Highly homologous miR-135a and miR-135b converting non-small cell lung cancer from suppression to progression via enhancer switching.

microRNAs (miRNAs) are short non-coding RNAs that have been increasingly recognized for their significant roles in the progression of cancer. Distinct miRNAs exhibit diverse functions attributed to variations in their sequences. As a result of possessing highly homologous seed sequences, these miRNAs target overlapping or similar gene sets, thus performing analogous roles. However, different from this sight, our study discovered that miR-135a-5p and miR-135b-5p, despite differing by only one nucleotide, exhibit distinct functional roles. Using non-small cell lung cancer (NSCLC) as a paradigm, our findings unveiled the downregulation of miR-135a-5p and upregulation of miR-135b-5p within NSCLC through TCGA database. Consequently, we further investigated their functional differences in A549 cells. Overexpression of miR-135b-5p enhanced the proliferation and migration capabilities of A549 cells, whereas miR-135a-5p transfection exhibited the opposite effect. We demonstrated that the activation of specific enhancers serves as a crucial mechanism underlying the disparate functions exerted by miR-135a-5p and miR-135b-5p in the context of NSCLC, consequently instigating a shift from inhibition to activation in NSCLC progression. Finally, we validated through animal experiments that miR-135b-5p promoted tumor progression, while miR-135a-5p exerted inhibitory effects on NSCLC development. This study offers a novel perspective for researchers to elucidate functional disparities exhibited by highly homologous miRNAs (miR-135a-5p and miR-135b-5p) in the context of NSCLC, along with the transition from inhibitory to progressive states in NSCLC. This study provides a solid foundation for future investigations into the functional roles of highly homologous miRNAs in pathological situation.

CMAUP database update 2024: extended functional and association information of useful plants for biomedical research.

Knowledge of the collective activities of individual plants together with the derived clinical effects and targeted disease associations is useful for plant-based biomedical research. To provide the information in complement to the established databases, we introduced a major update of CMAUP database, previously featured in NAR. This update includes (i) human transcriptomic changes overlapping with 1152 targets of 5765 individual plants, covering 74 diseases from 20 027 patient samples; (ii) clinical information for 185 individual plants in 691 clinical trials; (iii) drug development information for 4694 drug-producing plants with metabolites developed into approved or clinical trial drugs; (iv) plant and human disease associations (428 737 associations by target, 220 935 reversion of transcriptomic changes, 764 and 154121 associations by clinical trials of individual plants and plant ingredients); (v) the location of individual plants in the phylogenetic tree for navigating taxonomic neighbors, (vi) DNA barcodes of 3949 plants, (vii) predicted human oral bioavailability of plant ingredients by the established SwissADME and HobPre algorithm, (viii) 21-107% increase of CMAUP data over the previous version to cover 60 222 chemical ingredients, 7865 plants, 758 targets, 1399 diseases, 238 KEGG human pathways, 3013 gene ontologies and 1203 disease ontologies. CMAUP update version is freely accessible at https://bidd.group/CMAUP/index.html.

NPASS database update 2023: quantitative natural product activity and species source database for biomedical research.

Quantitative activity and species source data of natural products (NPs) are important for drug discovery, medicinal plant research, and microbial investigations. Activity values of NPs against specific targets are useful for discovering targeted therapeutic agents and investigating the mechanism of medicinal plants. Composition/concentration values of NPs in individual species facilitate the assessments and investigations of the therapeutic quality of herbs and phenotypes of microbes. Here, we describe an update of the NPASS natural product activity and species source database previously featured in NAR. This update includes: (i) new data of ∼95 000 records of the composition/concentration values of ∼1 490 NPs/NP clusters in ∼390 species, (ii) extended data of activity values of ∼43 200 NPs against ∼7 700 targets (∼40% and ∼32% increase, respectively), (iii) extended data of ∼31 600 species sources of ∼94 400 NPs (∼26% and ∼32% increase, respectively), (iv) new species types of ∼440 co-cultured microbes and ∼420 engineered microbes, (v) new data of ∼66 600 NPs without experimental activity values but with estimated activity profiles from the established chemical similarity tool Chemical Checker, (vi) new data of the computed drug-likeness properties and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties for all NPs. NPASS update version is freely accessible at http://bidd.group/NPASS.

Ultrasound had high accuracy in measuring hip joint capsule thickness.

BACKGROUND: The hip joint capsule is an essential component of hip joint function and stability, and its thickness is closely associated with certain medical conditions, surgical outcomes, and rehabilitation treatments. Currently, in clinical practice, hip joint capsule thickness is predominantly measured using magnetic resonance imaging (MRI), with limited utilization of ultrasound examinations for this purpose. METHODS: We retrospectively evaluated patients who visited our Sports Medicine Department between February 2017 and March 2023 and underwent both hip joint MRI and ultrasound imaging on the same side. All patients had undergone preoperative hip joint MRI and ultrasound examinations, with the time gap between the two examinations not exceeding three months. Measurements of hip joint capsule thickness were taken on both MRI and ultrasound images for the same patients to analyze their consistency. Additionally, we measured the alpha angle, lateral center-edge angle, acetabular anteversion angle, and femoral anteversion angle of the patients' hip joints and analyzed their correlation with hip joint capsule thickness measure by ultrasound. RESULTS: A total of 307 patients were included in this study, with hip joint capsule thickness measured by MRI and ultrasound being 5.0 ± 1.2 mm and 5.0 ± 1.5 mm, respectively. The Bland-Altman analysis demonstrates good agreement or consistency. The paired t-test resulted in a p-value of 0.708, indicating no significant statistical difference between the two methods. The correlation analysis between acetabular anteversion angle and ultrasound-measured capsule thickness yielded a p-value of 0.043, indicating acetabular anteversion angle and capsular thickness may have negative correlation. CONCLUSIONS: The measurements of joint capsule thickness obtained through ultrasound and MRI showed good consistency, suggesting that ultrasound can be used in clinical practice as a replacement for MRI in measuring hip joint capsule thickness. There was a significant correlation between acetabular anteversion angle and hip joint capsule thickness, indicating potential for further research in this area.

Degradation of Sodium Acetate by Catalytic Ozonation Coupled with MnOx/NiOOH-Modified Fly Ash.

Fly ash, a type of solid waste generated in power plants, can be utilized as a catalyst carrier to enhance its value-added potential. Common methods often involve using a large amount of alkali for preprocessing, resulting in stable quartz and mullite forming silicate dissolution. This leads to an increased specific surface area and pore structure. In this study, we produced a catalyst composed of MnOx/NiOOH supported on fly ash by directly employing nickel hydroxide and potassium permanganate to generate metal active sites over the fly ash surface while simultaneously creating a larger specific surface area and pore structure. The ozone catalytic oxidation performance of this catalyst was evaluated using sodium acetate as the target organic matter. The experimental results demonstrated that an optimal removal efficiency of 57.5% for sodium acetate was achieved, surpassing even that of MnOx/NiOOH supported catalyst by using γ-Al2O3. After loading of MnOx/NiOOH, an oxygen vacancy is formed on the surface of fly ash, which plays an indirect oxidation effect on sodium acetate due to the transformation of ozone to •O2- and •OH over this oxygen vacancy. The reaction process parameters, including varying concentrations of ozone, sodium acetate, and catalyst dosage, as well as pH value and the quantitative analysis of formed free radicals, were examined in detail. This work demonstrated that fly ash could be used as a viable catalytic material for wastewater treatment and provided a new solution to the added value of fly ash.

Modulating autophagy to boost the antitumor efficacy of TROP2-directed antibody-drug conjugate in pancreatic cancer.

Pancreatic cancer, characterized by a dismal prognosis and limited treatment options, persists as a formidable challenge in oncology. Trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugates have achieved great success in solid tumors such as breast cancer and uroepithelial carcinoma. However, their efficacy against pancreatic cancer was insufficient in clinical trials, necessitating an imperative exploration of underlying mechanisms and new therapeutic strategies. In this study, we indicated that αTROP2-MMAE, an antibody-drug conjugate targeting TROP2, induced apoptosis through the caspase-9/PARP pathway and exerted potent antitumor effects against TROP2-positive pancreatic cancer. Simultaneously, RNA sequencing suggested significant changes in autophagy after αTROP2-MMAE treatment. The formation of autophagosomes and activation of autophagic flux were markedly induced through mechanisms associated with suppressing the activation of the Akt/mTOR pathway. The addition of pharmacological inhibitors of autophagy enhanced the cytotoxicity and apoptosis caused by αTROP2-MMAE, revealing the cytoprotective role of autophagy in TROP2-positive pancreatic cancer. In the subcutaneous xenograft model using BxPC3 cells, the combined administration of αTROP2-MMAE and an autophagy inhibitor elevated the tumor inhibition rate of αTROP2-MMAE from 71.6 % to 99.0 %, resulting in the eradication of tumors in half of the mice. Collectively, our research demonstrated for the first time the cytoprotective role of autophagy in TROP2-targeted antibody-drug conjugate therapy for pancreatic cancer, providing new perspectives for mechanistic exploration and therapeutic strategies in the treatment of pancreatic cancer.

miR-1246 promotes osteosarcoma cell migration via NamiRNA-enhancer network dependent on Argonaute 2.

High metastatic propensity of osteosarcoma leads to its therapeutic failure and poor prognosis. Although nuclear activation miRNAs (NamiRNAs) are reported to activate gene transcription via targeting enhancer and further promote tumor metastasis, it remains uncertain whether NamiRNAs regulate osteosarcoma metastasis and their exact mechanism. Here, we found that extracellular vesicles of the malignant osteosarcoma cells (143B) remarkably increased the migratory abilities of MNNG cells representing the benign osteosarcoma cells by two folds, which attributed to their high miR-1246 levels. Specially, miR-1246 located in nucleus could activate the migration gene expression (such as MMP1) to accelerate MNNG cell migration through elevating the enhancer activities via increasing H3K27ac enrichment. Instead, MMP1 expression was dramatically inhibited after Argonaute 2 (AGO2) knockdown. Notably, in vitro assays demonstrated that AGO2 recognized the hybrids of miR-1246 and its enhancer DNA via PAZ domains to prevent their degradation from RNase H and these protective roles of AGO2 may favor the gene activation by miR-1246 in vivo. Collectively, our findings suggest that miR-1246 could facilitate osteosarcoma metastasis through interacting with enhancer to activate gene expression dependent on AGO2, highlighting the nuclear AGO2 as a guardian for NamiRNA-targeted gene activation and the potential of miR-1246 for osteosarcoma metastasis therapy.

Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy.

BACKGROUND: The main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain. METHODS: Molecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB. RESULTS: After anti-PD-L1 administration, tumor-infiltrating ST2+ regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8+ T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells. CONCLUSIONS: In this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.

Ferroptosis-enhanced chemotherapy for triple-negative breast cancer with magnetic composite nanoparticles.

Triple-negative breast cancer (TNBC) causes great suffering to patients because of its heterogeneity, poor prognosis, and chemotherapy resistance. Ferroptosis is characterized by iron-dependent oxidative damage by accumulating intracellular lipid peroxides to lethal levels, and plays a vital role in the treatment of TNBC based on its intrinsic characteristics. To identify the relationship between chemotherapy resistance and ferroptosis in TNBC, we analyzed the single cell RNA-sequencing public dataset of GSE205551. It was found that the expression of Gpx4 in DOX-resistant TNBC cells was significantly higher than that in DOX-sensitive TNBC cells. Based on this finding, we hypothesize that inducing ferroptosis by inhibiting the expression of Gpx4 can reduce the resistance of TNBC to DOX and enhance the therapeutic effect of chemotherapy on TNBC. Herein, dihydroartemisinin (DHA)-loaded polyglutamic acid-stabilized Fe3O4 magnetic nanoparticles (Fe3O4-PGA-DHA) was combined with DOX-loaded polyaspartic acid-stabilized Fe3O4 magnetic nanoparticles (Fe3O4-PASP-DOX) for ferroptosis-enhanced chemotherapy of TNBC. Compared with Fe3O4-PASP-DOX, Fe3O4-PGA-DHA + Fe3O4-PASP-DOX demonstrated significantly stronger cytotoxicity against different TNBC cell lines and achieved significantly more intracellular accumulation of reactive oxygen species and lipid peroxides. Furthermore, transcriptomic analyses demonstrated that Fe3O4-PASP-DOX-induced apoptosis could be enhanced by Fe3O4-PGA-DHA-induced ferroptosis and Fe3O4-PGA-DHA + Fe3O4-PASP-DOX might trigger ferroptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR/GPX4 pathway. Fe3O4-PGA-DHA + Fe3O4-PASP-DOX showed superior anti-tumor efficacy on MDA-MB-231 tumor-bearing mice, providing great potential for improving the therapeutic effect of TNBC.

A novel fusion protein consisting of anti-ANGPTL3 antibody and interleukin-22 ameliorates diabetic nephropathy in mice.

Introduction: The pathogenic mechanisms of diabetic nephropathy (DN) include podocyte injury, inflammatory responses and metabolic disorders. Although the antagonism of Angiopoietin-like protein 3 (ANGPTL3) can alleviate proteinuria symptoms by inhibiting the activation of integrin αvß3 on the surface of podocytes, it can not impede other pathological processes, such as inflammatory responses and metabolic dysfunction of glucolipid. Interleukin-22 (IL-22) is considered to be a pivotal molecule involved in suppressing inflammatory responses, initiating regenerative repair, and regulating glucolipid metabolism. Methods: Genes encoding the mIL22IgG2aFc and two chains of anti-ANGPTL3 antibody and bifunctional protein were synthesized. Then, the DN mice were treated with intraperitoneal injection of normal saline, anti-ANGPTL3 (20 mg/kg), mIL22Fc (12 mg/kg) or anti-ANGPTL3 /IL22 (25.3 mg/kg) and irrigation of positive drug losartan (20mg/kg/d) twice a week for 8 weeks. Results: In this research, a novel bifunctional fusion protein (anti-ANGPTL3/IL22) formed by the fusion of IL-22 with the C-terminus of anti-ANGPTL3 antibody exhibited favorable stability and maintained the biological activity of anti-ANGPTL3 and IL-22, respectively. The fusion protein showed a more pronounced attenuation of proteinuria and improved dysfunction of glucolipid metabolism compared with mIL22Fc or anti-ANGPTL3. Our results also indicated that anti-ANGPTL3/IL22 intervention significantly alleviated renal fibrosis via inhibiting the expression of the inflammatory response-related protein nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) p65 and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Moreover, transcriptome analysis revealed the downregulation of signaling pathways associated with injury and dysfunction of the renal parenchymal cell indicating the possible protective mechanisms of anti-ANGPTL3/IL22 in DN. Conclusion: Collectively, anti-ANGPTL3/IL22 bifunctional fusion protein can be a promising novel therapeutic strategy for DN by reducing podocyte injury, ameliorating inflammatory response, and enhancing renal tissue recovery.

Hymecromone: a clinical prescription hyaluronan inhibitor for efficiently blocking COVID-19 progression.

Currently, there is no effective drugs for treating clinically COVID-19 except dexamethasone. We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid (HA). As the inhibitor of HA synthesis, hymecromone is an approved prescription drug used for treating biliary spasm. Here, we aimed to investigate the relation between HA and COVID-19, and evaluate the therapeutic effects of hymecromone on COVID-19. Firstly, HA was closely relevant to clinical parameters, including lymphocytes (n = 158; r = -0.50; P < 0.0001), C-reactive protein (n = 156; r = 0.55; P < 0.0001), D-dimer (n = 154; r = 0.38; P < 0.0001), and fibrinogen (n = 152; r = 0.37; P < 0.0001), as well as the mass (n = 78; r = 0.43; P < 0.0001) and volume (n = 78; r = 0.41; P = 0.0002) of ground-glass opacity, the mass (n = 78; r = 0.48; P < 0.0001) and volume (n = 78; r = 0.47; P < 0.0001) of consolidation in patient with low level of hyaluronan (HA < 48.43 ng/mL). Furthermore, hyaluronan could directly cause mouse pulmonary lesions. Besides, hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression. Moreover, 89% patients with hymecromone treatment had pulmonary lesion absorption while only 42% patients in control group had pulmonary lesion absorption (P < 0.0001). In addition, lymphocytes recovered more quickly in hymecromone-treated patients (n = 8) than control group (n = 5) (P < 0.05). These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.

Dynamic expression of FAM83D in peripheral organs at different ages in mice.

The family with sequence similarity 83 member (FAM83D) plays important role in the process of cell division as well as tumour progression. However, the role of FAM83D in tissue development was not well explored. Here, we assessed transcriptional levels of FAM83D and other possibly related genes in organs of mice at different ages and methylation level of FAM83D promoter. Our results indicate the trend of FAM83D expression in mouse testis, liver, lung and small intestine, and its relationship to CYCLINB1 and KI67. Finally, we found no effect of promoter methylation status on FAM83D expression during mice development.