Background: Colon adenocarcinoma (COAD) is a highly heterogeneous disease, which is the second most common cancer in females and third in males. Collagen type I alpha 2 (COL1A2) has been documented to be involved in the carcinogenesis of multiple tumors; however, the expression and prognostic significance of COL1A2 and its underlying mechanism in COAD remains unclarified. Materials and Methods: The general profile of COL1A2, its expression pattern, and prognostic value were systematically assessed through various bioinformatics tools. The protein level of COL1A2 was verified in COAD patients using immunohistochemistry analysis. In addition, enrichment analyses were performed to explore the possible regulatory pathways of COL1A2 in COAD. Results: The mRNA and protein levels of COL1A2 were significantly increased in COAD than that in normal tissues (P < 0.05). The COL1A2 expression tended to increase along with cancer stages and nodal metastasis status in COAD, while the promoter methylation levels of COL1A2 might negatively related to its mRNA expression. Survival analysis showed that COL1A2 was a reliable predictor for distinguishing the status of disease-specific survival (DSS), overall survival (OS), and progression-free survival (PFS), and might serve as a robust independent prognostic biomarker for DSS and OS in COAD patients (P < 0.05). The enrichment analysis showed focal adhesion as the most possible regulatory pathway by COL1A2. Conclusion: Collectively, COL1A2 functioned as an independent prognostic biomarker and might be a potential therapeutic target in COAD.
Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that has been implicated in the pathological cell death associated with various disorders including neurodegenerative diseases (e.g., Friedreich's ataxia (FRDA), Alzheimer's disease, and Parkinson's disease), stroke, and traumatic brain injury. Recently, we showed that lipophilic methylene blue (MB) and methylene violet (MV) analogues both promoted increased frataxin levels and mitochondrial biogenesis, in addition to their antioxidant activity in cultured FRDA cells. Presently, we report the synthesis of series of lipophilic phenothiazine analogues that potently inhibit ferroptosis. The most promising compounds (1b-5b) exhibited an improved protection compared to the parent phenothiazine against erastin- and RSL3-induced ferroptotic cell death. These analogues have equivalent or better potency than ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), that are among the most potent inhibitors of this regulated cell death described so far. They represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models such as FRDA.
Abstract It is of great significance for quality control to realize the discrimination for baijiu from different brands and origins. Strong-aroma-type baijiu (SAB), one of the most important Chinese aroma-type baijiu, exhibits the largest variety and market share. In this study, we proposed colorimetric sensor arrays based on gold nanoparticles (AuNPs) modified with different amino acids (AAs) to recognize the organic acids, and further distinguish different SABs. Three representative AAs, namely methionine (Met), tryptophan (Trp), and histidine (His), were selected to modify the AuNPs surface. The investigation of the effect of the main ingredients of SAB on AA@AuNPs aggregation confirmed that this aggregation mainly resulted from organic acids. Moreover, this aggregation was successfully used for differentiating 11 organic acids. Different pH conditions can not only cause changes of the content of organic acids in baijiu, but also disrupt the balance among flavor substances of baijiu to some extent. Consequently, the AA@AuNPs arrays under two pH conditions have been successfully applied to distinguish 14 kinds of SABs from different brands and origins. The proposed colorimetric sensor method is simple, rapid, and visualized and provides a potential application prospect for the quality control of baijiu and other alcoholic beverages.
Sauce-aroma Baijiu (SAB) is one of the most famous Baijius in China; SAB has more than 500 aroma compounds in it. However, the key aroma compound in SAB flavor remains unclear. Volatiles play an important role in SAB aroma and are highly correlated to SAB quality. In the present study, 63 volatile compounds were quantified among 66 SAB samples using gas chromatography with flame ionization detector (GC-FID). The authors analyzed odor contributions and volatile compound correlations in two quality groups of SAB samples. Moreover, an odor activity value (OAV) ratio-based random forest classifier was used to explain the volatile compound relationship differentiations between the two quality groups. Our results proved higher quality SABs had richer aromas and indicated a set of fruity-like ethyl valerate, green- and malt-like isobutyraldehyde and malt-like 3-methylbutyraldehyde and sweet-like furfural, had closer co-abundance correlations in higher quality SABs. These results indicated that the aroma and contributions of volatile compounds in SABs should be analyzed not only with compound odor activity values, but also the correlations between different aroma compounds.
Abstract Background Macrophages play the important roles in the diabetes and sepsis-related intestinal injury. Accumulating evidence suggests that transcription factors act as the fundamental link between macrophage polarization and tissue injury. However, the underlying mechanisms of transcription factors regulating macrophage polarization-related intestinal injury remain unclear under diabetes and sepsis conditions. Methods The cecal ligation and puncture (CLP)-induced sepsis models were established in both wild type (WT) and diabetic male mice. Clodronate liposome (Cls) was used to deplete macrophage. HE staining, inflammatory cytokines (TNF-α, IL-1β and IL-6) and intestinal mucosal barrier function markers (occludin, ZO-1, LPS and iFABP) were used to elevated intestinal damage. MicroRNA-array, RNA-seq and bioinformatic analysis were performed to detect the microRNA and mRNA expression and the potential regulation mechanism. In vitro, high glucose and LPS, miR-3061 mimics and Snail siRNA stimulation of RAW264.7 cells were cultured for further mechanism studies. Luciferase reporter assay was used to confirm the interplay between microRNA and its target genes. Results Compared to WT CLP mice, the diabetic CLP mice showed severe intestinal damage characterized by significantly increased Chui’s scores, expression of inflammatory cytokines (TNF-α, IL-1β and IL-6), serum LPS and iFABP concentration and reduced tight junction protein occluding and ZO-1 levels. Macrophage deplettion exhibited reverse the intestinal damage caused by CLP. The bioinformatic analysis identified that miR-3061/Snail1 might be a potential regulation axis of macrophage polarization. Furthermore, high glucose and LPS stimulation increased M1 macrophage and reduced levels of miR-3061, which was negatively associated with Snail1 in RAW264.7 cells. Mechanistic researches demonstrated that miR-3061 regulated macrophage polarization by targeting Snail1 mRNA 3′-untranslated region (3’‐UTR). Moreover, miR-3061 overexpression suppressed Snail1 expression, inhibited M1 macrophage and inflammatory cytokines. Conclusion This study elucidated that diabetes exacerbated sepsis-induced intestinal injury by promoting M1 macrophage polarization, and further demonstrated that the miR-3061/Sani1 axis may be the potential target of macrophage polarization.
This study was performed to determine the efficacy of conversion therapy in intrahepatic cholangiocarcinoma (IHCC) and explore the feasibility of cancer organoid to direct the conversion therapy of IHCC. Patient data were retrospectively reviewed in this study and cancer organoids were established using tissues obtained from two patients. A total of 42 patients with IHCC received conversion therapy, 9 of whom were downstaged successfully, and another 157 patients were initially resectable. Kaplan–Meier curves showed that the successfully downstaged patients had a significantly improved overall survival compared to those in whom downstaging was unsuccessful (p = 0.017), and had a similar overall survival to that of initially resectable patients (p = 0.965). The IHCC organoid was successfully established from one of two obtained tissues. Routine hematoxylin and eosin staining and immunohistological staining found the organoid retained the histopathological characteristics of the original tissues. Whole exome sequencing results indicated the IHCC organoid retained appropriately 87% of the variants in the original tissue. Gemcitabine and paclitaxel exhibited the strongest inhibitory effects on the cancer organoid as determined using drug screening tests, consistent with the levels of efficacy observed in the patient from whom it was derived. This study indicates that conversion therapy could improve the survival of patients with IHCC despite its low success rate, and it may be directed by cancer organoids though this is merely a proof of feasibility.
Abstract The present study intends to clarify the hypothesis that isocitrate dehydrogenase 1 (IDH1) mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis through the in vitro and in vivo experiments. Cholangiocarcinoma RBE cell line was transfected with IDH1 R132C mutation plasmids and treated with erastin to induce ferroptosis, which were then microscopically photographed. Cell viability rate was calculated by trypan blue staining. The lipid ROS level was determined by using flow cytometer. The BALB/c nude mice were injected subcutaneously with IDH1 knockout (KO), WT, or R132C mutation cell line, followed by injecting erastin intraperitoneally. The tumor tissue was surgically separated for the measurement of tumor volume and weight. The results showed that IDH1 mutant RBE cell line are sensitive to erastin-induced ferroptosis, evidenced by the increased number of propidium iodide-positive cells, the decreased cell viability, and increased lipid ROS level. However, current targeted inhibitors of IDH1 mutation (AG120 and IDH305) reversed these effects caused by IDH1 mutation. The in vivo experiment showed that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis. This study indicated that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis.
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