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•Swelling index of FGB (115) was higher than that of guar gum hydrogel.•Swelling index of sand soil increased from 16.28% to 35.53% with 0.5 wt.% FGB hydrogel.•Water retention time of ...sandy soil increased from 2 to 11.5 days with 0.5 wt.% FGB hydrogel.•The cycles (water absorption and water loss) of soil-FGB can continue more than ten times at a temperature of 50 °C.•The FGB has swift self-healing capability and injectable performance.
In order to explore a novel type of agricultural water-retaining agent, borax crosslinked fenugreek galactomannan-borax hydrogel (FGB) was synthesized. The hydrogel was characterized by thermogravimetric analysis, FT-IR, XRD, and SEM. The largest swelling index of FGB (115) was higher than that of guar gum hydrogel (70) at pH 9. The water absorption capacity of sandy soil was studied by mixing the hydrogel with soil, then FGB was evaluated as a latent water retention agent. Results showed that the swelling index of sandy soil increased from 16.28% to 35.53% with 0.5 wt.% hydrogel added. The water retention time increased from 2 to 11.5 days at 20 °C and 60 % humidity. Furthermore, more than ten cycles of water absorption and water loss of soil-FGB were carried out at 50 °C at a relatively stable water retention capacity. This low-cost, environmentally friendly hydrogel has great application potential in agriculture for soil water conservation.
Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of ...gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4−/− mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.
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•Gpx4 deficiency in myeloid cells increases severity of polymicrobial sepsis in mice•Caspase-11-dependent pyroptosis mediates septic death in Gpx4Mye−/− mice•GPX4 decreases lipid peroxidation to block PLCG1-mediated GSDMD activity and pyroptosis•Antioxidant activity of vitamin E promotes survival during sepsis in Gpx4Mye−/− mice
Kang et al. demonstrate that glutathione peroxidase 4 (GPX4) serves a protective role in mice undergoing septic shock. Myeloid-specific deficiency of Gpx4 coordinates lipid peroxidation-dependent caspase-11 activation and gasdermin D-mediated pyroptosis during polymicrobial sepsis. Vitamin E administration reverses Gpx4Mye−/− susceptibility, thereby revealing a potential target for therapeutic intervention for lethal infection.
Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which ...metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2-EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis.
An accumulation of evidence indicates that long noncoding RNAs are involved in the tumorigenesis and progression of pancreatic cancer (PC). In this study, we investigated the functions and molecular ...mechanism of action of LINC00941 in PC. Quantitative PCR was used to examine the expression of LINC00941 and miR-335-5p in PC tissues and cell lines, and to investigate the correlation between LINC00941 expression and clinicopathological features. Plasmid vectors or lentiviruses were used to manipulate the expression of LINC00941, miR-335-5p, and ROCK1 in PC cell lines. Gain or loss-of-function assays and mechanistic assays were employed to verify the roles of LINC00941, miR-335-5p, and ROCK1 in PC cell growth and metastasis, both in vivo and in vitro. LINC00941 and ROCK1 were found to be highly expressed in PC, while miR-335-5p exhibited low expression. High LINC00941 expression was strongly associated with larger tumor size, lymph node metastasis, and poor prognosis. Functional experiments revealed that LINC00941 silencing significantly suppressed PC cell growth, metastasis and epithelial-mesenchymal transition. LINC00941 functioned as a molecular sponge for miR-335-5p, and a competitive endogenous RNA (ceRNA) for ROCK1, promoting ROCK1 upregulation, and LIMK1/Cofilin-1 pathway activation. Our observations lead us to conclude that LINC00941 functions as an oncogene in PC progression, behaving as a ceRNA for miR-335-5p binding. LINC00941 may therefore have potential utility as a diagnostic and treatment target in this disease.
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•Development of slender nano-ribbons from spherical xyloglucan nanoparticles by degalactosylation.•The transition results from stronger hydrophobic interaction.•Reduced number of ...hydrophilic galactose caused decreased water solubility.
As a common side-chain residue of polysaccharide, galactose plays a significant role in multiple aspects of the macromolecules. This study showed how degalactosylation induced drastic self-assembly transition of xyloglucan from spherical aggregates toward ribbon-like aggregates, and how it led to largely decreased water solubility and apparent viscosity within a short range of galactose removal ratio. To better understand this phenomenon, the size of the ellipsoid-like aggregated nanoparticles were carefully measured and compared, and it was found out that those nanoparticles which lost more galactose residues turned out to be more slender and tend to bind and stack closely in parallel, thereby forming huge ribbon-like aggregates. The galactose residue is considered as the hydrophilic group, and the decreased number of which caused a more hydrophobic behavior.
Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk signatures and their effects on ...the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains hazy. This study aimed to conduct novel hypoxia-related prognostic signatures and improve HCC prognosis and treatment.
Differentially expressed hypoxia-related genes (HGs) were identified with the gene set enrichment analysis (GSEA). Univariate Cox regression was utilized to generate the tumor hypoxia-related prognostic signature, which consists of 3 HGs, based on the least absolute shrinkage and selection operator (LASSO) algorithm. Then the risk score for each patient was performed. The prognostic signature's independent prognostic usefulness was confirmed, and systematic analyses were done on the relationships between the prognostic signature and immune cell infiltration, somatic cell mutation, medication sensitivity, and putative immunological checkpoints.
A prognostic risk model of four HGs (FDPS, SRM, and NDRG1) was constructed and validated in the training, testing, and validation datasets. To determine the model's performance in patients with HCC, Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves analysis was implemented. According to immune infiltration analysis, the high-risk group had a significant infiltration of CD4+ T cells, M0 macrophages, and dendritic cells (DCs) than those of the low-risk subtype. In addition, the presence of TP53 mutations in the high-risk group was higher, in which LY317615, PF-562271, Pyrimethamine, and Sunitinib were more sensitive. The CD86, LAIR1, and LGALS9 expression were upregulated in the high-risk subtype.
The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Pancreatic cancer is one of the most lethal human cancers.
N
6
-methyladenosine (m
6
A), a common eukaryotic mRNA modification, plays critical roles in both physiological and ...pathological processes. However, its role in pancreatic cancer remains elusive.
Methods
LC/MS was used to profile m
6
A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m
6
A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14.
Results
We found that the m
6
A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m
6
A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo
,
via direct targeting of the downstream
PERP
mRNA (p53 effector related to PMP-22) in an m
6
A-dependent manner. Methylation of the target adenosine lead to increased
PERP
mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells.
Conclusions
Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m
6
A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have become a standard therapy in patients with EGFR-activating mutations. Unfortunately, acquired resistance eventually limits the clinical ...effects and application of EGFR-TKIs. Studies have shown that suppression of epithelial-mesenchymal transition (EMT) and the interleukin (IL)-6/STAT3 pathway may abrogate this acquired mechanism of drug resistance of TKIs. This study aims to investigate the effect of metformin on sensitizing EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal.
The effect of metformin on reversing TKI resistance was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, invasion assay, flow cytometry analysis, immunostaining, Western blot analysis, and xenograft implantation.
In this study, metformin, a widely used antidiabetic agent, effectively increased the sensitivity of TKI-resistant lung cancer cells to erlotinib or gefitinib. Metformin reversed EMT and decreased IL-6 signaling activation in TKI-resistant cells, while adding IL-6 to those cells bypassed the anti-TKI-resistance effect of metformin. Furthermore, overexpression or addition of IL-6 to TKI-sensitive cells induced TKI resistance, which could be overcome by metformin. Finally, metformin-based combinatorial therapy effectively blocked tumor growth in xenografts with TKI-resistant cancer cells, which was associated with decreased IL-6 secretion and expression, EMT reversal, and decreased IL-6-signaling activation in vivo.
Metformin, generally considered nontoxic and remarkably inexpensive, might be used in combination with TKIs in patients with non-small cell lung cancer, harboring EGFR mutations to overcome TKI resistance and prolong survival.
The Hippo signaling pathway plays a crucial role in regulating tissue homeostasis, organ size, tumorigenesis and cancer chemoresistance when deregulated. Physiologically, the Hippo core kinase ...cassette that consists of mamma-lian STE20-like protein kinase 1/2 (MST1/2), and large tumour suppressor 1/2 (LATS1/2), together with the adaptor proteins Salvador homologue 1 (SAV1) and MOB kinase activator 1 (MOB1), tightly restricts the activities of homologous oncoproteins Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) to low levels. However, how the Hippo kinase cassette core components are simultaneously inhibited, to exhibit constitutively inactivated Hippo signaling and activated YAP/TAZ in cancer remains puzzling. Herein, we reported that miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival. These findings provide a novel mechanism for Hippo signaling inactivation in cancer, indicating not only a potentially pivotal role for miR-181c in the progression of pancreatic cancer, but also may represent a new therapeutic target and prognostic marker.
Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the ...molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer.
In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway.
linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth.
The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.
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