Recent Developments of Nontraditional Single-Molecule Toroics.

Single-molecule toroics (SMTs), defined as a type of molecules with toroidal arrangement of magnetic moment associated with bi-stable non-magnetic ground states, are promising candidates for high-density information storage and the development of molecule based multiferroic materials with linear magneto-electric coupling and multiferroic behavior. The design and synthesis of SMTs by arranging the magnetic anisotropy axis in a circular pattern at the molecular level have been of great interest to scientists for last two decades since the first detection of the SMT behavior in the seminal Dy3 molecules. DyIII ion has long been the ideal candidate for constructing SMTs due to its Kramer ion nature as well as high anisotropy. Nevertheless, other LnIII ions such as TbIII and HoIII ions, as well as some paramagnetic transition metal ions, have also been used to construct many nontraditional SMTs. Therefore, we review the progress in the studies of SMTs based on the nontraditional perspective, ranging from the 3D topological to 1D&2D&3D polymeric SMTs, and 3d-4f to non Dy-based SMTs. We hope the understanding we provide about nontraditional SMTs will be helpful in designing novel SMTs.

A risk signature of ubiquitin-specific protease family predict the prognosis and therapy of kidney cancer patients.

Ubiquitin-specific proteases (USPs) are closely related to protein fate and cellular processes through various molecular signalling pathways, including DNA damage repair, p53, and transforming growth factor-ß (TGF-ß) pathways. In recent years, increasing evidence has revealed the pivotal role of ubiquitination in tumorigenesis of KIRC. However, USPs' molecular mechanism and clinical relevance in kidney cancer still need further exploration. Our study first determined prognosis-related ubiquitin-specific proteases (PRUSPs) in KIRC. We found these genes co-expressed with each other and might regulate different substrates. Based on the USPs' expression, the PRUSPs risk signature was constructed to predict the survival probability of KIRC patients. The patients in high-PRUSPs-risk group showed a low survival rate. ROC and calibration curve indicated a discriminate capacity of the signature, and uni-/multi-variate Cox regression analysis revealed that the PRUSPs score is an independent prognostic factor. In different KIRC clinical subgroups and external validation cohorts (including E-MTAB-1980 and TCGA-KIRP cohorts), the PRUSPs risk signature showed strong robustness and practicability. Further analysis found that high-risk group showed activation of immune-related pathways and high PD-1/CTLA4 expression, revealing that high-risk patients might be sensitive to immunotherapy. In summary, we constructed the USPs risk signature to predict kidney cancer prognosis, which provided the theoretical foundation for further clinical or pre-clinical experiments.

Thermal and Reactive Oxygen Species Dual-Responsive OEGylated Polysulfides with Oxidation-Tunable Lower Critical Solution Temperatures.

In this work, two monomethoxy oligo(ethylene glycol) (OEG)-substituted episulfides are prepared and a series of polysulfides are synthesized with subsequent ring-opening polymerization. The OEGylated polysulfides exhibit thermal and reactive oxygen species (ROS) dual-responsive behavior. Their lower critical solution temperatures (LCSTs) are close to human body temperature and depend on the degree of polymerization and OEG length. Notably, the LCST of the polysulfide increases linearly with the oxidation degree by H2 O2 , showing a highly tunable change regulated by the ratio between hydrophobic sulfide and hydrophilic sulfoxide/sulfone in the backbone. Further, the OEGylated polysulfide can act as a ROS scavenger to protect red blood cells (RBCs) from oxidative damage in an RBCs aging model in vitro. This work paves a facile way to synthesize LCST-tunable polysulfides, which hold great promise in biological applications.

Transcriptional repressor GATA binding 1-mediated repression of SRY-box 2 expression suppresses cancer stem cell functions and tumor initiation.

Cancer stem cells (CSCs) have been reported in a variety of cancers. SRY-box 2 (SOX2) is a member of the SOX family of transcription factors and has been shown to play a critical role in maintaining the functions of CSCs and promoting tumor initiation. However, the underlying mechanisms for the transcriptional regulation of the SOX2 gene in CSCs are unclear. In this study, using in silico and experimental approaches, we identified transcriptional repressor GATA binding 1 (TRPS1), an atypical GATA-type transcription factor, as a critical transcriptional regulator that represses SOX2 expression and thereby suppresses cancer stemness and tumorigenesis. Mechanistically, TRPS1 repressed SOX2 expression by directly targeting the consensus GATA-binding element in the SOX2 promoter as elucidated by ChIP and luciferase reporter assays. Of note, in vitro mammosphere formation assays in culture and in vivo xenograft tumor initiation experiments in mouse models revealed that TRPS1-mediated repression of SOX2 expression suppresses CSC functions and tumor initiation. Taken together, our study provides detailed mechanistic insights into CSC functions and tumor initiation by the TRPS1-SOX2 axis.

Tricho-rhino-phalangeal syndrome 1 protein functions as a scaffold required for ubiquitin-specific protease 4-directed histone deacetylase 2 de-ubiquitination and tumor growth.

BACKGROUND: Although numerous studies have reported that tricho-rhino-phalangeal syndrome type I (TRPS1) protein, the only reported atypical GATA transcription factor, is overexpressed in various carcinomas, the underlying mechanism(s) by which it contributes to cancer remain unknown. METHODS: Both overexpression and knockdown of TRPS1 assays were performed to examine the effect of TRPS1 on histone deacetylase 2 (HDAC2) protein level and luminal breast cancer cell proliferation. Also, RT-qRCR, luciferase reporter assay and RNA-sequencing were used for transcription detection. Chromatin immunoprecipitation (ChIP) using H4K16ac antibody in conjunction with qPCR was used for determining H4K16ac levels in targeted genes. Furthermore, in vitro cell proliferation assay and in vivo tumor xenografts were used to detect the effect of TRPS1 on tumor growth. RESULTS: We found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation. We detected repression of a set of cellular growth-related genes by the TRPS1-USP4-HDAC2 axis indicating it is essential in tumor growth. In vitro and in vivo experiments confirmed that silencing TRPS1 reduced tumor growth, whereas overexpression of HDAC2 restored tumor growth. CONCLUSION: Our study deciphered the TRPS1-USP4-HDAC2 axis as a novel mechanism that contributes to tumor growth. Significantly, our results revealed the scaffolding function of TPRS1 in USP4-directed HDAC2 de-ubiquitination and provided new mechanistic insights into the crosstalk between TRPS1, ubiquitin, and histone modification systems leading to tumor growth.

The effect of mast cells on the biological characteristics of prostate cancer cells.

AIM OF THE STUDY: To investigate the effects of mast cells on the proliferation, invasion, and metastasis of prostate cancer cells. MATERIAL AND METHODS: The mast cell P815 and prostate cancer LNCaP cells were chosen using a Transwell chamber to construct a two-cell cocultured in vitro model to observe the migration of mast cells to prostate cancer cells. RESULTS: In the migration experiment, the migration rate of mast cells from the experimental group (%) was 10.167 ±0.833, the mast cell migration rate (%) of the control group was 0.833 ±0.208, and the difference was statistically significant (p < 0.05). The MTT test showed that the OD value of cells in each group over time increased gradually, and 24 h after LNCaP cells were cocultured with different concentrations of mast cells, the OD value was significantly higher than that of the control group (p < 0.05). QRT-PCR and western blot results showed that, compared with the control group, E-cad expression from the experimental group was significantly weakened; N-cad and vimentin expression increased (p < 0.05), and c-kit and SCF expression from experimental group were significantly higher than that of the control group (p < 0.05). After the addition of c-kit neutralising antibodies, compared with the control group, the mast cell migration rate of experimental group decreased significantly and prostate cancer cell proliferation significantly decreased (p < 0.05). CONCLUSIONS: Mast cells could promote the proliferation of prostate cancer cells and the occurrence of epithelial mesenchymal transition (EMT), which could promote the invasion and metastasis of prostate cancer cells.

[Risks of diabetes mellitus and impaired glucose tolerance induced by intermittent versus continuous androgen-deprivation therapy for advanced prostate cancer].

OBJECTIVE: To investigate the correlation of intermittent androgen-deprivation therapy (IADT) and continuous androgen-deprivation therapy (CADT) for advanced prostate cancer (PCa) with the risks of secondary diabetes mellitus (DM) and impaired glucose tolerance (IGT). METHODS: We conducted a retrospective case-control study of the advanced PCa patients treated by IADT or CADT in our hospital from January 2013 to December 2015. Based on the levels fasting blood glucose and 2-hour postprandial blood glucose, results of oral glucose tolerance test, and clinical symptoms of the patients, we statistically analyzed the IADT- or CADT-related risk factors for DM and IGT and the relationship of the body mass index (BMI), hypertension, smoking, and alcohol consumption with secondary DM and IGT. RESULTS: IADT was given to 53 (46.5%) of the patients, aged (69.1 ± 4.3) years, and CADT to 61 (53.5%), aged (70.2 ± 5.7) years. No statistically significant differences were observed in clinical characteristics between the two groups of patients (P > 0.05). BMI, blood pressure, smoking and drinking exhibited no significant influence on the development of DM or IGT either in the IADT (P > 0.05) or the CADT group. The incidence of IGT was significantly lower in the IADT than in the CADT group (P = 0.03), but that of DM showed no statistically significant difference between the two groups (P = 0.64). CONCLUSIONS: Compared with CADT, IADT has a lower risk of IGT and a higher safety in the treatment of advanced prostate cancer.

FeIII -Doped Two-Dimensional C3 N4 Nanofusiform: A New O2 -Evolving and Mitochondria-Targeting Photodynamic Agent for MRI and Enhanced Antitumor Therapy.

Local hypoxia in tumors, as well as the short lifetime and limited action region of 1 O2 , are undesirable impediments for photodynamic therapy (PDT), leading to a greatly reduced effectiveness. To overcome these adversities, a mitochondria-targeting, H2 O2 -activatable, and O2 -evolving PDT nanoplatform is developed based on FeIII -doped two-dimensional C3 N4 nanofusiform for highly selective and efficient cancer treatment. The ultrahigh surface area of 2D nanosheets enhances the photosensitizer (PS) loading capacity and the doping of FeIII leads to peroxidase mimetics with excellent catalytic performance towards H2 O2 in cancer cells to generate O2 . As such tumor hypoxia can be overcome and the PDT efficacy is improved, whilst at the same time endowing the PDT theranostic agent with an effective T 1 -weighted in vivo magnetic resonance imaging (MRI) ability. Conjugation with a mitochondria-targeting agent could further increase the sensitivity of cancer cells to 1 O2 by enhanced mitochondria dysfunction. In vitro and in vivo anticancer studies demonstrate an outstanding therapeutic effectiveness of the developed PDT agent, leading to almost complete destruction of mouse cervical tumor. This development offers an attractive theranostic agent for in vivo MRI and synergistic photodynamic therapy toward clinical applications.

[Comparison of the volume and localization of internal gross target volume and planning target volume delineated by clips and seroma based on 4D-CT scan for external-beam partial breast irradiation after breast conserving surgery].

OBJECTIVE: To explore the differences in volume and localization of the internal gross target volume and planning target volume delineated by clips and/or seroma based on four-dimensional computed tomography (4D-CT) during free-breathing in breast cancer patients after breast conserving surgery. METHODS: Fifteen breast cancer patients after breast-conserving surgery (BCS) were recruited for external-beam partial breast irradiation (EB-PBI). On the ten sets CT images, the gross tumor volumes (GTV) formed by the clips, the seroma, and both the clips and seroma were delineated and defined as GTVc, GTVs and GTVc+s, respectively. Ten GTVc, GTVs and GTVc+s on the ten sets CT images produced the IGTVc, IGTVs, IGTVc+s. The PTVc, PTVs, PTVc+s were created by adding 15 mm to the IGTVc, IGTVs, IGTVc+s, respectively. The IGTV and PTV volume and distance between the centers of IGTVc, IGTVs, IGTVc+s and PTVc, PTVs, PTVc+s were all recorded. Conformity index (CI) and degree of inclusion (DI) were calculated for IGTV/IGTV and PTV/PTV, respectively. RESULTS: The volume of IGTVc+s[(35.73 ± 19.77) cm³] was significantly larger than the IGTVc [(28.35 ± 17.54) cm³] and IGTVs [(24.19 ± 21.53) cm³] (P < 0.05), and the volume of PTVc+s [(191.59 ± 69.74) cm³] was significantly larger than that of the PTVc [(161.53 ± 61.07) cm³] and PTVs [(148.98 ± 62.22)cm³] (P < 0.05). There were significant differences between the DIs of IGTVc in IGTVc+s and IGTVc+s in IGTVc, the DIs of IGTVs in IGTVc+s and IGTVc+s in IGTVs, the DIs of PTVc in PTVc+s and PTVc+s in PTVc, and the DIs of PTVs vs. PTVc+s and PTVc+s in PTVs (P < 0.05 for all). The CI of IGTVc/IGTVc+s (0.63 ± 0.14) and the CI of IGTVs/IGTVc+s (0.54 ± 0.17) were significant larger than that of the CI of IGTVc/IGTVs (0.40 ± 0.14)(P < 0.05). There were non-significant differences among the CI of PTVc/PTVs, PTVc/PTVc+s and PTVs/PTVc+s (0.73 ± 0.12, 0.78 ± 0.13 vs. 0.75 ± 0.17). The DIs and CIs of IGTV/IGTV and PTV/PTV were negatively correlated with their centroid distance (P < 0.05). CONCLUSIONS: There are volume difference and spatial mismatch between the target volumes delineated on the basis of surgical clips and seroma. The DI and CI between the PTVs are larger than that between the IGTV. External-beam partial breast irradiation should be implemented based on the PTV that is defined based on both seroma and surgical clips.

Polyphenolic oligomer-derived multienzyme activity for the treatment of ischemic Stroke through ROS scavenging and blood-brain barrier restoration.

Oxidative stress and blood-brain barrier (BBB) injury are two major stress disorders before and after ischemic stroke (IS) therapy. The intense inflammatory response also causes damage to nerve cells, affecting the repair of brain tissue. In this study, polyphenolic nanoparticles (PPNs) with strong free radical scavenging ability were designed to treat IS multimodally. To investigate the mechanism of polyphenolic polymerization, solid nanoparticles were synthesized using four kinds of polyphenol compounds as the basic unit under the control of temperature. The form of polymerization between monomers with different structures led to changes in the chemical properties of the corresponding nanoparticles as well as the antioxidant capacity at the cellular level. Particularly, PPNs can significantly improve cerebral infarction and penetrate and repair the BBB, and even downregulate levels of inflammatory cytokines. Molecular signaling pathway studies have shown that PPNs can provide comprehensive treatment of IS by promoting the expression of tight junction protein and enhancing the activity of antioxidant enzymes. Therefore, PPNs combined with the antioxidant, anti-inflammatory and BBB repair ability not only provide a perfect therapeutic pathway but also give ideas for the development of natural material carriers that have a wide application prospect.

H2O2-Responsive Polymeric Micelles of Biodegradable Aliphatic Poly(carbonate)s as Promising Therapeutic Agents for Inflammatory Diseases.

Excessive amounts of reactive oxygen species (ROS) cause various biological damages and are involved in many diseases, such as cancer, inflammatory and thrombotic complications, and neurodegenerative diseases. Thus, ROS-responsive polymers with inherent ROS scavenging activity and biodegradability are extremely needed for the efficient treatment of ROS-related diseases. Here, this work fabricates the amphiphilic diblock copolymer PEG-b-PBC via ring-opening polymerization (ROP) of phenylboronic acid ester conjugated cyclic carbonate monomer. The copolymer easily forms micelles (BCM) and scavenges ROS rapidly. BCM not only releases the delivered drug but degrades to produce the small molecules p-hydroxybenzyl alcohol (HBA) with anti-inflammatory capability in the presence of H2O2. BCM can reduce the oxidative stress of human umbilical vein endothelial cells (HUVEC) and the levels of inflammatory factors secreted by macrophages, showing antioxidative and anti-inflammatory activity. Finally, BCM exerts a significant capability to reduce the complications of inflammation and thrombosis in vivo. The biodegradable aliphatic poly(carbonate)s have the potential to be used for drug delivery systems (DDS) for diseases induced by reactive oxygen species.

Myricetin Oligomer Triggers Multi-Receptor Mediated Penetration and Autophagic Restoration of Blood-Brain Barrier for Ischemic Stroke Treatment.

Restoration of blood-brain barrier (BBB) dysfunction, which drives worse outcomes of ischemic stroke, is a potential target for therapeutic opportunities, whereas a sealed BBB blocks the therapeutics entrance into the brain, making the BBB protection strategy paradoxical. Post ischemic stroke, hypoxia/hypoglycemia provokes the up-regulation of transmembrane glucose transporters and iron transporters due to multiple metabolic disorders, especially in brain endothelial cells. Herein, we develop a myricetin oligomer-derived nanostructure doped with Ce to bypass the BBB which is cointermediated by glucose transporters and iron transporters such as glucose transporters 1 (GLUT1), sodium/glucose cotransporters 1 (SGLT1), and transferrin(Tf) reporter (TfR). Moreover, it exhibits BBB restoration capacity by regulating the expression of tight junctions (TJs) through the activation of protective autophagy. The myricetin oligomers scaffold not only acts as targeting moiety but is the prominent active entity that inherits all diverse pharmacological activities of myricetin. The suppression of oxidative damage, M1 microglia activation, and inflammatory factors makes it a multitasking nanoagent with a single component as the scaffold, targeting domain and curative components.

Gelatin/heparin coated bio-inspired polyurethane composite fibers to construct small-caliber artificial blood vessel grafts.

Long-term patency and ability for revascularization remain challenges for small-caliber blood vessel grafts to treat cardiovascular diseases clinically. Here, a gelatin/heparin coated bio-inspired polyurethane composite fibers-based artificial blood vessel with continuous release of NO and biopeptides to regulate vascular tissue repair and maintain long-term patency is fabricated. A biodegradable polyurethane elastomer that can catalyze S-nitrosothiols in the blood to release NO is synthesized (NPU). Then, the NPU core-shell structured nanofiber grafts with requisite mechanical properties and biopeptide release for inflammation manipulation are fabricated by electrospinning and lyophilization. Finally, the surface of tubular NPU nanofiber grafts is coated with heparin/gelatin and crosslinked with glutaraldehyde to obtain small-caliber artificial blood vessels (ABVs) with the ability of vascular revascularization. We demonstrate that artificial blood vessel grafts promote the growth of endothelial cells but inhibit the growth of smooth muscle cells by the continuous release of NO; vascular grafts can regulate inflammatory balance for vascular tissue remodel without excessive collagen deposition through the release of biological peptides. Vascular grafts prevent thrombus and vascular stenosis to obtain long-term patency. Hence, our work paves a new way to develop small-caliber artificial blood vessel grafts that can maintain long-term patency in vivo and remodel vascular tissue successfully.

Perfluorocarbon Nanoparticles Incorporating Ginkgolide B: Artificial O2 Carriers with Antioxidant Activity and Antithrombotic Effect.

Ischemic stroke primarily leads to insufficient oxygen delivery in ischemic area. Prompt reperfusion treatment for restoration of oxygen is clinically suggested but mediates more surging reactive oxygen species (ROS) generation and oxidative damage, known as ischemia-reperfusion injury (IRI). Therefore, the regulation of oxygen content is a critical point to prevent cerebral ischemia induced pathological responses and simultaneously alleviate IRI triggered by the sudden oxygen restoration. In this work, we constructed a perfluorocarbon (PFC)-based artificial oxygen nanocarrier (PFTBA-L@GB), using an ultrasound-assisted emulsification method, alleviates the intracerebral hypoxic state in ischemia stage and IRI after reperfusion. The high oxygen solubility of PFC allows high oxygen efficacy. Furthermore, PFC has the adhesion affinity to platelets and prevents the overactivation of platelet. The encapsulated payload, ginkgolide B (GB) exerts its anti-thrombosis by antagonism on platelet activating factor and antioxidant effect by upregulation of antioxidant molecular pathway. The versatility of the present strategy provides a practical approach to build a simple, safe, and relatively effective oxygen delivery agent to alleviate hypoxia, promote intracerebral oxygenation, anti-inflammatory, reduce intracerebral oxidative stress damage and thrombosis and caused by stroke.

[Influence of registration based on different reference markers on the displacement of the geometry consisted of all clips in the cavity for external-beam partial breast irradiation at moderate deep inspiration breath holding].

OBJECTIVE: To investigate the influence of registration based on different reference markers on the displacement of the geometry consisted of all clips in the cavity for external-beam partial breast irradiation at moderate deep inspiration breath holding assisted by active breathing control device. METHODS: Twenty-seven early stage breast cancer patients feasible for external beam partial breast irradiation (EB-PBI) were selected. The patients undertaken three-dimensional computed tomography (3DCT) simulation scan at moderate deep inspiration breath holding (mDIBH) assisted by active breathing control device, and two sets of mDIBH CT images were got and transferred to the Pinnacle 3 planning system. All of the silver clips were delineated and a geometry consisted of all clips were generated. On the account of automatic registration of mDIBH CT images, manual registration was carried out based separately on the topside clip in the cavity, the labeled skin at anterior surface of the cavity at central level and the metal mark on the body surface near the cavity, then the displacements of center of the geometry in left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions based separately on the three registrations were measured. RESULTS: The displacements of center of the geometry in LR, AP and SI directions based on registration of the clips, the labeled skin and the metal mark were (0.61 ± 0.62)mm vs. (1.11 ± 1.21)mm vs. (1.31 ± 1.55)mm, (0.63 ± 0.59)mm vs. (0.92 ± 0.93)mm vs. (1.19 ± 1.24)mm and (0.91 ± 0.96)mm vs. (2.13 ± 2.12)mm vs. (1.93 ± 1.55)mm, respectively. Compared the displacements of center of the geometry in the same direction between the three registrations, significant differences were found only in SI direction between clip registration and skin registration, clip registration and mark registration (t = 5.045, 7.210 and P = 0.025, 0.007) . Compared the displacements of center of the geometry between three dimensional directions for each reference registration, there was no significant difference (all P > 0.05). CONCLUSIONS: When EB-PBI is carried out in state of mDIBH, measurement of the intrafraction displacement based on registration of the clip in the cavity is a reasonable selection. Otherwise, excessive margin enlargement of PTV in SI direction will be generated if the regional skin or metal mark is selected as registration reference.

[Clinical effect of Shenfu injection combined with glucocorticoid on patients with acute left heart failure complicated with bronchospasm].

OBJECTIVE: To investigate the clinical effect of Shenfu injection combined with glucocorticoid in the treatment of acute left heart failure complicated with bronchospasm. METHODS: A prospective study was conducted.Ninety patients with acute left heart failure complicated with bronchospasm admitted to Huai'an Second People's Hospital from January 2021 to July 2022 were selected and divided into conventional treatment group, hormone therapy group and combined treatment group according to random number table method, with 30 cases in each group. All patients in the 3 groups received basic Western medicine treatment. On this basis, the conventional treatment group was given 0.25-0.50 g aminophylline injection plus 5% glucose injection or 0.9% sodium chloride injection (diabetes patients) 100 mL slow intravenous infusion, 1-2 times a day. In the hormone treatment group, 1 mg of budesonide suspension for inhalation was diluted to 2 mL by 0.9% sodium chloride injection, twice a day, and applied until 48 hours after the pulmonary wheezing disappeared. The combined treatment group was given glucocorticoid combined with Shenfu injection 80 mL plus 5% glucose injection or 0.9% sodium chloride injection (diabetes patients) 250 mL intravenously, once a day. All treated for 1 week. The general data, traditional Chinese medicine (TCM) syndrome score, TCM syndrone efficacy index, acute left heart failure efficacy, bronchospasm efficacy, systolic blood pressure (SBP), mean arterial pressure (MAP), serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level and safety of the 3 groups were compared. The patients were followed up for 6 months, and the mortality and re-hospitalization rate of the 3 groups were recorded. RESULTS: Among the 90 patients, a total of 83 patients completed the study, excluding the cases dropped due to death and other reasons. There were 29 cases in the combined treatment group, 25 cases in the hormone therapy group and 29 cases in the conventional treatment group. There were no significant differences in age, gender, course of disease, and previous history (history of diabetes, history of hypertension, history of hyperlipidemia) among the 3 groups. Therefore, they were comparable. The difference of TCM syndrome score before and after treatment, TCM syndrome efficacy index of combined treatment group and hormone therapy group were higher than those of conventional treatment group [difference of TCM syndrome score: 15.14±5.74, 13.24±5.75 vs. 10.62±5.87, TCM syndrome efficacy index: (67.84±14.31)%, (59.94±14.26)% vs. (48.92±16.74)%, all P < 0.05], and the difference of TCM syndrome score and TCM syndrome efficacy index of combined treatment group were higher than those of hormone treatment group (both P < 0.05). The total effective rate of acute left heart failure and bronchospasm in the combined treatment group was significantly higher than that in the conventional treatment group (total effective rate of acute left heart failure: 96.55% vs. 75.86%, total effective rate of bronchospasm: 93.10% vs. 65.52%, both P < 0.05). The difference of serum NT-proBNP before and after treatment in combination therapy group and hormone therapy group was significantly higher than that in conventional treatment group (ng/L: 7 922.86±5 220.31, 7 314.92±4 450.28 vs. 4 644.79±3 388.23, all P < 0.05), and the difference of serum NT-proBNP before and after treatment in the combined treatment group was significantly higher than that in the hormone treatment group (P < 0.05). There were no significant differences in SBP difference, MAP difference, mortality and re-hospitalization rate among the 3 groups. No adverse reactions occurred in the 3 groups during treatment. CONCLUSIONS: Shenfu injection combined with glucocorticoid is effective in the treatment of patients with acute left heart failure complicated with bronchospasm. It is superior to glucocorticoid and aminophylline in relieving bronchospasm, reducing NT-proBNP level and improving total effective rate, and has good prognosis and safety.

ROS-responsive phenylboronic ester-based nanovesicles as multifunctional drug delivery systems for the treatment of inflammatory and thrombotic complications.

Inflammatory and thrombotic complications and a low loading of dual drugs with different hydrophilicities remain challenges to treat thrombosis with drug delivery systems (DDSs). Here, the reactive oxygen species (ROS)-responsive amphiphilic block polymer poly(ethylene glycol)-b-2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)oxy)-ethyl methacrylate (PEG-b-PTBEM) was synthesized and nanovesicles (PPTV) were prepared successfully for the drug delivery platform by controlling the hydrophilic/hydrophobic ratio of molecular chains and molecular self-assembly. The anti-inflammatory drug indomethacin (IDM) was loaded in the wall of nanovesicles and the thrombolytic enzyme nattokinase (NK) was encapsulated in the aqueous cavity of nanovesicles. Both drugs could be rapidly released at the site of thrombosis and/or inflammation with an excessive ROS concentration. The dual drug-loaded nanovesicles not only eliminated ROS, but also alleviated inflammation and dissolved the generated thrombus, showing significant therapeutic efficacy in the in vivo mouse model of carrageenan tail thrombosis. Therefore, drug-delivery nanovesicles play multiple roles in the treatment of inflammation-induced thrombotic disorders, which offer a promising treatment for inflammatory and thrombotic complications.

Chlorogenic Acid-Conjugated Nanoparticles Suppression of Platelet Activation and Disruption to Tumor Vascular Barriers for Enhancing Drug Penetration in Tumor.

Hypercoagulation threatens the lives of cancer patients and cancer progression. Platelet overactivation attributes to the tumor-associated hypercoagulation and maintenance of the tumor endothelial integrity, leading to limited intratumoral perfusion of nanoagents into solid tumors in spite of the enhanced penetration and retention effect (EPR). Therefore, the clinical application of nanotherapeutics in solid cancer still faces great challenges. Herein, this work establishes platelet inhibiting nanoagents based on FeIII -doped C3 N4 coloaded with the chemotherapy drug and the antiplatelet drug chlorogenic acid (CA), further opening tumor vascular endothelial junctions, thereby disrupting the tumor vascular endothelial integrity, and enhancing drug perfusion. Moreover, CA not only damages the cancer cells but also potentiates the cytotoxicity induced by the chemotherapy drug doxorubicin, synergistically ablating the tumor tissue. Further, the introduction of CA relieves the original causes of the hypercoagulable state such as tissue factor (TF), thrombin, and matrix metalloproteinases (MMPs) secreted by cancer cells. It is anticipated that the hypercoagulation- and platelet-inhibition strategy by integration of phenolic acid CA into chemotherapy provides insights into platelet inhibition-assisted theranostics based on nanomedicines.

Bioactive fibrous scaffolds with programmable release of polypeptides regulate inflammation and extracellular matrix remodeling.

Inflammation manipulation and extracellular matrix (ECM) remodeling for healthy tissue regeneration are critical requirements for tissue engineering scaffolds. To this end, the bioactive polycaprolactone (PCL)-based scaffolds are fabricated to release aprotinin and thymosin ß4 (Tß4) in a programmable manner. The core part of the fiber is composed of hyaluronic acid and Tß4, and the shell is PCL, which is further coated with heparin/gelatin/aprotinin to enhance biocompatibility. The in vitro assay demonstrates that the controlled release of aprotinin prevents initial excessive inflammation. The subsequent release of Tß4 after 3 days induces the transition of macrophages from M1 into M2 polarization. The manipulation of inflammatory response further controls the expression of transforming growth factor-ß and fibroblast activation, which oversee the quantity and quality of ECM remodeling. In addition, the gradual degradation of the scaffold allows cells to proliferate within the platform. In vivo implant evaluation convinces that PCL-based scaffolds possess the high capability to control the inflammatory response and restore the ECM to normal conditions. Hence, our work paves a new way to develop tissue engineering scaffolds for inflammation manipulation and ECM remodeling with peptide-mediated reactions.

Bioinspired Platelet-Anchored Electrospun Meshes for Tight Inflammation Manipulation and Chronic Diabetic Wound Healing.

Tight manipulation of the initial leukocytes infiltration and macrophages plasticity toward the M2 phenotype remain a challenge for diabetic wound healing. Inspired by the platelet function and platelet-macrophage interaction, a platelet-anchored polylactic acid-b-polyethylene glycol-b-polylactic acid (PLA-PEG-PLA) electrospun dressing is developed for inflammatory modulation and diabetic wounds healing acceleration. PLA-PEG-PLA electrospun meshes encapsulated with thymosin ß4 (Tß4) and CaCl2 is fabricated with electrospinning, followed by immersion of electrospun mesh in platelet-rich plasma to firmly anchor the platelets. It is demonstrated that the anchored platelets on electrospun mesh can enhance the initial macrophage recruitment and control the Tß4 release from electrospun meshes to facilitate the macrophages polarization to the M2 phenotype. The inflammatory regulation promotes the expression of vascular endothelial growth factor and the migration of vascular endothelial cells for angiogenesis, resulting in accelerated diabetic wounds healing. Therefore, this work paved a new way to design platelet-inspired electrospun meshes for inflammation manipulation and diabetic wound healing.