Periodontitis is a common infectious disease. Recent studies have indicated that the progression of periodontitis may be regulated by interactions between host immunity and periodontopathic bacteria. Although periodontopathic bacteria can destroy periodontal tissue, a dysfunctional host immune response triggered by the bacteria can lead to more severe and persistent destruction. Toll-like receptors (TLRs), a type of pattern recognition receptor (PRR) that recognizes pathogens, have been implicated in host innate immune responses to periodontopathic bacteria and in the activation of adaptive immunity. TLR-targeted drugs may hold promise to treat periodontal disease. This review summarizes recent studies on the role of TLRs in periodontitis and discusses areas needing further research. We believe TLRs may be an effective biomarker for the prevention, diagnosis, and treatment of periodontitis in the near future.

Acute lung injury (ALI) is a pulmonary disorder, which can result in fibrosis of the lung tissues. Recently, mesenchymal stem cell (MSC) has become a novel therapeutic method for ALI. However, the potential mechanism by which MSC regulates the progression of ALI remains blurry. The present study focused on investigating the mechanism underneath MSC-reversed lung injury and fibrosis. At first, we determined that coculture with MSC led to the inactivation of NF-κB signaling and therefore suppressed hedgehog pathway in LPS-treated MLE-12 cells. Besides, we confirmed that MSC-exosomes were responsible for the inhibition of EMT process in LPS-treated MLE-12 cells through transmitting miRNAs. Mechanism investigation revealed that MSC-exosome transmitted miR-182-5p and miR-23a-3p into LPS-treated MLE-12 cells to, respectively, target Ikbkb and Usp5. Of note, Usp5 interacted with IKKβ to hamper IKKβ ubiquitination. Moreover, co-inhibition of miR-182-5p and miR-23a-3p offset the suppression of MSC on EMT process in LPS-treated MLE-12 cells as well as in LPS-injured lungs of mice. Besides, the retarding effect of MSC on p65 nuclear translocation was also counteracted after co-inhibiting miR-182-5p and miR-23a-3p, both in vitro and in vivo. In summary, MSC-exosome transmitted miR-23a-3p and miR-182-5p reversed the progression of LPS-induced lung injury and fibrosis through inhibiting NF-κB and hedgehog pathways via silencing Ikbkb and destabilizing IKKβ.

Receptor interacting protein kinase-1 and -3 (RIP1 and RIP3) are essential mediators of cell death processes and participate in inflammatory responses. Our group recently demonstrated that gene deletion of Rip3 or pharmacological inhibition of RIP1 attenuated pathogenesis of abdominal aortic aneurysm (AAA), a life-threatening degenerative vascular disease characterized by depletion of smooth muscle cells (SMCs), inflammation, negative extracellular matrix remodeling, and progressive expansion of aorta. The goal of this study was to develop drug candidates for AAA and other disease conditions involving cell death and inflammation. We screened 1141 kinase inhibitors for their ability to block necroptosis using the RIP1 inhibitor Necrostatin-1s (Nec-1s) as a selection baseline. Positive compounds were further screened for cytotoxicity and virtual binding to RIP3. A cluster of top hits, represented by GSK2593074A (GSK’074), displayed structural similarity to the established RIP3 inhibitor GSK’843. In multiple cell types including mouse SMCs, fibroblasts (L929), bone marrow derived macrophages (BMDM), and human colon epithelial cells (HT29), GSK’074 inhibited necroptosis with an IC50 of ~3 nM. Furthermore, GSK’074, but not Nec-1s, blocked cytokine production by SMCs. Biochemical analyses identified both RIP1 and RIP3 as the biological targets of GSK’074. Unlike GSK’843 which causes profound apoptosis at high doses (>3 µM), GSK’074 showed no detectable cytotoxicity even at 20 µM. Daily intraperitoneal injection of GSK’074 at 0.93 mg/kg significantly attenuated aortic expansion in two mouse models of AAA (calcium phosphate: DMSO 66.06 ± 9.17% vs GSK’074 27.36 ± 8.25%, P < 0.05; Angiotensin II: DMSO 85.39 ± 15.76% vs GSK’074 36.28 ± 5.76%, P < 0.05). Histologically, GSK’074 treatment diminished cell death and macrophage infiltration in aneurysm-prone aortae. Together, our data suggest that GSK’074 represents a new class of necroptosis inhibitors with dual targeting ability to both RIP1 and RIP3. The high potency and minimum cytotoxicity make GSK’074 a desirable drug candidate of pharmacological therapies to attenuate AAA progression and other necroptosis related diseases.

Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes, as well as the regulation of host genes. Given the important role of microRNAs (miRNAs) in regulating fundamental cellular processes, in this study, we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced, and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected lymphoma cell lines. EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NF-κB activation but independent of functional p53. Furthermore, overexpression of miR-34a was not toxic in several B lymphoma cell lines, and inhibition of miR-34a impaired the growth of EBV-transformed cells. This study identifies a progrowth role for a tumor-suppressive miRNA in oncogenic-virus-mediated transformation, highlighting the importance of studying miRNA function in different cellular contexts.