Genetic analysis of impaired healing responses after periodontal therapy in type 2 diabetes: Clinical and in vivo studies.

OBJECTIVE: This study aims to investigate the mechanisms underlying the impaired healing response by diabetes after periodontal therapy. BACKGROUND: Outcomes of periodontal therapy in patients with diabetes are impaired compared with those in patients without diabetes. However, the mechanisms underlying impaired healing response to periodontal therapy have not been sufficiently investigated. MATERIALS AND METHODS: Zucker diabetic fatty (ZDF) and lean (ZL) rats underwent experimental periodontitis by ligating the mandibular molars for one week. The gingiva at the ligated sites was harvested one day after ligature removal, and gene expression was comprehensively analyzed using RNA-Seq. In patients with and without type 2 diabetes (T2D), the corresponding gene expression was quantified in the gingiva of the shallow sulcus and residual periodontal pocket after non-surgical periodontal therapy. RESULTS: Ligation-induced bone resorption and its recovery after ligature removal were significantly impaired in the ZDF group than in the ZL group. The RNA-Seq analysis revealed 252 differentially expressed genes. Pathway analysis demonstrated the enrichment of downregulated genes involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. PPARα and PPARγ were decreased in mRNA level and immunohistochemistry in the ZDF group than in the ZL group. In clinical, probing depth reduction was significantly less in the T2D group than control. Significantly downregulated expression of PPARα and PPARγ were detected in the residual periodontal pocket of the T2D group compared with those of the control group, but not in the shallow sulcus between the groups. CONCLUSIONS: Downregulated PPAR subtypes expression may involve the impaired healing of periodontal tissues by diabetes.

Role of reactive oxygen species (ROS) in the regulation of adipogenic differentiation of human maxillary/mandibular bone marrow-derived mesenchymal stem cells.

BACKGROUND: Maxillary/mandibular bone marrow-derived mesenchymal stem cells (MBMSCs) exhibit a unique property of lower adipogenic potential than other bone marrow-derived MSCs. However, the molecular mechanisms regulating the adipogenesis of MBMSCs remain unclear. This study aimed to explore the roles of mitochondrial function and reactive oxygen species (ROS) in regulating the adipogenesis of MBMSCs. METHODS AND RESULTS: MBMSCs exhibited significantly lower lipid droplet formation than iliac BMSCs (IBMSCs). Moreover, the expression levels of CCAAT/enhancer-binding protein ß (C/EBPß), C/EBPδ, and early B cell factor 1 (Ebf-1), which are early adipogenic transcription factors, and those of peroxisome proliferator-activated receptor-γ (PPARγ) and C/EBPα, which are late adipogenic transcription factors, were downregulated in MBMSCs compared to those in IBMSCs. Adipogenic induction increased the mitochondrial membrane potential and mitochondrial biogenesis in MBMSCs and IBMSCs, with no significant difference between the two cell types; however, intracellular ROS production was significantly enhanced only in IBMSCs. Furthermore, NAD(P)H oxidase 4 (NOX4) expression was significantly lower in MBMSCs than in IBMSCs. Increased ROS production in MBMSCs by NOX4 overexpression or treatment with menadione promoted the expression of early adipogenic transcription factors but did not induce that of late adipogenic transcription factors or lipid droplet accumulation. CONCLUSIONS: These results suggest that ROS may be partially involved in the process of MBMSC adipogenic differentiation from undifferentiated cells to immature adipocytes. This study provides important insights into the tissue-specific properties of MBMSCs.

Evidence Linking PPARG Genetic Variants with Periodontitis and Type 2 Diabetes Mellitus in a Brazilian Population.

The peroxisome proliferator-activated receptor gamma (PPARG) gene encodes a transcription factor involved in the regulation of complex metabolic and inflammatory diseases. We investigated whether single nucleotide polymorphisms (SNPs) and haplotypes of the PPARG gene could contribute with susceptibility to develop periodontitis alone or together with type 2 diabetes mellitus (T2DM). Moreover, we evaluated the gene-phenotype association by assessing the subjects' biochemical and periodontal parameters, and the expression of PPARG and other immune response-related genes. We examined 345 subjects with a healthy periodontium and without T2DM, 349 subjects with moderate or severe periodontitis but without T2DM, and 202 subjects with moderate or severe periodontitis and T2DM. PPARG SNPs rs12495364, rs1801282, rs1373640, and rs1151999 were investigated. Multiple logistic regressions adjusted for age, sex, and smoking status showed that individuals carrying rs1151999-GG had a 64% lower chance of developing periodontitis together with T2DM. The CCGT haplotype increased the risk of developing periodontitis together with T2DM. The rs1151999-GG and rs12495364-TC were associated with reduced risk of obesity, periodontitis, elevated triglycerides, and elevated glycated hemoglobin, but there was no association with gene expression. Polymorphisms of the PPARG gene were associated with developing periodontitis together with T2DM, and with obesity, lipid, glycemic, and periodontal characteristics.

The Expression Profile of Dental Pulp-Derived Stromal Cells Supports Their Limited Capacity to Differentiate into Adipogenic Cells.

Mesenchymal stromal cells (MSCs) can self-renew, differentiate into specialised cells and have different embryonic origins-ectodermal for dental pulp-derived MSCs (DPSCs) and mesodermal for adipose tissue-derived MSCs (ADSCs). Data on DPSCs adipogenic differentiation potential and timing vary, and the lack of molecular and genetic information prompted us to gain a better understanding of DPSCs adipogenic differentiation potential and gene expression profile. While DPSCs differentiated readily along osteogenic and chondrogenic pathways, after 21 days in two different types of adipogenic induction media, DPSCs cultures did not contain lipid vacuoles and had low expression levels of the adipogenic genes proliferator-activated receptor gamma (PPARG), lipoprotein lipase (LPL) and CCAAT/enhancer-binding protein alpha (CEBPA). To better understand this limitation in adipogenesis, transcriptome analysis in undifferentiated DPSCs was carried out, with the ADSC transcriptome used as a positive control. In total, 14,871 transcripts were common to DPSCs and ADSCs, some were unique (DPSCs: 471, ADSCs: 1032), and 510 were differentially expressed genes. Detailed analyses of overrepresented transcripts showed that DPSCs express genes that inhibit adipogenic differentiation, revealing the possible mechanism for their limited adipogenesis.

Ameliorating effect of lipo-ATRA treatment on the expression of TIG3 and its suppressing effect on PPARγ gene expression in lung cancer animal model.

This study aimed to find out the molecular therapeutic effect of lipo-ATRA on tumour suppressor TIG3 and cell proliferative biomarker PPARγ in B (a) P-induced lung cancer model. In RT-PCR study, ATRA- and lipo-ATRA-treated mice samples showed relatively higher TIG3 expression and decreased PPARγ expression (Band density) than cancer control. Among treatments, lipo-ATRA showed vital effect than free ATRA by enhancing TIG3 and decreasing PPARγ. The qPCR results also showed significant (p ≤ 0.05) difference in both TIG3 and PPAR (RQ values of TIG3, lipo-ATRA 23.85 ± 1.29; free ATRA 10.43 ± 1.81 and for PPARγ, lipo-ATRA 4.707 ± 1.21; free ATRA 15.78 ± 2.34). From this, we conclude that liposomal ATRA formulation is most preferable for prolonged delivery of ATRA at targeted site to favour molecular action. It implies that the therapeutic effect of lipo-ATRA in lung cancer was exhibited by ameliorating the TIG3 expression and by suppressing the expression of PPARγ.

Effect of matrix stiffness on the proliferation and differentiation of umbilical cord mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are a compatible cellular alternative for regenerative medicine and tissue engineering because of their powerful multipotency. Matrix stiffness plays a profound role on stem cell behavior. Nevertheless, the effect of matrix stiffness on umbilical cordmesenchymal stem cells (UC-MSCs) remains unexplored. To conduct an in-depth exploration, we cultured UC-MSCs on different stiffness (Young's modulus: 13-16, 35-38, 48-53, and 62-68 kPa) polyacrylamide gels coated with fibronectin. We found that the proliferation and adhesion of UC-MSCs varied when cultured on the different matrices, and the spreading capacity was stronger as the stiffness increased (*P<0.05). Real-time quantitative PCR results showed that the soft matrix promoted adipogenic differentiation, with higher expression levels of adipocytic markers like PPARγ and C/EBPα (*P<0.05). In contrast, cells tended to differentiate into muscle when cultured on the 48-53 kPa matrix, which was validated by increased expression of myogenic makers like desminand MOYG (*P<0.05). Moreover, increased expression of osteoblastic makers (*P<0.05), such as ALP, collagen type I, osteocalcin, and Runx2, confirmed that cells differentiated into bone on the high-stiffness matrix.

Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. METHODS: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. RESULTS: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. CONCLUSIONS: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.

Relationship between renal function and periodontal disease in community-dwelling elderly women with different genotypes.

OBJECTIVES: The aim of this study was to examine the association between periodontal disease and renal function in elderly women with different genotypes. MATERIAL AND METHODS: A total of 332 postmenopausal never-smoking women were analysed. Poor renal function was defined as serum cystatin C > 0.91 mg/l. Periodontal disease markers such as periodontal inflamed surface area (PISA) were evaluated. Selected variables, including PISA quartile, body mass index (BMI), HbA1C and age in Arg allele carriers and non-carriers based on the beta-3 adrenergic receptor, or between Ala allele carriers and non-carriers based on peroxisome proliferator-activated receptor gamma, were analysed using multiple logistic regression analysis. RESULTS: The odds ratios of serum cystatin C level and PISA (fourth quartile) were significantly positive for both Arg (2.52; p = 0.035) and Ala allele non-carriers (2.36; p = 0.021). A significant association was also found between serum cystatin C level and BMI for both Arg (1.18; p = 0.001) and Ala allele non-carriers (1.12; p = 0.003). CONCLUSION: The results of this study suggest that periodontal inflammation might be associated with renal function. Furthermore, in both the Arg and Ala allele non-carriers, the associations between BMI and PISA for renal function became stronger.

Nanoparticle mediated PPARγ gene delivery on dental implants improves osseointegration via mitochondrial biogenesis in diabetes mellitus rat model.

Diabetes mellitus (DM) has a detrimental effect on osseointegration, stability and longevity of implants due to osteoporosis. In this study, PPARγ-loaded dental implants were investigated for the improvement of osseointegration and peri-implantitis. Chitosan gold nanoparticles conjugated with PPARγ cDNA were introduced on titanium mini-implant surfaces for PPARγ release to rat mandibular. DM-induced rat mandible showed structural changes such as decreased bone mass and increased inflammatory molecules, and diminution of PPARγ expression and bone formation molecules compared to normal rats. PPARγ induced bone formation via reduction of inflammatory molecules even under glucose oxidative stress. Furthermore, PPARγ strongly activated mitochondrial biogenesis and cell viability via p-AMK and Wnt/ß-catenin signaling. Consequently, PPARγ gene delivery on regional dental implants contributed osseointegration, new bone formation and mineralization in DM-induced rats. This study demonstrates that PPARγ can be used as a therapeutic gene with dental implantation in diabetic patients since regional PPARγ expression enhances osseointegration and implant longevity.

PPARγ gene polymorphism, C-reactive protein level, BMI and periodontitis in post-menopausal Japanese women.

BACKGROUND: Several studies have reported inconsistent results regarding the association between the PPARγPro12Ala polymorphism and obesity. Obese individuals had higher C-reactive protein (CRP) levels compared with those of normal weight, and PPARγ activation could significantly reduce serum high-sensitive CRP level. We have previously suggested that the Pro12Ala polymorphism represents a susceptibility factor for periodontitis, which is a known risk factor for increased CRP level. OBJECTIVES: The aim was to investigate associations between PPARγ gene polymorphism, serum CRP level, BMI and/or periodontitis among post-menopausal Japanese women. MATERIALS AND METHODS: The final sample in this study comprised 359 post-menopausal Japanese women. Periodontal parameters, including PD, CAL and BOP, were measured per tooth. PPARγPro12Ala genotype was determined by PCR-RFLP. Hs-CRP value was measured by a latex nephelometry assay. RESULTS: No significant differences in age, BMI or periodontal parameters were found between the genotypes. The percentages of sites with PD ≥ 4 mm were significantly higher among the hsCRP ≥ 1 mg/l group than the hsCRP < 1 mg/l group (p = 0.003). Positive correlations were found between serum hsCRP levels and the percentages of sites with PD ≥ 4 mm (p = 0.043) in PPARγ Ala allele carriers, and BMI (p = 0.033) in non-carriers. After adjustment for model covariates, BMI was significantly associated with serum hsCRP level. CONCLUSION: The PPARγPro12Ala polymorphism was not independently associated with periodontitis, serum CRP level or BMI in post-menopausal Japanese women. However, serum hsCRP level correlated with periodontitis in Ala allele carriers, and with BMI in non-carriers.

Common target genes of palatal and gingival fibroblasts for EMD: the microarray approach.

BACKGROUND AND OBJECTIVE: Connective tissue grafts are frequently applied, together with Emdogain(®) , for root coverage. However, it is unknown whether fibroblasts from the gingiva and from the palate respond similarly to Emdogain. The aim of this study was therefore to evaluate the effect of Emdogain(®) on fibroblasts from palatal and gingival connective tissue using a genome-wide microarray approach. MATERIAL AND METHODS: Human palatal and gingival fibroblasts were exposed to Emdogain(®) and RNA was subjected to microarray analysis followed by gene ontology screening with Database for Annotation, Visualization and Integrated Discovery functional annotation clustering, Kyoto Encyclopedia of Genes and Genomes pathway analysis and the Search Tool for the Retrieval of Interacting Genes/Proteins functional protein association network. Microarray results were confirmed by quantitative RT-PCR analysis. RESULTS: The transcription levels of 106 genes were up-/down-regulated by at least five-fold in both gingival and palatal fibroblasts upon exposure to Emdogain(®) . Gene ontology screening assigned the respective genes into 118 biological processes, six cellular components, eight molecular functions and five pathways. Among the striking patterns observed were the changing expression of ligands targeting the transforming growth factor-beta and gp130 receptor family as well as the transition of mesenchymal epithelial cells. Moreover, Emdogain(®) caused changes in expression of receptors for chemokines, lipids and hormones, and for transcription factors such as SMAD3, peroxisome proliferator-activated receptor gamma and those of the ETS family. CONCLUSION: The present data suggest that Emdogain(®) causes substantial alterations in gene expression, with similar patterns observed in palatal and gingival fibroblasts.

FoxO1-modulated macrophage polarization regulates osteogenesis via PPAR-γ signaling.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

A rat model of Charcot-Marie-Tooth disease 1A recapitulates disease variability and supplies biomarkers of axonal loss in patients.

Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peripheral myelin protein 22 gene causes the most frequent subform Charcot-Marie-Tooth 1A. Patients develop a slowly progressive dysmyelinating and demyelinating peripheral neuropathy and distally pronounced muscle atrophy. The amount of axonal loss determines disease severity. Although patients share an identical monogenetic defect, the disease progression is strikingly variable and the impending disease course can not be predicted in individual patients. Despite promising experimental data, recent therapy trials have failed. Established clinical outcome measures are thought to be too insensitive to detect amelioration within trials. Surrogate biomarkers of disease severity in Charcot-Marie-Tooth 1A are thus urgently needed. Peripheral myelin protein 22 transgenic rats harbouring additional copies of the peripheral myelin protein 22 gene ('Charcot-Marie-Tooth rats'), which were kept on an outbred background mimic disease hallmarks and phenocopy the variable disease severity of patients with Charcot-Marie-Tooth 1A. Hence, we used the Charcot-Marie-Tooth rat to dissect prospective and surrogate markers of disease severity derived from sciatic nerve and skin tissue messenger RNA extracts. Gene set enrichment analysis of sciatic nerve transcriptomes revealed that dysregulation of lipid metabolism associated genes such as peroxisome proliferator-activated receptor gamma constitutes a modifier of present and future disease severity. Importantly, we directly validated disease severity markers from the Charcot-Marie-Tooth rats in 46 patients with Charcot-Marie-Tooth 1A. Our data suggest that the combination of age and cutaneous messenger RNA levels of glutathione S-transferase theta 2 and cathepsin A composes a strong indicator of disease severity in patients with Charcot-Marie-Tooth 1A, as quantified by the Charcot-Marie-Tooth Neuropathy Score. This translational approach, utilizing a transgenic animal model, demonstrates that transcriptional analysis of skin biopsy is suitable to identify biomarkers of Charcot-Marie-Tooth 1A.

Peroxisome proliferator-activated receptor (PPAR) γ polymorphism, vitamin D, bone mineral density and periodontitis in postmenopausal women.

OBJECTIVES: PPARg regulates bone metabolism and inflammation. Our previous study suggested PPARg Pro12Ala polymorphism to represent a susceptibility factor for periodontitis in pregnant Japanese women. Several recent papers have drawn attention to a possible link between low bone mineral density (BMD) and periodontitis in postmenopausal women. Since the pathogenesis for both involve bone remodeling, they might share common risk factors such as gene polymorphisms and vitamin D level. The present study investigated possible associations between the PPARgPro12Ala polymorphism, periodontitis, BMD and serum 25(OH)D in postmenopausal Japanese women. MATERIALS AND METHODS: PPARgPro12Ala genotypes of 359 women were determined by PCR-RFLP. BMD and periodontal parameters of each woman were measured. Serum 25(OH)D levels were determined by radioimmunoassay. RESULTS: PPARgPro12Ala polymorphism was not associated with periodontitis or BMD as an independent factor. Serum 25(OH)D was significantly higher in Ala allele carriers compared to non-carriers. Only in the Ala allele carriers, positive correlations were found between mean clinical attachment level and BMD, between BMD and 25(OH)D, and between percentage of sites with probing depth ≥ 4 mm and 25(OH)D. CONCLUSIONS: PPARgPro12Ala polymorphism was not independently associated with periodontitis or BMD. However, the polymorphism might be a modulator of the relationship between the two conditions in postmenopausal Japanese women.

Contribution of gene polymorphisms on 3p25 to salivary gland carcinoma, ameloblastoma, and odontogenic keratocyst in the Chinese Han population.

OBJECTIVE: This study aimed to investigate the contribution of gene polymorphisms in 3p25 to salivary gland carcinoma (SGC), ameloblastoma (AM), and odontogenic keratocyst (OKC) in the Chinese Han population. STUDY DESIGN: Sixteen tag-single nucleotide polymorphisms (SNPs) within 5 genes (SYN2, TIMP4, PPARG, RAF1, and IQSEC1) in 3p25 were genotyped in 411 individuals with or without SGC, AM, and OKC. Genotype, clinical phenotype, and bioinformatics analyses were performed to evaluate the function of candidate SNPs. RESULTS: SYN2-rs3773364, TIMP4-rs3755724, PPARG-rs10865710, and PPARG-rs1175544 were related to decreased SGC susceptibility, whereas IQSEC1-rs2600322 and IQSEC1-rs2686742 decreased and increased AM risk, respectively. Stratification analysis revealed that the significance of the identified SNPs was stronger in females or individuals younger than 46 years in SGC. PPARG-rs10865710 and PPARG-rs1175544 were associated with lower lymph node metastasis. SYN2-rs3773364 and PPARG-rs1175544 were associated with favorable SGC patient survival. Functional assessments linked PPARG-rs1175544 to PPARG expression regulation. Linkage disequilibrium analysis revealed a haplotype (SYN2-rs3773364-A, TIMP4-rs3817004-A, and TIMP4-rs3755724-C) associated with decreased susceptibility to SGC. Generalized multifactor dimensionality reduction analysis indicated the gene-gene interactions among IQSEC1, TIMP4, and PPARG in SGC, AM, and OKC progression. CONCLUSIONS: These variants play important roles in the progression of SGC, AM, and OKC in the Chinese Han population and may be considered biomarkers for early diagnosis and prognosis prediction.

Gene expression profile of dental pulp cells during differentiation into an adipocyte lineage.

Gene regulation during in vitro differentiation into adipocytes was examined in rat dental pulp-derived cells. Insulin, 3-isobutyl-1-methylxanthine, and dexamethasone were added to induce adipogenesis. Cells containing lipid droplets were observed after induction as in 3T3 L1 cells. Rat dental pulp-derived cells showed their potential to differentiate into adipocytes in vitro. In both types of cells, the pluripotent markers Oct-3/4 and Sox2 were downregulated during differentiation, whereas the expression of Nanog was not significantly changed during differentiation. Interestingly, in the dental pulp-derived cells, the level of Oct-3/4 was transiently induced at 1 week after induction and then significantly decreased during differentiation. Based on the expression profiles determined using GeneChip Arrays, 3418 probes across 10 clusters showed a difference in expression at 1, 2, and 3 weeks after induction versus before induction. Notably, genes in the PPAR signaling pathway including Pparγ, Fabp4, and the C/EBP family were upregulated by more than 3-fold. Upregulation of the PPAR pathways seems to be a critical signal transduction pathway in this differentiation system. These findings indicate that dental pulp-derived cells are a potential source of adipogenic cells, and their gene expression profile could be useful in future regenerative medicine applications.

PPARγ transcription effect on naturally occurring O-prenyl cinnamaldehydes and cinnamyl alcohol derivatives.

Background: PPARγ is known to be a key regulator of metabolism and storage of lipids and glucose and to be implicated in the pathology of severe syndromes like obesity, diabetes, atherosclerosis and cancer. Methods: As a continuation of the authors' studies on oxyprenylated secondary metabolites as effective PPARγ agonists, the authors describe herein the chemical synthesis of natural O-prenyl cinnamaldehydes and cinnamyl alcohols and preliminary data on their in vitro effects on PPARγ transcription. Results: Among the panel of eight compounds tested, three - namely, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)acrylaldehyde, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)prop-2-en-1-ol and boropinal A - exerted activity in a dose-dependent manner. Conclusion:O-prenyl cinnamaldehydes and cinnamyl alcohols have the potential to effectively interact with PPARγ receptor.

Porphyromonas gingivalis exacerbates the progression of fatty liver disease via CD36-PPARγ pathway.

Periodontal diseases have been reported to have a multidirectional association with metabolic disorders. We sought to investigate the correlation between periodontitis and diabetes or fatty liver disease using HFD-fed obese mice inoculated with P. gingivalis. Body weight, alveolar bone loss, serological biochemistry, and glucose level were determined to evaluate the pathophysiology of periodontitis and diabetes. For the evaluation of fatty liver disease, hepatic nonalcoholic steatohepatitis (NASH) was assessed by scoring steatosis, inflammation, hepatocyte ballooning and the crucial signaling pathways involved in liver metabolism were analyzed. The C-reactive protein (CRP) level and NASH score in P. gingivalis-infected obese mice were significantly elevated. Particularly, the extensive lobular inflammation was observed in the liver of obese mice infected with P. gingivalis. Moreover, the expression of metabolic regulatory factors, including peroxisome proliferator-activated receptor γ (Pparγ) and the fatty acid transporter Cd36, was up-regulated in the liver of P. gingivalis-infected obese mice. However, inoculation of P. gingivalis had no significant influence on glucose homeostasis, insulin resistance, and hepatic mTOR/AMPK signaling. In conclusion, our results indicate that P. gingivalis can induce the progression of fatty liver disease in HFD-fed mice through the upregulation of CD36-PPARγ axis. [BMB Reports 2021; 54(6): 323-328].

Interleukin-4 improves white matter integrity and functional recovery after murine traumatic brain injury via oligodendroglial PPARγ.

Long-term neurological recovery after severe traumatic brain injury (TBI) is strongly linked to the repair and functional restoration of injured white matter. Emerging evidence suggests that the anti-inflammatory cytokine interleukin-4 (IL-4) plays an important role in promoting white matter integrity after cerebral ischemic injury. Here, we report that delayed intranasal delivery of nanoparticle-packed IL-4 boosted sensorimotor neurological recovery in a murine model of controlled cortical impact, as assessed by a battery of neurobehavioral tests for up to five weeks. Post-injury IL-4 treatment failed to reduce macroscopic brain lesions after TBI, but preserved the structural and functional integrity of white matter, at least in part through oligodendrogenesis. IL-4 directly facilitated the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-producing oligodendrocytes in primary cultures, an effect that was attenuated by selective PPARγ inhibition. IL-4 treatment after TBI in vivo also failed to stimulate oligodendrogenesis or improve white matter integrity in OPC-specific PPARγ conditional knockout (cKO) mice. Accordingly, IL-4-afforded improvements in sensorimotor neurological recovery after TBI were markedly impaired in the PPARγ cKO mice compared to wildtype controls. These results support IL-4 as a potential novel neurorestorative therapy to improve white matter functionality and mitigate the long-term neurological consequences of TBI.

Suppressor Effects of Sodium Pentaborate Pentahydrate and Pluronic F68 on Adipogenic Differentiation and Fat Accumulation.

Obesity is a major public health problem worldwide and a risk factor for certain diseases, including cardiovascular disease, diabetes, cancer, and depression. Unfortunately, currently available anti-obesity drugs have failed in the long-term maintenance of weight control. It has been a challenge to design novel drugs that could potentially treat obesity or prevent uncontrolled weight-gain which lies underneath the pathology of obesity. Since obesity in a way is a consequence of the accumulating new mature adipocytes from undifferentiated precursors which is a process also termed as adipogenesis, drugs that might control adipogenesis could be beneficial for the treatment of obesity. In the current study, combined effect of sodium pentaborate pentahydrate (NaB) and pluronic F68 on adipogenic differentiation was examined by administering various combinations of the two agents to human adipose-derived stem cells (hADSCs) in in vitro. Immunocytochemistry and quantitative RT-PCR were performed to evaluate the levels of adipogenesis-promoting genes such as peroxisome proliferator-activated receptor-γ (PPARγ), fatty acid binding protein (FABP4), and adiponectin. Results indicated that expressions of all these three genes were restrained. Furthermore, Oil Red O staining revealed that lipid vesicle formation was reduced in hADSCs treated with differentiation medium containing NaB/F68 combination. Finally, expression levels of Hippo pathway kinases Lats2, MST1, and scaffold protein Sav1 were reduced in these cells, suggesting a possible link between Hippo pathway-dependent downregulation of PPARγ and the NaB/F68 treatment. Herein, we showed that combination of NaB and F68 curtails adipocyte differentiation by inhibiting the adipogenic transcriptional program leading to a decrease in lipid accumulation in adipocytes even at very low doses, thereby uncovered a striking opportunity to use this combination in obesity treatment.