Exogenous Drugs Research Articles

Specific mode electroacupuncture stimulation opens the blood-brain barrier of the infarcted border zone in rats during MCAO/R recovery via modulation of tight junction protein expression by VEGFA and NF-κB.

The blood-brain barrier (BBB) strictly limits the entry of most exogenous therapeutic drugs into the brain, which brings great challenges to the drug treatment of refractory central diseases, including the treatment of ischemic stroke. Our previous studies have shown that specific mode electroacupuncture stimulation (SMES) can temporarily open the BBB, but with the mechanisms largely unknown. This study explored whether SMES opens the BBB in the infarcted border zone of rats during middle cerebral artery occlusion/reperfusion recovery, and whether this is related to p65 or vascular endothelial growth factor A (VEGFA) modulation of tight junction protein expression through in vivo and in vitro studies. Evans blue, FITC-dextran, mouse-derived nerve growth factor (NGF), and transendothelial electrical resistance values were used to evaluate the permeability of the BBB. Additionally, microvascular endothelial cells and astrocytes were utilized for in vitro study. Immunofluorescence, immunohistochemistry, western blot, and ELISA were employed to assess related protein expression. SMES significantly increased vascular permeability for Evans blue and NGF in the infarcted border zone, and increased the expression of VEGFA by activating p-p65, thereby reducing the expression of tight junction proteins Occludin and ZO-1. Correspondingly, oxygen glucose deprivation/reoxygenation activated p-p65 in and induced VEGFA secretion from astrocytes in vitro. Their conditioned medium reduced the expression of Occludin in bEnd.3 cells and increased the permeability of FITC-dextran. The mechanism of SMES opening infarcted border zone BBB is partly related to its actions on p65, VEGFA, and tight junction proteins.

Identification of competing endogenous RNA networks associated with circRNA and lncRNA in TCDD-induced cleft palate development

2,3,7,8 -tetrachlorodibenzo-p-dioxin (TCDD) is a teratogen that can induce cleft palate formation, a common birth defect. Competing endogenous RNAs (ceRNAs), including circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), indirectly regulate gene expression via sharing microRNAs (miRNAs). Nevertheless, the mechanism by which they act as ceRNAs to regulate palatal development remains to be explored in greater detail. Here, the cleft palate model of C57BL/6 N pregnant mice was constructed by gavage of TCDD (64 ug/kg) on gestation day (GD) 10.5, and the palatal shelves were taken on gestation day (GD) 14.5 for whole-transcriptome sequencing to investigate the underlying mechanisms of the roles of circRNAs and lncRNAs as ceRNAs in cleft palate. Sequencing results revealed that 293 lncRNA, 589 circRNA, 47 miRNA, and 138 messenger RNA (mRNA) were significantly dysregulated, and the cytochrome P450 (CYP) enzymes and the aryl hydrocarbon receptor (AhR) pathway play key roles in the induction of cleft palate upon exposure to TCDD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed the function of TCDD function was mainly related to the metabolic processes of intracellular compounds, including the metabolic processes of cellular aromatic compounds and the metabolism of exogenous drugs by cytochrome P450, etc. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) indicated that the circRNA_1781/miR-30c-1–3p/PKIB and XR_380026.2/miR-1249–3p/DNAH10 ceRNA networks were hypothesized to be a hub involved in palatal development suggesting that the circRNA_1781/miR-30c-1–3p/PKIB and XR_380026.2/miR-1249–3p/DNAH10 ceRNA networks may be critical for palatogenesis, setting the foundation for the investigation of cleft palate.

Unveiling Current Advances in Bioelectronic Medicine: A Comprehensive Review

Background: Bioelectronic medicine is an emerging therapy that makes use of neural signals and the nervous system to help in the treatment of injuries and diseases. The nervous sys-tem consists of disciplined circuits that involve the communication of every major organ of the human body as all the organs of the human body are regulated and controlled by neural circuits. Objective: The objective of this review is to overview the current implementations of bioelectron-ic medicines within the human body. The main target is to heal the body without administering a wide array of exogenous drugs. On understanding these neural circuits at a molecular level, it could be possible to understand, manipulate, and modify the body’s functioning with the help of electrical impulses to modify neural impulses. Methods: The literature related to bioelectronic medicines, and their applications was collected through different websites, academic research portals, and databases, sorted, and presented in this review. Results: Bioelectronic medicine is emerging as a cutting-edge area in healthcare, demonstrating its potential to transform the diagnosis and management of inflammation and related conditions. With established efficacy in a variety of disorders and marketed available treatments, it highlights an enormous shift toward individualized and specialized therapeutic approaches, providing prom-ise for improved outcomes and a higher quality of life for patients worldwide. Conclusion: The study focuses on potential advances in bioelectronic medicine for alleviating in-flammation and inflammatory disorders such as rheumatoid arthritis, diabetes, and spinal cord in-jury. Bioelectronic treatments provide innovative therapeutic options with the potential for con-siderable clinical effects.

A cytochrome P450 monooxygenase (CYP337B5) plays a key role in regulating juvenile hormone biosynthesis and degrading chlorantraniliprole in Spodoptera frugiperda (Lepidoptera: Noctuidae)

Cytochrome P450 monooxygenase (P450) has been shown to be involved in the detoxification metabolism of exogenous drugs or regulates the endogenous synthesis of juvenile hormone III (JH III). However, it is not yet known whether a particular P450 gene involved in the metabolism also affects the synthesis of juvenile hormones. Fall armyworm (FAW, Spodoptera frugiperda) showed a significant increase in juvenile hormone I (JH I) and juvenile hormone II (JH II) under chlorantraniliprole stress, and 11 chlorantraniliprole resistance-related P450 genes were significantly up-regulated. Among them, CYP337B5 was not only overexpressed in the midgut and head of FAW larvae, but also significantly increased in the female and male adult stages with high JH I and JH II titers. Injecting double-stranded RNA significantly reduced the metabolism rate of chlorantraniliprole in FAW and inhibited the production of juvenile hormones. Additionally, the degradation rates of chlorantraniliprole were significantly increased along with the production of various metabolites when incubated in vitro using recombinant CYP337B5; and JH I and JH II were also increased to some extent by 1.2 and 0.5 times. The results show that CYP337B5 is efficiently involved in the metabolism of chlorantraniliprole and specifically involved in the synthesis of JH I and JH II. We show that some P450s may have dual functions of endogenous hormone synthesis and exogenous substance metabolism in insects, which may be the root cause of the cost of drug resistance in insects.

Sensitive and accurate monitoring of urinary albumin and point-of-care testing using a fluorescent probe with anti-interference capacity against exogenous drugs

Fluorescent probes have been reported for monitoring urinary albumin (u-ALB) to enable early diagnosis of kidney diseases and facilitate regular point-of-care testing (POCT) for chronic kidney disease (CKD) patients. However, the albumin can bind hydrophobic drugs through host-guest interactions, which may result in decreased accuracy of probes at regular drug sites and hamper POCT of albuminuria since CKD patients often need to take medications routinely. Herein, we reported a novel fluorescent probe (NC-2) by molecular engineering of a reported AIEgen (NC-1). The introduction of a non-conjugated ring moiety to the molecular rotor granted the NC-2 enhanced sensitivity with a limit of detection in urine of 8.7 mg/L, which is below l the threshold of microalbuminuria (30 mg/L). Moreover, the NC-2 was found to preferentially bind to the FA1 site of ALB, conferring it with excellent anti-interference capacities against exogenous drug molecules and metabolites. Simulation experiments using lab-spiked urine samples containing common drugs taken by CKD patients demonstrated that the probe could provide satisfied detecting accuracy (80–90 %). Furthermore, a paper-based device was constructed and achieved on-site detection of u-ALB in qualitative and semi-quantitative manners. Findings in this work were of great significance to the development of fluorescent probes for accurate detection of ALB in complex urine samples and the further achievement of fluorescence-based POCT for CKD.

Characteristics of expression of proteomic markers in women with “thin” endometrium and their importance for the therapeutic effects of the use of exogenous estradiol: A prospective cohort comparative study

Aim. To analyze the relationship between the expression of proteomic markers [estrogen (ER) and progesterone (PR) receptors, LIF, FOXA1, FOXA2] of endometrial receptivity and indicators of the levels of sex steroids [estradiol (E2) and progesterone (P)] in the peripheral blood during the “implantation window” in women with a history of reproductive dysfunction with “thin” endometrium (TE) and evaluate their significance for the therapeutic effect of using estradiol drugs. Materials and methods. The prospective cohort comparative study was conducted. The main group included 52 patients with TE (7 mm according to ultrasound on preovulatory days), the comparison group consisted of 62 women with normal endometrial thickness (≥7 mm according to ultrasound), women of both groups with reproductive dysfunctions of unknown reason; the control group included 16 healthy women. Aspiration biopsy of the endometrium was performed on the 6–8 days after ovulation (LH +6–8), as well as venipuncture to obtain a sample of peripheral blood to determine the E2, P levels. A combined histological and immunohistochemical study of endometrial samples was performed (ER, PR, LIF, FOXA1, FOXA2). The therapeutic effects of estradiol drugs were assessed in a cohort of women from the main group with TE (n=16 out of 26, those who have not changed their reproductive plans). Results. All women had ovulatory values of progesterone [P≥16.1 nmol/l (LH +6–8)] and normoestrogenemia in the blood (p0.05). According to the results of the correlation analysis, there were no associations between the E2, P levels and the value of M-echo, and no relationships were found between the E2, P levels and the expression of ER, PR, LIF, FOX-proteins. It was revealed that there are significant positive relationships between M-echo and FOXA2 expression in the endometrium (r=0.422; p0.001). Conditional threshold values for the ER, PR expression (LH +6–8) were determined, the excess of which is associated with abnormal expression of LIF, FOX-proteins: for PR in the glands – 105 and 285, for ER in glands – 145, for ER in the stroma – 155. It was found that usual doses of estradiol drugs (1–1.5 mg/day) are capable of increasing endometrial proliferation in women with TE, provided that the expression of ER, PR, LIF, FOX-proteins in their endometrium is similar to healthy women. Increased doses of estradiol drugs (4 mg/day) in women with TE had a significant effect in the form of an increase M-echo value and/or pregnancy in cases where the endometrial expression of LIF, FOX-proteins was comparable with healthy women, even in the presence of hormone-receptor interactions in the endometrium that are different from healthy women. Spontaneous pregnancy in participants of the main group with hypoplastic endometrium in our study occurred in 5 women in whom the expression characteristics of FOXA1 and/or FOXA2 in the endometrium were comparable to healthy women. Conclusion. TE is not the only marker of an imbalance of proteomic molecules, but it determines a greater likelihood of impaired expression of ER, PR, LIF, FOX-proteins in the endometrium. In women with an unclear reason of fertility disorders, it is necessary to conduct an in-depth examination of endometrial samples. Characteristics of endometrial expression ER, PR, LIF, FOX-proteins and the usefulness of hormone-receptor interactions in the TE in women with a history of reproductive disorders can be markers for predicting the effectiveness of the use of exogenous estradiol drugs in women in order to enhance endometrial proliferation with an initially low M-echo.

DNA-DEPENDENT PROTEIN KINASE INHIBITOR INDUCES APOPTOSIS IN COLON CANCER CELLS

Objectives: Among all types of DNA damage, DNA double-strand breaks (DSBs) are considered the most deleterious form induced by either endogenous factors (oxi-dative damages, mismatches, altered chromatin structures, and missing, or modified nucleotides) or exogenous factors, i.e., ultraviolet (UV) radiation, ionizing radiation (IR), and chemicals or drugs. DNA-dependent protein kinase (DNA-PK) plays a crucial role in repairing DSBs through non-homologous end joining (NHEJ). Cells lacking DNA-PK exhibit heightened sensitivity to IR and various DNA-damaging agents. The inhibition of DNA-PK further intensifies cellular susceptibility to IR and DNA-damaging agents. Several small molecules that inhibit DNA-PK have been developed. This study aimed to evaluate the effect of DNA-PK inhibitor (DNA-PKi) NU7441 on the HCT116 cell line. Methods: DNA-PKi NU7441 was used to assess the effect on anti-proliferation and induction of apoptosis on the HCT116 colorectal cancer cell line. Cells were cultured under standard conditions; crystal violet and apoptosis assay were applied to evaluate cell proliferation and apoptosis. Data were analysed using GraphPad Prism 8.4. Results: DNA-PKi effectively inhibited HCT116 colon cancer cell growth via crystal violet assay (p < 0.01). In addition, DNA-PKi also induced programmed cell death in the HCT116 cell line (p < 0.05). Conclusion: DNA-PKi NU7441 suppressed cell proliferation and induced apoptosis in the HCT116 colon cancer cell line.

Structure of mavacamten-free human cardiac thick filaments within the sarcomere by cryoelectron tomography

Heart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological requirements. Changes in calcium concentration regulate the thin filament activation. A separate but linked mechanism regulates the thick filament activation, which frees sufficient myosin heads to bind the thin filament, thereby producing the required force. Thick filaments contain additional nonmyosin proteins, myosin-binding protein C and titin, the latter being the protein that transmits applied tension to the thick filament. How these three proteins interact to control thick filament activation is poorly understood. Here, we show using 3-D image reconstruction of frozen-hydrated human cardiac muscle myofibrils lacking exogenous drugs that the thick filament is structured to provide three levels of myosin activation corresponding to the three crowns of myosin heads in each 429Å repeat. In one crown, the myosin heads are almost completely activated and disordered. In another crown, many myosin heads are inactive, ordered into a structure called the interacting heads motif. At the third crown, the myosin heads are ordered into the interacting heads motif, but the stability of that motif is affected by myosin-binding protein C. We think that this hierarchy of control explains many of the effects of length-dependent activation as well as stretch activation in cardiac muscle control.

Calcium signaling in oocyte quality and functionality and its application.

Calcium (Ca2+) is a second messenger for many signal pathways, and changes in intracellular Ca2+ concentration ([Ca2+]i) are an important signaling mechanism in the oocyte maturation, activation, fertilization, function regulation of granulosa and cumulus cells and offspring development. Ca2+ oscillations occur during oocyte maturation and fertilization, which are maintained by Ca2+ stores and extracellular Ca2+ ([Ca2+]e). Abnormalities in Ca2+ signaling can affect the release of the first polar body, the first meiotic division, and chromosome and spindle morphology. Well-studied aspects of Ca2+ signaling in the oocyte are oocyte activation and fertilization. Oocyte activation, driven by sperm-specific phospholipase PLCζ, is initiated by concerted intracellular patterns of Ca2+ release, termed Ca2+ oscillations. Ca2+ oscillations persist for a long time during fertilization and are coordinately engaged by a variety of Ca2+ channels, pumps, regulatory proteins and their partners. Calcium signaling also regulates granulosa and cumulus cells' function, which further affects oocyte maturation and fertilization outcome. Clinically, there are several physical and chemical options for treating fertilization failure through oocyte activation. Additionally, various exogenous compounds or drugs can cause ovarian dysfunction and female infertility by inducing abnormal Ca2+ signaling or Ca2+ dyshomeostasis in oocytes and granulosa cells. Therefore, the reproductive health risks caused by adverse stresses should arouse our attention. This review will systematically summarize the latest research progress on the aforementioned aspects and propose further research directions on calcium signaling in female reproduction.

The effects of different vasovasostomy techniques on motility of vas deferens (vas motility following vasovasostomy).

Vasovasostomy is used to correct vas deferens (VD) transections encountered during surgery or to reverse sterilization vasectomies. Achieving vasal patency is the primary goal and the success is assessed on various factors including VD patency, flow rates, and pregnancy rates. While preserving vas motility is not a major concern in surgical practice, it is worth noting that VD has peristaltic activity which plays crucial role during ejaculation. Any disruption in its motility could potentially lead to negative outcomes in the future. We conducted an experimental study to assess vas motility changes following vasovasostomy. The study was approved by Gazi University, Animals Ethic Committee. Twenty-four rats were allocated to four groups. Left-sided VD was harvested in control group (Gr1). The rest of the animals were subjected to transection of VD. Gr2 and 3 underwent microscopic and macroscopic anastomosis, respectively, while Gr4 underwent vasal approximation. After 12weeks, all left-sided VD were resected, electrical field stimulation (EFS) and exogenous drugs were applied to induce contractions. Statistical analyses were performed and p value < 0.05 was regarded as statistically significant. The first and second phases of EFS-induced contractile responses(CR) increased for Gr3 and decreased for Gr4 at submaximal and maximal frequencies. An increase only at maximal frequency for second phase EFS-induced CR was encountered for Gr2. α-β-methylene-ATP-induced CR decreased for Gr3 and 4. Noradrenaline-induced CR increased for Gr2, and 3 and decreased for Gr4. The results suggest that vasovasostomy performed using a surgical technique that minimizes disruption or damage to VD may have a favorable impact on motility.

Placing steroid hormones within the human ABCC3 transporter reveals a compatible amphiphilic substrate-binding pocket.

The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple physiological processes and is involved in diverse human diseases such as intrahepatic cholestasis of pregnancy, which is caused by the intracellular accumulation of bile acids and estrogens. Here, we report three cryogenic electron microscopy structures of ABCC3: in the apo-form and in complexed forms bound to either the conjugated sex hormones β-estradiol 17-(β-D-glucuronide) and dehydroepiandrosterone sulfate. For both hormones, the steroid nuclei that superimpose against each other occupy the hydrophobic center of the transport cavity, whereas the two conjugation groups are separated and fixed by the hydrophilic patches in two transmembrane domains. Structural analysis combined with site-directed mutagenesis and ATPase activity assays revealed that ABCC3 possesses an amphiphilic substrate-binding pocket able to hold either conjugated hormone in an asymmetric pattern. These data build on consensus features of the substrate-binding pocket of MRPs and provide a structural platform for the rational design of inhibitors.

P-614 Endometrial preparation: effect of estrogen levels before the embryo transfer on the live birth rate from 14825 freezing-all cycles

Abstract Study question Is there a difference in live birth rate during discrepant estrogen levels before the embryo transfer following either hormone replacement therapy (HRT) or natural cycle(NC)? Summary answer The higher estrogen level on the day before embryo transfer may reduce the live birth rate in either HRT or NC. What is known already The endometrial preparation of frozen embryo transfer cycle is to synchronize of endometrium and embryo under the condition of exogenous estrogen and progesterone drugs in HRT or follicle monitoring in NC. Estrogen is crucial and different estrogen levels could imply variations on endometrial preparation. Information on the effect of discrepant estrogen levels before the embryo transfer on reproductive outcomes of women undergoing freezing-all cycles is scarce. Study design, size, duration Retrospective cohort study including 14825 first frozen embryo transfers following IVF/ICSI undergoing freezing-all cycles from January 2016 to December 2020. A total of 12305 (83.0%) patients received NC while 2520 (17.0%) received HRT. Participants/materials, setting, methods Effect of estrogen levels on live birth rates, stratifified by deciles and ROC to determine the cutoff values for estrogen level on the day before embryo transfer.Multivariable logistic regression analysis was performed to adjust for confounders. Main results and the role of chance The live birth rate was 44.7% and 52.4% in HRT and NC respectively. The live birth rate of HRT began to decline when the estrogen level was P60 in the deciles which the cut-off values of ROC was closed with the estrogen level was 891.6 pg/ml. The lower level of estrogen on the day before embryo transfer in HRT corresponds to a higher live birth rate（51.4% vs 32.9%）.The cut-off values of ROC in NC was statistically different with the estrogen level was 194.4 pg/ml. The lower level of estrogen on the day before embryo transfer in NC corresponds to a higher live rate（53.0% vs 48.6%）.After adjusting the possible confounding factors by multivariate logistic regression, it was found that the estrogen level on the day before embryo transfer in HRT and NC was the independent influencing factor of live birth rate with the OR of 0.57 (0.47,0.68) and 0.82 (0.74,0.90), respectively. Limitations, reasons for caution The greatest limitation of this study is its retrospective study. On the other hand, this study was performed using non-PGT cycle, although this is unlikely to affect the results,we cannot exclude the possibility that euploid embryo responds differently to endometrial state in comparison to aneuploid embryo. Wider implications of the findings In freezing-all cycles, the higher estrogen level on the day before embryo transfer may reduce the live birth rate in either HRT or NC. Clinicians should pay attention to the control of estrogen level in luteal phase. Trial registration number Nona

Advances in extracellular vesicle-based combination therapies for spinal cord injury.

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits. The currently available treatments involve surgical, medical, and rehabilitative strategies. However, none of these techniques can markedly reverse neurological deficits. Recently, extracellular vesicles from various cell sources have been applied to different models of spinal cord injury, thereby generating new cell-free therapies for the treatment of spinal cord injury. However, the use of extracellular vesicles alone is still associated with some notable shortcomings, such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons. Therefore, this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury, including the combination of extracellular vesicles with nanoparticles, exogenous drugs and/or biological scaffold materials, which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles. We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Spatiotemporally resolved metabolomics and isotope tracing reveal CNS drug targets.

Deconvolution of potential drug targets of the central nervous system (CNS) is particularly challenging because of the complicated structure and function of the brain. Here, a spatiotemporally resolved metabolomics and isotope tracing strategy was proposed and demonstrated to be powerful for deconvoluting and localizing potential targets of CNS drugs by using ambient mass spectrometry imaging. This strategy can map various substances including exogenous drugs, isotopically labeled metabolites, and various types of endogenous metabolites in the brain tissue sections to illustrate their microregional distribution pattern in the brain and locate drug action-related metabolic nodes and pathways. The strategy revealed that the sedative-hypnotic drug candidate YZG-331 was prominently distributed in the pineal gland and entered the thalamus and hypothalamus in relatively small amounts, and can increase glutamate decarboxylase activity to elevate γ-aminobutyric acid (GABA) levels in the hypothalamus, agonize organic cation transporter 3 to release extracellular histamine into peripheral circulation. These findings emphasize the promising capability of spatiotemporally resolved metabolomics and isotope tracing to help elucidate the multiple targets and the mechanisms of action of CNS drugs.

Propofol-Induced Developmental Neurotoxicity: From Mechanisms to Therapeutic Strategies.

Propofol is the most commonly used intravenous general anesthetic in clinical anesthesia, and it is also widely used in general anesthesia for pregnant women and infants. Some clinical and preclinical studies have found that propofol causes damage to the immature nervous system, which may lead to neurodevelopmental disorders and cognitive dysfunction in infants and children. However, its potential molecular mechanism has not been fully elucidated. Recent in vivo and in vitro studies have found that some exogenous drugs and interventions can effectively alleviate propofol-induced neurotoxicity. In this review, we focus on the relevant preclinical studies and summarize the latest findings on the potential mechanisms and therapeutic strategies of propofol-induced developmental neurotoxicity.

Single-cell thermometry with a nanothermocouple probe.

Herein, a nanopipette-based thermocouple probe that possesses high temperature resolution, rapid response, good reversibility and stability was constructed and successfully applied for single-cell temperature sensing. Different intracellular temperatures were observed in diverse types of cells, which reveals differences in their metabolism levels. Temperature responses of cancer and normal cells against various exogenous drugs were also demonstrated. The spatially resolved temperature sensing of three-dimensional cell culture models unveils the existence of their inner temperature gradients. This work would facilitate drug screening and disease diagnosis.

Evaluation of exogenous therapeutic protein activity under confinement and crowding effects.

Dysfunction of intracellular proteins is frequently associated with various diseases, such as cancer. The exogenous proteins in cells are usually assembled with specific configurations due to physiological confinement/crowding to exhibit novel features in the protein structure, folding or conformational stability, distinguished with their behaviors in buffer solutions. Here, we synthesized exogenous proteins under confined/crowded conditions, to explore protein activity within cells. The findings suggested that the confinement and crowding effects on protein activity are heterogeneous; they showed an inhibitory effect on HRP by decreasing Km from ∼9.5- and ∼21.7-fold and Vmax from ∼6.8- and ∼20.2-fold lower than that of dilute solutions. Interestingly, the effects on Cyt C seem to be more complicated, and crowding exerts a positive effect by increasing Km ∼ 3.6-fold and Vmax ∼ 1.5-fold higher than that of dilute solutions; however, confinement exhibits a negative effect by decreasing Km ∼2.0 and Vmax ∼8.3 times. Additionally, in contrast to traditional nanoparticle-based confinement models, we synthesized a biodegradable nanoparticle to mimic the confined space, and the biggest advantage of this novel model is that the particles can be degraded and thus it can provide more intuitive observations of the properties of the target proteins under confinement and after release. Furthermore, we also evaluated protein activity in different cellular environments, indicating that the exogenous protein activity was closely related to the crowdedness of cellular environments, and the inhibition of protein activity in MDA-MB-231 cancer cells was more obvious than in HEK293 normal cells. Finally, SAXS analysis revealed the correlation between the protein conformation and the different environments. Our work will provide a unique method for precisely assessing whether the target cellular environments are native matrix in which specific exogenous protein drugs are delivered to function or whether they display a therapeutic role, which is of great significance for screening and development of new drugs.

Ulcerative colitis alleviation of colon-specific delivered rhamnolipid/fullerene nanocomposites via dual modulation in oxidative stress and intestinal microbiome.

As a typical inflammatory bowel disease (IBD), ulcerative colitis (UC) has become prevalent worldwide in recent years. Though several materials have been proved to be effective in reducing intestinal oxidative stress to alleviate UC symptoms, dependence on high doses of exogenous drugs amplifies their safety risk for patients. To address this challenge, an oral therapy based on colon-targeting delivery of low-dose rhamnolipid (RL)/fullerene (C60) nanocomposites has been reported. With high biocompatibility being verified, RL/C60 largely mitigated the inflammation of mice with colitis shortly after its oral administration. Not only this, but also the intestinal microbiome of diseased mice was remarkably restored to the near-healthy level by our composites. Specifically, RL/C60 significantly promoted the colonization of intestinal probiotics and suppressed the biofilm formation of pathogenic bacteria, which is beneficial for reshaping the intestinal barrier. A close relationship of cytokines and oxidoreductases levels with gut flora further revealed that a change in RL/C60-induced intestinal microecology effectively improved the organismal immune system, which can be considered important for long-time recovery from UC.

Applications and prospects of different functional hydrogels in meniscus repair.

The meniscus is a kind of fibrous cartilage structure that serves as a cushion in the knee joint to alleviate the mechanical load. It is commonly injured, but it cannot heal spontaneously. Traditional meniscectomy is not currently recommended as this treatment tends to cause osteoarthritis. Due to their good biocompatibility and versatile regulation, hydrogels are emerging biomaterials in tissue engineering. Hydrogels are excellent candidates in meniscus rehabilitation and regeneration because they are fine-tunable, easily modified, and capable of delivering exogenous drugs, cells, proteins, and cytokines. Various hydrogels have been reported to work well in meniscus-damaged animals, but few hydrogels are effective in the clinic, indicating that hydrogels possess many overlooked problems. In this review, we summarize the applications and problems of hydrogels in extrinsic substance delivery, meniscus rehabilitation, and meniscus regeneration. This study will provide theoretical guidance for new therapeutic strategies for meniscus repair.

Red Blood Cells as Drug Delivery and Imaging Agents: An Update

Red blood cells are essential physiologic cellular components that are produced constantly at abundant levels throughout life, making them an easily obtainable vehicle for both targeted cellular delivery of exogenous drugs as well as non-invasive in vivo imaging of the vasculature. As red blood cells are readily acquired in sufficient quantities and minimally immunogenic by nature, red blood cell-based agents may allow delivery of pharmaceuticals into the body under conditions of both reduced toxicity and increased physiologic half-life, when compared to the non-carrier-based drug equivalent. Research efforts in this area have recently seen major advances that are likely to accelerate the translation of red blood cell-based carrier methods into the clinical setting in the near future. This includes the coupling of therapeutic agents to the external surface of red blood cells, as well as more refined methods for internal encapsulation of drugs within red blood cells or cell-based derivatives. Here we review some of the more recent advances in the field regarding the loading of various therapeutic agents onto red blood cells as well as the use of red blood cell based imaging agents for in vivo vascularity imaging.