Role of prostaglandin E2 and its receptors in chronic liver disease.

Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common culprits. Prostaglandin E2 (PGE2), produced in the liver, is an important lipid mediator derived from the ω-6 polyunsaturated fatty acid, arachidonic acid, and plays a critical role in hepatic homeostasis. The physiological effects of PGE2 are mediated through four classes of E-type prostaglandin (EP) receptors, namely EP1, EP2, EP3 and EP4. In recent years, an increasing number of studies has been done to clarify the effects of PGE2 and EP receptors in regulating liver function and the pathogenesis of CLD to create a new potential clinical impact. In this review, we overview the biosynthesis and regulation of PGE2 and discuss the role of its synthesizing enzymes and receptors in the maintenance of normal liver function and the development and progress of CLD. We also discuss the potential of the PGE2-EP receptors system in treating CLD with various etiologies.

Revolutionizing Neurocare: Biomimetic Nanodelivery Via Cell Membranes.

Brain disorders represent a significant challenge in medical science due to the formidable blood-brain barrier (BBB), which severely limits the penetration of conventional therapeutics, hindering effective treatment strategies. This review delves into the innovative realm of biomimetic nanodelivery systems, including stem cell-derived nanoghosts, tumor cell membrane-coated nanoparticles, and erythrocyte membrane-based carriers, highlighting their potential to circumvent the BBB's restrictions. By mimicking native cell properties, these nanocarriers emerge as a promising solution for enhancing drug delivery to the brain, offering a strategic advantage in overcoming the barrier's selective permeability. The unique benefits of leveraging cell membranes from various sources is evaluated and advanced technologies for fabricating cell membrane-encapsulated nanoparticles capable of masquerading as endogenous cells are examined. This enables the targeted delivery of a broad spectrum of therapeutic agents, ranging from small molecule drugs to proteins, thereby providing an innovative approach to neurocare. Further, the review contrasts the capabilities and limitations of these biomimetic nanocarriers with traditional delivery methods, underlining their potential to enable targeted, sustained, and minimally invasive treatment modalities. This review is concluded with a perspective on the clinical translation of these biomimetic systems, underscoring their transformative impact on the therapeutic landscape for intractable brain diseases.

miR-99b/let-7e/miR-125a cluster suppresses pancreatic cancer through regulation of NR6A1.

This experiment investigates how the miR-99b/let-7e/miR-125a cluster regulates the mechanism of NR6A1 involved in the invasive and metastatic effects of pancreatic cancer (PCa). Bioinformatics prediction and dual luciferase reporter gene assay were applied to verify the targeted relationship between miR-99b/let-7e/miR-125a and NR6A1. ASPC1 cells underwent transfection with lentiviruses to overexpress miR-99b/let-7e/miR-125a (individual or together) to explore functions of miR-99b/let-7e/miR-125a cluster governing NR6A1 in PCa. The detection of tumorigenesis was verified by tumor formation assay in nude mice in vivo, and mouse models of liver metastasis of PCa observed cell metastasis of PCa. MiR-99b/let-7e/miR-125a cluster was screened for differential expression in PCa. NR6A1 was confirmed as a target gene of the miR-99b/let-7e/miR-125a cluster. Findings demonstrated that overexpression of the miR-99b/let-7e/miR-125a cluster inhibited cell invasion, metastasis, proliferation, and tumorigenesis in PCa. Conversely, overexpressed NR6A1, a crucial gene in the miR-99b/let-7e/miR-125a cluster, promoted cell invasion, migration, and proliferation in PCa. Moreover, the overexpression of the miR-99b/let-7e/miR-125a cluster inhibited liver metastases and tumor formation. Thus, the study concludes that the miR-99b/let-7e/miR-125a cluster impedes the invasion and metastasis of PCa cells via targeting the NR6A1 gene.

Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors.

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 µM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 µM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.

TIMELESS promotes the proliferation and migration of lung adenocarcinoma cells by activating EGFR through AMPK and SPHK1 regulation.

BACKGROUND: Lung adenocarcinoma (LUAD) has high morbidity and is prone to recurrence. TIMELESS (TIM), which regulates circadian rhythms in Drosophila, is highly expressed in various tumors. Its role in LUAD has gained attention, but the detailed function and mechanism have not been clarified completely at present. METHODS: Tumor samples from patients with LUAD patient data from public databases were used to confirm the relationship of TIM expression with lung cancer. LUAD cell lines were used and siRNA of TIM was adopted to knock down TIM expression in LUAD cells, and further cell proliferation, migration and colony formation were analyzed. By using Western blot and qPCR, we detected the influence of TIM on epidermal growth factor receptor (EGFR), sphingosine kinase 1 (SPHK1) and AMP-activated protein kinase (AMPK). With proteomics analysis, we comprehensively inspected the different changed proteins influenced by TIM and did global bioinformatic analysis. RESULTS: We found that TIM expression was elevated in LUAD and that this high expression was positively correlated with more advanced tumor pathological stages and shorter overall and disease-free survival. TIM knockdown inhibited EGFR activation and also AKT/mTOR phosphorylation. We also clarified that TIM regulated the activation of SPHK1 in LUAD cells. And with SPHK1 siRNA to knock down the expression level of SPHK1, we found that EGFR activation were inhibited greatly too. Quantitative proteomics techniques combined with bioinformatics analysis clarified the global molecular mechanisms regulated by TIM in LUAD. The results of proteomics suggested that mitochondrial translation elongation and termination were altered, which were closely related to the process of mitochondrial oxidative phosphorylation. We further confirmed that TIM knockdown reduced ATP content and promoted AMPK activation in LUAD cells. CONCLUSIONS: Our study revealed that siTIM could inhibit EGFR activation through activating AMPK and inhibiting SPHK1 expression, as well as influencing mitochondrial function and altering the ATP level; TIM's high expression in LUAD is an important factor and a potential key target in LUAD.

Lysine Deprivation Suppresses Adipogenesis in 3T3-L1 Cells: A Transcriptome Analysis.

Growing evidence proves that amino acid restriction can reverse obesity by reducing adipose tissue mass. Amino acids are not only the building blocks of proteins but also serve as signaling molecules in multiple biological pathways. The study of adipocytes' response to amino acid level changes is crucial. It has been reported that a low concentration of lysine suppresses lipid accumulation and transcription of several adipogenic genes in 3T3-L1 preadipocytes. However, the detailed lysine-deprivation-induced cellular transcriptomic changes and the altered pathways have yet to be fully studied. Here, using 3T3-L1 cells, we performed RNA sequencing on undifferentiated and differentiated cells, and differentiated cells under a lysine-free environment, and the data were subjected to KEGG enrichment. We found that the differentiation process of 3T3-L1 cells to adipocytes required the large-scale upregulation of metabolic pathways, mainly on the mitochondrial TCA cycle, oxidative phosphorylation, and downregulation of the lysosomal pathway. Single amino acid lysine depletion suppressed differentiation dose dependently. It disrupted the metabolism of cellular amino acids, which could be partially reflected in the changes in amino acid levels in the culture medium. It inhibited the mitochondria respiratory chain and upregulated the lysosomal pathway, which are essential for adipocyte differentiation. We also noticed that cellular interleukin 6 (IL6) expression and medium IL6 level were dramatically increased, which was one of the targets for suppressing adipogenesis induced by lysine depletion. Moreover, we showed that the depletion of some essential amino acids such as methionine and cystine could induce similar phenomena. This suggests that individual amino acid deprivation may share some common pathways. This descriptive study dissects the pathways for adipogenesis and how the cellular transcriptome was altered under lysine depletion.

The genetic and clinical spectrum in a cohort of 39 families with complex inherited peripheral neuropathies.

With complicated conditions and a large number of potentially causative genes, the diagnosis of a patient with complex inherited peripheral neuropathies (IPNs) is challenging. To provide an overview of the genetic and clinical features of 39 families with complex IPNs from central south China and to optimize the molecular diagnosis approach to this group of heterogeneous diseases, a total of 39 index patients from unrelated families were enrolled, and detailed clinical data were collected. TTR Sanger sequencing, hereditary spastic paraplegia (HSP) gene panel, and dynamic mutation detection in spinocerebellar ataxia (SCAs) were performed according to the respective additional clinical features. Whole-exome sequencing (WES) was used in patients with negative or unclear results. Dynamic mutation detection in NOTCH2NLC and RCF1 was applied as a supplement to WES. As a result, an overall molecular diagnosis rate of 89.7% was achieved. All 21 patients with predominant autonomic dysfunction and multiple organ system involvement carried pathogenic variants in TTR, among which nine had c.349G > T (p.A97S) hotspot variants. Five out of 7 patients (71.4%) with muscle involvement harbored biallelic pathogenic variants in GNE. Five out of 6 patients (83.3%) with spasticity reached definite genetic causes in SACS, KIF5A, BSCL2, and KIAA0196, respectively. NOTCH2NLC GGC repeat expansions were identified in all three cases accompanied by chronic coughing and in one patient accompanied by cognitive impairment. The pathogenic variants, p.F284S and p.G111R in GNE, and p.K4326E in SACS, were first reported. In conclusion, transthyretin amyloidosis with polyneuropathy (ATTR-PN), GNE myopathy, and neuronal intranuclear inclusion disease (NIID) were the most common genotypes in this cohort of complex IPNs. NOTCH2NLC dynamic mutation testing should be added to the molecular diagnostic workflow. We expanded the genetic and related clinical spectrum of GNE myopathy and ARSACS by reporting novel variants.

Discovery of a miniaturized PROTAC with potent activity and high selectivity.

The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC.

pH- and Temperature-responsive Hydrogels Based on Tertiary Amine-modified Polypeptides for Stimuli-responsive Drug Delivery.

pH- and temperature-responsive hydrogels have attracted considerable attention due to their responsiveness to dual physiologically-relevant stimuli. In this study, we developed stimuli-responsive hydrogels based on monomethoxy poly(ethylene glycol) (mPEG)-polypeptide block copolymers containing various tertiary amine pendants (EEP-TAs). The EEP-TAs were synthesized via ring-opening copolymerization of α-amino acid N-carboxyanhydrides, and further modified post-polymerization with click chemistry. The EEP-TAs exhibited an α-helix-to-ß-sheet transition when the pH was increased from 4.0 to 7.4. At elevated polymer concentrations, aqueous solutions of the EEP-TAs underwent thermo-induced sol-gel phase transitions, which were dependent on the pH. The hydrogels almost fully degraded within 3 weeks in the subcutaneous layer of mice and exhibited good histocompatibility in vivo. Additionally, doxorubicin (DOX)-loaded hydrogels exhibited pH-responsive drug release profiles in vitro, which were composed of rapid release at acidic pH and more sustained release at neutral pH. Thus, these polypeptide hydrogels hold potential as depots for environment-responsive delivery of therapeutic agents.

Elective Endovascular vs Open Repair for Elective Abdominal Aortic Aneurysm in Patients ≥80 years of Age: A Systematic Review and Meta-Analysis.

OBJECTIVE: To provide updated, pooled evidence on clinical outcomes among octogenarians (aged ≥80 years) with abdominal aortic aneurysm (AAA) managed by elective endovascular repair, compared to conventional open repair. METHODS: PubMed, Embase, and Scopus databases were systematically searched. Studies that were either observational or randomized controlled trials were considered for the review. Included studies were conducted in elderly subjects (≥80 years) with AAA, and clinical and mortality outcomes were compared between endovascular and open surgical repair. Those reporting on outcomes of patients with urgent repair were excluded. The primary outcomes of interest were mortality and risk of complications. The pooled effect sizes were reported as odds ratio (OR) for categorical outcomes and weighted mean difference (WMD) for continuous outcomes. STATA software was used for statistical analysis. RESULTS: The meta-analysis included 15 studies. Compared to those undergoing open repair, patients receiving endovascular repair had significantly reduced risk of immediate post-operative mortality (OR .23, 95% CI: .20, .27), overall complication (OR .30, 95% CI: .20, .44), cardiac (OR .23, 95% CI: .16, .35), renal (OR .29, 95% CI: .18, .46), pulmonary (OR .14, 95% CI: .09, .21) and bleeding related (OR .59, 95% CI: .42, .83) complications. The risk of mortality at latest follow up (at 36 months and 60 months) was similar in the two groups. The total blood loss (ml) (WMD -1126.47, 95% CI: -1497.81, -755.13), operative time (min) (WMD -29.40, 95% CI: -56.19, -2.62), length of intensive care unit stay (days) (WMD -2.27, 95% CI: -3.43, -2.12) and overall hospital stay (days) (WMD -6.64, 95% CI: -7.60, -5.68) was significantly lower in those undergoing endovascular repair. CONCLUSIONS: Endovascular repair appears to be better than open repair of AAA in this high-risk, frail population, with respect to short term outcomes. The benefits of reduced risk of short term mortality, complications, and better peri and post-operative outcomes may be considered when making a choice between these two surgical approaches. Randomized controlled trials are needed to provide reliable evidence on the effect of EVAR on long term survival.

Identification of Co-Expression Modules and Genes Associated With Tumor Progression in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a common head-and-neck cancer with a deficiency of early diagnosis and poor prognosis. To identify potential diagnostic and prognostic markers of OSCC, we firstly used weighted gene co-expression network analysis (WGCNA) to build a co-expression module from GSE42743. Next, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on specified units from selected modules utilizing Database for Annotation, Visualization, and Integrated Discovery (DAVID). Additionally, we identified and validate hub genes of these specified modules from multiple datasets like GEPIA and TCGA. In total 16 co-expression modules were built by 17,238 genes of 74 tumor samples utilizing WGCNA. Through pathway and functional enrichment analysis, the turquoise module was most firmly relevant to the cell cycle, oocyte meiosis, and p53 signaling pathway. Hub genes VRK1, NUP37, HMMR, SPC25, and RUVBL1 were identified to be related to oral cancer at both molecular level and clinical levels. The expressions of these genes differed in tumor tissues and normal tissues. Meanwhile, patients with high hub gene expression had a poor prognosis clinically. To conclude, five hub genes were identified to be relevant to oral cancer from the molecular level and the clinical level. Therefore, the detection of these genes was of great significance. They can be regarded as diagnostic and prognostic biomarkers for oral cancer. Also, they could shed light on the improvement of patients' overall survival and prognosis, which needs further analysis in the future.

Identification of a new small molecule that initiates ferroptosis in cancer cells by inhibiting the system Xc- to deplete GSH.

Ferroptosis is a non-apoptotic cell death characterized by iron-mediated ROS accumulation and increasing lipid peroxidation. The activation of ferroptosis results in the destruction of cancer cells and overcoming the drug resistance associated with existing chemotherapeutic agents. It is essential to develop new ferroptosis inducers to provide new opportunities for cancer therapy. In this study, we found a small molecule Compound 8 which we had demonstrated to inhibit tumor growth in vivo initiated ferroptosis. Compound 8 treatment elevated the ferroptosis-related genes PTGS2 and CHAC1 mRNA levels in tumor cells. Ferroptosis inhibitors but not the necroptosis inhibitor or the apoptosis inhibitor can suppress the cell death induced by Compound 8. Compound 8 causes overall greater quantity of lipid peroxidation than the classic ferroptosis inducer Erastin through Flow cytometry analysis. The non-targeted lipidomic analysis also showed Compound 8 treatment resulted in oxidized lipid metabolites, similar to Erastin. The mechanism research showed that Compound 8 initiated ferroptosis by inhibiting the system Xc- to deplete GSH. Based on our previous study that Compound 8 blocked the interaction of PKM2 and VDAC3 (a regulator of ferroptosis) to inhibit tumor growth in vivo, Compound 8 may also trigger ferroptosis by regulating VADC3. Thus, Compound 8 not only will offer a potential tumor therapeutic alternative, but also provide an entrance to explore the new mechanism of ferroptosis.

Identification of the alpha linolenic acid metabolism-related signature associated with prognosis and the immune microenvironment in nasopharyngeal carcinoma.

Background: Tumor metabolism is important for cancer progression. Nevertheless, the role of the metabolism pathway and related molecules in nasopharyngeal carcinoma (NPC) is limited. Methods: Open-accessed data was downloaded from The Cancer Genome Atlas database. All the analysis was performed using the R software and the package in R environments. Results: In our study, we firstly explored the role of 21 metabolism-related pathways in NPC patients. We found that the steroid biosynthesis and biosynthesis of unsaturated fatty acids were risk factors, while the alpha linolenic acid metabolism was a protective factor. Then, the alpha linolenic acid metabolism aroused our interest. A total of 128 differentially expressed genes (DEGs) were identified, including 71 downregulated and 57 upregulated genes identified between high and low alpha linolenic acid metabolism level. Based on these DEGs, we constructed a prognosis model including DEFB4B, FOXL2NB, MDGA2, RTL1, SLURP2, TMEM151B and TSPAN19, which showed great prediction efficiency in both training and validation cohorts. Clinical correlation analysis showed that high-risk patients might have worse clinical pathology parameters. Pathway enrichment analysis showed that riskscore was positively correlated with angiogenesis, DNA repair, G2/M checkpoints, IL6/JAK/STAT3 signaling, KRAS signaling up, WNT beta-catenin signaling, PI3K/AKT/mTOR signaling, yet positively correlated with inflammatory response, xenobiotic metabolism, TNF-α signaling via NFKB and interferon-gamma response. Immune infiltration analysis showed that the riskscore was positively correlated with the M2 and M0 macrophages, but negatively correlated with neutrophils, plasma cells, follicular helper T cells and resting dendritic cells Moreover, we found that the low-risk patients might be more sensitive to immunotherapy and lapatinib. Conclusions: In all, our study identified the genes associated with alpha linolenic acid metabolism and constructed an effective prognosis model which could robustly predict NPC patients prognosis.

Polymeric Nanoreactors with Chemically Tunable Redox Responsivity.

Bioresponsive nanomaterials are increasingly important in a variety of applications such as disease imaging, drug delivery, and tissue engineering. However, it remains a big challenge to manipulate response efficacy of such materials for performance optimization in a highly complex milieu in vivo. Here, we developed chemically adjustable nanoreactors (CANs) with the structure of polymeric cores and albumin shells to achieve tunable redox responsivity. In vitro characterization demonstrates stable, spherical nanoparticles of the CANs with a particle size of about 50 nm. The fluorescence activation ratios of the CANs are determined by various albumin modification densities on the shell. Meanwhile, the response sensitivity of the CANs to GSH levels (0.6-4 mM) can be tuned by acid-base properties of polymeric blocks in the core. This unique tunable redox responsivity enables the CANs suitable for probe optimization in cancer imaging both in vivo and at histological levels. Overall, this study offers a new design strategy for manipulation on performance of core/shell nanoreactors or bioresponsive nanomaterials.

Prognostic Significance of NLR, PLR, LMR and Tumor Infiltrating T Lymphocytes in Patients Undergoing Surgical Resection for Hilar Cholangiocarcinoma.

Objective: This study evaluated the prognostic significance of preoperative neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and tumor-infiltrating lymphocytes (TILs), and whether these preoperative blood inflammatory indicators were associated with TILs in hilar cholangiocarcinoma (HCCA). Methods: A total of 76 patients with HCCA who underwent radical resection were included. Data on their clinicopathologic characteristics, perioperative features, and survival outcomes were analyzed. The optimal cutoff levels for the NLR, PLR and LMR were defined by using the web application Cut-off Finder. The densities of specific immune cells (CD3+, CD4+, CD8+) within the tumor microenvironment were examined by immunohistochemical. The association of the number of CD3+, CD4+ and CD8+ T cells infiltration in the local tumor microenvironment with preoperative NLR, PLR and LMR level was analyzed. Survival curves were calculated using the Kaplan-Meier estimate. Univariate and multivariate logistic regression models were used to identify factors associated with overall survival. Results: The optimal cutoff value of preoperative NLR, PLR and LMR was 2.00, 117.60, and 4.02, respectively. NLR was significantly negatively correlated with CD3+ and CD8+ T cell infiltration, but not with CD4+ T cells. PLR had no correlation with CD3+, CD4+, or CD8+ T cell infiltration, while LMR had a significantly positive correlation with CD3+ T cells infiltration but not with CD4+ or CD8+ T cells. In the multivariate logistic regression model, T stage, lymph node metastasis, CA19-9 and LMR were independent risk factors associated with overall survival (OS). Survival curves indicated that HCCA patients with low CD3+ T cells infiltration and low preoperative LMR live shorter than others. Conclusions: LMR played as an independent factor for predicting the survival in patients with HCCA after R0 radical resection. A high LMR was associated with an accumulation of CD3+ T cells in HCCA.

Genome-wide identification and expression analysis of the R2R3-MYB gene family in tobacco (Nicotiana tabacum L.).

BACKGROUND: The R2R3-MYB transcription factor is one of the largest gene families in plants and involved in the regulation of plant development, hormone signal transduction, biotic and abiotic stresses. Tobacco is one of the most important model plants. Therefore, it will be of great significance to investigate the R2R3-MYB gene family and their expression patterns under abiotic stress and senescence in tobacco. RESULTS: A total of 174 R2R3-MYB genes were identified from tobacco (Nicotiana tabacum L.) genome and were divided into 24 subgroups based on phylogenetic analysis. Gene structure (exon/intron) and protein motifs were especially conserved among the NtR2R3-MYB genes, especially members within the same subgroup. The NtR2R3-MYB genes were distributed on 24 tobacco chromosomes. Analysis of gene duplication events obtained 3 pairs of tandem duplication genes and 62 pairs of segmental duplication genes, suggesting that segmental duplications is the major pattern for R2R3-MYB gene family expansion in tobacco. Cis-regulatory elements of the NtR2R3-MYB promoters were involved in cellular development, phytohormones, environmental stress and photoresponsive. Expression profile analysis showed that NtR2R3-MYB genes were widely expressed in different maturity tobacco leaves, and however, the expression patterns of different members appeared to be diverse. The qRT-PCR analysis of 15 NtR2R3-MYBs confirmed their differential expression under different abiotic stresses (cold, salt and drought), and notably, NtMYB46 was significantly up-regulated under three treatments. CONCLUSIONS: In summary, a genome-wide identification, evolutionary and expression analysis of R2R3-MYB gene family in tobacco were conducted. Our results provided a solid foundation for further biological functional study of NtR2R3-MYB genes in tobacco.

Ginsenoside compound K inhibits the proliferation, migration and invasion of Eca109 cell via VEGF-A/Pi3k/Akt pathway.

OBJECTIVE: Esophageal cancer, one of the most common cancers in the upper digestive tract and is one of the leading cancer-related mortality worldwide. Accumulating studies found that Ginsenoside compound K (CK) has significantly anti-tumor effects, especially in the suppression of proliferation, migration, as well as invasion in various human cancers. While the effects of Ginsenoside CK in esophageal cancer have not been well studied. In our present study, we aim to explore the functions and mechanisms of Ginsenoside CK in the progression of esophageal cancer cells (Eca109). METHODS: Cell Counting Kit-8 (CCK-8), wound healing, transwell and flow cytometry assays were applied to analyze the effects of Ginsenoside CK in the progression of Eca109 cell, western blot assay was used to investigate the potential downstream signaling pathway after Ginsenoside CK treatment. RESULTS: Our study found that Ginsenoside CK can suppress cell proliferation, migration and invasion of Eca109 cell. Furthermore, the flow cytometry showed that Ginsenoside CK increased of apoptosis rates in Eca109 cell. The western blot results indicated that Ginsenoside CK decreased the expression of VEGF-A, P-Pi3k and P-Akt proteins. Moreover, the knockdown of VEGF-A gene could suppress cell proliferation, migration, invasion and induce apoptosis in Eca109 cell, and the expression of P-Pi3k and P-Akt proteins were significantly downregulated. CONCLUSIONS: Our study suggests that Ginsenoside CK inhibits the proliferation, migration, invasion, and induced apoptosis of Eca109 cell by blocking VEGF-A/Pi3k/Akt signaling pathway.

Comparison of Safety of Different Vaccine Boosters Following Two-Dose Inactivated Vaccines: A Parallel Controlled Prospective Study.

A vaccine booster to maintain high antibody levels and provide effective protection against COVID-19 has been recommended. However, little is known about the safety of a booster for different vaccines. We conducted a parallel controlled prospective study to compare the safety of a booster usingfour common vaccines in China. In total, 320 eligible participants who had received two doses of an inactivated vaccine were equally allocated to receive a booster of the same vaccine (Group A), a different inactivated vaccine (Group B), an adenovirus type-5 vectored vaccine (Group C), or a protein subunit vaccine (Group D). A higher risk of adverse reactions, observed up to 28 days after injection, was found in Groups C and D, compared to Group A, with odds ratios (OR) of 11.63 (95% confidence interval (CI): 4.22-32.05) and 4.38 (1.53-12.56), respectively. Recipients in Group C were more likely to report ≥two reactions (OR = 29.18, 95% CI: 3.70-229.82), and had a higher risk of injection site pain, dizziness, and fatigue. A gender and age disparity in the risk of adverse reactions was identified. Despite the majority of reactions being mild, heterologous booster strategies do increase the risk of adverse reactions, relative to homologous boosters, in subjects who have had two doses of inactive vaccine.

Manganese-based multifunctional nanoplatform for dual-modal imaging and synergistic therapy of breast cancer.

Manganese has recently been exploited for cancer immunotherapy, fenton-like reaction-mediated chemo-dynamic therapy, and magnetic resonance imaging. The integration of multiple roles of manganese into one platform is of great significance for cancer theranostics and tumor inhibition. Here, we designed a multifunctional nanoplatform based on manganese, which consisted of a manganese-containing inner core and a phospholipid bilayer shell co-loaded with glucose oxidase (GOx), paclitaxel (PTX), and a NIR fluorescent dye (NanoMn-GOx-PTX). In a pH-dependent manner, the nanoplatform released manganese ions and payloads inside the tumor cells. In vitro characterization and cellular experiments indicated that NanoMn-GOx-PTX could catalyze the conversion of glucose into reactive oxygen species (ROS) through a cascade Fenton-like reaction as well as release free PTX. The consumption of glucose, ROS production, and the chemotherapeutic effect of PTX contributed to the superior cytotoxicity and apoptosis of 4T1 cancer cells. Moreover, NanoMn-GOx-PTX effectively induced the production of large amounts of type I interferon and pro-inflammatory cytokines in vivo, activating the innate immune response. Through the synergistic functions of the above components, NanoMn-GOx-PTX exerted the strongest anti-tumor effect in 4T1 tumor-bearing models. Therefore, the manganese-based nanoplatform could serve as a promising theranostic tool for breast cancer therapy. STATEMENT OF SIGNIFICANCE: 1) This nanoplatform can be used as a universal tool for delivering proteins and anticancer drugs into cells; 2) The PEG-modified phospholipid bilayer shell plays a significant role in retarding the release of overloaded manganese ions and drugs in a pH-sensitive manner; 3) The released Mn2+ has the ability to enhance T1 contrast in magnetic resonance imaging; 4) The released Mn2+ can function as nanoadjuvants to activate the cGAS-STING pathway and effectively induce the natural immune response;5) The overloaded manganese ions are combined with glucose oxidase to form a cascade reaction system, indirectly converting glucose into ROS to induce oxidative damage of tumor tissue.

PTENα functions as an immune suppressor and promotes immune resistance in PTEN-mutant cancer.

PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. PTEN mutations have been implicated in immune regulation, however, the underlying mechanism is largely unknown. Here, we report that PTENα, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8+ T cell-mediated cytotoxicity, PTENα leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTENα-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTENα-inactive mutations. Furthermore, germline deletion of Ptenα in mice increases cell susceptibility to immune attack through augmenting stress granule formation and limiting synthesis of peroxidases, leading to massive oxidative cell death and severe inflammatory damage. We propose that PTENα protects tumor from T cell killing and thus PTENα is a potential target in antitumor immunotherapy.