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Protein overexpression of toll-like receptor 4 and myeloid differentiation factor 88 in oral squamous cell carcinoma and clinical significance.

ABSTRACT: Oral squamous cell carcinoma (OSCC) is the most common type of malignancy of the head and neck. In the present study, the expression of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) was evaluated in 55 OSCC tissues and their corresponding adjacent tissues using immunohistochemistry and reverse-transcription quantitative PCR. The results indicated that TLR4 and MyD88 were overexpressed in OSCC. Furthermore, high expression of MyD88 was negatively associated with a poor degree of differentiation, recurrence and metastasis of the tumor and was positively associated with underlying disease, including hypertension, heart disease and diabetes mellitus. Furthermore, high expression of TLR4 was positively associated with a long growth time of the tumor. In conclusion, the present study evaluated the expression levels of TLR4 and MyD88 in OSCC, as well as the association between them and clinicopathological factors, to provide markers for the prognosis and treatment of OSCC. These two genes may serve as biomarkers to optimize OSCC treatment, setting a new direction for stratifying patients and developing precise and personalized treatment regimens; the TLR4/MyD88 pathway may serve as a potential therapeutic target in the future.

SUBMITTER: Li L

PROVIDER: S-EPMC8456488 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo investigate the effect of Taohong Siwu decoction (, TSD) on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.MethodsSixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group: control group, model group, atorvastatin group (AT, 2.0 mg/kg), and TSD groups (20, 10, 5 g/kg) after 7 d of acclimation. The model of atherosclerosis was successfully established except the control group by high fat diet (HFD) and vitamin D2. Biochemical analyzers were used to detect the levels of triglyceride (TG), total cholestero (TC), low density lipoprotein-cholesterol (LDL-C) and high density lipid-cholesterol (HDL-C) in blood lipid. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were determined by enzyme-linked immunosorbent assay. Sudan IV staining and Hematoxylin and eosin staining (HE staining) were performed to observe the pathological changes in aortic tissue. Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins. The expression of target proteins was further detected by quantitative real time polymerase chain reaction (qRT-PCR) and Western blot analysis.ResultsThe results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma. Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor (TLR4), myeloid differentiation primary response protein 88 (MyD88), and nuclear factor kappa-B (NF-κB). The results of qRT-PCR and Western blot analysis showed that the mRNA and protein expressions of TLR4, MyD88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.ConclusionsTSD can ameliorate atherosclerosis in rats, and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/MyD88/NF-κB signal pathway.

Project description:Partial hepatectomy (PH) consistently results in an early increase of circulating interleukin-6 (IL-6), which is thought to play a major role in liver regeneration. Activation of this cytokine after PH requires the adaptor protein, MyD88, but the specific MyD88-related receptors involved remain unidentified. It is also unknown whether the magnitude of IL-6 elevation determines the extent of subsequent hepatocyte proliferation. Here, we uncovered artifacts in the assessment of circulating IL-6 levels when using cardiac puncture in mice after PH. By using retro-orbital bleed sampling, we show that the circulating levels of IL-6 after PH were not directly correlated with the extent of hepatocyte DNA synthesis in individual mice. The IL-6 increase after PH was attenuated in all lipopolysaccharide-hyporesponsive mouse strains studied (e.g., C3H/HeJ, Tlr4 null, Cd14 null, Tlr2,4,9 null, and Tlr2,4-Caspase1 null) and was severely abrogated in Myd88 null mice. Despite attenuated IL-6 levels, Tlr4 null mice showed normal signaling downstream of IL-6 and normal hepatocyte proliferation. In contrast, Myd88 null mice showed severe impairments in signal transducer and activator of transcription 3 phosphorylation and Socs3 induction, but had enhanced and prolonged extracellular signal-related kinase 1 and 2 phosphorylation in the first 6 hours after PH. Unexpectedly, these changes were associated with accelerated initiation of hepatocyte proliferation, as assessed by hepatocyte bromodeoxyuridine incorporation, phospho-histone H3 immunostaining, and cyclin E and A protein expression.TLR-4 signaling contributes to IL-6 activation after PH, but the Tlr4-independent component appears sufficient for ensuring intact signaling downstream of IL-6. The lack of correlation between IL-6 levels and hepatocyte proliferation after PH, and the accelerated start of hepatocyte proliferation in Myd88 null mice despite abrogated cytokine activation, may highlight relevant antiproliferative effects of IL-6 signaling, possibly via Socs3, in the regulation of liver regeneration.

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Protein overexpression of toll-like receptor 4 and myeloid differentiation factor 88 in oral squamous cell carcinoma and clinical significance.

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