Pathological mechanisms of amyotrophic lateral Sclerosis.

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

Immune checkpoint blockade therapy mitigates systemic inflammation and affects cellular FLIP-expressing monocytic myeloid-derived suppressor cells in non-progressor non-small cell lung cancer patients.

Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1ß-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1ß in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.

"Open Sesame" to the complexity of pattern recognition receptors of myeloid-derived suppressor cells in cancer.

Pattern recognition receptors are primitive sensors that arouse a preconfigured immune response to broad stimuli, including nonself pathogen-associated and autologous damage-associated molecular pattern molecules. These receptors are mainly expressed by innate myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells. Recent investigations have revealed new insights into these receptors as key players not only in triggering inflammation processes against pathogen invasion but also in mediating immune suppression in specific pathological states, including cancer. Myeloid-derived suppressor cells are preferentially expanded in many pathological conditions. This heterogeneous cell population includes immunosuppressive myeloid cells that are thought to be associated with poor prognosis and impaired response to immune therapies in various cancers. Identification of pattern recognition receptors and their ligands increases the understanding of immune-activating and immune-suppressive myeloid cell functions and sheds light on myeloid-derived suppressor cell differences from cognate granulocytes and monocytes in healthy conditions. This review summarizes the different expression, ligand recognition, signaling pathways, and cancer relations and identifies Toll-like receptors as potential new targets on myeloid-derived suppressor cells in cancer, which might help us to decipher the instruction codes for reverting suppressive myeloid cells toward an antitumor phenotype.

Resveratrol ameliorates liver fibrosis induced by nonpathogenic Staphylococcus in BALB/c mice through inhibiting its growth.

BACKGROUND: The altered gut microbiota is implicated in the pathogenesis of liver fibrosis. Resveratrol is a candidate for the treatment of liver fibrosis, which could ameliorate the dysregulation of gut microbiota in mice. This study aimed to clarify the role and mechanism of resveratrol in gut microbiota during liver fibrosis. METHODS: A mouse model of liver fibrosis induced by CCl4 was conducted to assess the effect of resveratrol on liver fibrosis. The changes of gut microbiota in liver fibrotic mice after resveratrol intervention were assessed using 16S ribosomal RNA sequencing. The mechanism of the gut microbiota dysregulation in liver fibrosis was investigated by Sirius red staining, immunohistochemical assay, bacterial translocation (BT), EUB338 fluorescence in situ hybridization, immunofluorescence, trans-epithelial electrical resistance analysis and paracellular permeability analysis. RESULTS: Resveratrol relieved CCl4-induced liver fibrosis. Besides, resveratrol restrained the gut microbiota Staphylococcus_lentus and Staphylococcus_xylosus in the liver fibrotic mice, and the Staphylococcus_xylosus and Staphylococcus_lentus facilitated the occurrence of BT and the cultures of them enhanced the permeability of intestine. The in vivo assay corroborated that the excessive Staphylococcus_xylosus and Staphylococcus_lentus canceled the protecting effect of resveratrol on liver fibrosis, and Staphylococcus_xylosus or Staphylococcus_lentus alone had a limited impact on the liver injury of normal mice. CONCLUSION: Resveratrol ameliorated liver fibrosis by restraining the growth of Staphylococcus_xylosus and Staphylococcus_lentus.

Predictors for the progression of hepatic cirrhosis to hepatocellular carcinoma under long-term antiviral therapy.

OBJECTIVE: Patients diagnosed with hepatitis B virus (HBV)-related hepatic cirrhosis have the potential for progression to hepatocellular carcinoma (HCC) even while undergoing long-term nucleos(t)ide analog (NA) therapy. This study investigated the predictors for the progression of hepatic cirrhosis to HCC under long-term NA therapy. METHODS: This retrospective study enrolled 898 patients diagnosed with HBV-related hepatic cirrhosis. They received NA therapy between January 2012 and January 2015. The values for the liver stiffness measurement (LSM), laboratory tests, and disease history were collected. The diagnostic specificity of the serum, was assessed with a receiver operating characteristic curve. RESULTS: The overall 2- and 3-year cumulative incidence of HCC was 6.8% and 15.15%, respectively. The LSM values were higher in the patients who had progressed to HCC. The serum PIVKA-II levels were more efficient than the serum AFP levels for the diagnosis of early HCC as the larger area under curve (0.866 vs. 0.687). The multivariate logistic regression analysis showed that HCC occurrence was significantly associated with the baseline LSM value (odds ratio = 1.035). At the end of the study, the death rate for the patients with larger LSM values was higher than that for those with lower LSM values (67.88% vs. 39.90%). CONCLUSION: Patients with HBV-related cirrhosis have the potential for progression to HCC even under long-term NA therapy. The LSM value and the serum PIVKA-II level are significant predictors of HCC occurrence.

Circular RNA hsa_circ_0056836 functions an oncogenic gene in hepatocellular carcinoma through modulating miR-766-3p/FOSL2 axis.

BACKGROUND: Circular RNA (circRNA) remains a tumour-related factor in various biological cells and plays regulatory roles in gene expression. It is a type of non-coding RNA, whereas the function of human circRNA in hepatocellular carcinoma (HCC) is still not clear yet. Our investigation used the HCC cell line to uncover the biological function of hsa_circ_0056836 in the development and progression of hepatocellular carcinoma. RESULTS: The present study showed that hsa_circ_0056836 revealed high expressions in HCC cell lines and tissues compared with corresponding controls. Silencing of Hsa_circ_0056836 decreased cell migration, proliferation and invasion. Silencing of hsa_circ_0056836 inhibited the development of HCC in xenograft nude mice. Mechanistically, we found that hsa_circ_0056836 directly bound to miR-766-3p, thereby alleviating the targeted inhibition of Fos-related antigen 2 (FOSL2). The results of this study indicated that hsa_circ_0056836 is a novel oncogenic RNA of vast potential as a tumor biomarker. CONCLUSION: In summary, the hsa_circ_0056836 / miR-766-3p / FOSL2 axis may serve as a promising strategy for HCC treatment. METHOD: First, the expressions of hsa_circ_0056836 in HCC tissues and corresponding para-cancerous tissues as well as in HCC cell lines and normal hepatocytes THLE-3 were detected by RT-PCR. Subcellular localization of hsa_circ_0056836 was confirmed by FISH. To detect the association between hsa_circ_0056836 and miR-766-3p, AGO2-RIP and Luciferase reporter assay were adopted. Loss of function study was applied to assess the role of hsa_circ_0056836 in HCC and to determine tumorigenesis in nude mice.

p65/miR-23a/CCL22 axis regulated regulatory T cells recruitment in hepatitis B virus positive hepatocellular carcinoma.

BACKGROUND: CCL22 played critical roles in Tregs recruitment. The upstream regulators modulating CCL22 in hepatocellular carcinoma (HCC) were not clearly understood. METHODS: MiR-23a, p-p65, p65, CCL22, and Foxp3 levels were monitored by RT-qPCR and western blotting. Immunofluorescence assay was used to perform the costaining of Foxp3 and CD4 on liver tissues. Transwell assay was applied to evaluate the migration ability of Tregs. Dual-luciferase assay was performed to determine relationship of miR-23a/CCL22 and p65/miR-23a. Chromatin immunoprecipitation (ChIP) was applied to detect the direct binding of p65 to miR-23a promoter. Xenograft tumor models were developed to investigate the functions of p65 and miR-23a in vivo. RESULTS: HBV infection was associated with reduced survival and increased Tregs recruitment in HCC patients. MiR-23a was decreased, whereas p65, CCL22, and Foxp3 were increased in HBV+ tumors. MiR-23a was inversely correlated with CCL22 and Foxp3 expression in HCC. MiR-23a directly targeted CCL22 3'UTR, leading to CCL22 reduction and attenuated Tregs recruitment. Meanwhile, p65 functioned as a transcription repressor of miR-23a by directly binding to its promoter. Inhibition of p65 induced miR-23 expression, leading to less CCL22 expression and Tregs recruitment in vitro. CCL22 was the indispensable effector underlying p65/miR-23a axis and Tregs recruitment. MiR-23a inhibitor promoted xenografted tumor growth accompanying with upregulation of CCL22, whereas p65 inhibition exerted opposite effects. CONCLUSION: Blockage of p65 disinhibited miR-23a expression, leading to CCL22 reduction and repress Tregs recruitment. Targeting p65/miR-23a/CCL22 axis was a novel approach for HBV+ HCC treatment.

Circular RNA MYLK promotes hepatocellular carcinoma progression by increasing Rab23 expression by sponging miR-362-3p.

BACKGROUND: CircRNA myosin light chain kinase (circRNA MYLK) has been shown to promote the progression of various tumor diseases. The purpose of this study was to explore the potential molecular mechanism of circMYLK in hepatocellular carcinoma (HCC). METHODS: The quantitative Real-Time PCR (qRT-PCR) was used to measure the expressions of circMYLK, miR-362-3p and Rab23 in HCC tissues and cell lines. Huh7 and Hep3B cells were selected to explore the role of circMYLK in proliferation, invasion and migration of HCC cells in vitro. The interaction among circMYLK, miR-362-3p and Rab23 was investigated by biological information and dual luciferase gene reporter assay. The effect of circMYLK on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. RESULTS: CircMYLK was highly expressed in HCC tissues and cell lines, which was associated with poor prognosis in HCC patients. In addition, knockdown of circMYLK remarkably inhibited the proliferation, invasion, and migration of Huh7 and Hep3B cells. MiR-362-3p was a direct target of circMYLK, and Rab23 was a direct target gene of miR-362-3p. Meanwhile, circMYLK was negatively correlated with the expression of miR-362-3p and positively correlated with Rab23 expression. Moreover, either overexpressed miR-362-3p or silencing Rab23 could observably suppress the enhanced proliferation, invasion, and migration induced by circMYLK in Huh7 and Hep3B cells. Finally, knockdown of circMYLK and overexpressed miR-362-3p could suppress the expression of Rab23, thus inhibiting the growth and proliferation of Hep3B cells in vivo. CONCLUSION: circMYLK promotes the occurrence and development of HCC by regulating the miR-362-3p/Rab23 axis, which provides a novel direction and theoretical basis for the early diagnosis and treatment of HCC.

Genetic Effects and Heterosis of Yield and Yield Component Traits Based on Gossypium Barbadense Chromosome Segment Substitution Lines in Two Gossypium Hirsutum Backgrounds.

We hybridized 10 chromosome segment substitution lines (CSSLs) each from two CSSL populations and produced 50 F1 hybrids according to North Carolina Design II. We analyzed the genetic effects and heterosis of yield and yield components in the F1 hybrids and parents in four environments via the additive-dominance genetic model. Yield and yield components of the CSSLs were controlled by combined additive and dominance effects, and lint percentage was mainly controlled by additive effects, but boll weight, boll number, seedcotton yield and lint yield were mainly controlled by dominance effects. We detected significant interaction effects between genetics and the environment for all yields traits. Similar interactions were detected between two CSSL populations (Pop CCRI 36 and Pop CCRI 45). Significant positive mid-parent heterosis was detected for all yield traits in both populations, and significant positive better-parent heterosis was also detected for all yield traits except lint percentage. The differences among parents were relatively small, but significant heterosis was detected for yield and yield components. Therefore, the relationship between heterosis and genetic distance for yield traits is complicated and requires further study. These CSSLs represent useful tools for improving yield and yield components in cotton.