Microenvironment-responsive smart hydrogels with antibacterial activity and immune regulation for accelerating chronic wound healing.

Current therapeutic strategies for chronic refractory wounds remain challenge owing to their unfavorable wound microenvironment and poor skin regeneration ability. Thus far, a regimen for effective chronic refractory wounds management involves bacterial elimination, alleviation of oxidative stress, inhibition of inflammatory response, and promotion of angiogenesis. In this work, an injectable glycopeptide hydrogel based on phenylboronic acid-grafted ϵ-polylysine (EPBA) and poly (vinyl alcohol) (PVA) with pH/reactive oxygen species (ROS) dual-responsive properties was prepared, which exerted intrinsic antibacterial and antioxidant properties. ROS-responsive micelles (MIC) loaded with herb-derived Astragaloside IV (AST) are introduced into the hydrogel before gelation. Attributed to the acidic condition and oxidative stress microenvironment of wound bed, the hydrogel gradually disintegrates, and the released EPBA could help to eliminate bacterial. Meanwhile, the subsequential release of AST could help to achieve anti-oxidation, anti-inflammatory, proangiogenic effects, and regulation of macrophage polarization to accelerate chronic wound healing. In addition, the wound repair mechanism of composite hydrogel accelerating skin regeneration was assessed by RNA-sequencing, exploring a range of potential targets and pathway for further study. Collectively, this multifunctional hydrogel dressing, matching different healing stages of tissue remodeling, holds a great potential for the treatment of chronic refractory wounds.

Multifunctional Hydrogel Enhances Inflammatory Control, Antimicrobial Activity, and Oxygenation to Promote Healing in Infectious Wounds.

Chronic infected wounds often fail to heal through normal repair mechanisms, and the persistent response of reactive oxygen species (ROS) and inflammation is a major contributing factor to the difficulty in their healing. In this context, we developed an ROS-responsive injectable hydrogel. This hydrogel is composed of ε-polylysine grafted (EPL) with caffeic acid (CA) and hyaluronic acid (HA) grafted with phenylboronic acid (PBA). Before the gelation process, a mixture CaO2@Cur-PDA (CCP) consisting of calcium peroxide (CaO2) coated with polydopamine (PDA) and curcumin (Cur) is embedded into the hydrogel. Under the conditions of chronic refractory wound environments, the hydrogel gradually dissociates. HA mimics the function of the extracellular matrix, while the released caffeic acid-grafted ε-polylysine (CE) effectively eliminates bacteria in the wound vicinity. Additionally, released CA also clears ROS and influences macrophage polarization. Subsequently, CCP further decomposes, releasing Cur, which promotes angiogenesis. This multifunctional hydrogel accelerates the repair of diabetic skin wounds infected with Staphylococcus aureus in vivo and holds promise as a candidate dressing for the healing of chronic refractory wounds.

Highly Bioadaptable Hybrid Conduits with Spatially Bidirectional Structure for Precision Nerve Fiber Regeneration via Gene Therapy.

Peripheral nerve deficits give rise to motor and sensory impairments within the limb. The clinical restoration of extensive segmental nerve defects through autologous nerve transplantation often encounters challenges such as axonal mismatch and suboptimal functional recovery. These issues may stem from the limited regenerative capacity of proximal axons and the subsequent Wallerian degeneration of distal axons. To achieve the integration of sensory and motor functions, a spatially differential plasmid DNA (pDNA) dual-delivery nanohydrogel conduit scaffold is devised. This innovative scaffold facilitates the localized administration of the transforming growth factor ß (TGF-ß) gene in the proximal region to accelerate nerve regeneration, while simultaneously delivering nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) to the distal region to mitigate Wallerian degeneration. By promoting autonomous and selective alignment of nerve fiber gap sutures via structure design, the approach aims to achieve a harmonious unification of nerve regeneration, neuromotor function, and sensory recovery. It is anticipated that this groundbreaking technology will establish a robust platform for gene delivery in tissue engineering.

Highly Biocompatible Polyester-Based Piezoelectric Elastomer with Antitumor and Antibacterial Activity for Ultrasound-Enhanced Piezoelectric Therapy.

Currently, the use of piezoelectric materials to provide sustainable and noninvasive bioelectric stimulation to eradicate tumor cells and accelerate wound healing has raised wide attention. The development of a multifunctional piezoelectric elastomer with the ability to perform in situ tumor therapy as well as wound repair is of paramount importance. However, current piezoelectric materials have a large elastic modulus and limited stretchability, making it difficult to match with the dynamic curvature changes of the wound. Therefore, by copolymerizing lactic acid, butanediol, sebacic acid, and itaconic acid to develop a piezoelectric elastomer (PLBSIE), we construct a new ultrasound-activated PLBSIE-based tumor/wound unified therapeutic platform. Excitedly, it showed outstanding piezoelectric performance and high stretchability, and the separated carrier could react with water to generate highly cytotoxic reactive oxygen species (ROS), contributing to effectively killing tumor cells and eliminating bacteria through piezoelectric therapy. In addition, ultrasound-triggered piezoelectric effects could promote the migration and differentiation of wound-healing-related cells, thus accelerating wound healing. Herein, such a piezoelectric elastomer exerted a critical role in postoperative tumor-induced wound therapy and healing with the merits of possessing multifunctional abilities. Taken together, the developed ultrasound-activated PLBSIE will offer a comprehensive treatment for postoperative osteosarcoma therapy.

Exosomal mRNAs for Angiogenic-Osteogenic Coupled Bone Repair.

Regenerative medicine in tissue engineering often relies on stem cells and specific growth factors at a supraphysiological dose. These approaches are costly and may cause severe side effects. Herein, therapeutic small extracellular vesicles (t-sEVs) endogenously loaded with a cocktail of human vascular endothelial growth factor A (VEGF-A) and human bone morphogenetic protein 2 (BMP-2) mRNAs within a customized injectable PEGylated poly (glycerol sebacate) acrylate (PEGS-A) hydrogel for bone regeneration in rats with challenging femur critical-size defects are introduced. Abundant t-sEVs are produced by a facile cellular nanoelectroporation system based on a commercially available track-etched membrane (TM-nanoEP) to deliver plasmid DNAs to human adipose-derived mesenchymal stem cells (hAdMSCs). Upregulated microRNAs associated with the therapeutic mRNAs are enriched in t-sEVs for enhanced angiogenic-osteogenic regeneration. Localized and controlled release of t-sEVs within the PEGS-A hydrogel leads to the retention of therapeutics in the defect site for highly efficient bone regeneration with minimal low accumulation in other organs.

Inhibition of IKKß via a DNA-Based In Situ Delivery System Improves Achilles Tendinopathy Healing in a Rat Model.

BACKGROUND: The inhibition of IKKß by the inhibitor 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridine carbonitrile (ACHP) is a promising strategy for the treatment of Achilles tendinopathy. However, the poor water solubility of ACHP severely hinders its in vivo application. Moreover, the effective local delivery of ACHP to the tendon and its therapeutic effects have not been reported. PURPOSE: To investigate the therapeutic effects of IKKß inhibition via injection of ACHP incorporated into a DNA supramolecular hydrogel in a collagenase-induced tendinopathy rat model. STUDY DESIGN: Controlled laboratory study. METHODS: Dendritic DNA, a Y-shaped monomer, and a crosslinking monomer were mixed with ACHP and self-assembled into an ACHP-DNA supramolecular hydrogel (ACHP-Gel). The effects of ACHP-Gel in tendon stem/progenitor cells were investigated via RNA sequencing and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 120 collagenase-induced rats were randomly assigned to 5 groups: blank, phosphate-buffered saline (PBS), DNA-Gel, ACHP, and ACHP-Gel. Healing outcomes were evaluated using biomechanic and histologic evaluations at 4 and 8 weeks. RESULTS: ACHP-Gel enhanced the solubility of ACHP and sustained its release for ≥21 days in vivo, which significantly increased the retention time of ACHP and markedly reduced the frequency of administration. RNA sequencing and qRT-PCR showed that ACHP effectively downregulated genes related to inflammation and extracellular matrix remodeling and upregulated genes related to tenogenic differentiation. The cross-sectional area (P = .024), load to failure (P = .002), stiffness (P = .039), and elastic modulus (P = .048) significantly differed between the ACHP-Gel and PBS groups at 8 weeks. The ACHP-Gel group had better histologic scores than the ACHP group at 4 (P = .042) and 8 weeks (P = .009). Type I collagen expression (COL-I; P = .034) and the COL-I/collagen type III ratio (P = .015) increased while interleukin 6 expression decreased (P < .001) in the ACHP-Gel group compared with the ACHP group at 8 weeks. CONCLUSION: DNA supramolecular hydrogel significantly enhanced the aqueous solubility of ACHP and increased its release-retention time. Injection frequency was markedly reduced. ACHP-Gel suppressed inflammation in Achilles tendinopathy and promoted tendon healing in a rat model. CLINICAL RELEVANCE: ACHP-Gel injection is a promising strategy for the treatment of Achilles tendinopathy in clinical practice.

Programmable DNA Hydrogel Provides Suitable Microenvironment for Enhancing TSPCS Therapy in Healing of Tendinopathy.

Tendon stem/progenitor cells (TSPCs) therapy is a promising strategy for enhancing cell matrix and collagen synthesis, and regulating the metabolism of the tendon microenvironment during tendon injury repair. Nevertheless, the barren microenvironment and gliding shear of tendon cause insufficient nutrition supply, damage, and aggregation of injected TSPCs around tendon tissues, which severely hinders their clinical application in tendinopathy. In this study, a TSPCs delivery system is developed by encapsulating TSPCs within a DNA hydrogel (TSPCs-Gel) as the DNA hydrogel offers an excellent artificial extracellular matrix (ECM) microenvironment by providing nutrition for proliferation and protection against shear forces. This delivery method restricts TSPCs to the tendons, significantly extending their retention time. It is also found that TSPCs-Gel injections can promote the healing of rat tendinopathy in vivo, where cross-sectional area and load to failure of injured tendons in rats are significantly improved compared to the free TSPCs treatment group at 8 weeks. Furthermore, the potential healing mechanism of TSPCs-Gel is investigated by RNA-sequencing to identify a series of potential gene and signaling pathway targets for further clinical treatment strategies. These findings suggest the potential pathways of using DNA hydrogels as artificial ECMs to promote cell proliferation and protect TSPCs in TSPC therapy.

Widely targeted volatileomics analysis reveals the typical aroma formation of Xinyang black tea during fermentation.

Xinyang black tea (XYBT) is characterized by the honey sugar-like aroma which is produced during the fermentation process. However, the formation of this typical aroma is still unclear. We here performed widely targeted volatileomics analysis combined with GC-MS and detected 116 aroma active compounds (AACs) with OAV > 1. These AACs were mainly divided into terpenoids, pyrazine, volatile sulfur compounds, esters, and aldehydes. Among them, 25 significant differences AACs (SDAACs) with significant differences in fermentation processes were identified, comprising phenylacetaldehyde, dihydroactinidiolide, α-damascenone, ß-ionone, methyl salicylate, and so forth. In addition, sensory descriptions and partial least squares discriminant analysis demonstrated that phenylacetaldehyde was identified as the key volatile for the honey sugar-like aroma. We further speculated that phenylacetaldehyde responsible for the aroma of XYBT was probably produced from the degradation of L-phenylalanine and styrene. In conclusion, this study helps us better understand the components and formation mechanism of the honey sugar-like aroma of XYBT, providing new insight into improving the processing techniques for black tea quality.

A resting-state functional MRI study in patients with vestibular migraine during interictal period.

To evaluate the spontaneous neuronal activities and the changes of brain functional network in patients with vestibular migraine (VM). Three groups including18 patients with VM, 21 patients with migraine without aura (MWoA) and 21 healthy controls (HCs) underwent the scanning of the resting-state fMRI. Covariance analysis and bonferroni multiple comparisons were used to obtain brain regions with significant differences in amplitude of low-frequency fluctuation (ALFF) values. Furthermore, the brain regions with the most significant differences of ALFF values were recognized as a region of interest (ROI) and functional connectivity (FC) analysis was performed in these regions. (1) ALFF: Compared with HCs, patients with VM showed significantly lower ALFF in the right putamen (P < 0.05), and significantly higher ALFF in the right lingual gyrus (P < 0.05). In addition, compared with MWoA patients, patients with VM showed significantly higher ALFF in the right lingual gyrus (P < 0.05). (2) Compared with HCs, VM patients showed significantly higher FC among the cerebellum, the left dorsolateral superior frontal gyrus and the right putamen (P < 0.05) but significantly lower FC among the left median cingulate, paracingulate gyri and the right putamen (P < 0.05). Compared with MWoA patients, VM patients showed significantly higher FC between the cerebellum and the right putamen (P < 0.05) but significantly lower FC among the left median cingulate, paracingulate gyri and the right putamen (P < 0.05). There are functional abnormalities in nociceptive, vestibular and visual cortex regions in patients with VM during the interictal period.

Synthesis of dual-stimuli responsive metal organic framework-coated iridium oxide nanocomposite functionalized with tumor targeting albumin-folate for synergistic photodynamic/photothermal cancer therapy.

The synergistic effects of photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted considerable attention in the field of cancer therapy because of its excellent anti-tumor effect. This work provides a novel pH/NIR responsive therapeutic nanoplatform, IrO2@ZIF-8/BSA-FA (Ce6), producing a synergistic effect of PTT-PDT in the treatment of osteosarcoma. Iridium dioxide nanoparticles (IrO2 NPs) with exceptional catalase-like activity and PTT effects were synthesized by a hydrolysis method and decorated with zeolitic imidazolate framework-8 (ZIF-8) shell layer to promote the physical absorption of Chlorin e6 (Ce6), and further functionalized with bovine serum albumin-folate acid (BSA-FA) for targeting tumor cells. The IrO2@ZIF-8/BSA-FA nanocomposite indicated an outstanding photothermal heating conversion efficiency of 62.1% upon laser irradiation. In addition, the Ce6 loading endows nanoplatform with the capability to induce cell apoptosis under 660 nm near-infrared (NIR) laser irradiation through a reactive oxygen species (ROS)-mediated mechanism. It was further testified that IrO2@ZIF-8/BSA-FA can function as a catalase and convert the endogenous hydrogen peroxide (H2O2) into oxygen (O2) to improve the local oxygen pressure under the acidic tumor microenvironment (TME), which could subsequently amplified PDT-mediated ROS cell-killing performance via relieving hypoxia microenvironment of tumor. Both in vitro and in vivo experimental results indicated that the nanomaterials were good biocompatibility, and could remarkably achieve tumor-specific and enhanced combination therapy outcomes as compared with the corresponding PTT or PDT monotherapy. Taken together, this work holds great potential to design an intelligent multifunctional therapeutic nanoplatform for cancer therapy.

Periventricular white matter hyperintensities are associated with gait and balance in patients with minor stroke.

Objective: Cerebral small vessel disease (CSVD) is associated with gait and balance deficits in older adults. However, the effect of CSVD-related brain injury on post-stroke mobility is unknown. This study aimed to investigate the association of CSVD with gait and balance impairment after a minor stroke. Methods: A total of 273 patients with a minor stroke (NIHSS ≤ 5 points) who were hospitalized at the Affiliated Hospital of Qingdao University were enrolled. The manifestations of white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), and cerebral microbleeds (CMB) were statistically analyzed according to magnetic resonance imaging results, and the total burden score of CSVD was calculated. Gait function was assessed by a 6-m walking speed test, and balance function was assessed by the timed-up-and-go (TUG) test. Linear regression analysis was applied to determine the association after adjusting for key variables. Results: The correlation results showed that in patients with minor stroke, age, sex, smoking history, and the infarct site were associated with gait speed, and age and the infarct site were associated with the TUG test. In the univariate linear regression model, periventricular white matter hyperintensities (PVWMH), deep white matter hyperintensities (DWMH), and the total burden of CSVD were correlated with gait speed, while only PVWMH correlated with the TUG test. After adjusting for confounders, only PVWMH were independent predictors of gait speed (ß = -0.089, p < 0.05) and the TUG test (ß = 0.517, p < 0.05). Conclusions: Our study confirmed that CSVD is associated with gait and balance disorders after a minor stroke. PVWMH are independent predictors of gait and balance disorders in patients with minor stroke. These findings should be confirmed in larger prospective studies.

Association of Cerebral Small Vessel Disease With Gait and Balance Disorders.

Cerebral small vessel disease (CSVD) is a common cerebrovascular disease and an important cause of gait and balance disorders. Gait and balance disorders can further lead to an increased risk of falls and a decreased quality of life. CSVD can damage gait and balance function by affecting cognitive function or directly disrupting motor pathways, and different CSVD imaging features have different characteristics of gait and balance impairment. In this article, the correlation between different imaging features of sporadic CSVD and gait and balance disorders has been reviewed as follows, which can provide beneficial help for standardized management of CSVD.

Corrigendum: The Effects of rs405509 on APOEε4 Non-carriers in Non-demented Aging.

[This corrects the article DOI: 10.3389/fnins.2021.677823.].

A novel hierarchical biofunctionalized 3D-printed porous Ti6Al4V scaffold with enhanced osteoporotic osseointegration through osteoimmunomodulation.

BACKGROUND: Femoral stem of titanium alloy has been widely used for hip arthroplasty with considerable efficacy; however, the application of this implant in patients with osteoporosis is limited due to excessive bone resorption. Macrophages participate in the regulation of inflammatory response and have been a topic of increasing research interest in implant field. However, few study has explored the link between macrophage polarization and osteogenic-osteoclastic differentiation. The present study aims to develop a novel hierarchical biofunctionalized 3D-printed porous Ti6Al4V scaffold with enhanced osteoporotic osseointegration through immunotherapy. METHOD: To improve the osteointegration under osteoporosis, we developed a hierarchical biofunctionalized 3D-printed porous Ti6Al4V scaffold (PT). Biomimetic extracellular matrix (ECM) was constructed inside the interconnected pores of PT in micro-scale. And in nano-scale, a drug cargo icariin@Mg-MOF-74 (ICA@MOF) was wrapped in ECM-like structure that can control release of icariin and Mg2+. RESULTS: In this novel hierarchical biofunctionalized 3D-printed porous Ti6Al4V scaffold, the macroporous structure provides mechanical support, the microporous structure facilitates cell adhesion and enhances biocompatibility, and the nanostructure plays a biological effect. We also demonstrate the formation of abundant new bone at peripheral and internal sites after intramedullary implantation of the biofunctionalized PT into the distal femur in osteoporotic rats. We further find that the controlled-release of icariin and Mg2+ from the biofunctionalized PT can significantly improve the polarization of M0 macrophages to M2-type by inhibiting notch1 signaling pathway and induce the secretion of anti-inflammatory cytokines; thus, it significantly ameliorates bone metabolism, which contributes to improving the osseointegration between the PT and osteoporotic bone. CONCLUSION: The therapeutic potential of hierarchical PT implants containing controlled release system are effective in geriatric orthopaedic osseointegration.

Osteogenic and anti-tumor Cu and Mn-doped borosilicate nanoparticles for syncretic bone repair and chemodynamic therapy in bone tumor treatment.

Critical bone defects caused by extensive excision of malignant bone tumor and the probability of tumor recurrence due to residual tumor cells make malignant bone tumor treatment a major clinical challenge. The present therapeutic strategy concentrates on implanting bone substitutes for defect filling but suffers from failures in both enhancing bone regeneration and inhibiting the growth of tumor cells. Herein, Cu and Mn-doped borosilicate nanoparticles (BSNs) were developed for syncretic bone repairing and anti-tumor treatment, which can enhance bone regeneration through the osteogenic effects of Cu2+ and Mn3+ ions and meanwhile induce tumor cells apoptosis through the hydroxyl radicals produced by the Fenton-like reactions of Cu2+ and Mn3+ ions. In vitro study showed that both osteogenic differentiation of BMSCs and angiogenesis of endothelial cells were promoted by BSNs, and consistently the critical bone defects of rats were efficiently repaired by BSNs through in vivo evaluation. Meanwhile, BSNs could generate hydroxyl radicals through Fenton-like reactions in the simulated tumor microenvironment, promote the generation of intracellular reactive oxygen species, and eventually induce tumor cell apoptosis. Besides, subcutaneous tumors of mice were effectively inhibited by BSNs without causing toxic side effects to normal tissues and organs. Altogether, Cu and Mn-doped BSNs developed in this work performed dual functions of enhancing osteogenesis and angiogenesis for bone regeneration, and inhibiting tumor growth for chemodynamic therapy, thus holding a great potential for syncretic bone repairing and anti-tumor therapy.

Adult-onset vanishing white matter in a patient with EIF2B3 variants misdiagnosed as multiple sclerosis.

BACKGROUND: Vanishing white matter (VWM) is an autosomal recessive disorder characterized by childhood ataxia with central hypomyelination. Adult-onset VWM should be considered as a differential diagnosis for suspected cases of multiple sclerosis (MS). METHODS: Targeted region sequencing (TRS) and Sanger sequencing validation were performed to identify and validate the likely pathogenic mutations in a family with VWM. RESULTS: The main clinical manifestations of the proband included decreased vision and sleepiness accompanied by atrophy of the corpus callosum, affected inner rim of the corpus callosum, decreased apparent diffusion coefficient value or persistent hyperintensity-diffusion-weighted imaging, atrophied optic nerve, and no recordable visual evoked potentials. Due to the slow development and atypical VWM image features, MS was initially suspected. After prednisone was administered, the patient's condition did not improve significantly, and other diseases were considered. The TRS and Sanger sequencing identified compound heterozygous mutations of EIF2B3 in the proband; c.965C > G /p.Ala322Gly in exon 8 and c.130G > A/p.Glu44Lys in exon 2 were missense mutations inherited from the mother and father, respectively. The proband's oldest brother had the same compound heterozygous mutations but showed no symptoms. CONCLUSION: This is the first report of adult-onset VWM in a Chinese family. Initially, MS was suspected, and genetic testing confirmed the diagnosis of VWM. This study may further broaden the clinical spectrum of EIF2B3, thus providing a foundation for further research on the pathogenesis and genetic therapy for VWM.

Precise Diabetic Wound Therapy: PLS Nanospheres Eliminate Senescent Cells via DPP4 Targeting and PARP1 Activation.

Diabetic ulcers, a difficult problem faced by clinicians, are strongly associated with an increase in cellular senescence. Few empirical studies have focused on exploring a targeted strategy to cure diabetic wounds by eliminating senescent fibroblasts (SFs) and reducing side effects. In this study, poly-l-lysine/sodium alginate (PLS) is modified with talabostat (PT100) and encapsulates a PARP1 plasmid (PARP1@PLS-PT100) for delivery to target the dipeptidyl peptidase 4 (DPP4) receptor and eliminate SFs. PARP1@PLS-PT100 releases encapsulated plasmids, displaying high selectivity for SFs over normal fibroblasts by targeting the DPP4 receptor, decreasing senescence-associated secretory phenotypes (SASPs), and stimulating the secretion of anti-inflammatory factors. Furthermore, the increased apoptosis of SFs and the disappearance of cellular senescence alleviates SASPs, accelerates re-epithelialization and collagen deposition, and significantly induces macrophage M2 polarization, which mediates tissue repair and the inflammatory response. This innovative strategy has revealed the previously undefined role of PARP1@PLS-PT100 in promoting diabetic wound healing, suggesting its therapeutic potential in refractory wound repair.

The relation between antihypertensive treatment and progression of cerebral small vessel disease: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cerebral small vessel disease is relevant to hypertension. We tried to figure out whether antihypertensive treatment is beneficial for this disease. METHODS: We systematically searched PubMed, Embase, and Cochrane electronic databases for randomized controlled trials about white matter hyperintensities (WMH), brain atrophy, microbleeds, and lacunar infarcts with antihypertensive treatment and performed a meta-analysis. RESULTS: We identified 7 trials on white matter hyperintensities and brain atrophy with antihypertensive treatment. Pooled analysis showed antihypertensive treatment performed positively in the progression of WMH (standardized mean difference, -0.22; 95% CI, -0.36 to -0.07, I^2 = 52%). And in the subgroup meta-analysis, only lower SBP controlled level (110-129 mm Hg) had effect on the progression of WMH (standardized mean difference, -0.37; 95% CI, -0.54 to -0.29, I^2 =0). The meta-regression showed larger difference of SBP in treatment groups having a smaller WMH progression. Antihypertensive treatment is not significant in the progression of brain atrophy (standardized mean difference, -0.02; 95% CI, -0.26 to 0.30, I^2 = 85%). Only 1 trial reported the new patients of lacunar infarcts in the follow-up, no association with antihypertensive treatment (odds ratio, 2.2; 95% CI, 0.4-12.1; P = .36). CONCLUSIONS: Antihypertensive treatment is beneficial for cerebral small vessel disease on white matter hyperintensities progression, but no impact on brain atrophy. And lower SBP level is more effective on the progression of WMH. There is not enough evidence to prove the relationship between antihypertensive treatment and lacunar stroke, microbleeds.

Per- and post-remote ischemic conditioning attenuates ischemic brain injury via inhibition of the TLR4/MyD88 signaling pathway in aged rats.

Remote ischemic conditioning (RIC), as an emerging protective method, might be used clinically to prevent ischemia-reperfusion injury (IRI) in ischemic stroke. In this study, we aim to investigate whether RIC performed either during brain ischemia or after reperfusion has a protective effect and further explore the mechanistic basis for the protective effects of RIC against IRI in an aged rat model. We investigated brain IRI in 16-18 months old SD rats. Animals underwent: (i) sham laparotomy, (ii) brain IRI, (iii) brain IRI + RIC during ischemia (IRI + RIperC), or (iv) brain IRI + RIC after reperfusion (IRI + RIpostC). RIC consists of three cycles of 10 min of hind limb ischemia followed by 10 min reperfusion. After 24 h of reperfusion, the infarct size, neurological deficit scores and brain oedema were assessed in all groups. The levels of IL-1ß, IL-6, TNF-α were measured by ELISA. The mRNA and protein expressions of TLR4, MyD88, TRAF6 and NF-κB were detected by RT-PCR and western blot. Both RIperC and RIpostC treatment attenuated the IRI-induced neuronal injury, reflected by reductions in the infarct size, neurological deficit scores and brain oedema. RIperC and RIpostC also can decrease the concentration of IL-1ß, IL-6, TNF-α in IRI. From the results of RT-PCR and western blot, we found that RIC decreased the mRNA and protein expression of TLR4, MyD88, TRAF6 and NF-κB compared to that in the IRI group. The present study suggested that RIC protected aged rats against IRI, and this protective effect might be mediated by inhibiting the TLR-4/MyD88/TRAF-6/NF-κB signaling pathway.