Inhibition of microRNA-122 alleviates pyroptosis by targeting dual-specificity phosphatase 4 in myocardial ischemia/reperfusion injury.

Pyroptosis is a type of programmed cell death that induces myocardial ischemia-reperfusion injury (I/RI), which leads to cardiac dysfunction and even lethal reperfusion injury. MiR-122 is a liver-specific miRNA associated with coronary heart disease, but its role in pyroptosis activation in myocardial I/RI remains unclear. Thus, this study aimed to determine whether miR-122 inhibition exerts myocardial I/RI protection in in vivo and in vitro models. An I/RI model was established in vivo using C57BL/J6 male mice. MiR-122 expression was upregulated in the heart tissues from the I/RI group. Quantitative results of echocardiography parameters showed that miR-122 inhibition improved cardiac function and downregulated interleukin (IL)-1ß, IL-18, caspase 1, and caspase 11. However, pretransfection with recombinant adeno-associated virus type 9 encoding a DUSP4-specific siRNA (AAV9-siDUSP4) blocked the protective effects of miR-122 inhibition. A hypoxia/reoxygenation (H/R) model was established to mimic the I/R condition in vitro using H9C2 cells. Results showed that miR-122 inhibition increased superoxide dismutase activity (SOD) and cell viability and decreased malondialdehyde (MDA) level, IL-1ß, IL-18, caspase 1, caspase 11, and cell death. These protective effects were abolished by transfection with DUSP4-specific siRNA. In summary, miR-122 expression is upregulated in I/RI, and miR-122 inhibition alleviates I/RI by suppressing pyroptosis through targeting DUSP4. Thus, miR-122 may be a novel therapeutic target for treating myocardial I/RI.

LIPG is a novel prognostic biomarker and correlated with immune infiltrates in lung adenocarcinoma.

BACKGROUND: Although many biomarkers for lung adenocarcinoma (LUAD) have been identified, their specificity and sensitivity remain unsatisfactory. Endothelial lipase gene (LIPG) plays an important role in a variety of cancers, but its role in lung adenocarcinoma remains unclear. METHODS: TCGA, GEO, K-M plotter, CIBERSORT, GSEA, HPA, and GDSC were used to analyze LIPG in LUAD. Data analysis was mainly achieved by R 4.0.3. RESULTS: The expression of LIPG in LUAD tissues was higher than that in adjacent normal tissues, especially in women, patients aged >65 years, and those with lymph node metastasis. High expression predicted a poor prognosis. The results of enrichment analysis suggest that LIPG may exert profound effects on the development of LUAD through multiple stages of lipid metabolism and immune system regulation. In addition, LIPG expression was significantly correlated with the expression levels of multiple immune checkpoint genes and the abundance of multiple immune infiltrates, including the activated memory CD4 T cell, M1 macrophage, neutrophil, plasma cells, and T follicular helper (Tfh) cells in the LUAD microenvironment content. At the same time, patients with high LIPG expression respond well to a variety of antitumor drugs and have a low rate of drug resistance. CONCLUSIONS: LIPG is a prognostic marker and is associated with lipid metabolism and immune infiltration in LUAD.

Immune checkpoint inhibitor (ICI) combination therapy compared to monotherapy in advanced solid cancer: A systematic review.

Aim: To evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) two-drug combination therapy in patients with advanced malignancy. Methods: We searched PubMed, PMC, EMBASE, EBSCO, Cochrane Central Register of Controlled Trials (CENTRAL), American Society of Clinical Oncology (ASCO and the European Society of Medical Oncology (ESMO) to identify primary research reporting the survival outcomes and safety of ICI combination therapy in patients with advanced malignancy. We performed a meta-analysis that evaluated the risk ratio (RR) and its 95% confidence interval (CI) for objective response rates (ORR) and disease control rates (DCR), hazard ratio (HR) and 95% CI for progression-free survival (PFS) and overall survival time (OS), and RR and 95% CI for adverse events (AEs). Results: The final 10 studies (15 cohorts) and 2410 patients were included in the meta-analysis. The ICI combination therapy resulted in improved ORR (RR 1.82, 95% CI 1.31-2.54, p = 0.0004), DCR (RR 1.41, 95% CI 1.29-1.55, p < 0.0001), PFS (HR 0.83, 95% CI 0.74-0.94, p = 0.003) and OS (HR 0.90, 95% CI 0.82-0.98, p = 0.02) in patients with advanced malignant tumors. The incidence of some high grade (≥3) AEs increased, such as fatigue, nausea, diarrhea, colitis, rash, pruritus, elevated transaminase and lipase. Conclusion: Our study showed that ICI combination therapy can improve ORR, DCR, PFS and OS in patients with advanced malignancy. Compared with ICI monotherapy, ICI combination therapy was more likely to induce severe AEs.

Shuangshen granules attenuate lung metastasis by modulating bone marrow differentiation through mTOR signalling inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Shuangshen granules (SSG) have been used to treat lung cancer patients with Qi deficiency and blood stasis for decades. According to clinical experience, SSG indeed improve the quality of life and prolong the survival time of patients with lung cancer after surgery. Each of the components herbs was proved to be effective in anti-cancer therapy. Both the American ginseng and notoginseng belong to genus Panax of the family Araliaceae. Preclinical and clinical studies demonstrated that ginsenosides of them have anti- or preventive activities to various tumors, including cancers of gastric, breast, liver, lung, ovarian, colon, melanoma and leukemia. PDS, such as ginsenoside Rb1, and PTS, such as ginsenoside Rg1 are the main anticancer compositions. Cordyceps sinensis had also been found effective in inhibiting tumour growth and metastasis, especially on tumour associated immune cells, such as macrophages. However, limited information is available regarding potential mechanisms of SSG. Myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, which is closely associated with poor clinical outcomes in cancer patients, may be the target of SSG, which regulate immune function. AIM OF THE STUDY: The present study aimed to explore whether SSG attenuate the differentiation of bone marrow cells (BMCs) into MDSCs by blocking the mTOR signalling, leading to the suppression of lung metastasis. MATERIALS AND METHODS: First, we observed the differentiation of BMCs into MDSCs in vitro and in vivo. BMCs were cultured alone or co-cultured with Lewis lung carcinoma (LLC) cell supernatant in vitro. The effects of different concentrations of SSG, or LLC cell supernatant as a control, on BMC differentiation were detected by flow cytometry and western blotting. Male C57BL/6J mice were subcutaneously implanted with LLC cells, and SSG were administered by gavage twice daily before and after implantation for 7 or 14 days, respectively. The tumour weight, proportion of MDSCs, presence of CD11b+Ly6C+Ly6G- and CD11b+Ly6C+Ly6G+ cells in the bone marrow, blood, and lungs, as well as the expression levels of differentiation-related proteins in the bone marrow and lungs were evaluated. RESULTS: SSG attenuated the differentiation of BMCs into MDSCs, and reduced the fraction of CD11b+Ly6C+Ly6G+ cells by inhibiting the mTOR/S6K1/Myc signalling pathway. In vivo, SSG attenuated differentiation-associated protein markers and reduced the fractions of MDSCs and CD11b+Ly6C+Ly6G+ cells in the bone marrow, blood, and lungs. In addition, SSG administration reduced the tumour weight and inhibited lung metastasis. CONCLUSIONS: SSG may reduce lung metastasis by attenuating BMC differentiation into CD11b+Ly6C+Ly6G+ cells by inhibiting mTOR signalling in vitro and in vivo.

Efficacy and safety of immune checkpoint inhibitors (ICIs) in extensive-stage small cell lung cancer (SCLC).

BACKGROUND: To evaluate the efficacy and safety of an immune checkpoint inhibitor (ICI) combined with chemotherapy in patients with advanced SCLC. METHODS: We searched published randomized-controlled trials (RCTs) to compare the effect of ICIs combined with chemotherapy and chemotherapy alone on SCLC. The extracted data included the number of people who achieved an objective response rate (ORR), the disease control rate (DCR), the hazard ratio (HR) of progression-free survival (PFS), and the overall survival (OS) with 95% confidence intervals (95% CI). RESULTS: Six RCTs involving 2477 patients were included. Compared with chemotherapy alone, patients receiving an ICI combined with chemotherapy had a significantly longer PFS (HR, 0.91; 95% CI 0.88-0.95, p < 0.00001) and OS (HR 0.92; 95% CI 0.89-0.96, p = 0.0001). The ORR increased, but the difference was not statistically significant (RR 1.05; 95% CI 0.99-1.12, p = 0.13). There was no significant difference in the DCR between the two treatment regimens; however, in patients treated with an ICI, fatigue, rashes, diarrhea, and elevated aminotransferase enzymes were significantly increased (p < 0.05). CONCLUSION: ICI combined with chemotherapy is superior to chemotherapy alone with respect to PFS and OS in patients with advanced SCLC.

Corrigendum to "New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy".

[This corrects the article DOI: 10.1155/2016/9720912.].

Biology of the Tongue Coating and Its Value in Disease Diagnosis.

Tongue diagnosis is one of the most important diagnostic tools in traditional Chinese medicine and has been verified for thousands of years. However, its subjectivity and repeatability has been disputed continuously. The tongue coating as the primary coverage of tongue diagnosis provides more objectivity and reproducibility due to its relatively clear molecular basis; it also has a close relationship with many system diseases and may be used as a potentially valuable disease diagnostic tool. This article describes the material basis of the tongue coating, including its biology (epithelial cells, blood cells, vascular endothelial cells, and bacteria) and its metabolites; moreover, we summarize the diseases that are most correlated with the tongue coating. This will be valuable not only for fundamental research of tongue diagnosis but also for the diagnosis and differential diagnosis of disease. We suppose that the tongue coating could serve as a valuable auxiliary diagnosis tool in many diseases, and more research should focus on how to colligate the various information about the tongue and provide useful information for disease diagnosis.

New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy.

The majority of basic and clinical studies have shown a protumor function of tumor-associated macrophages (TAMs), which represent a large proportion of matrix cells. TAMs promote tumorigenesis, and their number is related to the malignancy degree and poor prognosis of many kinds of tumors. Macrophage plasticity makes it possible to change the tumor microenvironment and remodel antitumor immunity during cancer immunotherapy. Increasing numbers of studies have revealed the effects of TAMs on the tumor microenvironment, for example, via promotion of tumor growth and tumorigenesis and through an increase in the number of cancer stem cells or via facilitation of angiogenesis, lymphangiogenesis, and metastasis. Investigators also proposed tumor-immunological treatments targeting TAMs by inhibiting TAM recruitment and differentiation, by regulating TAM polarization, and by blocking factors and pathways associated with the protumor function of TAMs. This comprehensive review presents recent research on TAMs in relation to prediction of poor outcomes, remodeling of the tumor immune microenvironment, and immunological targeted therapies.

Ginsenoside Rg3 Serves as an Adjuvant Chemotherapeutic Agent and VEGF Inhibitor in the Treatment of Non-Small Cell Lung Cancer: A Meta-Analysis and Systematic Review.

Objective. To evaluate ginsenoside Rg3 combined with chemotherapy for non-small-cell lung cancer (NSCLC) treatment, in a meta-analysis. Materials and Methods. We searched PubMed, EMBASE, the Cochrane Library, the China National Knowledge Infrastructure, and the VIP and Wanfang databases for eligible studies. We manually searched for printed journals and relevant textbooks. Statistical analyses were performed with Revman 5.3 and STATA 14.0 software packages. Results. Twenty studies were included. Ginsenoside Rg3 combined with chemotherapy could enhance response, improve disease control, prolong overall survival, improve patient quality of life, reduce leucocyte count decrease due to chemotherapy, reduce vascular endothelial growth factor expression in peripheral blood, and increase CD4/CD8 T cell ratio. Conclusion. Ginsenoside Rg3 combined with chemotherapy may enhance short-term efficacy and overall survival, alleviate treatment-induced side effects, reduce vascular endothelial growth factor expression, increase CD4/CD8 T cell ratio, and serve as a potential therapeutic regimen for NSCLC. However, considering the limitations, the conclusion should be interpreted carefully, and these results need to be confirmed by more high-quality trials.

Association between Tumor Vasculogenic Mimicry and the Poor Prognosis of Gastric Cancer in China: An Updated Systematic Review and Meta-Analysis.

Background. Vasculogenic mimicry can promote tumor growth and metastasis. This article is aimed at conducting a systematic meta-analysis to explore the clinicopathological and prognostic significance of vasculogenic mimicry and gastric cancer. Methods. We searched Pubmed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and the VIP and Wanfang Database for eligible studies. We manually searched for printed journals and relevant textbooks. Subgroups analyses were performed based on the region, manuscript quality, methods of vasculogenic mimicry identification, pathology, and number of patients. Results. Nine studies with 997 patients were included in this meta-analysis. A significant association was observed between vasculogenic mimicry-positive patients and those with gastric cancer with poor overall survival (hazard ratio = 2.24, 95% confidence interval: 1.45-3.47), poor pathological grading, high tumor node metastasis clinical stage, lymph node metastasis, deep tumor invasion, and distant metastasis. Conclusions. Vasculogenic mimicry is associated with a poor prognosis in patients with gastric cancer in China. Clinical studies with large samples are needed worldwide and standardized protocols should be adopted in the future to achieve a better understanding of the relationship between gastric cancer and vasculogenic mimicry.

Shenfu decoction as adjuvant therapy for improving quality of life and hepatic dysfunction in patients with symptomatic chronic heart failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu decoction (SFD) is a water extract of the dried root or root stalk of Panax ginseng C. A. Mey (Asian ginseng) and the lateral root of Aconitum carmichaeli Debx (prepared by Fuzi, Heishunpian in Chinese). It has been used to treat heart failure for over a thousand years. The main active components of SFD, ginsenosides and higenamine, enhance heart contractility, increase the coronary blood supply, improve ischemic myocardial metabolism, scavenge free radicals and protect myocardial ultrastructure. AIM OF THE STUDY: To investigate the effect of SFD on quality of life (QOL) and hepatic function in symptomatic chronic heart failure (CHF) patients. MATERIALS AND METHODS: Forty patients enrolled in the study were randomized into two groups: an SFD group (18 cases) and a control group (22 cases). All the patients received standard heart failure therapy, and the SFD group patients were also treated with Shenfu granules for 14 days as an adjunctive therapy. The effects of SFD on QOL, plasma alanine aminotransferase (ALT) level, cardiac function, left ventricular ejection fraction (LVEF) and tumor necrosis factor-α (TNF-α) level were studied. ALT threshold in hepatic injury are 21U/L for men and 17U/L for women. RESULTS: Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores were improved by 35.27±10.72 vs. 23.87±11.96 in the SFD and control groups respectively (p<0.01). Subgroup analysis of the MLHFQ results demonstrated that both physical and emotional scores were significantly higher in the SFD group (21.00±5.66 vs. 16.75±6.25, p<0.05; 4.64±4.84 vs. 1.13±2.85, p<0.05). Circulating ALT was significantly decreased by SFD (13.3IU/L vs. 0.6IU/L, p<0.01). The grading of cardiac function and LVEF were increased by 1.6±0.5 vs. 1.1±0.3 and 18%±13% vs. 8%±8% in the SFD and control groups respectively (p<0.05 and p<0.05). The level of TNF-α declined more in SFD than control group (64.8±5.0 to 57.6±4.1, p<0.05; vs. 61.6±5.9 vs. 57.7±3.2. p>0.05). CONCLUSION: Compared with standard heart failure treatment, oral SFD as an adjuvant therapy significantly improved QOL and hepatic injury in CHF patients.

Short peptide sequence identity between human viruses and HLA-B27-binding human 'self' peptides.

Molecular mimicry and arthritogenic peptides form the basis of hypotheses that attempt to explain the pathogenesis of HLA-B27-positive ankylosing spondylitis (AS). We propose, therefore, that certain human viruses may possess peptide sequences that mimic HLA-B27-binding human 'self' peptides which might induce or play a significant role in AS. In the present study, we performed bioinformatic analysis, using BLASTP, of the human virus proteome and HLA-B27-binding human 'self' peptides including peptides derived from arthritogenic sequences. We identified that some HLA-B27-binding peptides, particularly those present in proteins of the cartilage and bone, are highly similar to those present in viruses known to cause chronic infection. We suggest that the identical short amino acid sequences shared between human viruses and HLA-B27 peptides may play a role in the pathogenesis of AS.