TBX5 Variants are Associated with Susceptibility to and the Incidence of Liver Cirrhosis and Hepatocellular Carcinoma in the Chinese Population: A Multicenter and Follow-Up Study.

Purpose: Liver cirrhosis (LC) and hepatocellular carcinoma (HCC) are progressions affected by genetic predispositions, and persistent hepatitis B virus infection also demonstrates genetic susceptibility. All HBV-related outcomes have been compared in parallel to identify risk polymorphism in HBV progression. Methods: The multiple-stage association study filtered and validated the risk SNPs for HBV progression and explored their association with persistent infection, with a total of 8906 subjects in China from three sites. Cox proportional hazards models and Kaplan-Meier Log rank tests were used to determine the time to the progressive event in relation to the risk SNPs. Results: Rs3825214 in TBX5 replicated a specific association with LC and HCC in 4 progression cohorts and was not related to persistent infection, naivety to HBV infection and natural clearance in 3 persistent cohorts. In combined samples, rs3825214 was associated with an increased risk of LC (P<0.001; OR = 1.98) and HCC (P<0.001; OR = 1.68). The results of bioinformatics analysis indicated that rs3825214 genotypes change RNA structure and intron excision ratio. In the follow-up of 571 hospital-based persistent HBV infection patients, ninety-three (16.29%) developed LC, and seventy-four (12.96%) progressed to HCC at a median follow-up of 5.1 years. Rs3825214 was associated with HCC and LC events in Cox proportional hazards models (P<0.001). Conclusion: We identified and confirmed that genetic variants in TBX5 are significantly associated with susceptibility to and the incidence of LC and HCC.

STK33 Phosphorylates Fibrous Sheath Protein AKAP3/4 to Regulate Sperm Flagella Assembly in Spermiogenesis.

Spermatogenesis defects are important for male infertility; however, the etiology and pathogenesis are still unknown. Herein, we identified two loss-of-function mutations of STK33 in seven individuals with non-obstructive azoospermia. Further functional studies of these frameshift and nonsense mutations revealed that Stk33-/KI male mice were sterile, and Stk33-/KI sperm were abnormal with defects in the mitochondrial sheath, fibrous sheath, outer dense fiber, and axoneme. Stk33KI/KI male mice were subfertile and had oligoasthenozoospermia. Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components A-kinase anchoring protein 3 and A-kinase anchoring protein 4, whose expression levels decreased in testis after deletion of Stk33. STK33 regulated the phosphorylation of A-kinase anchoring protein 3/4, affected the assembly of fibrous sheath in the sperm, and played an essential role in spermiogenesis and male infertility.

Association of male factors with recurrent pregnancy loss.

The role of male factors in recurrent pregnancy loss (RPL) is receiving increased attention since sperm quantity and quality, male genetic mutations, as well as epigenetic modifications, have all been associated with RPL. A growing number of studies have been published on the relationship between male factors and RPL; however, these reports are limited due to small sample sizes, inconsistent inclusion criteria, and detection methods. Herein, we investigate the effects of several male factors on RPL from a genetic and non-genetic perspective to aid clinicians in determining the etiology and optimal treatment strategy for patients with RPL.

Somatic nuclear auto-antigenic sperm protein sensitizes human breast cancer cells to 5-Fluorouracil.

PURPOSE: To assess the potential role of nuclear auto-antigenic sperm protein (NASP) in the cellular sensitivity to 5-Fluorouracil (5-FU) in breast cancer cells. METHODS: The expression of two NASP isotypes, namely somatic NASP (sNASP) and testis NASP (tNASP) in breast cancer lines were detected under 5-FU treatment using real-time polymerase chain reaction and western blot assays. NASP effect on cellular viability and apoptosis under 5-FU treatment were evaluated. The interaction between NASP and its downstream proteins were evaluated using the co-immunoprecipitation (Co-IP) assays. RESULTS: 5-FU significantly decreased the mRNA and protein expression levels of sNASP. Inhibition of sNASP increased cellular viability, colony formation ability, but reduced apoptosis in tested cell lines in response to 5-FU, which were reversed by sNASP over-expression. Further study reveals 5-FU disrupts sNASP/TNF receptor-associated factor 6 (TRAF6) complex, potentiates cellular sensitivity to 5-FU via NK-kB. CONCLUSION: Our findings suggest sNASP is a novel molecular target having potential to overcome the resistance to 5-FU in breast cancer cells.

Dynamic Changes of Antibodies to SARS-CoV-2 in Close Contacts.

INTRODUCTION: Close contacts of individuals with COVID-19 may directly gain immunity against SARS-CoV-2 despite lacking a detectable infection. This study examined SARS-CoV-2-specific antibodies levels based on gender, age, and exposure source in close contacts of individuals with COVID-19 and compared antibody levels to patients with an asymptomatic or symptomatic COVID-19 infection. METHODS: Two patients had confirmed COVID-19 infections at a community hospital in Qiongzhong, Hainan province. Contact tracing identified all individuals in the community who had been exposed to the two patients during the 14 days before their diagnoses. Close contacts quarantined for 14 days, underwent two SARS-CoV-2 tests, and were screened for SARS-CoV-2-specific antibodies at 7 and 12 weeks after the end of quarantine. SARS-CoV-2-specific antibody levels for the close contacts were compared to those for patients with an asymptomatic or symptomatic COVID-19 infection at 7 and 12 weeks after their diagnoses. RESULTS: Contact tracing identified 10,573 individuals in the community, including 360 (3.4%) close contacts. At 7 weeks, 30 (8.33%) close contacts were positive for SARS-CoV-2-specific antibodies (IgG, n = 26 [7.22%]; IgM, n = 4 [1.11%]), which were lower than the proportion of patients with an asymptomatic (IgG, 100% [12/12]) or symptomatic (IgG, 93.6% [44/47]) COVID-19 infection. SARS-CoV-2-specific IgM antibody levels were significantly higher in close contacts who were exposed through a relative compared to a doctor-patient relationship (P = 0.032). SARS-CoV-2-specific IgG antibody levels were significantly higher in close contacts aged <18 years vs 18-64 years (P = 0.014). At 12 weeks, SARS-CoV-2-specific IgG antibody levels among close contacts were significantly lower than among patients with an asymptomatic (P = 0.004) or symptomatic COVID-19 infection (P < 0.001). CONCLUSION: Immune protection conferred by close contact is short term and unlikely to contribute to herd immunity. There remains an unmet public health need for mass vaccination of populations to increase levels of protective antibodies and achieve and maintain herd immunity.

XPG is Modulated by miR-4715-3p and rs873601 Genotypes in Lung Cancer.

OBJECTIVE: XPG (Xeroderma pigmentosum group G, XPG), a single strand-specific DNA endonuclease in the nucleotide excision repair pathway, has been implicated in lung cancer. Potentially functional rs873601 in XPG is consistently associated with gastrointestinal cancer, and miR-4715-3p, targeting 3UTR of XPG, also influences the process of gastrointestinal carcinogenesis, however, the relationships between XPG and miR-4715-3p and rs873601 in lung cancer have not been elucidated. METHODS: A case-control study included 264 lung cancer patients and 264 cancer-free healthy controls and was designed to determine the relationships between rs873601 and lung cancer and the effect of miR-4715-3p on XPG expression in lung cancer. Fifty matched cases and controls were randomly selected from the lung cancer and control groups to assess the relationships between the expression levels of miR-4715-3p and XPG determined by using qRT-PCR. The association of rs873601 with lung cancer was analyzed by mass spectrometry, and function prediciton of rs873601 genotypes explored by web-based bioinformatics. RESULTS: miR-4715-3p in the lung cancer group was significantly increased compared with that in the control group (P = 0.011), upregulation of miR-4715-3p correlated with an increase in XPG mRNA (r = 0.399, P <0.05) in the lung cancer group. The AA genotype was associated with increased risk of lung cancer compared with the AG and GG genotypes of rs873601 (AG vs AA: OR = 0.231, 95% CI: 0.155-0.345, P <0.001 GG vs AA: OR = 0.300, 95% CI: 0.131-0.719, P = 0.003). The genetic association remained significant after adjustment for age, sex, smoking, and drinking, and rs873601-AA was associated with an increase in XPG mRNA in the lung cancer group. The results of web-based bioinformatics analysis indicated rs873601 genotypes might change XPG-RNA stability and bindability between XPG and miR-4715-3p. CONCLUSION: Our data characterized that miR-4715-3p and rs873601 genotypes modified XPG expression in lung cancer. These findings may help to elucidate the mechanisms governing lung cancer.

LncRNA PRNCR1 rs1456315 and CCAT2 rs6983267 Polymorphisms on 8q24 Associated with Lung Cancer.

BACKGROUND: Long noncoding RNA single nucleotide polymorphisms (lncRNA-SNPs) PCAT1 rs710886, PRNCR1 rs1456315 and CCAT2 rs6983267 on 8q24 region present generalizability in the susceptibility to multiple cancers, however, the influence of rs710886, rs1456315 and rs6983267 on lung cancer has not been assessed. The aim of this study was to investigate associations between three lncRNA-SNPs and lung cancer. METHODS: A case-control study was performed on 438 patients with lung cancer and 456 healthy controls in the Han population from southern China. The collected samples were genotyped by the TaqMan genotyping, and the association with clinical characteristics, including age, gender, drinking status, smoking status, pathological types and clinical stages were analyzed. And the SNP function prediction was based on lncRNASNP2, RNAfold and GTEx. RESULTS: The rs1456315 T allele increased the risk of lung cancer [OR=1.95, 95% CI (1.58-2.43), P=0.003] compared to the rs1456315 C allele, and rs1456315 significantly increased the risk of lung cancer in the dominant model [OR=1.86, 95% CI (1.16-3.00), P=0.002]. The rs6983267 G allele, compared with the T allele, increased the risk of lung cancer [OR=1.29, 95% CI (1.07-1.57), P=0.007], and rs6983267 was identified as a risk factor for lung cancer [OR=1.28, 95% CI (1.06-1.55), P=0.003] in the additive model. Both rs1456315 and rs6983267 demonstrated significance after adjusting for the smoking status, drinking status and age. The structure prediction found rs6983267 and rs1456315 influence the secondary structure of its lncRNA. The results from lncRNASNP2 indicated that rs6983267 and rs1456315 change gain/loss target of miRNAs. CONCLUSION: PRNCR1 rs1456315 and CCAT2 rs6983267 on 8q24 region are significantly associated with lung cancer in the Han population of southern China and alter the potential biological function in bioinformatic analysis, and the results further extended generalism of the susceptibility of cancer-associated lncRNA-SNPs to lung cancer and underlying mechanism involved in lung cancer.

Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles.

Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.

Proteomics analysis of asthenozoospermia and identification of glucose-6-phosphate isomerase as an important enzyme for sperm motility.

Asthenozoospermia, in which sperm motility is affected, is one of the primary causes of male infertility. However, the exact mechanism responsible for the defective motility remains unknown. It is important to identify the precise proteins or pathways involved in sperm motility. The present study analyzed five asthenozoospermic sperm samples and five healthy controls using TMT-based quantitative method and identified 152 differentially expressed proteins, with 84 upregulated and 68 downregulated in asthenozoospermia. Four proteins (GPI, MDH1, PGAM1 and PGAM2) were found in several over-represented energy metabolism pathways using bioinformatics analysis. Glucose-6-phosphate isomerase (GPI), a rate-limiting enzyme converting glucose-6-phosphate to fructose-6-phosphate, was found to be significantly decreased in asthenozoospermia by Western blotting and ELISA on an extended sample size. Furthermore, substitution of glucose with fructose-6-phosphate significantly promoted asthenozoospermic sperm motility in vitro. Taken together, our results suggest that the poor motility of sperm in asthenozoospermia may partly result from defects in GPI-associated energy metabolism. SIGNIFICANCE: To identify the key proteins or pathways involved in sperm motility, the accurate TMT-based quantitative method was applied to characterize protein profiles of asthenozoospermic sperm. GPI, an enzyme involved in energy metabolism, was found to be differentially abundant, and validated by extended sample analysis. The supplement of the product of GPI, fructose-6-phosphate, could significantly improve sperm motility. Our study could provide new insights into the molecular basis of sperm motility and the improvement of motility in asthenozoospermia.

Salicylic acid (SA)-eluting bone regeneration scaffolds with interconnected porosity and local and sustained SA release.

In previous work, we observed that localized and sustained delivery of an anti-inflammatory drug, salicylic acid (SA), via a SA-based polymer (SAP) powder significantly enhanced diabetic bone regeneration through long-term mitigation of local inflammation. In this study, SAP was formulated into uniform microspheres and then sintered into a scaffold with an interconnected porous structure and modulus suitable for bone regeneration. The SAP scaffolds have ∼45% SA loading, which is the highest among drug-eluting bone regeneration scaffolds to-date. In addition, the scaffold provides localized, controlled and sustained SA release that has been proven to enhance diabetic bone regeneration. With the combination of physical (interconnected porosity) and chemical therapeutic features (high drug loading and sustained release), the novel SAP scaffolds offer unique therapeutic advantages and are promising diabetic bone regeneration candidates. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 311-318, 2017.

Sustained, localized salicylic acid delivery enhances diabetic bone regeneration via prolonged mitigation of inflammation.

Diabetes is a metabolic disorder caused by insulin resistance and/or deficiency and impairs bone quality and bone healing due to altered gene expression, reduced vascularization, and prolonged inflammation. No effective treatments for diabetic bone healing are currently available, and most existing treatments do not directly address the diabetic complications that impair bone healing. We recently demonstrated that sustained and localized delivery of salicylic acid (SA) via an SA-based polymer provides a low-cost approach to enhance diabetic bone regeneration. Herein, we report mechanistic studies that delve into the biological action and local pharmacokinetics of SA-releasing polymers shown to enhance diabetic bone regeneration. The results suggest that low SA concentrations were locally maintained at the bone defect site for more than 1 month. As a result of the sustained SA release, a significantly reduced inflammation was observed in diabetic animals, which in turn, yielded reduced osteoclast density and activity, as well as increased osteoblastogenesis. Based upon these results, localized and sustained SA delivery from the SA-based polymer effectively improved bone regeneration in diabetic animals by affecting both osteoclasts and osteoblasts, thereby providing a positive basis for clinical treatments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2595-2603, 2016.

Pinosylvin-Based Polymers: Biodegradable Poly(Anhydride-Esters) for Extended Release of Antibacterial Pinosylvin.

Pinosylvin is a natural stilbenoid known to exhibit antibacterial bioactivity against foodborne bacteria. In this work, pinosylvin is chemically incorporated into a poly(anhydride-ester) (PAE) backbone via melt-condensation polymerization, and characterized with respect to its physicochemical and thermal properties. In vitro release studies demonstrate that pinosylvin-based PAEs hydrolytically degrade over 40 d to release pinosylvin. Pseudo-first order kinetic experiments on model compounds, butyric anhydride and 3-butylstilbene ester, indicate that the anhydride linkages hydrolyze first, followed by the ester bonds to ultimately release pinosylvin. An antibacterial assay shows that the released pinosylvin exhibit bioactivity, while in vitro cytocompatibility studies demonstrate that the polymer is noncytotoxic toward fibroblasts. These preliminary findings suggest that the pinosylvin-based PAEs can serve as food preservatives in food packaging materials by safely providing antibacterial bioactivity over extended time periods.

Linear, Mannitol-Based Poly(anhydride-esters) with High Ibuprofen Loading and Anti-Inflammatory Activity.

Sugar alcohols, such as mannitol and xylitol, are biocompatible polyols that have been used to make highly cross-linked polyester elastomers and dendrimers for tissue engineering and drug delivery. However, research that utilizes the secondary hydroxyl groups as sites for pendant bioactive attachment and subsequent polymerization is limited. This work is the first report of a linear, completely biodegradable polymer with a sugar alcohol backbone and chemically incorporated pendant bioactives that exhibits sustained bioactive release and high bioactive loading (∼70%). With four pendant esters per repeat unit, this poly(anhydride-ester) has high loading and biodegrades into three biocompatible products: bioactive, sugar alcohol, and alkyl-based diacid. Ibuprofen serves as a representative bioactive, whereas mannitol is a representative polyol. Polymerization was achieved through reaction with (trimethylsilyl)ethoxyacetylene. Drug release via polymer degradation was quantified by high performance liquid chromatography. Additionally, a cytocompatibility study with fibroblast cells was performed to elucidate the polymer's suitability for in vivo use and a cyclooxygenase-2 (COX-2) assay was performed on the degradation media to ensure that released ibuprofen retained its anti-inflammatory activity. This work enables the future development of novel, biodegradable polymers exhibiting two key features: (i) polymer backbones with easily modified pendant groups, such as targeting moieties, and (ii) high drug loading using a multitude of bioactive classes.

Ferulic Acid-Based Polymers with Glycol Functionality as a Versatile Platform for Topical Applications.

Ferulic acid-based polymers with aliphatic linkages have been previously synthesized via solution polymerization methods, yet they feature relatively slow ferulic acid release rates (∼11 months to 100% completion). To achieve a more rapid release rate as required in skin care formulations, ferulic acid-based polymers with ethylene glycol linkers were prepared to increase hydrophilicity and, in turn, increase ferulic acid release rates. The polymers were characterized using nuclear magnetic resonance and Fourier transform infrared spectroscopies to confirm chemical composition. The molecular weights, thermal properties (e.g., glass transition temperature), and contact angles were also obtained and the polymers compared. Polymer glass transition temperature was observed to decrease with increasing linker molecule length, whereas increasing oxygen content decreased polymer contact angle. The polymers' chemical structures and physical properties were shown to influence ferulic acid release rates and antioxidant activity. In all polymers, ferulic acid release was achieved with no bioactive decomposition. These polymers demonstrate the ability to strategically release ferulic acid at rates and concentrations relevant for topical applications such as skin care products.

Enzymatic Polymerization of an Ibuprofen-Containing Monomer and Subsequent Drug Release.

Novel ibuprofen-containing monomers comprising naturally occurring and biocompatible compounds were synthesized and subsequently polymerized via enzymatic methods. Through the use of a malic acid sugar backbone, ibuprofen was attached as a pendant group, and then subsequently polymerized with a linear aliphatic diol (1,3-propanediol, 1,5-pentanediol, or 1,8-octanediol) as comonomer using lipase B from Candida antarctica, a greener alternative to traditional metal catalysts. Polymer structures were elucidated by nuclear magnetic resonance and infrared spectroscopies, and thermal properties and molecular weights were determined. All polymers exhibited sustained ibuprofen release, with the longer chain, more hydrophobic diols exhibiting the slowest release over the 30 d study. Polymers were deemed cytocompatible using mouse fibroblasts, when evaluated at relevant therapeutic concentrations. Additionally, ibuprofen retained its chemical integrity throughout the polymerization and in vitro hydrolytic degradation processes. This methodology of enzymatic polymerization of a drug presents a more environmentally friendly synthesis and a novel approach to bioactive polymer conjugates.

Salicylic Acid-Based Polymers for Guided Bone Regeneration Using Bone Morphogenetic Protein-2.

Bone morphogenetic protein-2 (BMP-2) is used clinically to promote spinal fusion, treat complex tibia fractures, and to promote bone formation in craniomaxillofacial surgery. Excessive bone formation at sites where BMP-2 has been applied is an established complication and one that could be corrected by guided tissue regeneration methods. In this study, anti-inflammatory polymers containing salicylic acid [salicylic acid-based poly(anhydride-ester), SAPAE] were electrospun with polycaprolactone (PCL) to create thin flexible matrices for use as guided bone regeneration membranes. SAPAE polymers hydrolyze to release salicylic acid, which is a nonsteroidal anti-inflammatory drug. PCL was used to enhance the mechanical integrity of the matrices. Two different SAPAE-containing membranes were produced and compared: fast-degrading (FD-SAPAE) and slow-degrading (SD-SAPAE) membranes that release salicylic acid at a faster and slower rate, respectively. Rat femur defects were treated with BMP-2 and wrapped with FD-SAPAE, SD-SAPAE, or PCL membrane or were left unwrapped. The effects of different membranes on bone formation within and outside of the femur defects were measured by histomorphometry and microcomputed tomography. Bone formation within the defect was not affected by membrane wrapping at BMP-2 doses of 12 µg or more. In contrast, the FD-SAPAE membrane significantly reduced bone formation outside the defect compared with all other treatments. The rapid release of salicylic acid from the FD-SAPAE membrane suggests that localized salicylic acid treatment during the first few days of BMP-2 treatment can limit ectopic bone formation. The data support development of SAPAE polymer membranes for guided bone regeneration applications as well as barriers to excessive bone formation.

Biodegradable salicylate-based poly(anhydride-ester) microspheres for controlled insulin delivery.

Salicylate-based poly(anhydride-esters) (PAEs) chemically incorporate salicylic acid (SA) into the polymer backbone, which is then delivered in a controlled manner upon polymer hydrolysis. In this work, a salicylate-based PAE is a carrier to encapsulate and deliver insulin. Polymer microspheres were formulated using a water/oil/water double-emulsion solvent evaporation technique. The microspheres obtained had a smooth surface, high protein encapsulation efficiency, and relatively low emulsifier content. Insulin was released in vitro for 15 days, with no signs of aggregation or unfolding of the secondary structure. The released insulin also retained bioactivity in vitro. Concurrently, SA was released from the microspheres with polymer degradation and anti-inflammatory activity was observed. Based upon these results, the formulated microspheres enable simultaneous delivery of insulin and SA, both retaining bioactivity following processing.

Biodegradable polyesters containing ibuprofen and naproxen as pendant groups.

Controlled release of nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen could be beneficial for the treatment of inflammatory diseases while reducing the side effects resulting from their continuous use. Novel biodegradable polyesters solely comprised of biocompatible components (e.g., tartaric acid, 1,8-octanediol, and ibuprofen or naproxen as pendant groups) have been synthesized using tin(II) 2-ethylhexanoate as catalyst at 130 °C and subsequently characterized to determine their structures and physicochemical properties. The polymers release the free drug (ibuprofen or naproxen) in vitro in a controlled manner without burst release, unlike the release rates achieved when the drugs are encapsulated in other polymers. These new biomaterials are not cytotoxic toward mouse fibroblasts up to 0.10 mg/mL. The drugs retain their chemical structure following hydrolytic degradation of the polymer, suggesting that bioactivity is preserved.

Locally delivered salicylic acid from a poly(anhydride-ester): impact on diabetic bone regeneration.

Diabetes mellitus (DM) involves metabolic changes that can impair bone repair, including a prolonged inflammatory response. A salicylic acid-based poly(anhydride-ester) (SA-PAE) provides controlled and sustained release of salicylic acid (SA) that locally resolves inflammation. This study investigates the effect of polymer-controlled SA release on bone regeneration in diabetic rats where enhanced inflammation is expected. Fifty-six Sprague-Dawley rats were randomly assigned to two groups: diabetic group induced by streptozotocin (STZ) injection or normoglycemic controls injected with citrate buffer alone. Three weeks after hyperglycemia development or vehicle injection, 5mm critical sized defects were created at the rat mandibular angle and treated with SA-PAE/bone graft mixture or bone graft alone. Rats were euthanized 4 and 12weeks after surgery, then bone fill percentage in the defect region was assessed by micro-computed tomography (CT) and histomorphometry. It was observed that bone fill increased significantly at 4 and 12weeks in SA-PAE/bone graft-treated diabetic rats compared to diabetic rats receiving bone graft alone. Accelerated bone formation in normoglycemic rats caused by SA-PAE/bone graft treatment was observed at 4weeks but not at 12weeks. This study shows that treatment with SA-PAE enhances bone regeneration in diabetic rats and accelerates bone regeneration in normoglycemic animals.