Dynamic RGD ligands derived from highly mobile cyclodextrins regulate spreading and proliferation of endothelial cells to promote vasculogenesis.

A thiolated RGD was incorporated into the threaded allyl-ß-cyclodextrins (Allyl-ß-CDs) of the polyrotaxane (PR) through a thiol-ene click reaction, resulting in the formation of dynamic RGD ligands on the PR surface (dRGD-PR). When maintaining consistent RGD density and other physical properties, endothelial cells (ECs) cultured on dRGD-PR exhibited significantly increased cell proliferation and a larger cell spreading area compared to those on the non-dynamic RGD (nRGD-PCL). Furthermore, ECs on dRGD-PR demonstrated elevated expression levels of FAK, p-FAK, and p-AKT, along with a larger population of cells in the G2/M stage during cell cycle analysis, in contrast to cells on nRGD-PCL. These findings suggest that the movement of the RGD ligands may exert additional beneficial effects in promoting EC spreading and proliferation, beyond their essential adhesion and proliferation-promoting capabilities, possibly mediated by the RGD-integrin-FAK-AKT pathway. Moreover, in vitro vasculogenesis tests were conducted using two methods, revealing that ECs cultured on dRGD-PR exhibited much better vasculogenesis than nRGD-PCL in vitro. In vivo testing further demonstrated an increased presence of CD31-positive tissues on dRGD-PR. In conclusion, the enhanced EC spreading and proliferation resulting from the dynamic RGD ligands may contribute to improved in vitro vasculogenesis and in vivo vascularization.

Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity.

Breast cancer, a pervasive malignancy affecting women, demands a diverse treatment approach including chemotherapy, radiotherapy, and surgical interventions. However, the effectiveness of doxorubicin (DOX), a cornerstone in breast cancer therapy, is limited when used as a monotherapy, and concerns about cardiotoxicity persist. Ginsenoside Rg3, a classic compound of traditional Chinese medicine found in Panax ginseng C. A. Mey., possesses diverse pharmacological properties, including cardiovascular protection, immune modulation, and anticancer effects. Ginsenoside Rg3 is considered a promising candidate for enhancing cancer treatment when combined with chemotherapy agents. Nevertheless, the intrinsic challenges of Rg3, such as its poor water solubility and low oral bioavailability, necessitate innovative solutions. Herein, we developed Rg3-PLGA@TMVs by encapsulating Rg3 within PLGA nanoparticles (Rg3-PLGA) and coating them with membranes derived from tumor cell-derived microvesicles (TMVs). Rg3-PLGA@TMVs displayed an array of favorable advantages, including controlled release, prolonged storage stability, high drug loading efficiency and a remarkable ability to activate dendritic cells in vitro. This activation is evident through the augmentation of CD86+CD80+ dendritic cells, along with a reduction in phagocytic activity and acid phosphatase levels. When combined with DOX, the synergistic effect of Rg3-PLGA@TMVs significantly inhibits 4T1 tumor growth and fosters the development of antitumor immunity in tumor-bearing mice. Most notably, this delivery system effectively mitigates the toxic side effects of DOX, particularly those affecting the heart. Overall, Rg3-PLGA@TMVs provide a novel strategy to enhance the efficacy of DOX while simultaneously mitigating its associated toxicities and demonstrate promising potential for the combined chemo-immunotherapy of breast cancer.

Organocatalytic diastereo- and atroposelective construction of N-N axially chiral pyrroles and indoles.

The construction of N-N axially chiral motifs is an important research topic, owing to their wide occurrence in natural products, pharmaceuticals and chiral ligands. One efficient method is the atroposelective dihydropyrimidin-4-one formation. We present herein a direct catalytic synthesis of N-N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC (N-heterocyclic carbenes) catalyzed (3 + 3) cycloaddition. Using our method, we are able to synthesize structurally diverse N-N axially chiral pyrroles and indoles with vicinal central chirality or bearing a 2,3-dihydropyrimidin-4-one moiety in moderate to good yields and excellent enantioselectivities. Further synthetic transformations of the obtained axially chiral pyrroles and indoles derivative products are demonstrated. The reaction mechanism and the origin of enantioselectivity are understood through DFT calculations.

Tumor-derived microvesicles for cancer therapy.

Extracellular vesicles (EVs) are vesicles with lipid bilayer structures shed from the plasma membrane of cells. Microvesicles (MVs) are a subset of EVs containing proteins, lipids, nucleic acids, and other metabolites. MVs can be produced under specific cell stimulation conditions and isolated by modern separation technology. Due to their tumor homing and large volume, tumor cell-derived microvesicles (TMVs) have attracted interest recently and become excellent delivery carriers for therapeutic vaccines, imaging agents or antitumor drugs. However, preparing sufficient and high-purity TMVs and conducting clinical transformation has become a challenge in this field. In this review, the recent research achievements in the generation, isolation, characterization, modification, and application of TMVs in cancer therapy are reviewed, and the challenges facing therapeutic applications are also highlighted.

Ratiometric antifouling electrochemical biosensors based on designed Y-shaped peptide and MXene loaded with Au@ZIF-67 and methylene blue.

Based on the designed inverted Y-shaped peptide and MXene nanocomposite (MXene-Au@ZIF-67), a ratiometric anti-pollution electrochemical biosensor was designed and applied to the detection of biomarkers in serum. Au@ZIF-67 inserted into the interior of MXene can not only prevent the accumulation of MXene but also provide a large amounts of binding sites for capturing biomolecules. A designed multifunctional Y-shaped peptide containing anchoring, antifouling, and recognition sequences was anchored onto MXene-Au@ZIF-67 through Au-S bonds. Electrochemical signal molecules, ferrocenecarboxylic acid (Fc) and methylene blue (MB), were modified to another end of multifunctional peptide and interior of MXene-Au@ZIF-67, respectively, to produce a ratiometric electrochemical signal. We selected prostate specific antigen (PSA) as the model compound. PSA specifically recognizes and cleaves the recognition segment in the Y-shaped peptide, and the signal of Fc is reduced, while the signal of MB remains unchanged. The ratiometric strategy endows the present biosensor high accuracy and sensitivity with a detection limit of 0.85 pg/mL. In addition, the sensing surface has good antifouling ability due to the antifouling sequence of the two branching parts of the Y-shaped peptide. More importantly, by replacing the recognition segment of peptides also other targets are accessible, indicating the potential application of the universal detection strategy to the detection of various biomarkers in clinical diagnosis.

Nanoarchitectonics of tannic acid based injectable hydrogel regulate the microglial phenotype to enhance neuroplasticity for poststroke rehabilitation.

BACKGROUND: Stroke is the second leading cause of mortality and disability worldwide. Poststroke rehabilitation is still unsatisfactory in clinics, which brings great pain and economic burdens to stroke patients. In this study, an injectable hydrogel in which tannic acid (TA) acts as not only a building block but also a therapeutic drug, was developed for poststroke rehabilitation. METHODS: TA is used as a building block to form an injectable hydrogel (TA gel) with carboxymethyl chitosan (CMCS) by multivalent hydrogen bonds. The morphology, rheological properties, and TA release behavior of the hydrogel were characterized. The abilities of the TA gel to modulate microglial (BV2 cells) polarization and subsequently enhance the neuroplasticity of neuro cells (N2a cells) were assessed in vitro. The TA gel was injected into the cavity of stroke mice to evaluate motor function recovery, microglial polarization, and neuroplasticity in vivo. The molecular pathway through which TA modulates microglial polarization was also explored both in vitro and in vivo. RESULTS: The TA gel exhibited sustainable release behavior of TA. The TA gel can suppress the expression of CD16 and IL-1ß, and upregulate the expression of CD206 and TGF-ß in oxygen and glucose-deprived (OGD) BV2 cells, indicating the regulation of OGD BV2 cells to an anti-inflammatory phenotype in vitro. This finding further shows that the decrease in synaptophysin and PSD95 in OGD N2a cells is effectively recovered by anti-inflammatory BV2 cells. Furthermore, the TA gel decreased CD16/iNOS expression and increased CD206 expression in the peri-infarct area of stroke mice, implying anti-inflammatory polarization of microglia in vivo. The colocalization of PSD95 and Vglut1 stains, as well as Golgi staining, showed the enhancement of neuroplasticity by the TA gel. Spontaneously, the TA gel successfully recovered the motor function of stroke mice. The western blot results in vitro and in vivo suggested that the TA gel regulated microglial polarization via the NF-κB pathway. CONCLUSION: The TA gel serves as an effective brain injectable implant to treat stroke and shows promising potential to promote poststroke rehabilitation in the clinic.

Ultrasensitive Ratiometric Electrochemiluminescence Sensor with an Efficient Antifouling and Antibacterial Interface of PSBMA@SiO2-MXene for Oxytetracycline Trace Detection in the Marine Environment.

The sensitivity and accuracy of electrochemiluminescence (ECL) sensors for detecting small-molecule pollutants in environmental water are affected not only by nonspecific adsorption of proteins and other molecules but also by bacterial interference. Therefore, there is an urgent need to develop an ECL sensor with antifouling and antibacterial functions for water environment monitoring. Herein, a highly efficient antifouling sensing interface (PSBMA@SiO2-MXene) based on zwitterionic sulfobetaine methacrylate (SBMA) antifouling nanospheres (NPs) and two-dimensional MXene nanosheets was designed for the sensitive detection of oxytetracycline (OTC), an antibiotic small-molecule pollutant. Specifically, SBMA with good hydrophilicity and electrical neutrality was connected to SiO2 NPs, thus effectively reducing protein and bacterial adsorption and improving stability. Second, MXene with a high specific surface area was selected as the carrier to load more antifouling NPs, which greatly improves the antifouling performance. Meanwhile, the introduction of MXene also enhances the conductivity of the antifouling interface. In addition, a ratio-based sensing strategy was designed to further improve the detection accuracy and sensitivity of the sensor by utilizing Au@luminol as an internal standard factor. Based on antifouling and antibacterial interfaces, as well as internal standard and ratiometric sensing strategies, the detection range of the proposed sensor was 0.1 ng/mL to 100 µg/mL, with a detection limit of 0.023 ng/mL, achieving trace dynamic monitoring of antibiotics in complex aqueous media.

Glutaraldehyde modified red blood cells delivering artesunate to the liver as a dual therapeutic and prophylactic antimalaria strategy.

Malaria can spread quickly in the population and develop rapidly. Patients with malaria usually die due to lack of timely and effective treatment. Artesunate (AS) is a highly effective and low-toxicity antimalarial drug, but its short half-life in the blood makes it difficult to control the malaria infection completely. Red blood cells (RBCs) have great biodegradability and can be employed to encapsulate various drugs. In this work, we employed RBCs as carriers to encapsulate AS and modified them with glutaraldehyde to construct an intelligent response drug delivery system (G-AS-RBCs) targeting the liver for antimalaria therapeutic and prophylactic activity. The G-AS-RBCs had a drug loading amount of 6.56 ± 0.14 mg 10-8 cells, suggesting excellent biocompatibility. G-AS-RBCs exhibited strong liver targeting efforts and can be maintained in the mice for at least 9 days, showing the potential for malaria prevention. The enrichment of AS in the liver was enhanced because of the natural liver targeting of erythrocytes and the enhancement of liver targeting by glutaraldehyde treatment. Furthermore, AS entrapped into RBCs also showed improved slow-release characteristics and achieved a better effect of inhibiting or killing the malaria parasite than free drugs. Therefore, this RBC-based strategy is expected to realize the prevention and treatment of malaria and has good application prospects.

Young MSM changed temporal HIV-1 epidemic pattern in Heilongjiang Province, China.

Background: Human immunodeficiency virus type 1 (HIV-1) epidemic in China is featured by geographical diversity of epidemic patterns. Understanding the characteristics of regional HIV-1 epidemic allows carrying out targeted prevention and controlling measures. This seven-year cross-sectional study was conducted in Heilongjiang, one province of Northeast China, where newly diagnosed infection is fast increasing yearly, but temporal HIV-1 epidemic trend is largely unknown. Methods: Information of 1,006 newly diagnosed HIV-1-infected participants were collected before antiretroviral therapy during 2010-2016 in Heilongjiang province. HIV-1 genotype was identified based on the viral gag and env gene sequences. Recent infection was determined by Limiting-Antigen Avidity assays. Comparison analyses on the median ages, CD4 counts, proportions of stratified age groups and CD4 count groups, and rates of recent HIV-1 infection among different population and sampling times were performed to understand temporal HIV-1 epidemic features. Results: Homosexual contact among men who have sex with men (MSM) was the main transmission route and CRF01_AE was the most dominant HIV-1 genotype. During 2010-2016, the HIV-1 epidemic showed three new changes: the median age continued to decline, the cases with a CD4 count more than 500 cells/µl (CD4hi cases) disproportionally expanded, and the recent HIV-1 infection rate steadily increased. MSM cases determined the temporal trend of HIV-1 epidemic here. Increase of young MSM cases (aged <30 years) made the main contribution to the younger age trend of MSM cases. These young MSM exhibited a higher median CD4 count, a higher proportion of CD4hi cases, and a higher rate of recent HIV-1 infection than cases aged 30 years and more. MSM infected by CRF01_AE virus mostly affected HIV-1 epidemic patterns among MSM population. Conclusion: Young MSM have become a new hotspot and vulnerable group for HIV-1 transmission in Heilongjiang Province, Northeast China. The rapid increase in the number of young MSM cases, mainly those with CRF01_AE infection, changed temporal HIV-1 epidemic pattern here. Measures for prevention and control of HIV-1 infection among this population are urgently needed in the future.

Lens Evaporation on Immiscible Liquid Surface with an Interfacial Cooling Effect.

A theoretical heat and mass transfer model of volatile liquid lens evaporation on the surface of an immiscible liquid substrate is established in toroidal coordinates. According to the coupled boundary conditions of heat and mass transfer at the lens surface as well as the interfacial cooling effect, the analytical solutions of the temperature field inside the lens and the vapor concentration field around the lens are derived for the first time. Compared with the isothermal model, the change of contact radius calculated by the present model agrees well with the experimental data, especially when the liquid substrate reaches a relatively high temperature. It also reveals that the temperature distribution inside the lens is not uniform, which is similar to the sessile droplet evaporation on a solid substrate surface. In addition, the excess temperature, heat flux, and evaporation flux of the lens-air interface increase monotonically from the lens center to the contact line. Finally, the influences of density ratio and evaporative cooling number E 0 on lens mass evaporation rate are analyzed, which shows that the lens mass evaporation rate decreases with increasing density ratio and evaporative cooling number.

Succinate: A Novel Mediator to Promote Atherosclerotic Lesion Progression.

Succinate is an important intermediate product of mitochondrial energy metabolism. Recent studies revealed that beyond its known traditional metabolic functions, succinate plays important roles in signal transduction, immunity, inflammation, and posttranslational modification. Recent studies showed that patients and mouse models with cardiovascular disease have high levels of serum succinate and succinate accumulation. Atherosclerosis (As) is the pathological basis of cardiovascular and peripheral vascular diseases, such as coronary heart disease, cerebral infarction, and peripheral vascular disease, and is a major factor affecting human health. This article reviews the progression of succinate in As diseases and its underlying mechanisms.

Krebs Cycle Rewired: Driver of Atherosclerosis Progression?

The tricarboxylic acid (TCA) cycle is the center of energy metabolism in eukaryotic cells and is dynamically adjusted according to the energy needs of cells. Macrophages are activated by inflammatory stimuli, and then two breakpoints in TCA cycle lead to the accumulation of intermediates. Atherosclerosis is a chronic inflammatory process. Here, the "non-metabolic" signaling functions of TCA cycle intermediates in the macrophage under inflammatory stimulation and the role of intermediates in the progression of atherosclerosis are discussed.

Research Progress on the Role of Intermediate Filament Vimentin in Atherosclerosis.

The cytoskeleton is a biopolymer network composed of intermediate filaments, actin, and microtubules, which is the main mechanical structure of cells. Vimentin is an intermediate filament protein that regulates the mechanical and contractile properties of cells, thereby reflecting their mechanical properties. In recent years, the "nonmechanical function" of vimentin inside and outside of cells has attracted extensive attention. The content of vimentin in atherosclerotic plaques is increased, and the serum secretion of vimentin in patients with coronary heart disease is remarkably increased. In this review, the mechanistic and nonmechanistic roles of vimentin in atherosclerosis progression were summarized on the basis of current studies.

Morphology Evolution of a Volatile Liquid Lens on Another Immiscible Liquid Surface Induced by Evaporation.

A theoretical model was established to predict the morphology evolution of a volatile liquid lens evaporation on another immiscible liquid substrate surface. The theoretical model considered the dynamic process of contact line motion. On the basis of the boundary conditions established at the contact line, the morphology change of the liquid lens was calculated by numerically solving the Young-Laplace differential equations for the three interfaces. The mass evaporation rate was calculated by the diffusion-controlled evaporation model. Then, an experimental system was established to record the process of a hexane lens evaporation on the surface of an ionic liquid with a depth of 4 mm. The calculated hexane lens radius variation matches well with the experimental measurements, which shows the rationality of the present model. The calculated results show that the evaporation pattern of the liquid lens follows the constant contact-angle evaporation mode for ∼70% of the lifetime. During the later stage of evaporation, the contact angle decreases, accompanied by contraction of the contact line, which is similar to the mixed evaporation mode in the later stage of sessile droplet evaporation on a solid substrate surface. Furthermore, the influences of the initial hexane lens volume and the ionic liquid temperature on the dynamic contact angle were theoretically summarized. This study helps to provide in-depth insights into regulating the lens evaporation process on another immiscible liquid substrate surface to control the particle deposition mode.

Efficacy and Mechanism of Active Fractions in Fruit of Amomum villosum Lour. for Gastric Cancer.

Amomi Fructus is the dried ripe fruit of Amomum villosum Lour. (A. villosum). It is a well-known traditional Chinese medicine widely used to treat gastrointestinal diseases, while the efficacy or mechanism of main components in Amomi Fructus on cancer treatment remains unknown. In this study, volatile oil of A. villosum (VOAV), total flavonoids of A. villosum (FNAV) and the other residue of A. villosum (RFAV) were distilled, extracted and separated as different active fractions of A. villosum. The cell toxicity test results indicated that VOAV and FNAV can effectively inhibit the cell growth of MFC cells. Flow cytometry test results confirmed that MFC cells were caused apoptosis after being treated with VOAV, FNAV or RFAV. VOAV, FNAV or RFAV induced MFC cells apoptosis through reactive oxygen species (ROS)-mediated mitochondrial pathway, evident by the increase of endogenous ROS and mitochondrial membrane potential collapse. In addition, FNAV exhibited robust inhibitory effects on MFC tumor growth, and could improve the health status of mice compared to that of mice in 5-FU treated group. To sum up, all the above results suggest that FNAV may be a good candidate for the development of new drugs for the treatment of gastric cancer.

Recent Advances in Cell Membrane-Derived Biomimetic Nanotechnology for Cancer Immunotherapy.

Immunotherapy will significantly impact the standard of care in cancer treatment. Recent advances in nanotechnology can improve the efficacy of cancer immunotherapy. However, concerns regarding efficiency of cancer nanomedicine, complex tumor microenvironment, patient heterogeneity, and systemic immunotoxicity drive interest in more novel approaches to be developed. For this purpose, biomimetic nanoparticles are developed to make innovative changes in the delivery and biodistribution of immunotherapeutics. Biomimetic nanoparticles have several advantages that can advance the clinical efficacy of cancer immunotherapy. Thus there is a greater push toward the utilization of biomimetic nanotechnology for developing effective cancer immunotherapeutics that demonstrate increased specificity and potency. The recent works and state-of-the-art strategies for anti-tumor immunotherapeutics are highlighted here, and particular emphasis has been given to the applications of cell-derived biomimetic nanotechnology for cancer immunotherapy.

Low shear stress-induced endothelial mesenchymal transformation via the down-regulation of TET2.

Atherosclerotic cardiovascular disease is the major cause of death worldwide. Low shear stress plays key roles on the initiation and progression of atherosclerosis (As). However, its underlying mechanism remains unclear. In this study, the effect of low shear stress on endothelial mesenchymal transformation (EndMT) and its underlying mechanism were explored. Results showed that in cultured human umbilical vein endothelial cells, low shear stress down-regulated the expression of TET2 and promoted EndMT. Loss of TET2 promoted EndMT with the Wnt/ß-catenin signaling pathway. The enhancement in EndMT induced by low shear stress was attenuated by TET2 overexpression. In apoE-/- mice subjected to carotid artery local ligation, the EndMT and atherosclerotic lesions induced by low shear stress was attenuated by TET2 overexpression. Taken together, low shear stress promoted EndMT through the down-regulation of TET2, indicating that intervention with EndMT or the up-regulation of TET2 might be an alternative strategy for preventing As.

Red Blood Cell Membrane-Camouflaged Tedizolid Phosphate-Loaded PLGA Nanoparticles for Bacterial-Infection Therapy.

Multiple drug resistance (MDR) in bacterial infections is developed with the abuse of antibiotics, posing a severe threat to global health. Tedizolid phosphate (TR-701) is an efficient prodrug of tedizolid (TR-700) against gram-positive bacteria, including methicillin-sensitive staphylococcus aureus (MSSA) and methicillin-resistant staphylococcus aureus (MRSA). Herein, a novel drug delivery system: Red blood cell membrane (RBCM) coated TR-701-loaded polylactic acid-glycolic acid copolymer (PLGA) nanoparticles (RBCM-PLGA-TR-701NPs, RPTR-701Ns) was proposed. The RPTR-701Ns possessed a double-layer core-shell structure with 192.50 ± 5.85 nm in size, an average encapsulation efficiency of 36.63% and a 48 h-sustained release in vitro. Superior bio-compatibility was confirmed with red blood cells (RBCs) and HEK 293 cells. Due to the RBCM coating, RPTR-701Ns on one hand significantly reduced phagocytosis by RAW 264.7 cells as compared to PTR-701Ns, showing an immune escape effect. On the other hand, RPTR-701Ns had an advanced exotoxins neutralization ability, which helped reduce the damage of MRSA exotoxins to RBCs by 17.13%. Furthermore, excellent in vivo bacteria elimination and promoted wound healing were observed of RPTR-701Ns with a MRSA-infected mice model without causing toxicity. In summary, the novel delivery system provides a synergistic antibacterial treatment of both sustained release and bacterial toxins absorption, facilitating the incorporation of TR-701 into modern nanotechnology.

Resolution enhancement of overlapping peaks of ion mobility spectrometry based on improved particle swarm optimization algorithm.

RATIONALE: Ion mobility spectrometry (IMS) is a powerful analytical tool that has been widely applied in many fields. However, the limited structural resolution of IMS results in peak overlapping in the analysis of samples with similar structures. We propose a novel method, improved particle swarm optimization (IPSO), for the separation of IMS overlapping peaks. METHODS: This method, which prevents local optimization, is used to identify the peak model coefficients of IMS. Moreover, we use the half-peak width characteristics of IMS to determine the particle position range, which eliminates impossible combinations of single peaks and reduces the difficulty of identification of coefficients. RESULTS: During a comparison in performance between IPSO and the genetic algorithm (GA), the results show that the maximum separation error of IPSO is only 1.45%, while the error of the GA is up to 17.43%. Moreover, the time consumed by IPSO is 95% less than that of the GA, and IPSO has a greater robustness under the same separation error conditions. CONCLUSIONS: The method proposed provides accurate analytical results in separating overlapping IMS peaks even in cases of severe overlaps, which greatly enhances the structural resolution of IMS.

Low shear stress induced vascular endothelial cell pyroptosis by TET2/SDHB/ROS pathway.

Vascular endothelial cell (VEC) inflammation induced by low shear stress plays key roles in the initiation and progression of atherosclerosis (As). Pyroptosis is a form of inflammatory programmed cell death that is critical for As. However, the effect of low shear stress on VEC pyroptosis and the underlying mechanisms were not clear. Here we show that low shear stress promoted VEC pyroptosis and reduced the expression of Ten-Eleven Translocation 2 (TET2) methylcytosine dioxygenase. Loss of TET2 resulted in the upregulation of the expression and activity of mitochondrial respiratory complex II subunit succinate dehydrogenase B (SDHB) by decreasing the recruitment of histone deacetylase 2, independent of DNA demethylation modification. The overexpression of SDHB mediated mitochondrial injury and increased the production of reactive oxygen species (ROS). The administration of ROS scavenger NAC alleviated VEC pyroptosis induced by SDHB overexpression and TET2 shRNA. These findings show that low shear stress induced endothelial cell pyroptosis through the TET2/SDHB/ROS pathway and offer new insights into As.