Comparison of the therapeutic effects of mesenchymal stem cells derived from human dental pulp (DP), adipose tissue (AD), placental amniotic membrane (PM), and umbilical cord (UC) on postmenopausal osteoporosis.

Background: Osteoporosis is a systemic bone disease characterized by bone loss and microstructural degeneration. Recent preclinical and clinical trials have further demonstrated that the transplantation of mesenchymal stem cells (MSCs) derived from human adipose tissue (AD), dental pulp (DP), placental amniotic membrane (AM), and umbilical cord (UC) tissues can serve as an effective form of cell therapy for osteoporosis. However, MSC-mediated osteoimmunology and the ability of these cells to regulate osteoclast-osteoblast differentiation varies markedly among different types of MSCs. Methods: In this study, we investigated whether transplanted allogeneic MSCs derived from AD, DP, AM, and UC tissues were able to prevent osteoporosis in an ovariectomy (OVX)-induced mouse model of osteoporosis. The homing and immunomodulatory ability of these cells as well as their effects on osteoblastogenesis and the maintenance of bone formation were compared for four types of MSCs to determine the ideal source of MSCs for the cell therapy-based treatment of OVX-induced osteoporosis. The bone formation and bone resorption ability of these four types of MSCs were analyzed using micro-computed tomography analyses and histological staining. In addition, cytokine array-based analyses of serological markers and bioluminescence imaging assays were employed to evaluate cell survival and homing efficiency. Immune regulation was determined by flow cytometer assay to reflect the mechanisms of osteoporosis treatment. Conclusion: These analyses demonstrated that MSCs isolated from different tissues have the capacity to treat osteoporosis when transplanted in vivo. Importantly, DP-MSCs infusion was able to maintain trabecular bone mass more efficiently with corresponding improvements in trabecular bone volume, mineral density, number, and separation. Among the tested MSC types, DP-MSCs were also found to exhibit greater immunoregulatory capabilities, regulating the Th17/Treg and M1/M2 ratios. These data thus suggest that DP-MSCs may represent an effective tool for the treatment of osteoporosis.

A breakthrough in periodontitis treatment: Revealing the pharmacodynamic substances and mechanisms of Kouqiangjie formula.

ETHNOPHARMACOLOGY RELEVANCE: Periodontitis, a complex inflammatory disease, significantly affects people's lives. Traditional Chinese multi-herbal formulas, composed of various herbs, exhibit their therapeutic efficacy holistically. Kouqiangjie Formula (KQJF), comprising 12 herbs including Rhizoma smilacis glabrae, Polygonatum sibiricum Delar. ex Redoute, Taraxacum mongolicum Hand.-Mazz, etc., has been clinically proven to effectively treat periodontitis. However, the potential active substances conferring these effects and their mechanisms of action remain unclear. AIM OF THE STUDY: The current investigation endeavours to utilize Ultra Performance Liquid Chromatography Quadrupole Time of Flight Mass Spectrometry (UPLC-Q-TOF-MS), network pharmacology, and in vivo animal experiment confirmation to explore the plausible bioactive compounds and operational mechanisms underpinning KQJF's therapeutic impact on periodontitis. MATERIALS AND METHODS: Using the UPLC-Q-TOF-MS technique, we deciphered the chemical constituents of KQJF. Network pharmacology was employed to earmark key bioactive elements, forecast principal targets, and operational pathways which were later substantiated through molecular docking. Experimental validations were carried out in a periodontitis animal model using a range of techniques, including micro-CT, H&E staining, qRT-PCR, and protein blotting procedures, providing comprehensive verification of our initial assumptions. RESULTS: Utilizing UPLC-Q-TOF-MS, we characterized 87 individual chemical constituents in KQJF. Network pharmacology revealed that 14 components, including senkyunolide A, glycycoumarin, licoflavonol, glycyrin, senkyunolide I, and senkyunolide H, form the key therapeutic basis of KQJF in targeting periodontitis. Significant targets and pathways were discerned as AKT1, MMP9, JUN, PTGS2, CASP3, TLR4, IL1ß, BCL2, PPARG, and pathways such as the TNF signaling pathway, NF-κB signaling pathway, osteoclast differentiation, and Wnt signaling pathway. Molecular docking demonstrated robust binding activity between these crucial targets and the key active ingredients. In vivo experimentation corroborated that, compared with the model group, KQJF significantly ameliorated symptoms and micro-CT imaging parameters of periodontitis in the rat model, down-regulating the expression of AKT1, MMP9, JUN, PTGS2, CASP3, TLR4, and IL1ß, while up-regulating the expression of BCL2 and PPARG. CONCLUSION: In summary, this study has pioneered a comprehensive exploration of the potential therapeutic constituents, targets, and mechanisms of KQJF for periodontitis treatment, adopting a synergistic strategy of "chemical component analysis-network pharmacology screening-in vivo animal experiment validation". This provides experimental evidence for the clinical application of KQJF and further in-depth research. Additionally, it presents an effective strategy for the research of other Chinese herbal formulations.

Dkk-1-TNF-α crosstalk regulates MC3T3E1 pre-osteoblast proliferation and differentiation under mechanical stress through the ERK signaling pathway.

The study aims to explore the role of the ERK signaling pathway in the crosstalk between Dkk-1 and TNF-α in MC3T3E1 pre-osteoblasts under cyclic tensile/compressive stress. A forced four-point bending system was used to apply cyclic uniaxial tensile/compressive strain (2000 µ, 0.5 Hz) to MC3T3E1 cells. Dkk-1 and TNF-α expression were upregulated in MC3T3E1 cells under compressive strain. Cell proliferation, the cell cycle, osteogenesis-related gene (Wnt5a, Runx2, Osterix) expression, ß-catenin expression, and the p-ERK/ERK ratio were significantly enhanced, whereas apoptosis, the RANKL/OPG ratio, and TNF-α expression were significantly attenuated, by Dkk-1 silencing. Dkk-1 expression increased and the effects of Dkk-1 silencing were reversed when exogenous TNF-α was added. Mechanically, TNF-α crosstalked with Dkk-1 through ERK signaling in MC3T3E1 cells. ERK signaling blockade impaired Dkk-1-induced TNF-α expression and TNF-α-mediated Dkk-1 expression. Dkk-1 and TNF-α crosstalked, partially through ERK signaling, in MC3T3E1 cells under compressive/tensile strain, synergistically modulating various biological behaviors of the cells. These findings not only provide mechanical insight into the cellular events and molecular regulation of orthodontic tooth movement (OTM), but also aid the development of novel strategies to accelerate OTM.

COX-2/PGE2/VEGF signaling promotes ERK-mediated BMSCs osteogenic differentiation under hypoxia by the paracrine action of ECs.

Understanding the crosstalk between endothelial cells (ECs) and bone-marrow mesenchymal stem cells (BMSCs) in response to hypoxic environments and deciphering of the underlying mechanisms are of great relevance for better application of BMSCs in tissue engineering. Here, we demonstrated that hypoxia promoted BMSCs proliferation, colony formation, osteogenic markers expression, mineralization, and extracellular signal-regulated protein kinase (ERK) phosphorylation, and that PD98059 (ERK inhibitor) blocked hypoxia-induced osteogenic differentiation. Hypoxia enhanced ECs migration, cyclooxygenase 2 (COX-2) and integrin αvß3 expression, and prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF) secretion. NS398 (selective COX-2 inhibitor) and LM609 (integrin αvß3 specific inhibitor) impaired the ECs response to hypoxia, and exogenous PGE2 partially reversed the effects of NS398. BMSCs: ECs co-culture under hypoxia upregulated BMSCs osteogenesis and ERK phosphorylation, as well as ECs migration, integrin αvß3 expression, and PGE2 and VEGF secretion. NS398 (pretreated ECs) lessened PGE2, VEGF concentrations of the co-culture system. NS398-treated ECs and AH6809 (combined EP1/2 antagonist)/L-798106 (selective EP3 antagonist)/L-161982 (selective EP4 antagonist)/SU5416 [VEGF receptor (VEGFR) inhibitor]-treated BMSCs impaired the co-cultured ECs-induced enhancement of BMSCs osteogenic differentiation. In conclusion, hypoxia enhances BMSCs proliferation and ERK-mediated osteogenic differentiation, and augments the COX-2-dependent PGE2 and VEGF release, integrin αvß3 expression, and migration of ECs. COX-2/PGE2/VEGF signaling is involved in intercellular BMSCs: ECs communication under hypoxia.

Implications of lysyl oxidase-like protein 3 expression in the periodontium of diabetic rats

Abstract Objectives Diabetes has been strongly associated with periodontal diseases. The periodontal ligament (PDL) has an abundant extracellular matrix (ECM). Lysyl oxidases (LOXs) are closely associated with various diseases caused by abnormal ECM functions, however, the role of LOXs in periodontal diseases induced by diabetes remains unclear. Methodology In this study, 8-week-old Zucker diabetic fatty rats were used to establish a type 2 diabetes mellitus (T2DM) model. After 9 and 16 weeks, hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical staining were performed. Results After 9 weeks, loose collagen fibers were found in the interradicular area of the diabetic group, in opposition to the control group. There were no significant differences in LOX expression between the diabetic and control groups (p>0.05). However, after 16 weeks, the diabetic group presented a disordered arrangement of the PDL, showing decreased collagen content and significantly increased lysyl oxidase-like protein 3 (LOXL3) expression when compared with the control group (p<0.05). This suggests that LOXL3 plays a significant role in periodontal histopathological changes in diabetic rats. Conclusion Our study showed elevated LOXL3 expression in the PDL of diabetic rats after 16 weeks, suggesting that LOXL3 may be involved in the occurrence and development of periodontal histopathological changes in diabetic rats. LOXL3 could be further used as an indicator for the early diagnosis of diabetic periodontitis in T2DM patients in clinical settings.

Association between Helicobacter pylori infection and the risk of colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: The existing evidence on the relationship between Helicobacter pylori infection and the risk of colorectal cancer is inconsistent. We conducted a systematic review with a meta-analysis to explore this relationship and to determine whether the relationship varies according to the study characteristics. METHODS: We searched the PubMed, OVID, EMBASE database, and the reference lists of pertinent articles published up to October 2019 by 2 researchers independently. Summary odds ratios (OR) with their 95% confidence intervals (CIs) were estimated using a random-effects model. RESULTS: Forty seven studies including 17,416 cases of colorectal cancer (CRC) and 55,811 cases of control were included. Overall, H. pylori infection was associated with an increased risk of CRC (OR = 1.70 95% CI 1.64-1.76, I = 97%), although there was significant heterogeneity among the studies. Subgroup analysis revealed that the positive correlation might vary by the design of study conducted. CONCLUSION: This meta-analysis demonstrates a positive association between H. pylori infection and the risk of colorectal cancer.

The TF-miRNA Coregulation Network in Oral Lichen Planus.

Oral lichen planus (OLP) is a chronic inflammatory disease that affects oral mucosa, some of which may finally develop into oral squamous cell carcinoma. Therefore, pinpointing the molecular mechanisms underlying the pathogenesis of OLP is important to develop efficient treatments for OLP. Recently, the accumulation of the large amount of omics data, especially transcriptome data, provides opportunities to investigate OLPs from a systematic perspective. In this paper, assuming that the OLP associated genes have functional relationships, we present a new approach to identify OLP related gene modules from gene regulatory networks. In particular, we find that the gene modules regulated by both transcription factors (TFs) and microRNAs (miRNAs) play important roles in the pathogenesis of OLP and many genes in the modules have been reported to be related to OLP in the literature.

Effects of Nidus Vespae extract and chemical fractions on glucosyltransferases, adherence and biofilm formation of Streptococcus mutans.

Nidus Vespae (the honeycomb of Polistes olivaceous, P. japonicus Saussure and Parapolybiavaria fabricius) have been extensively used in traditional Chinese medicine, given their multiple pharmacological activities, including antimicrobial, anti-inflammatory, anti-virus, anti-tumor and anesthetic properties. The present study evaluated the anti-glucosyltransferases (GTFs) activity, anti-adherence and anti-biofilm properties of 95% ethanol/water extract, cyclohexane/ethyl acetate, petroleum ether/ethyl acetate and chloroform/methanol fractions of Nidus Vespae. Chloroform/methanol fraction showed a remarkable capacity for inhibiting the adherence of Streptococcus mutans ATCC 25175 to saliva-coated hydroxyapatite disc (S-HA) at sub-MC concentrations. In addition, the Nidus Vespae extract and chemical fractions significantly inhibited the activity of cell-associated and extracellular GTFs at sub-MIC concentrations, and the chloroform/methanol fraction was the most effective one. For the anti-biofilm activity assays, minimum biofilm inhibition concentrations (MBIC50) and minimum biofilm reduction concentrations (MBRC50) were determined using the microdilution method. The chloroform/methanol fraction showed the highest anti-biofilm activities with a MBIC50 of 8mg/ml and a MBRC(50) of 16mg/ml against Streptococcus mutans ATCC 25175. The significant inhibition of GTFs activity and biofilm formation demonstrated by Nidus Vespae shows it to be a promising natural product for the prevention of dental caries.