CD73/adenosine axis exerts cardioprotection against hypobaric hypoxia-induced metabolic shift and myocarditis in a sex-dependent manner.

BACKGROUND: Clinical and experimental studies have shown that the myocardial inflammatory response during pathological events varies between males and females. However, the cellular and molecular mechanisms of these sex differences remain elusive. CD73/adenosine axis has been linked to anti-inflammatory responses, but its sex-specific cardioprotective role is unclear. The present study aimed to investigate whether the CD73/adenosine axis elicits sex-dependent cardioprotection during metabolic changes and myocarditis induced by hypobaric hypoxia. METHODS: For 7 days, male and female mice received daily injections of the CD73 inhibitor adenosine 5'- (α, ß-methylene) diphosphate (APCP) 10 mg/kg/day while they were kept under normobaric normoxic and hypobaric hypoxic conditions. We evaluated the effects of hypobaric hypoxia on the CD73/adenosine axis, myocardial hypertrophy, and cardiac electrical activity and function. In addition, metabolic homeostasis and immunoregulation were investigated to clarify the sex-dependent cardioprotection of the CD73/adenosine axis. RESULTS: Hypobaric hypoxia-induced cardiac dysfunction and adverse remodeling were more pronounced in male mice. Also, male mice had hyperactivity of the CD73/adenosine axis, which aggravated myocarditis and metabolic shift compared to female mice. In addition, CD73 inhibition triggered prostatic acid phosphatase ectonucleotidase enzymatic activity to sustain adenosine overproduction in male mice but not in female mice. Moreover, dual inhibition prostatic acid phosphatase and CD73 enzymatic activities in male mice moderated adenosine content, alleviating glycolytic shift and proinflammatory response. CONCLUSION: The CD73/adenosine axis confers a sex-dependent cardioprotection. In addition, extracellular adenosine production in the hearts of male mice is influenced by prostatic acid phosphatase and tissue nonspecific alkaline phosphatase.

A narrative review of plant and herbal medicines for delaying diabetic atherosclerosis: an update and future perspectives.

Due to their high prevalence and incidence, diabetes and atherosclerosis are increasingly becoming global public health concerns. Atherosclerosis is one of the leading causes of morbidity and disability in type 1 and/or type 2 diabetes patients. Atherosclerosis risk in diabetic patients is obviously higher than that of non-diabetic individuals. Diabetes-related glycolipid metabolism disorder has been shown to play a central role in atherosclerosis development and progression. Hyperglycemia and dyslipidemia increase the risks for atherosclerosis and plaque necrosis through multiple signaling pathways, such as a prolonged increase in reactive oxygen species (ROS) and inflammatory factors in cardiovascular cells. Notwithstanding the great advances in the understanding of the pathologies of diabetes-accelerated atherosclerosis, the current medical treatments for diabetic atherosclerosis hold undesirable side effects. Therefore, there is an urgent demand to identify novel therapeutic targets or alternative strategies to prevent or treat diabetic atherosclerosis. Burgeoning evidence suggests that plant and herbal medicines are closely linked with healthy benefits for diabetic complications, including diabetic atherosclerosis. In this review, we will overview the utilization of plant and herbal medicines for the treatment of diabetes-accelerated atherosclerosis. Furthermore, the underlying mechanisms of the ethnopharmacological therapeutic potentials against diabetic atherosclerosis are gathered and reviewed. It is foreseeable that the natural constituents from medicinal plants might be a new hope for the treatment of diabetes-accelerated atherosclerosis.

Carbon Nanohorns/Pt Nanoparticles/DNA Nanoplatform for Intracellular Zn2+ Imaging and Enhanced Cooperative Phototherapy of Cancer Cells.

Superfluous zinc ion (Zn2+) in living cells has been identified as a potential tumor biomarker for early cancer diagnosis and cancer progression monitoring. In this paper, we developed a novel carbon nanohorns/Pt nanoparticles/DNA (CNHs/Pt NPs/DNA) nanoplatform based on the clamped hybridization chain reaction (c-HCR) process for intracellular Zn2+ imaging and enhanced cooperative phototherapy of cancer cells. Cross-shaped DNAzyme (c-DNAzyme), hairpin DNA1, hairpin DNA2, and aptamer DNA were adsorbed onto the surfaces of CNHs/Pt NPs, and the fluorescence of carboxytetramethyl-rhodamine was also quenched. After entering the living cells, the c-DNAzyme was cleaved to output trigger DNA in the existence of intracellular Zn2+ and initiate the c-HCR process for fluorescence amplification. Compared with the single HCR process triggered by a single DNAzyme, the c-HCR process could further improve the amplification efficiency and sensitivity. In addition, such a nanoprobe possesses a catalysis-enhanced photodynamic effect by Pt NP generation of oxygen in a tumor microenvironment and increases the photothermal effect by loading of Pt NPs on CNHs, indicating that this is a promising biological method for cancer diagnosis and cancer cell therapy.

DNAzyme-Powered Three-Dimensional DNA Walker Nanoprobe for Detection Amyloid ß-Peptide Oligomer in Living Cells and in Vivo.

Amyloid ß-peptide oligomer (AßO) is widely acknowledged as the promising biomarker for the diagnosis of Alzheimer's disease (AD). In this work, we designed a three-dimensional (3D) DNA walker nanoprobe for AßO detection and real-time imaging in living cells and in vivo. The presence of AßO triggered the DNAzyme walking strand to cleave the fluorophore (TAMRA)-labeled substrate strand modified on the gold nanoparticle (AuNP) surface and release TAMRA-labeled DNA fragment, resulting in the recovery of fluorescent signal. The entire process was autonomous and continuous, without external fuel strands or protease, and finally produced plenty of TAMRA fluorescence, achieving signal amplification effect. The nanoprobe enabled the quantitative detection of AßO in vitro, and the limit of detection was 22.3 pM. Given the good biocompatibility of 3D DNA walker nanoprobe, we extended this enzyme-free signal amplification method to real-time imaging of AßO. Under the microscope, nanoprobe accurately located and visualized the distribution of AßO in living cells. Moreover, in vivo imaging results showed that our nanoprobe could be used to effectively distinguish the AD mice from the wild-type mice. This nanoprobe with the advantages of great sensitivity, high specificity, and convenience, provides an outstanding prospect for AD's early diagnosis development.

Estrogen and calcium handling proteins: new discoveries and mechanisms in cardiovascular diseases.

Estrogen deficiency is considered to be an important factor leading to cardiovascular diseases (CVDs). Indeed, the prevalence of CVDs in postmenopausal women exceeds that of premenopausal women and men of the same age. Recent research findings provide evidence that estrogen plays a pivotal role in the regulation of calcium homeostasis and therefore fine-tunes normal cardiomyocyte contraction and relaxation processes. Disruption of calcium homeostasis is closely associated with the pathological mechanism of CVDs. Thus, this paper maps out and summarizes the effects and mechanisms of estrogen on calcium handling proteins in cardiac myocytes, including L-type Ca2+ channel, the sarcoplasmic reticulum Ca2+ release channel named ryanodine receptor, sarco(endo)plasmic reticulum Ca2+-ATPase, and sodium-calcium exchanger. In so doing, we provide theoretical and experimental evidence for the successful design of estrogen-based prevention and treatment therapies for CVDs.

Target-Induced Core-Satellite Nanostructure Assembly Strategy for Dual-Signal-On Fluorescence Imaging and Raman Quantification of Intracellular MicroRNA Guided Photothermal Therapy.

Integrating biological detection and treatment into one system is a smart therapeutic maneuver for efficient cancer treatment. Herein, a target-activated core-satellite nanostructure (CS nanostructure) assembly built on gold nanobipyramids motor (AuNBPs motor)/gold nanoparticle probe (AuNP probe) exhibiting simultaneous dual signal-on imaging, quantification of intracellular microRNA-21 (miR-21), and photothermal therapy (PTT) for cancer is designed. Of note, when the AuNBPs motor/AuNP probe enters into cells, miR-21 triggers the reaction between AuNBPs motor and AuNP probe, resulting in the formation of CS nanostructure assembly. The process of assembling the CS nanostructure is accompanied with strong fluorescent signals from TAMRA and surface-enhanced Raman scattering (SERS) signals from adenine. The fluorescent signal is leveraged to image the intracellular miR-21 level, whereas the SERS signal is utilized for absolute quantification of intracellular miR-21, and the CS nanostructure acts as the photosensitizer for PTT. This strategy can successfully image and quantify miR-21 in a single cell, and also distinguish normal cells from tumor cells. Moreover, under the guidance of fluorescence signal, the assembly kills tumor cells and inhibits tumor growth via PTT. In vitro and in vivo results prove that the proposed strategy possesses enormous potential for application in the diagnosis and treatment of cancer.

Multifunctional Fe3O4@Polydopamine@DNA-Fueled Molecular Machine for Magnetically Targeted Intracellular Zn2+ Imaging and Fluorescence/MRI Guided Photodynamic-Photothermal Therapy.

For the precise treatment of tumors, it is necessary to develop a theranostic nanoplatform that has both diagnostic and therapeutic functions. In this article, we designed a new theranostic probe for fluorescence imaging of Zn2+ and fluorescence/MRI guided magnetically targeted photodynamic-photothermal therapy. The fluorescence imaging of Zn2+ was based on an endogenous ATP-driven DNA nanomachine that could perform repetitive stand displacement reaction. It modifies all units on a single PDA/Fe3O4 nanoparticle containing a hairpin-locked initiated strand activated by a target molecule in cells, a two-stranded fuel DNA triggered by ATP, and a two-stranded DNA track responding to an initiated strand and fuel DNA. After entering the cell, the intracellular target Zn2+ initiates the nanomachine via an autocatalytic cleavage reaction, and the machine programmatically and gradually runs on the assembled DNA track via fuel DNA driving and the intramolecular toehold-mediated stand displacement reaction. The Fe3O4 core first exhibits magnetic targeting, increasing the ability of nanoparticles to enter tumor cells at the tumor site. The Fe3O4 could also be employed as a powerful magnetic resonance imaging (MRI) contrast agent and guided therapy. Using 808 nm laser and 635 nm laser irradiation together at the tumor site, the PDA nanoshell produced an excellent photothermal effect and the TMPyP4 molecules entering the cell generated reactive oxygen species, followed by cell damage. A series of reliable experiments suggested that the Fe3O4@PDA@DNA nanoprobe showed superior fluorescence specificity, MRI, a remarkable photothermal/photodynamic therapy effect, and favorable biocompatibility. This theranostic nanoplatform offered a split-new insight into tumor fluorescence and MRI diagnosis as well as effective tumor therapy.

Estrogen regulation of cardiac cAMP-L-type Ca2+ channel pathway modulates sex differences in basal contraction and responses to ß2AR-mediated stress in left ventricular apical myocytes.

BACKGROUNDS/AIM: Male and female hearts have many structural and functional differences. Here, we investigated the role of estrogen (E2) in the mechanisms of sex differences in contraction through the cAMP-L-type Ca2+channel pathway in adult mice left ventricular (LV) apical myocytes at basal and stress state. METHODS: Isolated LV apical myocytes from male, female (Sham) and ovariectomised mice (OVX) were used to investigate contractility, Ca2+ transients and L-type Ca2+ channel (LTCC) function. The levels of ß2AR, intracellular cAMP, phosphodiesterase (PDE 3 and PDE 4), RyR2, PLB, SLN, and SERCA2a were compared among the experimental groups. RESULTS: We found that (1) intracellular cAMP, ICaL density, contraction and Ca2+ transient amplitudes were larger in Sham and OVX + E2 myocytes compared to male and OVX. (2) The mRNA expression of PDE 3 and 4 were lower in Sham and OVX + E2 groups compared with male and OVX groups. Treatment of myocytes with IBMX (100 µM) increased contraction and Ca2+ transient amplitude in both sexes and canceled differences between them. (3) ß2AR-mediated stress decreased cAMP concentration and peak contraction and Ca2+ transient amplitude only in male and OVX groups but not in Sham or OVX + E2 groups suggesting a cardioprotective role of E2 in female mice. (4) Pretreatment of OVX myocytes with GPR30 antagonist G15 (100 nM) abolished the effects of E2, but ERα and ERß antagonist ICI 182,780 (1 µM) did not. Moreover, activation of GPR30 with G1 (100 nM) replicated the effects of E2 on cAMP, contraction and Ca2+ transient amplitudes suggesting that the acute effects of E2 were mediated by GPR30 via non-genomic signaling. (5) mRNA expression of RyR2 was higher in myocytes from Sham than those of male while PLB and SLN were higher in male than Sham but no sex differences were observed in the mRNA of SERCA2a. CONCLUSION: Collectively, these results demonstrate that E2 modulates the expression of genes related to the cAMP-LTCC pathway and contributes to sex differences in cardiac contraction and responses to stress. We also show that estrogen confers cardioprotection against cardiac stress by non-genomic acute signaling via GPR30.

Estrogen deficiency compromised the ß2AR-Gs/Gi coupling: implications for arrhythmia and cardiac injury.

Estrogen and ß2-adrenergic receptors (ß2AR) play important roles in the processes that protect the heart. Here, we investigated how ovariectomy influenced the ß2AR downstream pathways in the context of catecholaminergic stress. In vivo and in vitro stress models were developed in female Sprague-Dawley (SD) rats by epinephrine (Epi) treatments. The cardiac function was evaluated at in vivo and in vitro levels in terms of contraction, rhythm, and injury. We found that myocardial contractility was not significantly different between Sham and ovariectomized (OVX) group rats in the normal state. However, Epi pretreatment decreased the contractility and increased abnormal rhythms especially in OVX group, which were attributed to lack of estrogen. Inhibition of the ß2AR-Gi-PI3K/p38MAPK pathway with ICI118,551, PTX or LY294002 increased contractility and aggravated Epi-induced injury on cardiomyocytes, decreased p38MAPK phosphorylation, and only increased arrhythmia in Sham group. These results indicated that OVX exacerbated cardiac injury and abnormal rhythms through ß2AR-Gi-PI3K and ß2AR-Gi-p38MAPK pathways, respectively. In normal state, the levels of activated Gi were similar in both groups, but those of cAMP and activated Gs were higher in OVX group. Epi treatment increased activated Gi (especially in Sham group) and activated Gs and cAMP in Sham group but decreased it in OVX group. These results suggested that estrogen increased the Gi activity in normal and stress states and Gs activity in stress state. These results indicated that lack of estrogen impaired the ß2AR-Gs/Gi coupling during stress which compromised cardiac contractility and increased abnormal rhythms.

[Electrophysiological identification of human induced pluripotent stem cell-derived cardiomyocytes].

The present study was aimed to characterize the electrophysiology of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). IMR90-4 cells were induced to differentiate into cardiomyocytes by temporal modulation of regulators of canonical Wnt signaling. The protein expression of cardiac troponin T (cTnT) was detected by immunofluorescence staining and flow cytometry, and the differentiation rate of hiPSC-CMs was calculated. The action potentials (APs) of hiPSC-CMs were recorded by patch clamp and used to classify different types of cardiomyocytes. The electrophysiological characteristics of hiPSC-CMs were further analyzed. The results showed that the cTnT positive rate of hiPSC-CMs was above 95%. hiPSC-CMs were differentiated into 3 types of cardiomyocytes based on the properties of AP: ventricular-, atrial- and nodal-like cells. In comparison with the other two types of cells, the APs of ventricular-like cells exhibited longer duration, higher amplitude and higher dV/dtmax. The nodal-like cells had the lowest dV/dtmax among all the three types. These results indicate that hiPSC can be differentiated into the cardiomyocytes with high purity and the differentiated hiPSC-CMs have similar electrophysiological characteristics to adult cardiomyocytes.

Benefits of Curcumin in the Vasculature: A Therapeutic Candidate for Vascular Remodeling in Arterial Hypertension and Pulmonary Arterial Hypertension?

Growing evidence suggests that hypertension is one of the leading causes of cardiovascular morbidity and mortality since uncontrolled high blood pressure increases the risk of myocardial infarction, aortic dissection, hemorrhagic stroke, and chronic kidney disease. Impaired vascular homeostasis plays a critical role in the development of hypertension-induced vascular remodeling. Abnormal behaviors of vascular cells are not only a pathological hallmark of hypertensive vascular remodeling, but also an important pathological basis for maintaining reduced vascular compliance in hypertension. Targeting vascular remodeling represents a novel therapeutic approach in hypertension and its cardiovascular complications. Phytochemicals are emerging as candidates with therapeutic effects on numerous pathologies, including hypertension. An increasing number of studies have found that curcumin, a polyphenolic compound derived from dietary spice turmeric, holds a broad spectrum of pharmacological actions, such as antiplatelet, anticancer, anti-inflammatory, antioxidant, and antiangiogenic effects. Curcumin has been shown to prevent or treat vascular remodeling in hypertensive rodents by modulating various signaling pathways. In the present review, we attempt to focus on the current findings and molecular mechanisms of curcumin in the treatment of hypertensive vascular remodeling. In particular, adverse and inconsistent effects of curcumin, as well as some favorable pharmacokinetics or pharmacodynamics profiles in arterial hypertension will be discussed. Moreover, the recent progress in the preparation of nano-curcumins and their therapeutic potential in hypertension will be briefly recapped. The future research directions and challenges of curcumin in hypertension-related vascular remodeling are also proposed. It is foreseeable that curcumin is likely to be a therapeutic agent for hypertension and vascular remodeling going forwards.

Estrogen Protects Vasomotor Functions in Rats During Catecholamine Stress.

The incidence of dysfunctional vasomotor diseases has mostly occurred in postmenopausal women but not in premenopausal women. Hence, this study sought to investigate the impact of estrogen deficiency during catecholamine stress on vasomotor function. Also, attempts were made to utilize estrogen replacement therapy to mitigate the adverse effects (pathological remodeling) of stress on the aortic vessels to preserve vasomotor functions. To do this, female Sprague-Dawley (SD) rats were ovariectomized (OVX) along with sham operations (Sham). Day 14 after OVX operation, 17-estradiol (E2) was subcutaneously implanted (OVX+E2). Day 35 after operation, stress was induced by isoproterenol (ISO) subcutaneous injections. Clinically relevant blood pressure indexes (systolic, diastolic, and mean atrial blood pressures) were assessed in the rats. Aortic vascular ring tensions were assessed in vitro to ascertain the impact of E2 on their vasomotor function. Aortic vascular rings (AVRs) from OVX+ISO exhibited a significant increase in contractility in response to phenylephrine than AVRs isolated from Sham+ISO rats. Also, sera levels of nitric oxide (NO) and endothelin-1 (ET-1) and the expression of p-eNOS/eNOS from vascular tissues were ascertained. We demonstrate that, during stress, E2 prevented excessive weight gain and OVX rats had higher blood pressures than those in the Sham group. Further, we showed that E2 decreases ET-1 expressions during stress while upregulating NO expressions via enhancing eNOS activities to facilitate vasomotor functions. Finally, histological assessment revealed the E2 treatments during stress preserved vasomotor functions by preventing excessive intima-media thickening and collagen depositions in the aortic vascular walls.

Proximity hybridization triggered hybridization chain reaction for label-free electrochemical homogeneous aptasensors.

A label-free homogeneous electrochemical aptasensor was developed for detection of thrombin based on proximity hybridization triggered hybridization chain reaction induced G-quadruplex formation. Thrombin promoted the formation of a complex via the proximity hybridization of the aptamer DNA strands, which unfolded the molecular beacon, the stem part of molecular beacon as a primer to initiate the hybridization chain reaction process. Thus, with the electrochemical indicator hemin selectively intercalated into the multiple G-quadruplexes, a significant electrochemical signal drop is observed, which is dependent on the concentration of the target thrombin. Thus, using this"signal-off" mode, label-free homogeneous electrochemical strategy for sensitive thrombin assay with a detection limit of 44 fM is realized. Furthermore, this method also exhibits additional advantages of simplicity and low cost, since both expensive labeling and sophisticated probe immobilization processes are avoided. Its high sensitivity, acceptable accuracy, and satisfactory versatility of analytes led to various applications in bioanalysis.

The cardiovascular aspect of COVID-19.

The coronavirus disease-2019 (COVID-19), an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2), has hit the world very hard by affecting millions of people across countries hence posing a major health threat on a global scale. This novel virus is thought to enter and cause infection in its host through the attachment of its structural protein known as the S-glycoprotein to angiotensin-converting enzyme 2 (ACE2). Given the rapid spread of COVID-19 with its consequences globally, it is mandatory that health caregivers and researchers across all disciplines abreast themselves with the potential effects that this novel virus may have on their fields and the medical society at large. During the infection, the cardiovascular system is affected by unknown pathomechanistic processes, hence accounting for an increased prevalence of cardiovascular diseases (CVDs) among COVID-19 patients. As cardiovascular researchers, we are more concerned about the cardiovascular aspect of SARS-CoV-2/COVID-19. Hence, this concise review addresses these aspects where CVD as a risk factor of COVID-19, the prevalence of CVDs in COVID-19, and the potential cardiovascular disorders which may evolve owing to COVID-19 are discussed. A better understanding of these issues will be pivotal to improve cardiovascular health during this SARS-CoV-2/COVID-19 pandemic and beyond.

Carbon nitride-based nanocaptor: An intelligent nanosystem with metal ions chelating effect for enhanced magnetic targeting phototherapy of Alzheimer's disease.

Metal ions imbalance, a well-established pathologic feature of alzheimer's disease (AD), ultimately results in the deposition of amyloid-ß peptide (Aß) proteins and Aß-induced neurotoxicity. Herein, to overcome these hurdles, an intelligent Aß nanocaptor with the capacity to chelate metal ions and targeted therapy is developed by anchoring carbon nitride (C3N4) nanodots to Fe3O4@mesoporous silica nanospheres, and decorated with benzothiazole aniline (BTA) (designated as B-FeCN). The C3N4 nanodots could effectively capture superfluous Cu2+ to suppress the formation of Cu2+-Aß complex thereby eliminating Aß aggregation. Simultaneously, the nanocaptor enables local low-temperature hyperthermia to promote the dissolution of preformed fiber precipitates, therefore, maximizing the therapeutic benefits. Owing to its favorable photothermal effect, the blood-brain barrier (BBB) permeability of the nanocaptor is noticeably ameliorated upon laser illumination, which conquers the limitations associated with traditional anti-AD drugs, as evidenced by in vivo and in vitro studies. Besides, leveraging on the magnetic properties of Fe3O4 core, the nanocaptor is magnetized to access to the targeted Aß regions under extrinsic magnetic field. BTA conjugation, which specifically binds to the ß2 position of the Aß fibers, executes specific targeting at Aß plaques, and synchronously endows the BTA-modified nanocaptor with fluorescent imaging property for sensitively detecting Aß aggregates. In view of these superiorities, nanocaptors combine metallostasis restoration and Aß targeted therapy can surmount the interference of copper ions, enhance BBB permeability and protect cells against Aß-induced neurotoxicity, which provides new avenues for developing neuroprotective nanosystems for the treatment of alzheimer's disease.

Biomimetic Nanotheranostics Camouflaged with Cancer Cell Membranes Integrating Persistent Oxygen Supply and Homotypic Targeting for Hypoxic Tumor Elimination.

Treatment resistance of the tumors to photodynamic therapy (PDT) owing to O2 deficiency largely compromised the therapeutic efficacy, which could be addressed via modulating oxygen levels by using O2 self-enriched nanosystems. Here, we report on augmenting the O2-evolving strategy based on a biomimetic, catalytic nanovehicle (named as N/P@MCC), constructed by the catalase-immobilized hollow mesoporous nanospheres by enveloping a cancer cell membrane (CCM), which acts as an efficient nanocontainer to accommodate nitrogen-doped graphene quantum dots (N-GQDs) and protoporphyrin IX (PpIX). Inheriting the virtues of biomimetic CCM cloaking, the CCM-derived shell conferred N/P@MCC nanovehicles with highly specific self-recognition and homotypic targeting toward cancerous cells, ensuring tumor-specific accumulation and superior circulation durations. N-GQDs, for the first time, have been evidenced as a new dual-functional nanoagents with PTT and PDT capacities, enabling the generation of 1O2 for PDT and inducing local low-temperature hyperthermia for thermally ablating cancer cells and infrared thermal imaging (IRT). Leveraging the intrinsic catalytic features of catalase, such N/P@MCC nanovehicles effectively scavenged the excessive H2O2 to sustainably evolve oxygen for a synchronous O2 self-supply and hypoxia alleviation, with an additional benefit because the resulting O2 bubbles could function as an echo amplifier, leading to the sufficient echogenic reflectivity for ultrasound imaging. Concurrently, the elevated O2 reacted with N-GQDs and PpIX to elicit a maximally increased 1O2 output for augmented PDT. Significantly, the ultrasound imaging coupled with fluorescence imaging, IRT, performs a tumor-modulated trimodal bioimaging effect. Overall, this offers a paradigm to rationally explore O2 self-supply strategies focused on versatile nanotheranostics for hypoxic tumor elimination.

A multifunctional nano-therapeutic platform based on octahedral yolk-shell Au NR@CuS: Photothermal/photodynamic and targeted drug delivery tri-combined therapy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease that results from synovial hyperplasia. The hyperplasia of synovium directly degrades cartilage by secreting matrix-degrading enzymes and inducing cartilage degradation and even loss of joint function. In this study, a metal/semiconductor composite, octahedral copper sulfide shell, and gold nanorod core (Au NR@CuS) is designed for, photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy (CT) combination therapy for RA to remove hyperplasia of the synovium. Upon laser irradiation, the coupling of the local surface electromagnetic field improves the electromagnetic field of the Au NR core and the absorption of light of the CuS shell, whereby the photothermal effect is enhanced. Due to the Fenton-like reactions and the integration of Au NR and CuS semiconductor photocatalyst inhibits hole recombination and provides a reaction site for photocatalysis, which introduces additional •OH to photodynamics therapy. In addition, the large octahedral void space in Au NR@CuS NPs can be used for loading a high quantity of drugs for chemotherapy, and modified with vasoactive intestinal peptide and hyaluronic acid (HA) formation VIP-HA-Au NR@CuS NPs to target synovial cells in RA. Under combination therapy, VIP-HA-Au NR@CuS NPs were shown to effectively inhibit the synovial cells and the edema degree of the CIA mouse was alleviated apparently. Both in vitro and in vivo studies indicate that the VIP-HA-Au NR@CuS NPs can provide a potential possibility for the treatment of RA.

Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses.

Chronic catecholamine stress (CCS) induces the occurrence of cardiomyopathy-pathological cardiac hypertrophy (PCH), which is characterized by left ventricular systolic dysfunction (LVSD). Recently, mounting evidence has implicated myocardial inflammation in the exacerbation of pathological cardiac remodeling. However, there are currently no well-defined treatment interventions or regimes targeted at both the attenuation of maladaptive myocardial hypertrophy and inflammation during CCS to prevent PCH. G protein-coupled receptor kinase 5 (GRK5) and adenylyl cyclases (ACs)-cAMP mediates both cardiac and inflammatory responses. Also, GRK5 and ACs are implicated in stress-induced LVSD. Herein, we aimed at preventing PCH during CCS via modulating adaptive cardiac and inflammatory responses by inhibiting GRK5 and/or stimulating ACs. Isoproterenol-induced cardiomyopathy (ICM) was modeled using 0.5 mg/100 g/day isoproterenol injections for 40 days. Alterations in cardiac and inflammatory responses were assessed from the myocardia. Similarities in the immunogenicity of cardiac troponin I (cTnI) and lipopolysaccharide under CCS were assessed, and Amlexanox (35 µM/ml) and/or Forskolin (10 µM/ml) were then employed in vitro to modulate adaptive inflammatory responses by inhibiting GRK5 or activating ACs-cAMP, respectively. Subsequently, Amlexanox (2.5 mg/100 g/day) and/or Forskolin (0.5 mg/100 g/day) were then translated into in vivo during CCS to modulate adaptive cardiac and inflammatory responses. The effects of Amlexanox and Forskolin on regulating myocardial systolic functions and inflammatory responses during CCS were ascertained afterward. PCH mice had excessive myocardial hypertrophy, fibrosis, and aggravated LVSD, which were accompanied by massive CD68+ inflammatory cell infiltrations. In vitro, Forskolin-AC/cAMP was effective than Amlexanox-GRK5 at downregulating proinflammatory responses during stress; nonetheless, Amlexanox and Forskolin combination demonstrated the most efficacy in modulating adaptive inflammatory responses. Individually, the translated Amlexanox and Forskolin treatment interventions were ineffective at subduing the pathological remodeling and sustaining cardiac function during CCS. However, their combination was potent at preventing LVSD during CCS by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. The treatment intervention attained its potency mainly via Forskolin-ACs/cAMP-mediated modulation of cardiac and inflammatory responses, coupled with Amlexanox inhibition of GRK5 mediated maladaptive cascades. Taken together, our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for preventing the occurrence of pathological cardiac hypertrophy during chronic stress.

Carbon Nanocage/Fe3O4/DNA-Based Magnetically Targeted Intracellular Imaging of Telomerase via Catalyzed Hairpin Assembly and Photodynamic-Photothermal Combination Therapy of Tumor Cells.

Human telomerase has been identified as a potential tumor biomarker for early cancer diagnosis and cancer progression monitoring. We construct a novel magnetic targeting carbon nanocage/Fe3O4/DNA (CNC/Fe3O4/DNA) nanoprobe for intracellular imaging of telomerase via the signal amplification strategy catalyzed hairpin assembly (CHA) and for photodynamic-photothermal therapy of tumor cells. Telomerase primer DNA, trigger DNA, hairpin DNA1 (H1), and hairpin DNA2 (H2) were adsorbed to the surface of CNC/Fe3O4 nanoparticles (CNC/Fe3O4 NPs), and the fluorescence of (chlorin e6) Ce6 was quenched by CNC/Fe3O4 NPs. After entering the living cell through magnetic targeting, the telomerase primer DNA can be extended in the presence of highly activated telomerase, leading to the issue of trigger DNA, which can initiate the CHA cycling process followed by the amplification of the fluorescence intensity. The in vitro detection results justified that the proposed nanoprobe showed good sensitivity and selectivity for telomerase. Confocal microscopy studies indicated that such a nanoprobe can be used to detect the activity of telomerase in living cells and the fluorescence signal was stronger under the guidance of a magnetic field. We successfully employed this nanoprobe to monitor the dynamic activity of telomerase in various types of tumor cells and normal cells and to damage tumor cells by photodynamic-photothermal combination therapy, which evidenced that this is a promising biological method for early cancer diagnosis and tumor cell therapy.

Proximity hybridization-triggered DNA assembly for label-free surface-enhanced Raman spectroscopic bioanalysis.

We have developed a versatile label-free surface-enhanced Raman spectroscopic platform for detecting various biotargets via proximity hybridization-triggered DNA assembly based on the 736 cm-1 Raman peak of adenine breathing mode. We initially immobilized the first probe to AuNPs and modified the second with poly adenine. Presence of target DNA or protein molecules assembled a sandwich complex that brought the poly adenine close to the AuNPs surface, generating Raman signals, that were proportional to target molecule concentration. These approach exhibits high sensitivity, with a detection limit of 5.4 pM, 47 fM, and 0.51 pg/mL for target DNA, thrombin and CEA, respectively. Owing to a one step proximity dependent complex formation, this technique is simple and can be completed within 40 min, making it a promising candidate for point-of-care testing applications.