Framework nucleic acid-based nanoparticles enhance temozolomide sensitivity in glioblastoma.

O6-methylguanine DNA methyltransferase (MGMT) is a crucial determinant of temozolomide (TMZ) sensitivity in patients with glioblastoma (GBM). The therapeutic potential of small interfering RNA (siRNA) targeting MGMT to enhance TMZ sensitivity has been hampered by serum nuclease degradation, off-target effects, poor accumulation at tumor sites, and low circulation in blood stream. In this study, we developed a framework nucleic acid-based nanoparticles (FNN), which is constructed from a six-helix DNA bundle, to encapsulate and protect siMGMT for improving TMZ sensitivity in GBM treatment. For better blood-brain barrier (BBB) penetration and GBM targeting, we conjugated Angiopep-2 (ANG) targeting modules to each end of the FNN. Nucleolin (NCL)-responsive locks were engineered along the sides of the six-helix DNA bundle, which safeguard siMGMT before tumor entry. Upon interaction with tumor-overexpressed NCL, these locks unlock, exposing siMGMT, this allows for effective suppression of MGMT, resulting in a significant improvement of TMZ therapeutic efficacy in GBM. This innovative strategy has the potential to transform the current treatment landscape for GBM.

Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention.

Temozolomide (TMZ) resistance remains the major obstacle in the treatment of glioblastoma (GBM). Lactylation is a novel post-translational modification that is involved in various tumors. However, whether lactylation plays a role in GBM TMZ resistance remains unclear. Here it is found that histone H3K9 lactylation (H3K9la) confers TMZ resistance in GBM via LUC7L2-mediated intron 7 retention of MLH1. Mechanistically, lactylation is upregulated in recurrent GBM tissues and TMZ-resistant cells, and is mainly concentrated in histone H3K9. Combined multi-omics analysis, including CUT&Tag, SLAM-seq, and RNA-seq, reveals that H3K9 lactylation is significantly enriched in the LUC7L2 promoter and activates LUC7L2 transcription to promote its expression. LUC7L2 mediates intron 7 retention of MLH1 to reduce MLH1 expression, and thereby inhibit mismatch repair (MMR), ultimately leading to GBM TMZ resistance. Of note, it is identified that a clinical anti-epileptic drug, stiripentol, which can cross the blood-brain barrier and inhibit lactate dehydrogenase A/B (LDHA/B) activity, acts as a lactylation inhibitor and renders GBM cells more sensitive to TMZ in vitro and in vivo. These findings not only shed light on the mechanism of lactylation in GBM TMZ resistance but also provide a potential combined therapeutic strategy for clinical GBM treatment.

IRP1 mediated ferroptosis reverses temozolomide resistance in glioblastoma via affecting LCN2/FPN1 signaling axis depended on NFKB2.

The prognosis of glioblastoma (GBM) patients is poor, and temozolomide (TMZ) resistance has become an important obstacle to its treatment effect. A growing number of researches have revealed the special characteristics of iron metabolism in GBM chemosensitivity. Iron regulatory protein 1 (IRP1) is an important protein for maintaining intracellular iron homeostasis. IRP1 has been indicated to have additional vital roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we unprecedentedly demonstrated that amplifying IRP1 signals can reverse TMZ resistance and suppress tumor growth in vivo via inhibiting NFKB2 in the noncanonical NF-κB signaling pathway. In addition, we identified that NFKB2 affected TMZ sensitivity of GBM by modulating the expression of LCN2 and FPN1. Taken together, this study established a role for the IRP1/NFKB2 pathway in regulating LCN2/FPN1 signaling axis among the progression of TMZ resistance, suggesting a potential innovative GBM therapeutic strategy.

The role of M6A modification in the regulation of tumor-related lncRNAs.

N 6-methyladenosine (m6A) is the most abundant modification in eukaryotic cells, and it regulates RNA transcription, processing, splicing, degradation, and translation. Long non-coding RNAs (lncRNAs), as transcriptional products with no or limited protein coding ability more than 200 nt in length, play an important role in epigenetic modification, mRNA transcription, splicing, stability, translation, and other biological functions. Extensive studies have shown that both m6A modification and lncRNAs are involved in the pathogenesis of various diseases, such as kinds of cancers, heart failure, Alzheimer's disease, periodontitis, human abdominal aortic aneurysm, and obesity. To date, m6A modification has been identified as an important biological function in enrichment and regulation of lncRNAs. In this review, we summarize the role of m6A modification in the regulation and function of tumor-related lncRNAs. Moreover, we discuss the potential applications and possible future directions in the field.

Design of a tomato classifier based on machine vision.

This paper attempts to design an automated, efficient and intelligent tomato grading method that facilitates the graded selling of the fruit. Based on machine vision, the color images of tomatoes with different morphologies were studied, and the color, shape and size were selected as the key features. On this basis, an automated grading classifier was created based on the surface features of tomatoes, and a grading platform was set up to verify the effect of the classifier. Specifically, the Hue value distributions of tomatoes with different maturities were investigated, and the Hue value ranges were determined for mature, semi-mature and immature tomatoes, producing the color classifier. Next, the first-order Fourier descriptor (1D- FD) was adopted to describe the radius sequence of tomato contour, and an equation was established to compute the irregularity of tomato contour, creating the shape classifier. After that, a linear regression equation was constructed to reflect the relationship between the transverse diameters of actual tomatoes and tomato images, and a classifier between large, medium and small tomatoes was produced based on the transverse diameter. Finally, a comprehensive tomato classifier was built based on the color, shape and size diameters. The experimental results show that the mean grading accuracy of the proposed method was 90.7%. This means our method can achieve automated real-time grading of tomatoes.

Hepatoprotective effects of Auricularia cornea var. Li. polysaccharides against the alcoholic liver diseases through different metabolic pathways.

The present work was designed to evaluate the antioxidation and hepatoprotective effects of Auricularia cornea var. Li. polysaccharides (APS) and enzymatic-extractable APS (EAPS) on the acute alcohol-induced alcoholic liver diseases (ALD). The in vitro antioxidant activities demonstrated that both APS and EAPS had strong reducing power and potential effects on scavenging reactive oxygen species. The in vivo mice experiments showed that the pretreatment with APS or EAPS showed potential hepatoprotective effects on the ALD possibly by increasing the antioxidant activities, reducing the lipid peroxidation, improving the alcohol metabolism, inhibiting the expression levels of inflammatory mediators and preventing the alcohol-induced histopathological alterations. In addition, the fourier-transform infrared (FT-IR), 1H and 13C nuclear magnetic resonance spectroscopy (NMR) and gas chromatography (GC) had been analyzed to obtained the primarily characteristics. The results indicated that abundant xylose and glucose contents probably had potential effects on possessing the bioactivities. The findings suggested that the A. cornea var. Li. might be considered as promising natural resource on exploring clinical drugs for the prevention and treatment with ALD and its complications.

The characterization, renoprotection and antioxidation of enzymatic and acidic exopolysaccharides from Hypsizigus marmoreus.

The present work was designed to investigate the characterization, as well as the antioxidation and renoprotection in streptozocin (STZ)-induced diabetic mice, of exopolysaccharides (EPS) and the enzymatic-EPS (EEPS) and acidic-EPS (AEPS) hydrolysates, which were separated from the fermentation liquor of Hypsizigus marmoreus. Animal results demonstrated that EPS, EEPS and AEPS had potential antioxidant and renoprotective effects, especially EEPS. Additionally, they were the most effective, reflecting increases in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), total antioxidant capacity (T-AOC), and albumin (ALB) of 168.33%, 124.8%, 268.17% 179.49%, and 68.71%, respectively, and decreases in the contents of malondialdehyde (MDA), lipid peroxide (LPO) and levels of serum urea nitrogen (BUN) and creatinine (CRE) by 70.58%, 58.43%, 23.97% and 29.60%, respectively, at a dose of 800 mg/kg compared to those of model mice. Three polysaccharides ameliorated the histopathological alterations which were observed in the kidney of diabetic mice. Furthermore, the characterization of polysaccharides had been expressed. These findings indicated that the EEPS from H. marmoreus possesses more effective renoprotection and antioxidation effects and provided insight into its potential clinical values on preventing diabetes.

Antioxidant and Hepatoprotective Activities of Polysaccharides from Spent Mushroom Substrates (Laetiporus sulphureus) in Acute Alcohol-Induced Mice.

In order to contribute to the exploitation and utilization of spent mushroom substrates (SMS) of Laetiporus sulphureus, hot-water-extractable polysaccharides (H-SMPS) and enzymatic-extractable polysaccharides (E-SMPS) were successfully isolated from SMS of L. sulphureus. Both H-SMPS and E-SMPS were found to have high reducing power and potential scavenging activities against hydroxyl, DPPH, and superoxide anion radicals. In vivo assays showed that the administration of H-SMPS and E-SMPS has potential hepatoprotective effects against alcohol-induced alcoholic liver disease (ALD), possibly brought about by improving liver function, increasing antioxidant status, and reducing lipid peroxidation. Furthermore, monosaccharide composition analysis showed that fucose may play a vital role in guaranteeing stronger hepatoprotection. These results may provide references for the exploitation of the SMS of L. sulphureus as a source of H-SMPS and E-SMPS, which in turn can be used as functional foods or natural drugs for the prevention of ALD and other liver diseases.

Development of new potato virus X-based vectors for gene over-expression and gene silencing assay.

Multiple plant viruses, including potato virus X (PVX), have been modified as vectors for expressing heterologous genes or silencing endogenous genes in plants. PVX-based vectors facilitate the functional analysis of genes in plant. However, they can only express one protein in a time. In this paper we report the construction of new vectors based on a 35S promoter-driven PVX infectious clone, pCaPVX100. Vector pCaPVX440 contains two additional subgenomic promoters and can be utilized to express two foreign genes at the same time. Plasmid pCaPVX760 is a CP minus vector and can be used to express foreign proteins through the gene substitution strategy. In addition, plasmid pCaPVX100 was engineered into a gene silencing vector (pCaPVX440-LIC) by introducing a ligation independent cloning (LIC) site into the vector. These results indicate that the newly developed PVX vectors are competent for multiple research purposes.

The complete genomic sequence of Tobacco vein banding mosaic virus and its similarities with other potyviruses.

The complete genomic sequence of an isolate of Tobacco vein banding mosaic virus (TVBMV-YND) from Yunnan, China was determined by sequencing overlapping cDNA fragments obtained by RT-PCR with degenerate and/or specific primers. The genome is composed of 9,570 nucleotides (nt) excluding the 3'-terminal poly (A) tail and contains one single open reading frame of 9,240 nt encoding a large polyprotein of 3,079 amino acids with predicted Mr of 348.6 kDa. Phylogenetic analysis of complete genomic sequences confirmed that TVBMV is a distinct species of the genus Potyvirus. Different parts of TVBMV-YND genome shared different levels of identity with other species of potyviruses, while most parts showed greatest identity with Chilli veinal mottle virus among the potyviruses with available complete genomic sequences. TVBMV-YND had a rare Q/N cleavage site for NIb/CP and uncommon RITC motif in HC-Pro that is crucial for aphid transmission of potyviruses.