SLC7A11-mediated cystine import protects against NDUFS7 deficiency-induced cell death in HEK293T cells.

Cell models of mitochondrial complex Ⅰ (CⅠ) deficiency display significant elevations in reactive oxygen species (ROS) levels and an increase in cellular apoptosis. However, the underlying mechanisms governing anti-apoptotic processes in CⅠ-deficient cells remain elusive. Here, we introduced a mutation in NDUFS7, a crucial subunit of CI, in HEK293T cells and found that the absence of NDUFS7 resulted in reduced cell proliferation, elevated cell death, and increased susceptibility to oxidative stress. Mechanismly, we revealed that the upregulation of SLC7A11 played a crucial role in mitigating cell death resulting from NDUFS7 deficiency. Specifically, the increased expression of SLC7A11 enhanced cystine import, which subsequently reduced cell death by promoting the biosynthesis of reduced glutathione (GSH). Collectively, our findings suggest that SLC7A11-mediated cystine import, representing a novel pathway independent of NADPH production, plays a vital role in protection against NDUFS7 deficiency-induced cell death. This novel pathway provides potential insights into the understanding of pathogenic mechanisms and the therapeutic management of mitochondrial disorders associated with CⅠ deficiency.

Alleviating Recombinant Tissue Plasminogen Activator-induced Hemorrhagic Transformation in Ischemic Stroke via Targeted Delivery of a Ferroptosis Inhibitor.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.

Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis.

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.

Double-balloon enteroscopy for the detection of GIST in a patient with neurofibromatosis type 1.

NF1 is an autosomal dominant hereditary disease, with a prevalence of at least 1 in 4000-5000 population. The diagnosis criteria of NF1 included typical manifestations such as café-au-lait spots, frecking in the axilla or inguinal region, multiple neurofibromas, Lisch nodeules, and distinctive osseous lesions. Genetic testing shows NF1 mutation. It is essential for tumor surveillance in NF1 patients because their life expectancy is about 54 years due to malignancy. A case of NF-1 patient receive laparoscopic small bowel resection and finally diagnosed as adenocarcinoma and ganglioneuroma. About 25% of NF1 patients had GISTs , most of them were asymptomatic and some may manifest with abdominal pain, bowel obstruction, or gastrointestinal bleeding. CT and MRI are commonly used imaging modalities for GIST in NF1, while they may be negative sometimes. As DBE a more practical and non-invasive method now, we consider it is a valuable method for screening and early detecting small intestine disease for NF1 patients.

Endoplasmic reticulum stress in skin aging induced by UVB.

Aging is a normal and complex biological process. Skin is located in the most superficial layer of the body, and its degree of aging directly reflects the aging level of the body. Endoplasmic reticulum stress refers to the aggregation of unfolded or misfolded proteins in the endoplasmic reticulum and the disruption of the calcium ion balance when cells are stimulated by external stimuli. Mild endoplasmic reticulum stress can cause a series of protective mechanisms, including the unfolded protein response, while sustained high intensity stimulation leads to endoplasmic reticulum stress and eventually apoptosis. Photoaging caused by ultraviolet radiation is an important stimulus in skin aging. Many studies have focused on oxidative stress, but increasing evidence shows that endoplasmic reticulum stress plays an important role in photoaging. This paper reviews the development and mechanism of endoplasmic reticulum stress (ERS) in skin photoaging, and provides research directions for targeting the ERS pathway to slow aging.

Th22 cells and the intestinal mucosal barrier.

T-helper 22 (Th22) cells represent a novel subset of CD4+ T cells that exhibit distinctive characteristics, namely the secretion of IL-22 while abstaining from secreting IL-17 and interferon-γ (IFN-γ). These cells serve as the primary source of IL-22, and both Th22 cells and IL-22 are believed to play a role in maintaining intestinal mucosal homeostasis in inflammatory bowel disease (IBD). However, the precise functions of Th22 cells and IL-22 in this context remain a subject of debate. In this work, we aimed to elucidate their impact on the integrity of the intestinal mucosal barrier by presenting an overview of the molecular structure characteristics and functional effects of Th22 cells and IL-22. Furthermore, we would explore targeted treatment approaches and potential therapeutic strategies focusing on the Th22 and IL-22 pathways.

Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes.

OBJECTIVE: To investigate the therapeutic effect and mechanism of metformin on knee OA in normal diet (ND) mice or high-fat diet (HFD)-induced obese mice. METHODS: Destabilization of the medial meniscus surgery was performed in ND mice or HFD mice, and metformin was administrated in drinking water or not. The changes of OA joint structure, infiltration and polarization of synovial macrophages and circulating and local levels of leptin and adiponectin were evaluated. In vitro, the effects of metformin on chondrocytes and macrophages, and of conditioned mediums derived from mouse abdominal fat on murine chondrogenic cell line ATDC5 and murine macrophage cell line RAW264.7, were detected. RESULTS: Metformin showed protective effects on OA, characterized by reductions on OARSI score [2.00, 95% CI (1.15, 2.86) for ND mice and 3.17, 95% CI (2.37, 3.96) for HFD mice] and synovitis score [1.17, 95% CI (0.27, 2.06) for ND mice and 2.50, 95% CI (1.49, 3.51) for HFD mice] after 10 weeks of treatment, and the effects were more significant in HFD mice than in ND mice. Mechanistically, in addition to decreasing apoptosis and matrix-degrading enzymes expression in chondrocytes as well as infiltration and pro-inflammatory differentiation of synovial macrophages, metformin reduced leptin secretion by adipose tissue in HFD mice. CONCLUSIONS: Metformin protects against knee OA which could be through reducing apoptosis and catabolism of chondrocytes, and suppressing infiltration and pro-inflammatory polarization of synovial macrophages. For obese mice, metformin has a greater protective effect in knee OA additionally through reducing leptin secretion from adipose tissue.

Enhanced osteoarthritis therapy by nanoengineered mesenchymal stem cells using biomimetic CuS nanoparticles loaded with plasmid DNA encoding TGF-ß1.

Mesenchymal stem cells (MSCs) therapy shows the potential benefits to relieve clinical symptoms of osteoarthritis (OA), but it is uncertain if it can repair articular cartilage lesions - the main pathology of OA. Here, we prepared biomimetic cupper sulfide@phosphatidylcholine (CuS@PC) nanoparticles (NPs) loaded with plasmid DNA (pDNA) encoding transforming growth factor-beta 1 (TGF-ß1) to engineer MSCs for enhanced OA therapy via cartilage regeneration. We found that the NPs not only promoted cell proliferation and migration, but also presented a higher pDNA transfection efficiency relative to commercial transfection reagent lipofectamine 3000. The resultant CuS/TGF-ß1@PC NP-engineered MSCs (termed CTP-MSCs) were better than pure MSCs in terms of chondrogenic gene expression, glycosaminoglycan deposition and type II collagen formation, favoring cartilage repair. Further, CTP-MSCs inhibited extracellular matrix degradation in interleukin-1ß-induced chondrocytes. Consequently, intraarticular administration of CTP-MSCs significantly enhanced the repair of damaged cartilage, whereas pure MSCs exhibited very limited effects on cartilage regeneration in destabilization of the medial meniscus (DMM) surgical instability mice. Hence, this work provides a new strategy to overcome the limitation of current stem cell therapy in OA treatment through developing more effective nanoengineered MSCs.

Emerging story of gut dysbiosis in spondyloarthropathy: From gastrointestinal inflammation to spondyloarthritis.

As a set of inflammatory disorders, spondyloarthritis (SpA) exhibits distinct pathophysiological, clinical, radiological, and genetic characteristics. Due to the extra-articular features of this disorder, early recognition is crucial to limiting disability and improving outcomes. Gut dysbiosis has been linked to SpA development as evidence grows. A pathogenic SpA process is likely to occur when a mucosal immune system interacts with abnormal local microbiota, with subsequent joint involvement. It is largely unknown, however, how microbiota alterations predate the onset of SpA within the "gut-joint axis". New microbiome therapies, such as probiotics, are used as an adjuvant therapy in the treatment of SpA, suggesting that the modulation of intestinal microbiota and/or intestinal barrier function may contribute to the prevention of SpA. In this review, we highlight the mechanisms of SpA by which the gut microbiota impacts gut inflammation and triggers the activation of immune responses. Additionally, we analyze the regulatory role of therapeutic SpA medication in the gut microbiota and the potential application of probiotics as adjunctive therapy for SpA.

Carboxymethyl chitosan-assisted MnOx nanoparticles: Synthesis, characterization, detection and cartilage repair in early osteoarthritis.

While the early detection and repair of cartilage lesions are crucial in the treatment of osteoarthritis (OA), they remain challenging because neither clinically used medicines nor magnetic resonance (MR) contrast agents can achieve detection and repair simultaneously. Here, we conjugated carboxymethyl chitosan (CMC) with a cartilage-targeting peptide (WYRGRL, termed WY) and then synthesized CMC-assisted manganese oxide nanoparticles (MnOx NPs). The resultant WY-CMC-MnOx NPs demonstrated an excellent biocompatibility and a good T1 relaxivity of 1.72 mM-1·s-1. Owing to their ultrasmall size and cartilage-targeting ability, the WY-CMC-MnOx NPs considerably increased the MR imaging quality of cartilage lesions compared to non-cartilage-targeting NPs. In contrast, clinically used gadolinium-diethylenetriamine pentaacetic acid (Gd-DPTA) failed to detect the cartilage lesions. Furthermore, WY-CMC-MnOx promoted chondrogenesis in mesenchymal stem cells, thereby enhancing OA therapy through efficient cartilage regeneration after intraarticularly injection in destabilization of medial meniscus (DMM) rat models. Our results indicate that WY-CMC-MnOx NPs are promising for use in the diagnosis and treatment of early OA.

Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells.

Traditional medication is not satisfied in rheumatoid arthritis (RA) therapy due to its long-term side effects and failure in cartilage repair. Nanomodification of mesenchymal stem cells (MSCs) holds promise for lifting such hurdles but delivering therapeutic nanomaterials (NPs) into MSCs remains challenging in this new strategy. Here, we show that CuS@MnO2 NPs functionalized with a short phage-selected MSC-targeting peptide enabled the NPs to be uptaken by MSCs. The resultant NP-modified MSCs, further loaded with metformin, significantly improved stem cell therapy of RA. Specifically, the NP-modified MSCs survived the RA-associated oxidized stress through regulating the stress by the superoxide dismutase (SOD)- and catalase (CAT)-like activity of the NPs. They also exhibited an increased capability of cell migration, anti-inflammation, and chondrogenesis due to the nanomodification, thereby effectively inhibiting synovial inflammation and reducing cartilage erosion to relieve RA symptoms in two rat models 28 days post intravenous injection. Our peptide-promoted NP-modified MSCs may be used to enhance therapeutic effects in treating not only RA but also other degenerative and inflammatory diseases.

Hierarchical functional nanoparticles boost osteoarthritis therapy by utilizing joint-resident mesenchymal stem cells.

Utilization of joint-resident mesenchymal stem cells (MSC) to repair articular cartilage is a promising strategy in osteoarthritis (OA) therapy but remains a considerable research challenge. Here, hierarchical targeting and microenvironment responsive peptide functionalized nanoparticles (NPs) are used to achieve cartilage repair in situ. Ultrasmall copper oxide (CuO) NPs are conjugated with type 2 collagen and MSC dual-targeting peptide (designated WPV) with a matrix metalloproteinase 2 (MMP-2)-sensitive sequence as a spacer to achieve hierarchical targeting. Guided by this peptide, WPV-CuO NPs initially penetrate cartilage and subsequently expose the inner MSC-targeted peptide to attract MSCs through MMP-2 clearance. CuO further promotes chondrogenesis of MSCs. In an anterior cruciate ligament transection rat model, intraarticular injection of WPV-CuO NPs induces significant reduction of cartilage destruction. The therapeutic mechanism involves inhibition of the PI3K/AKT/mTOR pathway, as determined via transcriptome analysis. In conclusion, a novel therapeutic strategy for OA has been successfully developed based on localized MSC recruitment and cartilage repair without transplantation of exogenous cells or growth factors.

Immunotherapy for Tumor Metastasis by Artificial Antigen-Presenting Cells via Targeted Microenvironment Regulation and T-Cell Activation.

Effective expansion of T-cells without ex vivo stimulation and maintenance of their antitumor functions in the complex tumor microenvironment (TME) are still daunting challenges in T-cell-based immunotherapy. Here, we developed biomimetic artificial antigen-presenting cells (aAPCs), ultrathin MnOx nanoparticles (NPs) functionalized with T-cell activators (anti-CD3/CD28 mAbs, CD), and tumor cell membranes (CMs) for enhanced lung metastasis immunotherapy. The aAPCs, termed CD-MnOx@CM, not only efficiently enhanced the expansion and activation of intratumoral CD8+ cytotoxic T-cells and dendritic cells after homing to homotypic metastatic tumors but also regulated the TME to facilitate T-cell survival through catalyzing the decomposition of intratumoral H2O2 into O2. Consequently, the aAPCs significantly inhibited the development of lung metastatic nodules and extended the survival of a B16-F10 melanoma metastasis model, while minimizing adverse events. Our work represents a new biomaterial strategy of inhibiting tumor metastasis through targeted TME regulation and in situ T-cell-based immunotherapy.

Deficiency of Endothelial Nitric Oxide Synthase (eNOS) Exacerbates Brain Damage and Cognitive Deficit in A Mouse Model of Vascular Dementia.

Vascular Dementia (VaD) accounts for nearly 20% of all cases of dementia. eNOS plays an important role in neurovascular remodeling, anti-inflammation, and cognitive functional recovery after stroke. In this study, we investigated whether eNOS regulates brain damage, cognitive function in mouse model of bilateral common carotid artery stenosis (BCAS) induced VaD. Late-adult (6-8 months) C57BL/6J and eNOS knockout (eNOS-/-) mice were subjected to BCAS (n=12/group) or sham group (n=8/group). BCAS was performed by applying microcoils to both common carotid arteries. Cerebral blood flow (CBF) and blood pressure were measured. A battery of cognitive functional tests was performed, and mice were sacrificed 30 days after BCAS. Compared to corresponding sham mice, BCAS in wild-type (WT) and eNOS-/- mice significantly: 1) induces short term, long term memory loss, spatial learning and memory deficits; 2) decreases CBF, increases ischemic cell damage, including apoptosis, white matter (WM) and axonal damage; 3) increases blood brain barrier (BBB) leakage, decreases aquaporin-4 (AQP4) expression and vessel density; 4) increases microglial, astrocyte activation and oxidative stress in the brain; 5) increases inflammatory factor interleukin-1 receptor-associated kinase-1(IRAK-1) and amyloid beta (Aß) expression in brain; 6) increases IL-6 and IRAK4 expression in brain. eNOS-/-sham mice exhibit increased blood pressure, decreased iNOS and nNOS in brain compared to WT-sham mice. Compared to WT-BCAS mice, eNOS-/-BCAS mice exhibit worse vascular and WM/axonal damage, increased BBB leakage and inflammatory response, increased cognitive deficit, decreased iNOS, nNOS in brain. eNOS deficit exacerbates BCAS induced brain damage and cognitive deficit.

CD133+Exosome Treatment Improves Cardiac Function after Stroke in Type 2 Diabetic Mice.

Cardiac complications post-stroke are common, and diabetes exacerbates post-stroke cardiac injury. In this study, we tested whether treatment with exosomes harvested from human umbilical cord blood derived CD133+ cells (CD133+Exo) improves cardiac function in type 2 diabetes mellitus (T2DM) stroke mice. Adult (3-4 m), male, BKS.Cg-m+/+Leprdb/J (db/db, T2DM) and non-DM (db+) mice were randomized to sham or photothrombotic stroke groups. T2DM-stroke mice were treated with phosphate-buffered saline (PBS) or CD133+Exo (20 µg, i.v.) at 3 days after stroke. T2DM sham and T2DM+CD133+Exo treatment groups were included as controls. Echocardiography was performed, and mice were sacrificed at 28 days after stroke. Cardiomyocyte hypertrophy, myocardial capillary density, interstitial fibrosis, and inflammatory factor expression were measured in the heart. MicroRNA-126 expression and its target gene expression were measured in the heart. T2DM mice exhibit significant cardiac deficits such as decreased left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), increased left ventricular diastolic dimension (LVDD), and reduced heart rate compared to non-DM mice. Stroke in non-DM and T2DM mice significantly decreases LVEF compared to non-DM and T2DM-sham, respectively. Cardiac dysfunction is worse in T2DM-stroke mice compared to non-DM-stroke mice. CD133+Exo treatment of T2DM-stroke mice significantly improves cardiac function identified by increased LVEF and decreased LVDD compared to PBS treated T2DM-stroke mice. In addition, CD133+Exo treatment significantly decreases body weight and blood glucose but does not decrease lesion volume in T2DM-stroke mice. CD133+Exo treatment of T2DM mice significantly decreases body weight and blood glucose but does not improve cardiac function. CD133+Exo treatment in T2DM-stroke mice significantly decreases myocardial cross-sectional area, interstitial fibrosis, transforming growth factor beta (TGF-ß), numbers of M1 macrophages, and oxidative stress markers 4-HNE (4-hydroxynonenal) and NADPH oxidase 2 (NOX2) in heart tissue. CD133+Exo treatment increases myocardial capillary density in T2DM-stroke mice as well as upregulates endothelial cell capillary tube formation in vitro. MiR-126 is highly expressed in CD133+Exo compared to exosomes derived from endothelial cells. Compared to PBS treatment, CD133+Exo treatment significantly increases miR-126 expression in the heart and decreases its target gene expression such as Sprouty-related, EVH1 domain-containing protein 1 (Spred-1), vascular cell adhesion protein (VCAM), and monocyte chemoattractant protein 1 (MCP1) in the heart of T2DM-stroke mice. CD133+Exo treatment significantly improves cardiac function in T2DM-stroke mice. The cardio-protective effects of CD133+Exo in T2DM-stroke mice may be attributed at least in part to increasing miR-126 expression and decreasing its target protein expression in the heart, increased myocardial capillary density and decreased cardiac inflammatory factor expression.

SUMO1 Deficiency Exacerbates Neurological and Cardiac Dysfunction after Intracerebral Hemorrhage in Aged Mice.

Small ubiquitin-like modifier 1 (SUMO1) reduces cardiac hypertrophy and induces neuroprotective effects. Previous studies have found that intracerebral hemorrhage (ICH) provokes cardiac deficit in the absence of primary cardiac diseases in mice. In this study, we tested the hypothesis that SUMO1 deficiency leads to worse brain and heart dysfunction after ICH and SUMO1 plays a key role in regulating brain-heart interaction after ICH in aged mice. Aged (18-20 months) female SUMO1 null (SUMO1-/-) mice and wild-type (WT) C57BL/6 J mice were randomly divided into four groups (n = 8/group): (1) WT-sham group, (2) SUMO1-/--sham group, (3) WT-ICH group, and (4) SUMO1-/--ICH group. Cardiac function was measured by echocardiography. Neurological and cognitive functional tests were performed. Mice were sacrificed at 10 days after ICH for histological and immunohistochemically staining. Compared with WT-sham mice, WT-ICH mice exhibited (1) significantly (P < 0.05) decreased SUMO1 expression in heart tissue, (2) evident neurological and cognitive dysfunction as well as brain white matter deficits, (3) significantly increased cardiac dysfunction, and (4) inflammatory factor expression in the heart and brain. Compared with WT-ICH mice, SUMO1-/--ICH mice exhibited significantly increased: (1) brain hemorrhage volume, worse neurological and cognitive deficits, and increased white matter deficits; (2) cardiac dysfunction and cardiac fibrosis; (3) inflammatory response both in heart and brain tissue. Aged SUMO1-deficient female mice subjected to ICH not only exhibit increased neurological and cognitive functional deficit but also significantly increased cardiac dysfunction and inflammatory cell infiltration into the heart and brain. These data suggest that SUMO1 plays an important role in brain-heart interaction.

HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia.

Background and purpose: Vascular dementia (VaD) is the second common cause of dementia after Alzheimer's disease in older people. Yet, there are no FDA approved drugs specifically for VaD. In this study, we have investigated the therapeutic effects of human umbilical cord blood cells (HUCBC) treatment on the cognitive outcome, white matter (WM) integrity, and glymphatic system function in rats subject to a multiple microinfarction (MMI) model of VaD. Methods: Male, retired breeder rats were subjected to the MMI model (800 ± 100 cholesterol crystals/300 µl injected into the internal carotid artery), and 3 days later were treated with phosphate-buffered saline (PBS) or HUCBC (5 × 106, i.v.). Sham rats were included as naïve control. Following a battery of cognitive tests, rats were sacrificed at 28 days after MMI and brains extracted for immunohistochemical evaluation and Western blot analysis. To evaluate the glymphatic function, fluorescent tracers (Texas Red dextran, MW: 3 kD and FITC-dextran, MW: 500 kD) was injected into the cisterna magna over 30 min at 14 days after MMI. Rats (3-4/group/time point) were sacrificed at 30 min, 3 h, and 6 h, and the tracer movement analyzed using laser scanning confocal microscopy. Results: Compared to control MMI rats, HUCBC treated MMI rats exhibit significantly improved short-term memory and long-term memory exhibited by increased discrimination index in novel object recognition task with retention delay of 4 h and improved novel odor recognition task with retention delay of 24 h, respectively. HUCBC treatment also improves spatial learning and memory as measured using the Morris water maze test compared to control MMI rats. HUCBC treatment significantly increases axon and myelin density increases oligodendrocyte and oligodendrocyte progenitor cell number and increases Synaptophysin expression in the brain compared to control MMI rats. HUCBC treatment of MMI in rats significantly improves glymphatic function by reversing MMI induced delay in the penetration of cerebrospinal fluid (CSF) into the brain parenchyma via glymphatic pathways and reversing delayed clearance from the brain. HUCBC treatment significantly increases miR-126 expression in serum, aquaporin-4 (AQP4) expression around cerebral vessels, and decreases transforming growth factor-ß (TGF-ß) protein expression in the brain which may contribute to HUCBC induced improved glymphatic function. Conclusions: HUCBC treatment of an MMI rat model of VaD promotes WM remodeling and improves glymphatic function which together may aid in the improvement of cognitive function and memory. Thus, HUCBC treatment warrants further investigation as a potential therapy for VaD.

Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats.

BACKGROUND AND PURPOSE: Diabetes elevates the risk of stroke, promotes inflammation, and exacerbates vascular and white matter damage post stroke, thereby hindering long term functional recovery. Here, we investigated the neurorestorative effects and the underlying therapeutic mechanisms of treatment of stroke in type 2 diabetic rats (T2DM) using exosomes harvested from bone marrow stromal cells obtained from T2DM rats (T2DM-MSC-Exo). METHODS: T2DM was induced in adult male Wistar rats using a combination of high fat diet and Streptozotocin. Rats were subjected to transient 2 h middle cerebral artery occlusion (MCAo) and 3 days later randomized to one of the following treatment groups: 1) phosphate-buffered-saline (PBS, i.v), 2) T2DM-MSC-Exo, (3 × 1011, i.v), 3) T2DM-MSC-Exo with miR-9 over expression (miR9+/+-T2DM-MSC-Exo, 3 × 1011, i.v) or 4) MSC-Exo derived from normoglycemic rats (Nor-MSC-Exo) (3 × 1011, i.v). T2DM sham control group is included as reference. Rats were sacrificed 28 days after MCAo. RESULTS: T2DM-MSC-Exo treatment does not alter blood glucose, lipid levels, or lesion volume, but significantly improves neurological function and attenuates post-stroke weight loss compared to PBS treated as well as Nor-MSC-Exo treated T2DM-stroke rats. Compared to PBS treatment, T2DM-MSC-Exo treatment of T2DM-stroke rats significantly 1) increases tight junction protein ZO-1 and improves blood brain barrier (BBB) integrity; 2) promotes white matter remodeling indicated by increased axon and myelin density, and increases oligodendrocytes and oligodendrocyte progenitor cell numbers in the ischemic border zone as well as increases primary cortical neuronal axonal outgrowth; 3) decreases activated microglia, M1 macrophages, and inflammatory factors MMP-9 (matrix mettaloproteinase-9) and MCP-1 (monocyte chemoattractant protein-1) expression in the ischemic brain; and 4) decreases miR-9 expression in serum, and increases miR-9 target ABCA1 (ATP-binding cassette transporter 1) and IGFR1 (Insulin-like growth factor 1 receptor) expression in the brain. MiR9+/+-T2DM-MSC-Exo treatment significantly increases serum miR-9 expression compared to PBS treated and T2DM-MSC-Exo treated T2DM stroke rats. Treatment of T2DM stroke with miR9+/+-T2DM-MSC-Exo fails to improve functional outcome and attenuates T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory effects in T2DM stroke rats. CONCLUSIONS: T2DM-MSC-Exo treatment for stroke in T2DM rats promotes neurorestorative effects and improves functional outcome. Down regulation of miR-9 expression and increasing its target ABCA1 pathway may contribute partially to T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory responses.

Emerging role of microRNAs in ischemic stroke with comorbidities.

Ischemic stroke is one of the major causes of global disability and death. Comorbidities in stroke are not only risk factors for an increased incidence of stroke, but also adversely impact stroke outcome. Stroke patients with co-morbidities have worse deficit, long term disability and high mortality rate and extended hospitalization stay. MicroRNAs (miRNAs) are noncoding RNA molecules, and are emerging as key molecular mediators of ischemic stroke and other diseases. Thus, focusing on the treatment of stroke and its comorbidities with miRNAs appears to be particularly important. In this review article, we provide an overview of the common comorbidities of hypertension, diabetes mellitus (DM) and hyperlipidemia in ischemic stroke. We also discuss specific miRNAs, including miR-126, miR-223, and miR-124 which are important in regulating ischemic stroke and describetheir effects as related to stroke and comorbidities. In addition, we provide an overview of roles of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in stroke with comorbidities.