Association of total cerebral small vessel disease burden with the cavitation of recent small subcortical infarcts.

BACKGROUND: Recent small subcortical infarcts (RSSIs) could evolve into cavitation (lacunes) or non-cavitation (white matter hyperintensities or disappearance) during the chronic period, but the factors involved remain unclear. PURPOSE: To explore the association between total cerebral small vessel disease (CSVD) burden and lesion cavitation. MATERIAL AND METHODS: We retrospectively selected 202 inpatients with an isolated RSSI who underwent baseline and follow-up magnetic resonance imaging (median interval = 16.6 months; interquartile range [IQR]=8.2-30.1). Inpatients were divided into cavitation and non-cavitation groups depending on whether a fluid-filled cavity formed. Data including demographic, clinical, and radiological features were collected and analyzed. To determine total CSVD burden, four imaging markers, including lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces, were rated and summed as a final practical score between 0 and 4. RESULTS: Overall, 137 (67.8%) patients progressed to cavitation and 65 (32.2%) to non-cavitation. Binary multivariable regression analysis showed that the baseline total CSVD burden (P = 0.005) and infarct diameter (P = 0.002) were independent risk factors for cavitation. A severe total burden (scores of 3-4) at baseline was independently related to cavitation (P = 0.001). Moreover, the total CSVD burden score varied from 2 (IQR=1-3) at baseline to 3 (IQR=2-4) at follow-up. The extent of the increase in total burden was correlated with cavitation (r = 0.201; P = 0.004). CONCLUSION: Total CSVD burden, both the baseline value and extent of increase, was positively associated with cavitation. RSSIs with severe total CSVD burden at baseline have a greater potential to become cavitated.

Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair.

The mechanisms underlying fibrogenic responses after injury are not well understood. Epithelial cell cycle arrest in G2/M after injury is a key checkpoint for determining wound-healing leading to either normal cell proliferation or fibrosis. Here, we identify a kidney- and liver-enriched circular RNA, circBNC2, which is abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insult. Loss of circBNC2 is at least partially mediated by upregulation of DHX9. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrate that circBNC2 acts as a negative regulator of cell G2/M arrest by encoding a protein that promotes formation of CDK1/cyclin B1 complexes. Restoring circBNC2 in experimentally-induced male mouse models of fibrotic kidney and liver, decreases G2/M arrested cell numbers with secretion of fibrotic factors, thereby mitigating extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increased G2/M arrest of epithelial cells are recapitulated in human ischemic reperfusion injury (IRI)-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that restoring circBNC2 might represent a potential strategy for therapeutic intervention in epithelial organ fibrosis.

A Randomized Controlled Trial of Repetitive Peripheral Magnetic Stimulation applied in Early Subacute Stroke: Effects on Severe Upper-limb Impairment.

OBJECTIVES: Repetitive peripheral magnetic stimulation (rPMS) is a non-invasive method that activates peripheral nerves and enhances muscle strength. This study aimed to investigate the effect of rPMS applied in early subacute stroke on severe upper extremity impairment. DESIGN: Randomized controlled trial. SETTING: Rehabilitation department of a university hospital. SUBJECTS: People aged 30-80 years with no practical arm function within four weeks of a first stroke. INTERVENTIONS: Participants were randomly assigned to either the rPMS group (n = 24, 20Hz and 2400 pulses of rPMS to triceps brachii and extensor digitorum muscles daily for two weeks in addition to conventional physiotherapy) or the control group (n = 20, conventional physiotherapy). MAIN MEASURES: The primary outcome was the upper extremity motor section of Fugl-Meyer Assessment after treatment. Secondary outcomes included Barthel Index and root mean square of surface electromyography for muscle strength and stretch-induced spasticity of critical muscles of the upper extremity. Data presented: mean (SD) or median (IQR). RESULTS: The rPMS group showed more significant improvements in the Fugl-Meyer Assessment (12.5 (2.5) vs. 7.0 (1.4), P < 0.001), Barthel Index (15 (5) vs. 10 (3.7), P < 0.001), and strength-root mean square (biceps brachii: 20.5 (4.8) vs. 6.2 (2.7), p < 0.001; triceps brachii: 14.9 (5.8) vs. 4.3 (1.2), p < 0.001; flexor digitorum: 5.1 (0.8) vs. 4.0 (1.1), p < 0.001) compared with the control group. CONCLUSION: In patients with no functional arm movement, rPMS of upper limb extensors improves arm function and muscle strength for grip and elbow flexion and extension.

Effects of high-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex on motor recovery in severe hemiplegic stroke: A randomized clinical trial.

BACKGROUND: The contralesional hemisphere compensation may play a critical role in the recovery of stroke when there is extensive damage to one hemisphere. There is little research on the treatment of hemiplegia by high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the contralesional cortex. OBJECTIVE: We conducted a 2-week randomized, sham-controlled, single-blind trial to determine whether high-frequency rTMS (HF-rTMS) over the contralesional motor cortex can improve motor function in severe stroke patients. METHODS: Forty-five patients with ischemic or hemorrhagic stroke in the middle cerebral artery territory were randomly assigned to treatment with 10 Hz rTMS (HF group), 1 Hz rTMS (LF group) or sham rTMS (sham group) applied over the contralesional motor cortex (M1) before physiotherapy daily for two weeks. The primary outcome was the change in the Fugl-Meyer Motor Assessment (FMA) Scale score from baseline to 2 weeks. The secondary endpoints included root mean square of surface electromyography (RMS-SEMG), Barthel Index (BI), and contralesional hemisphere cortical excitability. RESULTS: The HF group showed a more significant improvement in FMA score (p < 0.05), BI (p < 0.005), contralesional hemisphere cortical excitability and conductivity (p < 0.05), and RMS-SEMG of the key muscles (p < 0.05) compared with the LF group and sham group. There were no significant differences between the LF group and sham group. There was a positive correlation between cortical conductivity of the uninjured hemisphere and recovery of motor impairment (p = 0.039). CONCLUSIONS: HF-rTMS over the contralesional cortex was superior to low-frequency rTMS and sham stimulation in promoting motor recovery in patients with severe hemiplegic stroke by acting on contralesional cortex plasticity. TRIAL REGISTRATION: Clinical trial registered with the Chinese Clinical Trial Registry at http://www.chictr.org.cn/showproj.aspx?proj=23264 (ChiCTR-IPR-17013580).

Efficacy of coupling intermittent theta-burst stimulation and 1 Hz repetitive transcranial magnetic stimulation to enhance upper limb motor recovery in subacute stroke patients: A randomized controlled trial.

BACKGROUND: Both 1 Hz repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS) are reported to benefit upper limb motor function rehabilitation in patients with stroke. However, the efficacy of combining 1 Hz rTMS and iTBS has not been adequately explored. OBJECTIVE: We aimed to compare the effects of 1 Hz rTMS and the combination of 1 Hz rTMS and iTBS on the upper limb motor function in the subacute phase post-stroke. METHODS: Twenty-eight participants were randomly assigned to three groups: Group A (1 Hz rTMS over the contralesional primary motor cortex (M1) and iTBS over the ipsilesional M1), Group B (contralesional 1 Hz rTMS and ipsilesional sham iTBS), and Group C (contralesional sham 1 Hz rTMS and ipsilesional sham iTBS). The participants received the same conventional rehabilitation accompanied by sessions of transcranial magnetic stimulation for two weeks (5 days one week). Motor-evoked potential (MEP), upper extremity Fugl-Meyer Assessment (UE-FMA), and Barthel Index (BI) were performed before and after the sessions. RESULTS: Group A showed greater UE-FMA, BI, and MEP amplitude improvement and more significant decrement in MEP latency compared to Group B and Group C in testable patients. Correlation analyses in Group A revealed a close relation between ipsilesional MEP amplitude increment and UE-FMA gain. CONCLUSIONS: The combining of 1 Hz rTMS and iTBS protocol in the present study is tolerable and more beneficial for motor improvement than the single use of 1 Hz rTMS in patients with subacute stroke.

A photothermal-triggered nitric oxide nanogenerator combined with siRNA for precise therapy of osteoarthritis by suppressing macrophage inflammation.

Although nitric oxide (NO) can be used to treat osteoarthritis (OA) by inhibiting inflammation, a method for the accurately controlled release of NO in inflammatory cells is still elusive. Herein, photothermal-triggered NO nanogenerators NO-Hb@siRNA@PLGA-PEG (NHsPP) were constructed by assembling photothermal-agents and NO molecules within nanoparticles. In the NHsPP nanoparticles the hemoglobin (Hb) nanoparticles can act as a NO carrier which can absorb near-infrared light at 650 nm (0.5 W cm-2) and convert it into heat to trigger the release of NO. Moreover, after loading Notch1-siRNA, precise treatment can be achieved. Furthermore, using the synergistic effect of photothermal therapy, the NHsPP nanoparticles achieved simultaneous treatment with NO, siRNA and PTT. Through this combination therapy, the therapeutic effect of the NHsPP nanoparticles was significantly enhanced compared to the treatment groups using only NO, siRNA or PTT. This combination therapy inhibits the inflammatory response effectively by reducing the level of pro-inflammatory cytokines and the macrophage response. Subsequently, guided by dual-modal imaging, the NHsPP nanoparticles can not only accumulate effectively in OA mice, but can also reduce the inflammatory response and efficiently prevent cartilage erosion, without causing toxic side effects in the major organs. Therefore, this novel photothermal nanoparticle-based NO-releasing system is expected to be a potential alternative for clinical inflammatory disease therapy and may provide image guidance when combined with other nanotherapy systems.

Drug Delivery System Based on Near-Infrared Light-Responsive Molybdenum Disulfide Nanosheets Controls the High-Efficiency Release of Dexamethasone To Inhibit Inflammation and Treat Osteoarthritis.

Intra-articular injection has unique advantages in the treatment of osteoarthritis (OA), although it risks rapid clearance of the therapeutic drugs in the joint cavity. Combining therapeutic agents with functionalized nanocarriers may provide an effective solution. Controlling the therapeutic concentration of the drug in the joint cavity through the drug-loading nanosystem can synergistically treat OA. Here, we proposed an intra-articular drug delivery nanosystem MoS2@CS@Dex (MCD), using the chitosan (CS)-modified molybdenum disulfide (MoS2) nanosheets as near-infrared (NIR) photo-responsive carriers, loaded with the anti-inflammatory drug dexamethasone (Dex). MCD responded to NIR light both in vitro and in vivo and triggered Dex release through photothermal conversion. This enabled the remote-controlled Dex release in the joint cavity by adjusting the radiation behavior of the NIR light. MCD prolonged the residence time of Dex in the joint cavity. The intra-articular injection of MCD in combination with NIR radiation ensured a significant increase in the therapeutic effect of Dex at low systemic doses, which attenuated the cartilage erosion in the OA caused by the secretion of inflammatory factors including TNF-α and IL-1ß. The toxicity and side effects on other internal organs during metabolism were reduced in the body. In addition, the photoacoustic imaging capability of MoS2 nanosheets was used to detect the metabolism of MCD in the joint cavity. Our research indicated that MCD has great potential to treat OA.

Functionalized chitosan-modified defect-related luminescent mesoporous silica nanoparticles as new inhibitors for hIAPP aggregation.

Human islet amyloid polypeptide (hIAPP or amylin) forms the amyloid deposits that is an important factor in the induction of type II diabetes. Accordingly, it is essential to efficiently and accurately inhibit the aggregation of hIAPP for the treatment and prevention of the disease. Here, defect mesoporous silica (DLMSN), with blue fluorescence, can perfectly achieve the accurate positioning in cells or organisms. DL@CS@NF cannot only specifically bind to a hIAPP monomer, but also effectively inhibit hIAPP aggregation, reduce cytotoxicity and overcome the instability and inefficiency of NF(N-Me)GA(N-Me)IL (NF). Furthermore, DL@CS@NF nanoparticles can significantly improve the survival rate of islet cells, stabilize the mitochondrial membrane potential, reduce the content of intracellular reactive oxygen species. In summary, DL@CS@NF nanoparticles may have broader implications in inhibiting the aggregation of hIAPP and reducing cytotoxicity.

Correction: Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response.

Correction for 'Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response' by Yanan Liu et al., J. Mater. Chem. B, 2019, 7, 586-597.

Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response.

Due to the anti-apoptotic effect employed by cells to protect themselves, recent research shows that photothermal therapy (PTT) can lead to heat shock response, thus reducing the effect of treatment on cancer cells. Small interfering RNA (siRNA), as an effective carrier of RNA interference, can silence the expression of heat shock protein, HSPs or BAG3 genes by inhibiting the expression of specific genes, and thereby inhibiting heat shock response and making cancer cells more sensitive to PTT. In this study, flower-like gold nanoparticles were used as a core for a layer-by-layer strategy to produce a safe and biodegradable nanoparticle platform for gene silencing and photothermal therapy. The results showed that when the mass ratio of the GNFs and siRNA was 20 : 1, the loading efficiency was above 90%, which can effectively silence the expression of BAG3 siRNA. We demonstrated that the GNFs-siRNA still had a good photothermal effect after siRNA modification. In vitro, the GNFs-siRNA showed good biocompatibility and effectively tumor killing properties after laser irradiation. Furthermore, the GNFs-siRNA with laser treatment significantly decreased the expression of BAG3 and remarkably inhibited tumor growth in vivo. This nanosystem establishes an optimized platform for future gene delivery and photothermal therapy.

Ru nanoparticles coated with γ-Fe2O3 promoting and monitoring the differentiation of human mesenchymal stem cells via MRI tracking.

Human mesenchymal stem cells (MSCs) can be successively passaged and can differentiate into multiple lineages. These attributes are important in tissue engineering, which has a great deal of attention in stem cell therapy. However, the effective labelling and tracking of MSCs in vivo remain major unresolved issues. Based on the use of iron oxides to label stem cells for magnetic resonance imaging (MRI), we synthesized nanoparticle (NPs) containing ruthenium (RuNPs), γ-Fe2O3@Ru (Fe2O3@Ru), and γ-Fe2O3@selenium (Fe2O3@Se) to label MSCs and promote osteogenic differentiation. Fe2O3@Ru and Fe2O3@Se could be used as T2-weighted MRI contrast agents. Fe2O3@Ru more effectively diffused in the cytoplasm and localized in the nuclei of MSCs, compared with Fe2O3@Se. RuNPs, Fe2O3@Ru, and Fe2O3@Se induced MSCs to differentiate into osteoblasts. Fe2O3@Ru, in particular, was a potent osteoinductive agent. Fe2O3@Ru also inhibited adipocytic differentiation. Promotion of the osteogenic differentiation of MSCs may be regulated by a Smad-dependent bone morphogenetic protein signaling pathway with reduced expression of CD44, CD73, and CD105. MSCs treated with Fe2O3@Ru NPs expressing osteoblast surface markers.

Reduction of bacterial adhesion on titanium-doped diamond-like carbon coatings.

A range of titanium doped diamond-like carbon (Ti-DLC) coatings with different Ti contents were prepared on stainless steel substrates using a plasma-enhanced chemical vapour deposition technique. It was found that both the electron donor surface energy and the surface roughness of the Ti-DLC coatings increased with increasing Ti contents in the coatings. Bacterial adhesion to the coatings was evaluated against Escherichia coli WT F1693 and Pseudomonas aeruginosa ATCC 33347. The experimental data showed that bacterial adhesion decreased with the increases of the Ti content, the electron donor surface energy and surface roughness of the coatings, while the bacterial removal percentage increased with the increases of these parameters. The Ti-DLC coatings reduced bacterial attachment by up to 75% and increased bacterial detachment from 15 to 45%, compared with stainless steel control.

Gd3+-Doped MoSe2 nanosheets used as a theranostic agent for bimodal imaging and highly efficient photothermal cancer therapy.

Recently, two dimensional transition metal dichalcogenides (TMDCs) being used as nanomedicine have aroused great interest because of their unique photothermal properties. A simple liquid-phase method was used to prepare gadolinium (Gd3+)-doped molybdenum selenide (MoSe2) nanosheets, and then using poly(ethylene glycol) (PEG) modification on the surface, MoSe2(Gd3+)-PEG nanosheets were obtained which had high stability in physiological solutions and showed no obvious toxicity in vivo. It revealed that Gd3+ used as a paramagnetic material for MoSe2(Gd3+)-PEG provided a strong contrast effect in magnetic resonance imaging, furthermore, the MoSe2 showed strong absorption in the near infrared region, and therefore, MoSe2(Gd3+)-PEG could be used as contrast agent for photoacoustic imaging (PAI). In in vitro experiments, it was found that MoSe2(Gd3+)-PEG could effectively increase the temperature to help kill cancer cells under laser irradiation. In vivo experiments showed that there was an enhanced permeation and retention effect in the tumor after intravenous injection measured using magnetic resonance/photoacoustic (MR/PA) bimodal imaging. After photothermal therapy, a significant suppression effect was achieved for tumors in mice by injection of these nanosheets with laser irradiation. This work emphasized that the simple doped TMDC nanomaterials when combined with treatment and imaging functions achieve a cancer therapy, which will provide a good opportunity for future diagnosis and treatment of cancer.

Polypeptide nano-Se targeting inflammation and theranostic rheumatoid arthritis by anti-angiogenic and NO activating AMPKα signaling pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disease and there is a lack of effective treatments. Nitric oxide (NO) plays an important role in inflammatory diseases, but the exact mechanism is not clear. We selected ruthenium complexes [Ru(Phen)2(4idip)](ClO4)2 (Ru) to induce the generation of NO in cells. SeNPs-PEG-RGD@Ru (Se@RuNPs) were prepared by modifying selenium nanoparticles with PEG, RGD and Ru. Se@RuNPs can promote uptake by Human Umbilical Vein Endothelial Cells (HUVECs) and trace the internalization and biodistribution. Experiments showed that Se@RuNPs target the abundant neovascular network of inflammatory sites to induce NO and promote the apoptosis of HUVECs and inhibit the growth of new vessels in local tissue. Moreover, NO activates autophagy by modulating signaling pathways related to AMPKα and mTOR, increasing the flux of autophagy, inhibiting the activity of NF-κB-p65, and modulating the levels of inflammatory cytokines. The exact mechanism of the inflammatory response regulated by NO is revealed. Histopathological analysis showed that the Se@RuNPs effectively reduced synovitis, cartilage corrosion and inflammatory cytokine expression levels, achieving satisfactory therapeutic effects. These unexpected results provide an effective strategy for target treatment of RA.

Overexpression of miR-18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood-tumor barrier via Krüppel-like factor 4-mediated downregulation of zonula occluden-1, claudin-5, and occludin.

miR-18a represses angiogenesis and tumor evasion by weakening vascular endothelial growth factor and transforming growth factor-ß signaling to prolong the survival of glioma patients, although it is thought to be an oncogene. This study investigates the potential effects of miR-18a on the permeability of the blood-tumor barrier (BTB) and its possible molecular mechanisms. An in vitro BTB model was successfully established. The endogenous expression of miR-18a in glioma vascular endothelial cells (GECs) was significantly lower than that in normal vascular ECs, and the overexpression of miR-18a significantly increased the permeability of the BTB as well as downregulating the mRNA and protein expressions of tight junction-related proteins zonula occluden-1 (ZO-1), claudin-5, and occludin in GECs. Dual luciferase reporter assays revealed that miR-18a bound to the 3'-untranslated region (3'UTR) of myocyte enhancer factor 2D (MEF2D). The overexpression of both miR-18a and MEF2D with the 3'UTR significantly weakened the effect caused by miR-18a of decreasing the mRNA and protein expressions of ZO-1, claudin-5 and occludin and of increasing the permeability of the BTB. Chromatin immunoprecipitation showed that MEF2D could directly bind to KLF4 promoter. This study shows that miR-18a targets and negatively regulates MEF2D, which further regulates tight junction-related proteins ZO-1, claudin-5, and occludin through transactivation of KLF4 and, finally, changes the permeability of the BTB. MiR-18a should garner growing attention because it might serve as a potential target in opening the BTB and providing a new strategy for the treatment of gliomas.

MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5.

The purposes of this study were to investigate the possible molecular mechanisms of miR-18a regulating the permeability of blood-tumor barrier (BTB) via down-regulated expression and distribution of runt-related transcription factor 1 (RUNX1). An in vitro BTB model was established with hCMEC/D3 cells and U87MG cells to obtain glioma vascular endothelial cells (GECs). The endogenous expressions of miR-18a and RUNX1 were converse in GECs. The overexpression of miR-18a significantly impaired the integrity and increased the permeability of BTB, which respectively were detected by TEER and HRP flux assays, accompanied by down-regulated mRNA and protein expressions and distributions of ZO-1, occludin and claudin-5 in GECs. Dual-luciferase reporter assay was carried out and revealed RUNX1 is a target gene of miR-18a. Meanwhile, mRNA and protein expressions and distribution of RUNX1 were downregulated by miR-18a. Most important, miR-18a and RUNX1 could reversely regulate the permeability of BTB as well as the expressions and distributions of ZO-1, occludin and claudin-5. Finally, chromatin immunoprecipitation verified that RUNX1 interacted with "TGGGGT" DNA sequence in promoter region of ZO-1, occludin and claudin-5 respectively. Taken together, our present study indicated that miR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of tight junction related proteins ZO-1, occludin and claudin-5, which would attract more attention to miR-18a and RUNX1 as potential targets of drug delivery across BTB and provide novel strategies for glioma treatment.