The global aging population has intensified the incidence of degenerative bone diseases and the therapeutic demand for traumatic bone injuries, thereby making bone regenerative medicine a research focus. There is a close connection and interaction between the skeletal system and the nervous system, and innervation plays an indispensable regulatory role in the process of bone regeneration: the sympathetic nervous system exerts a negative regulatory effect during bone regeneration, while the parasympathetic nervous system plays a positive regulatory role in this process. Nerve fibers within bones are distributed alongside blood vessels, with their density decreasing from the periosteum to the cancellous bone. Nerve signals regulate bone regeneration either by directly acting on target cell receptors or indirectly modulating the metabolism of the local microenvironment (such as the levels of inflammatory factors and the supply of nutrients). A variety of neuropeptides (e.g., calcitonin gene-related peptide, substance P, neuropeptide Y, vasoactive intestinal peptide, etc.) play a crucial role in bone tissue, constructing a "neuro-osseous" regulatory axis, which in turn regulates the osteoblast-osteoclast balance, angiogenesis, and the homeostasis of the local microenvironment. This review focuses on the neural regulatory mechanisms in bone regeneration, with an emphasis on sorting out the functions of key neuropeptides and related neurotransmitters. Neuropeptides are the core mediators of neuro-osseous interaction; however, the interaction network among neuropeptides remains to be further clarified, which requires the application of advanced in vitro models such as three-dimensional bioprinted bone models and organoid technology, as well as cutting-edge techniques like single-cell sequencing for analysis. In the future, the integration of neural regulation strategies with traditional bone regeneration technologies, along with the expansion into interdisciplinary fields such as neuro-vascular and neuro-muscular fields, is expected to provide new directions for the treatment of bone defects and large maxillofacial tissue defects, and promote the transformation of regenerative medicine from prosthetic treatment to functional and neurotized tissue regeneration.

Objective: To investigate the influencing factors for delay in healthcare-seeking, definitive diagnosis and identification in patients with pulmonary tuberculosis (PTB) in Minhang District, Shanghai Municipality, so as to provide the basis for effectively reducing delay in PTB patients. Methods: Data of PTB patients in Minhang District from 2017 to 2022 were collected from the Infectious Disease Reporting Information System of Chinese Disease Prevention and Control Information System. The prevalence rates of delay in healthcare-seeking, definitive diagnosis and identification were analyzed, and factors affecting delay in healthcare-seeking, definitive diagnosis and identification were identified using multivariable logistic regression models. Results: A total of 4 214 PTB patients were reported in Minhang District from 2017 to 2022, including 2 802 males and 1 412 females, with a male-to-female ratio of 1.98∶1. The majority of patients were aged 25 to <45 years (1 664 cases, 39.49%). The prevalence rates of delay in healthcare-seeking, definitive diagnosis and identification were 36.81%, 30.21% and 38.09%, respectively. Delay in healthcare-seeking was associated with the year (2018, OR=0.708; 2019, OR=0.549; 2020, OR=0.670; 2021, OR=0.682), gender (female, OR=1.199), occupation (worker, OR=1.379; housekeeping service/housework/unemployed, OR=1.481), case identification route (symptom-based consultation, OR=11.159), and level of the first-diagnosed hospital (city-level, OR=1.528). Delay in definitive diagnosis was associated with age (45 to <65 years, OR=1.476), occupation (commercial service, OR=0.687; housekeeping service/housework/unemployed, OR=0.672), household registration (non-local, OR=0.820), case identification route (symptom-based consultation, OR=0.616), pathogen test result (negative/not tested, OR=1.903), and the level of the first-diagnosed hospital (city-level, OR=0.311). Delay in identification was associated with the year (2018, OR=0.785; 2019, OR=0.647; 2020, OR=0.790; 2021, OR=0.710), occupation (commercial service, OR=0.687), household registration (non-local, OR=0.848) and level of the first-diagnosed hospital (city-level, OR=0.560) Conclusions Year, gender, occupation, case identification route and level of the first-diagnosed hospital are influencing factors for delay in healthcare-seeking in PTB patients. Age, occupation, household registration, case identification route, pathogen test result and level of the first-diagnosed hospital are influencing factors for delay in definitive diagnosis. Year, occupation, household registration and level of the first-diagnosed hospital are influencing factors for delay in identification.

Lemborexant is a new drug for the treatment of insomnia.It is a dual orexin receptor antagonist that competitively binds to two orexin receptors,OX1R and OX2R,inhibits orexin neuro-transmission,and regulates the sleep-wake rhythm.This article comprehensively reviews the discovery of the drug target,basic information,clin-ical studies,safety assessment,and limitation anal-ysis of lemborexant,aiming to provide a compre-hensive understanding of the current research sta-tus and achievements of this drug in clinical prac-tice.

The global aging population has intensified the incidence of degenerative bone diseases and the therapeutic demand for traumatic bone injuries, thereby making bone regenerative medicine a research focus. There is a close connection and interaction between the skeletal system and the nervous system, and innervation plays an indispensable regulatory role in the process of bone regeneration: the sympathetic nervous system exerts a negative regulatory effect during bone regeneration, while the parasympathetic nervous system plays a positive regulatory role in this process. Nerve fibers within bones are distributed alongside blood vessels, with their density decreasing from the periosteum to the cancellous bone. Nerve signals regulate bone regeneration either by directly acting on target cell receptors or indirectly modulating the metabolism of the local microenvironment (such as the levels of inflammatory factors and the supply of nutrients). A variety of neuropeptides (e.g., calcitonin gene-related peptide, substance P, neuropeptide Y, vasoactive intestinal peptide, etc.) play a crucial role in bone tissue, constructing a "neuro-osseous" regulatory axis, which in turn regulates the osteoblast-osteoclast balance, angiogenesis, and the homeostasis of the local microenvironment. This review focuses on the neural regulatory mechanisms in bone regeneration, with an emphasis on sorting out the functions of key neuropeptides and related neurotransmitters. Neuropeptides are the core mediators of neuro-osseous interaction; however, the interaction network among neuropeptides remains to be further clarified, which requires the application of advanced in vitro models such as three-dimensional bioprinted bone models and organoid technology, as well as cutting-edge techniques like single-cell sequencing for analysis. In the future, the integration of neural regulation strategies with traditional bone regeneration technologies, along with the expansion into interdisciplinary fields such as neuro-vascular and neuro-muscular fields, is expected to provide new directions for the treatment of bone defects and large maxillofacial tissue defects, and promote the transformation of regenerative medicine from prosthetic treatment to functional and neurotized tissue regeneration.

Lemborexant is a new drug for the treatment of insomnia.It is a dual orexin receptor antagonist that competitively binds to two orexin receptors,OX1R and OX2R,inhibits orexin neuro-transmission,and regulates the sleep-wake rhythm.This article comprehensively reviews the discovery of the drug target,basic information,clin-ical studies,safety assessment,and limitation anal-ysis of lemborexant,aiming to provide a compre-hensive understanding of the current research sta-tus and achievements of this drug in clinical prac-tice.

OBJECTIVES: This study aimed to explore the functions and potential regulatory targets of local macrophages in nonalcoholic fatty liver combined with Porphyromonas gingivalis (P. gingivalis)infection. METHODS: Single-cell RNA sequencing was used to analyze the phenotypes and functional changes in various cells in the liver tissue of nonalcoholic steatohepatitis (NASH) mice fed with P. gingivalis. Real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay, and immunofluorescence staining were applied to observe the inflammation and expression levels of macrophage antigen presenting functional markers in the NASH liver. Oil red staining was performed to observe the accumulation of local adipose tissue in the NASH liver. Results were verified through RT-PCRand RNA sequencing using P. gingivalis-lipopolysaccharide treated mouse peritoneal macrophages. RESULTS: In comparison with healthy livers with Kupffer cells, the NASH liver combined with P. gingivalis infection-related macrophages showed significant heterogeneity. C1qb, C1qc, Mafb, Apoe, and Cd14 were highly expressed, but Cd209a, H2-Aa, H2-Ab1, and H2-DMb1, which are related to the antigen presentation function, were weakly expressed. Further in vivo and in vitro investigations indicated that the activation and infiltration of these macrophages may be due to local P. gingivalis-lipopolysaccharide accumulation. CONCLUSIONS P. gingivalis-lipopolysaccharide induces a local macrophage immunotolerance phenotype in nonalcoholic fatty liver, which may be the key mechanism of periodontitis pathogen infection that promotes NASH inflammation and pathogenesis. This study further clarifies the dysfunction and regulatory mechanisms of macrophages in the pathogenesis of P. gingivalis-infected NASH, thereby providing potential therapeutic targets for its clinical treatment.
Mice ; Animals ; Non-alcoholic Fatty Liver Disease/pathology* ; Kupffer Cells/pathology* ; Porphyromonas gingivalis ; Lipopolysaccharides/metabolism* ; Inflammation/pathology* ; Macrophages/metabolism* ; Mice, Inbred C57BL

Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells (MSCs) are essential for periodontal regeneration. However, the hypoxic periodontal microenvironment during periodontitis induces the apoptosis of MSCs. Apoptotic bodies (ABs) are the major product of apoptotic cells and have been attracting increased attention as potential mediators for periodontitis treatment, thus we investigated the effects of ABs derived from MSCs on periodontitis. MSCs were derived from bone marrows of mice and were cultured under hypoxic conditions for 72 h, after which ABs were isolated from the culture supernatant using a multi-filtration system. The results demonstrate that ABs derived from MSCs inhibited osteoclast differentiation and alveolar bone resorption. miRNA array analysis showed that miR-223-3p is highly enriched in those ABs and is critical for their therapeutic effects. Targetscan and luciferase activity results confirmed that Itgb1 is targeted by miR-223-3p, which interferes with the function of osteoclasts. Additionally, DC-STAMP is a key regulator that mediates membrane infusion. ABs and pre-osteoclasts expressed high levels of DC-STAMP on their membranes, which mediates the engulfment of ABs by pre-osteoclasts. ABs with knock-down of DC-STAMP failed to be engulfed by pre-osteoclasts. Collectively, MSC-derived ABs are targeted to be engulfed by pre-osteoclasts via DC-STAMP, which rescued alveolar bone loss by transferring miR-223-3p to osteoclasts, which in turn led to the attenuation of their differentiation and bone resorption. These results suggest that MSC-derived ABs are promising therapeutic agents for the treatment of periodontitis.
Humans ; Osteoclasts ; Alveolar Bone Loss/therapy* ; Cell Differentiation ; MicroRNAs ; Periodontitis/therapy* ; Extracellular Vesicles ; Apoptosis ; Mesenchymal Stem Cells

Delayed wound healing in diabetes is a global challenge, and the development of related drugs is a clinical problem to be solved. In this study, purpurolide C (PC), a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum, was found to promote diabetic wound healing. To investigate the key regulation targets of PC, in vitro RNA-seq, molecular docking calculations, TLR4-MD2 dimerization SDS-PAGE detection, and surface plasmon resonance (SPR) were performed, indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation. Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing. Furthermore, a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC (PC@MLIP MN) was developed, which overcame the poor water solubility and weak skin permeability of PC, so that successfully punctured the skin and delivered PC to local tissues, and accurately regulated macrophage polarization in diabetic wound management. Overall, PC is an anti-inflammatory small molecule compound with a well-defined structure and dual-target regulation, and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.

Objective: To observe the effects of acupuncture at Yuan-Primordial and Luo-Connecting points by host-guest combination plus Tuina (Chinese therapeutic massage) on the third lumbar transverse process syndrome. Methods: A total of 88 patients with the third lumbar transverse process syndrome were selected and divided into an observation group and a control group according to the random number table method, with 44 cases in each group. The control group was treated with Tuina, and the observation group was treated with additional acupuncture at Yuan-Primordial and Luo-Connecting points by host-guest combination. The clinical efficacy of the two groups was compared after treatment. The changes in the scores of physical signs, Roland-Morris disability questionnaire (RMDQ), Oswestry disability index (ODI), Quebec back pain disability scale (QBPDS), and pain factors [including serum prostaglandin (PG) E2, neuropeptide Y (NPY), and matrix metalloproteinase-3 (MMP-3)] were observed. Results: After treatment, the total effective rate in the observation group was 93.2％, higher than 75.0％ in the control group; the difference between the two groups was statistically significant (P<0.05). Compared with those before treatment, the scores of physical signs and each low back pain scale, and the levels of serum pain factors in the two groups were decreased (P<0.05), and those in the observation group were lower than those in the control group (P<0.05). Conclusion: Acupuncture at Yuan-Primordial and Luo-Connecting points by host-guest combination plus Tuina is effective in the treatment of the third lumbar transverse process syndrome; it can improve the patient's physical signs, relieve low back pain, and reduce the levels of serum pain factors.

Objective::Microchannels are associated with the progression of atherosclerotic vulnerable plaques. However, in patients with culprit optical coherence tomography (OCT)-defined plaque erosion, the knowledge of microchannels and culprit lesion vulnerability is limited. The aim of this study was to investigate culprit lesion characteristics in patients with ST-segment elevated myocardial infarction (STEMI) caused by plaque erosion with and without microchannels using OCT.Methods::In all, 348 STEMI patients with plaque erosion who underwent OCT of the culprit lesion at the 2 nd Affiliated Hospital of Harbin Medical University (Harbin, China) from August 2014 to December 2017 were included and divided into the microchannel group ( n= 116, 33.3%) and no-microchannel group ( n = 232, 66.7%). The clinical characteristics and OCT-derived plaque features were compared between both groups. Results::Among the 348 STEMI patients with plaque erosion, culprit lesions with microchannels had higher incidence of lipid plaque (59.5% vs. 45.3%, P= 0.012); calcification (41.4% vs. 24.6%, P= 0.002); spotty calcification (30.2% vs. 18.1%, P= 0.014); macrophages accumulation (72.4% vs. 45.7%, P < 0.001); and cholesterol crystals (32.8% vs. 14.2%, P < 0.001) than those without microchannels. In addition, minimal lumen area was smaller ((1.9 ± 0.9) mm 2vs. (2.8 ± 2.3) mm 2, P < 0.001) and lumen area stenosis was greater ((71.3% ± 13.4%) vs. (65.3% ± 19.3%), P= 0.001) in the microchannel group than in the no-microchannel group. Conclusion::In patients with STEMI caused by plaque erosion, one-third manifested typical microchannel characteristics, and those with microchannels were associated with more severe luminal stenosis and more vulnerable plaque features than those without microchannels.