Purpose: To explore the risk factors that may predict the lymph node metastasis potential of these lesions and new prevention strategies in papillary thyroid carcinoma patients. Materials and Methods: In total, 9,369 papillary thyroid carcinoma patients with 37.17% lymph node metastasis were analyzed (Revman 5.3 software) in this study. The PubMed and Embase databases were used for searching works systematically that were published through to January 22, 2020. Results: Several factors were related to the increased risk of lymph node metastasis in patients with papillary thyroid carcinoma: age <45 years (pooled OR = 1.52, 95% CI = 1.14–2.01, p <0.00001); gender = male (pooled OR = 1.68, 95% CI = 1.51–1.87, p <0.00001); multifocality (pooled OR = 2.05, 95% CI = 1.45–2.89, p <0.0001); tumor size ≥1.0 cm (pooled OR = 3.53, 95% CI = 2.62–4.76, p <0.00001); tumor location at the upper pole 1/3 (pooled OR =1.46, 95% CI = 1.04–2.04, p = 0.03); capsular invasion + (pooled OR = 3.48, 95% CI = 1.69–7.54, p = 0.002); and extrathyroidal extension + (pooled OR = 2.03, 95% CI= 1.78–2.31, p <0.00001). However, tumor bilaterality (pooled OR = 0.85, 95% CI = 0.54–1.34, p = 0.49) and Hashimoto's thyroditis (pooled OR = 1.08, 95% CI = 0.79–1.49, p = 0.62) showed no correlation with lymph node metastasis in papillary thyroid carcinoma patients. Conclusion: The systematic review and meta-analysis defined several significant risk factors of lymph node metastasis in papillary thyroid cancer patients: age (1 cm), tumor location (1/3 upper), capsular invasion, and extra thyroidal extension. Bilateral tumors and Hashimoto's thyroiditis were unrelated to lymph node metastasis in patients with papillary thyroid cancer.

Background. Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC‐related mutant genes have been identified. Whether the BRAF^V600E mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAF^V600E mutation potential of these lesions and new prevention strategies in PTC patients. Methods. A total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAF^V600E mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021. Results. The following variables were associated with an increased risk of BRAF^V600E mutation in PTC patients: age ≥ 45 years (OR = 1.39, 95%CI = 1.21–1.60, p < 0.00001), male gender (OR = 1.13, 95%CI = 0.99–1.28, p = 0.06), multifocality (OR = 1.22, 95%CI = 1.07–1.40, p = 0.004), lymph node metastasis (OR = 1.33, 95%CI = 0.79–2.23, p = 0.28), extrathyroidal extension + (OR = 1.61, 95%CI = 1.06–2.44, p = 0.03), vascular invasion + (OR = 2.04, 95%CI = 1.32–3.15, p = 0.001), and tumor node metastasis stage (OR = 1.61, 95%CI = 1.38–1.88, p < 0.00001). In addition, tumor size (>1 cm) (OR = 0.51, 95%CI = 0.32–0.81, p = 0.005) and distant metastasis (OR = 0.69, 95%CI = 0.22–2.21, p = 0.54) had no association or risk with BRAF^V600E mutation in PTC patients. Conclusion. Our systematic review identified the following significant risk factors of BRAF^V600E mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAF^V600E mutation in PTC patients.

The study aimed to identify the key active components in Silybum marianum (S. marianum) and determine how they protect against nonalcoholic fatty liver disease (NAFLD). TCMSP, DisGeNET, UniProt databases, and Venny 2.1 software were used to identify 11 primary active components, 92 candidate gene targets, and 30 core hepatoprotective gene targets in this investigation, respectively. The PPI network was built using a string database and Cytoscape 3.7.2. The KEGG pathway and GO biological process enrichment, biological annotation, as well as the identified hepatoprotective core gene targets were analyzed using the Metascape database. The effect of silymarin on NAFLD was determined using H&E on pathological alterations in liver tissues. The levels of liver function were assessed using biochemical tests. Western blot experiments were used to observe the proteins that were expressed in the associated signaling pathways on the hepatoprotective effect, which the previous network pharmacology predicted. According to the KEGG enrichment study, there are 35 hepatoprotective signaling pathways. GO enrichment analysis revealed that 61 biological processes related to the hepatoprotective effect of S. marianum were identified, which mainly involved in response to regulation of biological process and immune system process. Silymarin was the major ingredient derived from S. marianum, which exhibited the hepatoprotective effect by reducing the levels of ALT, AST, TC, TG, HDL-C, LDL-C, decreasing protein expressions of IL-6, MAPK1, Caspase 3, p53, VEGFA, increasing protein expression of AKT1. The present study provided new sights and a possible explanation for the molecular mechanisms of S. marianum against NAFLD. GRAPHICAL ABSTRACT

Costunolide, a sesquiterpene isolated from Vladimiria souliei (Franch.) Ling, is known to exhibit anti-inflammatory, anti-viral, and anti-tumor activities. However, the effects of costunolide on liver injury are poorly understood. The current study aimed to investigate the hepatoprotective effects of costunolide against lipopolysaccharide (LPS) and D-galactosamine-induced acute liver injury (ALI) in mice. The results indicated that costunolide (40 mg/kg) could significantly improve the pathological changes of hepatic tissue, and reduced the LPS and D-galactosamine-induced increases of alanine aminotransferase (from 887.24 ± 21.72 to 121.67 ± 6.56 IU/L) and aspartate aminotransferase (from 891.01 ± 45.24 to 199.94 ± 11.53 IU/L) activities in serum. Further research indicated that costunolide significantly reduced malondialdehyde content (from 24.56 ± 1.39 to 9.17 ± 0.25 nmol/ml) and reactive oxygen species (from 203.34 ± 7.68 to 144.23 ± 7.12%), increased the activity of anti-oxidant enzymes superoxide dismutase (from 153.74 ± 10.33 to 262.27 ± 8.39 U/ml), catalase (from 6.12 ± 0.30 to 12.44 ± 0.57 U/ml), and total anti-oxidant capacity (from 0.64 ± 0.06 to 6.29 ± 0.11 U/ml) in hepatic tissues. Western blot results revealed that costunolide may trigger the anti-oxidative defense system by inhibiting kelch-like ECH-associated protein 1 and nuclear factor-related factor 2 (cytosol), increasing nuclear factor-related factor 2 (nucleus), heme oxygenase-1 and NAD (P) H quinone oxidoreductase 1 activity. Moreover, costunolide significantly decreased the protein expression of proinflammatory cytokines including interleukin 1β, interleukin 6, and tumor necrosis factor. Pretreatment with costunolide could reduce the expression of toll-like receptor 4, myeloid differentiation factor 88, p65 (Nucleus), phosphorylated IκB kinase α/β, inhibitor of nuclear factor kappa-B kinase, inhibitor kappa Bα and prevent the expression of phosphorylated inhibitor kappa B kinase which repressed translocation of p65 from cytoplasm to nucleus. In addition, pretreatment with costunolide also inhibited hepatocyte apoptosis by reducing the expression of B-cell lymphoma 2 associated X, cytochrome C, cysteinyl aspartate specific proteinase 3, cysteinyl aspartate specific proteinase 8 and cysteinyl aspartate specific proteinase 9, and by increasing B-cell lymphoma 2. From the above analysis, the protective effects of costunolide against LPS and D-galactosamine-induced ALI in mice may be attributed to its anti-oxidative activity in nuclear factor-related factor 2 signaling pathways, anti-inflammatory suppression in nuclear factor-kappa B signaling pathways, and inhibition of hepatocyte apoptosis. Thus, costunolide may be a potential therapeutic agent in attenuating LPS and D-galactosamine -induced ALI in the future.

Background: Whether metformin is related to nonalcoholic fatty liver disease (NAFLD) is controversial. Our aim was to investigate the relationship between metformin and NAFLD that may predict the metformin potential of these lesions and new prevention strategies in NAFLD patients. Methods: The meta-analysis was analyzed by Revman 5.3 softwares systematically searched for works published through July 29, 2022. Network pharmacology research based on databases, Cytoscape 3.7.1 software and R software respectively. Results: The following variables were associated with metformin in NAFLD patients: decreased of alanine aminotransferase (ALT) level (mean difference [MD] = −10.84, 95% confidence interval [CI] = −21.85 to 0.16, P = .05); decreased of aspartate amino transferase (AST) level (MD = −4.82, 95% CI = −9.33 to −0.30, P = .04); decreased of triglyceride (TG) level (MD = −0.17, 95% CI = −0.26 to −0.08, P = .0002); decreased of total cholesterol (TC) level (MD = −0.29, 95% CI = −0.47 to −0.10, P = .003); decreased of insulin resistance (IR) level (MD = −0.42, 95% CI = −0.82 to −0.02, P = .04). In addition, body mass index (BMI) (MD = −0.65, 95% CI = −1.46 to 0.16, P = .12) had no association with metformin in NAFLD patients. 181 metformin targets and 868 NAFLD disease targets were interaction analyzed, 15 core targets of metformin for the treatment of NAFLD were obtained. The effect of metformin on NAFLD mainly related to cytoplasm and protein binding, NAFLD, hepatitis B, pathway in cancer, toll like receptor signaling pathway and type 2 diabetes mellitus (T2DM). The proteins of hypoxia inducible factor-1 (HIF1A), nuclear factor erythroid 2-related factor (NFE2L2), nitric oxide synthase 3 (NOS3), nuclear receptor subfamily 3 group C member 1 (NR3C1), PI3K catalytic subunit alpha (PIK3CA), and silencing information regulator 2 related enzyme 1 (SIRT1) may the core targets of metformin for the treatment of NAFLD. Conclusion: Metformin might be a candidate drug for the treatment of NAFLD which exhibits therapeutic effect on NAFLD patients associated with ALT, AST, TG, TC and IR while was not correlated with BMI. HIF1A, NFE2L2, NOS3, NR3C1, PIK3CA, and SIRT1 might be core targets of metformin for the treatment of NAFLD.