Antitumor activity of dictamnine against colorectal cancer through induction of ferroptosis and inhibition of M2 macrophage polarization via the MAPK signaling.

Colorectal cancer (CRC) is an aggressive cancer type globally. Surgery and chemotherapy are often ineffective at curing CRC. Dictamnine is a natural product derived from Dictamnus dasycarpus Turcz. root bark and possesses multi-pharmacological properties, including anticancer effects. Nevertheless, the biological roles and the possible mechanism of dictamnine in CRC are still unclear. Here, we demonstrated that dictamnine blocked cell viability and proliferation in DLD-1 human colorectal adenocarcinoma cells and LoVo human colon cancer cells. Dictamnine triggered CRC cell ferroptosis, as evidenced by enhanced levels of reactive oxygen species, malondialdehyde, and Fe2+ levels, alongside downregulation of glutathione peroxidase 4 protein expression. In addition, CD163 (HPA ID: HPA046404) was highly expressed and CD68 (HPA ID: CAB000051) was lowly expressed in CRC tissues and CRC cell culture medium-cultured THP-1 monocytes-derived macrophages. The patients with CD163 low-expression lived much longer than those with CD163 high-expression, indicating that M2 polarization of macrophages was related to poor prognosis of CRC. Dictamnine markedly inhibited CD163 protein expression, transforming growth factor-ß and arginase 1 mRNA expressions and IL-10 production in macrophages with CRC cell co-culture, suggesting that dictamnine impeded M2 polarization of macrophages. Mechanistically, dictamnine repressed ERK phosphorylation in CRC cells. The treatment with the ERK activator tBHQ counteracted the effects of dictamnine on CRC cell proliferation and ferroptosis, as well as its inhibitory effect on M2 polarization of macrophages. Results of a xenograft model showed that dictamnine effectively hindered CRC tumor growth in vivo. Collectively, these data provide evidence for the clinical trials of dictamnine as a novel drug for CRC therapy.

Regulatory function and mechanism research for m6A modification WTAP via SUCLG2-AS1- miR-17-5p-JAK1 axis in AML.

Acute myeloid leukemia (AML), characterized by the abnormal accumulation of immature marrow cells in the bone marrow, is a malignant tumor of the blood system. Currently, the pathogenesis of AML is not yet clear. Therefore, this study aims to explore the mechanisms underlying the development of AML. Firstly, we identified a competing endogenous RNA (ceRNA) SUCLG2-AS1-miR-17-5p-JAK1 axis through bioinformatics analysis. Overexpression of SUCLG2-AS1 inhibits proliferation, migration and invasion and promotes apoptosis of AML cells. Secondly, luciferase reporter assay and RIP assay validated that SUCLG2-AS1 functioned as ceRNA for sponging miR-17-5p, further leading to JAK1 underexpression. Additionally, the results of MeRIP-qPCR and m6A RNA methylation quantification indicted that SUCLG2-AS1(lncRNA) had higher levels of m6A RNA methylation compared with controls, and SUCLG2-AS1 is regulated by m6A modification of WTAP in AML cells. WTAP, one of the main regulatory components of m6A methyltransferase complexes, proved to be highly expressed in AML and elevated WTAP is associated with poor prognosis of AML patients. Taken together, the WTAP-SUCLG2-AS1-miR-17-5p-JAK1 axis played essential roles in the process of AML development, which provided a novel therapeutic target for AML.

Identification of RECK as a protective prognostic indicator and a tumor suppressor through regulation of the ERK/MAPK signaling pathway in gastric cancer.

BACKGROUND: Gastric cancer (GC) ranks as the fifth most common cancer worldwide and is characterized by its significant heterogeneity and unfavorable prognosis. Thus, identifying efficient prognostic factors and understanding the underlying molecular mechanisms in GC are essential for improving patient outcomes. In this study, we aimed to investigate the role of RECK (reversion-inducing cysteine-rich protein with Kazal motifs) in the prognostic significance and molecular mechanisms of its biological function in GC. METHODS: Multiple bioinformatics strategies were performed to detect the potential functions and prognostic efficiency of RECK in GC. Rescue experiments revealed that the molecular mechanism by which RECK in inhibited tumor proliferation, migration, and invasion was mediated by ERK/MAPK signaling in AGS and HGC-27 cells. Using integrated bioinformatics analysis and western blot assay, we investigated the potential interaction between CALD1 and RECK. RESULTS: Our findings revealed significantly decreased RECK expression in GC samples compared to normal samples and RECK was identified as a promising predictor for the prognosis of GC patients. Moreover, upregulation of RECK demonstrated a distinctly positive association with a high-immunity and low-metastasis microenvironment in GC. Mechanistically, the antitumour effects of RECK on hampering tumor cell growth, migration, and invasion were mediated by the ERK/MAPK signaling pathway. In addition, we also illustrated that RECK inhibited the phosphorylation of CALD1 mediated by decreased phosphorylation of ERK. CONCLUSIONS: RECK is a promising prognostic biomarker and may shape a high-tumor-immunity and low-metastasis microenvironment in patients with GC. Moreover, RECK exerted its tumor-suppressive effects by the inactivation of ERK/MAPK signaling in GC cells.

Novaferon gene modification promotes NK92 cell anti-tumor activity.

With significant developments in chimeric antigen receptor T-cell therapy, adoptive immunotherapy has unlocked new levels of treatment for malignancies. Natural killer (NK) cells are promising alternative immune effector cells for this strategy. Multiple anti-tumor therapies are largely dependent on type I interferon (IFN) signaling. Type I IFNs enhance NK cell cytotoxicity. Novaferon (nova) is an unnatural, novel IFN-like protein produced by gene shuffling of IFN-α with strong biological activity. To augment the antitumor activity of NK cells, we generated NK92-nova cells that stably express nova. We found that NK92-nova cells mediated enhanced pan-cancer antitumor activity compared to NK92-vec cells. The increased antitumor activity was associated with the enhanced secretion of cytokines, such as IFN-γ, perforin, and granzyme B. Meanwhile, most of the activating receptors were upregulated in the NK92-nova cells. After co-culture with NK92-nova cells, the expression of NKG2D ligands on the HepG2 cells increased, resulting in an enhanced susceptibility of HepG2 cells to NK92 cell-mediated cytolysis. NK92-nova cells significantly inhibited HepG2 tumor growth in a xenograft model without systemic toxicity. Therefore, NK92-nova cells are a novel and safe strategy for cancer immunotherapy.

Chronic Remote Ischemic Conditioning on Mild Hypertension in the Absence of Antihypertensive Medication: A Multicenter, Randomized, Double-Blind, Proof-of-Concept Clinical Trial.

BACKGROUND: Exploratory studies have shown that remote ischemic conditioning (RIC) has the potential to lower blood pressure (BP). We investigated whether chronic RIC reduces BP for hypertension. METHODS: This is a multicenter, randomized, double-blind, parallel-controlled trial. Patients with an office BP of 130/80 to 160/100 mm Hg and a 24-hour average BP ≥125/75 mm Hg not on antihypertensive medications were recruited. After a 1-week compliance screening phase, they were randomly assigned in a 1:1 ratio to receive RIC or sham RIC twice daily for 4 weeks. The primary efficacy outcome was the change in 24-hour average systolic BP from baseline to 4 weeks. Safety events were assessed over the study period. RESULTS: Ninety-five participants were randomly allocated to the RIC (n=49) and sham RIC (n=46) groups. In the intention-to-treat analysis, the reduction in 24-hour average systolic BP was greater in the RIC group than the sham RIC group (-4.6±9.5 versus -0.9±6.8 mm Hg; baseline-adjusted between-group mean difference: -3.6 mm Hg [95% CI, -6.9 to -0.3 mm Hg]; adjusted P=0.035). The per-protocol analysis showed that 24-hour average systolic BP reduced -5.9±8.6 mm Hg in the RIC group and -0.7±6.7 mm Hg in the sham RIC group (baseline-adjusted between-group mean difference: -5.2 mm Hg [95% CI, -8.5 to -1.9 mm Hg]; adjusted P=0.002). No major adverse events were reported in both groups. CONCLUSIONS: RIC is safe in patients with mild hypertension and may lower BP in the absence of antihypertensive medications. However, the effects of RIC on clinical outcomes in these patients require further investigation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04915313.

Identification and Analysis of Stress-Associated Proteins (SAPs) Protein Family and Drought Tolerance of ZmSAP8 in Transgenic Arabidopsis.

Stress-associated proteins (SAPs), a class of A20/AN1 zinc finger proteins, play vital roles in plant stress response. However, investigation of SAPs in maize has been very limited. Herein, to better trace the evolutionary history of SAPs in maize and plants, 415 SAPs were identified in 33 plant species and four species of other kingdoms. Moreover, gene duplication mode exploration showed whole genome duplication contributed largely to SAP gene expansion in angiosperms. Phylogeny reconstruction was performed with all identified SAPs by the maximum likelihood (ML) method and the SAPs were divided into five clades. SAPs within the same clades showed conserved domain composition. Focusing on maize, nine ZmSAPs were identified. Further promoter cis-elements and stress-induced expression pattern analysis of ZmSAPs indicated that ZmSAP8 was a promising candidate in response to drought stress, which was the only AN1-AN1-C2H2-C2H2 type SAP in maize and belonged to clade I. Additionally, ZmSAP8 was located in the nucleus and had no transactivation activity in yeast. Overexpressing ZmSAP8 enhanced the tolerance to drought stress in Arabidopsis thaliana, with higher seed germination and longer root length. Our results should benefit the further functional characterization of ZmSAPs.

Rapidly progressive IgA nephropathy: clinicopathological characteristics and outcomes assessed according to the revised definition of the KDIGO 2021 Guideline.

BACKGROUND: Rapidly progressive immunoglobulin A nephropathy (RPIgAN) is a severe clinical phenotype of IgAN associated with a poor outcome. The recently published Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Guideline for the Management of Glomerular Diseases has proposed a new definition for RPIgAN that is based simply on a ≥50% decline in the estimated glomerular filtration rate (eGFR) over ≤3 months. METHODS: In 1677 IgAN patients followed at a single centre in China, we evaluated the utility of this new definition to identify the highest-risk IgAN patients who might be suitable for combination immunosuppressive therapy. RESULTS: The proportion of a ≥50% decline in eGFR over ≤3 months was 5.2%. The majority of these patients had reversible causes, with only 2.3% (39/1677) meeting the KDIGO 2021 criteria for RPIgAN. These patients had a significantly higher risk for end-stage kidney disease (ESKD) than non-RPIgAN patients (logrank P < 0.001). RPIgAN was an independent risk factor for ESKD [hazard ratio 3.99 (95% confidence interval 2.25-7.09); P <0.001]. A minority of the RPIgAN patients (25.6%) had ≥50% crescents. There was no significant difference in the risk for ESKD between patients in the RPIgAN group with ≥50% crescents and ˂50% crescents (logrank P = 0.27). Patients with RPIgAN and ≥50% crescents had a higher risk for ESKD than patients with non-RPIgAN and ≥50% crescents (logrank P = 0.04). CONCLUSIONS: These data support the validity of the KDIGO 2021 definition but require independent validation in other non-Chinese cohorts.

Remodeling of occluded internal carotid artery in vessel wall magnetic resonance imaging.

OBJECTIVE: The purpose of the present study was to investigate the remodeling pattern of the extracranial occluded internal carotid artery (OICA) by vessel wall magnetic resonance imaging (VWI). METHODS: Thirty-nine atherosclerotic OICAs from 32 consecutive cases underwent 3-Tesla VWI to acquire pre- and post-contrast T1-weighted two-dimensional fluid-attenuated inversion recovery fast spin echo sequences. 25 symptomatic CAs exhibited ipsilateral downstream cerebral ischemia or ophthalmic artery embolism within last three months. The 14 remaining CAs were asymptomatic. Twenty-four CAs from 22 patients with atherosclerosis but no stenosis were recruited as control group. The outer wall area (OWA) was calculated based on the outer contour of the carotid artery drawn on the pre-contrast VWI. Negative remodeling was defined as a lower OWA compared to that of control group. RESULTS: Clinical characteristics including age, sex and vascular risk factors showed no significant difference between the occluded and control group. However, the OWA was lower in the occluded group than in the control group (0.63 versus 0.90 cm2, p = 0.004). For all OICAs, the OWA was larger in symptomatic cases than asymptomatic cases (0.71 versus 0.49cm2, p = 0.025). Using a cutoff value of 0.44, the sensitivity and specificity of OWA for detecting symptomatic OICA were 0.88 and 0.57, respectively. Heterogeneous signal intensity and enhancement were more often observed at the proximal than the distal segment of occlusion (p < 0.001). The inter-observer agreement regarding the evaluation of VWI characteristics was desirable (κ = 0.805 ∼ 0.847). CONCLUSIONS: Negative remodeling is prevalent in OICA, especially in asymptomatic cases.

KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is challenging in clinical practice due to the poor understanding of molecular mechanisms and limited therapeutic targets. Herein, the work aimed to use bioinformatics to identify a promising molecular target for LUAD therapy. METHODS: Differentially expressed genes (DEGs) from the Cancer Genome Atlas (TCGA) dataset were used for a weighted gene co-expression network analysis (WGCNA) to screen the hub gene. After a prognostic estimation with meta-analysis and COX regression analysis, we performed a function analysis on the corresponding gene. The ESTIMATE and CIBERSORT methods were adopted to analyze the association of the hub gene with the tumor microenvironment (TME). A cohort of functional assays was conducted to establish the functional roles of the hub gene in A549 and PC-9 cells. RESULTS: Our screen identified KIF11 as a prognostic factor, which indicated the poor overall survival and the worse progression-free survival in LUAD patients. Additionally, KIF11 was primarily involved in cell cycle, TME alteration and tumor-infiltrating immune cells proportions. KIF11 knockdown exerted inhibitory effects on cell proliferation, migration, and invasion. Results of the flow cytometry analysis revealed that KIF11 knockdown induced a G2/M phase arrest and improved apoptosis in LUAD cells. CONCLUSIONS: KIF11 is essential for LUAD cell proliferation and metastasis, and it may serve as an independent prognostic factor as well as a promising therapeutic target for LUAD patients.

Evaluation of the Oxford classification in immunoglobulin A vasculitis with nephritis: a cohort study and meta-analysis.

BACKGROUND: Similarities in clinicopathological presentations in immunoglobulin A (IgA) nephropathy and IgA vasculitis with nephritis (IgAVN) raise the question of the utility of the Oxford classification in the latter. The aim of this study was to evaluate the Oxford classification in IgAVN. METHODS: We conducted a retrospective cohort study and meta-analysis following systematic searching of the MEDLINE and Excerpta Medica Database (EMBASE) databases between January 2009 and September 2019. We modeled the association of 30 and 50% decline in estimated glomerular filtration rate or end-stage renal disease with pathologic lesions of the Oxford classification including mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), interstitial fibrosis/tubular atrophy (T) and crescents (C). Results were pooled using random-effects meta-analysis. RESULTS: The cohort study included 132 patients, and only T lesion was an independently risk factor in IgAVN. The meta-analysis yielded six retrospective studies with 721 patients and 139 endpoints. In multivariate model, T lesion was significantly associated with renal outcome (hazard ratio = 2.45, P = 0.007). M and C lesions could not predict renal outcome without evidence of heterogeneity. E and S lesions could not predict renal outcome with evidence of heterogeneity (I 2 = 66.6%; P = 0.01, and I 2 = 65.8%; P = 0.03, respectively). Subgroup analysis showed that the possible reasons to the heterogeneity were from usage of immunosuppressant, sample size and follow-up time. CONCLUSIONS: The study suggests that the Oxford classification could not be fully validated in IgAVN. Higher portion of immunosuppressant especially before renal biopsy might be the main confounder for the predictive value of Oxford classification in IgAVN.

Eosinophilic peritonitis and nephrotic syndrome in Kimura's disease: a case report and literature review : Eosinophilic peritonitis in Kimura's disease.

BACKGROUND: Eosinophilic peritonitis is a relatively rare entity. Kimura's disease is a rare chronic inflammatory disorder of unknown etiology, characterized by subcutaneous nodules mainly in the head and neck region, regional lymphadenopathy and occasional involvement of kidney. There is currently no report of eosinophilic peritonitis in Kimura's disease. CASE PRESENTATION: A 44-year-old Chinese man presented with abdominal distention, nausea, vomiting and edema in lower limbs for 1 month. Laboratory data showed elevated eosinophils in peripheral blood and ascites, nephrotic syndrome with progressively renal dysfunction, and elevated IgE. Ultrasonography of lymph nodes showed multiple lymphadenopathy in bilateral inguinal regions. Surgical excision was performed for one of the enlarged lymph nodes and histopathology revealed diagnosis of Kimura's disease. Renal biopsy indicated focal segmental glomerulosclerosis (FSGS) and acute tubulointerstitial nephritis with infiltration of eosinophils in renal interstitium. The patient was prescribed with oral prednisolone therapy (30 mg/day), and underwent continuous ambulatory peritoneal dialysis (CAPD). The peripheral and peritoneal eosinophil count decreased rapidly and normalized within 2 days. Forty-five days after prednisolone therapy, partial remission of nephrotic syndrome and decrease of serum creatinine were achieved while peritoneal dialysis dosage had decreased. Inguinal lymph nodes gradually shrunk in size. The overall conditions remain stable afterwards. CONCLUSIONS: This rare case highlighted the clinical conundrum of a patient presenting with eosinophilic peritonitis, lymphadenopathy, nephrotic syndrome and renal failure associated with Kimura's disease. The remarkable eosinophilia, pathology of lymph node and kidney, as well as significant response to steroids should guide towards the diagnosis.

Integrated analysis of a ceRNA network reveals potential prognostic lncRNAs in gastric cancer.

Long noncoding RNAs (lncRNAs) have important biological functions as competing endogenous RNAs (ceRNAs) in tumors, yet the functions and regulatory mechanisms of lncRNA-related ceRNAs in gastric cancer have not been fully elucidated. In this study, we constructed a lncRNA-miRNA-mRNA ceRNA network and identified potential lncRNA biomarkers in gastric cancer. Basing on the RNA profiles downloaded from The Cancer Genome Atlas (TCGA) platform, the gastric cancer-specific differentially expressed lncRNAs, miRNAs, and mRNAs were screened for constructing a ceRNA network using bioinformatic tools. The enrichment analysis of the biological processes in Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathways was performed on the ceRNA-related DEmRNAs. According to the modularization of protein-protein interaction (PPI) network, we extracted a ceRNA subnetwork and analyzed the correlation between the expression of the lncRNAs involved and specific clinical features of patients. Next, the expression of highly up-regulated in liver cancer (HULC) and RP11-314B1.2 showed significant changes in several pathological processes involved in gastric cancer, and nine lncRNAs were found to be correlated with the overall survival of patients with gastric cancer. Through the univariate and multivariate Cox regression analyses, two lncRNAs (LINC00106 and RP11-999E24.3) were identified and utilized to establish a risk score model for assessing the prognosis of patients. The analysis results were also partially verified using quantitative real-time PCR. The findings from this study indicate that HULC, RP11-314B1.2, LINC00106, and RP11-999E24.3 could be considered as potential therapeutic targets or prognostic biomarkers in gastric cancer, and provide a new perspective for cancer pathogenesis research.

Circular RNA profiling of neutrophil transcriptome provides insights into asymptomatic Moyamoya disease.

Moyamoya disease (MMD) is a rare cerebrovascular disorder with higher incidences in Eastern Asian countries but the natural course remains uncertain. Circular RNAs (circRNAs) have been implicated in brain disorders, but their role in the development of MMD is unclear. Neutrophil depletion has been shown to affect stem cell migration, fate, and therapeutic outcomes. We investigated the circRNAs expression profile of neutrophil transcriptome in patients with asymptomatic MMD. Microarray based circRNAs profiling was determined between neutrophil samples from patients with asymptomatic MMD and healthy subjects. The microarray results were followingly confirmed by quantitative reverse-transcription PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses (KEGG) were adopted for annotation and predicting the functions of differentially expressed circRNAs. From this comparative circRNA microarray analysis of neutrophil samples from patients with asymptomatic MMD and healthy subjects, 123 circRNAs were identified differentially expressed between the two groups. Of these, 54 were upregulated and 69 were downregulated compared to controls (fold change >2.0 and P < 0.05). GO and KEGG analyses revealed that the differentially expressed circRNAs were mainly involved in immune responses, angiogenesis and metabolism in asymptomatic MMD. Besides, the hypoxia inducing factor-1α signaling pathway was found to be the critical pathway involved in the angiogenesis of disease pathogenesis. This is a pilot study on the neutrophils from the asymptomatic MMD and aberrantly expressed circRNAs in the profiling obtained by high-throughput microarray may help provide insights into MMD.

Selecting Multiple Biomarker Subsets with Similarly Effective Binary Classification Performances.

Biomarker detection is one of the more important biomedical questions for high-throughput 'omics' researchers, and almost all existing biomarker detection algorithms generate one biomarker subset with the optimized performance measurement for a given dataset. However, a recent study demonstrated the existence of multiple biomarker subsets with similarly effective or even identical classification performances. This protocol presents a simple and straightforward methodology for detecting biomarker subsets with binary classification performances, better than a user-defined cutoff. The protocol consists of data preparation and loading, baseline information summarization, parameter tuning, biomarker screening, result visualization and interpretation, biomarker gene annotations, and result and visualization exportation at publication quality. The proposed biomarker screening strategy is intuitive and demonstrates a general rule for developing biomarker detection algorithms. A user-friendly graphical user interface (GUI) was developed using the programming language Python, allowing biomedical researchers to have direct access to their results. The source code and manual of kSolutionVis can be downloaded from http://www.healthinformaticslab.org/supp/resources.php.

Improvement of Eco-Efficiency in China: A Comparison of Mandatory and Hybrid Environmental Policy Instruments.

China's environmental problems have long been criticized. The Communist Party of China (CPC) and the government have increasingly paid attention to developing environmental protection and included the construction of an ecological civilization in the "Five-in-One" development strategy. The improvement of regional eco-efficiency is an important way to realize the coordinated development of the entire society, and environmental policy instruments are a powerful means to enhance regional eco-efficiency. This paper categorizes environmental policy instruments into mandatory, hybrid, and voluntary types. Based on panel data from 31 provinces in China from 2005 to 2015, the paper discusses the impact of environmental policy instruments on regional eco-efficiency and the means of the impact. The research shows that (1) mandatory and hybrid environmental policy instruments play a significant role in promoting regional eco-efficiency, while the role of voluntary instruments is not significant in promoting regional eco-efficiency; (2) hybrid and mandatory environmental policy instruments have negative interactions; and (3) the level of economic development will positively affect the role of hybrid environmental policy instruments in promoting regional eco-efficiency but negatively affect the role of mandatory instruments in promoting regional efficiency.

A novel schiff base zinc coordination compound inhibits proliferation and induces apoptosis of human osteosarcoma cells.

Various kinds of schiff base metal complexes have been proven to induce apoptosis of tumor cells. However, it remains largely unknown whether schiff base zinc complexes induce apoptosis in human cancer cells. Here, we synthesized a novel schiff base zinc coordination compound (SBZCC) and investigated its effects on the growth, proliferation and apoptosis of human osteosarcoma MG-63 cells. A novel SBZCC was synthesized by chemical processes and used to treat MG-63 cells. The cell viability was determined by CCK-8 assay. The cell cycle progression, mitochondrial membrane potential and apoptotic cells were analyzed by flow cytometry. The apoptosis-related proteins levels were determined by immunoblotting. Treatment of MG-63 cells with SBZCC resulted in inhibition of cell proliferation and cell cycle arrest at G1 phase. Moreover, SBZCC significantly reduced the mitochondrial membrane potential and induced apoptosis, accompanied with increased Bax/Bcl-2 and FlasL/Fas expression as well as caspase-3/8/9 cleavage. Our results demonstrated that the synthesized novel SBZCC could inhibit the proliferation and induce apoptosis of MG-63 cells via activating both the mitochondrial and cell death receptor apoptosis pathways, suggesting that SBZCC is a promising agent for the development as anticancer drugs.