Effect of Engineered Cyanobacterial Capsules on a Neurogenic Bladder after Spinal Cord Injury

Xiaowei Z., Guoli Z., Skutella T., Kiening K., Unterberg A., Younsi A.

Abstract Microglia are present throughout the central nervous system and are vital in neural repair, nutrition, phagocytosis, immunological regulation, and maintaining neuronal function. In a healthy spinal cord, microglia are accountable for immune surveillance, however, when a spinal cord injury occurs, the microenvironment drastically changes, leading to glial scars and failed axonal regeneration. In this context, microglia vary their gene and protein expression during activation, and proliferation in reaction to the injury, influencing injury responses both favorably and unfavorably. A dynamic and multifaceted injury response is mediated by microglia, which interact directly with neurons, astrocytes, oligodendrocytes, and neural stem/progenitor cells. Despite a clear understanding of their essential nature and origin, the mechanisms of action and new functions of microglia in spinal cord injury require extensive research. This review summarizes current studies on microglial genesis, physiological function, and pathological state, highlights their crucial roles in spinal cord injury, and proposes microglia as a therapeutic target.

Zheng J., Chen T., Wang K., Peng C., Zhao M., Xie Q., Li B., Lin H., Zhao Z., Ji Z., Tang B.Z., Liao Y.

Santos-Merino M., Sakkos J.K., Singh A.K., Ducat D.C.

Photosynthetic organisms need to balance the rate of photosynthesis with the utilization of photosynthetic products by downstream reactions. While such "source/sink" pathways are well-interrogated in plants, analogous regulatory systems are unknown or poorly studied in single-celled algal and cyanobacterial species. Towards the identification of energy/sugar sensors in cyanobacteria, we utilized an engineered strain of Synechococcus elongatus PCC 7942 that allows experimental manipulation of carbon status. We conducted a screening of all two-component systems (TCS) and serine/threonine kinases (STKs) encoded in S. elongatus PCC 7942 by analyzing phenotypes consistent with sucrose-induced relaxation of sink inhibition. We narrowed the candidate sensor proteins by analyzing changes observed after sucrose feeding. We show that a clustered TCS network containing RpaA, CikB, ManS and NblS are involved in the regulation of genes related to photosynthesis, pigment synthesis, and Rubisco concentration in response to sucrose. Altogether, these results highlight a regulatory TCS group that may play under-appreciated functions in carbon partitioning and energy balancing in cyanobacteria.

Wang W., Gao Y., Xu W., Xu Y., Zhou N., Li Y., Zhang M., Tang B.Z.

AbstractChronic wounds caused by bacterial infections have become a major challenge in the medical field. Hypoxia condition in the chronic wound area extremely induces the generation of reactive oxygen species (ROS) and up‐regulates the expression of hypoxia‐inducible factor (HIF‐1α), both of which can enhance the production of pro‐inflammatory M1 subtype macrophages while reducing the anti‐inflammatory M2 subtype macrophages. Besides, the bacteria‐formed biofilms in the chronic wound area also hinder the penetration of therapeutic agents. Encouraged by the natural motors automatically executing tasks, we hypothesize that supplying sufficient oxygen (O2) would simultaneously drive therapeutic agent movement, rescue the hypoxic microenvironment, and disrupt the vicious cycle of inflammation. Here, we develop small organic molecule‐based nanoparticles (2TT-mC6B@Cu5.4O NPs) that possess high photothermal conversion efficiency and enzymatic activities, including superoxide dismutase‐, catalase‐, and glutathione peroxidase‐like activity. 2TT-mC6B@Cu5.4O NPs exhibit superior ROS scavenging and O2 production abilities in synergistically relieving inflammatory microenvironment and deep penetration of 2TT-mC6B@Cu5.4O NPs in the chronic wound tissues. By combining the photothermal property, 2TT-mC6B@Cu5.4O NPs can effectively eliminate bacteria in biofilms to promote wound healing. Furthermore, transcriptome analysis and in vivo experiments further demonstrate that 2TT-mC6B@Cu5.4O NPs effectively inhibit biological activities inside bacteria and alleviate hypoxia in deep tissue infections.This article is protected by copyright. All rights reserved

Pope L.E., Dixon S.J.

Ferroptosis is an iron-dependent lethal mechanism that can be activated in disease and is a proposed target for cancer therapy. Ferroptosis is defined by the overwhelming accumulation of membrane lipid peroxides. Ferroptotic lipid peroxidation is initiated on internal membranes and then appears at the plasma membrane, triggering lethal ion imbalances and membrane permeabilization. Sensitivity to ferroptosis is governed by the levels of peroxidizable polyunsaturated lipids and associated lipid metabolic enzymes. A different network of enzymes and endogenous metabolites restrains lipid peroxidation by interfering with the initiation or propagation of this process. This emerging understanding is informing new approaches to treat disease by modulating lipid metabolism to enhance or inhibit ferroptosis.

Sangari S., Chen B., Grover F., Salsabili H., Sheth M., Gohil K., Hobbs S., Olson A., Eisner‐Janowicz I., Anschel A., Kim K., Chen D., Kessler A., Oudega M., Kwon B.K., et. al.

ObjectiveA motor complete spinal cord injury (SCI) results in the loss of voluntary motor control below the point of injury. Some of these patients can regain partial motor function through inpatient rehabilitation; however, there is currently no biomarker to easily identify which patients have this potential. Evidence indicates that spasticity could be that marker. Patients with motor complete SCI who exhibit spasticity show preservation of descending motor pathways, the pathways necessary for motor signals to be carried from the brain to the target muscle. We hypothesized that the presence of spasticity predicts motor recovery after subacute motor complete SCI.MethodsSpasticity (Modified Ashworth Scale and pendulum test) and descending connectivity (motor evoked potentials) were tested in the rectus femoris muscle in patients with subacute motor complete (n=36) and motor incomplete (n=30) SCI. Motor recovery was assessed by using the International Standards for Neurological Classification of Spinal Cord Injury and the American Spinal Injury Association Impairment Scale (AIS). All measurements were taken at admission and discharge from inpatient rehabilitation.ResultsWe found that motor complete SCI patients with spasticity improved in motor scores and showed AIS conversion to either motor or sensory incomplete. Conversely, patients without spasticity showed no changes in motor scores and AIS conversion. In incomplete SCI patients, motor scores improved and AIS conversion occurred regardless of spasticity.InterpretationThese findings indicate that spasticity represents an easy‐to‐use physiological biomarker to predict motor recovery after severe SCI. This knowledge can improve inpatient rehabilitation effectiveness for complete SCI patients.This article is protected by copyright. All rights reserved.

Marquez-Ortiz R.A., Tesic V., Hernandez D.R., Akhter B., Aich N., Boudreaux P.M., Clemons G.A., Wu C.Y., Lin H.W., Rodgers K.M.

Ischemic damage to the brain and loss of neurons contribute to functional disabilities in many stroke survivors. Recovery of neuroplasticity is critical to restoration of function and improved quality of life. Stroke and neurological deficits occur in both adults and children, and yet it is well documented that the developing brain has remarkable plasticity which promotes increased post-ischemic functional recovery compared with adults. However, the mechanisms underlying post-stroke recovery in the young brain have not been fully explored. We observed opposing responses to experimental cerebral ischemia in juvenile and adult mice, with substantial neural regeneration and enhanced neuroplasticity detected in the juvenile brain that was not found in adults. We demonstrate strikingly different stroke-induced neuroimmune responses that are deleterious in adults and protective in juveniles, supporting neural regeneration and plasticity. Understanding age-related differences in neuronal repair and regeneration, restoration of neural network function, and neuroimmune signaling in the stroke-injured brain may offer new insights for the development of novel therapeutic strategies for stroke rehabilitation.

Zhou L., Lan K., Huang X., Huang Y., Jin Y., Lu S., Guo Y., Su L., Peng Y., Deng Z., Yang J., Qian S., Lou W., Chu X., Guo H., et. al.

AbstractAccording to International Diabetes Federation Diabetes Atlas statistics, diabetic retinopathy (DR) is the leading cause of vision loss in blinding diseases. The underlying cause of retinal vasculopathy progression in diabetic patients is hyperglycemia and hypoxia features in microvascular region. Hence, cyanobacteria are used as carriers to load both gold nanoparticles (Au NPs) with glucose oxidase‐like activity and iridium nanoparticles (Ir NPs) with catalase‐like activity, respectively (Cyano@Au@Ir). The Au NPs nanozyme first degrades glucose into hydrogen peroxide, which is further decomposed into H2O and O2 by the Ir NPs to complete the cascade hypoglycemic reaction. Based on the unique light transmittance of eyeball and the accumulation of light in the retinal area, the sustainable O2 production by Cyano greatly alleviates the hypoxia of microenvironment, leading to the decrease of angiogenic growth factor and hypoxia‐inducible factor expressions. Simultaneously, the highly expressed peroxide in the DR microenvironment can also be eliminated by Ir NPs for anti‐inflammatory property. Furthermore, it is demonstrated in DR animal model that Cyano@Au@Ir significantly reduces neovascular progression and vascular leakage. This novel treatment mode fundamentally degrades blood glucose, continuously supplies O2, and scavenges free radicals for comprehensive microenvironment regulation, providing inspirations for solving fundus complications of DR.

Hu X., Xu W., Ren Y., Wang Z., He X., Huang R., Ma B., Zhao J., Zhu R., Cheng L.

AbstractSpinal cord injury (SCI) remains a severe condition with an extremely high disability rate. The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system. In the past few decades, researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling, but the results have not been ideal. Recently, new pathological mechanisms of SCI, especially the interactions between immune and neural cell responses, have been revealed by single-cell sequencing and spatial transcriptome analysis. With the development of bioactive materials and stem cells, more attention has been focused on forming intermediate neural networks to promote neural regeneration and neural circuit reconstruction than on promoting axonal regeneration in the corticospinal tract. Furthermore, technologies to control physical parameters such as electricity, magnetism and ultrasound have been constantly innovated and applied in neural cell fate regulation. Among these advanced novel strategies and technologies, stem cell therapy, biomaterial transplantation, and electromagnetic stimulation have entered into the stage of clinical trials, and some of them have already been applied in clinical treatment. In this review, we outline the overall epidemiology and pathophysiology of SCI, expound on the latest research progress related to neural regeneration and circuit reconstruction in detail, and propose future directions for SCI repair and clinical applications.

Ding Z., Liang X., Wang J., Song Z., Guo Q., Schäfer M.K., Huang C.

Bone cancer pain (BCP) impairs patients' quality of life. However, the underlying mechanisms are still unclear. This study investigated the role of spinal interneuron death using a pharmacological inhibitor of ferroptosis in a mouse model of BCP. Lewis lung carcinoma cells were inoculated into the femur, resulting in hyperalgesia and spontaneous pain. Biochemical analysis revealed that spinal levels of reactive oxygen species and malondialdehyde were increased, while those of superoxide dismutase were decreased. Histological analysis showed the loss of spinal GAD65+ interneurons and provided ultrastructural evidence of mitochondrial shrinkage. Pharmacologic inhibition of ferroptosis using ferrostatin-1 (FER-1, 10 mg/kg, intraperitoneal for 20 consecutive days) attenuated ferroptosis-associated iron accumulation and lipid peroxidation and alleviated BCP. Furthermore, FER-1 inhibited the pain-associated activation of ERK1/2 and COX-2 expression and prevented the loss of GABAergic interneurons. Moreover, FER-1 improved analgesia by the COX-2 inhibitor Parecoxib. Taken together, this study shows that pharmacological inhibition of ferroptosis-like cell death of spinal interneurons alleviates BCP in mice. The results suggest that ferroptosis is a potential therapeutic target in patients suffering on BCP and possibly other types of pain.

Ma M., Wang R., Xu M.

Thorium is a byproduct of the rare earth mining industry and can be utilized as fuel for the next-generation nuclear power facilities, which may pose health risks to the population. Although published literature has shown that the toxicity of thorium possibly originates from its interactions with iron/heme-containing proteins, the underlying mechanisms are still largely unclear. Since the liver plays an irreplaceable role in iron and heme metabolism in the body, it is essential to investigate how thorium affects iron and heme homeostasis in hepatocytes. In this study, we first assessed the liver injury in mice exposed to tetravalent thorium (Th(IV)) in the form of thorium nitrite via the oral route. After a two-week oral exposure, thorium accumulation and iron overload were observed in the liver, which are both closely associated with lipid peroxidation and cell death. Transcriptomics analysis revealed that ferroptosis, which has not previously been documented in cells for actinides, is the main mechanism of programmed cell death induced by Th(IV). Further mechanistic studies suggested that Th(IV) could activate the ferroptotic pathway through disrupting iron homeostasis and generating lipid peroxides. More significantly, the disorder of heme metabolism, which is crucial for maintaining intracellular iron and redox homeostasis, was found to contribute to ferroptosis in hepatocytes exposed to Th(IV). Our findings may shed light on a key mechanism of hepatoxicity in response to Th(IV) stress and provide in-depth understanding of the health risk of thorium.

Ruan H., Li Y., Wang C., Jiang Y., Han Y., Li Y., Zheng D., Ye J., Chen G., Yang G., Deng L., Guo M., Zhang X., Tang Y., Cui W.

Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and are difficult to cure, mainly due to the limited neuron regeneration and the glial scar formation. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanocarriers at the injured site (Dual-EV). Results prove that the Dual-EV could target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro . Furthermore, 10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health. Click chemistry extracellular vesicle/peptide/chemokine nanomissiles repair central nervous systems (CNS) injuries by targeting blood vessels, recruiting neural stem cells (NSCs) and inducing their differentiation into neurons.

Gao J., Xia Z., Vohidova D., Joseph J., Luo J.N., Joshi N.

Emerging therapies based on localized delivery of siRNA to lungs have opened up exciting possibilities for treatment of different lung diseases. Localized delivery of siRNA to lungs has shown to result in severalfold higher lung accumulation than systemic route, while minimizing non-specific distribution in other organs. However, to date, only 2 clinical trials have explored localized delivery of siRNA for pulmonary diseases. Here we systematically reviewed recent advances in the field of pulmonary delivery of siRNA using non-viral approaches. We firstly introduce the routes of local administration and analyze the anatomical and physiological barriers towards effective local delivery of siRNA in lungs. We then discuss current progress in pulmonary delivery of siRNA for respiratory tract infections, chronic obstructive pulmonary diseases, acute lung injury, and lung cancer, list outstanding questions, and highlight directions for future research. We expect this review to provide a comprehensive understanding of current advances in pulmonary delivery of siRNA.

Bai X., Liu X., Deng Z., Wei D., Zhang D., Xi H., Wang Q., He M., Yang Y.

Spinal cord injury is a serious traumatic disease. As Ferroptosis has been increasingly studied in recent years, it has been found to be closely related to the pathophysiological processes of spinal cord injury. Iron overload, reactive oxygen species accumulation, lipid peroxidation and glutamate accumulation associated with Ferroptosis are all present in spinal cord injury, and thus Ferroptosis is thought to be involved in the pathological processes secondary to spinal cord injury. This article highlights the relationship between Ferroptosis and spinal cord injury, lists substances that improve spinal cord injury by inhibiting Ferroptosis, and concludes with a discussion of the problems that may be encountered in the clinical translation of Ferroptosis inhibitors as a means of enabling their faster use in clinical treatment.

Liu S., Yang H., Ho M.Y., Xing B.