Lactic acid responsive sequential production of hydrogen peroxide and consumption of glutathione for enhanced ferroptosis tumor therapy.

Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H2O2) into hydroxyl radicals (•OH) by Ir3+-mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H2O2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H2O2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy.

Polycarboxyl ionic liquid functionalized Yb-MOFs nanoballs based dual-wavelength responsive photoelectrochemical aptasensor for the simultaneous determination of AFB1 and OTA.

Developing an accurate and precise approach for the simultaneous detection of ochratoxin A (OTA) and aflatoxin B1 (AFB1) is significant for food safety surveillance. Herein, a photoelectrochemical sensing platform was constructed based on polycarboxylic ionic liquid functionalized metal-organic framework integrated with gold nanoparticles (Yb-MOFs@AuNPs). Sulfhydryl functionalized hairpin DNA (hDNA) was immobilized on a Yb-MOFs@AuNPs modified glassy carbon electrode (GCE) surface through Au-S bond. After blocking residual active binding sites with BSA, gold nanoparticles-labeled AFB1 aptamer (AuNPs-Apt 1) and gold nanorods-labeled OTA aptamer (AuNRs-Apt 2) were introduced to construct a photoelectrochemical aptasensor for the simultaneous determination of AFB1 and OTA. Due to the surface plasmon resonance effect and the nanometer size effect of gold nanomaterials, the photoelectrochemical aptasensor can output photocurrent responses as being excited with different wavelengths at 520 nm and 808 nm, respectively. When the AFB1 and OTA concentration in the range of 0.001-50.0 ng mL-1, a good linear relationship between the photocurrent difference (ΔI) before and after recognizing targets and the logarithm of AFB1 or OTA concentration was obtained. The detection limits for AFB1 and OTA were 0.40 pg mL-1 and 0.19 pg mL-1, respectively. AFB1 and OTA in corn samples were detected simultaneously by the photoelectrochemical aptasensor.

Blocking of FGFR4 signaling by F30 inhibits hepatocellular carcinoma cell proliferation through HMOX1-dependent ferroptosis pathway.

Excessive activation of FGF19/fibroblast growth factor receptor 4 (FGFR4) signaling is associated with poor survival of patients with hepatocellular carcinoma (HCC). FGFR4 inhibitors show promise for HCC treatment. F30, an indazole derivative designed through computer-aided drug design targeting FGFR4, demonstrated anti-HCC activity as described in our previous studies. However, the precise molecular mechanisms underlying F30's anticancer effects remain largely unexplored. We report here that F30 could effectively induce ferroptosis in HCC cells. The concentrations of cellular ferrous iron, the peroxidation of cell membranes and the homeostasis of reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG) were dysregulated by F30, thereby affecting cellular redox status. Induction of ferroptosis in HCC by F30 was inhibited by specific ferroptosis inhibitor ferrostatin-1. F30 upregulates various ferroptosis-related genes, including the heme oxygenase enzymes 1 (HMOX1), a key mediator of redox regulation. Surprisingly, F30-induced ferroptosis in HCC is dependent on HMOX1. The dysregulation of cellular ferrous iron concentrations and cell membrane peroxidation was rescued when knocking down HMOX1 with specific small interfering RNA. These findings shed light on the molecular mechanisms underlying FGFR4-targeting F30's anti-HCC effects and suggest that FGFR4 inactivation could be beneficial for HCC treatment involving ferroptosis.

Tannic acid and zinc ion coordination of nanase for the treatment of inflammatory bowel disease by promoting mucosal repair and removing reactive oxygen and nitrogen species.

Colon mucosal overexpression of reactive oxygen and nitrogen species (RONS) accelerates the development of inflammatory bowel disease (IBD) and destroys the mucosa and its barrier. IBD can be alleviated by removing RONS from the inflamed colon. The preparation of strong and efficient nanoantioxidants remains a challenge despite the development of numerous nanoantioxidants. In this paper, Zn-TA nanoparticles with fine hollow microstructure (HZn-TA) were successfully prepared and could be effectively used to treat IBD. In the first step, ZIF-8 nanoparticles were synthesized by a one-pot method. On this basis, HZn-TA nanoparticles were etched by TA, and a multifunctional nanase was developed for the treatment of IBD. RONS, including reactive oxygen species (ROS) and nitric oxide (NO), can be eliminated to increase cell survival following Hydrogen peroxide (H2O2) stimulation, including reactive oxygen species (ROS) and nitric oxide (NO with hydrogen peroxide (H2O2). In a model for preventing and delaying acute colitis, clearance of RONS has been shown to reduce intestinal inflammation in mice by reducing colon damage, proinflammatory cytokine levels, the spleen index, and body weight. Intestinal mucosal healing can be promoted by HZn-TA nanoparticles, which can upregulate zonula occludens protein 1 (ZO-1) and claudin-1 expression. Based on the results of this study, HZn-TA nanoparticles were able to effectively treat IBD with minimal adverse effects by being biocompatible, multienzyme active, and capable of scavenging RONS. Therefore, we pioneered the application of HZn-TA nanoparticles for the treatment of IBD, which are capable of clearing RONS without significant adverse effects. STATEMENT OF SIGNIFICANCE: ➢ HZn-TA nanoparticles were successfully prepared and could be effectively used to treat IBD. ➢ Intestinal mucosal healing can be promoted by HZn-TA nanoparticles, which can upregulate ZO-1 and claudin-1 expression. ➢ HZn-TA nanoparticles were able to effectively treat IBD with minimal adverse effects by being biocompatible, multienzyme active, and capable of scavenging RONS.

H2S-Releasing Versatile Montmorillonite Nanoformulation Trilogically Renovates the Gut Microenvironment for Inflammatory Bowel Disease Modulation.

Abnormal activation of the intestinal mucosal immune system, resulting from damage to the intestinal mucosal barrier and extensive invasion by pathogens, contributes to the pathogenesis of inflammatory bowel disease (IBD). Current first-line treatments for IBD have limited efficacy and significant side effects. An innovative H2S-releasing montmorillonite nanoformulation (DPs@MMT) capable of remodeling intestinal mucosal immune homeostasis, repairing the mucosal barrier, and modulating gut microbiota is developed by electrostatically adsorbing diallyl trisulfide-loaded peptide dendrimer nanogels (DATS@PDNs, abbreviated as DPs) onto the montmorillonite (MMT) surface. Upon rectal administration, DPs@MMT specifically binds to and covers the damaged mucosa, promoting the accumulation and subsequent internalization of DPs by activated immune cells in the IBD site. DPs release H2S intracellularly in response to glutathione, initiating multiple therapeutic effects. In vitro and in vivo studies have shown that DPs@MMT effectively alleviates colitis by eliminating reactive oxygen species (ROS), inhibiting inflammation, repairing the mucosal barrier, and eradicating pathogens. RNA sequencing revealed that DPs@MMT exerts significant immunoregulatory and mucosal barrier repair effects, by activating pathways such as Nrf2/HO-1, PI3K-AKT, and RAS/MAPK/AP-1, and inhibiting the p38/ERK MAPK, p65 NF-κB, and JAK-STAT3 pathways, as well as glycolysis. 16S rRNA sequencing demonstrated that DPs@MMT remodels the gut microbiota by eliminating pathogens and increasing probiotics. This study develops a promising nanoformulation for IBD management.

Bone age assessment based on three-dimensional ultrasound and artificial intelligence compared with paediatrician-read radiographic bone age: protocol for a prospective, diagnostic accuracy study.

INTRODUCTION: Radiographic bone age (BA) assessment is widely used to evaluate children's growth disorders and predict their future height. Moreover, children are more sensitive and vulnerable to X-ray radiation exposure than adults. The purpose of this study is to develop a new, safer, radiation-free BA assessment method for children by using three-dimensional ultrasound (3D-US) and artificial intelligence (AI), and to test the diagnostic accuracy and reliability of this method. METHODS AND ANALYSIS: This is a prospective, observational study. All participants will be recruited through Paediatric Growth and Development Clinic. All participants will receive left hand 3D-US and X-ray examination at the Shanghai Sixth People's Hospital on the same day, all images will be recorded. These image related data will be collected and randomly divided into training set (80% of all) and test set (20% of all). The training set will be used to establish a cascade network of 3D-US skeletal image segmentation and BA prediction model to achieve end-to-end prediction of image to BA. The test set will be used to evaluate the accuracy of AI BA model of 3D-US. We have developed a new ultrasonic scanning device, which can be proposed to automatic 3D-US scanning of hands. AI algorithms, such as convolutional neural network, will be used to identify and segment the skeletal structures in the hand 3D-US images. We will achieve automatic segmentation of hand skeletal 3D-US images, establish BA prediction model of 3D-US, and test the accuracy of the prediction model. ETHICS AND DISSEMINATION: The Ethics Committee of Shanghai Sixth People's Hospital approved this study. The approval number is 2022-019. A written informed consent will be obtained from their parent or guardian of each participant. Final results will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200057236.

Platinum-Loaded Cerium Oxide Capable of Repairing Neuronal Homeostasis for Cerebral Ischemia-Reperfusion Injury Therapy.

Effective neuroprotective agents are required to prevent neurological damage caused by reactive oxygen species (ROS) generated by cerebral ischemia-reperfusion injury (CIRI) following an acute ischemic stroke. Herein, it is aimed to develop the neuroprotective agents of cerium oxide loaded with platinum clusters engineered modifications (Ptn -CeO2 ). The density functional theory calculations show that Ptn -CeO2 could effectively scavenge ROS, including hydroxyl radicals (·OH) and superoxide anions (·O2 - ). In addition, Ptn -CeO2 exhibits the superoxide dismutase- and catalase-like enzyme activities, which is capable of scavenging hydrogen peroxide (H2 O2 ). The in vitro studies show that Ptn -CeO2 could adjust the restoration of the mitochondrial metabolism to ROS homeostasis, rebalance cytokines, and feature high biocompatibility. The studies in mice CIRI demonstrate that Ptn -CeO2 could also restore cytokine levels, reduce cysteine aspartate-specific protease (cleaved Caspase 3) levels, and induce the polarization of microglia to M2-type macrophages, thus inhibiting the inflammatory responses. As a result, Ptn -CeO2 inhibits the reperfusion-induced neuronal apoptosis, relieves the infarct volume, reduces the neurological severity score, and improves cognitive function. Overall, these findings suggest that the prominent neuroprotective effect of the engineered Ptn -CeO2 has a significant neuroprotective effect and provides a potential therapeutic alternative for CIRI.

Developing and validating the model of tumor-infiltrating immune cell to predict survival in patients receiving radiation therapy for head and neck squamous cell carcinoma.

Background: Radiotherapy (RT) is a mainstay of head and neck squamous cell carcinoma (HNSCC) treatment. Due to the influence of RT on tumor cells and immune/stromal cells in microenvironment, some studies suggest that immunologic landscape could shape treatment response. To better predict the survival based on genomic data, we developed a prognostic model using tumor-infiltrating immune cell (TIIC) signature to predict survival in patients undergoing RT for HNSCC. Methods: Gene expression data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Data from HNSCC patients undergoing RT were extracted for analysis. TIICs prevalence in HNSCC patients was quantified by gene set variation analysis (GSVA) algorithm. TIICs and post-RT survival were analyzed using univariate Cox regression analysis and used to construct and validate a tumor-infiltrating cells score (TICS). Results: Five of 26 immune cells were significantly associated with HNSCC prognosis in the training cohort (all P<0.05). Kaplan-Meier (KM) survival curves showed that patients in the high TICS group had better survival outcomes (log-rank test, P<0.05). Univariate analyses demonstrated that the TICS had independent prognostic predictive ability for RT outcomes (P<0.05). Patients with high TICS scores showed significantly higher expression of immune-related genes. Functional pathway analyses further showed that the TICS was significantly related to immune-related biological process. Stratified analyses supported integrating TICS and tumor mutation burden (TMB) into individualized treatment planning, as an adjunct to classification by clinical stage and human papillomavirus (HPV) infection. Conclusions: The TICS model supports a personalized medicine approach to RT for HNSCC. Increased prevalence of TIIC within the tumor microenvironment (TME) confers a better prognosis for patients undergoing treatment for HNSCC.

Efficacy and safety of olmesartan medoxomil­amlodipine besylate tablets (Sevikar®) in older patients with essential hypertension: Subgroup analysis from the Sevikar study.

Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Dual-Functional Laser-Guided Magnetic Nanorobot Collectives against Gravity for On-Demand Thermo-Chemotherapy of Peritoneal Metastasis.

Combining hyperthermic intraperitoneal chemotherapy with cytoreductive surgery is the main treatment modality for peritoneal metastatic (PM) carcinoma despite the off-target effects of chemotherapy drugs and the ineluctable side effects of total abdominal heating. Herein, a laser-integrated magnetic actuation system that actively delivers doxorubicin (DOX)-grafted magnetic nanorobot collectives to the tumor site in model mice for local hyperthermia and chemotherapy is reported. With intraluminal movements controlled by a torque-force hybrid magnetic field, these magnetic nanorobots gather at a fixed point coinciding with the position of the localization laser, moving upward against gravity over a long distance and targeting tumor sites under ultrasound imaging guidance. Because aggregation enhances the photothermal effect, controlled local DOX release is achieved under near-infrared laser irradiation. The targeted on-demand photothermal therapy of multiple PM carcinomas while minimizing off-target tissue damage is demonstrated. Additionally, a localization/treatment dual-functional laser-integrated magnetic actuation system is developed and validated in vivo, offering a potentially clinically feasible drug delivery strategy for targeting PM and other intraluminal tumors.

Functionalized MoS2-nanosheets with NIR-Triggered nitric oxide delivery and photothermal activities for synergistic antibacterial and regeneration-promoting therapy.

Bacterial infection in skin and soft tissue has emerged as a critical concern. Overreliance on antibiotic therapy has led to numerous challenges, including the emergence of multidrug-resistant bacteria and adverse drug reactions. It is imperative to develop non-antibiotic treatment strategies that not only exhibit potent antibacterial properties but also promote rapid wound healing and demonstrate biocompatibility. Herein, a novel multimodal synergistic antibacterial system (SNO-CS@MoS2) was developed. This system employs easily surface-modified thin-layer MoS2 as photothermal agents and loaded with S-nitrosothiol-modified chitosan (SNO-CS) via electrostatic interactions, thus realizing the combination of NO gas therapy and photothermal therapy (PTT). Furthermore, this surface modification renders SNO-CS@MoS2 highly stable and capable of binding with bacteria. Through PTT's thermal energy, SNO-CS@MoS2 rapidly generates massive NO, collaborating with PTT to achieve antibacterial effects. This synergistic therapy can swiftly disrupt the bacterial membrane, causing protein leakage and ATP synthesis function damage, ultimately eliminating bacteria. Notably, after effectively eliminating all bacteria, the residual SNO-CS@MoS2 can create trace NO to promote fibroblast migration, proliferation, and vascular regeneration, thereby accelerating wound healing. This study concluded that SNO-CS@MoS2, a novel multifunctional nanomaterial with outstanding antibacterial characteristics and potential to promote wound healing, has promising applications in infected soft tissue wound treatment.

Variation of sexual dimorphism and asymmetry in disease expression of inflammatory arthritis among laboratory mouse models with different genomic backgrounds.

Sex difference has shown in the arthritis diseases in human population and animal models. We investigate how the sex and symmetry vary among mouse models with different genomic backgrounds. Disease data of sex and limbs accumulated in the past more than two decades from four unique populations of murine arthritis models were analyzed. They are (1) interleukin-1 receptor antagonist (IL-1ra) deficient mice under Balb/c background (Balb/c KO); (2) Mice with collagen II induced arthritis under DBA/1 background; (3) Mice with collagen II induced arthritis under C57BL/6 (B6) background and (4) A F2 generation population created by Balb/c KO X DBA/1 KO. Our data shows that there is a great variation in sexual dimorphism for arthritis incidence and severity of arthritis in mice harboring specific genetic modifications. For a F2 population, the incidence of arthritis was 57.1% in female mice and 75.6% in male mice. There was a difference in severity related to sex in two populations: B6.DR1/ B6.DR4 (P < 0.001) and F2 (P = 0.023) There was no difference Balb/c parental strain or in collagen-induced arthritis (CIA) in DBA/1 mice. Among these populations, the right hindlimbs are significantly higher than the scores for the left hindlimbs in males (P < 0.05). However, when examining disease expression using the collagen induced arthritis model with DBA/1 mice, sex-dimorphism did not reach statistical significance, while left hindlimbs showed a tendency toward greater disease expression over the right. Sexual dimorphism in disease expression in mouse models is strain and genomic background dependent. It sets an alarm that potential variation in sexual dimorphism among different racial and ethnic groups in human populations may exist. It is important to not only include both sexes and but also pay attention to possible variations caused by disease expression and response to treatment in all the studies of arthritis in animal models and human populations.

Hyperthermia-embolization-immunotherapy: a potent trio in advancing cancer treatment.

Yang et al. recently demonstrated the high potential of liquid metal microspheres (LM MSs) in cancer therapy. By amplifying the effects of magnetic hyperthermia and embolization, LM MSs not only target primary tumors, but also potentiate immune defenses. This dual-action approach effectively curtails distant tumor growth, marking a pivotal advancement in cancer immunotherapy.

Low-intensity pulsed ultrasound reduces lymphedema by regulating macrophage polarization and enhancing microcirculation.

Background: Conventional therapies reduce lymphedema but do not cure it because they cannot modulate the pathophysiology of secondary lymphedema. Lymphedema is characterized by inflammation. We hypothesized that low-intensity pulsed ultrasound (LIPUS) treatment could reduce lymphedema by enhancing anti-inflammatory macrophage polarization and microcirculation. Methods: The rat tail secondary lymphedema model was established through the surgical ligation of lymphatic vessels. The rats were randomly divided into the normal, lymphedema, and LIPUS treatment groups. The LIPUS treatment (3 min daily) was applied 3 days after establishing the model. The total treatment period was 28 days. Swelling, fibro adipose deposition, and inflammation of the rat tail were evaluated by HE staining and Masson's staining. The photoacoustic imaging system and laser Doppler flowmetry were used to monitor microcirculation changes in rat tails after LIPUS treatment. The cell inflammation model was activated with lipopolysaccharides. Flow cytometry and fluorescence staining were used to observe the dynamic process of macrophage polarization. Results: After 28 days of treatment, compared with the lymphedema group, the tail circumference and subcutaneous tissue thickness of rats in the LIPUS group were decreased by 30%, the proportion of collagen fibers and the lymphatic vessel cross-sectional area was decreased, and tail blood flow was increased significantly. Cellular experiments revealed a decrease in CD86+ macrophages (M1) after LIPUS treatment. Conclusion: The transition of M1 macrophage and the promotion of microcirculation could be responsible for the beneficial effect of LIPUS on lymphedema.

Hybrid Hydrogel Loaded with Chlorhexidine⊂ß-CD-MSN Composites as Wound Dressing.

Background: Much attention has been paid to sustained drug release and anti-infection in wound management. Hydrogels, which are biocompatible materials, are promising tools for controlled drug release and infective protection during wound healing. However, hydrogels also demonstrate limitations in the highly efficient treatment of wounds because of the diffusion rate. In this work, we explored pH-sensitive hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties. Methods: We constructed a hybrid gelatin methacrylate (GelMA) system with sustainable antibacterial properties combining hyaluronic acid (HA)-coated mesoporous silica nanoparticles (MSN), which loaded host-guest complexes of chlorhexidine (CHX) with ß-cyclodextrins (ß-CD) (CHX⊂CD-MSN@HA@GelMA). The release mechanism of CHX was explored using UV-vis spectra after intermittent diffusion of CHX. The hybrid hydrogels were characterized, and the drug content in terms of the release profile, bacterial inhibition, and in vivo experiments were investigated. Results: Except for dual protection from both hydrogels, MSN in the HA improved the drug loading efficiency to promote the local drug concentration. It showed that complicated CHX-loaded MSN releases CHX more gradually and over a longer duration than CHX-loaded MSNs. This demonstrated a 12-day CHX release time and antibacterial activity, primarily attributable to the capacity of ß-CD to form an inclusion complex with CHX. Meanwhile, in vivo experiments revealed that the hydrogels safely promote skin wound healing and enhance therapeutic efficacy. Conclusion: We constructed pH-sensitive CHX⊂CD-MSN@HA@GelMA hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties. The combination of ß-CD and MSN would be better suited to release a reduced rate of active molecules over time (slow delivery), making them great candidates for wound dressing anti-infection materials.

Radiotherapy plus camrelizumab and irinotecan for oligometastatic esophageal squamous cell carcinoma patients after first-line immunotherapy plus chemotherapy failure: An open-label, single-arm, phase II trial.

BACKGROUND AND PURPOSE: Immunotherapy has revolutionized the treatment of advanced and metastatic esophageal squamous cell carcinoma (ESCC), but most patients eventually developed disease progression. Immuno-resistance is becoming an unavoidable clinical problem. Oligometastasis is a limited-metastatic state, and patients at this stage should be evaluated for the addition of metastasis-directed local intervention, which may be associated with improved prognosis. As an immunomodulator, radiotherapy may exhibit synergistic effect when added to immunotherapy. This study assessed the efficacy and safety of low-dose radiotherapy plus immunotherapy and second-line chemotherapy in oligometastatic ESCC. MATERIALS AND METHODS: In this phase II trial (ChiCTR2000040533), oligometastatic ESCC patients after first-line immunotherapy plus chemotherapy failure were treated with low dose radiotherapy plus camrelizumab and second-line irinotecan chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. Abscopal response rate (ARR) and abscopal control rate (ACR) were also been explored. RESULTS: Between November 19, 2018 and March 17, 2021, 49 patients were enrolled. With a median follow-up of 12.8 months, median PFS and OS were 6.9 months (95%CI, 4.6-9.3) and 12.8 months (95%CI, 10.1-15.5), respectively. ORR was 40.8% (95%CI, 27.3-55.7). DCR was 75.5% (95%CI, 60.8-86.2). ARR was 34.7% (95%CI, 22.1-49.7). ACR was 69.4% (95%CI, 54.4-81.3). The most common adverse effects of any grade were myelosuppression, weight loss and fatigue. Grade 3 or 4 treatment-related adverse events occurred in 31 (63.3%) patients, with the most common being leukopenia (30.6%). No treatment-related deaths occurred. CONCLUSION: Low dose radiotherapy plus camrelizumab and irinotecan exhibited survival benefit with manageable safety for oligometastatic ESCC patients after first-line immunotherapy plus chemotherapy failure. It deserves to be validated in a larger trial.

Efficacy and safety of curcumin in diabetic retinopathy: A protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common complications of diabetes and has become a major global cause of blindness. Curcumin, an extract of Curcuma longa (turmeric), is effective in preventing and treating diabetes. Recent studies have shown that curcumin can delay DR development. However, there has been no systematic review of its treatment of DR. This study will conduct a systematic review and meta-analysis of currently published randomized controlled trials (RCT) of curcumin for treating DR patients to evaluate its efficacy and safety. METHODS: We will search the relevant studies of curcumin in the treatment of DR in PubMed, Medline, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases from their respective inception dates to May 2022. A meta-analysis of the data extracted from qualified RCTs will be conducted, including the progression of DR, visual acuity, visual field, macular edema, quality of life, and adverse events. The meta-analysis will be performed using Review Manager 5.4.1 software, and the results will be based on either random-effects or fixed-effects models, depending on the heterogeneity. The Grading of Recommendations, Development, and Evaluation (GRADE) system will be used to evaluate the reliability and quality of evidence. RESULTS: The results of this study will provide sound and high-quality evidence for the efficacy and safety of curcumin in the treatment of DR. CONCLUSION: This study will be the first meta-analysis to comprehensively assess the efficacy and safety of curcumin in the treatment of DR and will provide helpful evidence for the clinical management of this disease. SYSTEMATIC REVIEW REGISTRATION: INPLASY202250002.

Transferrin-targeted iridium nanoagglomerates with multi-enzyme activities for cerebral ischemia-reperfusion injury therapy.

Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological condition with high mortality. In particular, reperfusion can stimulate overproduction of reactive oxygen species (ROS) and activation of inflammation, causing severe secondary injuries to the brain. Despite tremendous efforts, it remains urgent to rationally design antioxidative agents with straightforward and efficient ROS scavenging capability. Herein, a potent antioxidative agent was explored based on iridium oxide nano-agglomerates (Tf-IrO2 NAs) via the facile transferrin (Tf)-templated biomineralization approach, and innovatively applied to treat CIRI. Containing some small-size IrO2 aggregates, these NAs possess intrinsic hydroxyl radicals (•OH)-scavenging ability and multifarious enzyme activities, such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Moreover, they also showed improved blood-brain barrier (BBB) penetration and enhanced accumulation in the ischemic brain via Tf receptor-mediated transcytosis. Therefore, Tf-IrO2 NAs achieved robust in vitro anti-inflammatory and cytoprotection effects against oxidative stress. Importantly, mice were effectively protected against CIRI by enhanced ROS scavenging activity in vivo, and the therapeutic mechanism was systematically verified. These findings broaden the idea of expanding Ir-based NAs as potent antioxidative agents to treat CIRI and other ROS-mediated diseases. STATEMENT OF SIGNIFICANCE: (1) The ROS-scavenging activities of IrO2 are demonstrated comprehensively, which enriched the family of nano-antioxidants. (2) The engineering Tf-IrO2 nano-agglomerates present unique multifarious enzyme activities and simultaneous transferrin targeting and BBB crossing ability for cerebral ischemia-reperfusion injury therapy. (3) This work may open an avenue to enable the use of IrO2 to alleviate ROS-mediated inflammatory and brain injury diseases.

A near-infrared photoelectrochemical aptasensing system based on Bi2O2S nanoflowers and gold nanoparticles for high-performance determination of MCF-7 cells.

Circulating tumor cells (CTCs) are commonly considered as the major cause of tumor metastasis and can eventually lead to death. Therefore, developing a high-performance method for the determination of CTCs is very significant for promoting the cancer survival rate. Photoelectrochemical biosensing systems have been extensively investigated and applied for bioassays. Herein, Bi2O2S nanoflowers were successfully prepared through a simple one-step hydrothermal method. After being integrated with gold nanoparticles with a diameter of ∼45 nm, AuNPs/Bi2O2S nanocomposites were coated onto an ITO electrode surface to build a photoelectrochemical sensing platform which can be excited with near-infrared light to produce photocurrent response. Subsequently, mercapto-group functionalized aptamer (SH-Apt) was fixed onto the AuNPs/Bi2O2S/ITO surface. Due to the overexpress of MUC1 protein in the cell membrane, MCF-7 cells were specifically trapped on the SH-Apt/AuNPs/Bi2O2S/ITO surface. The introduce of MCF-7 cells lead to an obvious decrease on the photocurrent response. The photocurrent variation shows a satisfied linear relationship to the logarithm of MCF-7 cells concentration ranged from 50 to 6 × 105 cell mL-1. The detection limit obtained is 17 cell mL-1. The PEC biosensor shows excellent sensitivity, selectivity and stability for sensing MCF-7 cells, even for determining MCF-7 cells in clinical serum samples.