Stimulated Cell Apoptosis Research Articles

A Highly Potent Os@Au‐TPA Coordination Structure‐Based Sonosensitizer for Tumor Sono‐Immunotherapies

AbstractUltrasound (US) becomes an appealing modality for stimulating or amplifying immune responses during cancer therapy, which is also termed sono‐immunotherapy. However, the clinical prospect has not been fully realized due to the scarcity of efficient sonosensitizers. Herein, for the first time a novel Os‐doped Au‐tri(pyridin‐4‐yl) amine coordination structure (Os@Au‐TPA)‐based sonosensitizer is originally designed and synthesized for sono‐immunotherapy of breast‐metastasized tumors. Impressively, Os@Au‐TPA shows much higher US‐mediated 1O2‐producing activity than Au‐TPA as well as the other traditional sonosensitizers, for example, ≈41.6 folds to ce6, 19.5 times to Protoporphyrin IX (PpIX), 12.0 to Indocyanine Green (ICG), and 11.1 to Iron phthalocyanine (Pc(Fe)). The Os@Au‐TPA can not only generate abundant ROS upon US irradiation to implement sonodynamic therapy (SDT), stimulating cell apoptosis and further immunogenic cell death, but can also generate O2 to alleviate hypoxia to promote the polarization of M2 to M1 macrophages to enhance tumor immunogenicity. As a result, when combined with PD‐L1 antibody, it remodels the immunosuppressive tumor microenvironment, achieves concurrent sonodynamic‐triggered immune activation, and eradicates both the original and distant‐metastasized tumors efficiently. This work not only provides a new strategy to construct potent sonosensitizers from pyridine‐metal coordination structures but also proves that sonosensitizers with high performance are crucial in boosting cancer sono‐immunotherapy.

EXPLORATION OF THE ACTIVE COMPOUNDS OF MORINGA OLEIFERA LAM AS HIV-1 REVERSE TRANSCRIPTASE INHIBITOR: A NETWORK PHARMACOLOGY AND MOLECULAR DOCKING APPROACH

Objective: This study aims to predict the active compound of Moringa oleifera for the treatment of Human Immunodeficiency Virus (HIV), specifically targeting the HIV-1 reverse transcriptase (HIV-1 RT) enzyme using network pharmacology and molecular docking approach. Methods: The active ingredients of M. oleifera, were screened from the Knapsack database. Subsequently, HIV-1 RT and its related target compounds were retrieved from the Genecard database. The analysis of common targets involved protein-protein interactions (PPI) analysis using string databases and constructing interaction IDs using Cytoscape software. Gene Ontology (GO) functional and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Molecular docking studies were conducted using AutoDock Vina software to validate the results of the network pharmacological analysis. Results: A total of 63 active ingredients and 8601 targets related to HIV-1 RT were identified. The network analysis, encompassing GO and KEGG enrichment, revealed strong associations of common targets with key signaling pathways such as Tumor Necrosis Factor (TNF), Toll Like Receptor (TLR), and apoptosis. Additionally, 11 compounds of M. oleifera including apigenin, benzyl isothiocyanate, benzylamine, caffeic acid, ferulic acid, epicatechin, kaempferol, gallic acid, luteolin, syringic acid and vanillin were identified as potential vital compounds. Molecular docking analysis highlighted apigenin and kaempferol as the most promising compounds, exhibiting the lowest binding affinity to the HIV-1 RT enzyme. These compounds correlated with caspase-3(CASP3), caspase-9 (CASP9), and BCL2 Apoptosis Regulator (BAX) protein, stimulating cell apoptosis through multiple pathways. Conclusion: The study highlighted that apigenin and kaempferol are potential compound of M. oleifera in HIV-1 treatment through inhibition activity at HIV-1 RT Enzyme.

Structural Maintenance of Chromosome Protein 4 Promotes the Progression of Cardia Adenocarcinoma via Regulation of the Wnt/β-catenin Signaling Pathway.

Structural maintenance of chromosome protein 4 (SMC4) is crucial for chromosome assembly and separation, but its role and mechanism in cardia adenocarcinoma (CA) are unknown. SMC4 expression levels were initially detected by protein profiling in 20 pairs of CA tumor tissues and adjacent normal tissues. The level of SMC4 expression in CA cells was then evaluated using a western blot analysis. Cell proliferation was evaluated by CCK-8 and clone formation tests. Scratch and transwell tests were used to investigate cell migration as well as invasion, while through the flow cytometry, we examined the cell apoptosis and progression of the cell cycle. The regulatory effects of the epithelial-mesenchymal transition (EMT) and the Wnt/β- catenin pathway were investigated using western blot. A tumorigenesis experiment was used to investigate the influence of SMC4 on tumor development in nude mice. This study showed overexpression of SMC4 in CA tissues and cells. Knockdown of SMC4 can significantly inhibit the proliferation, migration and invasion, stimulate cell apoptosis, induce cell cycle arrest in the G0/G1 phase of CA cells, and inhibit tumor growth in vivo. In addition, down-regulation of SMC4 resulted in decreased expression of Bcl-2, Cyclin D1, CDK4, CDK6, β-catenin, phosphorylated GSK-3β, N-cadherin, and Vimentin, with an increased level of proteins, i.e., Bax, cleaved-caspase3, and E-cadherin. When SMC4 was overexpressed, these effects were reversed. SMC4 can facilitate the biological progression of CA, suggesting that SMC4 could be a potential therapeutic target for the disease.

Optimization of ultrasound-assisted extraction of Imperata cylindrica polysaccharides and evaluation of its anti-oxidant and amelioration of uric acid stimulated cell apoptosis

An efficient, cost-effective and environmentally friendly ultrasound-assisted hot water method for Imperata cylindrica polysaccharide (ICPs) extraction was developed. According to the response surface results, the optimal ultrasonic time was 85 min, ultrasonic power was 192.75 W, temperature was 90.74 °C, liquid–solid ratio was 26.1, and polysaccharide yield was 28.50 %. The polysaccharide mainly consisted of arabinose (Ara), galactose (Gal), and glucose (Glc), with a molecular weight of 62.3 kDa. Ultrasound-assisted extraction of Imperata cylindrica polysaccharide (UICP) exhibited stronger anti-oxidant activity and ability to ameliorate cellular damage due to uric acid stimulation compared with traditional hot water extraction of Imperata cylindrica polysaccharide (ICPC-b). It also exhibited higher thermal stability, indicating its potential value for applications in the food industry.

Retraction Note: Anti-breast Cancer Activity of Co(II) Complex by Inhibiting Cell Viability and Stimulating Cell Apoptosis

Retraction Note: Anti-breast Cancer Activity of Co(II) Complex by Inhibiting Cell Viability and Stimulating Cell Apoptosis

Design of a nanozyme-based magnetic nanoplatform to enhance photodynamic therapy and immunotherapy

The tumor microenvironment, particularly the hypoxic property and glutathione (GSH) overexpression, substantially inhibits the efficacy of cancer therapy. In this article, we present the design of a magnetic nanoplatform (MNPT) comprised of a photosensitizer (Ce6) and an iron oxide (Fe3O4)/manganese oxide (MnO2) composite nanozyme. Reactive oxygen species (ROS), such as singlet oxygen (1O2) radicals produced by light irradiation and hydroxyl radicals (·OH) produced by catalysis, are therapeutic species. These therapeutic substances stimulate cell apoptosis by increasing oxidative stress. This apoptosis then triggers the immunological response, which combines photodynamic therapy and T-cell-mediated immunotherapy to treat cancer. Furthermore, MNPT can be utilized as a contrast agent in magnetic resonance and fluorescence dual-modality imaging to give real-time tracking and feedback on treatment.

Design, synthesis and evaluation of dihydro-1H-indene derivatives as novel tubulin polymerisation inhibitors with anti-angiogenic and antitumor potency

Angiogenesis plays an important role in tumour generation and progression, which is used to supply nutrients and metastasis. Herein, a series of novel dihydro-1H-indene derivatives were designed and evaluated as tubulin polymerisation inhibitors by binding to colchicine site, exhibiting anti-angiogenic activities against new vessel forming. Through structure-activity relationships study, compound 12d was found to be the most potent derivative possessing the antiproliferative activity against four cancer lines with IC50 values among 0.028−0.087 µM. Compound 12d bound to colchicine site on tubulin and inhibited tubulin polymerisation in vitro. In addition, compound 12d induced cell cycle arrest at G2/M phase, stimulated cell apoptosis, inhibited tumour metastasis and angiogenesis. Finally, the results of in vivo assay suggested that compound 12d could prevent tumour generation, inhibit tumour proliferation and angiogenesis without obvious toxicity. Collectively, all these findings suggested that compound 12d is a novel tubulin polymerisation inhibitor deserving further research.

Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives.

Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.

Identification and verification of a novel anoikis-related gene signature with prognostic significance in clear cell renal cell carcinoma.

Clear cell renal cell carcinomas (ccRCCs) are the most common form of renal cancer in the world. The loss of extracellular matrix (ECM) stimulates cell apoptosis, known as anoikis. A resistance to anoikis in cancer cells is believed to contribute to tumor malignancy, particularly metastasis; however, the potential influence of anoikis on the prognosis of ccRCC patients is not fully understood. In this study, anoikis-related genes (ARGs) with discrepant expression were selected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The anoikis-related gene signature (ARS) was built using a combination of the univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses. ARS was also evaluated for their prognostic value. We explored the tumor microenvironment and enrichment pathways between different clusters of ccRCC. We also examined differences in clinical characteristics, immune cell infiltration and drug sensitivity between the high- and low-risk sets. In addition, we utilized three external databases and quantitative real-time polymerase chain reaction (qRT-PCR) to validate the expression and prognosis of ARGs. Eight ARGs (PLAUR, HMCN1, CDKN2A, BID, GLI2, PLG, PRKCQ and IRF6) were identified as anoikis-related prognostic factors. According to Kaplan-Meier (KM) analysis, ccRCC patients with high-risk ARGs have a worse prognosis. The risk score was found to be a significant independent prognostic indicator. According to tumor microenvironment (TME) scores, stromal score, immune score, and estimated score of the high-risk group were superior to those of the low-risk group. There were significant differences between the two groups regarding the amount of infiltrated immune cells, immune checkpoint expression as well as drug sensitivity. A nomogram was constructed using ccRCC clinical features and risk scores. The signature and the nomogram both performed well in predicting overall survival (OS) for ccRCC patients. According to a decision curve analysis (DCA), clinical treatment options for patients with ccRCC could be improved using this model. The results of validation from external databases and qRT-PCR were basically agreement with findings in TCGA and GEO databases. The ARS serving as biomarkers may provide an important reference for individual therapy of ccRCC patients.

Ellipticine induces apoptosis and mitochondrial dysfunction in human endometriosis cell lines by activating MAPK signaling pathway

Purpose: To assess the effect of ellipticine (EPT), an alkaloid isolated from the Oleaceae family, on endometriosis, and to identify its possible mechanisms of action.
 Methods: Human endometriosis-like cell lines exposed to EPT were subjected to bromodeoxyuridine/5-bromo-2´-deoxyuridine and proliferating cell nuclear antigen staining. Flow cytometry and immunoblot analyses were used to assess the effect of EPT on cell apoptosis. Mitochondrial damage was determined by JC-1 staining and immunoblotting. Immunoblot assays were performed to determine the effects of EPT on the MAPK pathway.
 Results: Ellipticine inhibited the viability of human endometriosis cell lines and stimulated cell apoptosis (p < 0.01). It further induced mitochondrial damage in human endometriosis cell lines (p < 0.01). Mechanistically, EPT acted on MAPK pathway, and induced apoptosis and mitochondrial dysfunction (p < 0.01) in human endometriosis cells.
 Conclusion: Ellipticine is a potential treatment strategy for the management of endometriosis. However, further exploration of this potential should be explored via in vivo studies.

Chronic exposure to yttrium induced cell apoptosis in the testis by mediating Ca2+/IP3R1/CaMKII signaling.

Environmental pollutants, such as rare earth elements, affect human health and particularly induce reproductive system injury. Yttrium (Y), one of the most widely used heavy rare earth elements, has been reported the cytotoxicity. However, the biological effects of Y3+ in the human body are largely unknown. To further investigate the effects of Y on the reproductive system, in vivo (rat models) and in vitro studies were performed. Histopathological and immunohistochemical examination were conducted, and western blotting assays were performed to detect the protein expression. TUNEL/DAPI staining were used to detect cell apoptosis, and the intracellular calcium concentrations were also determined. Long-term exposure to YCl3 in rats produced significant pathological changes. YCl3 treatment could induce cell apoptosis in vivo and in vitro. In addition, YCl3 enhanced the concentration of cytosolic Ca2+ and up regulated the expression of IP3R1/CaMKII axis in Leydig cells. However, inhibition of IP3R1 and CaMKII with 2-APB and KN93, respectively, could reverse these effects. Long-term exposure to yttrium could induce testicular injury by stimulating cell apoptosis, which might be associated with activation of Ca2+/IP3R1/CaMKII axis in Leydig cells.

Houttuynia cordata polysaccharides alleviate ulcerative colitis by restoring intestinal homeostasis

Houttuynia cordata is traditionally used as phytoantibiotics for treating lung disease in China. Houttuynia cordata polysaccharides (HCPs) have been reported to alleviate influenza virus-induced intestinal and lung immune injury by regulating the gut-lung axis. The present study aims to investigate the effects and mechanisms of HCPs on ulcerative colitis (UC). Male C57BL/6 mice were induced by dextran sodium sulfate (DSS) to establish the UC animal model. Our results showed that HCPs significantly reduced the weight loss and the shortening of colon length in colitis mice, and relieved the pathological damage of colon mucosa and inhibited the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, etc. It was suggested that HCPs could significantly improve DSS-induced colitis in mice. HCPs directly protected intestinal epithelial cells, ameliorated epithelial barrier dysfunction and cell apoptosis, which was also proved in H2O2 stimulated cell apoptosis model. HCPs inhibited inflammation in the colon, which was related to suppressing the infiltration of macrophages, inhibiting the expression of pro-inflammatory cytokines and proteins (TLR4, NF-κB), and restoring the dysfunction of Th17 and Treg cells. HCPs also restored the alteration of intestinal flora induced by DSS, increased the abundance ofFirmicutes and Bacteroides, and reduced the abundance of Proteobacteria. This study confirmed the protective effect of Houttuynia cordata polysaccharide extracted from traditional Chinese medicine on ulcerative colitis, of which the mechanism was closely related to the maintenance of intestinal homeostasis (intestinal barrier, immune cells, and intestinal bacteria).

Let-7c-5p Represses Cisplatin Resistance of Lung Adenocarcinoma Cells by Targeting CDC25A.

Cisplatin broadly functions as a routine treatment for lung adenocarcinoma (LUAD) patients. However, primary and acquired cisplatin resistances frequently occur in the treatment of LUAD patients, seriously affecting the therapeutic effect of cisplatin in patients. We intended to illustrate the impact of let-7c-5p/cell division cycle 25A (CDC25A) axis on cisplatin resistance in LUAD. Expression of let-7c-5p and CDC25A was analyzed via quantitative real-time polymerase chain reaction. The interaction between the two was verified by dual-luciferase reporter detection. For detecting half-maximal inhibitory concentration value of cisplatin in LUAD cells and cell proliferation, we separately applied Cell Counting Kit-8 and colony formation assays. Furthermore, we measured cell apoptosis and cell cycle distribution via flow cytometry, as well as cell cycle-related protein expression via Western blot. Let-7c-5p was evidently downregulated in LUAD, while CDC25A was remarkably upregulated. Let-7c-5p upregulation arrested LUAD cells to proliferate, stimulated cell apoptosis, and arrested cell cycle in G0/G1 phase, thus enhancing sensitivity of LUAD cells to cisplatin. In terms of mechanism, CDC25A was directly targeted by let-7c-5p, and the influence of let-7c-5p overexpression on LUAD proliferation, apoptosis, cell cycle, and cisplatin resistance could be reversed by CDC25A upregulation. Let-7c-5p improved sensitivity of LUAD cells to cisplatin by modulating CDC25A, and let-7c-5p/CDC25A axis was an underlying target for the intervention of LUAD cisplatin resistance.

Circ_0008068 facilitates the oral squamous cell carcinoma development by microRNA-153-3p/acylgycerol kinase (AGK) axis

ABSTRACT Oral squamous cell carcinoma (OSCC) is a common cancer with high recurrence, metastasis rates and poor prognosis. Circular RNAs (circRNAs) take part in regulating OSCC. Herein, we examined the role of circ_0008068 in OSCC. The circ_0008068, Katanin p60 ATPase-containing subunit A-like 1 (KATNAL1) mRNA, microRNA-153-3p (miR-153-3p) and acylgycerol kinase (AGK) contents were indicated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Moreover, in vitro and in vivo assays were conducted to scrutinize the effects of circ_0008068 on OSCC. Additionally, the contact between miR-153-3p and circ_0008068 or AGK was assessed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Thereafter, we found that the appearance of circ_0008068 and AGK was increased, and miR-153-3p content was diminished in OSCC. Circ_0008068 lack subdued cell proliferation, migration, invasion, tube formation and glycolysis metabolism, but stimulated cell apoptosis in OSCC. In addition, circ_0008068 bound to miR-153-3p to modulate the expression of its target AGK. Besides, miR-153-3p was validated to act as a tumor suppressor in OSCC tumorigenesis by suppressing AGK. Additionally, circ_0008068 knockdown also attenuated tumor growth in nude mice. In all, circ_0008068 expedited the growth of OSCC by miR-153-3p/AGK axis. Abbreviations: OSCC: Oral squamous cell carcinoma; AGK: Acylgycerol kinase; CircRNA: Circular RNA; KATNAL1: Katanin p60 ATPase-containing subunit A-like 1; qRT-PCR: Quantitative real-time polymerase chain reaction; miRNAs/miRs: MicroRNAs; RIP: RNA immunoprecipitation; 3′UTR3’: -untranslated region; HK2: Hexokinase 2; LDHA Lactate dehydrogenase A; IHC: Immunohistochemistry; CCK8: Cell counting kit-8; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase

Leydig cell function in adult male rats is disrupted by perfluorotetradecanoic acid through increasing oxidative stress and apoptosis.

Perfluorotetradecanoic acid (PFTeDA) is a long-chain perfluoroalkyl compound with increased applications. Its effect on Leydig cell function and its underlying mechanism remain unclear. Male Sprague-Dawley rats (60 days old) were gavaged with PFTeDA at doses of 0, 1, 5, and 10 mg/kg/day from 60 to 87 days after birth. PFTeDA significantly reduced serum testosterone levels at 1 mg/kg and higher doses, while markedly increasing serum luteinizing hormone level at 10 mg/kg and follicle-stimulating hormone at ≥1 mg/kg. PFTeDA significantly reduced the sperm number at the cauda of epididymis at ≥1 mg/kg. PFTeDA also reduced the number of CYP11A1-positive Leydig cells due to increased apoptosis shown by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. PFTeDA significantly repressed the expression of Cyp17a1 and Star and their proteins at 1-10 mg/kg, while it increased the expression of Srd5a1 and its protein (an immature Leydig cell biomarker) at 10 mg/kg. PFTeDA markedly increased testicular malondialdehyde level, while inhibiting antioxidants (SOD1, SOD2, and CAT), triggering oxidative stress, thereby further inducing BAX and CASP3 while inhibiting BCL2, which led to cell apoptosis. PFTeDA also reduced DHH level secreted by Sertoli cells, which indirectly affected Leydig cell function. PFTeDA inhibited testosterone secretion in primary Leydig cells in vitro by increasing reactive oxygen species and inducing apoptosis at 50 μM. In conclusion, PFTeDA inhibits the function of Leydig cells by inducing oxidative stress and subsequently stimulating cell apoptosis.

Brefeldin A Induces Apoptosis, Inhibits BCR-ABL Activation, and Triggers BCRABL Degradation in Chronic Myeloid Leukemia K562 Cells.

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Under the guidance of cytotoxic activity, crude extracts of 55 fungal strains from the medicinal mangrove Acanthus ilicifolius were evaluated, and one potent cytotoxic natural compound, brefeldin A (BFA), was discovered from Penicillium sp. (HS-N-29). This study was aimed to determine the cytotoxic activity of BFA and the effect on the activation and expression of BCR-ABL in K562 cells. We evaluated cytotoxic activity by MTT assay and soft agar clone assay; apoptosis and cell cycle distribution by Muse cell analyzer. The protein level of BCR-ABL and signaling molecules was detected by western blotting, and the mRNA level of BCR-ABL was determined by RT-PCR. BFA inhibited cell proliferation, induced G2/M cell cycle arrest, and stimulated cell apoptosis in K562 cells. Importantly, for the first time, we revealed that BFA inhibited the activation of BCR-ABL and consequently inhibited the activation of its downstream signaling molecules in K562 cells. Moreover, we found BFA degraded BCR-ABL without affecting its transcription in K562 cells, and BFA-induced BCR-ABL degradation was related to caspase activation, while not to autophagy or ubiquitinated proteasome degradation pathway. Our present results indicate that BFA acts as a dual functional inhibitor and degrader of BCR-ABL, and BFA is a potential compound for chemotherapeutics to overcome CML.

Serum exosomal miR-16-5p functions as a tumor inhibitor and a new biomarker for PD-L1 inhibitor-dependent immunotherapy in lung adenocarcinoma by regulating PD-L1 expression.

ObjectivesWe aimed at investigating whether serum exosomal miR‐16‐5p could be utilized as an immunotherapy biomarker in lung adenocarcinoma (LUAD) patients administered by programmed cell death ligand‐1 (PD‐L1) inhibitors, and to evaluate its functions in LUAD progression.MethodsSixty LUAD sufferers and 20 healthy controls (HCs) were covered in this work. We applied both IHC and WB to examine PD‐L1 level in clinical tissue samples and utilized WB to quantify PD‐L1 expression in LUAD cells and LUAD xenograft tissues, respectively. Transmission electron microscopy (TEM), WB, and nanoparticle tracking analysis (NTA) were executed to confirm the exosomes isolated from serum specimens and cell culture media. To quantify of exosomal miR‐16‐5p level from serum and culture medium of cultured cell, qRT‐PCR experiment was utilized. The connection between tissue PD‐L1 level and serum exosomal miR‐16‐5p expression in PD‐L1‐positive sufferers administered by PD‐L1 inhibitors was verified using Spearman correlation coefficient analysis. In addition, the overall survival (OS) and progression‐free survival (PFS) rates among PD‐L1 inhibitor managed sufferers were acquired through a follow‐up visit. Finally, we used a group of assays, including 5‐bromo‐2′‐dexoyuridine (BrdU) and colony formation test, wound healing experiment, flow cytometry, and nude mice xenograft experiment, to explore the functions of circulating exosomal miR‐16‐5p on LUAD cell proliferation, apoptosis, and migration, as well as tumor development, respectively.ResultsPD‐L1 expression was positively related to T stage (tumor size stage), and PD‐L1 inhibitor treatment reduced the PD‐L1 expression and mitigated T stage in PD‐L1‐positive LUAD sufferers. For PD‐L1‐positive LUAD sufferers, elevated PD‐L1 expression or reduced serum exosomal miR‐16‐5p level were linked to longer PFS and OS upon PD‐L1 inhibitor treatment. The number of exosomes in patient's serum was more than that in the serum of healthy individuals, and PD‐L1 inhibitor treatment decreased the number of serum‐derived exosomes in PD‐L1‐positive LUAD sufferers. Exosome‐derived miR‐16‐5p was downregulated in patient's serum and cell culture medium, and this was negatively linked to tumor stage and PD‐L1 expression. Meanwhile, PD‐L1 inhibitor treatment could increase the serum exosomal miR‐16‐5p expression, and the expression change of serum exosomal miR‐16‐5p was diametrically related to PD‐L1 after the treatment. Moreover, the overexpression of PD‐L1 accelerated tumor growth and decreased the exosomal miR‐16‐5p content in cell culture media, while exosomal miR‐16‐5p overexpression in cell culture media inhibited tumor development by decreasing the PD‐L1 expression. Exosomal miR‐16‐5p overexpression in cell culture media also depressed LUAD cell proliferation and migration, and stimulated cell apoptosis, especially in the cells which cultured in the mediums with PD‐L1 inhibitor in vitro.ConclusionsSerum exosomal miR‐16‐5p may be a latent tumor inhibitor and a new biomarker for PD‐L1 inhibitor‐dependent immunotherapy in LUAD by regulating the PD‐L1 expression.

Pterostilbene regulates cell proliferation and apoptosis in non-small-cell lung cancer via targeting COX-2.

Non-small-cell lung cancer (NSCLC), occupying a great proportion of lung cancer, threatens the health of patients, and the cyclooxygenase-2 (COX-2) expression is found to be upregulated in lung cancer. Pterostilbene (PTE) is perceived as a novel method for clinical therapy due to its high performance. However, the mechanism underlying and the interaction between PTE and COX-2 remain vague. We simulated radiation circumstances and transfected cells with the interference of PTE and COX-2. Our results showed that radiation or PTE treatment alone restrained cell proliferation and viability while stimulating cell apoptosis, and the above properties were strengthened when the two were in combination. The COX-2 expression was promoted by radiation but was reduced by PTE. PTE reversed the effects of radiation on the COX-2 expression. COX-2 knockdown suppressed COX-2 expression and proliferation and enhanced apoptosis of cells suffering radiation, while COX-2 overexpression reversed the inhibition of PTE. Our study suggested PTE regulated NSCLC cell proliferation and apoptosis via targeting COX-2, which might shed a light on cancer therapy.

Fucosyltransferase 8 is Overexpressed and Influences Clinical Outcomes in Lung Adenocarcinoma Patients.

Background: Lung adenocarcinoma (LUAD), the most prevalent type of lung cancer, is often metastatic and has a poor prognosis. Recent studies have demonstrated an important role for fucosyltransferase 8 (FUT8) in carcinogenesis and cancer progression. Methods: A meta-analysis with 15 eligible datasets from Gene Expression Omnibus (GEO) was performed to explore the expression of FUT8 in LUAD. The results were further verified in The Cancer Genome Atlas (TCGA) database, followed by survival analysis using Kaplan-Meier plotter. We also validated the protein expression of FUT8 by immunohistochemistry (IHC). In vitro experiments were conducted to determine the biological effects of FUT8 in LUAD cells. Results: The meta-analysis showed the FUT8 expression in LUAD tissues was significantly higher than those in normal lung tissues [standard mean difference (SMD): 1.40; 95% confidence interval (CI): .95–1.85]. The results of TCGA database verified the expression of FUT8 increased in LUAD tissues versus normal tissues. IHC analyses indicated that the protein levels of FUT8 were up-regulated in LUAD, and elevated FUT8 expression was significantly correlated with poor prognosis in LUAD patients. Multivariable Cox regression analysis revealed that FUT8 expression was an independent prognostic factor. Besides, in vitro experiments showed that knockdown of FUT8 in LUAD cells markedly restrained cell proliferation, and stimulated cell apoptosis. Conclusion: This study indicates that increased FUT8 expression is correlated with shortened survival of LUAD patients and might favor the progression of the disease.

Exosomal circ_0001190 Regulates the Progression of Gastric Cancer via miR-586/SOSTDC1 Axis.

Gastric cancer (GC) is the fifth most common cancer, which has a significant impact on human health. Recent researches have shown that circular RNAs (circRNAs) could affect the progress of GC, but the mechanism still indistinct. In this work, we explored the roles of circ_0001190 in GC. The levels of circ_0001190, microRNA-586 (miR-586) and sclerostin domain containing 1 (SOSTDC1) were detected by quantitative RT-PCR and western blot in GC. The cell functions were scrutinized by cell counting kit-8 assay, 5-Ethynyl-29-deoxyuridine assay, flow cytometry assay, tube formation assay, transwell assay, and western blot. Furthermore, the relationship between miR-586 and circ_0001190 or SOSTDC1 was identified by dual-luciferase reporter assay. Finally, the xenograft model test was implemented to demonstrate the effect of exosomal circ_0001190 in vivo. The levels of circ_0001190 and SOSTDC1 were downregulated, and the miR-586 level was increased in GC. For functional assay, circ _0001190 overexpression inhibited cell vitality, cell proliferation, angiogenesis, cell migration and invasion, whereas stimulated cell apoptosis in GC cells. Circ _0001190 served as a miR-586 sponge to adjust the expression of SOSTDC1. Additionally, miR-586 could promote the advancement of GC by interfering SOSTDC1. Exosomal circ_0001190 overexpression inhibited the development of GC by miR-586/SOSTDC1 axis, which proposed a potential targeted therapy for GC cure.