Adaptive Capacity of a DNA Polymerase Clamp-loader ATPase Complex.

The ability of mutations to facilitate adaptation is central to evolution. To understand how mutations can lead to functional adaptation in a complex molecular machine, we created a defective version of the T4 clamp-loader complex, which is essential for DNA replication. This variant, which is ∼5,000-fold less active than the wild type, was made by replacing the catalytic domains with those from another phage. A directed-evolution experiment revealed that multiple substitutions to a single negatively charged residue in the chimeric clamp loader-Asp 86-restore fitness to within ∼20-fold of wild type. These mutations remove an adventitious electrostatic repulsive interaction between Asp 86 and the sliding clamp. Thus, the fitness decrease of the chimeric clamp loader is caused by a reduction in affinity between the clamp loader and the clamp. Deep mutagenesis shows that the reduced fitness of the chimeric clamp loader is also compensated for by lysine and arginine substitutions of several DNA-proximal residues in the clamp loader or the sliding clamp. Our results demonstrate that there is a latent capacity for increasing the affinity of the clamp loader for DNA and the sliding clamp, such that even single-point mutations can readily compensate for the loss of function due to suboptimal interactions elsewhere.

Comparing the effects of team-based and problem-based learning strategies in medical education: a systematic review.

BACKGROUND: Recently, there has been a concerted effort within medical schools to depart from conventional lecture-based learning approaches to alternative teaching methods such as team-based learning (TBL) and problem-based learning (PBL), with the aim of enhancing both student engagement and instructional efficacy. Despite this shift, a comprehensive review that directly compares the impacts of PBL and TBL methods in medical education is lacking. This study seeks to address this gap by conducting a meta-analysis that compares the effects of TBL and PBL in the context of medical education. METHODS: Studies from Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and Chinese Wanfang Database were searched, from inception to July 11, 2023. A meta-analysis was performed using Stata 14.0, and a total of 10 studies (including 752 participants) were included. The standardized mean difference (SMD) was used to estimate pooled effects. Heterogeneity was detected using the I2 statistic and further explored using meta-regression analysis. RESULTS: Compared with PBL, TBL significantly increased the number of theoretical tests (SMD = 0.37, 95% CI: 0.02-0.73). Additionally, TBL greatly improved teamwork skills compared with PBL. However, there were no significant differences between the TBL and PBL groups concerning practical skill scores, learning interest, or understanding skills. CONCLUSION: TBL in the theoretical aspects of medical education appears to be more effective than PBL in improving theoretical test scores and teamwork skills, providing evidence for the implementation of TBL in medical education.

A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity.

Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age-related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non-aggresomal mitochondrion-associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs contain ubiquitinated cytosolic proteins, autophagy receptor p62, and mitochondrial proteins. MAPAs are segregated from mitochondria in a FIS1-dependent manner and can subsequently be degraded via autophagy. Although the FUNDC1/HSC70 pathway promotes the degradation of unfolded cytosolic proteins, excessive accumulation of unfolded proteins on the mitochondria prior to MAPA formation impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. We suggest that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.

A New Class of Proton Conductors with Dramatically Enhanced Stability and High Conductivity for Reversible Solid Oxide Cells.

Reversible solid oxide cells based on proton conductors (P-ReSOCs) have potential to be the most efficient and low-cost option for large-scale energy storage and power generation, holding promise as an enabler for the implementation of intermittent renewable energy technologies and the widespread utilization of hydrogen. Here, the rational design of a new class of hexavalent Mo/W-doped proton-conducting electrolytes with excellent durability while maintaining high conductivity is reported. Specifically, BaMo(W)0.03 Ce0.71 Yb0.26 O3-δ exhibits dramatically enhanced chemical stability against high concentrations of steam and carbon dioxide than the state-of-the-art electrolyte materials while retaining similar ionic conductivity. In addition, P-ReSOCs based on BaW0.03 Ce0.71 Yb0.26 O3-δ demonstrate high peak power densities of 1.54, 1.03, 0.72, and 0.48 W cm-2 at 650, 600, 550, and 500 °C, respectively, in the fuel cell mode. During steam electrolysis, a high current density of 2.28 A cm-2 is achieved at a cell voltage of 1.3 V at 600 °C, and the electrolysis cell can operate stably with no noticeable degradation when exposed to high humidity of 30% H2 O at -0.5 A cm-2 and 600 °C for over 300 h. Overall, this work demonstrates the promise of donor doping for obtaining proton conductors with both high conductivity and chemical stability for P-ReSOCs.

A zinc transporter, transmembrane protein 163, is critical for the biogenesis of platelet dense granules.

Lysosome-related organelles (LROs) are a category of secretory organelles enriched with ions such as calcium, which are maintained by ion transporters or channels. Homeostasis of these ions is important for LRO biogenesis and secretion. Hermansky-Pudlak syndrome (HPS) is a recessive disorder with defects in multiple LROs, typically platelet dense granules (DGs) and melanosomes. However, the underlying mechanism of DG deficiency is largely unknown. Using quantitative proteomics, we identified a previously unreported platelet zinc transporter, transmembrane protein 163 (TMEM163), which was significantly reduced in BLOC-1 (Dtnbp1sdy and Pldnpa)-, BLOC-2 (Hps6ru)-, or AP-3 (Ap3b1pe)-deficient mice and HPS patients (HPS2, HPS3, HPS5, HPS6, or HPS9). We observed similar platelet DG defects and higher intracellular zinc accumulation in platelets of mice deficient in either TMEM163 or dysbindin (a BLOC-1 subunit). In addition, we discovered that BLOC-1 was required for the trafficking of TMEM163 to perinuclear DG and late endosome marker-positive compartments (likely DG precursors) in MEG-01 cells. Our results suggest that TMEM163 is critical for DG biogenesis and that BLOC-1 is required for the trafficking of TMEM163 to putative DG precursors. These new findings suggest that loss of TMEM163 function results in disruption of intracellular zinc homeostasis and provide insights into the pathogenesis of HPS or platelet storage pool deficiency.

NF-κB downstream miR-1262 disturbs colon cancer cell malignant behaviors by targeting FGFR1.

Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions in vitro using cancer cells and in vivo using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors in vitro and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model in vivo. miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.

GelMA Hydrogel as a Promising Delivery System for Osthole in the Treatment of Rheumatoid Arthritis: Targeting the miR-1224-3p/AGO1 Axis.

Rheumatoid arthritis (RA) is a multifaceted, chronic, progressive autoimmune disease. This study aims to explore the potential benefits of an enhanced drug delivery system utilizing optimized Gelatin Methacryloyl (GelMA) vectors in RA management. We evaluated the levels of miR-1124-3p and AGO1 in RA tissues and cell lines using qPCR, WB, and immunofluorescence. The effects of osthole on inflammatory response and joint morphology were determined by qPCR, H&E staining, and micro-CT. The data showed that miR-1224-3p was downregulated in RA tissues and HUM-iCell-s010RA cells, while the overexpression of miR-1224-3p in HUM-iCell-s010RA cells reduced the expression of IL-6 and IL-1ß. Luciferase assay demonstrated that AGO1 was a direct target gene of miR-1224-3p. Additionally, osthole treatment increased miR-1224-3p levels and decreased AGO1 expression. The release data showed that osthole loaded on GelMA was released at a slower rate than free osthole. Further studies in a mouse model of CIA confirmed that osthole-loaded GelMA was more effective in attenuating osteopenia in RA as well as alleviating autoimmune arthritis. These findings suggest that osthole can regulate the miR-1224-3p/AGO1 axis in RASFs cells and has the potential to be developed as a clinical anti-RA drug. GelMA could provide a new approach to long-term RA treatment.

Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction.

Autophagy including mitophagy serves as an important regulatory mechanism in the heart to maintain the cellular homeostasis and to protect against heart damages caused by myocardial infarction (MI). The current study aims to dissect roles of general autophagy and specific mitophagy in regulating cardiac function after MI. By using Beclin1+/- , Fundc1 knockout (KO) and Fundc1 transgenic (TG) mouse models, combined with starvation and MI models, we found that Fundc1 KO caused more severe mitochondrial and cardiac dysfunction damages than Beclin1+/- after MI. Interestingly, Beclin1+/- caused notable decrease of total autophagy without detectable change to mitophagy, and Fundc1 KO markedly suppressed mitophagy but did not change the total autophagy activity. In contrast, starvation increased total autophagy without changing mitophagy while Fundc1 TG elevated total autophagy and mitophagy in mouse hearts. As a result, Fundc1 TG provided much stronger protective effects than starvation after MI. Moreover, Beclin1+/- /Fundc1 TG showed increased total autophagy and mitophagy to a level comparable to Fundc1 TG per se, and completely reversed Beclin1+/- -caused aggravation of mitochondrial and cardiac injury after MI. Our results reveal that mitophagy but not general autophagy contributes predominantly to the cardiac protective effect through regulating mitochondrial function.

A Nonstoichiometric Niobium Oxide/Graphite Composite for Fast-Charge Lithium-Ion Batteries.

Electrification of transportation has spurred the development of fast-charge energy storage devices. High-power lithium-ion batteries require electrode materials that can store lithium quickly and reversibly. Herein, the design and construction of a Nb2 O5-δ /graphite composite electrode that demonstrates remarkable rate capability and durability are reported. The presence of graphite enables the formation of a dominant Nb12 O29 phase and a minor T-Nb2 O5 phase. The high rate capability is attributed to the enhanced electronic conductivity and lower energy barriers for fast lithium diffusion in both Nb12 O29 and T-Nb2 O5 , as unraveled by density functional theory calculations. The excellent durability or long cycling life is originated from the coherent redox behavior of Nb ions and high reversibility of lithium intercalation/deintercalation, as revealed by operando X-ray absorption spectroscopy analysis. When tested in a half-cell at high cycling rates, the composite electrode delivers a specific capability of 120 mAh g-1 at 80 C and retains over 150 mAh g-1 after 2000 cycles at 30 C, implying that it is a highly promising anode material for fast-charging lithium-ion batteries.

A novel compound heterozygous SPG7 variant is associated with progressive spastic ataxia and persecutory delusions found in Chinese patients: two case reports.

BACKGROUND: Hereditary spastic paraplegia 7 (SPG7) is one of the subtypes of autosomal-recessive hereditary spastic paraplegia, which is a clinically heterogeneous neurodegenerative disorder. SPG7 often displays a complicated phenotype, including optic atrophy, ophthalmoparesis, and impaired emotional communication. In the Chinese population, sporadic cases of SPG7 variant-associated spastic ataxia are rarely reported. CASE PRESENTATION: We carefully analysed the clinical features, imaging and genetic tests of two sporadic patients with SPG7, both from the Hebei region of China. One patient presented with progressive bilateral lower limb weakness, spastic-ataxia and no cognitive impairment. Brain MRI revealed mild cerebellar atrophy. Genetic analysis revealed c.1150_1151insCTAC (p.G384Afs*13) frameshift variant and exon1-3 heterozygous deletion. The other patient presented with progressive bilateral lower limb weakness, ataxia, dysarthria and a mild psychosis associated with persecutory delusions, which drew almost no attention, in addition to mild cognitive impairments characterized by a decrease in verbal memory and executive function. Genetic analysis identified two heterozygous variants in the SPG7 gene: c.1150_1151insCTAC (p.G384Afs*13) and c.1496delC (p.Q500Sfs*13). CONCLUSIONS: The c.1496delC (p.Q500Sfs*13) variant in exon 11 has not been reported before. The c.1150_1151insCTAC variant is speculated to be a hotspot variant in the Chinese population. Patients with SPG7 may have cognitive impairments and psychosis, displaying specific characteristics, which should be of concern.

MolMiner: You Only Look Once for Chemical Structure Recognition.

Molecular structures are commonly depicted in 2D printed forms in scientific documents such as journal papers and patents. However, these 2D depictions are not machine readable. Due to a backlog of decades and an increasing amount of printed literatures, there is a high demand for translating printed depictions into machine-readable formats, which is known as Optical Chemical Structure Recognition (OCSR). Most OCSR systems developed over the last three decades use a rule-based approach, which vectorizes the depiction based on the interpretation of vectors and nodes as bonds and atoms. Here, we present a practical software called MolMiner, which is primarily built using deep neural networks originally developed for semantic segmentation and object detection to recognize atom and bond elements from documents. These recognized elements can be easily connected as a molecular graph with a distance-based construction algorithm. MolMiner gave state-of-the-art performance on four benchmark data sets and a self-collected external data set from scientific papers. As MolMiner performed similarly well in real-world OCSR tasks with a user-friendly interface, it is a useful and valuable tool for daily applications. The free download links of Mac and Windows versions are available at https://github.com/iipharma/pharmamind-molminer.

The PagKNAT2/6b-PagBOP1/2a Regulatory Module Controls Leaf Morphogenesis in Populus.

Leaf morphogenesis requires precise regulation of gene expression to achieve organ separation and flat-leaf form. The poplar KNOTTED-like homeobox gene PagKNAT2/6b could change plant architecture, especially leaf shape, in response to drought stress. However, its regulatory mechanism in leaf development remains unclear. In this work, gene expression analyses of PagKNAT2/6b suggested that PagKNAT2/6b was highly expressed during leaf development. Moreover, the leaf shape changes along the adaxial-abaxial, medial-lateral, and proximal-distal axes caused by the mis-expression of PagKNAT2/6b demonstrated that its overexpression (PagKNAT2/6b OE) and SRDX dominant repression (PagKNAT2/6b SRDX) poplars had an impact on the leaf axial development. The crinkle leaf of PagKNAT2/6b OE was consistent with the differential expression gene PagBOP1/2a (BLADE-ON-PETIOLE), which was the critical gene for regulating leaf development. Further study showed that PagBOP1/2a was directly activated by PagKNAT2/6b through a novel cis-acting element "CTCTT". Together, the PagKNAT2/6b-PagBOP1/2a module regulates poplar leaf morphology by affecting axial development, which provides insights aimed at leaf shape modification for further improving the drought tolerance of woody plants.

Effect of lentivirus-mediated miR-182 targeting FGF9 on hallux valgus.

The pathogenesis of hallux valgus is not clearly understood. However, genetics research about hallux valgus is rare. Therefore, the present study aimed to explore the pathogeny of hallux valgus from the perspective of genetics. Human samples were collected from normal bone tissue and hallux valgus region bone tissue. The bone samples were studied using real time-PCR, western blot and immunohistochemical. Lentivirus-mediated miR-182 transfected osteoblasts and tested the expression of FGF9 mRNA with real time-PCR. To test alkaline phosphatase activity, number of calcium nodules and proliferation of osteoblast with enzymatic activity analysis, calcium nodules stained and MTT assay. We found that (1) FGF9 expressed in hallux valgus region bone tissue was significantly higher than normal bone tissue. (2) miR-182 expression levels in hallux valgus region bone tissue were notably lower than those of normal bone tissue. (3) miR-182 could negatively regulate the expression of FGF9 in osteoblasts. (4) FGF9 may enhance osteoblasts proliferation. We have demonstrated that miR-182 promotes the formation of bone by targeting FGF9, implicating an essential role of miR-182 in the etiology of hallux valgus. Moreover, miR-182 might potentially be a therapeutic target for hallux valgus treatment.

3D-printing magnesium-polycaprolactone loaded with melatonin inhibits the development of osteosarcoma by regulating cell-in-cell structures.

Melatonin has been proposed as a potent anticarcinogen presents a short half-life for osteosarcoma (OS). Cell-in-cell (CIC) structures play a role in the development of malignant tumors by changing the tumor cell energy metabolism. This study developed a melatonin-loaded 3D printed magnesium-polycaprolactone (Mg-PCL) scaffold and investigated its effect and molecular mechanism on CIC in OS. Mg-PCL scaffold was prepared by 3D-printing and its characteristic was determined. The effect and molecular mechanism of Mg-PCL scaffold as well as melatonin-loaded Mg-PCL on OS growth and progression were investigated in vivo and in vitro. We found that melatonin receptor 1 (MT1) and CIC expressions were increased in OS tissues and cells. Melatonin treatment inhibit the key CIC pathway, Rho/ROCK, through the cAMP/PKA signaling pathway, interfering with the mitochondrial physiology of OS cells, and thus playing an anti-invasion and anti-metastasis role in OS. The Mg-PCL-MT could significantly inhibit distant organ metastasis of OS in the in vivo model. Our results showed that melatonin-loaded Mg-PCL scaffolds inhibited the proliferation, invasion and metastasis of OS cells through the CIC pathway. The Mg-PCL-MT could be a potential therapeutics for OS.

Open Curettage With Bone Augmentation for Symptomatic Tumors and Tumor-like Lesions of Calcaneus: A Comparison of Bioactive Glass Versus Allogeneic Bone.

Few studies have characterized the clinical outcomes of 45S5 Bioglass® applied as a bone graft to that of allogeneic bone applied in calcaneal open curettage. Therefore, the purpose of the present investigation was to compare the outcomes of patients with calcaneal tumors and tumor-like lesions treated by open curettage with 45S5 Bioglass® or allogeneic bone. Of the 31 patients who underwent open curettage (18 cases of unicameral bone cysts, 7 cases of aneurysmal bone cysts, and 6 cases of intraosseous lipoma), 16 (52%) received grafts with 45S5 Bioglass® and 15 (48%) with allogeneic bone. All the feet achieved bone fusion according to the modified Neer radiographic classification system at the last follow-up examination. The mean bone ingrowth time for the grafts with 45S5 Bioglass® versus allogeneic bone was 3.71 ± 0.86 versus 4.46 ± 1.04 months (p = .038), the mean bone healing time was 4.86 ± 0.93 versus 5.73 ± 1.07 months (p = .021), and the mean incision drying time was 7.2 ± 1.8 versus 8.2 ± 1.5 days (p = .047), respectively. No differences were found in the postoperative American Orthopaedic Foot and Ankle Society ankle-hindfoot scale scores between the 2 groups (p = .213). These results show that 45S5 Bioglass® can better facilitate the formation of new bone with a faster drying time of the incision than allogeneic bone. Although both materials can benefit the clinical outcomes of calcaneal tumors and tumor-like lesions, further studies are needed to observe the long-term complications and lesion recurrence rates.

Glycopeptide Self-Assembly Modulated by Glycan Stereochemistry through Glycan-Aromatic Interactions.

Carbohydrates are often utilized to provide hydrophilicity and hydroxyl-based hydrogen bonds in self-assembling glycopeptides, affording versatile scaffolds with wide applicability in biomedical research. However, how stereochemistry of carbohydrates impacts the self-assembly process remains unclear. Here we have established a dimeric tyrosine-rich glycopeptide system for probing the corresponding hydrogelating behavior under the influence of site- and stereospecific glycosylations. Comparison of 18 glycoforms bearing monosaccharides at Tyr4 and Tyr4' shows that the glycopeptides with either α- or ß-anomers exhibit contrary gelating abilities, when the glycan moieties contain axial hydroxyl groups. A high-resolution X-ray crystallographic structure of the ß-galactose-containing gelator, along with other results from spectroscopic, microscopic, and rheological experiments, indicate an unusual carbohydrate-aromatic CH-π bonding that promotes glycopeptide self-assembly. These mechanistic findings, particularly evidence obtained at the angstrom scale, illuminate an unconventional role that carbohydrates can play in building supramolecules. Potential biomaterials exploiting the CH-π bond-based stabilization, as exemplified by an enzyme-resistant hydrogel, may thus be developed.

Integrative structural modeling of a multidomain polo-like kinase.

Polo-like kinase 1 (PLK1) is a key regulator and coordinator for mitotic signaling that contains two major functional units of a kinase domain (KD) and a polo-box domain (PBD). While individual domain structures of the KD and the PBD are known, how they interact and assemble into a functional complex remains an open question. The structural model from the KD-PBD-Map205PBM heterotrimeric crystal structure of zebrafish PLK1 represents a major step in understanding the KD and the PBD interactions. However, how these two domains interact when connected by a linker in the full length PLK1 needs further investigation. By integrating different sources of structural data from small-angle X-ray scattering, hydroxyl radical protein footprinting, and computational sampling, here we report an overall architecture for PLK1 multidomain assembly between the KD and the PBD. Our model revealed that the KD uses its C-lobe to interact with the PBD via the site near the phosphopeptide binding site in its auto-inhibitory state in solution. Disruption of this auto-inhibition via site-directed mutagenesis at the KD-PBD interface increases its kinase activity, supporting the functional role of KD-PBD interactions predicted for regulating the PLK1 kinase function. Our results indicate that the full length human PLK1 takes dynamic structures with a variety of domain-domain interfaces in solution.

CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction.

CavityPlus is a web server that offers protein cavity detection and various functional analyses. Using protein three-dimensional structural information as the input, CavityPlus applies CAVITY to detect potential binding sites on the surface of a given protein structure and rank them based on ligandability and druggability scores. These potential binding sites can be further analysed using three submodules, CavPharmer, CorrSite, and CovCys. CavPharmer uses a receptor-based pharmacophore modelling program, Pocket, to automatically extract pharmacophore features within cavities. CorrSite identifies potential allosteric ligand-binding sites based on motion correlation analyses between cavities. CovCys automatically detects druggable cysteine residues, which is especially useful to identify novel binding sites for designing covalent allosteric ligands. Overall, CavityPlus provides an integrated platform for analysing comprehensive properties of protein binding cavities. Such analyses are useful for many aspects of drug design and discovery, including target selection and identification, virtual screening, de novo drug design, and allosteric and covalent-binding drug design. The CavityPlus web server is freely available at http://repharma.pku.edu.cn/cavityplus or http://www.pkumdl.cn/cavityplus.

Mitophagy in Cardiomyocytes and in Platelets: A Major Mechanism of Cardioprotection Against Ischemia/Reperfusion Injury.

Mitophagy, a process that selectively removes damaged organelles by autolysosomal degradation, is an early cellular response to ischemia. Mitophagy is activated in both cardiomyocytes and platelets during ischemia/reperfusion (I/R) and heart disease conditions. We focus on the molecular regulation of mitophagy and highlight the role of mitophagy in cardioprotection.

NIPA2 regulates osteoblast function via its effect on apoptosis pathways in type 2 diabetes osteoporosis.

Type 2 diabetes osteoporosis has recently become a hot topic in the study of diabetic complications, but the specific mechanism of its development remains unclear. Non-imprinted in Prader-Willi/Angelman syndrome region protein 2 (NIPA2), a highly-selective magnesium ion transporter, has been found to be associated with type 2 diabetes. In this study we aimed to investigate the specific role and mechanism of NIPA2 in the pathogenesis of type 2 diabetes osteoporosis. We first used western blotting, PCR, immunofluorescence, and magnesium ion probes to detect changes of NIPA2 and intracellular magnesium levels in osteoblasts at different concentrations of advanced glycation end products (AGEs). We then up- or down-regulated NIPA2 using a lentivirus and analyzed apoptotic biomarkers as well as the osteogenic ability of osteoblasts. We found that AGEs dose-dependently down-regulated the expression of NIPA2 in osteoblasts. NIPA2 also regulated osteoblast apoptosis by affecting the intracellular magnesium level and further affecting the osteogenic capacity of osteoblasts. Our study revealed the changes of NIPA2 in response to AGEs in the environment, as well as its function and mechanism in osteoblasts, demonstrating its important role in the pathogenesis of type 2 diabetes osteoporosis. The study suggests that NIPA2 is a potential target for the treatment of type 2 diabetes osteoporosis.