeth. METHODS: Twenty-five implants from 25 patients who underwent single maxillary anterior tooth implantation with simultaneous bone grafting were selected as the study subjects. Based on the bone grafting techniques, the patients were divided into a test group (L-shaped technique with guided bone regeneration combined with concentrated growth factor, 11 cases) and a control group (traditional guided bone regeneration combined with concentrated growth factor, 14 cases). The early discomfort and wound healing conditions in the two groups at two weeks after surgery were compared. The horizontal bone thickness, vertical bone thickness, and grayscale values in the augmentation area were measured immediately postsurgery and six months after surgery. Implant stability, hard tissue resorption within six months, and grayscale values were compared between the two groups. RESULTS: Differences in early discomfort, wound healing, implant stability, and grayscale values between the two groups were not statistically significant (P>0.05). Vertical bone thickness in the test group was significantly better than that in the control group at six months after surgery (P<0.05). The variation in horizontal bone thickness in the test group was significantly higher than that in the control group (P<0.05). CONCLUSIONS The application of the L-shape technique with concentrated growth factor for horizontal bone defects in the anterior maxillary area yielded satisfactory short-term results in terms of bone augmentation, early discomfort, wound healing, and implant stability at six months after surgery.
Humans ; Maxilla/diagnostic imaging* ; Intercellular Signaling Peptides and Proteins/therapeutic use* ; Wound Healing ; Bone Transplantation/methods* ; Dental Implantation, Endosseous/methods* ; Bone Regeneration ; Male ; Female ; Adult ; Dental Implants, Single-Tooth ; Middle Aged

Peri-implantitis is a pathologic condition associated with dental plaque that occurs in the implant tissue and is characterized by inflammation of the mucous membrane surrounding the implant, followed by the progressive loss of supporting bone. In this study, a case of guided bone regeneration therapy based on plaque control of peri-implant inflammation was reported. Four years after surgery for the left second premolar implant, the patient presented with "left lower posterior tooth swelling and discomfort for more than 2 years". The X-ray periapical film showed a decrease in distal bone mineral density of implant, and the clinical diagnosis was peri-implantitis of the left second premolar. Implants underwent guided bone regeneration and regular periodontal maintenance treatment. Re-examination at 3.5 months, 11 months, 18 months, and 7 years showed that the alveolar bone height and bone mineral density were stable, and the periodontal depth became shallow. However, the gingival recession was mild. In the present case, follow-up at 7 years demonstrated that the clinical periodontal indexes could be remarkably improved after complete periodontal treatment for peri-implantitis, and the alveolar bone could be well restored and regenerated.
Humans ; Peri-Implantitis/etiology* ; Follow-Up Studies ; Bone Regeneration ; Guided Tissue Regeneration, Periodontal/methods* ; Dental Plaque/prevention & control* ; Male ; Female ; Dental Implants/adverse effects*