Relationship between stress hyperglycaemic ratio and incidence of in-hospital cardiac arrest in patients with acute coronary syndrome: a retrospective cohort study.

BACKGROUND: The stress hyperglycaemic ratio (SHR), a new marker that reflects the true hyperglycaemic state of patients with acute coronary syndrome (ACS), is strongly associated with adverse clinical outcomes in these patients. Studies on the relationship between the SHR and in-hospital cardiac arrest (IHCA) incidence are limited. This study elucidated the relationship between the SHR and incidence of IHCA in patients with ACS. METHODS: In total, 1,939 patients with ACS who underwent percutaneous coronary intervention (PCI) at the Affiliated Hospital of Zunyi Medical University were included. They were divided into three groups according to the SHR: group T1 (SHR ≤ 0.838, N = 646), group T2 (0.838< SHR ≤ 1.140, N = 646), and group T3 (SHR3 > 1.140, N = 647). The primary endpoint was IHCA incidence. RESULTS: The overall IHCA incidence was 4.1% (N = 80). After adjusting for covariates, SHR was significantly associated with IHCA incidence in patients with ACS who underwent PCI (odds ratio [OR] = 2.6800; 95% confidence interval [CI] = 1.6200-4.4300; p<0.001), and compared with the T1 group, the T3 group had an increased IHCA risk (OR = 2.1800; 95% CI = 1.2100-3.9300; p = 0.0090). In subgroup analyses, after adjusting for covariates, patients with ST-segment elevation myocardial infarction (STEMI) (OR = 3.0700; 95% CI = 1.4100-6.6600; p = 0.0050) and non-STEMI (NSTEMI) (OR = 2.9900; 95% CI = 1.1000-8.1100; p = 0.0310) were at an increased IHCA risk. After adjusting for covariates, IHCA risk was higher in patients with diabetes mellitus (DM) (OR = 2.5900; 95% CI = 1.4200-4.7300; p = 0.0020) and those without DM (non-DM) (OR = 3.3000; 95% CI = 1.2700-8.5800; p = 0.0140); patients with DM in the T3 group had an increased IHCA risk compared with those in the T1 group (OR = 2.4200; 95% CI = 1.0800-5.4300; p = 0.0320). The restriction cubic spline (RCS) analyses revealed a dose-response relationship between IHCA incidence and SHR, with an increased IHCA risk when SHR was higher than 1.773. Adding SHR to the baseline risk model improved the predictive value of IHCA in patients with ACS treated with PCI (net reclassification improvement [NRI]: 0.0734 [0.0058-0.1409], p = 0.0332; integrated discrimination improvement [IDI]: 0.0218 [0.0063-0.0374], p = 0.0060). CONCLUSIONS: In patients with ACS treated with PCI, the SHR was significantly associated with the incidence of IHCA. The SHR may be a useful predictor of the incidence of IHCA in patients with ACS. The addition of the SHR to the baseline risk model had an incremental effect on the predictive value of IHCA in patients with ACS treated with PCI.

Modulation of Dendritic Cell Function via Nanoparticle-Induced Cytosolic Calcium Changes.

Calcium nanoparticles have been investigated for applications, such as drug and gene delivery. Additionally, Ca2+ serves as a crucial second messenger in the activation of immune cells. However, few studies have systematically studied the effects of calcium nanoparticles on the calcium levels and functions within immune cells. In this study, we explore the potential of calcium nanoparticles as a vehicle to deliver calcium into the cytosol of dendritic cells (DCs) and influence their functions. We synthesized calcium hydroxide nanoparticles, coated them with a layer of silica to prevent rapid degradation, and further conjugated them with anti-CD205 antibodies to achieve targeted delivery to DCs. Our results indicate that these nanoparticles can efficiently enter DCs and release calcium ions in a controlled manner. This elevation in cytosolic calcium activates both the NFAT and NF-κB pathways, in turn promoting the expression of costimulatory molecules, antigen-presenting molecules, and pro-inflammatory cytokines. In mouse tumor models, the calcium nanoparticles enhanced the antitumor immune response and augmented the efficacy of both radiotherapy and chemotherapy without introducing additional toxicity. Our study introduces a safe nanoparticle immunomodulator with potential widespread applications in cancer therapy.

Association of the triglyceride glucose-body mass index with the extent of coronary artery disease in patients with acute coronary syndromes.

BACKGROUND: Studies have shown that insulin resistance is strongly associated with the development of cardiovascular disease, and the triglyceride glucose-body mass index (TyG-BMI index) is considered to be a reliable surrogate marker of insulin resistance. There are limited studies on the relationship between TyG-BMI index and the extent of coronary artery disease in patients with acute coronary syndrome (ACS). This study aimed to investigate the relationship between TyG-BMI index and the extent of coronary artery disease in patients with ACS. METHODS: Overall, 2,317 patients with ACS who underwent percutaneous coronary intervention at the Affiliated Hospital of Zunyi Medical University were included in this study. The TyG-BMI index was grouped according to the tertile method. The extent of coronary artery disease in patients with ACS was quantitatively assessed using the SYNTAX score, which was categorised as low (≤ 22), intermediate (23-32), and high risk (≥ 33). RESULTS: In the overall population, multivariate logistic regression analyses showed that TyG-BMI index was associated with mid/high SYNTAX score in patients with ACS (odds ratio [OR] = 1.0041; 95% confidence interval [CI] = 1.0000-1.0079; p = 0.0310). Subgroup analyses showed that TyG-BMI index was an independent risk factor for mid/high SYNTAX score in female ACS patients after adjusting for multiple confounders (OR = 1.0100; 95% CI = 1.0000-1.0200; p = 0.0050), and that the risk of mid/high SYNTAX score was 2.49 times higher in the T3 group (OR = 2.4900; 95% CI = 1.2200-5.0600; p = 0.0120). Restricted cubic spline analysis showed a linear correlation between TyG-BMI index and complex coronary artery disease (SYNTAX score > 22) in women with ACS. In female ACS patients, inclusion of the TyG-BMI index did not improve the predictive power of the underlying risk model (net reclassification improvement: 0.0867 [-0.0256-0.1989], p = 0.1301; integrated discrimination improvement: 0.0183 [0.0038-0.0329], p = 0.0135). CONCLUSIONS: TyG-BMI index is linearly associated with the degree of complex coronary artery disease in female ACS patients. However, the inclusion of the TyG-BMI index did not improve the predictive power of the underlying risk model for female ACS patients.

GLUT1 Mediates the Metabolic Reprogramming and Inflammation of CCR2$

BACKGROUND: Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced heart failure (HF) patients with higher abundance of CCR2+ macrophages are more likely to experience adverse remodeling. The precise mechanism of CCR2+ macrophages in how they affect the progression of dilated cardiomyopathy remains unknown. METHODS: Cardiac biopsy samples from dilated cardiomyopathy patients (DCM) were used for immunohistochemistry and immunofluorescence staining. PCR is employed to identify the IL-1ß, IL-6, TNF-α, TGF-ß, MMP2, MMP9, PKM1, PKM1, GLUT1, GLUT2, GLUT3, GLUT4, PDK1, PFKFB3, PFK1 and HK2 mRNA expression of CCR2+ monocytes/macrophages from the peripheral blood of DCM patients. Seahorse was used to evaluate the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of CCR2+ monocytes/macrophages. 2-DG was used to simulate a lack of glucose. Lentivirus containing GLUT1 inhibitory sequence was used to knockdown GLUT1 gene expression of CCR2+ monocytes/macrophages. Western Blot and immunofluorescence staining was used to evaluate the expression of NLRP3. RESULTS: Immunostaining results of cardiac biopsy tissue from dilated cardiomyopathy (DCM) patients demonstrated that the progression to HF was associated with an increase in the number of CCR2+ macrophages. PCR results demonstrated that CCR2 monocytes and macrophages derived from the blood of DCM patients expressed elevated levels of inflammatory factors and up regulation of glycolysis related genes. In addition, OCR and glucose uptake experiments confirmed that increased glucose uptake of these cells was associated with greater inflammation and correlated with a worsening of cardiac function. limiting the glucose supply to CCR2+ monocytes and macrophages, or suppressing the activity of glucose transporter 1 (GLUT1) could reduce inflammation levels. CONCLUSIONS: These results suggest that CCR2+ monocytes and macrophages rely on metabolic reprogramming to trigger inflammatory response and contribute to myocardial injury and the progression of DCM.

Targeting cytokine-like protein FAM3D lowers blood pressure in hypertension.

Current antihypertensive options still incompletely control blood pressure, suggesting the existence of uncovered pathogenic mechanisms. Here, whether cytokine-like protein family with sequence similarity 3, member D (FAM3D) is involved in hypertension etiology is evaluated. A case-control study exhibits that FAM3D is elevated in patients with hypertension, with a positive association with odds of hypertension. FAM3D deficiency significantly ameliorates angiotensin II (AngII)-induced hypertension in mice. Mechanistically, FAM3D directly causes endothelial nitric oxide synthase (eNOS) uncoupling and impairs endothelium-dependent vasorelaxation, whereas 2,4-diamino-6-hydroxypyrimidine to induce eNOS uncoupling abolishes the protective effect of FAM3D deficiency against AngII-induced hypertension. Furthermore, antagonism of formyl peptide receptor 1 (FPR1) and FPR2 or the suppression of oxidative stress blunts FAM3D-induced eNOS uncoupling. Translationally, targeting endothelial FAM3D by adeno-associated virus or intraperitoneal injection of FAM3D-neutralizing antibodies markedly ameliorates AngII- or deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Conclusively, FAM3D causes eNOS uncoupling through FPR1- and FPR2-mediated oxidative stress, thereby exacerbating the development of hypertension. FAM3D may be a potential therapeutic target for hypertension.

Single-Dose Rifapentine in Household Contacts of Patients with Leprosy.

BACKGROUND: Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. METHODS: We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. RESULTS: A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. CONCLUSIONS: The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

Tanshinone IIA-loaded nanoparticles and neural stem cell combination therapy improves gut homeostasis and recovery in a pig ischemic stroke model.

Impaired gut homeostasis is associated with stroke often presenting with leaky gut syndrome and increased gut, brain, and systemic inflammation that further exacerbates brain damage. We previously reported that intracisternal administration of Tanshinone IIA-loaded nanoparticles (Tan IIA-NPs) and transplantation of induced pluripotent stem cell-derived neural stem cells (iNSCs) led to enhanced neuroprotective and regenerative activity and improved recovery in a pig stroke model. We hypothesized that Tan IIA-NP + iNSC combination therapy-mediated stroke recovery may also have an impact on gut inflammation and integrity in the stroke pigs. Ischemic stroke was induced, and male Yucatan pigs received PBS + PBS (Control, n = 6) or Tan IIA-NP + iNSC (Treatment, n = 6) treatment. The Tan IIA-NP + iNSC treatment reduced expression of jejunal TNF-α, TNF-α receptor1, and phosphorylated IkBα while increasing the expression of jejunal occludin, claudin1, and ZO-1 at 12 weeks post-treatment (PT). Treated pigs had higher fecal short-chain fatty acid (SCFAs) levels than their counterparts throughout the study period, and fecal SCFAs levels were negatively correlated with jejunal inflammation. Interestingly, fecal SCFAs levels were also negatively correlated with brain lesion volume and midline shift at 12 weeks PT. Collectively, the anti-inflammatory and neuroregenerative treatment resulted in increased SCFAs levels, tight junction protein expression, and decreased inflammation in the gut.

Epicardial Adipose Tissue and Diabetic Cardiomyopathy.

Diabetes is a long-term chronic disease, and cardiovascular disease is the leading cause of death. Diabetic cardiomyopathy (DCM), one of the cardiovascular complications of diabetes, has many uncertain factors. Epicardial fat, as the heart fat bank, functions as fatty tissue and is the heart's endocrine organ. The existence of diabetes affects the distribution of heart fat and promotes the secretion of adipokine. In different pathological conditions, it can promote the secretion of pro-inflammatory adipokine, reactive oxygen species, oxidative stress, and even autophagy, thus affecting cardiac function. In this paper, we will elaborate on the mechanism of epicardial fat in the pathogenesis of diabetic cardiomyopathy.

Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection.

AIMS: Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) and serve as an early indicator and therapeutic target remains elusive. METHODS AND RESULTS: Single-cell RNA sequencing analysis showed aberrant endothelial TJ expressions in the thoracic aortas of patients with TAAD. In a ß-aminopropionitrile (BAPN)-induced TAAD mouse model, endothelial TJ function was disrupted in the thoracic aortas at an early stage (5 and 10 days) as observed by a vascular permeability assay, while the intercellular distribution of crucial TJ components was significantly decreased by en face staining. For the non-invasive detection of endothelial TJ function, two dextrans of molecular weights 4 and 70 kDa were conjugated with the magnetic resonance imaging (MRI) contrast agent Gd-DOTA to synthesize FITC-dextran-DOTA-Gd and rhodamine B-dextran-DOTA-Gd. MRI images showed that both probes accumulated in the thoracic aortas of the BAPN-fed mice. Particularly, the mice with increased accumulated signals from 5 to 10 days developed TAAD at 14 days, whereas the mice with similar signals between the two time points did not. Furthermore, the protease-activated receptor 2 inhibitor AT-1001, which seals TJs, alleviated the BAPN-induced impairment of endothelial TJ function and expression and subsequently reduced TAAD incidence. Notably, endothelial-targeted ZO-1 conditional knockout increased TAAD incidence. Mechanistically, vascular inflammation and edema were observed in the thoracic aortas of the BAPN-fed mice, whereas these phenomena were attenuated by AT-1001. CONCLUSION: The disruption of endothelial TJ function is an early event prior to TAAD formation, herein serving as a potential indicator and a promising target for TAAD.

Chinese Medicine as Supporting Therapy for Psoriasis: Past, Present, and Future.

Psoriasis is a chronic skin disease and an important health concern. Western medicine and therapies are the main treatment strategies for psoriasis vulgaris (PV); however, the overall prognosis of patients with PV is still poor. Therefore, PV prevention is especially crucial. Chinese medicine (CM) has a long history of treating psoriasis, and it has unique wisdom in different cognitive angles and treatment modes from modern medicine. In this review, we first summarized the herbs and ancient CM formulas that have therapeutic effects on PV. Second, the research status and obstacles to the current development of CM in modern medicine were reviewed. Finally, the future of CM in the context of precision medicine and integrated medicine was discussed. After a detailed reading of the abundant literature, we believe that CM, through thousands of years of continuous development and clinical practice, has achieved high effectiveness and safety for PV treatment, despite its surrounding controversy. Moreover, precise analyses and systematic research methods have provided new approaches for the modernization of CM in the future. The treatment of PV with CM is worth popularizing, and we hope it can benefit more patients.

Tanshinone IIA-Loaded Nanoparticle and Neural Stem Cell Therapy Enhances Recovery in a Pig Ischemic Stroke Model.

Induced pluripotent stem cell-derived neural stem cells (iNSCs) are a multimodal stroke therapeutic that possess neuroprotective, regenerative, and cell replacement capabilities post-ischemia. However, long-term engraftment and efficacy of iNSCs is limited by the cytotoxic microenvironment post-stroke. Tanshinone IIA (Tan IIA) is a therapeutic that demonstrates anti-inflammatory and antioxidative effects in rodent ischemic stroke models and stroke patients. Therefore, pretreatment with Tan IIA may create a microenvironment that is more conducive to the long-term survival of iNSCs. In this study, we evaluated the potential of Tan IIA drug-loaded nanoparticles (Tan IIA-NPs) to improve iNSC engraftment and efficacy, thus potentially leading to enhanced cellular, tissue, and functional recovery in a translational pig ischemic stroke model. Twenty-two pigs underwent middle cerebral artery occlusion (MCAO) and were randomly assigned to a PBS + PBS, PBS + iNSC, or Tan IIA-NP + iNSC treatment group. Magnetic resonance imaging (MRI), modified Rankin Scale neurological evaluation, and immunohistochemistry were performed over a 12-week study period. Immunohistochemistry indicated pretreatment with Tan IIA-NPs increased iNSC survivability. Furthermore, Tan IIA-NPs increased iNSC neuronal differentiation and decreased iNSC reactive astrocyte differentiation. Tan IIA-NP + iNSC treatment enhanced endogenous neuroprotective and regenerative activities by decreasing the intracerebral cellular immune response, preserving endogenous neurons, and increasing neuroblast formation. MRI assessments revealed Tan IIA-NP + iNSC treatment reduced lesion volumes and midline shift. Tissue preservation and recovery corresponded with significant improvements in neurological recovery. This study demonstrated pretreatment with Tan IIA-NPs increased iNSC engraftment, enhanced cellular and tissue recovery, and improved neurological function in a translational pig stroke model.

Knockdown of CD146 promotes endothelial-to-mesenchymal transition via Wnt/ß-catenin pathway.

PURPOSE: Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) proteins and leads to the maladaptive changes in myocardium. Endothelial cells (ECs) undergoing mesenchymal transition contributes to the occurrence and development of cardiac fibrosis. CD146 is an adhesion molecule highly expressed in ECs. The present study was performed to explore the role of CD146 in modulating endothelial to mesenchymal transition (EndMT). METHODS: C57BL/6 mice were subjected to subcutaneous implantation of osmotic minipump infused with angiotensin II (Ang Ⅱ). Adenovirus carrying CD146 short hairpin RNA (shRNA) or CD146 encoding sequence were infected into cultured human umbilical vein endothelial cells (HUVECs) followed by stimulation with Ang II or transforming growth factor-ß1 (TGF-ß1). Differentially expressed genes were revealed by RNA-sequencing (RNA-Seq) analysis. Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blot and immunofluorescence staining, respectively. RESULTS: CD146 was predominantly expressed by ECs in normal mouse hearts. CD146 was upregulated in ECs but not fibroblasts and myocytes in hearts of Ang II-infused mice and in HUVECs stimulated with Ang Ⅱ. RNA-Seq analysis revealed the differentially expressed genes related to EndMT and Wnt/ß-catenin signaling pathway. CD146 knockdown and overexpression facilitated and attenuated, respectively, EndMT induced by Ang II or TGF-ß1. CD146 knockdown upregulated Wnt pathway-related genes including Wnt4, LEF1, HNF4A, FOXA1, SOX6, and CCND3, and increased the protein level and nuclear translocation of ß-catenin. CONCLUSIONS: Knockdown of CD146 exerts promotional effects on EndMT via activating Wnt/ß-catenin pathway and the upregulation of CD146 might play a protective role against EndMT and cardiac fibrosis.

Preparation, Characterization and Application of Epitaxial Grown BiOBr (110) Film on ZnFe2O4 Surface with Enhanced Photocatalytic Fenton Oxidation Properties.

A novel BiOBr photocatalyst was epitaxially grown in situ onto the surface of ZnFe2O4, a ferroelectric material with a strong polarization effect. The formatted BiOBr/ZnFe2O4 composite (BOB/ZFO) showed excellent photocatalytic degradation performance of tetracycline antibiotics (TCs). One of the composites with ZnFe2O4 content of 10% (BOB/ZFO-10) showed the best properties; the degradation efficiency of TCs upon visible light irradiation for 180 min was 99.2%, which was 3.58 times higher than that of pure phase BiOBr. The functions of ZnFe2O4 are assumed to be such that the addition of this ferroeletric material not only regulated the spontaneous polarization of BiOBr in the process of synthesis, but also resulted in the construction of Z-scheme heterostructures due to the appropriate staggered band structure of BiOBr and ZnFe2O4. In the presence of ferroelectric material ZnFe2O4, the local structure of BiOBr may be distorted accordingly, resulting in preferential growth of a (110) crystal facet of BiOBr and enhancement of spontaneous polarization, which promotes the efficient separation of photogenerated electron-hole pairs of ZnFe2O4 and BiOBr, and therefore enhances the redox capacity of the photocatalytic degradation of organic pollutants.

Biologics for Non-Cancer Dermatological Diseases: Analysis on China's Clinical Trial Registration Trend From 2016 to 2020.

Background: In the past 5 years, China has quickly followed US's steps to approve the new drug application of biologics for dermatological diseases. There is an increasing interest in the current biologic landscape and further potentials in China. Our study aims to analyze features of clinical trials on non-cancer dermatological biologics and synthesize recent achievements and impediments, in order to forecast the development trends in China. Methods: Three registers (the Chinese Clinical Trial Registry, Center for Drug Evaluation, and ClinicalTrials.gov) were searched for clinical trials of non-cancer dermatological biologics initiated between 2016 and 2020 in mainland China. Trial information (the first posted year, sponsor type, study phase and site, recruitment status, disease, drug target, and drug registration type) and certain study design (selection of the control group, primary efficacy outcome, and inclusion of patient-reported outcome for non-phase I or II trials only) information were extracted and analyzed. Results: A total of 60 trials were identified. The number of registered dermatological biologic trials significantly increased with an annual increase of 59% from 2016 to 2020, primarily driven by psoriasis (47/60, 78.3%) and atopic dermatitis (6/60, 10.0%) trials. The tumor necrosis factor (TNF)-α and interleukin (IL)-17 remained the hottest drug targets (17/60, 28.3% for TNF-α and 18/60, 30.0% for IL-17). In addition to TNF-α and IL-17, many new psoriasis drug targets came into place since 2018 (IL-12/23) and 2019 (IL-36 and glucagon-like peptide-1 (GLP-1)). Thirty percent (18/60) of the trials were conducted for biosimilar products, all of which were sponsored by local pharmaceutical companies and 88.9% of which were targeting on TNF-α. Targets of IL-36, IL-5, and IgE were only available in trials sponsored by global companies. Conclusion: There was great progress on the innovation of dermatological biologics in the past 5 years in China in terms of surged number of clinical trials, increased biosimilars and "me-too" drugs which greatly improved patient access to novel treatments, execution of parallel clinical trials, and improved hospital GCP office and regulatory environment. Further efforts for local pharmaceutical companies should include relocating resources to exploring novel drug targets and dermatological diseases other than psoriasis or atopic dermatitis. Systematic Review Registration: [website], identifier [registration number].

7-Dehydrocholesterol Encapsulated Polymeric Nanoparticles As a Radiation-Responsive Sensitizer for Enhancing Radiation Therapy.

Therapeutics that can be activated by radiation in situ to enhance the efficacy of radiotherapy are highly desirable. Herein, 7-Dehydrocholesterol (7-DHC), a biosynthetic precursor of cholesterol, as a radiosensitizer, exploiting its ability to propagate the free radical chain reaction is explored. The studies show that 7-DHC can react with radiation-induced reactive oxygen species and in turn promote lipid peroxidation, double-strand breaks, and mitochondrial damage in cancer cells. For efficient delivery, 7-DHC is encapsulated into poly(lactic-co-glycolic acid) nanoparticles, forming 7-DHC@PLGA NPs. When tested in CT26 tumor bearing mice, 7-DHC@PLGA NPs significantly enhanced the efficacy of radiotherapy, causing complete tumor eradication in 30% of the treated animals. After treatment, 7-DHC is converted to cholesterol, causing no detectable side effects or hypercalcemia. 7-DHC@PLGA NPs represent a radiation-responsive sensitizer with great potential in clinical translation.

Ginsenoside Rb1 ameliorates Glycemic Disorder in Mice With High Fat Diet-Induced Obesity via Regulating Gut Microbiota and Amino Acid Metabolism.

Accumulating evidences suggested an association between gut microbiome dysbiosis and impaired glycemic control. Ginsenoside Rb1 (Rb1) is a biologically active substance of ginseng, which serves anti-diabetic effects. However, its working mechanism especially interaction with gut microbes remains elusive in detail. In this study, we investigated the impact of Rb1 oral supplementation on high fat diet (HFD) induced obesity mice, and explored its mechanism in regulating blood glucose. The results showed that higher liver weight and lower cecum weight were observed in HFD fed mice, which was maintained by Rb1 administration. In addition, Rb1 ameliorated HFD induced blood lipid abnormality and improved insulin sensitivity. Several mRNA expressions in the liver were measured by quantitative real-time PCR, of which UCP2, Nr1H4, and Fiaf were reversed by Rb1 treatment. 16S rRNA sequencing analysis indicated that Rb1 significantly altered gut microbiota composition and increased the abundance of mucin-degrading bacterium Akkermansia spp. compared to HFD mice. As suggested via functional prediction, amino acid metabolism was modulated by Rb1 supplementation. Subsequent serum amino acids investigation indicated that several diabetes associated amino acids, like branched-chain amino acids, tryptophan and alanine, were altered in company with Rb1 supplementation. Moreover, correlation analysis firstly implied that the circulation level of alanine was related to Akkermansia spp.. In summary, Rb1 supplementation improved HFD induced insulin resistance in mice, and was associated with profound changes in microbial composition and amino acid metabolism.

Potassium Iodide Nanoparticles Enhance Radiotherapy against Breast Cancer by Exploiting the Sodium-Iodide Symporter.

Iodine has shown promise in enhancing radiotherapy. However, conventional iodine compounds show fast clearance and low retention inside cancer cells, limiting their application as a radiosensitizer. Herein, we synthesize poly(maleic anhydride-alt-1-octadecene) coated KI nanoparticles (PMAO-KI NPs) and evaluate their potential for enhancing radiotherapy. Owing to the polymer coating, the KI core of PMAO-KI NPs is not instantly dissolved in aqueous solutions but slowly degraded, allowing for controlled release of iodide (I-). I- is transported into cells via the sodium iodide symporter (NIS), which is upregulated in breast cancer cells. Our results show that PMAO-KI NPs can enhance radiation-induced production of reactive oxygen species such as hydroxyl radicals. When tested in vitro with MCF-7 cells, PMAO-KI NPs promote radiation-induced DNA double-strand breaks and lipid peroxidation, causing a drop in cancer cell viability and reproductivity. When tested in MCF-7 bearing mice, PMAO-KI NPs show significant radiosensitizing effects, leading to complete tumor eradication in 80% of the treated animals without inducing additional toxicity. Overall, our strategy exploits electrolyte nanoparticles to deliver iodide into cancer cells through NIS, thus promoting radiotherapy against breast cancer.

Nanoconjugates to enhance PDT-mediated cancer immunotherapy by targeting the indoleamine-2,3-dioxygenase pathway.

BACKGROUND: Photodynamic therapy (PDT) may elicit antitumor immune response in addition to killing cancer cells. However, PDT as a monotherapy often fails to induce a strong immunity. Immune checkpoint inhibitors, which selectively block regulatory axes, may be used in combination with PDT to improve treatment outcomes. Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme and an important meditator of tumor immune escape. Combination therapy with PDT and IDO-targeted immune checkpoint blockage is promising but has been seldom been explored. METHODS: Herein we report a composite nanoparticle that allows for simultaneous delivery of photosensitizer and IDO inhibitor. Briefly, we separately load ZnF16Pc, a photosensitizer, and NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor, into ferritin and poly(lactide-co-glycolic)-block-poly(ethylene glycol) (PEG-PLGA) nanoparticles; we then conjugate these two compartments to form a composite nanoparticle referred to as PPF NPs. We tested combination treatment with PPF NPs first in vitro and then in vivo in B16F10-tumor bearing C57/BL6 mice. RESULTS: Our results showed that PPF NPs can efficiently encapsulate both ZnF16Pc and NLG919. In vivo studies found that the combination treatment led to significantly improved tumor suppression and animal survival. Moreover, the treatment increased tumor infiltration of CD8+ T cells, while reducing frequencies of MDSCs and Tregs. 30% of the animals showed complete tumor eradication, and they successfully rejected a second tumor inoculation. Overall, our studies introduce a unique composite nanoplatform that allows for co-delivery of photosensitizer and IDO inhibitor with minimal inter-species interference, which is ideal for combination therapy.

Intracisternal administration of tanshinone IIA-loaded nanoparticles leads to reduced tissue injury and functional deficits in a porcine model of ischemic stroke.

BACKGROUND: The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model. RESULTS: Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm3) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (-37.30 ± 3.67 vs. -46.33 ± 0.73%) and white matter integrity (-19.66 ± 5.58 vs. -30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm3) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs. CONCLUSION: The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients.

FAP-Targeted Photodynamic Therapy Mediated by Ferritin Nanoparticles Elicits an Immune Response against Cancer Cells and Cancer Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) are present in many types of tumors and play a pivotal role in tumor progression and immunosuppression. Fibroblast-activation protein (FAP), which is overexpressed on CAFs, has been indicated as a universal tumor target. However, FAP expression is not restricted to tumors, and systemic treatment against FAP often causes severe side effects. To solve this problem, a photodynamic therapy (PDT) approach was developed based on ZnF16Pc (a photosensitizer)-loaded and FAP-specific single chain variable fragment (scFv)-conjugated apoferritin nanoparticles, or αFAP-Z@FRT. αFAP-Z@FRT PDT efficiently eradicates CAFs in tumors without inducing systemic toxicity. When tested in murine 4T1 models, the PDT treatment elicits anti-cancer immunity, causing suppression of both primary and distant tumors, i.e. abscopal effect. Treatment efficacy is enhanced when αFAP-Z@FRT PDT is used in combination with anti-PD1 antibodies. Interestingly, it is found that the PDT treatment not only elicits a cellular immunity against cancer cells, but also stimulates an anti-CAFs immunity. This is supported by an adoptive cell transfer study, where T cells taken from 4T1-tumor-bearing animals treated with αFAP PDT retard the growth of A549 tumors established on nude mice. Overall, our approach is unique for permitting site-specific eradication of CAFs and inducing a broad spectrum anti-cancer immunity.