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Background: Translationally controlled tumor protein (TCTP), which has been verified to have a proinflammatory activity, plays an important role in allergy. However, it remains unclear whether TCTP has an impact on the acute rejection (AR) after liver transplantation., Methods: Three protocols were used to delineate the role of TCTP in AR after liver transplantation. First, in rat orthotopic liver transplantation (OLT), the expression of TCTP was measured by enzyme-linked immunosorbent assay (ELISA), real-time PCR, Western blot and immunofluorescence assays. Second, in mixed lymphocyte reaction (MLR), the role of TCTP in lymphocyte proliferation was measured by carboxyfluorescein succinimidyl ester (CFSE) labeling and the impact of TCTP on inflammatory factor release was detected by cytokine arrays. Third, in human OLT, the level of serum TCTP was detected by ELISA, and the relationship between TCTP and model for early allograft function (MEAF) score was assessed by Spearman's correlation., Results: In rat OLT, AR resulted in great harm to allografts, manifesting as deterioration of liver function, increasing inflammatory factors and infiltrating lymphocytes. Meanwhile, TCTP was overexpressed in serum and allografts. Higher level of TCTP was associated with higher rejection activity index (RAI). In an MLR protocol, TCTP knockdown inhibited the proliferation of mixed inflammatory cells and significantly suppressed the release of 15 cytokines and chemokines. In human OLT, the serum TCTP was up-regulated within a week after operation. Additionally, the increasing speed of serum TCTP positively correlated with MEAF scores (r = 0.449; P = 0.0088)., Conclusions: Up-regulated TCTP positively affects AR after liver transplantation., (Copyright © 2020. Published by Elsevier B.V.)

Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover (Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABA A receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.

Aims: Obesity is characterized as a chronic state of low-grade inflammation with progressive immune cell infiltration into adipose tissue. Adipose tissue macrophages play a critical role in the establishment of chronic inflammatory states and metabolic dysfunctions. Inonotus ( I .) sanghuang and its extract polyphenols exhibit anti-carcinogenesis, anti-inflammatory, and anti-oxidant activities. However, the action of I. sanghuang polyphenols in obesity-related inflammation has not been reported. The aim of this study was to explore the anti-inflammatory action of polyphenols from I. sanghuang extract (ISE) in macrophages and the interaction between macrophages and adipocytes. Materials and Methods: RAW264.7 macrophages were stimulated with LPS or conditioned medium of hypertrophied 3T3-L1 adipocytes or cocultured with differentiated adipocytes in the presence of different doses of ISE. The inflammatory cytokines were evaluated by ELISA, the MAPK, NF-κB, and IL-6/STAT3 signals were determined by immunoblotting, and the migrated function of macrophages was determined by migration assay. Results: ISE suppressed the inflammatory mediators including NO, TNF-α, IL-6, and MCP-1 induced by either LPS or conditioned medium derived from 3T3-L1 adipocytes. ISE also decreased the production of these inflammatory mediators in cocultures of 3T3-L1 adipocytes and RAW264.7 macrophages. Furthermore, ISE blocked RAW264.7 macrophages migration toward 3T3-L1 adipocytes in cocultures. Finally, this effect of ISE might be mediated via inhibiting ERK, p38, and STAT3 activation. Conclusions: Our findings indicate the possibility that ISE suppresses the interaction between macrophages and adipocytes, attenuates chronic inflammation in adipose tissue and improves obesity-related insulin resistance and complication, suggesting that ISE might be a valuable medicinal food effective in improving insulin resistance and metabolic syndrome.

Endometritis is the most common bovine uterine disease following parturition. The role of prostaglandin E2 (PGE2) in the regulation of endometrial inflammation and repair is well understood. Excess PGE2 is also generated in multiple inflammatory diseases, including endometritis. However, it remains unclear whether PGE2 is associated with pathogen-induced inflammatory damage to the endometrium. To clarify the role of PGE2 in pathogen-induced inflammatory damage, this study evaluated the production of PGE2, inflammatory factors, and damage-associated molecular patterns (DAMPs) in cultured Escherichia coli-infected bovine endometrial tissue. PGE2 production was significantly higher in E. coli-infected tissue, and in E. coli-infected tissue treated with 15-prostaglandin dehydrogenase (15-PGDH) inhibitors, as compared to uninfected tissue. Phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1) were also upregulated in E. coli-infected tissue, while concentrations of arachidonic acid (AA), leukotrienes, DAMPs, and other proinflammatory factors increased. The accumulation of PGE2 clearly damaged the cultured tissue. Treatment with the COX-2, mPGES-1, EP4, and protein kinase A (PKA) inhibitors decreased the production of PGE2, inflammatory factors, and DAMPs, simultaneously alleviating the E. coli-induced endometrial tissue damage. Therefore, the PGE2 that was generated by COX-2 and mPGES-1 accumulated, and this pathogenic PGE2 increased inflammatory damage by upregulating inflammatory factors and DAMPs in E. coli-infected bovine endometrial tissue. This upregulation of inflammatory factors and DAMPs might be regulated by the EP4-PKA signaling pathway.

Background: Pancreatitis-associated protein (PAP) is a pancreatic secretory protein belongs to the group VII of C-type lectin family. Emerging evidence suggests that PAP plays a protective effect in inflammatory diseases. In the present study, we newly identified a 16-amino-acid peptide (named PAPep) derived from C-type lectin-like domain (CTLD) of human PAP with potent anti-inflammatory activity using both in vivo and in vitro assays., Methodology/principal Findings: We assessed the anti-inflammatory effect of PAPep on endotoxin-induced uveitis (EIU) in rats and demonstrated that intravitreal pretreatment of PAPep concentration-dependently attenuated clinical manifestation of EIU rats, reduced protein leakage and cell infiltration into the aqueous humor (AqH), suppressed tumor necrosis factor (TNF)-α, interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein (MCP)-1 production in ocular tissues, and improved histopathologic manifestation of EIU. Furthermore, PAPep suppressed the LPS-induced mRNA expression of TNF-α and IL-6 in RAW 264.7 cells, inhibited protein expression of ICAM-1 in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) as well as U937 cells adhesion to HUVECs. Western blot analysis in ocular tissues and different cell lines revealed that the possible mechanism for this anti-inflammatory effect of PAPep may depend on its ability to inhibit the activation of NF-kB signaling pathway., Conclusions/significance: Our studies provide the first evidence that the sequence of PAPep is within the critically active region for the anti-inflammatory function of PAP and the peptide may be a promising candidate for the management of ocular inflammatory diseases.

Abstract Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover (Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABAA receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.

Immune response is an important factor in determining the fate of bone replacement materials, in which macrophages play an important role. It is a new idea to design biomaterials with immunomodulatory function to reduce inflammation and promote bone integration by regulating macrophages polarization. In this work, the immunomodulatory properties of CaP Zn-Mn-Li alloys and the specific mechanism of action were investigated. We found that the CaP Zn0.8Mn0.1Li alloy promoted the polarization of macrophages toward M2 and reduced inflammation, which could effectively upregulate osteogenesis-related factors and promote new bone formation, indicating the important role of macrophages polarization in biomaterial induction of osteogenesis. In vivo studies further demonstrated that CaP Zn0.8Mn0.1Li alloy could stimulate osteogenesis better than other Zn-Mn-Li alloys implantations by regulating macrophages polarization and reducing inflammation. In addition, transcriptome results showed that CaP Zn0.8Mn0.1Li played an important regulatory role in the life process of macrophages, activating Toll-like receptor signaling pathway, which participated in the activation and attenuation of inflammation, and accelerated bone integration. Thus, by preparing CaP coatings on the surface of Zn-Mn-Li alloys and combining the bioactive ingredient with controlled release, the biomaterial will be imbibed with beneficial immunomodulatory properties that promote bone integration. [ABSTRACT FROM AUTHOR]

Sinomenine (SIN), an alkaloid extracted from the root of S. acutum. sinomenine , has been shown to have antiarrhythmic, antioxidant, and anti-inflammatory effects in myocardial ischemia-reperfusion injury (MIRI) ex vivo. In this study, we investigated the cardioprotective effects of SIN in an in vivo mouse model of MIRI. Adult male C57BL/6J mice received SIN (80 mg/kg) for 5 days and underwent 30 min of percutaneous occlusion of the left anterior descending artery (LAD) followed by 24 h of reperfusion. Results showed that pretreatment with SIN significantly reduced myocardial infarct size and concentrations of markers of cardiac injury and improved left ventricular ejection fraction (EF) and shortening fraction (FS) in MIRI mice. The SIN pretreatment prevented the MIRI-induced decrease in the expression levels of Bcl-2, increase in the expression levels of caspase-3, caspase-9, and Bax, and increase in the number of TUNEL-positive cells in ischemic heart tissue. It was also found that pretreatment with SIN prevented the MIRI-induced oxidative stress imbalance in ischemic heart tissue, as shown by the increase in total antioxidant capacity (T-AOC) and glutathione (GSH) and the decrease in malondialdehyde (MDA), reactive oxygen species (ROS), and dihydroethidium (DHE) density. Further studies showed that the stimulus of cardiac ischemia/reperfusion caused a remarkable increase in the expression levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) mRNA in ischemic heart tissue, which was effectively prevented by pretreatment with SIN. These results demonstrate that SIN can attenuate MIRI-induced cardiac injury in vivo by preventing oxidative stress, inflammation, and apoptosis. [ABSTRACT FROM AUTHOR]

Strategies for treating myocardial ischemia in the clinic usually include re-canalization of the coronary arteries to restore blood supply to the myocardium. However, myocardial reperfusion insult often leads to oxidative stress and inflammation, which in turn leads to apoptosis and necrosis of myocardial cells, for which there are no standard treatment methods. The aim of this study was to determine the pharmacological effect of indole-3-carbinol (I3C), a phytochemical found in most cruciferous vegetables, in a mouse model of myocardial ischemia/reperfusion injury (MIRI). Our results showed that I3C pretreatment (100 mg/kg, once daily, i. p.) prevented the MIRI-induced increase in infarct size and serum creatine kinase (CK) and lactate dehydrogenase (LDH) in mice. I3C pretreatment also suppressed cardiac apoptosis in MIRI mice by increasing the expression levels of the anti-apoptotic protein Bcl-2 and decreasing the expression levels of several apoptotic proteins, including Bax, caspase-3, and caspase-9. In addition, I3C pretreatment was found to reduce the levels of parameters reflecting oxidative stress, such as dihydroethidium (DHE), malondialdehyde (MDA), reactive oxygen species (ROS), and nitric oxide (NO), while increasing the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC) and glutathione (GSH), in MIRI-induced ischemic heart tissue. I3C pretreatment was also able to remarkably decrease the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) mRNA in ischemic heart tissue. These results demonstrate that administration of I3C protects the heart from MIRI through its anti-apoptotic, antioxidant, and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Purpose: The aim was to investigate the effect and underlying mechanism of anti-vascular endothelial growth factor (anti-VEGF) in diabetic macular edema (DME) by optical coherence tomography angiography (OCTA). Methods: Twenty-five eyes in 18 treatment-naïve patients with DME were included. All eyes were imaged by OCTA at baseline and 1 week after monthly intravitreal aflibercept injection (IAI). Visual acuity was measured as best corrected visual acuity (BCVA). Additional parameters were evaluated by OCTA, including central macular thickness (CMT), the number of hyperreflective foci (HRF), foveal avascular zone (FAZ), vessel density (VD) in the deep capillary plexus (DCP), the en-face area of cystoid edema in DCP segmentation, and subretinal fluid (SRF) height. Results: The mean time between baseline and final follow-up by OCTA was 79.24 ± 38.15 (range, 28–163) days. Compared with baseline, BCVA was increased significantly after the 3rd IAI, while CMT was decreased significantly from the 1st IAI. SRF height and the area of cystoid edema in DCP segmentation were decreased significantly after the 2nd IAI compared with baseline. The number of HRF was decreased significantly after the 1st IAI (8.87 ± 9.38) compared with baseline (11.22 ± 10.63). However, FAZ's area and perimeter as well as VD in DCP showed no significant changes post-treatment. Conclusion: Anti-VEGF is effective in treating DME, improving visual acuity and decreasing macular edema. The decreased HRF indicates anti-inflammatory effects of aflibercept to deactivate retinal microglia/macrophages. The decreased cystoid edema and SRF height indicated improved drainage function of Müller glial cells and retinal pigment epithelium after IAI. [ABSTRACT FROM AUTHOR]

• PGE 2 promotes cytokines and DAMPs expression in heat killed S. aureus treated bovine endometrial tissue regulated by EP4-p38 MAPK pathway. • S. aureus adhere and invade into bovine endometrial epithelial cells associated with PGE 2 generation. • The strategy of decreasing PGE 2 accumulation is helpful in reducing the inflammation stage caused by S. aureus. S. aureus isolated from bacterial bovine endometritis is common in epidemiological reports, but is often ignored as a subclinical pathogenic microorganism. In a previous study, we showed that live S. aureus (LSA) and heat killed S. aureus (HK–SA) induce different inflammatory responses in bovine endometrial tissue, and possibly being associated with the accumulation of prostaglandin E2 (PGE 2). Thus, in this study, we varied PGE 2 concentrations using inhibitors or agonists in HK–SA-treated bovine endometrial tissues. The results demonstrated that PGE 2 has a positive relationship with IL-6, TNF-α, and damage-associated molecular patterns (DAMPs; e.g., HMGB-1 and HABP-1) expression and tissues damage, and is regulated by the EP4-p38 MAPK pathway. We concluded that lipoproteins of S. aureus are associated with PGE 2 generation. To further explore the relationship between LSA and PGE 2 accumulation, we used the S. aureus strain SA113 lipoprotein knockout (SA113Δlpl) to infect bovine endometrial epithelial cells (BECs). LSA decreased PGE 2 , cAMP, EP4, IL-6, IL-8, cAMP secretion, and the MAPK and PKA signaling pathways when infected with SA113Δlpl, as compared with SA113-infected groups. Moreover, the adhesion and invasion of BECs were similarly downregulated when lipoproteins in S. aureus were knocked out. The results of this study show that PGE 2 is involved in both HK–SA- and LSA-induced inflammatory responses in the bovine endometrium. We suggest that S. aureus infection is associated with bovine endometritis, and although HK–SA and LSA induce different inflammatory responses, the strategy of decreasing PGE 2 accumulation is helpful in reducing the inflammation stage caused by S. aureus. [ABSTRACT FROM AUTHOR]

Highlights: [•] miR-93 is downregulated in the eyes of LPS-induced EIU rats. [•] miR-93 is downregulated in LPS-treated RAW 264.7 cells. [•] miR-93 inhibits LPS-induced inflammatory cytokine production. [•] miR-93 inhibits LPS-induced activation of NF-κB signaling through IRAK4. [Copyright &y& Elsevier]

Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response. [ABSTRACT FROM AUTHOR]

Keywords: Inonotus sanghuang; polyphenols; inflammation; obesity; NF- B signaling; MAPK signaling EN Inonotus sanghuang polyphenols inflammation obesity NF- B signaling MAPK signaling N.PAG N.PAG 2 02/02/21 20210128 NES 210128 In the original article, there was a mistake in the total STAT3 expression of western blotting data in Figure 7B as published. Inonotus sanghuang, polyphenols, inflammation, obesity, NF- B signaling, MAPK signaling. [Extracted from the article]

Abstract: Thrombomodulin (TM) is a single-transmembrane glycoprotein receptor for thrombin, which is best known as a cofactor for thrombin-mediated activation of anticoagulant protein C. C-type lectin-like domain (CTLD) of TM has distinct coagulation/fibrinolysis-independent anti-inflammatory properties. Here we found anti-inflammatory effects of a novel peptide (GC31) from CTLD of TM in endotoxin-induced uveitis, which was characterized by a reduction of leukocyte counts, protein concentration, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 levels in aqueous humor. Through in vitro experiments, we further found that GC31 suppressed TNF-α and interleukin (IL)-6 expressions in lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells and interrupted LPS-induced nuclear factor-κB (NF-κB) activation. These data indicate a beneficial role of peptide GC31 in preventing intraocular inflammatory response, especially uveitis. [Copyright &y& Elsevier]

Purpose: Adiponectin has been shown to exert potent anti-inflammatory activities in a range of systemic inflammatory diseases. This study aimed to investigate the potential therapeutic effects of KS23, a globular adiponectin-derived peptide, on endotoxin-induced uveitis (EIU) in rats and lipopolysaccharide (LPS)-stimulated mouse macrophage-like RAW 264.7 cells. Methods: EIU was induced in Lewis rats by subcutaneous injection of LPS into a single footpad. KS23 or phosphate-buffered saline (PBS) was administered immediately after LPS induction via intravitreal injection. Twenty-four hours later, clinical and histopathological scores were evaluated, and the aqueous humor (AqH) was collected to determine the infiltrating cells, protein concentration, and levels of inflammatory cytokines. In vitro , cultured RAW 264.7 cells were stimulated with LPS in the presence or absence of KS23, inflammatory cytokine levels in the supernatant, nuclear translocation of nuclear factor kappa B (NF-κB) subunit p65, and the expression of NF-kB signaling pathway components were analyzed. Results: KS23 treatment significantly ameliorated the clinical and histopathological scores of EIU rats and reduced the levels of infiltration cells, protein, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the aqueous humor. Consistently, KS23 decreased the expression of TNF-α and IL-6 in the supernatant of LPS-stimulated RAW 264.7 cells and inhibited the LPS-induced nuclear translocation of NF-κB p65 and the phosphorylation of IKKα/β/IκBα/NF-κB. Conclusion: The in vivo and in vitro results demonstrated the anti-inflammatory effects of the peptide KS23 and suggested that KS23 is a compelling, novel therapeutic candidate for the treatment of ocular inflammation. [ABSTRACT FROM AUTHOR]

Background: L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of L-theanine in myocardial ischemia-reperfusion injury (MIRI). Methods: The cardioprotective effects and mechanisms of L-theanine and the role of Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling were investigated in MIRI mice using measures of cardiac function, oxidative stress, and apoptosis. Results: Administration of L-theanine (10 mg/kg, once daily) suppressed the MIRI-induced increase in infarct size and serum creatine kinase and lactate dehydrogenase levels, as well as MIRI-induced cardiac apoptosis, as evidenced by an increase in Bcl-2 expression and a decrease in Bax/caspase-3 expression. Administration of L-theanine also decreased the levels of parameters reflecting oxidative stress, such as dihydroethidium, malondialdehyde, and nitric oxide, and increased the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC), glutathione (GSH), and superoxide dismutase (SOD) in ischemic heart tissue. Further analysis showed that L-theanine administration suppressed the MIRI-induced decrease of phospho-JAK2 and phospho-STAT3 in ischemic heart tissue. Inhibition of JAK2 by AG490 (5 mg/kg, once daily) abolished the cardioprotective effect of L-theanine, suggesting that the JAK2/STAT3 signaling pathway may play an essential role in mediating the anti-I/R effect of L-theanine. Conclusions: L-theanine administration suppresses cellular apoptosis and oxidative stress in part via the JAK2/STAT3 signaling pathway, thereby attenuating MIRI-induced cardiac injury. L-theanine could be developed as a potential drug to alleviate cardiac damage in MIRI. [ABSTRACT FROM AUTHOR]

Background: Lipid peroxidation is a characteristic metabolic manifestation of diabetic retinopathy (DR) that causes inflammation, eventually leading to severe retinal vascular abnormalities. Selenium (Se) can directly or indirectly scavenge intracellular free radicals. Due to the narrow distinction between Se's effective and toxic doses, porous Se@SiO2 nanospheres have been developed to control the release of Se. They exert strong antioxidant and anti-inflammatory effects. Methods: The effect of anti-lipid peroxidation and anti-inflammatory effects of porous Se@SiO2 nanospheres on diabetic mice were assessed by detecting the level of Malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), decreased reduced/oxidized glutathione (GSH/GSSG) ratio, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL) -1β of the retina. To further examine the protective effect of porous Se@SiO2 nanospheres on the retinal vasculopathy of diabetic mice, retinal acellular capillary, the expression of tight junction proteins, and blood–retinal barrier destruction was observed. Finally, we validated the GPX4 as the target of porous Se@SiO2 nanospheres via decreased expression of GPX4 and detected the level of MDA, GSH/GSSG, TNF-α, IFN-γ, IL -1β, wound healing assay, and tube formation in high glucose (HG) cultured Human retinal microvascular endothelial cells (HRMECs). Results: The porous Se@SiO2 nanospheres reduced the level of MDA, TNF-α, IFN-γ, and IL -1β, while increasing the level of GPX4 and GSH/GSSG in diabetic mice. Therefore, porous Se@SiO2 nanospheres reduced the number of retinal acellular capillaries, depletion of tight junction proteins, and vascular leakage in diabetic mice. Further, we identified GPX4 as the target of porous Se@SiO2 nanospheres as GPX4 inhibition reduced the repression effect of anti-lipid peroxidation, anti-inflammatory, and protective effects of endothelial cell dysfunction of porous Se@SiO2 nanospheres in HG-cultured HRMECs. Conclusion: Porous Se@SiO2 nanospheres effectively attenuated retinal vasculopathy in diabetic mice via inhibiting excess lipid peroxidation and inflammation by target GPX4, suggesting their potential as therapeutic agents for DR. [ABSTRACT FROM AUTHOR]

• tFNA-Que can alleviate radiation-induced oxidative stress and inflammation. • tFNA-Que presents a straightforward and efficient synergistic delivery nano-system. Radiation cystitis (RC) has impacted millions globally with high morbidity and a dearth of effective strategies. Earlier research indicated that quercetin (Que) could alleviate radiation-induced bladder damage. However, Que's limited application arises from issues such as poor water solubility, rapid degradation, and low oral bioavailability. To address these challenges, a nano-system, named tFNA-Que, has been developed for Que delivery, utilizing the tetrahedral framework nucleic acid (tFNA). Due to the anti-inflammatory, antioxidant, and delivery capabilities of tFNA, it is purposefully designed as an efficient carrier for delivering Que. The tFNA-Que formulation exhibits an easily synthesized structure, stable performance, sustained release, good water solubility, robust cellular internalization ability, desirable biocompatibility, and biosafety. As a result, tFNA-Que can alleviate radiation-induced oxidative stress and inflammation while promoting angiogenesis in RC. In summary, the synthesis of tFNA-Que presents a straightforward and efficient synergistic delivery nano-system, making it as a promising candidate for RC treatment. [ABSTRACT FROM AUTHOR]