Radiotherapy-sensitized cancer immunotherapy via cGAS-STING immune pathway by activatable nanocascade reaction.

Radiotherapy-induced immune activation holds great promise for optimizing cancer treatment efficacy. Here, we describe a clinically used radiosensitizer hafnium oxide (HfO2) that was core coated with a MnO2 shell followed by a glucose oxidase (GOx) doping nanoplatform (HfO2@MnO2@GOx, HMG) to trigger ferroptosis adjuvant effects by glutathione depletion and reactive oxygen species production. This ferroptosis cascade potentiation further sensitized radiotherapy by enhancing DNA damage in 4T1 breast cancer tumor cells. The combination of HMG nanoparticles and radiotherapy effectively activated the damaged DNA and Mn2+-mediated cGAS-STING immune pathway in vitro and in vivo. This process had significant inhibitory effects on cancer progression and initiating an anticancer systemic immune response to prevent distant tumor recurrence and achieve long-lasting tumor suppression of both primary and distant tumors. Furthermore, the as-prepared HMG nanoparticles "turned on" spectral computed tomography (CT)/magnetic resonance dual-modality imaging signals, and demonstrated favorable contrast enhancement capabilities activated by under the GSH tumor microenvironment. This result highlighted the potential of nanoparticles as a theranostic nanoplatform for achieving molecular imaging guided tumor radiotherapy sensitization induced by synergistic immunotherapy.

Cancer Radiosensitization Nanoagent to Activate cGAS-STING Pathway for Molecular Imaging Guided Synergistic Radio/Chemo/Immunotherapy.

Immunotherapy has emerged as an innovative strategy with the potential to improve outcomes in cancer patients. Recent evidence indicates that radiation-induced DNA damage can activate the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to enhance the antitumor immune response. Even so, only a small fraction of patients currently benefits from radioimmunotherapy due to the radioresistance and the inadequate activation of the cGAS-STING pathway. Herein, this work integrates hafnium oxide (HfO2) nanoparticles (radiosensitizer) and 7-Ethyl-10-hydroxycamptothecin (SN38, chemotherapy drug, STING agonist) into a polydopamine (PDA)-coated core-shell nanoplatform (HfO2@PDA/Fe/SN38) to achieve synergistic chemoradiotherapy and immunotherapy. The co-delivery of HfO2/SN38 greatly enhances radiotherapy efficacy by effectively activating the cGAS-STING pathway, which then triggers dendritic cells maturation and CD8+ T cells recruitment. Consequently, the growth of both primary and abscopal tumors in tumor-bearing mice is efficiently inhibited. Moreover, the HfO2@PDA/Fe/SN38 complexes exhibit favorable magnetic resonance imaging (MRI)/photoacoustic (PA) bimodal molecular imaging properties. In summary, these developed multifunctional complexes have the potential to intensify immune activation to realize simultaneous cancer Radio/Chemo/Immunotherapy for clinical translation.

Prophylactic administration of metformin reduces gestational diabetes mellitus incidence in the high-risk populations: a meta-analysis : Metformin for gestational diabetes prevention.

Metformin exerts a good efficacy for gestational diabetes mellitus (GDM) treatment by regulating gluconeogenesis and insulin resistance, while no consensus about its preventive effect on GDM is reached yet. Thus, this meta-analysis aimed to comprehensively investigate the prophylactic administration of metformin in pregnant women at high risk of GDM. Databases (EMBASE, PubMed, Cochrane, CNKI, Wanfang, CQVIP) were searched to screen papers concerning the GDM prevention using metformin in women at high risk of GDM (polycystic ovary syndrome (PCOS), obese, and pregestational insulin resistance patients) until January 2023. Our study showed that five cohort studies and fifteen randomized controlled trials (RCTs) involving 3911 women were included. Pooled analysis showed that prophylactic metformin treatment (vs. control treatment) greatly reduced GDM rate (relative risk (RR) = 0.59, 95% confidence intervals (CI): 0.43-0.80). Subgroup analyses also revealed that prophylactic metformin treatment (vs. control treatment) decreased the GDM rate in the following patients' types: (1) in Asians (RR = 0.31, 95% CI: 0.23-0.41), (2) in PCOS patients (RR = 0.42, 95% CI: 0.26-0.68), and (3) in patients receiving high dose of metformin (mean dose > 1000 mg) (RR = 0.59, 95% CI: 0.42-0.83). Concerning the quality of involved studies, the overall risk of bias was low. Egger's test implied that no publication bias existed in the findings. Moreover, sensitivity analysis suggested the pleasing robustness of the results. In conclusion, prophylactic metformin reduces GDM incidence in high-risk pregnant women, indicating its early-application benefits.

A high accuracy measurement method based on vortex polar axis rotation phase-shifting interferometry (VPAR-PSI).

For higher precision phase shift measurement, based on the characteristics of vortex beam, the manuscript introduces phase shift directly through the polar axis rotation of the vortex beam. Compared to traditional grey-scale modulation, the proposed VPAR-PSI method introduces a phase-shifting directly instead of changing the grey-scale, which not only can largely reduce the deviation caused by traditional PSI phase modulation via grey-scale change, but also can effectively avoid the non-linearity between grey-scale and phase of traditional PSI. For verifying the effectiveness of the method proposed in this manuscript, a simulation experiment, sample experiment, and VPAR-PSI and PSI comparison experiment were conducted. The results show that the proposed VPAR-PSI has a high phase-shifting and demodulation accuracy, and can be well implemented to measurement of optical components. The comparative experimental show that compared to conventional PSI, the measurement results of VPAR-PSI have smaller envelope values (mean envelope reduction of 1.4202λ), smaller RMS and standard deviation (the values decreased by 0.3515, 0.3067, and the percentage decreases were 59.69%, 59.71% respectively), proving that the VPAR-PSI technique are more accurate and stable. © 2020 Published by Elsevier Ltd. Selection and/or peer-review under responsibility of Global Science and Technology Forum Pte Ltd.

Proton pump inhibitor-enhanced nanocatalytic ferroptosis induction for stimuli-responsive dual-modal molecular imaging guided cancer radiosensitization.

Although radiotherapeutic efficiency has been revealed to be positively correlated with ferroptosis, the neutral/alkaline cytoplasm pH value of tumor cells remains an intrinsic challenge for efficient Fenton/Fenton-like reaction-based ferroptosis induction. Herein, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles (HGMP NPs) were designed as a ferroptosis inducer, which could specifically release Mn2+ in tumor cells to activate the Fenton-like reaction for ferroptosis induction. Proton pump inhibitors (PPIs) were synchronously administered for cytoplasm pH level regulation by inhibiting V-H+-ATPases activity, enhancing Fenton-like reaction-based ferroptosis induction. Moreover, reactive oxygen species production was facilitated via the glucose oxidase triggered cascade catalytic reaction by utilizing intracellular ß-D-glucose for H2O2 self-supply and generation of additional cytoplasm H+. The PPI enhanced ferroptosis inducing nanosystem effectively inhibited tumor growth both in vitro and in vivo for tumor-specific ferroptosis induction and radiotherapy sensitization, suggesting that PPI administration could be an efficient adjuvant to reinforce Fenton/Fenton-like reaction-based ferroptosis induction for radiosensitization. STATEMENT OF SIGNIFICANCE: The cytoplasm pH value of tumor cells is typically neutral to alkaline, which is higher than that of the Fenton/Fenton-like reaction desired acidic environments, hindering its efficiency. In this study, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles were synthesized as a ferroptosis inducer, which could specifically release Mn2+ via depleting glutathione and then activate the Fenton-like reaction in the tumor microenvironment. The glucose oxidase was applied for H2O2 self-supply and addition of cytoplasm H+ to further boost the Fenton-like reaction. We found that proton pump inhibitors (PPIs) increased intracellular acidification by inhibiting the activity of V-H+-ATPases to enhance the Fenton reaction-based ferroptosis induction, suggesting PPIs administration could be a feasible strategy to reinforce ferroptosis induction for radiosensitization.

Efficacy and Safety of Eplerenone for Treating Chronic Kidney Disease: A Meta-Analysis.

Background: In recent years, a large amount of clinical evidence and animal experiments have demonstrated the unique advantages of mineralocorticoid receptor antagonists (MRA) for treating chronic kidney disease (CKD). Aims: Accordingly, the present study aimed to systematically assess the second-generation selective MRAs eplerenone's safety and effectiveness for treating CKD. Methods: Four databases (PubMed, The Cochrane Library, Embase, and Web of Science) were searched for randomized controlled trials (RCT) correlated with eplerenone for treating CKD up to September 21, 2022. By complying with the inclusion and exclusion criteria, literature screening, and data extraction were conducted. Results: A total of 19 randomized controlled articles involving 4501 cases were covered. As suggested from the meta-analysis, significant differences were reported with the 24-h urine protein (MD = -42.23, 95% confidence interval [CI] = -76.72 to -7.73, P = 0.02), urinary albumin-creatinine ratio (UACR) (MD = -23.57, 95% CI = -29.28 to -17.86, P < 0.00001), the systolic blood pressure (SBP) (MD = -2.73, 95% CI = -4.86 to -0.59, P = 0.01), and eGFR (MD = -1.56, 95% CI = -2.78 to -0.34, P = 0.01) in the subgroup of eplerenone vs placebo. The subgroups of eplerenone vs placebo (MD = 0.13, 95% CI = 0.07 to 0.18, P < 0.00001) and eplerenone vs thiazide diuretic (MD = 0.18, 95% CI = 0.13 to 0.23, P < 0.00001) showed the significantly increased potassium levels. However, no statistical significance was reported between the eplerenone treatment groups and the control in the effect exerted by serum creatinine (MD=0.03, 95% CI = -0.01 to 0.07, P = 0.12) and diastolic blood pressure (DBP) (MD = 0.11, 95% CI = -0.41 to 0.63, P = 0.68). Furthermore, significant risks of hyperkalemia were reported in the eplerenone group (K+ ≥ 5.5 mmol/l, RR = 1.70, 95%CI = 1.35 to 2.13, P=<0.00001; K+≥6.0 mmol/l, RR = 1.61, 95% CIs = 1.06 to 2.44, P = 0.02), respectively. Conclusions: Eplerenone has beneficial effects on CKD by reducing urinary protein and the systolic blood pressure, but it also elevates the risk of hyperkalemia.

Actoeside mitigated the renal proximal tubule cells damage triggered by high glucose through miR-766/VCAM1/NF-κB signalling pathway.

CONTEXT: Diabetic nephropathy (DN) triggered by diabetes mellitus is one of the primary causes of end-stage renal failure worldwide. OBJECTIVE: This study intends to explore the function and potential mechanism of actoeside on renal proximal tubule (HK-2) cells damage induced by high-glucose (HG). METHODS: The DN model was established in HK-2 cells with 30 mM HG treatment. The viability, apoptosis and inflammation of HK-2 cells were analysed severally via CCK-8, flow cytomery and ELISA. The key factors related to NF-κB were detected by western blotting. RESULTS: Actoeside attenuated the HG-induced HK-2 cells damage. The differentially expression of miR-766 and VCAM1 in DN patients was reversed by actoeside. Moreover, the increased phosphorylation levels of p65 NF-κB/IκBα induced by HG were attenuated by actoeside. CONCLUSIONS: Actoeside promoted the growth and repressed the apoptosis and inflammation of HK-2 cells via miR-766/VCAM1/NF-κB signalling pathway, affording a promising idea for the treatment of DN.

Expanded endoscopic endonasal transsphenoidal approach to determine morphological characteristics and clinical considerations of the cavernous sinus venous spaces.

The study aimed at investigating the morphological characteristics and interconnected regularities of the cavernous sinus (CS) venous spaces using an expanded endoscopic endonasal transsphenoidal approach. Surgical dissections were performed for 15-colored silicon-injected human head specimens. The CS venous spaces were examined for their morphological and clinical characteristics using an expanded endoscopic endonasal transsphenoidal approach. The intracavernous course of the internal carotid artery (ICA) divided the CS venous spaces into four interconnected virtual compartments: medial, anteroinferior, posterosuperior, and lateral. The CS venous spaces had peculiar morphological characteristics; the medial compartment was C-shaped while the anteroinferior compartment resembled a boat's bow. The mean distances from the medial border of the inferior horizontal segment of cavernous ICA to the mid-line of the pituitary gland (PG) were 6.07 ± 1.61 mm (left) and 5.97 ± 1.89 mm (right); the mean distances from the medial border of the subarachnoid segment of cavernous ICA to the mid-line of the PG were 5.77 ± 1.16 mm (left) and 5.63 ± 1.17 mm (right); the mean distances from the medial border of the anterior vertical segment of cavernous ICA to the mid-line of the PG were 10.27 ± 1.74 mm (left) and 10.47 ± 1.90 mm (right). Morphological characteristics and the knowledge of the interconnected regularities of the CS venous spaces may help surgeons accurately locate the neurovascular structure, and thus may contribute to the effective prediction of tumor invasion and extension during endoscopic CS surgery.

Rapid synthesis of 'yolk-shell'-like nanosystem for MR molecular and chemo-radio sensitization.

Though amounts of attempts about nanomedicine for chemo-radiotherapy have been made, more efficient strategies for chemo-radio therapy enhancement still need to be studied and perfected. Herein, a 'yolk-shell'-like nanostructure (Bi2S3@mBixMnyOz nanosystem) was facilely constructed by directly using radiosensitizer Bi2S3 nanorods (NRs) as a partial sacrificial template. Then, the chemotherapeutic drug doxorubicin (DOX) loaded PEGylated Bi2S3@mBixMnyOz nanosystem (PBmB-DOX) was constructed, which could realize tumor microenvironment (TME)-responsive drug release for chemotherapy sensitivity enhancement. And the Bi2S3 NRs core could deposit more radiant energy to improve the radiotherapy sensitivity. Meanwhile, the compounds shell could catalyze H2O2 to generate O2, so as to alleviate tumor hypoxia for further chemo-radio therapy sensitization enhancement. More importantly, ferroptosis was participated in the process of PBmB-induced therapy via glutathione (GSH)-depletion mediated GPX4 inactivation, together with Mn ions induced chemodynamic therapy (Fenton-like reaction), which made additional contributions to increase the therapeutic efficacy. Last but not least, the GSH-stimulated degradation of compounds shell could contribute to self-enhanced T1-MR imaging activation, which allowed on-demand tumor diagnosis. In this work, the synthetic strategy that directly using Bi2S3 NRs as a partial sacrificial template to rapidly synthesize the 'yolk-shell'-like nanostructure for nanomedical application has rarely been reported before. And the in vitro and in vivo results suggest that our 'yolk-shell'-like PBmB-DOX nanosystem holds great promise to regulate TME for tumor-specific diagnosis and synergistic therapy.

Efficacy and safety of eplerenone treatment for patients with diabetic nephropathy: A meta-analysis.

Diabetic nephropathy (DN), which is correlated with an increased risk of cardiovascular disease, significantly elevates the morbidity and mortality of patients with diabetes. Recently, the benefits of mineralocorticoid receptor antagonists in chronic kidney disease (CKD), such as their anti-inflammatory and anti-fibrotic properties, have been discovered. Thus, the present meta-analysis aimed to systematically assess the efficacy and safety of eplerenone treatment in patients with DN. Six electronic databases-PubMed, The Cochrane Library, Embase, Web of Science, CNKI (China National Knowledge Infrastructure), and CBM(Chinese BioMedical Literature Database)-were searched to retrieve randomized controlled trials that assessed eplerenone treatment in patients with DN and were published up to July 31, 2021. Eight randomized controlled trials involving 838 patients were included. Between the eplerenone treatment groups and controls, significant differences were identified in 24-h urine protein levels (mean difference [MD], -19.63 [95% CI, -23.73 to -15.53], P < 0.00001), microalbuminuria (MD, -7.75 [95% CI, -9.75 to -5.75], P < 0.00001), urinary albumin-creatinine ratio (MD, -48.29 [95% CI, -64.45 to -32.14], P < 0.00001), systolic blood pressure (SBP) (MD, -2.49 [95% CI, -4.48 to -0.50], P = 0.01), serum potassium levels (MD, 0.19 [95% CI, 0.13 to 0.24], P < 0.00001), and levels of the renal fibrosis indicator laminin (MD, -8.84 [95% CI, -11.93 to -5.75], P < 0.00001). However, for the effect of estimated glomerular filtration rate (MD, 1.74 [95% CI, -0.87 to 4.35], P = 0.19) and diastolic blood pressure (MD, -0.51 [95% CI, -1.58 to 0.57], P = 0.36), the differences between the two groups were not significant. In addition, no noticeable difference was identified in the adverse events of hyperkalemia and cough between them. These findings suggest that eplerenone exerts beneficial effects on DN by significantly reducing urinary albumin or protein excretion, SBP, and laminin levels, without increasing the incidence of hyperkalemia and other adverse events.

Functionalized Au@Cu-Sb-S Nanoparticles for Spectral CT/Photoacoustic Imaging-Guided Synergetic Photo-Radiotherapy in Breast Cancer.

BACKGROUND: Radiotherapy (RT) is clinically well-established cancer treatment. However, radioresistance remains a significant issue associated with failure of RT. Phototherapy-induced radiosensitization has recently attracted attention in translational cancer research. METHODS: Cu-Sb-S nanoparticles (NPs) coated with ultra-small Au nanocrystals (Au@Cu-Sb-S) were synthesized and characterized. The biosafety profiles, absorption of near-infrared (NIR) laser and radiation-enhancing effect of the NPs were evaluated. In vitro and in vivo spectral computed tomography (CT) imaging and photoacoustic (PA) imaging were performed in 4T1 breast cancer-bearing mice. The synergetic radio-phototherapy was assessed by in vivo tumor inhibition studies. RESULTS: Au@Cu-Sb-S NPs were prepared by in situ growth of Au NCs on the surface of Cu-Sb-S NPs. The cell viability experiments showed that the combination of Au@Cu-Sb-S+NIR+RT was significantly more cytotoxic to tumor cells than the other treatments at concentrations above 25 ppm Sb. In vitro and in vivo spectral CT imaging demonstrated that the X-ray attenuation ability of Au@Cu-Sb-S NPs was superior to that of the clinically used Iodine, particularly at lower KeV levels. Au@Cu-Sb-S NPs showed a concentration-dependent and remarkable PA signal brightening effect. In vivo tumor inhibition studies showed that the prepared Au@Cu-Sb-S NPs significantly suppressed tumor growth in 4T1 breast cancer-bearing mice treated with NIR laser irradiation and an intermediate X-ray dose (4 Gy). CONCLUSION: These results indicate that Au@Cu-Sb-S integrated with spectral CT, PA imaging, and phototherapy-enhanced radiosensitization is a promising multifunctional theranostic nanoplatform for clinical applications.

MiR-1297 attenuates high glucose-induced injury in HK-2 cells via targeting COL1A2.

BACKGROUND: In this study, we aimed to explore whether COL1A2 and miR-1297 participated in the progression of diabetic nephropathy (DN) in vitro and classified the underlying mechanisms. METHODS: d-Glucose (30 mM; high glucose, HG)-stimulated HK-2 cells were used to mimic DN condition. RNA and non-coding RNA profiles were from Gene Expression Omnibus (GEO) database. The interaction between miR-1297 and COL1A2 was measured by dual-luciferase reporter assay. Gene Set Enrichment Analysis (GSEA) method was conducted to analyse COL1A2-associated signalling pathways. The role of miR-1297/COL1A2 in biological behaviours of HG-induced HK-2 cells were analysed by cell counting kit-8 and apoptosis assays. RESULTS: Bioinformatics analysis revealed that COL1A2 was up-regulated in DN tissues. We predicted and verified miR-1297 as the regulatory miRNA of COL1A2, and the expression of miR-1297 was decreased in DN tissues and HG-stimulated HK-2 cells. Overexpression of miR-1297 could promote cell proliferation and inhibit apoptosis to protect HK-2 cells from HG-induced damage. And knockdown of COL1A2 enhanced the protective effects of miR-1297 on HG-stimulated HK-2 cells. GSEA results revealed that several inflammatory pathways were enriched in COL1A2 high-expression group. Meanwhile, transfection of miR-1297 reduced the phosphorylation of NFκB and expression of three important pro-inflammatory genes including cytokine CCL5, adhesion molecules ICAM1 and VCAM1 via targeting COL1A2. These results suggested that miR-1297 protected HG-treated HK-2 cells probably through suppressing inflammation via targeting COL1A2. CONCLUSION: This study sheds a light on the role miR-1297/COL1A2 in DN progression and provides a novel promising therapy strategy for suppressing DN progression.

[Anti-injury effect of hydrogen-enriched water in a rat model of liver injury induced by aflatoxin B1].

The purpose of this study was to investigate the anti-injury effect and protective mechanism of hydrogen-enriched water in a rat model of acute liver injury induced by aflatoxin B1 (AFB1). Healthy male Sprague-Dawley (SD) rats were randomly divided into control group, model group (AFB1 group) and hydrogen-enriched water treatment group (AFB1+H2 group). The rat model of acute liver injury induced by AFB1 was established by single intragastric administration of AFB1 (2.0 mg/kg), and then the rats were treated with hydrogen-enriched water intragastrically. HE staining was used to observe the pathological changes of liver tissue. Blood samples were taken from vena cava to measure serum liver function indexes. Live tissue was sampled to detect malondialdehyde (MDA) and reduced glutathione (GSH) contents. Western blot was used to detect phosphorylation levels of MAPK signaling pathway proteins (ERK, JNK and p38 MAPK). The results showed that, compared with the AFB1 group, the AFB1+H2 group exhibited increased body weights, alleviated acute liver injury, decreased activities of serum glutamic-pyruvic transaminase and glutamic oxaloacetic transaminase, as well as total bilirubin level in the serum. Meanwhile, hydrogen-enriched water decreased MDA content and increased GSH content in liver tissue. AFB1-increased phosphorylation levels of ERK, JNK and p38 MAPK in liver tissue were down-regulated significantly by hydrogen-enriched water treatment. These results suggest that hydrogen-enriched water can alleviate liver injury induced by AFB1, and its mechanism may be related to the reduction of oxidative stress and the inhibition of MAPK signal transduction pathway activation.

Preparation and characterization of 3D porous conductive scaffolds with magnetic resonance enhancement in tissue engineering.

Magnetic resonance imaging (MRI), as a diagnostic tool in tissue engineering, has received widespread attention because of its ability to consistently provide degradation and absorption of implants in vivo. For some specific human tissues and organs, such as nerves, muscles and myocardium, their regeneration requires tissue engineering scaffolds have a good electrical conductivity. Graphene oxide (GO) has been extensively studied as a conductive biomaterial having mechanical reinforcement. Based on the above, we propose an MRI conductive scaffold containing gelatin (Gel)/gelatin-polycaprolactone (Gel-PCL)/ultra-small paramagnetic iron oxide (USPIO)/graphene oxide (GO) (Gel/Gel-PCL/USPIO/GO). Their physical and chemical properties as well as biocompatibility are measured in vitro. The purpose of doping USPIO was developed for non-invasive monitoring of tissue engineered implants and tissue reconstruction. Functional modification of GO to match electrophysiological requirement. Co-culture with bone marrow mesenchymal stem cells showed good biocompatibility. Blood experiments have also demonstrated the feasibility of scaffolds as tissue engineered implants. The USPIO-labeled conductive scaffold, as an effective image-guided and electrically stimulating implant, appears to be a reconstruction platform for specific tissues and organs.