Notes

Protection against vascular dementia by way of immunotherapeutic blockade involving renin-angiotensin system in a rat style.
High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. INTERPRETATION A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND DFG, BMBF and Sino-German Cooperation Project. Volatile organic compounds (VOCs) are produced by the human metabolism, inflammation and gut microbiota and form the basis of innovative volatomics research. VOCs detected through breath and faecal analysis hence serve as attractive, non-invasive biomarkers for diagnosing and monitoring irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). This review describes the clinical applicability of volatomics in discriminating between IBS, IBD and healthy volunteers with acceptable accuracy in breath (70%-100%) and faecal (58%-85%) samples. Promising compounds are propan-1-ol for diagnosing and monitoring of IBD patients, and 1-methyl-4-propan-2-ylcyclohexa-1,4-diene as biomarker for IBS diagnosis. However, these VOCs often seem to be related to inflammation and probably will need to be used in conjunction with other clinical evidence. Furthermore, three interventional studies underlined the potential of VOCs in predicting treatment outcome and patient follow-up. This shows great promise for future use of VOCs as non-invasive breath and faecal biomarkers in personalised medicine. However, properly designed studies that correlate VOCs to IBD/IBS pathogenesis, while taking microbial influences into account, are still key before clinical implementation can be expected. selleck compound CRISPR and associated Cas nucleases are genetic engineering tools revolutionizing innovative approaches to cancer and inherited diseases. CRISPR-directed gene editing relies heavily on proper DNA sequence alignment between the guide RNA (gRNA)/CRISPR complex and its genomic target. Accurate hybridization of complementary DNA initiates gene editing in human cells, but inherent gRNA sequence variation that could influence the gene editing reaction has been clearly established among diverse genetic populations. As this technology advances toward clinical implementation, it will be essential to assess what degree of gRNA variation generates unwanted and erroneous CRISPR activity. With the use of a system in which a cell-free extract catalyzes nonhomologous end joining (NHEJ) and homology-directed repair (HDR), it is possible to observe a more representative population of all forms of gene editing outcomes. In this manuscript, we demonstrate CRISPR/Cas complexation at heterologous binding sites that facilitate precise and error-prone HDR. The tolerance of mispairing between the gRNA and target site of the DNA to enable HDR is surprisingly high and greatly influenced by polarity of the donor DNA strand in the reaction. These results suggest that some collateral genomic activity could occur at unintended sites in CRISPR-directed gene editing in human cells. Long non-coding RNAs (lncRNAs) gradually show critical regulatory roles in many malignancies. However, the lncRNAs implicated in colon cancer recurrence are largely unknown. In this study, we searched the lncRNAs associated with metastasis and recurrence of colon cancer using GEO datasets. We focused on a novel lncRNA long non-coding RNA associated with poor prognosis of colon cancer (LNAPPCC), which is highly expressed in colon cancer. Increased expression of LNAPPCC is positively associated with metastasis, recurrence, and poor survival of colon cancer patients. LNAPPCC promotes colon cancer cell proliferation, migration, and in vivo xenograft growth and liver metastasis. Mechanistic investigations revealed that LNAPPCC binds EZH2, represses the binding of EZH2 to PCDH7 promoter, downregulates histone H3K27me3 level in PCDH7 promoter, and activates PCDH7 expression. Intriguingly, we also found that PCDH7 activates ERK/c-FOS signaling, increases the binding of c-FOS to LNAPPCC promoter, and activates LNAPPCC expression. Therefore, LNAPPCC and PCDH7 form a positive regulatory loop via EZH2 and ERK/c-FOS. The positive correlations between the expression of LNAPPCC, PCDH7, phosphorylated ERK, and phosphorylated c-FOS are detected in colon cancer tissues. Furthermore, depletion of PCDH7 or the adding of ERK inhibitor abolished the oncogenic roles of LNAPPCC in colon cancer. In summary, this study identified a novel lncRNA LNAPPCC that is highly expressed in colon cancer and associated with poor prognosis of colon cancer patients. LNAPPCC exerts oncogenic roles in colon cancer via forming a positive feedback loop with PCDH7. Targeting LNAPPCC/EZH2/PCDH7/ERK/c-FOS signaling axis represents a potential therapeutic strategy for colon cancer. Hemophilia A (HemA) patients are currently treated with costly and inconvenient replacement therapy of short-lived factor VIII (FVIII) protein. Development of lipid nanoparticle (LNP)-encapsulated mRNA encoding FVIII can change this paradigm. LNP technology constitutes a biocompatible and scalable system to efficiently package and deliver mRNA to the target site. Mice intravenously infused with the luciferase mRNA LNPs showed luminescence signals predominantly in the liver 4 h after injection. Repeated injections of LNPs did not induce elevation of liver transaminases. We next injected LNPs carrying mRNAs encoding different variants of human FVIII (F8 LNPs) into HemA mice. A single injection of B domain-deleted F8 LNPs using different dosing regimens achieved a wide range of therapeutic activities rapidly, which can be beneficial for various usages in hemophilia treatment. The expression slowly declined yet remained above therapeutic levels up to 5-7 days post-injection. Furthermore, routine repeated injections of F8 LNPs in immunodeficient mice produced consistent expression of FVIII over time. In conclusion, F8 LNP treatment produced rapid and prolonged duration of FVIII expression that could be applied to prophylactic treatment and potentially various other treatment options. Our study showed potential for a safe and effective platform of new mRNA therapies for HemA. Circular RNA (circRNA), as a kind of novel identified non-coding RNA, has become the focus of attention for its vital physiological and pathological roles. However, the function and mechanism of circRNAs in the regulation of cancer progression are largely unknown. In the present study we found a circRNA termed circHMCU whose expression was associated with poor prognosis. It was upregulated in cell lines with high metastatic potential compared with its parental cell line and in breast cancer tissues compared with normal tissues. In vitro results proved that circHMCU could significantly promote proliferation, migration, and invasion abilities of breast cancer cells via affecting the G1 phase cell cycle checkpoint and the epithelial-mesenchymal transition (EMT) pathway. Further in vivo studies showed that overexpression of circHMCU contributed to rapid proliferation and lung metastasis of breast cancer. For determination of the mechanisms, bioinformatics analysis revealed two complementary sequences within circHMCU for let-7 microRNAs, which was validated by a luciferase reporter assay. Finally, let-7 microRNAs could rescue the functions of circHMCU in breast cancer via suppressing the expression of MCY, HMGA2, and CCND1. Taken together, our findings demonstrated that circHMCU exerted oncogenic functions in breast cancer and could be a used as a novel biomarker in the diagnosis and prognosis of breast cancer. Neural tube defects (NTDs) result in prenatal mortality and lifelong morbidity, and available treatments have limited efficacy. We previously suggested that prenatal bone marrow-derived mesenchymal stem cell (BMSC) transplantation could treat neuron deficiency in NTD rats; however, BMSC-based therapy is limited by the low survival rate of BMSCs when used to treat severe NTDs. Herein, a new therapy using combined BMSC transplantation and small interfering RNA of collapsin response mediator protein 4 (CRMP4 siRNA), which was identified as a novel potential target for the NTD treatment, is proposed. The intra-amniotic CRMP4 siRNA, BMSC, and CRMP4 siRNA + BMSC injections repaired skin lesions, improved motor neural function, reduced neuronal apoptosis, and promoted expression of neural differentiation-related molecules and neurotrophic factors in the spinal cord of spina bifida rat fetuses. Therapeutic effects in the CRMP4 siRNA + BMSC injection group were superior to those of the CRMP4 siRNA only or BMSC only injection groups. CRMP4 siRNA + BMSC injection resulted in a 45.38% reduction in the skin lesion area and significantly shorter latency and higher amplitude of motor-evoked potentials (MEPs) in spina bifida fetuses. Our results suggest that intrauterine Ad-CRMP4 siRNA delivery with BMSCs is an innovative platform for developing fetal therapeutics to safely and efficaciously treat NTDs. Intestinal ischemia-reperfusion (I/R) injury is a life-threatening vascular emergency and has long been a disturbing problem for surgeons. Oxidative stress is considered a vital factor in I/R injury. Metformin has anti-oxidative properties and protects against I/R injury. The present study aimed to investigate whether Metformin protects against intestinal I/R injury and reveal the protective mechanism of Metformin. I/R injury was induced in mice by temporary superior mesenteric artery occlusion, and Caco-2 cells were subjected to OGD/R to establish an in vitro model. Different doses of Metformin were administered in vivo and in vitro. We found that I/R injury led to intestinal barrier disruption and cell death by examining histopathological results and the intestinal barrier index, including TER, tight junction proteins and serum biomarkers. We confirmed the existence of pyroptosis in intestinal I/R injury. Moreover, we confirmed the role of pyroptosis in intestinal I/R injury by silencing the gasdermin D (GSDMD). Then, we confirmed that Metformin treatment protected barrier function against intestinal I/R injury and reduced oxidative stress and the inflammatory response. Importantly, Metformin reduced pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and the N-terminus of GSDMD. Knocking down the GSDMD could reversed the protective effects of Metformin, which showed pyroptosis was one of the major cell death pathways controlled by Metformin treatment in setting of intestinal I/R injury. We also discovered that Metformin suppressed the expression of TXNIP and the interaction between TXNIP and NLRP3. We performed siRNA knockdown and found that the protective effects were abolished, which further confirmed our findings. In conclusion, we believe that Metformin protects against intestinal I/R injury in a TXNIP-NLRP3-GSDMD-dependent manner.
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