Increased ROS Levels Research Articles

Anemoside B4, a new pyruvate carboxylase inhibitor, alleviates colitis by reprogramming macrophage function.

Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), whichwas found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to itsmolecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA),a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation andoxidative stress. These findings shed more light on thepossibilities ofPC as a potential new target for treating colitis.

CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS.

Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) play essential roles in promoting cholangiocarcinoma (CCA) cell survival by mediating paracrine crosstalk between tumor and cancer-associated fibroblasts (CAFs), indicating the potential of PDGFR as a target for CCA treatment. Clinical trials evaluating PDGFR inhibitors for CCA treatment have shown limited efficacy. Furthermore, little is known about the role of PDGF/PDGFR expression and the mechanism underlying PDGFR inhibitors in CCA related to Opisthorchis viverrini (OV). Therefore, we examined the effect of PDGFR inhibitors in OV-related CCA cells and investigated the molecular mechanism involved. We found that the PDGF and PDGFR mRNAs were overexpressed in CCA tissues compared to resection margins. Notably, PDGFR-α showed high expression in CCA cells, while PDGFR-β was predominantly expressed in CAFs. The selective inhibitor CP-673451 induced CCA cell death by suppressing the PI3K/Akt/Nrf2 pathway, leading to a decreased expression of Nrf2-targeted antioxidant genes. Consequently, this led to an increase in ROS levels and the promotion of CCA apoptosis. CP-673451 is a promising PDGFR-targeted drug for CCA and supports the further clinical investigation of CP-673451 for CCA treatment, particularly in the context of OV-related cases.

Potential impacts of bisphenols on prostate cells: An overview of cytotoxicity, proliferation, oxidative stress, apoptosis, and ER-stress response activation

This study aimed to evaluate the toxic effects of Bisphenol A (BPA), Bisphenol F (BPF) and Bisphenol S (BPS) on PNT1A and PC-3 cells, focusing on their effects on endoplasmic reticulum (ER) stress and related pathways. PNT1A and PC-3 were treated with BPA, BPF and BPS at concentrations of 0.1, 1 and 10 μM for 48 h cytotoxicity, BrdU cell proliferation, ROS generation, apoptosis detection, gene expression analysis and Western blot analysis were performed. BPA induced proliferation and late apoptosis in PNT1A cells, whereas it induced both late apoptosis and early apoptosis in PC-3 cells. BPF and BPS induced late apoptosis in PC-3 cells. Increased ROS levels were observed in PNT1A cells exposed to 1–10 μM BPA. BPA, BPF and BPS increased the expression levels of ER stress-related genes in PNT1A cells. Furthermore, exposure to BPA increased the expression of ER stress-related CHOP/DDIT3 protein in PNT1A cells. These findings highlight the potential health risks associated with BPA, BPF and BPS exposure and emphasize the importance of investigating the underlying mechanisms by which these chemicals may affect human health. Further research is required to comprehensively understand the role of ER stress pathways in cellular responses to these substances.

Development of Acridone Derivatives: Targeting c-MYC Transcription in Triple-Negative Breast Cancer with Inhibitory Potential.

Breast cancer, especially the aggressive triple-negative subtype, poses a serious health threat to women. Unfortunately, effective targets are lacking, leading to a grim prognosis. Research highlights the crucial role of c-MYC overexpression in this form of cancer. Current inhibitors targeting c-MYC focus on stabilizing its G-quadruplex (G4) structure in the promoter region. They can inhibit the expression of c-MYC, which is highly expressed in triple-negative breast cancer (TNBC), and then regulate the apoptosis of breast cancer cells induced by intracellular ROS. However, the clinical prospects for the application of such inhibitors are not promising. In this research, we designed and synthesized 29 acridone derivatives. These compounds were assessed for their impact on intracellular ROS levels and cell activity, followed by comprehensive QSAR analysis and molecular docking. Compound N8 stood out, significantly increasing ROS levels and demonstrating potent anti-tumor activity in the TNBC cell line, with excellent selectivity shown in the docking results. This study suggests that acridone derivatives could stabilize the c-MYC G4 structure. Among these compounds, the small molecule N8 shows promising effects and deserves further investigation.

Regulation of miR-61 and col-19 via TGF-β and Notch signalling in Caenorhabditis elegans against Klebsiella aerogenes infection

Klebsiella aerogenes, previously known as Enterobacter aerogenes, is a gram-negative bacterium typically present in the gastrointestinal tract. While numerous studies reported the pathogenicity and drug resistance of this bacterium there remains a lack of comprehensive research on K. aerogenes induced alterations in the host cellular mechanisms. In this study, we identify a previously uncharacterized C. elegans miR-61 that defines an evolutionarily conserved miRNA important for development and innate immunity regulation through Notch and TGF-β signaling pathway. We employed C. elegans wild-type (N2) as well as mutant strains, such as TGF-β (sma-6) and notch-signaling pathway mutants (adm-4 and mir-61). Our results have demonstrated that the K. aerogenes infected mutants exhibited significantly reduced survival rate, reduced pharyngeal pumping, altered swimming and chemotactic behavior. Moreover, K. aerogenes affects the healthspan by increasing ROS level in the mutants. The gene expression analysis revealed that K. aerogenes upregulated egl-30, tph-1 and sod-1 in adm-4, mir-61 mutants not in sma-6. The in-silico analysis indicated an interaction between mir-61 and col-19, which was confirmed by the upregulation of miR-61 expression and the downregulation of col-19 in sma-6, adm-4, and wild-type strains. These findings suggest that C. elegans activates mir-61 and col-19 regulation through the Notch and TGF-β signaling pathway against K. aerogenes infection.

Hydrogen sulfide ameliorates hypertension and vascular dysfunction induced by insulin resistance in rats by reducing oxidative stress and activating eNOS

Hydrogen sulfide (H2S) is a gasotransmitter implied in metabolic diseases, insulin resistance, obesity, and type 2 Diabetes Mellitus. This study aimed to determine the effect of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor), L-Cysteine (L-Cys; substrate of H2S producing enzymes) and DL-Propargylglycine (DL-PAG; cystathionine-gamma-lyase inhibitor) on the vascular dysfunction induced by insulin resistance in rat thoracic aorta. For this purpose, 72 animals were divided into two main sets that received: 1) tap water (control group; n = 12); and 2) fructose 15% w/v in drinking water [insulin resistance group (IR); n = 60] for 20 weeks. After 16 weeks, the group 2 was divided into five subgroups (n = 12 each), which received daily i. p. injections during 4 weeks of: 1) non-treatment (control); 2) vehicle (phosphate buffer saline; PBS, 1 ml/kg); 3) NaHS (5.6 mg/kg); 4) L-Cys (300 mg/kg); and (5) DL-PAG (10 mg/kg). Hemodynamic variables, metabolic variables, vascular function, ROS levels and the expression of p-eNOS and eNOS were determined. IR induced: 1) hyperinsulinemia; 2) increased HOMA-index; 3) decreased Matsuda index; 4) hypertension, vascular dysfunction, increased ROS levels; 5) increased iNOS, and 6) decreased CSE, p-eNOS and eNOS expression. Furthermore, IR did not affect contractile responses to norepinephrine. Interestingly, NaHS and L-Cys treatment, reversed IR-induced impairments and DL-PAG treatment decreased and increased the HOMA and Matsuda index, respectively. Taken together, these results suggest that NaHS and L-Cys decrease the metabolic and vascular alterations induced by insulin resistance by reducing oxidative stress and activating eNOS. Thus, hydrogen sulfide may have a therapeutic application.

PeFtsH5 negatively regulates the biological stress response in Phalaenopsis equestris mitochondria

Mitochondrial homeostasis plays a crucial role in determining cell fate by direct influence on cell apoptosis and autophagy. The ATP and Zn2+-dependent protease FtsH are of paramount importance in maintaining mitochondrial homeostasis. In Phalaenopsis equestris, three mitochondrial FtsH proteases were identified, one of which was encoded by the PeFtsH5 gene. This gene encoded a distinctive mitochondrial protein featuring a unique domain within the FtsH family. Down-regulating the expression of the PeFtsH5 homolog in Nicotiana benthamiana resulted in elevated expression levels of SA synthesis-related genes, leading to enhanced disease resistance. However, this down-regulation also caused cellular damage. Similarly, in P. equestris, the down-regulation of PeFtsH5 expression promoted the expression of defense response genes, leading to accelerated apoptosis and increased ROS levels. Nonetheless, this down-regulation also positively influenced plant resistance to biotic stress. Notably, the PeFtsH5 (i-AAA) protein, as revealed by dual membrane experiments, could form homopolymers exclusively, as it did not interact with the other two mitochondrial FtsH proteases. Consequently, this mitochondrial FtsH protease functioned as a homopolymer within P. equestris cells. The findings of this study elucidated the role of PeFtsH5 in responding to biological stress and provided new insights into its potential molecular mechanism. The result presented in this study hold promise for future research endeavors examining the regulatory effects of mitochondrial proteases on mitochondrial homeostasis and the development of stress-resistant P. equestris varieties through breeding programs.

Nano-plastics and gastric health: Decoding the cytotoxic mechanisms of polystyrene nano-plastics size

Gastrointestinal diseases exert a profound impact on global health, leading to millions of healthcare interventions and a significant number of fatalities annually. This, coupled with escalating healthcare expenditures, underscores the need for identifying and addressing potential exacerbating factors. One emerging concern is the pervasive presence of microplastics and nano-plastics in the environment, largely attributed to the indiscriminate usage of disposable plastic items. These nano-plastics, having infiltrated our food chain, pose a potential threat to gastrointestinal health. To understand this better, we co-cultured human gastric fibroblasts (HGF) with polystyrene nano-plastics (PS-NPs) of diverse sizes (80, 500, 650 nm) and meticulously investigated their cellular responses over a 24-hour period. Our findings revealed PS particles were ingested by the cells, with a notable increase in ingestion as the particle size decreased. The cellular death induced by these PS particles, encompassing both apoptosis and necrosis, showcased a clear dependence on both the particle size and its concentration. Notably, the larger PS particles manifested more potent cytotoxic effects. Further analysis indicated a concerning reduction in cellular membrane potential, alongside a marked increase in ROS levels upon PS particles exposure. This suggests a significant disruption of mitochondrial function and heightened oxidative stress. The larger PS particles were especially detrimental in causing mitochondrial dysfunction. In-depth exploration into the PS particles impact on genes linked with the permeability transition pore (PTP) elucidated that these PS particles instigated an internal calcium rush. This surge led to a compromise in the mitochondrial membrane potential, which in tandem with raised ROS levels, further catalyzed DNA damage and initiated cell death pathways. In essence, this study unveils the intricate mechanisms underpinning cell death caused by PS particles in gastric epithelial cells and highlighting the implications of PS particles on gastrointestinal health. The revelations from this research bear significant potential to shape future healthcare strategies and inform pertinent environmental policies.

ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules.

Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.

OsLEA1b Modulates Starch Biosynthesis at High Temperatures in Rice

High temperatures accelerate the accumulation of storage material in seeds, often leading to defects in grain filling. However, the mechanisms regulating grain filling at high temperatures remain unknown. Here, we want to explore the quality factors influenced by the environment and have identified a LATE EMBROYGENESIS ABUNDANT gene, OsLEA1b, a heat-stress-responsive gene in rice grain filling. OsLEA1b is highly expressed in the endosperm, and its coding protein localizes to the nucleus and cytoplasm. Knock-out mutants of OsLEA1b had abnormal compound starch granules in endosperm cells and chalky endosperm with significantly decreased grain weight and grain number per panicle. The oslea1b mutants exhibited a lower proportion of short starch chains with degrees of polymerization values from 6 to 13 and a higher proportion of chains with degrees from 14 to 48, as well as significantly lower contents of starch, protein, and lipid compared to the wild type. The difference was exacerbated under high temperature conditions. Moreover, OsLEA1b was induced by drought stress. The survival rate of oslea1b mutants decreased significantly under drought stress treatment, with significant increase in ROS levels. These results indicate that OsLEA1b regulates starch biosynthesis and influences rice grain quality, especially under high temperatures. This provides a valuable resource for genetic improvement in rice grain quality.

Targeting the survival kinase DYRK1B: A novel approach to overcome radiotherapy-related treatment resistance

BackgroundCancer cell survival under stress conditions is a prerequisite for the development of treatment resistance. The survival kinase DYRK1B is a key regulator of stress survival pathways and might thereby also contribute to radiation resistance. Here we investigate the strategy of targeting DYRK1B in combination with ionizing radiation (IR) to enhance tumor cell killing under stress conditions. MethodsDYRK1B expression, ROS formation and DNA damage were investigated under serum-starvation (0.1% FBS), hypoxia (0.2%, 1% O2) and IR. The combined treatment modality of IR and DYRK1B inhibition was investigated in 2D and in spheroids derived from the colorectal cancer cell line SW620, and in primary patient-derived colorectal carcinoma (CRC) organoids. ResultsExpression of DYRK1B was upregulated under starvation and hypoxia, but not in response to IR. The small molecule DYRK1B inhibitor AZ191 and shRNA-mediated DYRK1B knockdown significantly reduced proliferative activity and clonogenicity of SW620 tumor cells alone and in combination with IR under serum-starved conditions, which correlated with increased ROS levels and DNA damage. Furthermore, AZ191 successfully targeted the hypoxic core of tumor spheroids while IR preferentially targeted normoxic cells in the rim of the spheroids. A combined treatment effect was also observed in CRC-organoids but not in healthy tissue-derived organoids. ConclusionCombined treatment with the DYRK1B inhibitor AZ191 and IR resulted in (supra-) additive tumor cell killing in colorectal tumor cell systems and in primary CRC organoids. Mechanistic investigations support the rational to target the stress-enhanced survival kinase DYRK1B in combination with irradiation to overcome hypoxia- and starvation-induced treatment resistances.

Chitosan-encapsulated naringenin promotes ROS mediated through the activation of executioner caspase-3.

We previously reported that chitosan nanoparticle-encapsulated Naringenin (CS-NPs/NAR) could scavenge free radicals at lower doses and be cytotoxic to cancer cells. The current study continues to focus on the mechanism behind CS-NPs/NAR-induced breast cancer cell (MDA-MB-231) death. MDA-MB-231 cells were treated with higher concentrations (100, 200, and 200µg) of Chitosan nanoparticles (CS-NPs), naringenin (NAR), and chitosan-encapsulated naringenin (CS-NPs/NAR). The cell viability, proliferation, and oxidative stress parameters, such as nitric oxide [NO], xanthine oxidase (XOD), and xanthine dehydrogenase (XDH) levels, were analyzed. ROS levels were determined through DCFDA analysis. MTT-based cell cytotoxicity and BrdU cell proliferation analysis depicted the cytotoxicity effects (37% and 29% for 24 and 48h) and exhibited a reduction in the proliferation of MDA-MB-231 by CS-NPs/NAR. A significant increase in NO content, XOD, a decrease in XDH, and an increase in ROS levels were observed upon treatment with CS-NPs/NAR. Fluorescent images suggested the increase in the ROS level upon treatment with CS-NPs/NAR in cancer cells, and the results suggested that it could induce apoptosis. Further, to confirm this, the activity of caspase-3 was analyzed through western blotting, and the result suggested that the higher concentration of CS-NPs/NAR has increased the activation of procaspase3 when compared to free NAR. Hence, the current investigation concludes that high doses of CS-NPs/NAR induce and increase oxidative stress and so increased activation of procaspase3 may lead to cancer cell apoptosis and reduction in cell proliferation.

Fucoidan isolated from the edible seaweed Sargassum fusiforme suppresses skin damage stimulated by airborne particulate matter

Particulate matter (PM) pollution is a major environmental factor to global health problems. It exposes to the skin of human body, induces skin diseases and aging. Sargassum fusiforme is rich in a variety of bioactive substances and possesses the potential to protect skin against PM-stimulated damage. The purpose of this study is to investigate the effect of the fucoidan (SF-F4) isolated from S. fusiforme on PM-stimulated skin damage in human keratinocytes (HaCaT cells) and human dermal fibroblasts (HDF cells). The results show that PM significantly increased ROS level and promoted the cell death in both HaCaT cells and HDF cells. However, SF-F4 effectively increased the viability of PM-treated HaCaT cells by inhibiting apoptosis via scavenging intracellular ROS. In addition, SF-F4 regulated the expressions of MMPs and pro-inflammatory molecules in PM-stimulated HDF cells in a concentration-dependent manner, thus, it increasing pro-collagen content of PM-stimulated HDF cells. In conclusion, the current findings indicate that SF-F4 can effective inhibit PM-induced oxidative stress and reduce the secretion of pro-inflammatory factors and MMPs in cells, thereby slowing down the triggering of skin damage, suggesting that SF-F4 may be a potential pharmaceutical or cosmetic ingredient.

The sensitivity of multipotent mesenchymal stromal cells to short-term hypoxic stress in vitro depends on the efficiency of homotypic communication through gap junctions

Gap junctions (GJ) provide metabolic cooperation between cells through the direct exchange of cytoplasmic components. We analyzed the effect of short-term hypoxic stress on the efficiency of communication through the GJs in cultured multipotent mesenchymal stromal cells (MSCs) and characterized the sensitivity of MSCs to short-term hypoxic stress depending on the GJ function. Mitotically inactive MSCs were used in the experiments, in which the GJs were blocked with a specific inhibitor – carbenoxolone. The MSCs were continuously cultured at 20% O2. Further, MSCs with blocked and working GJs were subjected to hypoxic stress (0.1%, 24 hours). The efficiency of GJ communication was attenuated under hypoxic stress. The combined action of GJ inhibition and hypoxic stress was accompanied by an increase in ROS level as compared to the MSCs after hypoxic stress only. MSCs with blocked GJs were less sensitive to short-term hypoxic stress in comparison with MSCs integrated into the common network through working GJs. It was manifested in attenuation of hypoxia-induced angiogenic activity of MSCs. The angiogenic effects of conditioned medium from the MSCs with blocked GJs were almost twice less, which seems to be related to differences in the angiogenic mediators’ profiles: VEGF level decreased and FGF-2 level increased, while the monocyte chemoattractant protein 3 (MCP-3) level was unchanged. Thus, a decrease in the efficiency of direct MSCs- MSCs communication had a negative effect on mostly requested MSCs activity – the ability to induce angiogenesis. We conclude that blocking of GJ communication in MSCs is a negative event that impairs the coordination of MSCs’ response to the microenvironmental factors, in particular hypoxic stress, and reduces their functional plasticity.

Discovery of C-3 isoxazole substituted thiochromone S,S-dioxide derivatives as potent and selective inhibitors for monoamine oxidase B (MAO-B)

Developing new scaffolds for highly potent and selective inhibitors of human Monoamine Oxidase B (hMAO-B) is a crucial objective in enhancing the efficacy and safety in the clinical treatment of neurodegenerative diseases. In this study, we have identified a series of C-3 isoxazole-substituted thiochromone S,S-dioxide derivatives that exhibit strong inhibitory activity against hMAO-B. The strategy of oxidizing thiochromone to thiochromone S,S-dioxide solves the key defect of extreme insolubility observed for thiochromone analogues. In addition, the sulfone group contributes extra hydrogen(H)-bonding interactions with Tyr435, which significantly increases the activity of thiochromone S,S-dioxide derivatives against hMAO-B. Furthermore, the presence of isoxazole group provides potential H-bonding interaction and electrostatic interaction with the residue of Tyr326, while the rigid aryl ring introduces a potential steric conflict with Phe208 of hMAO-A to improve both potency and selectivity. In our investigations, several compounds (9c, 10c, 10e, 10g, 10l and 10m) demonstrate remarkable single-digit nanomolar potency. These compounds exhibit favorable cytotoxicity profiles in both differentiated SH-SY5Y and HVSMC cells, without apparent cardiotoxic effects. Moreover, compounds 10e and 10h do not lead to an increase in ROS levels in differentiated SH-SY5Y cells, further demonstrating their potential as safe and effective hMAO-B inhibitors. These findings indicate that the C-3 isoxazole substituted thiochromone S,S-dioxide analogues are potential leading compounds for the development of selective inhibitors with high potency.

Unveiling the potential of angiotensin-converting enzyme as a therapeutic target in head and neck squamous carcinoma

This study investigated the effects of ACE inhibition on Head and Neck Squamous Cell Carcinoma (HNSCC), tumor progression, and the relation of ACE2, AGTR1, ACE, and MAS1 expression with HNSCC patient` survival. ACE inhibitor (Captopril) treatment was applied into Swiss male mice. ACE2, AGTR1, ACE, and MAS1 expression levels were analyzed in HNSCC tumor tissues from The Cancer Genome Atlas (TCGA) database. ACE inhibition reduced cell viability, proliferation, migration, and invasion, increased ROS levels, and induced apoptosis in SCC9 cells. Neoplastic angiogenesis was suppressed by ACE inhibition in the CAM assay. ACE inhibition also reduced the incidence of severe dysplasia/carcinoma in the histological analysis. TCGA data revealed that lower ACE2 levels were associated with poorer survival outcomes, while increased AGTR1 expression correlated with a higher risk of death in HPV-negative patients. ACE upregulation and higher MAS1 expression were observed in HNSCC tumor tissues. ACE inhibition demonstrated anti-cancer effects in HNSCC cells and suppressed neoplastic angiogenesis. It also reduced histological aggressiveness and showed potential predictive value for ACE2 and AGTR1 expression levels in HNSCC. These findings suggest the therapeutic potential of ACE inhibitors in HNSCC treatment, requiring further investigation and validation in clinical settings.

A multivalent polyphenol–metal-nanoplatform for cascade amplified chemo-chemodynamic therapy

Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting intracellular hydrogen peroxide (H2O2) into cytotoxic oxidizing hydroxyl radicals (⋅OH). However, the therapeutic efficiency of CDT is compromised due to the insufficient endogenous H2O2 and metal catalysts in tumor cells. The use of multivalent polyphenols with multiple hydroxyl functions provides a facile yet robust means for efficient CDT augmentation. For this purpose, we reported herein the construction of polyphenol–metal nanoparticles (NPs) via a phenol–metal coordination strategy. The uniqueness of this study is the preparation of only one polymer construct with multivalency that can afford various supramolecular interactions for simultaneous “one-pot” loading of different therapeutic species, i.e., doxorubicin (DOX), glucose oxidases (GOD), and Fe3+ and further co-self-assembly into a stabilized nanomedicine for cascade amplified chemo-chemodynamic therapy. Specifically, the tumor intracellular acidic pH-triggered DOX release could serve for chemotherapy as well as enhance the intracellular H2O2 level. Together with the extra H2O2 and gluconic acid produced by the GOD-triggered glucose consumption, DOX@POAD-Fe@GOD NPs promoted Fe3+participation in the Fe-mediated Fenton reaction for cascade amplified chemo-chemodynamic therapy. Notably, this formulation displayed a greater anti-tumor effect with a tumor inhibition ratio 1.6-fold higher than that of free DOX in a BALB/c mice model bearing 4T1 tumors. Overall, the multivalent polyphenol–metal nanoplatform developed herein integrates chemotherapy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great potential for clinical translations. Statement of significanceChemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insufficient endogenous H2O2 and metal catalysts in tumor cells. To develop a facile yet robust strategy for efficient CDT augmentation, we reported herein construction of a multivalent polyphenol–metal nanoplatform, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol–metal coordination strategy. This nanoplatform integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsulation of doxorubicin (DOX), Fe3+, and glucose oxidases (GOD), but also for cascade amplified chemo-chemodynamic therapy. Specifically, the intracellular acidic pH-triggered dissociation of DOX@POAD-Fe@GOD NPs promoted the release of Fe3+, DOX, and GOD for significantly increased ROS levels that can accelerate Fenton reactions for cascaded chemotherapy, starvation therapy, and CDT with amplified antitumor efficiency in vivo.

Phytosphingosine inhibits the growth of lung adenocarcinoma cells by inducing G2/M-phase arrest, apoptosis, and mitochondria-dependent pathway cell death in vitro and in vivo

In order to search for novel antitumor drugs with high efficiency and low toxicity, the anti-lung cancer activity of phytosphingosine was studied. Phytosphingosine is widely distributed in fungi, plants, animals, and has several biological activities, including anti-inflammation and anti-tumor. However, its anti-lung cancer activity needs to be further investigated. The effects and pharmacological mechanisms of phytosphingosine on lung cancer treatment were investigated both in vitro and in vivo. The results showed that phytosphingosine inhibited the growth of lung cancer cell lines. Phytosphingosine induced apoptosis through a mitochondria-mediated pathway, phytosphingosine arrested the cell cycle at the G2/M phase and induced apoptosis in a dose-dependent manner by increasing Bax/Bcl-2 ratio, which caused the decrease of mitochondrial membrane potential to promote the release of cytochrome C, caspase 9 and 3, and degrade PARP in A549 cells. The results showed that phytosphingosine could damage the mitochondrial functions, increase ROS levels, and arrest the cell cycle at the G2/M stages. Finally, phytosphingosine also inhibited the growth of tumor in mice. Taken together, phytosphingosine suppressed the growth of lung cancer cells both in vitro and in vivo and had potential application in the research and development of antitumor drugs. The aim of the present study was to explain the theoretical basis of phytosphingosine therapy for lung cancer and providing new possibilities for lung cancer treatment.

Selaginellin derivatives from Selaginella tamariscina and evaluation for anti-breast cancer activity

A phytochemical investigation of Selaginella tamariscina led to the isolation of 17 selaginellin derivatives. Their inhibitory activities against breast cancer cells were screened, and preliminary structure-activity relationships were also established. Among them, dimeric selaginellin 17 showed potential activity against MDA-MB-231 cells with an IC50 value of 3.2 ± 0.1 μM, corresponding to 4-fold higher potency than the reference compound 5-FU (IC50 14.8 ± 0.2 μM). Mechanistic studies indicated that 17 could cause G2/M phase arrest in MDA-MB-231 cells and induce apoptosis accompanied by increased ROS levels.

Serpina3c attenuates adipose tissue and heart damage during obesity by inhibiting oxidative stress and endoplasmic reticulum stress

Abstract Background Adipose tissue (AT) dysfunction is closely associated with obesity-related heart damage. Serpina3c which is highly expressed in mature adipocytes, is a secreted serine protease inhibitor that can regulate AT function. The present study aimed to investigate the effect of Serpina3c on AT and heart during obesity. Methods Wild type (WT) and Serpina3c knockout (3cKO) mice were fed with high-fat diet (HFD) for 20 weeks. AAV-mediated overexpression of Serpina3c was injected locally in epididymal white adipose tissue (eWAT) to examine the effect of Serpina3c. Palmitic acid was established to interfere with the differentiated mature 3T3L1 cells of Serpina3c knockdown (3cKD) or overexpression (3cOV) and corresponding control groups. RNA-seq of mature 3T3L1 cells was performed to assess the effect of Serpina3c on the transcriptome. Results Decrease of Serpina3c protein in AT of obese mice induced by HFD. The body weight and serum cholesterol, triglycerides, free fatty acid and pro-inflammatory cytokines were increased significantly in 3cKO mice. Increased inflammation, fibrosis and apoptosis of AT as well as cardiac fat deposition, inflammation and apoptosis were detected, and the impairment of cardiac diastolic function was aggravated in KO mice. Overexpression of Serpina3c in eWAT alleviated these adverse phenotypes. Through RNA-seq, we found endoplasmic reticulum stress (ERS)-related genes were significantly increased in 3cKD group, but significantly down-regulated in 3cOV group. Oxidative stress was generally considered to be the upstream of ERS, and we detected a significant increase in ROS levels in 3cKO group. Serpina3c alleviated ERS and production of pro-inflammatory cytokines in adipocytes by inhibiting NOX4 and iNOS mediated oxidative stress. Conclusion Our results highlight a protective role for Serpina3c as a novel adipocytokine in the obesity-related heart damage, with Serpina3c conferring protection through inhibiting NOX4 and iNOS mediated oxidative stress to negatively regulate ERS and inflammation in adipocytes.Schematic illustration