Phage therapy holds great promise for resolving the ever-worsening crisis of antibiotic resistance, but it also faces many challenges. One of the issues hampering phage therapy is the short blood residence time of bacteriophages. We have previously identified, through in vivo phage display, a blood circulation-prolonging peptide (BCP1) that was capable of significantly prolonging the blood retention time of a doxorubicin-loaded human ferritin nanocage, leading to enhanced therapeutic efficacy against tumors. Herein, we aimed to extend the application of BCP1 to anti-bacterial phage therapy. Methods: A genetically engineered M13 phage, BCP1-BGL, that displayed the BCP-1 peptide and expressed the restriction endonuclease Bgl II, was constructed. Taking advantage of the fact that BCP1 harbors an RGD motif (a three amino-acid sequence Arg-Gly-Asp with the ability to bind to integrins) and exerts its circulation-prolonging activity primarily through interaction with platelets, we further designed and fabricated a biomimetic phage-platelet hybrid nanoparticle (PPHN) via the physical binding of the BCP1-BGL phage to the platelet membrane nanoparticles derived via a repeated freeze-thaw procedure. A series of experiments in vitro and in vivo were conducted to reveal the long circulation and anti-bacterial capacities of BCP1-BGL phages and PPHNs. Results: The resulting PPHNs possessed a hydrodynamic size of 368 nm in deionized water, with each spherical membranous nanoparticle harboring approximately 12 rod-shaped phage particles stably bound to its surface. PPHNs, which were superior to the BCP1-BGL phages that displayed significantly prolonged anti-bacterial action in vivo against Escherichia coli infection, exhibited further extended blood retention time and optimal anti-bacterial performance in both the prophylactic and treatment approaches. Conclusion: Our work demonstrated a novel strategy in engineering biomimetic phage-based nanoparticles with improved blood retention and anti-bacterial performance and may have implications in phage therapy.

Leukemias and their bone marrow microenvironment are known to undergo dynamic changes over the course of disease. However, relatively little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of leukemia cell dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1-2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells.

Borrelia burgdorferi is a tick-borne spirochete that causes Lyme borreliosis (LB). After an initial tick bite, it spreads from the deposition site in the dermis to distant tissues of the host. It is generally believed that this spirochete disseminates via the hematogenous route. Borrelia persica causes relapsing fever and is able to replicate in the blood stream. Currently the exact dissemination pathway of LB pathogens in the host is not known and controversially discussed.

The heart is widely acknowledged as the unique driver of blood circulation. Recently, we discovered a flow-driving mechanism that can operate without imposed pressure, using infrared (IR) energy to propel flow. We considered the possibility that, by exploiting this mechanism, blood vessels, themselves, could propel flow. We verified the existence of this driving mechanism by using a three-day-old chick-embryo model. When the heart was stopped, blood continued to flow for approximately 50 minutes, albeit at a lower velocity. When IR was introduced, the postmortem flow increased from ~41.1 ± 25.6 μm/s to ~153.0 ± 59.5 μm/s (n = 6). When IR energy was diminished under otherwise physiological conditions, blood failed to flow. Hence, this IR-dependent, vessel-based flow-driving mechanism may indeed operate in the circulatory system, complementing the action of the heart.

The body of the ascidian tunicate Corella inflata is relatively transparent. Thus, the circulatory system can be visualized by injecting high molecular weight fluorescein labeled dextran into the heart or the large vessels at the ends of the heart without surgery to remove the body wall. In addition, after staining with neutral red, the movement of blood cells can be easily followed to further characterize the circulatory system. The heart is two gently curved concentric tubes extending across the width of the animal. The inner myocardial tube has a partial constriction approximately in the middle. As in other tunicates, the heart is peristaltic and periodically reverses direction. During the branchial phase blood leaves the anterior end of the heart by two asymmetric vessels that connect to the two sides of the branchial basket. Blood then flows in both transverse directions through a complex system of ducts in the basket into large ventral and dorsal vessels which carry blood back to the visceral organs in the posterior of the animal. During the visceral phase blood leaves the posterior end of the heart in two vessels that repeatedly bifurcate and fan into the stomach and gonads. Blood velocity, determined by following individual cells in video frames, is high and pulsatory near the heart. A double peak in velocity at the maximum may be due to the constriction in the middle of the heart tube. Blood velocity progressively decreases with distance from the heart. In peripheral regions with vessels of small diameter blood cells frequently collide with vessel walls and cell motion is erratic. The estimated volume of blood flow during each directional phase is greater than the total volume of the animal. Circulating blood cells are confined to vessels or ducts in the visible parts of the animal and retention of high molecular weight dextran in the vessels is comparable to that seen in vertebrates. These are characteristics of a closed circulatory system.

Recently, a complex microbiome was comprehensibly characterized in the serum and ascitic fluid of cirrhotic patients. In the current study, we investigated for the first time the induction of inflammatory pathways and Nitric Oxide, as well as the systemic hemodynamics in conjunction with the blood microbiome in a Child-Pugh class B cirrhotic cohort.

In water, amphiphilic block copolymers (BCPs) can self-assemble into various micelle structures depicting curved liquid/liquid interface. Crystallization, which is incommensurate with this curved space, often leads to defect accumulation and renders the structures leaky, undermining their potential biomedical applications. Herein we report using an emulsion-solution crystallization method to control the crystallization of an amphiphilic BCP, poly (L-lactide acid)-b-poly (ethylene glycol) (PLLA-b-PEG), at curved liquid/liquid interface. The resultant BCP crystalsomes (BCCs) structurally mimic the classical polymersomes and liposomes yet mechanically are more robust thanks to the single crystal-like crystalline PLLA shell. In blood circulation and biodistribution experiments, fluorophore-loaded BCCs show a 24 h circulation half-life and a 8% particle retention in the blood even at 96 h post injection. We further demonstrate that this good performance can be attributed to controlled polymer crystallization and the unique BCC nanostructure.

Scientific theories take centuries to come into existence and they keep on evolving. Uncountable intellectual minds work on these theories; some fail to do anything about it; some add a little after tremendous efforts, and some people give remarkable and unforgettable contribution.As far as credit is concerned, the person who is able to prove the theory by his facts and who clears the maximum doubts by his observations, experimentations, facts and reasoning, gets the credit for that theory, and this should be done with honesty.The theory of pulmonary circulation took more than 2000 years to come into existence as we know it today. With the passage of time different people were given credit. Some say that it was given to Galen; some say it was Michael Servetus; others say that Realdus Columbus was the real discoverer; some gave the credit to Ibn Nafis, and finally people gave the credit to William Harvey. But after the rediscovery of Ibn Nafis' manuscript no.62243 titled Sharah al Tashreeh al Qanoon, or "Commentary on the anatomy of Canon of Avicenna" in 1924 AD in Europe, it became clear that Ibn Nafis had described the pulmonary circulation almost 300 years before Harvey, and the historians like Aldo Mieli, Max Mayrhoff, Edward Coppola etc. clearly state that Ibn Nafis is the real discoverer of the pulmonary circulation and that he should be given the credit for the discovery of the pulmonary circulation.

To date, the ability of nanoplatforms to achieve excellent therapeutic responses is hindered by short blood circulation and limited tumor accumulation/penetration. Herein, a soft mesoporous organosilica nanoplatform modified with hyaluronic acid and cyanine 5.5 are prepared, denoted SMONs-HA-Cy5.5, and comparative studies between SMONs-HA-Cy5.5 (24.2 MPa) and stiff counterparts (79.2 MPa) are conducted. Results indicate that, apart from exhibiting a twofold increase in tumor cellular uptake, the soft nanoplatforms also display a remarkable pharmacokinetic advantage, resulting in considerably improved tumor accumulation. Moreover, SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration, achieving 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts. Results further reveal that the soft nanoplatforms have an easier extravasation from the tumor vessels, diffuse farther in the dense extracellular matrix, and reach deeper tumor tissues compared to the stiff ones. Specifically, the soft nanoplatforms generate a 16-fold improvement (43 vs. 2.72 μm) in diffusion distance in tumor parenchyma. Based on the significantly improved blood circulation and tumor accumulation/penetration, a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5. The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones.

Excessive intake of high-lipid foods and lifestyle changes can easily cause hyperlipidemia. Hyperlipidemia is clinically considered a major risk factor for cardiovascular disease, which is the second leading cause of death worldwide. In this study, the effects of a Vitis labrusca extract (HP01) on coagulation, platelet aggregation, and lipid metabolism were investigated in hyperlipidemic rats. A rat model of high-fat diet- (HFD-) induced hyperlipidemia was used. Hemostatic parameters and lipid levels were investigated after HP01 treatment of hyperlipidemic rats. Different doses of HP01 (200 mg/kg/day and 400 mg/kg/day, p.o.) were administered for 3 weeks, and prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet aggregation and bleed time (BT) were determined. The levels of thromboxane B(2) (TXB(2)) and serotonin were measured using enzyme-linked immunosorbent assay kits. Simultaneously, hepatic function and blood fat indexes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), malondialdehyde (MDA), and glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were also measured. In comparison with the data obtained for rats in the untreated HFD group, HP01 (200 mg/kg) treatment prolonged PT but did not affect aPTT. HP01 treatment did not alter plasma TXB(2), PGI2, or serotonin levels. However, HP01 showed some effects in improving liver function by reducing the levels of hepatic lipids. ALT, MDA, and hepatic TG levels significantly decreased, whereas GSH, GPx, CAT, and SOD levels significantly increased. These results confirm the HP01 extract will improve thromboplastic and the liver metabolic disorders in hyperlipidemia by oxidative stress response.

Astrocytes provide neurons with essential metabolic and structural support, modulate neuronal circuit activity and may also function as versatile surveyors of brain milieu, tuned to sense conditions of potential metabolic insufficiency. Here we show that astrocytes detect falling cerebral perfusion pressure and activate CNS autonomic sympathetic control circuits to increase systemic arterial blood pressure and heart rate with the purpose of maintaining brain blood flow and oxygen delivery. Studies conducted in experimental animals (laboratory rats) show that astrocytes respond to acute decreases in brain perfusion with elevations in intracellular [Ca2+]. Blockade of Ca2+-dependent signaling mechanisms in populations of astrocytes that reside alongside CNS sympathetic control circuits prevents compensatory increases in sympathetic nerve activity, heart rate and arterial blood pressure induced by reductions in cerebral perfusion. These data suggest that astrocytes function as intracranial baroreceptors and play an important role in homeostatic control of arterial blood pressure and brain blood flow.

Establishing functional circulation in bioengineered tissue after implantation is vital for the delivery of oxygen and nutrients to the cells. Native cartilage is avascular and thrives on diffusion, which in turn depends on proximity to circulation. Here, we investigate whether a gridded three-dimensional (3D) bioprinted construct would allow ingrowth of blood vessels and thus prove a functional concept for vascularization of bioengineered tissue. Twenty 10 × 10 × 3-mm 3Dbioprinted nanocellulose constructs containing human nasal chondrocytes or cell-free controls were subcutaneously implanted in 20 nude mice. Over the next 3 months, the mice were sequentially imaged with a 7 T small-animal MRI system, and the diffusion and perfusion parameters were analyzed. The chondrocytes survived and proliferated, and the shape of the constructs was well preserved. The diffusion coefficient was high and well preserved over time. The perfusion and diffusion patterns shown by MRI suggested that blood vessels develop over time in the 3D bioprinted constructs; the vessels were confirmed by histology and immunohistochemistry. We conclude that 3D bioprinted tissue with a gridded structure allows ingrowth of blood vessels and has the potential to be vascularized from the host. This is an essential step to take bioengineered tissue from the bench to clinical practice.

Biodegradable amphiphilic poly (ethylene glycol) (PEG) based ether-anhydride terpolymer, consisting of PEG, 1, 3-bis (p-carboxyphenoxy) propane (CPP) and sebacic acid (SA), namely PEG-CPP-SA terpolymer, was employed to self-assemble into micelles by adding water into a solution of the terpolymer in tetrahydrofuran (THF). The shape of polyanhydride micelles can be regulated by simply adjusting the water addition rate, where spherical, rod-like and comb-like micelles can obtained under water addition rate of 20, 3 and 1 ml/h, respectively. The effect of micellar morphologies on the cellular internalization and intracellular distribution were characterized qualitatively with cervical cancer cells (HeLa cells) and hepatoma cells (HepG2 cells) by fluorescence microscopy, confocal laser scanning microscopy (CLSM), flow cytometry (FCM) and transmission electron microscopy (TEM). The results reveal that the cellular uptake of micelles are micelle-shape-dependent (rod-like micelles may possess the highest cellular internalization rate) and cell-type-specific. Each endocytic pathway can make a contribution to this process in different degree. Moreover, blood circulation experiments of these micelles were carried out, demonstrating that comb-like micelles have a relatively longer blood circulating feature, which may due to its irregular shape help to increase the sensitivity to fluid forces and allows them to tumble and align with the blood flow.

Minimizing the interaction of nanomedicines with the mononuclear phagocytic system (MPS) is a critical challenge for their clinical translation. Conjugating polyethylene glycol (PEG) to nanomedicines is regarded as an effective approach to reducing the sequestration of nanomedicines by the MPS. However, recent concerns about the immunogenicity of PEG highlight the demand of alternative low-fouling polymers as innovative coating materials for nanoparticles. Herein, a highly hydrophilic sulfoxide-containing polymer-poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA)-is used for the surface coating of iron oxide nanoparticles (IONPs). It is found that the PMSEA polymer coated IONPs have a more hydrophilic surface than their PEGylated counterparts, and demonstrate remarkably reduced macrophage cellular uptake and much less association with human plasma proteins. In vivo study of biodistribution and pharmacokinetics further reveals a much-extended blood circulation (≈2.5 times longer in terms of elimination half-life t 1/2) and reduced accumulation (approximately two times less) in the organs such as the liver and spleen for IONPs coated by PMSEA than those by PEG. It is envisaged that the highly hydrophilic sulfoxide-containing polymers have huge potential to be employed as an advantageous alternative to PEG for the surface functionalization of a variety of nanoparticles for long circulation and improved delivery.

Cell-free DNA (cfDNA) (e.g. fetal- or tumor-derived DNA) is DNA found in the blood circulation. It is now widely investigated as a biomarker for prenatal screening, tumor diagnosis, and tumor monitoring as "liquid biopsies". However, the biological and biochemical aspects of cfDNA remain unclear. Although cfDNA is considered to be mainly derived from dead cells, information is scarce as to whether it is apoptotic or necrotic and what kinds of endonucleases or DNases are involved. We induced in vivo hepatocyte necrosis and apoptosis in mice deficient in DNase1L3 (also named DNase γ) and/or caspase-activated DNase (CAD) genes with acetaminophen overdose and anti-Fas antibody treatments. We found that (i) DNase1L3 was the endonuclease responsible for generating cfDNA in acetaminophen-induced hepatocyte necrosis and (ii) CAD and DNase1L3 cooperated in producing cfDNA for anti-Fas mediated hepatocyte apoptosis.

Closed circulatory systems (CCS) underlie the function of vertebrate organs, but in long bones their structure is unclear, although they constitute the exit route for bone marrow (BM) leukocytes. To understand neutrophil emigration from BM, we studied the vascular system of murine long bones. Here we show that hundreds of capillaries originate in BM, cross murine cortical bone perpendicularly along the shaft and connect to the periosteal circulation. Structures similar to these trans-cortical-vessels (TCVs) also exist in human limb bones. TCVs express arterial or venous markers and transport neutrophils. Furthermore, over 80% arterial and 59% venous blood passes through TCVs. Genetic and drug-mediated modulation of osteoclast count and activity leads to substantial changes in TCV numbers. In a murine model of chronic arthritic bone inflammation, new TCVs develop within weeks. Our data indicate that TCVs are a central component of the CCS in long bones and may represent an important route for immune cell export from the BM.

Some of the main concerns with in vivo application of naked small interfering RNA are rapid degradation and urinary excretion resulting in a short plasma half-life. In this study we investigated how conjugation of polyethylene glycol (PEG) with variable chain length affects siRNA pharmacokinetics and biodistribution. The PEG chains were conjugated to chemically stabilized siRNA at the 5' terminal end of the passenger strand using click chemistry. The siRNA conjugate remained functionally active and showed significantly prolonged circulation in the blood stream after intravenous injection. siRNA conjugated with 20kDa PEG (PEG20k-siRNA) was most persistent, approximately 50% PEG20k-siRNA remained 1h post-injection, while the uncoupled siRNA was rapidly removed >90% at 15min. In vivo fluorescent imaging of the living animal showed increased concentration of siRNA in peripheral tissue and delayed urine excretion when coupled to PEG 20k. Biodistribution studies by northern blotting revealed equal distribution of conjugated siRNA in liver, kidney, spleen and lung without significant degradation 24 h post-injection. Our study demonstrates that PEG conjugated siRNA can be applied as a delivery system to improve siRNA bioavailability in vivo and may potentially increase the efficiency of siRNA in therapeutic applications.

Yunnan Baiyao is a famous Chinese patent medicine in Yunnan Province. However, its mechanism for promoting blood circulation and removing blood stasis is not fully explained. Our study used metabonomics technology to reveal the regulatory effect of Yunnan Baiyao on small molecular metabolites in promoting blood circulation and removing blood stasis, and exploring the related urine biomarkers. The coagulation function, blood rheology, and pathological results demonstrated that after Yunnan Baiyao treatment, the pathological indexes in rats with epinephrine hydrochloride-induced blood stasis syndrome improved and returned to normal levels. This is the basis for the effectiveness of Yunnan Baiyao. UPLC-G2Si-HDMS was used in combination with multivariate statistical analysis to conduct metabonomic analysis of urine samples. Finally, using mass spectrometry technology, 28 urine biomarkers were identified, clarifying the relevant metabolic pathways that play a vital role in the Yunnan Baiyao treatment. These were used as the target for Yunnan Baiyao to promote blood circulation and remove blood stasis. This study showed that metabolomics strategies provide opportunities and conditions for a deep and systematic understanding of the mechanism of action of prescriptions.

The quantitative EEG (QEEG), regional cerebral blood flow (rCBF) and circulation time of 17 patients were examined semisimultaneously thrice during the first 3 months after a cerebral supratentorial infarction. The EEG was quantified according to normalized slope descriptor technique in nine patients and by means of a combined period and amplitude analysis in eight patients. Intravenously injected isotopes 133Xenon and 99TcmO4 were used for blood flow and circulation time measurements. The QEEG-values improved during the whole follow-up period. Cerebral blood flow stayed low for all 3 months and did not alter during this period, while initially prolonged circulation time to some extent improved within 2 weeks remaining, however, prolonged even thereafter. A tendency for a positive correlation between QEEG and rCBF values in the infarcted hemisphere could be seen.

Normovolemic hemodilution was used in 81 patients as preparation to reconstructive operation for the occlusion of main arteries of extremities. Regional hemodynamics was studied in 18 of them. It was established that acute hemodilution substantially increased the volume and tissue blood flow, regional systolic arterial pressure distal to the occlusion of the main vessel and reestablished the vessel tone. The oxygen transport became normal in the zones with preserved main blood flow and considerably increased in the places distal to the occlusion of the main artery.