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Magnesium promotes vascularization and osseointegration in diabetic states

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International Journal of oral Science 2024年第1期16卷 122-133页

作者： Linfeng Liu Feiyu Wang Wei Song Danting Zhang Weimin Lin Qi Yin Qian Wang Hanwen Li Quan Yuan Shiwen Zhang state key laboratory of oral diseases&national center for Stomatology&national clinical research center for oral diseases&West China Hospital of Stomatology Sichuan UniversityChengduChina state key laboratory of oral diseases&national center for Stomatology&national clinical research center for oral diseases&department of oral Implantology West China Hospital of StomatologySichuan UniversityChengduChina

Diabetes has long been considered a risk factor in implant therapy and impaired wound healing in soft and hard oral tissues.Magnesium has been proved to promote bone healing under normal conditions.Here,we elucidate the mechanism by which Mg^(2+)promotes angiogenesis and osseointegration in diabetic status.We generated a diabetic mice model and demonstrated thealveolar bone healing was compromised,with significantly decreased angiogenesis.We then developed Mg-coating implants with hydrothermal synthesis.These implants successfully improved the vascularization and osseointegration in diabetic status.Mechanically,Mg^(2+)promoted the degradation of Kelch-like ECH-associated protein 1 (Keap1) and the nucleation of nuclear factor erythroid 2-related factor 2 (Nrf2) by up-regulating the expression of sestrin 2 (SESN2) in endothelial cells,thus reducing theelevated levels of oxidative stress in mitochondria and relieving endothelial cell dysfunction under hyperglycemia.Altogether,our data suggested that Mg^(2+)promoted angiogenesis and osseointegration in diabetic mice by regulating endothelial mitochondria metabolism.

关键词： healing diabetic impaired

The essential roles of m^(6)A modification in osteogenesis and common bone diseases

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Genes & diseases 2024年第1期11卷 335-345页

作者： Yuxi Gu Yidan Song Yihua Pan Jun Liu state key laboratory of oral diseases&national clinical research center for oral diseases Department of OrthodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuan 610041China

N6-methyladenosine(m^(6)A)is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs.It affects the fate of the modified RNA,including its stability,splicing,and translation,and plays an important role in post-transcriptional regulation.Bones play a key role in supporting and pro-tecting muscles and other organs,facilitating the movement of the organism,ensuring blood production,etc.Bone diseases such as osteoarthritis,osteoporosis,and bone tumors are serious public health problems.The processes of bone development and osteogenic differen-tiation require the precise regulation of gene expression through epigenetic mechanisms including histone,DNA,and RNA modifications.As a reversible dynamic epigenetic mark,m^(6)A modifications affect nearly every important biological process,cellular component,and molecular function,including skeletal development and homeostasis.In recent years,studies have shown that m^(6)A modification is involved in osteogenesis and bone-related diseases.In this review,we summarized the proteins involved in RNA m^(6)A modification and the latest progress in elucidating the regulatory role of m^(6)A modification in bone formation and stem cell direc-tional differentiation.We also discussed the pathological roles and potential molecular mech-anisms of m^(6)A modification in bone-related diseases like osteoporosis and osteosarcoma and suggested potential areas for new strategies that could be used to prevent or treat bone de-fects and bone diseases.

关键词： Bone diseases m^(6)A modification Osteogenesis Regulatory role Stem cells

Sema3A secreted by sensory nerve induces bone formation under mechanical loads

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International Journal of oral Science 2024年第1期16卷 62-72页

作者： Hongxiang Mei Zhengzheng Li Qinyi Lv Xingjian Li Yumeng Wu Qingchen Feng Zhishen Jiang Yimei Zhou Yule Zheng Ziqi Gao Jiawei Zhou Chen Jiang Shishu Huang Juan Li state key laboratory of oral diseases&national center for Stomatology&national clinical research center for oral diseases&West China Hospital of Stomatology Sichuan UniversityChengduChina department of Orthopedic Surgery and Orthopedic research Institute West China HospitalSichuan UniversityChengduChina

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A(Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM) model. Firstly, bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs) within 24 hours.Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.

关键词： Sema3A formation overload

Genomic alterations in oral multiple primary cancers

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International Journal of oral Science 2024年第1期16卷 145-153页

作者： Wen Wang Qian Wang Shiying Sun Pengfei Zhang Yuyu Li Weimin Lin Qiwen Li Xiao Zhang Zhe Ma Haiyan Lu Hebei key laboratory of Stomatology Hebei Clinical Research Center for Oral DiseasesHebei Medical UniversityShijiazhuangChina department of Orthodontics School and Hospital of StomatologyHebei Medical UniversityShijiazhuangChina state key laboratory of oral diseases&national center for Stomatology&national clinical research center for oral diseases&West China Hospital of Stomatology Sichuan UniversityChengduChina department of Preventive Dentistry School and Hospital of StomatologyHebei Medical UniversityShijiazhuangHebeiChina

oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer, while some patients may develop oral multiple primary cancers (MPCs) with unclear etiology. This study aimed to investigate the clinicopathological characteristics and genomic alterations of oral MPCs. Clinicopathological data from patients with oral single primary carcinoma (SPC, n=202) and oral MPCs (n=34) were collected and compared. Copy number alteration (CNA) analysis was conducted to identify chromosomal-instability differences among oral MPCs, recurrent OSCC cases, and OSCC patients with lymph node metastasis. Whole-exome sequencing was employed to identify potential unique gene mutations in oral MPCs patients. Additionally, CNA and phylogenetic tree analyses were used to gain preliminary insights into the molecular characteristics of different primary tumors within individual patients. Our findings revealed that, in contrast to oral SPC, females predominated the oral MPCs (70.59%), while smoking and alcohol use were not frequent in MPCs.Moreover, long-term survival outcomes were poorer in oral MPCs. From a CNA perspective, no significant differences were observed between oral MPCs patients and those with recurrence and lymph node metastasis. In addition to commonly mutated genes such as CASP8, TP53 and MUC16, in oral MPCs we also detected relatively rare mutations, such as HS3ST6 and RFPL4A. Furthermore, this study also demonstrated that most MPCs patients exhibited similarities in certain genomic regions within individuals, and distinct differences of the similarity degree were observed between synchronous and metachronous oral MPCs.

关键词： alterations metastasis oral

A DNA tetrahedron-based ferroptosis-suppressing nanoparticle: superior delivery of curcumin and alleviation of diabetic osteoporosis

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Bone research 2024年第1期12卷 227-239页

作者： Yong Li Zhengwen Cai Wenjuan Ma Long Bai En Luo Yunfeng Lin state key laboratory of oral diseases&national center for Stomatology&national clinical research center for oral diseases West China Hospital of StomatologySichuan UniversityChengduSichuan 610041PR China department of oral and Maxillofacial Surgery Affiliated Stomatological HospitalSouthwest Medical UniversityLuzhouSichuan 646000PR China Sichuan Provincial Engineering research center of oral Biomaterials ChengduSichuan 610041China

Diabetic osteoporosis(DOP)is a significant complication that poses continuous threat to the bone health of patients with diabetes;however,currently,there are no effective treatment strategies.In patients with diabetes,the increased levels of ferroptosis affect the osteogenic commitment and differentiation of bone mesenchymal stem cells(BMSCs),leading to significant skeletal changes.To address this issue,we aimed to target ferroptosis and propose a novel therapeutic approach for the treatment of DOP.We synthesized ferroptosis-suppressing nanoparticles,which could deliver curcumin,a natural compound,to the bone marrow using tetrahedral framework nucleic acid(tFNA).This delivery system demonstrated excellent curcumin bioavailability and stability,as well as synergistic properties with tFNA.Both in vitro and in vivo experiments revealed that nanoparticles could enhance mitochondrial function by activating the nuclear factor E2-related factor 2(NRF2)/glutathione peroxidase 4(GPX4)pathway,inhibiting ferroptosis,promoting the osteogenic differentiation of BMSCs in the diabetic microenvironment,reducing trabecular loss,and increasing bone formation.These findings suggest that curcumin-containing DNA tetrahedron-based ferroptosissuppressing nanoparticles have a promising potential for the treatment of DOP and other ferroptosis-related diseases.

关键词： curcumin osteoporosis diabetic

Metabolic memory:mechanisms and diseases

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1086-1114页

作者： Hao Dong Yuezhang Sun Lulingxiao Nie Aimin Cui Pengfei Zhao Wai Keung Leung Qi Wang state key laboratory of oral diseases&national center for Stomatology&national clinical research center for oral diseases West China Hospital of StomatologySichuan UniversityChengduChina department of Prosthodontics West China Hospital of StomatologySichuan UniversityChengduChina Periodontology and Implant Dentistry Division Faculty of DentistryThe University of Hong KongHong KongChina

Metabolic diseases and their complications impose health and economic burdens worldwide.Evidence from past experimental studies and clinical trials suggests our body may have the ability to remember the past metabolic environment,such as hyperglycemia or hyperlipidemia,thus leading to chronic inflammatory disorders and other diseases even after the elimination of these metabolic environments.The long-term effects of that aberrant metabolism on the body have been summarized as metabolic memory and are found to assume a crucial role in states of health and disease.Multiple molecular mechanisms collectively participate in metabolic memory management,resulting in different cellular alterations as well as tissue and organ dysfunctions,culminating in disease progression and even affecting offspring.The elucidation and expansion of the concept of metabolic memory provides more comprehensive insight into pathogenic mechanisms underlying metabolic diseases and complications and promises to be a new target in disease detection and management.Here,we retrace the history of relevant research on metabolic memory and summarize its salient characteristics.We provide a detailed discussion of the mechanisms by which metabolic memory may be involved in disease development at molecular,cellular,and organ levels,with emphasis on the impact of epigenetic modulations.Finally,we present some of the pivotal findings arguing in favor of targeting metabolic memory to develop therapeutic strategies for metabolic diseases and provide the latest reflections on the consequences of metabolic memory as well as their implications for human health and diseases.

关键词： diseases metabolism alterations

Lung microbiome:new insights into the pathogenesis of respiratory diseases

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Signal Transduction and Targeted Therapy 2024年第2期9卷 652-678页

作者： Ruomeng Li Jing Li Xikun Zhou department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China state key laboratory of oral diseases National Clinical Research Center for Oral DiseasesChinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduSichuan 610041China

The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial community.The microbiome of healthy lungs is mainly derived from the upper respiratory tract(URT)microbiome but also has its own characteristic flora.The selection mechanisms in the lung,including clearance by coughing,pulmonary macrophages,the oscillation of respiratory cilia,and bacterial inhibition by alveolar surfactant,keep the microbiome transient and mobile,which is different from the microbiome in other organs.The pulmonary bacteriome has been intensively studied recently,but relatively little research has focused on the mycobiome and virome.This up-to-date review retrospectively summarizes the lung microbiome’s history,composition,and function.We focus on the interaction of the lung microbiome with the oropharynx and gut microbiome and emphasize the role it plays in the innate and adaptive immune responses.More importantly,we focus on multiple respiratory diseases,including asthma,chronic obstructive pulmonary disease(COPD),fibrosis,bronchiectasis,and pneumonia.The impact of the lung microbiome on coronavirus disease 2019(COVID-19)and lung cancer has also been comprehensively studied.Furthermore,by summarizing the therapeutic potential of the lung microbiome in lung diseases and examining the shortcomings of the field,we propose an outlook of the direction of lung microbiome research.

关键词： respiratory diseases Lung

Drug-loading ZIF-8 for modification of microporous bone scaffold to promote vascularized bone regeneration

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Chinese Chemical Letters 2024年第6期35卷 358-364页

作者： Xin Zhang Junyu Chen Xiang Pei Linxin Yang Liang Wang Luona Chen Guangmei Yang Xibo Pei Qianbing Wan Jian Wang state key laboratory of oral diseases National Clinical Research Center for Oral DiseasesChengdu 610041China department of Prosthodontics West China Hospital of StomatologySichuan UniversityChengdu 610041China

Surface modification of microporous bone scaffolds using nanoparticles has been broadly studied in bone tissue engineering.Aiming at improving vascularized bone regeneration(VBR),zeolitic imidazolate framework-8(ZIF-8)was encapsulated with dimethyloxallyl glycine(DMOG)and the drug-carrying nanoparticles(D@Z)could be uniformly coated onto the surface of the bone scaffold.The osteogenic and angiogenic actions of D@Z are closely correlated with the amount of slowly released DMOG,and in general,exhibited a favorable association.Then,the D7.5@Z group,which showed the greatest capacity to induce in vitro osteogenesis-angiogenesis coupling,was utilized for surface modification of the bone scaffold.Biological processes including phosphate-containing compound metabolic process,cell differentiation,cell proliferation and cell motility might contribute to enhanced ability to induce VBR by the coated scaffold and signaling pathways such as Rap1,Ras,phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT)and vascular endothelial growth factor(VEGF)signaling pathways participated in these processes.Finally,as depicted by in vitro real time-polymerase chain reaction(RT-PCR),Western blot(WB)and in vivo cranial bone defect model,the microporous scaffold coated with nano-D7.5@Z greatly promoted VBR.To conclude,nano-D@Z has significant promise for practical application in modification of microporous bone scaffolds to enhance VBR,and DMOG loading quantity has a beneficial influence on D@Z to improve osteogenesis-angiogenesis coupling.

关键词： Drug-loading nanoparticles Surface coating Microporous bone scaffold Vascularization bone regeneration

Transdermal treatment for malignant melanoma by aptamer-modified tetrahedral framework nucleic acid delivery of vemurafenib

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Chinese Chemical Letters 2024年第4期35卷 260-267页

作者： Dexuan Xiao Tianyu Chen Tianxu Zhang Sirong Shi Mei Zhang Xin Qin Yunkun Liu Longjiang Li Yunfeng Lin state key laboratory of oral diseases National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu 610041China Sichuan Provincial Engineering research center of oral Biomaterials Chengdu 610041China department of Head and Neck Oncology National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu 610041China

Melanoma is one of the most malignant skin tumors, whose high invasion is generally associated with BRAF gene mutation. Although new chemotherapeutic drugs, such as vemurafenib, have been developed to inhibit the growth of melanoma, these drugs are usually administered intravenously or orally, resulting in toxic side effects on major tissues and organs. Tetrahedral framework nucleic acids(tFNAs) are a novel type of DNA nanostructures with excellent biocompatibility and versatility which have been proven to penetrate through skin barrier with ease. In this study, we prepared t FNAs with vemurafenib and connected DNA aptamer AS1411 at the apex of t FNAs(AS1411-tFNAs/vemurafenib). On one hand, AS1411-tFNAs/vemurafenib could kill melanoma cells by blocking the mutated BRAF gene in vitro. Compared with free vemurafenib, AS1411-tFNAs/vemurafenib had no obvious toxicity to normal cells. On the other hand,AS1411-tFNAs could transfer vemurafenib to cross through the skin barrier and permeate into tumor tissues. In vivo, transdermal delivery of AS1411-t FNAs/vemurafenib could inhibit the growth of human A375melanoma, whose inhibiting effect was stronger than intravenous administration of vemurafenib. These results demonstrated the application prospects of tFNAs combined with chemotherapeutic drugs in skin tumors.

关键词： Melanoma Vemurafenib DNA nanostructure Transdermal treatment Side effect